A novel ruthenium-silver based antimicrobial potentiates aminoglycoside activity against Pseudomonas aeruginosa.
The rapid dissemination of antibiotic resistance combined with the decline in the discovery of novel antibiotics represents a major challenge for infectious disease control that can only be mitigated by investments in novel treatment strategies. Alternative antimicrobials, including silver, have regained interest due to their diverse mechanisms of inhibiting microbial growth. One such example is AGXX, a broad-spectrum antimicrobial that produces highly cytotoxic reactive oxygen species (ROS) to inflict extensive macromolecular damage. Due to the connections identified between ROS production and antibiotic lethality, we hypothesized that AGXX could potentially increase the activity of conventional antibiotics. Using the gram-negative pathogen Pseudomonas aeruginosa, we screened possible synergistic effects of AGXX on several antibiotic classes. We found that the combination of AGXX and aminoglycosides tested at sublethal concentrations led to a rapid exponential decrease in bacterial survival and restored the sensitivity of a kanamycin-resistant strain. ROS production contributes significantly to the bactericidal effects of AGXX/aminoglycoside treatments, which is dependent on oxygen availability and can be reduced by the addition of ROS scavengers. Additionally, P. aeruginosa strains deficient in ROS detoxifying/repair genes were more susceptible to AGXX/aminoglycoside treatment. We further demonstrate that this synergistic interaction was associated with a significant increase in outer and inner membrane permeability, resulting in increased antibiotic influx. Our study also revealed that AGXX/aminoglycoside-mediated killing requires an active proton motive force across the bacterial membrane. Overall, our findings provide an understanding of cellular targets that could be inhibited to increase the activity of conventional antimicrobials. IMPORTANCE The emergence of drug-resistant bacteria coupled with the decline in antibiotic development highlights the need for novel alternatives. Thus, new strategies aimed at repurposing conventional antibiotics have gained significant interest. The necessity of these interventions is evident especially in gram-negative pathogens as they are particularly difficult to treat due to their outer membrane. This study highlights the effectiveness of the antimicrobial AGXX in potentiating aminoglycoside activities against P. aeruginosa. The combination of AGXX and aminoglycosides not only reduces bacterial survival rapidly but also significantly re-sensitizes aminoglycoside-resistant P. aeruginosa strains. In combination with gentamicin, AGXX induces increased endogenous oxidative stress, membrane damage, and iron-sulfur cluster disruption. These findings emphasize AGXX's potential as a route of antibiotic adjuvant development and shed light on potential targets to enhance aminoglycoside activity.


Intrinsic beta-sympathomimetic activity of dilevalol, R, R-isomer of labetalol.
The potency and selectivity of the intrinsic beta-sympathomimetic activity (ISA) of dilevalol were studied with isolated guinea-pig trachea and pithed rat. This drug relaxed the contracture of isolated guinea-pig tracheal preparation induced by histamine in a dose-dependent manner. The dose-response curves of dilevalol and labetalol were shifted to the right with propranolol pretreatment. The relaxing potency of dilevalol was approximately 4.7 times more potent than that of labetalol. Dilevalol markedly reduced the diastolic blood pressure with only a slight increase of heart rate in pithed rats, while isoproterenol and pindolol caused moderate to marked positive chronotropic effects in proportion to their hypotensive effects. These results suggest that dilevalol has more potent ISA than labetalol and shows more beta 2-adrenoceptor selectivity than pindolol.


Utilization of coronary computed tomography angiography for rapid risk stratification in emergency chest pain units.
Coronary computed tomography angiography (CCTA) is a well-known method for evaluating anatomic coronary stenosis, but the reliability of CCTA to predict cardiovascular events is an issue of controversy. In this prospective observational study, 58 patients with acute chest pain and low-to-moderate risk were selected and CCTA was performed on them. During follow up, the occurrence of major adverse cardiac events (MACE), defined as, cardiac death, myocardial infarction or coronary revascularization, were evaluated. Sensitivity, specificity, and positive and negative predictive values of CCTA for the occurrence of MACE, at the six-month follow up, were also evaluated. A total of nine (15.5 %) were positive in terms of the MACE criteria and they all had positive CCTA results. It seemed that there was 100% sensitivity for CCTA in predicting the occurrence of MACE. Forty-nine patients had no MACE, among whom 48 patients had negative CCTA. The specificity of CCTA in predicting the occurrence of MACE was 98%. All patients with positive CCTA showed significant stenosis in angiography. It appears that CCTA allows us to predict the prognosis of patients with acute chest pain and low-to moderate-risk in terms of MACE occurrence.


Risk Factors for a False-Negative Result of Sentinel Node Biopsy in Patients with Clinically Node-Negative Breast Cancer.
Although sentinel lymph node biopsy (SLNB) can accurately represent the axillary lymph node (ALN) status, the false-negative rate (FNR) of SLNB is the main concern in the patients who receive SLNB alone instead of ALN dissection (ALND). We analyzed 1,886 patientswho underwent ALND after negative results of SLNB,retrospectively. A logistic regression analysis was used to identify risk factors associated with a falsenegative (FN) result. Cox regression model was used to estimate the hazard ratio of factors affecting disease-free survival (DFS). Tumor located in the upper outer portion of the breast, lymphovascular invasion, suspicious node in imaging assessment and less than three sentinel lymph nodes (SLNs) were significant independent risk factors for FN in SLNB conferring an adjusted odds ratio of 2.10 (95% confidence interval [CI], 1.30 to 3.39), 2.69 (95% CI, 1.47 to 4.91), 2.59 (95% CI, 1.62 to 4.14), and 2.39 (95% CI, 1.45 to 3.95), respectively. The prognostic factors affecting DFS were tumor size larger than 2 cm (hazard ratio [HR], 1.86; 95% CI, 1.17 to 2.96) and FN of SLNB (HR, 2.51; 95% CI, 1.42 to 4.42) in SLN-negative group (FN and true-negative), but in ALN-positive group (FN and true-positive), FN of SLNB (HR, 0.64; 95% CI, 0.33 to 1.25) did not affect DFS. In patients with risk factors for a FN such as suspicious node in imaging assessment, upper outer breast cancer, less than three harvested nodes, we need attention to find another metastatic focus in non-SLNs during the operation. It may contribute to provide an exact prognosis and optimizing adjuvant treatments.


Production of cadmium sulfide quantum dots by the lithobiontic Antarctic strain Pedobacter sp. UYP1 and their application as photosensitizer in solar cells.
Microbes are present in almost every environment on Earth, even in those with extreme environmental conditions such as Antarctica, where rocks may represent the main refuge for life. Lithobiontic communities are composed of microorganisms capable of colonizing rocks and, as it is a not so well studied bacterial community, they may represent a very interesting source of diversity and functional traits with potential for biotechnological applications. In this work we analyzed the ability of Antarctic lithobiontic bacterium to synthesize cadmium sulfide quantum dots (CdS QDs) and their potential application in solar cells. A basaltic andesite rock sample was collected from Fildes Peninsula, King George Island, Antarctica, and processed in order to isolate lithobiontic bacterial strains. Out of the 11 selected isolates, strain UYP1, identified as Pedobacter, was chosen for further characterization and analysis due to its high cadmium tolerance. A protocol for the biosynthesis of CdS QDs was developed and optimized for this strain. After 20 and 80 min of synthesis, yellow-green and orange-red fluorescent emissions were observed under UV light, respectively. QDs were characterized through spectroscopic techniques, dynamic light scattering analysis, high-resolution transmission electron microscopy and energy dispersive x-ray spectroscopy. Nanostructures of 3.07 nm, composed of 51.1% cadmium and 48.9% sulfide were obtained and further used as photosensitizer material in solar cells. These solar cells were able to conduct electrons and displayed an open circuit voltage of 162 mV, a short circuit current density of 0.0110 mA cm-2, and had an efficiency of conversion up to 0.0016%, which is comparable with data previously reported for solar cells sensitized with biologically produced quantum dots. We report a cheap, rapid and eco-friendly protocol for the production of CdS QDs by an Antarctic lithobiontic bacterium, Pedobacter, a genus that was not previously reported as a quantum dot producer. The application of the biosynthesized QDs as sensitizer material in solar cells was validated.


Th(iv) and Ce(iv) napthylsalophen sandwich complexes: characterization of unusual thorium fluorescence in solution and solid-state.
The synthesis, characterization, and electronic spectroscopy of two ML2 sandwich complexes, where M = Ce(iv) or Th(iv) and L = napthylsalophen2- are described. The ThL2 complex, unlike the isovalent CeL2, complex possesses unusual fluorescence properties in both solution and solid-state. These observations are explained with TD-DFT.


Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes.
Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.


Regional variations and deprivation are linked to poorer access to laparoscopic and robotic colorectal surgery: a national study in England.
Laparoscopic and now robotic colorectal surgery has rapidly increased in prevalence; however, little is known about how uptake varies by region and sociodemographics. The aim of this study was to quantify the uptake of minimally invasive colorectal surgery (MIS) over time and variations by region, sociodemographics and ethnicity. Retrospective analysis of routinely collected healthcare data (Clinical Practice Research Datalink linked to Hospital Episode Statistics) for all adults having elective colorectal resectional surgery in England from 1 January 2006 to 31 March 2020. Sociodemographics between modalities were compared and the association between sociodemographic factors, region and year on MIS was compared in multivariate logistic regression analysis. A total of 93,735 patients were included: 52,098 open, 40,622 laparoscopic and 1015 robotic cases. Laparoscopic surgery surpassed open in 2015 but has plateaued; robotic surgery has rapidly increased since 2017, representing 3.2% of cases in 2019. Absolute differences up to 20% in MIS exist between regions, OR 1.77 (95% CI 1.68-1.86) in South Central and OR 0.75 (95% CI 0.72-0.79) in the North West compared to the largest region (West Midlands). MIS was less common in the most compared to least deprived (14.6% of MIS in the most deprived, 24.8% in the least, OR 0.85 95% CI 0.81-0.89), with a greater difference in robotic surgery (13.4% vs 30.5% respectively). Female gender, younger age, less comorbidity, Asian or 'Other/Mixed' ethnicity and cancer indication were all associated with increased MIS. MIS has increased over time, with significant regional and socioeconomic variations. With rapid increases in robotic surgery, national strategies for procurement, implementation, equitable distribution and training must be created to avoid worsening health inequalities.


