Angiotensin converting enzyme activity in infancy is related to birth weight.
(a) To measure infant angiotensin converting enzyme (ACE) activity in healthy term infants at birth and during the first three months of life. (b) To determine the relation between serum ACE activity and infant feeding practice during this period. (c) To investigate the relation between serum ACE activity and birth weight and other potential contributing factors including acid-base status at birth, gestation, and maternal ACE genotype. Prospective study of term infants, with clinical and feeding data collected from parents and medical records, and serum ACE measured in the infant at birth and 1 and 3 months of age, and in the mother at the time of birth and one to three months after birth. At birth and 1 and 3 months of age, infant serum ACE activity was twice that of maternal ACE activity. Infant ACE activity at birth and 1 and 3 months did not significantly differ between breast and formula fed infants. There was a highly significant negative correlation between infant ACE activity at 3 months and birth weight (r = -0.52; p < 0.001). This persisted after the conversion of birth weights to z scores (r = -0.34; p = 0.03). ACE activity at 3 months was also related to placental weight (r = -0.30; p = 0.02) and maternal age (r = -0.30; p = 0.05). The strong correlation between serum ACE activity and birth weight z score persisted after adjustment for maternal age and placental weight (r = -0.34; p = 0.03). As ACE is increasingly identified as a risk factor for cardiovascular disease, serum ACE activity in infancy may contribute to the link between low birth weight and later cardiovascular events.


Police perspectives on the economic considerations of providing healthcare in short-term custodial settings in Australia.
Providing appropriate healthcare to people in short-term police custody settings (i.e. watch-houses) is challenging due to the complexity of detainee health needs and the limitations of the custodial environment. However, little is known about how detainee healthcare is managed in Australia, including economic considerations. This study had two aims: (1) to understand police perspectives on the costs associated with the delivery of healthcare to watch-house detainees in Queensland, Australia and (2) to scope the applicability of the Prison Healthcare Expenditure Reporting Checklist (PHERC) tool for the Australian watch-house context. The study employed an exploratory qualitative descriptive approach. A purposive sample comprised 16 watch-house staff from six regions in Queensland, Australia, interviewed between April and November 2021. A key finding was that police viewed healthcare expenditure as a major, but largely unavoidable cost for Australian watch-houses. Participants reported that direct expenditure comprised mostly of in-house healthcare services (of which there were a variety of models), but also costs of medication and health-related consumables. Indirect costs included costs of escorting and guarding detainees requiring transfer to hospital for health assessment and treatment. Participants reported that the PHERC was not applicable to the Australian watch-house context. Future research should explore the cost-effectiveness of different watch-house healthcare delivery models and how best to measure this.


Statistical linkage analysis of substitutions in patient-derived sequences of genotype 1a hepatitis C virus nonstructural protein 3 exposes targets for immunogen design.
Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver failure and liver cancer, affecting around 3% of the world's population. The extreme sequence variability of the virus resulting from error-prone replication has thwarted the discovery of a universal prophylactic vaccine. It is known that vigorous and multispecific cellular immune responses, involving both helper CD4(+) and cytotoxic CD8(+) T cells, are associated with the spontaneous clearance of acute HCV infection. Escape mutations in viral epitopes can, however, abrogate protective T-cell responses, leading to viral persistence and associated pathologies. Despite the propensity of the virus to mutate, there might still exist substitutions that incur a fitness cost. In this paper, we identify groups of coevolving residues within HCV nonstructural protein 3 (NS3) by analyzing diverse sequences of this protein using ideas from random matrix theory and associated methods. Our analyses indicate that one of these groups comprises a large percentage of residues for which HCV appears to resist multiple simultaneous substitutions. Targeting multiple residues in this group through vaccine-induced immune responses should either lead to viral recognition or elicit escape substitutions that compromise viral fitness. Our predictions are supported by published clinical data, which suggested that immune genotypes associated with spontaneous clearance of HCV preferentially recognized and targeted this vulnerable group of residues. Moreover, mapping the sites of this group onto the available protein structure provided insight into its functional significance. An epitope-based immunogen is proposed as an alternative to the NS3 epitopes in the peptide-based vaccine IC41. Despite much experimental work on HCV, a thorough statistical study of the HCV sequences for the purpose of immunogen design was missing in the literature. Such a study is vital to identify epistatic couplings among residues that can provide useful insights for designing a potent vaccine. In this work, ideas from random matrix theory were applied to characterize the statistics of substitutions within the diverse publicly available sequences of the genotype 1a HCV NS3 protein, leading to a group of sites for which HCV appears to resist simultaneous substitutions possibly due to deleterious effect on viral fitness. Our analysis leads to completely novel immunogen designs for HCV. In addition, the NS3 epitopes used in the recently proposed peptide-based vaccine IC41 were analyzed in the context of our framework. Our analysis predicts that alternative NS3 epitopes may be worth exploring as they might be more efficacious.


Pepsinogens and gastrointestinal symptoms in mountain marathon runners.
Although there are various descriptive reports concerning exercise-induced gastrointestinal distress, the role of gastrointestinal hormones and/or enzymes is not definitively established. In this study we investigated the behaviour of pepsinogens (PGI and PGII) after an endurance race performed at an altitude of 4,300 m by 13 well-trained marathon runners, with the aim to establish their interrelationship with gastrointestinal distress and with the modifications of gastrin and cortisol. The athletes showed a significant rise in gastrin (p < 0.01) and in cortisol (p < 0.01) and a significant decrease in PGI (p < 0.01) and PGII (p < 0.05) after the race. The PGI/PGII ratio presented small variations indicating that heavy exercise has less effects on PGs than those observed for gastrin. Gastrointestinal symptoms occurred in 6 athletes (46%) during the race and in 8 athletes (62%) after the race. No relationship was found between gastrointestinal symptoms and hormonal modifications after the race. A control group of 5 subjects was used: they (n = 5) did not show any significant modification of gastrin and PGs during the period spent at the above altitude, indicating that travel, altitude and acclimatization, food and beverages, do not influence the behaviour of these hormones. Conversely, they presented a significant decrease of cortisol (p < 0.05) linked to the circadian rhythm. The data of the present study indicate that the potential damage of gastrointestinal apparatus in mountain marathon runners is not related to the above mentioned hormones.


Early obstetric discharge: does it make a difference to health outcomes?
Clinicians in several countries have expressed concerns about possible adverse effects of shortening obstetric length of stay. A population-based survey of 1366 mothers who gave birth in Victoria, Australia, in 1993 was used to investigate social and obstetric characteristics of mothers discharged home 'early', and to assess whether shorter stays were associated with adverse health outcomes, or a lesser degree of satisfaction, or both. Women's views and experiences of length of hospital stay were gathered via a statewide postal survey of women who gave birth in a 2-week period; 62.5% (n = 1336) responded. Assessment of the relationship between length of stay (1-2 days vs. > or = 5 days, and 3-4 days vs. > or = 5 days) and four main outcome measures (infant feeding at 6 weeks, period prevalence of feeding problems, maternal confidence and depression) showed no association between these variables and length of stay after adjusting for other obstetric and social factors in separate regression analyses. For stays of 3-4 days, the adjusted odds ratio (OR) for formula feeding at 6 weeks was 1.35 [95% confidence interval (CI) 0.9-1.9]; for feeding problems OR = 0.87 [0.7-1.2]; for lacking confidence OR = 0.81 [0.6-1.2]; and for depression OR = 0.96 [0.7-1.4]. Large randomised trials of early obstetric discharge are required to resolve continuing uncertainties about the safety, and possible benefits of shorter hospital stays.


Systematic implications of chromosomal data from two insular species of Peromyscus from the Gulf of California.
G- and C-banded karyotypes for two insular species of deer mice, Peromyscus slevini and P. sejugis, are described and analyzed relative to the evolutionary relationship of these species to and their inclusion within the P. maniculatus species group. The chromosomal phenotype of P. slevini is unique among all banded karyotypes reported for Peromyscus, and comparison with published karyotypes suggests that P. slevini has systematic affinities with either the P. boylii or P. mexicanus species groups. The karyotypic data for P. sejugis clearly align these mice with P. maniculatus and provide a diagnostic character that supports the specific distinction between these taxa.


Homo- and Heterovalent Neoglycoproteins as Ligands for Bacterial Lectins.
Click chemistry gives access to unlimited set of multivalent glycoconjugates to explore carbohydrate-protein interactions and discover high affinity ligands. In this study, we have created supramolecular systems based on a carrier protein that was grafted by Cu(I)-catalyzed azide-alkyne cycloaddition with tetravalent glycodendrons presenting αGal, βGal and/or αFuc. Binding studies of the homo- (4 a-c) and heterovalent (5) neoglycoproteins (neoGPs) with the LecA and LecB lectins from P. aeruginosa has first confirmed the interest of the multivalent presentation of glycodendrons by the carrier protein (IC50 up to 2.8 nM). Moreover, these studies have shown that the heterovalent display of glycans (5) allows the interaction with both lectins (IC50 of 10 nM) despite the presence of unspecific moieties, and even with similar efficiency for LecB. These results demonstrate the potential of multivalent and multispecific neoGPs as a promising strategy to fight against resistant pathogens.


Musculoskeletal modelling of human ankle complex: Estimation of ankle joint moments.
A musculoskeletal model for the ankle complex is vital in order to enhance the understanding of neuro-mechanical control of ankle motions, diagnose ankle disorders and assess subsequent treatments. Motions at the human ankle and foot, however, are complex due to simultaneous movements at the two joints namely, the ankle joint and the subtalar joint. The musculoskeletal elements at the ankle complex, such as ligaments, muscles and tendons, have intricate arrangements and exhibit transient and nonlinear behaviour. This paper develops a musculoskeletal model of the ankle complex considering the biaxial ankle structure. The model provides estimates of overall mechanical characteristics (motion and moments) of ankle complex through consideration of forces applied along ligaments and muscle-tendon units. The dynamics of the ankle complex and its surrounding ligaments and muscle-tendon units is modelled and formulated into a state space model to facilitate simulations. A graphical user interface is also developed during this research in order to include the visual anatomical information by converting it to quantitative information on coordinates. Validation of the ankle model was carried out by comparing its outputs with those published in literature as well as with experimental data obtained from an existing parallel ankle rehabilitation robot. Qualitative agreement was observed between the model and measured data for both, the passive and active ankle motions during trials in terms of displacements and moments.


