Optimal anti-platelet therapy for older patients with acute coronary syndrome: a network meta-analysis of randomized trials comprising 59,284 older patients.
The aim of this study was to identify the optimal anti-platelet therapy in older acute coronary syndrome (ACS) patients with a mean age ≥ 60 years by comparing the efficacy and safety of different anti-platelet therapies. The selection of antiplatelet therapy in older patients with ACS is a clinical challenge. Numerous evidences indicate that the de-escalation of dual anti-platelet therapy (DAPT) or P2Y12 inhibitor monotherapy may reduce bleeding risk without increasing thrombotic events. However, there is a lack of systematic reviews and optimal strategy analysis regarding older ACS patients. Randomized controlled trials (RCTs) of anti-platelet therapy in older ACS patients were identified. Major adverse cardiovascular events (MACE) were the primary outcome. Secondary outcomes included all death, cardiovascular death, myocardial infarction, stroke, stent thrombosis, and trial-defined major bleeding. Frequentist and Bayesian network meta-analyses were conducted. Treatments were ranked on posterior probability. Summary odds ratios (ORs) were estimated using Bayesian network meta-analysis. A total of 12 RCTs including 59,284 older ACS patients treated with five anti-platelet strategies were included. Ticagrelor monotherapy after 3 months DAPT was comparable to the other strategies (OR 0.73; 95% CI 0.32-1.6) in terms of MACE risk. Additionally, P score analysis and SUCRA Bayesian analysis showed that it was the most beneficial treatment for all deaths, cardiovascular death and revascularization. For safety, although there was no significant difference in direct comparisons, both SUCRA Bayesian (0.806) and P score (0.519) analysis suggested that ticagrelor monotherapy was the safest strategy. The current evidence demonstrated that ticagrelor monotherapy after 3 months DAPT may be a promising approach for achieving a more favorable balance between risk and benefit for older ACS patients, with a relatively low bleeding risk and without an increased risk of MACE events. Moreover, it remains the preferred option for clinical outcomes such as all death, CV death and revascularization. Further high-quality and long-term studies are required to validate anti-platelet therapies among older ACS patients.


A comparison of canal preparation with nickel-titanium and stainless steel instruments.
Maintaining the original canal path during instrumentation is a challenge in narrow curved canals. This study compared the maintenance of the original canal path of curved root canals during instrumentation with nickel-titanium (Mac) hand files, nickel-titanium engine-driven files, and stainless steel (K-Flex) files. Canal path maintenance was determined by superimposing instrumentation radiographs over an initial file radiograph and examining for discrepancies. Nickel-titanium hand and engine-driven instruments maintained the original canal path in all cases. The incidence of deviation from the original canal path during instrumentation with stainless steel files increased with file size. The difference between nickel-titanium groups and stainless steel became statistically significant with instruments larger than size 30. In this study, nickel-titanium files were more effective in maintaining the original canal path of curved root canals when the apical preparation was enlarged beyond size 30.


FLVCR1-related disease as a rare cause of retinitis pigmentosa and hereditary sensory autonomic neuropathy.
FLVCR1 encodes for a transmembrane heme exporter protein and it is known to cause a rare form of syndromic retinitis pigmentosa: posterior column ataxia with retinitis pigmentosa. Recently, the FLVCR1-associated phenotype has been expanded with sporadic reports of hereditary sensory-autonomic neuropathy or non-syndromic retinitis pigmentosa. Here, we report a 23-year- old female with early onset hypomyelinating sensory-autonomic neuropathy and retinitis pigmentosa. Both features were present since childhood. The patient developed signs of advanced retinitis pigmentosa by the age of 10 years leading to legal blindness after the age of 18. Following candidate gene panel testing, which was negative, whole exome sequencing revealed compound heterozygous pathogenic FLVCR1 variants: NM_014053.3: c.3G > T; p.(Met1?) and NM_014053.3: c.730G > A; p.(Gly244Ser), the latter variant is novel. In this report we highlight the association of retinitis pigmentosa with hypomyelinating sensory-autonomic neuropathy, which could be underdiagnosed due to variable severity. To summarize, the phenotypic heterogeneity of FLVCR1 variants is broad and should include retinitis pigmentosa along with range of neurological features.


Effect of ethidium bromide on the digestion of chromatin DNA with micrococcal nuclease.
Intercalation of ethidium bromide into DNA influences the rate of its digestion with micrococcal nuclease in opposite directions depending on whether it is free DNA or DNA in chromatin. In the case of free DNA the binding of ethidium bromide, starting from a very low concentration, results in the inhibition of the rate of digestion (increasing constantly with the increase of the ethidium bromide/nucleotide ratio). In contrast to free DNA the digestion rate as well as the overall amount of nuclease susceptible DNA is increased upon ethidium bromide binding to chromatin, with maximum enhancement around the saturation of intercalation sites. The saturation of intercalation sites in chromatin leads also to the disappearance of the typical micrococcal nuclease digestion pattern of DNA upon gel electrophoresis. Instead, a random cleavage pattern is observed. These data indicate that partial unwinding of chromatin DNA by ethidium bromide results in unmasking new sites for nuclease action. Interpretation of this finding in terms of the nucleosomal structure of chromatin and the mode of ethidium bromide binding to chromatin DNA indicates that newly unmasked sites are localized within the core particle DNA.


GFA-protein gene expression on the astroglia in cow and rat brains.
The distribution of messenger RNA for glial fibrillary acidic protein (GFA-protein) of cow and rat brains was studied by an in situ hybridization technique using a tritium-labeled cDNA probe and autoradiography. The results were compared to the findings of GFA-protein immunohistochemistry. The signals of GFA-protein mRNA were detected on the perikaryal cytoplasm of astroglia observed in the following areas: the subpial area and the white matter of the cerebrum and cerebellum of the cow and the rat; gray matter of cow spinal cord; the thalamus, pontine reticular formation and white matter of the rat brainstem. All of these areas contain astroglia which are strongly positive for GFA-protein immunohistochemistry. On the other hand, we could detect no GFA-protein mRNA-positive glial cells in the areas where astroglia are negative for this immunostaining. These results indicate that the regional differences in the amount of GFA-protein in astroglia depend primarily on the degree of expression of their GFA-protein gene.


[Characterization of hepatic hydatid cysts of pseudotumor form. Scanner versus echography].
The authors report about a series of 38 patients with hepatic cysts (HHC) that had a pseudotumoral form on sonography (type IV in Gharbi's classification), that were explored both with sonography and with CT. While sonography had made the diagnosis of HHC possible in 4 cases out of 38 only, CT easily established this diagnosis in all cases. In addition, the latter technique has demonstrated the various tissue components accounting for the pseudotumoral sonographic image (hydatid sand, parietal calcifications, daughter cysts, intracystic air). It also allows assessing the number of sites and, better than with sonography, the signs of rupture of a hydatid cysts.


Do adolescents want to avoid pregnancy? Attitudes toward pregnancy as predictors of pregnancy.
To document the extent to which adolescents feel ambivalent towards getting pregnant and to examine the relationship between pregnancy attitudes and the occurrence of a pregnancy one year later. Demographic correlates of pregnancy attitudes also were examined. This was a prospective study using a subsample of the National Longitudinal Study of Adolescent Health (Add Health) data base. The sample was 4869 adolescent females in grades 9 through 11 who completed two interviews at a one year interval. Logistic regression analyses were used to predict occurrence of a pregnancy at wave 2 from attitudes toward pregnancy at wave 1. A substantial number of adolescent females (15%-30%) reported some degree of ambivalence toward becoming pregnant relative to their peers. Adolescent females' attitudes towards pregnancy were predictive of the occurrence of a pregnancy one year later. Additionally, demographic correlates of the pregnancy attitude were identified, including differences due to ethnicity, age, relationship status, mother's education level, and whether the adolescent came from a one or a two parent home. Results suggest that a significant minority of adolescents have some ambivalence toward pregnancy relative to their peers and that these attitudes are predictive of the occurrence of pregnancy.


Reduction of pneumonia risk by an angiotensin I-converting enzyme inhibitor in elderly Japanese inpatients according to insertion/deletion polymorphism of the angiotensin I-converting enzyme gene.
We have reported that use of angiotensin I-converting enzyme (ACE) inhibitor, which is a class of antihypertensive agent that induces cough, is an independent factor in reducing risk of pneumonia among elderly inpatients. Insertion/deletion (I/D) polymorphism of the ACE gene (ACE) has been associated with the risk of pneumonia in elderly individuals. However, the ability of ACE inhibitors to reduce pneumonia-related morbidity in individuals with the ACE polymorphism is unclear. Therefore we determined the association of ACE inhibitor use and ACE genotypes with reduction of pneumonia risk in the Japanese elderly population. We conducted a hospital-based, retrospective, case-control study to evaluate the effect of an ACE inhibitor and ACE polymorphism on incidence of pneumonia. Case subjects were pneumonia patients (N = 105) >or=65 years of age, during an 8-month period of a nonwinter season. Control subjects (n = 420) were elderly patients who were frequency matched to the case subjects by age (within +/- 2 years) and gender. Data were collected on medication with the ACE inhibitor temocapril and on known risk factors for pneumonia. The significances of differences for the risk factors were analyzed using univariate and multivariate comparisons of the case and control subjects. After adjustment for potential confounders by multiple logistic regression analysis, the odds ratio (OR) estimates for pneumonia were 0.458 (95% confidential interval [CI]: 0.230 to 0.909, P = .026) for ACE inhibitor use. Conditional logistic regression analysis according to ACE genotypes revealed significant reduction of pneumonia risk by use of temocapril compared with that in nonhypertensive individuals (ie, the reference group) in those with ACE ID + II (OR: 0. 416, 95% CI: 0.177 to 0.976, P = .044), but not in those with ACE DD (OR: 0.706, 95% CI: 0.198 to 2.518, P = .592). These results suggest that use of an ACE inhibitor is beneficial for reducing risk of pneumonia, particularly in individuals with the ACE genotypes ID + II.


Tedisamil blocks BK-type Ca(2+)-dependent K(+) channels and modulates action potentials in rat hippocampal neurons.
Tedisamil, a bradycardic compound in heart, also acts on K(+) channels in neurons. We determined the actions of tedisamil on action potentials in CA1 pyramidal neurons in hippocampal slices and on BK-type Ca(2+)-activated K(+) channel activity in inside-out patches excised from hippocampal neurons. In slices, tedisamil (5 microM) attenuated the fast afterhyperpolarization (AHP) and prolonged the repolarization phase of the action potential. Additionally, the compound induced burst-firing activity and enhanced the slow AHP that follows a train of action potentials. The single channel data showed tedisamil actions to be consistent with open channel blockade of the BK-type of K(+) channel. Together, the results are consistent with the possibility that prolongation of the action potential by tedisamil is mediated by a tetraethylammonium-like effect of the agent to block BK-type Ca(2+)-activated K(+) channels. The study also points to a number of effects that may contribute to the known nervous system toxicity induced by tedisamil.


