Sleep-disordered breathing (SDB) is a highly prevalent condition, and is associated with many debilitating chronic diseases. The role of untreated obstructive sleep apnea (OSA) in arterial hypertension has bee...
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Πέμπτη 25 Μαΐου 2017
Cerebral white matter lesion burden is associated with the degree of aortic valve calcification and predicts peri-procedural cerebrovascular events in patients undergoing transcatheter aortic valve implantation (TAVI)
Objectives
To investigate the impact of aortic valve calcification and brain morphology on acute peri-procedural cerebrovascular events (CVEs) in patients undergoing transcatheter aortic valve implantation (TAVI).
Background
Aortic valve calcification and stenosis can be assessed with echocardiography. Cerebral magnetic resonance imaging (MRI) depicts and quantifies morphological signs of hypoperfusion and vascular embolism, which is of special interest in patients with severe aortic stenosis. Furthermore, subjects who undergo TAVI are prone to suffer of clinically silent peri-procedural CVEs.
Methods
A total of 119 patients referred to TAVI were investigated for aortic valve calcification using trans-esophageal echocardiography. Cerebral MRI prior to and immediate after implantation was performed in all patients using a dedicated scan protocol. Prior to TAVI, brain morphology was characterized. Post TAVI, brains were investigated for the onset of acute peri-procedural CVEs using diffusion weighted imaging (DWI).
Results
Seventy-eight patients (65.5%) revealed acute peri-procedural CVEs on MRI after TAVI with a favor of the left hemisphere (57.5%). The degree of valve calcification was associated with peri-procedural CVEs. Patients with a high WML burden had an increased risk for CVEs ((OR) 2.36 (95% CI: 1.09–5.15; P = 0.037)), especially when distributed periventricular ((OR: 3.27; 95% CI: 1.47–7.26; P = 0.0038)).
Conclusion
In patients undergoing TAVI, the degree of aortic valve calcification and periventricular WML burden were correlated with acute peri-procedural CVEs. Future studies are needed to evaluate their independent value for the long-term clinical outcome.
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Flu-like illness, fever, malaise and chills, followed by severe nonpleuritic chest pain and shortness of breath
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
Outcomes Following Operative Treatment of Adolescent Mallet Fractures
Abstract
Background
Many surgeons advocate for surgical intervention of adult mallet fractures that involve either subluxation of the distal interphalangeal (DIP) joint or those that involve more than one-third of the articular surface. However, the efficacy of operative treatment and complication rates are unclear regarding the adolescent population.
Questions/Purposes
The goal of this study is to evaluate the clinical outcomes following operative fixation of bony mallet fractures in the adolescent population.
Methods
Seventeen patients with bony mallet fractures treated surgically were retrospectively reviewed. Twelve patients were treated by closed reduction with extension block pinning. The other patients underwent an open reduction and pin fixation. The average age was 15.2 years (13–18). Most injuries were sport related. The average time from injury to presentation was 17 days and from injury to surgery was 24.5 days. Nine patients had subluxation at the DIP joint and all involved at least one-third of the articular surface.
Results
The average time from surgery to pin removal was 28 days (19–46). All distal phalanx physis were closed or nearly closed. One patient reported pain at the final follow-up. Two patients (11.8%) had major complications. One had an extension contracture postoperatively, did not attend therapy, and re-fractured 5 months later requiring reoperation. The second was treated delayed (32 days) and lost fixation, requiring revision surgery and antibiotics for a superficial infection. Two patients with delayed treatment (32 and 44 days) had an extensor lag (11.8%).
Conclusions
Operative treatment of mallet fractures with subluxation or involving more than one-third of the articular surface appears effective. Pin removal 4 weeks postoperatively appears adequate. Complications occurred with delayed presentation and non-compliance.
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Abundance and diversity of ammonia-oxidizing archaea in a biological aerated filter process
Abstract
Ammonia-oxidizing archaea (AOA) represent an important group of ammonia-oxidizing microorganisms that are able to convert ammonia to nitrite, a function which is crucial for the removal of nitrogen from wastewater. In this study, we investigated the abundance and diversity of AOA in a full-scale wastewater treatment plant (WWTP) which used a biological aerated filter (BAF) as the main processing mode. According to the quantitative PCR results, AOA clearly outnumbered ammonia-oxidizing bacteria (AOB) during the whole process. The abundance of AOA amoA genes in the filter layer of BAF was highest with the value varied from 6.32 × 103 to 3.8 × 104 copies/ng DNA. The highest abundance of AOB amoA genes was 1.32 × 102 copies/ng DNA, recorded in the effluent of the ACTIFLO® settling tank. The ratios of AOA/AOB in the WWTP were maintained at two or three orders of magnitude. Most AOA obtained from the WWTP fell within the Nitrosopumilus cluster. The abundance of AOA and AOB was significantly correlated with ammonium nitrogen concentrations and pH value. The community structure of AOA was significantly influenced by dissolved oxygen concentrations, pH value and chemical oxygen demand.
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Aptamer-conjugated PEGylated quantum dots targeting epidermal growth factor receptor variant III for fluorescence imaging of glioma
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A Story in Black and White
Strong engagement from expert radiologists is essential in ensuring the optimal function of a multidisciplinary group focused on the treatment of head and neck cancer. Active participation in multidisciplinary conference can be among the most rewarding roles for radiologists. Despite many benefits to radiologist involvement in multidisciplinary teams, there are obstacles and challenges that can prevent full participation. This article highlights the key issues that should be considered by radiologists and multidisciplinary team leaders when planning participation in a new or existing multidisciplinary group that focuses on the care of patients with head and neck cancer.
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Chronicles of a reductase: Biochemistry, genetics and physio-pathological role of GSNOR
Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Salvatore Rizza, Giuseppe Filomeni
S-nitrosylation is a major redox posttranslational modification involved in cell signaling. The steady state concentration of S-nitrosylated proteins depends on the balance between the relative ability to generate nitric oxide (NO) via NO synthase and to reduce nitrosothiols by denitrosylases. Numerous works have been published in last decades regarding the role of NO and S-nitrosylation in the regulation of protein structure and function, and in driving cellular activities in vertebrates. Notwithstanding an increasing number of observations indicates that impairment of denitrosylation equally affects cellular homeostasis, there is still no report providing comprehensive knowledge on the impact that denitrosylation has on maintaining correct physiological processes and organ activities.Among denitrosylases, S-nitrosoglutathione reductase (GSNOR) represents the prototype enzyme to disclose how denitrosylation plays a crucial role in tuning NO-bioactivity and how much it deeply impacts on cell homeostasis and human patho-physiology.In this review we attempt to illustrate the history of GSNOR discovery and provide the evidence so far reported in support of GSNOR implications in development and human disease.
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Source:Free Radical Biology and Medicine, Volume 110
Author(s): Salvatore Rizza, Giuseppe Filomeni
S-nitrosylation is a major redox posttranslational modification involved in cell signaling. The steady state concentration of S-nitrosylated proteins depends on the balance between the relative ability to generate nitric oxide (NO) via NO synthase and to reduce nitrosothiols by denitrosylases. Numerous works have been published in last decades regarding the role of NO and S-nitrosylation in the regulation of protein structure and function, and in driving cellular activities in vertebrates. Notwithstanding an increasing number of observations indicates that impairment of denitrosylation equally affects cellular homeostasis, there is still no report providing comprehensive knowledge on the impact that denitrosylation has on maintaining correct physiological processes and organ activities.Among denitrosylases, S-nitrosoglutathione reductase (GSNOR) represents the prototype enzyme to disclose how denitrosylation plays a crucial role in tuning NO-bioactivity and how much it deeply impacts on cell homeostasis and human patho-physiology.In this review we attempt to illustrate the history of GSNOR discovery and provide the evidence so far reported in support of GSNOR implications in development and human disease.
Graphical abstract
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Cyclophosphamide and acrolein induced oxidative stress leading to deterioration of metaphase II mouse oocyte quality
Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Roohi Jeelani, Sana N. Khan, Faten Shaeib, Hamid-Reza Kohan-Ghadr, Sarah R. Aldhaheri, Tohid Najafi, Mili Thakur, Robert Morris, Husam M. Abu-Soud
Cyclophosphamide (CTX) is a chemotherapeutic agent widely used to treat ovarian, breast, and hematological cancers as well as autoimmune disorders. Such chemotherapy is associated with reproductive failure and premature ovarian insufficiency. The mechanism by which CTX and/or its main metabolite, acrolein, affect female fertility remains unclear, but it is thought to be caused by an overproduction of reactive oxygen species (ROS). Here, we investigated the effect of CTX on metaphase II mouse oocytes obtained from treated animals (120mg/kg, 24h of single treatment), and oocytes directly exposed to increasing concentrations of CTX and acrolein (n=480; 0, 5, 10, 25, 50, and 100μM) with and without cumulus cells (CCs) for 45min which correlates to the time of maximum peak plasma concentrations after administration. Oocytes were fixed and subjected to indirect immunofluorescence and were scored based on microtubule spindle structure (MT) and chromosomal alignment (CH). Generation of ROS was evaluated using the Cellular Reactive Oxygen Species Detection Assay Kit. Deterioration of oocyte quality was noted when oocytes were obtained from CTX treated mice along with CTX and acrolein treated oocytes in a dose-dependent manner as shown by an increase in poor scores. Acrolein had an impact at a significantly lower level as compared to CTX, plateau at 10μM versus 50μM, respectively. These variation is are associated with the higher amount of ROS generated with acrolein exposure as compared to CTX (p<0.05). Utilization of antioxidant therapy and acrolein scavengers may mitigate the damaging effects of these compounds and help women undergoing such treatment.