Cancer Survival Data Representation for Improved Parametric and Dynamic Lifetime Analysis.
Survival functions are often characterized by a median survival time or a 5-year survival. Whether or not such representation is sufficient depends on tumour development. Different tumour stages have different mean survival times after therapy. The validity of an exponential decay and the origins of deviations are substantiated. The paper shows, that representation of survival data as logarithmic functions visualizes differences better, which allows for differentiating short- and long-term dynamic lifetime. It is more instructive to represent the changing lifetime expectancy for an individual who has survived a certain time, which can be significantly different from the initial expectation just after treatment. Survival data from 15 publications on cancer are compared and re-analysed based on the well-established: (i) exponential decay (ii) piecewise constant hazard (iii) Weibull model and our proposed parametric survival models, (iv) the two-τ and (v) the sliding-τ model. The new models describe either accelerated aging or filtering out of defects with numerical parameters with a physical meaning and add information to the usually provided log-rank P-value or median survival. The statistical inhomogeneity in a group by mixing up different tumour stages, metastases and treatments is the main origin for deviations from the exponential decay.


Multi-channel Wireless Implantable Brain-Computer Interface System.
The implantable brain-computer interface has been widely used in recent years due to its great application potential and research value. Few neural implants have been designed to gather neural spikes, which require a higher sampling frequency than ECoG and LFPs. These systems are still constrained by low channel counts and their bulky size. Furthermore, wire connection is still used in many neural interfaces for further data analysis, facing challenges such as tissue infection, limited movement, and increased noise interference. To address the aforementioned problems, this paper presents a compact multi-channel wireless implantable brain-computer interface system that meets the requirements of spike signals collection and miniaturization. A WiFi module is utilized to transmit information between the system and terminal equipment to eliminate the tethering effects. A 128-channel signal acquisition module, consisting of two pieces of commercial digital electrophysiology amplifier chips, is designed to realize high channel counts for capturing spike events. The proposed system has successfully recorded the analog spike signals from a digital neural signal simulator.


Prevalence of rheumatologic manifestations of chronic hepatitis C virus infection among Egyptians.
Chronic hepatitis C virus (HCV) viremia has been known to provoke a plethora of autoimmune syndromes referred to as extrahepatic manifestations of chronic HCV infection. Aim of the current study was to assess the prevalence of rheumatologic manifestations among Egyptians with hepatitis C infection and its' association with cryoglobulin profile. The current research represents a cross-sectional study where patients with chronic HCV infection attending the outpatient clinic of the National Hepatology and Tropical Medicine Research Institute over a period of 1 year were interviewed. Patients with decompensated liver disease, on interferon therapy, having end-stage renal disease or coexisting viral infection like hepatitis B surface antibody positive patients were all excluded from the research. Laboratory investigations as well as serological assay including cryoglobulin profile, rheumatoid factor, antinuclear antibody, HCV-PCR were performed. Three hundred and six patients having chronic HCV infection were interviewed in this research. The overall estimated prevalence of rheumatologic manifestations in the current research was 16.39%, chronic fatigue syndrome 9.5%, sicca symptoms 8.8%, arthralgia 6.5%, fibromyalgia 1.9%, myalgia 1.3%, arthritis 0.7%, cryoglobulinemic vasculitis 0.7%, autoimmune hemolytic anemia 0.7%, thrombocytopenia 0.7%. Xerophthalmia was significantly present in male population (p = 0.04), whereas fibromyalgia, cryoglobulinemic vasculitis, arthritis, and autoimmune hemolytic anemia were significantly present in female population under study (p < 0.05). In chronic HCV genotype 4 infection, the prevalence of rheumatologic manifestations was 16.3% with chronic fatigue syndrome and sicca symptoms being the most common with no significant correlation to the degree of elevation of liver disease or viral load.


Disentangling plastic and genetic changes in body mass of Siberian jays.
Spatial and temporal phenotypic differentiation in mean body size is of commonplace occurrence, but the underlying causes remain often unclear: both genetic differentiation in response to selection (or drift) and environmentally induced plasticity can create similar phenotypic patterns. Studying changes in body mass in Siberian jays (Perisoreus infaustus) over three decades, we discovered that mean body mass declined drastically (ca. 10%) over the first two decades, but increased markedly thereafter back to almost the initial level. Quantitative genetic analyses revealed that although body mass was heritable (h(2) = 0.46), the pronounced temporal decrease in body mass was mainly a product of phenotypic plasticity. However, a concomitant and statistically significant decrease in predicted breeding values suggests a genetic component to this change. The subsequent increase in mean body mass was indicated to be entirely due to plasticity. Selection on body mass was estimated to be too weak to fully account for the observed genetic decline in body mass, but bias in selection differential estimates due to environmental covariance between body mass and fitness is possible. Hence, the observed body mass changes appear to be driven mainly by phenotypic plasticity. Although we were not able to identify the ecological driver of the observed plastic changes, the results highlight the utility of quantitative genetic approaches in disentangling genetic and phenotypic changes in natural populations.


Biomimetic Mineralization of Tumor Targeted Ferromagnetic Iron Oxide Nanoparticles Used for Media of Magnetic Hyperthermia.
The magnetic hyperthermia has been recognized as a useful therapeutic modality for malignant tumors, and IONPs have received a great deal of attentions for potential biomedical applications. The aims of this paper are to design a biomimetic mineralization procedure to synthesize the ferromagnetic and tumor targeting Fe3O4 nanoparticles, to conjugate bioactive molecule on particles, to analyze properties of product. IONPs were synthesized with the WSG-PF127 as the mineralization templates, which were mixed by conjugating the peptide WSG on the surface of PF127. And the influence of different conditions, such as templates, temperature, stirring speed on the particles was investigated. Above the critical micelle concentration (CMC), the catenulate PF127 molecules were assembled into the hollow sphere-like micelle, and the morphology and size of the IONPs mineralized inside the hollow cores of PF127 micelles could be controlled due to the space restricted effect. The saturation magnetization was increased due to the higher crystallinity degree of the WSG-PF127-IONPs, the cytocompatibility was improved by the WSG-PF127 wrapped around the IONPs, and the targetability was endowed via the mediation of the peptide-WSG conjugated on hydrophilic segments of PF127 molecular chains. The iron oxide nanoparticles with homogenous morphology, uniform size, and excellent ferromagnetism have been successfully mineralized under the regulation of the PF127 micelles coupled with the peptide-WSG. The improved ferromagnetism, the negligible cytotoxicity to HUVECs, and the targetability to tumor cells of the biomimetically mineralized IONPs coupled with WSG-PF127 have greater potential to be applied as the active tumor targeted media for magnetic hyperthermia.


Invasive Aspergillosis Mimicking Metastatic Lung Cancer.
In a patient with a medical history of cancer, the most probable diagnosis of an 18FDG-avid pulmonary mass combined with intracranial abnormalities on brain imaging is metastasized cancer. However, sometimes a differential diagnosis with an infectious cause such as aspergillosis can be very challenging as both cancer and infection are sometimes difficult to distinguish. Pulmonary aspergillosis can present as an infectious pseudotumour with clinical and imaging characteristics mimicking lung cancer. Even in the presence of cerebral lesions, radiological appearance of abscesses can look like brain metastasis. These similarities can cause significant diagnostic difficulties with a subsequent therapeutic delay and a potential adverse outcome. Awareness of this infectious disease that can mimic lung cancer, even in an immunocompetent patient, is important. We report a case of a 65-year-old woman with pulmonary aspergillosis disseminated to the brain mimicking metastatic lung cancer.


Effect of Semecaprus anacardium on diabetes-induced alterations in the activities of marker enzymes and antioxidant enzymes in type 2 diabetes induced cardiac vascular damage model in rats.
Semecarpus anacardium is a commonly used drug in the Siddha system of medicine for curing various metabolic disorders. The cardio protective effect of the drug in Type 2 diabetes-induced cardiovascular complications was studied in rats by feeding them with a high fat diet for 2 weeks followed by intra peritoneal injection of streptozotocin at a moderate dosage of 2*35 mg/kg/ b.wt 24 hr apart and leaving them for 8 weeks to develop cardiovascular complications. The effect of the drug was studied by analyzing levels of blood glucose, insulin, HbA1c, marker enzymes, the antioxidative enzymes and the levels of lipid peroxides in Type 2 diabetic rats. Diabetic rats were treated with SA at a dosage of 300 mg/kg/b.wt. for 8 weeks and the results were compared with diabetic rats treated with the combination therapy drugs metformin at a dosage of 100 mg/kg/b.wt and atorvastatin at a dosage of 10 mg/kg/b.wt for 8 weeks. The drug SA significantly decreased the blood glucose levels and also HbA1c levels while improving glucose tolerance at the same time. The levels of marker enzymes and lipid peroxides were significantly increased in diabetic rats when compared with control rats. On the other hand significant decreases in the levels of antioxidative enzymes were observed in diabetic rats. Upon treatment with the drug SA, all of these abnormalities were restored to near normalcy. The present study thereby establishes the protective effect of the drug against diabetes-induced cardiac damage.


Observational cohort study examining apolipoprotein E status and preoperative neuropsychological performance as predictors of post-operative delirium in an older elective arthroplasty population.
delirium following surgery is common and is associated with negative outcomes. Preoperative cognitive impairment has been shown to be a risk factor for post-operative delirium. Often the cognitive tests used are cumbersome. This study tests the hypothesis that the quantification of brain vulnerability, using Apolipoprotein E (ApoE) status and neuropsychological tests, both traditional and more easily administered, can quantify the risk of post-operative delirium following elective primary arthroplasty surgery. this observational cohort study recruited participants aged 65 years or older admitted prior to elective primary hip or knee arthroplasty. Baseline data was collected and participants underwent neuropsychological testing and had blood taken for ApoE genotyping preoperatively. Post-operatively participants were assessed daily for delirium using the Confusion Assessment Method (CAM) and charts were reviewed where possible for reports of delirium. Univariate and multivariate analyses of preoperative factors were undertaken to identify independent predictors of delirium. between March 2012 and October 2014, 315 participants completed the study with an overall incidence of post-operative delirium of 40/315 (12.7%). Of these 18 fulfilled the CAM criteria for delirium and 22 were deemed delirious by consensus decision based on chart review. ApoE genotype was not associated with post-operative delirium in this cohort. Time taken to complete Colour Trails 2, errors in mini mental state examination and level of pain preoperatively were independent predictors of post-operative delirium. this study challenges the assertion that ApoE4 genotype predicts post-operative delirium. It replicates previous work suggesting cognitive impairment predicts post-operative delirium and shows for the 1st time that simple cognitive tests can be as effective as more detailed tests.


