New Scoring System for Predicting Mortality in Patients with COVID-19.
We aimed to develop a novel mortality scoring system for inpatients with COVID-19 based on simple demographic factors and laboratory findings. We reviewed and analyzed data from patients who were admitted and diagnosed with COVID-19 at 10 hospitals in Daegu, South Korea, between January and July 2020. We randomized and assigned patients to the development and validation groups at a 70% to 30% ratio. Each point scored for selected risk factors helped build a new mortality scoring system using Cox regression analysis. We evaluated the accuracy of the new scoring system in the development and validation groups using the area under the curve. The development group included 1232 patients, whereas the validation group included 528 patients. In the development group, predictors for the new scoring system as selected by Cox proportional hazards model were age ≥70 years, diabetes, chronic kidney disease, dementia, C-reactive protein levels >4 mg/dL, infiltration on chest X-rays at the initial diagnosis, and the need for oxygen support on admission. The areas under the curve for the development and validation groups were 0.914 [95% confidence interval (CI) 0.891-0.937] and 0.898 (95% CI 0.854-0.941), respectively. According to our scoring system, COVID-19 mortality was 0.4% for the low-risk group (score 0-3) and 53.7% for the very high-risk group (score ≥11). We developed a new scoring system for quickly and easily predicting COVID-19 mortality using simple predictors. This scoring system can help physicians provide the proper therapy and strategy for each patient.


High ward occupancy, bedspacing, and 60 day mortality for patients with myocardial infarction, stroke, and heart failure.
To study the consequences of crowded wards among patients with cardiovascular disease. This is a cohort study among 201 801 patients with 258 807 admissions who were acutely admitted for myocardial infarction (N = 107 895), stroke (N = 87 336), or heart failure (N = 63 576) to any Norwegian hospital between 2008 and 2016. The ward admitting most patients with the given clinical condition was considered a patient's home ward. We compared patients with the same condition admitted when home ward occupancy was different, at the same hospital and during comparable time periods. Occupancy was standardized such that a one-unit difference corresponded to the interquartile range in occupancy in the given month. One interquartile increase in home ward occupancy was associated with 7% higher odds of admission to an alternate ward [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.09 to 1.11], and length of stay was shorter (-0.10 days, 95% CI -0.18 to -0.09). Patients with heart failure had 15% higher odds of admission to alternate wards (OR 1.15, 95% CI 1.08 to 1.23) and increased mortality [hazard ratio (HR) 1.08, 95% CI 1.03 to 1.15]. We found no apparent effect on mortality for patients with myocardial infarction (HR 0.99, 95% CI 0.94 to 1.05) or stroke (HR 1.00, 95% CI 0.96 to 1.05). Patients with heart failure had higher risk of admission to alternate wards when home ward occupancy was high. These patients may be negatively affected by full wards.


Polysomnographic characteristics of neuroleptic-induced akathisia.
To investigate nocturnal leg movement activity and other polysomnographic features in patients with neuroleptic-induced akathisia (NIA), all-night polysomnography was performed in nine patients with NIA and compared with nine healthy individuals and eight unmedicated patients with depression. Patients with NIA displayed a pattern of leg movement activity during sleep similar to healthy individuals and depressed patients. In addition, eight of nine patients with NIA exhibited 10- to 40-second bursts of increased leg muscle tone before sleep onset. Although the significance of this finding is unclear, it is possible that it may be a pathophysiological correlate of NIA.


Perineural cell tumor. Immunocytochemical and ultrastructural characterization. Relationship to other peripheral nerve tumors with a review of the literature.
A perineurial cell tumor occurred in the shoulder girdle of a 47 year old woman. Light microscopy demonstrated a well-differentiated spindle-cell neoplasm of uncertain histogenesis. Immunocytochemical staining for S-100 protein was negative. Ultrastructural study revealed tumor cells with characteristics of perineurium, e.g. large numbers of micropinocytotic vesicles, numerous intercellular junctions, and elongated cell processes surrounded by basal lamina. Tumors of perineurial cells should be distinguished from the commonly recognized schwannomas as well as from various soft tissue lesions so that their biologic behavior can be better defined. A review of three other reported cases of perineurial cell tumors suggested that these tumors are benign and are usually located in the extremities and shoulder girdle. In addition, perineurial cell proliferation has been identified in other lesions of peripheral nerves, such as neurofibromas and localized hypertrophic neuropathy. Immunocytochemical and ultrastructural study of spindle-cell lesions with unusual histologic features may reveal that perineurial cell proliferation occurs more frequently than currently recognized.


Size and specimen-dependent strategy for x-ray micro-ct and tem correlative analysis of nervous system samples.
Correlative approaches are a powerful tool in the investigation of biological samples, but require specific preparation procedures to maintain the strength of the employed methods. Here we report the optimization of the embedding protocol of nervous system samples for a correlative synchrotron X-ray computed microtomography (micro-CT) and transmission electron microscopy (TEM) approach. We demonstrate that it is possible to locate, with the micrometric resolution of micro-CT, specific volumes of interest for a further ultrastructural characterization to be performed with TEM. This approach can be applied to samples of different size and morphology up to several cm. Our optimized method represents an invaluable tool for investigating those pathologies in which microscopic alterations are localized in few confined regions, rather than diffused in entire tissues, organs or systems. We present a proof of concept of our method in a mouse model of Globoid Cells Leukodistrophy.


Efficacy of Nilotinib in a CML Patient Expressing the Three-way Complex Variant Translocation t(2;9;22).
Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome, resulting from the reciprocal translocation involving chromosomes 9 and 22. About 5-10% of newly diagnosed patients in chronic-phase (CP) CML show complex additional chromosomal aberrations (ACA), that may involve one or more chromosomes in addition to 9 and 22. Data concerning the prognostic significance of ACA in CP-CML subjects at diagnosis are controversial. Furthermore, there is no evidence showing that selection of imatinib (IM) or second-generation tyrosine kinase inhibitors (2G-TKI) would be of benefit for these patients. We report the three-way complex variant translocation t(2;9;22) in a CP-CML patient. Conventional cytogenetic analysis was employed to identify the ACA. Multiplex reverse transcription-PCR was used to identify the BCR-ABL1 transcript and its levels were measured using quantitative real-time-PCR. This rare ACA t(2;9;22) in our young patient displayed primary resistance to IM, but was responsive to second-line treatment with nilotinib. CP-CML patients exhibiting this rare aberration at diagnosis may benefit from a 2G-TKI therapy compared to IM.


Resistance to PARP-Inhibitors in Cancer Therapy.
The pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) family of proteins have shown promising results in preclinical studies and clinical trials as a monotherapy or in combination therapy for some cancers. Thus, usage of PARP-inhibitors (PARPi) in cancer therapy is bound to increase with time, but resistance of cancer cells to PARPi is also beginning to be observed. Here we review different known and potential mechanisms by which: (i) PARPi kill cancer cells; and (ii) cancer cells develop resistance to PARPi. Understanding the lethality caused by PARPi and the countermeasures deployed by cancers cells to survive PARPi will help us rationalize the use of this new class of drugs in cancer therapy.


[Retroperitoneal leiomyosarcoma (case report)].
After a short introduction about the retroperitoneal tumors classification the Authors write on the management of this tumor. They present their case report: surgical treatment of retroperitoneal leiomyosarcoma. Actually the role of surgical strategy in the management of resectable retroperitoneal tumors is the most important than adjuvant therapy, even if the surgery must be very demolitive.


Exogenous steroids for menopausal symptoms and breast/endometrial cancer risk.
A literature search was performed to collect information concerning hormone replacement therapy (HRT) for menopausal symptoms by exogenous steroids and breast and endometrial cancer risk. Relevant studies in English were selected from Medline. HRT can alleviate vasomotor symptoms at least partially. HRT in women >50 years of age induces increased risk of breast and endometrial cancer. In women <50 years of age, HRT does not completely negate the breast cancer risk reduction by premature menopause. No data exist on endometrial cancer risk in these young women taking HRT. In conclusions, the decision to use HRT should be weighed against the risks and discouraged in women older than 50 years of age and after breast cancer. Counseling should be performed in an individual manner.


Attempted Synthesis of Vinca Alkaloids Condensed with Three-Membered Rings.
Our successful work for the synthesis of cyclopropanated vinblastine and its derivatives by the Simmons⁻Smith reaction was followed to build up further three-membered rings into the 14,15-position of the vindoline part of the dimer alkaloid. Halogenated 14,15-cyclopropanovindoline was prepared by reactions with iodoform and bromoform, respectively, in the presence of diethylzinc. Reactions of dichlorocarbene with vindoline resulted in the 10-formyl derivative. Unexpectedly, in the case of the dimer alkaloids vinblastine and vincristine, the rearranged products containing an oxirane ring in the catharanthine part were isolated from the reactions. The attempted epoxidation of vindoline and catharanthine also led to anomalous rearranged products. In the epoxidation reaction of vindoline, an o-quinonoid derivative was obtained, in the course of the epoxidation of catharanthine, a hydroxyindolenine type product and a spiro derivative formed by ring contraction reaction, were isolated. The coupling reaction of vindoline and the spiro derivative obtained in the epoxidation of catharanthine did not result in a bisindole alkaloid. Instead, two surprising vindoline trimers were discovered and characterized by NMR spectroscopy and mass spectrometry.


Does prediction error drive one-shot declarative learning?
The role of prediction error (PE) in driving learning is well-established in fields such as classical and instrumental conditioning, reward learning and procedural memory; however, its role in human one-shot declarative encoding is less clear. According to one recent hypothesis, PE reflects the divergence between two probability distributions: one reflecting the prior probability (from previous experiences) and the other reflecting the sensory evidence (from the current experience). Assuming unimodal probability distributions, PE can be manipulated in three ways: (1) the distance between the mode of the prior and evidence, (2) the precision of the prior, and (3) the precision of the evidence. We tested these three manipulations across five experiments, in terms of peoples' ability to encode a single presentation of a scene-item pairing as a function of previous exposures to that scene and/or item. Memory was probed by presenting the scene together with three choices for the previously paired item, in which the two foil items were from other pairings within the same condition as the target item. In Experiment 1, we manipulated the evidence to be either consistent or inconsistent with prior expectations, predicting PE to be larger, and hence memory better, when the new pairing was inconsistent. In Experiments 2a-c, we manipulated the precision of the priors, predicting better memory for a new pairing when the (inconsistent) priors were more precise. In Experiment 3, we manipulated both visual noise and prior exposure for unfamiliar faces, before pairing them with scenes, predicting better memory when the sensory evidence was more precise. In all experiments, the PE hypotheses were supported. We discuss alternative explanations of individual experiments, and conclude the Predictive Interactive Multiple Memory Signals (PIMMS) framework provides the most parsimonious account of the full pattern of results.


