Leaching of Glyphosate and Aminomethylphosphonic Acid through Silty Clay Soil Columns under Outdoor Conditions.
Glyphosate [-(phosphono-methyl)-glycine] is the main herbicide used in the Chianti vineyards. Considering the pollution risk of the water table and that the vineyard tile drain may deliver this pollutant into nearby streams, the objective of the present study was to estimate the leaching losses of glyphosate under natural rainfall conditions in a silty clay soil in the Chianti area. The leaching of glyphosate and its metabolite (aminomethylphosphonic acid [AMPA]) through soils was studied in 1-m-deep soil columns under outdoor conditions over a 3-yr period. Glyphosate was detected in the leachates for up to 26 d after treatments at concentrations ranging between 0.5 and 13.5 μg L. The final peak (0.28 μg L) appeared in the leachates approximately 319 d after the first annual treatment. Aminomethylphosphonic acid first appeared (21.3 μg L) in the soil leachate 6.8 d after the first annual treatment. Aminomethylphosphonic acid detection frequency and measured concentration in the leachates were more than that observed for the glyphosate. Aminomethylphosphonic acid was detected in 20% of the soil leachates at concentrations ranging from 1 to 24.9 μg L. No extractable glyphosate was detected in the soil profile. However, the AMPA content in the lowest layer ranged from 13.4 to 21.1 mg kg, and on the surface layer, it ranged from 86.7 to 94 mg kg. Overall, these results indicate that both glyphosate and AMPA leaching through a 1-m soil column may be potential groundwater contaminants.


The influence of timing of radiation therapy following breast-conserving surgery on 10-year disease-free survival.
The Dutch guidelines advise to start radiation therapy (RT) within 5 weeks following breast-conserving surgery (BCS). However, much controversy exists regarding timing of RT. This study investigated its effect on 10-year disease-free survival (DFS) in a Dutch population-based cohort. All women diagnosed with primary invasive stage I-IIIA breast cancer in 2003 treated with BCS+RT were included. Two populations were studied. Population 1 excluded patients receiving chemotherapy before RT. Analyses were stratified for use of adjuvant systemic therapy (AST). Population 2 included patients treated with chemotherapy, and compared chemotherapy before (BCS-chemotherapy-RT) and after RT (BCS-RT-chemotherapy). DFS was estimated using multivariable Cox regression. Locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were secondary outcomes. Population 1 (n=2759) showed better DFS and DMFS for a time interval of >55 than a time interval of <42 days. Patients treated with AST showed higher DFS for >55 days (hazards ratio (HR) 0.60 (95% confidence interval (CI): 0.38-0.94)) and 42-55 days (HR 0.64 (95% CI: 0.45-0.91)) than <42 days. Results were similar for DMFS, while timing did not affect LRRFS and OS. For patients without AST, timing was not associated with DFS, DMFS and LLRFS, but 10-year OS was significantly lower for 42-55 and >55 days compared to <42 days. In population 2 (n=1120), timing did not affect survival in BCS-chemotherapy-RT. In BCS-RT-chemotherapy, DMFS was higher for >55 than <42 days. Starting RT shortly after BCS seems not to be associated with a better long-term outcome. The common position that RT should start as soon as possible following surgery in order to increase treatment efficacy can be questioned.


A new instrument for automated microcontact printing with stamp load adjustment.
An instrument for automated microcontact printing (microCP) on microscope slides is described. The movement of the stamp, which is actuated by a computer controlled pneumatic actuator, is precisely guided until it makes contact with the substrate. As a consequence, the absolute position of the microprinted patterns is reproducible over a series of substrates with 1 mum standard deviation. Exchange of substrates and stamps is a quick and simple procedure. This makes possible the microprinting of adjacent or superimposable patterns, with different products, in a reproducible manner. Furthermore, a novel approach is described for adjusting the load on the stamp during contact. Two adjustable screws are set up so that their length (with reference to the substrate holder) limits the stamp compression during contact. The load on the stamp is proportional to the stamp compression and from the experimental point of view, this is controlled by the operator adjusting the screws. This makes possible the microCP with stamps incorporating large surface features as well as stamps with isolated features raised on the surface. For proof of concept, automated microCP of a single parallelepiped polydimethylsiloxane feature, with a surface of 2 cm x 30 microm and a height of 25 mum, is demonstrated inside a microfluidic channel without roof collapse. A second example is provided with a single cross feature, possessing an overall surface of 140 x 140 microm(2) and a height of 14 microm. Potential applications of this versatile, inexpensive and compact instrument are discussed. The machine's potential for high throughput also makes it suitable for mass production applications.


Hemodynamic management of acute brain injury caused by cerebrovascular diseases: a survey of the European Society of Intensive Care Medicine.
The optimal hemodynamic targets and management of patients with acute brain injury are not completely elucidated, but recent evidence points to important impact on clinical outcomes. We performed an international survey with the aim to investigate the practice in the hemodynamic targets, monitoring, and management of patients with acute ischemic stroke (AIS), intracranial hemorrhage (ICH) and subarachnoid hemorrhage (SAH). This survey was endorsed by the European Society of Intensive Care (ESICM). An electronic questionnaire of 76 questions divided in 4 sections (general information, AIS, ICH, SAH specific questions) was available between January 2022 to March 2022 on the ESICM website. One hundred fifty-four healthcare professionals from 36 different countries and at least 98 different institutions answered the survey. Routine echocardiography is routinely performed in 37% of responders in AIS, 34% in ICH and 38% in SAH. Cardiac output monitoring is used in less than 20% of cases by most of the responders. Cardiovascular complications are the main reason for using advanced hemodynamic monitoring, and norepinephrine is the most common drug used to increase arterial blood pressure. Most responders target fluid balance to neutral (62% in AIS, 59% in ICH,44% in SAH), and normal saline is the most common fluid used. Large variability was observed regarding the blood pressure targets. Hemodynamic management and treatment in patients with acute brain injury from cerebrovascular diseases vary largely in clinical practice. Further research is required to provide clear guidelines to physicians for the hemodynamic optimization of this group of patients.


Label-free surface-enhanced Raman spectroscopy for detection of colorectal cancer and precursor lesions using blood plasma.
Fecal based tests have limited diagnostic values in detecting adenomatous polyps, the precursor lesions to colorectal cancer (CRC). Surface enhanced Raman spectroscopy (SERS) using silver nanoparticles as substrate is a multiplexed analytical technique capable of detecting biomolecules with high sensitivity. This study utilizes SERS to analyze blood plasma for detecting both CRC and adenomatous polyps for the first time. Blood plasma samples are collected from healthy control subjects and patients diagnosed with adenomas and CRC. Using a real-time Raman system, SERS spectra for blood plasma samples are measured in 1 s. The collected SERS spectra are analyzed with partial least squares-discriminant analysis. Classification of normal versus CRC plus adenomatous polyps achieved diagnostic sensitivity of 86.4% and specificity of 80%. The results suggest that blood plasma SERS analysis could be a potential screening test to detect both CRC and adenomas.


Dying for love: Perimenopausal degeneration of vaginal microbiome drives the chronic inflammation-malignant transformation of benign prostatic hyperplasia to prostatic adenocarcinoma.
Prostatic carcinoma is the second commonest cancer in males and is so common as to become almost holoendemic with advancing age. The recent demonstration that far from being benign, "benign" prostatic hypertrophy is a likely a reaction of the prostate to chronic untreated lower genital tract infection, and that this chronic inflammation is likely the usual precursor to the frequent occurrence of prostatic carcinoma has far reaching implications. The obvious source for the chronic inflammatory stimulus in the prostate is the documented dramatically altered lower female genital microbiota associated with the menopause. Hence the major hypothesis is that prostatic cancer may arise due to chronic infection and inflammation in the prostate gland consequent upon the altered microbiome of the menopausal female genital tract. This has implications for testing and diagnosis, treatment, population health and personal hygiene practices. It suggests that male dyspareunia, although almost never encountered in clinical practice may in fact be relatively common in older males, and in particular if diagnosed, represents a critical opportunity for therapeutic intervention to interrupt the chronic inflammation - cancer transformation and progression which has been well documented in other tissues. It implies that the coordinated application of next generation sequencing to the microbiome of the lower genital tracts of male and female couples, including seminal fluid, will have both research applications to further explore this sequence, as well as finding application as a potential population level screening procedure as is presently done for the "Thin Prep" cervical screening for human papillomavirus in females. Moreover this insight opens up new opportunities for chemointervention and chemoprevention for this important clinicopathological progression. These considerations give rise to the exciting possibility that prostatic malignancy may be preventable by various methods of local hygiene in the female partner or some antibacterial method in males. Since the long term application of oral antibiotics is likely to be of limited efficacy this indicates the need for new antimicrobial solutions.


Field Determination of Nitrate Formation Pathway in Winter Beijing.
Particulate nitrate (pNO3-) has often been found to be the major component of fine particles in urban air-sheds in China, the United States, and Europe during winter haze episodes in recent years. However, there is a lack of knowledge regarding the experimentally determined contribution of different chemical pathways to the formation of pNO3-. Here, for the first time, we combine ground and tall-tower observations to quantify the chemical formation of pNO3- using observationally constrained model approach based on direct observations of OH and N2O5 for the urban air-shed. We find that the gas-phase oxidation pathway (OH+NO2) during the daytime is the dominant channel over the nocturnal uptake of N2O5 during pollution episodes, with percentages of 74% in urban areas and 76% in suburban areas. This is quite different from previous studies in some regions of the US, in which the uptake of N2O5 was concluded to account for a larger contribution in winter. These results indicate that the driving factor of nitrate pollution in Beijing and different regions of the US is different, as are the mitigation strategies for particulate nitrate.


