Malaria parasites tolerate a broad range of ionic environments and do not require host cation remodelling.
Malaria parasites grow within erythrocytes, but are also free in host plasma between cycles of asexual replication. As a result, the parasite is exposed to fluctuating levels of Na(+) and K(+) , ions assumed to serve important roles for the human pathogen, Plasmodium falciparum. We examined these assumptions and the parasite's ionic requirements by establishing continuous culture in novel sucrose-based media. With sucrose as the primary osmoticant and K(+) and Cl(-) as the main extracellular ions, we obtained parasite growth and propagation at rates indistinguishable from those in physiological media. These conditions abolish long-known increases in intracellular Na(+) via parasite-induced channels, excluding a requirement for erythrocyte cation remodelling. We also dissected Na(+) , K(+) and Cl(-) requirements and found that unexpectedly low concentrations of each ion meet the parasite's demands. Surprisingly, growth was not adversely affected by up to 148 mM K(+) , suggesting that low extracellular K(+) is not an essential trigger for erythrocyte invasion. At the same time, merozoite egress and invasion required a threshold ionic strength, suggesting critical electrostatic interactions between macromolecules at these stages. These findings provide insights into transmembrane signalling in malaria and reveal fundamental differences between host and parasite ionic requirements.


A narrative review on Naringin and Naringenin as a possible bioenhancer in various drug-delivery formulations.
Naringenin belongs to the flavanones and is mainly found in fruits (grapefruit and oranges) and vegetables. Naringenin exhibits lipid-lowering and insulin-like characteristics and is used to treat osteoporosis, cancer and cardiovascular disorders. Their incorporation into drug formulations offers several advantages, including enhanced solubility, improved bioavailability and targeted delivery. Naringin-based formulations are beneficial in cancer, for example controlling breast and prostate cancer by inhibition of CYP19. Naringin suppresses the PI3K/AKT signalling pathway, it triggers autophagy, which effectively halts the proliferation of gastric cancer cells. Naringin and naringenin co-administration or pre-administration has enhanced the target drug's potency and produced a synergistic effect. This published study demonstrates the potential applications of Naringin and Naringenin as recognized bio-enhancers.


Ion Channels Involvement in Neurodevelopmental Disorders.
Inherited and sporadic mutations in genes encoding for brain ion channels, affecting membrane expression or biophysical properties, have been associated with neurodevelopmental disorders characterized by epilepsy, cognitive and behavioral deficits with significant phenotypic and genetic heterogeneity. Over the years, the screening of a growing number of patients and the functional characterization of newly identified mutations in ion channels genes allowed to recognize new phenotypes and to widen the clinical spectrum of known diseases. Furthermore, advancements in understanding disease pathogenesis at atomic level or using patient-derived iPSCs and animal models have been pivotal to orient therapeutic intervention and to put the basis for the development of novel pharmacological options for drug-resistant disorders. In this review we will discuss major improvements and critical issues concerning neurodevelopmental disorders caused by dysfunctions in brain sodium, potassium, calcium, chloride and ligand-gated ion channels.


Megakaryocyte and platelet abnormalities in a patient with a W33C mutation in the conserved SH3-like domain of myosin heavy chain IIA.
Heterozygous mutations in MYH9, which encodes non-muscle myosin heavy chain IIA (MHC-IIA), result in autosomal dominant inherited MYH9-related disorders characterised by macro-thrombocytopenia, granulocyte inclusions, variable sensorineural deafness, cataracts and nephritis. MHC-IIA is assembled into a complex consisting of two pairs of light chains and two heavy chains, where the latter contain a neck region, SH3-like, motor and rod domains. We describe a patient with a Trp33Cys missense mutation in the SH3-like domain of MHC-IIA. Abnormal platelet function was observed using platelet aggregometry with the agonists epinephrine and adenosine diphosphate (ADP). Patient granulocytes and megakaryocytes, but not platelets, contained abnormal MHC-IIA inclusions visualised by confocal immunofluorescence or electron microscopy. Megakaryocytes grown in culture were smaller and contained hypolobulated nuclei compared to controls. Bone marrow-derived megakaryocytes revealed a preponderance of immature forms, the presence of structurally diverse inclusion bodies, and frequent emperipolesis as assessed by electron microscopy. Platelets and leukocytes contained indistinguishable amounts of total MHC-IIA determined by immunoblotting. Molecular modelling studies indicated that mutation of Trp33 destabilises the interface between the SH3-like and motor domain of MHC-IIA, which is close to previously described motor domain mutations, implying an important structural and/or functional role for this region in MHC-IIA.


Human papillomavirus expression and p53 gene mutations in squamous cell carcinoma.
To determine the incidence of human papillomavirus (HPV) infection and p53 gene mutation expression in squamous cell carcinomas (SCCs) of the oral cavity and tonsils, to correlate the presence of HPV and p53 gene mutation with known clinical and pathological features of SCC, and to determine whether infection with HPV or the presence of p53 gene mutations are independent prognosticators of patient survival. To accomplish this goal, 58 patients with SCCs of the oral cavity and 42 patients with SCCs of the tonsils were randomly examined. The cases examined met the criteria of 5-year clinical follow-up, availability of complete staging information and treatment history, and the presence of paraffin-embedded tumor specimens. Immunohistochemical tests were performed to identify the mutant p53 protein. Human papillomavirus identification was accomplished with polymerase chain reaction, with confirmation via restriction fragment length polymorphisms. The incidence of p53 gene mutation expression for this series was 66%. Human papillomavirus infection was found in 11 patients (11%). There was a trend toward increased p53 gene mutation expression with advancing stage of tumor in the oral cavity cancer group, although this was less evident in the tonsil cancer population. The p53 gene mutation status was found not to correlate with the histological grade of the tumor, patient age or sex, recurrence rates, or survival status. Like p53 expression, there were no correlations found between the presence of HPV and age, sex, histological grade, or recurrence rates. However, a correlation did exist between HPV and survival status in the tonsil cancer group, with improved survival noted among patients with tonsil cancers infected with HPV compared with those not infected with HPV. A significant correlation existed with both p53 gene mutation status and HPV status with respect to alcohol and tobacco use. The presence of the p53 gene mutation positively correlated with increased tobacco and alcohol use, whereas infection with HPV predicted a significantly lower rate of alcohol and tobacco consumption. Human papillomavirus infection is an independent risk factor for the development of oral cavity and tonsil SCCs in those patients with a relatively low alcohol and tobacco use history. Conversely, there is a strong association between heavy alcohol and tobacco use and mutation of the p53 gene. Neither p53 gene mutation nor HPV infection serve as prognosticators of tumor behavior in SCCs of the oral cavity or tonsils, with the exception of improved survival noted among patients with tonsil cancers infected with HPV.


Bone marrow transplantation (BMT) and gene replacement therapy (GRT) in sickle cell anemia.
Sickle cell anemia (SCA) forms one of the neglected tropical disease of genetic aetiology Unlike many complex genetic diseases inherited on a multiallelic pattern, SCA is a hemoglobinopathy of Mendelian type genetic inheritance. The SCA trait is inherited through a recessive autosomal link, with the homozygotes (SS) manifesting clinical disease, while the heterozygoste (AS) are clinically normal-exept in states of hypoxia or severe infection. Review of relevant literature on bone marrow transplantation and gene replacement therapy in sickle cell anaemia was obtained from texts and Pubmed search. The exact genetic disorder assailing SCA is the production of mutant or abnormal beta peptide chains in which the amino acid Glutamine has been substituted with valine. The issuing Haemoglobin polymerizes when deoxygenated,causing constituent RBCs to sickle, haemolyse and block small blood vessels- a clinical state that manifests as haemolytic anemia, aplasia, thrombo-embolic phenomenon, or painful crises. Unfortunately, up to day, there is no cure to SCA, and management only aims at preventing or ameliorating attacks. By virtue of its well defined and localized genetic aetiopathophysiology, and the advances in gene replacement therapy and regenerative medicine, we argue here the case for Bone marrow transplantation (BMT) and Gene replacement therapy (GRT) in sickle cell anemia.


Dose response and safety of cizolirtine citrate (E-4018) in patients with pain following extraction of third molars.
The objectives of this study were to determine the dose response and safety of the oral analgesic cizolirtine citrate (E-4018) in patients with postoperative pain after third molar extraction. This was a placebo-controlled, double-blind, randomised, parallel-group study. Doses of E-4018 were 50 mg, 100 mg, or 150 mg. The primary outcome measure of efficacy was patient assessment of pain severity, determined from serial visual analogue scales (VAS) over a four-hour investigation period. Other efficacy measures included the number of patients taking escape analgesic and the time before it was taken, and an overall assessment of pain relief on a four-point categorical scale. There was no significant difference between any of the E-4018 treatment groups and placebo in terms of the AUC for VAS pain scores over time. The percentages of patients who took paracetamol within five hours of their dose were 100%, 95%, 78% and 82% for the placebo, 50 mg, 100 mg and 150 mg E-4018 groups, respectively. The time to first use of paracetamol was significantly different for the 100 mg and 150 mg E-4018 groups compared to placebo. There were 17 adverse events, of which five were possibly related to the study medication (one in the placebo group and four in the 150 mg E-4018 group). We conclude that there was a dose-related trend in the percentage of patients requiring paracetamol within five hours of their study medication, and in the percentage of patients that recorded the treatment as providing good or excellent treatment of pain. There was, however, no firm evidence of a dose-related analgesic effect over the dose range of Cizolirtine chosen for this study. E-4018 was well tolerated in all patients.


Expanding the genetic map of maize with the intermated B73 x Mo17 (IBM) population.
The effects of intermating on recombination and the development of linkage maps were assessed in maize. Progeny derived from a common population (B73 x Mo17) before and after five generations of intermating were genotyped at the same set of 190 RFLP loci. Intermating resulted in nearly a four-fold increase in the genetic map distance and increased the potential for improved genetic resolution in 91% of the intervals evaluated. This mapping population and related information should connect research involving dense genetic maps, physical mapping, gene isolation, comparative genomics, analysis of quantitative trait loci and investigations of heterosis.


