[Pharmacological profiles of mycophenolate mofetil (CellCept), a new immunosuppressive agent].
Mycophenolate mofetil (MMF, CellCept), a semisynthetic derivative of mycophenolic acid (MPA) produced by a fungus, is an inhibitor of the inosine monophosphate dehydrogenase (IMPDH) enzyme (IC50 = 25 nM) that catalyzes the synthesis of guanosine monophosphate (GMP) from inosine. GMP is an essential nucleoside for purine synthesis during cell division. As T and B-lymphocytes almost exclusively use the de novo pathway of purine synthesis, these cells are particularly sensitive to the inhibitory action of MMF. It has a mechanism of action distinct from cyclosporine and tacrolimus. Although MMF does not affect cytokine production, by inhibiting the rate-limiting enzyme IMPDH in the de novo synthesis of purines, it inhibits the proliferation of T and B-lymphocytes, the production of antibodies, and the generation of cytotoxic T lymphocytes. Reversal of acute allograft rejection and increased survival of kidney, heart and bone marrow cell allograft has been shown in several animal studies. Moreover, it was suggested that MMF combined with CsA prevented the acute rejection, and approximately half of the animals became long-term survivors. The Ministry of Health and Welfare approved MMF in 1999 for use for rejection treatment in renal transplantation based on several prospective, randomized and blind efficacy trials.


Right to Left Intrapulmonary Shunt in a Case with COVID-19-associated Pneumonia.
The clinical manifestations of coronavirus disease 2019 (COVID-19)-associated pneumonia show a wide range of variations. It ranges from mild hypoxemia without significant signs of respiratory distress, to rapid clinically deteriorating course with severe hypoxemia. Unexplained severe hypoxemia, associated with platypnea, triggers the possibility of ventilation-perfusion (V/Q) mismatch, ranging from intrapulmonary shunts (IPS) to alveolar dead space ventilation. In the literature, very few cases with COVID-19-pneumonia have been reported with IPS. Herein, we report a COVID-19 confirmed 45-year male patient, who developed IPS without apparent pulmonary perfusion defect on lung perfusion scintigraphy. The patient had no cardiovascular disease except chronic pulmonary hypertension secondary to interstitial lung disease. The clinical manifestations combined with nuclear imaging features enabled in making the ultimate diagnosis. The patient's clinical condition improved on appropriate clinical management, using high flow oxygen combined with intravenous steroids and anticoagulants. Key Words: COVID-19, Adult respiratory distress syndrome, Right to left shunt, Lung perfusion scintigraphy, Platypnea.


Changes in the centrifugal gating effect on somatosensory evoked potentials depending on the level of contractile force.
In this study, we investigated the somatosensory evoked potentials (SEPs) during the preparatory period of self-initiated plantar flexion at different force levels of muscle contraction and elucidated the mechanism behind the centrifugal gating effect on somatosensory information processing. We recorded SEPs following stimulation of the tibial nerve at the popliteal fossa during the preparatory period of a 20% maximal voluntary contraction (MVC) and 50% MVC. The preparatory period was divided into two sub-periods based on the components of movement-related cortical potentials, the negative slope (NS sub-period) and the Bereitschaftspotential (BP sub-period). The subjects were instructed to concentrate on the movement and not to pay attention to the continuous electrical stimulation. Pre-movement SEPs were averaged separately during the two sub-periods under each MVC condition. The mean amplitudes of BP and NS were larger during the 50% MVC than the 20% MVC. As for the components of SEPs, during the NS sub-period the amplitude of P30 under the 50% MVC and N40 under both conditions were significantly smaller than that in the stationary sequence, and N40 amplitude was significantly smaller during the 50% MVC than the 20% MVC. During the BP sub-period, the amplitude of P30 and N40 during the 50% MVC was significantly smaller than during the stationary sequence, while it was not significantly different between the 20% and 50% MVCs. In conclusion, the extent of the centrifugal gating effect on SEPs was dependent on the activities of motor-related areas, which generated the NS and BP.


Immunolocalization of Sphingolipid Catabolism Enzymes along the Nephron: Novel Early Urinary Biomarkers of Renal Damage.
The objective of this study was to investigate whether the activity of enzymes involved in sphingolipid catabolism could be biomarkers to predict early renal damage in streptozotocin (STZ)-induced diabetic rats and Angiotensin II (Ang II)-induced hypertension rats. Diabetic and hypertensive rats had no changes in plasma creatinine concentration. However, transmission electron microscopy (TEM) analysis showed slight ultrastructural changes in the glomeruli and tubular epithelial cells from diabetic and hypertensive rats. Our results show that the acid sphingomyelinase (aSMase) and neutral sphingomyelinase (nSMase) activity increased in the urine of diabetic rats and decreased in hypertensive rats. Only neutral ceramidase (nCDase) activity increased in the urine of diabetic rats. Furthermore, the immunofluorescence demonstrated positive staining for the nSMase, nCDase, and sphingosine kinase (SphK1) in glomerular mesangial cells, proximal tubule, ascending thin limb of the loop of Henle, thick ascending limb of Henle's loop, and principal cells of the collecting duct in the kidney. In conclusion, our results suggest that aSMase and nCDase activity in urine could be a novel predictor of early slight ultrastructural changes in the nephron, aSMase and nCDase as glomerular injury biomarkers, and nSMase as a tubular injury biomarker in diabetic and hypertensive rats.


[The pharmacologic and biochemical effects of unsaturated phospholipids].
The review deals with the analysis of the recent publications indicating the important biological function of essential phospholopids (EP) in the cell and in the organism as a whole. The protective mechanism of action of EP in diseases of the liver, atherosclerosis, ischemic heart disease, myocardial infarction determined by their high biological activity in some pathological conditions associated with lipid metabolism disturbance is discussed. The efficiency of the biological action of EP is determined by the depends on the type of phospholipids, the form of phospholipid preparations, their charge, and also on the routes of their administration.


ZIF nano-dagger coated gauze for antibiotic-free wound dressing.
Nano-dagger coated gauze was bactericidal against both Gram-positive and Gram-negative bacteria, with log reduction >7 for Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Compared with the commercially available Ag gauze, the ZIF-L nano-dagger coated gauze was more biocompatible with a lower haemolytic activity, less cytotoxicity and improved wound healing performance. Animal studies showed that the ZIF-L coated gauze can effectively kill bacteria in a S. aureus wound infection model in mice. This novel nano-dagger coated gauze offers an effective and safe alternative for patients to protect against wound infections. This study demonstrates the first application of a MOF coating as an antibiotic-free wound dressing with potent antimicrobial activity and improved biocompatibility.


[Quality of life in gerodontology].
In clinical decision-making on whether or not to treat an oral disease and on making a choice from the spectrum of treatment options, the influence of the treatment on the physical and psycho-social well-being of the patient should play a crucial role. This awareness originates from gerodontology. To assess the value of a potential treatment, the concept quality of life has been advanced and various related questionnaires have been developed and employed. In the meantime, doubts have arisen about the value of these questionnaires. The present-day trend is to return to so-called qualitative research, which consists of systematic interviews of groups of older people using open-ended questions without making use of structured response options.


HIV treatments optimism and sexual behaviour among gay men in Sydney and Melbourne.
To investigate associations between gay men's optimism and sexual behaviour in the context of new HIV treatments. Cross-sectional surveys (using anonymous, self-completed questionnaires) were conducted in Sydney during February 1998 (n = 2200) and in Melbourne during January 1998 (n = 1891). Gay men were recruited at social and sex-on-premises venues, clinics and fair days/carnivals. In a multivariate analysis, unprotected anal intercourse with casual partners (UAIC) was associated with being recruited at a sex-on-premises venue (rather than a clinic or fair day/carnival), HIV positivity, having been tested for HIV less than 6 months ago (rather than over 2 years ago or never having been tested), and not having a regular partner. Over and above these factors, UAIC was associated with agreement with the statements 'An HIV-positive person who is on combination therapy is unlikely to transmit HIV' and 'I'm less worried about HIV infection than I used to be'. The data reveal a significant relationship between UAIC and certain aspects of optimism in the context of new HIV treatments. Whereas the direction of causality cannot be specified, there is a clear need for HIV and sexual health education programmes to clarify issues of viral load, new and drug resistant strains of HIV, and other infectious agents.


Electroacupuncture stimulation to modulate neural oscillations in promoting neurological rehabilitation.
Electroacupuncture (EA) stimulation is a modern neuromodulation technique that integrates traditional Chinese acupuncture therapy with contemporary electrical stimulation. It involves the application of electrical currents to specific acupoints on the body following acupuncture. EA has been widely used in the treatment of various neurological disorders, including epilepsy, stroke, Parkinson's disease, and Alzheimer's disease. Recent research suggests that EA stimulation may modulate neural oscillations, correcting abnormal brain electrical activity, therefore promoting brain function and aiding in neurological rehabilitation. This paper conducted a comprehensive search in databases such as PubMed, Web of Science, and CNKI using keywords like "electroacupuncture," "neural oscillations," and "neurorehabilitation", covering the period from year 1980 to 2023. We provide a detailed overview of how electroacupuncture stimulation modulates neural oscillations, including maintaining neural activity homeostasis, influencing neurotransmitter release, improving cerebral hemodynamics, and enhancing specific neural functional networks. The paper also discusses the current state of research, limitations of electroacupuncture-induced neural oscillation techniques, and explores prospects for their combined application, aiming to offer broader insights for both basic and clinical research.


Evaluation of a microtiter plate fluorescent-antibody assay for rapid detection of human cytomegalovirus infection.
The use of monoclonal antibody (MAb) p63-27, which is reactive with the major immediate-early human cytomegalovirus (HCMV) protein pp72, was explored for the rapid diagnosis of HCMV viruria. The rapid assay detected all but 1 of 19 specimens identified by standard virus isolation methods from 1,676 newborn urine specimens, achieving a sensitivity of 94.5% and a specificity of 100%. The monoclonal antibody recognized 260 randomly obtained clinical isolates of HCMV, indicating the suitability of this reagent for use in screening assays. The sensitivity of the microtiter plate method declined rapidly for specimen from older infants and children with congenital CMV infection and virus-infected children attending a day-care center and was judged to be unacceptable for screening populations in this age group.


