Organochlorine pesticide contamination of ground water in the city of Hyderabad.
Organochlorine pesticides are ubiquitous and persistent organic pollutants used widely throughout the world. Due to the extensive use in agriculture, organic environmental contaminants such as HCH, DDT along with other organochlorine pesticides are distributed globally by transport through air and water. The main aim of present study is to determine contamination levels of organochlorine pesticides in the ground water of Hyderabad City. Water samples were collected from 28 domestic well supplies of the city. For this study, random sampling technique was applied, all the samples were collected in high purity glass bottles and refrigerated at 4 degrees C until analysis. Solid Phase Extraction (SPE) is used for the extraction of organochlorine pesticide residues in water sample. The collected water samples were pre-filtered through a 0.45 microg glass fiber filter (Wattman GF/F) to remove particulate matter and were acidified with hydrochloric acid (6N) to pH 2.5. Methanol modifier (BDH, for pesticide residue analysis, 10 mL) was added to water sample for better extraction. SPE using pre-packed reversed phase octadecyl (C-18 bonded silica) contained in cartridges was used for sample preparation. Prior to the extraction, the C-18 bonded phase, which contains 500 mg of bonded phase, was washed with 20 mL methanol. The sample was mixed well and allowed to percolate through the cartridges with flow rate of 10-15 mL/min under vacuum. After sample extraction, suction continued for 15 min to dry the packing material and pesticides trapped in the C-18 bonded phases were eluted by passing 10 mL hexane and fraction was evaporated in a gentle steam of Nitrogen. In all samples pesticide residues were analyzed by GC (Chemito-8510) with Ni63 ECD detector. Helium was used as carrier gas and nitrogen was used as make up gas. The injection technique was split/split less. All the samples analyzed were found to be contaminated with four pesticides i.e. DDT, beta-Endosulfan, alpha-Endosulfan and Lindane. DDT was found to range between 0.15 and 0.19 microg L(-1), beta-Endosulfan ranges between 0.21 and 0.87 microg L(-1), alpha-Endosulfan ranges between 1.34 and 2.14 microg L(-1) and Lindane ranges between 0.68 and 1.38 microg L(-1) respectively. These concentrations of pesticides in the water samples were found to be above their respective Acceptable Daily Intake (ADI) values for Humans.


Geographic access to buprenorphine prescribers for patients who use public transit.
Urban Medicaid enrollees with opioid use disorder often rely on public transit to reach buprenorphine prescribers. Research has not shown whether public transit provides this population with adequate geographic access to buprenorphine prescribers. We examined travel times to buprenorphine prescribers by car and public transit in urban areas, and determined whether car-based Medicaid regulatory standards produce their intended geographic coverage. We obtained data for this study from the Substance Abuse and Mental Health Services Administration's Buprenorphine Practitioner Locator, Microsoft Bing Maps, and the American Community Survey. We examined four urban counties at the centers of the metropolitan statistical areas with the highest 2017 accidental drug poisoning death rates: Kanawha, WV; Montgomery, OH; Philadelphia, PA; and St. Louis City, MO. These counties comprised 696 census tracts representing 1,038,564 households. We calculated travel times from each census tract center to the nearest buprenorphine prescribers by car and public transit, and compared that to 30-min regulatory standards and by whether census tracts had below median levels of car access. We calculated Global Moran's I statistics to determine whether spatial clustering was present among census tracts with limited access to buprenorphine prescribers. Households in all but two census tracts could access a buprenorphine prescriber within 30 min by car. However, households in 12.1% (84) of census tracts could not do so by public transit. The correlation between car- and public transit-based travel times to the nearest buprenorphine prescriber was 0.11 (95% CI = 0.07-0.22). More than 15% (47,918) of households in the two less densely populated counties could not travel to the nearest prescriber in 30 min and resided in census tracts where access to cars was relatively low. There was no evidence of spatial clustering among census tracts with public transit travel times exceeding 30 min, or among census tracts with public transit travel times exceeding 30 min and below median values of access to cars. Geographic access to buprenorphine prescribers is overestimated by regulatory standards that apply car-based travel time estimates, which are a weak proxy for public transit-based travel times. Since geographic areas with limited access to buprenorphine prescribers do not tend to cluster near one another, individually targeted interventions may be necessary to improve buprenorphine access and utilization.


Intratumor injection as a more effective means of porphyrin administration for photodynamic therapy.
Photodynamic therapy (PDT) with hematoporphyrin derivative (HpD) as the photosensitizer is a promising new cancer treatment. The major drawback of this procedure is the resulting skin photosensitivity. Patients must remain in subdued light for four to six weeks to avoid cutaneous phototoxicity. In this study, we examine the possibility of reducing the skin photosensitization while maintaining the tumor phototoxic effect by administering the drug directly into the tumor. A subcutaneously implanted mouse bladder tumor (MBT-2) was used. HpD was administered either intraperitoneally (I.P.; 20 mg./kg. b.w.) or by intratumor injection (I.T.; 0.4 mg./cc tumor). The concentrations of HpD in tumor and various tissues (skin, muscle, liver, spleen, kidney, bladder and whole blood) were analyzed at various times after the injection, by 3H-HpD method and by a fluorometric method. Results indicated that at three to 96 hours after the administration, porphyrin levels in tumor were about three to 15 times higher by I.T. than by I.P. injection, while the concentrations in skin and other tissues were 1.3 to 10 times lower. Consequently, at 24 hours after injection ratios between tumor to skin porphyrin were 14 to 92 times higher for I.T. than I.P. injection. Higher porphyrin levels in tumor and lower in normal tissues would indicate lower skin photosensitivity, systemic cytotoxicity and possible greater tumor photosensitivity. This method of porphyrin administration may be useful for the PDT of certain single lesions that are accessible for direct injection.


Interaction of metal ions with D-glucobenzothiazoline: isolation and characterization of the resultant products.
Six different metal-ion complexes of D-glucobenzothiazoline were synthesized and characterized by analytical and spectral techniques. Formation of different types of species (ML and ML(2)) were observed with Cu(2+), Ag(+), Cd(2+), Hg(2+), and Zn(2+) ions. Existence of an anomeric mixture in the case of the Cu(2+) complex is identified from the EPR spectra, and the results were further supported by the simulated spectra. The structures were proposed based on different studies.


Diagnostic errors in older patients: a systematic review of incidence and potential causes in seven prevalent diseases.
Misdiagnosis, either over- or underdiagnosis, exposes older patients to increased risk of inappropriate or omitted investigations and treatments, psychological distress, and financial burden. To evaluate the frequency and nature of diagnostic errors in 16 conditions prevalent in older patients by undertaking a systematic literature review. Cohort studies, cross-sectional studies, or systematic reviews of such studies published in Medline between September 1993 and May 2014 were searched using key search terms of "diagnostic error", "misdiagnosis", "accuracy", "validity", or "diagnosis" and terms relating to each disease. A total of 938 articles were retrieved. Diagnostic error rates of >10% for both over- and underdiagnosis were seen in chronic obstructive pulmonary disease, dementia, Parkinson's disease, heart failure, stroke/transient ischemic attack, and acute myocardial infarction. Diabetes was overdiagnosed in <5% of cases. Over- and underdiagnosis are common in older patients. Explanations for over-diagnosis include subjective diagnostic criteria and the use of criteria not validated in older patients. Underdiagnosis was associated with long preclinical phases of disease or lack of sensitive diagnostic criteria. Factors that predispose to misdiagnosis in older patients must be emphasized in education and clinical guidelines.


Ethanol inhibits neural cell-cell adhesion.
Gestational exposure to ethanol causes defects in neuronal migration, fasciculation, and synaptogenesis, developmental events that depend on the patterned expression and function of cell adhesion molecules (CAMs). Recombinant human osteogenic protein-1 (hOP-1) increases cell-cell adhesion and promotes cell clustering in proliferating neuroblastoma x glioma hybrid NG108-15 cells by strongly inducing N-CAM and L1. Here we show that concentrations of ethanol achieved during social drinking inhibit hOP-1-induced cell clustering without affecting cell proliferation, the induction and cell surface expression of N-CAM and L1, or the alternative splicing and sialylation of N-CAM. This inhibition was reproduced by other alcohols in proportion to their chain length, but not by teratogenic anticonvulsants or phenylalanine. Ethanol inhibition of hOP-1 morphogenesis was inversely proportional to the concentration of hOP-1 and, hence, to the levels of N-CAM and L1. Low concentrations of ethanol (IC50 5-10 mM) inhibited cell-cell adhesion in hOP-1-treated cells, and this action too was reproduced more potently by propanol and butanol. Ethanol may perturb brain and skeletal development by inhibiting CAM-mediated cell-cell interactions.


Local administration of curcumin-loaded nanoparticles enhances periodontal repair in vivo.
The aim was to assess the influence of local application of curcumin-loaded nanoparticles on an experimental model of periodontal repair. Periodontitis was induced by ligatures on both lower first molars of rats. After 15 days, ligatures were removed ("treatment") and animals were randomly allocated to three experimental groups (n = 8/group): (i) 0.05 mg/ml curcumin-loaded nanoparticles, (ii) empty nanoparticles (vehicle control), and (iii) sterile saline (negative control). Experimental treatments were administered locally on days 0, 3, 5, 7, 9, and 11 after ligature removal. Animals were euthanized at 7 and 14 days. Bone repair was assessed by microcomputer tomography (µCT). Histological sections were stained with hematoxylin/eosin (H/E), Picrosirius Red, and Masson's trichrome. Expression of Runx-2 was studied by immunohistochemistry. Gene expression of Itgam, Arg1, and Inos was assessed by RT-qPCR. At 7 days, there was increased gene expression of Itgam and Arg1 and of the relative expression of Arg1/Inos in curcumin-treated animals, but no difference in any other outcomes. At 14 days, curcumin-loaded nanoparticles significantly increased bone repair and collagen content, as well as the number of osteocytes, percentage of extracellular matrix, and expression of Runx2. The results demonstrate that local administration of curcumin-loaded nanoparticles enhanced tissue repair in an experimental model of periodontal repair. Nanoparticle-encapsulated curcumin enhances early post-treatment repair of periodontal tissues.


