Intraoperative Assessment of Facial Nerve Trunk Width in Early Childhood With Cervicofacial Lymphatic Malformation

Background: Facial nerve damage during head and neck surgery has long been an important issue. However, few publications on the gross anatomy of the facial nerve are available in the young population. The aim of this study was to provide in vivo measurements of the facial nerve trunk during lymphatic malformation (LM) resection and to determine the association between the trunk width and patient- and disease-related variables. Methods: We conducted a retrospective analysis of 11 consecutive pediatric patients (11 facial nerve trunks) who underwent cervicofacial LM resection. The facial nerve of the affected side was dissected, and its trunk width at bifurcation was measured using calipers under a microscope during the operation. Results: Eleven patients younger than 6 years were enrolled. The median width of the facial nerve in patients younger than 1 year was 1.15 mm; it was 2.5 mm in those older than 1 year. Trunk width was significantly greater in patients older than 1 year than those younger than 1 year, whereas no statistical significance was found when comparing other age groups. Patient weight was positively correlated with trunk width, whereas LM grade and diameter showed no significant correlation. Conclusions: The significantly greater width of the facial nerve trunk in LM patients older than 1 year than those younger than 1 year suggests that the age of 1 may be a threshold for facial nerve hypertrophy and growth acceleration. This study provides informative in vivo data to help understand facial nerve characteristics in young patients.

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Treatment of Advanced Kienböck Disease With a Vascularized Radial Bone Flap Wrapped in the Pronator Quadratus

Purpose: In the present study, we aimed to assess the radiologic and clinical outcomes after excision of the lunate, insertion of a vascularized radial bone flap wrapped in the pronator quadratus, and distraction with an external fixator of the joint, for the treatment of avascular necrosis of the lunate with carpal height collapse, fragmentation, and perilunar osteoarthritic changes. Materials and Methods: From May 2006 to July 2014, a total of 25 patients (13 men and 12 women; mean age, 38.7 years; age range, 28–52 years) with advanced Kienböck disease were treated with excision of the lunate and insertion of a vascularized radial bone flap wrapped in the pronator quadratus, followed by distraction with an external fixator of the joint; all these patients met our inclusion criteria, including symptomatic avascular necrosis of the lunate with carpal collapse and osteoarthritis of the wrist. We evaluated the scaphocapitate angle for radiologic assessment. Moreover, the overall clinical results were graded by using the wrist range of motion, modified Mayo wrist score, and disabilities of the arm, shoulder, and hand score. Results: All the patients exhibited improved symptoms, and subsequently returned to their work and recreational activities. The mean scaphocapitate angles and carpal height ratio improved from 33.7 degrees (range, 32.1–35.7 degrees) and 0.46 degrees (range, 0.42–0.51 degrees) preoperatively to 56.3 degrees (range, 54.7–59.8 degrees) and 0.50 degrees (range, 0.46–0.56 degrees) at the follow-up, respectively. The final average range of motion was as follows: wrist flexion, 73 degrees (range, 62–81 degrees); and extension, 76 degrees (range, 69–88 degrees). The average postoperative modified Mayo wrist score and disabilities of the arm, shoulder, and hand score were 91 points (range, 80–100 points) and 11 points (range, 2–24 points), respectively. Conclusion: We suggest that the excision of the lunate and insertion of a vascularized radial bone flap wrapped in the pronator quadratus, followed by distraction with an external fixator of the joint, is a reliable method for the treatment of Kienböck disease with collapse or fragmentation of the lunate, and achieves high functional scores, increased range of movement, and relief of pain, without any complications.

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The Dawn of Transparency: Insights from the Physician Payment Sunshine Act in Plastic Surgery

Background: The Physician Payments Sunshine Act (PSSA) is a government initiative that requires all biomedical companies to publicly disclose payments to physicians through the Open Payments Program (OPP). The goal of this study was to use the OPP database and evaluate all nonresearch-related financial transactions between plastic surgeons and biomedical companies. Methods: Using the first wave of OPP data published on September 30, 2014, we studied the national distribution of industry payments made to plastic surgeons during a 5-month period. We explored whether a plastic surgeon's scientific productivity (as determined by their h-index), practice setting (private versus academic), geographic location, and subspecialty were associated with payment amount. Results: Plastic surgeons (N = 4195) received a total of US $5,278,613. The median (IQR) payment to a plastic surgeon was US $115 (US $35–298); mean, US $158. The largest payment to an individual was US $341,384. The largest payment category was non-CEP speaker fees (US $1,709,930) followed by consulting fees (US $1,403,770). Plastic surgeons in private practice received higher payments per surgeon compared with surgeons in academic practice (median [IQR], US $165 [US $81–$441] vs median [IQR], US $112 [US $33–$291], rank-sum P

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Ectropion in Facial Tissue Expansion in the Pediatric Population: Incidence, Risk Factors, and Treatment Options

Background: Despite advances in the field of tissue expansion, the face is especially difficult to reconstruct using this technique due to its dynamic nature and high incidence of distortional scarring. This article aimed to review complications seen in pediatric facial tissue expansion, specifically ectropion, as well as its restorative treatment. Methods: A retrospective chart review of pediatric patients treated by tissue expansion for congenital facial lesions, trauma, or burns at Children's Hospital Los Angeles from January 2000 to present was performed. Patients were analyzed for preoperative diagnosis, reconstruction area, tissue expander location, number and fill volume of expanders, incidence of complications, including ectropion, and type of revision surgery. Results: A total of 88 patients with 150 expander reconstructions were examined. The total complication rate was 43.1% with an 11.3% rate of ectropion. Of the 10 cases of ectropion, 9 were treated with canthoplasty, whereas 1 was managed conservatively. In addition to canthoplasty, full-thickness skin graft was preformed in 1 patient, Z-plasty in 1, and lid switch in 2. Discussion: Tissue expansion is a safe and effective method of reconstruction for facial defects in the pediatric population despite complication rates being higher than other areas of the body. Specifically, ectropion can be a devastating complication, often requiring surgical correction. As such, careful planning should go into orientation and design of the reconstruction, and staged procedures should be strongly considered. Additionally, and possibly the most important, is setting patient and parental expectation about the possibility of ectropion and the necessity often for multiple corrective surgeries.

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Ear Aesthetics: Investigation by the Use of an Online Viral Survey

Introduction: The ear is a key facial feature and yet few studies have previously assessed ear aesthetics. This study aimed to assess the anatomical components of the ear that have the greatest impact on the perception of ear aesthetics. Materials and Methods: Three photographs of a male adult ear (close-up, lateral, posterior) were digitally manipulated such that in each, 1 anatomical element of the ear was either enlarged or reduced. A complete set of 16 photographs including a repeat of the original ear as a control were randomized and entered into an online survey that required respondents to rate the attractiveness of each ear on a scale of 1 (least attractive) to 10 (most attractive). The survey was disseminated using email and social media. Results: A total of 248 responses were received, 155 women and 92 men. Respondents were grouped by demographics of age and occupation. Reducing (R) or enlarging (E) the helix (R, P = 0.0256; E, P = 0.003), concha (R, P = 0.0002; E, P =

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Cosmetics, Vol. 4, Pages 9: A Validated HPLC Method for the Determination of Vanillyl Butyl Ether in Cosmetic Preparations

A specific HPLC (High-Performance Liquid Chromatography) method has been developed and validated for the determination of vanillyl butyl ether in cosmetic products. The extraction procedure with an isopropanol water 1:1 mixture is described. The method uses a RP-C-18 column with isocratic elution and an ultraviolet (UV) detector. The mobile phase consists of a mixture of acetonitrile and buffer (Na2HPO4 20 mM in water) (30:70 v/v) with a variable flow rate. The method was validated with respect to accuracy, precision (repeatability and reproducibility), specificity and linearity. The procedure described here is simple, selective and reliable for routine quality control analysis and stability tests of commercially available cosmetic products.

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Heroin addiction

Heroin addiction: Physical addiction to heroin, often with concurrent use of other opiates when heroin itself is not available. Treatment is by opiates withdrawal, either gradual or sudden. Medication may be used to ease the physical effects of withdrawal, which include goosebumps, cramping, body aches, nausea, and intense craving. Opiate blockers and agonist/antagonist drugs may be used to alleviate the symptoms and speed up the withdrawal process and assist the addict with maintaining compliance. Methadone is used for a slow gradual withdrawal. Additional interventions are counseling, 12 step program, treatment with antidepressants and mood stabilizers.

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Understanding the FRET Signatures of Interacting Membrane Proteins [Methods and Resources]

Forster Resonant Energy Transfer (FRET) is an indispensable experimental tool for studying membrane proteins. Currently, two models are available for researchers to determine the oligomerization state of membrane proteins in a static quenching FRET experiment: the model of Veatch and Stryer derived in 1977, and the Kinetic Theory-based model for intra-oligomeric FRET, derived in 2007. Because of confinement in two-dimensions, a substantial amount of FRET is generated by energy transfer between fluorophores located in separate oligomers in the 2-D bilayer. This inter-oligomeric FRET (also known as stochastic, bystander, or proximity FRET), is not accounted for in either model. Here, we use the Kinetic Theory formalism to describe the dependence of the FRET efficiency measured in an experiment, that is, the total apparent FRET efficiency, on the inter-oligomeric FRET due to random proximity within the bilayer, and the intra-oligomeric FRET resulting from protein-protein interactions. We find that data analysis with both models without considerations for the proximity FRET leads to incorrect conclusions about the oligomeric state of the protein. We show that the knowledge of the total surface densities of fluorophore-labeled membrane proteins is essential for correctly interpreting the measured total apparent FRET efficiency. We also find that bulk, two-color, static quenching FRET experiments are most well-suited for the study of monomeric, dimerizing, or dimeric proteins, but have limitations in discerning the order of larger oligomers. The theory and methodology described in this work will allow researchers to extract meaningful parameters from static quenching FRET measurements in biological membranes.