Quantitative pertechnetate thyroid scintigraphy and the ultrasonographic appearance of the thyroid gland in clinically normal horses.
We characterized the scintigraphic and sonographic appearance of the thyroid gland in clinically normal horses to establish the value of these modalities for assessment of the thyroid gland in this species. Horses were divided into two age groups. One group consisted of eight horses between 3 and 10 years of age and the other of seven horses between 11 and 20 years of age. Total T4 concentrations were within the laboratory reference interval in all horses. Thyroid to salivary (T/S) ratio, percent dose uptake of pertechnetate (Na99mTcO4) and thyroid lobe volume were calculated. The echogenicity of thyroid lobes and presence of nodules was documented. The two groups were compared using appropriate parametric and nonparametric statistics. Mean total T4 concentration was lower in older horses. Sixty minute mean +/- standard deviation (SD) T/S ratios for old vs. young horses were 5.8 +/- 3.0 and 5.3 +/- 2.2, respectively. Sixty-minute median and interquartile ranges for percent dose uptake of pertechnetate for old vs. young horses were 3.64% (1.5-3.98%) and 2.55% (2.33-2.90%), respectively. Mean +/- SD thyroid lobe volume for old vs. young horses were 18.93 +/- 5.16 cm 3 and 13.55 +/- 3.56 cm3, respectively. Differences between groups were not significant. Most thyroid lobes were hyper or isoechoic to the sternocephalicus muscle. Prevalence of thyroid nodules did not differ between groups. Further study is needed to determine if thyroidal percent dose uptake is significantly different in horses with thyroid dysfunction and if it is clinically useful.


Responses of HMO medical directors to trust building in managed care.
Managed care organizations (MCOs) are facing intense criticism at national, state, and local levels and battling initiatives that would impose stricter regulation. Medical directors of HMOs were surveyed regarding their organizations' strategies of communication, the programs they have instituted to build trust, and their commitment to sponsoring family and patient support groups. The responses obtained from 252 directors indicate that nonprofit and free-standing organizations are more likely than either for-profit HMOs or organizations that are part of a chain to sponsor community activities and programs and to offer family and patient support groups. Staff- and group-model HMOs are more likely than other organizational configurations to initiate many types of "trust programs." The results indicate that more dispersed and "virtual-type" organizations must explore ways to respond meaningfully to community concerns--and to public health, prevention, and health promotion needs as well--while continuing to improve their practice patterns.


Processing of auditory novelty across the cortical hierarchy: An intracranial electrophysiology study.
Under the predictive coding hypothesis, specific spatiotemporal patterns of cortical activation are postulated to occur during sensory processing as expectations generate feedback predictions and prediction errors generate feedforward signals. Establishing experimental evidence for this information flow within cortical hierarchy has been difficult, especially in humans, due to spatial and temporal limitations of non-invasive measures of cortical activity. This study investigated cortical responses to auditory novelty using the local/global deviant paradigm, which engages the hierarchical network underlying auditory predictive coding over short ('local deviance'; LD) and long ('global deviance'; GD) time scales. Electrocorticographic responses to auditory stimuli were obtained in neurosurgical patients from regions of interest (ROIs) including auditory, auditory-related and prefrontal cortex. LD and GD effects were assayed in averaged evoked potential (AEP) and high gamma (70-150 Hz) signals, the former likely dominated by local synaptic currents and the latter largely reflecting local spiking activity. AEP LD effects were distributed across all ROIs, with greatest percentage of significant sites in core and non-core auditory cortex. High gamma LD effects were localized primarily to auditory cortex in the superior temporal plane and on the lateral surface of the superior temporal gyrus (STG). LD effects exhibited progressively longer latencies in core, non-core, auditory-related and prefrontal cortices, consistent with feedforward signaling. The spatial distribution of AEP GD effects overlapped that of LD effects, but high gamma GD effects were more restricted to non-core areas. High gamma GD effects had shortest latencies in STG and preceded AEP GD effects in most ROIs. This latency profile, along with the paucity of high gamma GD effects in the superior temporal plane, suggest that the STG plays a prominent role in initiating novelty detection signals over long time scales. Thus, the data demonstrate distinct patterns of information flow in human cortex associated with auditory novelty detection over multiple time scales.


Malignant pancreatic extra-gastrointestinal stromal tumor diagnosed by ultrasound guided fine needle aspiration cytology. A case report with a review of the literature.
Pancreatic extra-gastrointestinal stromal tumors are extremely uncommon neoplasm. To the best of our knowledge, only eleven cases have been reported in the literature. All the case reports published mostly involve diagnoses made on surgical pathology. A 40-year-old male patient presented with asthenia, mild abdominal pain, severe anemia and weight loss. Contrast-enhanced computed tomography of the abdomen revealed a heterogeneously enhancing mass (6.5x6.0 cm) in the body and head of the pancreas. Ultrasound-guided fine needle aspiration (US-FNA) was performed on the mass of the pancreas before a pancreaticoduodenectomy. A cytological diagnosis of pancreatic malignant mesenchymal neoplasm was made. The final diagnosis of primary pancreatic extra-gastrointestinal stromal tumor was confirmed by histopathological examination and immunohistochemical findings (CD117 positivity). This case was diagnosed by percutaneous transabdominal ultrasound, rather than endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) which had been used in three previous cases. We report a very unusual case of pancreatic extra-gastrointestinal stromal tumor which was diagnosed by US-FNA cytology. Although this is uncommon in the pancreas, extra-gastrointestinal stromal tumors should be considered in the differential diagnosis of solid and cystic pancreatic masses on cytology.


A review of the surveillance systems of influenza in selected countries in the tropical region.
Influenza viruses cause annual epidemics of respiratory tract disease that affect all age groups. Many developing countries do not have an influenza surveillance system or adequate laboratory capacity for virus detection. The objective of this study was to describe the influenza surveillance systems in the different countries in the tropics and to identify outstanding research needs. A questionnaire was designed and sent to 52 NICs and MoHs in the different countries in tropical Asia and Africa to gather information on the surveillance systems, sentinel sites, specimen and data collection, and laboratory testing. Replies were received from 32 NICs and MoHs (61.5% response)--17 were located in tropical Asia and 15 in Africa. There are 20 WHO recognized NICs in tropical Asia and 14 in tropical Africa, all with virus isolation and polymerase chain reaction (PCR) testing capacity. Of the Asian countries, only Hong Kong and Singapore reported that the patient population from the sites represents the broader community. In tropical Africa, only Senegal has sentinel sites distributed all over the country contributing to the geographic representativeness of the surveillance system. The rest of the countries in Africa have just established their influenza surveillance system in the past decade and are working toward geographic expansion of the ILI and SARI sites. Limited laboratory capacity or infrastructure to perform influenza surveillance makes difficult to justify the importance of influenza vaccine or other influenza control measures as a strategy for improving population health in the tropical region.


Phytoplankton size-scaling of net-energy flux across light and biomass gradients.
Many studies examine how body size mediates energy use, but few investigate how size simultaneously regulates energy acquisition. Furthermore, rarely energy fluxes are examined while accounting for the role of biotic and abiotic factors in which they are nested. These limitations contribute to an incomplete understanding of how size affects the transfer of energy through individuals, populations, and communities. Here we characterized photosynthesis-irradiance (P-I) curves and per-cell net-energy use for 21 phytoplankton species spanning across four orders of magnitude of size and seven phyla, each measured across six light intensities and four population densities. We then used phylogenetic mixed models to quantify how body size influences the energy turnover rates of a species, and how this changes across environments. Rate-parameters for the P-I curve and net-energy budgets were mostly highly correlated and consistent with an allometric size-scaling exponent of <1. The energy flux of a cell decreased with population density and increased with light intensity, but the effect of body size remained constant across all combinations of treatment levels (i.e. no size×populationdensity interaction). The negative effect of population density on photosynthesis and respiration is mostly consistent with an active downregulation of metabolic rates following a decrease in per-cell resource availability, possibly as an adaptive strategy to reduce the minimum requirements of a cell and improve its competitive ability. Also, because an increase in body size corresponds to a less-than-proportional increase in net-energy (i.e. exponent<1), we propose that volume-specific net-energy flux can represent an important cost of evolving larger body sizes in autotrophic single-cell organisms.


Effects of Positive Reinforcement Training and Novel Object Exposure on Salivary Cortisol Levels under Consideration of Individual Variation in Captive African Elephants (Loxodonta africana).
Dealing with potential stress in species that have high husbandry requirements, such as elephants, is a challenge for zoos. The objective of the present study was to determine whether positive reinforcement training (PRT) and exposure to a novel object (NOV) for enrichment induced a salivary cortisol response indicative of activation of the hypothalamic-pituitary-adrenal (HPA) axis and which factors determine individual variation in this regard in captive African elephants. We repeatedly sampled the saliva of ten animals (three zoos) for the analysis of cortisol (SACort) before and up to 60 min (in 10-15 min intervals) after the onset of PRT (three repeats) or NOV (nine repeats), which lasted 10 min. There was considerable individual variation in SACort in response to PRT or NOV. Using mixed models, we were able to control these and to reveal that PRT was associated with high SACort before and relatively low SACort after PRT, while NOV induced a moderate SACort increase. The individual differences in SACort were related to age and sex (NOV), while the effects of zoo, handling method (free vs. protected contact) and reproductive and social status were variable. We conclude that positive affective states, such as anticipation or arousal, should be taken into account when interpreting the differences in the SACort responses between PRT and NOV. In addition, understanding the individuality of stress will support management decisions aimed at promoting captive elephant welfare.