Rationale, design and conduct of a comprehensive evaluation of a school-based peer-led anti-smoking intervention in the UK: the ASSIST cluster randomised trial [ISRCTN55572965].
To date, no school-based intervention has been proven to be effective in preventing adolescent smoking, despite continuing concern about smoking levels amongst young people in the United Kingdom. Although formal teacher-led smoking prevention interventions are considered unlikely to be effective, peer-led approaches to reducing smoking have been proposed as potentially valuable. ASSIST (A Stop Smoking in Schools Trial) is a comprehensive, large-scale evaluation to rigorously test whether peer supporters in Year 8 (age 11-12) can be recruited and trained to effect a reduction in smoking uptake among their fellow students. The evaluation is employing a cluster randomised controlled trial (RCT) design with secondary school as the unit of randomisation, and is being undertaken in 59 schools in South East Wales and the West of England. Embedded within the trial are an economic evaluation of the intervention costs, a process evaluation to provide detailed information on how the intervention was delivered and received, and an analysis of social networks to consider whether such a peer group intervention could work amongst schoolchildren in this age group. Schools were randomised to either continue with normal smoking education (n = 29 schools, 5562 students), or to do so and additionally receive the ASSIST intervention (n = 30 schools, 5481 students). No schools withdrew once the trial had started, and the intervention was successfully implemented in all 30 schools, with excellent participation rates from the peer supporters. The primary outcome is regular (weekly) smoking, validated by salivary cotinine, and this outcome has been obtained for 94.4%, 91.0% and 95.6% of eligible students at baseline, immediate post-intervention, and one-year follow-up respectively. Comprehensive evaluations of complex public health interventions of this scale and nature are rare in the United Kingdom. This paper demonstrates the feasibility of conducting cluster RCTs of complex public health interventions in schools, and how the rigour of such designs can be maximised both by thorough implementation of the protocol and by broadening the scope of questions addressed in the trial by including additional evaluative components.


The modern spectrum of biopsy-proven renal disease in Chinese diabetic patients-a retrospective descriptive study.
Renal biopsies performed in diabetic patients are increasing and becoming more complex. Comprehensive data on modern spectrum of biopsy-proven renal disease in Chinese diabetic patients are lacking. In a nationwide renal biopsy survey including 71,151 native biopsies from 2004 to 2014, diabetic patients were identified according to the clinical diagnosis from referral records. The clinical data were extracted from referral records and pathological reports. A total of 1,604 diabetic patients, including 61 patients with T1DM, were analyzed in this study. The median age is 51.39 ± 11.37 years. Male patients accounted for 58% of the population. We found that only 44.7% of diabetic patients had the isolated pathological diagnosis of diabetic nephropathy (DN), while 49.1% had non-diabetic renal disease (NDRD) alone, and 6.2% had NDRD superimposed on DN. Nephrotic syndrome (n = 824, 51.4%) was the most common clinical indication for renal biopsy. Among 887 patients with NDRD, membranous nephropathy (n = 357) was the leading diagnosis, followed by IgA nephropathy (n = 179). Hypertensive renal disease (n = 32), tubulointerstitial nephropathy (n = 27) and acute tubular necrosis (n = 16) accounted for 3.5%, 2.9%, 1.7% of the NDRD cases respectively. Nearly a half (49.2%) of patients with T1DM had NDRD. Over 55% diabetic patients with kidney disease were diagnosed as non-diabetic renal disease, among which MN and IgAN were the most common two pathological types.


Maturation of testicular tissue from infant monkeys after xenografting into mice.
In juvenile monkeys, precocious puberty can be induced by administration of gonadotropins resulting in testicular somatic cell maturation and germ cell differentiation. It is, however, unknown whether testicular maturation can also be induced in younger monkeys. Here we used testis tissue xenografting to investigate whether infant monkey testis tissue will undergo somatic cell maturation and/or spermatogenesis in response to endogenous adult mouse gonadotropins or exogenous gonadotropins. Testicular tissue pieces from 3- and 6-month-old rhesus monkeys were grafted to immunodeficient, castrated mice. Recipient mice were either left untreated or treated with pregnant mare serum gonadotropin and/or human chorionic gonadotropin twice weekly and were killed 28 weeks after grafting. Testicular maturation in grafted tissue was assessed based on morphology and the most advanced germ cell type present and by immunohistochemistry for expression of proliferating cell nuclear antigen, Mullerian-inhibiting substance, and androgen receptor. Testis grafts, irrespective of donor age or treatment, contained fewer germ cells than donor tissue. Grafts from 6-month-old donors showed tubular expansion with increased seminiferous tubule diameter and lumen formation, whereas those harvested from gonadotropin-treated mice contained elongated spermatids. Grafts from 3-month-old donors recovered from gonadotropin-treated mice contained pachytene spermatocytes, whereas those recovered from untreated mice showed only slight tubular expansion. Immunohistochemistry revealed that exposure to exogenous gonadotropins supported Sertoli cell maturation, irrespective of donor age. These results indicate that sustained gonadotropin stimulation of immature (<12 months old) monkey testis supports Sertoli cell maturation, thereby terminating the unresponsive phase of the germinal epithelium and allowing complete spermatogenesis in testis tissue from infant rhesus monkeys.


[Changes in collagen structure under the influence of mechanical dispersion].
Air-dry collagen isolated from cattle retinal layer by means of alkaline-salt treatment was crushed in a laboratory vibro-mill at 80-150 degrees K. Mechanochemical transformations were studied by means of viscosimetry, polarimetry, ESR-spectroscopy and electron microscopy. Mechanical tensions induce breakage of covalent bonds of polypeptide chains, accompanied by a decrease of protein molecular mass, and of lateral interactions, which results in loosening of collagen structure and partial denaturation.


Low-cost preventive screening using carotid ultrasound in patients with diabetes.
Diabetes and atherosclerosis are the predominant causes of stroke and cardiovascular disease (CVD) both in low- and high-income countries. This is due to the lack of appropriate medical care or high medical costs. Low-cost 10-year preventive screening can be used for deciding an effective therapy to reduce the effects of atherosclerosis in diabetes patients. American College of Cardiology (ACC)/American Heart Association (AHA) recommended the use of 10-year risk calculators, before advising therapy. Conventional risk calculators are suboptimal in certain groups of patients because their stratification depends on (a) current blood biomarkers and (b) clinical phenotypes, such as age, hypertension, ethnicity, and sex. The focus of this review is on risk assessment using innovative composite risk scores that use conventional blood biomarkers combined with vascular image-based phenotypes. AtheroEdge™ tool is beneficial for low-moderate to high-moderate and low-risk to high-risk patients for the current and 10-year risk assessment that outperforms conventional risk calculators. The preventive screening tool that combines the image-based phenotypes with conventional risk factors can improve the 10-year cardiovascular/stroke risk assessment.


Nocturia in Spanish patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH).
This study aimed to assess the prevalence of nocturia and its impact on quality of life (QoL) in Spanish patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH). This was a Spanish, multicentre, cross-sectional study. Outpatients aged 60 years and over with LUTS/BPH, a prostate size > or = 25 g, untreated for LUTS/BPH and responding to the International Prostate Symptom Score (I-PSS) were included. Nocturia was defined as > or = 2 nocturnal voids/night. The Spanish version of the Nocturia-specific Quality of Life (N-QoL) questionnaire assessed the impact of nocturia on QoL, with a low score indicating a poor QoL due to nocturia. A total of 502 patients were included; mean age 68.1 +/- 5.7 years, mean I-PSS 14.9 +/- 7.1, mean prostate size 50.9 +/- 20 g. The overall prevalence of nocturia was 83.1% (95% confidence interval [CI]: 79.8-86.4). Patients with nocturia had a lower score on the overall N-QoL questionnaire and the sleep/energy and bother/concern domains than those without nocturia (p < 0.001); 42.9% of patients with nocturia stated that they had a good-very good QoL compared to 90.6% in those without nocturia (p < 0.001). This study shows a high prevalence of nocturia in Spanish LUTS/BPH patients. Nocturia negatively impacts on the QoL of LUTS/BPH patients, which is reflected in worse sleep, reduced energy levels and increased bother and concern. Therefore adequate treatment of this symptom is necessary.


TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation.
TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.


Hydroxyapatite coated implants. Total hip arthroplasty in the young patient and patients with avascular necrosis.
Two high risk groups for total hip arthroplasty, 136 patients (155 hips) younger than 50 years of age (average age, 38 years) and 44 patients (53 hips) with the diagnosis of avascular necrosis, have a minimum followup of 5 years and a mean followup of 6.8 years. The average Harris Hip Score at last followup totaled 93 and 90, respectively, and thigh pain was reported in 1.3% and 3.8%, respectively. All patients in both groups received the same hydroxyapatite coated femoral stem and the mechanical failure was 0%. No stem was revised for aseptic loosening, 100% of stems were bony stable by radiographic criteria, new bone formation was progressive about the femoral stem, and 0% endosteal lysis was found. The acetabular components had a mechanical failure rate of 10% and 7.5%, respectively, without osteolysis, and an additional 7% and 7.5% failure as a direct result of progressive osteolysis. The results with the porous press fit and hydroxyapatite threaded sockets were far superior to that of the smooth hydroxyapatite press fit sockets and socket failure was associated with thin polyethylene liners and the use of 32-mm head diameters. These findings show a high success rate with a nonporous hydroxyapatite coated titanium femoral stem. However, hydroxyapatite on a smooth acetabular component yielded less predictable results indicating that for long term fixation of the acetabulum an interlock of bone is preferred.