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Myroilysin is a New Bacterial Member of the M12A Family of Metzincin Metallopeptidases and Activated by a Cysteine-switch Mechanism [Protein Structure and Folding]

Proteases play important roles in all living organisms and also have important industrial applications. Family M12A metalloproteases, mainly found throughout the animal kingdom, belong to the metzincin protease family and are synthesized as inactive precursors. So far, only flavastacin and myroilysin, isolated from bacteria, were reported to be M12A proteases, whilst the classification of myroilysin is still conflicting due to the lack of structural information. Here, we report the crystal structures of pro-myroilysin from bacterium Myroides sp. cslb8. The catalytic zinc ion of pro-myroilysin, at the bottom of a deep active site, is coordinated by three histidine residues in the conserved motif HEXXHXXGXXH; the cysteine residue in the pro-peptide coordinates the catalytic zinc ion and inhibits myroilysin activity. Structure comparisons revealed that myroilysin shares high similarity with the members of the M12A, M10A and M10B families of metalloproteases. However, a unique ″ cap″ structure tops the active site cleft in the structure of pro-myroilysin, and this ″ cap″ structure does not exist in the above structure-reported subfamilies. Further structure-based sequence analysis revealed that myroilysin appears to belong to the M12A family, but pro-myroilysin uses a ″ cysteine-switch″ activation mechanism with a unique segment including the conserved cysteine residue while other reported M12A family proteases use ″ aspartate-switch″ activation mechanism. Thus, our results suggest that myroilysin is a new bacterial member of the M12A family with an exceptional cysteine-switch activation mechanism. Our results shed new light on the classification of M12A family, and may suggest a divergent evolution of M12 family.

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A staging system for correct phenotype interpretation of mouse embryos harvested on embryonic day 14 (E14.5)

Abstract

We present a simple and quick system for accurately scoring the developmental progress of mouse embryos harvested on embryonic day 14 (E14.5). Based solely on the external appearance of the maturing forelimb, we provide a convenient way to distinguish six developmental sub-stages. Using a variety of objective morphometric data obtained from the commonly used C57BL/6N mouse strain, we show that these stages correlate precisely with the growth of the entire embryo and its organs. Applying the new staging system to phenotype analyses of E14.5 embryos of 58 embryonic lethal null mutant lines from the DMDD research programme (https://dmdd.org.uk) and its pilot, we show that homozygous mutant embryos are frequently delayed in development. To demonstrate the importance of our staging system for correct phenotype interpretation, we describe stage-specific changes of the palate, heart and gut, and provide examples in which correct diagnosis of malformations relies on correct staging.

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Teres major muscle – insertion footprint

Abstract

Teres major muscle (TM) and latissimus dorsi muscle (LD) are frequently used in muscle transfers around the shoulder girdle. Some authors have suggested harvesting techniques in which the muscle is detached in continuity with a bone segment. Information on the bony attachment footprint of these muscles is lacking. The purpose of this study was to investigate the region of attachment of the TM to facilitate safe and complete harvesting with a bone segment where it is indicated, and to determine the relationship of the TM footprint with that of the LD. Twenty-eight upper extremities of 14 human cadavers (six female, eight male) were investigated during the students’ dissection course in the winter term 2012. The attachment footprints were photographed and the images were processed with ImageJ Version 1.46r. The TM attachment footprint at the crest of the lesser tubercle had an average dimension of 187 ± 89 mm². It was 49.6 ± 7.9 mm long and 7.4 ± 2.5 mm wide. The bony attachment of the LD within the bicipital groove, just below the tendon of the long head of the biceps muscle, had an area of 94 ± 37 mm². It was 36.5 ± 8 mm long and 3.7 ± 1.2 mm wide. Both muscles were separated by 4.4 ± 1.7 mm and their attachments overlapped in the craniocaudal direction by 24.4 ± 12.4 mm. Earlier studies have investigated the dimensions of the muscles’ tendons close to the attachment not the bony attachment itself. The dimension of the attachment of the TM was larger than that of the LD. The ratio between the footprint areas was approximately 2:1. This information should be considered by surgeons undertaking transfers, which include a bony segment of the muscle insertion.

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IJMS, Vol. 18, Pages 364: Role of Cortico-Cancellous Heterologous Bone in Human Periodontal Ligament Stem Cell Xeno-Free Culture Studied by Synchrotron Radiation Phase-Contrast Microtomography

This study was designed to quantitatively demonstrate via three-dimensional (3D) images, through the Synchrotron Radiation Phase-Contrast Microtomography (SR-PhC-MicroCT), the osteoinductive properties of a cortico-cancellous scaffold (Osteobiol Dual Block—DB) cultured with human Periodontal Ligament Stem Cells (hPDLSCs) in xeno-free media. In vitro cultures of hPDLSCs, obtained from alveolar crest and horizontal fibers of the periodontal ligament, were seeded onto DB scaffolds and cultured in xeno-free media for three weeks. 3D images were obtained by SR-PhC-microCT after one and three weeks from culture beginning. MicroCT data were successively processed with a phase-retrieval algorithm based on the Transport of Intensity Equation (TIE). The chosen experimental method, previously demonstratively applied for the 3D characterization of the same constructs in not xeno-free media, quantitatively monitored also in this case the early stages of bone formation in basal and differentiating conditions. Interestingly, it quantitatively showed in the xeno-free environment a significant acceleration of the mineralization process, regardless of the culture (basal/differentiating) medium. This work showed in 3D that the DB guides the osteogenic differentiation of hPDLSCs in xeno-free cultures, in agreement with 2D observations and functional studies previously performed by some of the authors. Indeed, here we fully proved in 3D that expanded hPDLSCs, using xeno-free media formulation, not only provide the basis for Good Manufacturing Practice (preserving the stem cells’ morphological features and their ability to differentiate into mesenchymal lineage) but have to be considered, combined to DB scaffolds, as interesting candidates for potential clinical use in new custom made tissue-engineered constructs.

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IJMS, Vol. 18, Pages 368: Twist2 Is Upregulated in Early Stages of Repair Following Acute Kidney Injury

The aging kidney is a marked by a number of structural and functional changes, including an increased susceptibility to acute kidney injury (AKI). Previous studies from our laboratory have shown that aging male Fischer 344 rats (24 month) are more susceptible to apoptosis-mediated injury than young counterparts. In the current studies, we examined the initial injury and early recovery phases of mercuric chloride-induced AKI. Interestingly, the aging kidney had decreased serum creatinine compared to young controls 1 day following mercuric chloride injury, but by day 4, serum creatinine was significantly elevated, suggesting that the aging kidney did not recover from injury. This conclusion is supported by the findings that serum creatinine and kidney injury molecule-1 (Kim-1) gene expression remain elevated compared to young controls at 10 days post-injury. To begin to elucidate mechanism(s) underlying dysrepair in the aging kidney, we examined the expression of Twist2, a helix-loop-helix transcription factor that may mediate renal fibrosis. Interestingly, Twist2 gene expression was elevated following injury in both young and aged rats, and Twist2 protein expression is elevated by mercuric chloride in vitro.

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IJMS, Vol. 18, Pages 367: Role of Autophagy and Apoptosis in Non-Small-Cell Lung Cancer

Non-small-cell lung cancer (NSCLC) constitutes 85% of all lung cancers, and is the leading cause of cancer-related death worldwide. The poor prognosis and resistance to both radiation and chemotherapy warrant further investigation into the molecular mechanisms of NSCLC and the development of new, more efficacious therapeutics. The processes of autophagy and apoptosis, which induce degradation of proteins and organelles or cell death upon cellular stress, are crucial in the pathophysiology of NSCLC. The close interplay between autophagy and apoptosis through shared signaling pathways complicates our understanding of how NSCLC pathophysiology is regulated. The apoptotic effect of autophagy is controversial as both inhibitory and stimulatory effects have been reported in NSCLC. In addition, crosstalk of proteins regulating both autophagy and apoptosis exists. Here, we review the recent advances of the relationship between autophagy and apoptosis in NSCLC, aiming to provide few insights into the discovery of novel pathogenic factors and the development of new cancer therapeutics.

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IJMS, Vol. 18, Pages 234: RNA-Seq Analyses for Two Silkworm Strains Reveals Insight into Their Susceptibility and Resistance to Beauveria bassiana Infection

The silkworm Bombyx mori is an economically important species. White muscardine caused by Beauveria bassiana is the main fungal disease in sericulture, and understanding the silkworm responses to B. bassiana infection is of particular interest. Herein, we investigated the molecular mechanisms underlying these responses in two silkworm strains Haoyue (HY, sensitive to B. bassiana) and Kang 8 (K8, resistant to B. bassiana) using an RNA-seq approach. For each strain, three biological replicates for immersion treatment, two replicates for injection treatment and three untreated controls were collected to generate 16 libraries for sequencing. Differentially expressed genes (DEGs) between treated samples and untreated controls, and between the two silkworm strains, were identified. DEGs and the enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the two strains exhibited an obvious difference. Several genes encoding cuticle proteins, serine proteinase inhibitors (SPI) and antimicrobial peptides (AMP) and the drug metabolism pathway involved in toxin detoxification were considered to be related to the resistance of K8 to B. bassiana. These results revealed insight into the resistance and susceptibility of two silkworm strains against B. bassiana infection and provided a roadmap for silkworm molecular breeding to enhance its resistance to B. bassiana.

