The effects of distal limb segment shortening on locomotor efficiency in sloped terrain: implications for Neandertal locomotor behavior.
Past studies of human locomotor efficiency focused on movement over flat surfaces and concluded that Neandertals were less efficient than modern humans due to a truncated limb morphology, which may have developed to aid thermoregulation in cold climates. However, it is not clear whether this potential locomotor disadvantage would also exist in nonflat terrain. This issue takes on added importance since Neandertals likely spent a significant proportion of their locomotor schedule on sloped, mountainous terrains in the Eurasian landscape. Here a model is developed that determines the relationship between lower limb segment lengths, terrain slope, excursion angle at the hip, and step length. The model is applied to Neandertal and modern human lower limb reconstructions. In addition, for a further independent test that also allows more climateterrain cross comparisons, the same model is applied to bovids living in different terrains and climates. Results indicate that: (1) Neandertals, despite exhibiting shorter lower limbs, would have been able to use similar stride frequencies per speed as longer-limbed modern humans on sloped terrain, due to their lower crural indices; and (2) shortened distal limb segments are characteristic of bovids that inhabit more rugged terrains, regardless of climate. These results suggest that the shortened distal lower limb segments of Neandertals were not a locomotor disadvantage within more rugged environments.


Dynamical footprint of falcipain-2 catalytic triad in hemoglobin-β-bound state.
Falcipain-2 (FP-2) is a member of papain family of cysteine proteases and the major hemoglobinase of the hemoglobin detoxification and hemozoin polymerization complex localized in the food vacuole of the plasmodium species. FP-2 is currently gaining clinical significance as the drug target of choice in combating malaria epidemic. Here, a theoretical FP-2/hemoglobin complex has been proposed and the dynamical footprint and energetics of binding have been investigated using molecular and quantum mechanics approaches. The mapped interaction interface comprises residues 34-51 of hemoglobin and cysteine-42/histidine-174/glutamine-36/asparagine-173/204 and subsites S1, S1', and S3 of FP-2. In hemoglobin-bound FP-2, asparagine-173 preferentially partners histidine-174, while glutamine-36 is preferred in ligand-free state. Cysteine-42 exhibits dihedral switch from 110° to 30° in free and bound states, respectively, with exclusion of water from the binding core upon hemoglobin binding. Hemoglobin similarly exhibits high occupancy within .2 nm distance with charged amido acid-rich subsites S1 and S3 of FP-2 functioning in tandem to reduce conformational flexibility of hemoglobin and facilitate the formation of a stabilizing anti-parallel β-sheet between Leucine-172-valine-176 of FP-2 and phenylalanine-45-asparate-47 of hemoglobin and to overcome the + 1.13e + 5 eV activation energy required to optimize the FP-2/hemoglobin-β conformation that precedes hydrolysis.


Characterization of Pulmonary Vein Dimensions Using High-Definition 64-Slice Computed Tomography prior to Radiofrequency Catheter Ablation for Atrial Fibrillation.
Background. Contrast-enhanced computed tomography is commonly acquired before radiofrequency catheter ablation (RFCA) for atrial fibrillation (AFib) to guide the procedure. We analyzed pulmonary vein (PV) ostial diameter and volumes on a high-definition 64-slice CT (HDCT) scanner in patients with AFib prior to RFCA. Methods and Results. This retrospective study included 50 patients (mean age 60.2 ± 11.4 years, 30 males) undergoing cardiac HDCT scanning before RFCA for drug refractory AFib and 50 age-, BMI-, and sex-matched controls with normal sinus rhythm undergoing HDCT. PV ostial diameter and volume were measured and calculated using a semiautomatic calliper tool. Total ostial PV volume was significantly increased in patients with AFib as compared to controls (P < 0.005). Similarly, total ostial PV diameter was significantly increased in AFib compared to controls (P < 0.001). In AFib, the largest PV volume and diameters were measured in right superior PV (P < 0.05 versus controls). The difference in PV volume between patients and controls was most pronounced in right superior PVs (P = 0.015). Right middle PVs were found more often in patients with AFib (16/50; 32%) than in normal subjects (7/50; 14%). Conclusion. Enlargement of PV ostial area and enlargement of volume are frequent findings in patients with drug refractory AFib. These parameters may add to the risk stratification for AFib recurrence following RFCA.


Effects of metiamide on the human stomach.
1. The effect of metiamide on gastric acidity in man has been studied. Solutions of hydrochloric acid or glucose were instilled into the stomach and the subsequent rates of gastric secretion and emptying, and the disappearance of acid within the stomach, were measured. 2. Metiamide inhibited the gastric secretory response to the instilled acid and glucose solutions but did not change the overall pattern of emptying of the instilled solutions. 3. During administration of metiamide, there was a net loss of acid from within the gastric lumen. The rate of disappearance of acid from the instilled acid solution was small and not sufficient in magnitude to account for the metiamide-evoked decrease in the concentration of acid secreted in response to pentagastrin. 4. We conclude that metiamide does not inhibit gastric secretion by altering the 'barrier' function of the gastric mucosa.


Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia.
Antiapoptotic BCL2 family members have been implicated in the pathogenesis of acute myelogenous leukemia (AML), but the functional significance and relative importance of individual proteins (e.g., BCL2, BCL-XL, and myeloid cell leukemia 1 [MCL1]) remain poorly understood. Here, we examined the expression of BCL2, BCL-XL, and MCL1 in primary human hematopoietic subsets and leukemic blasts from AML patients and found that MCL1 transcripts were consistently expressed at high levels in all samples tested. Consistent with this, Mcl1 protein was also highly expressed in myeloid leukemic blasts in a mouse Myc-induced model of AML. We used this model to test the hypothesis that Mcl1 facilitates AML development by allowing myeloid progenitor cells to evade Myc-induced cell death. Indeed, activation of Myc for 7 days in vivo substantially increased myeloid lineage cell numbers, whereas hematopoietic stem, progenitor, and B-lineage cells were depleted. Furthermore, Mcl1 haploinsufficiency abrogated AML development. In addition, deletion of a single allele of Mcl1 from fully transformed AML cells substantially prolonged the survival of transplanted mice. Conversely, the rapid lethality of disease was restored by coexpression of Bcl2 and Myc in Mcl1-haploinsufficient cells. Together, these data demonstrate a critical and dose-dependent role for Mcl1 in AML pathogenesis in mice and suggest that MCL1 may be a promising therapeutic target in patients with de novo AML.


Intrinsically Disordered Proteins Drive Emergence and Inheritance of Biological Traits.
Prions are a paradigm-shifting mechanism of inheritance in which phenotypes are encoded by self-templating protein conformations rather than nucleic acids. Here, we examine the breadth of protein-based inheritance across the yeast proteome by assessing the ability of nearly every open reading frame (ORF; ∼5,300 ORFs) to induce heritable traits. Transient overexpression of nearly 50 proteins created traits that remained heritable long after their expression returned to normal. These traits were beneficial, had prion-like patterns of inheritance, were common in wild yeasts, and could be transmitted to naive cells with protein alone. Most inducing proteins were not known prions and did not form amyloid. Instead, they are highly enriched in nucleic acid binding proteins with large intrinsically disordered domains that have been widely conserved across evolution. Thus, our data establish a common type of protein-based inheritance through which intrinsically disordered proteins can drive the emergence of new traits and adaptive opportunities.


Intracellular sphingosine releases calcium from lysosomes.
To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC.


IRF6 Is Directly Regulated by ZEB1 and ELF3, and Predicts a Favorable Prognosis in Gastric Cancer.
Interferon regulatory factor 6 (IRF6) acts as a tumor suppressor and controls cell differentiation in ectodermal and craniofacial tissues by regulating expression of target genes. However, its function in gastric cancer (GC) remains unknown to date. In this study, we found that the IRF6 expression was significantly downregulated in GC. And the decreased expression of IRF6 was clinically correlated with poor prognosis of GC. Moreover, loss-of-function and gain-of-function studies showed that IRF6 was negatively regulated by ZEB1 but positively regulated by ELF3. Additionally, transcription factor ZEB1 and ELF3 could directly bind on IRF6 promoter, which suggested that transcription factor IRF6 is transcriptionally regulated by ZEB1 and ELF3. Nevertheless, we found that IRF6 expression was negatively related to its promoter methylation in TCGA stomach cancer cohorts. The downregulation of IRF6 in GC might be due to the overexpression of ZEB1 and the DNA methylation of IRF6 promoter.


Airway smooth muscle tone increases airway responsiveness in healthy young adults.
Force adaptation, a process whereby sustained spasmogenic activation (viz., tone) of airway smooth muscle (ASM) increases its contractile capacity, has been reported in isolated ASM tissues in vitro, as well as in mice in vivo. The objective of the present study was to assess the effect of tone on airway responsiveness in humans. Ten healthy volunteers underwent methacholine challenge on two occasions. One challenge consisted of six serial doses of saline followed by a single high dose of methacholine. The other consisted of six low doses of methacholine 5 min apart followed by a higher dose. The cumulative dose was identical for both challenges. After both methacholine challenges, subjects took a deep inspiration (DI) to total lung capacity as another way to probe ASM mechanics. Responses to methacholine and the DI were measured using a multifrequency forced oscillation technique. Compared with a single high dose, the challenge preceded by tone led to an elevated response measured by respiratory system resistance (Rrs) and reactance at 5 Hz. However, there was no difference in the increase in Rrs at 19 Hz, suggesting a predominant effect on smaller airways. Increased tone also reduced the efficacy of DI, measured by an attenuated maximal dilation during the DI and an increased renarrowing post-DI. We conclude that ASM tone increases small airway responsiveness to inhaled methacholine and reduces the effectiveness of DI in healthy humans. This suggests that force adaptation may contribute to airway hyperresponsiveness and the reduced bronchodilatory effect of DI in asthma.