Dynamics of muscle fibre growth during postnatal mouse development.
Postnatal growth in mouse is rapid, with total skeletal muscle mass increasing several-fold in the first few weeks. Muscle growth can be achieved by either an increase in muscle fibre number or an increase in the size of individual myofibres, or a combination of both. Where myofibre hypertrophy during growth requires the addition of new myonuclei, these are supplied by muscle satellite cells, the resident stem cells of skeletal muscle. Here, we report on the dynamics of postnatal myofibre growth in the mouse extensor digitorum longus (EDL) muscle, which is essentially composed of fast type II fibres in adult. We found that there was no net gain in myofibre number in the EDL between P7 and P56 (adulthood). However, myofibre cross-sectional area increased by 7.6-fold, and length by 1.9-fold between these ages, resulting in an increase in total myofibre volume of 14.1-fold: showing the extent of myofibre hypertrophy during the postnatal period. To determine how the number of myonuclei changes during this period of intense muscle fibre hypertrophy, we used two complementary mouse models: 3F-nlacZ-E mice express nlacZ only in myonuclei, while Myf5nlacZ/+ mice have beta-galactosidase activity in satellite cells. There was a approximately 5-fold increase in myonuclear number per myofibre between P3 and P21. Thus myofibre hypertrophy is initially accompanied by a significant addition of myonuclei. Despite this, the estimated myonuclear domain still doubled between P7 and P21 to 9.2 x 103 microm3. There was no further addition of myonuclei from P21, but myofibre volume continued to increase, resulting in an estimated approximately 3-fold expansion of the myonuclear domain to 26.5 x 103 microm3 by P56. We also used our two mouse models to determine the number of satellite cells per myofibre during postnatal growth. Satellite cell number in EDL was initially approximately 14 satellite cells per myofibre at P7, but then fell to reach the adult level of approximately 5 by P21. Postnatal fast muscle fibre type growth is divided into distinct phases in mouse EDL: myofibre hypertrophy is initially supported by a rapid increase in the number of myonuclei, but nuclear addition stops around P21. Since the significant myofibre hypertrophy from P21 to adulthood occurs without the net addition of new myonuclei, a considerable expansion of the myonuclear domain results. Satellite cell numbers are initially stable, but then decrease to reach the adult level by P21. Thus the adult number of both myonuclei and satellite cells is already established by three weeks of postnatal growth in mouse.


Nasal tip surgery for cleft nose in Asians.
"Collapsed nasal tip," one of the most characteristic features of cleft lip nose, resembles the effect of pushing the nose tip with a finger and is especially noticeable among Asians. The authors examined a rhinoplasty technique for improving collapsed nasal tip. Using an intercartilaginous incision, the distal nasal framework, including the alar cartilages, and the caudal septum were widely exposed. A septal extension graft was fixed to the caudal septum, and the alar cartilages were precisely sutured to the extension graft using markings transferred to the extension graft. This procedure was applied to 15 Asian rhinoplasties, with all patients having substantial improvement in the shape of their nasal tip. Comparing those with and without a history of rhinoplasty, effecting a projection of the nasal tip was more difficult in patients with a history of previous rhinoplasties. The advantages of this technique include inconspicuous scarring and versatility in the modification of the nasal tip. Rhinoplasty during the growth period should be planned with consideration of future augmentation rhinoplasties.


Hyperlipaemia intensifies the course of acute oedematous and acute necrotising pancreatitis in the rat.
Serum triglyceride concentrations higher than 10 to 20 mmol/l are probably a risk factor for developing acute pancreatitis in humans. To therefore analyse the influence of hyperlipaemia on the course of acute oedematous and acute necrotising pancreatitis in rats. Male Wistar rats were used in all experiments. Six different groups of animals were used: two groups without pancreatitis (controls), two with acute oedematous pancreatitis, and two with acute necrotising pancreatitis. One group from each pair was treated with Triton WR 1339, which induces endogenous hyperlipaemia. Blood samples were taken from all subjects to measure triglyceride, cholesterol, amylase, and lipase. Pancreatic tissue samples were taken and the degree of pancreatic damage was judged microscopically. In the control groups no significant changes occurred, either in serum enzyme activities or in histology. The hyperlipaemic subgroup of animals with acute oedematous pancreatitis developed significantly higher (p < 0.001) serum amylase activities and a greater degree of histological damage (p < 0.01) than the animals of the non-hyperlipaemic acute oedematous pancreatitis group. In the animals with necrotising pancreatitis, serum lipase activity and the histological degree of pancreatic damage were significantly higher in the hyperlipaemic animals than in the non-hyperlipaemic animals. This study shows that hyperlipaemia intensifies the course of acute oedematous and acute necrotising pancreatitis in rats.


Dietary protein restriction and the progression of chronic renal disease: what have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group.
The Modification of Diet in Renal Disease (MDRD) Study was the largest randomized clinical trial to test the hypothesis that protein restriction slows the progression of chronic renal disease. However, the primary results published in 1994 were not conclusive with regard to the efficacy of this intervention. Many physicians interpreted the failure of the MDRD Study to demonstrate a beneficial effect of protein restriction over a 2- to 3-yr period as proving that this therapy does not slow disease progression. The authors believe that this viewpoint is incorrect, and is the result of misinterpretation of inconclusive evidence as evidence in favor of the null hypothesis. Since then, numerous secondary analyses of the MDRD Study have been undertaken to clarify the effect of protein restriction on the rate of decline in GFR, urine protein excretion, and onset of end-stage renal disease. This review describes some of the principles of secondary analyses of randomized clinical trials, presents the results of these analyses from the MDRD Study, and compares them with results from other randomized clinical trials. Although these secondary results cannot be regarded as definitive, the authors conclude that the balance of evidence is more consistent with the hypothesis of a beneficial effect of protein restriction than with the contrary hypothesis of no beneficial effect. Until additional data become available, physicians must continue to make recommendations in the absence of conclusive results. The authors suggest that physicians incorporate the results of these secondary analyses into their interpretation of the findings of the MDRD Study.


[Surgical treatment of complicated duodenal ulcer: experience and prospects].
The article discloses the results of the surgery of 696 patients with completed duodenal ulcers. The organ-preserving treatment was provided for 31.8% of patients, and stomach resection was performed on 68.2% of patients. Postoperative mortality was found to be 0.6% and was not related to the surgery nature. The postoperative term of hospital treatment made up 11.8 +/- 2.4 days. A complex hospital examination of patients during early and late postoperative periods showed that methods for treatment of complicated duodenal ulcers with the use of new surgical technologies allow choosing an optimum operation providing a high level of life quality.


In vitro analysis of finasteride activity against Candida albicans urinary biofilm formation and filamentation.
Candida albicans is the 3rd most common cause of catheter-associated urinary tract infections, with a strong propensity to form drug-resistant catheter-related biofilms. Due to the limited efficacy of available antifungals against biofilms, drug repurposing has been investigated in order to identify novel agents with activities against fungal biofilms. Finasteride is a 5-α-reductase inhibitor commonly used for the treatment of benign prostatic hyperplasia, with activity against human type II and III isoenzymes. We analyzed the Candida Genome Database and identified a C. albicans homolog of type III 5-α-reductase, Dfg10p, which shares 27% sequence identity and 41% similarity to the human type III 5-α-reductase. Thus, we investigated finasteride for activity against C. albicans urinary biofilms, alone and in combination with amphotericin B or fluconazole. Finasteride alone was highly effective in the prevention of C. albicans biofilm formation at doses of ≥16 mg/liter and the treatment of preformed biofilms at doses of ≥128 mg/liter. In biofilm checkerboard analyses, finasteride exhibited synergistic activity in the prevention of biofilm formation in a combination of 4 mg/liter finasteride with 2 mg/liter fluconazole. Finasteride inhibited filamentation, thus suggesting a potential mechanism of action. These results indicate that finasteride alone is highly active in the prevention of C. albicans urinary biofilms in vitro and has synergistic activity in combination with fluconazole. Further investigation of the clinical utility of finasteride in the prevention of urinary candidiasis is warranted.


Understanding renal posttransplantation anemia in the pediatric population.
Advances in renal transplantation management have proven to be beneficial in improving graft and patient survival. One of the properties of a well-functioning renal allograft is the secretion of adequate amounts of the hormone erythropoietin to stimulate erythropoiesis. Posttransplantation anemia (PTA) may occur at any point in time following transplantation, and the cause is multifactoral. Much of our understanding of PTA is based on studies of adult transplant recipients. The limited number of studies that have been reported on pediatric renal transplant patients appear to indicate that PTA is prevalent in this patient population. Erythropoietin deficiency or resistance is commonly associated with iron deficiency. An understanding of the risk factors, pathophysiology and management of PTA in the pediatric renal transplant population may provide guidelines for clinicians and researchers in the pursuit of larger prospective randomized control studies aimed at improving our limited knowledge of PTA. Recognition of PTA through regular screening and evaluation of the multiple factors that may contribute to its development are recommended after transplantation.


Domain-Specific Pre-training Improves Confidence in Whole Slide Image Classification.
Whole Slide Images (WSIs) or histopathology images are used in digital pathology. WSIs pose great challenges to deep learning models for clinical diagnosis, owing to their size and lack of pixel-level annotations. With the recent advancements in computational pathology, newer multiple-instance learning-based models have been proposed. Multiple-instance learning for WSIs necessitates creating patches and uses the encoding of these patches for diagnosis. These models use generic pre-trained models (ResNet-50 pre-trained on ImageNet) for patch encoding. The recently proposed KimiaNet, a DenseNet121 model pre-trained on TCGA slides, is a domain-specific pre-trained model. This paper shows the effect of domain-specific pre-training on WSI classification. To investigate the effect of domain-specific pre-training, we considered the current state-of-the-art multiple-instance learning models, 1) CLAM, an attention-based model, and 2) TransMIL, a self-attention-based model, and evaluated the models' confidence and predictive performance in detecting primary brain tumors - gliomas. Domain-specific pre-training improves the confidence of the models and also achieves a new state-of-the-art performance of WSI-based glioma subtype classification, showing a high clinical applicability in assisting glioma diagnosis. We will publicly share our code and experimental results at https://github.com/soham-chitnis10/WSI-domain-specific.