Is Teledermoscopy Ready to Replace Face-to-Face Examinations for the Early Detection of Skin Cancer? Consumer Views, Technology Acceptance, and Satisfaction with Care.
Previous cross-sectional research indicates high acceptance of mobile teledermoscopy-enhanced skin self-examination (SSE) by consumers based on the technology acceptance model (TAM) domains: perceived usefulness, ease of use, compatibility, attitude and intention, subjective norms, facilitator, and trust. However, no study has assessed this outcome longitudinally among people who actually used the technology in their own homes. Participants were living in Brisbane, Australia, aged 18 years or older, and at high risk of skin cancer. Participants randomly assigned to the intervention group (n = 98) completed a self-administered questionnaire on mobile teledermoscopy acceptance for skin cancer detection both before use and after performing mobile teledermoscopy-enhanced SSE in their homes. The survey included a 25-item scale assessing seven TAM domains. Item scores ranged from 5 (strongly agree) to 1 (strongly disagree). Participants also answered survey questions on satisfaction with use of teledermoscopy, and a 9-item "thoughts about melanoma" scale that measures cancer worry. Participants were 19-73 years old, had high skin cancer risk, blue or grey eyes (53.1%), fair or very fair skin (88.8%), and previous skin cancer treatments (61.2%). Participants were more accepting of mobile teledermoscopy at baseline: mean TAM score of 4.15 (SE 0.05); their level of acceptance decreased significantly after teledermoscopy use: mean score 3.94 (SE 0.05; p = 0.001). In linear regression analysis, the decrease in TAM scores was similar across demographic and skin cancer risk categories. Ninety-two percent (n = 90) of participants agreed that mobile teledermoscopy was easy to use. The mean score of the "thoughts about melanoma" scale did not change significantly from baseline to follow-up. Consumers had high TAM scores before they used mobile teledermoscopy within a randomised control trial. At the end of the intervention period, TAM scores decreased, although participants' average score still indicated "agreement" that mobile teledermoscopy was acceptable.


Semantic network mapping of religious material: testing multi-agent computer models of social theories against real-world data.
Agent-based modeling allows researchers to investigate theories of complex social phenomena and subsequently use the model to generate new hypotheses that can then be compared to real-world data. However, computer modeling has been underutilized in regard to the understanding of religious systems, which often require very complex theories with multiple interacting variables (Braxton et al. in Method Theory Study Relig 24(3):267-290, 2012. doi: 10.1163/157006812X635709 ; Lane in J Cogn Sci Relig 1(2):161-180, 2013). This paper presents an example of how computer modeling can be used to explore, test, and further understand religious systems, specifically looking at one prominent theory of religious ritual. The process is continuous: theory building, hypothesis generation, testing against real-world data, and improving the model. In this example, the output of an agent-based model of religious behavior is compared against real-world religious sermons and texts using semantic network analysis. It finds that most religious materials exhibit unique scale-free small-world properties and that a concept's centrality in a religious schema best predicts its frequency of presentation. These results reveal that there adjustments need to be made to existing models of religious ritual systems and provide parameters for future models. The paper ends with a discussion of implications for a new multi-agent model of doctrinal ritual behaviors as well as propositions for further interdisciplinary research concerning the multi-agent modeling of religious ritual behaviors.


Hovering between suffering and enduring: the meaning of living with serious chronic illness.
Illness is part of life and hence always has a place in a life history. All that went on before the time of the illness, how life was in the past and what hopes and dreams were interrupted and changed, all influence the experiences of illness. The authors interviewed 5 women and 5 men with different kinds of serious chronic illnesses and used phenomenological hermeneutic method to interpret the transcribed interviews. They present the findings in three major themes: experiencing the body as a hindrance, being alone in illness, and struggling for normalcy. Participants seemed to hover between an escape from the emotional suffering pain of illness and the emotionless state of enduring. The comprehensive understanding illuminated that living with a serious chronic illness means living a life that is hovering between enduring and suffering but also including the process of reformulation of the self.


On differences between the preovulatory luteinizing hormone surges of 4- and 5-day cyclic rats.
Preovulatory LH surges were studied in rats with ovarian cycles of 4 days (4d-rats) and 5 days (5d-rats). In 5d-rats the maximal peak height was about twice that observed in 4d-rats, whereas in 4d-rats peaks occurred about 1-5 h later than in 5d-rats and were much less consistently timed. From experiments in which LH releasing hormone (LH-RH) was infused into pentobarbitone-blocked pro-oestrous rats, it was concluded that (a) differences between the two types of preovulatory LH surges originate within the central nervous system, and (b) pro-oestrous LH-RH secretion may not be restricted to the period in which increased LH levels in blood were found, but may exceed this period for a considerable time.


Procedural Treatments for Knee Osteoarthritis: A Review of Current Injectable Therapies.
Knee osteoarthritis is a common painful degenerative condition affecting the aging Canadian population. In addition to pain and disability, osteoarthritis is associated with depression, comorbid conditions such as diabetes, and increased caregiver burden. It is predicted to cost the Canadian healthcare system $7.6 billion dollars by 2031. Despite its high cost and prevalence, controversy persists in the medical community regarding optimal therapies to treat knee osteoarthritis. A variety of medications like nonsteroidal anti-inflammatories and opioids can cause severe side effects with limited benefits. Total knee arthroplasty, although a definitive management, comes with risk such as postoperative infections, revisions, and chronic pain. Newer injectable therapies are gaining attention as alternatives to medications because of a safer side effect profile and are much less invasive than a joint replacement. Platelet-rich plasma is beginning to replace the more common injectable therapies of intra-articular corticosteroids and hyaluronic acid, but larger trials are needed to confirm this effect. Small studies have examined prolotherapy and stem cell therapy and demonstrate some benefits. Trials involving genicular nerve block procedures have been successful. As treatments evolve, injectable therapies may offer a safe and effective pathway for patients suffering from knee osteoarthritis.


Islet Amyloid in Patients With Diabetes Due to Exocrine Pancreatic Disorders, Type 2 Diabetes, and Nondiabetic Patients.
Amyloid deposits are a typical finding in pancreatic islets from patients with type 2 diabetes. Whether this is linked to the pathogenesis of type 2 diabetes is currently unknown. Therefore, we compared the occurrence of islet amyloid in patients with type 2 diabetes, diabetes secondary to pancreatic disorders, and nondiabetic individuals. Pancreatic tissue from 15 nondiabetic patients, 22 patients with type 2 diabetes, and 11 patients with diabetes due to exocrine pancreatic disorders (chronic pancreatitis, pancreatic carcinoma) were stained for insulin, amyloid, and apoptosis. β-cell area, amyloid deposits, and β-cell apoptosis were quantified by morphometric analysis. The proportion of islets containing amyloid deposits was significantly higher in both type 2 diabetes and diabetes due to exocrine pancreatic disorders than in healthy subjects. Islets with both amyloid and apoptosis were observed more frequently in type 2 diabetes and significantly more so in diabetes due to exocrine pancreatic disorders. In both diabetic groups, apoptotic ß-cells were found significantly more frequently in islets with more prominent amyloid deposits. The occurrence of amyloid deposits in both type 2 diabetes and diabetes secondary to exocrine pancreatic disorders suggests that islet amyloid formation is a common feature of diabetes mellitus of different etiologies and may be associated with a loss of pancreatic ß-cells.


Alterations in neutrophil superoxide production following piroxicam therapy in patients with rheumatoid arthritis.
Twenty patients with classical rheumatoid arthritis were enrolled in a study to determine the effects of piroxicam therapy on neutrophil function as defined by chemotaxis and superoxide anion (O2-) production. T-lymphocyte chemotaxis was also evaluated in these patients. Leukocytes were obtained from these subjects initially, after two weeks of placebo treatment, and subsequently after four and 10 weeks of piroxicam therapy (20 mg, once daily). Responses were compared to simultaneously tested normal controls and to the patient's own cells obtained at the different time points. Studies showed that four and 10 weeks of piroxicam therapy resulted in significantly suppressed neutrophil O2- production in response to phorbol myristate acetate (PMA) and formyl methionyl leucyl phenylalanine (FMLP). O2- production in response to opsonized zymosan was not significantly affected after four weeks of therapy, but was significantly reduced after 10 weeks of therapy when compared to the patient's own cell response after two weeks of placebo treatment. Unlike O2- production, PMN random migration and chemotaxis in response to C5a or FMLP did not differ significantly from normal or untreated patient controls. Analysis of T-lymphocyte migration showed that T-cell random migration or migration to the chemokinetic agent, casein, was not significantly altered by piroxicam therapy. However, when T lymphocytes were tested for chemotaxis in response to lymphocyte-derived chemotactic factor for T cells (LCF), T cell migration was significantly suppressed after 10 weeks of therapy. Furthermore, when T cells from these subjects were cultured for 24 h, random migration was significantly reduced after four and 10 weeks of piroxicam therapy when compared to the patient prior to therapy, and migration in response to LCF was suppressed after four weeks of therapy when compared to normal controls. These data indicate that in patients with rheumatoid arthritis, treatment with piroxicam will significantly suppress PMN O2- production and may also alter the locomotor capacity of T lymphocytes. These actions may contribute to the antiinflammatory effects of piroxicam.


Doxycycline in serum and bronchial secretions.
The concentration of doxycycline hydrochloride was measured in serum and bronchial secretions in five patients with chronic bronchitis receiving doxycycline orally in normal therapeutic dosage for seven days (200 mg day 1, 100 mg days 2 to 7). After the loading dose of 200 mg, serum concentrations ranged between 5-40 and 3-45 mug/ml (mean 4-33 mug/ml) at 3 hours, declining to between 2-28 and 1-21 mug/ml (mean 1-71 mug/ml) at 23 hours. The mean serum levels for days 2 to 7 were 2-15, 1-79, and 1-38 at 3, 8, and 23 hours respectively. There was considerable individual variability and a wide range of concentrations of doxycycline in the sputum (0-07 to 2-10 mug/ml, mean 0-34 mug/ml). During the course of treatment there was a progressive increase in sputum levels and sputum/serum concentration ratios. There was no correlation between sputum concentration and degree of purulence. The clinical efficacy of doxycycline does not appear to be related to sputum concentration, although the progressive increase in sputum doxycycline levels may be relevant in preventing recurrence of acute infection when the drug is administered as long-term prophylactic therapy.


The effects of relaxation on reducing depression, anxiety and stress in women who underwent mastectomy for breast cancer.
Breast cancer is one of the most frequent malignancies among Iranian women. These patients suffer from a wide range of physical and mental (depression, anxiety and stress) signs and symptoms during the diagnostic and therapeutic processes. Despite the improvement in survival rates due to advances in medical care, different types of psychosocial interventions are still growingly needed considering the increasing number of cancer patients with longer survival times. The objective of this study was to determine the effect of relaxation on depression, anxiety and stress in women who underwent mastectomy for breast cancer. This clinical trial was conducted during about 4.5 months in a referral chemotherapy clinic of a teaching hospital in Isfahan, Iran. The participants consisted of 48 breast cancer patients who were selected by simple random sampling. They were randomly assigned into two groups of control and case. The control group was treated only by usual medical therapy, whereas the case group was treated by combined medical-relaxation therapy. Data collection tools were the validated Depression, Anxiety and Stress Scale (DASS42) and a demographic questionnaire. Data were analyzed by SPSS using descriptive statistics, repeated measures analysis of variance (ANOVA), chi-square test and paired t-test.. The baseline mean scores of depression, anxiety and stress were not significantly different between the case and control groups. However, the scores in the case group improved significantly after the treatment (p < 0.05). On the contrary, such improvement was not seen in the control group. Relaxation therapy can be effective in the improvement of depression, anxiety and stress. Therefore, it can be recommended as an effective care program in patients with malignant disorders.


