Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity.
Pathogenic variants in mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) increase risk for Lynch syndrome and related cancers. We quantified tumour characteristics to assess variant pathogenicity for germline MMR genes. Among 4740 patients with cancer with microsatellite instability (MSI) and immunohistochemical (IHC) results, we tested MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios which we used to compute a tumour characteristic likelihood ratio (TCLR) for each variant. Predictive performance of TCLR in combination with in silico predictors, and a multifactorial variant prediction (MVP) model that included allele frequency, co-occurrence, co-segregation, and clinical and family history information was assessed. Compared with non-carriers, carriers of germline pathogenic/likely pathogenic (P/LP) variants were more likely to have abnormal MSI/IHC status (p<0.0001). Among 150 classified missense variants, 73.3% were accurately predicted with TCLR alone. Models leveraging in silico scores as prior probabilities accurately classified >76.7% variants. Adding TCLR as quantitative evidence in an MVP model (MVP +TCLR Pred) increased the proportion of accurately classified variants from 88.0% (MVP alone) to 98.0% and generated optimal performance statistics among all models tested. Importantly, MVP +TCLR Pred resulted in the high yield of predicted classifications for missense variants of unknown significance (VUS); among 193 VUS, 62.7% were predicted as P/PL or benign/likely benign (B/LB) when assessed according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Our study demonstrates that when used separately or in conjunction with other evidence, tumour characteristics provide evidence for germline MMR missense variant assessment, which may have important implications for genetic testing and clinical management.


The role of micro RNAs let7c, 100 and 218 expression and their target RAS, C-MYC, BUB1, RB, SMARCA5, LAMB3 and Ki-67 in prostate cancer.
The aim of this study is to verify the expression of proteins that are controlled by miR-let7c, 100 and 218 using immunohistochemistry in tissue microarray representative of localized and metastasized the lymph nodes and bone prostate cancer. To verify the expression of proteins that are controlled by miR-let7c (C-MYC, BUB1, RAS) 100 (SMARCA5, RB) and 218 (LAMB3) and cell proliferation (Ki-67) we used immunohistochemistry and computerized image system ImageJ MacBiophotonics in three tissue microarrays representative of localized prostate cancer and lymph node and bone metastases. miRNA expression was evaluated by qRT-PCR using 60 paraffin blocks to construct the tissue microarray representative of localized disease. RAS expression was increased in localized prostate cancer and bone metastases compared to the lymph nodes (p=0.017). RB showed an increase in expression from localized prostate cancer to lymph node and bone metastasis (p=0.036). LAMB3 was highly expressed in localized and lymph node metastases (p<0.001). Cell proliferation evaluated by Ki-67 showed an increase from localized prostate cancer to metastases (p<0.001). We did not found any relationship between C-MYC (p=0.253), BUB1 (p=0.649) and SMARCA5 (p=0.315) protein expression with prognosis or tumor behavior. We found that the expression of RAS, RB, LAMB3 and Ki-67 changed in the different stages of prostate cancer. Furthermore, we confirmed the overexpression of the miRNAs let7c, 100 and 218 in localized prostate cancer but failed to show the control of protein expression by the putative controller miRNAs using immunohistochemistry.


[Immature cutaneous hemangiomas. Epidemiologic study of 351 cases].
The purpose of this study was to determine the course of cutaneous immature angiomas in a population of 362 children examined in a pediatric dermatology unit from 1975 to 1982. 461 angiomas were observed in these patients: 110 were of the naevus flammaeus type (port wine stain) including 23 forehead salmon patches. 351 were immature angiomas (IA)--strawberry angiomas. 3.5 p. 100 of children were afflicted of two types of hemangiomas. Results concerning the 282 patients with 351 IA are detailed as followed: average follow-up: 2 years; sex-ratio M/S 1.9, most of them Caucasians. Prematurity (data obtained prospectively during 1982): 19 p. 100; clinical features: dermal: 253, subcutaneous: 35, mixed pattern 63; 2 IA or more were detected in 12 p. 100 of the patients; site: head and neck; 49 p. 100, trunk: 21 p. 100, upper limbs: 14.5 lower limbs: 12 p. 100, genitals 3.5 p. 100; maximal size during follow-up: less than 1 cm: 36 p. 100, between 1 and 3 cm: 43 p. 100, more than 3 cm; 21 p. 100; time of onset: 51 p. 100 were noted at birth, 35 p. 100 during the first month, 13 p. 100 after the first month. Course of untreated IA is shown in figure 1. At the end of follow-up, spontaneous evolution in 52 patients was judged; very good in 44 p. 100, good in 41 p. 100, poor or bad in 15 p. 100. Minor complications (ulceration, infection, bleeding) were observed in 12.8 p. 100. Functional impairment requiring therapy was present in 2/4 plantar IA, 3/30 eyelid IA, 3/3 IA with laryngeal involvement.(ABSTRACT TRUNCATED AT 250 WORDS)