MHC, mate choice and heterozygote advantage in a wild social primate.
Preferences for mates carrying dissimilar genes at the major histocompatibility complex (MHC) may help animals increase offspring pathogen resistance or avoid inbreeding. Such preferences have been reported across a range of vertebrates, but have rarely been investigated in social species other than humans. We investigated mate choice and MHC dynamics in wild baboons (Papio ursinus). MHC Class II DRB genes and 16 microsatellite loci were genotyped across six groups (199 individuals). Based on the survey of a key segment of the gene-rich MHC, we found no evidence of mate choice for MHC dissimilarity, diversity or rare MHC genotypes. First, MHC dissimilarity did not differ from random expectation either between parents of the same offspring or between immigrant males and females from the same troop. Second, female reproductive success was not influenced by MHC diversity or genotype frequency. Third, population genetic structure analysis revealed equally high genotypic differentiation among troops, and comparable excess heterozygosity within troops for juveniles, at both Mhc-DRB and neutral loci. Nevertheless, the age structure of Mhc-DRB heterozygosity suggested higher longevity for heterozygotes, which should favour preferences for MHC dissimilarity. We propose that high levels of within-group outbreeding, resulting from group-living and sex-biased dispersal, might weaken selection for MHC-disassortative mate choice.


A Combined four-mRNA Signature Associated with Lymphatic Metastasis for Prognosis of Colorectal Cancer.
Background: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Lymph node metastasis (LNM) is a common mode of metastasis of CRC. However, the combined mRNA biomarkers associated with LNM of CRC that can effectively predict CRC prognosis have not been reported yet. Methods: To identify biomarkers that are associated with LNM, we collected data from the The Cancer Genome Atlas (TCGA) database. The edgeR package was searched to seek LNM-related genes by comparisons between cancer samples and normal colorectal tissues and between LNM and non-LNM (NLNM) of CRC. Univariate and multivariate regression analysis of genes in the intersection to build gene signature associated with independent prognosis of CRC, and then verified by Kaplan-Meier curve and log-rank test, receiver operating characteristic (ROC) curve was used to determine the efficiency of survival prediction of our four-mRNA signature. Finally, the potential molecular mechanisms and properties of these gene signature were also explored with functional and pathway enrichment analysis. Results: 329 mRNAs were up-regulated in CRC tissues with LNM, and 8461 mRNAs were up-regulated in CRC tissues, the intersection is 100 mRNAs. After univariate and multivariate Cox regression analysis of 100 mRNAs, a novel four LNM related mRNAs (EPHA8, KRT85, GABRA3, and CLPSL1) were screened as independent prognostic indicators of CRC. Surprisingly, the four-mRNA signature can predict the prognosis of CRC patients independently of clinical factors andthe area under the curve (AUC) of the ROC is 0.730. The novel four-mRNA signature was used to identify high and low-risk groups. Stratified analysis indicated the risk score based on four-mRNA signature was an independent prognostic indicator for female, T3+T4, N1+N2 ,stage III+IV and patients with no new tumor event. Functional annotation of this risk model in high-risk patients revealed that pathways associated with neuroactive ligand-receptor interaction, estrogen signaling pathway, and steroid hormone biosynthesis. Conclusions: By conducting TCGA data mining, our study demonstrated that a four-mRNA signature associated with LNM can be used as a combined biomarker for independent prognosis of CRC.


Applying the bioisosterism strategy to obtain lead compounds against SARS-CoV-2 cysteine proteases: An in-silico approach.
SARS-CoV-2 cysteine proteases are essential nonstructural proteins due to their role in the formation of the virus multiple enzyme replication-transcription complex. As a result, those functional proteins are extremely relevant targets in the development of a new drug candidate to fight COVID-19. Based on this fact and guided by the bioisosterism strategy, the present work has selected 126 out of 1050 ligands from DrugBank website. Subsequently, 831 chemical analogs containing bioisosteres, some of which became structurally simplified, were created using the MB-Isoster software, and molecular docking simulations were performed using AutoDock Vina. Finally, a study of physicochemical properties, along with pharmacokinetic profiles, was carried out through SwissADME and ADMETlab 2.0 platforms. The promising results obtained with the molecules encoded as DB00549_BI_005, DB04868_BI_003, DB11984_BI_002, DB12364_BI_006 and DB12805_BI_004 must be confirmed by molecular dynamics studies, followed by in vitro and in vivo empirical tests that ratify the advocated in-silico results.


Uncemented Metal-Backed Tantalum Patellar Components in Total Knee Arthroplasty Have a High Fracture Rate at Midterm Follow-Up.
There is interest in uncemented total knee arthroplasty due to the hope for long-term biologic fixation, but limited data are available regarding uncemented tantalum patellar components. The purpose of this study was to evaluate the radiographic outcomes of uncemented tantalum patellar implants at midterm follow-up. We retrospectively reviewed a consecutive series of 30 knees in 29 patients who underwent cementless total knee arthroplasty with an uncemented metal-backed tantalum patella between September 2006 and April 2009. Patients were required to have a minimum radiographic follow-up of 2 years. Anteroposterior and lateral radiographs of the knee were evaluated for signs of implant fracture or gross loosening. Clinical follow-up was obtained by reviewing each patient's most recent orthopedic record. Thirty knees in 29 patients met inclusion criteria. The mean age of the cohort was 59.1 years with a mean body mass index of 31.9 kg/m2. Mean postoperative radiographic follow-up time was 5.5 years. Six fractures of the patellar component were noted. This represented a fracture rate of 20% among the entire cohort and 35% among the 17 knees with visible patellae on anteroposterior radiograph. All fractures had a transverse pattern. No gross patellar component loosening was noted. Among patients with component fractures, 2 required revisions for instability and 1 revision was for infection. Our results suggest a minimum 20% rate of component fracture at midterm follow-up. Although many of these patellar component fractures were asymptomatic, they have the potential to impact revision rates in the longer term.


"I know what love means." Gender-based violence in the lives of urban adolescents.
In focus groups designed to probe violence and fighting, urban youth emphasized the impact of gender-based violence in their lives. We used this opportunity to qualitatively explore how gender-based violence affects the lives of urban adolescents. Thirteen structured focus group interviews were held with youth from three high-violence settings: a large, urban high school, a training center for disadvantaged youth, and a school for adjudicated youth. Participants were 120 urban, predominant African American youth and young adults ages 14-22. Seven focus groups were conducted with females and six with males. Participants did not talk about violence without discussing the gender-based violence they experienced in a number of social roles: as witnesses to family violence, as victims of intimate partner and dating violence, or as peer observers of harassing and violent behavior. Male participants felt that other males used violence as a way of maintaining a sense of power over their partners. Participants of both genders struggled to identify the boundaries between playing, harassment, and abuse. Female participants suggested that females sometimes wanted males to hit them, interpreting this violence as a sign of commitment. Similarly, females struggled to determine if gender-based violence could be a reflection of love. Gender-based violence is a significant issue in the lives of urban adolescents. Youth experienced gender-based violence in a number of contexts and roles, and many had concluded that such violence was sometimes acceptable. Prevention strategies should start early and address the spectrum of youths' experiences.


The Effect of Formulation Excipients and Thermal Treatment on the Release Properties of Lisinopril Spheres and Tablets.
Multiparticulate systems are used in the development of controlled release systems. The objective of this study was to determine the effect of the wax level, the type of excipient, and the exposure of the tablets to thermal treatment on drug release. Spheres from multiparticulate system with different wax levels and excipients were developed using the drug Lisinopril and compressed into tablets; these tablets were analyzed to determine the drug release. All tablets contained constant level of Lisinopril (10% w/w) and Compritol (30% and 50% w/w). Also, as a diluent, all of them contained 30% w/w Avicel and 30% w/w dibasic calcium phosphate or lactose, or 60% Avicel. Tablets compacted from spheres prepared by extruder/marumerizer and using 30% w/w lipid and 60% Avicel released 84% of drug at six hours of dissolution testing, while tablets of the same composition but prepared using 30% dibasic calcium phosphate and 30% Avicel released 101%. When the tablets were thermally treated, the drug release reduced. As the percent of lipid increased in the formulation, the drug release decreased. Compaction of tablets prepared from spheres with wax has potential for controlling the drug release.


Risk of methylphenidate-induced prehypertension in normotensive adult smokers with attention deficit hyperactivity disorder.
The authors studied predictors of methylphenidate-induced increases in blood pressure (BP). In this secondary analysis of a randomized, double-blind, placebo-controlled smoking cessation trial, nonhypertensive adult smokers with attention deficit hyperactivity disorder randomized to osmotic-release oral system methylphenidate (OROS-MPH) (n=115) were matched one-to-one on baseline systolic BP (SBP) (±5 mm Hg) with participants randomized to placebo (n=115) and followed for 10 weeks. In adjusted mixed linear models of SBP and diastolic BP (DBP), baseline normal SBP (P<.0001) and DBP (P<.0001) were associated with significant OROS-MPH-induced increases compared with placebo, whereas significant increases were not observed in participants with baseline prehypertensive SBP (P=.27) and DBP (P=.79). Participants randomized to OROS-MPH with baseline normal BP had increased odds of developing either systolic (odds ratio [OR], 3.32; 95% confidence interval [CI], 1.41-8.37; P=.006) or diastolic prehypertension (OR, 4.32; 95% CI, 1.56-14.0; P=.004) compared with placebo using simple logistic regression. The authors demonstrated an augmented OROS-MPH-induced BP elevation and risk of prehypertension in adults with baseline normal BP. Significantly increased BP was not observed in adults with baseline prehypertension.


