Dog bite injuries among American Indian and Alaska Native children.
To examine dog bites among American Indian (AI) and Alaska Native (AN) children visiting Indian Health Service and tribal health facilities. We retrospectively analyzed hospitalizations and outpatient visits with a diagnosis of dog bite between 2001 and 2008 in AI/AN children aged <20 years. Rates of dog bite hospitalizations and outpatient visits were estimated by age group, sex, region, and number and location of open wounds using Indian Health Service data. Analyses of hospitalizations for the general US population aged<20 years used the Nationwide Inpatient Sample. The average annual dog bite hospitalization rate was higher among AI/AN children in Alaska (6.1/100,000 population) and the Southwest region (5.3/100,000) compared with the general US child population (3.1/100,000; 95% CI, 2.9-3.3/100,000). The average annual outpatient visit rate in AI/AN children was highest in the Alaska (596.4/100,000), Southwest (540.0/100,000), and Northern Plains West (537.6/100,000) regions. The hospitalization rate was highest in both AI/AN and US males aged<5 years, and outpatient visit rates were highest in AI/AN males aged 5-9 years. Open wounds diagnoses were most commonly seen on the head, neck, and face in hospitalized children (45.5% of open wounds in AI/AN children, 59.3% in US children; SE, 1.0%) and on the leg in AI/AN outpatients (35.6%). Dog bites represent a significant public health threat in AI/AN children in the Alaska, the Southwest, and Northern Plains West regions of the US. Enhanced animal control and education efforts should reduce dog bite injuries and associated problems with pets and stray dogs, such as emerging infectious diseases.


Quantification of the antipsychotics flupentixol and haloperidol in human serum by high-performance liquid chromatography with ultraviolet detection.
A high-performance liquid chromatography (HPLC) method was developed for quantification of both isomers of the thioxanthene neuroleptic flupentixol and of the butyrophenone derivative haloperidol in human serum. After extraction with diethyl ether-n-heptane (50:50, v/v), an isocratic normal-phase HPLC system with a Hypersil cyanopropyl silica column (250x4.6 mm, 5 microm particle size) was used with ultraviolet detection at 254 nm and elution with a mixture of 920 ml acetonitrile, 110 ml methanol, 30 ml 0.1 M ammonium acetate, and 50 microl triethylamine. The limit of quantitation of 0.5 ng/ml and 0.3 ng/ml for flupentixol and haloperidol, respectively, was sufficient to quantify both compounds in serum after administration of clinically adjusted doses. The suitability of the described method for therapeutic drug monitoring and clinical pharmacokinetic studies was assessed by analysis of more than 100 trough level serum samples.


Accelerated evolution of a minimal 63-amino acid dual transcription factor.
Transcription factors control gene expression in all life. This raises the question of what is the smallest protein that can support such activity. In nature, Cro from bacteriophage λ is one of the smallest known repressors (66 amino acids), and activators are typically much larger (e.g., λ cI, 237 amino acids). Previous efforts to engineer a minimal activator from λ Cro resulted in no activity in vivo in cells. In this study, we show that directed evolution results in a new Cro activator-repressor that functions as efficiently as λ cI in vivo. To achieve this, we develop phagemid-assisted continuous evolution (PACEmid). We find that a peptide as small as 63 amino acids functions efficiently as an activator and/or repressor. To our knowledge, this is the smallest protein activator that enables polymerase recruitment, highlighting the capacity of transcription factors to evolve from very short peptide sequences.


The role of nitric oxide in melanoma.
Nitric oxide (NO) is a small gaseous signaling molecule that mediates its effects in melanoma through free radical formation and enzymatic processes. Investigations have demonstrated multiple roles for NO in melanoma pathology via immune surveillance, apoptosis, angiogenesis, melanogenesis, and on the melanoma cell itself. In general, elevated levels of NO prognosticate a poor outcome for melanoma patients. However, there are processes where the relative concentration of NO in different environments may also serve to limit melanoma proliferation. This review serves to outline the roles of NO in melanoma development and proliferation. As demonstrated by multiple in vivo murine models and observations from human tissue, NO may promote melanoma formation and proliferation through its interaction via inhibitory immune cells, inhibition of apoptosis, stimulation of pro-tumorigenic cytokines, activation of tumor associated macrophages, alteration of angiogenic processes, and stimulation of melanoma formation itself.


Uncovering the cytochrome P450-catalyzed methylenedioxy bridge formation in streptovaricins biosynthesis.
Streptovaricin C is a naphthalenic ansamycin antibiotic structurally similar to rifamycins with potential anti-MRSA bioactivities. However, the formation mechanism of the most fascinating and bioactivity-related methylenedioxy bridge (MDB) moiety in streptovaricins is unclear. Based on genetic and biochemical evidences, we herein clarify that the P450 enzyme StvP2 catalyzes the MDB formation in streptovaricins, with an atypical substrate inhibition kinetics. Furthermore, X-ray crystal structures in complex with substrate and structure-based mutagenesis reveal the intrinsic details of the enzymatic reaction. The mechanism of MDB formation is proposed to be an intramolecular nucleophilic substitution resulting from the hydroxylation by the heme core and the keto-enol tautomerization via a crucial catalytic triad (Asp89-His92-Arg72) in StvP2. In addition, in vitro reconstitution uncovers that C6-O-methylation and C4-O-acetylation of streptovaricins are necessary prerequisites for the MDB formation. This work provides insight for the MDB formation and adds evidence in support of the functional versatility of P450 enzymes.


Assessment of the Real-Life Usage of Intravitreal Dexamethasone Implant in the Treatment of Chronic Diabetic Macular Edema in France.
Intravitreal steroids, including dexamethasone implant (Ozurdex(®)), are effective for the treatment of diabetic macular edema (DME). However, the dosing regimen for Ozurdex in DME is unclear, and thus, this study was designed to evaluate the dosing regimen for dexamethasone in real-life clinical practice. Results are presented from 3 studies based on a questionnaire that was sent out by e-mail to physicians; the monitoring of drugs dispensing over time through pharmacies; and the French Social Security database for 2011 and 2012. Data are presented as the average number of dexamethasone treatments per year and the time interval between injections. Study 1 involved 111 ophthalmologists and assessed DME prescriptions. The number of injections per year and the time interval between 2 successive injections were measured as 2.3 and 4.8 months, respectively. In study 2, the survey incorporated 570 prescriptions from retail pharmacies; the mean follow-up period was 13.7 months, and 2.3 injections were administered per year with a time interval between injections of 5.2 months. In study 3, relating to the reimbursements by social security, 114 patients were initially identified and, among these, 15 patients were treated with Ozurdex. Over the course of a 25-month follow-up period, an average of 2.5 Ozurdex implants were injected per year with 4.7 months between injections. The average number of dexamethasone implant injections was consistent between studies with an average of 2.4 injections per year and 4.9 months between treatments. This highlights the need for a study to evaluate the optimal treatment frequency in DME.


Contribution of anthropogenic pollutant sources to greenhouse gas emissions: a case study from a developing country.
Anthropogenic greenhouse gas (GHG) emissions are the primary cause of climate change, one of the biggest challenges for humankind. To tackle this problem, the international community is looking for ways to reduce GHG emissions. To create reduction strategies in a city/province/country, there is a need for an inventory that provides emission amounts from different sectors. This study aimed to develop a GHG emission inventory for Karaj, a megacity in Iran, using international guidelines such as AP-42 and ICAO, and IVE software. The emissions of mobile sources were accurately calculated by a bottom-up method. The results showed that power plant with 47% of the total emissions is the primary GHG contributor in Karaj. Residential and commercial units with 27% and mobile sources with 24% of the total emissions play a critical role in emitting GHGs in Karaj. On the other hand, the industrial units and the airport have negligible (2%) contribution to the total emissions. Subsequent estimates showed that GHG emissions per capita and per GDP of Karaj were 6.03 t per person and 0.47 t per thousand US dollars, respectively. These amounts are higher than the global averages (4.97 t per person and 0.3 t per thousand US dollars). The relatively high GHG emissions in Karaj are due to the sole reliance on the consumption of fossil fuels. To reduce emissions, mitigation strategies such as developing renewable energy sources, switching to low-emission transportation, and raising public awareness should be implemented.


Gastric emptying in an animal model of human diabetes type 1: relation to endocrine cells.
Gastric emptying was measured in female non-obese diabetic (NOD) mice with a duration of diabetes of 28-35 days. As controls, age- and sex-matched BLAB/cJ mice were used. Gastric emptying of diabetic mice was significantly slower than that of controls. The faeces weight and water content were significantly higher in diabetic mice than controls. The endocrine cells known to correlate with gastric emptying, namely secretin, serotonin, peptide YY (PYY) and enteroglucagon cells, were identified by immunocytochemistry and quantified by computer image analysis. The densities of duodenal secretin, serotonin and colonic PYY cells in NOD mice were significantly higher than that of control mice. Changes in these three endocrine cell types may play a role in delayed gastric emptying and in the manifestation of diarrhoea in this animal model of human diabetes type 1.


Environmental and occupational determinants of myelodysplastic syndrome: A case-control study from Pakistan.
Myelodysplastic syndromes (MDS) are heterogeneous group of haematopoietic stem cell disorders and have variable reduction in the production of red cells, platelets and mature granulocytes. We conducted a case-control study evaluating the environmental and occupational determinants as risk factors of MDS. A case-control study was conducted including 150 de novo MDS cases and 450 age and gender-matched controls. Disease characteristics, sociodemographics and exposure to environmental and occupational determinants were collected through a questionnaire. Chi-square test was applied to observe association, and binary logistic regression was applied to predict the odds of having MDS. A total of 600 participants were analysed. Those who were exposed to arsenic (OR 31.81, CI: 19.0-53.0, P-value: .000), benzene (OR 1.564, CI: 1.07-2.27, P-value: .01) using natural source of water (OR 3.563, CI: 2.29-5.53, P-value: .000) and smokers (OR 3.1, P-value: .000) were more likely to have MDS. Unmarried were less likely to acquire MDS than married (OR 0.239, CI: 0.15-0.36, P-value: .000), Sindhi speaking were 1.419 times more likely to have MDS than participants speaking other languages. Uneducated participants were more likely to have MDS than educated and powder milk users were more likely to have MDS than dairy milk users. Our results revealed that arsenic, use of natural source of water and benzene exposure might lead to higher risk of acquiring MDS. This study would be helpful to understand the aetiology of disease in Pakistani population.


