A sexual shift induced by silencing of a single insulin-like gene in crayfish: ovarian upregulation and testicular degeneration.
In sequential hermaphrodites, intersexuality occurs naturally, usually as a transition state during sexual re-differentiation processes. In crustaceans, male sexual differentiation is controlled by the male-specific androgenic gland (AG). An AG-specific insulin-like gene, previously identified in the red-claw crayfish Cherax quadricarinatus (designated Cq-IAG), was found in this study to be the prominent transcript in an AG cDNA subtractive library. In C. quadricarinatus, sexual plasticity is exhibited by intersex individuals in the form of an active male reproductive system and male secondary sex characters, along with a constantly arrested ovary. This intersexuality was exploited to follow changes caused by single gene silencing, accomplished via dsRNA injection. Cq-IAG silencing induced dramatic sex-related alterations, including male feature feminization, a reduction in sperm production, extensive testicular degeneration, expression of the vitellogenin gene, and accumulation of yolk proteins in the developing oocytes. Upon silencing of the gene, AG cells hypertrophied, possibly to compensate for low hormone levels, as reflected in the poor production of the insulin-like hormone (and revealed by immunohistochemistry). These results demonstrate both the functionality of Cq-IAG as an androgenic hormone-encoding gene and the dependence of male gonad viability on the Cq-IAG product. This study is the first to provide evidence that silencing an insulin-like gene in intersex C. quadricarinatus feminizes male-related phenotypes. These findings, moreover, contribute to the understanding of the regulation of sexual shifts, whether naturally occurring in sequential hermaphrodites or abnormally induced by endocrine disruptors found in the environment, and offer insight into an unusual gender-related link to the evolution of insulins.


Protection of the human research participant: A structured review.
The history of health research, and concerns about the protection of human participants, dates back as far as the 1800s. The regulation, legislation and ethics-review requirements regarding the protection of the human research participants cause lively debates among researchers and scientists. The objective of this article is to share the findings of a structured review that was aimed at investigating the impact of and challenges with regard to the legislation, governance and research regulations aimed at protecting human research participants. The thematic analysis of the findings revealed dissatisfaction with diverse operational practices; different legislation and regulation practices; and institutional governance. Simplified and universally agreed-upon regulations and operational practices are needed, as is a common understanding of all concepts relating to ethical research conduct.


Effects of Triple Therapy in Patients With Non-Valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention Regarding Thromboembolic Risk Stratification.
The effects of dual antiplatelet therapy (DAPT) and triple therapy (TT: DAPT plus oral anticoagulation) in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) regarding to CHA2DS2-VASc score remain undefined.We compare the effect of TT vs. DAPT in this setting regarding the CHA2DS2-VASc score. In a prospective multicenter registry, 585 patients (75.2% male, 73.2 ± 8.2 years) with AF undergoing PCI were followed up during 1 year. Of them, 157 (26.8%) had a CHA2DS2-VASc=1, and 428 (73.2%) had a CHA2DS2-VASc ≥2. TT was prescribed in 51.6% with CHA2DS2-VASc=1 and in 55.5% with CHA2DS2-VASc ≥ 2. Patients with CHA2DS2-VASc=1 receiving TT had a similar thromboembolism rate to those on DAPT (1.2% vs. 1.3%, P=0.73), but more total (19.5% vs. 6.9%, P=0.01) and a tendency to more major (4.9% vs. 0%, P=0.06) bleeding. However, patients with CHA2DS2-VASc ≥ 2 receiving TT had a lower thromboembolism rate (1.7% vs. 5.3%, P=0.03) and a trend towards more bleeds (21.8% vs. 15.6%, P=0.06), with an excess of major bleeding (8.4% vs. 3.1%, P=0.01). Rates of major adverse cardiac events (MACE) in both CHA2DS2-VASc subgroups were similar, irrespective of treatment. In a Cox multivariate analysis, TT was associated to major bleeding, but not with MACE. In patients with AF and CHA2DS2-VASc=1 undergoing PCI, the use of TT involves a high risk of bleeding without a significant benefit in preventing thromboembolism.


A Total Synthesis of (±)-Leuconodines D and E.
A new synthetic route for a short synthesis of (±)-leuconodines D and E was developed. The rapid construction of the diaza[188.8.131.52]fenestrane core was achieved through a sequence involving a Pd-catalyzed aerobic oxidative Heck cross-coupling reaction for the construction of indole δ-lactam containing a full-carbon quaternary center, an epoxidative cyclization for the assembly of pyrroloindole, and a ring-closing metathesis for the construction of the piperidine ring. As a result, the total synthesis of (±)-leuconodine E (2) was achieved for the first time within a 10-step linear sequence, and a more concise total synthesis of (±)-leuconodine D (1) was accomplished within a 12-step linear sequence from the commercially available tryptophol.


Minor head injury in children: current management practices of pediatricians, emergency physicians, and family physicians.
To describe variation in the clinical management of minor head trauma in children among primary care and emergency physicians. A survey of pediatricians, family physicians, and emergency physicians drawn from a random sample of members of the American Academy of Pediatrics, the American Academy of Family Physicians, and the appropriate American Medical Association specialty listings, respectively. Physicians were given clinical vignettes describing children presenting with normal physical examination results after minor head trauma. Different clinical scenarios (brief loss of consciousness or seizures) were also presented. Information was gathered on initial and subsequent management steps most commonly used by the physician. Surveys were returned by 765 (51%) of 1500 physicians. Of these, 303 (40%) were pediatricians, 269 (35%) family practitioners, and 193 (25%) emergency physicians. For minor head trauma without complications, observation at home was the most common initial physician management choice (n = 547, 72%). Observation in office or hospital was chosen by 81 physicians (11%). Head computed tomographic (CT) scan was chosen by 7 physicians (1%) and skull x-ray by 24 physicians (3%) as the first management option. Most physicians (n = 445, 80%) who initially chose observation at home would obtain a CT scan if the patient showed clinical deterioration. In the original scenario, if the patient had also sustained a loss of consciousness, 383 physicians (58%) altered management. Of these, 120 (18%) chose CT, 13 (2%) chose skull x-ray, 1 (1%) chose magnetic resonance imaging, 141 (21%) chose inpatient observation, and 125 (19%) chose a combination of CT scanning and observation. With seizures, 595 (90%) altered management, with 176 physicians (27%) choosing CT scan, 5 (1%) skull x-ray, 60 (9%) inpatient observation, and 299 (45%) a combination of radiological evaluation and observation. Most physicians surveyed chose clinic or home observation for initial management of minor pediatric head trauma. Clinical management was more varied when patients had sustained either loss of consciousness or seizures. Further study of the appropriate management of minor head trauma in children is needed to guide physicians in their care.


The Relationship between the Worker's Safety Attitude and the Registered Accidents.
Millions of workers are the victims of different kinds of accidents every year throughout the world. The purpose of this study was to investigate the relationships between safety attitude and occurrence of the occupational accidents. This investigation was a cross-sectional study performed in a gas refinery in south of Iran in 2008. Sample size of this study was 176 people. To determine the value of worker's safety attitude a validated 5 degrees questionnaire was used. Different statistic analyses including Chi-square, t-test and Logistic Regression were used by Spss11.5 to analyze the data. The Cronbachs alpha coefficient was found to be 0.97 in this investigation. In the study population, the average age was 31.67(+/- 5.89), the average work experience was 5.65 (+/- 4.29) and the average of the safety attitude was 188.52(+/- 14.84) and only 28.7% were injured through accidents. The relationship between safety attitude of the workers and the accidents occurred was significant (P< 0.0001). The relationship between safety attitude of the workers and the accidents occurred was significant, although the relation was not significant for graduate workers. No significant relationship was found between safety attitude and accident in accordance with worker's age and work experience.


A randomized trial of methotrexate in newly diagnosed patients with type 1 diabetes mellitus.
The aim of this study was to determine whether low-dose, oral methotrexate therapy would prolong the remission phase at the onset of Type 1 diabetes. Ten newly diagnosed, nonacidotic, ICA-positive, Type 1 diabetics were randomly assigned to receive either methotrexate (5 mg/m(2)/week) or no immunosuppressive treatment. The study was not blinded and no placebo was given. Endogenous insulin production was assessed every 3 months by fasting and Sustacal-stimulated C-peptide levels. Methotrexate therapy was not beneficial in prolonging islet survival as assessed by fasting and stimulated C-peptide levels. Insulin requirements were generally lower in the control group, and islet failure, determined by an insulin requirement of >0.7 u/kg/day, occurred earlier for those receiving MTX (P < 0.02). Side effects of methotrexate treatment were minimal. There was no benefit from methotrexate therapy, and methotrexate therapy was associated with an earlier increase in insulin requirements.


Diagnostic utility of BRAFV600E mutation testing in thyroid nodules in elderly patients.
Thyroid cancer is a rare disease characterized by the subtle appearance of a nodule. Fine-needle cytology (FNC) is the first diagnostic procedure used to distinguish a benign from a malignant nodule. However, FNC yields inconclusive results in about 20% of cases. BRAF(V600E) mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC); its high prevalence makes this oncogene a useful marker to refine inconclusive FNC results. However, the prevalence of the BRAF(V600E) mutation depends on detection methods, geographical factors, and age. The aim of this study is to determine the prevalence of BRAF(V600E) mutation and its utility as a diagnostic tool in elderly subjects. FNC from 92 PTC patients were subjected to the analysis of BRAF mutation by pyrosequencing and direct sequencing; age-dependent prevalence was also determined. BRAF mutation analysis was successful in all FNC specimens. BRAF(V600E) was documented in 62 (67.4%) and in 58 (63.0%) PTCs by pyrosequencing and direct sequencing, respectively. BRAF(V600E) prevalence did not correlate with patient's age at diagnosis. Twenty out of 32 PTCs (62.5%) were correctly diagnosed by BRAF mutation analysis in inconclusive FNC results. Detection of BRAF(V600E) in cytology specimens by pyrosequencing is a useful diagnostic adjunctive tool in the evaluation of thyroid nodules also in elderly subjects.