Neuronal gene expression and function in the growth-stimulated R28 retinal precursor cell line.
Proliferative retinal progenitor cells that express neuronal characteristics are potentially useful for developmental studies and as experimental graft material. The continuously-growing R28 retinal cell line has been distributed to over 60 laboratories for a variety of studies, yet has not been fully characterized. In this study, we tested the hypothesis that the proliferative R28 retinal cell line contains subpopulations of cells that express neuronal mRNAs and proteins characteristic of CNS neurons. To this end, we sought to determine the potential retinal, neuronal, and growth-related characteristics of this retinal cell line through gene expression profiling, coupled with confirmatory immunocytochemistry and electrophysiology. Despite expression of growth-stimulatory oncogenes and growth-promoting factors, subpopulations of R28 cells express abundant retinal and neuronal markers, as well as the functional capacity to respond to specific neurotransmitters such as dopamine, acetylcholine, serotonin, and glycine. Proliferative R28 cells retain functional neuronal properties that may prove useful in future studies of neuronal differentiation and development.


Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C.
Cilnidipine is a novel dihydropyridine (DHP) antagonist. However, its pharmacological effects on vascular DHP-sensitive L-type channels and protein kinase C (PKC)-mediated arterial contraction is incompletely understood. To address this issue, we studied the effects of cilnidipine on multi-subunit, C-class L-type Ca2+ channels in rat aortic A7r5 cells, as well as on Ca2+ channel (L-type) alpha1C-b and (T-type) alpha1G subunits in the Xenopus oocyte expression system. Cilnidipine dose- and time-dependently inhibited Ba2+ currents in A7r5 cells, with half-maximal inhibitions (IC50) at 10 nmol/l after 10 min. Unlike classical pharmacological Ca2+ channel blockers, cilnidipine's block of Ca2+ currents did not reach steady-state levels within 10 min, indicating steady-state half-maximal inhibition of native, multi-subunit L-type channels at < 10 nmol/l. In contrast, smooth muscle alpha1Cb currents were blocked by cilnidipine at much higher doses (steady-state IC50, 20 micromol/l) whereas alpha1G currents were not inhibited by cilnidipine (30 micromol/l). Cilnidipine dose-dependently inhibited depolarization- and Ca2+-induced contractions of rat aortic rings, with an IC50 of 10 nmol/l at 10 min. However, the onset of the effects was very slow, with approximately 71% inhibition by 3 nmol/l cilnidipine after 90 min exposure to cilnidipine. In contrast, cilnidipine did not inhibit phorbol 12-myristate-13-acetate (100 nmol/l)-mediated contractions. We conclude that cilnidipine represents an extremely slow-acting DHP that targets multi-subunit L-type channels, but not PKC in arterial smooth muscle. Because cilnidipine is less potent in cells expressing the pore-forming alpha1C-b subunit, the data further suggest that this unique slow-acting mechanism of cilnidipine is mediated by a complex interaction of cilnidipine with alpha1C-b and accessory channel subunits.


Participation in continuing medical education of general practitioners in New Zealand.
Continuing professional education has become increasingly recognized as an essential element of a professional's working life. Because participation in continuing education is usually on a voluntary basis, it is essential that organizers of continuing education understand the patterns of participation among their prospective clientele. Such an understanding can help identify areas of deficiency in program provisions as well as indicate possible ways of rectifying them. The study reported here surveyed approximately one-third of all general practitioners in New Zealand on their present participation in continuing medical education (CME), their attitudes toward continuing learning, and their specific preferences for future CME programs. Although overall rates of CME participation are very high, there are nonetheless significant variations in the amount of continuing education that general practitioners undertake. The rate of CME participation appears to be linked with the general practitioner's degree of involvement in a wide range of professional activities, and those general practitioners who are only minimally involved have lower rates of CME participation.


Epitaxial growth of few-layer MoS2(0001) on FeS2{100}.
Physical vapour deposition of Mo on an FeS2{100} surface was performed at 170 K. Near-epitaxial growth of MoS2(0001) overlayers of the order of 1 nm thickness was observed when the Mo-covered substrate was subsequently heated to 600 K.


Pyroptosis and gasdermins-Emerging insights and therapeutic opportunities in metabolic dysfunction-associated steatohepatitis.
In recent years, there has been a rapid expansion in our understanding of regulated cell death, leading to the discovery of novel mechanisms that govern diverse cell death pathways. One recently discovered type of cell death is pyroptosis, initially identified in the 1990s as a caspase-1-dependent lytic cell death. However, further investigations have redefined pyroptosis as a regulated cell death that relies on the activation of pore-forming proteins, particularly the gasdermin family. Among the key regulators of pyroptosis is the inflammasome sensor NOD-like receptor 3 (NLRP3), a critical innate immune sensor responsible for regulating the activation of caspase-1 and gasdermin D. A deeper understanding of pyroptosis and its interplay with other forms of regulated cell death is emerging, shedding light on a complex regulatory network controlling pore-forming proteins and cell fate. Cell death processes play a central role in diseases such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, autoinflammatory disorders, and cancer. Cell death often acts as a starting point in these diseases, making it an appealing target for drug development. Yet, the complete molecular mechanisms are not fully understood, and new discoveries reveal promising novel avenues for therapeutic interventions. In this review, we summarize recent evidence on pathways and proteins controlling pyroptosis and gasdermins. Furthermore, we will address the role of pyroptosis and the gasdermin family in metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Additionally, we highlight new potential therapeutic targets for treating metabolic dysfunction-associated steatohepatitis and other inflammatory-associated diseases.


The effects of two spacers on white organic light-emitting diodes.
The authors have demonstrated highly efficient white organic light-emitting diodes (WOLEDs) by using two emissive materials as a dopant, 1,4-Bis[2-(4'-diphenylaminobiphenyl-4-yl)vinyl]benzene (DABPV-ph) and iridium(III) bis(5-acetyl-2-phenylpyridinato-N,C2') acetylacetonate ((acppy)2Ir (acac)). In these WOLEDs, 2-methyl-9,10-di(2-naphthyl)anthracene (MADN), and 4,4'-N,N'-dicarbazole-biphenyl (CBP) were used as a spacer among the three emissive layers. The maximum luminous efficiency of the three devices with no spacer, MADN and CBP as a spacer were 11.50, 8.32, and 25.70 cd/A at 0.08, 12.7, and 0.01 mA/cm2 and the Commission Internationale De L'Eclairage (CIE(x, y)) coordinates were (x = 0.21, y = 0.34), (x = 0.21, y = 0.34), and (x = 0.33, y = 0.33) at 11 V, respectively.


Automated image morphometry of lobular breast carcinoma.
To analyze the role of automated image morphometry (AIM) in distinguishing infiltrating lobular carcinoma (ILC) of the breast from benign, borderline and infiltrating ductal carcinoma (IDC). Only histopathologically proven lobular carcinoma, ductal carcinoma, borderline lesions and benign breast lesions were selected for the study. There were 19 cases of ILC and 30 cases of IDC, 20 cases of benign lesions (fibroadenoma, 18; fibrocystic disease, 1; and fibroadenosis, 1); 10 cases were borderline lesions (mild epithelial hyperplasia, 3; moderate epithelial hyperplasia, 2; florid epithelial hyperplasia 4; intraductal papillary carcinoma, 1). In all cases hematoxylin and eosin-stained slides were used for AIM. At least 100 cells from each case were subjected to analysis randomly with an image cytometer with Leica Quantimet 600 software (Cambridge, England). Nuclear area, diameter, perimeter, convex perimeter, convex area and roundness were measured in each case with random, unbiased selection of cells and 40 x objectives (one pixel = 0.46 microm). AIM data on the cases were analyzed in relation to final cytologic diagnosis. All the nuclear morphometric features of ILC were much lower than those of IDC and borderline lesions, whereas nuclear morphometric data on ILC were only marginally more than those on benign cases. ANOVA showed that mophometric data were significant (P < .05) in all the variables between ILC and IDC. However, there was no significant difference between ILC, and borderline and benign cases. Image morphometry may be useful in distinguishing ILC from IDC on cytologic smears. However, morphometric data may not be helpful in distinguishing benign and borderline lesions from ILC.


Molecular and functional characterization of human bone marrow adipocytes.
Adipocytes are a cell population largely located in the human bone marrow cavity. In this specific microenvironment where adipocytes can interact with a variety of different cells, the role of fat is mainly unknown. To our knowledge, this report is the first to characterize mature adipocytes isolated from human bone marrow (BM-A) molecularly and functionally to better understand their roles into the hematopoietic microenvironment. Healthy BM-A were isolated after collagenase digestion and filtration. We studied the morphology of BM-A, their gene expression and immunophenotypic profile and their functional ability in the hematopoietic microenvironment, comparing them with adipocytes derived from adipose tissue (AT-A). BM-A showed a unilocular lipid morphology similar to AT-A and did not lose their morphology in culture; they showed a comparable pattern of stem cell-surface antigens to AT-A. In line with these observations, molecular data showed that BM-A expressed some embryonic stem cells genes, such as Oct4, KLf4, c-myc, Gata4, Tbx1, and Sox17, whereas they did not express the stem cell markers Sox2 and Nanog. Moreover, BM-A had long telomeres that were similar to bone marrow mesenchymal stem cells. Notably, BM-A supported the survival and differentiation of hematopoietic stem cells in long-term cultures. These results showed that BM-A are stromal cells with a gene expression pattern that distinguished them from AT-A. BM-A showed stem cell properties through their hematopoietic supporting function, which was certainly linked to their role in the maintenance of the bone marrow microenvironment. Depending on specific demands, BM-A may acquire different functions based on their local environment.