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Source:Free Radical Biology and Medicine, Volume 110
Author(s): Roohi Jeelani, Sana N. Khan, Faten Shaeib, Hamid-Reza Kohan-Ghadr, Sarah R. Aldhaheri, Tohid Najafi, Mili Thakur, Robert Morris, Husam M. Abu-Soud
Cyclophosphamide (CTX) is a chemotherapeutic agent widely used to treat ovarian, breast, and hematological cancers as well as autoimmune disorders. Such chemotherapy is associated with reproductive failure and premature ovarian insufficiency. The mechanism by which CTX and/or its main metabolite, acrolein, affect female fertility remains unclear, but it is thought to be caused by an overproduction of reactive oxygen species (ROS). Here, we investigated the effect of CTX on metaphase II mouse oocytes obtained from treated animals (120mg/kg, 24h of single treatment), and oocytes directly exposed to increasing concentrations of CTX and acrolein (n=480; 0, 5, 10, 25, 50, and 100μM) with and without cumulus cells (CCs) for 45min which correlates to the time of maximum peak plasma concentrations after administration. Oocytes were fixed and subjected to indirect immunofluorescence and were scored based on microtubule spindle structure (MT) and chromosomal alignment (CH). Generation of ROS was evaluated using the Cellular Reactive Oxygen Species Detection Assay Kit. Deterioration of oocyte quality was noted when oocytes were obtained from CTX treated mice along with CTX and acrolein treated oocytes in a dose-dependent manner as shown by an increase in poor scores. Acrolein had an impact at a significantly lower level as compared to CTX, plateau at 10μM versus 50μM, respectively. These variation is are associated with the higher amount of ROS generated with acrolein exposure as compared to CTX (p<0.05). Utilization of antioxidant therapy and acrolein scavengers may mitigate the damaging effects of these compounds and help women undergoing such treatment.
Graphical abstract
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Prognostic impact of the cumulative dose and dose intensity of everolimus in patients with pancreatic neuroendocrine tumors
Abstract
The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. One hundred and sixteen patients (62 males and 54 females, median age 55 years) with advanced PNETs were treated with everolimus for ≥3 months. According to a Receiver operating characteristics (ROC) analysis, patients were stratified into two groups, with CD ≤ 3000 mg (Group A; n = 68) and CD > 3000 mg (Group B; n = 48). The response rate and toxicity were comparable in the two groups. However, patients in group A experienced more dose modifications than patients in group B. Median OS was 24 months in Group A while in Group B it was not reached (HR: 26.9; 95% CI: 11.0–76.7; P < 0.0001). Patients who maintained a DI higher than 9 mg/day experienced a significantly longer OS and experienced a trend to higher response rate. Overall, our study results showed that both CD and DI of everolimus play a prognostic role for patients with advanced PNETs treated with everolimus. This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.
The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. Median OS was 24 months in Group A (with cumulative dose ≤ 3000 mg) while in Group B (with cumulative dose > 3000 mg), it was not reached (HR: 26.9; 95% CI: 11.0–76.7; P < 0.0001). This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.
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Le rôle du fenugrec dans la survenue d’anomalie de fermeture du tube neural : un signal d’alerte depuis le Maroc
Résumé
Le fenugrec compte parmi les plus anciennes plantes médicinales et culinaires, il est très utilisé au Maroc et en Méditerranée. En phytothérapie, les graines de la plante sont indiquées pour stimuler l'appétit chez la femme enceinte, pour soulager l'inflammation, pour traiter la dysenterie, la dyspepsie, la toux chronique, la bronchite, les névralgies, pour faciliter l'accouchement et comme galactogènes. Malheureusement, peu de données fondées sur des fondements scientifiques sont offertes par la littérature pour confirmer les vertus thérapeutiques attribuées à ces graines. Les premiers événements indésirables liés à la consommation de cette plante ont été déclarés entre le mois de mars et le mois d'août 2006 par le Centre marocain de pharmacovigilance; Skalli a rapporté huit cas de malformations (hydrocéphalie et spinabifida) coïncidant avec l'ingestion au cours de la grossesse de graines de fenugrec. Plusieurs travaux ont confirmé par la suite ce fait clinique. Le but de notre travail est de rapporter les données locales et nationales sur la relation entre la consommation du fenugrec durant la grossesse et l'apparition de malformations du tube neural en s'appuyant sur certaines études qui confirment cette relation.
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Longitudinal assessment of brain-derived neurotrophic factor in Sardinian psychotic patients (LABSP): a protocol for a prospective observational study
Introduction
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Brain-derived neurotrophic factor (BDNF) plays a crucial role in neurodevelopment, synaptic plasticity and neuronal function and survival. Serum and plasma BDNF levels are moderately, but consistently, decreased in patients with schizophrenia (SCZ) compared with healthy controls. There is a lack of knowledge, however, on the temporal manifestation of this decline. Clinical, illness course and treatment factors might influence the variation of BDNF serum levels in patients with psychosis. In this context, we propose a longitudinal study of a cohort of SCZ and schizophrenic and schizoaffective disorder (SAD) Sardinian patients with the aim of disentangling the relationship between peripheral BDNF serum levels and changes of psychopathology, cognition and drug treatments.
Methods and analysisLongitudinal assessment of BDNF in Sardinian psychotic patients (LABSP) is a 24-month observational prospective cohort study. Patients with SAD will be recruited at the Psychiatry Research Unit of the Department of Medical Science and Public Health, University of Cagliari and University of Cagliari Health Agency, Cagliari, Italy. We will collect BDNF serum levels as well as sociodemographic, psychopathological and neurocognitive measures. Structured, semistructured and self-rating assessment tools, such as the Positive and Negative Syndrome Scale for psychopathological measures and the Brief Assessment of Cognition in Schizophrenia for cognitive function, will be used.
Ethics and disseminationThis study protocol was approved by the University of Cagliari Health Agency Ethics Committee (NP2016/5491). The study will be conducted in accordance with the principles of good clinical practice, in the Declaration of Helsinki in compliance with the regulations. Participation will be voluntary and written informed consent will be obtained for each participant upon entry into the study. We plan to disseminate the results of our study through conference presentations and publication in international peer-reviewed journals. Access to raw data will be available in anonymised form upon request to the corresponding author.
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Translation, adaptation and validation of two versions of the Chronic Liver Disease Questionnaire in Malaysian patients for speakers of both English and Malay languages: a cross-sectional study
Objective
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We aimed to adapt, translate and validate the Chronic Liver Disease Questionnaire (CLDQ) in Malaysian patients with chronic liver diseases of various aetiologies.
SettingTertiary level teaching institution in Malaysia.
ParticipantsThe validation process involved 211 adult patients (English language n=101, Malay language n=110) with chronic liver disease. Characteristics of the study subjects were as follows: mean (SD) age was 56 (12.8) years, 58.3% were male and 41.7% female. The inclusion criteria were patients 18 years or older with chronic hepatitis and/or liver cirrhosis of any aetiology. The exclusion criteria were as follows: presence of hepatic encephalopathy, ongoing treatment with interferon and presence of other chronic conditions that have an impact on health-related quality of life (HRQOL).
MethodsA cross-sectional study was conducted. Cultural adaptation of the English version of the CLDQ was performed, and a Malay version was developed following standard forward–backward translation by independent native speakers. Psychometric properties of both versions were determined by assessing their internal consistency, test–retest reliability and discriminant and convergent validity.
ResultsCronbach’s alpha for internal consistency across the various domains of the CLDQ was 0.95 for the English version and 0.92 for the Malay version. Test–retest analysis showed excellent reliability with an intraclass correlation coefficient of 0.89 for the English version and 0.93 for the Malay version. The average scores of both the English and Malay versions of the CLDQ demonstrated adequate discriminant validity by differentiating between non-cirrhosis (English 6.3, Malay 6.1), compensated cirrhosis (English 5.6, Malay 6.0) and decompensated cirrhosis (English 5.1, Malay 4.9) (p<0.001). Convergent validity showed that correlation was fair between the English (=0.59) and Malay (p=0.47) CLDQ versions with the EQ-5D, a generic HRQOL instrument.
ConclusionThe English and Malay versions of the CLDQ are reliable and valid disease-specific instruments for assessing HRQOL in Malaysian patients with chronic liver disease.
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Effects of continuous positive airway pressure on neurocognitive architecture and function in patients with obstructive sleep apnoea: study protocol for a multicentre randomised controlled trial
Objectives
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Many clinical studies have indicated that obstructive sleep apnoea (OSA), the most common chronic sleep disorder, may affect neurocognitive function, and that treatment for continuous positive airway pressure (CPAP) has some neurocognitive protective effects against the adverse effects of OSA. However, the effects of CPAP treatment on neurocognitive architecture and function remain unclear. Therefore, this multicentre trial was designed to investigate whether and when neurocognitive architecture and function in patients with OSA can be improved by CPAP treatment and to explore the role of gut microbiota in improving neurocognitive function during treatment.
Methods/designThis study will be a multicentre, randomised, controlled trial with allocation concealment and assessor blinding. A total of 148 eligible patients with moderate to severe OSA will be enrolled from five sleep centres and randomised to receive CPAP with best supportive care (BSC) intervention or BSC intervention alone. Cognitive function, structure and function of brain regions, gut microbiota, metabolites, biochemical variables, electrocardiography, echocardiography, pulmonary function and arterial stiffness will be assessed at baseline before randomisation and at 3, 6 and 12 months.
Ethics and disseminationThis study has been approved by the Medical Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital (approval number 2015-79). The results from this study will be published in peer-reviewed journals and at relevant conferences.
Trial registration numberNCT02886156; pre-results.
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The SUPER study: protocol for a randomised controlled trial comparing follicle-stimulating hormone and clomiphene citrate for ovarian stimulation in intrauterine insemination
Objective
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To study the effectiveness of four cycles of intrauterine insemination (IUI) with ovarian stimulation (OS) by follicle-stimulating hormone (FSH) or by clomiphene citrate (CC), and adherence to strict cancellation criteria.
SettingRandomised controlled trial among 22 secondary and tertiary fertility clinics in the Netherlands.
Participants732 women from couples diagnosed with unexplained or mild male subfertility and an unfavourable prognosis according to the model of Hunault of natural conception.
InterventionsFour cycles of IUI–OS within a time horizon of 6 months comparing FSH 75 IU with CC 100 mg. The primary outcome is ongoing pregnancy conceived within 6 months after randomisation, defined as a positive heartbeat at 12 weeks of gestation. Secondary outcomes are cancellation rates, number of cycles with a monofollicular or with multifollicular growth, number of follicles >14 mm at the time of ovulation triggering, time to ongoing pregnancy, clinical pregnancy, miscarriage, live birth and multiple pregnancy. We will also assess if biomarkers such as female age, body mass index, smoking status, antral follicle count and endometrial aspect and thickness can be used as treatment selection markers.