Assessment of Mean Platelet Volume in Patients with Resistant Hypertension, Controlled Hypertension and Normotensives.
Patients with resistant hypertension are at increased risk for cardiovascular events. Mean platelet volume (MPV) is an accepted biomarker of platelet activation and considered as a risk factor for cardiovascular disease. The aim of this study was to determine whether MPV levels are higher in resistant hypertensive (RHTN) patients than in controlled hypertensive (CHTN) patients and healthy normotensive controls. 279 consecutive patients were included in this study. Patients were divided into three groups: Resistant hypertension patient group [n=78; mean age 56.8±9.8; 42 males (53.8%)]; controlled hypertension patient group [n=121; mean age 54.1±9.6; 49 males (40.5%)]; and normotensive control group [n=80; mean age 49.8±8.5; 34 males (42.5%)]. Physical examination, laboratory work-up, and 24-hour ambulatory blood pressure measurement (ABPM) were performed in all participants. The mean platelet volume levels were significantly higher in RHTN group than in the CHTN and normotensive groups (p<0.001). In correlation analysis office systolic and diastolic blood pressure was positively correlated with MPV. Our study demonstrated that MPV, as an important indicator of platelet activation, was statistically higher in RHTN patients than in CHTN and in normotensive subjects. Elevated MPV levels may help to determine a high risk group for atherosclerosis in RHTN patients.


Protective effect of unstable angina in coronary artery bypass surgery.
To test the hypothesis that recent ischaemic episodes in unstable cases have a protective effect on coronary artery bypass graft (CABG) patients. Twenty unstable patients with ischaemic episodes within 3 days before operation were compared with 20 stable patients. Haemodynamic data were monitored up to the first postoperative day. Biochemical markers were measured up to the second postoperative day. The cardiac index decreased at 1 and 6 h after declamping in the stable group (89% and 97% of baseline) but increased in unstable patients (104% and 122%, p =0.038 and 0.036, respectively). The depression in the right ventricular stroke work index was significantly attenuated in the unstable group (58%, 67% and 83% in stable and 90%, 97% and 117% in unstable patients, p = 0.027, 0.010 and 0.049 at 1 and 6 h after declamping and 1st POD). The release of cardiac troponin I (CTnI) and CK-MB was significantly lower in the unstable group at 6 h after declamping (5.6 +/- 2.9 and 19.0 +/- 6.3 microg/l in unstable vs 17.4 +/- 9.6 and 25.8 +/- 12.3 microg/l in stable patients, p = 0.000 and 0.039, respectively). Recent unstable angina before CABG might act as an ischaemic preconditioning stimulus and could improve haemodynamic function and cellular viability. Delayed preconditioning most likely causes this protective effect.


Differential effects of the new central adrenergic agonist modafinil and d-amphetamine on sleep and early morning behaviour in elderlies.
Modafinil (CRL 40476) is a new central alpha-adrenergic agonist with vigilance-promoting properties. In a double-blind, placebo-controlled sleep laboratory study its single-dose effects on sleep and early morning behaviour were investigated and compared with d-amphetamine. Ten elderly healthy volunteers (mean age: 68 years) spent 12 nights in the sleep laboratory: one adaptation night, one baseline night, five drug nights (100 mg and 200 mg modafinil; 10 mg and 20 mg d-amphetamine; placebo) and five subsequent washout nights. The drugs were administered orally in one week intervals at 10:00 p.m., and all-night somnopolygraphic investigations were performed between 10:30 p.m. and 6:00 a.m. A self-rating scale for sleep and awakening quality as well as psychometric tests were completed in the morning. d-amphetamine caused a dose-dependent impairment of sleep maintenance and sleep architecture, while modafinil did not. Thus, a significant reduction of total sleep time, REM-sleep and sleep stage 2 was seen after d-amphetamine when compared to placebo and 100 mg modafinil. Corresponding with these objective results, subjective sleep quality deteriorated significantly only after 20 mg d-amphetamine as compared to placebo. Morning investigations revealed an increase of CFF after 20 mg d-amphetamine. Pulse rate, evening and morning blood pressure remained unchanged. These findings suggest a different mode of action of the two compounds.


[Incorporation of H3-thymidine into the oocytes of a sterlet in the early meiotic prophase].
DNA synthesis in meiotic oocytes of the sterlet (A. ruthenus) has been studied during early prophase stages using H3-thymidine. The pattern of H3-thymidine incorporation is similar to that in oocytes of Amphibia and Osteichthyes. In the oogonia as well as in the leptotene and zygotene oocytes, the label is predominantly localized over chromosomes. An intensive incorporation of H3-thymidine into the material of the heterochromatic "cap" has been observed during pachytene. Thus, the main synthesis of extra DNA in the sterlet oocytes occurs during pachytene. No DNA in synthesized by the diplotene oocytes.


The influence of partial gastrectomy for gastric cancer on the spontaneous disappearance of Helicobacter pylori: A single-center prospective study.
Helicobacter pylori (HP) eradication is recommended after endoscopic treatment of early gastric cancer (EGC). Cases of spontaneous HP resolution after partial gastrectomy due to environmental changes have been reported; however, there is no evidence for the efficacy of HP eradication in suppressing carcinogenesis and also no reports on the natural history of HP after partial gastrectomy in gastric cancer (GC). To report the natural history of HP in patients with GC and HP infection after partial gastrectomy. We prospectively studied the rate of spontaneous disappearance of HP after partial gastrectomy in patients with GC. From April 2016 to May 2020, 80 patients underwent partial gastrectomy, including 9 cases of proximal gastrectomy (PG), and 71 cases of distal gastrectomy (DG). The presence of HP was confirmed in the stool antigen test 1 year after operation, HP infection persisted in 46 patients (57.5%) and disappeared in 34 patients (42.5%). In univariate analysis, only proton pump inhibitor (PPI) use was a significant contributing factor for the spontaneous resolution of HP infection, especially in the DG group. However, there was no difference in the rates of HP disappearance between Billroth-I and Roux-en-Y reconstructions in the DG group. The HP spontaneously disappeared in 42.5% of the GC patients within 1 year after partial gastrectomy. Further investigation in a larger cohort is needed to elucidate the underlying mechanisms.


Coping strategies of women seeking infertility treatment in southern Ghana.
Infertility is a health problem faced by an estimated 15% of women of childbearing age in Ghana. This study explores the coping strategies adopted by 615 women seeking infertility treatment in southern Ghana. Both closed and open-ended questions were used through a survey conducted using face-to-face interviews in three languages at three health sites--a hospital, a health centre and a private clinic. The findings suggest that the majority of the women preferred to keep issues of their fertility problems to themselves. The reason could be due to the associated stigma of infertility. Further, the majority of the women coped through drawing on their Christian faith. Others also coped through the support they received from their husbands, their occupation by way of achieving economic independence, and some avoided situations that reminded them of their infertility problem. The findings should have implications for health personnel as some strategies infertile women use may do more harm than good.


SERS-Based Quantification of Biomarker Expression at the Single Cell Level Enabled by Gold Nanostars and Truncated Aptamers.
Surface-enhanced Raman spectroscopy (SERS)-based biosensors have been used increasingly over the past few years for cancer detection and diagnosis. SERS-based imaging offers excellent sensitivity and has advantages over other detection techniques such as fluorescence. In this study, we developed a novel biosensor to detect the cancer biomarker epithelial cell adhesion molecule (EpCAM) and quantify its expression at the single cell level. EpCAM is one of the most commonly expressed markers on a variety of cancer cells; importantly it has been suggested that reduction of its expression levels could be associated with the epithelial to mesenchymal transition (EMT) and thus to the onset of metastasis. Therefore, monitoring variations in expression levels of this membrane biomarker would improve our ability to monitor cancer progression. The described substrate-based biosensor was developed employing gold nanostars functionalized with EpCAM aptamer molecules and was able to quantify subnanomolar concentrations of EpCAM protein in solution. Importantly, we demonstrated its use to quantify EpCAM expression on the surface of two cancer cells, MCF-7 and PC-3. We also compared the binding efficiency of two EpCAM DNA aptamers of different lengths and observed a substantial improvement in the sensitivity of detection by employing the shorter aptamer sequence, probably due to the reduced number of conformations possible at room temperature with the truncated oligonucleotide. Detailed characterization of the substrates was carried out using both SERS maps and atomic force microscopy. These substrate-based diagnostic devices promise to be relevant for monitoring phenotype evolutions in cancer cells, blood, and other bodily fluids, thus improving our ability to follow in real time disease onset and progression.


Triclosan inhibits enoyl-reductase of type I fatty acid synthase in vitro and is cytotoxic to MCF-7 and SKBr-3 breast cancer cells.
Human type I fatty acid synthase has been proposed as a chemotherapeutic target for the treatment of breast cancer based on the inactivation of human beta-ketoacyl synthase activity by cerulenin. Triclosan, a common antibiotic, functions by inhibiting the enoyl-reductase enzymes of type II fatty acid synthases in susceptible bacteria. If triclosan is an inhibitor of human fatty acid synthase and if inhibition of fatty acid synthase is toxic to breast cancer cell lines, triclosan could prove to be a lead compound for the treatment of breast cancer. Consequently, the inhibitory activity of triclosan against vertebrate type I fatty acid synthases and its effects on breast cancer lines in cell culture were investigated. The inhibitory activities of triclosan against human and goose fatty acid synthases and each of the partial reactions were investigated using spectrophotometric assays. The ability of triclosan at various concentrations to inhibit growth and reduce the viability of MCF-7 and SKBr-3 cells in culture was evaluated. Kinetic studies showed triclosan to be a slow binding inhibitor of human and goose type I fatty acid synthase and to inhibit the partial activity of enoyl-reductase with IC(50) values between 10 and 50 microM. Triclosan at similar concentrations was also shown to inhibit both viability and growth of MCF-7 and SKBr-3 cells in culture. The results corroborate the hypothesis that fatty acid synthase may be a target of breast cancer chemotherapy and suggest that inhibitors of the enoyl-reductase partial activity of fatty acid synthase may have chemotherapeutic potential.


A review of a two-phase population study of multiple chemical sensitivities.
In this review we summarize the findings of a two-phase study of the prevalence, symptomatology, and etiology of multiple chemical sensitivities (MCS). We also explore possible triggers, the potential linkage between MCS and other disorders, and the lifestyle alterations produced by MCS. The first phase of the study consisted of a random sampling of 1,582 individuals from the Atlanta, Georgia, metropolitan area to determine the reported prevalence of a hypersensitivity to common chemicals. In this phase, 12.6% of the sample reported a hypersensitivity. Further questioning of individuals with a hypersensitivity indicated that 13.5% (1.8% of the entire sample) reported losing their jobs because of their hypersensitivity. The second phase was a follow-up questioning of the respondents who initially reported hypersensitivity. In this phase, we found that individuals with hypersensitivity experience a variety of symptoms and triggers. A significant percentage (27.5%) reported that their hypersensitivity was initiated by an exposure to pesticides, whereas an equal percentage (27.5%) attributed it to solvents. Only 1.4% had a history of prior emotional problems, but 37.7% developed these problems after the physical symptoms emerged. This suggests that MCS has a physiologic and not a psychologic etiology.