Role of Endovascular Treatment in Dysfunctional Hemodialysis Fistulae: A Single Center Experience.
Arteriovenous fistulas (AVFs) are the preferred route of hemodialysis in end-stage renal disease. However, recurrent patency loss is an obstacle in long-term maintenance. Endovascular treatments may provide a durable option for prolongation of patency in AVFs. Retrospective observational study was done on 46 patients with AVF for hemodialysis in the Department of Diagnostic and Interventional Radiology for a period of 1 year from September 2020 to August 2021. The characters of dysfunctional fistulas and results of various interventional procedures were assessed for technical and clinical success rates. Short-term follow-up records of patients were assessed for post-intervention primary patency (PIPP) and post-intervention assisted primary patency (PIAPP) of various procedures. The most successful outcomes post intervention were seen in radio-cephalic fistulas formed more than 1 year ago with juxta-anastomotic narrowing. The overall technical success rate was 89.13% with a PIPP of 78.26% and a PIAPP of 82.60% at 3 months. PTA had better technical success rates (88.23%) as compared to dysfunctional segments with thrombosis that underwent angioplasty and thromboaspiration (84.2%). Central venous stenosis undergoing PTA and stenting had a 100% success rate. At 3 months follow-up, PIPP was better among the angioplasty plus thromboaspiration group (73.7%), while PIAPP rate was better in the angioplasty subgroup at 82.35%. Endovascular intervention is the first-line treatment in dysfunctional AVFs attributable to the multitude of options available, all of which have comparable outcomes, high success rates, and notable short-term patency.


Repurposing of FDA approved drugs against Salmonella enteric serovar Typhi by targeting dihydrofolate reductase: an in silico study.
Drug-resistant Salmonella enteric serovar Typhi (S. Typhi) poses a vital public health issue. To overcome drug resistance issues, the development of effective drugs with novel mechanism(s) of action is required. In this regard, drug repurposing is a viable alternative approach to find novel drugs to overcome drug resistance. Therefore, a FDA-approved-drug-library containing 1930 drugs was analyzed against the dihydrofolate reductase (DHFR) of S. Typhi using deep learning regression algorithms. Initially, a total of 500 compounds were screened, followed by rescreening by molecular docking. Further, from screened compounds by molecular docking, the top eight compounds were subjected to molecular dynamics (MD) simulation. Analysis of MD simulation resulted in four potential compounds, namely; Duvelisib, Amenamevir, Lifitegrast and Nilotinib against the DHFR enzyme. During the MD simulation, these four drugs achieved good stability during the 100 ns trajectory period at 300 K. Further to know the insights of the complex's stability, we calculated RMSF, RG, SASA and interaction energy for the last 60 ns trajectory period because all complexes showed the stability after 40 ns trajectory period. MM-PBSA analysis of the last 10 ns of MD trajectories showed the stability of the complexes. From our results, we conclude that these drugs can also be useful for treating typhoid fever and can inhibit S. Typhi by interfering with the function of the DHFR enzyme. Communicated by Ramaswamy H. Sarma.


[Dementia and pseudodementia in the municipality of Ringkobing].
Social services estimated on September 1, 1997 that 221 individuals out of a population of about 16,000 in the whole of Ringkøbing County were believed to suffer from dementia. Citizens believed to suffer from dementia were offered an assessment by a trained nurse and a general practitioner. In the following six months, 119 people were screened by the nurse with the Mini Mental State Examination, the Geriatric Depression Scale-15 and Gottfries-Brane-Steen scale for evaluating functional deficiencies in demented patients. In addition, somatic and laboratory screening was done by the GP's. Approximately 40 citizens or 33% were not found to suffer from dementia but suffered from other illnesses. One year later all the GP's answered questionnaires concerning number of cases of depression, hypothyroidism, vitamin B12 deficiency or other illnesses not earlier known to the GP. Twenty-two diseases were identified and six patients improved.


The prevalence of childhood overweight/obesity and the epidemic changes in 1985-2000 for Chinese school-age children and adolescents.
This paper describes the nationwide prevalence of childhood overweight/obesity in Chinese urban population. Data sets of boys and girls aged 7-18 yrs were collected from the series of Chinese national surveillance on students' constitution and health between 1985 and 2000 were divided into five socioeconomic groups, while WGOC BMI-reference was used as definitions of overweight and obesity. In 2000, the prevalence of childhood obesity/overweight in the coastal big cities, followed by that of the coastal middle/small cities, had reached the average level of the developed countries. The prevalence of obesity was low in most of the inland cities at an early stage of epidemic overweight. The epidemic manifested a gradient distribution in groups, which was closely related to socioeconomic status of the populations. A dramatic and steady increasing trend was witnessed among all sex-age subgroups in these urban groups, and the increments in obesity/overweight are exceptionally high in recent 5 years, and the prospect of epidemic obesity in China is in no way optimistic. Preventive program should be focused on the improvement of the balance between caloric intake and energy expenditure, and interventions aimed at changing children's life styles.


Substance Use Among Young Mothers: An Analysis of Facebook Posts.
Substance use among young pregnant women is a common and significant public health concern associated with a number of adverse outcomes for both mothers and infants. Social media posts by young women can provide valuable, real-world insight into their perceptions of substance use immediately before and during pregnancy. The aim of this study was to characterize the frequency and content of posts regarding substance use in the year before pregnancy and during pregnancy among young mothers. Facebook posts were mined from young pregnant women (age, 16-24 years) who consented from 2 Midwest primary care clinics that serve a predominantly low-income community. Natural language processing was used to identify posts related to substance use by keyword searching (eg, drunk, drugs, pot, and meth). Using mixed-methods techniques, 2 investigators iteratively coded and identified major themes around substance use from these mined Facebook posts. Outcome measures include the frequency of posts and major themes expressed regarding substance use before and during pregnancy. Women in our sample (N=43) had a mean age of 21 (SD 2.3) years, and the largest subgroup (21/43, 49%) identified as non-Hispanic black; 26% (11/43) identified as non-Hispanic white; 16% (7/43) as Hispanic; and 9% (4/43) as non-Hispanic mixed race, Native American, or other. The largest subgroup (20/43, 47%) graduated high school without further education, while 30% (13/43) completed only some high school and 23% (10/43) completed at least some postsecondary education. Young women discussed substance use on social media before and during pregnancy, although compared with the year before pregnancy, the average frequency of substance-related posts during pregnancy decreased. Themes identified included craving alcohol or marijuana, social use of alcohol or marijuana, reasons for abstaining from substance use, and intoxication. Facebook posts reveal that young pregnant women discuss the use of substances, predominantly alcohol and marijuana. Future work can explore clinical opportunities to prevent and treat substance use before and during pregnancy among young, at-risk mothers.


Treatment of the patient with primary familial heterozygous hypercholesterolemia.
Familial heterozygous hypercholesterolemia (FH) is a genetically linked lipid disorder that involves elevations in total cholesterol and LDL cholesterol. About 5% of patients with coronary heart disease have FH. Treatment options include dietary therapy, weight optimization, exercise, and drug treatment. A case study of a patient who has undergone 4 years of treatment for FH after a diagnosis of coronary heart disease is presented. Nursing care was instrumental in the patient's compliance with and adherence to the treatment plan.


DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free system.
Cell-cycle checkpoints induced by DNA damage or replication play critical roles in the maintenance of genomic integrity during cell proliferation. Biochemical analysis of checkpoint pathways has been greatly facilitated by the use of cell-free systems made from Xenopus eggs. In the present study, we describe a human cell-free system that reproduces a DNA-dependent checkpoint pathway acting on the Chk1 protein kinase. In this system, double-stranded DNA oligonucleotides induce the phosphorylation of Chk1 at activating sites targeted by ATR [ATM (ataxia telangiectasia mutated)- and Rad3-related] and ATM kinases. Phosphorylation of Chk1 is dependent on the interaction of Claspin, a protein first identified in Xenopus as a Chk1-binding protein. We show that the DNA-dependent binding of Chk1 to Claspin requires two phosphorylation sites, Thr916 and Ser945, which lie within the Chk1-binding domain of Claspin. Using a phosphopeptide derived from the consensus motif of these sites, we show that the interaction of Claspin with Chk1 is required for the ATR/ATM-dependent phosphorylation of Chk1. Using a panel of protein kinase inhibitors, we provide evidence that Chk1 is phosphorylated at an additional site in response to activation of the checkpoint response, probably by autophosphorylation. Claspin is phosphorylated in the Chk1-binding domain in an ATR/ATM-dependent manner and is also targeted by additional kinases in response to double-stranded DNA oligonucleotides. This cell-free system will facilitate further biochemical analysis of the Chk1 pathway in humans.


Sulfatase 1 promotes the motor neuron-to-oligodendrocyte fate switch by activating Shh signaling in Olig2 progenitors of the embryonic ventral spinal cord.
In the developing ventral spinal cord, motor neurons (MNs) and oligodendrocyte precursor cells (OPCs) are sequentially generated from a common pool of neural progenitors included in the so-called pMN domain characterized by Olig2 expression. Here, we establish that the secreted Sulfatase 1 (Sulf1) is a major component of the mechanism that causes these progenitors to stop producing MNs and change their fate to generate OPCs. We show that specification of OPCs is severely affected in sulf1-deficient mouse embryos. This defect does not rely on abnormal patterning of the spinal cord or failure in maintenance of pMN progenitors at the onset of OPC specification. Instead, the efficiency of OPC induction is reduced, only few Olig2 progenitors are recruited to generate OPCs, meanwhile they continue to produce MNs beyond the normal timing of the neuroglial switch. Using the chicken embryo, we show that Sulf1 activity is required precisely at the stage of the MN-to-OPC fate switch. Finally, we bring arguments supporting the view that Sulf1 controls the level of Sonic Hedgehog (Shh) signaling activity, behaving as an enhancer rather than an obligatory component in the Shh pathway. Our study provides additional insights into the temporal control of Olig2 progenitor cell fate change by the identification of Sulf1 as an extracellular timing signal in the ventral spinal cord.