Multiple particle tracking microrheology measured using bi-disperse probe diameters.
Multiple particle tracking microrheology (MPT) is a powerful tool for quantitatively characterizing rheological properties of soft matter. Traditionally, MPT uses a single particle size to characterize rheological properties. But in complex systems, MPT measurements with a single size particle can characterize distinct properties that are linked to the materials' length scale dependent structure. By varying the size of probes, MPT can measure the properties associated with different length scales within a material. We develop a technique to simultaneously track a bi-disperse population of probe particles. 0.5 and 2 μm particles are embedded in the same sample and these particle populations are tracked separately using a brightness-based squared radius of gyration, Rg2. Bi-disperse MPT is validated by measuring the viscosity of glycerol samples at varying concentrations. Bi-disperse MPT measurements agree well with literature values. This technique then characterizes a homogeneous poly(ethylene glycol)-acrylate:poly(ethylene glycol)-dithiol gelation. The critical relaxation exponent and critical gelation time are consistent and agree with previous measurements using a single particle. Finally, degradation of a heterogeneous hydrogenated castor oil colloidal gel is characterized. The two particle sizes measure a different value of the critical relaxation exponent, indicating that they are probing different structures. Analysis of material heterogeneity shows measured heterogeneity is dependent on probe size indicating that each particle is measuring rheological evolution of a length scale dependent structure. Overall, bi-disperse MPT increases the amount of information gained in a single measurement, enabling more complete characterization of complex systems that range from consumer care products to biological materials.


[Role of diagnostic laparoscopy in the treatment plan of gastric cancer].
To assess the clinical value of the diagnostic laparoscopy in choosing treatment strategies for patients with gastric cancer. Retrospective analysis was performed on clinical and pathological data collected from 2 023 patients undergoing gastric cancer surgery in the Zhongshan Hospital of Fudan University from 2009 to 2014. All the patients were diagnosed as gastric cancer by endoscopic biopsy and staged by imaging examination before surgery. During the diagnostic laparoscopy procedure, a small periumbilical incision was made and a pneumoperitoneum with CO2 under 10-15 mmHg was established through a port. A 10 mm trocar was put in, and the camera was inserted. Two 5 mm trocars were put in two ports which located in midclavicular line two fingers under the left and right costal margin and then the instruments were inserted. A thorough inspection included ascites, the abdominal cavity, liver, diaphragm, spleen, greater omentum, colon, small intestine, mesentery, adnexa (female) and pelvic floor. If the tumor located at the posterior part of the stomach, the gastrocolic ligament was opened in order to look for carcinomatosis in the omental bursa. The accuracy rate of diagnostic laparoscopy in diagnosing adjacent organ invasion and intra-abdominal metastasis was calculated, and the rate of adjusting treatment plans after diagnostic laparoscopy was also calculated. There were 52.7%(1 067/2 023) of patients underwent diagnostic laparoscopy. The accuracy rate of diagnostic laparoscopy in evaluating adjacent organ invasion and intra-abdominal metastasis were 98.3%(1 049/1 067) and 98.1%(1 047/1 067) respectively. Besides, 14 patients with stage T4b and 32 with intra-abdominal metastasis, which were missed by imaging examination, were diagnosed by diagnostic laparoscopy. The treatment plans of 9.3% (99/1 067) of patients were changed after diagnostic laparoscopy, and 65 (6.1%) cases of non-therapeutic laparotomy were avoided. However, 18 cases of adjacent organ invasion and 20 cases of intra-abdominal metastasis were still missed by diagnostic laparoscopy, and 12 cases received non-therapeutic laparotomy. Diagnostic laparoscopy has considerable value in assessing adjacent organ invasion and intra-abdominal metastasis and has great clinical significance in making precise treatment plans.


Repair of spondylolysis in young fast bowlers.
Fast bowling in the game of cricket requires repetitive spinal extension, lateral deviation, lumbar flexion and thoracodorsal rotation. Back pain is common, and it has been shown that pars interarticularis defects had occurred in over 50% of a group of teenage fast bowlers. Many of these defects will heal, but some cause chronic pain which prevents bowling, although other activities may be painless. We report the successful results of local screw fusion of the pars interarticularis defects in ten bowlers, and recommend this method for this small group of sportsmen.


Neurofibromin-deficient Schwann cells have increased lysophosphatidic acid dependent survival and migration-implications for increased neurofibroma formation during pregnancy.
Neurofibromas are the clinical hallmark of neurofibromatosis Type 1 (NF1), a genetic disorder caused by mutations of the NF1 tumor suppressor gene, which encodes neurofibromin that functions as a GTPase activating protein (GAP) for Ras. During pregnancy, up to 50% of existing neurofibromas enlarge and as many as 60% of new neurofibromas appear for the first time. Lysophosphatidic acid (LPA) is a prototypic lysophospholipid that modulates cell migration and survival of Schwann cells (SCs) and is made in increasing concentrations throughout pregnancy. We addressed the influence of LPA on the biochemical and cellular functions of SCs with a homozygous mutation of the murine homologue of the NF1 gene (Nf1-/-). LPA promoted F-actin polymerization and increased migration and survival of Nf1-/- SCs as compared to wild type (WT) SCs. Furthermore, LPA induced a higher level of Ras-GTP and Akt phosphorylation in Nf1-/- SCs as compared to WT cells. Pharmacologic inhibition or siRNA for the p85beta regulatory subunit of Class I A PI3-K significantly reduced LPA-induced Schwann cell survival and migration. Introduction of NF1-GRD reconstitution was sufficient to normalize the LPA-mediated motility of Nf1-/- SCs. As LPA modulates excessive cell survival and motility of Nf1-/- SCs, which are the tumorigenic cells in NF1, targeting PI3-K may be a potential therapeutic approach in diminishing the development and progression of neurofibromas in pregnant women with NF1.


Prostate-derived sterile 20-like kinase 1-alpha induces apoptosis. JNK- and caspase-dependent nuclear localization is a requirement for membrane blebbing.
We have demonstrated previously that full-length prostate-derived sterile 20-like kinase 1-alpha (PSK1-alpha) binds to microtubules via its C terminus and regulates their organization and stability independently of its catalytic activity. Here we have shown that apoptotic and microtubule-disrupting agents promote catalytic activation, C-terminal cleavage, and nuclear translocation of endogenous phosphoserine 181 PSK1-alpha and activated N-terminal PSK1-alpha-induced apoptosis. PSK1-alpha, unlike its novel isoform PSK1-beta, stimulated the c-Jun N-terminal kinase (JNK) pathway, and the nuclear localization of PSK1-alpha and its induction of cell contraction, membrane blebbing, and apoptotic body formation were dependent on JNK activity. PSK1-alpha was also a caspase substrate, and the broad spectrum caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone or mutation of a putative caspase recognition motif ((916)DPGD(919)) blocked nuclear localization of PSK1-alpha and its induction of membrane blebs. Additional inhibition of caspase 9 was needed to prevent cell contraction. PSK1-alpha is therefore a bifunctional kinase that associates with microtubules, and JNK- and caspase-mediated removal of its C-terminal microtubule-binding domain permits nuclear translocation of the N-terminal region of PSK1-alpha and its induction of apoptosis.


Proximal changes in signal transduction that modify CD8+ T cell responsiveness in vivo.
The antigen dose conditions the functional properties of CD8(+) T cells generated after priming. At relatively low antigen doses, efficient memory T cells may be generated, while high antigen doses lead to tolerance. To determine the mechanisms leading to such different functional outcomes, we compared the proximal TCR signal transduction of naive cells, to that of memory or high-dose tolerant cells generated in vivo. In vivo activation led to the constitutive phosphorylation of CD3epsilon, recruiting Zap70, in both memory and tolerant cells. In tolerant cells, these phenomena were much more marked, the CD3epsilon and zeta chains no longer associated, and the Src kinases p56Lck and p59Fyn were inactive. Therefore, when the antigen load overcomes the capacities of immune control, a new mechanism intervenes to block signal transduction: the recruitment of Zap70 to CD3epsilon becomes excessive, leading to TCR complex destabilization, Src kinase dysfunction, and signal arrest.


Composite mandibulectomy: a novel animal model.
Segmental mandibular defects can result after the treatment of various pathologic processes, including osteoradionecrosis, tumor resection, or fracture nonunion with sequestration. The variety of etiologies and the frequency of occurrence make the reconstruction of segmental mandibular defects a topic of significant interest. Despite these incentives, a well-established small-animal model of the segmental mandibulectomy, including composite resection, does not exist. The objective of this study is the creation of a reliable animal model that can be used to study the reconstruction of en bloc mandibular defects. Surgical techniques and an array of reconstructive options are described. Description of an animal model. Animal laboratory at a quaternary care university medical center. We present an Animal Research Oversight Committee-approved prospective analysis of survival operations in the rat model. A detailed, stepwise description of surgical technique and relevant intraoperative anatomy is presented. Postoperative management, early pitfalls, surgical complications, and future applications are discussed. A total of 72 operations were performed by a single individual between July and October 2010. Two intraoperative and 9 postoperative complications were recognized. There were 6 orocutaneous fistulas, 2 abscesses, and 1 seroma. There were 4 fatalities, which were attributed to anesthetic complications (2, intraoperative), hematoma formation (1, postoperative), and foreign-body aspiration (1, postoperative). This novel animal model reliably replicates the en bloc segmental mandibular defects seen in our patient population and can be manipulated to achieve a wide variety of research objectives.


History of acupuncture research.
The acupuncture has been practiced in China for more than 3000 years and was spread to Europe and American from the sixteenth to the nineteenth century. The history of acupuncture research was initiated in the eighteenth century and developed rapidly since then. In the past, physicians tried hard to apply acupuncture into clinical practice, while scientists were focused on the possible characteristics of acupoints and meridians. In the modern time, scientists have strived hard to evaluate the real effectiveness of acupuncture and the underlying physiological and biological mechanisms of acupuncture. Reviewing research history from past to present, we are delighted to witness this wonderful development. Accumulated evidences that acupuncture is beneficial in various conditions significantly enhanced our understanding the mechanisms of acupuncture treatment. However, there is still no conclusive evidence in acupuncture clinical studies. The clinical research still needs great improving, while the basic research results need to be appropriately transformed into clinical outcomes. Based on current achievements, we believe that although the challenges and difficulties exist, a more collaborative, innovative, and integrated approach will help us to achieve further progress in future acupuncture research.