Antinuclear antibodies (ANA) as a criterion for classification and diagnosis of systemic autoimmune diseases.
The classification and diagnosis of systemic autoimmune diseases are frequently based on a collection of criteria composed of clinical, laboratory, imaging, and pathology elements that are strongly associated with the respective disease. Autoantibodies are a distinctive hallmark and have a prominent position in the classification criteria of many autoimmune diseases. The indirect immunofluorescence assay on HEp-2 cells (HEp-2 IFA), historically known as the antinuclear antibody test, is a method capable of detecting a wide spectrum of autoantibodies. A positive HEp-2 IFA test is part of the classification criteria for systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA), as well as the diagnostic criteria for autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). A positive HEp-2 IFA test can appear as different morphological patterns that are indicative of the most probable autoantibody specificities in the sample. Only some of the HEp-2 IFA patterns are associated with the specific autoantibodies relevant to SLE, JIA, AIH, and PBC, whereas some other patterns occur mainly in non-related conditions and even in apparently healthy individuals. This paper provides a critical review on the subject and proposes that the classification and diagnostic criteria for SLE, JIA, AIH, and PBC could be improved by a modification on the HEp-2 IFA (ANA) criterion in that the staining patterns accepted for each of these diseases should be restricted according to the respective relevant autoantibody specificities.


Timing of laparoscopic cholecystectomy for acute cholecystitis: a prospective non randomized study.
To study the timing of laparoscopic cholecystectomy for patients with acute cholecystitis. Between January 2002 and December 2005, all American Society of Anesthesiologists classification (ASA) I, II and III patients with acute cholecystitis were treated laparoscopically during the urgent (index) admission. The patients were divided into three groups according to the timing of surgery: (1) within the first 3 d, (2) between 4 and 7 d and (3) beyond 7 d from the onset of symptoms. The impact of timing on the conversion rate, morbidity and postoperative hospital stay was studied. One hundred and twenty-nine patients underwent laparoscopic cholecystectomy for acute cholecystitis during the index admission. Thirty six were assigned to group 1, 58 to group 2, and 35 to group 3. The conversion rate and morbidity for the whole cohort of patients were 4.6% and 10.8%, respectively. There was no significant difference in the conversion rate, morbidity and postoperative hospital stay between the three groups. Laparoscopic cholecystectomy for acute cholecystitis during the index admission is safe, regardless of the time elapsed from the onset of symptoms. This policy can result in an overall shorter hospitalization.


Case Report: The First Direct Evidence of Gnathostoma spinigerum Migration through Human Lung.
Gnathostomiasis is a helminthic infection caused by the third-stage larvae of nematodes of the genus Gnathostoma. The life cycle in humans starts with an enteric phase, with the worm perforating the gastric or intestinal mucosa to reach the peritoneal cavity and migrating through the human body. Subsequent penetration through the diaphragm may produce pleuropulmonary symptoms. We herein present a previously healthy 56-year-old Thai man from Southern Thailand who was an ex-smoker presented with chronic dry cough progressing to hemoptysis after consuming grilled swamp eels and freshwater fish. Chest computed tomography showed consolidation at the lingular segment, and the differential diagnosis was primary lung cancer and pulmonary tuberculosis. The lung tissue biopsied during bronchoscopy displayed segments of organisms with the phenotypic characteristics of Gnathostoma spp., and abundant eosinophils were seen in the alveolar tissue. Gnathostoma spinigerum infection was confirmed by a Western blot assay for G. spinigerum-specific 24-kDa reactive band. The patient received albendazole, and a follow-up chest radiograph revealed improvement in the consolidation in the lung and reduction in hemoptysis. We report the first direct evidence including pathology and immunohistochemistry of Gnathostoma invasion via the human lung, with clinical and radiographic presentations mimicking either malignancy or chronic infection.


Compression of the peroneal nerve by a cyst in a seven-year-old child.
Compressions of the peroneal nerve are rare since only some sixty such cases have been described since 1921. The authors report a new observation of compression extrinsic to the peroneal nerve by a synovial cyst, the source of which was the upper fibulo-tibial joint, in a child of seven years. As far as we know, this is the youngest age found in the relevant literature. Because of a swiftly appearing painful swelling, along with complete paralysis of the peroneal nerve, an electromyogram and a nuclear magnetic resonance were performed, with a view to confirming the diagnosis and to clarifying the topography of the cyst. The removal of the latter led to the child being cured with complete recovery of the peroneal nerve within three months.


Insulin receptor substrate is a mediator of phosphoinositide 3-kinase activation in quiescent pancreatic cancer cells.
Phosphoinositide 3-kinase (PI3K) is activated in pancreatic cancer cells and plays a central role in their proliferation, survival, and drug resistance. Although the mechanism is unclear, PI3K activation in these cells could be due to physical interaction between its regulatory subunit (p85) and specific tyrosine kinases or their mediators. Consistent with this possibility, PI3K was precipitated with anti-phosphotyrosine antibodies and Akt phosphorylation was blocked by the tyrosine kinase inhibitors SU6656 and PD158780 in quiescent pancreatic cancer cells. Pull-down assays with a fusion protein (GST-p85NC-SH2), and coimmunoprecipitation studies, indicated that the insulin receptor substrate (IRS), and not the epidermal growth factor and insulin-like growth factor receptors or the Src tyrosine kinase, was physically associated with PI3K in these cells. Our data also indicated that SU6656 and PD158780 inhibited Akt activation in pancreatic cancer cells by interfering with the ability of IRS-1 to recruit PI3K. Furthermore, IRS-1 was phosphorylated on a p85-binding site (Y(612)), and IRS-specific small interfering RNA potently inhibited activation of PI3K and Akt in transfected cells. Taken together, these observations indicate that IRS is a mediator of PI3K activation in quiescent pancreatic cancer cells.


Salt Removal from Microliter Sample Volumes by Multiple Phase Microelectromembrane Extractions Across Free Liquid Membranes.
A new concept for rapid and efficient salt removal from minute volumes of saline samples is presented by using multiple phase microelectromembrane extraction (μ-EME). A disposable μ-EME unit is filled with five consecutive plugs of immiscible aqueous and organic solutions; the aqueous sample forms the central phase and is encompassed by two free liquid membranes (FLMs) and two extraction solutions. Salt cations and anions migrate in opposite directions from the sample solution on application of 300 V dc electric potential, cross the neighboring FLM, and are transferred to the corresponding extraction solution. At the same time, the two FLMs selectively eliminate μ-EME transfers of target analytes, which are retained in the sample, and the resulting salt-free sample is then used for subsequent analysis. At optimized conditions (FLMs consisted of 1-pentanol and extraction solutions of deionized water and 100 mM NH4OH), more than 99.3% NaCl was removed from samples containing physiological NaCl concentrations. Simultaneously, more than 95% of model biochemical species (human serum albumin, neurotensin, creatinine, glycine, and alanine) were retained in the samples for subsequent analyses. Good quality capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C4D) electropherograms and interference-free electrospray ionization mass spectrometry (ESI-MS) spectra of selected biochemical species were obtained after μ-EME salt removal from samples containing micromolar concentrations of the target analytes and 150 mM of NaCl.


The Evolving Treatment Landscape of Advanced Renal Cell Carcinoma in Patients Progressing after VEGF Inhibition.
Despite significant changes in the therapeutic landscape of renal cell carcinoma, the majority of patients with metastatic disease eventually progress after first-line treatment with vascular endothelial growth factor receptors (VEGFR) tyrosine kinase inhibitor (TKI) therapy. Understanding existing data on subsequent therapies is crucial to define an optimal treatment sequence following first-line failure. This review examines the data supporting currently approved agents in this setting and provides a framework for decision-making regarding treatment sequencing beyond first-line therapy with VEGFR TKIs.


[FAT1 inhibits cell proliferation of esophageal squamous cell carcinoma through regulating the expression of CDK4/CDK6/CCND1 complex].
Objective: To explore the expression of FAT1 in esophageal squamous cell carcinoma (ESCC) tissues, and its effect on cell proliferation. Methods: The expression levels of FAT1 protein in human ESCC tissues and matched adjacent normal tissues were determined by immunohistochemistry (IHC). Lentivirus based knockdown of FAT1 was carried out in YSE2 and Colo680N cell lines and 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) assays was performed to examine the effect of FAT1 on the proliferation of these ESCC cells. Colony formation assay was used to detect the colony formation ability. Flow cytometry was performed to analyze the cell cycle and apoptosis. The expression levels of cell cycle markers in FAT1 knock out ESCC cell lines were detected by real-time quantitative reverse transcription polymerase chain reaction(qRT-PCR) and Western blot. Results: The relative expression of FAT1 in ESCC tissues was 66.97±21.53, significantly lower than 78.13±16.76 of adjacent normal tissues(P<0.05). Knockdown of FAT1 promoted cell proliferation and colony formation. In YSE2 cell, the division time in negative control (NC) group was (1 570±51) min, significantly longer than (1 356±31) min in shFAT1 group. In Colo680N cell, division time in NC group was (1 532±53) min, significantly longer than (1 290±30) min in shFAT1 group (P<0.05). Knockdown of FAT1 promoted G1-to S-phase transition and resulted in the upregulation of CDK4/CDK6/CCND1. Conclusion: FAT1 inhibits the proliferation and G1-to S-phase transition of ESCC cells through regulating the protein expression of CDK4/CDK6/CCND1 complex.


Self-alignment of low-valent octanuclear palladium atoms.
A linear tetraphosphine, meso-bis[(diphenylphosphinomethyl)phenylphosphino]methane (dpmppm) was used to synthesize linear octapalladium-extended metal atom chains as discrete molecules of [Pd8(μ-dpmppm)4](BF4)4 (1) and [Pd8(μ-dpmppm)4L2](BF4)4 (L=2,6-xylyl isocyanide (XylNC; 2), acetonitrile (3), and N,N-dimethylformamide (dmf; 4)), which are stable in the solution states and show interesting temperature-dependent photochemical properties in the near IR region. Variable temperature NMR studies demonstrated that at higher temperature T≈140 °C the Pd8 chains were dissociated into Pd4 fragments, which were thermodynamically self-aligned to restore the Pd8 chains at lower temperature T<60 °C. The coldspray ionization mass spectra suggested a possibility for further aggregation of the linear tetrapalladium units.