Jeopardized Myocardium Defined by Late Gadolinium Enhancement Magnetic Resonance Imaging Predicts Survival in Patients With Ischemic Cardiomyopathy: Impact of Revascularization.
Background The prognostic impact of jeopardized myocardium ( JM ) in patients with advanced ischemic cardiomyopathy ( ICM ) is unclear. We hypothesized that JM is an independent predictor of mortality in patients with advanced ICM . Methods and Results Patients with ICM who underwent cardiac magnetic resonance imaging between January 2002 and January 2013 were included in our study. JM was identified as a vascular territory with <50% myocardial scarring on cardiac magnetic resonance imaging and with >70% stenosis in a major coronary vessel that was not subsequently revascularized. A propensity score was developed for revascularization. A multivariable Cox proportional hazards model was used to evaluate the association of JM with all-cause mortality. We evaluated 631 patients over a mean follow-up of 5.1 years. Overall, 336 patients underwent subsequent revascularization during the follow-up period, among whom 23% had remaining JM , while 295 patients were medically treated (57% with JM ). There were 204 deaths (32%). On multivariable analysis, JM (hazard ratio, 1.88; 95% confidence interval, 1.38-2.55 [ P<0.001]) was independently associated with all-cause mortality after adjusting for multiple other factors. The risk associated with the presence of JM increased by 5% for every 10-unit increase in left ventricular end-systolic volume index. Conclusions JM is an independent and incremental predictor of mortality in patients with advanced ICM . Patients undergoing revascularization with residual JM had similar risk of mortality compared with medically treated patients with JM . The risk associated with JM significantly increased in the presence of worsening adverse left ventricular remodeling. Cardiac magnetic resonance viability assessment may provide important risk stratification in patients with ICM .


The insertion domain 1 of class IIA dimeric glycyl-tRNA synthetase is a rubredoxin-like zinc ribbon.
The insertion domain 1 (ID1) of class IIA dimeric glycyl-tRNA synthetase (α2GRS) is an appended domain in the core catalytic region of the enzyme. ID1 has been shown to play a role in tRNA aminoacylation, mediating interaction with the acceptor arm of tRNA and diadenosine tetraphosphate (Ap4A) synthesis. Mutations in α2GRS, including those in the ID1 region, have been implicated in distal hereditary motor neuropathy-V (dHMN-V) and Charcot-Marie-Tooth (CMT) disease. Through sequence and structure based evolutionary analysis, we show that ID1 of α2GRS is a rubredoxin-like zinc ribbon domain. The zinc-chelating cysteines of ID1 are well conserved in all archaeal versions of the enzyme and also in several eukaryotes, which most likely have acquired them via horizontal gene transfer from bacteria; but in all other eukaryotes, the zinc-chelating residues are not preserved. ID1 from bacteria display a selective preservation of zinc-binding residues, ranging from complete conservation to complete loss. The ID1 from different organisms harbor variable-sized non-conserved insertions between the two zinc-binding half-sites of the zinc ribbon. Three of the previously identified CMT-associated mutations in α2GRS, viz., human D146N, mouse C157R and human S211F, are located in the zinc ribbon region of ID1. Interestingly, human Asp146 which is implicated in the synthesis of Ap4A, a molecule known to act during neuronal transmission, has also been reported to be mutated in dHMN-V, suggesting a possible link between hereditary motor neuropathy and Ap4A synthesis.


Streptococcal cell wall-induced arthritis. Requirements for neutrophils, P-selectin, intercellular adhesion molecule-1, and macrophage-inflammatory protein-2.
Immune arthritis in rat ankle joints was induced by intra-articular injection of streptococcal cell was extract (SCW), followed 21 days later by i.v. injection of SCW. This results in a monoarticular arthritis characterized by an influx of neutrophils and mononuclear cells, a 35-fold increase in urinary excretion of 8-hydroxy-deoxyguanosine (8-OH-dGUA; an index of free radical production), ankle edema, and joint damage/destruction. Neutrophil depletion substantially reduced the intensity of ankle edema. Ab-induced blockade of P-selectin or ICAM-1 also reduced the intensity of ankle edema and the influx of neutrophils. Blockade of TNF-alpha or IL-1 resulted in nearly complete and persistent reduction in ankle edema and profound reductions in the accumulation of neutrophils and mononuclear cells in affected joints. Finally, blocking of macrophage-inflammatory protein-2 reduced ankle edema and neutrophil accumulation during the first 2 days after i.v. challenge with SCW. These data indicate that SCW-induced arthritis is neutrophil dependent and that the recruitment of neutrophils and subsequent joint edema requires ICAM-1, P-selectin, and macrophage-inflammatory protein-2, as well as TNF-alpha and IL-1.


Robotic hepatobiliary surgery: update on the current status.
An update on the current status of robotic hepatobiliary surgery based on a review of the available literature. A literature search was performed using the PubMed database with search phrases "robotic hepatectomy", "robotic liver resection", "robotic liver surgery", "robotic hepatobiliary surgery", and "robotic biliary reconstruction". We selected articles with high volume case series or case controlled series. As a result of our literature search we will focus on the 9 major articles on robotic liver resection (RLR) with 235 patients undergoing RLR for a total of 244 liver resections. In addition a brief update on robotic biliary reconstruction will also be presented based on the above articles and recent review articles. Indications for robotic liver resection included both benign (N.=72, 29.5%) and malignant disease (N.=172, 70.5%). The most common indication was colorectal liver metastasis (N.=87, 50.6%) and hepatocellular carcinoma (N.=57, 33%). The most common type of resection was subsegmental (N.=55, 22.5%), with a significant number of major hepatectomies (N.=80, 32.8%). Overall conversion rate was 7.8%, with majority converted to open (N.=18) and one converted to hand assisted. The overall complication rate was 11.8% (N.=29). No perioperative mortality was reported. Preliminary results show that robotic assisted laparoscopic hepatobiliary surgery has materialized as a new technique that combines the advantages of laparoscopy with the dissection, suturing and articulation of robotics. This more closely approximates open surgery. The preliminary data demonstrates that RLR can be applied in major hepatobiliary centers safely. Future comparative studies are needed to determine if this is of significant benefit over current open techniques.


Inhibition of spinal dorsal horn neuronal responses to noxious skin heating by lateral hypothalamic stimulation in the cat.
The responses of single lumbar dorsal horn units to noxious radiant heating (50 degrees C, 10 s) of glabrous foot pad skin were recorded in cats anesthetized with sodium pentobarbital and 70% N2O. The heat-evoked responses of each of 38 units were markedly reduced during electrical stimulation (100-ms trains at 100 Hz, 3/s, 25-300 microA) in the lateral hypothalamic area (LH). LH sites at which stimulation inhibited dorsal horn unit heat-evoked responses were mapped by systematically varying the position of the stimulating electrode. Inhibition was generated at posterior through anterior hypothalamic levels in a region extending laterally from the periventricular gray (PVG) to the cerebral peduncles on both sides and ventrally to the base of the brain. The magnitude of inhibition increased with graded increases in LH stimulation intensity. Respective mean current intensities at threshold for generating inhibition were 27.6 +/- 17.4 (SD) microA for contralateral and 30.1 +/- 23.7 microA for ipsilateral LH stimulation. Dorsal horn unit responses to a series of graded noxious heat stimuli generally increased linearly from threshold (38-45 degrees C) to 52 degrees C. The slopes of such linear temperature-response functions were reduced, with no significant change in threshold, when the temperature series was repeated during concomitant ipsilateral LH stimulation. Contralateral LH stimulation produced similar slope reductions but additionally produced a significant mean threshold increase of 1.7 degrees C. The inhibitory effect of LH stimulation was significantly reduced in nine units from a mean of 28 +/- 18% of control to a mean of 59 +/- 18% following systemic administration of the serotonin (5-hydroxytryptamine, 5-HT) antagonist, methysergide (0.3-1 mg/kg). Possible functional relationships of LH with brain stem inhibitory systems and its role in analgesic mechanisms are discussed.


Host Transcriptional Regulatory Genes and Microbiome Networks Crosstalk through Immune Receptors Establishing Normal and Tumor Multiomics Metafirm of the Oral-Gut-Lung Axis.
The microbiome has shown a correlation with the diet and lifestyle of each population in health and disease, the ability to communicate at the cellular level with the host through innate and adaptative immune receptors, and therefore an important role in modulating inflammatory process related to the establishment and progression of cancer. The oral cavity is one of the most important interaction windows between the human body and the environment, allowing the entry of an important number of microorganisms and their passage across the gastrointestinal tract and lungs. In this review, the contribution of the microbiome network to the establishment of systemic diseases like cancer is analyzed through their synergistic interactions and bidirectional crosstalk in the oral-gut-lung axis as well as its communication with the host cells. Moreover, the impact of the characteristic microbiota of each population in the formation of the multiomics molecular metafirm of the oral-gut-lung axis is also analyzed through state-of-the-art sequencing techniques, which allow a global study of the molecular processes involved of the flow of the microbiota environmental signals through cancer-related cells and its relationship with the establishment of the transcription factor network responsible for the control of regulatory processes involved with tumorigenesis.


Emergence of a dual-catalytic RNA with metal-specific cleavage and ligase activities: the spandrels of RNA evolution.
In vitro selection, or directed molecular evolution, allows the isolation and amplification of rare sequences that satisfy a functional-selection criterion. This technique can be used to isolate novel ribozymes (RNA enzymes) from large pools of random sequences. We used in vitro evolution to select a ribozyme that catalyzes a novel template-directed RNA ligation that requires surprisingly few nucleotides for catalytic activity. With the exception of two nucleotides, most of the ribozyme contributes to a template, suggesting that it is a general prebiotic ligase. More surprisingly, the catalytic core built from randomized sequences actually contains a 7-nt manganese-dependent self-cleavage motif originally discovered in the Tetrahymena group I intron. Further experiments revealed that we have selected a dual-catalytic RNA from random sequences: the RNA promotes both cleavage at one site and ligation at another site, suggesting two conformations surrounding at least one divalent metal ion-binding site. Together, these results imply that similar catalytic RNA motifs can arise under fairly simple conditions and that multiple catalytic structures, including bifunctional ligases, can evolve from very small preexisting parts. By breaking apart and joining different RNA strands, such ribozymes could have led to the production of longer and more complex RNA polymers in prebiotic evolution.


[Carbamoyl phosphate biosynthesis in Streptococci].
Nine streptococcal strains belonging to different serological groups (A, B, C, D) were shown to synthesize carbamoyl phosphate from ammonium hydrocarbonate and ATP. The reaction was catalyzed by carbamate kinase (EC 18.104.22.168). The speed of the reaction was evaluated according to the increase of the content of citrullin (the combination of carbamate kinase and ornithine transcarbamoylase). The representatives of different serological groups were found to have quantitative differences in carbamate kinase activity: the highest specific activity (13 nmol of citrullin per minute in 1 mg of dried microbial biomass) was detected in group A streptococci, while group D streptococci showed the lowest specific activity (0.5 nmol).