Anti-diabetic functions of soy isoflavone genistein: mechanisms underlying its effects on pancreatic β-cell function.
Type 2 diabetes is a result of chronic insulin resistance and loss of functional pancreatic β-cell mass. Strategies to preserve β-cell mass and a greater understanding of the mechanisms underlying β-cell turnover are needed to prevent and treat this devastating disease. Genistein, a naturally occurring soy isoflavone, is reported to have numerous health benefits attributed to multiple biological functions. Over the past 10 years, numerous studies have demonstrated that genistein has anti-diabetic effects, in particular, direct effects on β-cell proliferation, glucose-stimulated insulin secretion and protection against apoptosis, independent of its functions as an estrogen receptor agonist, antioxidant, or tyrosine kinase inhibitor. Effects are structure-specific and not common to all flavonoids. While there are limited data on the effects of genistein consumption in humans with diabetes, there are a plethora of animal and cell-culture studies that demonstrate a direct effect of genistein on β-cells at physiologically relevant concentrations (<10 μM). The effects appear to involve cAMP/PKA signaling and there are some studies that suggest an effect on epigenetic regulation of gene expression. This review focuses on the anti-diabetic effects of genistein in both in vitro and in vivo models and potential mechanisms underlying its direct effects on β-cells.


Mapping outcomes for recovery of consciousness in studies from 1986 to 2020: a scoping review protocol.
Historically, heterogeneous outcome assessments have been used to measure recovery of consciousness in patients with disorders of consciousness (DoC) following traumatic brain injury (TBI), making it difficult to compare across studies. To date, however, there is no comprehensive review of clinical outcome assessments that are used in intervention studies of adults with DoC. The objective of this scoping review is to develop a comprehensive inventory of clinical outcome assessments for recovery of consciousness that have been used in clinical studies of adults with DoC following TBI. The methodological framework for this review is: (1) identify the research questions, (2) identify relevant studies, (3) select studies, (4) chart the data, (5) collate, summarise and report results and (6) consult stakeholders to drive knowledge translation. We will identify relevant studies by searching the following electronic bibliographic databases: PubMed, Scopus, EMBASE, PsycINFO and The Cochrane Library (including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and Cochrane Methodology Register). Criteria for article inclusion are published in the English-language, peer-reviewed studies of interventions aimed at facilitating recovery of consciousness among adults (> 18 years) with DoC following a severe TBI, published from January 1986 to December 2020. Articles meeting inclusion criteria at this stage will undergo a full text review. We will chart the data by applying the WHO International Classification of Functioning, Disability and Health Framework to identify the content areas of clinical outcome assessments. To support knowledge translation efforts, we will involve clinicians and researchers experienced in TBI care throughout the project from conceptualisation of the study through dissemination of results. No ethical approval is required for this study as it is not determined to be human subjects research. Results will be presented at national conferences and published in peer-reviewed journals. CRD42017058383.


Twenty-first-century climate change impacts on marine animal biomass and ecosystem structure across ocean basins.
Climate change effects on marine ecosystems include impacts on primary production, ocean temperature, species distributions, and abundance at local to global scales. These changes will significantly alter marine ecosystem structure and function with associated socio-economic impacts on ecosystem services, marine fisheries, and fishery-dependent societies. Yet how these changes may play out among ocean basins over the 21st century remains unclear, with most projections coming from single ecosystem models that do not adequately capture the range of model uncertainty. We address this by using six marine ecosystem models within the Fisheries and Marine Ecosystem Model Intercomparison Project (Fish-MIP) to analyze responses of marine animal biomass in all major ocean basins to contrasting climate change scenarios. Under a high emissions scenario (RCP8.5), total marine animal biomass declined by an ensemble mean of 15%-30% (±12%-17%) in the North and South Atlantic and Pacific, and the Indian Ocean by 2100, whereas polar ocean basins experienced a 20%-80% (±35%-200%) increase. Uncertainty and model disagreement were greatest in the Arctic and smallest in the South Pacific Ocean. Projected changes were reduced under a low (RCP2.6) emissions scenario. Under RCP2.6 and RCP8.5, biomass projections were highly correlated with changes in net primary production and negatively correlated with projected sea surface temperature increases across all ocean basins except the polar oceans. Ecosystem structure was projected to shift as animal biomass concentrated in different size-classes across ocean basins and emissions scenarios. We highlight that climate change mitigation measures could moderate the impacts on marine animal biomass by reducing biomass declines in the Pacific, Atlantic, and Indian Ocean basins. The range of individual model projections emphasizes the importance of using an ensemble approach in assessing uncertainty of future change.


Evaluation of the PHQ-9 Item 3 as a screen for sleep disturbance in primary care.
Sleep disturbance is a significant problem for adults presenting to primary care. Though it is recommended that primary care providers screen for sleep problems, a brief, effective screening tool is not available. The aim of this preliminary study was to test the utility of item three of the Patient Health Questionnaire-9-item (PHQ-9) as a self-report screening test for sleep disturbance in primary care. This was a cross-sectional survey of male VA primary care patients in Syracuse and Rochester, NY. Sensitivity and specificity statistics were calculated as well as positive and negative predictive value to determine both whether the PHQ-9 item-3 can be used as an effective sleep screen in primary care and at what PHQ item-3 cut score patients should be further assessed for sleep disturbance. One hundred and eleven male, VA primary care patients over the age of 18 and without gross neurological impairment participated in this one-session, in-person study. During the research session, patients completed several questionnaires, including a basic demographic questionnaire, the PHQ-9, and the Insomnia Severity Index (ISI). PHQ-9 item 3 significantly correlated with the total score on the ISI (r = 0.75, p < 0.0001). A cut score of 1 on the PHQ-9 item 3, indicating sleep disturbance at least several days in the last two weeks, showed the best balance of sensitivity (82.5%) and specificity (84.5%) as well as positive (78.4%) and negative (91%) predictive value. Item 3 of the PHQ-9 shows promise as a screener for sleep problems in primary care. Using this one-item of a popular screening measure for depression in primary care allows providers to easily screen for two important issues without unnecessarily adding significant burden.


Effect of ischemia on calcium-dependent fluorescence transients in rabbit hearts containing indo 1. Correlation with monophasic action potentials and contraction.
The effects of acute global ischemia on cytosolic calcium transients were studied in perfused rabbit hearts loaded with the fluorescent calcium indicator indo 1. Indo 1-loaded hearts were illuminated at 360 nm, and fluorescence was recorded simultaneously at 400 and 550 nm from the epicardial surface of the left ventricle. The F400/F550 ratio was calculated by an analog circuit, which allowed cancellation of optical motion artifact. Resulting calcium transients demonstrated a rapid upstroke and slow decay similar to those recorded in isolated ventricular myocytes. Global ischemia rapidly suppressed contraction, but it produced a concurrent increase in the systolic and diastolic levels of the calcium transients, together with an increase in the duration of the peak. The effects of ischemia were reversed by reperfusion, inhibited by verapamil, and mimicked by perfusion of nonischemic hearts with acidified (CO2-rich) solution. In addition to elevation of the calcium transients, ischemia caused a pattern of intracellular calcium alternans that was discernible after 2-3 minutes. The pattern of alternans was stable at a given epicardial site, but it could be out of phase at different sites. Similar nonuniformities were observed in contraction strength and in the duration of monophasic action potentials recorded immediately adjacent to the fiber-optic probe. Abnormalities in intracellular calcium may be a causal factor in the loss of electrical and mechanical synchrony in the acutely ischemic heart.


Structures of neurexophilin-neurexin complexes reveal a regulatory mechanism of alternative splicing.
Neurexins are presynaptic, cell-adhesion molecules that specify the functional properties of synapses via interactions with trans-synaptic ligands. Neurexins are extensively alternatively spliced at six canonical sites that regulate multifarious ligand interactions, but the structural mechanisms underlying alternative splicing-dependent neurexin regulation are largely unknown. Here, we determined high-resolution structures of the complex of neurexophilin-1 and the second laminin/neurexin/sex-hormone-binding globulin domain (LNS2) of neurexin-1 and examined how alternative splicing at splice site #2 (SS2) regulates the complex. Our data reveal a unique, extensive, neurexophilin-neurexin binding interface that extends the jelly-roll β-sandwich of LNS2 of neurexin-1 into neurexophilin-1. The SS2A insert of LNS2 augments this interface, increasing the binding affinity of LNS2 for neurexophilin-1. Taken together, our data reveal an unexpected architecture of neurexophilin-neurexin complexes that accounts for the modulation of binding by alternative splicing, which in turn regulates the competition of neurexophilin for neurexin binding with other ligands.


Platelet-derived growth factor-A and its receptor are expressed in separate, but adjacent cell layers of the mouse embryo.
The localized developmental expression of murine platelet-derived growth factor A (PDGF-A) was compared to that of its receptor (Pdgfra). Our in situ hybridization study included germ layers of primitive streak embryos, early axial structures (dermatome, myotome, sclerotome, floor plate), the skin and some of its derivatives (hair and mammary gland), the developing forelimb, the branchial arches and various sense organs (otic vesicle, olfactory epithelium and the eye). We report that PDGF-A and Pdgfra are expressed in separate, but adjacent cell layers in these structures and that in most, the ligand is expressed in the epithelium, whereas the receptor in the mesenchyme. This localization corresponds to classical experimental evidence for developmental interactions across cell layers. We suggest that the spatio-temporal regulation of PDGF-A and Pdgfra, and other related systems, represents one model for the spatial regulation of receptor-ligand interactions.