Combining two independent indirect methods as a new possibility for screening the illegal use of growth promotants.
In this study the possibilities of combined indirect screening methods for the growth promotants clenbuterol and estradiol-17 beta benzoate and the combination of both these agents were investigated. Three groups of 5 male goat kids (two months of age) were treated for 4 weeks; clenbuterol per os, 10 micrograms/day/kg body weight via milkreplacer twice a day; 2 mg estradiol-17 beta benzoate weekly per i.m. injection; combined clenbuterol per os+estradiol-17 beta benzoate per injection. Five animals were not treated and served as controls. Nuclear Magnetic Resonance (NMR) was used as an initial tool to monitor the urine composition. The analysis of NMR spectra showed, that most treated animals had increased L-lactate/creatine ratios (L/C-ratio) in their urine, compared to control animals. For screening, L-lactate/creatine ratios could be determined directly in urine--in a simple, quick and inexpensive manner--by using enzymatic methods and an autoanalyzer. Histologically clenbuterol induced degenerative changes in the urethral and glandular epithelium of the prostate. Changes consisted of vacuolization of the epithelium and necrosis with nuclear pyknosis and fragmentation. Estradiol-17 beta benzoate induced metaplastic changes in the glandular tissue of the goat prostate. In combination with estradiol-17 beta benzoate, characteristics of both agents could be observed. The histological methods and observed effects can be used directly for screening. The combination of independent histological and L/C-ratio methods looks very promising with respect to screening of growth promotants. Since in both cases effects of growth promotants are detected, it may be expected that this approach is not limited to goats or clenbuterol and estradiol alone.


Self-assembled magnetic bead biosensor for measuring bacterial growth and antimicrobial susceptibility testing.
Bacterial antibiotic resistance is one of the major concerns of modern healthcare worldwide, and the development of rapid, growth-based, antimicrobial susceptibility tests is key for addressing it. The cover image shows a self-assembled asynchronous magnetic bead rotation (AMBR) biosensor developed for rapid detection of bacterial growth. Using the biosensors, the minimum inhibitory concentration of a clinical E. coli isolate can be measured within two hours, where currently tests take 6-24 hours. A 16-well prototype is also constructed for simple and robust observation of the self-assembled AMBR biosensors.


Evaluation of high concentration intranasal and intravenous desmopressin in pediatric patients with mild hemophilia A or mild-to-moderate type 1 von Willebrand disease.
The objective of the study was to evaluate the safety and efficacy of high-concentration intranasal desmopressin (HCIN-DDAVP) 1.5 mg/mL, in patients weighing < or = 50 kg with mild hemophilia A or mild type 1 von Willebrand disease (VWD). This was a single-center, nonrandomized, open-label, single-dose trial of HCIN-DDAVP. Nine boys with hemophilia A, 8 girls with mild VWD, and 8 boys with mild VWD were evaluated. HCIN-DDAVP responses were compared with historic IV-DDAVP responses in 13 of the patients. HCIN-DDAVP administration resulted in statistically significant mean increases in factor VIII procoagulant activity, ristocetin cofactor, and von Willebrand factor antigen levels in each of the 3 study groups. Mean (+/- 1 SD) increase in factor VIII procoagulant activity was 25.7 +/- 11.9 U/dL in mild hemophilia A. Ristocetin cofactor increased 108.5 +/- 53.8 U/dL in girls and 95.8 +/- 36.0 U/dL in boys with mild VWD. Intravenous desmopressin acetate responses were comparable to HCIN-DDAVP responses in patients who received both preparations. Adverse events were mild and resolved without intervention. We conclude that administration of 150 microg of high concentration intranasal desmopressin is safe and effective in patients weighing < or = 50 kg with mild hemophilia A or mild type 1 VWD.


A descriptive report of the effects of a 16-month xylitol chewing-gum programme subsequent to a 40-month sucrose gum programme.
A previous caries trial (Belize studies) involved the usage of sucrose chewing-gum for a period of 40 months in one group of initially 10-year-old subjects in an environment of high sugar consumption, high caries activity, and limited access to restorative care. After the termination of the 40-month supervised sucrose gum usage, the 109 subjects of the original sucrose group retrieved at the endpoint of the original trial were invited to participate in a xylitol chewing-gum programme (involving the usage of the '100% pellet-shaped formular') for 16 months. The average daily consumption level of xylitol was up to 14 g per subject, normally used in seven daily chewing episodes. Although most subjects used chewing-gum at schools and received their gum portions from a school official, gum chewing during these 16 months was mostly unsupervised. After 16 months, 83 subjects (76%; mean age 14.9 years) were retrieved. The caries status of these subjects was examined by the same calibrated, blinded examiners as in the original trial. To mask the examiners, 141 similar non-participating subjects were recruited from the same school classes and were examined in a random order with the gum-using subjects, according to the same standard routine. The intensified xylitol gum usage for 16 months was associated with a reduction of the mean DMFS score from 10.9 (at 40 months) to 9.3 (at 56 months, p = 0.0013) and a reduction in caries rate from 20.1 caries onsets per 1,000 surface-years (40-month period average rate) to 10.2 caries onsets per 1,000 surface-years. The reduction in DMFS score resulted mostly from the change in the D component of the index and possibly reflected a stabilisation of the caries process and rehardening of some caries lesions to a non-progressive carious state.


Mobile health clinic for the medical management of clinical sequelae experienced by survivors of the 2013-2016 Ebola virus disease outbreak in Sierra Leone, West Africa.
An Ebola survivor Mobile Health Clinic (MHC) was established to implement lasting changes in communities it operates by providing effective and efficient mobile healthcare. After months of development, the MHC solution was operationalised in February 2015, aiming to provide integrated primary healthcare services to address the medical and psychosocial needs of Ebola virus (EBOV) survivors living in areas with low medical coverage. A total of 910 medical consultations for 246 EBOV survivors were performed between 7 February 2015 and 10 June 2016. Females constituted 148 (60.2%) whereas 6 (2.44%) were children under 5 years of age. The most common complication was arthralgia 185 (75.2%), headache 98 (39.8%), abdominal pain 167 (68%), myalgia 182 (73.6%), and skin disease 25 (10%). Moreover, ocular problems were diagnosed in 84 survivors (34.1%), and 60 (24.4%) suffered from psycho-trauma. Some 16 female survivors (10.8%) had miscarriages, whereas 9 (6.1%) had complaints of oligomenorrhea, 7 (4.7%) loss of sexual desire and 4 (2.7%) premature menopause. Five male survivors (5.1%) reported erectile dysfunction and 10 (10.2%) loss of sexual desire. At least 221 (89.8%) reported more than one complication. Other infectious diseases were common and no clinically relevant differences were established from haematology and clinical biochemistry laboratory results. Ibuprofen, paracetamol, anti-malaria drugs and antibiotics were the most common medicines prescribed. Community participation is critical for implantation of MHC among EBOV survivors. Future strategies for the mobile clinics should include enrolment of survivors at discharge from treatment centres with close monitoring follow-up activities, to address sequelae as they arise, to reduce the potential for development of long-term disabilities.


The influence of birth weight and body mass in early adulthood on early coronary heart disease risk among Danish men born in 1953.
This study examines the joint and separate influence of birth weight and body mass in young adulthood on subsequent coronary heart disease (CHD) risk. A cohort of 9,143 men born in Copenhagen, Denmark, in 1953, for whom information on birth weight and body weight and height around age 19 years were retrieved from birth certificates and conscript records, respectively, were followed from 1978 until 2005 (between age 25 and 52 years) for incident fatal and non-fatal CHD. Data on CHD were obtained through record linkage to the Cause of Death Registry and the National Patient Registry. During follow-up, a total of 475 men had a CHD diagnosis. Men with low birth weight, high body mass index (BMI) at age 19, a father from the working class, and low educational level at age 19 had an increased risk for CHD. Birth weight was inversely associated with CHD only in men with BMI of 25 kg/m(2) or above. Adjustment for childhood social circumstances and educational status at age 19 had minor influence on the estimates. In conclusion, BMI in young adulthood seems to be strongly associated with the risk of CHD before age 52, and birth weight seem to modify the association. The risk estimates is highest for individuals with a combination of low birth weight and overweight in young adulthood.


Heart Rate Variability Discriminates Competitive Levels in Professional Soccer Players.
Heart rate variability (HRV) has been increasingly used to monitor team sports athletes. Besides the traditional time domain indices (i.e., the SD of successive RR intervals [SDNN] and the root mean square difference of successive normal RR intervals [RMSSD]), recently the use of the stress score (SS), which is an inverse function of the SD2 index derived from the Poincaré plot, and the sympathetic/parasympathetic ratio (S/PS) to monitor soccer players has been proposed. However, the reliability of these new indices and the ability of HRV to differentiate between soccer competitive levels are unknown. The aim of this study was to analyze the reliability of the different HRV-derived indices in professional soccer players during the competitive period and to compare HRV of professional soccer players from 3 teams of distinct competitive levels (i.e., Italian Second Division [2D], European League [EL], and Champions League [CL]). Fifty-four male professional soccer players from 3 different teams of 2 European countries (Italy and Germany) participated in the study. The intraclass correlation coefficient values of the HRV indices varied from 0.78 (very large) to 0.90 (near perfect). The coefficient of variation (CV) values for RMSSD and SDNN were all <5.00%, although the CV for SS was 6.13% and for S/PS, it was 21.33%. Both the CL and EL groups, assumed to be internationally qualified, presented higher lnRMSSD and lnSDNN and lower lnSS and S/PS than the 2D. Therefore, the HRV can be considered reliable in professional soccer players and is able to differentiate between international- and national-level players.


Honeybees enhance reproduction without affecting the outcrossing rate in endemic Pedicularis densispica (Orobanchaceae).
There has been substantial debate in recent years surrounding the impact of introduced honeybees on native biota. This study reports on an investigation of Pedicularis densispica, a subalpine annual herb endemic to Southwest China, in an attempt to determine the impact of introduced domestic honeybees on pollen dispersal and thus on their reproductive success and mating system. Honeybees were introduced into the study site in 2004, and a sudden seasonal pollinator shift from bumblebees to honeybees was observed. Intra- and inter-plant visits by different pollinators were recorded in the field in 2003 and 2004. Fruit and seed sets prior to and after the pollinator shift were measured. Experimental pollinations were performed to characterize the breeding system. Outcrossing rates at the seed stage were estimated for both years using RAPD markers. Our results indicated that honeybees foraged between plants more frequently than bumblebees did. Our results also revealed that the introduction of honeybees significantly enhanced reproductive success. However, no significant difference was detected between the outcrossing rates due to bumblebee and honeybee pollination. P. densispica was almost completely outcrossing ( T(m) = 0.956 and 0.967, respectively in 2003 and 2004) but partially self-compatible. This study presents the first report of the outcrossing rate in the genus pedicularis and reveals a limited influence of pollination on the mating system in P. densispica. The pollinator shift did not reduce reproductive success of the plants and honeybees may be used to augment pollinator services for nectariferous P. densispica.