Molecular hydrogen potentiates beneficial anti-infarct effect of hypoxic postconditioning in isolated rat hearts: a novel cardioprotective intervention.
Generation of free radicals through incomplete reduction of oxygen during ischemia-reperfusion (I/R) is well described. On the other hand, molecular hydrogen (H2) reduces oxidative stress due to its ability to react with strong oxidants and easily penetrate cells by diffusion, without disturbing metabolic redox reactions. This study was designed to explore cardioprotective potential of hypoxic postconditioning (HpostC) against I/R (30 min global I - 120 min R) in isolated rat hearts using oxygen-free Krebs-Henseleit buffer (KHB). Furthermore, the possibility to potentiate the effect of HpostC by H2 using oxygen-free KHB saturated with H2 (H2 + HpostC) was tested. HPostC was induced by 4 cycles of 1-minute perfusion with oxygen-free KHB intercepted by 1-minute perfusion with normal KHB, at the onset of reperfusion. H2 + HPostC was applied in a similar manner using H2-enriched oxygen-free KHB. Cardioprotective effects were evaluated on the basis of infarct size (IS, in % of area at risk, AR) reduction, post-I/R recovery of heart function, and occurrence of reperfusion arrhythmias. HPostC significantly reduced IS/AR compared with non-conditioned controls. H2 present in KHB during HPostC further decreased IS/AR compared with the effect of HPostC, attenuated severe arrhythmias, and significantly restored heart function (vs. controls). Cardioprotection by HpostC can be augmented by molecular hydrogen infusion.


Coverage by the public health services of medication and vaccines for the population with diabetes mellitus.
This study analyzed the coverage by the public health service of expenses with medication and vaccines for the adult population of São Paulo with self-reported diabetes mellitus in 2003 and the implications for access to medicines and vaccination campaigns programs. Data were collected by the Multicenter Health Survey of São Paulo. The Unified Health System (SUS) was widely used by the population for vaccination against influenza and pneumonia and there was significant private sector participation for coverage of expenses with medication, with an estimated coverage of 38% by SUS. There were no significant differences in the prevalence of use of public services for vaccination among the categories of variables studied, suggesting a universal distribution of vaccination by the public health service. Unlike vaccinations, in 2003 the coverage of medication expenses by the public health service was recent in Brazil, which may explain the low level of coverage. An analysis of coverage of vaccination and medication expenses in diabetes mellitus population since 2003 may contribute to be the basis for policies to broaden access of the population to health services.


Diagnosing arrhythmogenic right ventricular cardiomyopathy by 2010 Task Force Criteria: clinical performance and simplified practical implementation.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is diagnosed by a complex set of clinical tests as per 2010 Task Force Criteria (TFC). Avoiding misdiagnosis is crucial to prevent sudden cardiac death as well as unnecessary implantable cardioverter-defibrillator implantations. This study aims to validate the overall performance of the TFC in a real-world cohort of patients referred for ARVC evaluation. We included patients consecutively referred to our centres for ARVC evaluation. Patients were diagnosed by consensus of three independent clinical experts. Using this as a reference standard, diagnostic performance was measured for each individual criterion as well as the overall TFC classification. Of 407 evaluated patients (age 38 ± 17 years, 51% male), the expert panel diagnosed 66 (16%) with ARVC. The clinically observed TFC was false negative in 7/66 (11%) patients and false positive in 10/69 (14%) patients. Idiopathic outflow tract ventricular tachycardia was the most common alternative diagnosis. While the TFC performed well overall (sensitivity and specificity 92%), signal-averaged electrocardiogram (SAECG, P = 0.43), and several family history criteria (P ≥ 0.17) failed to discriminate. Eliminating these criteria reduced false positives without increasing false negatives (net reclassification improvement 4.3%, P = 0.019). Furthermore, all ARVC patients met at least one electrocardiogram (ECG) or arrhythmia criterion (sensitivity 100%). The TFC perform well but are complex and can lead to misdiagnosis. Simplification by eliminating SAECG and several family history criteria improves diagnostic accuracy. Arrhythmogenic right ventricular cardiomyopathy can be ruled out using ECG and arrhythmia criteria alone, hence these tests may serve as a first-line screening strategy among at-risk individuals.


Local oestrogen for vaginal atrophy in postmenopausal women.
Vaginal atrophy is a frequent complaint of postmenopausal women; symptoms include vaginal dryness, itching, discomfort and painful intercourse. Systemic treatment for these symptoms in the form of oral hormone replacement therapy is not always necessary. An alternative choice is oestrogenic preparations administered vaginally (in the form of creams, pessaries, tablets and the oestradiol-releasing ring). This is an update of a Chochrane systematic review; the original version was first published in October 2006. The objective of this review was to compare the efficacy and safety of intra-vaginal oestrogenic preparations in relieving the symptoms of vaginal atrophy in postmenopausal women. We searched the following databases and trials registers to April 2016: Cochrane Gynaecology and Fertility Group Register of trials, The Cochrane Central Register of Controlled Trials (CENTRAL; 2016 issue 4), MEDLINE, Embase, PsycINFO, DARE, the Web of Knowledge, OpenGrey, LILACS, PubMed and reference lists of articles. We also contacted experts and researchers in the field. The inclusion criteria were randomised comparisons of oestrogenic preparations administered intravaginally in postmenopausal women for at least 12 weeks for the treatment of symptoms resulting from vaginal atrophy or vaginitis. Two review authors independently assessed trial eligibility and risk of bias and extracted the data. The primary review outcomes were improvement in symptoms (participant-assessed), and the adverse event endometrial thickness. Secondary outcomes were improvement in symptoms (clinician-assessed), other adverse events (breast disorders e.g. breast pain, enlargement or engorgement, total adverse events, excluding breast disorders) and adherence to treatment. We combined data to calculate pooled risk ratios (RRs) (dichotomous outcomes) and mean differences (MDs) (continuous outcomes) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I(2) statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. We included 30 RCTs (6235 women) comparing different intra-vaginal oestrogenic preparations with each other and with placebo. The evidence was low to moderate quality; limitations were poor reporting of study methods and serious imprecision (effect estimates with wide confidence intervals)1. Oestrogen ring versus other regimensOther regimens included oestrogen cream, oestrogen tablets and placebo. There was no evidence of a difference in improvement in symptoms (participant assessment) either between oestrogen ring and oestrogen cream (odds ratio (OR) 1.33, 95% CI 0.80 to 2.19, two RCTs, n = 341, I(2) = 0%, low-quality evidence) or between oestrogen ring and oestrogen tablets (OR 0.78, 95% CI 0.53 to 1.15, three RCTs, n = 567, I(2) = 0%, low-quality evidence). However, a higher proportion of women reported improvement in symptoms following treatment with oestrogen ring compared with placebo (OR 12.67, 95% CI 3.23 to 49.66, one RCT, n = 67). With respect to endometrial thickness, a higher proportion of women who received oestrogen cream showed evidence of increase in endometrial thickness compared to those who were treated with oestrogen ring (OR 0.36, 95% CI 0.14 to 0.94, two RCTs, n = 273; I(2) = 0%, low-quality evidence). This may have been due to the higher doses of cream used. 2. Oestrogen tablets versus other regimensOther regimens in this comparison included oestrogen cream, and placebo. There was no evidence of a difference in the proportions of women who reported improvement in symptoms between oestrogen tablets and oestrogen cream (OR 1.06, 95% CI 0.55 to 2.01, two RCTs, n = 208, I(2) = 0% low-quality evidence). A higher proportion of women who were treated with oestrogen tablets reported improvement in symptoms compared to those who received placebo using a fixed-effect model (OR 12.47, 95% CI 9.81 to 15.84, two RCTs, n = 1638, I(2) = 83%, low-quality evidence); however, using a random-effect model did not demonstrate any evidence of a difference in the proportions of women who reported improvement between the two treatment groups (OR 5.80, 95% CI 0.88 to 38.29). There was no evidence of a difference in the proportions of women with increase in endometrial thickness between oestrogen tablets and oestrogen cream (OR 0.31, 95% CI 0.06 to 1.60, two RCTs, n = 151, I(2) = 0%, low-quality evidence).3. Oestrogen cream versus other regimensOther regimens identified in this comparison included isoflavone gel and placebo. There was no evidence of a difference in the proportions of women with improvement in symptoms between oestrogen cream and isoflavone gel (OR 2.08, 95% CI 0.08 to 53.76, one RCT, n = 50, low-quality evidence). However, there was evidence of a difference in the proportions of women with improvement in symptoms between oestrogen cream and placebo with more women who received oestrogen cream reporting improvement in symptoms compared to those who were treated with placebo (OR 4.10, 95% CI 1.88 to 8.93, two RCTs, n = 198, I(2) = 50%, low-quality evidence). None of the included studies in this comparison reported data on endometrial thickness. There was no evidence of a difference in efficacy between the various intravaginal oestrogenic preparations when compared with each other. However, there was low-quality evidence that intra-vaginal oestrogenic preparations improve the symptoms of vaginal atrophy in postmenopausal women when compared to placebo. There was low-quality evidence that oestrogen cream may be associated with an increase in endometrial thickness compared to oestrogen ring; this may have been due to the higher doses of cream used. However there was no evidence of a difference in the overall body of evidence in adverse events between the various oestrogenic preparations compared with each other or with placebo.


Impact of setting insecurity on Cognitive Processing Therapy implementation and outcomes in eastern Democratic Republic of the Congo.
Background: While evidence is growing for the efficacy of trauma-focused mental health interventions in low- and middle-income countries, concerns have been raised about whether these types of interventions can be effectively delivered in contexts with ongoing conflict and violence. Cognitive Processing Therapy (CPT) has been shown to be effective in reducing sexual violence survivors' psychological symptoms in eastern Democratic Republic of the Congo (DRC), a region with a history of chronic conflict. Objective: The purpose of the present study is to assess the degree to which exposure to different levels of ongoing insecurity impacts effectiveness of an evidence-based trauma-focused psychotherapy for sexual violence survivors. Method: Participants were 158 female sexual violence survivors receiving CPT in seven communities in South Kivu. Participants completed weekly assessments of their symptoms of PTSD and depression as part of CPT. Degree of site insecurity was categorized as high or low levels of ongoing insecurity based on information collected from supervisors and clinicians. Hierarchical linear modelling was used to examine change over time moderated by level of insecurity at the site. Results: Overall, women reported a significant reduction in psychological symptoms over time (b = -2.04, p <.001). Residing in a site of greater insecurity was associated with higher initial symptoms (b = 5.91, p <.01), but similar improvement over time (b = -0.30, p =.10) compared to women living in relatively more secure sites. High rates of attendance and treatment completion were observed. Conclusions: These results support the effectiveness of trauma-focused therapies when provided in a well-structured and well-supervised program even in contexts of ongoing conflict and violence.