Perioperative ultrasound applied to diagnosis and decision making in anesthesia.
Ultrasound is a portable and safe technology that is increasingly used to assist anesthetic procedures and has been integrated into the routine practice of a wide range of invasive procedures. As a complementary diagnostic tool, publications related to perioperative support other than vascular access and nerve blocks are currently lacking. Given the growing interest of anesthesiologists in acquisition of knowledge and skills of ultrasound, we propose a systematic review of the diagnosis, decision making or change in perioperative management of non-cardiac surgical patients derived from ultrasound practice. Of 1112 references found in electronic databases, 62 studies resulted from the screening process. A complete critical reading of 19 full-text publications was carried out with quantitative analysis of 1825 ultrasound examinations including echocardiography, neck and laryngeal ultrasound, pulmonary ultrasound and abdominal ultrasound, all of them performed by anesthesiologists. Diagnosis applied ultrasound and decision making during perioperative period resulted in change in the management of 31% with 95% CI of 21.06 to 42.04 and odds ratio of 2.68 (1.77 to 4.06) related to hemodynamic, airway and respiratory perioperative management. Since most of the articles included in this review are observational studies with inherent design concerns, there is an urgent requirement for randomized controlled trials in this area. As anesthesiologists become more comfortable and knowledgeable in ultrasound applied to the perioperative support, emergence of protocols with multidisciplinary ultrasound exploration is expected to allow an improvement in perioperative safety.


Persistent primitive trigeminal artery associated with monocular blindness and external carotid-vertebral artery anastomosis.
In this paper, we present 2 rare cases of persistent embryonic anastomoses. In one case, the patient presented with persistent trigeminal artery along with multiple foci of cerebral infarction as well as central retinal artery thrombosis. In the other case, the patient had direct anastomosis of the vertebral artery with ipsilateral external carotid artery as well as pontine infarction, aneurysm, and unilateral hypoplasia of the vertebral artery. The findings in these cases may shed light on the clinical presentation of such persistent anastomoses and aid their detection in clinical settings.


Angelica sinensis polysaccharide prevents mitochondrial apoptosis by regulating the Treg/Th17 ratio in aplastic anemia.
Angelica sinensis polysaccharide (ASP) is an effective medicine for aplastic anemia (AA). The present study aims to investigate whether mitochondrial apoptosis in aplastic anemia could be corrected by ASP by adjusting an abnormal level of regulatory T cell (Treg)/ IL-17 secreting CD4 T cell (Th17) ratio. BALB/c mice were treated with 5.0 Gy Co60 γ -radiation. Then 2 × 106 lymph node cells from DBA/2 donor mice were transplanted within 4 h after radiation. The mice in the various groups were fed saline or ASP for 2 weeks. For the in vitro experiment, bone marrow nucleated cells (BMNCs) and Treg cells were sorted from the mice on the 2nd day of modeling, and then cultured with or without ASP. The mice treated with the medium dose of ASP for 14 days showed increased white blood cell (WBC), red blood cell (RBC), platelet (PLT), BMNC counts and Lin-Sca-1 + c-Kit+ (LSK) populations viability compared with the mice in the AA group mice. The data showed that ASP decreased damage to the mitochondrial outer membrane, improved the stabilization of the mitochondrial membrane, and corrected the abnormal levels of ROS and mitochondrial-associated apoptosis proteins, including the Bcl-2/Bax ratio and caspase-3 and caspase-9 expression, in BMNCs which were sorted from the bone marrow cells of AA mice. The changes to the p-P38/P38 and Treg/Th17 ratios induced by AA were also reversed by the medium dose of ASP. The same ASP effect including the Bcl-2/Bax and p-P38/P38 ratio, caspase-3 and caspase-9 expression of BMNCs were observed in vivo. The viability of Treg cells were increased by treatment of ASP in vivo. ASP might prevent mitochondrial apoptosis to restore the function of hematopoietic stem cells by suppressing abnormal T-cell immunity in AA.


Identification in humans of HPV-16 E6 and E7 protein epitopes recognized by cytolytic T lymphocytes in association with HLA-B18 and determination of the HLA-B18-specific binding motif.
Human papilloma virus type 16 (HPV-16) is the HPV most frequently associated with cervical carcinoma in humans. For the prevention or treatment of cervical carcinoma, the E6 and E7 oncoproteins appear to be good targets for vaccine-induced cytotoxic T lymphocytes (CTL). Lipopeptide vaccination is an efficient way of stimulating cellular responses. However, to synthesize effective lipopeptides, it is necessary to define which epitopes are immunogenic. In this study we first determined that peptide 80 - 88 of the E6 protein was recognized by CTL from a healthy donor in association with the HLA-B18 molecule. We then defined the HLA-B18 anchoring peptide motif by testing the binding of various short peptides with the HLA-B18 molecule and showed that it was related to the HLA-A1-specific peptide motif. Furthermore, in analyzing the potential E7 epitopes susceptible to associating with HLA-B18, we demonstrated that peptide E7 44 - 52 gave the strongest binding. It could also be recognized by CTL from peripheral blood mononuclear cells (PBMC) of the same healthy donor. Finally, with PBMC from a patient with a cervical intraepithelial neoplasia grade 3, we found CTL which recognized the E6 80 - 88 epitope. We have hence identified two peptides encoded by the E6 and E7 proteins which are presented by the HLA-B18 molecule and could be included in a vaccine against HPV-16.


Degradation of components in drug formulations: a comparison between HPLC and DSC methods.
Information about the stability of drug components and drug formulations is needed to predict the shelf-life of the final products. The studies on the interaction between the drug and the excipients may be carried out by means of accelerated stability tests followed by analytical determination of the active principle (HPLC and other methods) and by means of the differential scanning calorimetry (DSC). This research has been focused to the acetyl salicylic acid (ASA) physical-chemical characterisation by using DSC method in order to evaluate its compatibility with some of the most used excipients. It was possible to show, with the DSC method, the incompatibility of magnesium stearate with ASA; the HPLC data confirm the reduction of ASA concentration in the presence of magnesium stearate. With the other excipients the characteristic endotherms of the drug were always present and no or little degradation was observed with the accelerated stability tests. Therefore, the results with the DSC method are comparable and in good agreement with the results obtained with other methods.


Predictors for quality of life of bladder cancer patients with ileal conduit: A cross-sectional survey.
To assess quality of life (QOL) and its influencing factors of bladder cancer patients after ileal conduit. From January 2012 to December 2013, a cross-sectional survey with questionnaires was performed in West China hospital, in which the effect of patient characteristics on their QOL was evaluated, and then the correlation of stomal self-management, social support and QOL of the patients were also explored. A total of 188 patients were included. Poor sexual life satisfaction was common among responders. There was a positive correlation between QOL and social support as well as the stomal self-management (all p ≤ 0.002). Additionally, the patients who were female, aged less than 60, participated in work, family income more than 4000¥ per month, a longer postoperative period, and without any stomal complications (all p < 0.05) would have a better QOL. The overall QOL of the patients was good except the satisfaction with sexual life. The better the stomal self-management and social support, the better the QOL. Personalized nursing care and health guidance should be provided to the patients, so as to improve their QOL and promote their health.


Soluble mediators produced by the crosstalk between microvascular endothelial cells and dengue-infected primary dermal fibroblasts inhibit dengue virus replication and increase leukocyte transmigration.
When dengue virus (DENV)-infected mosquitoes use their proboscis to probe into human skin during blood feeding, both saliva and virus are released. During this process, cells from the epidermis and dermis layers of the skin, along with small blood vessels, may get exposed to or infected with DENV. In these microenvironments of the skin, the presence of DENV initiates a complex interplay among the DENV-infected and non-infected neighboring cells at the initial bite site. Previous studies suggested that DENV-infected human dermal fibroblasts (HDFs) participate in the immune response against DENV by secreting soluble mediators of innate immunity. In the present study, we investigated whether DENV-infected HDFs activate human dermal microvascular endothelial cells (HDMECs) in co-cultures. Our results suggest that co-cultures of DENV-infected HDFs and HDMECs elicit soluble mediators that are sufficient to reduce viral replication, activate HDMECs, and induce leukocyte migration through HDMEC monolayers. These effects were partly dependent on HDF donor and DENV serotype, which may provide novel insights into the natural variation in host susceptibility to DENV disease.


Long term changes in atmospheric N and S throughfall deposition and effects on soil solution chemistry in a Scots pine forest in the Netherlands.
In a Scots pine forest the throughfall deposition and the chemical composition of the soil solution was monitored since 1984. (Inter)national legislation measures led to a reduction of the deposition of nitrogen and sulphur. The deposition of sulphur has decreased by approximately 65%. The total mineral-nitrogen deposition has decreased by ca. 25%, which is mainly due to a reduction in ammonium-N deposition (-40%), since nitrate-N deposition has increased (+50%). The nitrogen concentration in the upper mineral soil solution at 10 cm depth has decreased, leading to an improved nutritional balance, which may result in improved tree vitality. In the drainage water at 90 cm depth the fluxes of NO3(-) and SO4(2-) have decreased, resulting in a reduced leeching of accompanying base cations, thus preserving nutrients in the ecosystem. It may take still several years, however, before this will meet the prerequisite of a sustainable ecosystem.


Assessment of the M.Sc. course in Occupational Medicine at the London School of Hygiene and Tropical Medicine, 1969--74.
The M.Sc. course in Occupational Medicine started in September 1969 at the London School of Hygiene and Tropical Medicine. Between 1969--74, ninety-eight doctors attended this 9 month full-time course. Thirty-four were British and sixty-four from overseas. A questionnaire was mailed to all of them. Eighty-four replied, i.e. a response rate of 86%. Thirty-one of the U.K. doctors and fifty-three of the overseas replied. The difference between the UK and overseas doctors working full-time in occupational medicine was very marked before and after the course. 100% of the U.K. doctors and 89% of the overseas thought their objectives of attending the course were fulfilled. 97% of the U.K. doctors said the course covered the problems of their country as compared with 77% of the overseas. 100% of the U.K. doctors found the knowledge gained of practical value to their work. Suggestions were also made on topics taught and on the practical instruction of the course. It appears that the M.Sc. course is successful and that the objectives outlined when starting the M.Sc. were to a great extent fulfilled. The new changes introduced this year 1976 in the organization and the content of the course are also discussed, and their advantages emphasized.