Early Transcriptomic Response to Burn Injury: Severe Burns Are Associated With Immune Pathway Shutdown.
Burn injury induces a systemic hyperinflammatory response with detrimental side effects. Studies have described the biochemical changes induced by severe burns, but the transcriptome response is not well characterized. The goal of this work is to characterize the blood transcriptome after burn injury. Burn patients presenting to a regional center between 2012 and 2017 were prospectively enrolled. Blood was collected on admission and at predetermined time points (hours 2, 4, 8, 12, and 24). RNA was isolated and transcript levels were measured with a gene expression microarray. To identify differentially regulated genes (false-discovery rate ≤0.1) by burn injury severity, patients were grouped by TBSA above or below 20% and statistically enriched pathways were identified. Sixty-eight patients were analyzed, most patients were male with a median age of 41 (interquartile range, 30.5-58.5) years, and TBSA of 20% (11%-34%). Thirty-five patients had % TBSA injury ≥20%, and this group experienced greater mortality (26% vs 3%, P = .008). Comparative analysis of genes from patients with </≥20% TBSA revealed 1505, 613, 380, 63, 1357, and 954 differentially expressed genes at hours 0, 2, 4, 8, 12, and 24, respectively. Pathway analysis revealed an initial up-regulation in several immune/inflammatory pathways within the ≥20% TBSA groups followed by shutdown. Severe burn injury is associated with an early proinflammatory immune response followed by shutdown of these pathways. Examination of the immunoinflammatory response to burn injury through differential gene regulation and associated immune pathways by injury severity may identify mechanistic targets for future intervention.


Identification of gene targets against dormant phase Mycobacterium tuberculosis infections.
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects approximately 2 billion people worldwide and is the leading cause of mortality due to infectious disease. Current TB therapy involves a regimen of four antibiotics taken over a six month period. Patient compliance, cost of drugs and increasing incidence of drug resistant M. tuberculosis strains have added urgency to the development of novel TB therapies. Eradication of TB is affected by the ability of the bacterium to survive up to decades in a dormant state primarily in hypoxic granulomas in the lung and to cause recurrent infections. The availability of M. tuberculosis genome-wide DNA microarrays has lead to the publication of several gene expression studies under simulated dormancy conditions. However, no single model best replicates the conditions of human pathogenicity. In order to identify novel TB drug targets, we performed a meta-analysis of multiple published datasets from gene expression DNA microarray experiments that modeled infection leading to and including the dormant state, along with data from genome-wide insertional mutagenesis that examined gene essentiality. Based on the analysis of these data sets following normalization, several genome wide trends were identified and used to guide the selection of targets for therapeutic development. The trends included the significant up-regulation of genes controlled by devR, down-regulation of protein and ATP synthesis, and the adaptation of two-carbon metabolism to the hypoxic and nutrient limited environment of the granuloma. Promising targets for drug discovery were several regulatory elements (devR/devS, relA, mprAB), enzymes involved in redox balance and respiration, sulfur transport and fixation, pantothenate, isoprene, and NAD biosynthesis. The advantages and liabilities of each target are discussed in the context of enzymology, bacterial pathways, target tractability, and drug development. Based on our bioinformatics analysis and additional discussion of in-depth biological rationale, several novel anti-TB targets have been proposed as potential opportunities to improve present therapeutic treatments for this disease.


Gestational thyrotoxicosis manifesting as wernicke encephalopathy: a case report.
The thyroid gland is physiologically stimulated in normal early pregnancy. This stimulated thyroid function is occasionally termed "gestational transient thyrotoxicosis". The cause of this thyrotoxicosis has been clarified to closely it associate with human chorionic gonadotropin (hCG). We encountered a pregnant patient with hyperemesis and thyrotoxicosis, who manifested symptoms of Wernicke encephalopathy. Although her serum hCG concentration transiently increased in accordance with the thyrotoxicosis, it was within normal limits for the gestational week. Both the thyrotoxicosis and a catabolic state due to the hyperemesis were thought to have induced a vitamin B1 deficiency, causing the Wernicke encephalopathy. This case suggests that pregnant patients with hyperemesis should undergo careful endocrinological and neurological evaluations.


Elevated serum advanced glycation endproducts in obese indicate risk for the metabolic syndrome: a link between healthy and unhealthy obesity?
Although obesity can predispose to the metabolic syndrome (MS), diabetes, and cardiovascular disease, not all obese subjects develop MS, hence the need for new indicators of risk for this syndrome. Advanced glycation end products (AGEs) correlate with factors involved in the MS, including inflammation and insulin resistance (IR). Because AGEs can be derived from food and are modifiable, it is important to determine whether they are a risk factor for MS. The objective of this study was to assess the association of endogenous and exogenous AGEs with MS criteria. The following data were collected in a cross-sectional study of subjects with and without the MS: serum AGEs (sAGEs) and mononuclear cell AGEs, metabolites, pro- and antiinflammatory markers, body fat mass measures, including abdominal magnetic resonance imaging, and caloric and dietary AGE (dAGE) consumption. The study was conducted in the general community. Participants included 130 MS and 139 non-MS subjects of both sexes, older than 50 years. sAGEs ((ϵ)N-carboxymethyllysine, methylglyoxal) were markedly elevated in obese persons with more than one other MS criteria but not in obese without MS criteria. sAGEs directly correlated with markers of IR (HOMA) and inflammation (leptin, TNFα, RAGE) and inversely with innate defenses (SIRT1, AGE receptor 1 [AGER1], glyoxalase-I, adiponectin). sAGEs correlated with dAGEs but not with calories, nutrient consumption, or fat mass measures. Consumption of dAGE, but not of calories, was markedly higher in MS than in non-MS. High sAGEs, a modifiable risk factor for IR, may indicate risk for the MS, type 2 diabetes, and cardiovascular disease. High dietary AGE consumption and serum AGE levels may link healthy obesity to at-risk obesity.


Identification and quantitation of capsular antigen in capsulated and noncapsulated strains of Haemophilus influenzae type b by crossed-immunoelectrophoresis.
Sonicated preparations of capsulated Haemophilus influenzae type b, two of its spontaneous mutants, one containing patches of capsules (class I variant) and the other noncapsulated (class II variant), and a noncapsulated strain of H. influenzae type d were analyzed by crossed-immunoelectrophoresis using unadsorbed antiserum to capsulated H. influenzae type b. Twenty common antigens were present in all four cultures. Two type b-specific antigens were also identified in the three H. influenzae type b cultures when antiserum adsorbed with H. influenzae type d sonicates (AdR) was used. One of these, the type b capsular antigen, cross-reacted with an antigen of Bacillus pumilus. Further adsorption of AdR with the B. pumilus sonicate reduced, but did not eliminate, the antibodies to the type b capsular antigen, although all antibodies to B. pumilus were removed. Sonication sheared the type b capsular antigen, resulting in an increase in its electrophoretic mobility in agarose gel. The capsular antigen from all three H. influenzae type b cultures had the same electrophoretic characteristics. Reproducible quantitation of sheared and unsheared capsular antigen was demonstrated by rocket immunoelectrophoresis. As little as 2.5 ng of polyribophosphate pentose was identified and measured. Capsulated H. influenzae type b contained 78 ng of polyribophosphate pentose per mug of cell protein; class I contained 20 ng and class II contained 4 ng. The small amount of type b capsular antigen present in the class II variant may account for its lack of detection in this organism before now.


Prospects for direct social perception: a multi-theoretical integration to further the science of social cognition.
In this paper we suggest that differing approaches to the science of social cognition mirror the arguments between radical embodied and traditional approaches to cognition. We contrast the use in social cognition of theoretical inference and mental simulation mechanisms with approaches emphasizing a direct perception of others' mental states. We build from a recent integrative framework unifying these divergent perspectives through the use of dual-process theory and supporting social neuroscience research. Our elaboration considers two complementary notions of direct perception: one primarily stemming from ecological psychology and the other from enactive cognition theory. We use this as the foundation from which to offer an account of the informational basis for social information and assert a set of research propositions to further the science of social cognition. In doing so, we point out how perception of the minds of others can be supported in some cases by lawful information, supporting direct perception of social affordances and perhaps, mental states, and in other cases by cues that support indirect perceptual inference. Our goal is to extend accounts of social cognition by integrating advances across disciplines to provide a multi-level and multi-theoretic description that can advance this field and offer a means through which to reconcile radical embodied and traditional approaches to cognitive neuroscience.


Dynamic reading in a digital age: new insights on cognition.
People increasingly read text displayed on digital devices, including computers, handheld e-readers, and smartphones. Given this, there is rapidly growing interest in understanding how the cognitive processes that support the reading of static text (e.g., books, magazines, or newspapers) might be adapted to reading digital texts. Evidence from recent experiments suggests a complex interplay of visual and cognitive influences on how people engage with digital reading. Although readers can strategically adjust their reading behaviors in response to their immediate reading context, the efficacy of these strategies depends on cognitive, metacognitive, and motivational factors. A better understanding of the factors that influence reading offers the promise of leveraging digital technologies to enhance the reading experience.


A Review on SIRtuins in Diabetes.
Type-2 Diabetes is a long lasting disease characterized by high glucose concentration in the blood due to insulin resistance. One of the recent treatment strategies is using activators against SIRT-1, which has been in clinical trials. Hence, it is necessary to know the effects of the SIRT-1 modulators against various metabolic pathways. Many cellular processes, including insulin secretion, cell cycle, and apoptosis are imperatively regulated by a family of mediators called SIRTuins. First known mammalian sirtuin, SIRT1 is a positive regulator of insulin secretion, which triggers glucose uptake and utilization. For the past decade, a major outstanding question is whether SIRT1 activation is a safe therapy for human diseases such as diabetes? This review summarizes and discusses the advances of the past decade and the challenges that will brazen out perplexity of this field. We also cover the physiological regulation of sirtuin (SIRT1) activity and how these modes of regulation may be exploited to manipulate SIRT1 activity in cells. Designing of drugs using advanced computational methods that specifically target SIRT1, and also, involvement of advanced biological methods for further understanding of sirtuin1 biology to afford new optimized treatments for diabetes and several age related human diseases. Hence, this review is a serial perspective of all the above topics.


Antibiotic Application and Resistance in Swine Production in China: Current Situation and Future Perspectives.
To meet increasing demand for animal protein, swine have been raised in large Chinese farms widely, using antibiotics as growth promoter. However, improper use of antibiotics has caused serious environmental and health risks, in particular Antimicrobial resistance (AMR). This paper reviews the consumption of antibiotics in swine production as well as AMR and the development of novel antibiotics or alternatives in China. The estimated application of antibiotics in animal production in China accounted for about 84240 tons in 2013. Overuse and abuse of antibiotics pose a great health risk to people through food-borne antibiotic residues and selection for antibiotic resistance. China unveiled a national plan to tackle antibiotic resistance in August 2016, but more support is needed for the development of new antibiotics or alternatives like plant extracts. Antibiotic resistance has been a major global challenge, so international collaboration between China and Europe is needed.