Renal excretion of vancomycinin in kidney disease.
The renal climination of vancomycin has been determined in 18 patients. In 4 anuric patients in intermittent haemodialysis the dosage of vancomycin necessary to treat infection with penicillin-resistantstrains of Staphylococcus aureus was determined. In 14 patients with varying degrees of renal insufficiency vancomycin, creatinine and 125-iothalamate clearances were measured and found to be closely correlated. After administration of the initial vancomycin dose and attainment of the serum concentration desired, the maintenance dose can be calculated on the basis of the GFR.


Calibration and Validation of the Youth Activity Profile as a Physical Activity and Sedentary Behaviour Surveillance Tool for English Youth.
Self-reported youth physical activity (PA) is typically overestimated. We aimed to calibrate and validate a self-report tool among English youth. Four-hundred-and-two participants (aged 9-16 years; 212 boys) wore SenseWear Armband Mini devices (SWA) for eight days and completed the self-report Youth Activity Profile (YAP) on the eighth day. Calibration algorithms for temporally matched segments were generated from the YAP data using quantile regression. The algorithms were applied in an independent cross-validation sample, and student- and school-level agreement were assessed. The utility of the YAP algorithms to assess compliance to PA guidelines was also examined. The school-level bias for the YAP estimates of in-school, out-of-school, and weekend moderate-to-vigorous PA (MVPA) were 17.2 (34.4), 31.6 (14.0), and -4.9 (3.6) min·week-1, respectively. Out-of-school sedentary behaviour (SB) was over-predicted by 109.2 (11.8) min·week-1. Predicted YAP values were within 15%-20% equivalence of the SWA estimates. The classification accuracy of the YAP MVPA estimates for compliance to 60 min·day-1 and 30 min·school-day-1 MVPA recommendations were 91%/37% and 89%/57% sensitivity/specificity, respectively. The YAP generated robust school-level estimates of MVPA and SB and has potential for surveillance to monitor compliance with PA guidelines. The accuracy of the YAP may be further improved through research with more representative UK samples to enhance the calibration process and to refine the resultant algorithms.


Complications of biopsy of the cervical lymph node.
The incidence of injury to the accessory nerve after biopsy of the cervical lymph nodes is difficult to ascertain. The deficits in trapezius muscle function can result in marked disability to the patient. We have presented the results of surgical exploration and repair in eight patients with injury to the accessory nerve during biopsy of the cervical lymph node. External and internal fascicular neurolysis and fascicle suturing when indicated were performed. Four patients received significant improvement in accessory nerve function and four had no improvement. Our findings agree with those reported in the literature that early recognition of accessory nerve dysfunction after biopsy of the posterior cervical lymph node with appropriate surgical therapy can yield excellent results in trapezius muscle function.


Sarcolemmal Na+-Ca2+ exchange activity in hearts subjected to hypoxia reoxygenation.
Although the occurrence of intracellular Ca2+ overload is known to be an important factor in hypoxia-reoxygenation injury, the exact mechanisms for this abnormality are not presently clear. Since Na+-Ca2+ exchange in the sarcolemmal membrane is considered to be involved in Ca2+ efflux, this study was undertaken to examine the effect of hypoxia reoxygenation on this system. Isolated rat hearts were made hypoxic by perfusing with a substrate-free medium gassed with 95% N2-5% CO2 and then reperfused with oxygenated normal medium. Hypoxia was found to markedly increase the resting tension and depress the ability of the heart to generate contractile force; reoxygenation resulted in partial recovery of these parameters. Sarcolemmal vesicles were isolated from control, hypoxic, and hypoxia-reoxygenated hearts, and the Na+-dependent Ca2+ uptake activity was measured at different times of incubation as well as at different concentrations of calcium. Sarcolemmal ATP-dependent Ca2+ accumulation was also measured for the purpose of comparison. A significant decrease in Na+-dependent Ca2+ uptake was observed in preparations from hearts made hypoxic for 10 min. Reoxygenation of 10-min hypoxic hearts resulted in a further depression of Na+-Ca2+ exchange activity. ATP-dependent Ca2+ accumulation was also depressed in hypoxic as well as reoxygenated hearts. These results suggest a defect in the Na+-Ca2+ exchange system and the ATP-dependent Ca2+ pump in the heart sarcolemmal membrane, and this may contribute to the occurrence of intracellular Ca2+ overload and functional abnormalities due to hypoxia-reoxygenation injury.


Defining the Therapeutic Range for Adalimumab and Predicting Response in Psoriasis: A Multicenter Prospective Observational Cohort Study.
Biologics have transformed management of inflammatory diseases. To optimize outcomes and reduce costs, dose adjustment informed by circulating drug levels has been proposed. We aimed to determine the real-world clinical utility of therapeutic drug monitoring in psoriasis. Within a multicenter (n = 60) prospective observational cohort, 544 psoriasis patients were included who were receiving adalimumab monotherapy and had at least one serum sample and Psoriasis Area and Severity Index (PASI) score available within the first year. We present models giving individualized probabilities of response for any given drug level: a minimally effective drug level of 3.2 μg/ml discriminates responders (PASI75 indicates 75% improvement in baseline PASI) from nonresponders, and gives an estimated PASI75 probability of 65% (95% confidence interval = 60-71). At 7 μg/ml, PASI75 probability is 81% (95% CI = 76-86); beyond 7 μg/ml, the drug level/response curve plateaus. Crucially, drug levels are predictive of response 6 months later, whether sampled early or at steady state. We confirm serum drug level to be the most important factor determining treatment response, highlighting the need to take drug levels into account when searching for biomarkers of response. This real-world study with pragmatic drug level sampling provides evidence to support the proactive measurement of adalimumab levels in psoriasis to direct treatment strategy, and is relevant to other inflammatory diseases.


[Study of shearing strength between layers of light curing composite Esterfill PHOTO].
There was determined shearing strength of monolit samples of light curing material and samples received by modeling of further layers on surfaces with and without inhibited layer and also tensile strength of layers connected with the help of light curing adhesive. The study was performed on enamel, dentine and cutting edge masses from set of light curing material Esterfill PHOTO for prosthetic purposes. The received results showed that shearing strength between layers of enamel, dentine and cutting edge masses of Esterfill PHOTO varied between 22 and 28 MPa and tensile force divided by the nominal surface area did not depend upon the way of sample modeling. Distraction zone represented half of the cone turn out of substrate. More rigid material chopped in the process of distraction lesser volume off substrate. For prosthetic purposes it was recommended to use the equipment allowing to combine the final photopolymerization of the article with annealing under high temperature conditions or make annealing of the ready article after photopolymerization.


Reduction of incidence of prematurity by folic acid supplementation in pregnancy.
Folic acid administered to pregnant Bantu, whose diet is low in folate, was associated with a significant reduction in the incidence of prematurity. No such effect could be demonstrated in White patients subsisting on an average Western diet. This suggests that folate deficiency may contribute to the "pregnancy wastage" in populations whose dietary folate intake is low, and is a further indication for folic acid supplementation during pregnancy in these groups.


New approach to evaluate late arm impairment and effects of dragon boat activity in breast cancer survivors.
To verify the applicability of a new approach based on the strength curves (SCs) methodology in late arm impairment in breast cancer (BC) survivors and to evaluate the effects of dragon boat (DB) activity on the late regaining of the muscle strength, upper limb impairment, and quality of life in patients undergoing surgery for BC.Retrospective observational study on 64 subjects (54.5 ± 9.7 years), 47 of them had undergone unilateral mastectomy surgery and were evaluated for late arm impairment. A clinical evaluation of the shoulder and compilation of functional assessment (DASH, Rowe, Constant-Murley) and quality of life (SF-36) scales were carried out. Assessment of muscle strength with SC obtained with isometric assessments and serratus anterior muscle test were performed.Differences between the SC are evident between healthy and operated subjects. Among the 3 groups of operated subjects the difference in strength is maximum at 0°. Statistically significant difference was found between operated and nonoperated only in SF-36 scale. No significant difference was found between groups for shoulder instability and winged scapula.The SC can be used in the study of upper limb impairment after surgery for BC: measurements carried out at 1st degrees of the range of motion are more useful for clinicians. DB activity is useful to reduce the late arm impairment.


Gentiana macrophylla flavonoids from Tibetan medicine decreases circ_0059665 to alleviate the progression of non-small cell lung cancer under hypoxia.
Gentiana macrophylla Pall. is a traditional Tibetan medicinal herb possessing antinociceptive and anti-inflammatory activities. Circular RNAs (circRNAs) have been identified to be involved in the tumorigenesis of non-small cell lung cancer (NSCLC). Here, this study focused on investigating the function and mechanism of Gentiana macrophylla flavonoids (GF) and circ_0059665 in NSCLC progression. The contents of mRNA and protein were detected using qRT-PCR and western blotting analysis. Cell proliferative and invasive abilities were evaluated by cell counting kit-8, EdU, colony formation and transwell assays, respectively. M2 macrophage polarization was analyzed by flow cytometry. GF treatment suppressed NSCLC cell proliferation, invasion and M2 macrophage polarization under hypoxic conditions. Circ_0059665 was highly expressed in NSCLC tissues and cells. Its expression was increased under hypoxic conditions but was reduced following GF treatment. Furthermore, circ_0059665 overexpression reversed the anticancer effects of GF on NSCLC cells under hypoxic conditions. Mechanistically, circ_0059665 acted as a sponge for miR-512-5p to regulate NOVA2 expression. Hypoxia decreased miR-512-5p levels, and increased NOVA2 levels in NSCLC cells, while these tendencies were abolished after GF treatment. Circ_0059665 silencing inhibited NSCLC cell proliferation, invasion and M2 macrophage polarization in hypoxic environments, which were counteracted by NOVA2 overexpression. Moreover, NOVA2 upregulation reversed the suppressive effects of GF on NSCLC cells with hypoxia treatment. In addition, GF impeded NSCLC tumor growth in vivo via suppressing circ_0059665. GF treatment in hypoxic environments suppressed NSCLC cell proliferation, invasion and M2 macrophage polarization via the circ_0059665/miR-512-5p/NOVA2 axis.