Attitudes toward schizophrenia in the general population, psychiatric staff, physicians, and psychiatrists: a web-based survey in Japan.
Little is known about possible differences in the attitudes toward schizophrenia between the general public and various healthcare professionals. After screening for the study enrollment, 197 subjects in the general population, 100 psychiatric staff (other than psychiatrists), 112 physicians (other than psychiatrists) and 36 psychiatrists were enrolled in a web-based survey using an Internet-based questionnaire format. To assess subjects' attitudes toward schizophrenia, we used a 13-item questionnaire created by Uçok et al. (2006), to which five items were added. These 18 items were subjected to exploratory factor analysis, which yielded three factors classified as "stigma," "underestimation of patients' abilities," and "skepticism regarding treatment." These factors were compared between the four groups using analysis of covariance (ANCOVA), controlling for potential confounders. The ANCOVA for the "stigma" factor showed that psychiatrists scored significantly lower than the other three groups. The ANCOVA for the "underestimation of patients' abilities" factor revealed that psychiatric staff scored significantly lower than the general population. The present results indicated that attitudes toward schizophrenia consist of at least three separable factors. Psychiatrists had the least negative attitudes toward schizophrenia, which was followed by the psychiatric staff, and attitudes of the general population and of physicians were equally stigmatizing.


3-Ferrocenyl-estra-1,3,5 (10)-triene-17-one: Synthesis, Crystal Structure, Hirshfeld Surface Analysis, DFT Studies, and Its Binding to Human Serum Albumin Studied through Fluorescence Quenching and In Silico Docking Studies.
3-ferrocenyl-estra-1,3,5 (10)-triene-17-one (2), [Fe(C5H5)(C24H25O3)], crystallizes in the monoclinic space group C2. The cyclopentadienyl (Cp) rings adopt a nearly eclipsed conformation, and the Cp plane is tilted by 87.66° with respect to the substituted phenyl plane. An average Fe-C(Cp) bond length of 2.040(13) Å was determined, similar to the one reported for ferrocene. Hirshfeld surfaces and two-dimensional fingerprint plots were generated to analyze weak intermolecular C-H···π and C-H···O interactions. Density functional theory studies revealed a 1.15 kcal/mol rotational barrier for the C3-O1 single bound. Fluorescence quenching studies and in silico docking studies suggest that human serum albumin forms a complex with 2 via a static mechanism dominated by van der Waals interactions and hydrogen bonding interactions.


[The expression of noncollagenous proteins and the tumor differentiation in oral maxillofacial osteosarcoma].
To study the significance of the osteocalcin bone sialoprotein and osteopontin in cell differentiation and matrix mineralization of osteosarcoma. Use immunohistochemistry method to detect the osteocalcin bone sialoprotein and osteopontin expressions in tumor cells and matrix of 50 cases of osteosarcoma. In tumor cells, the high expression rates of BSP, OPN (30.0%,10.0%, respectively) in fibroblastic osteosarcoma were significantly lower than those of osteoblastic group (75.0%,64.3%, respectively). Other high expression rates of OC, BSP, OPN in or among different groups had no significant difference. In unmineralized neoplastic bone matrix OC, BSP, OPN were weakly expressed. In mineralized neoplastic bone matrix the high positive rates of BSP,OPN (81.4%,76.7% ) were significantly higher than that of OC(4.6% ). But OC was expressed strongly in mature bone. In tumor cells of the osteosarcoma expression of OC,BSP,OPN were accompanied by the cell differentiation. It seemed that during the formation and mineralization of neoplatic bone, BSP,OPN,OC had a relatively close relations with mineralization and they showed some extent sequensed expression.


Prediction of medical sciences students' performance on high-stakes examinations using machine learning models: a protocol for a systematic review.
Predicting medical science students' performance on high-stakes examinations has received considerable attention. Machine learning (ML) models are well-known approaches to enhance the accuracy of determining the students' performance. Accordingly, we aim to provide a comprehensive framework and systematic review protocol for applying ML in predicting medical science students' performance on high-stakes examinations. Improving the current understanding of the input and output features, preprocessing methods, setting of ML models and required evaluation metrics seems essential. A systematic review will be conducted by searching the electronic bibliographic databases of MEDLINE/PubMed, EMBASE, SCOPUS and Web of Science. The search will be limited to studies published from January 2013 to June 2023. Studies explicitly predicting student performance in high-stakes examinations and referencing their learning outcomes and use of ML models will be included. Two team members will first screen literature meeting the inclusion criteria at the title, abstract and full-text levels. Second, the Best Evidence Medical Education quality framework rates the included literature. Later, two team members will extract data, including the studies' general data and the ML approach's details. Finally, the information consensus will be reached and submitted for analysis. The synthesised evidence from this review provides helpful information for medical education policy-makers, stakeholders and other researchers in adopting the ML models to evaluate medical science students' performance in high-stakes exams. This systematic review protocol summarises findings of existing publications rather than primary data and does not require an ethics review. The results will be disseminated in publications of peer-reviewed journals.


Development and evaluation of modifications to the Sickness Impact Profile for head injury.
Three modifications were made to the Sickness Impact Profile, a behavior-based measure of health status, to improve its sensitivity to the effects of head injury. (1) Additional items were included to capture head injury sequelae and behaviors typical of young adults, the age group to which head injury most frequently occurs. (2) Subjects individually excluded behaviors irrelevant to them, thus allowing the score to better reflect injury-related changes. (3) The different areas of functioning on the Sickness Impact Profile were reweighted to reflect global judgments of the construct's contribution to overall functioning rather than the sum of the item contributions. Only the first modification is head-injury specific. The others, are relevant to any disease or injury. The performance of the modifications was evaluated in a longitudinal study of 102 head injured and 102 comparison subjects tested at 1 and 12 months after injury. The evaluation of the modifications was based on their ability to distinguish head injury from comparison subjects and on the strength of their relationship with measures of brain dysfunction. Despite a few statistically significant improvements in discrimination, differences of a practical degree were not obtained. The standard Sickness Impact Profile performed well and is recommended for evaluation of day-to-day functioning in head injury studies.


Retinal cells integrate into the outer nuclear layer and differentiate into mature photoreceptors after subretinal transplantation into adult mice.
Vision impairment caused by degeneration of photoreceptors, termed retinitis pigmentosa, is a debilitating condition with no cure presently available. Cell-based therapeutic approaches represent one treatment option by replacing degenerating or lost photoreceptors. In this study the potential of transplanted primary retinal cells isolated from neonatal mice to integrate into the outer nuclear layer (ONL) of adult mice and to differentiate into mature photoreceptors was evaluated. Retinal cells were isolated from retinas of transgenic mice ubiquitously expressing enhanced green fluorescence protein (EGFP) at either postnatal day (P) 0, P1 or P4 and transplanted into the subretinal space of adult wild-type mice. One week to 11 months post-transplantation experimental retinas were analyzed for integration and differentiation of donor cells. Subsequent to transplantation some postnatal retinal cells integrated into the ONL of the host and differentiated into mature photoreceptors containing inner and outer segments as confirmed by immunohistochemistry and electron microscopy. Notably, the appearance of EGFP-positive photoreceptors was not the result of fusion between donor cells and endogenous photoreceptors. Retinal cells isolated at P4 showed a significant increase in their capacity to integrate into the ONL and to differentiate into mature photoreceptors when compared with cells isolated at P0 or P1. As cell suspensions isolated at P4 are enriched in cells committed towards a rod photoreceptor cell fate it is tempting to speculate that immature photoreceptors may have the highest integration and differentiation potential and thus may present a promising cell type to develop cell replacement strategies for diseases involving rod photoreceptor loss.


Coccydynia relieved by a tarsal tunnel block: a case series.
This case series describes, for the first time, to the author's knowledge, a novel treatment for coccydynia. Tarsal tunnel block with lignocaine only brought relief of chronic coccydynia lasting more than 6 months in three patients. The author adopts the theory that the myelin sheath of the posterior tibial nerve will convey the lipid-soluble lignocaine upward toward the dorsal root ganglia and the nerve roots of the lumbar spine through the uninterrupted myelin sheath, which is itself mainly formed of lipids. The author thinks that most coccyx pain is actually a radiating pain from the lumbar spine, which is not always apparent on magnetic resonance imaging of the lumbar spine. Certainly, the author acknowledges that large-scale studies need to be done to prove the efficacy of this new technique and to prove that the myelin sheath can convey the lignocaine chemical upward. Three Arab patients presented with chronic coccydynia of more than 6 months' duration in whom conservative management had failed to control their symptoms. They had no past medical history of significance and no history of trauma. The results of physical examination of all of the patients were normal apart from tenderness on palpation of the coccyx. They all received local coccyx injection with steroids on two occasions, which failed to relieve their pain. One patient underwent manipulation under anesthesia, and one underwent coccygectomy with no pain relief. Magnetic resonance imaging results were reported to be normal in two of them, whereas the other one had a prolapsed disc at the L4/L5 level. The three patients described pain relief 30 minutes after tarsal tunnel block with lignocaine only lasting more than 6 months. All patients had heel anesthesia 15 minutes after the tarsal tunnel injection, which lasted only 1 hour. Tarsal tunnel block with lignocaine can relieve coccyx pain for a long time. Tarsal tunnel block can be done to achieve heel anesthesia before injection of lignocaine into the plantar fascia in patients with plantar fasciitis.


Dynamical conductivity of disordered quantum chains.
We study the transport properties of a one-dimensional quantum system with disorder. We numerically compute the frequency dependence of the conductivity of a fermionic chain with nearest-neighbor interaction and a random chemical potential by using the Chebyshev matrix product state (CheMPS) method. As a benchmark, we investigate the noninteracting case first. Comparison with exact diagonalization and analytical solutions demonstrates that the results of CheMPS are reliable over a wide range of frequencies. We then calculate the dynamical conductivity spectra of the interacting system for various values of the interaction and disorder strengths. In the high-frequency regime, the conductivity decays as a power law, with an interaction-dependent exponent. This behavior is qualitatively consistent with the bosonized field theory predictions, although the numerical evaluation of the exponent shows deviations from the analytically expected values. We also compute the characteristic pinning frequency at which a peak in the conductivity appears. We confirm that it is directly related to the inverse of the localization length, even in the interacting case. We demonstrate that the localization length follows a power law of the disorder strength with an exponent dependent on the interaction, and find good quantitative agreement with the field theory predictions. In the low-frequency regime, we find a behavior consistent with the one of the noninteracting system ω 2 ( ln ω ) 2 independently of the interaction. We discuss the consequences of our finding for experiments in cold atomic gases.