Discovery of novel secretome CAZymes from Penicillium sclerotigenum by bioinformatics and explorative proteomics analyses during sweet potato pectin digestion.
Novel selective enzymatic refining of sweet potato processing residues requires judicious enzyme selection and enzyme discovery. We prepared a pectinaceous cell wall polysaccharide fraction from sweet potato using an enzymatic a treatment to preserve the natural linkages and substitutions. Polysaccharide composition and linkage analysis data confirmed the pectinaceous polysaccharide fraction to be a rhamnogalacturonan I-rich fraction with a high content of arabinogalactan Type I. We hypothesized that the post-harvest tuber pathogenic fungus Penicillium sclerotigenum would harbor novel enzymes targeting selective sweet potato pectin modification. As part of the study, we also report the first genome sequence of P. sclerotigenum. We incubated the sweet potato pectinaceous fraction with P. sclerotigenum. Using proteomics accompanied by CUPP-bioinformatics analysis, we observed induced expression of 23 pectin-associated degradative enzymes. We also identified six abundantly secreted, induced proteins that do not correspond to known CAZymes, but which we suggest as novel enzymes involved in pectin degradation. For validation, the predicted CUPP grouping of putative CAZymes and the exo-proteome data obtained for P. sclerotigenum during growth on sweet potato pectin were compared with proteomics and transcriptomics data reported previously for pectin-associated CAZymes from Aspergillus niger strain NRRL3. The data infer that P. sclerotigenum has the capacity to express several novel enzymes that may provide novel opportunities for sweet potato pectin modification and valorization of sweet potato starch processing residues. In addition, the methodological approach employed represents an integrative systematic strategy for enzyme discovery.


C1q/Tumor Necrosis Factor-Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways.
Cell therapy remains the most promising approach against ischemic heart injury. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for cardiac repair after myocardial infarction. CTRP9 (C1q/tumor necrosis factor-related protein-9) is a novel prosurvival cardiokine with significantly downregulated expression after myocardial infarction. Here we tested a hypothesis that CTRP9 might be a cardiokine required for a healthy microenvironment promoting implanted stem cell survival and cardioprotection. Mice were subjected to myocardial infarction and treated with adipose-derived mesenchymal stem cells (ADSCs, intramyocardial transplantation), CTRP9, or their combination. Survival, cardiac remodeling and function, cardiomyocytes apoptosis, and ADSCs engraftment were evaluated. Whether CTRP9 directly regulates ADSCs function was determined in vitro. Discovery-drive approaches followed by cause-effect analysis were used to uncover the molecular mechanisms of CTRP9. Administration of ADSCs alone failed to exert significant cardioprotection. However, administration of ADSCs in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9 (P<0.05 or P<0.01 versus CTRP9 alone), suggesting a synergistic effect. Administration of CTRP9 at a dose recovering physiological CTRP9 levels significantly prolonged ADSCs retention/survival after implantation. Conversely, the number of engrafted ADSCs was significantly reduced in the CTRP9 knockout heart. In vitro study demonstrated that CTRP9 promoted ADSCs proliferation and migration, and it protected ADSCs against hydrogen peroxide-induced cellular death. CTRP9 enhances ADSCs proliferation/migration by extracellular regulated protein kinases (ERK)1/2-matrix metallopeptidase 9 signaling and promotes antiapoptotic/cell survival via ERK-nuclear factor erythroid-derived 2-like 2/antioxidative protein expression. N-cadherin was identified as a novel CTRP9 receptor mediating ADSCs signaling. Blockade of either N-cadherin or ERK1/2 completely abolished the previously noted CTRP9 effects. Although CTRP9 failed to promote ADSCs cardiogenic differentiation, CTRP9 promotes superoxide dismutase 3 expression and secretion from ADSCs, protecting cardiomyocytes against oxidative stress-induced cell death. We provide the first evidence that CTRP9 promotes ADSCs proliferation/survival, stimulates ADSCs migration, and attenuates cardiomyocyte cell death by previously unrecognized signaling mechanisms. These include binding with N-cadherin, activation of ERK-matrix metallopeptidase 9 and ERK-nuclear factor erythroid-derived 2-like 2 signaling, and upregulation/secretion of antioxidative proteins. These results suggest that CTRP9 is a cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue, thereby enhancing stem cell therapeutic efficacy.


Osteomyelitis in patients who have sickle-cell disease. Diagnosis and management.
Fifteen patients who had sickle-cell disease and osteomyelitis (affecting thirty bones) were treated with operative decompression and parenteral administration of antibiotics between 1973 and 1988. Organisms were isolated on culture of specimens of bone from all fifteen patients. Parenteral antibiotic therapy was continued for a minimum of six weeks after operative decompression. The osteomyelitis resolved in twenty-nine (97 per cent) of the thirty affected bones after follow-up ranging from two to fifteen years. With their compromised immune status and poor circulation of blood in bone, patients who have sickle-cell disease and osteomyelitis are prone to have complications. In our series, the complications included an adhesive pericapsulitis of the shoulder in two patients, avascular necrosis of the humeral head in one, and a pathological fracture of the femur in one. In four of the fifteen patients, chronic osteomyelitis persisted, but in three of the four, the infections of bone healed six to fourteen months after the initial operative decompression. Staphylococcus aureus was isolated on culture of specimens of bone from eight to the fifteen patients; Salmonella, from six; and Proteus mirabilis, from one. Although Salmonella has been cited as the principal causative organism of osteomyelitis in patients who have sickle-cell disease, in our experience Staphylococcus aureus was the most common infecting organism. Therefore, Salmonella may not be the most common cause of osteomyelitis associated with sickle-cell disease in all countries or in all areas of a particular country.


[Adder bites--clinical picture, diagnosis and management].
Adder bites are occasionally occurring envenoming emergencies. More than ten percent of the clinical courses are severe and even life-threatening. Children and elderly patients are over-represented in this group. Common symptoms comprise local edema, abdominal pain and vomiting, arterial hypotension and neurological disorders. First steps in the management are immobilization of the affected extremity, reassurance of the patient and application of analgetics. Anaphylaxis may occur and requires status adapted treatment. Persistent circulatory shock, protracted gastrointestinal or severe neurological symptoms, as well as rapidly progressing edema and airway obstruction are indications for antivenom treatment. Administration of antivenom results in prompt clinical improvement and in a significantly shorter hospital stay.


Arrangement of photosystem II and ATP synthase in chloroplast membranes of spinach and pea.
We used cryoelectron tomography to reveal the arrangements of photosystem II (PSII) and ATP synthase in vitreous sections of intact chloroplasts and plunge-frozen suspensions of isolated thylakoid membranes. We found that stroma and grana thylakoids are connected at the grana margins by staggered lamellar membrane protrusions. The stacking repeat of grana membranes in frozen-hydrated chloroplasts is 15.7 nm, with a 4.5-nm lumenal space and a 3.2-nm distance between the flat stromal surfaces. The chloroplast ATP synthase is confined to minimally curved regions at the grana end membranes and stroma lamellae, where it covers 20% of the surface area. In total, 85% of the ATP synthases are monomers and the remainder form random assemblies of two or more copies. Supercomplexes of PSII and light-harvesting complex II (LHCII) occasionally form ordered arrays in appressed grana thylakoids, whereas this order is lost in destacked membranes. In the ordered arrays, each membrane on either side of the stromal gap contains a two-dimensional crystal of supercomplexes, with the two lattices arranged such that PSII cores, LHCII trimers, and minor LHCs each face a complex of the same kind in the opposite membrane. Grana formation is likely to result from electrostatic interactions between these complexes across the stromal gap.


Sympathetic hyperplasia and neuroblastomas in transgenic mice expressing polyoma middle T antigen.
Transgenic mice carrying a cDNA to the polyoma virus middle T (mT) antigen linked to the thymidine kinase promoter were generated to study the consequences of deregulated expression of mT-associated tyrosine kinase activity in a wide variety of tissues. Four independent transgenic founder animals were obtained, from one of which was established a transgenic line. This mouse and all its offspring developed multiple neuroblastomas between 2 and 3 months of age. Expression of the transgene (assayed by tyrosine kinase assay and in situ hybridization) was restricted to the neurons of the central and peripheral nervous tissue, probably because of a positional effect of the transgene integration. Characteristic preneoplastic lesions in the sympathetic ganglia and in the adrenal medulla were identified from which the neuroblastomas originated. The tumors arising in these mice show striking analogies to human neuroblastomas, including the sites of development of the tumors, their histological and ultrastructural appearance, and the expression of diagnostic markers, such as synaptophysin, and high expression of the N-myc oncogene. This animal model thus provides a unique tool for studying growth control in sympathetic neuroblasts and the pathogenesis of neuroblastoma.


Venus upper atmosphere neutral composition: preliminary results from the pioneer venus orbiter.
Measurements in situ of the neutral composition and temperature of the thermosphere of Venus are being made with a quadrupole mass spectrometer on the Pioneer Venus orbiter. The presence of many gases, incluiding the major constituents CO(2), CO, N(2), O, and He has been confirmed. Carbon dioxide is the most abundant constituent at altitudes below about 155 kilometers in the terminator region. Above this altitude atomic oxygen is the major constituent, with O/CO(2) ratios in the upper atmosphere being greater than was commonly expected. Isotope ratios of O and C are close to terrestrial values. The temperature inferred from scale heights above 180 kilometers is about 400 K on the dayside near the evening terminator at a solar zenith angle of about 69 degrees . It decreases to about 230 K when the solar zenith angle is about 90 degrees .


cRGD/TAT Dual-Ligand Reversibly Cross-Linked Micelles Loaded with Docetaxel Penetrate Deeply into Tumor Tissue and Show High Antitumor Efficacy in Vivo.
The application of cell-penetrating peptides like TAT for in vivo targeted delivery is limited because the penetration behavior is not cell-specific. Herein, we designed cRGD and TAT comodified cross-linkable micelles (cRGD/TAT CMs), in which the TAT peptide was shielded by relatively long poly(ethylene glycol) (PEG) chains. Docetaxel (DTX)-loaded cRGD/TAT CMs were very stable with minimal drug leakage under physiological conditions, whereas rapid DTX release took place in a reductive environment. Flow cytometry showed that the cRGD/TAT CMs with molar ratios of 20% cRGD and 10% TAT (cRGD20/TAT10 CMs) were selectively and efficiently taken up by ανβ3-overexpressing U87MG glioma cells, with 8.3-fold and 18.3-fold higher uptake than cRGD20 CMs and PEG CMs, respectively. DTX-loaded cRGD20/TAT10 CMs exhibited a high cytotoxicity in U87MG cells, leading to rapid apoptosis of the tumor cells. Uptake mechanism studies revealed that cRGD20/TAT10 CMs mainly employed the caveolae-mediated endocytotic pathway and efficiently escaped from the lysosomes. Notably, cRGD20/TAT10 CMs had a long circulating time of 6.25 h in vivo, due to cross-linking of the micelles and shielding of the TAT peptide. Moreover, DTX-loaded cRGD20/TAT10 CMs exhibited a significantly higher accumulation and deeper penetration in subcutaneous U87MG glioma tissue compared to cRGD20 CMs and PEG CMs, leading to superior antitumor efficacy in vivo. Therefore, this dual-ligand strategy provides an effective way to realize tumor-specific penetration and inhibition.