[Dietary prevention of protein-energy malnutrition during early postoperative period in elderly patients with gastroduodenal diseases].
The modified diet of postoperative rehabilitation program in elderly patients with gastroduodenal ulcers and prognosis of development of protein-energy malnutrition (PEM) is presented. It is shown that early initiated special diet in postoperative period, blocks mechanisms of malnutrition and can significantly improve the functional status of the small intestine and activate, thus, membrane digestion, which leads to normalization of all types of metabolism in elderly patients. In comparison with control group, where 72% of patients in postoperative period had malnutrition, malnutrition in the study group revealed a mild degree in only 17.3% of patients.


Post-translational activation introduces a free radical into pyruvate formate-lyase.
Pyruvate formate-lyase (formate acetyltransferase; EC 188.8.131.52) of Escherichia coli cells is post-translationally interconverted between inactive and active forms. Conversion of the inactive to the active form is catalyzed by an Fe2+-dependent activating enzyme and requires adenosylmethionine and dihydroflavodoxin. This process is shown here to introduce a paramagnetic moiety into the structure of pyruvate formate-lyase. It displays an EPR signal at g = 2 with a doublet splitting of 1.5 mT and could comprise an organic free radical located on an amino acid residue of the polypeptide chain. Hypophosphite was discovered as a specific reagent that destroys both the enzyme radical and the enzyme activity; it becomes covalently bound to the protein. The enzymatic generation of the radical, which is linked to adenosylmethionine cleavage into 5'-deoxyadenosine and methionine, possibly occurs through an Fe-adenosyl complex. These results suggest a radical mechanism for the catalytic cycle of pyruvate formate-lyase.


Search for magnetic monopoles in sqrt[s]=7 TeV pp collisions with the ATLAS detector.
This Letter presents a search for magnetic monopoles with the ATLAS detector at the CERN Large Hadron Collider using an integrated luminosity of 2.0 fb(-1) of pp collisions recorded at a center-of-mass energy of sqrt[s]=7 TeV. No event is found in the signal region, leading to an upper limit on the production cross section at 95% confidence level of 1.6/ϵ fb for Dirac magnetic monopoles with the minimum unit magnetic charge and with mass between 200 GeV and 1500 GeV, where ϵ is the monopole reconstruction efficiency. The efficiency ϵ is high and uniform in the fiducial region given by pseudorapidity |η|<1.37 and transverse kinetic energy 600-700<E(kin)sinθ<1400 GeV. The minimum value of 700 GeV is for monopoles of mass 200 GeV, whereas the minimum value of 600 GeV is applicable for higher mass monopoles. Therefore, the upper limit on the production cross section at 95% confidence level is 2 fb in this fiducial region. Assuming the kinematic distributions from Drell-Yan pair production of spin-1/2 Dirac magnetic monopoles, the efficiency is in the range 1%-10%, leading to an upper limit on the cross section at 95% confidence level that varies from 145 fb to 16 fb for monopoles with mass between 200 GeV and 1200 GeV. This limit is weaker than the fiducial limit because most of these monopoles lie outside the fiducial region.


Focused and Sustained Attention Is Modified by a Goal-Based Rehabilitation in Parkinsonian Patients.
Rehabilitation for patients with Parkinson's disease (PD) is based on cognitive strategies that exploit attention. Parkinsonians exhibit impairments in divided attention and interference control. Nevertheless, the effectiveness of specific rehabilitation treatments based on attention suggests that other attentional functions are preserved. Data about attention are conflicting in PD, and it is not clear whether rehabilitative treatments that entail attentional strategies affect attention itself. Reaction times (RTs) represent an instrument to explore attention and investigate whether changes in attentional performances parallel rehabilitation induced-gains. RTs of 103 parkinsonian patients in "on" state, without cognitive deficits, were compared with those of a population of 34 healthy controls. We studied those attentional networks that subtend the use of cognitive strategies in motor rehabilitation: alertness and focused and sustained attention, which is a component of the executive system. We used visual and auditory RTs to evaluate alertness and multiple choices RTs (MC RTs) to explore focused and sustained attention. Parkinsonian patients underwent these tasks before and after a 4-week multidisciplinary, intensive and goal-based rehabilitation treatment (MIRT). Unified Parkinson's Disease Rating Scale (UPDRS) III and Timed Up and Go test (TUG) were assessed at the enrollment and at the end of MIRT to evaluate the motor-functional effectiveness of treatment. We did not find differences in RTs between parkinsonian patients and controls. Further, we found that improvements in motor-functional outcome measures after MIRT (p < 0.0001) paralleled a reduction in MC RTs (p = 0.014). No changes were found for visual and auditory RTs. Correlation analysis revealed no association between changes in MC RTs and improvements in UPDRS-III and TUG. These findings indicate that alertness, as well as focused and sustained attention, are preserved in "on" state. This explains why Parkinsonians benefit from a goal-based rehabilitation that entails the use of attention. The reduction in MC RTs suggests a positive effect of MIRT on the executive component of attention and indicates that this type of rehabilitation provides benefits by exploiting executive functions. This ensues from different training approaches aimed at bypassing the dysfunctional basal ganglia circuit, allowing the voluntary execution of the defective movements. These data suggest that the effectiveness of a motor rehabilitation tailored for PD lies on cognitive engagement.


The role of left prefrontal cortex in language and memory.
This article reviews attempts to characterize the mental operations mediated by left inferior prefrontal cortex, especially the anterior and inferior portion of the gyrus, with the functional neuroimaging techniques of positron emission tomography and functional magnetic resonance imaging. Activations in this region occur during semantic, relative to nonsemantic, tasks for the generation of words to semantic cues or the classification of words or pictures into semantic categories. This activation appears in the right prefrontal cortex of people known to be atypically right-hemisphere dominant for language. In this region, activations are associated with meaningful encoding that leads to superior explicit memory for stimuli and deactivations with implicit semantic memory (repetition priming) for words and pictures. New findings are reported showing that patients with global amnesia show deactivations in the same region associated with repetition priming, that activation in this region reflects selection of a response from among numerous relative to few alternatives, and that activations in a portion of this region are associated specifically with semantic relative to phonological processing. It is hypothesized that activations in left inferior prefrontal cortex reflect a domain-specific semantic working memory capacity that is invoked more for semantic than nonsemantic analyses regardless of stimulus modality, more for initial than for repeated semantic analysis of a word or picture, more when a response must be selected from among many than few legitimate alternatives, and that yields superior later explicit memory for experiences.


Atypical vascular lesions after surgery and radiation of the breast: a clinicopathologic study of 32 cases analyzing histologic heterogeneity and association with angiosarcoma.
We report the clinicopathologic study of 32 cases of atypical vascular lesions (AVLs) after surgery and radiation of the breast, which were referred to us in consultation over a 17-year period. The patients, all women, ranged in age from 41 to 95 years (mean 61 y). The lesions developed within the radiation field from 1 to 12 years (median 6.0 y) after therapy. They occurred as one (n=18) or more (n=10) flesh-colored papules or erythematous patches/plaques ranging in size from 1 to 60 mm (mean 8.0 mm, median 4.0 mm). Tumors could be divided into 2 histologic types: a lymphatic type (LT) (n=22) and a vascular type (VT) (n=10). LT AVLs consisted predominantly of thin-walled, variably anastomosing lymphatic vessels that were usually confined to the superficial dermis but occasionally extended into the deep dermis and even subcutis. The VT (n=10) typically consisted of small, irregularly dispersed, often blood-filled, pericyte-invested, capillary-sized vessels involving the superficial or deep dermis. VTs were often associated with extravasated erythrocytes, hemosiderin, and a surrounding minor LT component. In 4 cases, endothelial atypia, consisting of nuclear and nucleolar enlargement, was noted. Follow-up of 21 patients with LT AVLs (1 to 106 mo; mean 47 mo) disclosed recurrence/additional lesions in 6, all of whom had additional surgery. Of the 21 patients, 17 are alive without disease, 1 is alive with disease, 1 died of breast carcinoma, 1 died of unknown causes, and 1 showed progressive histologic changes in the AVLs over a period of 5 years resulting in a well-differentiated angiosarcoma. Follow-up in 8 patients with VT AVL (2 to 181 mo; mean 40 mo) disclosed that 6 were alive and well, but 2 of the 4 patients whose lesions displayed endothelial atypia had additional complications. One patient underwent a mastectomy that revealed extensive residual AVL and the second developed a high-grade angiosarcoma after 14 months. We conclude that AVLs encompass a wider spectrum of changes than previously appreciated, ranging from superficial lymphatic proliferations to more complex lymphatic and capillary vascular lesions. There seems to be an association of AVL with angiosarcoma that differs depending on the histologic features, with the VT AVLs having the higher risk. In the 2 patients who developed angiosarcoma, morphologic evidence suggested AVLs to be a precursor rather than simply a risk factor. Future outcome and management studies should take into account these differences.


One-stage nasal soft tissue reconstruction with local flaps.
Because of better public education and earlier diagnosis of skin tumors, the number of soft tissue defects of the nose with limited size and depth after tumor resection is increasing. A variety of surgical methods such as skin grafts, regional flaps such as forehead flap, and local flaps have been described. The method of choice is dependent on the defect size, localization, skin structure and the wishes and expectations, and general condition of the patient. Nasal reconstruction for soft tissue defects in the supratip area, dorsum, and sidewalls using local rotation and/or advancement flaps is our primary option. But achieving supreme results with these non-subunit-based techniques is still a challenge. Showing schematic figures and case studies, this article is aimed at assisting surgeons in the planning and decision making of which flap is appropriate for the reconstruction of soft tissue defects of the nose.


Polycyclic aromatic hydrocarbon exposure results in altered CRH, reproductive, and thyroid hormone concentrations during human pregnancy.
Polycyclic aromatic hydrocarbons (PAHs) are byproducts of incomplete combustion reactions and are ubiquitous in the environment, leading to widespread human exposure via inhalation and ingestion pathways. PAHs have been implicated as endocrine disrupting compounds in previous animal and in vitro studies, but human studies are currently lacking. Pregnant women and their developing fetuses are particularly susceptible populations to environmental contaminants, in part because alterations in hormone physiology during gestation can have adverse consequences on the health of the pregnancy. We utilized data on 659 pregnant women from the PROTECT longitudinal birth cohort in Puerto Rico to assess associations between repeated measures of 8 urinary hydroxylated PAH (OH-PAH) metabolites and 9 serum hormones during gestation. Urine samples were collected at 3 study visits (median gestational ages of 18, 22, and 26 weeks at each visit, respectively) and serum samples were collected at the first and third study visits. Linear mixed effects models were used to ascertain longitudinal associations between OH-PAHs and hormones, and sensitivity analyses were employed to assess potential nonlinearity and differences in associations on the basis of fetal sex and timing of biomarker measurement. Among the multiple positive associations we observed between OH-PAHs and CRH, estriol, progesterone, T3, and the ratio of T3 to T4, and inverse associations with testosterone, the most notable are a 24.3% increase (95% CI: 13.0, 36.7) in CRH with an interquartile range (IQR) increase in 1-hydroxyphenanthrene and a 17.2% decrease (95% CI: 8.13, 25.4) in testosterone with an IQR increase in 1-hydroxynapthalene. Many associations observed were dependent on fetal sex, and some relationships showed evidence of nonlinearity. These findings demonstrate the importance of studying PAH exposures during pregnancy and highlight the potential complexity of their impacts on the physiology of human pregnancy.