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Klotho expression in long bones regulates FGF23 production during renal failure [Research]

Circulating levels of bone-derived fibroblast growth factor 23 (FGF23) increase early during acute and chronic kidney disease and are associated with adverse outcomes. Membrane-bound Klotho acts as a permissive coreceptor for FGF23, and its expression was recently found in osteoblasts/osteocytes. We hypothesized that Klotho in bone cells is part of an autocrine feedback loop that regulates FGF23 expression during renal failure. Thus, we induced renal failure in mice with targeted deletion of Klotho in long bones. Uremic wild-type (KL^fl/fl) and knockout (Prx1-Cre;KL^fl/fl) mice both responded with reduced body weight, kidney atrophy, hyperphosphatemia, and increased bone turnover. Importantly, long bones of Prx1-Cre;KL^fl/fl mice but not their axial skeleton failed to increase FGF23 expression as observed in uremic KL^fl/fl mice. Consequently, Prx1-Cre;KL^fl/fl mice had significantly lower serum FGF23 and parathyroid hormone levels, and higher renal 1-α-hydroxylase expression, serum 1,25-dihydroxyvitamin D, and calcium levels than KL^fl/fl mice. These results were confirmed in two independent models of renal failure, adenine diet induced and 5/6 nephrectomy. Moreover, FGF23-treated bone cells required Klotho to increase FGF23 mRNA and ERK phosphorylation. In summary, our novel findings show that Klotho in bone is crucial for inducing FGF23 production upon renal failure. We propose the presence of an autocrine feedback loop in which Klotho senses the need for FGF23.—Kaludjerovic, J., Komaba, H., Sato, T., Erben, R. G., Baron, R., Olauson, H., Larsson, T. E., Lanske, B. Klotho expression in long bones regulates FGF23 production during renal failure.

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Differential effects of anoctamins on intracellular calcium signals [Research]

The Ca²⁺ activated Cl^– channel TMEM16A [anoctamin (ANO)1] is homologous to yeast Ist2 and has been shown to tether the cortical endoplasmic reticulum (ER) to the plasma membrane. We therefore examined whether ANO1 and other members of the ANO family affect intracellular Ca²⁺ ([Ca²⁺]_i) signals. It is shown that expression of ANO1 augments Ca²⁺ store release upon stimulation of GPCRs, whereas knockdown of ANO1, or lack of Ano1 expression in Ano1^–/– animals as shown in an earlier report, inhibits Ca²⁺ release. ANO6, and -10 show similar effects, whereas expression of ANO4, -8, and -9 attenuate filling of the ER store. The impact of ANO1 and -4 were examined in more detail. ANO1 colocalized and interacted with IP₃R, whereas ANO4 colocalized with SERCA Ca²⁺ pumps and interacted with ORAI-1 channels, respectively. ANO1 Cl currents were rapidly activated exclusively through Ca²⁺ store release, and remained untouched by influx of extracellular Ca²⁺. In contrast expression of ANO4 caused a delayed activation of membrane-localized ANO6 channels, solely through store operated Ca²⁺ entry via ORAI. Ca²⁺ signals were inhibited by knocking down expression of endogenous ANO1, -5, -6, and -10 and were also reduced in epithelial cells from Ano10^–/– mice. The data suggest that ANOs affect compartmentalized [Ca²⁺]_i signals, which may explain some of the cellular defects related to ANO mutations.—Cabrita, I., Benedetto, R., Fonseca, A., Wanitchakool, P., Sirianant, L., Skryabin, B. V., Schenk, L. K., Pavenstädt, H., Schreiber, R., Kunzelmann, K. Differential effects of anoctamins on intracellular calcium signals.

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Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance [Research]

Although chemotherapy is designed to eradicate tumor cells, it also has significant effects on normal tissues. The platinum-induced fatty acid, 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid), induces systemic resistance to a broad range of DNA-damaging chemotherapeutics. We show that 16:4(n-3) exerts its effect by activating splenic F4/80⁺/CD11b^low macrophages, which results in production of chemoprotective lysophosphatidylcholines (LPCs). Pharmacologic studies, together with analysis of expression patterns, identified GPR120 on F4/80⁺/CD11b^low macrophages as the relevant receptor for 16:4(n-3). Studies that used splenocytes from GPR120-deficient mice have confirmed this conclusion. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA₂ activity in these splenic macrophages and secretion of the resistance-inducing lipid mediator, lysophosphatidylcholine(24:1). These studies identify a novel and unexpected function for GPR120 and suggest that antagonists of this receptor might be effective agents to limit development of chemotherapy resistance.—Houthuijzen, J. M., Oosterom, I., Hudson, B. D., Hirasawa, A., Daenen, L. G. M., McLean, C. M., Hansen, S. V. F., van Jaarsveld, M. T. M., Peeper, D. S., Jafari Sadatmand, S., Roodhart, J. M. L., van de Lest, C. H. A., Ulven, T., Ishihara, K., Milligan, G., Voest, E. E. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance.

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Hexokinase II-derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells [Research]

Overexpression of mitochondria-bound hexokinase II (HKII) in cancer cells plays an important role in their metabolic reprogramming and protects them against apoptosis, thereby facilitating their growth and proliferation. Here, we show that covalently coupling a peptide that corresponds to the mitochondrial membrane–binding N-terminal domain of HKII (pHK) to a short, penetration-accelerating sequence (PAS) enhances the cellular uptake, mitochondrial localization, and cytotoxicity of the peptide in HeLa cells. Further analysis revealed that pHK-PAS depolarized mitochondrial membrane potential, inhibited mitochondrial respiration and glycolysis, and depleted intracellular ATP levels. The effects of pHK-PAS were correlated with dissociation of endogenous full-length HKII from mitochondria and release of cytochrome c. Of significance, pHK-PAS treatment of noncancerous HEK293 cells resulted in substantially lower cytotoxicity. Thus, pHK-PAS effectively disrupted the mitochondria-HKII association in cancer cells, which led to mitochondrial dysfunction and, finally, apoptosis. Our results demonstrate the potential of the pHK-PAS cell-penetrating peptide as a novel therapeutic strategy in cancer.—Woldetsadik, A. D., Vogel, M. C., Rabeh, W. M., Magzoub, M. Hexokinase II–derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells.

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Reduced mitochondrial activity in colonocytes facilitates AMPK{alpha}2-dependent inflammation [Research]

Intestinal inflammation is associated with low levels of mucosal ATP, highlighting the importance of mitochondrial function associated with ATP production in the pathophysiology of the disease. In the inflamed colon of humans and mice, we found decreased levels of mitochondrial complex cytochrome c oxidase I/IV and lower ATP levels. Thus, we generated colonic ⁰ cells with reduced mitochondrial function linked to ATP production by selective depletion of mitochondrial DNA. In these cells, RNA sequencing revealed a substantial number of differentially expressed transcripts, among which 240 belonged to inflammatory pathways activated in human inflamed colon and TNF-α-treated cells (false discovery rate < 0.05). TNF-α treatment of colonic ⁰ cells augmented IL-8 expression by 9-fold (P < 0.01) via NF-B compared to TNF-α-treated control. Moreover, reduced mitochondrial function facilitated TNF-α-mediated NF-B luciferase promoter activity as a result of lowered inhibitory IBα (nuclear factor of light polypeptide gene enhancer in B cells inhibitor, α), leading to elevated NF-B. In cells with reduced mitochondrial function, TNF-α facilitated AMPKα2 activation by 8-fold (P < 0.01), which was involved in NF-B-dependent IL-8 expression. Last, in human and mouse colon, anti-TNF-α treatment restored reduced mitochondria-dependent inflammation. We propose that selective targeting of this novel mechanism provides new treatment opportunities for intestinal inflammation.—Heller, S., Penrose, H. M., Cable, C., Biswas, D., Nakhoul, H., Baddoo, M., Flemington, E., Crawford, S. E., Savkovic, S. D. Reduced mitochondrial activity in colonocytes facilitates AMPKα2-dependent inflammation.

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TNFSF15 inhibits VEGF-stimulated vascular hyperpermeability by inducing VEGFR2 dephosphorylation [Research]

Vascular hyperpermeability is critical in ischemic diseases, including stroke and myocardial infarction, as well as in inflammation and cancer. It is well known that the VEGF–VEGFR2 signaling pathways are pivotal in promoting vascular permeability; however, counterbalancing mechanisms that restrict vascular permeability to maintain the integrity of blood vessels, are not yet fully understood. We report that TNF superfamily member 15 (TNFSF15), a cytokine largely produced by vascular endothelial cells and a specific inhibitor of the proliferation of these same cells, can inhibit VEGF-induced vascular permeability in vitro and in vivo, and that death receptor 3 (DR3), a cell surface receptor of TNFSF15, mediates TNFSF15-induced dephosphorylation of VEGFR2. Src homology region 2 domain–containing phosphatase-1 (SHP-1) becomes associated with DR3 upon TNFSF15 interaction with the latter. In addition, a protein complex consisting of VEGFR2, DR3, and SHP-1 is formed in response to the effects of TNFSF15 and VEGF on endothelial cells. It is plausible that this protein complex provides a structural basis for the molecular mechanism in which TNFSF15 induces the inhibition of VEGF-stimulated vascular hyperpermeability.—Yang, G.-L., Zhao, Z., Qin, T.-T., Wang, D., Chen, L., Xiang, R., Xi, Z., Jiang, R., Zhang, Z.-S., Zhang, J., Li. L.-Y. TNFSF15 inhibits VEGF-stimulated vascular hyperpermeability by inducing VEGFR2 dephosphorylation.

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Government should ringfence funding for national cancer strategy, urges charity

Funding to deliver the government’s cancer strategy for England must be ringfenced if the plan is to succeed by 2020, a leading charity has said.The five year blueprint for improving cancer outcomes...