Health promotion lifestyle interventions for weight management in psychosis: a systematic review and meta-analysis of randomised controlled trials.
Psychiatric patients have more physical health problems and much shorter life expectancies compared to the general population, due primarily to premature cardiovascular disease. A multi-causal model which includes a higher prevalence of risk factors has provided a valid explanation. It takes into consideration not only risks such as gender, age, and family history that are inherently non-modifiable, but also those such as obesity, smoking, diabetes, hypertension, and dyslipidemia that are modifiable through behavioural changes and improved care. Thus, it is crucial to focus on factors that increase cardiovascular risk. Obesity in particular has been associated with both the lifestyle habits and the side effects of antipsychotic medications. The present systematic review and meta-analysis aims at collecting and updating available evidence on the efficacy of non-pharmacological health promotion programmes for psychotic patients in randomised clinical trials. We systematically reviewed the randomised controlled trials from 1990 onward, in which psychoeducational and/or cognitive-behavioural interventions aimed at weight loss or prevention of weight gain in patients with psychosis had been compared to treatment as usual. We carried out a meta-analysis and pooled the results of the studies with Body Mass Index as primary outcome. The results of the meta-analysis show an effect toward the experimental group. At the end of the intervention phase there is a -0.98 kg/m(2) reduction in the mean Body Mass Index of psychotic subjects. Notably, prevention studies with individual psychoeducational programmes that include diet and/or physical activity seem to have the highest impact. When compared with treatment as usual in psychotic patients, preventive and individual lifestyle interventions that include diet and physical activity generally prove to be effective in reducing weight. Physical screening and monitoring programmes are well accepted by patients and can be implemented in a variety of settings. A weight loss of 0.98 points in the Body Mass Index corresponds to a loss of 3.12% of the initial weight. This percentage is below the 5% to 10% weight loss deemed sufficient to improve weight-related complications such as hypertension, type II diabetes, and dyslipidemia. However, it is reported that outcomes associated with metabolic risk factors may have greater health implications than weight changes alone. Therefore, in addition to weight reduction, the assessment of metabolic parameters to monitor other independent risk factors should also be integrated into physical health promotion and management in people with mental disorders.


Further investigations regarding the role of trimethyllysine for cytochrome c uptake into mitochondria.
1. A mutant of the iso-1-cytochrome c gene from Saccharomyces cerevisiae has been constructed which contains an Arg codon, replacing the normal trimethylated Lys at position 77. 2. This mutated gene was cloned into a pGem 1 vector and used for the in vitro translation of yeast iso-1-cytochrome c. 3. Utilizing an in vitro mitochondria binding assay, it was found that the mutant cytochrome c could transverse the yeast mitochondrial membrane, however the amount of protein incorporated was 3-fold less that of the trimethylated wild type. 4. Omission of the protein methyltransferase from assays containing the wild type cytochrome c caused only a slight reduction (15%) in the amount of protein incorporated. 5. These results suggest while the lysine residue 77 of apocytochrome c is important for mitochondria uptake, the methylation of this residue seems to play a relatively minor role.


The prehospital quick SOFA score is associated with in-hospital mortality in noninfected patients: A retrospective, cross-sectional study.
This study aimed to determine the accuracy of the quick Sequential Organ Failure Assessment (qSOFA) score in predicting mortality among prehospital patients with and without infection. This single-center, retrospective, cross-sectional study was conducted among patients who arrived via the emergency medical services (EMS). We calculated the qSOFA score and Modified Early Warning Score (MEWS) from prehospital records. We identified patients as infected if they received intravenous antibiotics at the emergency department or within the first 24 hours. Receiver operating characteristic analysis was used to evaluate and compare the performance of the qSOFA score, each physiological parameter, and the MEWS in predicting admission and in-hospital mortality in patients with and without infection. Multivariate analysis was used to evaluate the qSOFA score and other risk factors. Out of 1574 prehospital patients, 47.1% were admitted and 3.2% died in the hospital. The performance of the qSOFA score in predicting in-hospital mortality in noninfected patients was 0.70, higher than for each parameter and the MEWS. The areas under the curve for the qSOFA+ model vs. the qSOFA- model was 0.77 vs. 0.68 for noninfected patients (p <0.05) and 0.71 vs. 0.68 for infected patients (p = 0.41). The likelihood ratio test comparing the qSOFA- and qSOFA+ groups demonstrated significant improvement for noninfected patients (p <0.01). Multivariate regression analysis for in-hospital mortality demonstrated that the qSOFA score is an independent prognosticator for in-hospital mortality, especially among noninfected patients (odds ratio, 3.60; p <0.01). In conclusion, the prehospital qSOFA score was associated with in-hospital mortality in noninfected patients and may be a beneficial tool for identifying deteriorating patients in the prehospital setting.


Identification of the volatile compounds produced in sterile fish muscle (Sebastes melanops) by Pseudomonas fragi.
Volatile compounds produced by Pseudomonas fragi strain 18 in sterile fish muscle (Sebastes melanops) were identified by combined gas-liquid chromatography and mass spectrometry. Compounds positively identified included dimethyl sulfide, acetaldehyde, ethyl acetate, ethyl alcohol, and dimethyl disulfide. Methyl mercaptan, ethyl butyrate, ethyl hexanoate, and butanone were tentatively identified by relative retention times of the authentic compounds. The fruity odor that developed in fish muscle during incipient spoilage was attributed to a synergistic flavor interaction involving the ethyl esters of acetate, butyrate, and hexanoate.


Molecular basis of weak D phenotypes.
A Rhesus D (RhD) red blood cell phenotype with a weak expression of the D antigen occurs in 0.2% to 1% of whites and is called weak D, formerly Du. Red blood cells of weak D phenotype have a much reduced number of presumably complete D antigens that were repeatedly reported to carry the amino acid sequence of the regular RhD protein. The molecular cause of weak D was unknown. To evaluate the molecular cause of weak D, we devised a method to sequence all 10 RHD exons. Among weak D samples, we found a total of 16 different molecular weak D types plus two alleles characteristic of partial D. The amino acid substitutions of weak D types were located in intracellular and transmembraneous protein segments and clustered in four regions of the protein (amino acid positions 2 to 13, around 149, 179 to 225, and 267 to 397). Based on sequencing, polymerase chain reaction-restriction fragment length polymorphism and polymerase chain reaction using sequence-specific priming, none of 161 weak D samples investigated showed a normal RHD exon sequence. We concluded, that in contrast to the current published dogma most, if not all, weak D phenotypes carry altered RhD proteins, suggesting a causal relationship. Our results showed means to specifically detect and to classify weak D. The genotyping of weak D may guide Rhesus negative transfusion policy for such molecular weak D types that were prone to develop anti-D.


Isolation and RFLP genotyping of Toxoplasma gondii from the mongoose (Herpestes auropunctatus) in Grenada, West Indies.
Little is known of the genetic diversity and epidemiology of Toxoplasma gondii infection in wildlife in Caribbean Islands. The prevalence and genetic diversity of T. gondii in mongooses (Herpestes auropunctatus) was investigated. During 2011 and 2012, 91 mongooses were trapped in different parts of Grenada, bled, euthanized, and examined at necropsy. Antibodies to T. gondii were found in 27 mongooses tested by the modified agglutination test (cut-off titer 25). Muscles (heart, tongue, neck) of 25 of the seropositive mongooses were bioassayed for T. gondii infection in mice. Viable T. gondii was isolated by bioassay in mice from four mongooses with MAT titers of 1:50 in two, 1:200 for one, and 1:400 for one mongoose. The four T. gondii isolates were further propagated in cell culture. Strain typing of T. gondii DNA extracted from cell-cultured tachyzoites using the 10 PCR-restriction fragment length polymorphism (RFLP) markers SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico revealed one isolate belongs to the Type III (ToxoDB #2) lineage, two to ToxoDB#7 lineage, and one to the ToxoDB #216 lineage. This is the first report of T. gondii isolation and genotyping in H. auropunctatus worldwide.


Estimation of independent and dependent components of non-invasive EMG using fast ICA: validation in recognising complex gestures.
The identification of a number of active muscles during complex actions is the useful information to identify different gestures. Biosignals such as surface electromyogram (sEMG) are a result of the summation of electrical activity of a number of sources. The complexity of the anatomy and actions makes it difficult in identifying the number of active sources from the multiple channel recordings. This paper addresses two applications of independent component analysis (ICA) on sEMG: the first one is to evaluate the use of ICA for the separation of bioelectric signals when the number of active sources may not be known. The second application is to identify complex hand gestures using decomposed sEMG. The theoretical analysis and experimental results demonstrate that the ICA is suitable for the separation of myoelectric signals. The results identify the usage of ICA for identifying complex gestures.


Stroke target identification guided by astrocyte transcriptome analysis.
Astrocytes support normal brain function, but may also contribute to neurodegeneration when they become reactive under pathological conditions such as stroke. However, the molecular underpinnings of this context-dependent interplay between beneficial and detrimental properties in reactive astrogliosis have remained incompletely understood. Therefore, using the RiboTag technique, we immunopurified translating mRNAs specifically from astrocytes 72 hr after transient middle cerebral artery occlusion in mice (tMCAO), thereby generating a stroke-specific astroglial translatome database. We found that compared to control brains, reactive astrocytes after tMCAO show an enrichment of transcripts linked to the A2 phenotype, which has been associated with neuroprotection. However, we found that astrocytes also upregulate a large number of potentially neurotoxic genes. In total, we identified the differential expression of 1,003 genes and 38 transcription factors, of which Stat3, Sp1, and Spi1 were the most prominent. To further explore the effects of Stat3-mediated pathways on stroke pathogenesis, we subjected mice with an astrocyte-specific conditional deletion of Stat3 to tMCAO, and found that these mice have reduced stroke volume and improved motor outcome 72 hr after focal ischemia. Taken together, our study extends the emerging database of novel astrocyte-specific targets for stroke therapy, and supports the role of astrocytes as critical safeguards of brain function in health and disease.