Development of an ex-vivo porcine lower urinary tract model to evaluate the performance of urinary catheters.
Intermittent catheterization is the gold standard method for bladder management in individuals with urinary retention and/or incontinence. It is therefore important to understand the performance of urinary catheters, especially on parameters associated to risks of developing urinary tract infections, and that may impact the quality of life for urinary catheter users. Examples of such parameters include, urine flowrate, occurrence of flow-stops, and residual urine left in the bladder after flow-stop. Reliable in-vitro and/or ex-vivo laboratory models represent a strong asset to assess the performance of urinary catheters, preceding and guiding in-vivo animal studies and/or human clinical studies. Existing laboratory models are generally simplified, covering only portions of the catheterization process, or poorly reflect clinical procedures. In this work, we developed an ex-vivo porcine lower urinary tract model that better reflects the catheterization procedure in humans and allows to investigate the performance of standard of care catheters. The performance of three standard of care catheters was investigated in the developed model showing significant differences in terms of flowrate. No differences were detected in terms of residual volume in the bladder at first flow-stop also when tuning the abdominal pressure to mimic a sitting down and standing up position. A newly discovered phenomenon named hammering was detected and measured. Lastly, mucosal suction was observed and measured in all standard of care catheters, raising the concern for microtrauma during catheterization and a need for new and improved urinary catheter designs. Results obtained with the ex-vivo model were compared to in-vivo studies, highlighting similar concerns.


Catalysis of proton reduction by a [BO4]-bridged dicobalt glyoxime.
We report the preparation of a dicobalt compound with two singly proton-bridged cobaloxime units linked by a central [BO4] bridge. Reaction of a doubly proton-bridged cobaloxime complex with trimethyl borate afforded the compound in good yield. Single-crystal X-ray diffraction studies confirmed the bridging nature of the [BO4] moiety. Using electrochemical methods, the dicobalt complex was found to be an electrocatalyst for proton reduction in acetonitrile solution. Notably, the overpotential for proton reduction (954 mV) was found to be higher than in the cases of two analogous single-site cobalt glyoximes under virtually identical conditions.


The involvement of proteases and protease inhibitors in neovascularization.
Bovine capillary endothelial cells have been found to respond to several stimuli by producing increased amounts of plasminogen activator and latent collagenase. These stimulators include the tumor promoter tetradecanoyl phorbol-13-acetate as well as crude preparations from a human hepatoma, bovine retinae, and mouse adipocytes, all of which are known to contain angiogenic factors. Endothelial cells and skin fibroblasts do not respond to these stimuli in the same way, indicating a specificity of the response. In addition, inhibitors of plasmin and vertebrate collagenase have been isolated from cartilage, a tissue resistant to neovascularization. We have proposed that these specific protease inhibitors confer on cartilage its antiangiogenic properties.


Intramolecular nucleophilic activation promoting efficient hydrolytic cleavage of DNA by (aqua)bis(dipyridoquinoxaline)copper(II) complex.
The axial aqua bound copper(II) complex [Cu(dpq)2(H2O)](ClO4)2, having a planar NN-donor heterocyclic base dipyridoquinoxaline (dpq) as the DNA minor groove binder, shows efficient hydrolytic cleavage of supercoiled DNA in the dark and in the absence of any external reagents, as evidenced from T4 ligase experiments, with a rate of 5.58 +/- 0.4 h(-1) and a rate enhancement of 1.55 x 10(8).


Gonadotrophin-releasing hormone and the control of ovulation rate by the FecB gene in Booroola ewes.
Booroola sheep carry a FecB gene that confers high fecundity. The aims of the present studies were to determine in homozygous carriers (BB) and non-carriers (++) of the Booroola FecB gene whether there are FecB differences in the secretory characteristics of GnRH in hypophyseal-portal blood of ovariectomized ewes (Expt 1) and whether differences in ovulation rate would occur following the administration of PMSG and pulsatile GnRH to ovary-intact Booroola ewes with hypothalamic-pituitary disconnection (HPD) (Expt 2). In Expt 1, no FecB gene-specific differences were noted for GnRH with respect to pulse frequency, pulse amplitude or overall secretion rate. Irrespective of genotype there were 1.9 +/- 0.2 GnRH pulses h-1 (n = 20 ewes; 10 BB and 10 ++ animals) and 1.9 +/- 0.1 pulses of immunoreactive (i) LH h-1. In Expt 2, ovulation was induced in the HPD ovary-intact animals on three occasions (e.g. 56, 393 and 423 days after HPD surgery) using a PMSG (200 or 400 iu)-GnRH pulse (250 ng i.v. for 96 h)-GnRH bolus (10 micrograms i.v.) regimen after pretreating the animals with GnRH pulses (250 ng i.v. for 14 days). On all occasions the ovulation rates were significantly higher (P < 0.05) in BB ewes (n = 6 or 7) than in ++ animals (n = 7). No differences between the genotypes were noted with respect to the mean concentrations of progesterone in plasma notwithstanding the differences in ovulation rates.(ABSTRACT TRUNCATED AT 250 WORDS)


Prevalence and predictors of probable depression in prostate cancer survivors.
The early diagnosis and treatment of depression are cancer care priorities. These priorities are critical for prostate cancer survivors because men rarely seek mental health care. However, little is known about the epidemiology of depression in this patient population. The goal of this study was to describe the prevalence and predictors of probable depression in prostate cancer survivors. The data were from a population-based cohort of North Carolinian prostate cancer survivors who were enrolled from 2004 to 2007 in the North Carolina-Louisiana Prostate Cancer Project (n = 1031) and were prospectively followed annually from 2008 to 2011 in the Health Care Access and Prostate Cancer Treatment in North Carolina study (n = 805). Generalized estimating equations were used to evaluate an indicator of probable depression (Short Form 12 mental composite score ≤48.9; measured at enrollment and during the annual follow-up) as a function of individual-level characteristics within the longitudinal data set. The prevalence of probable depression fell from 38% in the year of the cancer diagnosis to 20% 6 to 7 years later. Risk factors for probable depression throughout the study were African American race, unemployment, low annual income, younger age, recency of cancer diagnosis, past depression, comorbidities, treatment decisional regret, and nonadherence to exercise recommendations. Depression is a major challenge for prostate cancer survivors, particularly in the first 5 years after the cancer diagnosis. To the authors' knowledge, this is the first study to demonstrate an association between treatment decisional regret and probable depression.


In silico replication of the genome-wide association results of the Type 1 Diabetes Genetics Consortium.
Recently, the Type 1 Diabetes Genetics Consortium (T1DGC) reported 22 novel type 1 diabetes (T1D)-associated loci identified by meta-analysis of three genome-wide association studies (GWASs) with a case-control design. However, the association of 10 of these 22 reported loci was not confirmed in the T1DGC family cohort (P > 0.1). To address concerns about potential bias from population stratification, this study aims to replicate the association in three independent GWAS cohorts, one of which was based on the stratification-proof transmission disequilibrium analysis. Three European-descent population samples were included in this study: 483 cases and both parents, a case-control cohort of 514 cases and 2027 controls, and an additional cohort of 1078 cases and 341 controls from the dbGaP database. Among the 22 SNPs reported by the T1DGC, we had high-quality genotypes for 15; the remaining were imputed. T1D association was replicated in seven loci after Bonferroni correction for 22 independent hypotheses. An additional eight loci had nominal (one-sided) significance of P < 0.1 in the same direction, giving a false discovery rate of 3.35%. The genetic susceptibility conferred by non-HLA loci in our family cohort with one affected offspring was higher than the T1DGC multiplex families. Reciprocally, the frequency of strongly predisposing HLA alleles in the multiplex families was higher. This study replicated T1D association with at least as many of these novel loci as expected from the power of our sample size, thus supporting the validity of the new discoveries.


Haematopoietic stem cell transplantation for severe autoimmune diseases in children: A review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation.
Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long-term disease control or cure, but therapy-related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence-based interspeciality guidelines and recommendations.


Multipurpose organically modified carbon nanotubes: from functionalization to nanotube composites.
We show that covalent functionalization of carbon nanotubes (CNTs) via 1,3-dipolar cycloaddition is a powerful method for enhancing the ability to process CNTs and facilitating the preparation of hybrid composites, which is achieved solely by mixing. CNTs were functionalized with phenol groups, providing stable dispersions in a range of polar solvents, including water. Additionally, the functionalized CNTs could easily be combined with polymers and layered aluminosilicate clay minerals to give homogeneous, coherent, transparent CNT thin films and gels.


Facilitators and Challenges to Maintaining Oral Health for Indigenous Communities Globally: A Qualitative Systematic Review.
Globally, Indigenous Peoples experience pervasive oral health inequities due to a complex interplay of social determinants of health including the sustained effects of colonisation, racism, and intergenerational disruption to Indigenous communities. This qualitative systematic review aimed to synthesise evidence related to facilitators and challenges that affect the ability of global Indigenous communities to maintain oral health. Two independent reviewers searched PubMed, SCOPUS, Web of Science, and Embase. Qualitative studies including illustrations from Indigenous Peoples regarding facilitators and challenges to oral health maintenance were considered. Included articles were critically appraised. The search identified 4,247 articles eligible for inclusion; 22 articles were included. Challenges and facilitators were synthesised across child, carer, community, and service levels during the meta-aggregation. The prioritisation of integrated oral health services, programs, and research that encompass multiple factors at various levels of influence are needed to strengthen the oral health of Indigenous communities.


The calcium content of mitochondria from brain subregions following short-term forebrain ischemia and recirculation in the rat.
A procedure was established for determining the calcium content of mitochondria isolated from rat brain subregions based on changes in fura-2 fluorescence after disruption of the organelles with Triton X-100 and sodium dodecyl sulfate. Mitochondria isolated from the forebrain of normal rats contained 2.5 +/- 0.9 nmol of calcium/mg of protein. A 30-min ischemic period produced an approximately twofold increase in the calcium content of mitochondria isolated from the dorsolateral striatum, a region in which most neurons die within 24 h after this period of ischemia. The calcium content of mitochondria from the paramedian cortex, a region in which there are few ischemia-susceptible neurons, tended to be similarly increased, although this difference was not statistically significant. Larger increases (to approximately five times control values) were seen in mitochondria isolated from both regions after 10 min of recirculation. By 1 h of recirculation, mitochondrial calcium had returned close to preischemic control values in both regions. Longer recirculation periods produced no further changes in the calcium content of mitochondria from the paramedian cortex. However, mitochondrial calcium was again increased in the dorsolateral striatum after 6 h (6.5 nmol of calcium/mg of protein) and 24 h (8.7 nmol of calcium/mg of protein) of recirculation. This regionally selective increase in calcium in the dorsolateral striatum preceded the period during which the majority of neurons in this region exhibit advanced degenerative changes. Thus, this increase may be an essential step, albeit a late one, in the development of neuronal loss.