[Experiment with a physiologically active culture of Chlorella on "Soiuz-9" spacecraft].
A physiologically-active culture of chlorella was for the first time exhibited on board the "Soyuz-9" spacecraft. The use of a special four-socket container made it possible to investigate in one experiment the effect of the factors of a space flight on the cells of algae developing in illumination during 1, 6 and 14 days. Besides that the effect of the flight conditions was studied on the culture of chlorells. Insignificant change in sensitivity of the cells to the effect of the flight factors depending upon the duration of their exposure in the active condition is shown.


Genetic diversity and divergence among native and translocated populations of the golden flathead goby Glossogobius aureus (Gobiiformes: Gobiidae) in Philippine lakes.
The golden flathead goby Glossogobius aureus is a native species in the Philippines, Australia, Japan, Taiwan, and many other countries in Asia. In the Philippines, it is an important food fish as it is commonly caught in major lakes. In this study, a total of 307 specimens morphologically identified as G. aureus were sampled from nine major lakes in the Philippines and were sequenced for their mitochondrial cytochrome b (cyt b) gene. Two hundred sixty of the 307 cyt b sequences had sequence similarities of ≥ 99% with G. aureus reference sequence in GenBank, while the remaining 47 (all from Lake Lanao) had sequence similarities of only 95% and were thus designated as Glossogobius cf. aureus and treated as a separate population. The sequences were then analyzed to examine the pattern of genetic diversity, relatedness, divergence, and demographic history among native and translocated populations of the species. Twenty-nine haplotypes were recovered, of which four haplotypes were shared among three to seven populations. Only one haplotype each was found in the native population in Lake Buhi and translocated population in Lake Paoay. Low haplotype and low nucleotide diversities were found for the populations in Laguna de Bay, Lanao, Bato, Buhi, Paoay, and Sebu lakes, which indicate founder event for the introduced populations in Lanao, Paoay, and Sebu lakes and recent genetic bottleneck for the native populations in Laguna de Bay, Bato, and Buhi. In contrast, high haplotype but low nucleotide diversities were found for the native populations of Taal, Naujan, and Buluan lakes, signifying a recent bottleneck followed by population expansion. Pairwise FST values showed generally large (FST = 0.168-0.249) to very large (FST = 0.302-1.000) genetic divergence between populations except between Laguna de Bay and Lake Bato, Laguna de Bay and Lake Buhi, and Lake Bato and Lake Buhi populations, which showed nonsignificant genetic differentiation. Lake Buluan and Lake Sebu populations showed moderate genetic differentiation (FST = 0.098). Neutrality tests showed significant negative Tajima's D and Fu's FS values only for the population from Laguna de Bay, which suggests that the population is undergoing expansion. These results are important for establishing scientifically sound strategies for effective conservation and sustainable exploitation of G. aureus in the Philippines.