Cytomorphologic consideration in malignant ascites with renal cell carcinoma: A report of two cases.
Effusions, especially peritoneal, are seen in less than 2% of patients with renal cell carcinoma (RCC). Since the tumor cells in RCC are bland and nondescript, the involvement of serous effusions is difficult to diagnose. An accurate recognition of malignant effusion and differentiation from reactive mesothelial cells is imperative. A 55-year-old male presented with gradually progressive ascites. Cytospin preparations from ascitic fluid showed reactive mesothelial cells admixed with few smooth-contoured clusters of cells with moderate cytoplasm, vesicular nuclei with prominent nucleolus. He had undergone nephrectomy for papillary RCC two years earlier. Another 36-year-old man underwent left nephrectomy for suspected RCC. Intra-operative ascitic fluid was sent for cytologic examination and showed numerous reactive mesothelial cells along with few clusters of cells with scant to moderate amount of cytoplasm, vesicular nucleus and a small nucleolus. Considering the histomorphology of the primary renal tumor in both cases, a cytologic diagnosis of malignant peritoneal effusion, morphologically compatible with RCC was rendered. RCC, due to its bland cytologic features, is easily overlooked in effusions. In a known patient, the cytopathologist must be extra vigilant to pick up the few cell clusters present in the fluid preparations and differentiate them from reactive mesothelial cells. A close inspection of the cytologic features and comparison with the histopathology of the primary tumor helps in making an accurate diagnosis.


Depression of glutamate and GABA release by presynaptic GABAB receptors in the entorhinal cortex in normal and chronically epileptic rats.
Presynaptic GABA(B) receptors (GABA(B)R) control glutamate and GABA release at many synapses in the nervous system. In the present study we used whole-cell patch-clamp recordings of spontaneous excitatory and inhibitory synaptic currents in the presence of TTX to monitor glutamate and GABA release from synapses in layer II and V of the rat entorhinal cortex (EC)in vitro. In both layers the release of both transmitters was reduced by application of GABA(B)R agonists. Quantitatively, the depression of GABA release in layer II and layer V, and of glutamate release in layer V was similar, but glutamate release in layer II was depressed to a greater extent. The data suggest that the same GABA(B)R may be present on both GABA and glutamate terminals in the EC, but that the heteroreceptor may show a greater level of expression in layer II. Studies with GABA(B)R antagonists suggested that neither the auto- nor the heteroreceptor was consistently tonically activated by ambient GABA in the presence of TTX. Studies in EC slices from rats made chronically epileptic using a pilocarpine model of temporal lobe epilepsy revealed a reduced effectiveness of both auto- and heteroreceptor function in both layers. This could suggest that enhanced glutamate and GABA release in the EC may be associated with the development of the epileptic condition.


Rates and predictors of success and failure in repeat epilepsy surgery: A meta-analysis and systematic review.
Medically refractory epilepsy is a debilitating disorder that is particularly challenging to treat in patients who have already failed a surgical resection. Evidence regarding outcomes of further epilepsy surgery is limited to small case series and reviews. Therefore, our group performed the first quantitative meta-analysis of the literature from the past 30 years to assess for rates and predictors of successful reoperations. A PubMed search was conducted for studies reporting outcomes of repeat epilepsy surgery. Studies were excluded if they reported fewer than five eligible patients or had average follow-ups < 1 year, and patients were excluded from analysis if they received a nonresective intervention. Outcomes were stratified by each variable of interest, and quantitative meta-analysis was performed to generate odds ratios (ORs) and 95% confidence intervals (CIs). Seven hundred eighty-two patients who received repeat resective epilepsy surgery from 36 studies were included. Engel I outcome was observed in 47% (n = 369) of patients. Significant predictors of seizure freedom included congruent over noncongruent electrophysiology data (OR = 3.6, 95% CI = 1.6-8.2), lesional over nonlesional epilepsy (OR = 3.2, 95% CI = 1.9-5.3), and surgical limitations over disease-related factors associated with failure of the first surgery (OR = 2.6, 95% CI = 1.3-5.3). Among patients with at least one of these predictors, seizure freedom was achieved in 58%. Conversely, the use of invasive monitoring was associated with worse outcome (OR = 0.4, 95% CI = 0.2-0.9). Temporal lobe over extratemporal/multilobe resection (OR = 1.5, 95% CI = 0.8-3.0) and abnormal over normal preoperative magnetic resonance imaging (OR = 1.9, 95% CI = 0.6-5.4) showed nonsignificant trends toward seizure freedom. This analysis supports considering further resection in patients with intractable epilepsy who continue to have debilitating seizures after an initial surgery, especially in the context of factors predictive of a favorable outcome.


Reducing stillbirths: prevention and management of medical disorders and infections during pregnancy.
An estimated two-thirds of the world's 3.2 million stillbirths occur antenatally, prior to labour, and are often overlooked in policy and programs. Poorly recognised, untreated or inadequately treated maternal infections such as syphilis and malaria, and maternal conditions including hypertensive disorders, are known risk factors for stillbirth. We undertook a systematic review of the evidence for 16 antenatal interventions with the potential to prevent stillbirths. We searched a range of sources including PubMed and the Cochrane Library. For interventions with prior Cochrane reviews, we conducted additional meta-analyses including eligible newer randomised controlled trials following the Cochrane protocol. We focused on interventions deliverable at the community level in low-/middle-income countries, where the burden of stillbirths is greatest. Few of the studies we included reported stillbirth as an outcome; most that did were underpowered to assess this outcome. While Cochrane reviews or meta-analyses were available for many interventions, few focused on stillbirth or perinatal mortality as outcomes, and evidence was frequently conflicting. Several interventions showed clear evidence of impact on stillbirths, including heparin therapy for certain maternal indications; syphilis screening and treatment; and insecticide-treated bed nets for prevention of malaria. Other interventions, such as management of obstetric intrahepatic cholestasis, maternal anti-helminthic treatment, and intermittent preventive treatment of malaria, showed promising impact on stillbirth rates but require confirmatory studies. Several interventions reduced known risk factors for stillbirth (e.g., anti-hypertensive drugs for chronic hypertension), yet failed to show statistically significant impact on stillbirth or perinatal mortality rates. Periodontal disease emerged as a clear risk factor for stillbirth but no interventions have reduced stillbirth rates. Evidence for some newly recognised risk factors for stillbirth, including periodontal disease, suggests the need for large, appropriately designed randomised trials to test whether intervention can minimise these risks and prevent stillbirths. Existing evidence strongly supports infection control measures, including syphilis screening and treatment and malaria prophylaxis in endemic areas, for preventing antepartum stillbirths. These interventions should be incorporated into antenatal care programs based on attributable risks and burden of disease.


Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.
Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. ClinicalTrials.gov Identifier: NCT02642393.


Relationship of peritoneal membrane transport characteristics to the nutritional status in CAPD patients.
The study was carried out to evaluate the role of individual peritoneal membrane transport characteristics in the nutritional status expressed as the composite nutritional index (CNI) METHODS: Cross-sectional analyses of the overall nutritional status of 147 continuous ambulatory peritoneal dialysis (CAPD) patients were performed using the CNI. CNIs based on a scoring system of 10 nutritional indices including subjective global assessment, biochemical parameters and anthropometry were compared according to the results of a standard peritoneal equilibration test (PET) RESULTS: Patients were classified as low (n = 16, 10.9%), low average (n=59, 40.2%), high average (n=54, 36.7%) and high (n=18, 12.2%) transporters based on the D/P(Cr) after 4 h dwells. The mean 4 h D/P(Cr) was 0.65 +/- 0.12 (0.34-0.95), and there was no significant correlation between D/P(Cr) and other demographic parameters such as age, duration of peritoneal dialysis and body surface area. D/P(Cr) was correlated with dialytic albumin loss (r=0.47, P<0.001), serum albumin (r=-0.46, P<0.001), serum creatinine (r= -0.38, P<0.001), serum TGF-1 (r=-0.37, P<0.01) and LBM(Cr) (r= -0.26, P<0.05). In high transporters, the serum albumin was significantly lower while dialysate protein and albumin losses were significantly greater compared with low transporters. Serum creatinine and IGF-1 concentrations as well as LBM(Cr) were also decreased in higher transporters. The mean CNI score was 8.1 +/- 4.9, with a range of 0-24. CNI was positively correlated with age, duration of peritoneal dialysis, incidence of peritonitis, CRP and dialytic protein loss, whereas it was inversely correlated with ultrafiltration volume, haemoglobin and NPNA. The CNI score was significantly higher in high transporters compared with low transporters (11.7 +/- 4.3 vs. 5.9 +/- 1.6, P < 0.01). There was also a significant correlation between D/P(Cr) and CNI (r = 0.29, P < 0.05). Multiple regression analysis revealed that the incidence of peritonitis, duration of CAPD, CRP and D/P(Cr) were the independent factors affecting the CNI. Peritoneal membrane transport characteristics correlate with the overall nutritional status of peritoneal dialysis patients assessed by the scoring system of the CNI, although it is associated with a different impact on the individual nutritional indices. The results of this cross-sectional study also suggest that a high permeability state is a risk factor for malnutrition in CAPD patients. Prospective studies evaluating the changes in nutritional parameters among patients with different membrane transport rates are needed to understand better the relationship of peritoneal membrane characteristics to the nutritional status of CAPD patients.


Calcium-mediated dual-mode regulation of cardiac sodium channel gating.
Intracellular Ca(2+) ([Ca(2+)](i)) can trigger dual-mode regulation of the voltage gated cardiac sodium channel (Na(V)1.5). The channel components of the Ca(2+) regulatory system are the calmodulin (CaM)-binding IQ motif and the Ca(2+) sensing EF hand-like (EFL) motif in the carboxyl terminus of the channel. Mutations in either motif have been associated with arrhythmogenic changes in expressed Na(V)1.5 currents. Increases in [Ca(2+)](i) shift the steady-state inactivation of Na(V)1.5 in the depolarizing direction and slow entry into inactivated states. Mutation of the EFL (Na(V)1.5(4X)) shifts inactivation in the hyperpolarizing direction compared with the wild-type channel and eliminates the Ca(2+) sensitivity of inactivation gating. Modulation of the steady-state availability of Na(V)1.5 by [Ca(2+)](i) is more pronounced after the truncation of the carboxyl terminus proximal to the IQ motif (Na(V)1.5(Delta1885)), which retains the EFL. Mutating the EFL (Na(V)1.5(4X)) unmasks CaM-mediated regulation of the kinetics and voltage dependence of inactivation. This latent CaM modulation of inactivation is eliminated by mutation of the IQ motif (Na(V)1.5(4X-IQ/AA)). The LQT3 EFL mutant channel Na(V)1.5(D1790G) exhibits Ca(2+) insensitivity and unmasking of CaM regulation of inactivation gating. The enhanced effect of CaM on Na(V)1.5(4X) gating is associated with significantly greater fluorescence resonance energy transfer between enhanced cyan fluorescent protein-CaM and Na(V)1.5(4X) channels than is observed with wild-type Na(V)1.5. Unlike other isoforms of the Na channel, the IQ-CaM interaction in the carboxyl terminus of Na(V)1.5 is latent under physiological conditions but may become manifest in the presence of disease causing mutations in the CT of Na(V)1.5 (particularly in the EFL), contributing to the production of potentially lethal ventricular arrhythmias.