Frequency of Alloicoccus otitidis, Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae in children with otitis media with effusion (OME) in Iranian patients.
To determine the presence of common bacterial agents of otitis media with effusion (OME), together with investigation these agent in the adenoid tissue and antimicrobial susceptibility pattern of isolated bacteria in Iranian children with OME. Polymerase chain reaction (PCR) and bacterial culture methods were used for detection and isolation of Alloicoccus otitidis, Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae in 63 middle ear fluid samples and 48 adenoid tissues from 48 OME patients. Fifteen patients were bilaterally affected. Antimicrobial susceptibility of all bacterial isolates were determined by disk agar diffusion (DAD) method. Bacteria were isolated from 47% (n=30) of the middle ear fluid samples and 79% (n=38) of the adenoid tissue specimens in OME patients. A. otitidis was the most common bacterial isolated from the middle ear fluid 23.8% by culture and 36.5% by PCR method. S. pneumoniae was the most prevalent pathogen (35.5% and 31.2% by culture and PCR) in the adenoid tissues. In 10 patients the same organisms were isolated from the middle ear fluid and adenoid tissue. Antimicrobial susceptibility pattern showed taht most isolates of bacteria were sensitive to ampicillin, Amoxicillin/Clavulanate and fluoroquinolones. The present study, being the first report on the isolation of A. otitidis by culture method in Iran and Asian countries, shows that A. otitidis is the most frequently isolated bacterium in Iranian children having otitis media with effusion. In this study A. otitidis, S. pneumoniae, H. influenzae and M. catarrhalis are the major bacterial pathogens in patients with OME and we found that ampicillin and Amoxicillin/Clavulanate have the excellent activity against bacterial agents in Iranian children with OME.


Incidence of Artifacts and Deviating Values in Research Data Obtained from an Anesthesia Information Management System in Children.
Vital parameter data collected in anesthesia information management systems are often used for clinical research. The validity of this type of research is dependent on the number of artifacts. In this prospective observational cohort study, the incidence of artifacts in anesthesia information management system data was investigated in children undergoing anesthesia for noncardiac procedures. Secondary outcomes included the incidence of artifacts among deviating and nondeviating values, among the anesthesia phases, and among different anesthetic techniques. We included 136 anesthetics representing 10,236 min of anesthesia time. The incidence of artifacts was 0.5% for heart rate (95% CI: 0.4 to 0.7%), 1.3% for oxygen saturation (1.1 to 1.5%), 7.5% for end-tidal carbon dioxide (6.9 to 8.0%), 5.0% for noninvasive blood pressure (4.0 to 6.0%), and 7.3% for invasive blood pressure (5.9 to 8.8%). The incidence of artifacts among deviating values was 3.1% for heart rate (2.1 to 4.4%), 10.8% for oxygen saturation (7.6 to 14.8%), 14.1% for end-tidal carbon dioxide (13.0 to 15.2%), 14.4% for noninvasive blood pressure (10.3 to 19.4%), and 38.4% for invasive blood pressure (30.3 to 47.1%). Not all values in anesthesia information management systems are valid. The incidence of artifacts stored in the present pediatric anesthesia practice was low for heart rate and oxygen saturation, whereas noninvasive and invasive blood pressure and end-tidal carbon dioxide had higher artifact incidences. Deviating values are more often artifacts than values in a normal range, and artifacts are associated with the phase of anesthesia and anesthetic technique. Development of (automatic) data validation systems or solutions to deal with artifacts in data is warranted.


Adaptive synchronization of a switching system and its applications to secure communications.
This paper studies the adaptive synchronization of a switching system with unknown parameters which switches between the Rössler system and a unified chaotic system. Using the Lyapunov stability theory and adaptive control method, the receiver system will achieve synchronization with the drive system and the unknown parameters would be estimated by the receiver. Then the proposed switching system is used for secure communications based on the communication schemes including chaotic masking, chaotic modulation, and chaotic shift key strategies. Since the system switches between two chaotic systems and the parameters are almost unknown, it is more difficult for the intruder to extract the useful message from the transmission channel. In addition, two new schemes in which the chaotic signal used to mask (or modulate) the transmitted signal switches between two components of a chaotic system are also presented. Finally, some simulation results are given to show the effectiveness of the proposed communication schemes.


A fatal intoxication case involving topiramate.
Topiramate belongs to a new group of anticonvulsive drugs primarily applied in treatment of epilepsy and in preventive therapy of migraines. Topiramate is structurally unrelated to other antiepileptic drugs and acts by multiple neurostabilizing mechanisms. However, the pharmacology of topiramate appears to be complex and some of its pharmacodynamic actions still remain to be elucidated. This case report documents a fatal intoxication involving topiramate. A 41-year old woman with a known history of psychiatric disorder was found unresponsive by her husband. Resuscitation efforts did not succeed and the woman was pronounced dead at the intensive care unit four hours later. At the scene, drug packages of topiramate, citalopram and flunitrazepam were found. Autopsy including histological examination revealed morphological signs of an acute intoxication and shock. A comprehensive toxicological analysis with GC-MS was performed on the deceased's autopsy samples (femoral blood, bile, kidney, gastric content). The results revealed the presence of topiramate at a concentration of 49mg/L in the femoral blood sample, thus clearly exceeding the therapeutic range. Additionally, citalopram (0.85mg/L) and flunitrazepam in traces (<2μg/L) were detected in peripheral blood. Based on the autopsy findings and toxicological results, the cause of death was primarily attributed to an intoxication with topiramate in combination with citalopram.


Investigation of peak pressure index parameters for people with spinal cord injury using wheelchair tilt-in-space and recline: methodology and preliminary report.
The purpose of this study was to determine the effect of the sensel window's location and size when calculating the peak pressure index (PPI) of pressure mapping with varying degrees of wheelchair tilt-in-space (tilt) and recline in people with spinal cord injury (SCI). Thirteen power wheelchair users were recruited into this study. Six combinations of wheelchair tilt (15°, 25°, and 35°) and recline (10° and 30°) were used by the participants in random order. Displacements of peak pressure and center of pressure were extracted from the left side of the mapping system. Normalized PPI was computed for three sensel window dimensions (3 sensels × 3 sensels, 5 × 5, and 7 × 7). At least 3.33 cm of Euclidean displacement of peak pressures was observed in the tilt and recline. For every tilt angle, peak pressure displacement was not significantly different between 10° and 30° recline, while center of pressure displacement was significantly different (P < .05). For each recline angle, peak pressure displacement was not significantly different between pairs of 15°, 25°, and 35° tilt, while center of pressure displacement was significantly different between 15° versus 35° and 25° versus 35°. Our study showed that peak pressure displacement occurs in response to wheelchair tilt and recline, suggesting that the selected sensel window locations used to calculate PPI should be adjusted during changes in wheelchair configuration.


A novel KCNJ5-insT149 somatic mutation close to, but outside, the selectivity filter causes resistant hypertension by loss of selectivity for potassium.
Understanding the function of the KCNJ5 potassium channel through characterization of naturally occurring novel mutations is key for dissecting the mechanism(s) of autonomous aldosterone secretion in primary aldosteronism. We sought for such novel KCNJ5 channel mutations in a large database of patients with aldosterone-producing adenomas (APAs). We discovered a novel somatic c.446insAAC insertion, resulting in the mutant protein KCNJ5-insT149, in a patient with severe drug-resistant hypertension among 195 consecutive patients with a conclusive diagnosis of APA, 24.6% of whom showed somatic KCNJ5 mutations. By site-directed mutagenesis, we created the mutated cDNA that was transfected, along with KCNJ3 cDNA, in mammalian cells. We also localized CYP11B2 in the excised adrenal gland with immunohistochemistry and immunofluorescence using an antibody specific to human CYP11B2. Whole-cell patch clamp recordings, CYP11B2 mRNA, aldosterone measurement, and molecular modeling were performed to characterize the novel KCNJ5-insT149 mutation. Compared with wild-type and mock-transfected adrenocortical cells, HAC15 cells expressing the mutant KCNJ5 showed increased CYP11B2 expression and aldosterone secretion. Mammalian cells expressing the mutated KCNJ5-insT149 channel exhibited a strong Na(+) inward current and, in parallel, a substantial rise in intracellular Ca(2+), caused by activation of voltage-gated Ca(2+) channels and reduced Ca(2+) elimination by Na(+)/Ca(2+) exchangers, as well as an increased production of aldosterone. This novel mutation shows pathological Na(+) permeability, membrane depolarization, raised cytosolic Ca(2+), and increased aldosterone synthesis. Hence, a novel KCNJ5 channelopathy located after the pore α-helix preceding the selectivity filter causes constitutive secretion of aldosterone with ensuing resistant hypertension in a patient with a small APA.


The structure of a T = 1 icosahedral empty particle from southern bean mosaic virus.
The structure of a T = 1 icosahedral particle (where T is the triangulation number), assembled from southern bean mosaic virus coat protein fragments that lacked the amino-terminal arm, was solved by means of model building procedures with the use of 6-angstrom resolution x-ray diffraction data. The icosahedral five-, three-, and twofold contacts were found to be similar, at this resolution, to the analogous contacts (icosahedral five-, quasi-three-, and quasi-twofolds) found in the parent T = 3 southern bean mosaic virus. However, the icosahedral fivefold contacts of the T = 3 structure are the most conserved in the T = 1 capsid. These results are consistent with a mechanism in which pentameric caps of dimers are the building blocks for the assembly of T = 1 and T = 3 icosahedral viruses.