Functional osteoclast-like transformation of cultured human myeloma cell lines.
Hyperactive osteoclastogenesis is a hallmark of multiple myeloma, a B cell neoplasia homing to bone marrow and resulting in multiple osteolytic lesions and skeleton devastation. We provide evidence that myeloma cells can themselves act as osteoclasts in vitro. By extending standard cultures of U-266 and MCC-2 myeloma cell lines, we found that subsets of adherent cells also expressed the osteoclast phenotype, including multinuclear morphology, cytoplasmic tartrate-resistant acid phosphatase, the calcitonin receptor and a specific osteoclast antigen. These subsets resorbed bone substrates by producing osteoclast enzymes as well as the characteristic redistribution of F-actin in their cytoskeleton, thus forming the sealing zone that is adopted by adherent osteoclasts to generate the acidified environment essential for bone resorption. Neither the phenotype nor the functional properties of osteoclasts were detected in parental non-adherent cells. In adherent cultures osteoclastogenesis was associated with deregulated expression of both receptor activator of nuclear transcription factor (NF)-kappaB (RANK) and its ligand RANK-L, which triggers cell maturation in osteoclast precursors. Resorption of bone substrates was prevented by a neutralising anti-RANK-L antibody. Our data indicate that osteoclast-like transformation of both U-266 and MCC-2 cellular models of human myeloma is dependent on RANK-L stimulation.


Plausibility of Daphnia magna as an alternative experimental model to evaluate effects on eicosanoid synthesis.
Eicosanoids play important roles in inflammation, allergy, fever, and immune responses. In the eicosanoid pathway, cyclooxygenase (COX) catalyzes the conversion of arachidonic acid to prostaglandins and is a crucial target of nonsteroidal anti-inflammatory drugs (NSAIDs). Thus, toxicological studies on the eicosanoid pathway are important for drug discovery and the evaluation of adverse health outcomes due to environmental contaminants. However, experimental models are limited owing to concerns regarding ethical standards. Thus, new alternative models for evaluating toxic effects on the eicosanoid pathway must be developed. To this end, we adopted an invertebrate species, Daphnia magna, as an alternative model. D. magna was exposed to ibuprofen, a major NSAID, for 6 and 24 h. Transcription of eicosanoid-related genes (pla2, cox, pgd synthase, pgd2r2, ltb4dh, and lox) was analyzed by qPCR, eicosanoids (arachidonic acid, prostaglandin F2, dihydroxy prostaglandin F2, and 5-hydroxyeicosatetraenoate) were quantified by multiple reaction monitoring, and enzyme-linked immunosorbent assay was used to determine protein levels of arachidonic acid and prostaglandin E2 (PGE2). After 6 h of exposure, transcription of the pla2 and cox genes was downregulated. In addition, the whole-body level of arachidonic acid, an upstream of COX pathway, increased by over 1.5-fold. The levels of PGE2, a downstream of COX pathway, decreased after 24 h of exposure. According to our results, it is expected that the eicosanoid pathway might be conserved in D. magna, at least partially. This indicates the plausibility of D. magna as an alternative model for the screening of new drugs or chemical toxicity.


A BAC contig of approximately 400 kb contains the classical class I major histocompatibility complex (MHC) genes of cattle.
A cattle BAC library derived from an MHC homozygous animal was screened for MHC class I genes. This revealed at least nine class I-related genes in a contig spanning approximately 400 kb, and several additional genes on other clones. The three classical class I genes expressed on this haplotype (A14) were shown to be distributed over a region at most 212 kb apart.


Virtual Patient Journey: a novel learning resource.
Virtual Patient Journey (VPJ) is a novel online resource that follows a patient through their illness and integrates first-person video content with in-video decision making, allowing the student to take on the responsibility of a health care professional. The aim of our project was to compare this new VPJ format with standard teaching tutorials. Third-year medical students selected from two Bristol hospitals were allocated to either the VPJ format or a typical tutorial-style teaching session. Both formats covered an identical level and scope of material and lasted the same length of time. Data were collected on pre- and post-test knowledge and confidence gain using self-reported questionnaires at the time of the teaching. The study recruited 30 students. The average knowledge gain for the VPJ group and for the tutorial group was 39% and 35%, respectively. The confidence increase was 2.4 and 1.8 on a scale of 1-10 for the VPJ and tutorial groups, respectively. Of the students who used the VPJ, 92% believed that it was a useful teaching resource and 96% enjoyed the VPJ experience and would re-watch the material at home. VPJ can expose students to clinical situations that they may not see on placement and can help to deliver a baseline level of clinical exposure and knowledge. Our VPJ may help overcome the rigidity of current virtual patients in teaching a range of core competencies and also allowing the students to take responsibility for a patient's care in a safe, controlled environment.


Role of limbic system in the control of hamster growth.
Rostral septal lesions accelerate somatic growth in adult hamsters. This study tested the hypothesis that this effect results from damage to fibers of passage by observing the effects of transections of septohippocampal and septohypothalamic connections on growth. We attempted to identify these fibers further by (a) measuring spectrofluorometrically changes in the monoamine concentrations in hippocampus, cerebral cortex, corpus striatum, and diencephalon, (b) staining the degenerating axons after septal lesions and the two cuts, and (c) examining the correspondence between such damage and the acceleration of growth. Both knife cuts accelerated somatic growth and were associated (as well as septal lesions) with significant depletions of serotonin (-27 to -57%) and norepinephrine (-27 to -60%) in the hippocampus, with less consistent depletions of these monoamines in the cerebral cortex, and with no changes in regional dopamine content. All three procedures were associated with degeneration in the hippocampal formation and its fiber systems. Thus, fibers interconnecting hippocampus and brainstem, and passing through septum, exert tonic suppression over somatic growth in adult hamsters.


Is it safe? Exploring positive and negative outcome changes following a web-based intervention for adolescents distressed by a visible difference (YP Face IT).
Despite the importance of making sure that psychological interventions are safe, research including both positive and negative effects of novel internet-delivered support is scarce. The aim of our study was to explore whether, and in what way, a new intervention for adolescents distressed by a visible difference (YP Face IT; YPF, Norwegian version) led to positive and/or negative outcome changes. Participants were 79 adolescents (62.00% girls; Mage = 13.84, SD = 1.73), with a visible difference. All had access to the YPF programme and answered questionnaires assessing social anxiety and body esteem pre- and post-intervention. Analyses included calculations of statistical as well as clinically significant and reliable changes. Results showed that fewer participants reported clinical levels of social anxiety and low body esteem after access to YPF. Results also indicated that participants who had a positive pre- to post-intervention change had lower levels of perceived self-worth pre-intervention, and spent more time on the intervention than those with a negative pre- to post change. Three participants showed a clinically significant negative and reliable change in social anxiety or body esteem from pre- to post-intervention. However, based on an examination of these participants' characteristics, preliminary findings support the safety of YPF.


Broadband Silicon-On-Insulator directional couplers using a combination of straight and curved waveguide sections.
Broadband Silicon-On-Insulator (SOI) directional couplers are designed based on a combination of curved and straight coupled waveguide sections. A design methodology based on the transfer matrix method (TMM) is used to determine the required coupler section lengths, radii, and waveguide cross-sections. A 50/50 power splitter with a measured bandwidth of 88 nm is designed and fabricated, with a device footprint of 20 μm × 3 μm. In addition, a balanced Mach-Zehnder interferometer is fabricated showing an extinction ratio of >16 dB over 100 nm of bandwidth.


Comparison Between the Original and Shortened Versions of the National Institutes of Health Stroke Scale in Ischemic Stroke Patients of Intermediate Severity.
The 15-item National Institutes of Health Stroke Scale (NIHSS) has been critiqued for its complexity and variability, and shortened versions have been proposed. This study aimed to compare the measurement properties of the original version with 3 shortened versions with 11, 8, and 5 items, respectively. Analyses were performed using data from an international, double-blind randomized controlled trial investigating the efficacy of MLC601 on stroke recovery in patients with ischemic stroke of intermediate severity (Chinese Medicine Neuroaid Efficacy on Stroke recovery [CHIMES]). To compare discriminative ability and responsiveness to change, the effect sizes of the NIHSS scores in relation to modified Rankin Scale, mini-mental status examination, and Barthel index were estimated using regression analysis. For both discriminative ability and responsiveness to change, the original version exhibited a larger effect size (0.55 and 0.84) in relation to modified Rankin Scale than the other 3 shortened versions (0.35-0.46 and 0.74-0.78). The original 15-item NIHSS retained information that made it more discriminative and responsive to change than the shortened versions. We recommend future clinical researchers to use the full version NIHSS to evaluate patients' stroke severity. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723.


Membrane gas diffusion measurements with MRI.
Gas transport across polymeric membranes is fundamental to many filtering and separation technologies. To elucidate transport mechanisms, and understand the behaviors of membrane materials, accurate measurement of transport properties is required. We report a new magnetic resonance imaging (MRI) methodology to measure membrane gas phase diffusion coefficients. The MRI challenges of low spin density and short gas phase relaxation times, especially for hydrogen gas, have been successfully overcome with a modified one-dimensional, single-point ramped imaging with T(1) enhancement, measurement. We have measured the diffusion coefficients of both hydrogen gas and sulfur-hexafluoride in a model polymeric membrane of potential interest as a gas separator in metal hydride batteries. The experimental apparatus is a modified one-dimensional diaphragm cell which permits measurement of the diffusion coefficient in experimental times of less than 1 min. The H(2) gas diffusion coefficient in the membrane was 0.54 +/- 0.01 mm(2)/s, while that of sulfur-hexafluoride was 0.14 +/- 0.01 mm(2)/s, at ambient conditions.


Usefulness of perfusion weighted magnetic resonance imaging with signal-intensity curves analysis in the differential diagnosis of sellar and parasellar tumors: preliminary report.
The most common pituitary tumors are adenomas, which however may be mimicked by other tumors that can show a very similar appearance in plain MRI. The aim of our study was to evaluate the usefulness of perfusion weighted MR imaging (PWI), including signal-intensity curves analysis in the differential diagnosis of sellar/parasellar tumors. Forty-one patients with sellar/parasellar tumors (23 macroadenomas, 10 meningiomas, 5 craniopharyngiomas, 1 intrasellar hemangioblastoma, 1 intrasellar prostate cancer metastasis, 1 suprasellar glioma), underwent plain MRI followed by PWI using a 1.5T unit. In each tumor, the mean and maximum values of relative cerebral blood volume (rCBV), as well as the relative peak height (rPH) and the relative percentage of signal intensity recovery (rPSR) were calculated. The high perfusion tumors were: macroadenomas, meningiomas, squamous-papillary type of craniopharyngiomas, hemangioblastoma, glioma and metastasis. The low perfusion neoplasms included adamantinomatous type of craniopharyngiomas. By comparing adenomas and meningiomas, we found statistically significant differences in the mean and maximum rCBV values (p=0.026 and p=0.019, respectively), but not in rPH and rPSR. The maximum rCBV values >7.14 and the mean rCBV values >5.74 with the typical perfusion curve were very suggestive of the diagnosis of meningioma. There were differences between adenomas and other high perfusion tumors in rPH and rPSR values. PWI can provide additional information helpful in differential diagnosis of sellar/parasellar tumors. In our opinion PWI, as an easy to perform and fast technique should be incorporated into the MR protocol of all intracranial neoplasms including sellar/parasellar tumors.