Role of neurohumoral systems for pressure induced left ventricular hypertrophy in experimental supravalvular aortic stenosis in rats.
We studied the role of the sympathetic nervous system and the renin angiotensin system for pressure induced left ventricular hypertrophy (LVH) in 135 rats with experimental supravalvular aortic stenosis (AS). We induced this condition by a silver clip on the ascending aorta, when body weight (BW) was 90 to 100 g. Sympathectomy by 6-OH-dopamine reduced LV norepinephrine content to less than 5%. The renin-angiotensin system was blocked by quinapril, which reduced serum angiotensin converting enzyme (ACE) activity to less than 5%. Aortic stenosis (LV peak systolic pressure 212 +/- 10 mm Hg) induced significant LVH with an increase of LV weight from 198 +/- 3 (sham) to 266 +/- 6 after 6 weeks and to 303 +/- 13 mg/100 g body weight after 12 weeks. Sympathectomy did not reduce LVH 6 weeks after induction of AS (260 +/- 6 mg/100 g body weight). Angiotensin converting enzyme inhibition initiated immediately after induction of AS did not alter the increase of LV mass after 6 weeks (250 +/- 7 mg/100 g body weight). Removing the silver clip 6 weeks after induction of AS resulted in a 90% regression of LVH after 6 more weeks. When ACE-inhibition was started after 6 weeks--ie, once LVH had developed--and maintained for another 6 weeks, an 80% regression of LVH was observed despite the persistent afterload elevation. Our findings of an afterload independent regression of LVH by ACE-inhibition emphasize an important role of the renin angiotensin system for the maintenance of pressure induced LVH.


Multiple Ablation Targets in Children: Multiple Accessory Pathways and Coexistent Arrhythmia.
The coexistence of different mechanisms of arrhythmia and multiple accessory pathways (MAPs) leading to multiple ablation targets is rarely seen in children, and data regarding these patients in the literature are limited. Herein, we aimed to evaluate patients who required multiple ablation applications, focusing on different targets during the procedures in children, and evaluating the characteristics of coexistent arrhythmia and MAPs, and the results of these procedures in children. Ablation procedures conducted between March 2009 and December 2018 were evaluated retrospectively, and patients with MAPs and/or coexistent arrhythmia who had undergone ablation procedures were included in the study. Among the 1210 patients who underwent ablation procedures, 52 patients (26 male, 26 female) were ablated for multiple targets. Of the 456 patients with APs, 21 had MAPs (4.6%) and of the 1210 patients who underwent ablation procedures, 31 patients had coexistent arrhythmia (2.5%). The patients had a mean age of 12.24 ± 3.4 (4-18) years and mean body weight of 45.17 ± 14.12 (17-74) kg. A total of 110 APs or foci were identified as quaternary in one patient, while it was triple in four patients. The procedures were unsuccessful in six targets of six patients. Although recurrence was observed in four patients, none were ablated for MAPs. Two complications were encountered, comprising ST segment depression that developed in one patient with Wolf-Parkinson-White syndrome, atrioventricular nodal re-entry tachycardia, and a temporary atrioventricular block during atrioventricular nodal re-entrant tachycardia ablation. The overall success rate according to the pathway/foci number was 94.5% (104/110), with a recurrence rate of 4.5% (5/110), and a complication rate of 1.8% (2/110). The patient success, recurrence, and complication rates were 88.4% (46/52), 7.6% (4/52), and 3.8% (2/52), respectively. In conclusion, the incidence of multiple arrhythmogenic foci and MAPs were not as low as expected in children. A structured and stepwise approach is mandatory for the diagnosis of the different mechanisms of tachycardia, even after successful ablation procedures. The success, recurrence, and complication rates were comparable with those of patients who had a solitary arrhythmogenic focus or solitary AP.


The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription.
The type I interferon (IFN) response is imperative for the establishment of the early antiviral immune response. Here we report the identification of the first type I IFN antagonist encoded by murine cytomegalovirus (MCMV) that shuts down signaling following pattern recognition receptor (PRR) sensing. Screening of an MCMV open reading frame (ORF) library identified M35 as a novel and strong negative modulator of IFNβ promoter induction following activation of both RNA and DNA cytoplasmic PRR. Additionally, M35 inhibits the proinflammatory cytokine response downstream of Toll-like receptors (TLR). Using a series of luciferase-based reporters with specific transcription factor binding sites, we determined that M35 targets NF-κB-, but not IRF-mediated, transcription. Expression of M35 upon retroviral transduction of immortalized bone marrow-derived macrophages (iBMDM) led to reduced IFNβ transcription and secretion upon activation of stimulator of IFN genes (STING)-dependent signaling. On the other hand, M35 does not antagonize interferon-stimulated gene (ISG) 56 promoter induction or ISG transcription upon exogenous stimulation of the type I IFN receptor (IFNAR). M35 is present in the viral particle and, upon MCMV infection of fibroblasts, is immediately shuttled to the nucleus where it exerts its immunomodulatory effects. Deletion of M35 from the MCMV genome and hence from the viral particle resulted in elevated type I IFN transcription and secretion in vitro and in vivo. In the absence of M35, lower viral titers are observed during acute infection of the host, and productive infection in the salivary glands was not detected. In conclusion, the M35 protein is released by MCMV immediately upon infection in order to deftly inhibit the antiviral type I IFN response by targeting NF-κB-mediated transcription. The identification of this novel viral protein reinforces the importance of timely countermeasures in the complex relationship between virus and host.


A mouse model with tamoxifen-inducible thyrocyte-specific cre recombinase activity.
We have created a mouse model expressing tamoxifen-inducible Cre recombinase (CreER(T2) ) under the control of the thyroglobulin (Tg) gene promoter to be able to study the role of defined genetic modifications in the regulation of thyroid function. We chose the thyroglobulin promoter, as it is expressed specifically in the thyroid. In order to obtain reliable expression under the control of the Tg promoter, we used a P1 artificial chromosome (PAC) containing a large piece of the Tg promoter. A tamoxifen inducible CreER(T2) construct was selected to avoid the possible consequences of the gene deletion for the development of the thyroid gland, and to study the role of gene deletion in the adult thyroid. Transgenic lines (TgCreER(T2) ) carrying this construct were generated and analyzed by crossing the TgCreER(T2) mice with the ROSA26LacZ reporter strain. The activity and specificity of the Cre recombinase was tested by staining for β-galactosidase activity and by immunohistochemistry using an anti-Cre-antibody. In the TgCreER(T2) xROSA26LacZ reporter line, Cre-mediated recombination occurred specifically in the thyrocytes only after tamoxifen administration, and no significant staining was observed in controls. The recombination efficiency was nearly complete, since almost all thyrocytes showed X-gal staining. We could also induce the recombination in utero by giving tamoxifen to the pregnant female. In addition, mice expressing TgCreER(T2) had no obvious histological changes, hormonal alterations, or different response to growth stimuli as compared to controls. These results demonstrate that the TgCreER(T2) mouse line is a powerful tool to study temporally controlled deletion of floxed genes in the thyroid.


CT-guided fine-needle aspiration of lung nodules: effect on outcome of using coaxial technique and immediate cytological evaluation.
To evaluate the risk of pneumothorax during CT-guided fine-needle aspiration (FNA) of lung nodules with single needle and coaxial needle techniques and to assess the effect on diagnostic accuracy of immediate cytological examination of lung FNA samples. This prospective study analysed 53 patients undergoing transthoracic FNA biopsy of lung. 36 cases were performed by a radiologist using a coaxial technique, with 17 cases performed by a radiologist using a direct single-needle method. Effect of technique on occurrence of pneumothorax was recorded. FNA samples from all the patients in the study were examined immediately on-site by a cytologist or MLSO to determine whether sufficient aspirate had been obtained. Provisional diagnosis at immediate examination was compared to final diagnosis following full pathological evaluation. Coaxial and non-coaxial groups were comparable for age and gender. Number of pleural passes was significantly lower in coaxial group (P < 0.01). Pneumothorax occurred in six (17%) of the 36 patients biopsied by coaxial technique, compared to four (24%) of the 17 patients by non-coaxial method (P = 0.55). Chest tube placement was required in four patients (11%) in the coaxial group, and two patients (12%) in the non-coaxial group (P = 0.85). A provisional cytological diagnosis was recorded for 74% of the patients in the study. 83% of the provisional reports were accurate on comparison with full pathology report. Specimen size was sufficient in 81% of cases. The use of coaxial technique for CT-guided lung FNA biopsy reduced the number of pleural passes but did not significantly reduce the occurrence of pneumothorax. Immediate cytological examination of FNA specimens provided an accurate provisional diagnosis in the majority of cases, and should be routinely employed.


[Insulin sensitivity in patients with adrenal incidentaloma].
Frequent use of modern imaging methods (such as ultrasound, CT and MRI) results in high incidence of accidentally discovered adrenal mass. Adrenal incidentalomas are accidentally discovered adrenal tumors by imaging methods without any prior suspicion of adrenal disease. Some studies have shown decreased insulin sensitivity in patients with adrenal incidentaloma. The objective of our study was to assess the insulin sensitivity in patients with adrenal incidentalom a. A total of 22 patients with accidentally discovered adrenal mass confirmed by CT/MRI were evaluated in our study. Average age was 53.31 +/- 26.5 years and average BMI 25.84 +/- 3.65 kg/m2. Control group consisted of 33 healthy subjects. Insulin sensitivity was assessed by short ITT (insulin tolerance test). Blood samples were taken before, 3, 6, 9, 12, 15, 20 and 30 minutes after i.v. bolus of regular insulin (0.05 IU/kg BW). Glycemia was determined by glucose oxidase method. Statistical analysis was done by ANCOVA, using BMI as covariate. Our results showed significantly lower insulin sensitivity in patients with adrenal incidentalomas comparing to the control group (4.95 +/- 0.58 vs. 6.62 +/- 0.47, p=0.015). Our patients with adrenal incidentalomas manifested lower insulin sensitivity what suggested further follow up and assessment of insulin sensitivity during endocrine evaluation of these patients.