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Cyclin F/FBXO1 interacts with HIV-1 Vif and restricts progeny virion infectivity by ubiquitination and proteasomal degradation of Vif through SCF Cyclin F E3 ligase machinery [Protein Synthesis and Degradation]

Cyclin F, also known as FBXO1, is the largest among all cyclins which oscillates in the cell cycle like other cyclins. Apart from being a G2/M cyclin, Cyclin F functions as the substrate binding subunit of SCFCyclin F E3 ubiquitin ligase. In a gene expression analysis performed to identify novel gene modulations associated with cell cycle dysregulation during HIV-1 infection in CD4+ T cells, we observed down-regulation of Cyclin F (CCNF) gene. Later, using gene over expression and knockdown studies, we identified that Cyclin F negatively influences HIV-1 viral infectivity without any significant impact on virus production. Subsequently, we found that Cyclin F negatively regulates the expression of viral protein, Vif (Viral infectivity factor), at the protein level. We also identified a novel host-pathogen interaction between Cyclin F and Vif protein in T cells during HIV-1 infection. Mutational analysis of a Cyclin F-specific amino acid motif in the C-terminal region of Vif shows rescue of the protein from Cyclin F-mediated down-regulation. Subsequently, we have shown that Vif is a novel substrate of the SCFCyclin F E3 ligase, where Cyclin F mediates ubiquitination and proteasomal degradation of Vif through physical interaction. Finally, we have shown that Cyclin F augments APOBEC3G expression through degradation of Vif to regulate infectivity of progeny virions. Taken together, our results demonstrate Cyclin F as a novel F-box protein which functions as an intrinsic cellular regulator of HIV-1 Vif and imparts a negative regulatory effect on maintenance of viral infectivity by restoring APOBEC3G expression.

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The potential benefit of levothyroxine treatment during pregnancy: another step forward

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Impact of food, alcohol and pH on modified-release hydrocortisone developed to treat congenital adrenal hyperplasia

Background

We developed a modified-release hydrocortisone, Chronocort, to replace the cortisol rhythm in patients with congenital adrenal hyperplasia. Food, alcohol and pH affect drug absorption, and it is important to assess their impact when replicating a physiological rhythm.

Subjects and methods

In vitro dissolution to study impact of alcohol and pH on Chronocort. A phase 1, three-period, cross over study in 18 volunteers to assess the impact of food on Chronocort and to compare bioavailability to immediate-release hydrocortisone.

Results

In vitro dissolution of Chronocort was not affected by gastrointestinal pH up to 6.0 nor by an alcohol content up to 20% v/v. Food delayed and reduced the rate of absorption of Chronocort as reflected by a longer T_max (fed vs fasted: 6.75 h vs 4.5 h, P = 0005) and lower C_max (549.49 nmol/L vs 708.46 nmol/L, ratio 77% with CI 71–85). Cortisol exposure was similar in fed and fasted state: Geo LSmean ratio (CI) AUC_0t for fed/fasted was 108.33% (102.30–114.72%). Cortisol exposure was higher for Chronocort compared to immediate-release hydrocortisone: Geo LSmean ratios (CI) 118.83% (111.58–126.54%); however, derived free cortisol showed cortisol exposure CIs were within 80.0–125.0%: Geo LSmean ratio (CI) for AUC_0t 112.73% (105.33–120.65%).

Conclusions

Gastric pH ≤6.0 and alcohol do not affect hydrocortisone release from Chronocort. Food delays Chronocort absorption, but cortisol exposure is similar in the fasted and fed state and exposure as assessed by free cortisol is similar between Chronocort and immediate-release hydrocortisone.

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External validation of the GREAT score to predict relapse risk in Graves disease: results from a multicenter, retrospective study with 741 patients

Context

First-line treatment in Graves’ disease is often done with antithyroid agents (ATD), but relapse rates remain high making definite treatment necessary. Predictors for relapse risk help guiding initial treatment decisions.

Objective

We aimed to externally validate the prognostic accuracy of the recently proposed Graves’ Recurrent Events After Therapy (GREAT) score to predict relapse risk in Graves’ disease.

Design, setting and participants

We retrospectively analyzed data (2004–2014) of patients with a first episode of Graves’ hyperthyroidism from four Swiss endocrine outpatient clinics.

Main outcome measures

Relapse of hyperthyroidism analyzed by multivariate Cox regression.

Results

Of the 741 included patients, 371 experienced a relapse (50.1%) after a mean follow-up of 25.6 months after ATD start. In univariate regression analysis, higher serum free T₄, higher thyrotropin-binding inhibitor immunoglobulin (TBII), younger age and larger goiter were associated with higher relapse risk. We found a strong increase in relapse risk with more points in the GREAT score from 33.8% in patients with GREAT class I (0–1 points), 59.4% in class II (2–3 points) with a hazard ratio of 1.79 (95% CI: 1.42–2.27, P < 0.001) and 73.6% in class III (4–6 points) with a hazard ratio of 2.24 (95% CI: 1.64–3.06, P < 0.001).

Conclusions

Based on this retrospective analysis within a large patient population from a multicenter study, the GREAT score shows good external validity and can be used for assessing the risk for relapse in Graves’ disease, which influence the initial treatment decisions.

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Modulation of SHBG binding to testosterone and estradiol by sex and morbid obesity

Objective

Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol.

Design

Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 ± 7 years) premenopausal women (n = 32) and men (n = 30), with normal weight and obesity (BMI >30 kg/m²).

Methods

SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritium-labeled hormones.

Results

Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI >40 kg/m²) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels was constant for testosterone, but not for estradiol. The influence of gender was maximal in morbid obesity, with men showing the highest binding/SHBG ratios.

Conclusions

The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender and showing different structure, affinities for testosterone and estradiol and also different immunoreactivity.

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A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues

Background

Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics.

Objective

To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs).

Design

Two retrospective cohorts (Rotterdam + Liège Acromegaly Survey (LAS), total n = 188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n = 83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels.

Results

For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P ≤ 0.001, P ≤ 0.001, P = 0.028 and P = 0.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of ±60 mg/week (21.3% within a range of ±20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (P ≤ 0.001) and predicted this dosage correctly in 77.1% of all patients within a range of ±60 mg/week (31.3% within a range of ±20 mg/week).

Conclusion

In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient’s weight was associated with the IGF-I normalization PEGV dosage.

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Prognostic significance of diffuse sclerosing variant papillary thyroid carcinoma: a systematic review and meta-analysis

Objective

Diffuse sclerosing variant papillary thyroid carcinoma (DSVPTC) is an uncommon variant of papillary thyroid carcinoma (PTC). The biological behaviors and prognostic outcomes of this variant, however, are still controversial. The aim of this systematic review and meta-analysis is to investigate the prognostic significance and outcomes of DSVPTCs in comparison with classical PTCs (cPTCs).

Methods

An electronic search was performed in five libraries: PubMed, Scopus, ISI, World Health Organization Global Health Library (WHO GHL) and Virtual Health Library (VHL) in June 2016. Published data were extracted and were pooled into odds ratios (OR), mean differences and corresponding 95% confidence intervals (CI) using random-effect model. Publication bias was analyzed using Egger’s regression test and funnel plot observation.

Results

From 315 articles, we included 16 articles comprising 732 DSVPTCs for meta-analysis. Overall, DSVPTC manifested more aggressive clinicopathological behaviors than cPTC such as higher rate of vascular invasion (OR: 5.33; 95% CI: 3.08–9.23), extrathyroidal extension (OR: 2.96; 95% CI: 2.04–4.30), lymph node metastasis (OR: 5.40; 95% CI: 2.82–10.35), distant metastasis (OR: 3.61; 95% CI: 1.89–6.88) and were more likely to relapse (OR: 2.83; 95% CI: 1.59–5.05). DSVPTC patients were associated with a worsened overall survival (HR: 1.89; 95% CI: 1.36–2.62).

Conclusion

DSVPTCs should be considered high-risk PTCs because of high propensity for tumor invasion, metastasis, relapse and mortality. Aggressiveness of DSVPTCs might be related to a different molecular pathway than that in cPTCs.

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Association of triiodothyronine levels with future development of metabolic syndrome in euthyroid middle-aged subjects: a 6-year retrospective longitudinal study

Background

Several cross-sectional studies have reported that thyroid hormone levels are associated with cardiovascular risk markers and metabolic syndrome (MetS) even in euthyroid subjects. However, the prognostic role of serum thyroid hormone levels in the risk of incident MetS has not been elucidated.

Aim

We aimed to investigate the associations of baseline serum thyroid hormone levels with the development of MetS in healthy subjects.

Methods

This 6-year, cross-sectional, longitudinal and follow-up study was conducted in 12 037 euthyroid middle-aged subjects without MetS subjected to comprehensive health examinations. Subjects were grouped according to total triiodothyronine (T3) quartiles. The hazard ratio (HR) for the development of MetS according to T3 quartiles was estimated using Cox proportional hazards model.

Results

During the 6-year period, 3544 incident cases of MetS (29%) were identified. The proportion of subjects with incident MetS increased across the T3 quartiles (P for trend <0.001). The HR and 95% confidence interval (CI) for the development of MetS were significantly higher in the highest T3 quartile compared with the lowest T3 quartile even after adjusting for confounding variables including gender, age and smoking (HR: 1.238, 95% CI: 1.128–1.358, P < 0.001).

Conclusion

In euthyroid middle-aged subjects, serum T3 levels are associated with increased risk for future development of MetS.

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Prognostic factors in ectopic Cushings syndrome due to neuroendocrine tumors: a multicenter study

Objective

Evidence is limited regarding outcome of patients with ectopic Cushing’s syndrome (ECS) due to neuroendocrine tumors (NETs).

Design

We assessed the prognostic factors affecting the survival of patients with NETs and ECS.

Methods

Retrospective analysis of clinicopathological features, severity of hormonal syndrome, treatments from a large cohort of patients with NETs and ECS collected from 17 Italian centers.