[Are age and urodynamic data correlated in women with stress urinary incontinence (SUI)?].
Our aim was to evaluate the impact of age on lower urinary tract function in women by means of urodynamics and modelized analysis of the recorded free uroflow curves. One hundred and fifty three women (age range: [30-93 years]; 6 decades A to F) with only SUI complaint underwent a urodynamic evaluation which included initial free uroflow, urethral pressure profile, cystometry and final free uroflow at bladder functional capacity. Modelized analysis was performed using the VBN mathematical micturition model; from comparison between recorded and computerized theoretical flow curves this model allows to determine two characteristic parameters: one of urethral obstruction and one of detrusor efficiency. No age-related changes were found in bladder capacity, peak flow rate in the first void and post residual volume. A significant increase of peak flow rate was noted in the second void for D and older. Bladder compliance decreased only from E. As usually described a decrease with age of the maximum urethral closure pressure occurred while the functional urethral length decreased only from E. A flat distribution of the VBN parameters was observed. This study shows the absence of age-associated changes in both urodynamic data and VBN parameters in a population of women with SUI and without any other disease. These findings reinforce the idea that chronological age does not strongly correlate with the physiological status.


Hepatic leiomyosarcoma: ultrastructural study and review of the differential diagnosis.
A primary leiomyosarcoma of the liver in a 12 year old female is reported. It is the eleventh such tumor to be recorded, the first to be documented in an adolescent and the first to be studied electron microscopically. By light microscopy the well differentiated portions of the tumor were characteristic of leiomyosarcoma. Ultrastructurally a minority of tumor cells contained myofilaments along with cytoplasmic dense bodies and marginal dense plaques, the most distinctive subcellular markers of smooth muscle cells. A brief review of the differential diagnosis is provided.


Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease.
Investigations of synaptic transmission and plasticity in mouse models of Huntington's disease (HD) demonstrate neuronal dysfunction long before the onset of classical disease indicators. Similarly, recent human studies reveal synaptic dysfunction decades before predicted clinical diagnosis in HD gene carriers. These studies guide premanifest tracking of disease and the development of treatment assessment tools. New discoveries of mechanisms underlying early neuronal dysfunction, including elevated pathogenic extrasynaptic NMDA receptor signaling, reduced synaptic connectivity and loss of brain-derived neurotrophic factor (BDNF) support have led to pharmacological interventions that can reverse or delay phenotype onset and disease progression in HD mice. Further understanding the primary effects of gene mutations associated with late-onset neurodegeneration should translate to novel treatments for HD families and guide therapeutic strategies for other neurodegenerative diseases.


The space of homogeneous probability measures on Γ\X¯maxS is compact: With an appendix by Jialun Li.
In this paper we prove that the space of homogeneous probability measures on the maximal Satake compactification of an arithmetic locally symmetric space is compact. As an application, we explain some consequences for the distribution of weakly special subvarieties of Shimura varieties.


Sialosis: 35 cases of persistent parotid swelling from two countries.
Diffuse, non-inflammatory, non-neoplastic enlargement of the major salivary glands (sialosis) is uncommon and has various systemic causes. This paper examines 35 patients whose persistent swelling of the parotid was diagnosed as sialosis, and shows that diabetes mellitus and alcoholism are the most common causes.


Exercise-induced abnormal blood pressure responses are related to subendocardial ischemia in hypertrophic cardiomyopathy.
We examined by thallium-201 scintigraphy whether exercise-induced abnormal blood pressure response (BPR) is related to myocardial ischemia. Hemodynamic instabilities during exercise in patients with hypertrophic cardiomyopathy (HCM) are considered to be caused by abnormal reflex control of vascular resistance. In 105 patients with HCM, exercise thallium scintigraphy was performed by means of a multistage, symptom-limited bicycle ergometer exercise test. Eighty-eight patients had normal BPR (> or = 25 mm Hg from baseline to peak exercise), and 17 had abnormal BPR (<25 mm Hg). Clinical characteristics including age, the prevalence of obstruction, New York Heart Association functional class and echocardiographic measurements were similar between the two groups. Left ventricular end-diastolic pressure was significantly higher in patients with abnormal BPR than in those with normal BPR (18+/-8 vs. 14+/-5 mm Hg, p < 0.05). Exercise-induced perfusion abnormalities including fixed and reversible perfusion defects, and left ventricular cavity dilatation (LVCD) were identified in 72 (69%) of 105 study patients. Left ventricular cavity dilatation indicates subendocardial hypoperfusion and is a marker of diffuse subendocardial ischemia. The prevalence of fixed or reversible perfusion defects was similar between the two groups. Patients with abnormal BPR had the higher prevalence of LVCD as compared to those with normal BPR (47.1 vs. 10%, p < 0.0002). Multiple logistic regression analysis revealed that LVCD was independently associated with abnormal BPR (odds ratio 3.76, 95% confidence interval 1.61 to 8.76). Exercise-induced abnormal BPRs in patients with HCM are related to subendocardial ischemia during exercise.


Executive and motor function in children with autism spectrum disorder.
The purpose of this study was to investigate the relationship between executive function, mainly attention and impulse control, and motor function impairment in children with ASD. Fifteen children with ASD (ages 8-14 years) were examined on their executive function using the Conners continuous performance test-3 and motor function using the movement assessment battery for children-2 (MABC-2). It was found that children with ASD were delayed on executive and motor function. This means that those effects were also observed in male children with Autism Spectrum Disorder (ASD) who had similar characteristics as the participants in the study. This study may have practical implications in the relationship between executive function and motor performance in children with ASD and for clinicians and educators working with children with ASD. Furthermore, the findings suggest that variability in reaction time may be a useful predictor of motor skill performance in children with ASD and may reflect underlying difficulties in executive function and future research is suggested.


Detection of an HLA-B*15 variant, HLA-B*15:109, in a Taiwanese individual.
One nucleotide replacement in codon 43 of HLA-B*15:27:01 results in a new allele, HLA-B*15:109.


Preventing the sexual transmission of AIDS during adolescence.
In order to be effective, the national effort to contain the spread of Acquired Immunodeficiency Syndrome (AIDS) must include a youth focus. Knowledge of adolescent sexual behavior, drug use, and sexually transmitted diseases suggests that many adolescents are in jeopardy of acquiring Human Immunodeficiency Virus (HIV) infections; and they are among those most likely to benefit from preventative efforts as they explore adult roles and lifestyles. Preventative education should particularly target gay and other homosexually active young men. Effective teaching uses a variety of approaches and media, both inside and outside the classroom. Learning about AIDS is most likely to effect behavioral change when accompanied by other programs to build social supports, self-esteem, and positive identity. The ethical and rational use of HIV antibody testing may be a helpful adjunct to education for certain adolescents. Ultimately, our society's ability to address complex, associated social issues will determine our ability to control AIDS.


Explaining the variation in 137Cs aggregated transfer factor for wild edible plants as a case study on Koshiabura (Eleutherococcus sciadophylloides) buds.
The aggregated transfer factor (Tag) is commonly used to represent the actual transfer of radiocesium from soil to wild edible plants, but the values have shown substantial variation since the Fukushima nuclear accident. To elucidate the factors causing this variation, we investigated the effects of spatial scale and vertical 137Cs distribution in the soil on the variation of Tag-137Cs values for one of the most severely contaminated wild edible plants, Eleutherococcus sciadophylloides Franch. et Sav. (Koshiabura). The variation in Tag-137Cs values was not reduced by direct measurement of 137Cs deposition in soil samples from the Koshiabura habitat, as a substitute for using spatially averaged airborne survey data at the administrative district scale. The 137Cs activity concentration in Koshiabura buds showed a significant positive correlation with the 137Cs inventories only in the organic horizon of soil from the Koshiabura habitat. The ratio of 137Cs inventories in the organic horizon to the total 137Cs deposition in soil exhibited substantial variation, especially in broad-leaved deciduous forests that Koshiabura primarily inhabits. This variation may be the cause of the wide range of Tag-137Cs values observed in Koshiabura buds when calculated from the total 137Cs deposition in soil.


SIGUEME: Technology-based intervention for low-functioning autism to train skills to work with visual signifiers and concepts.
People with low-functioning ASD and other disabilities often find it difficult to understand the symbols traditionally used in educational materials during the learning process. Technology-based interventions are becoming increasingly common, helping children with cognitive disabilities to perform academic tasks and improve their abilities and knowledge. Such children often find it difficult to perform certain tasks contained in educational materials since they lack necessary skills such as abstract reasoning. In order to help these children, the authors designed and created SIGUEME to train attention and the perceptual and visual cognitive skills required to work with and understand graphic materials and objects. A pre-test/post-test design was implemented to test SIGUEME. Seventy-four children with low-functioning ASD (age=13.47, SD=8.74) were trained with SIGUEME over twenty-five sessions and compared with twenty-eight children (age=12.61, SD=2.85) who had not received any intervention. There was a statistically significant improvement in the experimental group in Attention (W=-5.497, p<0.001). There was also a significant change in Association and Categorization (W=2.721, p=0.007) and Interaction (W=-3.287, p=0.001). SIGUEME is an effective tool for improving attention, categorization and interaction in low-functioning children with ASD. It is also a useful and powerful instrument for teachers, parents and educators by increasing the child's motivation and autonomy.


Molecular characterization and quantification of the follicle-stimulating hormone receptor in turbot (Scophthalmus maximus).
Molecular cloning, characterization, and functional analysis of follicle-stimulating hormone receptor (FSHR) in female turbot (Scophthalmus maximus) were evaluated. Results showed that the full-length FSHR cDNA was 3824 bp long and contained a 2202 bp open reading frame that encoded a mature protein of 733 amino acids (aa) and a signal peptide of 18 aa. Multiple sequence analyses showed that turbot FSHR has high homology with the corresponding genes of other teleosts and significant homology with that of Hippoglossus hippoglossus. Turbot FSHR has the typical structural architecture of glycoprotein hormone receptors consisting of a large N-terminal extracellular domain, seven transmembrane domains and short C-terminal intracellular domain. FSHR mRNA was found to be abundant in the ovaries, but deficient in eyes, intestine, brain, muscle, gills, spleen, stomach, heart and kidney. Furthermore, FSHR mRNA was found to increase gradually from pre-vitellogenesis to migratory nucleus stages, with the highest values observed during the late vitellogenesis stage of the reproductive cycle. However, FSHR mRNA was found to decrease dramatically during the atresia stage. Meanwhile, functional analysis with HEK293T cells continual expressing FSHR demonstrated that FSHR was specifically stimulated by ovine FSH, but not ovine LH. These results indicate that turbot FSHR is mainly involved in the stimulation of vitellogenesis, regulation of oocyte maturation as well as promotion of ovarian development via specific ligand binding. These findings open doors to further investigation of physiological functions of FSHR, which will be valuable for fish reproduction and broodstock management.