The multiple uses of fluorescent proteins to visualize cancer in vivo.
Naturally fluorescent proteins have revolutionized biology by enabling what was formerly invisible to be seen clearly. These proteins have allowed us to visualize, in real time, important aspects of cancer in living animals, including tumour cell mobility, invasion, metastasis and angiogenesis. These multicoloured proteins have allowed the colour-coding of cancer cells growing in vivo and enabled the distinction of host from tumour with single-cell resolution. Visualization of many aspects of cancer initiation and progression in vivo should be possible with fluorescent proteins.


Diphenylamine-2-carboxylate (DPC) inhibits both Cl- conductance and cyclooxygenase of canine tracheal epithelium.
Diphenylamine-2-carboxylate (DPC) decreases Cl- conductance (GCl) in epithelia and cells of several tissues, an effect which has been ascribed to blockade of conductive Cl- channels. However, one DPC derivative, flufenamic acid, is a clinically useful non-steroidal anti-inflammatory agent, the mechanism of action of which involves the blockade of arachidonic acid metabolism by cyclooxygenase. Because GCl in canine tracheal epithelium is stimulated by exogenous prostaglandins and induction of cyclooxygenase activity, we tested the hypothesis that DPC inhibits dog tracheal epithelium GCl through inhibition of cyclooxygenase. DPC inhibited the short circuit current of amiloride-pretreated tissues by 50% at 0.138 mmol/l and by more than 95% at 3 mmol/l. Isoproterenol reversed the inhibition seen at 0.1 mmol/l DPC and stimulated current above control (indomethacin-pretreated) levels. Higher concentrations of DPC diminished the stimulation of current by subsequent exposure to isoproterenol, such that there was little effect of isoproterenol in the presence of 3 mmol/l DPC. DPC, 0.1 mmol/l, also blocked stimulation of current by exogenous arachidonic acid, but not of exogenous prostaglandins PGE or PGD. The metabolism of 3H-arachidonic acid to 3H-PGD2, monitored by HPLC, was completely blocked by 0.1 mmol/l DPC. We conclude that the isoproterenol/prostaglandin reversible blockade of GCl by DPC can be attributed to inhibition of arachidonic acid metabolism.


Improved photostability, reduced skin permeation and irritation of isotretinoin by solid lipid nanoparticles.
The aim of this study was to develop new solid lipid nanoparticles of isotretinoin (IT-SLNs) and evaluate the ability of IT-SLNs to improve photostability, reduce skin permeation and irritating effects. IT-SLNs were prepared by the hot high pressure homogenization method. Size, zeta potential and morphological characteristics of the preparations were assessed by transmission electron microscopy (TEM) and thermotropic properties with differential scanning calorimetry (DSC). IT-SLNs had a small average diameter of 74.05 ± 8.91 nm and high encapsulation efficiency (EE) of 80.6 ± 1.2 %. The results showed that the entrapment of IT into SLNs reduced significantly its photodegradation. The in vitro permeation data showed that IT-SLNs can accumulate in the different layers of the skin and prevent systemic uptake of IT in mouse skin. IT-SLNs also significantly increased IT accumulation in the different layers of the stratum corneum of human skin. IT-SLN formulation was significantly less irritating compared to commercial IT-GEL, which shows its potential for improving skin tolerability and being a carrier for topical delivery of IT.


Dazoxiben-induced changes in the thromboxane/prostacyclin balance in the lateral cochlear wall of the guinea pig.
Dazoxiben, a thromboxane synthetase inhibitor, was infused i.v. in a first group of guinea pigs. Saline was given to a second group of animals as controls. Subsequently, the lateral cochlear walls of each animal were prepared and analyzed for thromboxane (TXA) and prostacyclin (PGI) using radioimmunoassay. These studies showed that dazoxiben crosses the blood-labyrinth barrier and shifts the TXA2/PGI2 balance in favor of the latter. The effects demonstrated are discussed with respect to the relevance of prostanoids in cochlear physiology.


[Vulvar vestibulitis syndrome: a clinicopathological study of 14 cases].
Vulvar vestibulitis syndrome (VVS) is one of the most frequent causes of superficial dyspareunia in young women. VVS has a pronounced psychological impact. The results of pathological studies published thus far are controversial. Fourteen women with VVS were included in this study and underwent vestibular biopsy. Vulvar biopsies were taken from the orifice of Bartholin's gland. The biopsy samples were stained with a standard stain and PAS and 25 serial sections were prepared for each specimen. The mean patient age was 26 years and VVS had been present for a mean 30 months. Extensive inflammation of mononuclear cells was observed in the vulvar chorionic epithelium. This inflammation was seen mainly around the minor vestibular glands. Mild exocytosis of lymphocytes was noted in the vestibular glands and ducts. Most studies concerning this disease report chronic inflammation of the vulvar vestibular mucosa. This inflammation is seen mainly around the minor vestibular glands. We report the same pattern in our study. Moreover, we observed some exocytosis into the epithelium of minor vestibular glands and the excretory duct. This aspect has not been reported to date, further supporting the individual nature of this entity.


Continuous cultivation of mixed-culture microalgae using anaerobic digestion effluent in photobioreactors with different strategies for adjusting nitrogen loading rate.
This study examined continuous mixed-culture microalgae cultivation for nutrient removal from anaerobic digestion (AD) effluents in photobioreactors, while altering the NH4+-N loading rate (NLR) by adjusting either the hydraulic retention time (HRT) (reactor set RH) or the influent NH4+-N concentration (reactor set RS). Both RH and RS demonstrated efficient nutrient removal and microalgae cultivation at NLRs of 4-10 mg NH4+-N/L∙d, reaching peak performance at 10 mg NH4+-N/L∙d. Within this range, RH obtained greater biomass yield and productivity, while RS maintained higher microalgal concentrations. The cultivated biomasses obtained from RH and RS had good settleability and suitable fatty acid compositions as a biodiesel feedstock, although their organic composition varied considerably with NLR and HRT. Parachlorella overwhelmingly dominated the reactors' microalgal communities throughout the experiment, co-existing with various microalgae-associated bacteria. Changes in NLR significantly influenced the bacterial community structures, underscoring its critical role in determining reactor performance and microalgal-bacterial community behavior.


Sexual dysfunction associated with prostate cancer treatment in Japanese men: a qualitative research.
We investigated the experiences of Japanese men with sexual dysfunction associated with various prostate cancer treatments. We included 38 Japanese men who underwent the following initial treatments for prostate cancer: radical prostatectomy (n = 10), external beam radiotherapy (n = 12), brachytherapy (n = 5), and androgen deprivation therapy (n = 11). Semi-structured interviews were conducted regarding sexual dysfunction associated with prostate cancer treatment. Data were analyzed using a content analysis method. To obtain a unique experience for each treatment, we confirmed and organized the treatment method from which the code that constituted each category was derived. The category reliability was calculated based on Scott's formula for the matching rate of the classification by three qualitative researchers. The criterion for good reliability was set at 70%. Japanese men with sexual dysfunction associated with prostate cancer treatments experienced the following: a desire to maintain sexual function and conflict in decision-making concerning the initial treatment for prostate cancer; a loss of values related to sexual dysfunction; an uncertainty regarding the consequences of sexual dysfunction; a sense of calm with fewer adverse effects of sexual dysfunction at the early treatment stage; an effort to accept sexual dysfunction; and management of their changed body at the later treatment stages. The concordance rates for the categories were 70% and 78%. Additionally, there were glimpses of experiences common to all treatments and trends in treatment-specific experiences. It is necessary to provide care based on the experience of Japanese men with sexual dysfunction after prostate cancer treatment.


[The technic of implanting peripheral nerves in the cerebral hemispheres of rabbits for experimental purposes].
An implantation method of the tibial nerve into the cerebral hemispheres of rabbits is reported. The operations were carried out in 10 adult animals of both sexes of the chinchilla race. All operations were got over well and without any complication within 12 to 14 weeks. 2 female rabbits had brought forth and up healthy animals.


X-linked hypogonadism, gynecomastia, mental retardation, short stature, and obesity--a new syndrome.
Five male members in four generations of the same family had hypogonadism, gynecomastia, mental retardation, obesity, and short stature. The X-linked mode of inheritance, the distinctive facies, the normal size of the hands and feet, and the true gynecomastia are the main characteristics. Endocrine evaluation and histologic studies of the testes suggest partial hypogonadotropic hypogonadism. This disorder represents a new syndrome distinct from others previously described.


Tubal ligation by colpotomy incision.
A five-year review of colpotomy tubal ligation performed on 585 patients within a private-practice setting in Columbus, Georgia, is analyzed. Operative time averaged under 30 minutes, and average hospital stay was less than 3 days. The major postoperative complication rate was less than 2%. The patient population is reviewed as to age, parity, previous contraception, and medical indications for sterilization. Surgical technique is discussed, and several suggestions are made, A follow-up of subsequent gynecologic procedures and the interval following colpotomy is then presented.


Chromosomal mobilization from a recA mutant of Pseudomonas putida.
A methyl methane sulfonate sensitive mutant of P. putida strain PpG1 is also extremely sensitive to UV-rays, compared to parent wild type cells. This mutant behaves typically as recombination less (recA) mutants of Escherichia coli and Pseudomonas aeruginosa, since as a recipient, it exhibits extremely low frequency of recombination following conjugational, transductional, and transformational gene transfer. Sex factor plasmids such as K-XYL or TOL can mobilize chromosomal genes equally well both from recA+ and recA801 donor cells, suggesting that host recombination functions are not necessary for mobilization of chromosomal genes by such plasmids.


[From plastic surgery to space conquest. First microsurgical procedure and first surgical procedure in man during weightlessness].
The authors present their experience of surgery in weightlessness conditions. Russians and Americans already focused on that subject but two questions were still unsolved: what was the limit of human skill in these extreme conditions and was it possible to operate a human under total safety? Between 2003 and 2007, using a 0G plane for our experiment, we focused on two goals: firstly, the conception of a microsurgical module to test complex microsurgical procedures in rats and secondly, the construction of a surgical workstation with specific air filtration device and define surgical and anaesthetic protocols to carry on a surgery in man. In September 2003, we succeeded to perform the microscopic report of a 0,5mm artery (which is the smallest we can suture in terrestrial conditions) by using seven stitches of 10 x 0 monofilament suture. The 27th of September 2007, we removed a lipoma from the forearm of a 47-year-old man. These experiments take place in a wide program of development of telesurgery controlled through satellite transmission with all forthcoming civil, military and humanitarian applications.


Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia.
SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered. We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery. We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19.


Rapid analysis of Baijiu volatile compounds fingerprint for their aroma and regional origin authenticity assessment.
Solid-phase microextraction - mass spectrometry (SPME-MS) and fast gas chromatography based electronic nose (GC-E-Nose) were used and compared for their suitability to distinguish Baijiu of various aroma types and geographical origin. Baijiu is a traditional Chinese distilled spirit produced with complex consortia of microorganisms, which results in very complex aroma compounds profiles. A total of 65 Baijiu samples representing 6 aromas were investigated. Strong aroma types from 3 regions were examined for their origin. Data acquired on two analytical systems were processed using uniform statistical approach. Data were pre-processed for multi-classification (OPLS-DA) models as well as for binary classification (PLS-DA) ones. Aroma and regional classification performed using OPLS-DA indicated that the approach based on SPME-MS had better fitness and prediction ability compared with GC-E-Nose. The total correct classification rate for SPME-MS was 94.44% for aroma and 100% for region, whereas for GC-E-Nose these values were 91.53% and 93.94% respectively.


Does hepatitis C virus infection increase risk for stroke? A population-based cohort study.
The relationship between hepatitis C virus infection and risk of stroke remains inconsistent. This study evaluates the risk of stroke in association with chronic hepatitis C infection in a longitudinal population-based cohort. We identified 4,094 adults newly diagnosed with hepatitis C infection in 2002-2004 from the Taiwan National Health Insurance Research Database. Comparison group consisted of 16,376 adults without hepatitis C infection randomly selected from the same dataset, frequency matched by age and sex. Events of stroke from 2002-2008 were ascertained from medical claims (International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM, codes 430-438). Multivariate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for potential associated factors including HCV infection, age, sex, low-income status, urbanization, cessation of cigarette smoking, alcohol-related illness, obesity, history of chronic diseases and medication use. During 96,752 person-years of follow-up, there were 1981 newly diagnosed stroke cases. The HRs of stroke associated with medical conditions such as hypertension, diabetes and heart disease were 1.48 (95% CI 1.33 to 1.65), 1.23 (95% CI 1.11 to 1.36) and 1.17 (95% CI 1.06 to 1.30), respectively, after adjustment for covariates. The cumulative risk of stroke for people with hepatitis C and without hepatitis C infections was 2.5% and 1.9%, respectively (p<0.0001). Compared with people without hepatitis C infection, the adjusted HR of stroke was 1.27 (95% CI 1.14 to 1.41) for people with hepatitis C infection. Chronic hepatitis C infection increases stroke risk and should be considered an important and independent risk factor.


Therapeutic Potential of Semaglutide, a Newer GLP-1 Receptor Agonist, in Abating Obesity, Non-Alcoholic Steatohepatitis and Neurodegenerative diseases: A Narrative Review.
Semaglutide, a peptidic GLP-1 receptor agonist, has been clinically approved for treatment of type 2 diabetes mellitus and is available in subcutaneous and oral dosage form. Diabetes, insulin resistance, and obesity are responsible for the pathological manifestations of non-alcoholic steatohepatitis (NASH). Similarly, insulin resistance in brain is also responsible for neurodegeneration and impaired cognitive functions. Observations from phase-3 clinical trials like SUSTAIN and PIONEER indicated anti-obesity potential of semaglutide, which was established in STEP trials. Various pre-clinical and phase-2 studies have indicated the therapeutic potential of semaglutide in non-alcoholic steatohepatitis and neurodegenerative disorders like Parkinson's and Alzheimer's disease. Significant weight reduction ability of semaglutide has been demonstrated in various phase-3 clinical trials, for which recently semaglutide became the first long-acting GLP-1 receptor agonist to be approved by the United States Food and Drug Administration for management of obesity. Various pre-clinical and clinical studies have revealed the hepatoprotective effect of semaglutide in NASH and neuroprotective effect in Parkinson's and Alzheimer's disease. Many GLP-1 receptor agonists have shown hepatoprotective and neuroprotective activity in animal and human trials. As semaglutide is an already clinically approved drug, successful human trials would hasten its inclusion into therapeutic treatment of NASH and neurodegenerative diseases. Semaglutide improves insulin resistance, insulin signalling pathway, and reduce body weight which are responsible for prevention or progression of NASH and neurodegenerative diseases.


Letter: Two cases of metastases to the scalp bone mimicking epidermoid cyst.
Metastatic skin tumors present with a variety of clinical manifestations. We herein present two cases of metastases to the scalp, invading the skull, which showed epidermoid cyst-like appearances.


A film-lever actuated switch technology for multifunctional, on-demand, and robust manipulation of liquids.
A lab-on-a-chip system with Point-of-Care testing capability offers rapid and accurate diagnostic potential and is useful in resource-limited settings where biomedical equipment and skilled professionals are not readily available. However, a Point-of-Care testing system that simultaneously possesses all required features of multifunctional dispensing, on-demand release, robust operations, and capability for long-term reagent storage is still a major challenge. Here, we describe a film-lever actuated switch technology that can manipulate liquids in any direction, provide accurate and proportional release response to the applied pneumatic pressure, as well as sustain robustness during abrupt movements and vibrations. Based on the technology, we also describe development of a polymerase chain reaction system that integrates reagent introduction, mixing and reaction functions all in one process, which accomplishes "sample-in-answer-out" performance for all clinical nasal samples from 18 patients with Influenza and 18 individual controls, in good concordance of fluorescence intensity with standard polymerase chain reaction (Pearson coefficients > 0.9). The proposed platform promises robust automation of biomedical analysis, and thus can accelerate the commercialization of a range of Point-of-Care testing devices.


Inherited factor V deficient neonate with galactosaemia.
Reporting a case of inherited factor V deficiency and galactosemia. A neonate was admitted with hematoma, jaundice, splenomegaly, diarrhea, anemia, abdominal ascites and bilateral cataracts that diagnosis of galactosaemia and factor V deficiency was established. Coinheritance of both coagulation disorder and metabolic disorder is very rare episode that was identified in a neonate. Our case indicates that in mild bleeding episodes of neonates that imitate of coagulation disorders should be considered promptly by pediatricians.


Determination of toxic heavy metals in indigenous medicinal plants used in Rawalpindi and Islamabad cities, Pakistan.
History of medicinal plants used in local healthcare systems dates back centuries as the user considers them safe from toxic effects. Present study was aimed to document the commonly used indigenous medicinal plants and to investigate the metal toxicity and impact of pollution load in most frequently used medicinal plants from study area. Semi-structured interviews and rapid appraisal approach were employed to record the ethnomedicinal information and toxic metals were analyzed through flame atomic absorption spectrophotometer. A total of 21 wild medicinal plants was reported, and 7 were screened for toxic metal analysis. Oral mode of application (93%) was the chief route of herbal remedy administration, and leaves were found to be used as major plant part against different diseases. Main sources of remedies were wild herb (68%) followed by wild trees (18%), wild spiny shrubs (09%) and wild shrubs (5%). Trend of metal concentration was found as Fe>Ni>Cr>Pb>Cu>Zn>Mn>Cd. Indigenous medicinal plants of both cities posed the toxicity risk for Ni, Cu, Fe and crossed the safety limits set by WHO. Medicinal plants of Rawalpindi were more toxic compared to the medicinal plants of Islamabad. Prolonged intake or over dose of these medicinal plants may lead to chronic accumulation of various elements that may cause severe hazardous effect upon human health.


Dose distribution of neutron beam and chromosome analysis.
Chromosome analysis using peripheral lymphocytes is a sensitive and reliable indicator of the biological effect of radiation at low radiation doses. In the present study, using this chromosome aberration analysis, we tried to investigate the radiation dose distribution within and around the radiation field of a 6 MeV neutron beam. The efficient induction of dicentrics and rings at the irradiation of neutrons compared to those of gamma or X rays especially in a lower dose range, results in a dominant linear component in the linear quadratic model in the dose response relation of a chromosome aberration formation. A marked increase of RBE (relative biological effectiveness) in a lower dose range of neutrons was demonstrated. The radiation doses of the neutron beam as a function of depth, estimated from the yields of dicentrics and rings in a water phantom revealed a fairly good agreement with doses that were physically obtained. The radiation portal margin of the neutron beam was demonstrated to be not as sharp due to a wide penumbra. This wide penumbra and high RBE value, especially at lower dose range of the neutron beam may contribute to the induction of secondary malignancies in the normal tissue surrounding the tumor mass.


[Experience in using new drug preparations for treating adult patients with acute intestinal infections].
Ciprofloxacin (Bayer, FRG), a derivative of hydroxyquinolone acid, was used for the treatment of patients with shigellosis and salmonellosis and for the sanitation of Salmonella carriers. The drug turned out to exert a positive effect on bacteriological sanitation of the body. In order to treat patients with food toxinfection of unknown etiology, use was made of intetrix (Farmacos, Socialist Federal Republic of Yugoslavia). Inclusion of the drug into combined treatment of patients with food toxinfections did not show any material advantages.


A mild thermal and acid-catalyzed rearrangement of O-aryl ethers into ortho-hydroxy arenes.
[reaction: see text] An unusual rearrangement of an O-aryl ether to an ortho-hydroxyaryl system was discovered during our studies on the synthesis of diazonamide A. We discuss the exploration of this rearrangement under mild thermal and both Brønsted and Lewis acid-catalyzed conditions.


Transcriptome analysis of mesenchymal stromal cells of the large and small intestinal smooth muscle layers reveals a unique gastrontestinal stromal signature.
Mesenchymal stromal cells in the muscle layer of the large intestine are essential for the regulation of intestinal motility. They form electrogenic syncytia with the smooth muscle and interstitial cells of Cajal (ICCs) to regulate smooth muscle contraction. Mesenchymal stromal cells are present in the muscle layer throughout the gastrointestinal tract. However, their area-specific characteristics remain ambiguous. In this study, we compared mesenchymal stromal cells from the large and small intestinal muscle layers. Histological analysis using immunostaining showed that the cells in the large and small intestines were morphologically distinct. We established a method to isolate mesenchymal stromal cells from wild-type mice with platelet-derived growth factor receptor-alpha (PDGFRα) as a marker on the cell surface and performed RNAseq. Transcriptome analysis revealed that PDGFRα+ cells in the large intestine exhibited increased expression levels of collagen-related genes, whereas PDGFRα+ cells in the small intestine exhibited increased expression levels of channel/transporter genes, including Kcn genes. These results suggest that mesenchymal stromal cells differ morphologically and functionally depending on gastrointestinal tract. Further investigations of the cellular properties of mesenchymal stromal cells in the gastrointestinal tract will aid in optimizing methods for the prevention and treatment of gastrointestinal diseases.