Phase II study of vincristine, bleomycin, mitomycin C and cisplatin (VBMP) in disseminated squamous cell carcinoma of the uterine cervix.
The objective of this study was to study the antitumor activity of the vincristine, bleomycin, mitomycin C and cisplatin (VBMP) scheme in patients with disseminated squamous cell carcinoma of the uterine cervix and to document its toxicity. VBMP consisted of vincristine 1.4 mg/m2 (max. 2 mg) i.v. day 1, bleomycin 15 mg/day by continuous i.v. infusion on day 1 + 2, mitomycin C 6 mg/m2 i.v. day 3 and cisplatin 50 mg/m2 i.v. day 4, and was given every 4 weeks. Bleomycin was withdrawn from the schedule after a cumulative dose of 300 mg (210 mg in patients over 60). Thereafter VMP continued (V + M day 1, P day 2) with the same interval. A median number of 4.5 (range 2-13) treatment cycles was given to 50 fully evaluable patients, 26 with only distant metastases (group A) and 24 with pelvic disease also (23 previously irradiated) (group B). All patients were < 70 years old, had a Karnofsky index >/=60, and measurable metastatic lesions outside previously irradiated areas. They all had normal organ functions and gave informed consent. Response in group A was 54% (31% complete), in group B 25% (all partial), 40% in all. Median time to progression in group A was 20 weeks and in group B 15 weeks; median survival was 42 weeks in group A, 32 weeks in group B, 37 weeks for all patients. Hematologic toxicity was cumulative and the majority of patients needed blood transfusions. Nonhematologic toxicity was acceptable, but in one patient pulmonary toxicity might have contributed to death. Although it is active, it is unclear whether this regimen is superior to cisplatin alone.


Maternal urinary phthalate metabolites in relation to gestational diabetes and glucose intolerance during pregnancy.
Phthalates are common plasticizer chemicals that have been linked to glucose intolerance in the general population, but there is only limited research on their association with gestational diabetes (GDM). We evaluated the association between 11 urinary phthalate metabolites and GDM, impaired glucose tolerance (IGT), and continuous blood glucose concentration during pregnancy in The Infant Development and Environment Study (TIDES). Based on prior study results, our primary analyses focused on monoethyl phthalate (MEP) in relation to our outcomes of interest. We used multi-variable logistic regression to examine the odds of GDM and IGT in relation to an interquartile-range (IQR) increase in natural log (ln)-transformed, specific gravity (SG)-adjusted first trimester (T1) and average of T1 and third trimester (T3) ("T1T3avg") phthalate metabolite concentrations. We fit linear regression models to examine the percent change in blood glucose per IQR increase in ln-transformed, SG-adjusted T1 and T1T3avg phthalates. In sensitivity analyses, we examined interactions between exposure and race. We adjusted for maternal age, maternal body mass index, study center, race/ethnicity, parity, and gestational age at glucose testing. In our sample of 705 pregnant women, we observed 60 cases of GDM, 90 cases of IGT, and an average GLT blood glucose of 113.6 ± 27.7 mg/dL. In our primary analysis, T1T3avg MEP was positively associated with GDM ([OR (95% CI) per IQR increase] T1T3avg MEP: 1.61 (1.10, 2.36)). In secondary analyses, most other phthalates were not found to be related to study outcomes, though some associations were noted. Sensitivity analyses indicated possible strong race-specific associations in Asians, though these results are based on a small sample size (n = 35). In alignment with our a priori selection, we documented an association between T1T3avg MEP and GDM. Additional phthalate metabolites were also found to be linked to glucose intolerance, with possible stronger associations in certain racial/ethnic subgroups. Given the prevalence of phthalate exposures and the growing evidence of associations with metabolic outcomes, future studies should continue to examine this question in diverse cohorts of pregnant women, particularly in those who may be at higher risk for GDM and IGT.