Data-Driven Insights through Industrial Retrofitting: An Anonymized Dataset with Machine Learning Use Cases.
Small and medium-sized enterprises (SMEs) often encounter practical challenges and limitations when extracting valuable insights from the data of retrofitted or brownfield equipment. The existing literature fails to reflect the full reality and potential of data-driven analysis in current SME environments. In this paper, we provide an anonymized dataset obtained from two medium-sized companies leveraging a non-invasive and scalable data-collection procedure. The dataset comprises mainly power consumption machine data collected over a period of 7 months and 1 year from two medium-sized companies. Using this dataset, we demonstrate how machine learning (ML) techniques can enable SMEs to extract useful information even in the short term, even from a small variety of data types. We develop several ML models to address various tasks, such as power consumption forecasting, item classification, next machine state prediction, and item production count forecasting. By providing this anonymized dataset and showcasing its application through various ML use cases, our paper aims to provide practical insights for SMEs seeking to leverage ML techniques with their limited data resources. The findings contribute to a better understanding of how ML can be effectively utilized in extracting actionable insights from limited datasets, offering valuable implications for SMEs in practical settings.


Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome.
A 2-year-old boy had acute fever, malaise, and somnolence with hepatomegaly, increased blood ammonia content (338 microM), high SGOT, low blood glucose content, and mild acidosis. A liver biopsy showed diffuse accumulation of lipid droplets in swollen hepatocytes, and abnormal urinary metabolites included beta-hydroxy-beta-methyl glutarate (HMG), beta-methylglutaconate, beta-hydroxyisovalerate, and beta-methylglutaric and glutaric acids. In cultured skin fibroblasts and liver, beta-hydroxy-beta-methyl glutaryl CoA lyase activity was about 10% of normal. Therefore, a genetic deficiency of HMGCoA lyase activity can cause a clinical syndrome similar to that of Reye syndrome when the patient is stressed by an acute viral infection.


P2Y2 receptor activation regulates the expression of acetylcholinesterase and acetylcholine receptor genes at vertebrate neuromuscular junctions.
At the vertebrate neuromuscular junction (nmj), ATP is known to be coreleased with acetylcholine from the synaptic vesicles. We have previously shown that the P2Y1 receptor is localized at the nmj. Here, we extend the findings to show that another nucleotide receptor, P2Y2, is also localized there and with P2Y1 jointly mediates trophic responses to ATP. The P2Y2 receptor mRNA in rat muscle increased during development and peaked in adulthood. The P2Y2 receptor protein was shown to become restricted to the nmjs during embryonic development, in chick and in rat. In both rat and chick myotubes, P2Y1 and P2Y2 are expressed, increasing with differentiation, but P2Y4 is absent. The P2Y2 agonist UTP stimulated there inositol trisphosphate production and phosphorylation of extracellular signal-regulated kinases, in a dose-dependent manner. These UTP-induced responses were insensitive to the P2Y1-specific antagonist MRS 2179 (2'-deoxy-N6-methyl adenosine 3',5'-diphosphate diammonium salt). In differentiated myotubes, P2Y2 activation induced expression of acetylcholinesterase (AChE) protein (but not control alpha-tubulin). This was shown to arise from AChE promoter activation, mediated by activation of the transcription factor Elk-1. Two Elk-1-responsive elements, located in intron-1 of the AChE promoter, were found by mutation to act in this gene activation initiated at the P2Y2 receptor and also in that initiated at the P2Y1 receptor. Furthermore, the promoters of different acetylcholine receptor subunits were also stimulated by application of UTP to myotubes. These results indicate that ATP regulates postsynaptic gene expressions via a common pathway triggered by the activation of P2Y1 and P2Y2 receptors at the nmjs.


Polyunsaturated fatty acid deficiencies: effects on hepatic plasma membrane fatty acid composition and enzyme activity.
Research on dietary polyunsaturated fatty acids (PUFA), on the activity of 5'nucleotidase and adenylate cyclase are largely contradictory due, mostly, to the absence of adequate control group. In this study; four different diets have been evaluated on the 5'nucleotidase and adenylate cyclase activities in rat liver plasma membranes. Wistar rats were given a semisynthetic diet in which lipids were supplied by 5% of either peanut oil (n-3 PUFA deficient diet), cod liver oil (n-6 PUFA deficient diet) partially hydrogenated palm oil (total PUFA deficient diet) and a mixture of peanut and rapeseed oil (control group). Liver plasma membranes were separated by using a Percoll gradient in a Beckman JA 20 centrifuge. 5'nucleotidase and adenylate cyclase activities were measured in a liquid scintilation detector by following the degradation of 3HAMP (adenosine monophosphate) and production of 3HcAMP (cyclic adenosine monophosphate) respectively. Animals fed the total PUFA deficient diet exhibited significant lower body weight and lower liver weight than did the control group. Low cholesterol concentrations were observed in animals deficient either in n-3 or total PUFA in relation to the control group. All dietary deficiencies studies provoked reduced phospholipid levels. Phosphatidylcholine and phosphatidylethanolamine were not modified whatever the deficiency studied. Phospholipids fatty acid composition was significantly modified by the diets studied. The specific activity of 5'nucleotidase in hepatic plasma membrane was independent of dietary PUFA. The catalytic unit of adenylate cyclase complex in totally deficient animals was augmented. The unit of the enzyme stimulated by the guanydyl imidodiphosphate (GppNHp) in n-3 PUFA deficient animals was augmented and reduced in animals receiving the n-6 PUFA deficient diet. In conclusion, our results show that each dietary PUFA deficiency modifies differently the proportions of phospholipid classes and their fatty acid composition. The mechanisms responsible for these modification remain to be elucidated. However, the phospholipid fatty acid changes did not influence the 5'nucleotidase activity except in the case of extreme excess which concerns more toxicology than nutritional modifications. Finally, the catalytic unit (Forskoline + GDP beta s) of adenylate cyclase complex and the regulatory unit (GppNHp) may be sensitive to alterations in PUFA composition.


Naloxone for opioid-exposed newborn infants.
Naloxone, a specific opioid antagonist, is available for the treatment of newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opioid. It is unclear whether newborn infants may benefit from this therapy and whether naloxone has any harmful effects. To determine the effect of naloxone on the need for and duration of neonatal unit stay in infants of mothers who received opioid analgesia prior to delivery or of mothers who have used a prescribed or non-prescribed opioid during pregnancy. We searched the following databases in February 2018: the Cochrane Central Register of Controlled Trials (the Cochrane Library 2018, Issue 1), MEDLINE (OvidSP), MEDLINE In process & Other Non-Indexed Citations (OvidSP), Embase (OvidSP), CINAHL (EBSCO), Maternity and Infant Care (OvidSP), and PubMed. We searched for ongoing and completed trials in the WHO International Clinical Trials Registry Platform and the EU Clinical Trials Register. We checked the reference lists of relevant articles to identify further potentially relevant studies. Randomised controlled trials comparing the administration of naloxone versus placebo, or no drug, or another dose of naloxone to newborn infants with suspected or confirmed in utero exposure to opioid. We extracted data using the standard methods of Cochrane Neonatal with separate evaluation of trial quality and data extraction by two review authors and synthesis of data using risk ratio, risk difference, and mean difference. We included nine trials, with 316 participants in total, that compared the effects of naloxone versus placebo or no drug in newborn infants exposed to maternal opioid analgesia prior to delivery. None of the included trials investigated infants born to mothers who had used a prescribed or non-prescribed opioid during pregnancy. None of these trials specifically recruited infants with cardiorespiratory or neurological depression. The main outcomes reported were measures of respiratory function in the first six hours after birth. There is some evidence that naloxone increases alveolar ventilation. The trials did not assess the effect on the primary outcomes of this review (admission to a neonatal unit and failure to establish breastfeeding). The existing evidence from randomised controlled trials is insufficient to determine whether naloxone confers any important benefits to newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opioid. Given concerns about the safety of naloxone in this context, it may be appropriate to limit its use to randomised controlled trials that aim to resolve these uncertainties.


Deciphering Treg cell roles in esophageal squamous cell carcinoma: a comprehensive prognostic and immunotherapeutic analysis.
Background: Esophageal squamous cell carcinoma (ESCC) is a prevalent and aggressive form of cancer that poses significant challenges in terms of prognosis and treatment. Regulatory T cells (Treg cells) have gained attention due to their influential role in immune modulation within the tumor microenvironment (TME). Understanding the intricate interactions between Treg cells and the tumor microenvironment is essential for unraveling the mechanisms underlying ESCC progression and for developing effective prognostic models and immunotherapeutic strategies. Methods: A combination of single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq analysis was utilized to explore the role of Treg cells within the TME of ESCC. The accuracy and applicability of the prognostic model were assessed through multi-dimensional evaluations, encompassing an examination of the model's performance across various dimensions, such as the mutation landscape, clinical relevance, enrichment analysis, and potential implications for immunotherapy strategies. Results: The pivotal role of the macrophage migration inhibitory factor (MIF) signaling pathway within the ESCC TME was investigated, with a focus on its impact on Treg cells and other subpopulations. Through comprehensive integration of bulk sequencing data, a Treg-associated signature (TAS) was constructed, revealing that ESCC patients with elevated TAS (referred to as high-TAS individuals) experienced significantly improved prognoses. Heightened immune infiltration and increased expression of immune checkpoint markers were observed in high-TAS specimens. The model's validity was established through the IMvigor210 dataset, demonstrating its robustness in predicting prognosis and responsiveness to immunotherapy. Heightened therapeutic benefits were observed in immune-based interventions for high-TAS ESCC patients. Noteworthy differences in pathway enrichment patterns emerged between high and low-TAS cohorts, highlighting potential avenues for therapeutic exploration. Furthermore, the clinical relevance of key model genes was substantiated by analyzing clinical samples from ten paired tumor and adjacent tissues, revealing differential expression levels. Conclusion: The study established a TAS that enables accurate prediction of patient prognosis and responsiveness to immunotherapy. This achievement holds significant implications for the clinical management of ESCC, offering valuable insights for informed therapeutic interventions.