Crosstalk between Alzheimer's disease and diabetes: a focus on anti-diabetic drugs.
Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM) are two of the most common age-related diseases. There is accumulating evidence of an overlap in the pathophysiological mechanisms of these two diseases. Studies have demonstrated insulin pathway alternation may interact with amyloid-β protein deposition and tau protein phosphorylation, two essential factors in AD. So attention to the use of anti-diabetic drugs in AD treatment has increased in recent years. In vitro, in vivo, and clinical studies have evaluated possible neuroprotective effects of anti-diabetic different medicines in AD, with some promising results. Here we review the evidence on the therapeutic potential of insulin, metformin, Glucagon-like peptide-1 receptor agonist (GLP1R), thiazolidinediones (TZDs), Dipeptidyl Peptidase IV (DPP IV) Inhibitors, Sulfonylureas, Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors, Alpha-glucosidase inhibitors, and Amylin analog against AD. Given that many questions remain unanswered, further studies are required to confirm the positive effects of anti-diabetic drugs in AD treatment. So to date, no particular anti-diabetic drugs can be recommended to treat AD.


[Sleep apnea. Improved quality of life with continuous positive pressure respiration].
Patients with obstructive sleep apnoea complain of excessive daytime sleepiness and unwanted sleep attacks. Treatment with nasal continuous positive airway pressure, CPAP, normalizes the sleep pattern and the daytime symptoms disappear. Twenty-five patients evaluated their situation by questionnaire before and during CPAP treatment. Treatment improved their working capacity and their social life. Almost all patients report treatment as giving them a new life, i.e. vastly improving their quality of life. CPAP treatment is cheap.


Ribosome binding to inosine-substituted mRNAs in the absence of ATP and mRNA factors.
Incubating ribosomes and eukaryotic initiation factor eIF3 with an inosine-substituted mRNA (where the mRNA secondary structure is strongly reduced) in the absence of ATP and other protein synthesis factors produces a 40 S ribosome.mRNA complex. When Met-tRNAMeti and eIF2 are added, a 60 S ribosome subunit attaches forming an 80 S ribosome.mRNA complex. ATP and the three mRNA factors, eIF4B, cap-site factor, and eIF4A, strongly stimulate the attachment of the 60 S subunit. In the absence of Met-tRNAMeti, the 60-S subunit does not attach, and adding ATP and the mRNA factors inhibits the accumulation of 40 S ribosome.inosine mRNA complexes. These results indicate that a 40 S ribosome, probably in a complex with eIF3, has an intrinsic capacity to attach to mRNA. Further, they suggest that Met-tRNAMeti may interact in a subsequent step to stabilize the 40 S ribosome.mRNA complex and allow the attachment of a 60 S ribosome subunit. Although seen most clearly with the inosine-substituted mRNAs, the 40 S ribosome reaction is also obtained with "guanosine" mRNA. A 40 S ribosome attaches to guanosine mRNA without ATP and mRNA factors when an incubation mixture containing ribosomes, eIF3, and mRNA is fixed with glutaraldehyde. In addition, a 40 S ribosome.guanosine mRNA complex can be obtained without glutaraldehyde in incubations containing ATP and the three mRNA factors in the absence of Met-tRNAMeti. The latter reaction is limited because of the instability of the 40 S ribosome.mRNA complex in the absence of Met-tRNA. Nevertheless, its authenticity is indicated by its full dependence upon ATP and the three mRNA factors. The lack of factor requirement for the formation of 40 S ribosome complexes with inosine-substituted mRNAs indicates that ATP and the three mRNA factors function primarily to unwind the secondary structure of a guanosine mRNA. Data relevant to a role for ATP in facilitating ribosome migration on an mRNA are also discussed.


Further improved stability criteria for uncertain T-S fuzzy systems with time-varying delay by (m,N)-delay-partitioning approach.
This paper mainly focuses on the robust stability criteria for uncertain T-S fuzzy systems with time-varying delay by (m,N)-delay-partitioning approach. A modified augmented LKF is established by partitioning the delay in all integral terms. Via taking into account of (i) the relationship between each subinterval and time-varying delay and (ii) the independent upper bounds of the delay derivative in the various delay intervals, some new results on tighter bounding inequalities such as Peng-Park׳s integral inequality and Free-Matrix-based integral inequality are introduced to effectively reduce the enlargement in bounding the derivative of LKF as much as possible, therefore, significant less conservative results can be expected in terms of es and LMIs, which can be solved efficiently with the Matlab LMI toolbox. Furthermore, it is worth mentioning that, when the delay-partitioning number m is fixed, the conservatism is gradually reduced with the increase of another delay-partitioning number N, but without increasing any computing burden. Finally, two numerical examples are included to show that the proposed method is less conservative than existing ones.


Characterization of grape C-repeat-binding factor 2 and B-box-type zinc finger protein in transgenic Arabidopsis plants under stress conditions.
Simultaneous induction of multiple stress tolerance by single-gene transfer is a powerful strategy to engineer crop plants to improve tolerance to environmental stress under field condition. The possibility of enhancement of multiple stress tolerance by four grape transcription factors that enhance low-temperature tolerance (VvCBF2, VvCBF4, VvCBFL, and VvZFPL) were analyzed using the Arabidopsis plants overexpressing these factors. Consequently, two of the four proteins, VvCBF2 and VvZFPL, were found to confer tolerance to cold, drought, and salinity stresses in Arabidopsis plants, but not to heat stress. Photosynthesis-related genes were down-regulated in both CBF2- and ZFPL-overexpressing plants, resulting in plant growth retardation. On the other hand, the overexpression of VvCBF2 activated the transcription of CBL-interacting protein kinase 7, a serine/threonine kinase involved in cold response, in Arabidopsis plants. Our study provides that one of grape CBF family, VvCBF2, and one of B-box ZFP family, VvZFPL, confer multiple stress tolerance to plants.


Safety, efficacy and prognostic impact of immune checkpoint inhibitors in older patients with genitourinary cancers.
Immunosenescence might impact immunotherapy (IT) in patients with advanced age. However, pivotal studies were not powered for this clinical question. Our aim is to explore toxicity (primary objective) and activity (secondary objective) of immune checkpoint inhibitors (ICIs) in patients with renal cell (RCC) and urothelial carcinoma (UC) older than 75 years compared to the younger population. Patients treated at our tertiary care Uro-oncology Department with atezolizumab, pembrolizumab, nivolumab or ipilimumab were retrospectively analyzed. Immune-related adverse events (irAEs) were determined and graded using the Common Terminology Criteria for Adverse Events (CTCAE v.4.0). Disease Control rate (DCR) was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). IrAEs and DCR were compared between patients ≥75 vs. <75 years, chi-squared test. Impact of age and other key clinical parameters on irAEs and DCR were tested in a binary logistic regression employing a backward selection. Impact of irAEs on oncological prognosis was assessed in log-rank and Cox regression analyses. We included 99 patients treated between 11/2015 and 01/2019. Frequency of irAEs (36.4% vs. 39.4%) and DCR (59.4% vs. 41.0%) was comparable between patients ≥75 vs. <75 years. Advanced age was not associated with irAEs or worse DCR. IrAEs occurrence correlated with better disease-specific survival in the univariate and multivariate analyses. IrAEs could be successfully treated with corticosteroids in 78.9% of cases. ICIs seem to be both safe and efficacious in an aging population with metastatic RCC or UC. Occurrence of irAEs predicted better prognosis.


Effect of teriparatide on bone mineral density and fracture in postmenopausal osteoporosis: meta-analysis of randomised controlled trials.
To determine the efficacy of teriparatide supplementation for improving bone mineral density (BMD) and fracture risk in postmenopausal osteoporosis and if effects vary with factors. We identified eight randomised controlled trials (n = 2388) using electronic databases, supplemented by a hand-search of the reference lists. All trials aimed to evaluate the efficacy of daily subcutaneous teriparatide injection in postmenopausal osteoporosis. The main outcomes were fracture risk and percentage change of BMD from baseline. Data were pooled by employing a random-effect model. In trials that reported BMD as an outcome, treatment was associated with an increase of bone mass of 8.14% [95% confidence interval (CI): 6.72-9.55%; eight trials, n = 2206] in spine and 2.48% (95% CI: 1.67-3.29%; seven trials, n = 1303) at the hip. In trials that reported fracture as an outcome, treatment was associated with a 70% risk reduction in vertebral fractures (risk ratio 0.30, 95% CI: 0.21-0.44; three trials, n = 1452) and 38% risk reduction in non-vertebral fractures (risk ratio 0.62, 95% CI: 0.44-0.87; three trials, n = 1842). The PTH treatment with total calcium intake more than 1500 mg was related to a significant increase in BMD gains at total hip (1.40% vs. 3.72%; p = 0.004). However, long-term duration did not appear to contribute to differences in responsiveness to teriparatide. Evidence supports the use of teriparatide in treatment of women with postmenopausal osteoporosis who are at risk for fracture. Further studies directly comparing concurrent therapy and calcium supplement with long-term duration are warranted.


Isolation and morphological characterization of El Tor cholera phages.
Five bacteriophages have been isolated for phage typing of Vibrio cholerae biotype El Tor. The morphology of these phages has been studied by electron microscopy.


An LH1-RC photocomplex from an extremophilic phototroph provides insight into origins of two photosynthesis proteins.
Rhodopila globiformis is the most acidophilic of anaerobic purple phototrophs, growing optimally in culture at pH 5. Here we present a cryo-EM structure of the light-harvesting 1-reaction center (LH1-RC) complex from Rhodopila globiformis at 2.24 Å resolution. All purple bacterial cytochrome (Cyt, encoded by the gene pufC) subunit-associated RCs with known structures have their N-termini truncated. By contrast, the Rhodopila globiformis RC contains a full-length tetra-heme Cyt with its N-terminus embedded in the membrane forming an α-helix as the membrane anchor. Comparison of the N-terminal regions of the Cyt with PufX polypeptides widely distributed in Rhodobacter species reveals significant structural similarities, supporting a longstanding hypothesis that PufX is phylogenetically related to the N-terminus of the RC-bound Cyt subunit and that a common ancestor of phototrophic Proteobacteria contained a full-length tetra-heme Cyt subunit that evolved independently through partial deletions of its pufC gene. Eleven copies of a novel γ-like polypeptide were also identified in the bacteriochlorophyll a-containing Rhodopila globiformis LH1 complex; γ-polypeptides have previously been found only in the LH1 of bacteriochlorophyll b-containing species. These features are discussed in relation to their predicted functions of stabilizing the LH1 structure and regulating quinone transport under the warm acidic conditions.