Ethics and disseminationThe study has been approved by the Medical Ethical Committee of the Academic Medical Centre and from the Dutch Central Committee on Research involving Human Subjects (CCMO NL 43131-018-13). Results will be disseminated through peer-reviewed publications and presentations at international scientific meetings.
Trial registration numberNTR4057.
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Chest pain and shortness of breath in cardiovascular disease: a prospective cohort study in UK primary care
Objective
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To determine characteristics associated with monthly chest pain and shortness of breath (SoB) during activity in cardiovascular disease (CVD) and trajectories of these symptoms over 10 months.
Study design and settingBaseline questionnaire was sent to patients aged ≥40 years from 10 UK general practices. Responders were sent monthly questionnaires for 10 months. For patients with CVD (ischaemic heart disease and heart failure), the association of sociodemographic characteristics, pain elsewhere and anxiety and depression with monthly reports of chest pain and SoB during activity were determined using multilevel, multinomial logistic regression. Common symptom trajectories were determined using dual trajectory latent class growth analysis.
Results661 patients with CVD completed at least 5 monthly questionnaires. Multiple other pain sites (relative risk ratio: 4.03; 95% CI 1.64 to 9.91) and anxiety or depression (relative risk ratio: 3.31; 95% CI 1.89 to 5.79) were associated with reporting weekly chest pain. Anxiety or depression (relative risk ratio: 4.10; 95% CI 2.72 to 6.17), obesity (relative risk ratio: 2.53; 95% CI 1.49 to 4.30), older age (80+: relative risk ratio: 2.51; 95% CI 1.19 to 5.26), increasing number of pain sites (4+: relative risk ratio: 4.64; 95% CI 2.35 to 9.18) and female gender (relative risk ratio: 1.81; 95% CI 1.20 to 2.75) were associated with reporting weekly SoB. Eight symptom trajectories were identified, with SoB symptoms more common than chest pain.
ConclusionsPotentially modifiable characteristics are associated with the experience of chest pain and SoB. Identified symptom trajectories may facilitate tailored care to improve outcomes in patients with CVD.
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Rib Geometry Explains Variation in Dynamic Structural Response: Potential Implications for Frontal Impact Fracture Risk
Abstract
The human thorax is commonly injured in motor vehicle crashes, and despite advancements in occupant safety rib fractures are highly prevalent. The objective of this study was to quantify the ability of gross and cross-sectional geometry, separately and in combination, to explain variation of human rib structural properties. One hundred and twenty-two whole mid-level ribs from 76 fresh post-mortem human subjects were tested in a dynamic frontal impact scenario. Structural properties (peak force and stiffness) were successfully predicted (p < 0.001) by rib cross-sectional geometry obtained via direct histological imaging (total area, cortical area, and section modulus) and were improved further when utilizing a combination of cross-sectional and gross geometry (robusticity, whole bone strength index). Additionally, preliminary application of a novel, adaptive thresholding technique, allowed for total area and robusticity to be measured on a subsample of standard clinical CT scans with varied success. These results can be used to understand variation in individual rib response to frontal loading as well as identify important geometric parameters, which could ultimately improve injury criteria as well as the biofidelity of anthropomorphic test devices (ATDs) and finite element (FE) models of the human thorax.
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Glial fibrillary acidic protein (GFAP) is a novel biomarker for the prediction of autoimmune diabetes [Research]
Glial fibrillary acidic protein (GFAP) is expressed in peri-islet Schwann cells as well as in glia cells and has been reported to be an autoantigen candidate for type 1 diabetes mellitus (T1DM). We confirmed that the production of the autoantibodies GFAP and glutamic acid decarboxylase 65 (GAD65) was increased and inversely correlated with the concentration of secreted C peptide in female nonobese diabetic mice (T1DM model). Importantly, the development of T1DM in female nonobese diabetic mice at 30 wk of age was predicted by the positive GFAP autoantibody titer at 17 wk. The production of GFAP and GAD65 autoantibodies was also increased in KK-Ay mice [type 2 diabetes mellitus (T2DM) model]. In patients with diabetes mellitus, GFAP autoantibody levels were increased in patients with either T1DM or T2DM, and were significantly associated with GAD65 autoantibodies but not zinc transporter 8 autoantibodies. Furthermore, we identified a B-cell epitope of GFAP corresponding to the GFAP autoantibody in both mice and diabetic patients. Thus, these results indicate that autoantibodies against GFAP could serve as a predictive marker for the development of overt autoimmune diabetes.—Pang, Z., Kushiyama, A., Sun, J., Kikuchi, T., Yamazaki, H., Iwamoto, Y., Koriyama, H., Yoshida, S., Shimamura, M., Higuchi, M., Kawano, T., Takami, Y., Rakugi, H., Morishita, R., Nakagumi, H. Glial fibrillary acidic protein (GFAP) is a novel biomarker for the prediction of autoimmune diabetes.
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Astronaut ophthalmic syndrome [Hypothesis]
During and after missions on the International Space Station, some astronauts experience ophthalmic changes, including choroidal folds, optic disc edema, cotton-wool spots, globe flattening, and refraction changes. Astronauts with ophthalmic issues had significantly higher plasma concentrations of metabolites that are associated with the 1-carbon metabolic pathway than those without ophthalmic issues. We hypothesized that genetic differences might explain the metabolite differences. Indeed, genetics and B vitamin status were significant predictors of ophthalmic issues. We now have developed a hypothesis regarding the mechanisms that link 1-carbon pathway genetics and the condition that we suggest calling, "astronaut ophthalmic syndrome." We maintain that this condition is genetically predisposed and is associated with endothelial dysfunction that is induced by oxidative stress. Subsequent edema can hinder cerebrospinal fluid efflux and can lead to locally increased pressures in the subarachnoid space within the orbit, which impinges on the optic nerve and/or eye in affected individuals. Confirming this hypothesis will help characterize the genetics of 1-carbon pathway metabolism, homocysteine, oxidative stress, endothelial dysfunction, and cardiovascular and potentially other diseases.—Zwart, S. R., Gibson, C. R., Gregory, J. F., Mader, T. H., Stover, P. J., Zeisel, S. H., Smith, S. M. Astronaut ophthalmic syndrome.
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Quantitative mass spectrometry analysis of PD-L1 protein expression, N-glycosylation and expression stoichiometry with PD-1 and PD-L2 in human melanoma [Research]
Quantitative assessment of key proteins that control the tumor-immune interface is one of the most formidable analytical challenges in immunotherapeutics. We developed a targeted mass spectrometry (MS) platform to quantify programmed cell death-1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2) at fmol/microgram protein levels in formalin fixed, paraffin-embedded sections from 22 human melanomas. PD-L1 abundance ranged 50-fold, from approximately 0.03 to 1.5 fmol/microgram protein and the PRM data were largely concordant with total PD-L1-positive cell content, as analyzed by immunohistochemistry (IHC) with the E1L3N antibody. PD-1 was measured at levels up to 20-fold lower than PD-L1, but the abundances were not significantly correlated (r2 = 0.062, p = 0.264). PD-1 abundance was weakly correlated (r2 = 0.3057, p = 0.009) with the fraction of lymphocytes and histiocytes in sections. PD-L2 was measured from 0.03 to 1.90 fmol/microgram protein and the ratio of PD-L2 to PD-L1 abundance ranged from 0.03 to 2.58. In 10 samples, PD-L2 was present at more than half the level of PD-L1, which suggests that PD-L2, a higher affinity PD-1 ligand, is sufficiently abundant to contribute to T-cell downregulation. We also identified five branched mannose and N-acetylglucosamine glycans at PD-L1 position N192 in all 22 samples. Extent of PD-L1 glycan modification varied by approximately 10-fold and the melanoma with the highest PD-L1 protein abundance and most abundant glycan modification yielded a very low PD-L1 IHC estimate, thus suggesting that N-glycosylation may affect IHC measurement and PD-L1 function. Additional PRM analyses quantified immune checkpoint/co-regulator proteins LAG3, IDO1, TIM-3, VISTA and CD40, which all displayed distinct expression independent of PD-1, PD-L1 and PD-L2. Targeted MS can provide a next-generation analysis platform to advance cancer immuno-therapeutic research and diagnostics.
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Cytotoxicity of the methanol extracts of Elephantopus mollis, Kalanchoe crenata and 4 other Cameroonian medicinal plants towards human carcinoma cells
Cancer still constitutes one of the major health concerns globally, causing serious threats on patients, their families, and the healthcare system.
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Effects of Dangguibuxue decoction on rat glomerular mesangial cells cultured under high glucose conditions
Dysfunction of glomerular mesangial cells (GMCs) plays an important role in pathogenesis of diabetic nephropathy. Here, we investigated the effects of ...
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Thymoquinone (TQ) inhibits the replication of intracellular Mycobacterium tuberculosis in macrophages and modulates nitric oxide production
Human tuberculosis, which is caused by the pathogen Mycobacterium tuberculosis, remains a major public health concern. Increasing drug resistance poses a threat of disease resurgence and continues to cause consid...
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Investigation of antioxidant, antimicrobial and toxicity activities of lichens from high altitude regions of Nepal
Several lichen species are reported to be used tradiationally in many theraupatic practices. Many lichen species are reported as sources of several bioactive natural compounds. Several lichen species of Nepal ...
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Urinary metabolomics study on the protective role of Orthosiphon stamineus in Streptozotocin induced diabetes mellitus in rats via 1H NMR spectroscopy
Orthosiphon stamineus (OS) is a herb known in ethnomedicine for treating diabetes mellitus (DM). In this study, a 1H NMR based urine metabolomics tool has been used for the first time ...
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Association of hepatitis status with surgical outcomes in patients with dual hepatitis B and C related hepatocellular carcinoma
The conception that serological hepatitis markers determined surgical prognosis of hepatocellular carcinoma (HCC) associated with hepatitis B (HBV) or hepatitis C (HCV) has been well defined. However, little i...
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Improving care for people with heart failure in Uganda: serial in-depth interviews with patients’ and their health care professionals
The short prognosis of patients with advanced heart failure (HF) and the associated multidimensional distress as illustrated in literature from high income countries necessitates the integration of palliative ...