Sexual dimorphism of sonic apparatus and extreme intersexual variation of sounds in Ophidion rochei (Ophidiidae): first evidence of a tight relationship between morphology and sound characteristics in Ophidiidae.
Many Ophidiidae are active in dark environments and display complex sonic apparatus morphologies. However, sound recordings are scarce and little is known about acoustic communication in this family. This paper focuses on Ophidion rochei which is known to display an important sexual dimorphism in swimbladder and anterior skeleton. The aims of this study were to compare the sound producing morphology, and the resulting sounds in juveniles, females and males of O. rochei. Males, females, and juveniles possessed different morphotypes. Females and juveniles contrasted with males because they possessed dramatic differences in morphology of their sonic muscles, swimbladder, supraoccipital crest, and first vertebrae and associated ribs. Further, they lacked the 'rocker bone' typically found in males. Sounds from each morphotype were highly divergent. Males generally produced non harmonic, multiple-pulsed sounds that lasted for several seconds (3.5 ± 1.3 s) with a pulse period of ca. 100 ms. Juvenile and female sounds were recorded for the first time in ophidiids. Female sounds were harmonic, had shorter pulse period (±3.7 ms), and never exceeded a few dozen milliseconds (18 ± 11 ms). Moreover, unlike male sounds, female sounds did not have alternating long and short pulse periods. Juvenile sounds were weaker but appear to be similar to female sounds. Although it is not possible to distinguish externally male from female in O. rochei, they show a sonic apparatus and sounds that are dramatically different. This difference is likely due to their nocturnal habits that may have favored the evolution of internal secondary sexual characters that help to distinguish males from females and that could facilitate mate choice by females. Moreover, the comparison of different morphotypes in this study shows that these morphological differences result from a peramorphosis that takes place during the development of the gonads.


Key concerns about the current state of bladder cancer: a position paper from the Bladder Cancer Think Tank, the Bladder Cancer Advocacy Network, and the Society of Urologic Oncology.
Bladder cancer is the fifth most common cancer in the United States and, on a per capita basis, is the most expensive cancer from diagnosis to death. Unfortunately, National Cancer Institute funding for bladder cancer is quite low when compared with other common malignancies. Limited funding has stifled research opportunities for new and established investigators, ultimately encouraging them to redirect research efforts to other organ sites. Waning interest of scientists has further fueled the cycle of modest funding for bladder cancer. One important consequence of this has been a lack of scientific advancement in the field. Patient advocates have decidedly advanced research efforts in many cancer sites. Breast, prostate, pancreatic, and ovarian cancer advocates have organized highly successful campaigns to lobby the federal government and the medical community to devote increased attention and funding to understudied malignancies and to conduct relevant studies to better understand the therapy, diagnosis, and prevention of these diseases. Bladder cancer survivors have lacked a coordinated advocacy voice until recently. A concerted effort to align bladder cancer advocates, clinicians, and urologic organizations is essential to define the greatest needs in bladder cancer and to develop related solutions. This position paper represents a collaborative discussion to define the most concerning trends and greatest needs in the field of bladder cancer as outlined by the Bladder Cancer Think Tank, the Bladder Cancer Advocacy Network, and the Society of Urologic Oncology.


Faster pulmonary oxygen uptake kinetics in trained versus untrained male adolescents.
Exercise training results in a speeding of pulmonary oxygen uptake (VO2) kinetics at the onset of exercise in adults; however, only limited research has been conducted with children and adolescents. The aim of the present study was to examine VO2 and muscle deoxygenation kinetics in trained and untrained male adolescents. Sixteen trained (15 +/- 0.8 yr, VO2peak = 54.7 +/- 6.2 mL x kg-1 x min-1, self-assessed Tanner stage range 2-4) and nine untrained (15 +/- 0.6 yr, VO2peak = 43.1 +/- 5.2 mL x kg-1 x min-1, Tanner stage range 2-4) male adolescents performed two 6-min exercise transitions from a 3-min baseline of 10 W to a workload equivalent to 80% lactate threshold separated by a minimum of 1 h of passive rest. Oxygen uptake (breath-by-breath) and muscle deoxygenation (deoxyhemoglobin signal from near-infrared spectroscopy) were measured continuously throughout baseline and exercise transition. The time constant of the fundamental phase of VO2 kinetics was significantly faster in trained versus untrained subjects (trained: 22.3 +/- 7.2 s vs untrained: 29.8 +/- 8.4 s, P = 0.03). In contrast, neither the time constant (trained: 9.7 +/- 2.9 s vs untrained: 10.1 +/- 3.4 s, P = 0.78) nor the mean response time (trained: 17.4 +/- 2.5 s vs untrained: 18.3 +/- 2.3 s, P = 0.39) of muscle deoxygenation kinetics differed with training status. The present data suggest that exercise training results in faster VO2 kinetics in male adolescents, although inherent capabilities cannot be ruled out. Because muscle deoxygenation kinetics were unchanged, it is likely that faster VO2 kinetics were due to adaptations to both the cardiovascular system and the peripheral musculature.


Evaluation of eight cephalosporins in hamster colitis model.
Eight commonly used cephalosporins were evaluated in the hamster colitis mode. They were all found to cause hemorrhagic cecitis and death within 10 days of being given as subcutaneous or oral challenges. Necropsy findings were indistinguishable from clindamycin-induced cecitis. Bacteria-free cecal filtrate obtained from hamsters dying of cephalosporin-induced cecitis contained toxin similar or identical to hat produced by Clostridium difficile isolated from the cecum of a hamster. Daily oral administration of poorly absorbed cephalosporins protected hamsters from clindamycin-induced cecitis and death as long as the cephalosporins were continued. The absorbable cephalosporins were ineffective in protecting hamsters from clindamycin-induced cecitis. This difference probably relates to the lower concentrations of absorbable cephalosporins maintained in the ceca of the hamsters. The possible correlation of these findings to human cases of cephalosporin-induced pseudomembranous colitis is discussed.


Efficacy of transrectal ultrasonography in the evaluation of hematospermia.
To assess the efficacy of transrectal ultrasonography (TRUS) in the evaluation of hematospermia. This study included 54 patients with hematospermia. Patients age range was between 25 and 75 years (mean=49.7 years). All patients were evaluated by TRUS using a biplane transducer and a Toshiba SSA-270A device. TRUS revealed one or more abnormalities in 51 patients (94.5%). Prostatic calcifications were found in 23 patients, ejaculatory duct calculi in 21, dilated ejaculatory ducts in 18, benign prostatic hyperplasia in 18, dilated seminal vesicles in 12, calcifications in seminal vesicles in 11, ejaculatory duct cyst in 6, prostatitis in 6, and periurethral Cowper gland mass in 1. TRUS is a noninvasive, safe method for the investigation of causes of hematospermia. We believe that it should be the first radiological investigation to be performed in patients presenting with hematospermia.


The MAL-ED study: a multinational and multidisciplinary approach to understand the relationship between enteric pathogens, malnutrition, gut physiology, physical growth, cognitive development, and immune responses in infants and children up to 2 years of age in resource-poor environments.
Highly prevalent conditions with multiple and complex underlying etiologies are a challenge to public health. Undernutrition, for example, affects 20% of children in the developing world. The cause and consequence of poor nutrition are multifaceted. Undernutrition has been associated with half of all deaths worldwide in children aged <5 years; in addition, its pernicious long-term effects in early childhood have been associated with cognitive and physical growth deficits across multiple generations and have been thought to suppress immunity to further infections and to reduce the efficacy of childhood vaccines. The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health (MAL-ED) Study, led by the Fogarty International Center of the National Institutes of Health and the Foundation for the National Institutes of Health, has been established at sites in 8 countries with historically high incidence of diarrheal disease and undernutrition. Central to the study is the hypothesis that enteropathogen infection contributes to undernutrition by causing intestinal inflammation and/or by altering intestinal barrier and absorptive function. It is further postulated that this leads to growth faltering and deficits in cognitive development. The effects of repeated enteric infection and undernutrition on the immune response to childhood vaccines is also being examined in the study. MAL-ED uses a prospective longitudinal design that offers a unique opportunity to directly address a complex system of exposures and health outcomes in the community-rather than the relatively rarer circumstances that lead to hospitalization-during the critical period of development of the first 2 years of life. Among the factors being evaluated are enteric infections (with or without diarrhea) and other illness indicators, micronutrient levels, diet, socioeconomic status, gut function, and the environment. MAL-ED aims to describe these factors, their interrelationships, and their overall impact on health outcomes in unprecedented detail, and to make individual, site-specific, and generalized recommendations regarding the nature and timing of possible interventions aimed at improving child health and development in these resource-poor settings.


Risk factors for chronic obstructive pulmonary disease in a European cohort of young adults.
Few studies have investigated the factors associated with the early inception of chronic obstructive pulmonary disease (COPD). We investigated COPD risk factors in an international cohort of young adults using different spirometric definitions of the disease. We studied 4,636 subjects without asthma who had prebronchodilator FEV(1)/FVC measured in the European Community Respiratory Health Survey both in 1991 to 1993 (when they were 20-44 yr old) and in 1999 to 2002. COPD was defined according to the Global Initiative for Chronic Obstructive Lung Disease fixed cut-off criterion (FEV(1)/FVC < 0.70), and two criteria based on the Quanjer and LuftiBus reference equations (FEV(1)/FVC less than lower limit of normal). COPD determinants were studied using two-level Poisson regression models. COPD incidence ranged from 1.85 (lower limit of normal [Quanjer]) to 2.88 (Global Initiative for Chronic Obstructive Lung Disease) cases/1,000/yr. Although about half of the cases had smoked less than 20 pack-years, smoking was the main risk factor for COPD, and it accounted for 29 to 39% of the new cases during the follow-up. Airway hyperresponsiveness was the second strongest risk factor (15-17% of new cases). Other determinants were respiratory infections in childhood and a family history of asthma, whereas the role of sex, age, and of being underweight largely depended on the definition of COPD used. COPD may start early in life. Smoking prevention should be given the highest priority to reduce COPD occurrence. Airway hyperresponsiveness, a family history of asthma, and respiratory infections in childhood are other important determinants of COPD. We suggest the need for a definition of COPD that is not exclusively based on spirometry.