Evidence of neurofibromatosis type 1 in a multi-morbid Inca child mummy: A paleoradiological investigation using computed tomography.
In this study, an Inca bundle was examined using computed tomography (CT). The primary aim was to determine the preservation status of bony and soft tissues, the sex, the age at the time of death, possible indicators for disease or even the cause of death, as well as the kind of mummification. A secondary aim was to obtain a brief overview of the wrapping in order to gain additional information on the cultural background. The bundle belongs to the Museum of Cultures in Basel, Switzerland, and was bought in Munich, Germany, in 1921. Radiocarbon dating of the superficial textile yielded a calibrated age between 1480 and 1650 AD. The mummy was investigated using multi-slice CT with slice thickness of 0.75 mm and 110 kilovolt. For standardized assessment of soft tissue preservation, a recently developed checklist was applied. CT revealed the mummy of a seven to nine year old boy with superior preservation of bony and soft tissues allowing detailed assessment. Indicators of neurofibromatosis type 1 (paravertebral and cutaneous neurofibromas, a breast neurofibroma, sphenoid wing dysplasia), Chagas disease (dilatation of the esophagus, stomach, rectum, and large amounts of feces), and lung infection (pleural adherence, calcifications), probably due to tuberculosis, were found. Furthermore, signs of peri-mortem violence (transection of the chest and a defect in the abdominal wall) were detected. CT images revealed a carefully performed wrapping. CT examination of the Inca bundle proved to be an important non-destructive examination method. Standardized assessment, especially of the soft tissue structures, allowed for diagnoses of several diseases, indicating a multi-morbid child at the time of death. The careful wrapping pointed to a ceremonial burial. Within the cultural background, the signs of fatal violence were discussed as a possible result of war, murder, accident, or human sacrifice.


Proton MR spectroscopy of the cerebellum and pons in patients with degenerative ataxia.
To investigate whether proton magnetic resonance (MR) spectroscopy is a useful complement to MR imaging in patients with degenerative ataxia. Brain MR imaging and single-voxel proton MR spectroscopy of the right cerebellar hemisphere and pons were performed in 30 patients with sporadic (n = 16) or inherited (n = 14) degenerative ataxia and in 20 healthy control subjects. Several indexes of brainstem and cerebellar atrophy were measured on MR images, as well as the N-acetylaspartate/creatine (NAA/Cr), choline/Cr (Cho/Cr), and myo-inositol/Cr (mI/Cr) ratios in the MR spectra. Differences between patients and subjects were evaluated with the Kruskal-Wallis and Mann-Whitney tests, whereas correlation of clinical, MR imaging, and spectroscopic data was assessed with nonparametric Spearman rank correlation. Measurements of brainstem and cerebellar atrophy obtained from MR images revealed patients had olivopontocerebellar atrophy (OPCA) (n = 11), spinal atrophy (SA) (n = 8), or corticocerebellar atrophy (CCA) (n = 4). Seven patients did not fulfill the criteria for any group and were considered undefined. In patients with OPCA, the pontine and cerebellar NAA/Cr and Cho/Cr ratios were significantly decreased when compared with those of the control subjects. Pontine and cerebellar NAA/Cr ratios were also significantly reduced in patients with SA and CCA. Five patients with undefined ataxia had a substantial decrease of pontine or cerebellar NAA/Cr ratio when compared with that of the control subjects. In patients with OPCA, the pontine NAA/Cr ratio (but not the atrophy measurements) showed a correlation (P =.04) with disability. MR spectroscopy is a useful complement to MR imaging in patients with degenerative ataxia.


[Features of the cytoarchitectonics of the periaqueductal gray of the cat midbrain].
When studying cytoarchitectonics of the midbrain periaqueductal gray (PAG) in cat four areas were distinguished: medial, dorsal, lateral rostral and lateral caudal. They differ in size and distribution density of neurons.


The tumor promoter teleocidin induces IL 2 receptor expression and IL 2-independent proliferation of human peripheral blood T cells.
In testing the recently discovered tumor promoter teleocidin (TCD), we found that like phorbol esters, TCD was mitogenic to human peripheral blood lymphocytes (PBL) and preferentially stimulated sheep erythrocyte-rosetted (ER) T cell-enriched populations. Stimulation of PBL with TCD induced synthesis and expression of receptors for interleukin 2 (IL 2), as shown by dot-blot analysis with the use of a synthetic oligonucleotide probe, cell surface staining with anti-Tac antibody followed by fluorescence-activated cell sorter analysis, and a functional proliferation assay in which TCD-stimulated cells were washed free of TCD and were recultured with human recombinant IL 2 (rIL 2). Increased expression of cell surface markers after TCD stimulation of PBL is not general, because TCD did not affect the expression of Leu-2a antigen, and it also reduced the density of Leu-3a and Leu-4 antigens. Stimulation of cultured, IL 2 receptor-positive PBL with rIL 2, but not TCD, was blocked by anti-rIL 2 antibodies. Furthermore, IL 2-specific mRNA was not detected in TCD-stimulated PBL, demonstrating that IL 2 was not required for TCD-induced T cell proliferation. In addition, TCD replaced IL 2 in inducing short-term proliferation of IL 2-dependent murine cytotoxic T cell lines. The findings that TCD induced IL 2-independent proliferation of T cells, and TCD and IL 2 synergized in inducing T cell proliferation, suggest that they initiate T cell proliferation via different mechanisms. The IL 2-independent activation of T cells, and the induction of IL 2 receptor expression by TCD, may be related to its ability to activate protein kinase C in cell membrane.


Geometric neural computing.
This paper shows the analysis and design of feedforward neural networks using the coordinate-free system of Clifford or geometric algebra. It is shown that real-, complex-, and quaternion-valued neural networks are simply particular cases of the geometric algebra multidimensional neural networks and that some of them can also be generated using support multivector machines (SMVMs). Particularly, the generation of radial basis function for neurocomputing in geometric algebra is easier using the SMVM, which allows one to find automatically the optimal parameters. The use of support vector machines in the geometric algebra framework expands its sphere of applicability for multidimensional learning. Interesting examples of nonlinear problems show the effect of the use of an adequate Clifford geometric algebra which alleviate the training of neural networks and that of SMVMs.


A Rare Case of a Direct Incarcerated Inguinal Hernia Containing an Epiploic Appendage and a Literature Review.
Inguinal hernias are a widespread condition, responsible for a large number of acute abdomen cases. Typically, indirect, rather than direct, hernias lead to complications, as a consequence of their narrower hernial defect. We report a 71-year-old male patient with a rather rare incidence of a direct incarcerated hernia who presented with acute pain in the left inguinal area at a university general hospital in Thessaloniki, Greece, in 2017. Upon clinical examination, an irreducible inguinal mass was palpated. Therefore, the existence of a complicated hernia was suspected. The patient underwent an emergency repair, during which it was established that the hernia was direct and incarcerated and that its sac contained an ischaemic epiploic appendage. The hernia was successfully repaired with mesh, the patient recovered uneventfully and was discharged five days later. Despite the rarity of complicated direct inguinal hernias, they should always be included in the differential diagnosis of irreducible groin masses as they can increase severe complications.


[Method for determination of individual normal values of blood pressure in humans].
The base of a methodology for evaluation of individual normal values of blood pressure (BP) was the determination of homeostatic reaction scale range of mechanism adaptation in each individual, which then were compared with test values of this parameter. Averaged values of dynamic arterial pressure were used to construct the scale. The values were obtained during daily monitoring, and in process of veloergometry test. The method of comparison of obtained values of blood pressure with the scale allowed to carry out pre-diagnostics of both hypertensive, and hypotensive disorders in each volunteer


MiR-34a-5p and miR-452-5p: The Novel Regulators of Pancreatic Endocrine Dysfunction in Diabetic Zucker Rats?
Objective: The pancreatic endocrinal system dominates the regulation of blood glucose levels in vivo, and the dysfunction of pancreatic endocrine β-cells is a major cause of the occurrence and development of Type 2 diabetes (T2D). Although microRNA (miRNA) have been found to be key regulators of pancreatic β-cells proliferation, differentiation and apoptosis, the underlying mechanism remains enigmatic. The aim of this study was to identify several novel miRNAs which might be involved in the etiopathogenesis of diabetic β-cells dysfunction. Methods: The miRNA expression profiles in the pancreas of high-fat diet (HFD) fed Zucker diabetic fatty (ZDF) rats and Zucker lean (ZL) rats feed with normal-fat diet (NFD) were detected by using miRNA microarray chip, and individually verified the most significant factors by quantitative real-time polymerase chain reaction (qRT-PCR) assay. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to predict the target genes related to each of the identified miRNAs and the functions of these target genes in different metabolic signaling pathways. Results: Compared with the ZL rats, a total of 24 differentially expressed miRNAs were detected in ZDF rats. Among which miR-34a-5p and miR-452-5p were the most significantly up-regulated and down-regulated respectively. These miRNAs have not been reported in rats' pancreas before. By GO and KEGG enrichment analyses, we found that miR-34a-5p could negatively regulate pancreatic β-cell proliferation through the involvement of Wnt signaling pathway. In addition, it was also found to regulate insulin secretion through the insulin signaling pathway to modulate blood glucose levels. At the same time, miR-452-5p was found to positively regulate the activity of the key rate-limiting enzyme branched-chain α-keto acid dehydrogenase-β (BCKDHB) in the catabolism of branched chain amino acids (BCAA), leading to mitochondrial dysfunction in pancreatic β-cells. Conclusions: miR-34a-5p and miR-452-5p were identified as the novel regulators of pancreatic endocrine dysfunction. These miRNAs might have the potential to be utilized as the new predictive biomarkers for the diagnosis of the occurrence and development of T2D, as well as the therapeutic targets for T2D treatment.