A versatile and general splitting technology for generating targeted YAC subclones.
Yeast artificial chromosomes (YAC) splitting technology was developed as a means to subclone any desired region of eukaryotic chromosomes from one YAC into new YACs. In the present study, the conventional YAC splitting technology was improved by incorporating PCR-mediated chromosome splitting technique and by adding autonomously replicating sequence (ARS) to the system. To demonstrate the performance of the improved method, a 60-kb region from within a 590-kb YAC (clone CIC9e2 from Arabidopsis thaliana chromosome 5) that could not be subcloned using the original method was split to convert into a replicating YAC. Two template plasmids, pSK-KCA and pSKCLY, were used to generate two splitting fragments by PCR. Two splitting fragments consisted of telomeric (C(4)A(2))(6) repeats, 400-bp target region, CEN4, H4ARS and Km(r) (selective marker for plant transformants), or CgLEU2. These splitting fragments were introduced into Saccharomyces cerevisiae harboring the 100-kb split YAC generated by splitting of the 590-kb YAC and containing the 60-kb region. Among 12 Leu(+) transformants, four exhibited the expected karyotype in which two newly split 40- and 60-kb chromosomes were generated. These results demonstrate that the improved method can convert a targeted region of a eukaryotic chromosome within a YAC into a replicating YAC.


U-shaped association between plasma C-peptide and sarcopenia: A cross-sectional study of elderly Chinese patients with diabetes mellitus.
Limited research exists regarding the relationship between fasting plasma C-peptide levels and sarcopenia. As a result, our study aimed to examine this association in elderly Chinese diabetic patients. This cross-sectional study included 288 elderly patients with diabetes mellitus from the Fourth People's Hospital in Guiyang who were enrolled prospectively between March 2020 and February 2023. The independent variable of interest was fasting plasma C-peptide, while the dependent variable was sarcopenia. Data on several covariates, including demographic factors, lifestyle habits, co-morbidities, anthropometric indicators, and laboratory indicators, were also collected. Of the 288 participants, 27.43% (79/288) had sarcopenia. After adjusting for potential confounding variables, we found a U-shaped association between fasting plasma C-peptide levels and sarcopenia, with inflection points identified at approximately 774 pmol/L and 939 mmol/L. Within the range of 50-744 pmol/L, each 100 pmol/L increase in CysC was associated with a 37% decrease in the odds of sarcopenia (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.49 to 0.83; P < 0.001). Additionally, within the range of 939-1694 pmol/L, each 100 pmol/L increase in fasting plasma C-peptide was associated with a 76% increase in the odds of sarcopenia (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.11 to 2.81; P = 0.017). Our study revealed a U-shaped association between fasting plasma C-peptide levels and the likelihood of sarcopenia, with lower risk in the range of 774-939 pmol/L. These findings may assist in the development of more effective prevention and treatment strategies for sarcopenia in elderly diabetic patients.


Global tuberculosis drug development pipeline: the need and the reality.
Drugs for tuberculosis are inadequate to address the many inherent and emerging challenges of treatment. In the past decade, ten compounds have progressed into the clinical development pipeline, including six new compounds specifically developed for tuberculosis. Despite this progress, the global drug pipeline for tuberculosis is still insufficient to address the unmet needs of treatment. Additional and sustainable efforts, and funding are needed to further improve the pipeline. The key challenges in the development of new treatments are the needs for novel drug combinations, new trial designs, studies in paediatric populations, increased clinical trial capacity, clear regulatory guidelines, and biomarkers for prediction of long-term outcome. Despite substantial progress in efforts to control tuberculosis, the global burden of this disease remains high. To eliminate tuberculosis as a public health concern by 2050, all responsible parties need to work together to strengthen the global antituberculosis drug pipeline and support the development of new antituberculosis drug regimens.


Specialized phosphate transport is essential for Staphylococcus aureus nitric oxide resistance.
Staphylococcus aureus is a major human pathogen capable of causing a variety of diseases ranging from skin and soft tissue infections to systemic presentations such as sepsis, endocarditis, and osteomyelitis. For S. aureus to persist as a pathogen in these environments, it must be able to resist the host immune response, including the production of reactive oxygen and nitrogen species (e.g., nitric oxide, NO·). Extensive work from our lab has shown that S. aureus is highly resistant to NO·, especially in the presence of glucose. RNA-seq performed on S. aureus exposed to NO· in the presence and absence of glucose showed a new system important for NO· resistance-phosphate transport. The phosphate transport systems pstSCAB and nptA are both upregulated upon NO·-exposure, particularly in the presence of glucose. Both are key for phosphate transport at an alkaline pH, which the cytosol of S. aureus becomes under NO· stress. Accordingly, the ΔpstSΔnptA mutant is attenuated under NO stress in vitro as well as in macrophage and murine infection models. This work defines a new role in infection for two phosphate transporters in S. aureus and provides insight into the complex system that is NO· resistance in S. aureus.IMPORTANCEStaphylococcus aureus is a bacterial pathogen capable of causing a wide variety of disease in humans. S. aureus is unique in its ability to resist the host immune response, including the antibacterial compound known as nitric oxide (NO·). We used an RNA-sequencing approach to better understand the impact of NO· on S. aureus in different environments. We discovered that inorganic phosphate transport is induced by the presence of NO·. Phosphate is important for the generation of energy from glucose, a carbon source favored by S. aureus. We show that the absence of these phosphate transporters causes lowered energy levels in S. aureus. We find that these phosphate transporters are essential for S. aureus to grow in the presence of NO· and to cause infection. Our work here contributes significantly to our understanding of S. aureus NO· resistance and provides a new context in which S. aureus phosphate transporters are essential.


EXPLORING CLINICAL VARIATIONS AND CO-MORBID TRENDS IN PD-MCI GROUPS.
Parkinson's Disease in Mild Cognitive Impairment (PD-MCI) is a complex condition characterized by a variety of cognitive problems that coexist with the physical symptoms of Parkinson's disease (PD). This study aims to examine the different medical indicators and associated tendencies among different PD-MCI groups. We investigated 132 people who had been given PD-MCI diagnoses. Utilizing SPSS, statistical evaluations are carried out. In overall PD-MCI variants, this investigation found that visuospatial ability and attentional/executive performance are the most impaired cognitive areas. It was also noticed that distinct PD-MCI groups had variances in their neurological characteristics, in multi domain amnesia (Non-Memory) PD-MCI patients exhibiting especially severe issues with unstable posture and walking. The intricacy of PD- Mild Cognitive Impairment (MCI) is highlighted by those results, which also imply that the interplay between mental and physical signs may be controlled by a number of interrelated factors, such as particular cognitive areas, brain surfaces, and the general level of cognitive impairment.


Using the Multi-Theory Model (MTM) of Health Behavior Change to Explain Yoga Practice.
Diverse groups, including college students, are being encouraged to practice yoga. Research suggests that college students fail to attain the mental and physical benefits of yoga practice. The purpose of this study was to utilize the fourth-generation, multi-theory model (MTM) of health behavior change to explain change regarding yoga practice of asanas, shava asana, pranayama, dhyana, yama and niyama among college students. This cross-sectional study relied on a quota sample of students 18 years and older attending Jackson State University, a historically black college in Jackson, Mississippi, United States. A 36-item face and content valid instrument was used to collect data. Stepwise multiple regression was used to analyze the survey data for identifying the best possible predictors of yoga practice. A statistical significance level of 0.05 was set a priori. A total of 70 participants, mean age 28.62 years (SD, 6.11), predominately female (84%) and black (87%) completed the survey. The initiation model constructs- changes in the physical environment (β = 3.99, P = .002) and behavioral confidence (β = 0.331, P = .008)-were significant, explaining 40% of the variability in the dependent variable. Practice change was statistically significant (F1,65 =7.569; P = .0001; adjusted R2 = 0.460) for the maintenance model, explaining 46% of the variability. The MTM model of health behavior change is effective for explaining the intent to initiate and maintain yoga behavior among college students.


Small Hexokinase 1 Peptide against Toxic SOD1 G93A Mitochondrial Accumulation in ALS Rescues the ATP-Related Respiration.
Mutations in Cu/Zn Superoxide Dismutase (SOD1) gene represent one of the most common causes of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder that specifically affects motor neurons (MNs). The dismutase-active SOD1 G93A mutant is responsible for the formation of toxic aggregates onto the mitochondrial surface, using the Voltage-Dependent Anion Channel 1 (VDAC1) as an anchor point to the organelle. VDAC1 is the master regulator of cellular bioenergetics and by binding to hexokinases (HKs) it controls apoptosis. In ALS, however, SOD1 G93A impairs VDAC1 activity and displaces HK1 from mitochondria, promoting organelle dysfunction, and cell death. Using an ALS cell model, we demonstrate that a small synthetic peptide derived from the HK1 sequence (NHK1) recovers the cell viability in a dose-response manner and the defective mitochondrial respiration profile relative to the ADP phosphorylation. This correlates with an unexpected increase of VDAC1 expression and a reduction of SOD1 mutant accumulation at the mitochondrial level. Overall, our findings provide important new insights into the development of therapeutic molecules to fight ALS and help to better define the link between altered mitochondrial metabolism and MNs death in the disease.


Acute decrease in net glutamate uptake during energy deprivation.
The extracellular glutamate concentration ([glu](o)) rises during cerebral ischemia, reaching levels capable of inducing delayed neuronal death. The mechanisms underlying this glutamate accumulation remain controversial. We used N-methyl-D-aspartate receptors on CA3 pyramidal neurons as a real-time, on-site, glutamate sensor to identify the source of glutamate release in an in vitro model of ischemia. Using glutamate and L-trans-pyrrolidine-2,4-dicarboxylic acid (tPDC) as substrates and DL-threo-beta-benzyloxyaspartate (TBOA) as an inhibitor of glutamate transporters, we demonstrate that energy deprivation decreases net glutamate uptake within 2-3 min and later promotes reverse glutamate transport. This process accounts for up to 50% of the glutamate accumulation during energy deprivation. Enhanced action potential-independent vesicular release also contributes to the increase in [glu](o), by approximately 50%, but only once glutamate uptake is inhibited. These results indicate that a significant rise in [glu](o) already occurs during the first minutes of energy deprivation and is the consequence of reduced uptake and increased vesicular and nonvesicular release of glutamate.