Early socioeconomic adversity and young adult diabetic risk: an investigation of genetically informed biopsychosocial processes over the life course.
The present study investigated a comprehensive model that integrates contributions of early socioeconomic adversity (ESA) and multiple polygenic scores (PGSs) through different mechanisms leading to diabetic risk in early adulthood. The study used prospective, longitudinal data from the National Longitudinal Study of Adolescent and Adult Health (Add Health) with a sample of 5,728 youth of European ancestry. The results showed that both ESA and PGSs were involved in different mechanisms. ESA contributed additively to educational failures, BMI, depressive symptoms, and diabetes risk over the life course (an additive process). Also, ESA launched a cascading process that connected these outcomes in a successively contingent manner. In addition to ESA, youths' multiple PGSs directly contributed to educational, psychological, and BMI outcomes. Multiple PGSs for education, BMI, and type 2 diabetes influenced not only youth outcomes that they were supposed to predict directly but also additional youth outcomes showing biological pleiotropy. The findings highlight the value of incorporating molecular genetic information into longitudinal developmental life course research and provide insight into malleable characteristics and appropriate timing for interventions addressing youth developmental and health outcomes.


How direction of illumination affects visually perceived surface roughness.
We examined visual estimation of surface roughness using random, computer-generated, three-dimensional (3D) surfaces rendered under a mixture of diffuse lighting and a punctate source. The angle between the tangent to the plane containing the surface texture and the direction to the punctate source was varied from 50 to 70 deg across lighting conditions. Observers were presented with pairs of surfaces under different lighting conditions and indicated which 3D surface appeared rougher. Surfaces were viewed either in isolation or in scenes with added objects whose shading, cast shadows, and specular highlights provided information about the spatial distribution of illumination. All observers perceived surfaces to be markedly rougher with decreasing illuminant angle. Performance in scenes with added objects was no closer to constant than that in scenes without added objects. We identified four novel cues that are valid cues to roughness under any single lighting condition but that are not invariant under changes in lighting condition. We modeled observers' deviations from roughness constancy as a weighted linear combination of these "pseudocues" and found that they account for a substantial amount of observers' systematic deviations from roughness constancy with changes in lighting condition.


von Willebrand factor abnormalities in aortic valve stenosis: Pathophysiology and impact on bleeding.
Acquired von Willebrand syndrome (AVWS) may complicate severe aortic valve stenosis, due to a reduction in the haemostatically more efficient large von Willebrand factor (VWF) multimers. This study was designed to analyse the relevance of VWF abnormalities and haemorrhagic diathesis in severe aortic valve stenosis. Forty-one consecutive patients undergoing valve replacement were investigated: seven had minor bleeding symptoms in their recent history; 10 (24.3%) had a reduced VWF collagen binding (VWF:CB) to VWF antigen ratio, and 33 (80.5%) had a decrease in large VWF multimers. The shortage of large multimers was not associated with any accumulation of small VWF multimers (apparently ruling out any increased VWF proteolysis), nor was there any increase in VWF propeptide, which excludes a shorter VWF survival. The risk of developing VWF abnormalities was higher in patients with rheumatic valve disease than in degenerative cases (p=0.025) and in valves with <50% of residual endothelial cells (p=0.004). Bleeders differed from non-bleeders in that they had a higher mean transvalvular gradient and a more marked decrease in large VWF multimers. VWF abnormalities did not exacerbate peri-operative blood loss, however - a finding consistent with the full correction of these VWF abnormalities, seen already on the first postoperative day and persisting for up to six months after surgery. According to the data obtained in our cohort of patients VWF abnormalities are common in severe aortic stenosis, particularly in cases of rheumatic valve disease, but loss of the largest multimers does not seem to cause clinical bleeding in most patients.


Optimal antiviral switching to minimize resistance risk in HIV therapy.
The development of resistant strains of HIV is the most significant barrier to effective long-term treatment of HIV infection. The most common causes of resistance development are patient noncompliance and pre-existence of resistant strains. In this paper, methods of antiviral regimen switching are developed that minimize the risk of pre-existing resistant virus emerging during therapy switches necessitated by virological failure. Two distinct cases are considered; a single previous virological failure and multiple virological failures. These methods use optimal control approaches on experimentally verified mathematical models of HIV strain competition and statistical models of resistance risk. It is shown that, theoretically, order-of-magnitude reduction in risk can be achieved, and multiple previous virological failures enable greater success of these methods in reducing the risk of subsequent treatment failures.


Correlation of the dynamics of native human acetylcholinesterase and its inhibited huperzine A counterpart from sub-picoseconds to nanoseconds.
It is a long debated question whether catalytic activities of enzymes, which lie on the millisecond timescale, are possibly already reflected in variations in atomic thermal fluctuations on the pico- to nanosecond timescale. To shed light on this puzzle, the enzyme human acetylcholinesterase in its wild-type form and complexed with the inhibitor huperzine A were investigated by various neutron scattering techniques and molecular dynamics simulations. Previous results on elastic neutron scattering at various timescales and simulations suggest that dynamical processes are not affected on average by the presence of the ligand within the considered time ranges between 10 ps and 1 ns. In the work presented here, the focus was laid on quasi-elastic (QENS) and inelastic neutron scattering (INS). These techniques give access to different kinds of individual diffusive motions and to the density of states of collective motions at the sub-picoseconds timescale. Hence, they permit going beyond the first approach of looking at mean square displacements. For both samples, the autocorrelation function was well described by a stretched-exponential function indicating a linkage between the timescales of fast and slow functional relaxation dynamics. The findings of the QENS and INS investigation are discussed in relation to the results of our earlier elastic incoherent neutron scattering and molecular dynamics simulations.


[Stevens-Johnson syndrome and toxic epidermal necrolysis in children].
The Stevens-Johnson syndrome (SJS) and the toxic epidermal necrolysis (TEN) are clinical conditions manifesting as adverse cutaneous reaction to drugs in majority of cases, constituting the same clinical spectrum, differing only in the severity of epidermolysis; both conditions are distinguished by their severity and extensiveness of skin lesions; it can also involve mucous membranes of eyes, respiratory, digestive and urogenital tracts. Two per 1,000,000 are affected annually, among them approximately 20% are children and both of them are considered as potentially fatal medical emergency conditions. Even though the condition was described 89 years ago, until now the exact pathophysiology has not been completely explained. An immune-mediated mechanism has been implicated in its origin, which involves cytotoxic lymphocytes, cytokines, Fas-ligand in keratinocyte apoptosis; genetic makers also has been identified in some racial groups (HLA-B*1520, HLA-B*5801) in relationship with specific susceptibility to certain drugs such as carbamazepine, allopurinol. In children there are no uniform criteria for classification of the skin lesions, neither for the treatment, however recently the authors describe better response of the patients with use intravenous immunoglobulin (IGIV).


Identification of consensus biomarkers for predicting non-genotoxic hepatocarcinogens.
The assessment of non-genotoxic hepatocarcinogens (NGHCs) is currently relying on two-year rodent bioassays. Toxicogenomics biomarkers provide a potential alternative method for the prioritization of NGHCs that could be useful for risk assessment. However, previous studies using inconsistently classified chemicals as the training set and a single microarray dataset concluded no consensus biomarkers. In this study, 4 consensus biomarkers of A2m, Ca3, Cxcl1, and Cyp8b1 were identified from four large-scale microarray datasets of the one-day single maximum tolerated dose and a large set of chemicals without inconsistent classifications. Machine learning techniques were subsequently applied to develop prediction models for NGHCs. The final bagging decision tree models were constructed with an average AUC performance of 0.803 for an independent test. A set of 16 chemicals with controversial classifications were reclassified according to the consensus biomarkers. The developed prediction models and identified consensus biomarkers are expected to be potential alternative methods for prioritization of NGHCs for further experimental validation.


Compromised axon initial segment integrity in EAE is preceded by microglial reactivity and contact.
Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal pathology in MS remain elusive. Evidence suggests that axonal pathology is a direct consequence of demyelination, as we and others have shown that the node of Ranvier disassembles following loss of myelin. In contrast to the node of Ranvier, we now show that the axon initial segment (AIS), the axonal domain responsible for action potential initiation, remains intact following cuprizone-induced cortical demyelination. Instead, we find that the AIS is disrupted in the neocortex of mice that develop experimental autoimmune encephalomyelitis (EAE) independent of local demyelination. EAE-induced mice demonstrate profound compromise of AIS integrity with a progressive disruption that corresponds to EAE clinical disease severity and duration, in addition to cortical microglial reactivity. Furthermore, treatment with the drug didox results in attenuation of AIS pathology concomitantly with microglial reversion to a less reactive state. Together, our findings suggest that inflammation, but not demyelination, disrupts AIS integrity and that therapeutic intervention may protect and reverse this pathology. GLIA 2016;64:1190-1209.


Haitian State Hospital Orthopedic Grand Rounds Series: A Virtual Curriculum to Address Global Surgery Needs.
Orthopedic Relief Services International (ORSI), in partnership with the Foundation for Orthopedic Trauma and the department of Orthopedic Surgery of La Paix University Hospital in Haiti, has developed a year-round Orthopedic Grand Round series. This series is moderated by Haitian faculty, features presentations by American orthopedic surgeons, and is broadcast to major state hospitals in Haiti for residents and attendings. To introduce clinical concepts and increase knowledge in an area that is medically underserved, especially in the field of orthopedics, through lectures that tailor to the educational needs of Haiti. Topics for lecture series are requested by Haitian attending orthopedic surgeons and residents in collaboration with American orthopedic surgeons to meet the educational needs of the residents in Haiti. These lectures reflect the case mix typically seen at state hospitals in Haiti and consider the infrastructural capacity of participating centers. Grand rounds are held an average of twice per month for an hour each, encompassing an educational lesson followed by an open forum for questions and case discussion. Feedback is taken from Haitian residents to ensure the sessions are beneficial to their learning. To date 95 sessions hosted by 32 lecturers have been completed over Zoom between the US and Haiti. The fourth year of the lecture series is currently ongoing with an expansion of topics. In an underserved medical area such as Haiti, programs that educate local surgeons are crucial to continuing the growth and development of the medical community. Programs like this have the potential to contribute to the educational infrastructure of countries in need, regardless of the specialty. The model of this program can be used to produce similar curricula in various specialties and areas around the world.