Class-constrained t-SNE: Combining Data Features and Class Probabilities.
Data features and class probabilities are two main perspectives when, e.g., evaluating model results and identifying problematic items. Class probabilities represent the likelihood that each instance belongs to a particular class, which can be produced by probabilistic classifiers or even human labeling with uncertainty. Since both perspectives are multi-dimensional data, dimensionality reduction (DR) techniques are commonly used to extract informative characteristics from them. However, existing methods either focus solely on the data feature perspective or rely on class probability estimates to guide the DR process. In contrast to previous work where separate views are linked to conduct the analysis, we propose a novel approach, class-constrained t-SNE, that combines data features and class probabilities in the same DR result. Specifically, we combine them by balancing two corresponding components in a cost function to optimize the positions of data points and iconic representation of classes - class landmarks. Furthermore, an interactive user-adjustable parameter balances these two components so that users can focus on the weighted perspectives of interest and also empowers a smooth visual transition between varying perspectives to preserve the mental map. We illustrate its application potential in model evaluation and visual-interactive labeling. A comparative analysis is performed to evaluate the DR results.


Risk factors for gastroenteritis associated with canal swimming in two cities in the Netherlands during the summer of 2015: A prospective study.
Urban canal swimming events are popular in the Netherlands. In 2015, two city canal swimming events took place, in Utrecht (Utrecht Singel Swim, USS) and in Amsterdam (Amsterdam City Swim, ACS). This prospective study characterizes the health risks associated with swimming in urban waters. Online questionnaires were sent to 160 (USS) and 2,692 (ACS) participants, with relatives of participants who did not swim completing the questionnaire as a control. Swimming water specimens and stool specimens of diarrheic participants in the ACS group were analysed. A total of 49% of USS and 51% of ACS swimmers returned their questionnaires. Nine percent of USS swimmers and 4% of non-swimmers reported gastrointestinal complaints (aRR 2.1; 95% CI: 0.3-16), while a total of 31% of ACS swimmers and 5% of non-swimmers reported gastrointestinal complaints (aRR 6.3; 95% CI: 4.1-9.5). AGI risk among ACS participants was directly related to increasing number of mouthfuls of water swallowed. Various norovirus genotypes were detected in five out of seven stool specimens taken from ACS participants and in all three tested ACS water samples. We conclude that the AGI risk among open-water swimmers in urban areas depends on the circumstances around the event. The epidemiological curve, the statistical association between swimming and AGI, and the microbiological evidence for norovirus in stool and water specimens suggest that AGI outbreak after the ACS event was due to water contamination by multiple norovirus strains, which is possibly linked to sewage overflow due to prior heavy rainfall. There is need for more targeted preventive measurements and recommendations for organizers, municipal authorities and participants to prevent this reoccurring in the future.


Medium-term Survival Following of Stroke in Yaoundé (Cameroon): a prospective observational cohort study.
With 5.7 million deaths per year, stroke is the second cause of mortality worldwide, and 70% of these deaths occur in developing countries especially in relation to inappropriate clinical pathways and resources. The aim of our study was to assess the survival rate of stroke patients within 90 days and to identify its determinants. It was a prospective observational cohort study over a period of 90 days after stroke. Patients were recruited between February and May 2015 in two tertiary hospitals in Yaoundé. The mortality rate was obtained by the Kaplan-Meier method. Multivariate analysis was performed using a Cox proportional hazards model. Sixty-six patients were enrolled of which 54 were followed up to 90 days. The overall mortality rate was 23.2% (95% CI: 12.5-87.5), more than two-thirds of the deaths occurred within the first 30 days. The mortality rates at days 14, 30, 60 day were 9.1% (95% CI: 3.0-16.7), 14.3% (95% CI: 6.3-23.8) and 21.1% (95% CI: 10.5-31.6) respectively. High systolic blood pressure and a low Glasgow coma score on admission were independent risk factors of mortality at 90 days. The stroke related mortality compels appropriate collective mobilization for an early and adequate management of stroke patients.


Updating and recalibrating causal probabilistic models on a new target population.
Very often the performance of a Bayesian Network (BN) is affected when applied to a new target population. This is mainly because of differences in population characteristics. External validation of the model performance on different populations is a standard approach to test model's generalisability. However, a good predictive performance is not enough to show that the model represents the unique population characteristics and can be adopted in the new environment. In this paper, we present a methodology for updating and recalibrating developed BN models - both their structure and parameters - to better account for the characteristics of the target population. Attention has been given on incorporating expert knowledge and recalibrating latent variables, which are usually omitted from data-driven models. The method is successfully applied to a clinical case study about the prediction of trauma-induced coagulopathy, where a BN has already been developed for civilian trauma patients and now it is recalibrated on combat casualties. The methodology proposed in this study is important for developing credible models that can demonstrate a good predictive performance when applied to a target population. Another advantage of the proposed methodology is that it is not limited to data-driven techniques and shows how expert knowledge can also be used when updating and recalibrating the model.


In vivo and in vitro models of demyelinating disease: endogenous factors influencing demyelinating disease caused by mouse hepatitis virus in rats and mice.
Intracerebral inoculation of JHM virus (JHMV), the neuropathic strain of mouse hepatitis virus, into Wistar Furth, Wistar Lewis, and Fischer 344 rats at various ages indicated that Wistar Furth rats are more susceptible to the virus than are the other strains. Fischer 344 and Wistar Lewis rats were more resistant to inoculation at 2 and 5 days of age and completely resistant by 10 days of age. In contrast, Wistar Furth rats which were very susceptible at both 2 and 5 days of age remained susceptible until 21 days of age. Intracerebral challenge of an F1 cross between Wistar Furth and Wistar Lewis rats at 10 days of age indicated that resistance to JHMV infection is dominant. Cyclophosphamide treatment 28 days after intracerebral inoculation exacerbated an inapparent infection, leading to paralysis in eight of nine and death in six of nine Wistar Furth test rats. In such immunosuppressed animals, grey- and white-matter lesions were noted throughout the central nervous system, in contrast to the purely demyelinating lesions noted previously. Since rats, unlike mice, were not susceptible to disease after intracerebral injection with the serorelated viscerotropic strain MHV-3, we wished to extend our understanding of the neurological disease process elicited by the two viruses in rodents. For this reason, various mouse strains, including some with recognized immunodeficiencies, were challenged by different routes of inoculation. Intraperitoneal infection of nude and beige mice with JHMV indicated that lack of natural killer cell functions does not markedly enhance the susceptibility to virus, whereas T-cell activity appears to be essential for resisting infection. JHMV and MHV-3 replication in peritoneal macrophages from highly resistant A/J mice was reduced in comparison with that noted in macrophages from susceptible C57BL6/J mice. An initial intraperitoneal inoculation of JHMV was able to protect C57BL6/J mice against fatal intracerebral challenge within 3 days, whereas A/J mice remained susceptible beyond day 3. The protective effect did not appear to result from increased levels of circulating interferon, preceded elevation in serum JHMV-neutralizing antibody titers, and persisted for at least several weeks after intraperitoneal inoculation. Based on the combined studies described here and on previous work by us and others, it appears that the factors influencing the outcome of coronavirus disease in rodents are age at inoculation, route of challenge, genetic constitution of the virus and host, and competence of the immune system, particularly cellular immunity involving T-cells.


Desire for parenthood and reproductive health knowledge in adolescents and young adults with sickle cell disease and their caregivers.
Sickle cell disease (SCD) and hydroxyurea have implications for fertility and reproductive health. The goal of this study was to examine desire for parenthood and reproductive health knowledge among a cohort of adolescent and young adult (AYA) with SCD receiving hydroxyurea and their caregivers at a large pediatric academic center. Patients with SCD were approached from September 2016 to July 2017 if they were: (1) 12-20 years old, (2) prescribed hydroxyurea for at least 6 months, (3) proficient in English, and (4) accompanied by a caregiver who was proficient in English and willing to participate. Participants self-reported sociodemographic characteristics and completed surveys to assess their/their child's desire for parenthood and other life goals, and reproductive health knowledge. Eighteen patient-caregiver dyads completed the study (78.3% of those eligible); 61.1% indicated that they wanted to have future biological children. Few participants reported receiving information about fertility (16.7% of AYA and 27.8% of caregivers) or birth control (11.1% of AYA and 22.2% of caregivers) from their/their child's health care provider, and the majority had received no information on these topics. Less than half of participants reported that SCD (22.2% of AYA and 50.0% of caregivers) or hydroxyurea (11.1% of AYA and 27.8% of parents) could potentially impair fertility. Biological parenthood was important to this cohort yet fertility and reproductive health knowledge was low, suggesting that clinicians should prioritize conversations about infertility risk and birth control options with AYA with SCD on hydroxyurea and their caregivers. More research is needed to identify optimal approaches to these discussions.


A comprehensive analysis of mRNA expression profiles of Esophageal Squamous Cell Carcinoma reveals downregulation of Desmoglein 1 and crucial genomic targets.
Esophageal Squamous Cell Carcinoma (ESCC) is a histological subtype of esophageal cancer that begins in the squamous cells in the esophagus. In only 19% of the ESCC-diagnosed patients, a five-year survival rate has been seen. This necessitates the identification of high-confidence biomarkers for early diagnosis, prognosis, and potential therapeutic targets for the mitigation of ESCC. We performed a meta-analysis of 10 mRNA datasets and identified consistently perturbed genes across the studies. Then, integrated with ESCC ATLAS to segregate 'core' genes to identify consequences of primary gene perturbation events leading to gene-gene interactions and dysregulated molecular signaling pathways. Further, by integrating with toxicogenomics data, inferences were drawn for gene interaction with environmental exposures, trace elements, chemical carcinogens, and drug chemicals. We also deduce the clinical outcomes of candidate genes based on survival analysis using the ESCC related dataset in The Cancer Genome Atlas. We identified 237 known and 18 novel perturbed candidate genes. Desmoglein 1 (DSG1) is one such gene that we found significantly downregulated (Fold Change =-1.89, p-value = 8.2e-06) in ESCC across six different datasets. Further, we identified 31 'core' genes (that either harbor genetic variants or are regulated by epigenetic modifications) and found regulating key biological pathways via adjoining genes in gene-gene interaction networks. Functional enrichment analysis showed dysregulated biological processes and pathways including "Extracellular matrix", "Collagen trimmer" and "HPV infection" are significantly overrepresented in our candidate genes. Based on the toxicogenomic inferences from Comparative Toxicogenomics Database we report the key genes that interacted with risk factors such as tobacco smoking, zinc, nitroso benzylmethylamine, and drug chemicals such as cisplatin, Fluorouracil, and Mitomycin in relation to ESCC. We also point to the STC2 gene that shows a high risk for mortality in ESCC patients. We identified novel perturbed genes in relation to ESCC and explored their interaction network. DSG1 is one such gene, its association with microbiota and a clinical presentation seen commonly with ESCC hints that it is a good candidate for early diagnostic marker. Besides, in this study we highlight candidate genes and their molecular connections to risk factors, biological pathways, drug chemicals, and the survival probability of ESCC patients.