[Interference microscopic determinations of dry mass of cell nuclei of normal and dysplastic epithelium, carcinoma in situ and cervical carcinoma cultivated in vitro (author's transl)].
Dry mass of cell nuclei was studied in 34 explant cultures of normal epithelium (8), persisting dysplasias (7), Ca in situ (9) and cervical carcinomas (10) by interference microscopic determination. Dysplasias, Ca in situ and carcinomas can be distinguished from normal epithelium by a significantly higher dry mass value. Such a difference does not exist between dysplasia and Ca in situ. The percentage of dispersion of the dry mass is significantly higher in carcinomas than in all other examined tissues. The biological meaning of these results is discussed. The interference microscopic determination of dry mass of the cell nuclei is a suitable parameter for the characterization of properties of cervical carcinomas and their intraepithelial prestages cultivated in vitro.


Prognosis of decompensated heart failure patients with preserved systolic function is predicted by NT-proBNP variations during hospitalization.
Almost half of heart failure (HF) patients have preserved left ventricular systolic function (LVSF). Although morbidity is similar in patients with preserved and depressed LVSF, clinicians have limited information on prognostic factors of patients with preserved LVSF. We aimed to evaluate the prognostic value of NT-proBNP in patients with decompensated HF regardless of LVSF. Patients hospitalised due to decompensated HF were followed for 6 months. The primary endpoint was death or hospital readmission. We evaluated 224 patients with NT-proBNP measured at admission and discharge and an echocardiogram performed. NT-proBNP decreased on average during hospitalization in patients with preserved LVSF (n=63) and in patients with depressed LVSF (n=161). The morbidity was not different between patients with preserved and depressed LVSF. Among patients with preserved LVSF, predictors of adverse events were serum creatinine, haemoglobin, NT-proBNP levels at discharge and the variation in NT-proBNP during hospitalisation. Among patients with depressed LVSF, predictors of adverse events were female gender, atrial fibrillation, non-prescription of ACE-inhibitor at discharge, NT-proBNP levels at discharge and the variation in NT-proBNP during hospitalisation. These results suggest that, in HF patients with preserved LVSF as in patients with depressed LVSF, NT-proBNP can play a role as a tool to identify patients at risk of an adverse outcome.


Retinoic acid-mediated repression of human papillomavirus 18 transcription and different ligand regulation of the retinoic acid receptor beta gene in non-tumorigenic and tumorigenic HeLa hybrid cells.
Human papillomavirus type 18 (HPV18) belongs to the group of genital papillomaviruses involved in the development of cervical carcinomas. Since retinoic acid (RA) is a key regulator of epithelial cell differentiation and a growth inhibitor in vitro of HPV18-positive HeLa cervical carcinoma cells, we have used HeLa and HeLa hybrid cells in order to analyse the effects of RA on expression of the HPV18 E6 and E7 oncogenes and of the cellular RA receptor genes RAR-beta and -gamma. We show here that RA down-regulates HPV18 mRNA levels apparently due to transcriptional repression. Transient cotransfection assays indicated that RARs negatively regulate the HPV18 upstream regulatory region and that the central enhancer can confer RA-dependent repression on a heterologous promoter. RA treatment resulted in induction of RAR-beta mRNA levels in non-tumorigenic HeLa hybrid cells, but not in tumorigenic hybrid segregants nor in HeLa cells. No alterations of the RAR-beta gene or of the HeLa RAR-beta promoter could be revealed by Southern and DNA sequence analysis, respectively. As determined by transient transfection assays, however, the RAR-beta control region was activated by RA more strongly in non-tumorigenic hybrid cells than in HeLa cells, thus indicating differences in trans-acting regulatory factors. Our data suggest that the RARs are potential negative regulators of HPV18 E6 and E7 gene expression, and that dysregulation of the RAR-beta gene either causatively contributes to or is an indicator of tumorigenicity in HeLa and HeLa hybrid cells.


Comprehensive analysis of N1-methylandenosine regulators and m1A-related mRNAs and lncRNAs as prognostic factors in bladder cancer.
Bladder cancer (BC) is a lethal malignancy and recurs frequently. m1A plays a vital role in maintaining the biological functions of non-coding RNAs. The Cancer Genome Atlas (TCGA) is a free website from where transcriptome data of BC were obtained. We chose m1A methylation regulators for this study. Six m1A methylation regulator genes have a higher expression in BC tissue compared to normal tissue. The aberrant expression of those m1A regulator genes was remarkably related to BC prognosis and clinicopathological features. First, m1A-related mRNAs and long noncoding RNAs (lncRNAs) were identified. Next, univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression were performed to get the optimum RNAs for the development of prognostic signatures. Also, a nomogram with T status, lncRNA risk scores and mRNA risk scores was constructed. It revealed an adequate capacity to predict the overall survival of BC cases in the training set as well as in the testing set and in the total TCGA cohort. In conclusion, m1A methylation regulator genes played an important role in predicting the overall survival of BC patients. In addition, m1A-related lncRNAs and mRNAs illustrated underlying mechanisms of tumorigenesis and development of BC.


Epidemiological trends and seasonal dynamics of tuberculosis in Southeastern Turkey.
Tuberculosis (TB) is an important public health issue. Determining TB trend and seasonal variability provides useful information for designing treatment strategies and control programs. The present study attempts to investigate the epidemiological trend and the seasonal variations. TB data containing 2450 cases were collected over a period of seven years in the province of Diyarbakir in southeast Turkey. Trend function and seasonal variability were investigated by statistical curve fitting, surface fitting, and autoregressive time series analysis. The study revealed a gradually decreasing trend in the number of TB cases over a period of seven years. Total TB incidence had seasonal variations (P = 0.04); there was a greater number of TB cases between April and July, with a peak in June. There were significant monthly seasonal variations with June peaks among females (P < 0.001), in patients in the age groups of 0-15 (P < 0.001) and 36-45 years (P < 0.001), in new cases (P < 0.001) and in the patients with pulmonary TB (P = 0.01). The extra-pulmonary TB cases peak in May (P = 0.01). Pulmonary TB and TB patients in the 36-45 age group had summer peak, while the other groups peaked at spring. Spring and summer peaks detected in total TB cases and in many subgroups indicate that multicenter and comprehensive clinical studies are needed to explain these variations.


Intraoperative Polaroid roentgenograms.
The introduction of a new Polaroid film (TPX) prompted an evaluation of all Polaroid films that are available, and a comparison with Kodak Xomat film was done both in the experimental mode and the clinical situation. Type TPX shows excellent definition but is still an experimental film. All the other Polaroid films (Types 52, 57, and TPX 10 x 8) produce images in twenty seconds. This is really the only advantage over the conventional Kodak X-Omat KS film processed as an x-ray film.


Psychodynamic personality profile in first-episode severe mental disorders.
The aim of this study was to relate measures of psychoanalytically derived personality traits to descriptive diagnosis and psychopathology in severe mental disorders. Sixty-one consecutive first-episode patients with schizophrenia, bipolar disorder and severe major depression were interviewed. Personality traits were assessed with the Karolinska Psychodynamic Profile (KAPP) and compared with the DSM-IV diagnosis and symptom clusters derived from the BPRS. There were no marked differences in personality traits between the three diagnostic groups, between schizophrenia and affective disorders or between psychotic and non-psychotic illness. However, personality traits had significant associations with symptoms, especially with the emotional retardation cluster. Our findings do not support the hypothesis that severe mental disorders would differ from each other in terms of long-standing psychodynamic personality profiles. Certain dysfunctional personality traits may predict especially negative emotional symptoms and possibly also predispose a person to them.


Haloperidol prevents the methamphetamine-induced apomorphine subsensitivity of dopamine metabolism in rat striatum.
Our previous experiment showed that the sensitivity of striatal dopaminergic metabolism to apomorphine was lowered after pretreating rats with methamphetamine. This study further demonstrated that haloperidol administered with methamphetamine prevented the effect of the methamphetamine pretreatment. Since gamma-butyrolactone was administered in combination with apomorphine so as to remove complications which might arise from the modification of impulse flow through the striatonigral feedback loop, it is possible that the observed effect of apomorphine upon striatal dopaminergic metabolism and its antagonism with haloperidol may be mediated by autoreceptors of dopaminergic axon terminals in rat striatum.


[Puberty, fertility and chronic diseases].
The onset of puberty is the sum of complex and multifactorial mechanisms resulting from the action of both activating and inhibiting factors, leading to the maturation of the gonads and the ability to reproduce. Many contributors to pubertal development are involved in fat mass acquisition and their action is relayed through the hypothalamus. It is therefore easy to understand how chronic diseases can affect the development of puberty and fertility apart from the specific impact of their molecular alteration. We have chosen cystic fibrosis and chronic renal disease as examples of chronic disorders affecting puberty through distinct mechanisms. As drugs are undistinguishable from chronic diseases, we also describe the impact of corticosteroids and chemotherapy on reproductive function. Last, we describe the surveillance and care of pubertal delay and its consequences (growth and bone mineralization) of patients affected with chronic disorders during adolescence.


The superstructure of chromatin and its condensation mechanism. III: Effect of monovalent and divalent cations X-ray solution scattering and hydrodynamic studies.
Solutions of rat liver and chicken erythrocyte chromatin at different ionic strengths were characterized by synchrotron X-ray solution scattering, ultracentrifugation, density and viscosity measurements. Previous observations on nuclei were extended to rat liver, calf thymus and yeast nuclei. It is shown that with monovalent cations condensation is independent of the nature of the cation whereas with divalent cations there are significant differences related to the preference of base binding over phosphate binding. The consistency of hydrodynamic and scattering results confirm the view that chromatin in solution at low ionic strength has a helix-like superstructure. A survey of X-ray and neutron scattering results in the literature shows that previous interpretations, e.g. in terms of a 10 nm filament, are incompatible with the experimental data at low resolution.


Effect of chronic ethanol treatment on peroxisomal acyl-CoA oxidase activity and lipid peroxidation in rat liver and heart.
Chronic ethanol administration was shown to increase catalase and acyl-CoA oxidase activities in rat myocardium but did not alter the activity of liver peroxisomal enzymes. As a result of alcohol consumption a 2-3-fold increase in the level of lipid peroxidation was observed in the heart tissue while in the liver the induction was much less pronounced.