Results

Our series included 110 patients, 58.2% female, with mean (±s.d.) age at diagnosis of 49.5 ± 15.9 years. The main sources of ectopic ACTH were bronchial carcinoids (BC) (40.9%), occult tumors (22.7%) and pancreatic (p)NETs (15.5%). Curative surgery was performed in 56.7% (70.2% of BC, 11% of pNETs). Overall survival was significantly higher in BC compared with pNETs and occult tumors (P = 0.033) and in G1-NETs compared with G2 and G3 (P = 0.007). Negative predictive factors for survival were severity of hypercortisolism (P < 0.02), hypokalemia (P = 0.001), diabetes mellitus (P = 0.0146) and distant metastases (P < 0.001). Improved survival was observed in patients who underwent NET removal (P < 0.001). Adrenalectomy improved short-term survival.

Conclusions

Multiple factors affect prognosis of ECS patients: type of NET, grading, distant metastases, severity of hypercortisolism, hypokalemia and diabetes mellitus. BCs have the highest curative surgical rate and better survival compared with occult tumors and pNETs. Hypercortisolism plays a primary role in affecting outcome and quality of life; therefore, prompt and vigorous treatment of hormonal excess by NET surgery and medical therapy should be a key therapeutic goal. In refractory cases, adrenalectomy should be considered as it affects outcome positively at least in the first 2 years.

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The role of hepatic trans-arterial chemoembolization in metastatic medullary thyroid carcinoma: a specialist center experience and review of the literature

Background

Liver metastases are relatively common in patients with metastatic medullary thyroid carcinoma (MTC), carrying a negative impact on disease prognosis. The options for selective therapy of liver metastases in MTC patients are limited to catheter-guided procedures such as trans-arterial chemoembolization (TACE). Data regarding the effectiveness and safety of this procedure in MTC are limited.

Aim

To explore the clinical outcome, survival and safety profile of TACE for liver metastases in a group of MTC patients.

Methods

Retrospective case series of patients treated at a single tertiary University Medical Center from 2005 to 2015.

Results

Seven consecutive patients (mean age 64.5 ± 10.9 years, 5 females) with histologically confirmed MTC with liver metastases were included. Metastatic involvement of the liver was less than 50% of the liver volume in all patients. The median size of the largest liver lesion was 40 ± 6.9 mm. The patients underwent in total 20 sessions of TACE. Clinical improvement as well as tumor response (PR) were observed in all patients. The median time to tumor progression was 38 months (range 8–126). Three patients were still alive at the end of the follow-up period (a median overall survival rate of 57 ± 44 months).

Conclusion

TACE in MTC patients with hepatic metastases is usually well tolerated and induces both clinical improvement and tumor response for prolonged periods of time in the majority of patients. This therapeutic option should always be considered, irrespective of the presence of extrahepatic metastasis.

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IJMS, Vol. 18, Pages 361: Single-Nucleotide Polymorphism of PPARγ, a Protein at the Crossroads of Physiological and Pathological Processes

Genome polymorphisms are responsible for phenotypic differences between humans and for individual susceptibility to genetic diseases and therapeutic responses. Non-synonymous single-nucleotide polymorphisms (nsSNPs) lead to protein variants with a change in the amino acid sequence that may affect the structure and/or function of the protein and may be utilized as efficient structural and functional markers of association to complex diseases. This study is focused on nsSNP variants of the ligand binding domain of PPARγ a nuclear receptor in the superfamily of ligand inducible transcription factors that play an important role in regulating lipid metabolism and in several processes ranging from cellular differentiation and development to carcinogenesis. Here we selected nine nsSNPs variants of the PPARγ ligand binding domain, V290M, R357A, R397C, F360L, P467L, Q286P, R288H, E324K, and E460K, expressed in cancer tissues and/or associated with partial lipodystrophy and insulin resistance. The effects of a single amino acid change on the thermodynamic stability of PPARγ, its spectral properties, and molecular dynamics have been investigated. The nsSNPs PPARγ variants show alteration of dynamics and tertiary contacts that impair the correct reciprocal positioning of helices 3 and 12, crucially important for PPARγ functioning.

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Medium chain length polyhydroxyalkanoates biosynthesis in Pseudomonas putida mt-2 is enhanced by co-metabolism of glycerol/octanoate or fatty acids mixtures

Publication date: May 2017
Source:International Journal of Biological Macromolecules, Volume 98
Author(s): Paul Fontaine, Ridha Mosrati, David Corroler
The synthesis of medium chain length polyhydroxyalkanoates (mcl-PHAs) by Pseudomonas putida mt-2 was investigated under nitrogen-rich then deficient conditions with glycerol/octanoate or long-chain fatty acids (LCFAs) as carbon sources. When mixed, glycerol and octanoate were co-assimilated regardless of nitrogen availability but provided that glycerol uptake has been already triggered under non-limiting nutrient conditions. This concomitant consumption allowed to enhance mcl-PHAs accumulation (up to 57% of cell dry weight (CDW)) under both non-limiting and nitrogen deficient conditions. Octanoate then mostly drove anabolism of the polyester with 3-hydroxyoctanoate (3HO) synthesized as the main monomer (83%). If the preferred PHA precursor octanoate was supplied, glycerol was mainly involved in cell growth and/or maintenance but very little in PHA production even under nitrogen starvation. P. putida cells accumulated higher amounts of mcl-PHAs when grown on mixtures of LCFAs compared to LCFAs supplied as single substrate (25% and 9% of CDW, respectively). However, only a weak enrichment of the polyester was observed after transfer of cells in a fresh nitrogen-free medium containing the same combination of LCFAs. Some typical units within the polyester were related to the LCFAs ratio supplied in the medium indicating that tailor-made monomers could be synthesized.



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Ganoderma atrum polysaccharide ameliorates anoxia/reoxygenation-mediated oxidative stress and apoptosis in human umbilical vein endothelial cells

Publication date: May 2017
Source:International Journal of Biological Macromolecules, Volume 98
Author(s): Yan-Song Zhang, Wen-Juan Li, Xian-Yi Zhang, Yu-Xin Yan, Shao-Ping Nie, De-Ming Gong, Xiao-Fang Tang, Ming He, Ming-Yong Xie
Ganoderma atrum polysaccharide (PSG-1), a main polysaccharide from Ganoderma atrum, possesses potent antioxidant capacity and cardiovascular benefits. The aim of this study was to investigate the role of PSG-1 in oxidative stress and apoptosis in human umbilical vein endothelial cells (HUVECs) under anoxia/reoxygenation (A/R) injury conditions. The results showed that exposure of HUVECs to A/R triggered cell death and apoptosis. Administration of PSG-1 significantly inhibited A/R-induced cell death and apoptosis in HUVECs. PSG-1-reduced A/R injury was mediated via mitochondrial apoptotic pathway, as evidenced by elevation of mitochondrial Bcl-2 protein and mitochondrial membrane potential, and attenuation of Bax translocation, cytochrome c release and caspases activation. Furthermore, PSG-1 enhanced the activities of superoxide dismutase, catalase and glutathione peroxidase and glutathione content, and concomitantly attenuated reactive oxygen species generation, lipid peroxidation and glutathione disulfide content. The antioxidant, N-acetyl-l-cysteine, significantly ameliorated all of these endothelial injuries caused by A/R, suggesting that antioxidant activities might play a key role in PSG-1-induced endothelial protection. Taken together, these findings suggested that PSG-1 could be as a promising adjuvant against endothelial dysfunction through ameliorating oxidative stress and apoptosis.

Graphical abstract

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Hybrid gels by conjugation of hyaluronic acid with poly(itaconic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5)undecane) copolymers

Publication date: May 2017
Source:International Journal of Biological Macromolecules, Volume 98
Author(s): Aurica P. Chiriac, Loredana Elena Nita, Alina Diaconu, Maria Bercea, Nita Tudorachi, Daniela Pamfil, Liliana Mititelu-Tartau
The approach of covalent conjugation for coupling synthetic polymers with biomolecules represents an appealing strategy to produce new compounds with distinctive properties for biomedical applications. In the present study we generated hybrid gels with tunable characteristics by using hyaluronic acid (HA) and four variants of poly(itaconic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5] undecane) (PITAU) copolymers, differing through the molar ratios between comonomers. The new bioconjugate compounds were realized by using a ″grafting to″ strategy, for further ensuring new ways for coupling of various bioactive compounds, taking into account that the grafted copolymers are dual sensitive to pH and temperature. The procedure of chemical crosslinking, by opening the anhydride cycle of the copolymer with the hydroxyl groups of hyaluronic acid, was used to prepare the bioconjugates. The chemical conjugation between HA and PITAU copolymers, as well as the structure of the new compounds, was confirmed by FTIR and NMR techniques. The physical properties of the new gels as thermal stability, swelling capacity, and rheological properties were investigated. The bioconjugate networks were also investigated as drug delivery carriers by using indomethacin as a model drug. In vitro and in vivo tests attested the homogeneity of the bioactive compounds as well as a good biochemical response, showing good biocompatibility for the new structures.

Graphical abstract

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Biotransformation of lignocellulosic materials into value-added products—A review

Publication date: May 2017
Source:International Journal of Biological Macromolecules, Volume 98
Author(s): Muhammad Bilal, Muhammad Asgher, Hafiz M.N. Iqbal, Hongbo Hu, Xuehong Zhang
In the past decade, with the key biotechnological advancements, lignocellulosic materials have gained a particular importance. In serious consideration of global economic, environmental and energy issues, research scientists have been re-directing their interests in (re)-valorizing naturally occurring lignocellulosic-based materials. In this context, lignin-modifying enzymes (LMEs) have gained considerable attention in numerous industrial and biotechnological processes. However, their lower catalytic efficiencies and operational stabilities limit their practical and multipurpose applications in various sectors. Therefore, to expand the range of natural industrial biocatalysts e.g. LMEs, significant progress related to the enzyme biotechnology has appeared. Owing to the abundant lignocellulose availability along with LMEs in combination with the scientific advances in the biotechnological era, solid-phase biocatalysts can be economically tailored on a large scale. This review article outlines first briefly on the lignocellulose materials as a potential source for biotransformation into value-added products including composites, fine chemicals, nutraceutical, delignification, and enzymes. Comprehensive information is also given on the purification and characterization of LMEs to present their potential for the industrial and biotechnological sector.