Activation of endothelial IKCa channels underlies NO-dependent myoendothelial feedback.
Agonist-induced vasoconstriction triggers a negative feedback response whereby movement of charged ions through gap junctions and/or release of endothelium-derived (NO) limit further reductions in diameter, a mechanism termed myoendothelial feedback. Recent studies indicate that electrical myoendothelial feedback can be accounted for by flux of inositol trisphosphate (IP3) through myoendothelial gap junctions resulting in localized increases in endothelial Ca(2+) to activate intermediate conductance calcium-activated potassium (IKCa) channels, the resultant hyperpolarization then conducting back to the smooth muscle to attenuate agonist-induced depolarization and tone. In the present study we tested the hypothesis that activation of IKCa channels underlies NO-mediated myoendothelial feedback. Functional experiments showed that block of IP3 receptors, IKCa channels, gap junctions and transient receptor potential canonical type-3 (TRPC3) channels caused endothelium-dependent potentiation of agonist-induced increase in tone which was not additive with that caused by inhibition of NO synthase supporting a role for these proteins in NO-mediated myoendothelial feedback. Localized densities of IKCa and TRPC3 channels occurred at the internal elastic lamina/endothelial-smooth muscle interface in rat basilar arteries, potential communication sites between the two cell layers. Smooth muscle depolarization to contractile agonists was accompanied by IKCa channel-mediated endothelial hyperpolarization providing the first demonstration of IKCa channel-mediated hyperpolarization of the endothelium in response to contractile agonists. Inhibition of IKCa channels, gap junctions, TRPC3 channels or NO synthase potentiated smooth muscle depolarization to agonists in a non-additive manner. Together these data indicate that rather being distinct pathways for the modulation of smooth muscle tone, NO and endothelial IKCa channels are involved in an integrated mechanism for the regulation of agonist-induced vasoconstriction.


Autophagy Mediates Tumor Suppression via Cellular Senescence.
Autophagy not only constitutes a robust barrier against malignant transformation at the cell-intrinsic level, but also contributes to the organismal control of potentially oncogenic cells. Recent data provide molecular insights into the mechanisms whereby oncogene hyperactivation induces autophagy to establish a permanent proliferative arrest commonly known as cellular senescence.


Systemic, bladder wall, and bladder tumor concentration of misonidazole following intravesical administration in the rat.
The hypoxic-cell radiosensitizer misonidazole was administered intravesically to normal and to bladder tumor-bearing female Fischer rats. Drug concentration was measured in the bladder wall, the tumor and in the serum using high pressure liquid chromatography at different times following administration. The data shows that misonidazole is readily adsorbed by the bladder wall and the tumor with tissue levels reaching up to 10 times those measured in the serum.


A murine cell possessing a dominant mutation affecting the regulation of interferon production: characterization by intraspecific hybrids.
Using intraspecific hybrids, we have demonstrated the dominant nature of two phenotypic markers present in a mutant mouse 3T6 cell line, designated 3T6-VrB2. These are, resistance to virus infection (Vr) and semiconstitutive synthesis of interferon (IFsc). Hybrids were formed by polyethylene glycol-mediated fusion between 3T6-VrB2, or its parent 3T6, and 2TG0-13, a triply marked derivative of mouse 3T3 cells. When tested for the Vr marker, 3T6-VrB2 X 2TG0-13 hybrid clones displayed a level of resistance to virus infection which was equal to or greater than that of 3T6-VrB2. Similarly, when tested for the IFsc marker, these hybrid clones were found to possess the capacity to confer an interferon-induced antiviral state in mouse L929 cells upon cocultivation. By comparison, clones derived from 3T6 X 2TG0-13 fusions produced high levels of virus and failed to confer an interferon-induced antiviral state in L929 cells.


Hemorheological and hemodynamic analysis of hypervolemic hemodilution therapy for cerebral vasospasm after aneurysmal subarachnoid hemorrhage.
Hypervolemic hemodilution therapy is effective for treating neurological deficits due to cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). We monitored various hemorheological and hemodynamic parameters to assess the effects of hypervolemic hemodilution therapy in SAH patients with cerebral vasospasm. Ninety-eight patients who underwent early craniotomy for aneurysm clipping surgery after SAH were studied. Fifty-one patients (52.0%) developed symptomatic vasospasm. The hematocrit level and red blood cell aggregability were measured daily from day 1 to day 14, whereas the circulating blood volume and cerebral blood flow were measured periodically. Cardiac output and pulmonary capillary wedge pressure were also measured using a Swan-Ganz catheter. The hematocrit level was decreased significantly to 29% to 32% by hypervolemic hemodilution therapy. Red blood cell aggregability increased until day 6 but was significantly reduced by therapy. Hypovolemia tended to develop after SAH. However, patients receiving hypervolemic hemodilution therapy became normovolemic to hypervolemic, with a significant increase of cardiac output and pulmonary capillary wedge pressure. At the onset of vasospasm, cerebral blood flow was significantly lower on the operated side than on the contralateral side, and it increased on both sides with therapy. Patients with SAH develop hypovolemia, hemodynamic depression, and increased red blood cell aggregability. Hypervolemic hemodilution therapy decreases hematocrit level and red cell aggregability while increasing cardiac output. Improvement of hemorheological and hemodynamic parameters by this therapy can reverse neurological deterioration due to cerebral vasospasm.


Chronic sublethal sediment toxicity testing using the estuarine amphipod, Melita plumulosa (Zeidler): evaluation using metal-spiked and field-contaminated sediments.
The present study describes the development of a 42-d chronic sublethal sediment toxicity test using the estuarine amphipod Melita plumulosa (Zeilder). This test was shown to predict the toxicity of metal-contaminated sediments previously found to adversely affect benthic community structure. Metals initially were tested individually by spiking reference sediment under conditions that ensured low metal concentrations in pore waters. Fertility was the most sensitive sublethal endpoint for copper- and zinc-spiked sediments, whereas cadmium-spiked sediments were not toxic to M. plumulosa, despite their high bioaccumulation of cadmium. The 42-d chronic sediment test was reproducible; however, variation between reference sediments collected from the same field location over time or from different locations did affect the reproduction of M. plumulosa. Sensitivity of M. plumulosa to metal-spiked sediments suggested that the interim sediment-quality guidelines (ISQGs) were too conservative. However, toxicity testing of sediments collected from field sites known to affect community assemblages significantly (p < 0.001) reduced the fertility of M. plumulosa, reflecting benthic community survey results and supporting the ISQGs. Bioaccumulation of cadmium and copper by M. plumulosa was elevated following chronic exposure to both laboratory and field-contaminated sediments; however, zinc bioaccumulation could be measured only in M. plumulosa exposed to field-contaminated sediments.


The influence of roasting procedure on the formation of mutagenic compounds in coffee.
Mutagenic products can be formed during the processing of food and especially as a result of heat treatment. Direct acting mutagenic activity was found in extracts of instant coffee and roasted coffee beans using Salmonella typhimurium TA100 in vitro. The mutagenic activities of the four pure coffee varieties examined (Coffea arabica Santos, Coffea arabica Columbia, Coffee robusta Indonesia, Coffee robusta Camerun) were within the same range. Twenty milligrams per plate freeze-dried powder prepared from aqueous roast coffee extracts induced between six and ten times the number of revertants found in the negative controls. Green coffee beans had no mutagenic activity. Mutagenicity increased with roasting time up to 4 min in the Probat drum roaster and then remained constant (i.e. no further increase after 8 min, the time normally used to roast coffee). The genotoxic compounds were quickly formed at temperatures below 220 degrees C (in normally roasted coffee the beans must reach a temperature of 220 degrees C). Mutagenic activity was independent of the roasting procedure (Jetzon procedure v. Probat drum roaster).


Investigation of the effects of pretreatment on the elemental composition of ash derived from selected Nigerian lignocellulosic biomass.
Lignocellulosic biomass is an important source of renewable energy and a potential replacement for fossil fuels. In this work, the X-ray fluorescence (XRF) method was used to analyze the elemental composition of raw and pretreated lignocellulosic biomass of cassava peels, corn cobs, rice husks, sugarcane bagasse, yam peels, and mixtures of cassava peels and yam peels, corn cobs and rice husks and all five biomass samples combined. The influence of particle size on elemental properties was investigated by screening the selected biomass into two size fractions, of an average of 300 and 435 µm, respectively. The total concentration of Mg, Al, Si, P, S, Cl, Ca, Ti, Cr, Mn, Fe, Co, Cu, Zn, Sn, Ni, Br, Mo, Ba, Hg, and Pb were determined for each of the biomass samples before and after the different pretreatments adopted in this study. From the results of the analysis, there was a significant reduction in the concentration of calcium in all the analyzed biomass after the alkaline pretreatment with rice husks biomass having the lowest concentration of 66 ppm after the alkaline pretreatment. The sulfur content of the acid pretreated biomass increased considerably which is likely due to the sulfuric acid used for the acid pretreatment. The fact that a mixture of biomass feedstock affects the properties of the biomass after pretreatment was validated in the mixed biomass of cassava peels and yam peels biomass as an example. The concentration of Mg in the mixed biomass was 1441 ppm but was 200 ppm and 353 ppm in individual cassava peels and yam peels respectively. The results of this study demonstrated that pretreated mixtures of biomass have varied elemental compositions, which could be an important factor affecting downstream processes, especially if a hybrid feedstock is used in a large-scale application.


[Critical remarks on an essay by K.T. Kalveram, "Factor analysis. Critical comments on a theoretical concept and its mathematical reformulation"].
The following contribution is a critical discussion of a paper by K. T. Kalveram Uber Faktorenanalyse. Kritik eines theoretischen Konzepts und seine mathematische Neuformulierung", which was published in this journal in 1970. In the following it is shown that Kalveram's attempt of a mathematical reformulation must be considered a failure, even if mathematical misrepresentations are not taken into account.


Convergence of genetic influences in comorbidity.
Predisposition to complex diseases is explained in part by genetic variation, and complex diseases are frequently comorbid, consistent with pleiotropic genetic variation influencing comorbidity. Genome Wide Association (GWA) studies typically assess association between SNPs and a single-disease phenotype. Fisher meta-analysis combines evidence of association from single-disease GWA studies, assuming that each study is an independent test of the same hypothesis. The Rank Product (RP) method overcomes limitations posed by Fisher assumptions, though RP was not designed for GWA data. We modified RP to accommodate GWA data, and we call it modRP. Using p-values output from GWA studies, we aggregate evidence for association between SNPs and related phenotypes. To assess significance, RP randomly samples the observed ranks to develop the null distribution of the RP statistic, and then places the observed RPs into the null distribution. ModRP eliminates the effect of linkage disequilibrium and controls for differences in power at tested SNPs, to meet RP assumptions in application to GWA data. After validating modRP based on both positive and negative control studies, we searched for pleiotropic influences on comorbid substance use disorders in a novel study, and found two SNPs to be significantly associated with comorbid cocaine, opium, and nicotine dependence. Placing these SNPs into biological context, we developed a protein network modeling the interaction of cocaine, nicotine, and opium with these variants. ModRP is a novel approach to identifying pleiotropic genetic influences on comorbid complex diseases. It can be used to assess association for related phenotypes where raw data is unavailable or inappropriate for analysis using other approaches. The method is conceptually simple and produces statistically significant, biologically relevant results.