Inducible polymorphous ventricular tachycardia following Mustard operation for transposition of the great arteries.
A 22-year-old woman with chronic atrial tachycardia following Mustard's operation for transposition of the great arteries presented with dizziness and ventricular tachycardia documented with dynamic 24-h electrocardiogram. During intracardiac electrophysiology study, programmed ventricular extrastimulation induced polymorphous ventricular tachycardia (torsades de pointes). This was prevented by intravenous administration of procainamide. We postulate that polymorphous ventricular tachycardia is a possible cause of death in patients with Mustard's operation. Postoperative electrophysiologic study may define those patients at risk to develop this potentially fatal arrhythmia.


Separation of the four stereoisomers of a potent inhibitor (L-694,458) of human leukocyte elastase and its determination in human plasma using achiral/chiral chromatography with column switching.
A stereoselective method based on high-performance liquid chromatography (HPLC) and ultraviolet detection at 235 nm for the separation of the four possible stereoisomers of compound 1 ((S-(R*,S*))-2-(4-((4-methylpiperazin-1-yl)carbonyl)phenoxy)-3,3-d iethyl-N-(1-(3,4-(methylenedioxy)phenyl)butyl)-4-oxo-1-azetidinecarbo xamide, L-694,458), a potent, selective, and orally active human leukocyte elastase (HLE) inhibitor, in human and monkey plasma has been developed. The molecule of 1 contains two chiral centers and is being developed as a single stereoisomer with the absolute configuration S and R in positions 'a' and 'b', respectively. Although the baseline separation of each of the two pairs of enantiomers (SS/RR and SR/RS) was achieved on a single chiral column (Chiralcel OD-H) using hexane methyl-t-butyl ether (MTBE)-methanol 80/10/10, (v/v/v) as a mobile phase (alpha(RS,SR) = 2.03, alpha(RR,SS) = 4.97), only partial separation of RS from RR was observed under these conditions (k'RS = 3.32, k'RR = 3.08). Baseline separation of all four stereoisomers from each other and from endogenous plasma components required the initial chromatography of the two diastereomeric racemates (SS/RR and SR/RS) on the achiral silica column (50 x 4.6 mm, 5 microm), followed by column switching and further separation of the stereoisomers on a Chiralcel OD-H column (250 x 4.6 mm, 5 microm) using isopropanol (IPA)-hexane diethylamine (DEA), 65/35/0.3, (v/v/v) on both columns as a mobile phase. The drug was extracted from basified (pH 11) plasma (1 ml) using liquid liquid extraction with MTBE. After evaporation of the extract to dryness, the residue was reconstituted in the mobile phase (200 microl) and part of the extract (125 microl) was injected into the HPLC system. Using this method, it was demonstrated that after oral dosing of monkeys at 40 mg kg(-1) with 1 the only stereoisomer detected in the post-dose plasma samples was the starting material 1, and no inversion of the configuration at positions 'a' and 'b' of 1 had occurred in vivo. Based on this observation, a non-chiral assay for 1 in human plasma was also developed. The method was validated in the concentration range 10-500 ng ml(-1) with the assay precision (expressed as the coefficient of variation, CV) better than 9% and assay accuracy in the range of 95-107% of the nominal concentrations at all concentrations within the standard curve range. The total run time in the non-chiral assay was 12 min. The details of both chiral and non-chiral methods are provided.


Sensory gating in intracranial recordings--the role of phase locking.
For patients with schizophrenia, a deficient gating (or filtering) of sensory input has been described. One major approach to study this sensory gating is to measure event-related potentials (ERPs) in response to paired clicks. In these experiments, sensory gating is quantified as amplitude reduction of the ERP components P50 and N100 from the 1st to the 2nd stimulus. In ERP studies brain electrical signals are averaged over single trials. Alterations in phase locking might be one factor contributing to the observed deficits in sensory gating, but findings have been inconclusive as yet. In particular, the contribution of different frequency bands to the deficit required further investigation. We studied N100 gating by intracranial recordings in a sample of epilepsy patients and subdivided the group into good and poor gators of the intracranial ERP component N100. Data were evaluated by frequency specific wavelet-based phase and power analyses. Poor N100 gators had an increased phase locking in the frequency range from 6.0-15.1 Hz after the 2nd stimulus, as compared to good gators. Other group differences were apparent already before the 2nd stimulus. Poor gators had less phase locked beta band activity (20.2-30.0 Hz) than good gators 200-315 ms after the onset of the 1st stimulus. Within the group of poor gators, lower values of phase locking in this frequency range were also associated with lower gating ratios. The reduced beta band response in response to the 1st stimulus may reflect poorer memory encoding of the 1st stimulus in poor gators. This in turn might lead to increased demands to process the 2nd stimulus.


Photodynamic therapy with hyperbranched poly(ether-ester) chlorin(e6) nanoparticles on human tongue carcinoma CAL-27 cells.
Hyperbranched polymers represent a new class of drug-delivery vehicle that can be used to prepare nanoparticles with uniform size distribution. In this study we prepared covalent conjugates between the photosensitizer chlorin(e6) and hyperbranched poly(ether-ester), HPEE. HPEE-ce6 nanoparticles were synthesized by carbodiimide-mediated reaction between HPEE and ce6, and characterized by ultraviolet-visible absorption spectroscopy (UV-Vis), and transmission electron microscopy (TEM). The uptake and phototoxicity of HPEE-ce6 nanoparticles towards human oral tongue cancer CAL-27 cells was detected by confocal laser scanning microscopy (CLSM) and MTT assay, respectively. The absorption peak of HPEE-ce6 nanoparticles was red-shifted 12-nm compared with ce6, and TEM showed uniform nanoparticles with a diameter of 50-nm. HPEE-ce6 nanoparticles were taken up by CAL-27 cells after 4h incubation and localized in the cytoplasm. The MTT assay showed a significantly (P<0.05) higher phototoxicity compared to free ce6 after 12 J/cm² of 660-nm laser illumination. This is the first time to our knowledge that hyperbranched polymers have been used in PDT drug delivery.


Effect of FXR agonist GW4064 in the treatment of hilar cholangiocarcinoma in rats.
The study objective was to observe the treatment effect of the farnesoid X receptor (FXR) agonist GW4064 in a rat model of hilar cholangiocarcinoma to explore a new therapeutic target for gene therapy for hilar cholangiocarcinoma. Eighty male Wistar rats were randomly divided into four groups (treatment group, model group, control group and sham operation group, 20 rats in each group). The four groups were fed a standard diet. The treatment group and the model group were injected with a suspension of cholangiocarcinoma QBC939 cells into the hilar bile duct with a microsyringe, the control group was injected with normal saline, and the sham operation group was not injected with anything. A modified tail suspension test (TST) was used to evaluate the vitality of the rats. At 4 weeks, one rat in the treatment group and model group was euthanized, and the changes in the hilar bile duct were recorded. The procedure was repeated at 6 weeks. After 6 weeks, hilar cholangiocarcinoma occurred in the treatment group and model group. Then, the treatment group was injected with GW4064 intraperitoneally at a dose of 50 mg/kg/day. One week after injection, the rats in the four groups were euthanized. Pathological examination confirmed that tumours had formed, and hilar bile duct tissues were taken from the four groups. FXR, Bsep, Ntcp and NF-κB expression in the hilar bile duct was detected by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. After three weeks, the rats in the treatment group and model group ate less, and their weight was significantly reduced. Six weeks later, hilar cholangiocarcinoma was detected in the treatment group and model group. After treatment with GW4064, the ratios of FXR/GAPDH mRNA, Bsep/GAPDH mRNA, Ntcp/GAPDH mRNA and NF-κBp65/GAPDH mRNA were significantly different among the four groups. Under a light microscope, FXR protein reacted with anti-FXR antibody, Bsep protein reacted with anti-Bsep antibody, Ntcp protein reacted with anti-Ntcp antibody and NF-κBp65 protein reacted with anti-NF-κBp65 antibody, and they showed granular expression. Every pathological section included 4,800 cells, and there were different numbers of positive cells in each group. FXR expression in the hilar cholangiocarcinoma of rats was significantly lower than that in normal hilar bile duct tissues. GW4064 increased the expression of FXR in tumour tissues. These findings suggest that FXR may be a new therapeutic target and that GW4064 may be helpful in the treatment of hilar cholangiocarcinoma.


Corneal lymphangiogenesis ameliorates corneal inflammation and edema in late stage of bacterial keratitis.
Lymphatic vessels play a crucial role in systemic immune response and regulation of tissue fluid homeostasis. Corneal lymphangiogenesis in bacterial keratitis has not been studied. In this study, we investigated the mechanism and the role of corneal lymphangiogenesis in a murine bacterial keratitis model using Pseudomonas aeruginosa. We first demonstrated that corneal lymphangiogenesis was enhanced mainly in the late stage of bacterial keratitis, contrary to corneal angiogenesis that started earlier. Corresponding to the delayed lymphangiogenesis, expression of the pro-lymphangiogenic factors VEGF-C and VEGFR-3 increased in the late stage of bacterial keratitis. We further found that F4/80 and CD11b positive macrophages played an essential role in corneal lymphangiogenesis. Notably, macrophages were specifically involved in corneal lymphangiogenesis in the late stage of bacterial keratitis. Finally, we demonstrated the beneficial role of corneal lymphangiogenesis in ameliorating the clinical course of bacterial keratitis. Our study showed that bacterial activity was not directly involved in the late stage of keratitis, while corneal lymphangiogenesis reduced corneal edema and clinical manifestation in the late stage of bacterial keratitis. These findings suggest that the process of lymphangiogenesis in bacterial keratitis ameliorates corneal inflammation and edema in the late stage of bacterial keratitis.


First aid knowledge of alpine mountaineers.
The study evaluates the knowledge of first aid in mountaineerers who climb routes of moderate difficulty in the western Alps. Additionally the mountaineer's ability to assess their own knowledge was investigated. An analysis of the mountain accidents in the same area showed the real need for knowledge. An investigation of a cohort of mountaineers who reached Margherita Hut (4559 m, Monte Rosa; n=283; 17 questions with five answers each (11 themes)). Knowledge in general is poor. Best results were obtained in relation to cardiac emergencies, altitude sickness, and hypovolaemic shock, and worst resulted with hypothermia, traumatic injuries, treatment of pain and management of emergencies. Although traumatic injuries represent about 50% of mountain accidents in the region, there was a general lack of basic knowledge on this subject. Self-assessment of the individuals level of knowledge and their need for further education was inadequate. Differences between sex, age, nationality, mountaineering professional experience (medical education) are discussed. First aid education of mountaineers must be improved. Adequate education should take into account the specific demands of alpine emergencies.