Artificial Neural Networks for Neuroscientists: A Primer.
Artificial neural networks (ANNs) are essential tools in machine learning that have drawn increasing attention in neuroscience. Besides offering powerful techniques for data analysis, ANNs provide a new approach for neuroscientists to build models for complex behaviors, heterogeneous neural activity, and circuit connectivity, as well as to explore optimization in neural systems, in ways that traditional models are not designed for. In this pedagogical Primer, we introduce ANNs and demonstrate how they have been fruitfully deployed to study neuroscientific questions. We first discuss basic concepts and methods of ANNs. Then, with a focus on bringing this mathematical framework closer to neurobiology, we detail how to customize the analysis, structure, and learning of ANNs to better address a wide range of challenges in brain research. To help readers garner hands-on experience, this Primer is accompanied with tutorial-style code in PyTorch and Jupyter Notebook, covering major topics.


Management of chemotherapy-induced neutropenic fever.
Fever occurs at high rates in patients with chemotherapy-induced neutropenia and is considered an oncologic emergency. Numerous algorithms have been developed to guide treatment decisions. Prompt care and the initiation of empiric antibiotic therapy are critically important universal aspects of these treatment-decision schemata. Fever may be the only sign of infection, as in patients with cancer who are undergoing chemotherapy, the immune response is attenuated. In the majority of cases, no etiology for neutropenic fever is uncovered; nonetheless, a thorough workup is essential. The workup allows practitioners to risk stratify patients as being at low or high risk for infectious complications so that appropriate care can be administered. Although it is important to note that there are management algorithms to follow, every patient may present and respond differently. We generally start with broad-spectrum monotherapy for Gram-negative bacteria and then consider whether Gram-positive or antifungal coverage is necessary based on the clinical picture, including factors such as duration and degree of neutropenia. It is important for all practitioners to understand how to care for patients with neutropenic fever because it is a common and treatable condition.


Leading causes of mortality of Asian Indians in California.
Asian Indians had one of the highest population growth rates in California between 1990 and 2000. However, few studies have examined common causes of death in this ethnic group in California. We examined leading causes of mortality in Asian Indians in California and analyzed differences across age and sex. Linear interpolation of 1990 and 2000 US Census data were used to calculate population sizes. California mortality data were examined to determine total number of Asian Indian deaths, and analyzed to determine causes of death across age (25-44, 45-64, > or = 65) and sex subgroups. International Classification of Diseases, 9th and 10th revision codes were used to aggregate causes of mortality into disease categories of cardiovascular diseases, cancers, diabetes, traumas/accidents/suicides, infections, and other conditions. Cardiovascular diseases were the leading cause of death for both sexes. Cancers were the second leading cause of death for both sexes. Diabetes and traumas/accidents/suicides were the next most common cause of mortality for females and males respectively. However, differences were found between age groupings across the sexes. This analysis confirms leading causes of death found in other densely-populated Asian Indian regions. It also sheds light on emerging conditions in this population in California. Although contributors to causes of mortality are discussed, more research is needed to understand the unique biological and socio-cultural determinants of disease in Asian Indians. Translation of this research into intervention strategies will reduce the burden of these diseases in this rapidly-growing population in California and the United States.


[Efficacy of naltrexone in the treatment of alcohol dependence disorder in women].
Alcoholism is a major public health problem. Although its prevalence is higher in men, the clinical and social repercussions of alcoholism in women are also of great concern, as they have differential characteristics in different vulnerability, and thus therapeutic implications. In recent years, we have seen an increase of the percentages of women with problems related to alcohol consumption in Spain. Several pharmacological treatments as the antagonist of the opioid receptors naltrexone have demonstrated efficacy in the treatment of dehabituation of alcoholism in males, however, there are no studies in the female population. This report is the first randomized study about the efficacy of naltrexone in the treatment of dehabituation in women with alcohol dependence disorder. In a 12 week, single-blind, randomized trial, we studied 100 women with alcohol dependence disorder (DSM-IV), evaluating the efficacy of adding naltrexone as adjunctive treatment to the dehabituation treatment. The naltrexone group showed a lower rate of alcohol relapse during the follow-up period (76 % vs. 46%; chi2=8.239; p=0.004), and significantly lower dropout rates (16% vs. 38 %; chi2=5.074; p=0.024). We also found a lower number of days of intoxication (2.88 vs. 14.64; t=2.732; p=0.011). Naltrexone shows efficacy as adjunctive treatment to maintain abstinence in women with alcohol dependence disorder. Further studies are needed to confirm the efficacy of this treatment and to find specific predictors of good outcome in women.


Targeting of Yersinia Yop proteins into the cytosol of HeLa cells: one-step translocation of YopE across bacterial and eukaryotic membranes is dependent on SycE chaperone.
Pathogenic Yersiniae adhere to and kill macrophages by targeting some of their Yop proteins into the eukaryotic cytosol. There is debate about whether YopE targeting proceeds as a direct translocation of polypeptide between cells or in two distinct steps, each requiring specific signals for YopE secretion across the bacterial envelope and for translocation into the eukaryotic cytosol. Here, we used the selective solubilization of the eukaryotic plasma membrane with digitonin to measure Yop targeting during Yersinia infections of HeLa cells. YopE, YopH, YopM and YopN were found in the eukaryotic cytosol but not in the extracellular medium. When bound to SycE chaperone in the Yersinia cytoplasm, YopE residues 1-100 are necessary and sufficient for the targeting of hybrid neomycin phosphotransferase. Electron microscopic analysis failed to detect an extracellular intermediate of YopE targeting, suggesting a one-step translocation mechanism.


Postnatal Growth Restriction Is Reduced If Birth Weight Is Used for Nutritional Calculations in ELBW Infants.
Since fluid and nutrition needs and delivery in ELBW infants are calculated based on their body weights, there could be a measurable difference in fluid, nutrition, and protein intake calculations based on birth weight (BW) or current weight of the infant, especially in the first two weeks of life. Theoretically, the use of current daily weight (CW) for calculations may result in decreased fluid, nutrition, and protein delivery as well as a cumulative protein deficit (cPD) over the first two weeks of life until the infant regains birth weight. However, there have been no clinical studies comparing the clinical and nutritional impact of these two strategies is unknown. Aims. The aims of this study were to quantify the amount of protein intake and to compare growth parameters at hospital discharge (as measured by discharge weight and head circumference percentiles) when using two different methodologies (BW vesrsus current daily weight until BW is regained) for calculating fluid and protein intake in the first two weeks after birth in ELBW infants. Methods. A retrospective review of infants weighing ≤ 1kg at birth was conducted from January 2005 to December 2009 (Phase 1; P1) and January 2012 to December 2014 (Phase 2; P2) in a tertiary care NICU. At this center, in P1 (2005-09) CW was exclusively used for calculating fluid, calorie, and protein administration till BW was regained. In P2 (2012-14), BW was exclusively used for all calculations. Both P1 and P2 periods were compared and analyzed for differences in demographics, nutritional intake, comorbid conditions, and growth outcomes. Results. We studied 146 infants with 84 and 62 infants in P1 and P2 periods, respectively. The mean gestational age was lower during Phase 1 (25.74 ±1.32 vs. 26.47 ±1.82 weeks. P value =0.01). However, the birth weights were not different between the two periods. When the multiple-regression analysis was done using a discharge weight of >10th percentile as the dependent variable, protein intake before regaining of BW (OR of 4.126 with 95th CI of 2.03-8.36, a P value of 0.00) and AGA status at birth (OR of 8.37 with 95th CI of 2.67-26.24) remained significant factors. Compared to P1, babies in P2 received 1g/kg/day more protein till BW was regained. In P1, 27% of babies who were appropriate for gestational age (AGA) for head circumference at birth became microcephalic by discharge, compared to 15.6% in P2 (p=0.03). Similarly, 75.3% of the babies who were AGA for weight at birth in P1 became small for gestational age (SGA) by discharge, compared to 16.7% in P2 (p=<0.0001). The number of days it took to regain BW was 9.6 days in P1 vs. 7 days in P2 (p=<0.0001). Conclusions. Basing nutrition calculations in ELBW on birth weight rather than current daily weight until the birth weight is regained resulted in significantly greater protein delivery, a significant decrease in the incidence of failure to thrive and smaller head circumference percentiles at discharge in ELBW infants.


Development and validation of four Leishmania species constitutively expressing GFP protein. A model for drug discovery and disease pathogenesis studies.
Green fluorescent protein (GFP)-parasite transfectants have been widely used as a tool for studying disease pathogenesis in several protozoan models and their application in drug screening assays has increased rapidly. In the past decade, the expression of GFP has been established in several Leishmania species, mostly for in vitro studies. The current work reports generation of four transgenic parasites constitutively expressing GFP (Leishmania mexicana, Leishmania aethiopica, Leishmania tropica and Leishmania major) and their validation as a representative model of infection. This is the first report where stable expression of GFP has been achieved in L. aethiopica and L. tropica. Integration of GFP was accomplished through homologous recombination of the expression construct, pRib1.2αNEOαGFP downstream of the 18S rRNA promoter in all species. A homogeneous and high level expression of GFP was detected in both the promastigote and the intracellular amastigote stages. All transgenic species showed the same growth pattern, ability to infect mammalian host cells and sensitivity to reference drugs as their wild type counterparts. All four transgenic Leishmania are confirmed as models for in vitro and possibly in vivo infections and represent an ideal tool for medium throughput testing of compound libraries.