Specific glycosylation site mutations of the insulin receptor alpha subunit impair intracellular transport.
The insulin receptor is a transmembrane protein found on multiple cell types. This receptor is synthesized as a 190-kDa proreceptor which is cleaved to produce mature alpha and beta subunits. The proreceptor contains 18 potential sites for N-linked glycosylation: 14 on the alpha subunit and 4 on the beta subunit. The codons for asparagine in the first four sites at the amino terminus of the alpha subunit were mutated to code for glutamine. This mutant receptor cDNA was stably transfected into NIH 3T3 cells. The insulin receptor produced in these cells remained in the proreceptor form; no mature alpha and beta subunits were produced. The proreceptor was slightly smaller on SDS-PAGE gels than the wild-type proreceptor and contained four less oligosaccharide chains by tryptic peptide mapping. The carbohydrate chains on the mutant proreceptor remained endoglycosidase H sensitive. However, in the presence of brefeldin A, these oligosaccharide chains could be processed to endoglycosidase H resistant chains. By immunofluorescence, the mutant proreceptor was shown to be localized to the endoplasmic reticulum. No insulin receptors could be found on the cell-surface either with cell surface labeling with biotin or with 125I-insulin binding. Thus, glycosylation of the first four N-linked glycosylation sites of the insulin receptor is necessary for the proper processing and intracellular transport of the receptor. This is in contrast to glycosylation at the four sites on the beta subunit which appear not to be important for processing but necessary for signal transduction. Therefore, N-linked glycosylation of the insulin receptor at specific sites has multiple distinctive roles.


A dual-transduction-integrated biosensing system to examine the 3D cell-culture for bone regeneration.
Three-dimensional (3D) cell cultures developed with living cells and scaffolds have demonstrated outstanding potential for tissue engineering and regenerative medicine applications. However, no suitable tools are available to monitor dynamically variable cell behavior in such a complex microenvironment. In particular, simultaneously assessing cell behavior, cell secretion, and the general state of a 3D culture system is of a really challenging task. This paper presents our development of a dual-transduction-integrated biosensing system that assesses electrical impedance in conjunction with imaging techniques to simultaneously investigate the 3D cell-culture for bone regeneration. First, we created models to mimic the dynamic deposition of the extracellular matrix (ECM) in 3D culture, which underwent osteogenesis by incorporating different amounts of bone-ECM components (collagen, hydroxyapatite [HAp], and hyaluronic acid [HA]) into alginate-based hydrogels. The formed models were investigated by means of electrical impedance spectroscopy (EIS), with the results showing that the impedances increased linearly with collagen and hyaluronan, but changed in a more complex manner with HAp. Thereafter, we created two models that consisted of primary osteoblast cells (OBs), which expressed the enhanced green fluorescent protein (EGFP), and 4T1 cells, which secreted the EGFP-HA, in the alginate hydrogel. We found the capacitance (associated with impedance and measured by EIS) increased with the increases in initial embedded OBs, and also confirmed the cell proliferation over 3 days with the EGFP signal as monitored by the fluorescent imaging component in our system. Interestingly, the change in capacitance is found to be associated with OB migration following stimulation. Also, we show higher capacitance in 4T1 cells that secret HA when compared to control 4T1 cells after a 3-day culture. Taken together, we demonstrate that our biosensing system is able to investigate the dynamic process of 3D culture in a non-invasive and real-time manner.


Quantifying the informativeness for biomedical literature summarization: An itemset mining method.
Automatic text summarization tools can help users in the biomedical domain to access information efficiently from a large volume of scientific literature and other sources of text documents. In this paper, we propose a summarization method that combines itemset mining and domain knowledge to construct a concept-based model and to extract the main subtopics from an input document. Our summarizer quantifies the informativeness of each sentence using the support values of itemsets appearing in the sentence. To address the concept-level analysis of text, our method initially maps the original document to biomedical concepts using the Unified Medical Language System (UMLS). Then, it discovers the essential subtopics of the text using a data mining technique, namely itemset mining, and constructs the summarization model. The employed itemset mining algorithm extracts a set of frequent itemsets containing correlated and recurrent concepts of the input document. The summarizer selects the most related and informative sentences and generates the final summary. We evaluate the performance of our itemset-based summarizer using the Recall-Oriented Understudy for Gisting Evaluation (ROUGE) metrics, performing a set of experiments. We compare the proposed method with GraphSum, TexLexAn, SweSum, SUMMA, AutoSummarize, the term-based version of the itemset-based summarizer, and two baselines. The results show that the itemset-based summarizer performs better than the compared methods. The itemset-based summarizer achieves the best scores for all the assessed ROUGE metrics (R-1: 0.7583, R-2: 0.3381, R-W-1.2: 0.0934, and R-SU4: 0.3889). We also perform a set of preliminary experiments to specify the best value for the minimum support threshold used in the itemset mining algorithm. The results demonstrate that the value of this threshold directly affects the accuracy of the summarization model, such that a significant decrease can be observed in the performance of summarization due to assigning extreme thresholds. Compared to the statistical, similarity, and word frequency methods, the proposed method demonstrates that the summarization model obtained from the concept extraction and itemset mining provides the summarizer with an effective metric for measuring the informative content of sentences. This can lead to an improvement in the performance of biomedical literature summarization.


Transition-metal-free synthesis of unsymmetrical diaryl chalcogenides from arenes and diaryl dichalcogenides.
A transition-metal-free synthetic method has been developed for the synthesis of unsymmetrical diaryl chalcogenides (S, Se, and Te) from diaryl dichalcogenides and arenes under oxidative conditions by using potassium persulfate at room temperature. Variously substituted arenes such as anisole, thioanisole, diphenyl ether, phenol, naphthol, di- and trimethoxy benzenes, xylene, mesitylene, N,N-dimethylaniline, bromine-substituted arenes, naphthalene, and diaryl dichalcogenides underwent carbon-chalcogen bond-forming reaction to give unsymmetrical diaryl chalcogenides in trifluoroacetic acid. To understand the mechanistic part of the reaction, a detailed in situ characterization of the intermediates has been carried out by (77)Se NMR spectroscopy by using diphenyl diselenide as the substrate. (77)Se NMR study suggests that electrophilic species ArE(+) is generated by the reaction of diaryl dichalcogenide with persulfate in trifluoroacetic acid. The electrophilic attack of arylchalcogenium ion on the arene may be responsible for the formation of the aryl-chalcogen bond.


Treatment of neuroendocrine tumors with somatostatin analogs.
Neuroendocrine tumors constitute a group of hormone producing tumors originating from neuroendocrine cells in different organs. Most tumors have a low proliferation index measured by Ki67 and the progression of the tumor is slow. However, many patients suffer from endocrine symptoms induced by the hormones produced and released by the tumor cells. For some patients these symptoms can be life- threatening as in midgut carcinoid patients suffering from carcinoid crises with extensive flushes and hypotension or in patients with severe diarrhea induced by tumors producing vasointestinal polypeptide. In many other patients the hormone-induced symptoms interfere with the ability to carry out ordinary daily activities. The introduction of somatostatin analogs in the treatment of these hormone related symptoms has made it possible to control most of them and has added significantly to the quality of life for this group of patients. Unfortunately, the clinical inhibitory effect on tumor growth has not been very good with only 5-10% of the patients showing an objective response. However, stabilization of tumor growth may be achieved in a significant number of patients. In the future, the hope is that development of new somatostatin analogs with broader receptor-binding profiles will give us new analogs which are more efficient with regard to their antiproliferative effect. This possibility will be studied in future trials.


Teebi hypertelorism syndrome.
Teebi (1987) described an autosomal dominant syndrome with resemblance to craniofrontonasal dysplasia. Here we present a 2 year 5 month old girl with Teebi syndrome showing a prominent forehead, hypertelorism, mild exophthalmos, downslanting palpebral fissures, a depressed nasal bridge, a broad nasal tip, a long philtrum, natal teeth, a thin upper lip, an everted lower lip, a small chin, low-set ears, preauricular fistulas, a short neck, mild pectus excavatum, an umbilical hernia, clinodactyly of the 5th fingers with mild radial deviation of the distal phalanges of the middle fingers, mild pes adductus, an ectopic kidney, and normal psychomotor development. Her mother and her grandmother had similar features.


A longitudinal study on growth and growth variables in dogs of four large breeds raised in domestic environments.
The main objective of this study was to describe the growth patterns of 4 large dog breeds [Newfoundland (NF), Labrador retriever (LR), Leonberger (LEO), and Irish wolfhound (IW)] raised in domestic environments and concomitant changes in 2 growth-related clinical variables: total serum alkaline phosphatase (ALP) and the circumference of the distal radius and ulna (CDRU). The second objective was to investigate whether these measurements were affected by a range of independent variables like age, sex, litter number, and birth weight. Seven hundred dogs were included in the study, and BW data, separated by breed and sex, were fitted to the Gompertz function. Birth weight, adjusted for litter number, differed significantly between sexes for 3 breeds (LEO, P = 0.004; NF, P = 0.02; LR, P = 0.009) and approached significance for IW (P = 0.07). Estimated mean BW increased rapidly during the first 100 d after birth in all 4 breeds, then plateaued, with maturity being reached between 351 (female LR) and 413 d (male NF). Estimated mature BW ranged from 30.8 kg for the female LR up to 65.7 kg for the male IW. Weight gain, as expressed by the derivative of the Gompertz function, reached its peak in the smallest breed (LR) at the youngest age, 89 d for the females and 95 d for males. Log-transformed BW was significantly related to age, breed, and sex, and the age x sex and age x breed interactions. Within breeds, age, birth weight, and litter number had a significant effect on log-transformed BW. The estimated average CDRU increased from 90 d of age toward a peak at 180 d. Thereafter, CDRU declined and stabilized at about 1 yr of age. The estimated total ALP concentrations decreased from 90 to 360 d of age, after which they stabilized, at mean concentrations varying among breeds from 98 to 131 IU/L. Maximum least squares mean total ALP concentrations were found at 3 mo of age in all breeds, with the greatest least squares mean concentration in the IW breed (713 IU/L). In a mixed model analysis of the complete data set, total ALP was affected (P < 0.001) by age, breed, and the interaction of age x breed. This study described the main factors influencing growth and provided reference data for other studies, including those related to nutrition and disorders of growth.