Identification and characterization of H-2d restricted CD4+ T cell epitopes on Lpp20 of Helicobacter pylori.
Previous investigation has demonstrated that CD4+ T cells play a crucial role in effective immunity against Helicobacter pylori (H.pylori) infection. It has been well proved that Lpp20 is one of major protective antigens that induce immune responses after H.pylori invades host. Therefore it is valuable to identify CD4+ T cell epitopes on Lpp20, which is uncharacterized. Putative epitopes of H-2d restricted CD4+ T cell on Lpp20 of H.pylori were predicted by the SYFPEITHI algorithm and then eight hypothetical epitope peptides were synthesized. After BALB/c mice were primed with recombinant Lpp20, splenic CD4+ T cells were isolated and stimulated with synthesized peptides to measure T cell proliferation and MHC restriction. Cytokine profile was determined by ELISA and real-time PCR. Two identified epitopes were used to immunize mice to investigate CD4+ T cell response by flow cytometry. Two of eight peptides were able to stimulate CD4+ T cell proliferation and were mapped to residues 83-97aa and 58-72aa on Lpp20 respectively. These two peptides additively stimulated Th1 cells to secrete IFN-γ. The percentage of CD4+ T cell from mice immunized with two identified epitopes respectively was higher than the control group. The identification and characterization of two CD4+ T cell epitopes of Lpp20 helps understand the protective immunity of Lpp20 in H.pylori infection and design effective epitope vaccines against H.pylori.


Xanthomonas hortorum - beyond gardens: Current taxonomy, genomics, and virulence repertoires.
Bacteria; Phylum Proteobacteria; Class Gammaproteobacteria; Order Lysobacterales (earlier synonym of Xanthomonadales); Family Lysobacteraceae (earlier synonym of Xanthomonadaceae); Genus Xanthomonas; Species X. hortorum; Pathovars: pv. carotae, pv. vitians, pv. hederae, pv. pelargonii, pv. taraxaci, pv. cynarae, and pv. gardneri. Xanthomonas hortorum affects agricultural crops, and horticultural and wild plants. Tomato, carrot, artichoke, lettuce, pelargonium, ivy, and dandelion were originally described as the main natural hosts of the seven separate pathovars. Artificial inoculation experiments also revealed other hosts. The natural and experimental host ranges are expected to be broader than initially assumed. Additionally, several strains, yet to be assigned to a pathovar within X. hortorum, cause diseases on several other plant species such as peony, sweet wormwood, lavender, and oak-leaf hydrangea. X. hortorum pathovars are mainly disseminated by infected seeds (e.g., X. hortorum pvs carotae and vitians) or cuttings (e.g., X. hortorum pv. pelargonii) and can be further dispersed by wind and rain, or mechanically transferred during planting and cultivation. Global trade of plants, seeds, and other propagating material constitutes a major pathway for their introduction and spread into new geographical areas. The propagules of some pathovars (e.g., X. horturum pv. pelargonii) are spread by insect vectors, while those of others can survive in crop residues and soils, and overwinter until the following growing season (e.g., X. hortorum pvs vitians and carotae). Control measures against X. hortorum pathovars are varied and include exclusion strategies (i.e., by using certification programmes and quarantine regulations) to multiple agricultural practices such as the application of phytosanitary products. Copper-based compounds against X. hortorum are used, but the emergence of copper-tolerant strains represents a major threat for their effective management. With the current lack of efficient chemical or biological disease management strategies, host resistance appears promising, but is not without challenges. The intrastrain genetic variability within the same pathovar poses a challenge for breeding cultivars with durable resistance. https://gd.eppo.int/taxon/XANTGA, https://gd.eppo.int/taxon/XANTCR, https://gd.eppo.int/taxon/XANTPE, https://www.euroxanth.eu, http://www.xanthomonas.org, http://www.xanthomonas.org/dokuwiki.


Lead neuropathy and electrophysiological studies in low level lead exposure: a critical review.
The literature on nerve conduction velocity (NCV) studies and electromyography in lead exposed populations was reviewed. All studies revealed some degree of defect in their experimental design. Disregarding these limitations, a consensus of the studies indicates that a mild slowing (7%) of motor and sensory NCV may be present in the median and posterior tibial nerves, but that ulnar and peroneal NCVs are not slowed in subjects with blood lead levels of less than 60 micrograms/dl. No clinical correlations to this mild slowing were reported in studies where concurrent motor and sensory examinations were performed. A majority of the studies did not find a correlation between blood lead level and NCV at blood lead levels below 70 ug/dl or length of exposure and NCV. Most studies of electromyographic activity in lead exposed population found abnormalities only in patients with blood lead levels above 60-70 ug/dl or in patients with lead colic or other systemic symptoms of lead intoxication. This review does not find evidence that the slowing of NCV in low level lead exposure is clinically significant or evidence that would suggest that it is a subclinical manifestation of clinical lead neuropathy in man.


Structural and functional comparisons of retroviral envelope protein C-terminal domains: still much to learn.
Retroviruses are a family of viruses that cause a broad range of pathologies in animals and humans, from the apparently harmless, long-term genomic insertion of endogenous retroviruses, to tumors induced by the oncogenic retroviruses and acquired immunodeficiency syndrome (AIDS) resulting from human immunodeficiency virus infection. Disease can be the result of diverse mechanisms, including tumorigenesis induced by viral oncogenes or immune destruction, leading to the gradual loss of CD4 T-cells. Of the virally encoded proteins common to all retroviruses, the envelope (Env) displays perhaps the most diverse functionality. Env is primarily responsible for binding the cellular receptor and for effecting the fusion process, with these functions mediated by protein domains localized to the exterior of the virus. The remaining C-terminal domain may have the most variable functionality of all retroviral proteins. The C-terminal domains from three prototypical retroviruses are discussed, focusing on the different structures and functions, which include fusion activation, tumorigenesis and viral assembly and lifecycle influences. Despite these genetic and functional differences, however, the C-terminal domains of these viruses share a common feature in the modulation of Env ectodomain conformation. Despite their differences, perhaps each system still has information to share with the others.


Counter-regulation of T cell effector function by differentially activated p38.
Unlike the MAP kinase (MAPK) cascade that phosphorylates p38 on the activation loop, T cell receptor (TCR) signaling results in phosphorylation on Tyr-323 (pY323, alternative pathway). Using mice expressing p38α and p38β with Y323F substitutions, we show that alternatively but not MAPK cascade-activated p38 up-regulates the transcription factors NFATc1 and IRF4, which are required for proliferation and cytokine production. Conversely, activation of p38 with UV or osmotic shock mitigated TCR-mediated activation by phosphorylation and cytoplasmic retention of NFATc1. Notably, UVB treatment of human psoriatic lesions reduced skin-infiltrating p38 pY323(+) T cell IRF4 and IL-17 production. Thus, distinct mechanisms of p38 activation converge on NFATc1 with opposing effects on T cell immunity, which may underlie the beneficial effect of phototherapy on psoriasis.


Caprine uterine and placental osteopontin expression is distinct among epitheliochorial implanting species.
Osteopontin (OPN) is the most highly up-regulated extracellular matrix/adhesion molecule in the uterus of humans and domestic animals as it becomes receptive to implantation. Studies in sheep and pigs have shown that OPN is a component of ovine and porcine histotroph characterized by a complex temporal and spatial pattern of uterine and conceptus expression involving immune, epithelial, and stromal cells. It is proposed that these expression events are orchestrated to contribute to conceptus attachment and placentation. However, differences in OPN expression between sheep and pigs have been detected that relate to differences in placentation. Therefore, this study examined OPN expression in the caprine uterus and conceptus to gain insight into mechanisms underlying OPN function(s) during pregnancy through comparative analysis of differences in placentation between pigs, sheep, and goats. Goats were hysterectomized (n = 5/day) on Days 5, 11, 13, 15, 17 or 19 of the estrous cycle, and Days 5, 11, 13, 15, 17, 19 or 25 of pregnancy. Slot-blot hybridization showed increases in endometrial OPN mRNA beginning on Day 17 of the estrous cycle and Day 19 of pregnancy. In situ hybridization localized OPN mRNA to endometrial glandular epithelium (GE), Day 25 myometrium, and cells scattered within the placenta hypothesized to be immune. Immunofluorescence microscopy detected OPN protein on the apical surface of endometrial lumenal epithelium (LE), in GE, and on conceptus (Tr). Western blot analysis detected primarily the native 70-kDa OPN protein in endometrial extracts from the estrous cycle and pregnancy, as well as in uterine flushings from pregnant goats. Co-induction of OPN and alpha-smooth muscle actin, but not desmin proteins, was observed in uterine stroma by Day 25 of pregnancy. OPN in cyclic GE, Day 25 myometrium, and desmin-negative endometrial stroma is unique and reflects subtle differences among superficial implanting species that correlate with the depth of Tr invasion.


Exosomes for hair growth and regeneration.
Exosomes are lipid bilayer vesicles, 30-200 nm in diameter, that are produced by cells and play essential roles in cell-cell communication. Exosomes have been studied in several medical fields including dermatology. Hair loss, a major disorder that affects people and sometimes causes mental stress, urgently requires more effective treatment. Because the growth and cycling of hair follicles are governed by interactions between hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs), a better understanding of the mechanisms responsible for hair growth and cycling through exosomes may provide new insights into novel treatments for hair loss. In this review, we focused on the comprehensive knowledge and recent studies on exosomes in the field of hair development and regeneration. We classified exosomes of several cellular origins for the treatment of hair loss. Exosomes and their components, such as microRNAs, are promising drugs for effective hair loss treatment.


Human Heart Failure Alters Mitochondria and Fiber 3D Structure Triggering Metabolic Shifts.
This study, utilizing SBF-SEM, reveals structural alterations in mitochondria and myofibrils in human heart failure (HF). Mitochondria in HF show changes in structure, while myofibrils exhibit increased cross-sectional area and branching. Metabolomic and lipidomic analyses indicate concomitant dysregulation in key pathways. The findings underscore the need for personalized treatments considering individualized structural changes in HF.