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Structural studies unravel the active conformation of apo ROR{gamma}t nuclear receptor and a common inverse agonism of two diverse classes of ROR{gamma}t inhibitors [Molecular Biophysics]
The nuclear receptor retinoid acid-related orphan receptor γt (RORγt) is a master regulator of the Th17/IL-17 pathway that plays crucial roles in the pathogenesis of autoimmunity. RORγt has recently emerged as a highly promising target for treatment of a number of autoimmune diseases. Through high-throughput screening we previously identified several classes of inverse agonists for RORγt. Here, we report the crystal structures for the ligand binding domain of RORγt in both apo and ligand-bound states. We show that apo RORγt adopts an active conformation capable of recruiting coactivator peptides and present a detailed analysis of the structural determinants that stabilize helix 12 (H12) of RORγt in the active state in the absence of a ligand. The structures of ligand-bound RORγt reveal that binding of the inverse agonists disrupts critical interactions that stabilize H12. This destabilizing effect is supported by ab initio calculations and experimentally by a normalized crystallographic B-factor analysis. Of note, the H12 destabilization in the active state shifts the conformational equilibrium of RORγt toward an inactive state, which underlies the molecular mechanism of action for the inverse agonists reported here. Our findings highlight that nuclear receptor structure and function are dictated by a dynamic conformational equilibrium and that subtle changes in ligand structures can shift this equilibrium in opposite directions, leading to a functional switch from agonists to inverse agonists.
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The Myocardin-related transcription factor MKL co-regulates the cellular levels of two profilin isoforms [Signal Transduction]
Megakaryoblastic leukemia (MKL)/ serum response factor (SRF)-mediated gene transcription is a highly conserved mechanism that connects dynamic reorganization of the actin cytoskeleton to regulation of expression of a wide range of genes including SRF itself and many important structural and regulatory components of actin cytoskeleton. In this study, we examined the possible role of MKL/SRF in the context of regulation of profilin (Pfn), a major controller of actin dynamics and actin cytoskeletal remodeling in cells. We demonstrated that despite being located on different genomic loci, two major isoforms of Pfn (Pfn1 and Pfn2) are co-regulated by a common mechanism involving the action of MKL that is independent of its SRF-related activity. We found that MKL co-regulates the expression of Pfn isoforms indirectly by modulating signal transducer and activator of transcription 1 (STAT1) and utilizing its SAP-domain function. Unexpectedly, our studies revealed that cellular externalization, rather than transcription of Pfn1, is affected by the perturbations of MKL. We further demonstrated that MKL can influence cell migration by modulating Pfn1 expression, indicating a functional connection between MKL and Pfn1 in actin-dependent cellular processes. Finally, we provide initial evidence supporting the ability of Pfn to influence MKL and SRF expression. Collectively, these findings suggest that Pfn may play a role in a possible feedback loop of the actin/MKL/SRF signaling circuit.
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Spermidine promotes Bacillus subtilis biofilm formation by activating expression of the matrix regulator slrR [Metabolism]
Ubiquitous polyamine spermidine is not required for normal planktonic growth of Bacillus subtilis but is essential for robust biofilm formation. However, the structural features of spermidine required for B. subtilis biofilm formation are unknown and so are the molecular mechanisms of spermidine-stimulated biofilm development. We report here that in a spermidine-deficient B. subtilis mutant, the structural analogue norspermidine, but not homospermidine, restored biofilm formation. Intracellular biosynthesis of another spermidine analogue, aminopropylcadaverine, from exogenously supplied homoagmatine also restored biofilm formation. The differential ability of C-methylated spermidine analogues to functionally replace spermidine in biofilm formation indicated that the aminopropyl moiety of spermidine is more sensitive to C-methylation, that it is essential for biofilm formation, but that the length and symmetry of the molecule is not critical. Transcriptomic analysis of a spermidine-depleted B. subtilis speD mutant uncovered a nitrogen-, methionine- and S-adenosylmethionine-sufficiency response, resulting in repression of gene expression related to purine catabolism, methionine and S-adenosylmethionine biosynthesis and methionine salvage, and signs of altered membrane status. Consistent with the spermidine requirement in biofilm formation, single-cell analysis of this mutant indicated reduced expression of the operons for production of the exopolysaccharide and TasA protein biofilm matrix components and SinR antagonist slrR. Deletion of sinR or ectopic expression of slrR in the spermidine-deficient ΔspeD background restored biofilm formation, indicating that spermidine is required for expression of the biofilm regulator slrR. Our results indicate that spermidine functions in biofilm development by activating transcription of the biofilm matrix exopolysaccharide and TasA operons through the regulator slrR.
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Guanine nucleotide exchange factor Epac2-dependent activation of the GTP-binding protein Rap2A mediates cAMP-dependent growth arrest in neuroendocrine cells [Neurobiology]
First messenger-dependent activation of MAPKs in neuronal and endocrine cells is critical for cell differentiation and function and requires guanine nucleotide exchange factor (GEF)- mediated activation of downstream Ras-family small GTPases, which ultimately lead to ERK, JNK, and p38 phosphorylation. Because there are numerous GEFs and also a host of Ras-family small GTPases, it is important to know which specific GEF-small GTPase dyad functions in a given cellular process. Here, we investigated the upstream activators and downstream effectors of signaling via the GEF Epac2 in the neuroendocrine NS-1 cell line. Three cAMP sensors, Epac2, PKA and NCS-Rapgef2 mediate distinct cellular outputs: p38-dependent growth arrest, CREB-dependent cell survival, and ERKdependent neuritogenesis, respectively, in these cells. Previously, we found that cAMP-induced growth arrest of PC12 and NS-1 cells requires Epac2-dependent activation of p38 MAPK, which posed the important question of how Epac2 engages p38 without simultaneously activating other MAPKs in neuronal and endocrine cells. We now show that the small GTP-binding protein Rap2A is the obligate effector for, and GEF substrate of, Epac2 in mediating growth arrest through p38 activation in NS-1 cells. This new pathway is distinctly parcellated from the GPCR → Gs → AC → cAMP → PKA → CREB pathway mediating cell survival, and the GPCR → Gs → AC → cAMP → NCS-Rapgef2 → B-Raf → MEK → ERK pathway mediating neuritogenesis in NS-1 cells.
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The First Crystal Structure of a Family 129 Glycoside Hydrolase from a Probiotic Bacterium Reveals Critical Residues and Metal Co-factors [Protein Structure and Folding]
The α-N-acetylgalactosaminidase from the probiotic bacterium Bifidobacterium bifidum (NagBb) belongs to the glycoside hydrolase (GH) family 129 and hydrolyzes the glycosidic bond of Tn antigen (GalNAcα1-Ser/Thr). NagBb is involved in assimilation of O-glycans on mucin glycoproteins by B. bifidum in the human gastrointestinal tract, but its catalytic mechanism has remained elusive because of a lack of sequence homology around putative catalytic residues and of other structural information. Here we report the X-ray crystal structure of NagBb, representing the first GH129 family structure, solved by the single-wavelength anomalous dispersion method based on sulfur atoms of the native protein. We determined ligand-free, GalNAc and inhibitor complex forms of NagBb and found that Asp-435 and Glu-478 are located in the catalytic domain at appropriate positions for direct nucleophilic attack at the anomeric carbon and proton donation for the glycosidic-bond oxygen, respectively. A highly conserved Asp-330 forms a hydrogen bond with the O4 hydroxyl of GalNAc in the -1 subsite, and Trp-398 provides a stacking platform for the GalNAc pyranose ring. Interestingly, a metal ion, presumably Ca2+, is involved in the recognition of the GalNAc N-acetyl group. Mutations at Asp-435, Glu-478, Asp-330, Trp-398, and residues involved in metal coordination (including an all-Ala quadruple mutant) significantly reduced the activity, indicating that these residues and the metal ion play important roles in substrate recognition and catalysis. Interestingly, NagBb exhibited some structural similarities to the GH101 endo-α-N-acetylgalactosaminidases, but several critical differences in substrate recognition and reaction mechanism account for the different activities of these two enzymes.
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Crosstalk between the H3K36me3 and H4K16ac histone epigenetic marks in DNA double-strand break repair [Gene Regulation]
Post-translational modifications of histone proteins regulate numerous cellular processes. Among these modifications, trimethylation of lysine 36 in histone H3 (H3K36me3) and acetylation of lysine 16 in histone H4 (H4K16ac) have important roles in transcriptional regulation and DNA damage response signaling. However, whether these two epigenetic histone marks are mechanistically linked remains unclear. Here, we discovered a new pathway through which H3K36me3 stimulates H4K16ac upon DNA double-strand break (DSB) induction in human cells. In particular, we examined, using Western blot analysis, the levels of H3K36me3 and H4K16ac in cells after exposure to various DSB-inducing agents, including neocarzinostatin, γ rays and etoposide, and found that H3K36me3 and H4K16ac were both elevated in cells upon these treatments. We also observed that the DSB-induced H4K16 acetylation was abolished in cells upon depletion of the histone methyltransferase gene SET-domain containing 2 (SETD2) and the ensuing loss of H3K36me3. Furthermore, the H3K36me3-mediated increase in H4K16ac necessitated lens epithelium-derived growth factor p75 splicing variant (LEDGF), which is a reader protein of H3K36me3, and the KAT5 (TIP60) histone acetyltransferase. Mechanistically, the chromatin-bound LEDGF, through its interaction with KAT5, promoted chromatin localization of KAT5, thereby stimulating H4K16 acetylation. Together, we unveiled a crosstalk between two important histone epigenetic marks and defined the function of this crosstalk in DNA DSB repair.