Practice parameters for the diagnosis and treatment of anal intraepithelial neoplasia (AIN) on behalf of the Italian Society of Colorectal Surgery (SICCR).
Squamous cell carcinoma (SCC) of the anus is a human papilloma virus (HPV) related malignancy that is preceded by anal intraepithelial neoplasia (AIN) making this cancer, at least theoretically, a preventable disease. In the past 10 years the diagnosis, management and nomenclature of AIN has dramatically changed. Increased life expectancy in human immunodeficiency virus (HIV) positive patients due to highly active antiretroviral therapy (HAART) has caused an increase in the incidence of SCC of the anus. While many experts recommend screening and treatment of anal high-grade squamous intraepithelial lesion (HSIL), there is no consensus on the optimal management these lesions. Therefore, there is a need to review the current evidence on diagnosis and treatment of AIN and formulate recommendations to guide management. Surgeons who are members of the Italian Society of Colorectal Surgery (SICCR) with a recognized interest in AIN were invited to contribute on various topics after a comprehensive literature search. Levels of evidence were classified using the Oxford Centre for Evidence-based Medicine of 2009 and the strength of recommendation was graded according to the United States (US) preventive services task force. These recommendations are among the few entirely dedicated only to the precursors of SCC of the anus and provide an evidence-based summary of the current knowledge about the management of AIN that will serve as a reference for clinicians involved in the treatment of patients at risk for anal cancer.


Mo(15)S(20): first evidence of a new molybdenum cluster type in a metastable solid-state compound.
The Mo(15)S(20) compound was obtained by thermal decomposition of the metastable binary Mo(15)S(19) in sealed silica tube at temperatures above 500 degrees C. Its crystal structure was solved and refined from a two-component composite crystal by X-ray diffraction in the hexagonal space group P6(3)/m and consists of an equal mixture of the original Mo(9)S(27) cluster unit and the classical one Mo(6)S(8)S(6) interconnected through Mo--S bonds. The Mo core of the Mo(9)S(27) unit is totally new and formed a tricapped trigonal prism. Quantum chemical calculations carried out in order to understand these trends as well as magnetic susceptibility measurements are also reported. The title compound becomes superconducting below 5 K.


Monoclonal antibody analysis of Listeria monocytogenes-induced cytotoxic lymphocytes.
An immunizing infection with Listeria monocytogenes provides a potent stimulus for the formation of prekiller lymphocytes. Their cytolytic potential is revealed when the cells are restimulated in vitro by Listeria antigens. Listeria monocytogenes-induced cytotoxic lymphocytes and the prekiller cells from which they are derived were characterized in respect to their surface antigenic markers. Using monoclonal antibodies, B-cell depleted lymphocytes from the thoracic duct of Listeria immune rats were fractionated into subsets by a combination of panning and sorting techniques. Listeria monocytogenes-induced cytotoxic lymphocytes and their prekiller cell precursors were demonstrated to have the phenotype W3/25-, OX8+, OX4+, W3/13+ (high density), OX19+ (low density), RT6.1-. The OX8+, RT6.1- subset, which contained prekiller cells, constituted approximately 6% of lymph-borne T cells. The data indicate that these microbial antigen-induced cytotoxic lymphocytes belong to a minor subset of peripheral T cells whose surface antigenic properties distinguish them from natural killer cells.


The Modern Value of Early Writings in Medicine and Dentistry.
This article illustrates three examples supporting the modern value of early writings in dentistry and medicine. First, by studying cases described in works published long before the era of genetic science, we are able to develop new hypotheses about familial conditions and their genetic roots. Tooth transposition is presented as an example. Second, old writings may lead us to valuable historical insights and perspectives in medicine that can be revealed only in retrospective analysis. An example of this kind of historical analysis uncovers why dentistry became unnaturally separated from mainstream medicine in the 19th century. Third, early writings become keys to unlocking forgotten knowledge that enriches our understanding of historically significant people and events. The discovery of Norman Kingsley's long forgotten pyrographic paintings after Rembrandt portraits is used as an example. Libraries, the traditional custodians of these valued old texts, must continue to be supported, and not undermined by the paperless digital revolution.


[Endurance training and cardial adaptation (athlete's heart)].
One essential function of the cardiovascular system is to provide an adequate blood supply to all organs, including the skeletal muscles at rest and during exercise. Adaptation to chronic exercise proceeds mainly via the autonomic nervous system. On the one hand, peripheral muscles influence the autonomic reactions through "feedback" control via ergoreceptors, in particular, mechano- and chemoreceptors. On the other hand, there is central control in the sense of a "feed forward" regulation, e. g., the reaction of an athlete before competition. Along with other influential factors, such as circulatory presso-, chemo-, and volume receptors, the incoming impulses are processed in vegetative centers.A cardiovascular reaction, then, is the result of nerval and humoral sympathetic and parasympathetic activity. At rest, the parasympathetic tone dominates. It reduces heart frequency and conduction velocity. The high vagal tone is initially reduced with increasing physical exertion and switches at higher intensity to increasingly sympathetic activation. This mechanism of reaction to exercise is supported by inverse central and peripheral transmissions.Chronic endurance training leads to an improved local aerobic capacity of the exercised musculature. At rest, it augments parasympathetic activity when the muscle mass is sufficiently large, i. e., 20-30% of the skeletal musculature. The extent of the adaptation depends on individual factors, such as scope, intensity of training, and type of muscle fiber. A higher vagal tone delays the increase in the sympathetic tone during physical exertion. The regulatory range of heart rate, contractility, diastolic function, and blood pressure is increased. In addition, adaptation results in functional and structural changes in the vascular system. Cardiocirculatory work is economized, and maximum performance and oxygen uptake are improved. Endurance training exceeding an individual limit causes harmonic enlargement and hypertrophy of the heart. The thickness of both, the septum and posterior wall increases to the same extent as the interior volume. The mass/volume ratio, and therefore the maximum systolic wall stress, remains constant in contrast to pathologic forms of hypertrophy. Adaptations, including function and size of the heart, show a regression in healthy inactive persons without any structural heart disease.


Cytoprotective activity of deboxamet: a possible interference with prostaglandin and prostacyclin metabolism in rat gastric mucosa.
Deboxamet (5-methoxy-2-methyl-3-indolyl-acetohydroxamic acid) is a new synthetic drug with anti-ulcer and anti-secretory activity. The authors evaluated the ability of deboxamet to protect the rat gastric mucosa against the intensive necroses induced experimentally by absolute ethanol, NaCl (25%), HCl (0.6 N), acetylsalicylic acid plus HCl, and sodium taurocholate plus HCl. Deboxamet, as compared with pirenzepine, sulglycotide and PGE2, displayed a cytoprotective activity against these necrotizing agents. The involvement of deboxamet with prostacyclin metabolism was also investigated. In order to assess the presence of PGI2-like substances, extracts of mucosa from rats treated orally with deboxamet and sulglycotide were assayed i) on isolated rabbit mesenteric artery, ii) for hypotensive effect in anaesthetized rat, and iii) for anti-platelet activity. Deboxamet, like sulglycotide, was able to raise the availability of prostacyclins in the rat gastric mucosa, which is an important action in maintaining its cellular integrity. However, our results cannot determine whether this activity is due to an enhanced biosynthesis or a decreased degradation of prostacyclins.


The role of the newer antimicrobial agents in obstetrics and gynecology.
The new antibiotics include interesting compounds--extended-spectrum cephalosporins and penicillins, combinations of older antibiotics plus beta-lactamase inhibitors, and new classes such as the monobactams and fluoroquinolones. In addition to extended spectrums, some of these compounds offer more favorable kinetics, less toxicity, or decreased cost. Several general conclusions might help place this array of new antibiotics in a useful clinical perspective. The newer antibiotics discussed here are no more effective than what is currently used. However, several have very good in-vitro activity against pelvic pathogens and are reasonable single-agent therapy in mild to moderate postpartum and postoperative infections. These antibiotics include cefoxitin, cefotetan, and piperacillin. Although moxalactam has good activity, its use is limited by concerns regarding bleeding disorders. Cefotaxime and cefoperazone have somewhat less favorable spectra, especially against anaerobes, yet in limited clinical trials are as effective as those cited above. Penicillin/beta-lactamase inhibitor combinations are currently being evaluated and appear to be reasonable choices. Although imipenem has an excellent in-vitro spectrum, it should probably be reserved for resistant cases. Aztreonam offers an alternative to gentamicin. However, in view of its greater cost, its use should be limited to patients in whom renal toxicity is a concern. For serious infections, combination therapy with clindamycin and gentamicin is our preference. For pelvic inflammatory disease, none of the agents is recommended as sole therapy due to the lack of coverage for chlamydia and frequent suboptimal coverage for anaerobes. Many of these agents have been effective for prophylaxis, but none has been shown to be superior to the older, less expensive agents such as cefazolin. Although many are effective in single doses, it is also likely that cefazolin is equally effective as a single dose. In addition, while most of the newer antibiotics are resistant to beta-lactamases themselves, they may induce their formation. This may ultimately result in limitations to the use of the relatively inexpensive prophylactic antibiotics.