A complementary approach to promoting professionalism: identifying, measuring, and addressing unprofessional behaviors.
Vanderbilt University School of Medicine (VUSM) employs several strategies for teaching professionalism. This article, however, reviews VUSM's alternative, complementary approach: identifying, measuring, and addressing unprofessional behaviors. The key to this alternative approach is a supportive infrastructure that includes VUSM leadership's commitment to addressing unprofessional/disruptive behaviors, a model to guide intervention, supportive institutional policies, surveillance tools for capturing patients' and staff members' allegations, review processes, multilevel training, and resources for addressing disruptive behavior.Our model for addressing disruptive behavior focuses on four graduated interventions: informal conversations for single incidents, nonpunitive "awareness" interventions when data reveal patterns, leader-developed action plans if patterns persist, and imposition of disciplinary processes if the plans fail. Every physician needs skills for conducting informal interventions with peers; therefore, these are taught throughout VUSM's curriculum. Physician leaders receive skills training for conducting higher-level interventions. No single strategy fits every situation, so we teach a balance beam approach to understanding and weighing the pros and cons of alternative intervention-related communications. Understanding common excuses, rationalizations, denials, and barriers to change prepares physicians to appropriately, consistently, and professionally address the real issues. Failing to address unprofessional behavior simply promotes more of it. Besides being the right thing to do, addressing unprofessional behavior can yield improved staff satisfaction and retention, enhanced reputation, professionals who model the curriculum as taught, improved patient safety and risk-management experience, and better, more productive work environments.


What factors are important to parents making decisions about neonatal research?
Although parents of neonates with congenital heart disease are often asked permission for their neonates to participate in research studies, little is known about the factors parents consider when making these decisions. To determine the reasons for parents' decisions about participation in research studies. Qualitative analysis of the unsolicited comments of 34 parents regarding reasons for agreeing or declining to participate in research studies. Parents' comments were offered spontaneously during interviews about clinical care decisions for neonates with congenital heart disease. Parents cited five types of reason for or against permitting their newborn to participate in research studies: societal benefit (n = 18), individual benefit for their infant (n = 16), risk of study participation (n = 10), perception that participation posed no harm (n = 9), and anti-experimentation views (n = 4). Addressing parental decision making in the light of these reasons could enhance the parental permission process for parents of critically ill neonates.


Maternal Caffeine Consumption during Pregnancy and Behavioral Disorders in 11-Year-Old Offspring: A Danish National Birth Cohort Study.
To examine the association between maternal caffeine consumption from coffee and tea during pregnancy and offspring behavioral disorders. We studied 47 491 children enrolled in the Danish National Birth Cohort between 1996 and 2002. Data on maternal coffee and tea consumption was collected at 15 and 30 weeks of gestation. When the child was 11 years old, the Strength and Difficulties Questionnaire was filled in by children, parents, and teachers. We estimated risk ratios (RRs) for offspring behavioral disorders. At 15 weeks of gestation 3% and 4% of the pregnant women consumed ≥8 cups/d of coffee or tea, respectively. Maternal coffee consumption ≥8 cups/d at 15 weeks of gestation was associated with increased risk of hyperactivity-inattention disorder (RR 1.47; 95% CI 1.18-1.83), conduct-oppositional disorders (RR 1.22; 95% CI 1.01-1.48), and any psychiatric disorder (RR 1.23; 95% CI 1.08-1.40). Maternal tea consumption ≥8 cups/d at 15 weeks of gestation was associated with increased risk of anxiety-depressive disorders (RR 1.28; 95% CI 1.09-1.52) and any psychiatric disorder (RR 1.24; 95% CI 1.11-1.40). An increased risk of hyperactivity-inattention disorder was observed with increasing daily caffeine consumption at 15 weeks of gestation. High maternal caffeine consumption from coffee and tea at 15 weeks of gestation was associated with behavioral disorders in 11-year-old offspring. We hypothesize that caffeine exposure may affect the fetal brain and program for behavioral disorders later in life. The fetal brain seems to be more sensitive to caffeine exposure at 15 weeks of pregnancy compared with 30 weeks of gestation.


Transmission electron microscopy of weakly scattering objects described by operator algebra.
An operator algebra description of Fourier optics is used to examine the imaging properties of transmission electron microscopy when applied to the study of weak specimens. Effects due to the curvature of the incident beam, the finite extent of the source, beam tilt, and objective aperture shift are examined. An expression for the contrast transfer function is derived that can account for either beam tilt in conjunction with a centered aperture or a shifted aperture in conjunction with an aligned beam. It shows that high phase contrast over a broad spatial-frequency range can be achieved by laterally shifting the objective aperture rather than defocusing the specimen, as is normally done.


Analgesic activity of piracetam: effect on cytokine production and oxidative stress.
Piracetam is a prototype of nootropic drugs used to improve cognitive impairment. However, recent studies suggest that piracetam can have analgesic and anti-inflammatory effects. Inflammatory pain is the result of a process that depends on neutrophil migration, cytokines and prostanoids release and oxidative stress. We analyze whether piracetam has anti-nociceptive effects and its mechanisms. Per oral pretreatment with piracetam reduced in a dose-dependent manner the overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone, formalin and complete Freund's adjuvant. Piracetam also diminished carrageenin-induced mechanical and thermal hyperalgesia, myeloperoxidase activity, and TNF-α-induced mechanical hyperalgesia. Piracetam presented analgesic effects as post-treatment and local paw treatment. The analgesic mechanisms of piracetam were related to inhibition of carrageenin- and TNF-α-induced production of IL-1β as well as prevention of carrageenin-induced decrease of reduced glutathione, ferric reducing ability and free radical scavenging ability in the paw. These results demonstrate that piracetam presents analgesic activity upon a variety of inflammatory stimuli by a mechanism dependent on inhibition of cytokine production and oxidative stress. Considering its safety and clinical use for cognitive function, it is possible that piracetam represents a novel perspective of analgesic.


Competitive Metabolite Profiling of Natural Products Reveals Subunit Specific Inhibitors of the 20S Proteasome.
We have developed a syringolin-based chemical probe and explored its utility for the profiling of metabolite extracts as potent inhibitors of the 20S proteasome. Activity-guided fractionation by competitive labeling allowed us to isolate and identify glidobactin A and C as well as luminmycin A from a Burkholderiales strain. The natural products exhibited unique subunit specificities for the proteolytic subunits of human and mouse constitutive and immunoproteasome in the lower nanomolar range. In particular, glidobactin C displayed an unprecedented β2/β5 coinhibition profile with single-digit nanomolar potency in combination with sufficiently high cell permeability. These properties render glidobactin C a promising live cell proteasome inhibitor with potent activity against human breast cancer cell lines and comparably low immunotoxicity.


MODIP revisited: re-evaluation and refinement of an automated procedure for modeling of disulfide bonds in proteins.
There have been several attempts to stabilize proteins through the introduction of engineered disulfide bonds. For reasons that are currently unclear, these have met with mixed success. Hence identification of locations where introduction of a disulfide cross-link will lead to protein stabilization is still a challenging task. A computational procedure, MODIP, was introduced more than a decade ago to select sites in protein structures that have the correct geometry for disulfide formation when replaced by Cys. In this study, we re-evaluated the stereochemical criteria used by MODIP for the selection and gradation of sites for modeling disulfides. We introduced steric criteria to check for energetically unfavorable non-bonded contacts with the modeled disulfide, since these can considerably offset the stabilizing effect of the cross-link. The performance of the refined procedure was checked for its ability to correctly predict naturally occurring disulfide bonds in proteins. A set of proteins in which disulfide bonds were introduced experimentally were analyzed with respect to MODIP predictions, stability and other parameters such as accessibility, residue depth, B-factors of the mutated sites, change in volume upon mutation and loop length enclosed by the disulfide. The analysis suggests that in addition to proper stereochemistry, stabilizing disulfides occur in regions of low depth, relatively high mobility, have a loop length greater than 25 and where the disulfide typically occupies a volume less than or equal to that of the original residues.


Differential display cloning of a novel rat cDNA (RNB6) that shows high expression in the neonatal brain revealed a member of Ena/VASP family.
We have used the differential display method to identify genes that control the neural cell development in CNS. Screening of the differential display bands that showed higher expression at neonate than at adult age enabled us to identify a novel rat cDNA (RNB6) coding for a protein of 393 amino acid residues. Database search revealed this gene as a rat homologue of the murine EVL, a member of Ena/VASP protein family that is implicated to be involved in the control of cell motility through actin filament assembly by their GP5 motifs. Although the precise characterization of EVL was not reported, our Northern blot and immunoblot analyses demonstrated that RNB6 expression in the brain gradually increases during embryonic development, reaches maximum at postnatal day 1 and decreases thereafter. Studies of tissue distribution revealed the expression of RNB6 not only in the brain but also in the spleen, thymus and testis. Histochemical analyses showed that RNB6 protein is mainly expressed in neurons and may be expressed in neural fibers. Our analyses suggest that RNB6 is critically involved in the development of CNS probably through the control of neural cell motility and/or including neuronal fiber extension.