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Conformational and functional transitions and in silico analysis of a serine protease from Conidiobolus brefeldianus (MTCC 5185)

Publication date: May 2017
Source:International Journal of Biological Macromolecules, Volume 98
Author(s): Ekta Shukla, Sanskruthi B. Agrawal, Sushama M. Gaikwad
This work describes functional and structural transitions of a novel protease isolated from Conidiobolus brefeldianus MTCC 5185 (Cprot), in detail using biophysical and bioinformatics tools. The commercial importance of Cprot in silk and leather industries made it an interesting candidate for structural investigations. Cprot possesses 8.2% α-helix, 31.1% β-sheet and 23.8% turns. The enzyme was found to be active over a wide pH range and up to 55°C. The protease was also stable in organic solvents up to 50% (v/v) concentration of alcohols and DMSO for >24h and in 2M guanidine hydrochloride for >12h. Cprot was also resistant to trypsin, chymotrypsin, proteinase K and fluorinated alcohols (5–10%). The melting temperatures observed for the native Cprot and for the enzyme treated under various stress conditions correlated well with the corresponding structural and functional transitions obtained. The structural information was supported by the homology model of its closest homologue from C. coronatus; revealing its similarity to PA clan of proteases (Proteases of mixed nucleophile, superfamily A), with His-64, Asp-113 and Ser-208 as putative catalytic triad. Three tryptophan residues in Cprot are surrounded by positively charged residues, as evident from solute quenching studies and homology model.



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CasuL: A new lectin isolated from Calliandra surinamensis leaf pinnulae with cytotoxicity to cancer cells, antimicrobial activity and antibiofilm effect

Publication date: May 2017
Source:International Journal of Biological Macromolecules, Volume 98
Author(s): Thamara Figueiredo Procópio, Leydianne Leite de Siqueira Patriota, Maiara Celine de Moura, Pollyanna Michelle da Silva, Ana Patrícia Silva de Oliveira, Lidiane Vasconcelos do Nascimento Carvalho, Thâmarah de Albuquerque Lima, Tatiana Soares, Túlio Diego da Silva, Luana Cassandra Breitenbach Barroso Coelho, Maira Galdino da Rocha Pitta, Moacyr Jesus Barreto de Melo Rêgo, Regina Celia Bressan Queiroz de Figueiredo, Patrícia Maria Guedes Paiva, Thiago Henrique Napoleão
This work describes the isolation of a lectin (CasuL) from the leaf pinnulae of Calliandra surinamensis and the evaluation of its cytotoxic, antimicrobial and antibiofilm properties. Proteins from pinnulae extract were precipitated with ammonium sulphate (60% saturation) and submitted to Sephadex G-75 chromatography, which yielded isolated CasuL (purification factor: 113). Native CasuL is an acidic protein (pI 5.82) with a relative molecular mass of 48kDa. This lectin is also an oligomeric protein composed of three subunits and mass spectrometry revealed similarities with a Sorghum bicolor protein. CasuL did not undergo unfolding when heated but changes in conformation and hemagglutinating activity were detected at basic pH. CasuL did not reduce the viability of human peripheral blood mononuclear cells but was toxic to leukemic K562 cells (IC50 67.04±5.78μg/mL) and breast cancer T47D cells (IC50: 58.75±2.5μg/mL). CasuL (6.25–800μg/mL) only showed bacteriostatic effect but was able to reduce biofilm formation by Staphylococcus saprophyticcus and Staphylococcus aureus (non-resistant and oxacillin-resistant isolates). CasuL showed antifungal activity against Candida krusei causing alterations in cell morphology and damage to cell wall. In conclusion, the pinnulae of C. surinamensis leaves contain a thermo-stable lectin with biotechnological potential as cytotoxic, antibiofilm, and antifungal agent.



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Isolation and characterization of a novel metalloprotease inhibitor from Bothrops alternatus snake serum

Publication date: May 2017
Source:International Journal of Biological Macromolecules, Volume 98
Author(s): Tatiana Z. Palacio, Norival A. Santos-Filho, José Cesar Rosa, Rui S. Ferreira, Benedito Barraviera, Suely V. Sampaio
Resistance of snakes and some other animals to snake envenomation has been attributed to soluble factors present in their tissues. Here we report the isolation of a novel metalloprotease inhibitor from Bothrops alternatus snake serum (named BaltMPI) with high purity, using a four-step chromatographic method. BaltMPI has molecular weights of 60.5 and 42.4kDa, as determined by SDS-PAGE and mass spectrometry, respectively, and pI=5.27. The first 60 amino acids from the N-terminal region of BaltMPI, determined by Edman’s degradation, showed high homology (97%) with the snake venom metalloprotease inhibitor (SVMPI) BJ46a and other SVMPIs (78–82%). The chromatographic fractions and purified BaltMPI exhibited anti-hemorrhagic activity against Batroxase and BjussuMP-I. BaltMPI was stable over wide ranges of pH (1, 5, 8, and 9) and temperature (−80, −20, 4, 60, and 100°C), and suppressed the fibrinogenolytic, fibrinolytic, and azocaseinolytic activities of Batroxase. BaltMPI specifically inhibited the activity of metalloproteases, without affecting the activity of serine proteases. Together, our results suggest that BaltMPI and other SVMPIs are promising molecules for the treatment of snake envenomation, in particular that caused by Bothrops sp.



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Secondary structural alterations in glucoamylase as an influence of protein aggregation

Publication date: May 2017
Source:International Journal of Biological Macromolecules, Volume 98
Author(s): Minhal Abidi, Afshin Iram, Mohammad Furkan, Aabgeena Naeem
Glucoamylase (EC 3.2.1.3) from Aspergillus niger possesses 31% α-helix, 36% β structure and rest aperiodic structure. A transition of glucoamylase structure in the presence of varying concentrations of glyoxal (GO) and trifluoroethanol (TFE) was studied by using multi-methodological approaches. At 20% GO, glucoamylase exists as molten globule state as evident by high tryptophan and ANS fluorescence, retention of secondary structure and loss of native tertiary structure. This state precedes the onset of the aggregation process and maximum is achieved at the highest concentration i.e. at 90% of GO. In parallel study TFE, on increasing concentration up to 25% induces secondary structure transformation leading to accumulation of intermolecular β sheets, altered tryptophan environment, high ANS and ThT fluorescence resulting in the formation of glucoamylase aggregates. Isothermal titration calorimetric curve is sigmoidal, indicating the weak binding of GO/TFE and glucoamylase. TEM studies showed that glucoamylase exists as globular and amorphous aggregates at 90% glyoxal and 25% TFE respectively. Further, TFE at 70% causes inhibition of enzyme aggregates; the majority of secondary structures observed at this concentration are α helices. Alpha helices being the main key player relocates glucoamylase native environment as evident by CD, FTIR and TEM. Hence induction of β sheet promotes protein aggregation and α helices inhibits protein aggregation.



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Erratum to: Advances in Therapy

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Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer

Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer

British Journal of Cancer advance online publication, February 9 2017. doi:10.1038/bjc.2017.19

Authors: Talia Golan, Tal Sella, Eileen M O'Reilly, Matthew H G Katz, Ron Epelbaum, David P Kelsen, Ayelet Borgida, Hannah Maynard, Hedy Kindler, Eitan Friedmen, Milind Javle & Steven Gallinger

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Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR+, HER2− advanced breast cancer: results from BOLERO-2

Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR+, HER2− advanced breast cancer: results from BOLERO-2

British Journal of Cancer advance online publication, February 9 2017. doi:10.1038/bjc.2017.25

Authors: Mary Ellen Moynahan, David Chen, Wei He, Patricia Sung, Aliaksandra Samoila, Daoqi You, Trusha Bhatt, Parul Patel, Francois Ringeisen, Gabriel N Hortobagyi, Jose Baselga & Sarat Chandarlapaty

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Cancer treatment scheduling and dynamic heterogeneity in social dilemmas of tumour acidity and vasculature

Cancer treatment scheduling and dynamic heterogeneity in social dilemmas of tumour acidity and vasculature

British Journal of Cancer advance online publication, February 9 2017. doi:10.1038/bjc.2017.5

Authors: Artem Kaznatcheev, Robert Vander Velde, Jacob G Scott & David Basanta

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Mammography service screening and breast cancer mortality in New Zealand: a National Cohort Study 1999–2011

Mammography service screening and breast cancer mortality in New Zealand: a National Cohort Study 1999–2011

British Journal of Cancer advance online publication, February 9 2017. doi:10.1038/bjc.2017.6

Authors: Stephen Morrell, Richard Taylor, David Roder, Bridget Robson, Marli Gregory & Kirsty Craig

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Commissioning through competition and cooperation in the English NHS under the Health and Social Care Act 2012: evidence from a qualitative study of four clinical commissioning groups

Objective

The Health and Social Care Act 2012 (‘HSCA 2012’) introduced a new, statutory, form of regulation of competition into the National Health Service (NHS), while at the same time recognising that cooperation was necessary. NHS England's policy document, The Five Year Forward View (‘5YFV’) of 2014 placed less emphasis on competition without altering the legislation. We explored how commissioners and providers understand the complex regulatory framework, and how they behave in relation to competition and cooperation.

Design

We carried out detailed case studies in four clinical commissioning groups, using interviews and documentary analysis to explore the commissioners’ and providers’ understanding and experience of competition and cooperation.