Cri-du-chat (5p-) syndrome presenting with cerebellar hypoplasia and hypospadias: prenatal diagnosis and aCGH characterization using uncultured amniocytes.
We present prenatal diagnosis of a de novo distal deletion involving 5p(5p15.1→pter) using uncultured amniocytes in a pregnancy with cerebellar hypoplasia, hypospadias and facial dysmorphisms in the fetus. We discuss the genotype-phenotype correlation and the consequence of haploinsufficiency of CTNND2, SEMA5A, TERT, SRD5A1 and TPPP. We speculate that haploinsufficiency of SRD5A1 and TPPP may be responsible for hypospadias and cerebellar hypoplasia, respectively, in this case.


An MD-based systematic study on the mechanical characteristics of a novel hybrid CNT/graphene drug carrier.
This paper is aimed to assess the mechanical properties of a hybrid graphene-carbon nanotube carrier embedded with doxorubicin (DOX). Utilizing molecular dynamics simulation, the results reveal that by increasing the temperature from 309 to 313 K, the elastic modulus of the GS/CNT/DOX carrier decreases from 0.8 to 0.74 TPa. Also, it is shown that the presence of chitosan molecules enhances the mechanical characteristics of the proposed nanocarrier. Taking the chirality of the graphene sheet into account, the results indicate that by increasing the size of the graphene sheet, the failure stress is slightly increased for the armchair type. However, this value decreases as the size of the zigzag sample increases. Additionally, the influence of aspect ratio on the elastic modulus, fracture stress, and fracture strain of these systems is systematically examined. It has been shown that the failure stress may change significantly with increasing this parameter, especially for carrier systems having zigzag carbon nanostructures. Moreover considering various voids content in the CNT structure, the weakening effect of defects is systematically explored. Also, the dependence of the mechanical features of the proposed hybrid carrier on the presence of DOX molecules is studied via MD simulations. Finally, we have investigated the role of CNT physical characteristics including its size and chirality on the results. Graphical abstract.


Low levels of sibship encourage use of larvae in western Atlantic bluefin tuna abundance estimation by close-kin mark-recapture.
Globally, tunas are among the most valuable fish stocks, but are also inherently difficult to monitor and assess. Samples of larvae of Western Atlantic bluefin tuna Thunnus thynnus (Linnaeus, 1758) from standardized annual surveys in the northern Gulf of Mexico provide a potential source of "offspring" for close-kin mark-recapture (CKMR) estimates of abundance. However, the spatial patchiness and highly skewed numbers of larvae per tow suggest sampled larvae may come from a small number of parents, compromising the precision of CKMR. We used high throughput genomic profiling to study sibship within and among larval tows from the 2016 standardized Gulf-wide survey compared to targeted sampling carried out in 2017. Full- and half-siblings were found within both years, with 12% of 156 samples in 2016 and 56% of 317 samples in 2017 having at least one sibling. There were also two pairs of cross cohort half-siblings. Targeted sampling increased the number of larvae collected per sampling event but resulted in a higher proportion of siblings. The combined effective sample size across both years was about 75% of the nominal size, indicating that Gulf of Mexico larval collections could be a suitable source of juveniles for CKMR in Western Atlantic bluefin tuna.


Stability analysis and selection of sugar beet (Beta vulgaris L.) genotypes using AMMI, BLUP, GGE biplot and MTSI.
The methods utilized to analyze genotype by environment interaction (GEI) and assess the stability and adaptability of genotypes are constantly changing and developing. In this regard, often instead of depending on a single analysis, it is better to use a combination of several methods to measure the nature of the GEI from various dimensions. In this study, the GEI was investigated using different methods. For this purpose, 18 sugar beet genotypes were evaluated in randomized complete block design in five research stations over 2 years. The additive effects analysis of the additive main effects and multiplicative interaction (AMMI) model showed that the effects of genotype, environment and GEI were significant for root yield (RY), white sugar yield (WSY), sugar content (SC), and extraction coefficient of sugar (ECS). The multiplicative effect's analysis of AMMI into interaction principal components (IPCs) showed that the number of significant components varies from one to four in the studied traits. According to the biplot of the mean yield against the weighted average of absolute scores (WAAS) of the IPCs, G2 and G16 for RY, G16 and G2 for WSY, G6, G4, and G1 for SC and G8, G10 and G15 for ECS were identified as stable genotypes with optimum performance. The likelihood ratio test showed that the effects of genotype and GEI was significant for all studied traits. In terms of RY and WSY, G3 and G4 had high mean values of the best linear unbiased predictions (BLUP), so they were identified as suitable genotypes. However, in terms of SC and ECS, G15 obtained high mean values of the BLUP. The GGE biplot method classified environments into four (RY and ECS) and three (WSY and SC) mega-environments (MEs). Based on the multi-trait stability index (MTSI), G15, G10, G6, and G1 were the most ideal genotypes.


Efficacy of reduced-intensity allogeneic stem cell transplantation in chemotherapy-refractory non-hodgkin lymphoma.
Chemotherapy sensitivity has been identified as an important prognostic factor in reduced-intensity allogeneic stem cell transplantation (RIST) for non-Hodgkin lymphoma (NHL). However, the effect of uniform salvage chemotherapy before RIST has not been studied prospectively. We examined whether the response to prospectively administered uniform salvage therapy (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and fludarabine) influenced the subsequent outcome of RIST in 28 patients with relapsed or refractory NHL. After RIST, overall survival (OS) at 36 months is 49%, whereas event-free survival (EFS) is 32%. In Cox model analyses, the response to chemotherapy was the best predictor of OS (P = .0006) and EFS (P = .0006) after RIST. Differentiating stable disease from progressive disease after salvage chemotherapy strengthened the association with survival. Among chemotherapy-sensitive patients, the median OS and EFS have not been reached. In patients with stable disease, OS and EFS at 24 months are 50% and 25%, respectively. In contrast, only 1 patient with progressive disease during salvage therapy survived longer than 12 months. These prospective data confirm the favorable prognosis for chemotherapy-sensitive NHL after RIST and suggest that chemotherapy resistance is not an absolute contraindication to RIST for NHL patients with stable disease during salvage therapy.


Treatment of antibody-mediated rejection including immunoadsorption during first year after renal transplantation--Clinical results and regulation of endothelial progenitor cells.
Antibody-mediated rejection (AMR) is associated with poor allograft survival. Therefore, effective treatment strategies are required. Extracorporeal strategies are increasingly included in treatment of antibody-mediated rejection to eliminate the detrimental alloantibodies. Yet, other mechanisms contributing to the beneficial effect of apheresis besides the removal of antibodies are under consideration. We retrospectively analyzed data of 427 transplant patients from 2006 to 2013 with special focus on occurrence, treatment - always including immunoadsorption - and 12-months outcome of antibody-mediated rejection. Besides, we prospectively monitored how the number and phenotype of endothelial progenitor cells in four patients experiencing antibody-mediated rejection changed during the treatment course of 6-20 sessions of immunoadsorption in comparison to seven patients subjected to immunoadsorption because of preparation for ABO-incompatible transplantation. 24 patients were diagnosed with acute AMR and treated with immunoadsorption resulting in patient and allograft survival of 100% and 87.5%, respectively. In patients with antibody-mediated rejection, the endothelial progenitor cell number after successful immunoadsorption therapy was always transiently decreased and the adhesive and migratory ability improved. This regulation of circulating endothelial precursor cells was not seen in patients undergoing repetitive immunoadsorptions before ABO-incompatible transplantation. Combined therapy with immunoadsorption allows a successful treatment of AMR. Treatment seems to be associated with a transient regulation of circulating endothelial precursor cells.


Konjac glucomannan attenuate high-fat diet-fed obesity through enhancing β-adrenergic-mediated thermogenesis in inguinal white adipose tissue in mice.
Konjac glucomannan (KGM) has been reported to prevent high-fat diet-induced obesity, and we study investigated whether dietary supplementation with KGM can prevent obesity by increasing energy expenditure in inguinal white adipose tissue (iWAT) of high-fat diet (HF) -fed mice. Weaned mice fed the control diet (Con), HF, or HF plus KGM (8%, w/w, HFK) were divided into three groups. The results showed that 10-week supplementation with KGM significantly reduced partial adipose tissue weight and body weight, and improved glucose tolerance. Compared to the HF group, plasma lipid concentrations in the HFK group were greatly decreased to the control level. Moreover, transcriptomic research has shown that genes that are mainly associated with energy and lipid metabolism are significantly altered in iWAT. Mechanistically, KGM stimulated thermogenesis by promoting the expression of uncoupling protein-1 (UCP1) and the β3-adrenergic receptor (ADR3β). Taken together, our results suggest that dietary supplementation with konjac glucomannan can effectively alleviate obesity induced by a high-fat diet by activating ADR3β-mediated iWAT thermogenesis. Dietary supplementation with KGM can effectively alleviate high fat diet- induced obesity mice by via activating ADR3β-mediated thermogenesis of iWAT.


How Pathogens Feel and Overcome Magnesium Limitation When in Host Tissues.
Host organisms utilize nutritional immunity to limit the availability of nutrients essential to an invading pathogen. Nutrients may include amino acids, nucleotide bases, and transition metals, the essentiality of which varies among pathogens. The mammalian macrophage protein Slc11a1 (previously Nramp1) mediates resistance to several intracellular pathogens. Slc11a1 is proposed to restrict growth of Salmonella enterica serovar Typhimurium in host tissues by causing magnesium deprivation. This is intriguing because magnesium is the most abundant divalent cation in all living cells. A pathogen's response to factors such as Slc11a1 that promote nutritional immunity may therefore reflect what the pathogen 'feels' in its cytoplasm, rather than the nutrient concentration in host cell compartments.


Esophageal atresia and tracheoesophageal fistula: success and failure rates in the United Arab Emirates.
The management of esophageal atresia (EA) and tracheoesophageal fistula (TEF) has improved markedly over the years, with a current overall survival of 80%-90%. This however, is not the case in developing countries, where mortality continues to be high. The results of treatment of 41 consecutive cases EA and/or TEF have been analyzed to determine factors pertinent to the outcome. The distribution of anomalies and a postoperative survival of 86.8% were comparable to those from developed countries. Aspiration pneumonia was unusually frequent in our patients (78%), but did not adversely influence outcome. Associated congenital anomalies as well as low birth weight continue to be important predictors of outcome in our setting. Our post-operative complications were similar to those from developed countries apart from a high incidence of stricture formation. This was attributed to gastroesophageal reflux, non-ventilation post-operatively, and the use of silk sutures to construct the anastomosis.