Effects of multi-sensory stimulation for people with dementia.
Over recent years multi-sensory stimulation (MSS) has become an increasingly popular approach to care and is used in several centres throughout Europe. This popularity could be explained by the limited alternatives available to staff and a widely held belief that MSS is a friendly and highly humane approach. A randomized controlled trial was therefore essential to evaluate the effectiveness and extent of the benefits of MSS. To assess whether MSS is more effective in changing the behaviour, mood and cognition of older adults with dementia than a control of activity (playing card games, looking at photographs, doing quizzes, etc.). A total of 136 patients from three countries [United Kingdom (UK), the Netherlands and Sweden] were randomized to MSS or activity groups. Patients participated in eight 30-minute sessions over 4 weeks. Ratings of behaviour and mood were taken before, during and after sessions to investigate immediate effects. Pre-, mid-, post-trial and follow-up assessments were taken to investigate any generalization of effects to cognition and behaviour and mood at home/on the ward or at the day hospital. There were limited short-term improvements for both the MSS and activity groups immediately after sessions, and limited short-term improvements between the groups during sessions. There were no significant differences between the groups when assessing change in behaviour, mood or cognition at home/on the ward or at the day hospital. In the UK, however, behaviour at the day hospital for both groups remained stable during the trial but deteriorated once the sessions had stopped, and active/disturbed behaviour at home improved but likewise deteriorated once sessions had stopped. Overall, MSS was found to be no more effective than an activity in changing the behaviour, mood or cognition of patients with dementia in the short- or long-term.


Development of histochemical and functional properties of baboon respiratory muscles.
We assessed morphological, histochemical, and physiological characteristics of respiratory muscles of a non-human primate, Papio cynocephalus, from midgestation through adult life. Samples were taken of diaphragm muscles for histochemical analysis, electron microscopy, and assessment of contractile properties and fatigability. Histochemical analyses were also performed on samples of intercostal muscles. Initially, developing fibers are type IIc but differentiate into types I and IIa fibers by term. We observed no IIb fibers in respiratory muscles of premature baboons. Beginning late in gestation, muscle fibers grew rapidly. After term, IIb fibers were found, and fiber size ranked by increasing mean fiber area became types I, IIa, and IIb. After term, we rarely observed type IIc fibers. In electron micrographs we observed large numbers of interfibrillar mitochondria in all muscle fibers of premature baboons but not in all IIb fibers of adults. Histochemical observations were supported by contractile properties. Muscles of premature baboons had significantly longer contraction and relaxation times than adult muscles. Muscles from premature baboons were more resistant to fatigue than those of adult baboons. We conclude that the fibers of respiratory muscles are high in oxidative capacity and are resistant to fatigue during gestation. Fatigue of the respiratory muscle fibers secondary to low oxidative capacity is not a likely cause of respiratory distress in premature baboons.


[Some properties of Bacillus subtilis strains active against rotting agents on strawberries and fruit].
This work was aimed at the study of biological and genetic peculiarities of the strains Bacillus subtilis 2/10 and 63z which were selected for protection of strawberries from Botrytis fructigena and for apples under storage. The obtained strains were shown to possess a broad spectrum of antagonistic activity against phytopathogenic fungi and bacteria and this activity was manifested at low temperatures specific for the agriculture production storage. These cultures were not toxigenic or pathogenic in respect of plants and hot-blooded. By RAPD-typing and sequencing of the cloned parts of DNA the genetic specificity of the selected cultures was shown compared with other Bacillus subtilis strains which had not been so active. A set of genetic primes was selected to allow one to reliably identify the given strains during production of biopreparations and to control their use in the field conditions.


Evolution of hypervariable region 1 of hepatitis C virus in primary infection.
The hypervariable region 1 (HVR-1) of the putative envelope encoding E2 region of hepatitis C virus (HCV) RNA was analyzed in sequential samples from three patients with acute type C hepatitis infected from different sources to address (i) the dynamics of intrahost HCV variability during the primary infection and (ii) the role of host selective pressure in driving viral genetic evolution. HVR-1 sequences from 20 clones per each point in time were analyzed after amplification, cloning, and purification of plasmid DNA from single colonies of transformed cells. The intrasample evolutionary analysis (nonsynonymous mutations per nonsynonymous site [Ka], synonymous mutations per synonymous site [Ks], Ka/Ks ratio, and genetic distances [gd]) documented low gd in early samples (ranging from 2. 11 to 7.79%) and a further decrease after seroconversion (from 0 to 4.80%), suggesting that primary HCV infection is an oligoclonal event, and found different levels and dynamics of host pressure in the three cases. The intersample analysis (pairwise comparisons of intrapatient sequences; rKa, rKs, rKa/rKs ratio, and gd) confirmed the individual features of HCV genetic evolution in the three subjects and pointed to the relative contribution of either neutral evolution or selective forces in driving viral variability, documenting that adaptation of HCV for persistence in vivo follows different routes, probably representing the molecular counterpart of the viral fitness for individual environments.


Amplification of the erotic enema deviance.
Use of enemas for sexual stimulation has been observed and named klismaphilia. Some klismaphiliacs indulge their taste for enemas in other wise normal sexual settings. Others combine it with fetishes, excretory and otherwise or with masturbation. Still others practice klismaphilia in homosexual or sadomasochistic settings or in group sex.


Magnesium, schizophrenia and manic-depressive disease.
Plasma magnesium (Mg) levels were estimated in 15 schizophrenic, 10 depressed, 6 manic and 6 presenile Alzheimer's disease patients and compared with those in 303 healthy controls. The schizophrenic and depressed patients showed lower levels, but the levels were normal in the other two groups. Mg levels increased on achieving clinical remission in the schizophrenic patients. A hypothesis is proposed according to which the high level of stress found in severely ill psychiatric patients can lead to marginal Mg deficiency in susceptible individuals. This could exacerbate symptoms such as anxiety, fear, hallucinations, weakness and somatic complaints.


Contact line dynamics near the pinning threshold: a capillary rise and fall experiment
We used video microscopy to study the pinning dynamics of air/water contact lines in vertical glass capillaries. Stick-slip behavior and avalanches are observed in tubes with rough interior walls and strong pinning forces. In tubes with smooth interior walls, we find that receding contact lines in falling water columns show no evidence of pinning, but advancing contact lines in rising water columns exhibit algebraic slow down. The measured value of the critical exponent beta varies from run to run, but it is always larger than unity. Furthermore, we find that the rise dynamics varies with the waiting time preceding the experiments. These observations led us to conclude that the wetting film on the surface and other microscopic changes in the slipping region near the contact line affect the macroscopic dynamics. We discuss the differences between the real system and the existing theories that might explain the results. We also present a brief review of other studies of contact line dynamics and a numerical study of a one-dimensional model.


The cortical subventricular zone-specific molecule Svet1 is part of the nuclear RNA coded by the putative netrin receptor gene Unc5d and is expressed in multipolar migrating cells.
Although Svet1 RNA is a widely used marker for the subventricular zone (SVZ) of the embryonic cerebral cortex, its function remains completely unknown. We report finding that Svet1 contains a high proportion of repetitive sequences and maps in the first intron of the putative Netrin receptor gene Unc5d. The direction of transcription of Svet1 is the same as that of Unc5d. The Svet1 RNA was detected in the nucleus but not in the cytoplasm. Both Svet1/Unc5d RNAs and UNC5D protein were localized in the multipolar cells in the SVZ throughout cortical development. These results suggest that Svet1 RNA is part of the sequence of the primary transcript of Unc5d in the nucleus that is spliced out before the mRNA is transported to the cytoplasm. Thus, the previously reported "SVZ-specific expression of the Svet1 RNA" in fact indicates putative involvement of UNC5D signaling in the multipolar migrating cells.


Pyruvate minimizes rtPA toxicity from in vitro oxygen-glucose deprivation and reoxygenation.
Clinical application of recombinant tissue plasminogen activator (rtPA) for stroke is limited by hemorrhagic transformation, which narrows rtPA's therapeutic window. In addition, mounting evidence indicates that rtPA is potentially neurotoxic if it traverses a compromised blood brain barrier. Here, we demonstrated that pyruvate protects cultured HT22 neuronal and primary microvascular endothelial cells co-cultured with primary astrocytes from oxygen glucose deprivation (OGD)/reoxygenation stress and rtPA cytotoxicity. After 3 or 6h OGD, cells were reoxygenated with 11mmol/L glucose±pyruvate (8mmol/L) and/or rtPA (10µg/ml). Measured variables included cellular viability (calcein AM and annexin-V/propidium iodide), reactive oxygen species (ROS; mitosox red and 2',7'-dichlorofluorescein diacetate), NADPH, NADP(+) and ATP contents (spectrophotometry), matrix metalloproteinase-2 (MMP2) activities (gelatin zymography), and cellular contents of MMP2, tissue inhibitor of metalloproteinase-2 (TIMP2), and phosphor-activation of anti-apoptotic p70s6 kinase, Akt and Erk (immunoblot). Pyruvate prevented the loss of HT22 cells after 3h OGD±rtPA. After 6h OGD, rtPA sharply lowered cell viability; pyruvate dampened this effect. Three hours OGD and 4h reoxygenation with rtPA increased ROS formation by about 50%. Pyruvate prevented this ROS formation and doubled cellular NADPH/NADP(+) ratio and ATP content. In endothelial cell monolayers, 3h OGD and 24h reoxygenation increased FITC-dextran leakage, indicating disruption of intercellular junctions. Although rtPA exacerbated this effect, pyruvate prevented it while sharply lowering MMP2/TIMP2 ratio and increasing phosphorylation of p70s6 kinase, Akt and Erk. Pyruvate protects neuronal cells and microvascular endothelium from hypoxia-reoxygenation and cytotoxic action of rtPA while reducing ROS and activating anti-apoptotic signaling. These results support the proposed use of pyruvate as an adjuvant to dampen the side effects of rtPA treatment, thereby extending rtPA's therapeutic window.


Identification and regulation of renin in human cultured mesangial cells.
Renin activity was measured in the incubation medium, and the cellular extract of human mesangial cells, which had been cultured in the presence of renin-free human plasma (three kidneys; 4-7 passages). Active renin and total renin obtained after trypsin treatment was estimated by radioimmunoassay of angiotensin I using renin-free human plasma as a substrate. Mesangial cell renin had characteristics similar to those of standard human renin; optimum enzymatic activity at pH 5.8, marked inhibition in the presence of two (monoclonal and polyclonal) human renin-specific antibodies and of SR 42128, a new potent statine-containing renin inhibitory peptide. The synthetic capability of the mesangial cells varied markedly with the original kidney (1-49 and 0.3-0.9 ng X h-1 X mg-1 for total renin in the medium and the cellular extract respectively). Renin was secreted mainly as inactive renin. Prostaglandin E2 (PGE2) and carba-prostaglandin I2 (PGI2) (a stable analogue) produced a dose-dependent (0.1-1.10 microM) increase in renin activity in both the cellular extract and the culture medium. Isoproterenol (200 microM) increased renin activity only in the medium. The effects of these agonists were more marked on inactive than on active renin. These results demonstrate that cultured human mesangial cells synthesize and release renin in a stable manner over a long period of culture, thus providing a useful tool for the in vitro study of renin secretion and its control.