Early glycogenesis in the uterine glandular cells of the rabbit induced by progestins: a quantitative investigation.
A single administration of progesterone (P) to primed immature rabbits induces the appearance of glycogen in uterine glandular cells. This phenomenon, which is rapid and transitory, precedes a mitotic surge in the glandular epithelium. Ultrastructural studies allowed us to observe the beginning of glycogenesis as early as 1 h after the injection of P. Quantitative image analysis in the course of a kinetic study showed that glycogen levels reached a maximum at the sixth h and after 24 h had fallen dramatically. Promegestone, a potent progestomimetic compound, gave similar results, but estradiol, testosterone and dexamethasone failed to induce the appearance of glycogen in the uterine glands. Mifepristone (RU 486) had an antagonistic effect on the action of P. These results suggest that early P-dependent glycogenesis in the endometrial glandular cells of the rabbit may play an important role in the increased rate of mitosis and cellular proliferation that are necessary events in preparing the endometrium for implantation.


Vertebral fusion dynamics in the thoracic and lumbar spine induced by allogenic demineralized bone matrix combined with autogenous bone marrow. An experimental study in rabbits.
The aim of this study was to examine the capability of grafts consisting of demineralized bone matrix combined with autogenous bone marrow to enhance fusion in the thoracic and lumbar spines in rabbits. Thirteen rabbits were operated on, using a posterior approach. A combined intertransverse and interspinous fusion was performed. Fusion was achieved first in the lumbar segments, then in the thoraco-lumbar segments and lastly in the thoracic segments. The best results were achieved in the lumbar spine, where complete fusion occurred in 83%. The combination of demineralized bone matrix and autogenous bone marrow proved to be a reliable transplant material for experimental spinal fusion.


Hernia uteri inguinalis in a case of ovotesticular disorder of sexual differentiation.
An 18-year-old phenotypic male presented with an irreducible left inguinal mass, gynecomastia, and hypospadias. This mass on exploration was found to be a nonfunctional uterus with ipsilateral ovary and was excised. Further investigation confirmed the presence of a contralateral testis and a genotype of 46, XX. This confirmed the diagnosis of ovotesticular disorder of sexual differentiation (formerly true hermaphroditism) with obstructed hernia uteri inguinalis. The patient was raised as a male. Subcutaneous mastectomy for gynecomastia and neourethra construction with full thickness skin graft for hypospadias were performed. Hernia uteri inguinalis is rarely seen in this condition with only 2 cases being reported worldwide thus far, including our case.


Beta-arrestin is involved in the desensitization but not in the internalization of the somatostatin receptor 2A expressed in CHO cells.
The interaction of beta-arrestin-1 with the somatostatin receptor type 2A (sst2A) was monitored using both biochemical and confocal imaging approaches. We show that, using transient transfection of either beta-arrestin-1 or its dominant negative Delta-arrestin-1 in CHO cells stably transfected with the sst2A, beta-arrestin-1 is colocalized with the receptor in endosomal vesicles after somatostatin-induced sequestration. However, this interaction leads to a role of beta-arrestin-1 in the desensitization of the sst2A rather than in the internalization process of the receptor-ligand complex.


The effect of internet-delivered cognitive behavioral therapy for depression and anxiety on quality of life: A meta-analysis of randomized controlled trials.
Although numerous studies have examined the effects of internet-delivered cognitive behavioral therapy (iCBT) for depression and anxiety on quality of life, no meta-analysis has yet been conducted to integrate the results of these studies. We conducted systematic searches in PubMed, Cochrane, and PsycInfo, which included terms for treatment type, modality of delivery, condition, and main outcome. We included studies that met the following inclusion criteria: (a) randomized controlled trials, (b) patients allocated to some form of the control condition, (c) patients receiving some type of treatment of anxiety and/or depression involving Internet-delivered Cognitive Behavioral Therapy, (d) use of a validated outcome measure assessing the level of quality of life, (e) conducted with adult participants diagnosed with anxiety disorder and/or unipolar depression, (f) papers written in English. We analyzed 40 randomized controlled trials with a total of 4289 participants that met inclusion criteria. The pooled between-group effect size for the quality of life overall score was small (g = 0.35, 95 % CI: 0.26-0.44, p = .0001), favoring iCBT over the control conditions. Regarding the distinct quality of life domains measured by the World Health Organization Quality of Life Assessment, a statistically significant difference between iCBT and control conditions was found only for the physical health domain (g = 0.56, 95 % CI: 0.06-1.07, p = .029), in favor of iCBT. In both cases, heterogeneity was moderate. While the effect on the quality of life is small (the overall quality of life score) to moderate (the physical health domain score), we conclude that iCBT for depression and anxiety may be a promising approach for improving the quality of life of patients.


Trisomy 17 as a marker for a subset of noninvasive thyroid nodules with focal features of papillary carcinoma: cytogenetic and molecular analysis of 62 cases and correlation with histological findings.
Differentiated carcinomas of the thyroid are divided into follicular thyroid carcinoma and papillary thyroid carcinoma (PTC), based on their propensity to invade and their cytological features [papillary carcinoma-type nuclear changes (PTC-NCs)]. PTC typically exhibits a diploid karyotype sometimes with inv10(q11.2q21.2), leading to rearranged RET gene. Follicular thyroid carcinomas are often aneuploid and may exhibit t(2;3)(q13;p25), resulting in PAX8-PPARgamma1 gene fusion. Isolated trisomy 17 has rarely been reported in thyroid lesions, and its significance is unknown. Our objective was to determine whether isolated trisomy 17 corresponds to a specific histological or molecular thyroid tumor subset. Nine cases with isolated trisomy 17 were critically reviewed and investigated for RAS and BRAF mutations and for RET and PAX8-PPARgamma1 rearrangements. All nine cases were noninvasive, exhibited follicular growth pattern, and showed PTC-NCs focally defined within the nodule: four were PTCs follicular variant within larger tumors, and five were follicular-patterned nodules with incomplete cytological features of papillary carcinoma (variable proportion of cells with PTC-NCs scattered inside the lesion). RAS, BRAF V600E mutation, RET or PAX8-PPARgamma1 rearrangements were not identified. One case had BRAF K601E mutation. Only two of the 53 control cases showed focal PTC-NCs. Isolated trisomy 17 is associated with focal papillary carcinoma changes in follicular-patterned thyroid nodules and may be a marker for this subset of thyroid lesions that are often difficult to classify.


A single tyrosine residue in the membrane-proximal domain of the granulocyte-macrophage colony-stimulating factor, interleukin (IL)-3, and IL-5 receptor common beta-chain is necessary and sufficient for high affinity binding and signaling by all three ligands.
The beta-chain of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) receptors functions as a communal receptor subunit and is often referred to as beta common (betac). Analogous to other shared receptor subunits including gp130 and the IL-2R gamma chain, betac mediates high affinity binding and signal transduction of all of its ligands. It is not clear, however, how these common receptor subunits can recognize several ligands and indeed whether they exhibit a common binding pocket to accomplish this. We have performed molecular modeling of betac based on the known structures of the growth hormone and prolactin receptors and targeted the putative F'-G' loop for mutagenesis. Substitution of this whole predicted loop region with alanines completely abrogated high affinity binding of GM-CSF, IL-3, and IL-5. Individual alanine substitutions across the loop revealed that a single residue, Tyr421, is critical for high affinity binding of GM-CSF, IL-3, and IL-5, whereas alanine substitution of adjacent residues has little or no effect on high affinity binding. Significantly, reintroducing Tyr421 into the polyalanine-substituted mutant restored high affinity ligand binding of GM-CSF, IL-3, and IL-5, indicating that within this region the tyrosine residue alone is sufficient for high affinity ligand interaction. Functional studies measuring STAT5 activation revealed that alanine substitution of Tyr421 severely impaired the ability of betac to signal. These results show for the first time that a single residue in a shared receptor subunit acts as a binding determinant for different ligands and may have implications for other receptor systems where communal receptor subunits exhibit hydrophobic residues in their putative F'-G' loops. These results also raise the possibility that a single compound targeted to this region may simultaneously inhibit the binding and function of multiple cytokines.


Role of the aryl hydrocarbon receptor (AhR) in lung inflammation.
Millions of individuals worldwide are afflicted with acute and chronic respiratory diseases, causing temporary and permanent disabilities and even death. Oftentimes, these diseases occur as a result of altered immune responses. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, acts as a regulator of mucosal barrier function and may influence immune responsiveness in the lungs through changes in gene expression, cell-cell adhesion, mucin production, and cytokine expression. This review updates the basic immunobiology of the AhR signaling pathway with regards to inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease, and silicosis following data in rodent models and humans. Finally, we address the therapeutic potential of targeting the AhR in regulating inflammation during acute and chronic respiratory diseases.


Bi-stable block by 4-aminopyridine of a transient K+ channel (Kv1.4) cloned from ferret ventricle and expressed in Xenopus oocytes.
1. Using the two-microelectrode, 'cut open' oocyte, and 'torn off' macropatch voltage clamp techniques, we studied the blocking effects of 4-aminopyridine (4-AP) on two cloned K+ channels expressed in Xenopus oocytes, an inactivating K+ channel isolated from ferret ventricle (FK1), and its NH2-terminal deletion mutant (delta NCO) which lacks fast N-type inactivation. 2. Experiments with a permanently charged, impermeant 4-AP derivative, 4-aminopyridine-methyliodide, indicated that the cationic form of 4-AP blocks at an intracellular site. 3. Block accumulated from pulse to pulse and was sensitive to the applied potential during hyperpolarizing deactivating pulses, indicating trapping of 4-AP in deactivated channels. For long trains of depolarizing pulses (-90 to +50 mV, 0.1 Hz), 4-AP block increased with decreasing pulse duration. Block of FK1 was much more sensitive to pulse duration than was block of delta NCO, consistent with competition between N-type inactivation and 4-AP binding. 4. To elucidate these mechanisms further, in the absence of fast N-type inactivation the following results were obtained on delta NCO channels: (1) application of 4-AP caused the appearance of apparent inactivation; (2) 4-AP, however, did not cause cross-over of deactivating tail currents; (3) 4-AP block developed with time for potentials positive to -40 mV; and (4) trapping of 4-AP by delta NCO was insensitive to the degree of C-type inactivation. 5. We conclude that the kinetics of 4-AP block of FK1 and delta NCO channels cannot be accounted for by either a pure open channel or closed channel blocking scheme.