Effects of estradiol on the thermoneutral zone and core temperature in ovariectomized rats.
Hot flushes represent a disorder of central thermoregulation characterized by the episodic activation of heat loss mechanisms. Although flushes are associated with estrogen withdrawal, there is little understanding of the effects of estrogen on thermoregulation in any species. It has been proposed that hormone withdrawal increases the sensitivity of hypothalamic neural pathways that control heat dissipation effectors. If so, we predicted that ovariectomized rats without estradiol treatment would activate tail skin vasodilatation (a major heat loss effector) at lower ambient temperatures and thereby lower the thermoneutral zone. The thermoneutral zone, defined as the range of ambient temperatures in which thermoregulation is achieved only by sensible (dry) heat loss, was evaluated based on properties of skin vasomotion. Core and tail skin temperatures were recorded in ovariectomized rats (with and without estradiol-17beta) exposed to ambient temperatures from 13 to 34 C in an environmental chamber. Rats without estradiol exhibited increased skin vasodilatation and a shift in the thermoneutral zone to lower ambient temperatures. Moreover, the ambient temperature threshold for skin vasodilatation was significantly lower in rats without estradiol treatment. At most ambient temperatures, average core temperature was unaffected by estradiol. However, at ambient temperatures of 32.5 C and above, untreated ovariectomized rats exhibited higher core temperatures compared with estradiol-treated rats. Thus, estradiol-17beta treatment enhanced the maintenance of core temperature during heat exposure. These findings support the hypothesis that estrogen withdrawal increases the sensitivity of thermoregulatory neural pathways and modifies the activation of heat loss mechanisms.


The prevalence and identification of risk factors for type 2 diabetes mellitus and impaired glucose tolerance in Kayseri, central Anatolia, Turkey.
Type 2 diabetes mellitus is a chronic disease which causes neurologic, cardiac, vascular, ocular and renal complications. The present study documented the prevalence of diabetes and associated risk factors in 1774 adults who were older than 30 years. An oral glucose tolerance test (OGTT) was conducted according to the World Health Organization (WHO) criteria. Of the 1452 subjects, 58 (4%) had diagnosed diabetes, 41 (2.9%) undiagnosed diabetes and 130 (9%) had impaired glucose tolerance. The total glucose intolerance was 15. 9%. The prevalences of type 2 diabetes mellitus (9.7%-4.1%) were significantly different in low occupational and high occupational activity groups, respectively (P<0.0001). The prevalence of type 2 diabetes mellitus was 17.9% among the hypertensive group (P<0.0001). The prevalence of type 2 diabetes mellitus was higher in smokers (P<0.05). Patients with diagnosed diabetes, undiagnosed diabetes and IGT were older, more obese and have higher blood glucose values, triglyceride values, systolic and diastolic blood pressures than healthy subjects (P<0.001). We conclude that type 2 diabetes mellitus and IGT prevalences are quite high in the urban area of Kayseri, central Anatolia and multivariate analysis indicated that low occupational activity, low leisure activity, family history for diabetes, hypertension and obesity were significant independent risk factors for diabetes mellitus.


The acute effects of sleep restriction therapy for insomnia on circadian timing and vigilance.
Sleep-restriction therapy (SRT) has been shown to improve insomnia symptoms by restricting sleep opportunity. Curtailment of time in bed affects the duration and consolidation of sleep, but also its timing. While recent work suggests that people with insomnia are characterised by misalignment between circadian and behavioural timing of sleep, no study has investigated if SRT modifies this relationship. The primary aim of the present study was to examine change in phase angle after 2 weeks of SRT. As a secondary aim, we also sought to assess the effect of SRT on psychomotor vigilance. Following a 1-week baseline phase, participants implemented SRT for 2 consecutive weeks. Phase angle was derived from the difference between the decimal clock time of dim light melatonin onset (DLMO) and attempted sleep time. Secondary outcomes included vigilance (assessed via hourly measurement during the DLMO laboratory protocol), sleep continuity (assessed via sleep diary and actigraphy), and insomnia severity. Eighteen participants meeting insomnia criteria (mean [SD] age 37.06 [8.99] years) took part in the study. Consistent with previous research, participants showed robust improvements in subjective and objective sleep continuity, as well as reductions in insomnia severity. The primary outcome (phase angle) was measurable in 15 participants and revealed an increase of 34.8 min (~0.58 hr; 95% confidence interval [CI] 0.01-1.15) from baseline to post-treatment (mean [SD] 2.27 [0.94] versus 2.85 [1.25] hr). DLMO remained relatively stable (20:49 versus 21:01 hours), while attempted sleep was 46.8 min later (~0.78 hr; 95%CI 0.41-1.15; 23:05 versus 23:52 hours). For psychomotor vigilance, reaction time was delayed (by 52.71 ms, 95% CI 34.44-70.97) and number of lapses increased (by 5.84, 95% CI 3.93-7.75) after SRT. We show that SRT increases phase angle during treatment, principally by delaying the timing of sleep attempt. Future studies are needed to test if an increase in phase angle is linked to clinical improvement. Finally, reduction in vigilance after SRT appears to be of similar magnitude to normal sleepers undergoing experimental sleep restriction, reinforcing the importance of appropriate safety advice during implementation.


IgG antibody response against Anopheles salivary gland proteins in asymptomatic Plasmodium infections in Narino, Colombia.
The humoral immune response against Anopheles salivary glands proteins in the vertebrate host can reflect the intensity of exposure to Anopheles bites and the risk of Plasmodium infection. In Colombia, the identification of exposure biomarkers is necessary due to the several Anopheles species circulating. The purpose of this study was to evaluate risk of malaria infection by measuring antibody responses against salivary glands extracts from Anopheles (Nyssorhynchus) albimanus and Anopheles (Nys.) darlingi and also against the gSG6-P1 peptide of Anopheles gambiae in people residing in a malaria endemic area in the Colombian Pacific coast. Dried blood spots samples were eluted to measure the IgG antibodies against salivary gland extracts of An. albimanus strains STECLA (STE) and Cartagena (CTG) and An. darlingi and the gSG6-P1 peptide by ELISA in uninfected people and microscopic and submicroscopic Plasmodium carriers from the Colombia Pacific Coast. A multiple linear mixed regression model, Spearman correlation, and Mann-Whitney U-test were used to analyse IgG data. Significant differences in specific IgG levels were detected between infected and uninfected groups for salivary glands extracts from An. albimanus and for gSG6-P1, also IgG response to CTG and gSG6-P1 peptide were positively associated with the IgG response to Plasmodium falciparum in the mixed model. The CTG and STE An. albimanus salivary glands extracts are a potential source of new Anopheles salivary biomarkers to identify exposure to the main malaria vector and to calculate risk of disease in the Colombian Pacific coast. Also, the gSG6-P1 peptide has the potential to quantify human exposure to the subgenus Anopheles vectors in the same area.


Performance of carrier phase recovery for electronically dispersion compensated coherent systems.
An analytical approach taking into account carrier phase estimation (CPE) is presented to predict performance of quadrature phase shift-keying (QPSK) systems using coherent detection. Using this approach, system performance is found as a function of symbol rate, local oscillator (LO) linewidth, chromatic dispersion (CD) and signal-to-noise ratio (SNR). A new expression is derived for the covariance matrix of the conditional probability density function (pdf) of the decision statistic. This pdf is used to find bit error rate (BER) semi-analytically. Our analytical derivation assumes perfect removal of data modulation which corresponds to an ideal decision feedback (DF) carrier recovery. The validity of the analytical pdf for predicting BER is verified for a wide range of system parameters of interest in long haul systems. In addition, our semi-analytical BER provides a lower bound for the Viterbi-Viterbi (VV) BER, while showing the analytical BER previously proposed in the literature shows an overly pessimistic prediction of VV BER performance. We show that inaccuracy in previous analysis stems from overly simple model for the CPE when compensating large accumulated dispersion electronically. Finally, we study extension of our results to quadrature amplitude modulation (QAM). Preliminary simulation results are promising but the accuracy of our semi-analytical approach for predicting BER should be investigated further.


Cardiovascular involvement in primary systemic vasculitis.
The primary systemic vasculitides are a group of autoimmune conditions characterised by occlusion, stenosis or aneurysmal dilatation of blood vessels secondary to intra-mural inflammation. Current therapy has converted the outlook of these diseases from death or severe morbidity to a remitting-relapsing condition in most instances. Longer survival, relapsing course of disease and chronic glucocorticoid therapy probably contribute to an increase in cardiovascular events and morbidity. This article reviews the available data for effect of primary systemic vasculitis on cardiovascular end points like coronary artery disease, congestive cardiac failure, hypertension and aortic aneurysm in all age groups. We examine the interplay between the activated endothelium, autoimmune mechanisms and treatment factors to produce a direct insult or increased atherogenic potential of primary systemic vasculitis. Recommendations to deal with cardiovascular end points are made.


Parallel visual cycles in the zebrafish retina.
Vertebrate vision necessitates continuous recycling of the chromophore 11-cis retinal (RAL). The classical (or canonical) visual cycle employs a number of enzymes located in the photoreceptor outer segment and RPE (retinal pigment epithelium) of the retina to regenerate 11-cis RAL from all-trans RAL. Cone-dominant species are believed to utilize a second, intra-retinal, pathway for 11-cis RAL generation, involving retinal Müller glia cells. This review summarizes the efforts made in zebrafish to gain a better understanding of the role of these two visual cycles for rod and cone photoreceptor chromophore recycling.