Inferring effective connectivity in the brain from EEG time series using dynamic Bayesian networks.
Effective connectivity, defined as the influence of a neuronal population on another, is known to have great significance for understanding the organization of the brain. Disruptions in the effective connectivity patterns occur in the case of neurological and psychopathological diseases. Therefore, it is important to develop models of effective brain connectivity from non-invasive neuroimaging data. In this paper, we propose to use dynamic Bayesian networks (DBN) to learn effective brain connectivity from electroencephalogram (EEG) data. DBNs use first order Markov chain to model EEG time series obtained from multiple electrodes. We explore effective brain connectivity in healthy and schizophrenic subjects using this framework. Fourier bootstrapping technique is used to identify the statistically significant pairs of interactions among electrodes.


Bilateral control of master-slave manipulators with constant time delay.
This paper presents a novel teleoperation controller for a nonlinear master-slave robotic system with constant time delay in communication channel. The proposed controller enables the teleoperation system to compensate human and environmental disturbances, while achieving master and slave position coordination in both free motion and contact situation. The current work basically extends the passivity based architecture upon the earlier work of Lee and Spong (2006) [14] to improve position tracking and consequently transparency in the face of disturbances and environmental contacts. The proposed controller employs a PID controller in each side to overcome some limitations of a PD controller and guarantee an improved performance. Moreover, by using Fourier transform and Parseval's identity in the frequency domain, we demonstrate that this new PID controller preserves the passivity of the system. Simulation and semi-experimental results show that the PID controller tracking performance is superior to that of the PD controller tracking performance in slave/environmental contacts.


Correlation between retinal nerve fibre layer thickness and optic nerve head size: an optical coherence tomography study.
To investigate the correlation between retinal nerve fibre layer (RNFL) thickness and optic nerve head (ONH) size in normal white subjects by means of optical coherence tomography (OCT). 54 eyes of 54 healthy subjects aged between 15 and 54 underwent peripapillary RNFL thickness measurement by a series of three circular scans with a 3.4 mm diameter (Stratus OCT, RNFL Thickness 3.4 acquisition protocol). ONH analysis was performed by means of six radial scans centred on the optic disc (Stratus OCT, Fast Optic Disc acquisition protocol). The mean RNFL values were correlated with the data obtained by ONH analysis. The superior, nasal, and inferior quadrant RNFL thickness showed a significant correlation with the optic disc area (R = 0.3822, p = 0.0043), (R = 0.3024, p = 0.026), (R = 0.4048, p = 0.0024) and the horizontal disc diameter (R = 0.2971, p = 0.0291), (R = 0.2752, p = 0.044), (R = 0.3970, p = 0.003). The superior and inferior quadrant RNFL thickness was also positively correlated with the vertical disc diameter (R = 0.3774, p = 0.0049), (R = 0.2793, p = 0.0408). A significant correlation was observed between the 360 degrees average RNFL thickness and the optic disc area and the vertical and horizontal disc diameters of the ONH (R = 0.4985, p = 0.0001), (R = 0.4454, p = 0.0007), (R = 0.4301, p = 0.0012). RNFL thickness measurements obtained by Stratus OCT increased significantly with an increase in optic disc size. It is not clear if eyes with large ONHs show a thicker RNFL as a result of an increased amount of nerve fibres or to the shorter distance between the circular scan and the optic disc edge.


Osteoclast morphology in autosomal recessive malignant osteopetrosis due to a TCIRG1 gene mutation.
Bone biopsies were performed before and 7 weeks after transplantation of HLA-compatible bone marrow from the sister of a 3-month-old male infant with malignant autosomal recessive osteopetrosis due to a mutation in the TCIRG1 (ATP6i) gene. The first biopsy showed broad, immature bony trabeculae and no medullary hematopoiesis. Only few osteoclasts were present and electron microscopy showed absence of ruffled borders. The post transplant biopsy revealed donor osteoclasts with ruffled borders and intracytoplasmic mineral crystals as proof of active bone resorption that had not yet been detectable radiographically. Osteopetrosis is a genetically heterogeneous disease. Definition at the DNA-level will enable comparison of treatment strategies and prenatal diagnosis. As shown in this patient, the autosomal recessive form caused by a TCIRG1 gene mutation may be amenable to bone marrow transplantation. Activity of donor osteoclasts can be demonstrated morphologically on biopsy, before bone remodeling becomes evident radiologically.


Hypolipidemic effect of steroid compound from Cestrum diurnum (Solanaceae: Solanales) in normocholesterolemic albino rat.
The present study was carried out to establish the hypolipidemic effect of a phyto-steroid compound isolated from the chloroform: methanol extract of fresh mature leaves of the plant Cestrum diurnum (Solanaceae: Solanales). Change in the haematological parameters was studied in normocholesterolemic albino rats after oral administration of single dose of isolated phytosteroid (2 mg/ day) up to 15 days and compared with control rats. Application of phytosteroid fraction resulted in a significant reduction in total plasma cholesterol and free cholesterol levels. The plasma triglyceride levels also decreased significantly. A sharp increase in the HDL cholesterol level and a significant decrease in the LDL and VLDL amount were also documented. Free fatty acid level was significantly low in treated rats.


Intravascular flipping technique for end-to-side microvascular anastomosis.
Recent advances in minimally invasive perforator flaps, such as the superficial circumflex iliac artery (SCIP) flap, have increased the demand for anastomosing vessels with diameters less than 0.8 mm. However, discrepancies in size can occur, underscoring the significance of end-to-side anastomosis. Nevertheless, the conventional interrupted end-to-side suturing technique with vessel turnover presents challenges in situations with a limited operative field, short vascular pedicle, and tiny vessels. Therefore, we developed an intravascular flipping technique for end-to-side microvascular anastomosis with an inside technique or rotation-outside technique. The study involved 20 rats and with 15 arteries in 10 rats undergoing the flipping technique with inside or outside rotation. Both the inside and rotation-outside techniques exhibited a 100% immediate patency rate in the rats; however, after 1 week, this decreased to 80% and 86%, respectively. The SCIP flap and replantation procedures were successfully performed. The flipping technique offers several advantages, including ease of vessel manipulation using nylon threads and vascular clips, improved vessel visualisation, and spontaneous widening of the vessel lumen.


Planned versus actual outcomes as a result of animal feeding operation decisions for managing phosphorus.
The paper explores how decisions made on animal feeding operations (AFOs) influence the management of manure and phosphorus. Variability among these decisions from operation to operation and from field to field can influence the validity of nutrient loss risk assessments. These assessments are based on assumptions that the decision outcomes regarding manure distribution will occur as they are planned. The discrepancy between planned versus actual outcomes in phosphorus management was explored on nine AFOs managing a contiguous set of 210 fields in south-central Wisconsin. A total of 2611 soil samples were collected and multiple interviews conducted to assign phosphorus index (PI) ratings to the fields. Spearman's rank correlation coefficients (r(S)) indicated that PI ratings were less sensitive to soil test phosphorus (STP) levels (r(S) = 0.378), universal soil loss equation (USLE) (r(S) = 0.261), ratings for chemical fertilizer application (r(S) = 0.185), and runoff class (r(S) = -0.089), and more sensitive to ratings for manure application (r(S) = 0.854). One-way ANOVA indicated that mean field STP levels were more homogenous than field PI ratings between AFOs. Kolmogorov-Smirnov (K-S) tests displayed several nonsignificant comparisons for cumulative distribution functions, S(x), of mean STP levels on AFO fields. On the other hand, the K-S tests of S(x) for PI ratings indicated that the majority of these S(x) functions were significantly different between AFOs at or greater than the 0.05 significance level. Interviews suggested multiple reasons for divergence between planned and actual outcomes in managing phosphorus, and that this divergence arises at the strategic, tactical, and operational levels of decision-making.


Shoulder surgery in the beach chair position is associated with diminished cerebral autoregulation but no differences in postoperative cognition or brain injury biomarker levels compared with supine positioning: the anesthesia patient safety foundation beach chair study.
Although controversial, failing to consider the gravitational effects of head elevation on cerebral perfusion is speculated to increase susceptibility to rare, but devastating, neurologic complications after shoulder surgery in the beach chair position (BCP). We hypothesized that patients in the BCP have diminished cerebral blood flow autoregulation than those who undergo surgery in the lateral decubitus position (LDP). A secondary aim was to examine whether there is a relationship between patient positioning during surgery and postoperative cognition or serum brain injury biomarker levels. Patients undergoing shoulder surgery in the BCP (n = 109) or LDP (n = 109) had mean arterial blood pressure (MAP) and regional cerebral oxygen saturation (rScO2) monitored with near-infrared spectroscopy. A continuous, moving Pearson correlation coefficient was calculated between MAP and rScO2, generating the variable cerebral oximetry index (COx). When MAP is in the autoregulated range, COx approaches zero because there is no correlation between cerebral blood flow and arterial blood pressure. In contrast, when MAP is below the limit of autoregulation, COx is higher because there is a direct relationship between lower arterial blood pressure and lower cerebral blood flow. Thus, diminished autoregulation would be manifest as higher COx. Psychometric testing was performed before surgery and then 7 to 10 days and 4 to 6 weeks after surgery. A composite cognitive outcome was determined as the Z-score. Serum S100β, neuron-specific enolase, and glial fibrillary acidic protein were measured at baseline, after surgery, and on postoperative day 1. After adjusting for age and history of hypertension, COx (P = 0.035) was higher and rScO2 lower (P < 0.0001) in the BCP group than in the LDP group. After adjusting for baseline composite cognitive outcome, there was no difference in Z-score 7 to 10 days (P = 0.530) or 4 to 6 weeks (P = 0.202) after surgery between the BCP and the LDP groups. There was no difference in serum biomarker levels between the 2 position groups : Compared with patients in the LDP, patients undergoing shoulder surgery in the BCP are more likely to have higher COx indicating diminished cerebral autoregulation and lower rScO2. There were no differences in the composite cognitive outcome between the BCP and the LDP groups after surgery after accounting for baseline Z-score.