Zebrafish models of Tauopathy.
Tauopathies are a group of incurable neurodegenerative diseases, in which loss of neurons is accompanied by intracellular deposition of fibrillar material composed of hyperphosphorylated forms of the microtubule-associated protein Tau. A zebrafish model of Tauopathy could complement existing murine models by providing a platform for genetic and chemical screens, in order to identify novel therapeutic targets and compounds with disease-modifying potential. In addition, Tauopathy zebrafish would be useful for hypothesis-driven experiments, especially those exploiting the potential to deploy in vivo imaging modalities. Several considerations, including conservation of specialized neuronal and other cellular populations, and biochemical pathways implicated in disease pathogenesis, suggest that the zebrafish brain is an appropriate setting in which to model these complex disorders. Novel transgenic zebrafish lines expressing wild-type and mutant forms of human Tau in CNS neurons have recently been reported. These studies show evidence that human Tau undergoes disease-relevant changes in zebrafish neurons, including somato-dendritic relocalization, hyperphosphorylation and aggregation. In addition, preliminary evidence suggests that Tau transgene expression can precipitate neuronal dysfunction and death. These initial studies are encouraging that the zebrafish holds considerable promise as a model in which to study Tauopathies. Further studies are necessary to clarify the phenotypes of transgenic lines and to develop assays and models suitable for unbiased high-throughput screening approaches. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases.


Involvement of dopaminergic and serotonergic systems in the neurobehavioral toxicity of lambda-cyhalothrin in developing rats.
In view of extensive uses of lambda-cyhalothrin, a new generation type II synthetic pyrethroid, human exposure is quite imminent. The present study has therefore been carried out to investigate effect of lambda-cyhalothrin on brain dopaminergic and serotonergic systems and functional alterations associated with them. Post-lactational exposure to lambda-cyhalothrin (1.0 mg/kg or 3.0 mg/kg body weight, p.o.) from PD22 to PD49 caused a significant decrease in the motor activity and rota-rod performance in rats on PD50 as compared to controls. Decrease in motor activity in lambda-cyhalothrin treated rats was found to persist 15 days after withdrawal of exposure on PD65 while a trend of recovery in rota-rod performance was observed. A decrease in the binding of ³H-Spiperone, known to label dopamine-D2 receptors in corpus striatum associated with decreased expression of tyrosine hydroxylase (TH)-immunoreactivity and TH protein was observed in lambda-cyhalothrin treated rats on PD50 and PD65 compared to controls. Increase in the binding of ³H-Ketanserin, known to label serotonin-2A receptors in frontal cortex was observed in lambda-cyhalothrin exposed rats on PD50 and PD65 as compared to respective controls. The changes were more marked in rats exposed to lambda-cyhalothrin at a higher dose (3.0 mg/kg) and persisted even 15 days after withdrawal of exposure. The results exhibit vulnerability of developing rats to lambda-cyhalothrin and suggest that striatal dopaminergic system is a target of lambda-cyhalothrin. Involvement of serotonin-2A receptors in the neurotoxicity of lambda-cyhalothrin is also suggested. The results further indicate that neurobehavioral changes may be more intense in case exposure to lambda-cyhalothrin continues.


Bleeding Outcomes After Left Atrial Appendage Closure Compared With Long-Term Warfarin: A Pooled, Patient-Level Analysis of the WATCHMAN Randomized Trial Experience.
The purpose of this study was to compare the relative risk of major bleeding with left atrial appendage (LAA) closure compared with long-term warfarin therapy. LAA closure is an alternative approach to chronic oral anticoagulation for the prevention of thromboembolism in patients with atrial fibrillation (AF). We conducted a pooled, patient-level analysis of the 2 randomized clinical trials that compared WATCHMAN (Boston Scientific, Natick, Massachusetts) LAA closure with long-term warfarin therapy in AF. A total of 1,114 patients were included, with a median follow-up of 3.1 years. The overall rate of major bleeding from randomization to the end of follow-up was similar between treatment groups (3.5 events vs. 3.6 events per 100 patient-years; rate ratio [RR]: 0.96; 95% confidence interval [CI]: 0.66 to 1.40; p = 0.84). LAA closure significantly reduced bleeding >7 days post-randomization (1.8 events vs. 3.6 events per 100 patient-years; RR: 0.49; 95% CI: 0.32 to 0.75; p = 0.001), with the difference emerging 6 months after randomization (1.0 events vs. 3.5 events per 100 patient-years; RR: 0.28; 95% CI: 0.16 to 0.49; p < 0.001), when patients assigned to LAA closure were able to discontinue adjunctive oral anticoagulation and antiplatelet therapy. The reduction in bleeding with LAA closure was directionally consistent across all patient subgroups. There was no difference in the overall rate of major bleeding in patients assigned to LAA closure compared with extended warfarin therapy over 3 years of follow-up. However, LAA closure significantly reduced bleeding beyond the procedural period, particularly once adjunctive pharmacotherapy was discontinued. The favorable effect of LAA closure on long-term bleeding should be considered when selecting a stroke prevention strategy for patients with nonvalvular AF. (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation; NCT00129545; and Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy [PREVAIL]; NCT01182441).


The horizon of bone organoid: A perspective on construction and application.
Bone defects repair and regeneration by various causes such as tumor resection, trauma, degeneration, etc. have always been a key issue in the clinics. As one of the few organs that can regenerate after adulthood, bone itself has a strong regenerative ability. In recent decades, bone tissue engineering technology provides various types of functional scaffold materials and seed cells for bone regeneration and repair, which significantly accelerates the speed and quality of bone regeneration, and many clinical problems are gradually solved. However, the bone metabolism mechanism is complicated, the research duration is long and difficult, which significantly restricts the progress of bone regeneration and repair research. Organoids as a new concept, which is built in vitro with the help of tissue engineering technology based on biological theory, can simulate the complex biological functions of organs in vivo. Once proposed, it shows broad application prospects in the research of organ development, drug screening, mechanism study, and so on. As a complex and special organ, bone organoid construction itself is quite challenging. This review will introduce the characteristics of bone microenvironment, the concept of organoids, focus on the research progress of bone organoids, and propose the strategies for bone organoid construction, study direction, and application prospects.


Eosinophil responses in sheep selected for high and low responsiveness to Trichostrongylus colubriformis.
A breeding programme, based on selection for faecal egg counts, has produced lines of sheep which demonstrate either increased resistance (high responder) or susceptibility (low responder) to challenge infection with T. colubriformis after vaccination with irradiated larvae. Circulating blood eosinophilia, a hallmark of helminth infections, was examined in third generation lambs from two separate selective matings and random bred control lambs. Numbers of eosinophils were higher in high responder lambs when compared to low responders after vaccination and challenge infections. Analysis of eosinophil counts confirmed a strong line effect and there was no evidence of a sex effect. Random bred lambs showed wide individual variations in eosinophil numbers and their response to infection. It was concluded that peripheral eosinophilia was more a measure of host responsiveness to infection than an indicator of helminthiasis. As such the eosinophil may serve as an indicator of the hosts ability to respond to T. colubriformis vaccination and infection.


Morphine activates omega-conotoxin-sensitive Ca2+ channels to release adenosine from spinal cord synaptosomes.
Morphine-induced release of adenosine from the spinal cord is believed to contribute to spinal antinociception. Although this release is Ca2+ dependent, little is known of the nature of this dependence. In this study, the effects of the dihydropyridine L-type Ca2+ channel agonist Bay K 8644 and the antagonist nifedipine, the N-type Ca2+ channel antagonist omega-conotoxin, and ruthenium red, a blocker of Ca2+ influx induced by capsaicin, on release of adenosine evoked by morphine were determined. The effect of partial depolarization with a minimally effective concentration of K+ on morphine-evoked release of adenosine also was examined. Morphine 10(-5)-10(-4) M produced a dose-dependent enhancement of adenosine release from dorsal spinal cord synaptosomes. Following the addition of 6 mM K+ (total K+ concentration of 10.7 mM), 10(-6) M morphine also enhanced release, and an additional component of action at 10(-8) M was revealed. Release was Ca(2+)-dependent as it was not observed in the absence of Ca2+ and presence of EGTA. Bay K 8644 (10 nM) and nifedipine (100 nM) had no effect on the release of adenosine evoked by morphine, but omega-conotoxin (100 nM) markedly reduced such release in both the absence and the presence of the additional 6 mM K+. Morphine-evoked adenosine release was not altered in the presence of a partially effective dose of capsaicin, nor by ruthenium red.(ABSTRACT TRUNCATED AT 250 WORDS)


Enantiodivergence by minimal modification of an acyclic chiral secondary aminocatalyst.
The development of enantiodivergent catalysis for the preparation of both enantiomers of a chiral compound is of importance in pharmaceutical and bioorganic chemistry. With the design of a class of reactive and stereoselective organocatalysts, acyclic chiral secondary amines, a method for achieving the enantiodivergence is developed simply by changing the secondary N-i-Bu- to N-Me-group within the catalyst architecture while maintaining the same absolute configuration of the catalysts, which modulates the catalyst conformation. This catalyst-controlled enantiodivergent method not only enables challenging asymmetric transformations to occur in an enantiodivergent manner but also features a high level of stereocontrol and broad scope that is demonstrated in eight different reactions (90 examples), all delivering both enantiomers of a range of structurally diverse products including hitherto less accessible, yet important, compounds in good yields with high stereoselectivities.


Assessment of Laparoscopic Spleen-Preserving Hilar Lymphadenectomy for Advanced Proximal Gastric Cancer Without Invasion Into the Greater Curvature: A Randomized Clinical Trial.
The survival benefit of laparoscopic total gastrectomy combined with spleen-preserving splenic hilar lymphadenectomy (LSTG) for locally advanced proximal gastric cancer (APGC) without invasion into the greater curvature remains uncertain. To compare the long-term and short-term efficacy of LSTG (D2 + No. 10 group) and conventional laparoscopic total gastrectomy (D2 group) for patients with APGC that has not invaded the greater curvature. In this open-label, prospective randomized clinical trial, a total of 536 patients with clinical stage cT2 to 4a/N0 to 3/M0 APGC without invasion into the greater curvature were enrolled from January 2015 to October 2018. The final follow-up was on October 31, 2021. Data were analyzed from December 2021 to February 2022. Eligible patients were randomized to the D2 + No. 10 group or the D2 group. The primary outcome was 3-year disease-free survival (DFS). The secondary outcomes were 3-year overall survival (OS) and morbidity and mortality within 30 days after surgery. Of 526 included patients, 392 (74.5%) were men, and the mean (SD) age was 60.6 (9.6) years. A total of 263 patients were included in the D2 + No. 10 group, and 263 were included in the D2 group. The 3-year DFS was 70.3% (95% CI, 64.8-75.8) for the D2 + No. 10 group and 64.3% (95% CI, 58.4-70.2; P = .11) for the D2 group, and the 3-year OS in the D2 + No. 10 group was better than that in the D2 group (75.7% [95% CI, 70.6-80.8] vs 66.5% [95% CI, 60.8-72.2]; P = .02). Multivariate analysis revealed that splenic hilar lymphadenectomy was not an independent protective factor for DFS (hazard ratio [HR], 0.86; 95% CI, 0.63-1.16) or OS (HR, 0.81; 95% CI, 0.59-1.12). Stratification analysis showed that patients with advanced posterior gastric cancer in the D2 + No. 10 group had better 3-year DFS (92.9% vs 39.3%; P < .001) and OS (92.9% vs 42.9%; P < .001) than those in the D2 group. Multivariate analysis confirmed that patients with advanced posterior gastric cancer could have the survival benefit from No. 10 lymph node dissection (DFS: HR, 0.10; 95% CI, 0.02-0.46; OS: HR, 0.12; 95% CI, 0.03-0.52). Although LSTG could not significantly improve the 3-year DFS of patients with APGC without invasion into the greater curvature, patients with APGC located posterior gastric wall may benefit from LSTG. ClinicalTrials.gov Identifier: NCT02333721.