Agricultural exposures and risk of childhood neuroblastoma: a systematic review and meta-analysis.
While neuroblastoma accounts for an estimated 8% of childhood cancers, it causes about 15% of childhood cancer deaths in the United States. The role of agricultural exposures in the development of neuroblastoma is unclear. We conducted a systematic review and meta-analysis of studies examining the relationship between agricultural exposures and neuroblastoma. MEDLINE, EMBASE, Scopus, and Google Scholar were searched in February 2022, identifying 742 publications. Seventeen articles met the inclusion criteria; all were published between 1985 and 2020 and included 14 case-control, one cross-sectional, and two cohort studies. Random and fixed effects models were used to calculate summary odds ratios (sORs) and 95% confidence intervals (CIs). An increased odds of developing neuroblastoma with parental exposure to any pesticides (sOR = 1.25, 95% CI: 1.03-1.48; 4 studies), insecticides (sOR = 1.55, 95% CI: 1.19-1.91; 3 studies), and residential exposure to crops/vegetables (sOR = 1.04, 95% CI: 1.01-1.06; 2 studies) was seen. Heterogeneity was low in all analyses, and no publication bias was evident. No significant associations were found with agricultural occupations, herbicides, and agricultural dusts. The studies were limited by exposure measurements and small sample sizes. Further studies are needed to explore mechanisms in the development of neuroblastoma in children with parental agricultural exposures, especially pesticides, and to improve methods of measuring agricultural-related exposures.


The vertebrate glycine receptor protein.
Glycine is a major inhibitory neurotransmitter in the central nervous system. The postsynaptic receptor for this amino acid is a transmembrane ion channel protein which, after affinity purification on an antagonist column, contains three polypeptides of Mr 48,000, 58,000 and 93,000. Biochemical and immunological data show that these polypeptides have different functional properties and topologies with respect to the postsynaptic membrane. A model summarizing the currently available structural data is presented.


Association between a polymorphism affecting an AP1 binding site in the promoter of the TCIRG1 gene and bone mass in women.
The TCIRG1 gene encodes a component of the osteoclast vacuolar proton pump and previous work has shown that inactivating mutations of the TCIRG1 cause autosomal recessive osteopetrosis. In order to determine whether allelic variation in TCIRG1 contributes to the regulation of bone mineral density (BMD) in normal individuals, we studied the relationship between polymorphisms of TCIRG1 and BMD in a population-based cohort of 739 perimenopausal women. Five common polymorphisms were identified: two in the promoter, a conservative change within exon 4, one within intron 4 and one within intron 11. One of the promoter polymorphisms (G-1102A) lay within a consensus recognition site for the AP1 transcription factor. There was a significant association between the G-1102A genotype and BMD at the lumbar spine ( P = 0.01) and femoral neck ( P = 0.03). The association remained significant after correcting for age, weight, height, menopausal status/HRT use and smoking ( P = 0.008 for spine BMD and P = 0.03 for hip BMD), and homozygotes for the -1100 "G" allele had BMD values significantly higher than individuals who carried the -1100 "A" allele at both spine ( P = 0.007) and hip ( P = 0.047). Subgroup analysis showed that the association between G-1102A and BMD was restricted to premenopausal women who comprised 50.6% of the study group. None of the other polymorphisms or haplotypes were significantly associated with BMD in the study group as a whole or in any subgroup. Functional studies will need to be performed to determine the mechanisms that underlie this association, but we conclude that, in this relatively large population, allelic variation at the G-1102A site of TCIRG1 accounts for part of the heritable component of BMD in Scottish women, possibly by affecting peak bone mass.


Hopelessness in Chinese adolescents in Hong Kong: demographic and family correlates.
Chinese secondary school students (N = 3,017) responded to measures of adolescent hopelessness, perceived parental behavioral control (indexed by parental knowledge, expectation, monitoring, discipline, and demandingness, as well as Chinese parental control attributes), parental psychological control, and parent-child relational qualities (satisfaction with parental control, child's readiness to communicate with the parents and perceived mutual trust). Results showed that roughly one-fifth of Chinese adolescents displayed signs of hopelessness and adolescent hopelessness was related to adolescent age and gender as well as parental education and marital status. Although parental behavioral control was negatively related to adolescent hopelessness, parental psychological control was positively associated with adolescent hopelessness. Participants perceived parent-child relational qualities to be better showed lower levels of hopelessness.


Fire fly luciferin as antioxidant and light emitter: the evolution of insect bioluminescence.
Insects are the main group with luminescent species among terrestrial animals. In this paper, we report that fire fly luciferin is endowed with antioxidant properties against oxidative and nitrosative stress. The luciferin reduces linoleate peroxidation in acellular tests and increases the viability of mammalian cells exposed to the oxidant tert-butyl hydroperoxide. Dehydrorhodamine-based tests indicate that fire fly luciferin also scavenges peroxynitrite, whereas parallel tests on cells showed a marked protection of cells subjected to the peroxynitrite generator SIN-1. Together, these results suggest that fire fly luciferin's antioxidant properties could help photocytes coping with the hyperoxidant conditions to which they are submitted during luminous emissions. These data could also suggest that the evolutionary foundation of the bioluminescent system could have been the luciferin, and not the luciferase, first serving as a scavenger of oxidants toxic to the cells, then as a light emitting substrate for luciferase precursors. Similarities with the evolutionary scenario proposed for marine bioluminescent organisms relying on coelenterazine suggest that the surprisingly high success rate observed in the independent emergence of bioluminescent animals could reflect the ease of transformation of antioxidant mechanisms into light-producing systems.


DNA-PK and P38 MAPK: A Kinase Collusion in Alzheimer's Disease?
The pathogenesis of Alzheimer's disease (AD), characterized by prevalent neuronal death and extracellular deposit of amyloid plaques, is poorly understood. DNA lesions downstream of reduced DNA repair ability have been reported in AD brains. Neurons predominantly use a mechanism to repair double-strand DNA breaks (DSB), which is non-homologous end joining (NHEJ). NHEJ requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK is a holoenzyme comprising the p460 kD catalytic subunit (DNA-PKcs) and its activator Ku, a heterodimer of p86 and p70 subunits. Ku first binds and then recruits DNA-PKcs to double-stranded DNA ends before NHEJ process begins. Studies have shown reduced NHEJ activity as well as DNA-PKcs and Ku protein levels in AD brains suggesting possible contribution of unrepaired DSB to AD development. However, normal aging brains also show reduced DNA-PKcs and Ku levels thus challenging the notion of any direct link between NHEJ and AD. Another kinase, p38 MAPK is induced by various DNA damaging agents and DSB itself. Increased DNA damage with aging could induce p38 MAPK and its induction may be sustained when DNA repair is compromised in the brain with reduced DNA-PK activity. Combined, these two events may potentially set the stage for an awry nervous system approaching AD.


A systemic review and meta-analysis of the effects of perioperative anticoagulant and antiplatelet therapy on bleeding complications in robot-assisted prostatectomy.
Robot-assisted prostatectomy is commonly performed for the management of prostate cancer. The literature has noted that prostate cancer patients are often prone to increased risk for thromboembolic complications. Normally, such situations call for long-term anticoagulant/antiplatelet therapy. However, the administration of these drugs is usually contraindicated prior to surgical intervention to limit intra- and post-operative hemorrhagic complications. Despite some recent evidence that continued administration of anticoagulant/antiplatelet drugs does not impact intra- and post-operative outcomes, no consensus in the literature exists concerning the influence of anticoagulant and antiplatelet drug administration on intra- and post-operative outcomes for robot-assisted prostatectomy. Our aim is to evaluate the influence of perioperative administration of anticoagulant and antiplatelet drugs in patients undergoing robot-assisted prostatectomy in terms of bleeding complication incidence, blood transfusion rate, blood loss, and hospital stay duration. The academic literature was systematically searched according to the PRISMA guidelines across five databases (Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE). Through this, we conducted a random-effect meta-analysis to evaluate the influence of perioperative administration of anticoagulant and antiplatelet drugs in patients undergoing robot-assisted prostatectomy in terms of bleeding complication incidence, blood transfusion rate, blood loss, and hospital stay duration. From 993 studies, eight eligible studies containing 2516 patients (mean age: 65.7± 3.6 years) were selected for inclusion. Meta-analysis revealed a higher bleeding complication prevalence for patients receiving anticoagulants (event rate: 10.6%) compared to those receiving antiplatelets (3.4%). We also noted longer hospital stay durations for anticoagulant group patients (Hedge's g: -0.30) compared to antiplatelet group counterparts (g: -0.01). The study provides preliminary evidence that anticoagulant drug administration results in higher bleeding complication incidence and longer hospital stay durations in patients undergoing robot-assisted prostatectomy relative to antiplatelet drug administration.


Effect of age and blood pressure on determination of normal fluid status in a general population using whole body and calf bioimpedance techniques.
Normal fluid status (dry weight) can be identified by hydration markers established in the healthy population. The general population average could be influenced by age with its accompanying physiological changes and/or illness. The aims of this study were (1) to evaluate the effect of age and systolic blood pressure (SBP) on these markers; (2) to compare mean values of hydration markers as assessed by different bioimpedance techniques. Subjects from the general population (n = 212, males 105, 57.1% White, 31.6% Black, and 11.3% others) were studied. Body weight, height and SBP were measured. Whole body and calf bioimpedance (Hydra 4200) methods were utilized with subjects in the supine position. Calf normalized resistivity (CNR), fluid overload (FO), extracellular (ECV) and intracellular (ICV) volume measurements ECV/total body water (TBW) were calculated. Subjects were stratified by age; young (Group1): 18-35 years; middle (Group2): 36-60 years, senior (Group3): 61-80 years. Body mass index (BMI), CNR, and ECV/TBW differed significantly between age groups, and genders. ECV and FO increased with age in males. Decreased CNR (indicating relative increased fluid load) (p < 0.001) and increased SBP (p < 0.001) were associated with age in all three groups. CNR in Group1 was the same as in 36.0% of subjects in Group2 and 12.5% of subjects in Group3. In those subjects in Group2 and Group3, with CNR levels comparable to Group1 subjects, SBP was lower than in their peers in each respective age group. In conclusion average CNR in Group1 represents the range of healthy subjects. Since CNR is correlated with age, subjects in Group2 and Group3 are more likely to have fluid overload. Although about a third of subjects in Group2 and Group3 were in the range of Group1, the age and associated factors should be considered when CNR is used to identify fluid status in senior patients.