Outcomes of combined lens extraction and goniosynechialysis in angle closure.
The aim of this study was to assess the effect of goniosynechialysis on intraocular pressure and medication requirement in patients with angle closure. A retrospective chart review. 51 eyes from 42 patients were included in the study. 17 had documented evidence of acute angle closure while 34 had chronic angle closure. Examination of the medical records of patients with synechial primary angle closure who underwent combined phacoemulsification and goniosynechialysis from 2003-2011 at 3 centres. Intraocular pressure and requirement for drops were the main outcome measures. Mean follow-up was 25.9 months for the acute group and 25.4 months for the chronic group. Mean preoperative intraocular pressure was 23.33 ± 14.41 mmHg on an average of 2.51 ± 1.3 medications. Mean postoperative intraocular pressure was lowered to 13.67 ± 2.41 (p ≤ 0.01) and medication usage was significantly lowered to 0.65 ± 0.87 (p ≤ 0.01). Subjects with documented acute symptomatic angle closure had higher preoperative intraocular pressure and a larger intraocular pressure fall post goniosynechialysis (from 30.41 mmHg ± 23 mmHg to 12.12 mmHg ± 2.32 mmHg) compared to those without such a documented episode (19.79 mmHg ± 4.37 mmHg to 14.44 mmHg ± 2.08 mmHg, p = 0.007). Both groups have similar postoperative need for glaucoma medication, 0.65 ± 0.93 vs 0.65 ± 0.85. Combined phacoemulsififcation and goniosynechialysis reduces intraocular pressure, medication requirements and need for further surgery in subjects with angle closure. The procedure is more effective in eyes with a previously documented acute symptomatic presentation of angle closure.


Selective withdrawal optimization in river-reservoir systems; trade-offs between maximum allowable receiving waste load and water quality criteria enhancement.
In this paper, a new systematic approach is designed to maximize the demand coverage and receiving waste load by river-reservoir systems while enhancing water quality criteria. The approach intends to control the reservoir eutrophication while developing a trade-off between the maximum receiving load and shortage on demand coverage. To simulate the system, a hybrid process-based and data-driven model is tailored. Initially, the two-dimensional hydrodynamics and water quality simulation model (CE-QUAL-W2) is linked with an effective single and/or multiple optimization algorithms (PSO) to evaluate the proposed scenarios. To increase the computational efficiencies, the simulation model is substituted with a surrogate model (ANN) in an adaptive-dynamically refined routine. The proposed method is illustrated by a case study in Iran, namely, Karkheh River Reservoir, for 180-monthly periods. The results showed the applicability of the methodology especially to solve high-dimensional multi-period complex water resource optimization problems. Also, the results demonstrated that eutrophication could be reduced under the optimal inflow phosphate control and reservoir operation, regulating the total phosphorous concentration in the reservoir.


Protection of lambs against enteric colibacillosis by vaccination of ewes.
Pregnant ewes were vaccinated twice, seven weeks and three weeks before lambing, with a multivalent formalin-killed Escherichia coli vaccine containing an added K99, F41 antigen preparation. Lambs born to vaccinated and unvaccinated ewes were exposed to oral infection with E coli B44 (09:K30, K99, F41). All 10 lambs from vaccinated ewes were protected whereas all 10 control lambs developed severe diarrhoea and five died or were killed in extremis. In the following year, previously immunised ewes were given a single dose of the vaccine two weeks before lambing. Eleven of their 12 lambs were protected against a similar challenge, which caused the death of six of eight control lambs and severe diarrhoea in the two survivors. Higher levels of antibody to the K99, F41 preparation were detected by enzyme-linked immunosorbent assay in the serum and colostrum from vaccinated ewes and in the serum of their lambs when compared with similar samples from control ewes and lambs.


E2F6 protein levels modulate drug induced apoptosis in cardiomyocytes.
The E2F/Rb pathway regulates cell growth, differentiation, and death. In particular, E2F1 promotes apoptosis in all cells including those of the heart. E2F6, which represses E2F activity, was found to induce dilated cardiomyopathy in the absence of apoptosis in murine post-natal heart. Here we evaluate the anti-apoptotic potential of E2F6 in neonatal cardiomyocytes (NCM) from E2F6-Tg hearts which showed significantly less caspase-3 cleavage, a lower Bax/Bcl2 ratio, and improved cell viability in response to CoCl2 exposure. This correlated with a decrease in the pro-apoptotic E2F3 protein levels. In contrast, no difference in apoptotic markers or cell viability was observed in response to Doxorubicin (Dox) treatment between Wt and Tg-NCM. Dox caused a rapid and dramatic loss of the E2F6 protein in Tg-NCM within 6h and was undetectable after 12h. The level of e2f6 transcript was unchanged in Wt NCM, but was dramatically decreased in Tg cells in response to both Dox and CoCl2. This was related to an impact of the drugs on the α-myosin heavy chain promoter used to drive the E2F6 transgene. By comparison in HeLa, Dox induced apoptosis through upregulation of endogenous E2F1 involving post-transcriptional mechanisms, while E2F6 was down regulated with induction of the Checkpoint kinase-1 and proteasome degradation. These data imply that E2F6 serves to modulate E2F activity and protect cells including cardiomyocytes from apoptosis and improve survival. Strategies to modulate E2F6 levels may be therapeutically useful to mitigate cell death associated disorders.


Hybrid-type, multicomponent interval training upregulates musculoskeletal fitness of adults with overweight and obesity in a volume-dependent manner: A 1-year dose-response randomised controlled trial.
This study examined the dose-response effects of a 1-year hybrid-type, multicomponent interval training programme (DoIT) on various musculoskeletal fitness parameters in inactive overweight and obese adults in a gym setting. Ninety-seven middle-aged (44.8 ± 5.2 years) individuals with overweight/obesity (31.2 ± 5.7 kg/m2) (66% female) were randomly assigned to the following groups: (i) no-intervention control (CON, n = 29), (ii) DoIT performed once weekly (DoIT-1, n = 24), (iii) DoIT performed twice weekly (DoIT-2, n = 23) and (iv) DoIT performed thrice weekly (DoIT-3, n = 21). DoIT was a time-efficient, intermittent-based, multicomponent exercise protocol using progressive loaded fundamental movement patterns with prescribed work-to-rest intervals (1:3-2:1) in a circuit format (2-3 rounds). Muscular strength, muscular endurance, flexibility, passive range of motion (PRoM), static balance and functional movement screen (FMS®) were assessed at baseline, 6 and 12 months following intervention. At post-training, all exercise groups exhibited superior changes than CON in (i) muscular strength (+13%-38%, p < 0.001); (ii) muscular endurance (+42%-159%, p < 0.001); (iii) flexibility (+12%-42%, p < 0.001); (iv) PRoM (+6%-50%, p = 0.001-0.026); (v) static balance (+61%-163%, p < 0.001); and (vi) FMS (+18%-39%, p < 0.001). Although a single exercise session/week improved musculoskeletal fitness, changes demonstrated a step-wise improvement with two and three sessions/week suggesting a dose-dependent response. The response rate to training was 100% for all exercise groups. These findings suggest that a multicomponent exercise approach incorporating bodyweight drills and resistance-based alternative modes performed under real-world conditions may improve several musculoskeletal fitness indicators in a dose-dependent manner in inactive, middle-aged adults with overweight/obesity.Trial registration: ClinicalTrials.gov identifier: NCT03759951.


Comparative Safety and Efficacy of Eight Antithrombotic Regimens for Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.
Antithrombotic therapy for patients with atrial fibrillation undergoing percutaneous coronary intervention is facing major treatment problems in clinical practice. We firstly conducted a Bayesian network meta-analysis to study the safety and efficacy of different antithrombotic regimens. Only randomized controlled trials from PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, and China National Knowledge Infrastructure were included in our study. The Bayesian random-effects model was used in this study. The primary safety and efficacy outcomes were major bleeding according to the criteria of Thrombolysis In Myocardial Infarction (TIMI) and trial-defined major adverse cardiovascular events, respectively. The secondary safety outcomes were combined TIMI major and minor bleeding, trial-defined primary bleeding events, and intracranial hemorrhage. The secondary efficacy outcomes were all-cause or cardiovascular mortality, myocardial infarction, stroke, stent thrombosis, and hospitalization. Total of 11,532 patients from the five randomized controlled trials were analyzed, of whom 8,426 were male. Compared with vitamin K antagonist (VKA) plus P2Y12 inhibitor, the odds ratios (95% credible intervals) for TIMI major bleeding were 1.70 (0.77-3.80) for VKA plus dual antiplatelet therapy (DAPT), 1.20 (0.30-4.60) for rivaroxaban plus P2Y12 inhibitor, 1.00 (0.25-3.90) for rivaroxaban plus DAPT, 0.76 (0.21-2.80) for dabigatran plus P2Y12 inhibitor, 0.71 (0.25-2.10) for apixaban plus P2Y12 inhibitor, 1.40 (0.52-3.80) for apixaban plus DAPT, and 1.00 (0.27-4.00) for edoxaban plus P2Y12 inhibitor. For trial-defined major adverse cardiovascular events, compared with VKA plus P2Y12 inhibitor, the odds ratios (95% credible intervals) were 1.10 (0.61-2.00) for VKA plus DAPT, 1.20 (0.45-3.70) for rivaroxaban plus P2Y12 inhibitor, 1.10 (0.38-3.20) for rivaroxaban plus DAPT, 1.10 (0.43-3.10) for dabigatran plus P2Y12 inhibitor, 1.00 (0.47-2.20) for apixaban plus P2Y12 inhibitor, 0.99 (0.46-2.20) for apixaban plus DAPT, and 1.20 (0.43-3.40) for edoxaban plus P2Y12 inhibitor. Apixaban plus P2Y12 inhibitor was the highest-ranking of safety outcomes and VKA plus P2Y12 inhibitor was the highest-ranking of efficacy outcomes other than trial-defined major adverse cardiovascular events. Apixaban plus P2Y12 inhibitor seems to be linked with fewer bleeding complications while retaining antithrombotic efficacy. Moreover, for most efficacy indicators, the ranking of VKA plus P2Y12 inhibitor is still very high. [www.crd.york.ac.uk/prospero/], identifier [CRD42020149894].