Use of one-piece valved tube and variable surface area explant for glaucoma drainage surgery.
The results of glaucoma surgery on 37 eyes of 36 patients after the use of a one-piece valved silicone explant are described. With a follow-up of 6 to 24 months, intraocular pressures (IOPs) averaging 8.0 to 17.3 mmHg were recorded. The maximum number of eyes receiving antiglaucoma medicines at any of the follow-up visits was six. These results were compared with the authors' previous results with the two-piece tube and gutter explant (ACTSEB). It was found that lower IOPs were obtained with fewer complications from overdrainage in the immediate postoperative period. This difference was attributed to the valve reducing but not preventing overdrainage and less chance of "fibrosis" blocking the tube/plate interface.


Evaluation of Simulated Lesions as Surrogates to Clinical Lesions for Thoracic CT Volumetry: The Results of an International Challenge.
To evaluate a new approach to establish compliance of segmentation tools with the computed tomography volumetry profile of the Quantitative Imaging Biomarker Alliance (QIBA); and determine the statistical exchangeability between real and simulated lesions through an international challenge. The study used an anthropomorphic phantom with 16 embedded physical lesions and 30 patient cases from the Reference Image Database to Evaluate Therapy Response with pathologically confirmed malignancies. Hybrid datasets were generated by virtually inserting simulated lesions corresponding to physical lesions into the phantom datasets using one projection-domain-based method (Method 1), two image-domain insertion methods (Methods 2 and 3), and simulated lesions corresponding to real lesions into the Reference Image Database to Evaluate Therapy Response dataset (using Method 2). The volumes of the real and simulated lesions were compared based on bias (measured mean volume differences between physical and virtually inserted lesions in phantoms as quantified by segmentation algorithms), repeatability, reproducibility, equivalence (phantom phase), and overall QIBA compliance (phantom and clinical phase). For phantom phase, three of eight groups were fully QIBA compliant, and one was marginally compliant. For compliant groups, the estimated biases were -1.8 ± 1.4%, -2.5 ± 1.1%, -3 ± 1%, -1.8 ± 1.5% (±95% confidence interval). No virtual insertion method showed statistical equivalence to physical insertion in bias equivalence testing using Schuirmann's two one-sided test (±5% equivalence margin). Differences in repeatability and reproducibility across physical and simulated lesions were largely comparable (0.1%-16% and 7%-18% differences, respectively). For clinical phase, 7 of 16 groups were QIBA compliant. Hybrid datasets yielded conclusions similar to real computed tomography datasets where phantom QIBA compliant was also compliant for hybrid datasets. Some groups deemed compliant for simulated methods, not for physical lesion measurements. The magnitude of this difference was small (<5.4%). While technical performance is not equivalent, they correlate, such that, volumetrically simulated lesions could potentially serve as practical proxies.


Draft Genome Sequence of Three Antibiotic-Resistant Leuconostoc mesenteroides Strains of Dairy Origin.
Leuconostoc mesenteroides is a lactic acid bacterium (LAB) commonly associated with fermented foods. Here, we report the genome sequence of three selected dairy strains, showing atypical antibiotic resistances (AR). Genome analysis provided a better understanding of the genetic bases of AR in Leuconostoc and its potential transferability among foodborne bacteria.


Effect of hypoxia on endothelium-dependent relaxation of canine and rabbit basilar arteries.
An important role of endothelium-dependent relaxation in the local regulation of vascular tone has been suggested. In the present study, the effect of hypoxia on endothelium-dependent relaxation was investigated in canine and rabbit basilar and in rabbit common carotid arteries in vitro, using an isometric tension recording method. Hypoxia was introduced by changing the gas mixture in the in vitro chamber from 95% O2-5% CO2 to 95% N2-5% CO2. Thrombin and acetylcholine were used to induce endothelium-dependent relaxation. Thrombin at 0.1 and 1.0 U/ml, respectively, caused dose-dependent relaxation of the canine basilar artery precontracted by 10(-6)M prostaglandin F2 alpha. Acetylcholine also evoked dose-dependent relaxation of rabbit basilar and common carotid arteries precontracted by serotonin. Under hypoxic conditions, the relaxing effect of thrombin or acetylcholine decreased both in canine and in rabbit arteries, although it was not significant in rabbit basilar arteries. It has been postulated that following subarachnoid haemorrhage, diffusion of oxygen to the walls of the major cerebral arteries might be impaired by the subarachnoid clot. This could cause hypoxia of the arteries and contribute to vasospasm by suppressing endothelium-dependent relaxation, as well as by enhancing the contractile responses of the cerebral arteries to the vasoconstrictor agents in the bloody cerebrospinal fluid.


Determining the impact of instrument variation and automated software algorithms on the TGT in hemophilia and normalized plasma.
Despite increasing recognition as a more precise test of in vivo hemostatic conditions, standardization of the thrombin generation test (TGT) continues to hinder its development as routine clinical practice. Prior efforts largely focused on comparing the effects of experimental conditions and different reagents. Commercialized kits, instruments and software have been introduced to calculate the TG curve and its parameters. However, modified versions of the TGT continue to be used worldwide on a variety of microplate reader instruments and processed using individualized algorithms. No prior study has compared the effect of instrument choice and its inherent noise profile on the processing of the TG curve and its common endpoint parameters. Hemophilia A plasma supplemented with buffer or Factor VIII, mimicking hemophilic or normalized samples respectively, was monitored for thrombin generation after activation with TF on six different fluorescent microplate readers. Each instrument was optimized for TGT signal recording prior to testing. An automated software package containing various mathematical algorithms was utilized to compute the TG curves and parameters, and compare different TG processing approaches. Instruments produced unique noise profiles and end-point parameters that were incomparable in absolute signal terms. Similar relative hemophilic responses were obtained across various instruments when the normalized plasma sample was used as an internal standard. Smoothing algorithms corrected destructive instrument noise. Instrument-induced errors from numerical differentiation during TG curve processing cannot be eliminated by external calibrators, and require careful qualification of the instrument and implementation of noise-reducing software algorithms.


Exact correction factor for estimating the OR in the presence of sparse data with a zero cell in 2 × 2 tables.
In case-control studies, odds ratios (OR) are calculated from 2 × 2 tables and in some instances, we observe small cell counts or zero counts in one of the cells. The corrections to calculate the ORs in the presence of empty cells are available in literature. Some of these include Yates continuity correction and Agresti and Coull correction. However, the available methods provided different corrections and the situations where each could be applied are not very apparent. Therefore, the current research proposes an iterative algorithm of estimating an exact (optimum) correction factor for the respective sample size. This was evaluated by simulating data with varying proportions and sample sizes. The estimated correction factor was considered after obtaining the bias, standard error of odds ratio, root mean square error and the coverage probability. Also, we have presented a linear function to identify the exact correction factor using sample size and proportion.


A Novel Anti-LILRB4 CAR-T Cell for the Treatment of Monocytic AML.
To effectively improve treatment for acute myeloid leukemia (AML), new molecular targets and therapeutic approaches need to be identified. Chimeric antigen receptor (CAR)-modified T cells targeting tumor-associated antigens have shown promise in the treatment of some malignancies. However, CAR-T cell development for AML has been limited by lack of an antigen with high specificity for AML cells that is not present on normal hematopoietic stem cells, and thus will not result in myelotoxicity. Here we demonstrate that leukocyte immunoglobulin-like receptor-B4 (LILRB4) is a tumor-associated antigen highly expressed on monocytic AML cells. We generated a novel anti-LILRB4 CAR-T cell that displays high antigen affinity and specificity. These CAR-T cells display efficient effector function in vitro and in vivo against LILRB4+ AML cells. Furthermore, we demonstrate anti-LILRB4 CAR-T cells are not toxic to normal CD34+ umbilical cord blood cells in colony-forming unit assays, nor in a humanized hematopoietic-reconstituted mouse model. Our data demonstrate that anti-LILRB4 CAR-T cells specifically target monocytic AML cells with no toxicity to normal hematopoietic progenitors. This work thus offers a new treatment strategy to improve outcomes for monocytic AML, with the potential for elimination of leukemic disease while minimizing the risk for on-target off-tumor toxicity.


Prognostic value of the molecular detection of circulating tumor cells using a multimarker reverse transcription-PCR assay for cytokeratin 19, mammaglobin A, and HER2 in early breast cancer.
To investigate the prognostic value of the molecular detection of circulating tumor cells (CTCs) using three markers [cytokeratin 19 (CK19), mammaglobin A (MGB1), and HER2] in early breast cancer. CK19mRNA+, MGB1mRNA+, and HER2mRNA+ cells were detected using real-time (CK19) and nested (MGB1 and HER2) reverse transcription-PCR in the peripheral blood of 175 women with stage I to III breast cancer before the initiation of adjuvant chemotherapy. The detection of CTCs was correlated with clinical outcome. In 10 patients, immunofluorescence staining experiments were done to investigate the coexpression of cytokeratin, MGB1, and HER2 in CTCs. CK19mRNA+, MGB1mRNA+, and HER2mRNA+ cells were detected in 41.1%, 8%, and 28.6% of the 175 patients, respectively. Patients had one of the following molecular profiles: CK19mRNA+/MGB1mRNA+/HER2mRNA+ (n = 8), CK19mRNA+/MGB1mRNA+/HER2mRNA- (n = 1), CK19mRNA+/MGB1mRNA-/HER2mRNA+ (n = 42), CK19mRNA+/MGB1mRNA-/HER2mRNA- (n = 21), CK19mRNA-/MGB1mRNA+/HER2mRNA- (n = 5), and CK19mRNA-/MGB1mRNA-/HER2mRNA- (n = 98). Double-immunofluorescence experiments confirmed the following CTC phenotypes: CK+/MGB1+, CK+/MGB1-, CK-/MGB1+, CK+/HER2+, CK+/HER2-, MGB1+/HER2-, and MGB1+/HER2+. In univariate analysis, the detection of CK19mRNA+, MGB1mRNA+, and HER2mRNA+ cells was associated with shorter disease-free survival (DFS; P < 0.001, P = 0.001, and P < 0.001, respectively), whereas the detection of CK19mRNA+ and MGB1mRNA+ cells was associated with worse overall survival (P = 0.044 and 0.034, respectively). In multivariate analysis, estrogen receptor-negative tumors and the detection of CK19mRNA+ and MGB1mRNA+ cells were independently associated with worse DFS. The detection of peripheral blood CK19mRNA+ and MGB1mRNA+ cells before adjuvant chemotherapy predicts poor DFS in women with early breast cancer.