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Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition. [Signal Transduction]
The mitochondrial network is a major site of ATP production through the coupled integration of the electron transport chain (ETC) with oxidative phosphorylation. In melanoma, arising from the Val600Glu mutation in the kinase v-RAF murine sarcoma viral oncogene homolog B (BRAFV600E), oncogenic signaling enhances glucose-dependent metabolism, while reducing mitochondrial ATP production. Likewise, when BRAFV600E is pharmacologically inhibited by targeted therapies (e.g. PLX-4032/Vemurafenib), glucose metabolism is reduced and cells increase mitochondrial ATP production to sustain survival. Therefore, collateral inhibition of oncogenic signaling and mitochondrial respiration may help enhance the therapeutic benefit of targeted therapies. Honokiol (HKL) is a well-tolerated small molecule that disrupts mitochondrial function; however its underlying mechanisms and potential utility with targeted anticancer therapies remain unknown. Using wild-type BRAF and BRAFV600E melanoma model systems, we demonstrate here that HKL administration rapidly reduces mitochondrial respiration by broadly inhibiting ETC complexes I, II, and V, resulting in decreased ATP levels. The subsequent energetic crisis induced two cellular responses involving cyclin-dependent kinases (CDKs). First, loss of CDK1-mediated phosphorylation of the mitochondrial division GTPase dynamin-related protein 1 promoted mitochondrial fusion, thus coupling mitochondrial energetic status and morphology. Second, HKL decreased CDK2 activity, leading to G1 cell cycle arrest. Importantly, while pharmacological inhibition of oncogenic MAPK signaling increased ETC activity, co-treatment with HKL ablated this response and vastly enhanced the rate of apoptosis. Collectively, these findings integrate HKL action with mitochondrial respiration and shape and substantiate a pro-survival role of mitochondrial function in melanoma cells following oncogenic MAPK inhibition.
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Non-shivering thermogenesis as a mechanism to facilitate sustainable weight loss
Summary
Currently, there is a significant percentage of the population who are or will be classified as obese, necessitating novel strategies to facilitate sustainable weight loss. Reductions in basal metabolic rate occur in the face of weight loss and pose formidable barriers to individuals attempting to sustain meaningful weight reductions. Here, we discuss the mechanisms by which non-shivering thermogenesis may provide insight into metabolic pathways that can become druggable targets to facilitate sustainable weight loss. Specifically, we highlight the fact that non-shivering thermogenesis results in activation and expansion of brown and beige adipose tissues as well as activates pathways in skeletal muscle which increase metabolic flux and activity of muscle fibres through futile calcium cycling across the endoplasmic reticulum all facilitating an increase in metabolism. Finally, we highlight the fact there are sexual dimorphisms with respect to these metabolic processes in keeping with the National Institutes of Health mandate of treating sex as a biologic variable.
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Thoraco-lumbar selective fusion in adolescent idiopathic scoliosis with Lenke C modifier curves: clinical and radiographic analysis at 10-year follow-up
Abstract
Purpose
To examine the radiological and clinical outcomes of a single-center case series of selective thoracic fusions (STF) in adolescent idiopathic scoliosis with Lenke C modifier curves, with a long-term follow-up.
Methods
We evaluated at 6 months and 10 years different radiological parameters on both thoracic and lumbar districts: coronal curves, sagittal curves, apical vertebral translation (AVT), and apical vertebral rotation (AVR). The clinical outcome was determined using the SRS 22 score. Data were also analyzed dividing the patients by their Risser and Lenke scores.
Results
In examining 90 patients we reported a radiological benefit from STF on both thoracic and lumbar districts. The corrections in the values of both coronal curves, AVT, and AVR are relevant at 6 months and do not significantly vary at the latest follow-up. Sagittal curves are not relevantly affected at any time point. All the SRS 22 score evaluations showed significant improvement at 6 months, in particular, the self-image analysis. A further improvement was also reported at 10 years, in particular in pain and function scores. At no time point were significant differences retrieved by comparing SRS 22 results as divided by Risser or Lenke grading systems.
Conclusions
STF is an effective treatment option both in clinical and radiographical terms. The results at 10-year follow-up confirm both the stability of the correction and the improvement of the clinical outcome scores. Risser and Lenke grading systems are not relevant variables predictive of clinical efficacy.
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Results of lumbar spondylodeses using different bone grafting materials after transforaminal lumbar interbody fusion (TLIF)
Abstract
Purpose
Can a mixture of hydroxyapatite (HA) and autologous bone from decompression sites produce similar results when used for transforaminal lumbar interbody fusion (TLIF)? In the current literature, autologous iliac crest bone grafts (ICBGs) have been reported the gold standard for this procedure. Indeed, to date, no clinical data have confirmed that a mixture of equal volumes of HA and local autologous bone produce similar results in term of fusion as the same volume of autologous ICBG alone.
Methods
Study design/setting This study was approved by the local ethics committee and completed in a prospective, randomized, single-blinded manner. The results of lumbar fusion using TLIF and different bone grafting materials were compared. Patient sample The patient sample included patients with spinal lumbar degenerative disease. Outcome measures The clinical outcome was determined using the Oswestry Low Back Pain Disability Questionnaire (ODI) and Visual Analog Scale (VAS). The radiological outcomes and fusion rates were determined with radiographs evaluated using the McAfee criteria and computed tomography (CT) data evaluated by the Williams criteria. Three blinded investigators (one radiologist and two orthopedic surgeons) assessed the data. The secondary variables included donor site morbidity. Methods The patients were admitted to our department for orthopedic surgery with degenerative lumbar pathologies (L2–S1) that required stabilization in one or two segments using a TLIF procedure. The patients were 18–80 years old. Only those patients who had degenerative lumbar pathologies and agreed to be educated about the study were included. The patients were divided into the following two randomized groups: group A: TLIF procedure using autologous ICBGs alone; and group B: TLIF procedure using local bone from decompression site mixed with hydroxyapatite. Each group received equal graft volumes. The mixture in group B consisted of equal volumes of local autograft (5 cc) and synthetic bone (5 cc). A graft volume of 10 cc was used at each fusion level. The patients were followed up at three appointments at 1.5, 6 and 12 months postoperatively. Every patient received detailed education about the course of the study.
Results
Forty-eight patients finished the study (2 patients dropped out). The radiographic fusion rate did not significantly differ between the two groups. Based on the CT criteria, 83.3% of the patients showed fusion in both groups after 12 months. Furthermore, 95.3% of the patients in group A and 91.7% of the patients in group B showed bony spondylodeses according to the radiographic criteria at the 12-month follow-up. The donor site morbidity consisted of one patient with a wound infection and one with a hematoma in group A and two patients with persistent pain in group B. Group A also included one patient with cage subsidence of 4 mm and archived fusion after 12 months. In group B, one patient had a pedicle screw breakage and achieved fusion after 6 months. The clinical outcomes were similar between the two groups. In both groups, the VAS and ODI data improved during the follow-up period (p < 0.05). No patients required additional surgeries.
Conclusions
Both groups demonstrated equivalent clinical outcomes. HA and autologous bone from decompression sites can achieve similar fusion rates to those achieved with identical volumes of the gold standard autologous graft. The graft mixture can be used for one- or two-level lumbar spondylodeses to avoid donor site morbidity.
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Incomplete burst fractures of the thoracolumbar spine: a review of literature
Abstract
Purpose
The purpose of this review was to analyze the biomechanical basis of incomplete burst fractures of the thoracolumbar spine, summarize the available treatment options with evidence from the literature, and to propose a method to differentiate fracture severity.
Methods
The injury pattern, classification, and treatment strategies of incomplete burst fractures of the thoracolumbal spine have been described following a review of the literature. All level I–III studies, studies with long-term results and comparative studies were included and summarized.
Results
Details of five randomized control trials were included. Additionally, three comparative studies and two studies with long-term outcomes were detailed in this review. The fracture severity reported in the included studies varied tremendously. Most classification used did not adequately describe the complexity of fracture configuration. A wide variety of treatment strategies were outlined, ranging from non-operative therapy to aggressive surgical intervention with combined anterior-posterior approaches. Thus, the treatment of incomplete burst fractures of the thoracolumbar spine is quite diverse and remains controversial.
Conclusions
Incomplete burst fractures can differ tremendously regarding the degree of instability they confer to the thoracolumbar spine. Based on a detailed review of the literature, it is clear that good results can be obtained with both non-operative and operative strategies to treat these injuries. In the authors' opinion, the intervertebral disc plays a key role in determining the long-term clinical and radiological outcome. Thus, an incorporation of the intervertebral disc pathology into the existing classification systems would be a valuable prognostic factor.
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Effect of Oxy133, an osteogenic oxysterol, on new bone formation in rat two-level posterolateral fusion model
Abstract
Purpose
The aim of our study was to determine the effect of Oxy133 and rhBMP2 on fusion rates and new bone formation in a rat posterolateral fusion (PLF) model. Furthermore, we examined whether Oxy133 could inhibit the adipogenesis that is often present in rhBMP2-induced fusions.
Methods
Sixty-four male Lewis rats underwent two levels PLF (L3–L5). All animals were randomly divided into eight groups based on the test compound that they received: control (DMSO), low-dose rhBMP2 (0.5 µg), high-dose rhBMP2 (5 µg), low-dose Oxy133 (5 mg), high-dose Oxy133 (20 mg), low rhBMP2 + high Oxy133, high rhBMP2 + high Oxy133, and low rhBMP2 + low Oxy133. Fusion rates were assessed 8 weeks after surgery with manual palpation and plain radiographs. Bone parameters were measured using microCT. Histology was used to evaluate adipogenesis.
Results
No fusion was observed in the control group. Based on the manual palpation, 100% fusion was observed in all other groups except in the low-dose rhBMP2 group (69%). At 8 weeks based on X-rays, 100% fusion was observed in the following groups: high-dose rhBMP2, low-dose Oxy133, and low rhBMP2 + low Oxy133. In the other groups, the fusion rates were between 95 and 97%, except for the low rhBMP2 group (72%). We observed similar values in BV/TV ratio at L3–4 when Oxy133 groups were compared to rhBMP2 groups alone (44.62% in high-dose Oxy133 vs. 41.47% in high-dose rhBMP2 and 47.18% in low-dose Oxy133 vs. 54.98% in low-dose rhBMP2). Trabecular thickness was slightly lower in Oxy133 groups compared to rhBMP2 when comparing low- and high-dose groups from each group (118.44 µm for high-dose Oxy133 vs. 122.39 µm for high-dose rhBMP2 and 123.51 µm for low-dose Oxy133 vs. 135.74 µm for low-dose rhBMP2). At the same time, trabecular separation was lower in Oxy133 groups compared to rhBMP2 groups. Similar trends in bone parameters were observed at the L4–5 levels. Fusion masses with low- and high-dose Oxy133 had significantly less adipocytes than rhBMP2 groups that showed robust adipocyte formation.