Diet, nutrients and metabolism: cogs in the wheel driving Alzheimer's disease pathology?
Alzheimer's disease (AD), the most common form of dementia, is a chronic, progressive neurodegenerative disease that manifests clinically as a slow global decline in cognitive function, including deterioration of memory, reasoning, abstraction, language and emotional stability, culminating in a patient with end-stage disease, totally dependent on custodial care. With a global ageing population, it is predicted that there will be a marked increase in the number of people diagnosed with AD in the coming decades, making this a significant challenge to socio-economic policy and aged care. Global estimates put a direct cost for treating and caring for people with dementia at $US604 billion, an estimate that is expected to increase markedly. According to recent global statistics, there are 35.6 million dementia sufferers, the number of which is predicted to double every 20 years, unless strategies are implemented to reduce this burden. Currently, there is no cure for AD; while current therapies may temporarily ameliorate symptoms, death usually occurs approximately 8 years after diagnosis. A greater understanding of AD pathophysiology is paramount, and attention is now being directed to the discovery of biomarkers that may not only facilitate pre-symptomatic diagnosis, but also provide an insight into aberrant biochemical pathways that may reveal potential therapeutic targets, including nutritional ones. AD pathogenesis develops over many years before clinical symptoms appear, providing the opportunity to develop therapy that could slow or stop disease progression well before any clinical manifestation develops.


Fibronectin deposition in delayed-type hypersensitivity. Reactions of normals and a patient with afibrinogenemia.
During development of delayed hypersensitivity (DH) skin reactions, fibronectin accumulates in two distinct sites: (a) the dermal interstitium in a pattern similar to fibrin and with a time course similar to that of fibrin deposition and mononuclear cell infiltration, and (b) blood vessel walls in a pattern suggestive of basement membrane staining and with a time course similar to that of endothelial cell proliferation. In vitro fibronectin can bind to monocytes or endothelial cells and simultaneously bind to fibrin or collagen matrices; by such interaction in vivo it may affect cell migration or proliferation. Thus, fibronectin deposition in DH reactions may facilitate cell-matrix interactions; however, the possibility exists that extravascular fibronectin accumulation may be only secondary to interstitial fibrin clot formation, and that blood vessel-associated fibronectin may be only a function of adsorption onto basement membrane (type IV) collagen. To address these possibilities, we investigated the association of fibronectin with fibrin, type IV collagen, and mononuclear cell infiltrates in DH reactions. Skin sites of DH reactions in normal volunteers were biopsied at 24, 48, and 72 h after intradermal challenge and examined by immunofluorescence technique. At all time points most of the interstitial fibronectin coincided with fibrin; however, some interstitial fibronectin was coincident with mononuclear cells positive for HLA-DR or monocyte-specific antigen. The coincidence of fibronectin with mononuclear cells was more apparent in a 48-h DH reaction from a patient with congenital afibrinogenemia. Vessel wall fibronectin was increased by 48 h after challenge and appeared as a fine linear band on the luminal side of a much thicker band of type IV collagen. Thus, the coincidence of extravascular fibronectin with mononuclear cells, its appearance without fibrin in the site from a patient with afibrinogenemia, and incomplete correspondence of vessel wall fibronectin with type IV collagen suggest that fibronectin localization in DH reactions involves endothelial cell and mononuclear cell binding as well as adsorption to fibrin and/or type IV collagen.


Prospective evaluation of sequential treatment of sclerotic chronic graft versus host disease with rituximab and nilotinib.
Sclerotic chronic graft vs. host disease (cGVHD) still has a large impact on morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). We performed the first prospective study to test whether sequential therapy of the anti-CD20 antibody rituximab followed by 6 months treatment with tyrosine kinase inhibitor nilotinib is a favorable treatment strategy for patients with sclerotic cGVHD. Twenty-nine patients were included, 24 were available for analysis. We observed objective responses in 71% of patients (two patients CR, 15 patients PR). Moreover, two out of five patients suffering from severe ulcerations showed complete resolution of ulcers. Observed responses lasted until the end of study follow-up. The majority of responding patients could reduce daily corticosteroid dose with more than 50%. Furthermore, CD5+ B-cells are significantly lower (p = 0.007) in responding patients at baseline, proposing a new biomarker predictive for response. In conclusion, sequential treatment of rituximab followed by nilotinib associates with a very high response rate in this difficult to treat patient population. CD5+ B-cells could assist in guiding treatment choices and might be a first step toward more personalized cGVHD treatment. This trial was registered at the Dutch clinical trial registry as NTR1222.


Effects of melatonin on noncardiogenic pulmonary edema secondary to adnexial ischemia-reperfusion in guinea pig.
Pulmonary edema has been shown to occur following ischemia-reperfusion injury in a variety of organs and effects of several pharmacological agents on ischemia-reperfusion-induced damage has been investigated previously. However, there are only a few studies in the literature about pulmonary injury following adnexial ischemia-reperfusion. In this study we aimed at investigating pulmonary changes following adnexial ischemia-reperfusion and the effects of melatonin on noncardiogenic pulmonary edema secondary to adnexial ischemia-reperfusion. A total of 32 Dunkin-Harley guinea pigs were randomly divided into four groups. In group I, oopherectomy was performed following adnexial torsion of three hours (ischemia). Adnexial torsion of three hours followed by a 3 hours detorsion period (reperfusion) and then oopherectomy was performed in remaining three groups. No therapy was given in group one and two while isotonic saline and melatonin was applied intraperitoneally in groups three and four, respectively. Serum malondialdehyde (MDA) levels of operated ovaries and lungs and polimorphonuclear leucocyte infiltration of lungs were determined. MDA levels in serum, ovary and lungs were higher in detorsion groups (groups II, III) than torsion group (group I) (p<0.01). Melatonin administration significantly decreased the polimorphonuclear leukocytes infiltration of lung parenchime and MDA levels in serum, ovaries and lungs (groups II and IV; groups III and IV; p<0.01, p<0.01). MDA levels and lung tissue PNL infiltration levels of melatonin administered detorsioned group was similar to those levels of only salphingo-oopherectomy performed group (Group I and IV, p>0.05). Pathophysiology of ischemia-reperfusion must be considered in the cases of adnexial torsion where detorsion is thought. As an antioxidant, melatonin administration might be helpful in decreasing post-operative morbidity by decreasing reperfusion injury of lungs.


Mineralization of aromatic compounds by brown-rot basidiomycetes - mechanisms involved in initial attack on the aromatic ring.
Benzaldehyde and its metabolic intermediates were effectively degraded by the brown-rot basidiomycetes Tyromyces palustris and Gloeophyllum trabeum. The pathway of benzaldehyde degradation was elucidated by the identification of fungal metabolites produced upon the addition of benzaldehyde and its metabolic intermediates. The oxidation and reduction occurred simultaneously, forming benzyl alcohol and benzoic acid as major products. Hydroxylation reactions, which seemed to be a key step, occurred on benzaldehyde and benzoic acid, but not on benzyl alcohol, to form corresponding 4-hydroxyl and 3,4-dihydroxyl derivatives. 1-Formyl derivatives were oxidized to 1-carboxyl derivatives at several metabolic stages. All of these reactions resulted in the formation of 3,4-dihydroxybenzoic acid. This was further metabolized via the decarboxylation reaction to yield 1,2,4-trihydroxybenzene, which may be susceptible to the ring-fission reaction. Ring-U-14C-labelled benzaldehyde and benzoic acid were effectively mineralized, clearly indicating that the brown-rot basidiomycetes are capable of metabolizing certain aromatic compounds to CO2 and H2O, despite the fact that brown-rot fungi cannot degrade polymeric lignin. Inhibitor experiments, using hydroxyl radical scavengers, catalase and cytochrome P450 inhibitors, strongly suggested that the aromatic hydroxylation reactions found in the brown-rot fungi are catalysed by intracellular enzyme(s), but not by Fenton-reaction-derived hydroxyl radicals.


Anterior hypopituitarism following traumatic brain injury.
To review evidence that there exists a substantial sub-population of patients with endocrine disorders as a result of traumatic brain injury (TBI) and to underscore the importance of screening patients with TBI considered most at risk for hypopituitarism with the goal of attaining beneficial effects in terms of morbidity and quality of life. Reviewed recent literature regarding the frequency of TBI-induced hypopituitarism. Studies by Kelly DF, Gaw Gonzalo IT, Cohan P, et al. Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: A preliminary report. Journal of Neurosurgery 2000;93:743-751, Lieberman SA, Oberoi AL, Gilkison CR, et al. Prevalence of neuroendocrine dysfunction in patients recovering from traumatic brain injury. Journal of Clinical Endocrinology and Metabolism 2001;86:2752-2756 and Aimaretti G, Ambrosio MR, Di Somma C, et al. Traumatic brain injury and subarachnoid haemorrhage are conditions at high risk for hypopituitarism. Screening study at 3 months after the brain injury, In press., found that about one-half to one-third of patients with TBI had anterior pituitary hormone deficiencies, including growth hormone (GH) deficiency in 15-21%, and subtle deficiencies in thyroid, adrenal and gonadal axes. One or more hormonal deficiencies produce diverse physical and psychological symptoms that may mimic symptoms attributed to brain trauma and may impair rehabilitation. A more general concern is the fact that hypopituitarism increases the risk of significant morbidity (e.g. ischaemic heart disease) and mortality (shortened life span). To attain maximal improvement in mental and physical functioning as well as in quality of life for victims of TBI, it is crucial that anterior pituitary hormonal function be assessed. Appropriate hormone replacement therapy for those patients with both TBI and TBI-induced pituitary function impairment could, for the first time, allow treatment and correction of underlying causes of TBI sequelae rather than merely symptomatic treatment.