Characteristics of the Exposure-Response Relationship of Particulate Matter and Mortality: A Time Series Analysis of 7 Cities in China.
To explore the characteristics of the exposure-response relationship of particulate matter concentration and mortality on the multicity scale in China. Generalized additive models were used to explore the short-term effects of particulate matter with an aerodynamic diameter of less than 10 μm (PM10) on mortality while adjusting for confounding variables, including seasonal periodicity, air temperature, relative humidity, day-of-the-week effect, and holiday effect. Additionally, possible PM10 thresholds for daily mortality were evaluated. In most cities, the relationships of PM10 concentration and daily cause-specific mortalities were all nearly linear when PM10 concentration was below 150 μg/m3. The estimated PM10 thresholds associated with nonaccidental and cardiovascular mortalities were 80 μg/m3 and 45 μg/m3, respectively. Our findings indicated that, at least in China, the PM10 pollutant has threshold effects.


Effects of thiamine in a patient with a variant form of branched-chian ketoaciduria.
A boy with the intermediate variant of branched-chain ketoaciduria was studied. Treatment with an amino acid mixture was discontinued at the age of 7.5 years. Reintroduction of normal protein-containing foods precipitated the biochemical abnormalities, characteristic of MSUD, which were relieved by 10 mg thiamine/day. Adaptation to this regiment developed and thiamine intake was increased to 100 mg/day, later to 1 000 mg/day. The patient developed well and had no attacks of ketoacidosis. 1-14C-leucine degradation in intact fibroblasts was 15% of controls and did not increase upon addition of thiamine to the incubation medium.


Topological Weaire-Thorpe models of amorphous matter.
Amorphous solids remain outside of the classification and systematic discovery of new topological materials, partially due to the lack of realistic models that are analytically tractable. Here we introduce the topological Weaire-Thorpe class of models, which are defined on amorphous lattices with fixed coordination number, a realistic feature of covalently bonded amorphous solids. Their short-range properties allow us to analytically predict spectral gaps. Their symmetry under permutation of orbitals allows us to analytically compute topological phase diagrams, which determine quantized observables like circular dichroism, by introducing symmetry indicators in amorphous systems. These models and our procedures to define invariants are generalizable to higher coordination number and dimensions, opening a route toward a complete classification of amorphous topological states in real space using quasilocal properties.


[Biochemical criteria of intrahepatic cholestasis in hepatitis B].
Properties differentiating 13 biochemical indexes of cholestasis within a group of patients suffering from acute virus hepatitis were examined. It has proved the existence of a set of parameters of optimal properties differentiating separate states of cholestasis. This set includes concentrations of bilirubin and cholesterol esters, together with the activity of alkaline phosphatase. The variables formed a function enabling to differentiate mathematically+ the states with and without cholestasis.


A plasma membrane pool of cholesteryl esters that may mediate the selective uptake of cholesteryl esters from high-density lipoproteins.
Selective uptake of high-density lipoprotein (HDL) cholesteryl esters without parallel uptake of HDL particles occurs by a nonendocytotic pathway that requires no specific apolipoprotein and results in the net delivery of cholesteryl esters to cells. Here we examine a reversibly cell-associated pool of cholesteryl ester tracer and its relationship to selective uptake. A fraction of cholesteryl ester tracer selectively taken up from HDL by rat primary or mouse Y1-BS1 adrenocortical cells was chased from the cells by subsequent incubation with unlabeled HDL. This pool of cholesteryl ester tracer was distinct from that irreversibly internalized, and in excess of that accounted for by dissociation of labeled HDL particles bound to the cell surface. In response to various metabolic effectors, cholesteryl ester tracer in this reversibly cell-associated pool of Y1-BS1 cells correlated linearly with irreversible selective uptake. Both reversibly and irreversibly cell-associated pools of cholesteryl ester tracer displayed similar saturation kinetics for uptake from HDL, and both pools correlated inversely with cell-free cholesterol levels. Cholesteryl ester tracer in the reversible pool was shown to serve as a precursor for irreversible selective uptake. A pool with properties similar to the reversibly cell-associated pool was identified in plasma membrane fractions; enough tracer was incorporated into this pool to account for the reversibly cell-associated pool of intact cells. The data suggest that a pool of cholesteryl esters in the plasma membrane is involved in selective uptake at a step prior to irreversible internalization.


Positron emission tomography study of the human hypothalamus during normal ageing and in ischemic and degenerative disorders.
Regional blood flow and oxygen metabolism were determined by positron emission tomography, using the steady state technique with 15O, in the hypothalamus and in the whole brain of fifty two normal persons and patients suffering from cerebral ischemia and degenerative dementia. During normal ageing regional blood flow and oxygen consumption appeared to increase slightly in the hypothalamus and to decrease in the whole brain in 24 persons. In the young age group the hypothalamus was more protected against ischemia than in the elderly group. In the aged group with cerebral ischemia and degenerative dementia regional blood flow and oxygen consumption were decreased in the hypothalamus to the same extent as in the whole brain.


Trypanosoma cruzi: sequence polymorphism of the gene encoding the Tc52 immunoregulatory-released factor in relation to the phylogenetic diversity of the species.
We have previously identified a Trypanosoma cruzi gene encoding a protein named Tc52 sharing structural and functional properties with the thioredoxin and glutaredoxin family involved in thiol-disulfide redox reactions. Gene targeting strategy and immunological studies allowed showing that Tc52 is among T. cruzi virulence factors. Taking into account that T. cruzi has a genetic variability that might be important determinant that governs the different behaviour of T. cruzi clones in vitro and in vivo, we thought it was of interest to analyse the sequence polymorphism of Tc52 gene in several reference clones. The DNA sequences of 12 clones which represent the whole genetic diversity of T. cruzi allowed showing that 40 amino-acid positions over 400 analysed are targets for mutations. A number of residues corresponding to putative amino-acids playing a role in GSH binding and/or enzymatic function and others located nearby are subject to mutations. Although the immunological analysis showed that Tc52 is present in parasite extracts from different clones, it is possible that the amino-acid differences could affect the enzymatic and/or the immunomodulatory function of Tc52 variants and therefore the parasite phenotype.


Binding site of a dextran-specific homogeneous IgM: thermodynamic and spectroscopic mapping by dansylated oligosaccharides.
The hapten binding properties of the homogeneous mouse IgM secreted by MOPC-104E were investigated. Hapten-association constants were determined either by equilibrium and displacement equilibrium dialysis or by fluorometric titrations of the protein with the fluorescent derivatives of the haptens. For the latter type of measurements, several oligosaccharides were derivatized to the corresponding dansylhydrazones. The synthesis, generally applicable to oligosaccharides with free reducing ends, is described. Analysis of the thermodynamic parameters for the binding of 18 haptens forms the basis for proposing a model of the binding site of MOPC-104E. This model is supported and refined by results of the measurements of linear and circular polarization of the fluorescence of the dansylated haptens. The binding site is proposed to consist of a cavity with about 12-A depth, complementary to a terminal nonreducing nigerosyl group. At the entrance to this cavity, a further subsite is identified forming interactions of lower specificity with an additional glucose unit.


Double-contrast artifacts.
With the increasing use of double-contrast technique in radiological evaluation of the gastrointestinal tract, certain artifacts peculiar to this mode of examination need to be identified. These artifacts arise because of: (a) the characteristics of the barium suspensions used for double-contrast studies; (b) the see-through effect obtained on double-contrast studies whereby opacities lying in front of or behind the organ being examined may simulate pathologic lesions; (c) infolding of the mucosa which may simulate pathology; (d) extraneous or foreign material which is frequently detected and must be differentiated from intrinsic disease; (e) certain anatomical structures such as the cardia, pylorus, and retrogastric structures which are seen with unusual clarity and detail and which, in some cases, may simulate pathology. In general, these artifacts may simulate diffuse superficial ulceration, discrete ulceration, or polypoid lesions. Familiarity with the double-contrast technique and an understanding of these artifacts will help to avoid diagnostic errors.


Inhibitory effects of everolimus in combination with paclitaxel on adriamycin-resistant breast cancer cell line MDA-MB-231.
We aimed to evaluate the therapeutic effects of paclitaxel in combination with mTOR inhibitor everolimus on adriamycin-resistant breast cancer cell line MDA-MB-231 (MDA-MB-231/ADR). MDA-MB-231/ADR cells were treated with different concentrations of paclitaxel and everolimus. The IC50 values after 48 h of treatment were measured by the MTT assay. The apoptosis rate and cell cycle were detected by flow cytometry. The protein expressions of Akt, PI3K, mTOR, p-pI3K, p-AKT and p-mTOR were detected by Western blot. When paclitaxel at ≥1.56 μg/ml was used, the growth of MDA-MB-231/ADR cells was inhibited more significantly than that of control group (P < 0.05). After treatment with ≥6.25 μg/ml everolimus, the cell growth was also suppressed more significantly (P < 0.05). The IC50 values of everolimus and paclitaxel were 32.50 μg/ml and 7.80 μg/ml, respectively. The inhibition rate of paclitaxel plus everolimus was significantly enhanced with increasing paclitaxel concentration (P < 0.001). After treatment with 7.80 μg/ml paclitaxel, the two drugs had best synergistic inhibitory effects on proliferation. Compared with drugs alone, the combination significantly promoted apoptosis (P < 0.001). The paclitaxel + everolimus group had significantly more cells in the G0-G1 phase than those of control and individual drug groups (P < 0.001). Everolimus significantly decreased mTOR and p-mTOR expressions compared with those of control group (P < 0.001). Compared with everolimus alone, the combination reduced the expressions more significantly (P < 0.05). Paclitaxel decreased the expression levels of PI3K, p-PI3K and p-AKT. Compared with paclitaxel alone, the combination significantly promoted the reduction of PI3K, p-PI3K and p-AKT expressions (P < 0.05). Everolimus can enhance the effect of paclitaxel on MDA-MB-231/ADR cells, inhibit cell proliferation, induce apoptosis and arrest cell cycle in the G1 phase mainly by down-regulating the expressions of key proteins in the mTOR signaling pathway.