Conclusion
In our study, both low-dose and high-dose Oxy133 produced solid fusions with bone densities similar or higher than in the BMP2 groups. High-dose Oxy133 group had significantly less adipocytes than high- or low-dose rhBMP2 groups. Furthermore, high-dose Oxy133 was able to significantly inhibit high-dose BMP2-induced adipogenesis when combined together. Consistent with the previous reports, our preliminary findings suggest that Oxy133 has a significant potential as an alternative to rhBMP2 in spine fusion.
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A tree species range in the face of climate change: cork oak as a study case for the Mediterranean biome
Abstract
Species distribution models are feasible methods for projecting theoretical responses of living organisms' occurrence under several future climate change scenarios. The major interest is focused on trees, which regulate the equilibrium within ecosystems and guarantee the survival of many life forms on the Earth. The repercussions of climatic drivers are expected to pose the strongest threats for the Mediterranean biome, an acknowledged hotspot of biodiversity. Here, we focused on cork oak (Quercus suber L.), a keystone species of many landscapes, sustaining a rich biodiversity, ecological processes and economic incomes. Results of 8 combined ecological modelling techniques and two Global Circulation Models highlight a broad contraction of the species potential range over the twenty-first century, both under intermediate and high emissions scenarios. Coupled northward and upward shifts are predicted, mostly pertaining Iberia and North Africa. The potential areas detected at Levantine will likely undergo disappearance. To exacerbate the impacts of climate change, the future of the ecosystems linked to cork oak remains uncertain, because of the expected implications on the phenotypic plasticity or evolutionary responses. A synergy among niche-based, physiological and eco-genetic investigations is strongly needed in the field of applied research, to improve the assessment of conservation and reforestation actions.
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Emerging Treatments in Eating Disorders
Abstract
Eating disorders (EDs), including anorexia nervosa, bulimia nervosa, and binge-eating disorder, constitute a class of common and deadly psychiatric disorders. While numerous studies in humans highlight the important role of neurobiological alterations in the development of ED-related behaviors, the precise neural substrate that mediates this risk is unknown. Historically, pharmacological interventions have played a limited role in the treatment of eating disorders, typically providing symptomatic relief of comorbid psychiatric issues, like depression and anxiety, in support of the standard nutritional and psychological treatments. To date there are no Food and Drug Administration-approved medications or procedures for anorexia nervosa, and only one Food and Drug Administration-approved medication each for bulimia nervosa (fluoxetine) and binge-eating disorder (lisdexamfetamine). While there is little primary interest in drug development for eating disorders, postmarket monitoring of medications and procedures approved for other indications has identified several novel treatment options for patients with eating disorders. In this review, I utilize searches of the PubMed and ClinicalTrials.gov databases to highlight emerging treatments in eating disorders.
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Evaluation of Penicillin Allergy in the Hospitalized Patient: Opportunities for Antimicrobial Stewardship
Abstract
Purpose of Review
Penicillin allergy is often misdiagnosed and is associated with adverse consequences, but testing is infrequently done in the hospital setting. This article reviews historical and contemporary innovations in inpatient penicillin allergy testing and its impact on antimicrobial stewardship.
Recent Findings
Adoption of the electronic medical record allows rapid identification of admitted patients carrying a penicillin allergy diagnosis. Collaboration with clinical pharmacists and the development of computerized clinical guidelines facilitates increased testing and appropriate use of penicillin and related β-lactams. Education of patients and their outpatient providers is the key to retaining the benefits of penicillin allergy de-labeling.
Summary
Penicillin allergy testing is feasible in the hospital and offers tangible benefits towards antimicrobial stewardship. Allergists should take the lead in this endeavor and work towards overcoming personnel limitations by partnering with other health care providers and incorporating technology that improves the efficiency of allergy evaluation.
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Pulse wave velocity and augmentation index are not independently associated with carotid atherosclerosis in patients with rheumatoid arthritis
Abstract
Arterial stiffness can enhance cardiovascular risk by increasing atherogenesis or adverse hemodynamic effects. We examined whether the arterial stiffness markers of aortic pulse wave velocity (PWV) and the augmentation index (AIx) are independently associated with carotid artery intima-media thickness (IMT) and plaque in patients with rheumatoid arthritis (RA). PWV and AIx were determined by brachial oscillometry using the Mobil-O-Graph® system and carotid IMT and plaque by ultrasound in 194 consecutive RA patients without established cardiovascular disease, chronic kidney disease, and diabetes at disease onset. In crude analysis, PWV was associated with IMT (β (95% CI) = 0.04 (0.03 to 0.05), p value < 0.0001) and plaque (OR (95% CI) = 1.69 (1.40 to 2.04), p value < 0.0001). Upon adjustment for the confounders of age, sex, mean blood pressure, body height, and cardiovascular risk factors comprising smoking, the atherogenic index, and diabetes, PWV was not related to IMT (β (95% CI) = 0.01 (−0.02 to 0.04), p value = 0.5) or plaque (OR (95% CI) = 0.99 (0.96 to 1.01), p value = 0.3). AIx was not associated with IMT in crude (β (95% CI) = −0.002 (−0.004 to 0.007), p value = 0.2) and adjusted analyses (β (95% CI) = −0.002 (−0.004 to 0.000), p value = 0.06). AIx was also unrelated to carotid plaque in crude (OR (95% CI) = 1.04 (0.60 to 1.82), p value = 0.9) and adjusted analyses (OR (95% CI) = 0.97 (0.94 to 1.01), p value = 0.1). PWV and AIx are not independently associated with subclinical carotid atherosclerosis in RA.
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Genetic test for anal cancer could identify those at high risk
A new test, based on a patient's epigenetics, could be an accurate and inexpensive way to find and treat those at highest risk of anal cancer - a disease with growing incidence in women, men who have sex with men (MSM) and people with HIV. The early...
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Behavior of Germanium and Silicon Nanowire Anodes with Ionic Liquid Electrolytes
ACS Nano
DOI: 10.1021/acsnano.7b01705
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Pharmaceutical Intermediate-Modified Gold Nanoparticles: Against Multidrug-Resistant Bacteria and Wound-Healing Application via an Electrospun Scaffold
ACS Nano
DOI: 10.1021/acsnano.7b01240
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Ultrasmall Magnetic CuFeSe2 Ternary Nanocrystals for Multimodal Imaging Guided Photothermal Therapy of Cancer
ACS Nano
DOI: 10.1021/acsnano.7b01032
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Pediatric invasive fungal rhinosinusitis: An investigation of 17 patients
To investigate outcomes of pediatric patients at a single institution with invasive fungal rhinosinusitis (IFRS) and to determine variables that impact overall survival.
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Letter to the Editor, regarding the article: "Prevalence of vestibular and balance disorders in children and adolescents according to age: A multi-centre study" (2017; 94: 36-39)
With great interest we read the article by Lee et al. “Prevalence of vestibular and balance disorders in children and adolescents according to age: A multi-centre study” (2017; 94: 36-39). In this study the authors investigated children and adolescents aged under 18 who visited the otolaryngology departments of eleven hospitals (mostly university hospitals) with dizziness as their main complaint. They concluded that in these patients, vestibular migraine (VM) and benign paroxysmal vertigo of childhood (BPVC) were the most common diseases, and prevalence of disease by age showed different distributions.
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Response to Letter to the Editor: Prevalence of vestibular and balance disorders in children and adolescents according to age category: A multi-center study in Korea
First, we thank you for your interesting comments on our study. This study was designed to identify the etiologies and prevalence of vestibular and balance disorders according to age categories, in children and adolescents, in a multi-center study.
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ImmunoCAP Assays: pros and cons in allergology
Allergen-specific IgE measurements together with the clinical history are the cornerstones of allergy diagnosis. During the past decades not only characterization and standardization of allergen extracts have improved but also assay technology. Here we discuss the uses, advantages, misinterpretations and limitations of ImmunoCAP IgE assays (Thermo Fisher Scientific/Phadia, Uppsala, Sweden) in the field of allergology. They can be performed as singleplex (ImmunoCAP) and since a decade also as multiplex (ISAC).
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Hematopoietic Stem Cell Transplantation For RelB Deficiency
HSCT conditioning is tolerated well by patients with RelB deficiency and leads to immune reconstitution.
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Prevention of food allergy development and suppression of established food allergy by neutralization of TSLP, IL-25 and IL-33
IL-25, IL-33 and TSLP are required to induce a mouse model of food allergy and all of these cytokines contribute to murine food allergy maintenance. This suggests an approach for suppressing human food allergy.
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Vitamin D supplementation during pregnancy: Effect on the neonatal immune system in a randomized controlled trial
Programming of the immune system during fetal development can influence asthma-related risk factors and outcomes in later life. Vitamin D is a well-recognized immune modulator, and deficiency of this nutrient during pregnancy is hypothesized to influence disease development in offspring.
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Stellagama the Rainbow Dragon
-- Read more on ScientificAmerican.com
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Childhood predictors of cardiovascular disease in adulthood. A systematic review and meta-analysis
Summary
Childhood obesity predicts the risk of adult adiposity, which is associated with the earlier onset of cardiovascular disease [adult atherosclerotic cardiovascular disease, ACVD: hypertension, increased carotid intima media thickness (CIMT) stroke, ischemic heart disease (IHD)] and dysglycaemia. Because it is not known whether childhood obesity contributes to these diseases, we conducted a systematic review of studies that examine the ability of measures of obesity in childhood to predict dysglycaemia and ACVD. Data sources were Web of Science, MEDLINE, PubMed, CINAHL, Cochrane, SCOPUS, ProQuest and reference lists. Studies measuring body mass index (BMI), skin fold thickness and waist circumference were selected; of 1,954 studies, 18 met study criteria. Childhood BMI predicted CIMT: odds ratio (OR), 3.39 (95% confidence interval (CI), 2.02 to 5.67, P < 0.001) and risk of impaired glucose tolerance in adulthood, but its ability to predict ACVD events (stroke, IHD; OR, 1.04; 95% CI, 1.02 to 1.07; P < 0.001) and hypertension (OR, 1.17, 95% CI 1.06 to 1.27, P = 0.003) was weak–moderate. Body mass index was not predictive of systolic BP (r −0.57, P = 0.08) and weakly predicted diastolic BP (r 0.21, P = 0.002). Skin fold thickness in childhood weakly predicted CIMT in female adults only (rs0.09, P < 0.05). Childhood BMI predicts the risk of dysglycaemia and abnormal CIMT in adulthood, but its ability to predict hypertension and ACVD events was weak and moderate, respectively. Skin fold thickness was a weak predictor of CIMT in female adults.