Setting/participants

We conducted 42 interviews with senior managers in commissioning organisations and senior managers in NHS and independent provider organisations (acute and community services).

Results

Neither commissioners nor providers fully understand the regulatory regime in respect of competition in the NHS, and have not found that the regulatory authorities have provided adequate guidance. Despite the HSCA 2012 promoting competition, commissioners chose mainly to use collaborative strategies to effect major service reconfigurations, which is endorsed as a suitable approach by providers. Nevertheless, commissioners are using competitive tendering in respect of more peripheral services in order to improve quality of care and value for money.

Conclusions

Commissioners regard the use of competition and cooperation as appropriate in the NHS currently, although collaborative strategies appear more helpful in respect of large-scale changes. However, the current regulatory framework contained in the HSCA 2012, particularly since the publication of the 5YFV, is not clear. Better guidance should be issued by the regulatory authorities.

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Associations of participation in community assets with health-related quality of life and healthcare usage: a cross-sectional study of older people in the community

Background

Community assets are promoted as a way to improve quality of life and reduce healthcare usage. However, the quantitative impact of participation in community assets on these outcomes is not known.

Methods

We examined the association between participation in community assets and health-related quality of life (HRQoL) (EuroQol-5D-5L) and healthcare usage in 3686 individuals aged ≥65 years. We estimated the unadjusted differences in EuroQol-5D-5L scores and healthcare usage between participants and non-participants in community assets and then used multivariate regression to examine scores adjusted for sociodemographic and limiting long-term health conditions. We derived the net benefits of participation using a range of threshold values for a quality-adjusted life year (QALY).

Results

50% of individuals reported participation in community assets. Their EuroQol-5D-5L scores were 0.094 (95% CI 0.077 to 0.111) points higher than non-participants. Controlling for sociodemographic characteristics reduced this differential to 0.081 (95% CI 0.064 to 0.098). Further controlling for limiting long-term conditions reduced this effect to 0.039 (95% CI 0.025 to 0.052). Once we adjusted for sociodemographic and limiting long-term conditions, the reductions in healthcare usage and costs associated with community asset participation were not statistically significant. Based on a threshold value of £20 000 per QALY, the net benefits of participation in community assets were £763 (95% CI £478 to £1048) per participant per year.

Conclusions

Participation in community assets is associated with substantially higher HRQoL but is not associated with lower healthcare costs. The social value of developing community assets is potentially substantial.

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Observational study of haemostatic dysfunction and bleeding in neonates with hypoxic-ischaemic encephalopathy

Objective

Evaluate the relationship between initial haemostatic parameters and the frequency and severity of bleeding in neonates with hypoxic–ischaemic encephalopathy (HIE).

Design

Retrospective observational cohort study.

Setting

2 academically affiliated level III neonatal intensive care units in Atlanta, Georgia.

Participants

98 neonates with moderate-to-severe HIE who underwent haemostatic testing within 12 hours of birth and were born from 1 January 2008 to 31 December 2013.

Primary and secondary outcome measures

Initial haemostatic dysfunction was defined as one or more of the following: prothrombin time (PT) ≥18 s, platelet count <100x10³/μL or fibrinogen <150 mg/dL. Bleeding assessed using the Neonatal Bleeding Assessment Tool and graded according to the WHO bleeding scale. The robust Poisson regression was used to evaluate the independent association between components of initial haemostatic dysfunction and bleeding.

Results

Among the 98 neonates evaluated, the prevalence of initial haemostatic dysfunction was 69% (95% CI 59% to 78%). 27 neonates (28%; 95% CI 19% to 38%) had abnormal bleeding events and 56 (57%) received at least 1 blood product transfusion. 3 neonates died from bleeding complications. The most common products transfused were fresh-frozen plasma (71%), followed by packed red blood cells (24%) and platelets (21%). In multivariable analysis, fibrinogen <150 mg/dL (adjusted relative risk 2.41, 95% CI 1.09 to 5.36) and platelet count <100x10³/μL (adjusted relative risk 2.59, 95% CI 1.30 to 5.16), but not initial PT, were associated with an increased risk of bleeding. The most severe bleeding occurred in neonates with a fibrinogen <150 mg/dL.

Conclusions

Among neonates with moderate-to-severe HIE, haemostatic dysfunction is prevalent and associated with an increased risk of bleeding and high transfusion burden. Further studies are needed to determine the appropriate transfusion approaches in this population to prevent bleeding.

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Specifying the content of home-based health behaviour change interventions for older people with frailty or at risk of frailty: an exploratory systematic review

Objectives

To identify trials of home-based health behaviour change interventions for frail older people, describe intervention content and explore its potential contribution to intervention effects.

Design

15 bibliographic databases, and reference lists and citations of key papers, were searched for randomised controlled trials of home-based behavioural interventions reporting behavioural or health outcomes.

Setting

Participants' homes.

Participants

Community-dwelling adults aged ≥65 years with frailty or at risk of frailty.

Primary and secondary outcome measures

Trials were coded for effects on thematically clustered behavioural, health and well-being outcomes. Intervention content was described using 96 behaviour change techniques, and 9 functions (eg, education, environmental restructuring).

Results

19 eligible trials reported 22 interventions. Physical functioning was most commonly assessed (19 interventions). Behavioural outcomes were assessed for only 4 interventions. Effectiveness on most outcomes was limited, with at most 50% of interventions showing potential positive effects on behaviour, and 42% on physical functioning. 3 techniques (instruction on how to perform behaviour, adding objects to environment, restructuring physical environment) and 2 functions (education and enablement) were more commonly found in interventions showing potential than those showing no potential to improve physical function. Intervention content was not linked to effectiveness on other outcomes.

Conclusions

Interventions appeared to have greatest impact on physical function where they included behavioural instructions, environmental modification and practical social support. Yet, mechanisms of effects are unclear, because impact on behavioural outcomes has rarely been considered. Moreover, the robustness of our findings is also unclear, because interventions have been poorly reported. Greater engagement with behavioural science is needed when developing and evaluating home-based health interventions.

PROSPERO registration number

ID=CRD42014010370

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Systematic review of the effective components of psychosocial interventions delivered by care home staff to people with dementia

Objectives

This review aims to understand what elements of psychosocial interventions are associated with improved outcomes for people with dementia to inform implementation in care homes.

Design

A systematic review of qualitative and quantitative intervention studies was undertaken.

Eligibility criteria for included studies

We included primary research studies evaluating psychosocial interventions that trained care home staff to deliver a specific intervention or that sought to change how staff delivered care to residents with dementia and reported staff and resident qualitative or quantitative outcomes.

Methods

We searched MEDLINE, PsychINFO and EMBASE electronic databases and hand-searched references up to May 2016. Quality of included papers was rated independently by 2 authors, using operationalised checklists derived from standard criteria. We discussed discrepancies and reached consensus. We conducted a narrative synthesis of quantitative and a thematic synthesis of qualitative findings to find what was effective immediately and in sustaining change.

Results

We identified 49 papers fulfilling predetermined criteria. We found a lack of higher quality quantitative evidence that effects could be sustained after psychosocial interventions finished with no evidence that interventions continued to work after 6 months. Qualitative findings suggest that staff valued interventions focusing on getting to know, understand and connect with residents with dementia. Successful elements of interventions included interactive training, post-training support, aiming to train most staff, retaining written materials afterwards and building interventions into routine care.

Conclusions

Psychosocial interventions can improve outcomes for staff and residents with dementia in care homes; however, many trial results are limited. Synthesis of qualitative findings highlight core components of interventions that staff value and feel improve care. These findings provide useful evidence to inform the development of sustainable, effective psychosocial interventions in care homes.

Trial registration number

CRD42015017621.

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Reducing falls after hospital discharge: a protocol for a randomised controlled trial evaluating an individualised multimodal falls education programme for older adults

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New beetle species bites army ant’s butt and hitches a ride

The beetle uses its mandibles to latch on to an army ant’s rear, where it blends in while moving to a new nest together with the ants

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New beetle species bites army ant’s butt and hitches a ride

The beetle uses its mandibles to latch on to an army ant’s rear, where it blends in while moving to a new nest together with the ants

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Government should ringfence funding for national cancer strategy, urges charity

Funding to deliver the government’s cancer strategy for England must be ringfenced if the plan is to succeed by 2020, a leading charity has said.The five year blueprint for improving cancer outcomes...

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[Editorial] Complexities of care in COPD

Chronic obstructive pulmonary disease (COPD) is responsible for 5% of global deaths annually. In the UK, it is the fifth biggest killer and the only major cause of death that is increasing; recent figures suggest inadequate approaches to COPD care might be responsible.

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[Editorial] Germany's science strategy is proudly international

In the current political climate of putting national interests first, with President Trump attempting to ban people from certain countries from entering the USA, and the UK Government creating an uncertain atmosphere for those born in EU countries, one report released last week makes uplifting reading. On Feb 1, the German National Parliament adopted a new strategy to strengthen international collaboration in education, science, and research. In the foreword to the document entitled Internationalisierung von Bildung, Wissenschaft und Forschung, Minister Johanna Wanka explains that science and research stands for openness and freedom of thinking.

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[Obituary] Joan Rodés

Leading hepatologist. He was born in Barcelona, Spain, on March 11, 1938, and died there of pulmonary disease on Jan 11, 2017, aged 78 years.

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[Correspondence] Dietary guidelines are not beyond criticism

Mann and colleagues (Aug 27, p 851)1 claim that criticisms of the dietary guidelines are not evidence-based. However, even by their own account, the promotion of reduced-fat dairy products in existing guidelines is not evidence-based, in view of the lack of association of dairy fat with cardiovascular risk, and the strong protective associations that exist between ruminant fatty acids and type 2 diabetes.2 This evidence contradicts the theory that the effect of dietary saturated fat on serum cholesterol is the cause of the association between serum cholesterol and cardiovascular disease.