Equine pulmonary aspergillosis with encephalitic, myocardial, and renal dissemination.
The cause of the death of a 16-month-old Brasileiro-de-Hipismo filly and a 3-year-old male Paint Horse with clinical manifestations of anemia and apathy from southern Brazil was investigated. These horses were maintained at the same stable; received hay as part of their diet and were submitted for routine necropsy evaluations. Significant gross findings included several nodules randomly distributed throughout the pulmonary lobes of both horses, and the kidneys, myocardium, and the frontal lobes of the cerebrum of the filly. Histopathological evaluation revealed pyogranulomatous bronchopneumonia in both horses; granulomatous interstitial nephritis, myocarditis, and encephalitis were observed in the filly. All lesions contained vasculitis and thrombosis associated with myriads of intralesional, branching, septate fungi consistent with Aspergillus spp.; intralesional fungi were more easily identified by the Grocott methenamine silver stain. Mycological culture of fresh pulmonary sections from both horses and the brain of the filly revealed pure growths of A. fumigatus. These findings confirmed the participation of A. fumigatus in the etiopathogenesis of the lesions observed in the lungs of both horses, and the cerebrum, myocardium and kidneys of the filly and might represent the first description of A. fumigatus-induced encephalitis in horses. Additionally, we believe that infection occurred during the ingestion of contaminated hay or by inhalation of spores within contaminated bedding that resulted in transient nasal mycosis, which progressed to pyogranulomatous bronchopneumonia in both horses with embolic encephalitic, myocardial, and renal dissemination of A. fumigatus occurring only in the filly.


Lateral gene transfer in eukaryotes.
Lateral gene transfer -- the transfer of genetic material between species -- has been acknowledged as a major mechanism in prokaryotic genome evolution for some time. Recently accumulating data indicate that the process also occurs in the evolution of eukaryotic genomes. However, there are large rate variations between groups of eukaryotes; animals and fungi seem to be largely unaffected, with a few exceptions, while lateral gene transfer frequently occurs in protists with phagotrophic lifestyles, possibly with rates comparable to prokaryotic organisms. Gene transfers often facilitate the acquisition of functions encoded in prokaryotic genomes by eukaryotic organisms, which may enable them to colonize new environments. Transfers between eukaryotes also occur, mainly into larger phagotrophic eukaryotes that ingest eukaryotic cells, but also between plant lineages. These findings have implications for eukaryotic genomic research in general, and studies of the origin and phylogeny of eukaryotes in particular.


Neighbourhood influence on the fourth dose of diphtheria-tetanus-pertussis vaccination.
Using 542,159 vaccination records from children born between April 1, 2007, and March 31, 2012, in the Michigan Care Improvement Registry and data from the American Community Survey, we determine if neighbourhood-level characteristics at the Census tract level and block level are associated with low uptake of the fourth dose of diphtheria-tetanus-acellular pertussis vaccine (DTaP4). This study was a cross-sectional study. We used exploratory factor analysis to determine important socio-economic factors at the Census block level and tract level. We then used generalised estimating equations to test the relationship between block- and tract-level socio-economic factors and DTaP4 uptake. DTaP4 coverage was 88.6% (95% confidence interval [CI]: 88.4%-88.7%) in Michigan. At the Census tract level, two factors surfaced as important for DTaP4 vaccination: 'affluence' (Cronbach's alpha = 0.88) and 'socio-economic disadvantage' (Cronbach's alpha = 0.89). At the Census block level, one factor was important: 'affluence' (Cronbach's alpha = 0.90). Affluence may relate to knowledge about medical exemptions and antivaccination sentiment, while socio-economic disadvantage may indicate limited access to healthcare resources. Children in high-affluence tracts had 1.08% lower vaccination coverage (95% CI: -1.62% to -0.55%) than children in low affluence tracts. Children in low socio-economic disadvantage tracts had 2.92% higher coverage than children in high socio-economic disadvantage tracts (95% CI: 2.58%-3.26%). This study articulates the need to further understand the contribution of neighbourhood-level characteristics, from both affluent and socioeconomically disadvantaged areas to low vaccination rates. Developing a better understanding of these social environmental factors will help determine useful community-level interventions to improve vaccination rates and reduce disease burden.


Viruses as groundwater tracers: using ecohydrology to characterize short travel times in aquifers.
Viruses are attractive tracers of short (<3 year) travel times in aquifers because they have unique genetic signatures, are detectable in trace quantities, and are mobile in groundwater. Virus "snaphots" result from infection and disappearance in a population over time; therefore, the virus snapshot shed in the fecal wastes of an infected population at a specific point in time can serve as a marker for tracking virus and groundwater movement. The virus tracing approach and an example application are described to illustrate their ability to characterize travel times in high-groundwater velocity settings, and provide insight unavailable from standard hydrogeologic approaches. Although characterization of preferential flowpaths does not usually characterize the majority of other travel times occurring in the groundwater system (e.g., center of plume mass; tail of the breakthrough curve), virus approaches can trace very short times of transport, and thus can fill an important gap in our current hydrogeology toolbox.


Development of pre and post-operative models to predict early recurrence of hepatocellular carcinoma after surgical resection.
Resection is the most widely used potentially curative treatment for patients with early hepatocellular carcinoma (HCC). However, recurrence within 2 years occurs in 30-50% of patients, being the major cause of mortality. Herein, we describe 2 models, both based on widely available clinical data, which permit risk of early recurrence to be assessed before and after resection. A total of 3,903 patients undergoing surgical resection with curative intent were recruited from 6 different centres. We built 2 models for early recurrence, 1 using preoperative and 1 using pre and post-operative data, which were internally validated in the Hong Kong cohort. The models were then externally validated in European, Chinese and US cohorts. We developed 2 online calculators to permit easy clinical application. Multivariable analysis identified male gender, large tumour size, multinodular tumour, high albumin-bilirubin (ALBI) grade and high serum alpha-fetoprotein as the key parameters related to early recurrence. Using these variables, a preoperative model (ERASL-pre) gave 3 risk strata for recurrence-free survival (RFS) in the entire cohort - low risk: 2-year RFS 64.8%, intermediate risk: 2-year RFS 42.5% and high risk: 2-year RFS 20.7%. Median survival in each stratum was similar between centres and the discrimination between the 3 strata was enhanced in the post-operative model (ERASL-post) which included 'microvascular invasion'. Statistical models that can predict the risk of early HCC recurrence after resection have been developed, extensively validated and shown to be applicable in the international setting. Such models will be valuable in guiding surveillance follow-up and in the design of post-resection adjuvant therapy trials. The most effective treatment of hepatocellular carcinoma is surgical removal of the tumour but there is often recurrence. In this large international study, we develop a statistical method that allows clinicians to estimate the risk of recurrence in an individual patient. This facility enhances communication with the patient about the likely success of the treatment and will help in designing clinical trials that aim to find drugs that decrease the risk of recurrence.


Environmental exposures and gene regulation in disease etiology.
Health or disease is shaped for all individuals by interactions between their genes and environment. Exactly how the environment changes gene expression and how this can lead to disease are being explored in a fruitful new approach to environmental health research, representative studies of which are reviewed here. We searched Web of Science and references of relevant publications to understand the diversity of gene regulatory mechanisms affected by environmental exposures with disease implications. Pharmaceuticals, pesticides, air pollutants, industrial chemicals, heavy metals, hormones, nutrition, and behavior can change gene expression through a broad array of gene regulatory mechanisms. Furthermore, chemically induced changes in gene regulation are associated with serious and complex human diseases, including cancer, diabetes and obesity, infertility, respiratory diseases, allergies, and neurodegenerative disorders such as Parkinson and Alzheimer diseases. The reviewed studies indicate that genetic predisposition for disease is best predicted in the context of environmental exposures. And the genetic mechanisms investigated in these studies offer new avenues for risk assessment research. Finally, we are likely to witness dramatic improvements in human health, and reductions in medical costs, if environmental pollution is decreased.


Vitamin D and athletes.
While it is well recognized that vitamin D is necessary for optimal bone health, emerging evidence is finding that adequate vitamin D intake reduces risk for conditions such as stress fracture, total body inflammation, infectious illness, and impaired muscle function. Studies in athletes have found that vitamin D status is variable and is dependent on outdoor training time (during peak sunlight), skin color, and geographic location. Although research has found that athletes generally do not meet the U.S. dietary reference intake for vitamin D, inadequate endogenous synthesis is the most probable reason for insufficient/deficient status. Given the recent findings, it is imperative that sports dietitians and physicians routinely assess vitamin D status and make recommendations to help athletes achieve a serum 25(OH)D concentration of >or=32 and preferably >or=40 ng.mL(-1). Further research is needed to determine the effect of vitamin D status on injury, training, and performance in athletes.


Novel information on the genetic factors involved in the development of diseases.
Nowadays full-genome sequencing allows achieving revolutionary progress in the modern medicine. As the result of a huge work on the study of the human genome and based on the results obtained, one can conclude that the single nucleotide polymorphisms are the reasons of the vast majority of non-communicable diseases as well as the diseases other than injuries and poisoning, i.e. the diseases where the cause is not obvious. To clarify the role of single nucleotide polymorphism in the occurrence of atrophic gastritis, it is required to perform full-genome sequencing and human genome scanning with a simultaneous mass serological screening of atrophic gastritis. As a result, it will be possible to establish which single nucleotide polymorphism is responsible for mild, moderate, and severe mucosal atrophy in the antrum and the body of the stomach. Serological screening of mild, moderate, and severe mucosal atrophy in the antrum and the body of the stomach can be made using GastroPanel.


[Studies of local treatment of psoriasis with a bifonazole-urea combination].
In a biometrically controlled study on psoriatic patients, we investigated the efficacy and tolerability of bifonazole 1% plus urea 20% cream. In each of our ten patients, two lesions were treated over a period of 29 to 40 days (34 days on the average). Therapeutic results were not satisfying with lesions on extremities in comparison to those on head and body. On head and trunk, the size of the lesions amounted to 11.8 and 10.3 cm2, resp., before treatment, 2.8 and 4.3 cm2, resp., after therapy. On the extremities, we only noticed a reduction in size from 15.8 cm2 before to 13.8 cm2 after treatment. In total, the therapy was considered successful in 14 of the 20 lesions. Especially those four patients who predominantly showed lesions of the sebopsoriatic type were well-improved. Thus this therapy is particularly recommended in case of sebopsoriasis.