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Analytical solutions of the Klein–Gordon equation for Manning–Rosen potential with centrifugal term through Nikiforov–Uvarov method
Abstract
We present approximate analytical solutions of the Klein–Gordon equation with arbitrary l state for the Manning–Rosen potential using the Nikiforov–Uvarov method and adopting the approximation scheme for the centrifugal term. We provide the bound state energy spectrum and the wave function in terms of the hypergeometric functions.
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Influence of electrical double-layer dispersion forces and size dependency on pull-in instability of clamped microplate immersed in ionic liquid electrolytes
Abstract
Plate-type clamped microplate is of the most common constructive elements for developing in-liquid-operating devices. While the electromechanical behavior of clamped microplate in non-liquid environments has exclusively been addressed in the literature, no theoretical studies have yet been conducted on precise modeling of the clamped microplate in electrolyte liquid. Herein, the electromechanical response and instability of the clamped microplate immersed in ionic electrolyte media are investigated. The electrochemical force field is determined using double layer theory and linearized Poisson–Boltzmann equation. The presence of dispersion forces, i.e., Casimir and van der Waals attractions, are included in the theoretical model considering the correction due to the presence of liquid media between the interacting surfaces (three-layer model). To this end, a kind of microplate has been designed, i.e., a square microplate with all edges clamped supported. The strain gradient elasticity is employed to model the size-dependent structural behavior of the clamped microplate. To solve the nonlinear constitutive equation of the system, Extended Kantorovich Method, is employed and the pull-in parameter of the microplate are extracted. Impacts of the dispersion forces and size effect on the instability characteristics are discussed as well as the effect of ion concentration and potential ratio. It is found that the significant difference between the pull-in instability parameters in the modified strain gradient theory and the classical theory for thin microplates is merely due to the consideration of size effect parameter in the modified strain gradient theory. To confirm the validity of formulations, the numerical values of the results are compared. The results predicted via the aforementioned approach are in excellent agreement with those in the literature. Some new examples are solved to demonstrate the applicability of the procedure.
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Ac transport properties of electrons in parallel-plate mesoscopic capacitors in series
Abstracts
In a self-consistent manner by taking into account three aspects: the frequency of the bias, geometry of the capacitor (e.g. plate separation) and the Fermi energy of the system, ac transport properties of electrons in parallel-plate mesoscopic capacitor in series under an bias are discussed. The charge density, the internal characteristic potential caused by electrons interaction and the size-dependent mesoscopic capacitance are calculated. Results show that these quantities are complex number with very small finite imaginary part in mesoscopic scale, and the current conservation is satisfied in our numerical calculation. Moreover, when the plate separation is large enough, the mesoscopic capacitance approaches to the geometric capacitance, and the imaginary parts vanish. When the plate separation is small, there are some differences between them.
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Post-operative fatal blood aspiration after routine lung surgery
When patients die shortly after an operation, the question of possible medical malpractice frequently arises. The clarification of medical malpractice claims is, therefore, a regularly encountered task in medicolegal practice. To be able to fulfill this task, medical examiners need to have a good understanding of the common complications that can occur after surgical procedures [13–15]. Although, the aspects that need to be clarified are often only vaguely defined, they may at times be so specific that they require specialist knowledge beyond the scope of the medical examiner’s training in general medicine.
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Identification and quantification of synthetic cannabinoids in ‛spice-like’ herbal mixtures: update of the German situation in early 2017
In addition, all SCs were quantified by a GC-MS method using JWH-018 as internal standard and corresponding response factors. While MDMB-CHMICA was detected in six out of 14 tested products (ranging from 6 to 20mg/g; average 10mg/g), 5F-Cumyl-P7AICA and Cumyl-PeGACLONE were detected in three (109 to 153mg/g; average 131mg/g) and five products (15 to 74mg/g; average 39mg/g), respectively.
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The use of pesticides in Belgian illicit indoor cannabis plantations
Although total size of illicit Belgian indoor cannabis plantations is unknown, official seizure data indicate that cannabis production in Belgium is on the rise. In 2007, police confiscated 466 indoor cannabis plantations in Belgium. By 2010 this number had risen to 979 and by 2015 to 1241 plantations. In 2015, 979 (79%) of the confiscated plantations had more than 5 plants and 529 (43%) had more than 50 plants (unpublished data from the Belgian Federal police). Plantations with more than 5 plants are most likely planted for commercial reasons.
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Peer Review in Forensic Science
Peer review is one of the central components of the scientific framework underpinning the publication process in journals, the awarding of grants and honours, and promotion of academics. It has long been held up as the premier approach to ensure the validity of methods and conclusions, to detect errors and fraud, and to improve the quality of learned papers (Bornmann, 2013). Courts have used peer review as an indicator of ‘good science’ and general acceptance within the relevant communities of experts, with landmark rulings such as Daubert and Kumho deeming peer review as an important factor in whether a scientific method can be accepted as valid (Daubert v Merrell Dow Pharmaceuticals, 1993; Kumho Tire Co.
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Editorial Board and Contents
Publication date: June 2017
Source:Trends in Immunology, Volume 38, Issue 6
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Source:Trends in Immunology, Volume 38, Issue 6
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Lipopolysaccharide Detection across the Kingdoms of Life
Publication date: Available online 24 May 2017
Source:Trends in Immunology
Author(s): Jonathan C. Kagan
Studies in recent years have uncovered a diverse set of eukaryotic receptors that recognize lipopolysaccharide (LPS), the major outer-membrane component of Gram-negative bacteria. Indeed, Toll-like receptors, G-protein-coupled receptors, integrins, receptor-like kinases, and caspases have emerged as important LPS-interacting proteins. In this review, the mammalian receptors that detect LPS are described. I highlight how no host protein is involved in all LPS responses, but a single lipid (phosphatidylinositol-4,5-bisphosphate) regulates many LPS responses, including endocytosis, phagocytosis, inflammation, and pyroptosis. I further describe LPS response systems that operate specifically in plants, and discuss potentially new LPS response systems that await discovery. This diversity of receptors for a single microbial product underscores the importance of host–microbe interactions in multiple kingdoms of life.
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Source:Trends in Immunology
Author(s): Jonathan C. Kagan
Studies in recent years have uncovered a diverse set of eukaryotic receptors that recognize lipopolysaccharide (LPS), the major outer-membrane component of Gram-negative bacteria. Indeed, Toll-like receptors, G-protein-coupled receptors, integrins, receptor-like kinases, and caspases have emerged as important LPS-interacting proteins. In this review, the mammalian receptors that detect LPS are described. I highlight how no host protein is involved in all LPS responses, but a single lipid (phosphatidylinositol-4,5-bisphosphate) regulates many LPS responses, including endocytosis, phagocytosis, inflammation, and pyroptosis. I further describe LPS response systems that operate specifically in plants, and discuss potentially new LPS response systems that await discovery. This diversity of receptors for a single microbial product underscores the importance of host–microbe interactions in multiple kingdoms of life.
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Malignant external otitis: The shifting treatment paradigm
Malignant external otitis (MEO) is an aggressive infection occurring in immunocompromised hosts. Increasing antimicrobial resistance is making the disease more difficult to treat.
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Limitations and artifacts in shear-wave elastography of the liver
Abstract
Recent studies have shown that real-time, two-dimensional shear-wave elastography (2D-SWE) can monitor liver fibrosis by measuring tissue elasticity (i.e., elastic modulus). Two clinical studies of 2D-SWE in the liver have shown that there are several practical issues that can compromise quantitation of liver tissue elasticity. Both general ultrasound (US) limitations and limitations in the 2D-SWE method itself resulted in significant variability in estimated liver elasticity. The most common US limitations were: poor acoustic window, limited penetration, and rib/lung shadows. The most common 2D-SWE limitations were: reverberations under the liver capsule, respiratory/cardiac motion, and vessel pulsation/loss of SWE signal. Based on these studies, scan protocols have been optimized to minimize the influence of these limitations on liver elasticity quantification. These refined protocols should move non-invasive SWE closer to becoming the preferred tool to diagnose and manage many chronic diseases of the liver.
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Author’s Reply: A Systematic Review of Complications Associated with Direct Implants vs. Tissue Expanders Following Wise Pattern Skin-Sparing Mastectomy
We would like to thank the authors who read with and subsequently provided a reply to our original article entitled: “A Systematic Review of Complications Associated with Direct Implants vs. Tissue Expanders Following Wise Pattern Skin-Sparing Mastectomy.”1,2 Firstly, regarding our methodology, the author’s put forth the notion that numbers 20 and 21 of the PRISMA guidelines were not followed correctly, as we did not provide confidence intervals or I2 values for the included studies. According to an erratum published on the PRISMA website (http://ift.tt/2rVS4D4), “The published PRISMA checklists contain an error in the wording for Item 21.
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[Editorial] National progress on antimicrobial resistance
On May 22, in the shadow of WHO Director-General elections, WHO, the Food and Agriculture Organization of the UN, and the World Organisation for Animal Health presented progress on the first open survey of countries' national action plan preparedness on Antimicrobial Resistance (AMR) at the 70th World Health Assembly.
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[Editorial] Purdah and the gagging of science
The UK's National Institute for Health Research (NIHR) has issued guidance discouraging publication of—and commentary on—NIHR-funded research for the remainder of the country's General Election purdah. Purdah is a controlled period restricting public-facing activity, intended to prevent influence on election outcomes (currently enforced from April 22 to June 8). Using purdah to control science communication is an abuse of its intended purpose, and is not part of the original code. The guidance prevents dissemination and commentary on all NIHR-funded research covering public health, social care, health-system finance and workforce, and “any other areas where there is a risk of political interpretation”.
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[Correspondence] New era for health in The Gambia?