Clinical evaluation of hydroxyapatite and β-tricalcium phosphate composite graft in the treatment of intrabony periodontal defect: A clinico-radiographic study.
Hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP) grafts have shown to be effective in promoting the clinical signs of periodontal regeneration in intrabony defects. The aim of our study was to clinically and radiographically evaluate the efficacy of HA and β-TCP composite bone graft material in the treatment of intrabony three-wall defect. Twenty patients participated in this study. Interproximal bony defects were surgically treated with a combination of HA-βTCP (biphasic calcium phosphate). Changes in clinical parameters such as gingival status, probing pocket depth, clinical attachment, and radiographic estimation of the amount of bone fill were evaluated after 6 months postoperatively. Student's "t" test. This treatment modality resulted in significant pocket depth reduction and clinical attachment gain which were observed to be 2.938 mm (47.04%) and 3.188 mm (29.09%), respectively. The defect fill as seen radiographically was 3.204 mm (63.195%). All the differences were highly significant and in favor of postoperative group. The results of this study suggest that HA-βTCP (biphasic calcium phosphate) provides an added regenerative effect in promoting the clinical resolution of intrabony three-wall defects in patients with periodontitis.


A time-lapse study of interactions between Echinostoma paraensei intramolluscan larval stages and adherent hemocytes from Biomphalaria glabrata and Helix aspersa.
In vitro interactions between intramolluscan stages (sporocyst, daughter rediae, and metacercariae) of the trematode parasite Echinostoma paraensei and adherent hemocytes from the gastropods Biomphalaria glabrata (intermediate host) and Helix aspersa (non-host) were visualized by time-lapse videomicroscopy. Hemocytes of either species not exposed to E. paraensei displayed extensive mobility and activity of cellular extensions. Image analysis disclosed no significant change in the total surface area occupied by hemocytes in a selected field of view over 2 hr. Echinostoma paraensei exerted life stage-specific effects on the behavior of B. glabrata hemocytes; the cells moved away from sporocysts and daughter rediae but not encysted metacercariae. In the presence of sporocysts, hemocytes rounded up, whereas hemocytes adjacent to rediae assumed a stringy, beady appearance. Hemocytes close to the parasite were affected more rapidly than more distant cells. In 2 hr, a hemocyte-free "halo" formed around the parasite larvae, significantly reducing the hemocyte-occupied surface area (to 43% by sporocysts and to 70% by rediae). The changes induced by sporocysts and rediae are similar to those noted in both in vivo and in vitro studies of the B. glabrata-E. paraensei model system and are interpreted as manifestations of parasite-mediated interference with host hemocyte function. Helix aspersa (non-host) hemocytes were not affected, suggesting that E. paraensei-mediated effects on hemocytes exhibit a degree of specificity.


miR-195 inhibits cell proliferation via targeting AEG-1 in hepatocellular carcinoma.
Emerging evidence has indicated that microRNAs (miRNAs) are frequently dysregulated and are fundamental in the pathogenesis of hepatocellular carcinoma (HCC). However, the roles of miR-195 in HCC have not been well elucidated. In the present study, the expression of miR-195 was determined to be markedly downregulated in HCC tissues and cell lines, as compared with normal liver cells. Restoration of miR-195 expression resulted in significant inhibition of the proliferation and tumorigenicity of HCC cells in vitro and in vivo. Gene expression data and luciferase reporter assays revealed that miR-195 is able to directly inhibit the expression of astrocyte elevated gene 1 (AEG-1) through interaction with its 3' untranslated region. Consistently, an inverse correlation between miR-195 and AEG-1 expression was observed in HCC tissues. Furthermore, the overexpression of AEG-1 was able to partially attenuate the miR-195-induced inhibition of cell growth and promotion of apoptosis. Taken together, these findings indicate that miR-195 functions as a tumor suppressor by inhibiting AEG-1. This pathway may provide new insights into the potential molecular mechanisms of HCC.


Rasch Analysis of the Italian version of Pain Catastrophizing Scale (PCS-I).
The aim of this study was to investigate the psychometric properties of the Italian version of the Pain Catastrophizing Scale (PCS-I) in patients with chronic low back pain. In a cross sectional study a total of 150 subjects with chronic low back pain were included. The Italian translation of the PCS was administered to all subjects. The properties of the Italian version of the PCS were explored by a Rasch analysis. The PCS-I, by means of few modifications, fitted the Rasch model and passed the independent t-test for a unidimensional scale. The response categories for item 2 ``I fell I can't go on'' needed to be collapsed from 4 to 3 levels. Only the item 7 ``I keep thinking to of other painful events'' showed fit residual that exceeded the chosen thresholds of ± 2.5. No Differential functioning (DIF) was observed for age, sex, marital status, BMI and smoking. The Italian version of PCS, with the purposed modifications, seems to reflect a unidimensional construct of Pain Catastrophizing. The scale seemed to be quite robust across age, sex, marital status, BMI and smoking. Targeting of the scale was moderate. A raw score to metric conversion was proposed.


HIV-1 Tat and AIDS-associated cancer: targeting the cellular anti-cancer barrier?
The acquired immunodeficiency syndrome (AIDS) is accompanied by a significant increase in the incidence of neoplasms. Several causative agents have been proposed for this phenomenon. These include immunodeficiency and oncogenic DNA viruses and the HIV-1 protein Tat. Cancer in general is closely linked to genomic instability and DNA repair mechanisms. The latter maintains genomic stability and serves as a cellular anti-cancer barrier. Defects in DNA repair pathway are associated with carcinogenesis. This review focuses on newly discovered connections of the HIV-1 protein Tat, as well as cellular co-factors of Tat, to double-strand break DNA repair. We propose that the Tat-induced DNA repair deficiencies may play a significant role in the development of AIDS-associated cancer.


Engineering Escherichia coli for l-homoserine production.
l-homoserine, a nonprotein amino acid, is used to synthesize many active substances in the industry. Here, to develop a robust l-homoserine-producing strain, Escherichia coli W3110 was used as a chassis to be engineered. Based on a previous construct with blocked competing routes for l-homoserine synthesis, five genes were overexpressed by promoter replacement strategy to increase the l-homoserine production, including enhancement of precursors for l-homoserine synthesis (ppc, thrA, and asd), reinforcement of the NADPH supply (pntAB) and efflux transporters (rhtA) to improve the l-homoserine production. However, the plasmid losing was to blame for the wildly fluctuating fermentation performance of engineered strains, ranging between 2.1 and 6.2 g/L. Then, a hok/sok toxin/antitoxin system was introduced into the free plasmid expression cassette to maintain the genetic stability of the episomal plasmid; consequently, the plasmid-losing rate sharply decreased, resulting in the engineered strain SHL17, which exhibited excellent stability in l-homoserine production, with 6.3 g/L in shake flasks and 44.4 g/L in a 5-L fermenter without antibiotic addition. This work verified the effective use of the hok/sok toxin/antitoxin system combined with promoter engineering to improve the genetic stability of E. coli episomal plasmids without antibiotics.


[One-step urethroplasty--indications, results and surgical peculiarities].
In a representative patient group the long-term results were examined after one-stage urethroplasty with a subcutaneous pedicle skin flap. The used modification in which an intact strip of epithelium is buried shows good to satisfactory results in 80% of the cases, but in more than 60% a diverticulum of the neourethra was found. Therefore, in 25% of all urethroplasties a secondary resection of the diverticulum was necessary. First experiences with the use of a skin patch to reconstruct the urethra have shown that formation of diverticula can be prevented by this technique. The pre-, intra- and postoperative measures (epilation, secretion drainage, temporary urinary diversion) which are necessary to achieve good functional results are presented in detail.


Effectiveness of a web-based intervention in reducing binge drinking among nightclub patrons.
OBJECTIVE To evaluate the effectiveness of a web-based intervention in reducing binge drinking among nightclub patrons after six months. METHODS We carried out a website survey with probabilistic sample in 31 nightclubs in the city of São Paulo, Brazil, which originated a randomized controlled trial with 1,057 participants. Those classified as problem drinkers (n = 465) using the Alcohol Use Disorders Identification Test were randomized into two study groups - intervention and control. The web-based intervention consisted of exposing the participants to a normative feedback screen about their alcohol consumption, characterizing the risks associated with amount consumed, money spent on drinks, drinking and driving, risk classification of Alcohol Use Disorders Identification Test, and tips to reduce damage. RESULTS There was a significant reduction in the practice of binge drinking in the week estimated at 38% among participants in the intervention group after six months (p < 0.05). However, there was no significant reduction in the outcomes when we analyzed the intervention and control groups and at baseline and after sixth months, simultaneously. CONCLUSIONS We cannot conclude that digital tools reduce the pattern of binge drinking among party goers in São Paulo. More studies are needed with this methodology because of its attractiveness to this type of group, given the privacy and speed that personalized information is transmitted.


Wii-based exercise program to improve physical fitness, motor proficiency and functional mobility in adults with Down syndrome.
People with Down syndrome (DS) usually display reduced physical fitness (aerobic capacity, muscle strength and abnormal body composition), motor proficiency impairments (balance and postural control) and physical functional limitations. Exergames can be an appealing alternative to enhance exercise engagement and compliance, whilst improving physical fitness and motor function. This study aims to analyse the effects of a Wii-based exercise program on physical fitness, functional mobility and motor proficiency of adults with DS. Twenty-seven adults with DS were randomly allocated to an experimental group (Wii; n = 14) or control group (n = 13). Participants in the experimental group completed a 2-month Wii-based exercise program, with three 1-h sessions per week that included training games for aerobic endurance, balance and isometric strength. Participants completed assessments regarding anthropometric measures, physical fitness, functional mobility and motor proficiency. Mixed ANOVA analysis showed a significant group by time interaction for aerobic endurance, explosive leg power and flexibility. Independent samples t-test for change scores indicated significant between-group differences favouring the experimental group regarding speed of limb movement, trunk strength and functional mobility, as well as a trend towards significance on body weight. Mann-Whitney's U test for change scores demonstrated between-group differences favouring the experimental group for visceral fat as well as running speed and agility. Large within-group effect sizes were observed for explosive leg power (d = 1.691), body weight (d = 1.281), functional mobility (d = 1.218), aerobic endurance (d = 1.020), speed of limb movement (d = 0.867) and flexibility (d = 0.818) in the experimental group. Our findings suggest that Wii-based exercise can be an effective tool to improve physical fitness, functional mobility and motor proficiency of adults with DS, including crucial measures such as aerobic capacity and lower limb strength. Exergames using Wii Fit or other equipment can be appealing alternatives for adults with DS to engage in regular physical activity, preventing sedentary behaviour and decreasing the risk to develop cardiovascular diseases.