Serum thyroxine level and cognitive decline in euthyroid older women.
Clinical and subclinical hypothyroidism is associated with cognitive impairment. This study investigated the association between thyroxine (T(4)) and thyroid-stimulating hormone (TSH) level and change over time in cognitive performance in a sample of older women with normal thyroid gland function. T(4) and TSH were measured at baseline in 628 women (> or = 65 years) enrolled in the Women's Health and Aging Study, a community-based study of physically impaired women. Cognitive function was assessed at baseline and after 1, 2, and 3 years, using the Mini-Mental State Examination (MMSE). Incident cognitive decline was defined as a decrease of more than one point/year in MMSE score between baseline and the end of the follow-up. The analysis included 464 subjects with normal thyroid gland function with a baseline and at least one follow-up MMSE. At baseline there was no association between T(4) and TSH level and cognitive function. In longitudinal analysis, adjusting for age, race, level of education, and other covariates, compared with women in the highest T(4) tertile (8.1 to 12.5 microg/dL), those in the lowest tertile (4.5 to 6.5 microg/dL) had a greater decline in MMSE score (-0.25 point/year vs -0.12 point/year; p = 0.04). A total of 95 women (20.5%) had cognitive decline during the study period (mean MMSE decline, 5.5 points). Compared with women in the highest T(4) tertile, those in the lowest tertile had a twofold risk of cognitive decline (adjusted relative risk, 1.97; 95% CI, 1.10 to 3.50). The results were not modified by baseline cognitive and physical function. There was no association between baseline TSH level and change in cognitive function. In older women, low T(4) levels, within the normal range, were associated with a greater risk of cognitive decline over a 3-year period. Thyroid hormone levels may contribute to cognitive impairment in physically impaired women.


Kinetic analysis of metsulphmyoglobin and metmyoglobin reduction by Fe(EDTA)2-.
Metsulphmyoglobin prepared from horse heart myoglobin was purified by ion-exchange chromatography to yield a product that on reduction with Fe(EDTA)2- has an A617/A561 ratio greater than 3.5:1. The kinetics of reduction of this purified metsulphmyoglobin and of native metmyoglobin by Fe(EDTA)2- were studied under various conditions of pH, ionic strength and temperature to compare the relative electron-transfer reactivities of a metallochlorin and a metalloporphyrin in identical protein environments. Although the rate of metsulphmyoglobin reduction is 2-7 times that of metmyoglobin under a variety of conditions, this difference can be more than compensated for by the reported difference in mid-point reduction potential between the two forms of the protein. The electrostatic and activation parameters observed for native metmyoglobin and metsulphmyoglobin are essentially identical, and small differences are found in the pH-dependence of the reduction reaction. These findings lead us to conclude that conversion of the porphyrin prosthetic group into a chlorin has relatively little effect on the electron-transfer reactivity of the central metal atom.


Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment.
Six patients with Hashimoto thyroiditis (HT) and associated encephalopathy (HE) are described and compared with 14 well-documented cases retrieved from the literature. HE typically affects patients when they are euthyroid and, in an appropriate clinical situation, antithyroid autoantibodies are the main indicators of HE. Since clinical features of HE are unspecific, other aetiologies such as infectious, metabolic, toxic, vascular, neoplastic, and paraneoplastic causes have to be excluded. Our own six cases and those from the literature show that two types of initial clinical presentation can be differentiated: a vasculitic type with stroke-like episodes and mild cognitive impairment in nine patients, and a diffuse progressive type with dementia, seizures, psychotic episodes or altered consciousness in 11 patients. These types may overlap, particularly in the long-term course without treatment. Response to steroids was usually excellent with complete remission in 80%. Eighteen of the 20 patients were women. Characteristic, though unspecific, findings were abnormal EEG (90%) and CSF (80%). Together with quantitative neuropsychological testing, these proved sensitive for monitoring the efficacy of therapy. Conversely, antithyroid autoantibody titres did not correlate with the severity or type of clinical presentation. The link between HE and HT is not clear. A pathogenetic role for antithyroid autoantibodies in the central nervous system seems unlikely.


Kinetics Model of Femtosecond Laser Ionization in Nitrogen and Comparison to Experiment.
A zero-dimensional kinetics simulation of femtosecond laser ionization in nitrogen is proposed that includes fast gas heating effects, electron scattering (elastic and inelastic) rate coefficients from BOLSIG+ and photoionization based on filamentation theory. Key rate coefficients possessing significant uncertainty are tuned (within the range of variation found in literature) to reproduce the time-varying signal acquired by a bandpass-filtered photomultiplier tube with good agreement up to several hundred nanoseconds. Separate spectral measurements calibrate the relative strength of signal components. Derived equations relate the model to experimental measurements in absolute units. Reactions contributing to the rate of change of important species are displayed in terms of absolute rate and relative fraction. In general, decreasing the gas density lengthens the duration of early reactions and delays the start of later reactions. The model agrees with data taken in a variable temperature and pressure free jet by an intensified camera. Results demonstrate that initial signal depends primarily on gas density and secondarily on gas temperature. The optimal (maximum) initial signal occurs at a gas density below atmospheric. Decreases in gas density alter the evolution of excited-state populations, postponing the peak (while reducing its value) and slowing the rate of decay. For the optimal case, populations are favorably shifted in time with respect to the gate delay (and width) to boost the signal. Reductions in gas temperature generally enhance initial signal due to elevated dissociative recombination of cluster ions (along with excited-state coupling from quenching and energy pooling).


Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis.
A major cause of tuberculosis (TB) resistance to the aminoglycoside kanamycin (KAN) is the Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. Upregulation of this enzyme is responsible for inactivation of KAN through acetylation of its amino groups. A 123 000-compound high-throughput screen (HTS) yielded several small-molecule Eis inhibitors that share an isothiazole S,S-dioxide heterocyclic core. These were investigated for their structure-activity relationships. Crystal structures of Eis in complex with two potent inhibitors show that these molecules are bound in the conformationally adaptable aminoglycoside binding site of the enzyme, thereby obstructing binding of KAN for acetylation. Importantly, we demonstrate that several Eis inhibitors, when used in combination with KAN against resistant Mtb, efficiently overcome KAN resistance. This approach paves the way toward development of novel combination therapies against aminoglycoside-resistant TB.


Electrochemical detection of microRNA-21 based on a Au nanoparticle functionalized g-C3N4 nanosheet nanohybrid as a sensing platform and a hybridization chain reaction amplification strategy.
Here, a sensitive sandwich-type electrochemical biosensor for microRNA-21 detection was reported. It was based on the use of a Au NP functionalized graphite-like carbon nitride nanosheet (g-C3N4 NS) nanohybrid (Au NPs-g-C3N4 NS) as a sensing platform and DNA concatemers containing methylene blue (MB) as a signal probe. The signal probe was prepared by using two different single strand DNAs with a complementary sequence (one of them labeled with MB at the 3' end) to form long concatemers via continuous hybridization chain reaction (HCR); thus numerous MB signal molecules were loaded on long concatemers. The biosensor was fabricated following the next step: a thiolated hairpin probe (HP) was first immobilized on the surface of the glassy carbon electrode (GCE) modified with a Au NPs-g-C3N4 NS nanohybrid. After it was blocked with MCH, the modified electrode was sequentially hybridized with microRNA-21 and a signal probe, respectively. As a result, a sandwich structure of HP-microRNA-signal probe covered the surface of the modified electrode. Differential pulse voltammetry (DPV) was employed to measure the sensing signal in phosphate buffered solution (0.10 M PBS, pH 7.4). The experimental conditions were optimized such as the hybridization time and the amount of g-C3N4 NS. The proposed biosensor exhibited a wide linear response range (1.0 fM to 500 nM) and a low limit of detection (0.33 fM; at S/N = 3) under the optimal conditions. Meanwhile, the biosensor could discriminate single base mismatched microRNA-21, indicating that the biosensor possessed high selectivity.


Lifecourse transitions, gender and drinking in later life.
Older people consume less alcohol than any other adult age group. However, in recent years survey data on alcohol consumption in the United Kingdom have shown that while younger age groups have experienced a decline in alcohol consumption, drinking behaviours among the elderly have not reduced in the same way. This paper uses data from the English Longitudinal Study of Ageing to analyse both the frequency and quantity of older adult's alcohol consumption using a lifecourse approach over a ten-year period. Overall drinking declined over time and the analysis examined how socio-economic characteristics, partnership, employment and health statuses were associated with differences in drinking behaviours and how these changed over time. Higher wealth and level of education were associated with drinking more and drinking more frequently for men and women. Poorer self-rated health was associated with less frequent consumption and older people with poor and deteriorating health reported a steeper decline in the frequency of alcohol consumption over time. Men who were not in a partnership drank more than other men. For women, loss of a partner was associated with a steeper decline in drinking behaviours. These findings have implications for programmes to promote responsible drinking among older adults as they suggest that, for the most part, characteristics associated with sustaining wellbeing in later life are also linked to consuming more alcohol.


Association between urinary sodium and circulating lipid levels: a Mendelian randomization study.
Urinary sodium was indicated to be associated with dyslipidemia, but inconsistent conclusions for this association exist across the present observational studies. This study aimed to evaluate the causal association between urinary sodium and circulating lipid levels [low-density lipoprotein cholesterol (LDL-C), triglycerides, and high-density lipoprotein cholesterol (HDL-C)] through Mendelian randomization. Univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) with pleiotropy-resistant methods were performed. Data for urinary sodium were obtained from the genome-wide association study (GWAS) from 446,237 European individuals. Data for lipid profiles were extracted from GWAS based on the UK Biobank (for the discovery analysis) and the Global Lipids Genetics Consortium (for the replication analysis). In the discovery analysis, UVMR provided evidence that per 1-unit log-transformed genetically increased urinary sodium was associated with a lower level of HDL-C level (beta = -0.32; 95% CI: -0.43, -0.20; p = 7.25E-08), but not with LDL-C and triglycerides. This effect was still significant in the further MVMR when considering the effect of BMI or the other two lipid contents. In contrast, higher genetically predicted triglycerides could increase urinary sodium in both UVMR (beta = 0.030; 95% CI: 0.020, -0.039; p = 2.12E-10) and MVMR analyses (beta = 0.029; 95% CI: 0.019, 0.037; p = 8.13E-10). Similar results between triglycerides and urinary sodium were found in the replication analysis. Increased urinary sodium may have weak causal effects on decreased circulating HDL-C levels. Furthermore, genetically higher triglyceride levels may have independent causal effects on increased urinary sodium excretion.