Health care services utilization in children with obstructive sleep apnea syndrome.
Little is known about the effects of obstructive sleep apnea syndrome (OSAS) on utilization of health care services in children. The present study compares medical service utilization by children with OSAS with that of healthy children. A cross-sectional study of 287 consecutively recruited children (1-18 years) with OSAS and no concomitant diseases and a control group matched by age, gender, and geographic location was conducted at the Clalit Health Care Services clinic in the southern region of Israel. Children in the study group underwent nocturnal polysomnography (PSG) studies. The control group (N = 1149) was randomly selected from the Clalit Health Care Services database. PSG was performed for the OSAS patients. Indices of health care utilization 1 year before the PSG study were analyzed. A 226% increase in health care utilization was noted among children with OSAS. Children up to 5 years of age consumed more health care resources than children over 5 years. Children with OSAS consumed more health care services than the control group at all ages. The leading components of this high cost are utilization of more hospital days, drugs, and visits to the emergency department. The severity of the OSAS correlates directly to total annual costs and independently to age (beta = 0.19). Children with OSAS are heavy consumers of health care services 1 year before any specific evaluation and treatment for apnea. Early diagnosis and intervention may be cost-effective.


Development and Feasibility of a Specialty-Specific National Surgical Quality Improvement Program (NSQIP): The Head and Neck-Reconstructive Surgery NSQIP.
The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) serves the need for continual quality assessment in general surgery. Previously, no parallel mechanism specific to head and neck oncologic surgery existed. To address the need for continual quality assessment in subspecialty surgery by adapting the ACS NSQIP platform for complex head and neck oncologic surgical procedures. With an institutional ACS NSQIP team's guidance, surgeons from the departments of head and neck surgery and plastic and reconstructive surgery developed disease- and procedure-specific preoperative, intraoperative, and postoperative variables specific to head and neck surgery requiring reconstruction. Collection occurred with 100% sampling and standard ACS NSQIP 30-day follow-up. After a pilot period, long-term functional outcomes were added to this platform. A total of 312 patients underwent head and neck surgery requiring reconstruction at an academic medical center between August 1, 2012, and June 30, 2013. Development of a specialty-specific head and neck surgery ACS NSQIP platform. The feasibility of adapting the ACS NSQIP platform to capture complex head and neck surgery metrics in all patients. Head and neck surgery-specific preoperative, intraoperative, and postoperative variables were added to the ACS NSQIP platform and evaluated in 312 patients (201 [64.4%] male). Only 42 patients (13.5%) had no preoperative risk factors, and 136 (43.6%) had 3 or more risk factors. The mean (SD) duration of operation was 9.4 (3.0) hours (range, 1.7-19.3 hours). The mean (SD) postoperative length of stay was 7.9 (4.7) days (range, 1-40 days), 58 patients (18.6%) had an unplanned return to the operating room, 23 patients (7.4%) were readmitted within 30 days, and 3 patients (1.0%) died within 30 days. More than half of the patients (160 [51.3%]) did not experience a postoperative occurrence. To our knowledge, this is the first comprehensive complex oncologic surgery outcomes platform derived from ACS NSQIP methods. The initial pilot demonstrates the ability to systematically capture head and neck surgery-specific variables with complete sampling. With multi-institutional expansion, increased accrual, and long-term patient-reported outcomes, we hope to set risk-adjusted benchmarks that may underpin quality improvement efforts in complex head and neck surgery.


Posttraumatic stress disorder and suicide among veterans with prostate cancer.
To evaluate the effect of a preexisting posttraumatic stress disorder (PTSD) diagnosis on suicide and non-suicide mortalities among men with newly diagnosed prostate cancer, and examine potential mediating factors for the relationship between PTSD and suicide. We used patient-level data from Veterans Health Administration electronic medical records to identify men (age ≥40 years) diagnosed with prostate cancer between 2004 and 2014. We used Fine and Gray regression model to estimate the risk for competing mortality outcomes (suicide, non-suicide, and alive). We used structural equation models to evaluate the mediating factors. Our cohort comprised 214,649 men with prostate cancer, of whom 12,208 (5.7%) had a preexisting PTSD diagnosis. Patients with PTSD compared to those without utilized more healthcare services and had lower risk cancer at diagnosis. Additionally, they experienced more suicide deaths (N = 26, 0.21% vs. N = 269, 0.13%) and fewer non-suicide deaths (N = 1399, 11.5% vs. N = 45,625, 22.5%). On multivariable analysis, PTSD was an independent suicide risk factor (HR = 2.35; 95% CI: 1.16, 4.78). Depression, substance use disorder, and any definitive prostate cancer treatment were partial mediators. However, PTSD was associated with lower non-suicide mortality risk (HR = 0.86; 95% CI: 0.77, 0.96). Patients with PTSD experienced greater suicide risk even after adjusting for important mediators. They may have experienced lower non-suicide mortality risk due to favorable physical health resulting from greater healthcare service use and early diagnosis of lower risk cancer. Our findings highlight the importance of considering psychiatric illnesses when treating patients with prostate cancer and the need for interventions to ameliorate suicide risk.


Cerebral hemodynamics in patients with carotid artery occlusion and contralateral moderate or severe internal carotid artery stenosis.
The purpose of this study was to evaluate cerebral hemodynamics in patients suffering from occlusion of the carotid artery (CA) and contralateral CA stenosis. Using transcranial Doppler ultrasonography, the cerebrovascular reactivity to hypercapnia in the middle cerebral arteries was evaluated by calculating the breath-holding index (BHI) of 69 symptomatic patients suffering from internal CA (ICA) occlusion and moderate or severe contralateral ICA stenosis. To evaluate which variables influenced BHIs ipsilateral to the site of ICA occlusion, a multiple stepwise linear regression analysis was performed that included the following factors: patient age, percentage of contralateral ICA stenosis, contralateral BHI, number of collateral pathways, and presence of hypertension, diabetes, smoking, and hyperlipidemia. An analysis of variance was conducted to evaluate the impact of the type of collateral vessels on the BHI. A regression analysis showed that the BHI ipsilateral to the site of ICA occlusion could be accounted for by the contralateral BHI (which was entered at the first step of the analysis, p < 0.001) and by the number of collateral pathways (which was entered at the second step, p = 0.033). Neither the degree of contralateral ICA stenosis nor the other variables could be added to improve the model. The analysis demonstrated that the absence of collateral pathways and the presence of the anterior communicating artery (ACoA) alone were associated with lower BHI values than those found in the presence of two or three collateral vessels, regardless of the presence of an anterior collateral pathway. On the basis of these data one can infer that the cerebral hemodynamic status of patients with occlusive disease of the CA is influenced by individual anatomical and functional characteristics. Because improvement in contralateral hemodynamics after surgical correction of an ICA stenosis can only be expected in the presence of an ACoA, the planning of strategies for influencing cerebral blood flow distal to an ICA occlusion and, in particular, the consideration of a contralateral carotid endarterectomy, should be preceded by a careful evaluation of the intracranial hemodynamic adaptive status of the patient. Particular attention should be paid to cerebrovascular reactivity and the number and type of collateral vessels that are present.


Decreased catalytic subunit mRNA levels and altered catalytic subunit mRNA structure in a cAMP-resistant Chinese hamster ovary cell line.
The mechanisms responsible for decreased levels of cAMP-dependent protein kinase activity in a mutant Chinese hamster ovary cell line have been examined. The cAMP-resistant Chinese hamster ovary 10260 cell line was found to possess only 20% of the cAMP-dependent protein kinase activity found in wild-type cells. The presence of decreased concentrations of the catalytic subunit in these cells was confirmed through binding studies using a radiolabeled, heat-stable inhibitor of the kinase. Cloned Chinese hamster ovary catalytic subunit cDNAs were isolated, characterized, and used as hybridization probes to examine the relative concentrations of catalytic subunit mRNAs in the wild-type and 10260 cell lines. A 40-50% decrease in the concentration of the mRNA for the C alpha isozyme of the catalytic subunit was observed in 10260 cells, as compared with wild-type. This decrease in catalytic subunit mRNA concentration probably accounts for a portion of the decreased kinase activity in the mutant cells. Further analysis of C alpha mRNA by polymerase chain reaction confirmed the decreased expression of C alpha mRNA in 10260 cells and further demonstrated the presence of two different species of C alpha mRNA in the 10260 cells. One species of C alpha cDNAs was indistinguishable from the wild-type cDNA, but the other species was shorter. Nucleotide sequence analysis of the amplified cDNAs led to the identification of a 191-base pair deletion in the shorter cDNA. Gene transfer studies using wild-type and 10260 C alpha cDNAs demonstrated that the longer cDNA from the 10260 cells produced wild-type activity, but the shorter cDNA was inactive. These studies suggest that at least two alterations in gene expression are responsible for decreased cAMP-dependent protein kinase activity in the 10260 cell line. One alteration results in an approximately 2-fold decrease in the concentrations of C alpha mRNA in the cells. The other change produces two species of C alpha mRNA; one of the C alpha mRNAs does not encode an active kinase.


Atrial fibrillation and the pharmacological treatment: the role of propafenone.
Atrial fibrillation is the most frequent cardiac rhythm disturbance, with prevalence increasing with age. This disease is a major risk factor for ischaemic stroke. The costs resulting from atrial fibrillation are really impressive. Pharmacological agents are the first line therapy for the management of atrial fibrillation. Antiarrhythmic drugs are used to terminate arrhythmias, as acute treatment for conversion of recent onset atrial fibrillation, and to maintain sinus rhythm, as chronic therapy for prevention of atrial fibrillation recurrences. Among antiarrhythmic agents, drugs that inhibit early sodium current (as propafenone) are proven effective in atrial fibrillation. In this review, the most relevant data on propafenone are provided. The development of a sustained-release formulation of propafenone allowed to reduce the wide fluctuations in plasma levels observed with the immediate release preparation, improving compliance and adherence to therapy, by simplifying the dosing regimen from 3 to 2 daily doses. Propafenone resulted an effective measure as acute treatment for conversion of recent onset atrial fibrillation, and to maintain sinus rhythm, as chronic therapy for prevention of atrial fibrillation recurrences. In several clinical studies, strong increases of arrhythmia-free periods as well as marked increases in time to recurrence of symptomatic atrial fibrillation, such as paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation were observed. In particular, well-designed clinical studies demonstrated in large patient populations the efficacy of propafenone at several doses. At the suggested doses propafenone is usually well tolerated. The risk of increased occurrence of regular supraventricular arrhythmia or paroxysmal supraventricular tachycardia has been overestimated for propafenone, because this adverse event was seen in all treatment groups, including placebo, with the same (and low) frequency.