Kinetics and mechanism of captopril oxidation in aqueous solution under controlled oxygen partial pressure.
The stability of captopril in aqueous solution at 32 degrees C was studied in the pH range 6.6 to 8.0 under controlled oxygen partial pressure (90-760 mm Hg) with and without the addition of cupric ion. The oxidation product, captopril disulfide, was found to be the sole degradation product. A change in reaction rate from first order to zero order occurs as the captopril concentration decreases. The concentration at which this transition takes place is a function of the pH, oxygen partial pressure, and cupric ion concentration. The apparent first-order rate constants show a first-order dependency on both the oxygen partial pressure and the cupric ion concentration. However, the apparent zero-order rate constants show a first-order dependency on oxygen partial pressure and a second-order dependency on cupric ion concentration. As the pH increases from 6.6 to 8.0, the first-order process becomes more predominant. A mechanism which consists of cupric ion- and molecular oxygen-catalyzed oxidation is proposed to explain those observations.


Dendritic cells engineered to express the Flt3 ligand stimulate type I immune response, and induce enhanced cytoxic T and natural killer cell cytotoxicities and antitumor immunity.
Tumor antigen presentation by dendritic cells (DCs) to T cells in lymphoid organs is crucial for induction of antitumor immune responses. Fms-like tyrosine kinase 3 ligand (Flt3L) is a regulator of hematopoietic cell development. To investigate the potential effect of Flt3L transgene expression on DC-based cancer vaccines, we constructed a recombinant adenovirus AdVFlt3L expressing Flt3L, transfected DCs with AdVFlt3L, and investigated the efficacy of antitumor immunity by vaccination of DC(Flt3L) engineered to express Flt3L transgene. Our data demonstrated that AdVFlt3L transfection up-regulated the expression of cytokine IL-1beta and chemokines MIP-1alpha, MIP-1beta, IP-10, MCP-1 and MIP-2, and stimulated DC(Flt3L) cell proliferation in vitro and migration toward regional lymph nodes in vivo. Our data also demonstrated that vaccination of Mut1-pulsed DC(Flt3L) cells was able to stimulate (i). a type 1 immune response comprising CD4(+) Th1 and CD8(+) Tc1 activation and (ii). around 2- and 3-fold enhanced tumor-specific cytotoxic T lymphocyte (CTL) and non-specific NK responses (p < 0.05) than vaccination with similarly pulsed control virus-transfected and untransfected DCs, respectively. More importantly, vaccination of Mut1-pulsed DC(Flt3L) cells induced enhanced antitumor immunity in vivo, even against poorly immunogenic 3LL tumor cells. Vaccinations of Mut1-pulsed DCs, DC(pLpA) and DC(Flt3L) all protected mice from challenge of low dose (0.5 x 10(5)) tumor cells. However, only vaccination of the last one was able to protect 63% (6/8) mice from challenge of high dose (3 x 10(5)) 3LL tumor cells (p < 0.01). DCs engineered to secrete Flt3L may offer a new strategy in DC-based cancer vaccines.


Ectopic right coronary artery arising from the left sinus of Valsalva: A rare variant.
An ectopic coronary artery is observed in 0.05-0.1% of angiographic series, may be of tangential origin or proximal endocardial pathway, may result in a slit hole that interferes with flow, and is associated with sudden death.


Ectopic liver masquerading as a floating intracaval mass.
Ectopic liver is defined as liver parenchyma situated outside the liver proper with no connection to native hepatic tissue. This rare developmental anomaly is most commonly described as an attachment to the gallbladder with an incidence <0.3%, but it has been reported in other locations within the abdomen and thorax.(2-4) Most cases are found incidentally in asymptomatic patients, but ectopic liver has been known to cause visceral or vascular obstruction.(4,5) Herein we present a unique case of ectopic liver attached by a thin stalk seemingly floating in the suprahepatic inferior vena cava.


Interactions of two food colourants with BSA: Analysis by Debye-Hückel theory.
We have focused on exploring pH- and ionic strength-modulated binding of acid red 1 (AR1) and acid green 50 (AG50) with bovine serum albumin (BSA) by fluorescence, UV-vis absorption and FTIR spectra. The results implied that the quenching mechanism of BSA-AR1/AG50 system was a static quenching, electrostatic force dominated the formation of BSA-AR1/AG50 complex, and the binding affinity of AR1 was greater than that of AG50 on the subdomain IIA of BSA. Moreover, their true thermodynamic binding constant (Keq), true free energy change (ΔG(0)I→0), and effective charge (ZP) in the anion receptor pocket of BSA were calculated using Debye-Hückel limiting law. The local charge bound by AR1/AG50 rather than the overall or surface charge of BSA played a key role in determining their interaction strength. Besides, the thermal and structural stabilization of BSA was discussed by analyzing the changes of Tm and Hurea without/with the addition of AR1/AG50, respectively.


Nurses' Perceptions Regarding End-of-life Care for Individuals with Non-cancer Diseases on Non-invasive Positive Pressure Ventilation-dependent: A Qualitative and Descriptive Study.
Palliative care is essential for patients requiring respiratory assistance through non-invasive positive pressure ventilation (NPPV). This study aimed to describe nurses' perception of individuals with NPPV and non-cancer terminal diseases in various clinical settings. This qualitative and descriptive study was conducted using semi-structured interviews with audio recordings with advanced practice nurses from different clinical settings and obtained their perceptions of end-of-life care for patients with NPPV. Five categories of nurses' perceptions were extracted: Difficulty with an uncertain prognosis, differences in symptom management by type of disease, benefits and weaknesses of NPPV on palliative care, influence of physicians' attitude toward palliative care and the nature of the medical institutions and influence of patient's age in palliative care. The nurses' perceptions showed differences and similarities across disease types. There is a need for skills improvement regardless of disease type to minimise the side effects of NPPV. Advanced care planning based on disease-specific characteristics and age-appropriate support and integration of palliative care into acute care is needed for terminal NPPV-dependent patients. Interdisciplinary efforts, as well as the pursuit of expertise in each field, are needed to provide good palliative and end-of-life care for NPPV users with non-cancer diseases.


Expression of osteopontin at sites of bone erosion in a murine experimental arthritis model of collagen-induced arthritis: possible involvement of osteopontin in bone destruction in arthritis.
To investigate the involvement of osteopontin (OPN) in bone destruction in a murine experimental arthritis model of collagen-induced arthritis (CIA). The expression of OPN was examined at both the messenger RNA (mRNA) and protein levels in various arthritic lesions in mice with CIA by in situ hybridization and immunohistochemistry, respectively. In addition, the expression of alpha(v)beta3 integrin, a receptor for OPN, the ligation of which is thought to be essential for bone resorption by osteoclasts, was examined by immunohistochemistry. Plasma concentrations of OPN were measured at different time points in the course of CIA by enzyme-linked immunosorbent assay. OPN mRNA was detected mainly at sites of bone erosion in arthritic lesions, where activated osteoclasts were present; OPN protein was also detected at sites of bone erosion. In the arthritic synovium, OPN was predominantly expressed in the synovial lining layer, but not in lymphoid aggregates. In addition, alpha(v)beta3 integrin was detected coincident with OPN at sites of bone erosion (bone-pannus junction). Plasma OPN levels were markedly elevated at the time points that corresponded to arthritis flares, and higher levels were maintained during the progression of arthritis. OPN may mediate bone resorption by osteoclasts in arthritis through ligation with its receptor, alpha(v)beta3 integrin. OPN may be a useful therapeutic target molecule in the prevention of bone destruction in arthritis.


Data on characteristics of reported cases of unilateral posterior reversible encephalopathy syndrome (PRES).
Data presented in this article are related to our article entitled "Unilateral posterior reversible encephalopathy syndrome: A case report" [1]. Cases of Posterior Reversible Encephalopathy Syndrome (PRES) involving unilateral lesions are very rare. We searched the PubMed database using keywords such as PRES, unilateral, and asymmetric and found a small number of cases to include in our review. We summarized the characteristics of these reported cases of unilateral PRES, including our case.


Ruptured distal middle cerebral artery aneurysm: Case report.
This report describes a rare case of a distal middle cerebral artery (dMCA) aneurysm. That developed a right intracerebral haematoma and subarachnoid haemorrhage. It was treated by surgical exploration and clipping via pterional approach. Clinical findings and surgical approaches of dMCA aneurysm are different from proximal middle cerebral artery (MCA) aneurysms. Microneurosurgical clipping is the most effective treatment of dMCA aneurysm. We comprehensively review the literature related to these rare aneurysms within the temporal lobe, surgical anatomy of the dMCA aneurysm.


Predictors of aneurysmal formation after surgical correction of aortic coarctation.
We sought to identify the predictors of aneurysmal formation after surgical correction of aortic coarctation. In 9% of patients, aneurysms develop late after corrective surgery of coarctation of the aorta, with a 36% mortality rate if left untreated. However, the predictors of postsurgical aneurysmal formation are unknown. Of 25 aortic aneurysms requiring corrective surgery 152 +/- 78 months after the initial coarctation repair, 8 were located in the ascending aorta (type A) and 17 at the site of previous repair (local type). Seventy-four patients without progression of the aortic diameter within 189 +/- 71 months after coarctation repair were used for categorical data analysis in an attempt to identify the predictors of postsurgical aneurysmal formation. Advanced age at coarctation repair (p = 0.004) and patch graft technique (p < 0.0005) independently predicted local aneurysmal formation. Type A aneurysm was univariately associated with the presence of a bicuspid aortic valve (p = 0.02), advanced age at coarctation repair (p = 0.044) and a high preoperative peak systolic pressure gradient of 74 +/- 21 mm Hg (p = 0.041). Conversely, multivariate analysis confirmed only the presence of a bicuspid aortic valve (p = 0.015) as an independent predictor of type A aneurysm. Receiver operating characteristic curve analysis revealed that 72% of patients with a postsurgical aneurysm had an operation at age 13.5 years or more, whereas 69% with no postsurgical aneurysm had an operation at a younger age. Use of the patch graft technique and late correction of coarctation can predict aneurysmal formation at the site of coarctation repair, although patients with a bicuspid aortic valve may be at risk for an aneurysm developing in the ascending aorta, particularly after late repair of aortic coarctation with high preoperative pressure gradients.