The influence of the stage of the estrous cycle and novel cows upon mounting activity of dairy cattle.
The objectives of this study were to determine directly if mounting activity in dairy cattle varied as a function of stage of the estrous cycle and to determine if mounting by cows could be stimulated when novel estrous cows were introduced. Detector cows were normally cycling. Estrous cows were ovariectomized and injected with estradiol cyprionate and progesterone to induce standing estrous behavior. Familiar estrous cows (prior exposure to detector cows) and novel estrous cows (no prior exposure to detector cows) encountered each detector cow (n = 19) in a one-on-one manner for a 10-min period. Mounting activity by detector cows was determined by observation on d 5, 10, 15, day of estrus and d 5 of the subsequent cycle (52). The first d 5 was considered an acclimation day and was deleted from the data because all estrous cows (n = 4) used were novel. These novel estrous cows then became familiar estrous cows on the subsequent days (10, 15, estrus, 52). On these days, familiar (n = 4) and novel (n = 2) estrous cows encountered individually each detector cow in a prearranged sequence. Stage of the estrous cycle influenced (P less than .001) the frequency of mounting by detector cows. Mounting activity of detector cows was inversely related (r = -.64, P less than .001) to concentrations of plasma progesterone. The introduction of novel estrous cows tended to stimulate (P = .07) mounting when all days were considered. In addition, the introduction of novel estrous cows stimulated (P less than .001) mounting on d 15 and 52. A second experiment was conducted to determine if the introduction of novel estrous cows stimulated mounting in the detector cows on the day of estrus if a longer encounter time (30 min) was used. A total of eight detector cows and eight estrous cows (four familiar and four novel) were used. When the detector cow was in standing estrus, she encountered one-on-one each of two familiar estrous cows and each of two novel estrous cows in a prearranged sequence for 30-min. The introduction of novel estrous cows stimulated (P = .001) mounting by the detector cows on the day of estrus (6.50 +/- .48 vs. 4.37 +/- .48 mounts for N and F cows, respectively). We conclude that mounting activity is reduced during midcycle and that the introduction of novel cows stimulated mounting activity on d 15, day of estrus and on d 5 of the estrous cycle.


The role of the cation in the solvation of cellulose by imidazolium-based ionic liquids.
We present a systematic molecular dynamics study examining the roles of the individual ions of different alkylimidazolium-based ionic liquids in the solvation of cellulose. We examine combinations of chloride, acetate, and dimethylphosphate anions paired with cations of increasing tail length to elucidate the precise role of the cation in solvating cellulose. In all cases we find that the cation interacts with the nonpolar domains of cellulose through dispersion interactions, while interacting electrostatically with the anions bound at the polar domains of cellulose. Furthermore, the structure and dimensions of the imidazolium head facilitate the formation of large chains and networks of alternating cations and anions that form a patchwork, satisfying both the polar and nonpolar domains of cellulose. A subtle implication of increasing tail length is the dilution of the anion concentration in the bulk and at the cellulose surface. We show how this decreased concentration of anions in the bulk affects hydrogen bond formation with cellulose and how rearrangements from single hydrogen bonds to multiple shared hydrogen bonds can moderate the loss in overall hydrogen bond numbers. Additionally, for the tail lengths examined in this study we observe only a very minor effect of tail length on the solvation structure and overall interaction energies.


Achilles tendon compositional and structural properties are altered after unloading by botox.
Tendon function and homeostasis rely on external loading. This study investigates the biological mechanisms behind tendon biomechanical function and how the mechanical performance is affected by reduced daily loading. The Achilles tendons of 16 weeks old female Sprague Dawley rats (n = 40) were unloaded for 5 weeks by inducing muscle paralysis with botulinum toxin injections in the right gastrocnemius and soleus muscles. The contralateral side was used as control. After harvest, the tendons underwent biomechanical testing to assess viscoelasticity (n = 30 rats) and small angle X-ray scattering to determine the structural properties of the collagen fibrils (n = 10 rats). Fourier transform infrared spectroscopy and histological staining (n = 10 rats) were performed to investigate the collagen and proteoglycan content. The results show that the stiffness increased in unloaded tendons, together with an increased collagen content. Creep and axial alignment of the collagen fibers were reduced. Stress-relaxation increased whereas hysteresis was reduced in response to unloading with botox treatment. Our findings indicate that altered matrix deposition relies on mechanical loading to reorganize the newly formed tissue, without which the viscoelastic behavior is impaired. The results demonstrate that reduced daily loading deprives tendons of their viscoelastic properties, which could increase the risk of injury.


Randomized clinical trial of intermittent pneumatic compression and low molecular weight heparin in trauma.
After trauma, up to 60 per cent of immobilized patients have been reported to develop a silent deep vein thrombosis (DVT). No large, prospective randomized trials have tested the efficacy of intermittent pneumatic compression (IPC) devices in these patients. A prospective randomized trial was performed of 442 patients who received thromboprophylaxis using either an IPC device or low molecular weight heparin (LMWH). Duplex imaging was performed on both legs on admission, and was repeated weekly thereafter until discharge, at 30 days or when there was a thrombotic event, whichever occurred first. There were no significant differences in time spent in intensive care, or the proportion of patients with pelvic fractures, spinal cord or head injuries between the two groups. Six patients (2.7 per cent) developed a DVT in the IPC group and one (0.5 per cent) in the LMWH group (P = 0.122). Pulmonary embolism occurred in one patient in each group. There were 13 minor bleeding episodes (four in the IPC group and nine in the LMWH group) and eight major bleeding episodes (four in each group), none of which required operative intervention. The low rate of thromboembolic complications and the cost savings suggest that IPC might be used safely and effectively for thromboprophylaxis in trauma patients.


Lipid differentiation in MP26 junction enriched membranes of bovine lens fiber cells.
The present study was undertaken to address the question whether lipid differentiation occurs in junctional domains which could imply a functional requirement for specific lipids in junctional structures. Junction enriched membranes were isolated from bovine lens fiber cells using Tris and urea treatment, and the presence of junctional structures was ascertained by electron microscopy. Enrichment in major intrinsic protein (MIP, MP26) was monitored by SDS polyacrylamide gel electrophoresis. Junctional lipids were extracted by a modified Folch procedure, to quantitatively recover cholesterol, and lipid classes were analyzed. While 99.5% of total lens protein was solubilized in the course of junction isolation, 43.9% of cell phospholipids (PL) and 64.1% of cell cholesterol (Chol) were conserved. Cholesterol was by far the predominant lipid in the junction enriched lens fiber cell membranes (833 nmol/mg protein) and was more abundant than all phospholipids combined (682 nmol/mg protein). In isolating the junctional membranes, cholesterol levels increased 144-fold, and average phospholipid levels increased 99-fold, which resulted in an increase in Chol/PL ratio from 0.84 to 1.22. Different phospholipids showed substantially different degrees of enrichment with highest enrichments seen for the phosphatidylethanolamine fraction (152-fold) and sphingomyelin (101-fold). Thus, the phospholipids of the junction enriched membranes consisted mainly of ethanolamine glycerophospholipids (37.3%) and sphingomyelin (28.6%), with lesser amounts of choline glycerophospholipids (23.5%) and phosphatidylserine (9.2%) present. Our data suggest that the MP26 junction enriched membranes of bovine lens fiber cells contain differentiated lipid domains, and that cholesterol, ethanolamine glycerophospholipids and sphingomyelin are the prevalent boundary lipids of the major intrinsic protein in these domains.


Copeptin concentration in cord blood in infants with early-onset sepsis, chorioamnionitis and perinatal asphyxia.
Vasopressin is one of the most important physiological stress and shock hormones. Copeptin, a stable vasopressin precursor, is a promising sepsis marker in adults. In contrast, its involvement in neonatal diseases remains unknown. The aim of this study was to establish copeptin concentrations in neonates of different stress states such as sepsis, chorioamnionitis and asphyxia. Copeptin cord blood concentration was determined using the BRAHMS kryptor assay. Neonates with early-onset sepsis (EOS, n = 30), chorioamnionitis (n = 33) and asphyxia (n = 25) were compared to a control group of preterm and term (n = 155) neonates. Median copeptin concentration in cord blood was 36 pmol/l ranging from undetectable to 5498 pmol/l (IQR 7 - 419). Copeptin cord blood concentrations were non-normally distributed and increased with gestational age (p < 0.0001). Neonates born after vaginal compared to cesarean delivery had elevated copeptin levels (p < 0.0001). Copeptin correlated strongly with umbilical artery pH (Spearman's Rho -0.50, p < 0.0001), umbilical artery base excess (Rho -0.67, p < 0.0001) and with lactate at NICU admission (Rho 0.54, p < 0.0001). No difference was found when comparing copeptin cord blood concentrations between neonates with EOS and controls (multivariate p = 0.30). The highest copeptin concentrations were found in neonates with asphyxia (median 993 pmol/l). Receiver-operating-characteristic curve analysis showed that copeptin cord blood concentrations were strongly associated with asphyxia: the area under the curve resulted at 0.91 (95%-CI 0.87-0.96, p < 0.0001). A cut-off of 400 pmol/l had a sensitivity of 92% and a specifity of 82% for asphyxia as defined in this study. Copeptin concentrations were strongly related to factors associated with perinatal stress such as birth acidosis, asphyxia and vaginal delivery. In contrast, copeptin appears to be unsuitable for the diagnosis of EOS.


Monoclonal Antibody L1Mab-13 Detected Human PD-L1 in Lung Cancers.
Programmed cell death ligand-1 (PD-L1) is a type I transmembrane glycoprotein expressed on antigen-presenting cells. It is also expressed in several tumor cells such as melanoma and lung cancer cells. A strong correlation has been reported between human PD-L1 (hPD-L1) expression in tumor cells and negative prognosis in cancer patients. Here, a novel anti-hPD-L1 monoclonal antibody (mAb) L1Mab-13 (IgG1, kappa) was produced using a cell-based immunization and screening (CBIS) method. We investigated hPD-L1 expression in lung cancer using flow cytometry, Western blot, and immunohistochemical analyses. L1Mab-13 specifically reacted hPD-L1 of hPD-L1-overexpressed Chinese hamster ovary (CHO)-K1 cells and endogenous hPD-L1 of KMST-6 (human fibroblast) in flow cytometry and Western blot. Furthermore, L1Mab-13 reacted with lung cancer cell lines (EBC-1, Lu65, and Lu99) in flow cytometry and stained lung cancer tissues in a membrane-staining pattern in immunohistochemical analysis. These results indicate that a novel anti-hPD-L1 mAb, L1Mab-13, is very useful for detecting hPD-L1 of lung cancers in flow cytometry, Western blot, and immunohistochemical analyses.