We appreciate Andrew Green's timely World Report (Feb 18, p 684)1 on The Gambia. At this crucial moment, The Gambia and west Africa face serious public health challenges. During the recent leadership change, the Economic Community of West African States (ECOWAS) gave vital diplomatic and military support to The Gambia. Continued ECOWAS-wide collaboration could improve overall public health, particularly in response to regional issues such as climate change. Gambian leaders must repair infrastructure corroded by decades of misgovernance that has left a depleted treasury and staggering debt load.
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[Correspondence] STREAM characterisation correction
In their discussion of modern management of acute myocardial infarction, Reed and colleagues (Jan 14, p 197)1 incorrectly assign our Strategic Reperfusion Early after Myocardial Infarction (STREAM) study to their section on rescue and facilitated percutaneous coronary intervention (PCI) and assert it “is not recommended”.2 STREAM was designed to address the needs of the large proportion of patients worldwide who present within 3 h of symptom onset and cannot undergo timely PCI within 1 h of first medical contact.
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[Comment] Financing preparedness at a national level
For far too long, the approach to pandemics has been one of panic and neglect: throwing money and resources at the problem when a serious outbreak occurs; then neglecting to sustain funding of preparedness when the news headlines move on. The result has been far too many lives lost and too much damage to human livelihoods. As news of new cases of Ebola virus disease in the DR Congo1 shows, the threat of deadly pathogens is ever present. New outbreaks will occur, but by investing in preparedness—in prevention, detection, containment, and control—their frequency and impact can be reduced.
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[Correspondence] STREAM characterisation correction – Authors' reply
We greatly appreciate the thoughtful response to our Seminar by Paul Armstrong and Frans Van de Werf. In our Seminar (Jan 14, p 197),1 we cite the Strategic Reperfusion Early after Myocardial Infarction (STREAM) study to support the statement that immediate or very early percutaneous coronary intervention (PCI) after fibrinolytic therapy has no ischaemic benefit and might cause harm by increasing bleeding.2 We feel that this is a justified application of this reference, because in STREAM, a greater proportion of patients who had intracranial haemorrhage in the fibrinolysis group was recorded compared with the proportion in the primary PCI only group (1·0% vs 0·2%; p=0·04), particularly in patients older than 75 years of age.
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[Comment] Offline: B-day—time to get real
It wasn't 9/11. But it felt like it. The shock of waking up on June 24, 2016, was palpable. Bewilderment and bereavement. Those of us who believed in the UK as an outward-looking European nation couldn't accept the fact that by the slimmest of majorities (51·9% vs 48·1%), Britain had voted to leave the European Union (EU). Even today, that sense of incomprehension, even trauma, is still felt by many. The Liberal Democrats have promised a final public vote on a Brexit settlement, together with an option to vote to stay in the EU.
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[Comment] A new chapter for the NCD Alliance: stronger together
The 70th World Health Assembly (WHA) coincides with a milestone in the history and development of the NCD Alliance (NCDA), and a new chapter for non-communicable disease (NCD) advocacy.
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[Comment] Respiratory medicine and critical care: a call for papers for ERS
The Lancet and The Lancet Respiratory Medicine would like to hear from authors of research papers in the fields of respiratory medicine and critical care, as the two journals are planning special issues to coincide with the 2017 European Respiratory Society (ERS) International Congress that will take place in Milan, Italy, on Sept 9–13, 2017.
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[Correspondence] The MERIDIAN trial: caution is needed
We congratulate Paul Griffiths and colleagues (Feb 4, p 538)1 for their Article showing that in-utero MRI changed prognostic information in at least 20% of cases of fetal brain abnormalities, and led to changes in clinical management in over a third of cases compared with ultrasound. However, we have several concerns about this Article.
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[Perspectives] When Big Men ruled global health: a cautionary tale
There was a time in world health efforts when Big Men (yes, all men, European and North American) had Big Ideas, backed by money and power. They had offices in places like the World Bank, UNICEF, and the Rockefeller Foundation. And they made scientific and programmatic decisions, financing and executing schemes that affected the survival and lives of hundreds of millions of people. When their decisions were sagacious and well executed the results could be breathtaking. Millions of children might in a single year be spared death from measles, for example, thanks to a targeted immunisation campaign.
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[World Report] Scott Gottlieb sworn in to head the FDA
Scott Gottlieb becomes commissioner of the FDA, as the agency's role is threatened by an administration adverse to regulation. Susan Jaffe, The Lancet's Washington correspondent, reports.
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[Obituary] Helen Carty
Leading paediatric radiologist. Born in Dungarvan, Ireland, on May 12, 1944, she died in Liverpool, UK, on April 23, 2017, aged 72 years.
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[World Report] Data reveal state of Venezuelan health system
Epidemiological data released by the Government of Venezuela after 2 years of silence betrays how the political and economic crisis has taken a toll on the health system. Barbara Fraser reports.
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[Perspectives] Parkinson's disease: what's in the name
It is 200 years since James Parkinson (1755–1824) published his observations on slowly and differentially developing involuntary movements, which he contended constituted “the same species” of disease. In An Essay on the Shaking Palsy, first published in May, 1817, Parkinson argued that specific forms of shaking, weakness, and altered posture and gait, together amounted to a previously uncharacterised “highly afflictive” malady. He called it “the Shaking Palsy” and rendered it in the Essay once only—and pointedly in brackets—as “(Paralysis Agitans)”.
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[Correspondence] Acromegaly in Lorenzo the Magnificent, father of the Renaissance
Lorenzo de' Medici (1449–92), also known as the Magnificent, was a statesman, patron of arts, and a key supporter of the Renaissance, a cultural movement in Italy that spread throughout Europe, marking the beginning of the Early Modern Age (from the 14th to the 17th century).
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[Series] Strategies for long-term preservation of kidney graft function
Kidney transplantation has become a routine procedure in the treatment of patients with kidney failure, and requires collaboration of experts from different disciplines, such as nephrology, surgery, immunology, pathology, infectious disease medicine, cardiology, and oncology. Grafts can be obtained from deceased or living donors, with different logistical requirements and implications for long-term graft patency. 1-year graft survival rates are greater than 95% in many centres but improvement of long-term function remains a challenge.
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[Series] Management of patients at risk of acute kidney injury
Acute kidney injury (AKI) is a multifaceted syndrome that occurs in different settings. The course of AKI can be variable, from single hit and complete recovery, to multiple hits resulting in end-stage renal disease. No interventions to improve outcomes of established AKI have yet been developed, so prevention and early diagnosis are key. Awareness campaigns and education for health-care professionals on diagnosis and management of AKI—with attention to avoidance of volume depletion, hypotension, and nephrotoxic interventions—coupled with electronic early warning systems where available can improve outcomes.
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[Correspondence] Artificial trachea transplantation is not ready for patients
Although one assignment of a university hospital is to develop health care, the safety of each and every patient treated can never be challenged. Therefore, I, as the Chief Executive Officer of Karolinska University Hospital, feel the urge to share the lessons learned from the world's first artificial trachea transplantations in patients.
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Swelling–twist interaction in fiber-reinforced hyperelastic materials: the example of azimuthal shear
Abstract
We study how fiber-reinforced materials will naturally undergo swelling deformations in which a relatively greater stretch occurs transverse to the fibers than in the fiber direction. This means that a pattern of initially curved fibers prior to swelling will tend to straighten out as swelling proceeds. This can lead to swelling-induced deformations with a high degree of localized shearing and significant overall twisting. Such a process is examined for a plane strain swelling deformation that combines twist with radial expansion. Analytical results are obtained for both types: small and large swelling. Of particular interest is the relation of the extensible fiber theory to a theory for inextensible fibers. We examine the extent to which the former approaches the latter in the limit as the fibers are taken to be progressively stiffer.
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Stokes flow singularity at a corner joining solid and porous walls at arbitrary angle
Abstract
Motivated by the internal flow geometry of spiral-wound membrane modules with ladder-type spacers, we consider the Stokes flow singularity at a corner that joins porous and solid walls at arbitrary wedge angle \(\varTheta \) . Seepage flux through the porous wall is coupled to the pressure field by Darcy's law; slip is described by a variant of the Beavers–Joseph boundary condition. On a macroscopic, outer length scale, the singularity appears like a jump discontinuity in the normal velocity, characterized by a non-integrable 1 / r divergence of the pressure. For arbitrary \(\varTheta \) , we develop an algebraic criterion to determine the admissible radial exponent(s) in a leading, inner similarity solution—which represents a weaker, integrable singularity in the pressure. A complete map of exponent versus \(\varTheta \) is provided for \(0< \varTheta < 2 \pi \) : this has an intricate structure with infinitely many solution branches clustering around \(\varTheta = \pi \) and \(\varTheta = 2 \pi \) . By generalizing the similarity form with a ( \(\ln r\) ) term and iterating on the slip and seepage conditions, we can carry the outer and inner power series to arbitrarily high order. Nevertheless, a numerical splice is required in between. For this purpose, we apply an iterative, numerical-asymptotic patching scheme described by Nitsche and Parthasarathi (J Fluid Mech 713:183–215, 2012). Detailed velocity and pressure profiles are calculated for three wedge angles ( \(\varTheta = 3\pi /4, \pi /2, \pi /4\) ) and two dimensionless slip lengths ( \(\sigma = 20, 40\) ). The general trends for decreasing wedge angle are (i) weakening of the pressure singularity, (ii) increasing magnitude of the radial component of velocity, and (iii) movement of the inner–outer transition farther from the corner. Wedges with \(\varTheta < \pi \) are seen to differ fundamentally from the flat wedge ( \(\varTheta = \pi \) ) previously considered by Nitsche and Parthasarathi (2012).
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Reply: Obstructive Sleep Apnea in Adults: The Role of Upper Airway and Facial Skeletal Surgery
No abstract available
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Validating Facial Aesthetic Surgery Results with the FACE-Q: Correction
No abstract available
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Discussion: Should Immediate Autologous Breast Reconstruction Be Considered in Women Who Require Postmastectomy Radiation Therapy? A Prospective Analysis of Outcomes
No abstract available
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In-Depth Review of Symptoms, Triggers, and Treatment of Occipital Migraine Headaches (Site IV)
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