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[Perspectives] Obesity

When does “large” become “obese”? In more technical terms, at what point does an acceptable variation in bodyweight become a pathological condition? And how does an individual's lifestyle become subject to public and medical scrutiny? A stroll round any gallery offers a striking insight into these questions. Contemporary stars may prefer the lean, tense lines of a Mario Testino photograph, but well into the Enlightenment European elites favoured the ample, sensuous contours of Peter Lely and Peter Paul Rubens.

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[Correspondence] Biopsy transcriptome expression profiling: proper validation is key

Philip J O'Connell and colleagues (Sept 3, p 983)1 describe a set of 13 genes they claim has high accuracy for prediction of several chronic allograft damage-related phenotypes in kidney transplants. Because of the large number of genes represented on a microarray chip, rigorous methods must be employed to avoid overfitting. We are concerned that the validation methods in this paper were performed incorrectly, leading to inflated estimates of predictive accuracies.

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[World Report] Alcohol industry looks to boost drinks sales in Africa

Alcohol manufacturers are setting their sights on the growing African market to increase sales of their products, often using aggressive advertising tactics to lure new drinkers. Chris McCall reports.

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[World Report] Scientists vigilant over circulating avian influenza viruses

UN agencies are closely monitoring avian influenza outbreaks in nearly 50 countries, including China, which has reported cases of H7N9 infection in people. Dara Mohammadi reports.

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[Comment] Maternal deaths in the UK: pre-eclampsia deaths are avoidable

Being pregnant in the UK has never been safer. The latest Confidential Enquiries into Maternal Deaths and Morbidity1 reported that fewer than one in 10 000 women died in or around pregnancy in the UK during 2012–14 (241 women within the triennium), the lowest rate recorded since such surveillance began in 1952 in England and Wales. This maternal mortality rate is lower than age-matched male death rates (5–17 per 10 000 population for men aged 20–44 years in England and Wales, 2014) such that a man is more likely to die while his partner is pregnant than she is.

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[Comment] Offline: Revolution—a prescription for health?

On Feb 19, 1917, amid bread shortages and sub-zero temperatures, Petrograd officials announced the imposition of food rationing. A slowly lengthening crack in Russian society now turned into a deep fracture. 4 days later, 100 000 workers took to the streets, shouting “Down with the Tsar!” A general strike soon followed. By Feb 26, amid mounting fear and anarchy, the police and army shot and killed 50 demonstrators. Mutiny ensued. The Revolution was set on an irreversible course. Government imploded.

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[Comment] Research misconduct and the INTERGROWTH-21st study

On Oct 20, 2016, a statement appeared on the WHO website, announcing that “An independent review commissioned by WHO has found that research ethics misconduct occurred in a study on foetal growth standards.”1 The study in question was the INTERGROWTH-21st study, led by researchers at the University of Oxford, UK, funded by the Bill & Melinda Gates Foundation (BMGF), and reported in several journals, including our own.2–5 Such a judgment by the world's foremost global health agency was serious, casting damaging light on a study of international importance.

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[World Report] Australia's new coal mine plan: a “public health disaster”

A huge new coal mine to be built inland has polarised opinion on climate change in Australia. Critics say that politicians are giving in to global warming sceptics. Chris McCall reports.

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[Perspectives] Insurrection, paternalism, and pleasure in the sanatorium

Most doctors are familiar with the sick role, a term coined by the sociologist Talcott Parsons in 1951. It posits that a patient lying in a hospital bed is confined, not only by the affliction they are trying to recover from, but also by a set of assumptions that having that disease confers. It is surely a sign of progress, that doctors now rail against the passivity and infantilisation that the sick role implies. We want our patients to collaborate with us, be active in the face of illness, rise up from their hospital beds before the sheets have even had a chance to get warm.

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[Editorial] Another kind of Zika public health emergency

A year ago, on Feb 1, 2016, WHO declared the Zika virus epidemic a public health emergency. In a brave show of leadership no doubt spurred by the embarrassment of failing to act sooner on the Ebola outbreak threats, Director-General Margaret Chan sounded the alarm about the potential links between Zika virus and rising neurological disorders despite a lack of conclusive data. By doing so she stimulated an international collective effort, scientific research, and funding that helped stabilise the crisis.

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[Perspectives] What Archie Cochrane learnt from a single case

The 18th-century physician Marcus Herz held that case reports were the means by which doctors “write experience into the world”. In broad terms they record how the diverse phenomena of illness are made sense of medically and which treatments are tried. But the search for explanations can prove elusive and case reports instead may revolve around clinical uncertainty and irresolution. Although today's case reports often follow standard approaches to medical problems, some feature novel situations that may confound readers' expectations.

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[Perspectives] Patricia Walker: pioneer in refugee health

It was as medical director of a refugee centre on the Thai–Cambodia border nearly 30 years ago when Pat Walker experienced the most difficult day of her professional life. “I was on an island off the coast of Thailand, caring for a Vietnamese woman with malaria who was in the early stages of labour”, Walker recalls. “The woman gave birth to a stillborn child and died a few hours later. That experience will never leave me, and has helped drive my passion for immigration and refugee health ever since”, she says.

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[Correspondence] Health professional associations and industry funding

The UK Royal College of Paediatrics and Child Health (RCPCH) announced in October, 2016, its decision to continue to accept funding from manufacturers of breast milk substitutes (BMS).1 This decision raises serious concerns about the college's impartiality and sets a harmful precedent for other health professional organisations. In order to protect the credibility and the authority of professional organisations that contribute to the formulation of public policy, they need to adopt codes of conduct and practices that protect their independence from vested interests.

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[Correspondence] Biopsy transcriptome expression profiling: proper validation is key – Authors' reply

Jeff Reeve and Philip F Halloran pose three questions regarding the derivation and validation of our predictive set of 13 genes:1 they suggest “overfitting” occurred; they question the accuracy of our methods with respect to external validation cohorts; and they claim our gene set is no better than “any random selection of 13 of these 10 000 probe sets”.

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[Correspondence] Dietary guidelines are not beyond criticism – Authors' reply

Henderson and colleagues have misinterpreted our Comment1 and the totality of evidence on which it is based. The issue is not whether or not dietary guidelines are beyond criticism but rather whether the criticisms are justified. A substantial body of observational, clinical trial, and experimental evidence summarised in our Comment support the recommendation to reduce total saturated fatty acids and that they might be replaced with unsaturated vegetable oils. Suggestions that some sources of saturated fatty acids might not be associated with adverse health outcomes and that some trans unsaturated fatty acids could be associated with reduced diabetes risk should be a stimulus for further research to enable dietary guidelines to be refined in the future.

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[Correspondence] South Sudan: aftermaths of 3 years of armed conflict

Celebrating its independence in July, 2011, South Sudan was declared the world's newest country. However, independence did not bring Africa's longest-running civil war in South Sudan to a termination. In December, 2013, the independence celebration was spoiled by the internal armed conflict between two rebelling parties, President Kiir and his former deputy Riek Machar.1

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Cancer treatment scheduling and dynamic heterogeneity in social dilemmas of tumour acidity and vasculature

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Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer

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Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR+, HER2− advanced breast cancer: results from BOLERO-2

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Mammography service screening and breast cancer mortality in New Zealand: a National Cohort Study 1999–2011

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Prophylactic use of a standardized botanical extract for the prevention of naturally occurring diarrhea in newborn Holstein calves

Publication date: Available online 9 February 2017
Source:Journal of Dairy Science
Author(s): A.G.V. Teixeira, B.L. Ribeiro, P.R.M. Junior, H.C. Korzec, R.C. Bicalho
The objectives of this study were to evaluate the prophylactic use of SB-300 (Jaguar Animal Health, San Francisco, CA), a standardized botanical extract isolated from the bark latex of Croton lechleri, on reducing fecal water losses and diarrhea events in Holstein bull calves individually housed under a restricted whole-milk feeding regimen (6 L/d) from 1 to 25 d of life. Fluid therapy administration due to dehydration, average weight gain, and the fecal microbiome were also evaluated. Bull calves used in this study were born from normal parturition, fed 4 L of pooled pasteurized colostrum by esophageal feeder, and moved to a research facility at Cornell University (Ithaca, NY). A double-blinded randomized clinical trial was designed to allocate a total of 40 newborn calves into 1 of 2 treatment groups: calves receiving (twice daily) a solution containing 500 mg of SB-300 added to the whole milk for the first 15 d of life (SB-300, n = 20) or a control group receiving sterile water added to whole milk for the same period (CTR, n = 20). Treatment solutions had a total volume of 10 mL per treatment. Data regarding fecal dry matter were collected to precisely measure water content in fecal samples and to define diarrhea events; the SB-300 group had significantly increased fecal dry matter during the study period. Additionally, significantly fewer events of diarrhea were observed for calves in the SB-300 group (16.9%) compared with calves in the CTR group (46.5%). Dehydration status was evaluated and treated accordingly; calves with moderate dehydration were offered oral electrolytes, and calves with severe dehydration were rescued with intravenous fluid therapy. Calves in the SB-300 group had fewer intravenous fluid therapies administered during the study period (1.6%) compared with the CTR group (3.1%). Overall fluid therapy administered (oral electrolytes plus intravenous fluids) was significantly higher for the CTR group (9.2%) compared with the SB-300 group (6.1%) during the study period. No differences in milk consumption, calf starter intake, or weight gain were observed between treatment groups. A single time increase in Bifidobacterium was observed on d 20 of life for the SB-300 group; otherwise, no differences in fecal microbiome profile were detected between treatment groups. These results suggest that 500 mg of SB-300 added to the milk for 15 d can reduce the incidence of diarrhea and reduce severe dehydration in milk-fed calves.



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