Tunable plasmonic nanoprobes for theranostics of prostate cancer.
Theranostic applications require coupling of diagnosis and therapy, a high degree of specificity and adaptability to delivery methods compatible with clinical practice. The tunable physical and biological effects of selective targeting and activation of plasmonic nanobubbles (PNB) were studied in a heterogeneous biological microenvironment of prostate cancer and stromal cells. All cells were targeted with conjugates of gold nanoparticles (NPs) through an antibody-receptor-endocytosis-nanocluster mechanism that produced NP clusters. The simultaneous pulsed optical activation of intracellular NP clusters at several wavelengths resulted in higher optical contrast and therapeutic selectivity of PNBs compared with those of gold NPs alone. The developed mechanism was termed "rainbow plasmonic nanobubbles." The cellular effect of rainbow PNBs was tuned in situ in target cells, thus supporting a theranostic algorithm of prostate cancer cell detection and follow-up guided destruction without damage to collateral cells. The specificity and tunability of PNBs is promising for theranostic applications and we discuss a fiber optic platform that will capitalize on these features to bring theranostic tools to the clinic.


Leptin as a modulator of neuroendocrine function in humans.
Leptin, a peptide hormone secreted by adipocytes in proportion of the amount of energy stored in fat, plays a central role in regulating human energy homeostasis. In addition, leptin plays a significant permissive role in the physiological regulation of several neuroendocrine axes, including the hypothalamic-pituitary-gonadal, -thyroid, -growth hormone, and -adrenal axes. Decreased levels of leptin, also known as hypoleptinemia, signal to the brain a state of energy deprivation. Hypoleptinemia can be a congenital or acquired condition, and is associated with alterations of the aforementioned axes aimed at promoting survival. More specifically, gonadotropin levels decrease and become less pulsatile under conditions of energy deprivation, and these changes can be at least partially reversed through leptin administration in physiological replacement doses. Similarly, leptin deficiency is associated with thyroid axis abnormalities including abnormal levels of thyrotropin-releasing hormone, and leptin administration may at least partially attenuate this effect. Leptin deficiency results in decreased insulin-like growth factor 1 levels which can be partially ameliorated through leptin administration, and leptin appears to have a much more pronounced effect on the growth of rodents than that of humans. Similarly, adrenal axis function is regulated more tightly by low leptin in rodents than in humans. In addition to congenital leptin deficiency, conditions that may be associated with decreased leptin levels include hypothalamic amenorrhea, anorexia nervosa, and congenital or acquired lipodystrophy syndromes. Accumulating evidence from proof of concept studies suggests that leptin administration, in replacement doses, may ameliorate neuroendocrine abnormalities in individuals who suffer from these conditions.


Multilocus sequence typing of bifidobacterial strains from infant's faeces and human milk: are bifidobacteria being sustainably shared during breastfeeding?
Bifidobacteria are considered to be one of the most important beneficial intestinal bacteria for infants, contributing to the priming of the mucosal immune system. These microbes can also be detected in mother's milk, suggesting a potential role of human milk in the colonisation of infant's gut. However, little is known about the timing of bacteria appearance in human milk, and whether human milk is the first source of inoculation. Here, we investigated whether specific strains are shared sustainably between maternal milk and infant's gut. Faecal samples and human milk were collected from 102 healthy mother-infant pairs (infant's faeces: meconium, 7, 30 days of age; mother's milk: once before delivery, colostrum, 7, 30 days after delivery). Bifidobacterial strains were isolated from these samples, and were discriminated by means of multilocus sequencing typing. No bifidobacteria were detected from human milk collected before delivery, or colostrum. Strains were isolated only from human milk samples obtained 7 days after birth or later. On the other hand, bifidobacterial strains were obtained from infant's faeces throughout the study period, sometimes as early as the first day of life (meconium). We have found that bifidobacterial species belonging to Bifidobacterium bifidum, Bifidobacterium breve, and Bifidobacterium longum subsp. longum could be identified as monophyletic between infant's faeces and their mother's milk. These strains were confirmed to be sustainably shared between maternal milk and infant's gut. Moreover, monophyletic strains were isolated at the same time point or earlier from infant's faeces than from human milk, and none were isolated earlier from human milk than from infant's faeces. Although it remains unclear whether human milk is the first source of microbes for infants, our results confirm that human milk is a reservoir of bifidobacteria, and specific strains are shared between infant's intestine and human milk during breastfeeding.


Elucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia: evidence of epistasis and competitive binding.
DISC1 influences susceptibility to psychiatric disease and related phenotypes. Intact functions of DISC1 and its binding partners, NDEL1 and NDE1, are critical to neurodevelopmental processes aberrant in schizophrenia (SZ). Despite evidence of an NDEL1-DISC1 protein interaction, there have been no investigations of the NDEL1 gene or the relationship between NDEL1 and DISC1 in SZ. We genotyped six NDEL1 single-nucleotide polymorphisms (SNPs) in 275 Caucasian SZ patients and 200 controls and tested for association and interaction between the functional SNP Ser704Cys in DISC1 and NDEL1. We also evaluated the relationship between NDE1 and DISC1 genotype and SZ. Finally, in a series of in vitro assays, we determined the binding profiles of NDEL1 and NDE1, in relation to DISC1 Ser704Cys. We observed a single haplotype block within NDEL1; the majority of variation was captured by NDEL1 rs1391768. We observed a significant interaction between rs1391768 and DISC1 Ser704Cys, with the effect of NDEL1 on SZ evident only against the background of DISC1 Ser704 homozygosity. Secondary analyses revealed no direct relationship between NDE1 genotype and SZ; however, there was an opposite pattern of risk for NDE1 genotype when conditioned on DISC1 Ser704Cys, with NDE1 rs3784859 imparting a significant effect but only in the context of a Cys-carrying background. In addition, we report opposing binding patterns of NDEL1 and NDE1 to Ser704 versus Cys704, at the same DISC1 binding domain. These data suggest that NDEL1 significantly influences risk for SZ via an interaction with DISC1. We propose a model where NDEL1 and NDE1 compete for binding with DISC1.


Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma.
CXCR4 receptor and its unique ligand, the CXCL12 chemokine, have been recently implicated in cancer metastasis. Evidence about the role of CXCR4/CXCL12 axis has been reported in several cancers including melanoma. Our goal was to investigate if CXCR4 expression has a prognostic value in malignant melanoma. Immunohistochemical expression of CXCR4 was evaluated on 71 specimens of primary cutaneous melanoma with a Breslow tumor thickness of >1 mm after radical resection. Associations between baseline patient features and tumors were analyzed by chi(2) test. The prognostic value of CXCR4 expression was evaluated by univariate and multivariate analyses adjusted by age, sex, Breslow tumor thickness, presence of ulceration, and sentinel lymph node metastases. CXCR4 expression was detected in 31 of 71 (43.6%) primary cutaneous melanomas. Membrane or cytoplasmic staining for CXCR4 protein was absent in 56% of the tumors. The positive cases were divided into three score classes according to their staining: low in 15 cases (21%), moderate in 10 (14%), and high in 6 (8%). After a median follow-up of 38 months, 26 patients progressed (16 of 26 expressed CXCR4) and 19 died (12 of 19 expressed CXCR4). The CXCR4 expression on tumor cells was correlated with an unfavorable prognosis with a median disease-free and overall survival of 22 and 35 months, respectively. The hazard ratios of relapse and death, compared with patients with CXCR4-negative tumors, were 2.5 (95% confidence interval, 1.2-6.1) and 3.1 (95% confidence interval, 1.1-7.2), respectively. Median time-to-event (progression and survival) was not reached in patients with CXCR4-negative tumors. In the multivariate analysis, CXCR4 expression, presence of ulceration, and sentinel lymph node status emerged as independent prognostic factors. This article provides the first evidence that CXCR4 expression could be an independent and powerful prognostic marker in primary cutaneous malignant melanomas.


Capecitabine with radiation is an effective adjuvant therapy in gastric cancers.
To analyze the outcome of patients who received concurrent capecitabine (Xeloda) and radiation (XRT) compared to the established concurrent 5-fluorouracil (5-FU) with radiation (5FU-RT) and fluoropyrimidine-based chemotherapy alone as adjuvant treatment in gastric cancers. All patients with gastric cancers who received adjuvant treatment at the National Cancer Centre Singapore between 1996 and 2006 were reviewed. Treatment outcomes of patients who received XRT were compared with those who had 5FU-RT or chemotherapy alone as adjuvant therapy for gastric cancers. A total of 108 patients were reviewed. Median age at diagnosis was 60. The majority of the patients (64.8%) had advanced stage III and IV disease (with no distant metastasis). All except 4 patients had D2 gastrectomy. Twenty one patients (19.4%) had positive surgical resection margins. Thirty three patients received XRT compared with 52 who had 5FU-RT and 23 who received chemotherapy alone. For the patients in the chemotherapy-only group, all had fluoropyrimidine-based therapy, with added cisplatin in 7 patients and epirubicin in 2 patients. Median recurrence-free survival was longer for the XRT group (52 mo) compared to the 5FU-RT (35 mo) and chemotherapy-only groups (25 mo) (P = 0.48). The patients in the XRT group achieved similar median overall survival (53 mo) as the 5FU-RT (54 mo) and the chemotherapy-only groups (44 mo) (P = 0.5). Capecitabine with concurrent radiation was as effective as concurrent 5FU with radiation or fluoropyrimidine-based chemotherapy alone when used as adjuvant treatment in patients with gastric cancers.


Bilateral thyrolinguofacial trunk: unusual and rare branching pattern of external carotid artery.
Prior knowledge of arterial supply to the head and neck is of substantial importance for well-planned surgeries involving the concerned region. We are reporting an unusual and rare variation in the branching pattern of external carotid artery in a 60-year-old female cadaver. A common trunk known as thyrolinguofacial trunk, originating from the anterior surface of the external carotid artery (right and left) giving of superior thyroid artery and a linguofacial trunk during a routine neck dissection. The linguofacial trunk then divided into a lingual and a facial artery. Vascular abnormalities are usually detected either on the dissection table or by the radiologists during imaging or accidently during surgeries leading to serious consequences.