[Correlation of active and inactive forms of phosphorylase and glycogen synthetase in the liver of the developing chick embryo].
The marked changes in the activity and ratio of the active and inactive forms of glycogen synthetase and phosphorylase were found in the liver of developing chick embryo. The activity of phosphorylase increased in the liver from the 8th day of incubation till the end of embryogenesis. The practically complete activation of the inactive form of this enzyme was noted in the end of embryogenesis. The activity of glycogen synthetase in the liver increased till the 17th day of incubation and sharply decreased more than 6 times thereafter. The maximum of the active form of glycogen synthetase (1/3 of total activity) was noted on the 17th day as well. The changes in the content of glycogen synthetase in the liver are synchronized with those in the activity and ratio of the active and inactive forms of glycogen synthetase. The role of changes in the concentration of glucose and glucose-6-phosphate in the control of ratio of the active and inactive forms of enzymes of glycogen metabolism is discussed.


Label-free high-resolution imaging of prostate glands and cavernous nerves using coherent anti-Stokes Raman scattering microscopy.
A custom built coherent anti-Stokes Raman scattering (CARS) microscope was used to image prostatic glands and nerve structures from 17 patients undergoing radical prostatectomy. Imaging of glandular and nerve structures showed distinctive cellular features that correlated to histological stains. Segmentation of cell nucleus was performed to establish a cell feature-based model to separate normal glands from cancer glands. In this study, we use a single parameter, average cell neighbor distance based on CARS imaging, to characterize normal and cancerous glandular structures. By combining CARS with our novel classification model, we are able to characterize prostate glandular and nerve structures in a manner that potentially enables real-time, intra-operative assessment of surgical margins and neurovascular bundles. As such, this method could potentially improve outcomes following radical prostatectomy.


Important drug-micronutrient interactions: A selection for clinical practice.
Interactions between drugs and micronutrients have received only little or no attention in the medical and pharmaceutical world in the past. Since more and more pharmaceutics are used for the treatment of patients, this topic is increasingly relevant. As such interactions - depending on the duration of treatment and the status of micronutrients - impact the health of the patient and the action of the drugs, physicians and pharmacists should pay more attention to such interactions in the future. This review aims to sensitize physicians and pharmacists on drug micronutrient interactions with selected examples of widely pescribed drugs that can precipitate micronutrient deficiencies. In this context, the pharmacist, as a drug expert, assumes a particular role. Like no other professional in the health care sector, he is particularly predestined and called up to respond to this task. The following article intends to point out the relevance of mutual interactions between micronutrients and various examples of widely used drugs, without claiming to be exhaustive.


Preparation of bispecific antibodies by chemical recombination of monoclonal immunoglobulin G1 fragments.
Preparation of bispecific antibodies by the chemical reassociation of monovalent fragments derived from monoclonal mouse immunoglobulin G1 is inefficient because of side reactions during reoxidation of the multiple disulfide bonds linking the heavy chains. These side reactions can be avoided by using specific dithiol complexing agents such as arsenite and effecting disulfide formation with a thiol activating agent such as 5,5'-dithiobis(2-nitrobenzoic acid). In this way bispecific antibodies were obtained in high yield and free of monospecific contaminants from monoclonal mouse immunoglobulin G1 fragments. The bispecific antibodies were used as agents for the selective immobilization of enzymes.


Physiological aspects and clinical sequelae of energy deficiency and hypoestrogenism in exercising women.
Amenorrhoea associated with reduced caloric intake and strenuous exercise leads to hypoestrogenism and is associated with clinical manifestations that include disordered eating, stress fractures, osteoporosis, and, as recently reported, a potential increase in the risk of premature cardiovascular disease. Disordered eating, menstrual irregularities and bone loss comprise the clinical condition known as the 'female athlete triad'. The aetiology of the triad is linked to a high prevalence of disordered eating and cognitive restraint. This results in inadequate caloric intake for high exercise energy expenditures that leads to energy deficiency. This in turn stimulates compensatory mechanisms, such as weight loss or energy conservation, subsequently causing a central suppression of reproductive function and concomitant hypoestrogenism. Because the aetiology of menstrual disturbances and the female athlete triad is causally linked to energy deficiency, there is no justification for fears that exercise itself is unhealthy for women. However, improved detection, monitoring, and treatment of all components of the triad in exercising women should be emphasized. This paper critically reviews the physiological aspects and clinical sequelae of energy deficiency and hypoestrogenism associated with the female athlete triad in exercising women.


The socioeconomic profile of alcohol-attributable mortality in South Africa: a modelling study.
Globally, illness and life expectancy follow a social gradient that puts people of lower socioeconomic status (SES) at higher risk of dying prematurely. Alcohol consumption has been shown to be a factor contributing to socioeconomic differences in mortality. However, little evidence is available from low- and middle-income countries. The objective of this study was to quantify mortality attributable to alcohol consumption in the adult (15+ years) general population of South Africa in 2015 by SES, age, and sex. A comparative risk assessment was performed using individual and aggregate data from South Africa and risk relations reported in the literature. Alcohol-attributable fractions (AAFs) and alcohol-attributable mortality rates were estimated for cause-specific mortality by SES, sex, and age. Monte Carlo simulation techniques were used to calculate 95% uncertainty intervals (UI). Overall, approximately 62,300 (95% UI 27,000-103,000) adults died from alcohol-attributable causes in South Africa in 2015, with 60% of deaths occurring in people in the low and 15% in the high SES groups. Age-standardized, alcohol-attributable mortality rates per 100,000 adults were highest for the low SES group (727 deaths, 95% UI 354-1208 deaths) followed by the middle (377 deaths, 95% UI 165-687 deaths) and high SES groups (163 deaths, 95% UI 71-289 deaths). The socioeconomic differences were highest for mortality from infectious diseases. People of low SES had a lower prevalence of current alcohol use but heavier drinking patterns among current drinkers. Among men, AAFs were elevated at low and middle SES, particularly for the middle and higher age groups (35+). Among women, AAFs differed less across SES groups and, in the youngest age group (15-34), women of high SES had elevated AAFs. Alcohol use contributed to vast socioeconomic differences in mortality. Where observed, elevated AAFs for people of low and middle SES arose from higher levels of consumption among current drinkers and not from the prevalence of current alcohol use per se. The findings can direct preventive measures and interventions on those at highest risk. Future research is needed to investigate socioeconomic differences in the risk functions relating alcohol use to cause-specific mortality.


Risk factors in asthmatic patients in Croatia.
The aim of this case-control study was to investigate whether some factors, that are associated with development of asthma, are significantly more present in the observed group of asthmatic patients, in comparison to the control group. Participants included 111 cases with asthma, and 108 controls with no asthma. Data obtained from cases and controls were compared according the sex. The study was performed using a specially developed questionnaire and data were collected from medical documentation of cases. Results showed that a significantly high proportion of cases had lower socio-economic status, higher proportion of atopic diseases, and were more exposed to dampness in working environment, and passive smoking, both at home and at work. Cases also exhibited poorer sustainment of physical strains and psychological stresses, and considered their life quality was greatly reduced by asthma. Among asthmatic participants, there were fewer current smokers and non-smokers, and more ex-smokers.


Infrared zone-scanning system.
Challenges encountered in designing an infrared viewing optical system that uses a small linear detector array based on a zone-scanning approach are discussed. Scanning is performed by a rotating refractive polygon prism with tilted facets, which, along with high-speed line scanning, makes the scanning gear as simple as possible. A method of calculation of a practical optical system to compensate for aberrations during prism rotation is described.


The ecology and fishery of the vendace (Coregonus albula) in the Baltic Sea.
Brackish water ecosystems often have high primary production, intermediate salinities, and fluctuating physical conditions and therefore provide challenging environments for many of their inhabitants. This is especially true of the Baltic Sea, which is a large body of brackish water under strong anthropogenic influence. One freshwater species that is able to cope under these conditions in the northern Baltic Sea is the vendace (Coregonus albula), a small salmonid fish. Here, we review the current knowledge of its ecology and fishery in this brackish water environment. The literature shows that, by competing for resources with other planktivores and being an important prey for a range of larger species, C. albula plays a notable role in the northern Baltic Sea ecosystem. It also sustains significant fisheries in the coastal waters of Sweden and Finland. We identify the need to better understand these C. albula populations in terms of the predator-prey interactions, distributions of anadromous and sea spawning populations and other putative (eco)morphs, extent of gene exchange between the populations, and effects of climate change on their future. In this regard, we recommend strengthening C. albula-related research and management efforts by improved collaboration and coordination between research institutions, other governmental agencies, and fishers, as well as by harmonization of fishery policies across national borders.


Application of artificial intelligence-based computer-assisted diagnosis on synthetic mammograms from breast tomosynthesis: comparison with digital mammograms.
To compare the diagnostic agreement and performances of synthetic and conventional mammograms when artificial intelligence-based computer-assisted diagnosis (AI-CAD) is applied. From January 2017 to April 2017, 192 patients (mean age 53.7 ± 11.7 years) diagnosed with 203 breast cancers were enrolled in this retrospective study. All patients underwent digital breast tomosynthesis (DBT) with digital mammograms (DM) simultaneously. Commercial AI-CAD was applied to the reconstructed synthetic mammograms (SM) from DBT and DM respectively and abnormality scores were calculated. We compared the median abnormality scores between DM and SM with the Wilcoxon signed-rank test and used the Bland-Altman analysis to evaluate agreements between the two mammograms and to investigate clinicopathological factors which might affect agreement. Diagnostic performances were compared using an area under the receiver operating characteristic curve (AUC). The abnormality scores showed a mean difference (bias) of - 3.26 (95% limits of agreement: - 32.69, 26.18) between the two mammograms by the Bland-Altman analysis. The concordance correlation coefficient was 0.934 (95% CI: 0.92, 0.946), suggesting high reproducibility. SM showed higher abnormality scores in cancer with distortion and occult findings, T1 and N0 cancer, and luminal type cancer than DM (all p ≤ 0.001). Diagnostic performance did not differ between the mammograms (AUC 0.945 for conventional mammograms, 0.938 for synthetic mammograms, p = 0.499). AI-CAD can also work well on synthetic mammograms, showing good agreement and comparable diagnostic performance compared to its application to DM. • AI-CAD which was developed based on imaging findings of digital mammograms can also be applied to synthetic mammograms. • AI-CAD showed good agreement and similar diagnostic performance when applied to both synthetic and digital mammograms. • With AI-CAD, synthetic mammograms showed relatively higher abnormality scores in cancer with distortion and occult findings, T1 and N0 cancer, and luminal type cancer than digital mammograms.