Higher urinary nitrate was associated with lower prevalence of congestive heart failure: results from NHANES.
Some studies have reported that nitrate intake from vegetables was inversely associated with many vascular diseases, but few studies have paid attention to the relationship between urinary nitrate and cardiovascular diseases (CVDs). This cross-sectional study aimed to explore the connections between urinary nitrate and prevalence of CVDs. The data of this study was collected from National Health and Nutrition Examination Survey (NHANES). Finally, several years' data of NHANES were merged into 14,894 observations. Logistic regression models were used to examine the associations between urinary nitrate and CVDs by using the "survey" package in R software (version 3.2.3). In the univariable logistic analysis, significant association was discovered between urinary nitrate and congestive heart failure, coronary heart disease, angina pectoris, myocardial infarction (all P < 0.001). By adjusting related covariates, the multivariable logistic analysis showed that the significant association only existed between urinary nitrate and congestive heart failure (OR = 0.651, 95% CI 0.507-0.838, P < 0.001). Compared to Q1 urinary nitrate level as reference, the risk for prevalent heart failure diminished along with increasing levels of urinary nitrates, (OR of Q2 level = 0.633, 95% CI 0.403-0.994), (OR of Q3 level = 0.425, 95% CI 0.230-0.783), (OR of Q4 level = 0.375, 95% CI 0.210-0.661), respectively. Moreover, urinary nitrate levels were associated with congestive heart failure in a dose-dependent manner in both 20-60 years group, 60+ years group and male, female group (P < 0.001, P = 0.011 and P = 0.009, P = 0.004). Independent of related covariates, higher urinary nitrate was associated with lower prevalent congestive heart failure.


Ceruletide suppresses endogenous dopamine release via vagal afferent system, studied by in vivo intracerebral dialysis.
Ceruletide, a cholecystokinin-related decapeptide, has been reported to have some therapeutic effects on tardive dyskinesia and other involuntary movement disorders. In order to clarify the effects of ceruletide on dopaminergic activity in the rat striatum, we measured the release of endogenous dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) after intraperitoneal administration of ceruletide (2, 20, 200 micrograms/kg) using in vivo intracerebral dialysis techniques. After administration of ceruletide (200 micrograms/kg), extracellular DA decreased significantly (P less than 0.05) for 0.5-3 h. The maximal reduction of extracellular DA (by 29%) was observed for 2-2.5 h. Extracellular DA was reduced (21%) by 20 but not by 2 micrograms/kg ceruletide. DOPAC and HVA did not change at any dose of ceruletide. We also demonstrated that bilateral subdiaphragmatic vagotomy blocked this inhibitory effect of ceruletide on DA release. These findings indicate that peripherally administered ceruletide suppresses endogenous DA release via the vagal afferent system.


Correction: A Species delimitation approach to uncover cryptic species in the South American fire ant decapitating flies (Diptera: Phoridae: Pseudacteon).
[This corrects the article DOI: 10.1371/journal.pone.0236086.].


Implications of pattern of tubal disease for microsurgery or in vitro fertilization in Lagos.
Tubal disease was found in 78 of 100 consecutive Nigerian patients who had laparoscopy for infertility, while 22 patients had patent tubes. Forty-two patients had bilateral tubal occlusion; 18 had unilateral occlusion, while 18 had gross pelvic adhesions. Forty-one patients had cornual block, and 10 had hydrosalpinges. Multiparas were more prone to unilateral tubal occlusion or gross pelvic adhesions compared with nulliparas. In 27 (35 percent) patients with tubal disease in vitro fertilization (IVF) would be the only suitable treatment, while in another 10 (12 percent) patients with hydrosalpinges, IVF probably offers a better prognosis than microsurgery.


Neuroimaging Phenotypes Associated With Risk and Resilience for Psychosis and Autism Spectrum Disorders in 22q11.2 Microdeletion Syndrome.
Identification of biological risk factors that contribute to the development of complex neuropsychiatric disorders such as psychosis and autism spectrum disorder (ASD) is key for early intervention and detection. Furthermore, parsing the biological heterogeneity associated with these neuropsychiatric syndromes will help us understand the neural mechanisms underlying psychiatric symptom development. The 22q11.2 microdeletion syndrome (22q11DS) is caused by a recurrent genetic mutation that carries significantly increased risk for developing psychosis and/or ASD. In this review, I provide an brief introduction to 22q11DS and discuss common phenotyping strategies that are used to assess psychosis and ASD in this population. I then summarize neuroimaging phenotypes associated with psychosis and ASD in 22q11.DS. Next, I discuss challenges within the field and provide practical suggestions to overcome these obstacles. Finally, I discuss future directions for moving 22q11DS risk and resilience research forward.


Hepatic low-level chemiluminescence during redox cycling of menadione and the menadione-glutathione conjugate: relation to glutathione and NAD(P)H:quinone reductase (DT-diaphorase) activity.
Formation of excited species such as singlet molecular oxygen during redox cycling (one-electron reduction-oxidation) was detected by low-level chemiluminescence emitted from perfused rat liver and isolated hepatocytes supplemented with the quinone, menadione (vitamin K3). Chemiluminescence was augmented when the two-electron reduction of the quinone catalyzed by NAD(P)H:quinone reductase was inhibited by dicoumarol, thus underlining the protective function of this enzyme also known as DT-diaphorase. Interference with NADPH supply by inhibition of energy-linked transhydrogenase by rhein or of mitochondrial electron transfer by antimycin A led to a depression in the level of photoemission. Unexpectedly, glutathione depletion of the liver led to a lowering of chemiluminescence elicited by menadione, whereas conversely the depletion of glutathione led to increased chemiluminescence levels when a hydroperoxide was added instead of the quinone. As the GSH conjugate of menadione, 2-methyl-3-glutathionyl-1,4-naphthoquinone, studied with microsomes, was shown also to be capable of redox cycling, we conclude that menadione-induced chemiluminescence of the perfused rat liver does not only arise from menadione itself but from the menadione-GSH conjugate as well. Therefore, the conjugation of the quinone with glutathione is not in itself of protective nature and does not abolish semiquinone formation. A biologically useful aspect of conjugate formation resides in the facilitation of biliary elimination from the liver. Nonenzymatic formation of the conjugate from menadione and GSH in vitro was found to be accompanied by the formation of aggressive oxygen species.


Links between Adolescents' Deep and Surface Learning Approaches, Problematic Internet Use, and Fear of Missing Out (FoMO).
This study was aimed at exploring links between adolescents' deep and surface approaches to learning, Fear of Missing Out (FoMO), and Problematic Internet Use (PIU) by using Partial Least Squares Structural Equation Modeling (PLS-SEM). The analysis corroborated the postulated positive links between surface learning, FoMO, and PIU. Moreover, the FoMO construct represented a complimentary mediation between the surface learning approach and PIU constructs. This study may lead to a plausible inference according to which both FoMO and surface learning share a common core characteristic of decreased levels of self-regulation that might lead to PIU. Having students acquire and practice skills of self-regulation might help them control their levels of FoMO, and consequently their PIU at schools or out-of-school learning environments.


The morphometric relationship of Upper Cave 101 and 103 to modern Homo sapiens.
Since the discovery of the Homo sapiens crania from the Upper Cave of Zhoukoudian in northern China (UC 101, UC 102, and UC 103), no clear consensus has arisen regarding their affinities with modern populations. We use linear craniofacial measurements to compare UC 101 and UC 103 to a worldwide sample of H. sapiens that includes Paleoamericans and Archaic Indians, and employ Mahalanobis distance analysis and associated unweighted, unrestricted canonical variate analysis for the comparisons. Analyses indicate that UC 101 has consistent affinities with Easter Island and European populations, whereas UC 103 has more tenuous similarities with Australo-Melanesian groups. Both fossils exhibit some similarities to certain Paleoamerican and Archaic Indian individuals, but rarely cluster together. Upper Cave 103 is more of an outlier to modern populations than is UC 101. The fossils are not representative of any group to which they have been compared, but may be part of the generalized population that was ancestral to Paleoamericans.


The early phase of critical illness is a progressive acidic state due to unmeasured anions.
Stewart's and Fencl's methods have recently been proposed to interpret acid-base disorders where traditional theory has proven inadequate. Our objectives were to evaluate: (1) the occurrence of acid-base disturbances in critically ill patients and their trend over the first 3 intensive care unit days, (2) whether Stewart's theory offers advantages over the traditional theory in the diagnosis of acid-base metabolic disturbances and (3) whether variables derived from Stewart's and Fencl's methods offer advantages over the traditional method to predict patient mortality. A prospective cohort study in a general intensive care unit. Blood samples were analysed for arterial blood gases, electrolytes and proteins. PaCO2, pH, bicarbonate, base excess, standard base-excess, sodium, potassium, chloride, phosphorous, calcium, magnesium and lactate were measured. Anion gap, Stewart's and Fencl's variables were calculated. When using Stewart's method, metabolic acidosis and metabolic alkalosis were found in 92.9% and 93.4% of samples, respectively. Corresponding figures obtained with the traditional method were 15% and 18.7%. In 245 (64.5%) samples, Stewart's method revealed that metabolic acidosis and alkalosis were simultaneously present, whereas the traditional method revealed a normal acid-base status. Strong ion gap increased significantly over the first 3 intensive care unit days. Strong ion gap and lactate were independent predictors of 28-day mortality. Metabolic acidosis by unmeasured anions is a clinically relevant phenomenon, which is correlated with mortality. Progressive metabolic acidosis may be ongoing in the early phase of critical illness despite the absence of acidaemia.


Faecal steroid loss in healthy subjects during short-term treatment with ursodeoxycholic acid.
Faecal steroid loss in healthy subjects during short-term treatment with ursodeoxycholic acid has been investigated. The data shows conclusively that lithocholic acid, a known co-mutagen and co-carcinogen is the major bacterial metabolite of ursodeoxycholic acid in the human intestine. Although ursodeoxycholic acid is now the drug of choice for dissolution of cholesterol gallstones, elevation of intestinal lithocholic acid may have long-term repercussions since it has been demonstrated that a high faecal lithocholic acid: deoxycholic acid ratio shows a positive correlation with the incidence of colorectal cancer.