The Experiences of Gay and Bisexual Men Post-Prostate Cancer Treatment: A Meta-Synthesis of Qualitative Studies.
Studies suggest that gay and bisexual men are affected by the psychological aspects of prostate cancer treatment differently than that of heterosexual men; however the data have not yet been synthesized. The focus of this meta-synthesis is to explore gay and bisexual men's experiences of prostate cancer posttreatment. Empirical research published in peer reviewed journals between January 1990 and January 2018 were identified in six databases: CINAHL, Cochrane, Medline, PsycINFO, PubMed, and Web of Science. Titles and abstracts were checked by two reviewers. The six studies that met the inclusion criteria were selected and reviewed for quality and the extracted data were then synthesized. The main themes that emerged were sexual impact, physical and psychological difficulties, challenges to intimacy, and support mechanisms. Gay and bisexual men can have specific sexual roles and developing prostate cancer and undergoing treatment may compromise their ability to perform their sexual role. The needs of heterosexual men were perceived to be accommodated more often than that of gay and bisexual men because of engrained heteronormativity in the health-care system. The review suggests that more support groups specifically for gay and bisexual men should be established, while urologists should cater to the sexual and masculine implications of treatment, and not frame problems for gay and bisexual men in heterosexual terms. By failing to address the salient needs and concerns of gay and bisexual men, health-care professionals are reinforcing invisibility and marginalization of gay and bisexual men with prostate cancer.


Echocardiographic features of idiopathic hemochromatosis.
To characterize cardiac involvement in idiopathic hemochromatosis, clinical records and 2-dimensional (2-D) echocardiograms of 24 patients with idiopathic hemochromatosis were reviewed. The 17 men and 7 women were 24 to 80 years old (mean 48). Of 19 patients without valvular, ischemic, hypertensive or other known heart disease, 7 (37%) had structural and functional echocardiographic abnormalities attributed to idiopathic hemochromatosis (group 1) and 12 had normal echocardiographic findings (group 2). Age, gender and laboratory markers of iron overload did not differentiate patients with cardiac dysfunction (group 1) from those without cardiac dysfunction (group 2). In group 1, echocardiographic abnormalities included chamber dilatation and global systolic dysfunction. Increased wall thickness was not a feature of idiopathic hemochromatosis. All group 1 patients had abnormal electrocardiographic findings and cardiomegaly on radiography. Despite therapeutic phlebotomy, 4 patients in this group died, between 0.5 and 30 months after echocardiography, because of congestive heart failure. In conclusion, there is a spectrum of cardiac dysfunction in idiopathic hemochromatosis. In patients with idiopathic hemochromatosis and left ventricular dysfunction, absolute wall thickness is normal. Survival is poor in patients with idiopathic hemochromatosis and severe left ventricular dysfunction.


Divergent effects of interleukin-4 (IL-4) on the granulocyte colony-stimulating factor and IL-3-supported myeloid colony formation from normal and leukemic bone marrow cells.
Human recombinant interleukin-4 (IL-4) was studied for its effects on myeloid progenitor cells from normal and leukemic bone marrow cells in the presence and absence of additional growth factors. IL-4 itself did not support myeloid cluster or colony formation (CFU-GM). However, cultures supplied with IL-4 (300 U/mL) and IL-3 demonstrated a significant decline in myeloid colony numbers (CFU-GM) compared with the effects of IL-3 alone: (48 +/- 27 v 88 +/- 27 CFU-GM/10(5) MNC). In contrast, IL-4 augmented the G-CSF-supported CFU-GM: (80 +/- 31 v 148 +/- 52 CFU-GM/10(5) MNC). The effects of IL-4 were not mediated by accessory cells because similar results were obtained with and without T-cell, B-cell, or adherent depleted cell fractions. Morphologic analysis of clusters (day 7) and the colonies (day 14) demonstrated that IL-4 enhanced myeloid colony formation in the presence of G-CSF, whereas the cultures supplied with IL-3 and IL-4 did not show a lineage-restricted decline of CFU-GM. A heterogeneity in growth response was observed in the leukemic counterpart. With the 3H-thymidine proliferation assay, IL-4 augmented the G-CSF-induced proliferation of acute myeloid leukemic (AML) cells in 4 of the 12 cases, while the IL-3-supported proliferation was antagonized in 3 of the 12 cases. In the blast colony assay, IL-4 suppressed the IL-3-supported AML-CFU in the majority of cases, but enhanced the G-CSF stimulated AML-CFU in 3 of 6 cases. These data demonstrate divergent effects of IL-4 on the normal myeloid progenitor cell in the presence of IL-3 or G-CSF, while a variability in responsiveness is observed in the leukemic counterpart.


The total numbers of cerebellar granule neurons in young and aged Fischer 344 and Wistar-Kyoto rats do not change as a result of lengthy ethanol treatment.
It is generally accepted that long term chronic ethanol consumption by young rats will lead to significant losses of cerebellar granule neurons (GN). A recent study in this laboratory showed, however, that 40 weeks of chronic ethanol consumption had no effect on the total numbers of GN in aged Fischer 344 rats (F344). The goals of the present study were to determine whether F344 GN were resistant to ethanol toxicity only in aged rats and whether resistance of GN in aged rats to ethanol toxicity occurred only in the F344 strain. To accomplish those goals, young and aged adult F344 and Wistar-Kyoto (WKY) rats were treated chronically with ethanol for 40 weeks during the first or second half of their life span. In each rat the total numbers of GN were estimated with the optical fractionator and the volumes of the GN layer were estimated according to Cavalieri's theorem. After the 40 weeks of ethanol, there were significant age-related differences in the total numbers of GN in the F344 rats. There were also significant strain-related differences in the total numbers of GN and volumes of the GN layer. There were no significant ethanol-related differences, however, in numbers of cerebellar GN or volumes of the GN layer in F344 rats or WKY rats. The results presented here show that consumption of ethanol over long periods of time had no effect on the total numbers of cerebellar GN or the granular layer volumes in young or aged F344 or WKY rats.


Counteraction of urea-induced protein denaturation by trimethylamine N-oxide: a chemical chaperone at atomic resolution.
Proteins are very sensitive to their solvent environments. Urea is a common chemical denaturant of proteins, yet some animals contain high concentrations of urea. These animals have evolved an interesting mechanism to counteract the effects of urea by using trimethylamine N-oxide (TMAO). The molecular basis for the ability of TMAO to act as a chemical chaperone remains unknown. Here, we describe molecular dynamics simulations of a small globular protein, chymotrypsin inhibitor 2, in 8 M urea and 4 M TMAO/8 M urea solutions, in addition to other control simulations, to investigate this effect at the atomic level. In 8 M urea, the protein unfolds, and urea acts in both a direct and indirect manner to achieve this effect. In contrast, introduction of 4 M TMAO counteracts the effect of urea and the protein remains well structured. TMAO makes few direct interactions with the protein. Instead, it prevents unfolding of the protein by structuring the solvent. In particular, TMAO orders the solvent and discourages it from competing with intraprotein H bonds and breaking up the hydrophobic core of the protein.


[Ultrastructural organization of the surface epithelium of gastric mucosa in vitamin A deficiency].
Under conditions of experimental A-avitaminosis in cells of superficial epithelium of the chicken stomach mucous membrane certain ultrastructural changes of cytoplasmic membranes takes place. Amount of transport vesicles decreases, regeneration of membranes in the Golgi complex cisterns, secretory vesicles and apical part of the external cellular membrane with development of apical erosions is disturbed. The problem on influence of the changes mentioned to the process of mucus formation, in particular to protein glycosylation in the Golgi complex is discussed. Insufficient vitamin A amount, getting into the organism results in a decreased resistivity of the stomach mucous membrane as a consequence of disturbances in processes of mucus formation and in safety of the apical part of the external cellular membrane of the superficial epithelium.


Pharmacologic and radioligand binding analysis of the actions of 1,4-dihydropyridine activator-antagonist pairs in smooth muscle.
The actions of the enantiomers of Bay K 8644 and 202-791 were studied in rat tail artery and guinea pig ileal longitudinal smooth muscle using pharmacologic and radioligand binding assays. (-)-(S)-Bay K 8644 (below 10(-7) M in rat tail artery and 3 X 10(-7) M in guinea pig ileum) and (+)-(S)-202-791 (below 10(-6) M) induced contractions and potentiated the responses to KCl depolarization in both smooth muscle preparations. In contrast, (+)-(R)-Bay K 8644 and (-)-(R)-202-791 inhibited the responses to KCl-induced depolarization. At higher concentrations, (-)-(S)-Bay K 8644 (10(-7) to 10(-6) M) and (+)-(S)-202-791 (10(-6) to 3 X 10(-5) M) in rat tail artery, and (-)-(S)-Bay K 8644 (3 X 10(-7) to 3 X 10(-6) M) in guinea pig ileal smooth muscle relaxed the tissues contracted maximally at lower concentrations of the same drug. Cross antagonism between 1,4-dihydropyridine activators was observed when (-)-(S)-Bay K 8644 (10(-7) to 10(-6) M) relaxed the maximum contraction in response to (+)-(S)-202-791. [3H]Nitrendipine bound in a tail arterial microsomal preparation to a single class of site, with KD of 3.63 X 10(-10) M and maximum binding of 552.7 fmol mg-1 protein. In both rat tail artery and guinea pig ileal smooth muscle, (-)-(S)-Bay K 8644, (+)-(R)-Bay K 8644, (+)-(S)-202-791 and (-)-(R)-202-791 inhibited specific [3H]nitrendipine binding competitively; the Kl values correlate well to the pharmacologic EC50 (for activators) or IC50 (for antagonists, measured against 80 mM KCl depolarization) values. The biphasic response to (-)-(S)-Bay K 8644 and (+)-(S)-202-791 suggests that the properties of Ca++ channel activation and antagonism may reside within a single 1,4-dihydropyridine molecule.


Provision of prehospital emergency medical services in Punjab, Pakistan: Case study of a public sector provider.
The availability and quality of emergency medical services in low- and middle-income countries, including Pakistan, are extremely limited. New models for prehospital emergency medical services provision have recently emerged across multiple sectors, and research on these models is urgently needed to inform current and future emergency medical services systems in low-resource settings. The objective of this case study was to provide a comprehensive description of the organizational structure and service delivery model of a public sector provider in the Punjab Province of Pakistan, Rescue 1122, with a focus on operations in Lahore. We used case study methodology to systematically describe the organizational model of Rescue 1122. Qualitative data were collected during an in-person site visit to Lahore in June 2013. Three sources were utilized-semi-structured in-depth interviews, document review, and nonparticipant observation. Data were analyzed according to the health system "building blocks" proposed by the World Health Organization. Rescue 1122 is based on a legal framework that provides public financing for EMS, resulting in financial stability for the service. The organization has also reportedly taken positive steps in engaging with communities, and in coordinating across EMS, fire and rescue. We noted benefits and challenges in scaling up the service to all districts in Punjab. Finally, some areas of improvement include supply chain management and expanded data utilization. Our case study highlights key components of the model, areas for strengthening, and opportunities for further research. Rescue 1122 provides an example of a government-financed and operated emergency medical system in a low-resource setting.