Structure, dynamics and reactions of protein hydration water.
The apparent simplicity of the water molecule belies the wide range of fascinating protein phenomena in which it participates. We review recent computer simulation work on buried, internal water molecules, discussing the thermodynamics of water molecule binding and the participation of water in proton transfer reactions. Surface water molecules are also considered, with emphasis on the modification of average solvent structure on a protein surface, the role of water in the protein dynamical 'glass' transition and a simplified description of the protein motions thereby activated.


Causal relationship between linoleic acid and type 2 diabetes and glycemic traits: a bidirectional Mendelian randomization study.
To investigate the causal relationships between linoleic acid and type 2 diabetes, and between linoleic acid and glycemic traits in European populations. This study employed a two-sample Mendelian randomization approach to infer causality between linoleic acid and type 2 diabetes, as well as between linoleic acid and glycemic traits, leveraging genetic variations. Data were sourced from genome-wide association study summary datasets. Random-effects inverse-variance weighted, weighted median, and MR-Egger methods were used for the two-sample Mendelian randomization analyses. Results were presented as odds ratios with a 95% confidence interval. Multiple sensitivity analyses were conducted to assess result robustness. MR findings indicated a correlation between linoleic acid levels and the risk of type 2 diabetes, fasting blood glucose, and glycated hemoglobin (HbA1c), but not with fasting insulin. Specifically: type 2 diabetes (OR: 0.811, 95% CI: 0.688-0.956, P=0.013<0.05),fasting blood glucose (β_IVW): -0.056, 95% CI: (-0.091,-0.021), P=0.002< 0.0125), glycated hemoglobin (β_IVW: -0.032, 95% CI: (-0.048,-0.015), P=0.0002< 0.0125) and Fasting insulin (β_IVW: -0.024, 95% CI: (-0.056,-0.008), P=0.136 >0.05).Reverse MR analyses showed a correlation between type 2 diabetes and reduced levels of linoleic acid (β_IVW: -0.033, 95% CI: (-0.059,-0.006), P=0.014<0.05). Multiple sensitivity analyses also detected study heterogeneity but found no evidence of horizontal pleiotropy. High levels linoleic acid can reduce the risk of type 2 diabetes, fasting blood glucose, and glycated hemoglobin, but has no significant relation with fasting insulin. Type 2 diabetes can lower linoleic acid levels; however, no significant causal relationship was observed between the three glycemic traits and reduced levels of linoleic acid.


Diagnostic evaluation of the MRP-8/14 for the emergency assessment of chest pain.
Elevated levels of myeloid-related protein (MRP)-8/14 (S100A8/A9) are associated with first cardiovascular events in healthy individuals and worse prognosis in patients with acute coronary syndrome (ACS). The diagnostic utility of MRP-8/14 in patients presenting to the emergency room with symptoms concerning for ACS is uncertain. MRP-8/14 was measured in serial serum and plasma samples in a single center prospective cohort-study of patients presenting to the emergency room with non-traumatic chest pain concerning for ACS. Final diagnosis was adjudicated by an endpoint committee. Of patients with baseline MRP-8/14 results (n = 411), the median concentration in serum was 1.57 μg/ml (25th, 75th: 0.87, 2.68) and in plasma was 0.41 μg/ml (<0.4, 1.15) with only moderate correlation between serum and plasma (ρ = 0.40). A final diagnosis of MI was made in 106 (26%). Peak serum MRP-8/14 was higher in patients presenting with MI (p < 0.001). However, the overall diagnostic performance of MRP-8/14 was poor: sensitivity 28% (95% CI 20-38), specificity 82% (78-86), positive predictive value 36% (26-47), and negative predictive value 77% (72-81). The area under the ROC curve for diagnosis of MI with MRP-8/14 was 0.55 (95% CI 0.51-0.60) compared with 0.95 for cTnI. The diagnostic performance was not improved in early-presenters, patients with negative initial cTnI, or using later MRP-8/14 samples. Patients presenting with MI had elevated levels of serum MRP-8/14 compared to patients with non-cardiac chest pain. However, overall diagnostic performance of MRP-8/14 was poor and neither plasma nor serum MRP-8/14 offered diagnostic utility comparable to cardiac troponin.


A Study on the Effects of the Use of Propofol in Experimental Model Inferior Epigastric Island Flap on Ischemia-Reperfusion Injury.
Problems concerning vascular blood flow are the most frequently encountered ones after flap applications. The flap tissue starts to develop ischemia in patients with a vascular blood flow insufficiency. And reperfusion starts in those patients in whom the ischemia is temporary, triggering an ischemia-reperfusion injury depending on the duration of the ischemia. The aim of this study was to evaluate the effect of propofol, which is an anesthetic agent known to have an antioxidant effect and a free radical scavenging feature on the ischemia-reperfusion injury created on an experimental epigastric island flap.Thirty Sprague-Dawley rats were used in the study. The rats were divided into 3 groups of 10 rats each. Inferior epigastric artery-based abdominal flaps were prepared in all the groups. In group 1 (sham), the flap was elevated but no ischemia was applied. In groups 2 (control) and 3 (propofol), the flap was exposed to ischemia for 2 hours after it was elevated. All the rats were sacrificed and biochemical and histopathological assessments were made on the tissue samples taken on the 14th day. As a result of a comparison between the groups, the flap viability rates and the superoxide dismutase, total antioxidant capacity, and catalase values were found to be significantly higher (P < 0.001) in the propofol group while the malondialdehyde and total oxidative stress values were lower (P < 0.001). Based on the data obtained from the present study, the use of propofol was observed to have a protective effect against ischemia-reperfusion injuries in flap surgeries.


Discovery of interstellar ketenyl (HCCO), a surprisingly abundant radical.
We have conducted radioastronomical observations of 9 dark clouds with the IRAM 30m telescope. We present the first identification in space of the ketenyl radical (HCCO) toward the starless core Lupus-1A and the molecular cloud L483, and the detection of the related molecules ketene (H2CCO) and acetaldehyde (CH3CHO) in these two sources and 3 additional dark clouds. We also report the detection of the formyl radical (HCO) in the 9 targeted sources and of propylene (CH2CHCH3) in 4 of the observed sources, which extends significantly the number of dark clouds where these molecules are known to be present. We derive a beam-averaged column density of HCCO of ~ 5 × 1011 cm-2 in both Lupus-1A and L483, which means that the ketenyl radical is just ~10 times less abundant than ketene in these sources. The non-negligible abundance of HCCO found implies that there must be a powerful formation mechanism able to counterbalance the efficient destruction of this radical through reactions with neutral atoms. The column densities derived for HCO, (0.5-2.7) ×1012 cm-2, and CH2CHCH3, (1.9-4-2) ×1013 cm-2, are remarkably uniform across the sources where these species are detected, confirming their ubiquity in dark clouds. Gas phase chemical models of cold dark clouds can reproduce the observed abundances of HCO, but cannot explain the presence of HCCO in Lupus-1A and L483 and the high abundances derived for propylene. The chemistry of cold dark clouds needs to be revised in the light of these new observational results.


A mathematical model for predicting toothbrush stiffness.
Both cleaning efficiency and gingival damage depend on the access of toothbrush bristles to sheltered areas and their ability to deliver sufficient force to remove plaque as they travel over tooth surfaces. A mathematical expression was therefore developed which relates bristle properties and features of brush construction to overall brush stiffness, in order to provide a framework for the prediction and systematic investigation of brush performance: Brush stiffness = 0.125E(DBDT)2NTPf/L3. This shows that brush stiffness is predominantly affected by bristle modulus (E), bristle and tuft diameter (DB and DT), the number of tufts (NT), the number of bristles per unit area packed into a tuft hole (Pf = packing factor), and the trim length of bristles (L). Bristle composition and shape had no measurable effect. The 0.125 factor is empirically derived and probably depends on visco-elastic, frictional, and other dynamic effects which were not examined. Thus, this is a first-order approximation, and further work must be done to account for bristle interactions and brushing rate, and to correlate stiffness with a measure of cleaning efficiency.


Molecular Malfeasance Mediating Myeloid Malignancies: The Genetics of Acute Myeloid Leukemia.
A remarkable number of different, but recurrent, structural cytogenetic abnormalities have been observed in AML, and the 2016 WHO AML classification system incorporates numerous distinct entities associated with translocations or inversions, as well as others associated with single gene mutations into a category entitled "AML with recurrent genetic abnormalities." The AML classification is heavily reliant on cytogenetic and molecular information based on conventional genetic techniques (including karyotype, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, single gene sequencing), but large-scale next generation sequencing is now identifying novel mutations. With targeted next generation sequencing panels now clinically available at many centers, detection of mutations, as well as alterations in epigenetic modifiers, is becoming part of the routine diagnostic evaluation of AML and will likely impact future classification schemes.