Advances in combined enzymatic extraction of ferulic acid from wheat bran.
Wheat bran could be utilised as feedstock for innovative and sustainable biorefinery processes. Here, an enzymatic hydrolysis process for ferulic acid (FA) extraction was optimised step by step for total wheat bran (Tritello) and then also applied to the outer bran layer (Bran 1). Proteins, reducing sugars, total phenols and FA were quantified. The highest FA yields (0.82-1.05 g/kg bran) were obtained either by rehydrating the bran by autoclaving (Tritello) or by steam explosion (Bran 1) using a bran/water ratio of 1:20, followed by enzymatic pre-treatment with Alcalase and Termamyl, to remove protein and sugars, and a final enzymatic hydrolysis with Pentopan and feruloyl esterase to solubilise phenol. FA was recovered from the final digestate via solid phase extraction. A 40-fold scale-up was also performed and the release of compounds along all the process steps and at increasing incubation times was monitored. Results showed that FA was initially present at a minimum level while it was specifically released during the enzymatic treatment. In the final optimized process, the FA extraction yield was higher than that obtained with NaOH control hydrolysis while, in comparison with other FA enzymatic extraction methods, fewer process steps were required and no buffers, strong acid/alkali nor toxic compounds were used. Furthermore, the proposed process may be easily scaled-up, confirming the feasibility of wheat bran valorisation by biorefinery processes to obtain valuable compounds having several areas of potential industrial exploitation.


[Impact of the Nursing Personnel Strengthening Act on minimally invasive surgery exemplified by right-sided hemicolectomy from an economic perspective].
In the past, a reduced length of postoperative hospital stay was considered a sufficient trade-off to refinance the additional costs associated with minimally invasive surgery; however, with the implementation of the Nursing Personnel Strengthening Act and disincorporation of nursing costs, this argumentation needs to be fundamentally reevaluated. Using right-sided hemicolectomy as an example, a retrospective case analysis was conducted. Cost reductions associated with the length of hospital stay were compared before and after the introduction of the revised German diagnosis-related groups (aG-DRG) and offset against the increased material and personnel costs. Among the analyzed cases, the utilization of minimally invasive surgical techniques led to a substantial cost reduction per case compared to conventional surgical treatment. After the introduction of the aG-DRGs the financial benefits of a shortened hospital stay are greatly diminished and cannot be used to refinance the expenses necessary to perform minimally invasive surgery. From a strictly economical perspective, there is a strong incentive to only perform open surgical procedures. Disincorporation of nursing costs has destabilized the fragile concept of indirect refinancing of advanced operative techniques by the financial incentives associated with a shorter hospital stay. In order to comply with statutory regulations to implicate a performance-based funding, there is an urgent necessity to adjust the grouping algorithms for minimally invasive surgical procedures to the corresponding flat rates.


Renal and ureteric trauma: diagnosis and management in Poland.
To analyse retrospectively kidney and ureteric injuries (the former often associated with multiple-organ trauma) and thus optimize diagnostic and treatment methods. The records and details of kidney and ureteric injures treated between 1995 and 1999 in 61 urological departments in Poland were analysed. In all, 887 kidney injuries were analysed; blunt trauma comprised 97%, with most injuries classified as renal contusion and minor parenchymal damage (687 cases). Intravenous urography was used in 80% of the patients and computed tomography in only 20%. In all, 234 patients (26%) underwent surgery; nephrectomy was the most common surgical treatment, in 170 patients (73% of those undergoing surgery). Complications occurred in 9% of patients after conservative treatment and in 5% after surgery. Of the 452 ureteric injuries, 340 (75%) were iatrogenic, 81 (18%) blunt injuries and 31 (7%) open injuries. Of the iatrogenic injuries 73% occurred during gynaecological procedures, 14% in general surgery and 14% in urological procedures. The most frequent diagnostic method was intravenous urography (244 cases), with retrograde pyelography (98) and ureteric catheterization in 125. The diagnosis was established immediately during surgery in 104 patients. The most frequent surgical treatment was uretero-neocystostomy (213, 47%), the others being a Boari flap (113, 25%), end-to-end anastomosis (92, 20%), reconstruction with an ileal loop (30, 7%) and autotransplantation (four, 1%). In Poland, patients with blunt kidney injuries often undergo surgery, with nephrectomy the most frequent procedure. Computed tomography with the intravenous administration of contrast medium should be considered the diagnostic method of choice for kidney injures. Catheterization of the ureters before surgery and an indigocarmine intravenous infusion (to stain the urine) when a ureteric injury is suspected may reduce the rate of iatrogenic injury and improve the rate of intraoperative diagnosis. We suggest catheterizing the ureters in any doubtful case to avoid injury, because prevention is better than treatment.


Distinct functional and conformational states of the human lymphoid tyrosine phosphatase catalytic domain can be targeted by choice of the inhibitor chemotype.
The lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, has recently been identified as a promising drug target for human autoimmunity diseases. Like the majority of protein-tyrosine phosphatases LYP can adopt two functionally distinct forms determined by the conformation of the WPD-loop. The WPD-loop plays an important role in the catalytic dephosphorylation by protein-tyrosine phosphatases. Here we investigate the binding modes of two chemotypes of small molecule LYP inhibitors with respect to both protein conformations using computational modeling. To evaluate binding in the active form, we built a LYP protein structure model of high quality. Our results suggest that the two different compound classes investigated, bind to different conformations of the LYP phosphatase domain. Binding to the closed form is facilitated by an interaction with Asp195 in the WPD-loop, presumably stabilizing the active conformation. The analysis presented here is relevant for the design of inhibitors that specifically target either the closed or the open conformation of LYP in order to achieve better selectivity over phosphatases with similar binding sites.


Integrated PET/MRI With 11C-CFT and 18F-FDG for levodopa response difference in Parkinson's disease.
Parkinson's disease is one of the most common neurodegenerative diseases. Excellent levodopa responsiveness has been proposed as a characteristic supporting feature in substantiating the PD diagnosis. However, a small portion of clinically established PD patients shows poor levodopa response. This study aims to investigate brain function alterations of PD patients with poor levodopa responsiveness by PET/MRI. A total of 46 PD patients were recruited. They all completed 11C-CFT PET/MRI scans and the acute levodopa challenge test. Among these 46 PD patients, 42 participants further underwent 18F-FDG PET/MRI scans. Clinical variables regarding demographic data, disease features and cognition scales were also collected. Based on the improvement rate of UPDRS-III, PD patients were divided into non-responders (improvement rate < 33 %) and responders (improvement rate ≥ 33 %). Statistical parametric zapping was performed to analyze molecular imaging. Dopaminergic uptake and metabolism of 70 brain regions were converted to quantitative values and expressed as standard uptake value (SUV). SUV was further normalized by the cerebellum. The resulting SUV ratios and clinical variables were then compared by SPSS. The difference between levodopa non-responders (n = 17) and responders (n = 29) in the UPDRS III baseline was statistically significant and the former had a lower UPDRS III baseline (19 (10, 32), p<0.05). In contrast, no statistical difference between these two groups was found in age, gender, disease duration, cognition, motor subtype and Hoehn-Yahr stage. Dopaminergic uptake differences between levodopa non-responders (n = 17) and responders (n = 29) were shown in the left inferior frontal cortex (1.00 ± 0.09 vs 1.07 ± 0.08, p < 0.05 and FDR < 0.2), the right posterior cingulum (1.10 ± 0.10 vs 1.20 ± 0.13, p < 0.05 and FDR < 0.2) and the right insula (1.21 ± 0.12 vs 1.30 ± 0.10, p < 0.05 and FDR < 0.2). The metabolic alterations between levodopa non-responders (n = 16) and responders (n = 26) were shown in the right supplementary motor area (1.30 (1.18, 1.39) vs 1.41 (1.31, 1.53), p < 0.05 and FDR < 0.2), right precuneus (1.37 ± 0.10 vs 1.47 ± 0.18, p < 0.05 and FDR < 0.2), right parietal cortex (1.14 ± 0.15 vs 1.27 ± 0.21, p < 0.05 and FDR < 0.2), right supramarginal gyrus (1.16 (1.12, 1.26) vs 1.25 (1.14, 1.46), p < 0.05 and FDR < 0.2), right postcentral gyrus (1.15 (1.08, 1.32) vs 1.24 (1.17, 1.39), p < 0.05 and FDR < 0.2), medulla (0.75 ± 0.07 vs 0.80 ± 0.07, p < 0.05 and FDR < 0.2), right rolandic operculum (1.25 (1.18, 1.32) vs 1.33 (1.25, 1.50), p < 0.05 and FDR < 0.2), right olfactory (0.95 (0.91, 1.01) vs 1.01 (0.95, 1.15), p < 0.05 and FDR < 0.2), the right insula (1.15 (1.06, 1.22) vs 1.21 (1.12, 1.35), p < 0.05 and FDR < 0.2) and the left cerebellum crus (0.96 (0.91, 1.01) vs 0.92 (0.86, 0.96), p < 0.05 and FDR < 0.2). PD patients with poor response to levodopa showed less severe impairment of baseline motor symptoms, more severe dopaminergic deficits in the left inferior frontal, right posterior cingulate cortex and the right insula, and lower metabolism in the right supplementary motor area, right precuneus, right parietal cortex, right supramarginal gyrus, right postcentral gyrus, medulla, right rolandic operculum, right olfactory, the right insula and higher metabolism in the left cerebellum crus.


Associations of cumulative violence and structural vulnerability with restless sleep among female sex workers in Baltimore, Maryland.
To investigate correlates of restless sleep among street-based female sex workers (FSW) in the United States, an understudied population experiencing high rates of structural vulnerabilities (e.g., homelessness, food insecurity) and trauma. Using data from a cohort of street-based cisgender FSW (n = 236; median age = 35 years, 68% non-Hispanic White), we examined cross-sectional associations of individual, interpersonal, and structural factors with frequent restless sleep over the past week (5-7 vs. <5 days). Participants reported a high prevalence of homelessness (62%), food insecurity (61%), daily heroin injection (53%), lifetime sexual or physical violence (81%), and frequent restless sleep (53%). Older age, food insecurity, poor self-rated health, and cumulative violence exposure were independently associated with frequent restless sleep. Frequent restless sleep was prevalent among FSW with higher odds among those experiencing intersecting vulnerabilities and multiple exposures to violence. Further research on sleep health in this population is needed to understand its role in health risks.