Highly size-controlled synthesis of metal nanoclusters by inert-gas condensation for nano-devices.
Metal nanoclusters were fabricated by inert-gas condensation in a sputtering reactor. From transmission electron microscopy, it was confirmed that copper nanoclusters with a high degree of monodispersity in size of about 5 nm were successfully produced. The conductance of the percolated nanocluster film was measured. In order to incorporate nano-scale arrangement characterizations in nano-devices being operated in air, aging experiments of the specimen after long time in air were carried. Negative temperature coefficient of resistance suggests that surface native copper oxide in core-shell structured nanoclusters was mainly responsible for the conductance, because copper oxide is known as semiconductor. After aged at higher than 100 degrees C, the conductance at room temperature didn't return to the original value. This irreversible phenomenon might be due to coarsening and/or coalescence of copper nanoclusters.


Building an adaptive brain across development: targets for neurorehabilitation must begin in infancy.
Much progress has been made toward behavioral and pharmacological intervention in intellectual disability, which was once thought too difficult to treat. Down syndrome (DS) research has shown rapid advances, and clinical trials are currently underway, with more on the horizon. Here, we review the literature on the emergent profile of cognitive development in DS, emphasizing that treatment approaches must consider how some "end state" impairments, such as language deficits, may develop from early alterations in neural systems beginning in infancy. Specifically, we highlight evidence suggesting that there are pre- and early postnatal alterations in brain structure and function in DS, resulting in disturbed network function across development. We stress that these early alterations are likely amplified by Alzheimer's disease (AD) progression and poor sleep. Focusing on three network hubs (prefrontal cortex, hippocampus, and cerebellum), we discuss how these regions may relate to evolving deficits in cognitive function in individuals with DS, and to their language profile in particular.


Efficacy of verteporfin photodynamic therapy on laser-induced choroidal neovascularization and the ancillary effect on diabetic microvasculopathy.
To demonstrate the efficacy of photodynamic therapy (PDT) in treating choroidal neovascularization (CNV) induced by laser photocoagulation for diabetic macular edema and its ancillary effect on surrounding diabetic microvascular abnormalities. A retrospective interventional case series study in a clinical practice setting of four patients with proliferative diabetic retinopathy and clinically significant macular edema who had developed classic CNV in proximity to the area of previous laser photocoagulation. The lesions were treated with verteporfin PDT and followed with serial fluorescein angiography. Compared to the pre-treatment angiogram, an acute reduction in leakage from CNV was noted as soon as 5 days post-PDT and persisted in some areas up to three months post-treatment within the zone of the typical dark choroid pattern. No evidence of any closure of microaneurysms was noted. Serial fluorescein angiograms demonstrate that PDT appears to have a beneficial effect on CNV induced by laser photocoagulation for diabetic macular edema without any tangible beneficial effect on diabetic microvasculopathy. PDT had no effect on existing microaneurysms.


General medical practitioners need to be aware of the theories on which our work depend.
When general practitioners and family physicians listen, reflect, and diagnose, we use 3 different theories of knowledge. This essay explores these theories to highlight an approach to clinical practice, inquiry, and learning that can do justice to the complex and uncertain world we experience. The following points are made: (1) A variety of approaches to research and audit are needed to illuminate the richness of experience witnessed by general medical practitioners. (2) Evidence about the past cannot predict the future except in simple, short-term, or slowly changing situations. (3) We consciously or unconsciously weave together evidence generated through 3 fundamental theories of knowledge, termed postpositivism, critical theory, and constructivism, to make sense of everyday experience. We call it listening, reflecting, and diagnosing. (4) These 3 fundamental theories of knowledge highlight different aspects within a world that is more complex, integrated, and changing than any single theory can reveal on its own; they frame what we see and how we act in everyday situations. (5) Moving appropriately between these different theories helps us to see a fuller picture and provides a framework for improving our skills as clinicians, researchers, and learners. (6) Narrative unity offers a way to bring together different kinds of evidence to understand the overall health of patients and of communities; evidence of all kinds provides discrete snapshots of more complex stories in evolution. (7) We need to understand these issues so we can create an agenda for clinical practice, inquiry, and learning appropriate to our discipline.


Cannabidiol enhanced the development of sensitization to the expression of methamphetamine-induced conditioned place preference in male rats.
Cannabis and ecstasy are illicit substances, and currently, there are no approved treatments for methamphetamine (METH) use disorder. Some studies have proposed that cannabidiol (CBD) decreases the motivation for METH seeking, but reports indicate that the therapeutic benefits are only for heroin. Here, we studied the interaction between CBD and METH during the sensitization phase on the rewarding effect of METH, using the conditioned place preference (CPP) paradigm to measure possible alterations in sensitivity. Our data showed that i. p. injection of METH created METH-induced CPP at two of the highest applied doses (1 and 2 mg/kg), and injection of METH during the sensitization period caused an establishment of METH-induced CPP at lower doses (0.25 and 0.5 mg/kg). Data also revealed that i. c.v. administration of CBD during the sensitization phase, shifted the establishment of METH-induced CPP toward a lower dose (0.5 mg/kg). Concurrent administration of CBD (10 μg/5 μl, i. c.v.) and METH (0.25 mg/kg, i. p.) during sensitization phase established METH-induced CPP with sub-threshold doses of METH (0.125, 0.25, and 0.5 mg/kg). Our results suggest the involvement of CBD and prior exposure to METH in creating sensitization to METH CPP.


Localizing value of optokinetic afternystagmus.
Previous reports have indicated that optokinetic afternystagmus (OKAN) becomes asymmetric after the occurrence of unilateral peripheral vestibular lesions, and suggested that OKAN may be used for localizing the side of the lesion. These studies did not take into account spontaneous nystagmus. We compared OKAN in 12 subjects with unilateral vestibular loss after resection of acoustic neuroma to OKAN in 30 normal subjects. After offsetting the data for spontaneous nystagmus, we calculated the initial amplitude, the time constant, and the slow-phase cumulative eye position (SCEP) parameters of OKAN. The directional asymmetry of parameters to rightward and leftward stimulation were also calculated. The mean SCEP, initial amplitude, and time constant parameters were reduced significantly in the patients, and each also showed a directional asymmetry, such that they were greater for stimulation toward the side of the lesion. The directional preponderance of the SCEP parameter had the highest sensitivity for the side of the lesion, being abnormally elevated in 58.3% of patients with unilateral loss. We conclude that OKAN might be useful in combination with other subtests of a battery, but that by itself OKAN is only moderately sensitive to unilateral peripheral vestibular loss.


Subgrouping of Japanese middle-aged women attending a menopause clinic using physical and psychological symptom profiles: a cross-sectional study.
Women in the menopausal transition and the postmenopausal period are affected with vasomotor symptoms, urogenital atrophy, sexual dysfunction, somatic symptoms, cognitive difficulty, sleep disturbance, and psychological problems. It is important to gain a better understanding of the complexity and diversity of climacteric disturbance in order to optimize treatments for individual patients. The aim of this study was to identify subgroups of Japanese perimenopausal and postmenopausal women attending a menopause clinic based on their physical and psychological symptom profiles. We administered the Menopausal Health-Related Quality of Life questionnaire to 491 Japanese women aged 40-64 years who had enrolled in the Systematic Health and Nutrition Education Program at the Menopause Clinic of the Tokyo Medical and Dental University Hospital between 2005 and 2012. We performed a principal component analysis followed by a hierarchical cluster analysis of the responses to 9 physical and 12 psychological items on the questionnaire. The first analysis extracted 3 principal components that defined the variance of physical and psychological symptom profiles: depression, somatic, and vasomotor/sleep. A subsequent cluster analysis was performed based on the 3 principal components to generate 4 clusters, CL8 (N = 162; 33.0%), CL6 (N = 111; 22.6%), CL5 (N = 102; 20.8%), and CL4 (N = 116; 23.6%). CL8 included women who only had mild-to-moderate musculoskeletal pains and tiredness. All women in CL6, CL5, and CL4 described their musculoskeletal pains and tiredness as moderate to severe. The women in CL5 also had moderate-to-severe vasomotor symptoms, while the women in CL4 also suffered from moderate-to-severe psychological symptoms, such as depression, anxiety, and insomnia. Distinct subgroups of Japanese perimenopausal and postmenopausal women were identified based on their symptom profiles. Menopausal symptoms were shown to accumulate in this population in the order of musculoskeletal pains and tiredness, vasomotor symptoms, and psychological symptoms.


School and community reopening during the COVID-19 pandemic: a mathematical modelling study.
Operating schools safely during the COVID-19 pandemic requires a balance between health risks and the need for in-person learning. Using demographic and epidemiological data between 31 July and 23 November 2020 from Toronto, Canada, we developed a compartmental transmission model with age, household and setting structure to study the impact of schools reopening in September 2020. The model simulates transmission in the home, community and schools, accounting for differences in infectiousness between adults and children, and accounting for work-from-home and virtual learning. While we found a slight increase in infections among adults (2.2%) and children (4.5%) within the first eight weeks of school reopening, transmission in schools was not the key driver of the virus resurgence in autumn 2020. Rather, it was community spread that determined the outbreak trajectory, primarily due to increases in contact rates among adults in the community after school reopening. Analyses of cross-infection among households, communities and schools revealed that home transmission is crucial for epidemic progression and safely operating schools, while the degree of in-person attendance has a larger impact than other control measures in schools. This study suggests that safe school reopening requires the strict maintenance of public health measures in the community.


Molecular Dynamics and Machine Learning Give Insights on the Flexibility-Activity Relationships in Tyrosine Kinome.
Tyrosine kinases are a subfamily of kinases with critical roles in cellular machinery. Dysregulation of their active or inactive forms is associated with diseases like cancer. This study aimed to holistically understand their flexibility-activity relationships, focusing on pockets and fluctuations. We studied 43 different tyrosine kinases by collecting 120 μs of molecular dynamics simulations, pocket and residue fluctuation analysis, and a complementary machine learning approach. We found that the inactive forms often have increased flexibility, particularly at the DFG motif level. Noteworthy, thanks to these long simulations combined with a decision tree, we identified a semiquantitative fluctuation threshold of the DGF+3 residue over which the kinase has a higher probability to be in the inactive form.