Association between variables used in the field substitution and post-stratification adjustment in the Belgian health interview survey and non-response.
Field substitution and post-stratification adjustment have been proposed to reduce non-response bias in population surveys. We investigated if variables involved in those techniques in the Belgian health interview survey 2004 are associated with non-response and assessed the impact of field substitution and post-stratification adjustment on the survey results. Data were obtained from all selected households (n = 12.204). The association between non-response and the selected variables was explored through multilevel logistic regression models with municipality and statistical sector as random effects. All investigated variables were significantly related with non-response. Especially households that could not be contacted differed substantially from those who participated. Only post-stratification had a clear impact on the survey results. Even if variables used in the field substitution procedure of health surveys are strongly associated with non-response, the impact of field substitution on the survey results may be minimal, either because there was no bias of relevance or it was not captured. The usefulness of field substitution to correct for non-response bias in population health surveys seems to be quite limited.


[Oesophageal perforations from instrumentation during high fibroscopy. Radiological signs (author's transl)].
The authors report on a survey of perforation following fibroscopy in the Hôpital Saint-Antoine. A total of 10,600 diagnostic examinations were reviewed and 5 perforations were recorded, to which must be added 2 perforations following oesophageal dilatation. A chesy X-ray, taken within 24 hours of the incident, showed, in most cases, the presence of air in the mediastinum with early signs of subcutaneous emphysema in the cervical or cervicothoracic regions. A hydro-pneumothorax in the right side of the chest was also observed in the cases studied, without air in the mediastinum. Oesophageal transit was studied by means of a water-soluble compound, and showed oesophageal effraction in only 4 cases, and in 3 of these cases it was possible to see the location of the orifice with precision.


Effect of temperature and growth media on the attachment of Listeria monocytogenes to stainless steel.
Listeria monocytogenes ATCC 19111 cultivated in nutrient-rich medium (brain heart infusion, BHI) or starved in minimal medium (10% filter sterilized pond water and 90% sterilized distilled water) were investigated for their initial attachment to austenitic stainless steel No. 4 with satin finish at 4 degrees C, 20 degrees C, 30 degrees C, 37 degrees C, or 42 degrees C. A droplet (10 microl) containing approximately 10(7) CFU/ml of L. monocytogenes suspended in BHI or minimal medium was placed on the stainless steel surface. After holding in saturated humidity for 3 h at the desired temperature the surface was washed and prepared for scanning electron microscopy (SEM). Using SEM, attachment of L. monocytogenes was determined by counting cells remaining on the surface. When L. monocytogenes cultivated in BHI were used, with the exception of the number of attached cells being lower at 42 degrees C than at 37 degrees C and 30 degrees C, the number of attached cells increased with increasing temperature (P<0.05). When L. monocytogenes starved in minimal medium were used, the number of attached cells also increased with increasing attachment temperature (P<0.05), but the number of attached cells at 42 degrees C was lower than that at the other temperatures. The attachment of L. monocytogenes to stainless steel surface was greater when cultivated in rich medium of BHI vs starved in the minimal medium.


Exploring pre-surgery donor-specific antibodies in the context of organ shortage in liver transplant.
There is a growing disparity between the number of liver transplant (LT) candidates and availability of suitable liver allografts. Antibody-mediated rejection (AMR), secondary to positive donor-specific antibodies (DSA), remains a concern in liver transplantation. This study aimed to correlate expression of DSA on pre-transplant screening and outcomes of LT, specifically development of AMR in liver allografts and liver function profile in the post-operative period. Data of consecutive patients undergoing orthotopic LT (OLT) at the South Australian Liver Transplant Unit was analysed. All patients underwent DSA testing pre-transplant. Within a cohort of 96 patients, over a post-OLT median follow-up of 849 days, only 2 patients (2%) developed AMR. While both patients had a positive DSA test preoperatively, overall DSA positivity was noted in 31% patients, with a specificity for prediction of AMR of 0.708. No significant association was noted between AMR (p = 0.092), T cell-mediated rejection/TCMR (p = 0.797) or late hepatic artery thrombosis/LHAT (p = 0.521). There was no significant interaction effect between DSA positivity and serum bilirubin or transaminases over a period of 100 days. AMR following LT is uncommon. A positive DSA pre-transplant does not imply a definite risk of AMR. Also, there does not exist a significant interaction in time between DSA expression and serum bilirubin or transaminase levels. Until there emerges evidence to the contrary, it appears reasonable to consider DSA-positive donors within the broad context of marginal donors in the context of a worldwide shortage of LT donor allografts.


Coactivator-associated arginine methyltransferase 1: A versatile player in cell differentiation and development.
Protein arginine methylation is a common post-translational modification involved in the regulation of various cellular functions. Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that asymmetrically dimethylates histone H3 and non-histone proteins to regulate gene transcription. CARM1 has been found to play important roles in cell differentiation and development, cell cycle progression, autophagy, metabolism, pre-mRNA splicing and transportation, and DNA replication. In this review, we describe the molecular characteristics of CARM1 and summarize its roles in the regulation of cell differentiation and development in mammals.


Akt and Hippo Pathways in Ewing's Sarcoma Tumors and Their Prognostic Significance.
Ewing's sarcoma tumor is an aggressive malignancy of bone and soft tissue in children and young adults. Despite advances in modern therapy, metastasis occurs and results in high mortality. Intracellular molecules Yap, Akt, mTOR, and Erk are signaling pathway members that regulate the proliferation of tumor cells. We studied the immunohistochemical expression of these proteins in 36 tumor samples from adult and pediatric patients with Ewing's sarcoma tumors. Patients' age, sex, tumor site, tumor size, clinical stage and survival (overall and disease-free survival) were collected. Tissue microarrays slides were stained with antibodies against Yap, Akt, mTOR, and Erk proteins. Tumors exhibited variable expression of Yap, Akt, mTOR, and Erk (from negative, low to high), with high levels of expression present in 31%, 53%, 77% and 0% respectively. Immunohistochemical expression of Akt was associated with worse overall and disease-free survival (p<0.05). The other biomarkers did not demonstrate any difference in survival between low versus high expression. Although Yap, Akt, mTOR, and Erk protein are all expressed in Ewing's sarcoma by immunohistochemistry, only Akt expression is associated with worse prognosis. Larger studies are needed to verify these results and plan targeted therapy, particularly against Akt.


[Distribution of B-lymphocyte subgroup CD20 and its clinical significance in patients with myasthenia gravis].
To assess the distribution and clinical significance of B-lymphocyte subgroup CD20 in patients with myasthenia gravis. B-lymphocyte subset CD20 was studied in patients with thymomas associated with or without myasthenia gravis using immunohistochemistry technique. The moderate and obvious aggregation of CD20 positive cells was found in patients with myasthenia gravis, there was a significant difference when compared with those patients without myasthenia gravis (chi(2) = 26.032, P < 0.01). There was negative correlation between the distribution of CD20 positive cells and the staging of thymomas (gamma = 0.07), and no correlation between the distribution and clinical type of myasthenia gravis (gamma < 0.4). The results of this study indicated that pathological changes of thymus are more important than those of thymomas itself in the pathogenesis of myasthenia gravis. The degree of B-lymphocyte subgroup aggregation can not truly reflect clinical status because of the heterogeneity of antibody against acetylcholine receptor.


Proteomic and functional data sets on synaptic mitochondria from rats with genetic ablation of Parkin.
In this paper, we provide proteomic and functional data for synaptic mitochondria from the striatum of rats with Parkin ablation. The quantitative proteomic data was obtained using SWATH-MS methodology and mitochondrial function was assessed through measurement of oxygen consumption rate using the Seahorse XF Analyzer. This data facilitates comparisons with previous proteomic and functional data obtained using the exact same methods. A complete set of proteomic data is contained in Supplementary Table 1.


Simultaneous and systematic analysis of cytostatic drugs in wastewater samples by ultra-high performance liquid chromatography tandem mass spectrometry.
Cytostatic drugs are compounds used to fight cancer, which may be excreted after administration to patients, and eventually reach wastewater. Given the high incidence of cancer and the properties of drugs, the drug concentrations in water systems should be evaluated. We present the optimization, development and application of a solid phase extraction (SPE) method for the determination of eight cytostatic compounds of different classes in wastewater and seawater samples. We compared four SPE cartridges prior to their determination by Ultra-High Performance Liquid Chromatography tandem Mass Spectrometry. For wastewater samples, the Oasis HLB cartridge gave the best recoveries, which were higher than 65% in most cases, achieving limit of detections (LODs) of 1.68-103.95 ng·L-1. In seawater samples, the Bond Elut cartridge afforded the best recoveries >70%, with LODs of 0.95-5.14 ng·L-1. The optimal procedure was applied in four hospital wastewater effluent samples taken during one year, and in different influents and effluents from wastewater treatment plants and seawater from marine outfalls taken in eight campaigns during two years, in Gran Canaria island (Spain). Results showed that etoposide was present in influents of wastewater treatment plants in several months and different wastewater treatment plants and hospital effluents in the range 375.8-5141 ng·L-1, while cyclophosphamide was present in some months in effluents from only one wastewater treatment plant and hospital effluents in the range 55.94-1212 ng·L-1. Vinblastine and vincristine were detected in one sample of hospital at concentrations of 1836 ng·L-1 and 1851 ng·L-1, respectively.


Renin-angiotensin system genes polymorphism in Egyptians with premature coronary artery disease.
Genetics polymorphism of the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and associated with coronary artery disease (CAD). We aimed to investigate the association between the RAS genes and premature CAD (PCAD) in Egyptians. 116 patients with PCAD, 114 patients with late onset CAD and 119 controls were included in the study. Angiotensin converting enzyme (ACE), angiotensin II receptor type 1 (ATR1) and angiotensinogen (AGT) genes polymorphisms were analyzed by polymerase chain reaction (PCR). We found that ACE DD, AGT TT and ATR1 CC increased the risk of PCAD by 2.7, 2.8 and 2.86 respectively). Smoking, hypertension, diabetes, total cholesterol, triglycerides and LDL cholesterol were independent risk factors for the development of PCAD. We conclude that the ACE DD, AGT TT and ATR1 CC genotypes may increase the susceptibility of an individual to have PCAD. The coexistence of CAD risk factors with these risky RAS genotypes may lead to the development of PCAD in Egyptian patients.