Immunity in human schistosomiasis mansoni. Regulation of protective immune mechanisms by IgM blocking antibodies.
After the demonstration of blocking antibodies during rat experimental schistosomiasis, the existence of such factors was investigated in human schistosomiasis. The depletion, in sera from S. mansoni-infected patients, of a given isotype (IgM) either by protein A-Sepharose (PAS) absorption or by fast protein liquid chromatography (FPLC) induced a significant increase in IgG-mediated killing of S. mansoni schistosomula by human eosinophils. Inhibition experiments showed that IgM-enriched fractions (PAS effluents) were able to inhibit eosinophil-dependent cytotoxicity mediated by IgG fractions (total sera or PAS eluates). Both IgG and IgM antibodies from infected human sera immunoprecipitated antigens of 30,000-40,000 Mr in the labeled detergent extracts of schistosomulum surface. The specificity of IgG and IgM for the 38,000 Mr antigen was suggested by competition experiments using two radiolabeled mAbs (IPLSm1, IPLSm3) directed against this antigen. Moreover, crossinhibition between IgG and IgM antibodies for the Mr 38,000 antigen could be directly demonstrated. The in vivo relevance of such IgM blocking antibodies in the context of human immunity to schistosomiasis was evaluated in two groups of children classified as resistant or susceptible to posttreatment reinfection. IgM antibodies specifically directed against the 38,000 Mr antigen were measured by a capture assay. The mean levels of IgM antibodies were significantly higher in the susceptible than in the resistant group both before and after treatment. These results are consistent with the idea that immunity to schistosomiasis could be attributable not only to the existence of antibodies with defined effector function, but also to the absence of blocking antibodies. The description of the existence in human schistosomiasis of antibody isotypes blocking the effector response against defined surface targets might lead to a new understanding of the mechanisms regulating immunity to reinfection against schistosomes and possibly other parasites.


Cochlear implant provider awareness of vaccination guidelines.
Guidelines for vaccination of cochlear implant (CI) recipients have been promulgated and updated by the Center for Disease Control and Prevention (CDC) to mitigate bacterial meningitis risk. The objective of this study was to survey current CI specialists on: 1) knowledge of current CDC CI recipient immunization recommendations, and 2) impediments to implementation of those guidelines. A survey to assess knowledge of the CI recipient vaccination guidelines was administered to the American Academy of Otolaryngology-Head and Neck surgery (AAO-HNS), the American Cochlear Implant Alliance (ACIA), and the American Neurotology Society (ANS). The members of the AAO-HNS and ACIA were invited to participate in the survey via an e-mail. The members of the ANS were polled during a session of their fall meeting. A total of 256 individuals participated: 64 from AAO, 59 from ACIA, and 133 from ANS. Participants reported knowledge of the vaccination guidelines as high among all groups and statistically similar. The survey indicated that the participants noted difficulty in obtaining age-group-specific immunizations. Vaccination status was not consistently reported. Cochlear implant providers have high awareness of vaccination guidelines but less detailed knowledge of age-specific recommendations. Obtaining age-specific vaccines is a challenge, as is consistent documentation of vaccination. Future efforts should be focused on improving knowledge of age-specific recommendations, easing access of age-specific vaccines, and improving documentation. NA. Laryngoscope, 128:2145-2152, 2018.


Time spent being sedentary and weight gain in healthy adults: reverse or bidirectional causality?
Whether obesity is a cause or a consequence of a sedentary lifestyle has not yet been fully elucidated, which leaves uncertainty about the direction of causality. We aimed to assess the longitudinal associations between objectively measured time spent being sedentary (sedentary time) and obesity indicators. The study was a prospective, population-based cohort study in 393 middle-aged healthy whites (n = 176 M, 217 F). Sedentary time (% of daytime hours) was measured by individually calibrated monitoring of the heart rate. Body weight (BW), body mass index (BMI), and waist circumference (WC) were assessed by standard clinical procedures. Fat mass (FM) was assessed with bioimpedance. All measurements were collected at baseline and at 5.6-y follow-up. At baseline, sedentary time was significantly correlated with FM (partial r = 0.10, P = 0.043) and WC (partial r = 0.11, P = 0.027) after adjustment for sex and age. At follow-up, sedentary time was significantly correlated with BW (partial r = 0.19, P < 0.0001), BMI (partial r = 0.20, P < 0.0001), WC (partial r = 0.15, P = 0.003), and FM (partial r = 0.19, P < 0.0001). Sedentary time did not predict any of the obesity indicators at follow-up. In contrast, BW (beta = 0.33; 95% CI: 0.15, 0.50), BMI (1.10; 0.58, 1.63), FM (0.59; 0.11, 0.40), and WC (0.44; 0.23, 0.66) predicted sedentary time at follow-up after adjustment for sex, baseline age, baseline sedentary time, baseline physical activity energy expenditure, and follow-up time. BMI, FM, and WC may predict sedentary time, but our results do not suggest that sedentary time predicts future obesity.


Crithmum maritimum L. Volatile Compound's Diversity Through Tunisian Populations: Use of a Plant Organ-Based Statistical Approach for Chemotype Identification.
This work aimed to investigate the variability of the chemical composition of the aromatic halophyte Crithmum maritimum L. essential oils according to the geographical origin and separated organs, using a statistical approach based on the multiple analysis of variance and the Principal Component Analyses. One hundred twenty samples were collected from three distinct bioclimatic regions (10 samples×3 provenances×4 organs). Hydrodistillation of separated organs (roots, stems, leaves and flowers) yielded 0.13 to 1.75 % of the dry matter. Chemical investigation of the volatile compounds by Gas chromatography-mass spectrometry showed that C. maritimum essential oils were dominated by monoterpenes hydrocarbons, oxygenated monoterpenes, and phenylpropanoids varying, respectively, from 33.3 to 66.9, from 7.8 to 46.6 and from 4.5 to 57.2 % according to organs and localities. Statistical analyses identified three different chemotypes depending on the geographic origin as follow: γ-Terpinene-Thymol methyl ether / Dillapiole / Thymol methyl ether-Dillapiole.


A Systematic Review of Proposed Rehabilitation Guidelines Following Anatomic and Reverse Shoulder Arthroplasty.
Total shoulder arthroplasty (TSA) is indicated for patients with glenohumeral arthritis. In this procedure, the humeral head and glenoid surface are replaced with prosthetic components. Reverse total shoulder arthroplasty (RTSA) is indicated for patients with glenohumeral arthritis and a poorly functioning rotator cuff. In this procedure, a glenosphere articulates with a humerosocket. While those surgeries are commonly performed, a thorough review of the literature is required to determine the areas of agreement and variations in postoperative rehabilitation. To describe the literature on rehabilitation protocols following anatomic TSA and RTSA. For this systematic review, a computerized search was conducted in medical databases from inception to May 21, 2018 for relevant descriptive studies on TSA and RTSA rehabilitation protocols. The methodological index for nonrandomized studies tool and the modified Downs and Black tool for randomized controlled trials were used for assessment of the individual studies. Sixteen studies met the inclusion criteria, of which 1 provided level I evidence, 1 provided level III evidence, 2 provided level IV evidence, and 12 provided level V evidence. Ten of the studies described rehabilitation guidelines for TSA and 6 described those for RTSA. Following TSA, the use of a sling was recommended for a duration that varied from 3 to 8 weeks, and 4 of the 10 published protocols included resisted exercise during the initial stage of healing (the first 6 weeks after surgery). Seven of 10 published protocols recommended limiting shoulder external rotation to 30° and that passive range of motion be fully restored by 12 weeks post surgery. Suggested use of a sling post RTSA varied from "for comfort only" to 6 weeks, motion parameters varied from no passive range of motion to precautionary range limits, and all protocols agreed on performing deltoid isometric exercises early post surgery. There was a high level of heterogeneity for the rehabilitation guidelines and associated precautions for both TSA and RTSA. The majority of published protocols were descriptive in nature. Published rehabilitation strategies following TSA and RTSA are based on biomechanical principles, healing time frames, and exercise loading principles, with little consistency among protocols. There is a need to determine optimal rehabilitation approaches post TSA and RTSA based on clinical outcomes. Therapy, level 5. J Orthop Sports Phys Ther 2019;49(5):337-346. doi:10.2519/jospt.2019.8616.


Paternal age and mental functions of progeny in man.
The effects of maternal age on the quality of offspring are well known. Those due to the father's age are less obvious, apart from the role of increasing paternal age in the onset of many dominant autosomal disorders. But an experimental model has demonstrated that, in rats, increasing paternal age, without any other anomalies, might produce a decreased learning capacity in progeny. The object of the epidemiological investigation presented here was to verify whether this effect might also occur in man. The study involved the distribution of scores obtained in psychometric tests by 18-year-old male subjects, according to their father's age at the time of their birth. This distribution indicated not only that increasing paternal age is accompanied by effects similar to those observed in animals, but also that very young paternal age was also related to these effects. Thus, the curve of such scores produced an inverted U-shape, with maximum scores obtained when the father was about thirty years of age. Maternal age did not appear to play a part in this event. These results pose the problem of identifying genetic and/or psychosocial factors which might have an impact on the quality of the conceptus.


Dendrochronological dates confirm a Late Prehistoric population decline in the American Southwest derived from radiocarbon dates.
The northern American Southwest provides one of the most well-documented cases of human population growth and decline in the world. The geographic extent of this decline in North America is unknown owing to the lack of high-resolution palaeodemographic data from regions across and beyond the greater Southwest, where archaeological radiocarbon data are often the only available proxy for investigating these palaeodemographic processes. Radiocarbon time series across and beyond the greater Southwest suggest widespread population collapses from AD 1300 to 1600. However, radiocarbon data have potential biases caused by variable radiocarbon sample preservation, sample collection and the nonlinearity of the radiocarbon calibration curve. In order to be confident in the wider trends seen in radiocarbon time series across and beyond the greater Southwest, here we focus on regions that have multiple palaeodemographic proxies and compare those proxies to radiocarbon time series. We develop a new method for time series analysis and comparison between dendrochronological data and radiocarbon data. Results confirm a multiple proxy decline in human populations across the Upland US Southwest, Central Mesa Verde and Northern Rio Grande from AD 1300 to 1600. These results lend confidence to single proxy radiocarbon-based reconstructions of palaeodemography outside the Southwest that suggest post-AD 1300 population declines in many parts of North America. This article is part of the theme issue 'Cross-disciplinary approaches to prehistoric demography'.