The epidemiological situation of brucellosis in Africa.
Brucellosis, as a geomedical literature survey has shown, is spread to a higher of lesser degree of incidence virtually over the whole African continent. Its epidemiological spectrum of host animals is especially rich amongst the domestic and wild animal species. All domestic animal species and 21 of 26 herbivorous and 5 of 12 carnivorous wild animal species screened yielded positive brucella antibody serotitres. Thus self-maintaining natural foci independent of the domestic stock have firmly been established. The mapping of the epidemiological situation must be based on survey data which should have been planned, exactly performed, analyzed and reported according to statistical rules. Unfortunately Africa is especially badly covered in the world literature in the field of brucellosis. Representing itself 32.0% (49/153) of the countries of the world, their Medical and Veterinary Departments contributed only 2.1% of the computerized world literature on brucellosis in the period 1969-74. This picture can be considerably changed by including the non-computerized "grey literature" of Department and Laboratory Annual Reports into the screening process. By introducing objective, mathematical criteria for determining the degree of incidence from the available data, the following results were obtained from the literature survey: brucellosis is known or suspected to exist in 40 of the 49 African countries (82%). In 20 (41%) of these countries it represents a major problem, in 10 (20.4%) a moderate problem in the other 10 countries a minor problem to human health and economy. Following the rule that brucellosis can be expected to exist everywhere in the world (with the exception of a few islands) where cattle, sheep and/or goats are kept unless it has been eliminated by vigourous measures of control, it may be expected that the remaining 9 African countries not yet reporting also harbour this chronic, zoonotic disease. 35 of the 40 countries reporting have found brucellosis regularly, 1 exceptionally among domestic animals, 5 among game animals. Only 17 of these 35 (48.5%) have scheduled the disease, even if its incidence has been reported to be high. Only 32 of the 49 countries report on human brucellosis. The main reservoirs of disease and risks of infection vary from place to place with the different main kinds of domestic stock, the animal husbandry and human consumption methods and habits. Thus mainly the cattle herds are the source of infection for those countries where large numbers of cattle are kept and the drinking of raw milk is the custom; however, there is no strict correlation between these two factors. Goats and sheep fill the epidemiological place in all those countries where the lack of marketable milk curtails its consumption; the small ruminants are kept as the main source of meat supply and in close contact with the farmers family within the compound or house.


Non-peptidic inhibitors of human leukocyte elastase. 1. The design and synthesis of pyridone-containing inhibitors.
Human leukocyte elastase (HLE) is a serine protease produced by neutrophils that has been implicated in diseases such as emphysema and cystic fibrosis. An HLE inhibitor may have therapeutic value in these diseases. An active site model of HLE bound to a tripeptidic trifluoromethyl ketone (TFMK) inhibitor, 2, was created from X-ray structures of HLE and porcine pancreatic elastase. Analysis of the model indicated a preferred binding conformation for the tripeptide and potentially important interactions between it and the enzyme. This information was used to aid in the design of a series of novel, pyridone-containing, non-peptidic HLE inhibitors such as 2-[3-[[(benzyloxy)carbonyl]amino]-2-oxo- 1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)ace tam ide (5b) (Ki = 280 +/- 78 nM). Inspection of the active site model suggested that a benzyl substituent at the 5-position of the pyridone ring might improve potency by forming a lipophilic interaction with the enzyme S2 pocket. Synthesis and biological evaluation of a series of 5-benzylpyridone TFMKs provided evidence for this proposition. Further analysis of the model indicated that substitution on the 3-amino group of the pyridone ring with a hydrogen bond acceptor could potentially lead to interactions with the NH atoms of glycine-218 and/or -219. The oxalate derivative 2-[5-benzyl- 3-(carboxycarbonyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifl uor o-1- isopropyl-2-oxopropyl)acetamide (5v) was synthesized and found to have a Ki of 48 +/- 9 nM. Unfortunately, none of the compounds tested was active in an in vivo model of HLE-induced lung injury when dosed orally.


Aspermia and recovery of spermatogenesis in cancer patients following incidental gonadal irradiation during treatment: a progress report.
The 11 patients in this study who received incidental gonadal irradiation from clinical therapy all became aspermic within 8-34 weeks following treatment. The estimated gonadal dose was 118-228 rads. Five of these patients have shown recovery of spermatogenesis; 3 of these have reached fertilizable concentrations. Recovery of semen sperm was noted at 44-77 weeks following treatment. The other 2 patients, after 110-176 weeks, have sub-fertile concentrations of semen sperm. Five patients have not been followed for a sufficient length of time to permit recovery to be noted.


Anti-C5 Antibody Tesidolumab Reduces Early Antibody-mediated Rejection and Prolongs Survival in Renal Xenotransplantation.
Pig-to-primate renal xenotransplantation is plagued by early antibody-mediated graft loss which precludes clinical application of renal xenotransplantation. We evaluated whether temporary complement inhibition with anti-C5 antibody Tesidolumab could minimize the impact of early antibody-mediated rejection in rhesus monkeys receiving pig kidneys receiving costimulatory blockade-based immunosuppression. Double (Gal and Sda) and triple xenoantigen (Gal, Sda, and SLA I) pigs were created using CRISPR/Cas. Kidneys from DKO and TKO pigs were transplanted into rhesus monkeys that had the least reactive crossmatches. Recipients received anti-C5 antibody weekly for 70 days, and T cell depletion, anti-CD154, mycophenolic acid, and steroids as baseline immunosuppression (n = 7). Control recipients did not receive anti-C5 therapy (n = 10). Temporary anti-C5 therapy reduced early graft loss secondary to antibody-mediated rejection and improved graft survival (P < 0.01). Deleting class I MHC (SLA I) in donor pigs did not ameliorate early antibody-mediated rejection (table). Anti-C5 therapy did not allow for the use of tacrolimus instead of anti-CD154 (table), prolonging survival to a maximum of 62 days. Inhibition of the C5 complement subunit prolongs renal xenotransplant survival in a pig to non-human primate model.


VirFinder: a novel k-mer based tool for identifying viral sequences from assembled metagenomic data.
Identifying viral sequences in mixed metagenomes containing both viral and host contigs is a critical first step in analyzing the viral component of samples. Current tools for distinguishing prokaryotic virus and host contigs primarily use gene-based similarity approaches. Such approaches can significantly limit results especially for short contigs that have few predicted proteins or lack proteins with similarity to previously known viruses. We have developed VirFinder, the first k-mer frequency based, machine learning method for virus contig identification that entirely avoids gene-based similarity searches. VirFinder instead identifies viral sequences based on our empirical observation that viruses and hosts have discernibly different k-mer signatures. VirFinder's performance in correctly identifying viral sequences was tested by training its machine learning model on sequences from host and viral genomes sequenced before 1 January 2014 and evaluating on sequences obtained after 1 January 2014. VirFinder had significantly better rates of identifying true viral contigs (true positive rates (TPRs)) than VirSorter, the current state-of-the-art gene-based virus classification tool, when evaluated with either contigs subsampled from complete genomes or assembled from a simulated human gut metagenome. For example, for contigs subsampled from complete genomes, VirFinder had 78-, 2.4-, and 1.8-fold higher TPRs than VirSorter for 1, 3, and 5 kb contigs, respectively, at the same false positive rates as VirSorter (0, 0.003, and 0.006, respectively), thus VirFinder works considerably better for small contigs than VirSorter. VirFinder furthermore identified several recently sequenced virus genomes (after 1 January 2014) that VirSorter did not and that have no nucleotide similarity to previously sequenced viruses, demonstrating VirFinder's potential advantage in identifying novel viral sequences. Application of VirFinder to a set of human gut metagenomes from healthy and liver cirrhosis patients reveals higher viral diversity in healthy individuals than cirrhosis patients. We also identified contig bins containing crAssphage-like contigs with higher abundance in healthy patients and a putative Veillonella genus prophage associated with cirrhosis patients. This innovative k-mer based tool complements gene-based approaches and will significantly improve prokaryotic viral sequence identification, especially for metagenomic-based studies of viral ecology.


Gcn5- and Elp3-induced histone H3 acetylation regulates hsp70 gene transcription in yeast.
The purpose of this study was to elucidate the mechanisms by which histone acetylation participates in transcriptional regulation of hsp70 (heat-shock protein 70) genes SSA3 and SSA4 in yeast. Our results indicated that histone acetylation was required for the transcriptional activation of SSA3 and SSA4. The HATs (histone acetyltransferases) Gcn5 (general control non-derepressible 5) and Elp3 (elongation protein 3) modulated hsp70 gene transcription by affecting the acetylation status of histone H3. Although the two HATs possessed overlapping function regarding the acetylation of histone H3, they affected hsp70 gene transcription in different ways. The recruitment of Gcn5 was Swi/Snf-dependent and was required for HSF (heat-shock factor) binding and affected RNAPII (RNA polymerase II) recruitment, whereas Elp3 exerted its roles mainly through affecting RNAPII elongation. These results provide insights into the effects of Gcn5 and Elp3 in hsp70 gene transcription and underscore the importance of histone acetylation for transcriptional initiation and elongation in hsp genes.


MR imaging of histiocytosis X in the central nervous system.
The magnetic resonance imaging features of two cases of histiocytosis X in the hypothalamus and one in the cerebral hemispheres are described. The lesions were best seen with spin-echo technique using a long repetition time (TR = 1580 msec) and long echo time (TE = 80 msec). Sagittal images provided the best anatomicotopographic evaluation of the lesions. Comparison with computed tomography with and without contrast enhancement showed an advantage with magnetic resonance imaging.


Achalasia cardia in mother and son.
Familial occurrence of achalasia cardia is rare. Most associations are among siblings or in monozygotic twins. Parent-child association is even rarer and only six such instances have been reported till date. We report a 29-year-old man with achalasia cardia and his mother who had the same illness two and half years later. Both of them were successfully treated with balloon dilatation.