Molecular signatures of virulence in the PB1-F2 proteins of H5N1 influenza viruses.
The PB1-F2 protein of influenza A viruses contributes to pathogenesis in animal models. Specific molecular signatures of virulence within PB1-F2 have been mapped for some functions. The 66S polymorphism may modulate interferon activity, and four C-terminal amino acids, 62L, 75R, 79R, and 82L, contribute to cytokine release and inflammatory responses in specific virus backgrounds. All available PB1-F2 sequences from H5N1 subtype influenza A viruses were analyzed. The majority (82.5%) of H5N1 sequences available in the Influenza Research Database code for PB1-F2 proteins with 4 or more of these virulence associated amino acids. Most of these are avian sequences from highly pathogenic strains isolated in Asia or Africa. The 66S polymorphism was uncommon (5.3% of sequences) but was found in association with the other 4 inflammatory amino acids in select highly pathogenic strains in Asia. These analyses suggest that if an H5N1 virus were to emerge as a pandemic strain, the PB1-F2 protein will be a contributor to pathogenesis. Research on the pathogenic effect of these signatures in an H5N1 background should be undertaken. Surveillance efforts should include sequencing of the PB1 gene segment and analysis for these molecular signatures to allow for the potential prioritization of resources during pandemic planning.


Placental biopsy for rapid fetal karyotyping in the second and third trimesters of pregnancy.
Rapid chromosomal analysis in the 2nd and 3rd trimester of gestation is desirable in cases of suspected or proven fetal malformation. The presence of any chromosomal aberration of the fetus influences the further prenatal and perinatal management of the pregnancy. Placental biopsy and preparation of trophoblast tissue after short term culture offers the possibility of getting satisfactory results within 2 to 3 days of biopsy. Fifty-seven patients underwent placental biopsy between the 16th and 36th weeks of gestation because of sonographically suspected or proven fetal malformation. In 51 of 57 cases fetal karyotyping was successful and no severe complications after biopsy were seen. Eight pathologic karyotypes were found. In 3 cases the chromosomal analysis yielded unsatisfactory results because of the inadequate quality of metaphases. In another 3 cases not enough chorionic tissue was aspirated in 2 biopsy attempts. In all other cases normal fetal karyotypes were found. Sonographically guided placental biopsy represents a simple method for fetal karyotyping and is a useful tool for the management of pregnancies with suspected or proven fetal malformation in the 2nd and 3rd trimester.


5 Alpha-reductase activity in human prostate cancer is related to the histological differentiation of the tumour.
We have measured the activities of two androgen metabolizing enzymes in tissue obtained from thirty-nine patients with carcinoma of the prostate (CaP). The enzyme activities were correlated to the histological differentiation of the tumours based on the Gleason Score and also compared to the activities measured in fourteen age matched patients with nodular prostatic hyperplasia (BPH). Although the mean values for the 5 alpha-reductase in CaP (9.29 +/- 1.47 pmol/mg protein/30 min) were found to be significantly lower than the corresponding values in BPH (16.26 +/- 3.04 pmol/mg protein/30 min) (P less than 0.05), there were nonetheless significant differences within the cancer group and these were totally dependent on the degree of differentiation of the tumour. A progressively suppressed enzyme activity was measured as the carcinomatous tissue became more anaplastic. No correlation was, however, observed between tumour bulk which was also estimated histologically and 5 alpha-reductase, indicating that the activity of this enzyme is purely a function of the histological grade of the cancer and as such 5 alpha-reductase could be used as a biochemical marker for tumour differentiation. We also measured the 3 alpha (beta)-hydroxysteroid dehydrogenase activities in cancer of the prostate but our findings indicated no significant differences between the various stages of the cancer. Furthermore we were unable to correlate the activities of this enzyme with that of the 5 alpha-reductase. Nonetheless two interesting patterns relating to the 3 alpha (beta)-hydroxysteroid dehydrogenase emerged.(ABSTRACT TRUNCATED AT 250 WORDS)


New thiophene derivative augments the antitumor activity of γ-irradiation against colorectal cancer in mice via anti-inflammatory and pro-apoptotic pathways.
Colorectal cancer (CRC) is one of the most common types of cancer worldwide and the second cause of cancer-related deaths. It usually starts as an inflammation that progresses to adenocarcinoma. The goal of the present study was to investigate the antitumor efficacy of a new thiophene derivative against CRC in mice and explore the possible associated molecular pathways. The potential of this thiophene derivative to sensitize the CRC tumor tissue to a low dose of gamma irradiation was also investigated. Adult male mice were divided into seven groups; control, group treated with dimethylhydrazine (DMH) for the induction of CRC. The DMH-group was further divided into six groups and treated with either cisplatin, thiophene derivative, γ-irradiation, cisplatin + γ-irradiation, thiophene derivative + γ-irradiation, or left untreated. DMH induced CRC as evidenced by the macroscopic examination of colon tissues and histopathology, and elevated the activities of cyclooxygenase2 (COX2) and nitric oxide synthase (iNOS). DMH also elevated kirsten rat sarcoma (KRAS) and downregulated the peroxisome proliferator activated receptor (PPARγ) as shown by RT-PCR and Western blotting. DMH exerted anti-apoptotic activity by reducing the expression of phosphorylated p53 and cleaved caspase3 at the gene and protein levels. The flow cytometry analysis showed that DMH elevated the necrosis and reduced the apoptosis compared to the other groups. The colon tissue from DMH-treated mice showed hyperplasia, aberrant crypt foci, loss of cell polarity, typical CRC of grade 4 with lymphocytes and macrophages infiltrating mucosa, muscularis mucosa, and submucosa score 3. Treatment with thiophene derivative or γ-irradiation ameliorated most of these deleterious effects of DMH. The concomitant action of thiophene derivative + γ-irradiation was typified by the better amelioration of tumor incidence and multiplicity, iNOS, PPARγ, p53, caspase 3, and histopathology of colon. Taken together, the new thiophene derivative is a promising therapeutic candidate for treatment of colorectal cancer in mice. It also sensitizes the CRC tumor to the ionizing radiation through anti-inflammatory and pro-apoptotic pathways.


An essential function for the calcium-promoted Ras inactivator in Fcgamma receptor-mediated phagocytosis.
Fc receptor (FcR)-mediated phagocytosis requires activation of the Rho GTPases Cdc42 and Rac1, but how they are recruited to the FcR is unknown. Here we show that the calcium-promoted Ras inactivator (CAPRI), a Ras GTPase-activating protein, functions as an adaptor for Cdc42 and Rac1 during FcR-mediated phagocytosis. CAPRI-deficient macrophages had impaired FcgammaR-mediated phagocytosis and oxidative burst, as well as defective activation of Cdc42 and Rac1. CAPRI interacted constitutively with both Cdc42 and Rac1 and translocated to phagocytic cups during FcgammaR-mediated phagocytosis. CAPRI-deficient mice had an impaired innate immune response to bacterial infection. These results suggest that CAPRI provides a link between FcgammaR and Cdc42 and Rac1 and is essential for innate immune responses.


Safety and tolerability of antidepressant co-treatment in acute major depressive disorder: results from a systematic review and exploratory meta-analysis.
Although antidepressant (AD) monotherapy is recommended first-line for major depressive disorder (MDD), AD + AD co-treatment is common. We conducted the first systematic review searching PubMed/MEDLINE/PsycInfo/Embase from database inception until 1 June 2015 for acute randomized trials in ≥ 20 adults with MDD comparing AD monotherapy with AD + AD co-treatment that reported quantitative data on adverse events (AEs). Meta-analyzing 23 studies (n = 2435, duration = 6.6 weeks) AD monotherapy and AD + AD co-treatment were similar regarding intolerability-related discontinuation (risk ratio [RR] = 1.38, 95% CI = 0.89 - 1.10) and frequency of ≥ 1 AE (RR = 1.19, 95% CI = 0.95 - 1.49). Nevertheless, AD + AD co-treatment was associated with significantly greater burden regarding 4/25 AEs (tremor: RR = 1.55, 95% CI = 1.01 - 2.38; sweating: RR = 1.95, 95% CI = 1.13 -3.38, ≥ 7% weight gain: RR = 3.15, 95% CI = 1.34 - 7.41; weight gain = 2.17, 95% CI = 0.71 - 3.63 kg), but not more CNS, gastrointestinal, sexual or alertness-related AEs. However, 11/25 AEs (44.0%) were reported in only 1 - 2 studies. Adding noradrenergic and specific serotonergic antidepressants (NaSSA) or tricyclic antidepressants (TCA) to selective serotonin reuptake inhibitors (SSRIs) was specifically associated with more AEs. The potential for increased AEs with AD + AD co-treatment needs to be considered vis-à-vis unclear efficacy benefits of this strategy. In particular, NaSSAs and TCAs should be added to SSRIs with caution. Clearly, more data on side-effect burden of AD + AD co-treatment are needed.


Long-term response to interferon therapy in chronic hepatitis B: importance of hepatitis B virus heterogeneity.
The long-term therapeutic efficacy of alpha IFN and the influence of preC variants on the type of response were evaluated in 25 patients with chronic hepatitis B, 14 HBeAg and 11 antiHBe positive patients, treated with alpha IFN and monitored for at least four years after discontinuing therapy. In both groups of patients, serum HBV-DNA became frequently undetectable by DNA dot blot during treatment, suggesting that alpha IFN has an antiviral effect both on HBeAg and antiHBe positive chronic carriers. However, long term follow up showed that the loss of viral DNA in antiHBe carriers was only transient, because all responder patients relapsed from 1 to 48 months after IFN withdrawal. In the HBeAg positive carriers, selection for preC mutants was observed at the end of follow up in 2 patients who seroconverted to antiHBe and remained viremic. Both the frequent occurrence of reactivations in antiHBe compared to HBeAg carriers, and the association of IFN therapy with preC mutant virus selection during long term post-treatment follow up observed in this study, indicate that preC variants are more resistant to IFN therapy than preC wild type HBV. Our data suggest therefore, that IFN therapy may be less frequently able to induce a permanent remission in patients infected with preC mutants.


Association between genotype at an exonic SNP in DISC1 and normal cognitive aging.
DISC1 is expressed in the hippocampus and has been identified as a possible genetic risk factor for both schizophrenia and bipolar disorder. These psychiatric illnesses are associated with impaired learning and memory. This study investigates the association of variation in DISC1 with cognitive function on the same general mental ability test (Moray House Test) at age 11 and age 79, and cognitive change between ages 11 and 79, in 425 people from the Lothian Birth Cohort 1921 (LBC1921). Tests of memory, non-verbal reasoning and executive function were also administered at age 79. The effect of genotype at a non-synonymous single nucleotide polymorphism in exon 11, rs821616, was studied. There was no direct effect of DISC1 genotype on any cognitive measure. However, there was a significant DISC1 genotype by sex interaction on Moray House Test scores at age 79, both before and after adjustment for cognitive ability at age 11 (p = 0.034 and 0.043, respectively). Women homozygous for the Cys allele had significantly lower cognitive ability scores than men at age 79, p = 0.003. Variation in DISC1 may therefore affect cognitive aging especially in women.