[Study of the effects of treatment with interferon for the advanced renal cell carcinoma based upon the survival rate].
There is no consistent acknowledgment with the effects of the prolongation of survival for the advanced renal cell carcinoma (RCC) treated with interferon (IFN). Therefore, we tried to study on the effects of such prolongation of survival for the advanced RCC through the comparative analysis between the patients treated with IFN and the patients treated with other treatment modalities in the past years. We differentiated the patients treated with IFN (recurrent patients after nephrectomy as Group I, and patients with stage 4B as Group II) from the patients treated with other modalities (recurrent patients after nephrectomy as Group III, and patients with stage 4B and Group IV). We compared the survival rate between the two groups (Groups I vs III, and Groups II vs IV). Regarding the various factors affecting prognosis of RCC, no significant difference was observed among these groups. 1) There observed a significantly favorable survival rate in the Group I compared with the Group III, and the same result was observed in the Group II compared with the Group IV. 2) In the patients with performance status (P.S.) 0 and low grade, there observed a significantly favourable survival rate in the Group I compared with the Group III, and the same result was observed in the Group II compared with the Group IV. Furthermore, in the patients with low stage, the Group I showed a significantly favourable survival rate compared with the Group III. 3) In the study on the number of metastatic organs (1, 2 and 3 organs or more), there observed a significantly favourable survival rate in the Group I compared with the Group III for all numbers of the metastatic organs. The same result was observed in the group II compared with the Group IV, except for the patient with 3 organs or more. Regarding the operative procedures for the metastatic side, the patients who did not receive the operative procedures showed a significantly favourable survival rate in the Group I compared with the Group III. The same result was observed in the Group II compared with the Group IV. 4) As to the survival rate based upon the response rate, only the patients with no change (N.C.) showed a significantly favourable survival rate in the Group I compared with the Group III. The same result was observed in the Group II compared with the Group IV. We conclude that the treatment with IFN for the advanced RCC would much contribute to the prolongation of the survival in comparison with the previous patients who received other treatments.


Relative effectiveness of medications for opioid-related disorders: A systematic review and network meta-analysis of randomized controlled trials.
Several pharmacotherapeutic interventions are available for maintenance treatment for opioid-related disorders. However, previous meta-analyses have been limited to pairwise comparisons of these interventions, and their efficacy relative to all others remains unclear. Our objective was to unify findings from different healthcare practices and generate evidence to strengthen clinical treatment protocols for the most widely prescribed medications for opioid-use disorders. We searched Medline, EMBASE, PsycINFO, CENTRAL, and ClinicalTrials.gov for all relevant randomized controlled trials (RCT) from database inception to February 12, 2022. Primary outcome was treatment retention, and secondary outcome was opioid use measured by urinalysis. We calculated risk ratios (RR) and 95% credible interval (CrI) using Bayesian network meta-analysis (NMA) for available evidence. We assessed the credibility of the NMA using the Confidence in Network Meta-Analysis tool. Seventy-nine RCTs met the inclusion criteria. Due to heterogeneity in measuring opioid use and reporting format between studies, we conducted NMA only for treatment retention. Methadone was the highest ranked intervention (Surface Under the Cumulative Ranking [SUCRA] = 0.901) in the network with control being the lowest (SUCRA = 0.000). Methadone was superior to buprenorphine for treatment retention (RR = 1.22; 95% CrI = 1.06-1.40) and buprenorphine superior to naltrexone (RR = 1.39; 95% CrI = 1.10-1.80). However, due to a limited number of high-quality trials, confidence in the network estimates of other treatment pairs involving naltrexone and slow-release oral morphine (SROM) remains low. All treatments had higher retention than the non-pharmacotherapeutic control group. However, additional high-quality RCTs are needed to estimate more accurately the extent of efficacy of naltrexone and SROM relative to other medications. For pharmacotherapies with established efficacy profiles, assessment of their long-term comparative effectiveness may be warranted. This systematic review has been registered with PROSPERO (https://www.crd.york.ac.uk/prospero) (identifier CRD42021256212).


Cx31.1 expression is modulated in HaCaT cells exposed to UV-induced damage and scrape-wounding.
Connexin31.1 (Cx31.1) is a gap junction protein associated with apoptosis. In the skin, apoptosis is modulated by diabetes. A HaCaT skin model investigated whether normal (NGI) and high glucose and insulin (HGI; diabetic) conditions altered Cx31.1 expression, and if these were apoptosis linked. Cx31.1 was found in HaCaT and HeLa Ohio cells, with HaCaT Cx31.1 protein increased in HGI conditions, and around apoptotic cells. HeLa Cx31.1 channels were noncommunicative. Post scrape-wounding, Cx31.1 increased at wound edges. Caspase 3/7 in scrape-wounds media (containing cells) elevated in HGI. UV exposure raised Cx31.1, and caspase 3/7, in NGI and HGI. UV reduced cell viability in NGI cells, although not significantly in HGI. Cx31.1 is modulated during HaCaT cell wound closure, and associated with 'diabetic' conditions. Cx31.1 expression matched apoptosis levels, higher in HGI cultures. Cx31.1 is noncommunicating, modulated after wounding, linked to apoptosis, and may be associated with tissue turn-over around diabetic wounds.


[The initial treatment of multitrauma patients].
Multitrauma is usually defined as injury to several organ systems. The more severe the injury, the higher is the mortality. It is essential that a trauma team assess and treat these patients using a rapid, structured approach in order to increase the survival. Damage control surgery and resuscitation should be applied in the very unstable patients. Following the initial treatment, an early activation and coordination of all involved specialties are very important.


Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells.
Serum C-reactive protein (CRP) levels are good predictors of the development of cardiovascular events in apparently healthy men and women. CRP has been believed to be produced exclusively by hepatocytes during the acute-phase response. Several lines of evidence have suggested that atherosclerotic arteries can also produce CRP. However, the cell types that produce CRP locally in the atherosclerotic arterial wall have not been clearly identified. Human coronary artery smooth muscle cells (HCASMCs) and human umbilical vein endothelial cells (HUVECs) were incubated with interleukin-1beta (IL-1beta), IL-6, their combination, tumor necrosis factor-alpha (TNF-alpha), or lipopolysaccharide (LPS) at different concentrations. The supernatants were concentrated and analyzed by a high-sensitivity enzyme-linked immunosorbent assay specific for human CRP. RNA was extracted from the HCASMCs for reverse transcriptase-polymerase chain reaction (RT-PCR) using specific primers for the CRP. Maximal CRP production was observed in HCASMCs after 48 hours of incubation with the combination of 25 ng/mL of IL-1beta and 10 ng/mL of IL-6, whereas incubation with IL-1beta or IL-6 alone only modestly induced CRP. Incubation with TNF-alpha (50 ng/mL) or LPS (1000 EU/mL) resulted in an increase in CRP production comparable to the IL-1beta and IL-6 combination. The induction of CRP in HCASMCs was independently confirmed by RT-PCR comparing the relative CRP mRNA levels. The induction of CRP production by HCASMCs was not reproduced in HUVECs, however. These results demonstrated that HCASMCs, but not HUVECs, could produce CRP in response to inflammatory cytokines. The locally produced CRP could directly participate in atherogenesis and the development of cardiovascular complications.


[Maximal respiratory pressures and exercise tolerance in patients with COPD].
Many authors reported respiratory muscle function impairment in patients with chronic obstructive pulmonary disease (COPD). Impaired respiratory muscle function may contribute exercise intolerance which is frequently observed in this disease. was to determine the influence of respiratory muscle function on exercise capacity in patients with COPD. 23 patients with stable COPD aged 62.7 +/- 9.3 years (6F, 17M; mean post-bronchodilator FEV1 = 47.9 +/-12.4% value predicted) participated in the study. Exercise capacity was assessed by the six-minute walk test and the incremental cardiopulmonary exercise test (CPET) on a treadmill. Maximal respiratory pressures (PImax, PEmax) were evaluated before and directly after CPET. The mean peak oxygen uptake (VO max) was 27.2 +/- 6.1 mlO2/min/kg and the mean distance walked during the 6MWT was 569.4 +/- 101.7 m. Both PIMax and PE max decreased significantly after maximal exercise (71.4 +/-23.0 vs 63.6 +/- 22.2 cmH2O, p = 0.001 and 124.9 +/- 46.5 vs 112.3 +/- 46.6 cm H2O, p = 0.02 respectively). No correlation between VO2max and the 6-minute walk distance and the maximal respiratory pressures was found. We observed a negative correlation between the 6-minute walk distance and the difference between the pre- and post CPET maximal inspiratory pressure. respiratory muscle function is impaired in patients with COPD but this does not affect exercise performance. Exercise causes a decrease of the respiratory muscle strength.


[Preoperative evaluation of coronary circulation].
It is not easy to define a plan for the preoperative assessment of the coronary circulation: some studies carried out in the context of vascular surgery are contradictory and no method has a sensitivity and specificity of 100%. Nevertheless, it is essential to select patients with a high risk of perioperative cardiac complications so that their medical treatment can be reinforced or anatomical correction envisaged. A first assessment is obtained from the history, the clinical examination and simple investigations (resting ECG, chest X-ray). Surgical operations which do not impose a major strain on the cardiovascular system do not require further investigations. The risk of postoperative cardiac complications is low in the absence of the nine risk factors defined by Goldman and/or an ischemic syndrome (residual angina after mild physical activity, unstable angina, myocardial infarct). The problem arises in patients with the Goldman risk factors and/or a history of coronary insufficiency and/or coronary insufficiency risk factors (diabetes, tobacco, hypercholesterolemia, age > 70 years, arterial hypertension), who require an operation likely to cause a particularly serious strain on the cardiovascular system. An exercise ECG, by the Holter method, is helpful, particularly in known or potential coronary arteriopaths who cannot exercise. Echocardiography under dobutamine has good sensitivity and good specificity when exercise is impossible. Thallium-dipyridamole scanning has not been shown to be helpful in vascular surgery. This method could be refined by a quantitative analysis of the number of areas and segments involved. Finally, patients showing ischaemic changes on continuous ECG recording, abnormalities on echocardiography under dobutamine, abnormalities on thallium-dipyridamole myocardial scanning or on exercise ECG, should be considered for coronary angiography with a view to a preliminary anatomical correction.