Hypocretin measurement: shelf age of radioimmunoassay kit, but not freezer time, influences assay variability.
The hypothalamic peptide hypocretin 1 (orexin A) may be assayed in cerebrospinal fluid to diagnose narcolepsy type 1. This testing is not commercially available, and factors contributing to assay variability have not previously been comprehensively explored. In the present study, cerebrospinal fluid hypocretin concentrations were determined in duplicate in 155 patient samples, across a range of sleep disorders. Intra-assay variability of these measures was analyzed. Inter-assay correlation between samples tested at Emory and at Stanford was high (r = 0.79, p < 0.0001). Intra-assay correlation between samples tested in duplicate in our center was also high (r = 0.88, p < 0.0001); intra-assay variability, expressed as the difference between values as a percentage of the higher value, was low at 9.4% (SD = 7.9%). Although both time the sample spent in the freezer (r = 0.16, p = 0.04) and age of the kit used for assay (t = 3.64, p = 0.0004) were significant predictors of intra-kit variability in univariate analyses, only age of kit was significant in multivariate linear regression (F = 4.93, p = 0.03). Age of radioimmunoassay kit affects intra-kit variability of measured hypocretin values, such that kits closer to expiration exhibit significantly more variability.


Development and Validation of the Overall Foot Health Questionnaire for Patients with Rheumatoid Arthritis: A Cross-Sectional Descriptive Analysis.
Background and Objectives: In general, patients with rheumatoid arthritis (RA) are ignorant of the physician's role and of RA-related feet problems. The aim of our study was to validate a questionnaire on the knowledge of different aspects of overall foot health in patients with RA. Materials and Methods: A cross-sectional descriptive analysis was carried out between March 2017 and April 2017. A questionnaire was designed and validated through the Delphi method to evaluate the knowledge about the illness, the repercussions on feet, medical podiatry care, and the role of the medical podiatrist. Results: After being checked by a panel of experts, all the items obtained a Cronbach's alpha over 0.70. Conclusions: The content of this questionnaire about the knowledge of different aspects of medical podiatry health in patients with RA has internal consistency.


Faunistic Composition and Spatial Distribution of Scorpions in North Khorasan Province Northeast of Iran.
Scorpions pose one of the most important public health and medical problems in tropical and subtropical regions of the world, especially in developing countries. This study was conducted to determine the fauna and spatial distribution of scorpions. In this descriptive study, scorpions were captured using ultra-violet (UV) light, pitfall traps and digging methods in North Khorasan Province, northeastern Iran in 2017. After being encoded, the collected scorpions were stored in plastic containers of 70% ethanol and then transferred to the medical entomology lab of Tehran University of Medical Sciences for species identification based on morphological keys. In addition, Arc Geographic Information System (GIS) 9.3 software was utilized for mapping spatial distribution of scorpions. Overall, 143 scorpions were captured and identified. All of collected scorpions belonged only to Buthidae family. They were also classified into four genera (Androctonus, Mesobuthus, Odontobuthus, Orthochirus) and five species: M. eupeus (59.44%), A. crassicauda (16.78%), O. doriae (12.59), M. (Olivierus) caucasicus (9.09%), and O. farzanpayi (2.10%). Furthermore, spatial distribution of scorpions was performed in this area. Regarding the diversity, high frequency and wide geographical distribution of scorpions and their long-term seasonal activity in this area, the probability of occurrence of scorpion sting is high. Therefore, in order to prevent the occurrence of this public health problem, health educational programs be implemented by health- care providers in the area.


A four-coordinate thionitrosyl complex of vanadium.
Addition of elemental sulfur to the vanadium nitride [(nacnac)V≡N(OAr)] forms the first thionitrosyl complex of vanadium, [(nacnac)V(NS)(OAr)]. Single crystal X-Ray diffraction studies and DFT calculations reveal an almost linear thionitrosyl ligand resulting from an extended π-resonance across the VNS moiety.


Isolation of novel microsatellite markers from Paralichthys lethostigma (Paralichthyidae) and their cross-species application in Pleuronectiformes.
We investigated the genetic diversity of the southern flounder Paralichthys lethostigma. Microsatellite-enriched libraries were constructed and novel microsatellite markers were developed and applied for genetic detection of wild populations. Cross-species amplification was also conducted in five pleuronectiforme species. Of 45 randomly selected and sequenced clones, 43 contained a CA or GA repeat motif. Fourteen pairs of primers were designed to investigate the polymorphism and genetic structure of a wild population collected from North Carolina State coastal waters. Two loci were monomorphic and 12 loci were polymorphic. The number of alleles per polymorphic locus ranged from 2 to 16, with an average of 7.3, and the expected heterozygosity per locus ranged from 0.10 to 0.92, with an average of 0.58. Cross-species amplification showed that most of the markers could successfully amplify Paralichthys olivaceus DNAs, few markers amplified in Verasper variegatus and Verasper moseri, and none of them could amplify Scophthatmus maximus and Cynoglossus semilaevis DNAs. The isolated polymorphic markers would be useful for the genetic breeding and assessment of genetic variation within the genus Paralichthys.


T cell signaling. Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion.
T cell responses are initiated by antigen and promoted by a range of costimulatory signals. Understanding how T cells integrate alternative signal combinations and make decisions affecting immune response strength or tolerance poses a considerable theoretical challenge. Here, we report that T cell receptor (TCR) and costimulatory signals imprint an early, cell-intrinsic, division fate, whereby cells effectively count through generations before returning automatically to a quiescent state. This autonomous program can be extended by cytokines. Signals from the TCR, costimulatory receptors, and cytokines add together using a linear division calculus, allowing the strength of a T cell response to be predicted from the sum of the underlying signal components. These data resolve a long-standing costimulation paradox and provide a quantitative paradigm for therapeutically manipulating immune response strength.


Emerging therapeutic targets for Gaucher disease.
Gaucher disease (GD) is an inherited metabolic disorder caused by mutations in the glucocerebrosidase (GBA1) gene. Although infusions of recombinant GBA ameliorate the systemic effects of GD, this therapy has no effect on the neurological manifestations. Patients with the neuronopathic forms of GD (nGD) are often severely disabled and die prematurely. The search for innovative drugs is thus urgent for the neuronopathic forms. Here we briefly summarize the available treatments for GD. We then review recent studies of the molecular pathogenesis of GD, which suggest new avenues for therapeutic development. Existing treatments for GD are designed to target the primary consequence of the inborn defects of sphingolipid metabolism, that is, lysosomal accumulation of glucosylceramide (GlcCer). Here we suggest that targeting other pathways, such as those that are activated as a consequence of GlcCer accumulation, may also have salutary clinical effects irrespective of whether excess substrate persists. These pathways include those implicated in neuroinflammation, and specifically, receptor-interacting protein kinase-3 (RIP3) and related components of this pathway, which appear to play a vital role in the pathogenesis of nGD. Once available, inhibitors to components of the RIP kinase pathway will hopefully offer new therapeutic opportunities in GD.


The role of coping humor in the physical and mental health of older adults.
This study examined the associations among coping humor, other personal/social factors and the health status of community-dwelling older adults. Survey questionnaires were completed with 73 community-dwelling older adults. Included were measures of coping humor, spirituality, self-efficacy, social support and physical and mental health status. Correlations across all variables showed coping humor to be significantly associated with social support, self-efficacy, depression and anxiety. Forward stepwise regression analyses showed that coping humor and self-efficacy contributed to outcome variance in measures of mental health status. Contrary to expectation, neither social support nor spirituality contributed to the total outcome variance on any of the dependent measures. The importance of social support, self-efficacy and spirituality in determining the quality of life of older adults is well supported in the literature. Coping humor as a mechanism for managing the inevitable health stresses of aging has received less attention. This study shows that coping humor and self efficacy are important factors for explaining health status in older adults. Correlations among coping humor, self efficacy and social support suggest that a sense of humor may play an important role in reinforcing self-efficacious approaches to the management of health issues.


Does usage of domestic heating influence internal environmental conditions and health?
Housing conditions are recognised as an important determinant of health. In the UK, interventions to improve domestic heating are in place with the expectation that they will improve health. As a component of evaluating such policies, this study assesses whether specific health outcomes are significantly associated with the extent and duration of domestic heating use, either directly or via a possible mediating effect of internal environmental conditions. Baseline data from a prospective controlled study evaluating the health effects of a publicly-funded programme of heating improvements in Scotland were used to assess associations among heating use, internal conditions, and three specific health outcomes. There were significant associations (P < 0.01) between measures of heating use and the presence of environmental problems in the home, such as mould and condensation. The presence of such problems was, in turn, found to be significantly predictive of two health outcomes derived from the SF-36 (P < 0.01) and of adult wheezing (P < 0.05). The direction of significant associations was highly consistent: greater levels of heating were associated with reduced likelihood of environmental problems, and the presence of environmental problems was linked to poorer health status. Heating use was not directly associated with the health outcomes considered. The study findings are consistent with a conceptual model in which health may be influenced by usage patterns of domestic heating, via the mediating effect of poor internal environmental conditions. Since these findings are based on cross-sectional data, interpretation must be carried out cautiously. However, if confirmed by planned future work they have important implications for policy initiatives relating to domestic heating and fuel poverty.


Computerized physician order entry of medications and clinical decision support can improve problem list documentation compliance.
The problem list is a key and required element of the electronic medical record (EMR). Problem lists may contribute substantially to patient safety and quality of care. Physician documentation of the problem list is often lower than desired. Methods are needed to improve accuracy and completeness of the problem list. An automated clinical decision support (CDS) intervention was designed utilizing a commercially available EMR with computerized physician order entry (CPOE) and CDS. The system was based on alerts delivered during inpatient medication CPOE that prompted clinicians to add a diagnosis to the problem list. Each alert was studied for a 2-month period after implementation. Measures included alert validity, alert yield, and accuracy of problem list additions. At a 450 bed teaching hospital, the number of medication orders which triggered alerts during all 2-month study periods was 1011. For all the alerts, the likelihood of a valid alert (an alert that occurred in patients with one of the predefined diagnoses) was 96+/-1%. The alert yield, defined as occuring when an alert led to addition of a problem to the problem list, was 76+/-2%. Accurate problem list additions, defined as additions of problems when the problem was determined to be present by expert review, was 95+/-1%. The CDS problem list mechanism was integrated into the process of medication order placement and promoted relatively accurate addition of problems to the EMR problem list.