One-Year Survival and Neurologic Outcomes After Pediatric Open-Chest Cardiopulmonary Resuscitation.
Limited data exist about neurobehavioral outcomes of children treated with open-chest cardiopulmonary resuscitation (CPR). Our objective was to describe neurobehavioral outcomes 1 year after arrest among children who received open-chest CPR during in-hospital cardiac arrest and to explore factors associated with 1-year survival and survival with good neurobehavioral outcome. The study is a secondary analysis of the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital Trial. Fifty-six children who received open-chest CPR for in-hospital cardiac arrest were included. Neurobehavioral status was assessed using the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at baseline before arrest and 12 months after arrest. Norms for VABS-II are 100 ± 15 points. Outcomes included 12-month survival, 12-month survival with VABS-II decreased by no more than 15 points from baseline, and 12-month survival with VABS-II of 70 or more points. Of 56 children receiving open-chest CPR, 49 (88%) were after cardiac surgery and 43 (77%) were younger than 1 year. Forty-four children (79%) were cannulated for extracorporeal membrane oxygenation (ECMO) during CPR or within 6 hours of return of spontaneous circulation. Thirty-three children (59%) survived to 12 months, 22 (41%) survived to 12 months with VABS-II decreased by no more than 15 points from baseline, and of the children with baseline VABS-II of 70 or more points 23 (51%) survived to 12 months with VABS-II of 70 or more points. On multivariable analyses, use of ECMO, renal replacement therapy, and higher maximum international normalized ratio were independently associated with lower 12-month survival with VABS-II of 70 or more points. Approximately one-half of children survived with good neurobehavioral outcome 1 year after open-chest CPR for in-hospital cardiac arrest. Use of ECMO and postarrest renal or hepatic dysfunction may be associated with worse neurobehavioral outcomes.


Whole-Genome Sequencing of Porcine Reproductive and Respiratory Syndrome Virus from Field Clinical Samples Improves the Genomic Surveillance of the Virus.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economic concern worldwide. There are currently large data sets available about the ORF5 gene of the virus, with thousands of sequences available, but little data are currently available on the full-length genome of PRRSV. We hypothesized that whole-genome sequencing (WGS) of the PRRSV genome would allow better epidemiological monitoring than ORF5 gene sequencing. PRRSV PCR-positive serum, oral fluid, and tissue clinical samples submitted to the diagnostic laboratory for routine surveillance or diagnosis of PRRSV infection in Québec, Canada, swine herds were used. The PRRSV reverse transcription-quantitative PCR Cq values of the processed samples varied between 11.5 and 34.34. PRRSV strain genomes were isolated using a poly (A)-tail method and were sequenced with a MiSeq Illumina sequencer. Ninety-two full-length PRRSV genomes were obtained from 88 clinical samples out of 132 tested samples, resulting in a PRRSV WGS success rate of 66.67%. Three important deletions in ORF1a were found in most wild-type (i.e., not vaccine-like) strains. The importance of these deletions remains undetermined. Two different full-length PRRSV genomes were found in four different samples (three serum samples and one pool of tissues), suggesting a 4.55% PRRSV strain coinfection prevalence in swine. Moreover, six PRRSV whole genomes (6.52% of PRRSV strains) were found to cluster differently than they did under the ORF5 classification method. Overall, WGS of PRRSV enables better strain classification and/or interpretation of results in 9.10% of clinical samples than ORF5 sequencing, as well as allowing interesting research avenues.


Initial Validation of a Brief Pictorial Measure of Caregiver Aggression: The Family Aggression Screening Tool.
In the present study, we report on the development and initial psychometric properties of the Family Aggression Screening Tool (FAST). The FAST is a brief, self-report tool that makes use of pictorial representations to assess experiences of caregiver aggression, including direct victimization and exposure to intimate partner violence. It is freely available on request and takes under 5 minutes to complete. Psychometric properties of the FAST were investigated in a sample of 168 high-risk youth aged 16 to 24 years. For validation purposes, maltreatment history was assessed using the Childhood Trauma Questionnaire; levels of current psychiatric symptoms were also assessed. Internal consistency of the FAST was good. Convergent validity was supported by strong and discriminative associations with corresponding Childhood Trauma Questionnaire subscales. The FAST also correlated significantly with multi-informant reports of psychiatric symptomatology. Initial findings provide support for the reliability and validity of the FAST as a brief, pictorial screening tool of caregiver aggression.


Catalase-Loaded Silica Nanoparticles Formulated via Direct Surface Modification as Potential Oxygen Generators for Hypoxia Relief.
Enzymes are biological catalysts that have many potential industrial and biomedical applications. However, the widespread use of enzymes in the industry has been limited by their instability and poor recovery. In biomedical applications, systemic administration of enzymes has faced two main challenges: limited bioactivity mostly due to rapid degradation by proteases and immunogenic activity, since most enzymes are from nonhuman sources. Herein, we propose a robust enzyme-encapsulation strategy to mitigate these limitations. Catalase (CAT) was encapsulated in nanoporous silica nanoparticles (CAT-SiNPs) by first chemically modifying the enzyme surface with a silica precursor, followed by silica growth and finally poly(ethylene glycol) (PEG) conjugation. The formulation was carried out in mild aqueous conditions and yielded nanoparticles (NPs) with a mean diameter of 230 ± 10 nm and a concentration of 1.3 ± 0.8 × 1012 NPs/mL. CAT-SiNPs demonstrated high enzyme activity, optimal protection from proteolysis by proteinase K and trypsin, and excellent stability over time. In addition, a new electrochemical assay was developed to measure CAT activity in a rapid, simple, and accurate manner without interference from chromophore usually present in biological samples. Concentrations of 2.5 × 1010 to 80 × 1010 CAT-SiNPs/mL not only proved to be nontoxic in cell cultures using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay but also conferred cell protection when cells were exposed to 1 mM hydrogen peroxide (H2O2). Finally, the ability of CAT-SiNPs to release oxygen (O2) when exposed to H2O2 was demonstrated in vivo using a rat model. Following the direct injection of CAT-SiNPs in the left kidney, partial pressure of oxygen (pO2) increased by more than 30 mmHg compared to the contralateral control kidney during the systemic infusion of safe levels of H2O2. This pilot study highlights the potential of CAT-SiNPs to generate O2 to relieve hypoxia in tissues and potentially sensitize tumors against radiation therapy.


Supramolecular Nanofibers Enhance Growth Factor Signaling by Increasing Lipid Raft Mobility.
The nanostructures of self-assembling biomaterials have been previously designed to tune the release of growth factors in order to optimize biological repair and regeneration. We report here on the discovery that weakly cohesive peptide nanostructures in terms of intermolecular hydrogen bonding, when combined with low concentrations of osteogenic growth factor, enhance both BMP-2 and Wnt mediated signaling in myoblasts and bone marrow stromal cells, respectively. Conversely, analogous nanostructures with enhanced levels of internal hydrogen bonding and cohesion lead to an overall reduction in BMP-2 signaling. We propose that the mechanism for enhanced growth factor signaling by the nanostructures is related to their ability to increase diffusion within membrane lipid rafts. The phenomenon reported here could lead to new nanomedicine strategies to mediate growth factor signaling for translational targets.


Development of synapses between identified sensory neurones and giant interneurones in the cockroach Periplaneta americana.
The cercal afferent, giant interneurone pathway in Periplaneta americana was used as a model for synapse formation. The morphology of the two identified filiform hair sensory neurones (FHSNs) and of two giant interneurones (GI2 and GI3) was followed throughout embryogenesis by cobalt injection. The FHSN axons enter the CNS at the 45% stage of embryogenesis, branch at 50% and form complete arborizations by 70%. The giant interneurones send out a primary dendrite at 45%. Secondary branches form between 50% and 60% and elaboration of the branching pattern takes place until 80% embryogenesis. At early stages the FHSN axons are within filopodial range of GI dendrites which may use these sensory processes as guidance cues. Synapse formation between the main FHSN axon shafts and GI dendrites was investigated by injection of the latter with HRP. From 55% to 65% the process is initiated by desmosome-like filopodial contacts, with subsequent vesicle clustering and formation of a small synaptic density. Numbers of contacts did not significantly increase after about 70%, but the number of synapses doubled between 65% and 75%, with each GI process becoming postsynaptic to two FHSN synapses and the presynaptic densities lengthening to become bars. From 75% embryogenesis to hatching there is a further small increase in synaptic bar length. In the first instar GI3 is postsynaptic to both FHSN axons, whereas GI2 forms very few synapses with the axon of the lateral FHSN (LFHSN). This imbalance of contacts is present throughout synaptogenesis, apart from some early filopodial contacts. GI3 forms synapses with the lateral side of the LFHSN axon from 60% embryogenesis but these are totally absent at hatching. The growth of glia along this side of the axon during the last 30% of development appears to be associated with degeneration of synapses in this region. Thus, as the dendrites of the GIs grow to form a miniature version of the adult without loss of branches, there is little evidence of an initial overproduction of FHSN-GI synapses. Similarly there is no evidence that GI2 forms 'incorrect' synapses with the axon of LFHSN. However, GI3 contacts are removed from an inappropriate region of a correct synaptic partner, LFHSN.


Hetero- and adaptive resistance to polymyxin B in OXA-23-producing carbapenem-resistant Acinetobacter baumannii isolates.
Resistance rates to polymyxin B in surveillance studies have been very low despite its increasing use worldwide as the last resort therapy for multidrug-resistant Gram-negative bacilli. However, two other resistance phenotypes, hetero- and adaptive resistance, have been reported to polymyxin. We aimed to investigate the presence of polymyxin B hetero- and adaptive resistance and evaluate its stability in carbapenem-resistant Acinetobacter baumannii (CRAB) clinical isolates. CRAB isolates were recovered from hospitalized patients at three Brazilian hospitals. Hetero-resistance was determined by population analysis profile (PAP). Adaptive resistance was evaluated after serial daily passages of isolates in Luria-Bertani broth containing increasing polymyxin B concentrations. MICs of polymyxin B of colonies growing at the highest polymyxin B concentration were further determined after daily sub-cultured in antibiotic-free medium and after storage at -80°C, in some selected isolates. Eighty OXA-23-producing CRAB isolates were typed resulting in 15 distinct clones. Twenty-nine randomly selected isolates (at least one from each clone) were selected for hetero- resistance evaluation: 26 (90%) presented growth of subpopulations with higher polymyxin B MIC than the original one in PAP. No isolate has grown at polymyxin B concentrations higher than 2 mg/L. Polymyxin B MICs of subpopulations remained higher than the original population after daily passages on antibiotic-free medium but returned to the same or similar levels after storage. Twenty-two of the 29 isolates (at least one from each clone) were evaluated for adaptive resistance: 12 (55%) presented growth in plates containing 64 mg/L of polymyxin B. Polymyxin B MICs decreased after daily passages on antibiotic-free medium and returned to the same levels after storage. The presence of subpopulations with higher polymyxin B MIC was extremely common and high-level adaptive resistance was very frequent in CRAB isolates.