Growth hormone deficiency and hypopituitarism in adults after complicated mild traumatic brain injury.
Traumatic brain injury is considered the main cause of hypopituitarism in adults, and GH deficiency appears to be the most frequent pituitary deficit. Most of the available studies have included all degrees of severity of trauma. We aimed to assess pituitary function and GH deficiency in adult patients at different time lengths after complicated mild TBI according to Glasgow Coma Scale. We also aimed to evaluate whether mild TBI patients with GH deficiency had developed alterations in the glycolipid profile. Forty-eight patients (34 men and 14 women) with complicated mild TBI were included in the study. Twenty-three patients were evaluated at 1 year (Group A) and 25 patients at 5 years or longer after the injury (Group B). All patients underwent basal hormonal evaluation for pituitary function. GH deficiency was investigated by the combined test (GH releasing hormone + arginine). The glycolipid profile was also evaluated. GH deficiency occurred in 8/23 patients (34.7 %) of Group A and in 12/25 patients (48 %) of Group B. In addition, two patients, one in each group, showed evidence of central hypothyroidism. Patients with GH deficiency, especially in Group A, presented a higher frequency of visceral adiposity and adverse metabolic profile as compared to no-GH deficiency patients. Patients examined at 1 year or several years from complicated mild TBI had a similarly high occurrence of isolated GH deficiency, which was associated with visceral adiposity and metabolic alterations. Our findings suggest that patients undergone complicated mild TBI should be evaluated for GH deficiency even after several years from trauma.


First Report of the Root-Knot Nematode Meloidogyne arenaria on Cheeseweed Mallow (Malva parviflora) in the United States.
During a 2010 field trial for examining alternatives to methyl bromide soil fumigation for the production of field-grown cut flowers, weeds were collected for identification and evaluated for their potential as hosts for plant pathogenic nematodes. In one cut flower field located in Martin County, FL, six cheeseweed mallow (Malva parviflora L.) plants were collected that had root-galling typical of infection by a root-knot nematode (Meloidogyne spp.). Field collected plants were used for species identification of the weed and maintained in the greenhouse for seed production. Several gravid female nematodes were extracted from field collected mallow roots and individually identified as Meloidogyne arenaria based on their esterase phenotype (PhastSystem, GE Healthcare) (1). A single egg mass was then extracted from the field collected mallow roots and inoculated onto a tomato plant (Solanum lycopersicum, 'Rutgers') grown in steamed builders sand in the greenhouse. The single egg mass culture was increased for 8 weeks, until galling was sufficient to produce adequate nematode inoculum to complete Koch's postulates on the original mallow host. Ten mallow plants were inoculated with single egg masses originally isolated from mallow and increased on tomato. Ten additional plants were maintained in the greenhouse as uninoculated controls. Inoculated and control mallow plants were grown in the greenhouse for 8 weeks, after which the roots were evaluated for galling, and root-knot nematode J2 were extracted from roots and soil and counted. All inoculated plants produced galled roots and control plants did not. Gravid females were extracted from mallow roots and identified as M. arenaria based on esterase phenotype as previously described. Ten gravid females for each DNA extraction were collected from mallow roots and DNA was isolated with the PowerSoil DNA Isolation Kit (MO BIO Laboratories, Inc., Carlsbad, CA). Identification of M. arenaria was confirmed by using species-specific primers F5'-TCGAGGGCATCTAATAAAGG-3' and R5'-GGGCTGAATAATCAAAGGAA-3' (2) and F5'-TCGGCGATAGAGGTAAATGAC-3' and R5'-TCGGCGATAGACACTACAACT-3' (4), which produced single amplicon bands of the expected size of 420 and 950 bp, respectively. This weed species has been reported as a host for M. javanica in Algeria and as an experimental host in Egypt (3), but this report, to our knowledge, constitutes the first documentation of Malva parviflora as a natural host of M. arenaria. The importance of weeds as hosts for plant parasitic nematodes cannot be over emphasized. As growers, particularly in Florida and California, continue to lose tools for broad-spectrum pest control, the ability of nematodes to reproduce on uncontrolled weeds will become increasingly important. References: (1) J. A. Brito et al. Nematology 10:757, 2008. (2) K. Dong et al. Nematropica 31:273, 2001. (3) M. Quader et al. Australas. Plant Pathol. 30:357, 2001. (4) C. Zijlstra et al. Nematology 2:847, 2000.


Therapeutic Value of Ginkgo biloba Extract EGb 761® in an Animal Model (Meriones unguiculatus) for Noise Trauma Induced Hearing Loss and Tinnitus.
Noise induced hearing loss (NIHL) is a common disease in modern societies and may lead to maladaptations within the auditory system that finally result in subjective tinnitus. Available therapies may only alleviate the symptoms rather than restore normal hearing. In a previous study we demonstrated that the prophylactic application of Ginkgo biloba extract EGb 761® significantly reduces NIHL and tinnitus development in our Mongolian gerbil (Meriones unguiculatus) animal model. Here, we tested whether the application of EGb 761® has beneficial effects after the formation of permanent NIHL and tinnitus. To this end we monitored the therapeutic effects of EGb 761® on noise trauma-induced changes in signal processing within the auditory system of our animal model by behavioral (acoustic startle response, ASR) and electrophysiological approaches (auditory brainstem responses, ABR). We found that-in contrast to vehicle-three weeks of daily oral EGb 761® treatment (100 mg/kg body weight) led to a restoration of hearing thresholds back to pre-trauma conditions. In addition, all 9 animals that displayed behavioral signs of subjective tinnitus showed improvement, with 7 of them showing complete relief of tinnitus symptoms during the time of EGb 761® treatment. After discontinuation of EGb 761® treatment, tinnitus related behavior reappeared in all but one of these animals while auditory thresholds remained restored. A detailed analysis of ABR waves revealed that EGb 761® treatment did not simply change auditory processing back to pre-trauma conditions, but led to subtle changes of ABR wave amplitude and latency at different levels of the auditory pathway, with an overall increase of response to low stimulus intensities and a decrease at high intensities. The functional relevance of these changes may be the observed improvement of hearing thresholds while at the same time suppression of responses to high stimulus intensities may point to a global inhibitory mechanism that counteracts tinnitus.


Understanding community pharmacy intervention practice: lessons from intervention researchers.
Community pharmacy (CP) is a setting with health promotion and public health potential which could include strategies with a nutrition promotion focus. Research embedded in this setting has explored and produced evidence to inform practice change to develop this potential. The experience of undertaking research in this setting may provide insight into the challenges and key features of intervention research practice. Exploring experienced-based knowledge presents as a productive area of research, extending what can be known beyond the bounds of what is measurable. This study aimed to understand the experience of intervention research in CP with a focus on nutrition and to develop guidance for future research practice (intervention design and implementation) in CP based on interventionists' reflections and practice wisdom. Semi-structured interviews were conducted with 9 researchers with experience in undertaking intervention research in CP with a nutrition component. Content analysis, constant comparison and interpretive description were used in the analysis and interpretation of interview data. Five key lessons were identified - 1) utilize existing capacity; 2) navigate and utilize social power and interests; 3) personalize engagement and recruitment; 4) consider the logistics and 5) intervention type considerations. Key challenges for translating research into practice and sustaining change included financial sustainability, physical constraints, logistics, collaboration, and practice change enablers. Personal reflections on research practice identified qualities, such as determination and skills in networking, as key for researching in CP. CP-embedded research is challenging given the complexity of the practice environment. The social context of CP appears central to intervention research and a nuanced understanding of the social context needs to be the basis for intervention design to inform successful implementation. Experience-based and insider knowledge is useful and needed for nuanced design and development of intervention research in CP.


[Cytotoxic effect of conjugates of L-lysine-alpha-oxidase with monoclonal antibodies on human tumor cells in vitro].
The conjugates of L-lysine alpha-oxidase and monoclonal antibodies ICO-80 towards CD-5 receptor were produced using glutaraldehyde. The cytotoxic effect of conjugates on Yurkat cells line appeared to be lower in comparison with the native enzyme. Negligible decrease of conjugate biological activity may be explained by the large molecular weight of conjugate, which is several times higher than the molecular weight of the native enzyme. Such conjugates can not penetrate into the cells. So they catalyze the hydrogen peroxide formation, the main damaging agent, probably only outside the cells. We suppose also that the free native enzyme penetrates into the cell and activates there the oxidative deamination of L-lysine and correspondingly the hydrogen peroxide formation. This may be the proper explanation for the higher cytotoxic effect of L-lysine alpha-oxidase on Yurkat cell line.


Combined impact of healthy lifestyle factors on colorectal cancer: a large European cohort study.
Excess body weight, physical activity, smoking, alcohol consumption and certain dietary factors are individually related to colorectal cancer (CRC) risk; however, little is known about their joint effects. The aim of this study was to develop a healthy lifestyle index (HLI) composed of five potentially modifiable lifestyle factors--healthy weight, physical activity, non-smoking, limited alcohol consumption and a healthy diet, and to explore the association of this index with CRC incidence using data collected within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. In the EPIC cohort, a total of 347,237 men and women, 25- to 70-years old, provided dietary and lifestyle information at study baseline (1992 to 2000). Over a median follow-up time of 12 years, 3,759 incident CRC cases were identified. The association between a HLI and CRC risk was evaluated using Cox proportional hazards regression models and population attributable risks (PARs) have been calculated. After accounting for study centre, age, sex and education, compared with 0 or 1 healthy lifestyle factors, the hazard ratio (HR) for CRC was 0.87 (95% confidence interval (CI): 0.44 to 0.77) for two factors, 0.79 (95% CI: 0.70 to 0.89) for three factors, 0.66 (95% CI: 0.58 to 0.75) for four factors and 0.63 (95% CI: 0.54 to 0.74) for five factors; P-trend<0.0001. The associations were present for both colon and rectal cancers, HRs, 0.61 (95% CI: 0.50 to 0.74; P for trend<0.0001) for colon cancer and 0.68 (95% CI: 0.53 to 0.88; P-trend<0.0001) for rectal cancer, respectively (P-difference by cancer sub-site=0.10). Overall, 16% of the new CRC cases (22% in men and 11% in women) were attributable to not adhering to a combination of all five healthy lifestyle behaviours included in the index. Combined lifestyle factors are associated with a lower incidence of CRC in European populations characterized by western lifestyles. Prevention strategies considering complex targeting of multiple lifestyle factors may provide practical means for improved CRC prevention.