An active carbon-nanotube polarizer-embedded electrode and liquid-crystal alignment.
We report a method for constructing an active optical polarizer using an aligned carbon nanotube (CNT) sheet that is flexible, bendable, transparent, conductive, and also serves to anchor liquid-crystal (LC) molecules. A horizontally aligned CNT sheet was obtained by mechanical stretching from a vertically grown CNT forest, which was then transferred onto a substrate. A liquid polymer was infiltrated into the CNT sheet followed by UV curing, while a part of the CNT sheet was still exposed on the film surface without polymer coating. The polymer-embedded CNT sheet (P-ECS) film with 10 layers of CNT sheets exhibited a good polarization efficiency of 87%, a sheet resistance of 340 Ω□-1, and excellent ability to align LC molecules. The high stability of the P-ECS film was confirmed from the very low variation of sheet resistance (2%) and transmittance (10%) observed during a bending test of 1000 cycles. In addition, a twisted nematic LC device constructed using the P-ECS films shows a good bright-dark switching performance. The P-ECS film functions simultaneously as a transparent electrode, a film-type polarizer, and a LC alignment layer, demonstrating the multi-functionality of the active CNT film. This study thus highlights a wide range of possible applications for active polarizers and flexible displays.


Salvage treatment in recurrent endometrial cancer of the pelvis and peritoneal cavity.
Regional recurrence of endometrial cancer is a challenging yet potentially curable group of patients without defined standard of care. Our aim is to determine optimal methods of salvage therapy for regionally recurrent endometrial cancer. Twenty-two cases of nodal, pelvic, or peritoneal cavity recurrences of endometrial cancer were identified from a single institution database. Univariable Cox proportional hazards models were used to estimate the risk of a second recurrence or death. Kaplan-Meier plots were used to estimate the probability of progression free survival and overall survival among patients in three cohorts: Multimodality therapy (surgery, chemotherapy, and external beam radiotherapy [EBRT] +/- vaginal brachytherapy), non-surgery (chemotherapy or EBRT, or both), and surgery cohort (surgery +/- chemotherapy OR EBRT). Thirteen recurrences (59%) were regional including the pelvic and paraaortic nodes, while nine recurrences (41%) were abdominal. For the entire cohort, the probability of progression free survival at 2 years was 51% (95% CI, 26% - 72%). The 2-year probability of progression free survival was 62% in the multimodality cohort, 40% in the non-surgery cohort, and 38% in the surgery cohort. The 2-year probability of overall survival was 69% (95% CI, 38% - 86%) across our population. At 40 months of follow up, the only living patients belonged to the multimodality cohort. We found no significant association of a definitive salvage regimen for recurrent endometrial cancer of the pelvis and peritoneal cavity. Aggressive use of multimodality therapy with surgery followed by tumor-directed radiotherapy and chemotherapy offers potentially curative therapy for these patients.


Size distribution and total number concentration of ultrafine and accumulation mode particles and hospital admissions in children and the elderly in Copenhagen, Denmark.
To study the association between short-term exposure to ultrafine particles and morbidity in Copenhagen, Denmark. We studied the association between urban background levels of the total number concentration of particles (NC(tot), 6-700 nm in diameter) measured at a single site (15 May 2001 to 31 December 2004) and hospital admissions due to cardiovascular (CVD) and respiratory disease (RD) in the elderly (age >or=65 years), and due to asthma in children (age 5-18 years). We examined these associations in the presence of PM(10), PM(2.5) (particulate matter <10 and 2.5 microm in diameter, respectively) and ambient gasses. We utilised data on size distribution to calculate NC(tot) for four modes with median diameters 12, 23, 57 and 212 nm, and NC(100) (number concentration of particles <100 nm in diameter) and examined their associations with health outcomes. We used a time series Poisson generalised additive model adjusted for overdispersion, season, day of the week, public holidays, school holidays, influenza, pollen and meteorology, with up to 5 days' lagged exposure. The adverse health effects of particulate matter on CVD and RD hospital admissions in the elderly were mainly mediated by PM(10) and accumulation mode particles with lack of effects for NC(100). For paediatric asthma, accumulation mode particles, NC(100) and nitrogen oxides (mainly from traffic related sources) were relevant, whereas PM(10) appeared to have little effect. Our results suggest that particle volume/mass from long-range transported air pollution is relevant for CVD and RD admissions in the elderly, and possibly particle numbers from traffic sources for paediatric asthma.


Neuromechanical Differences Between Successful and Failed Sit-to-Stand Movements and Response to Rehabilitation Early After Stroke.
Recovery of the sit-to-stand (StS) movement early after stroke could be improved by targeting physical therapy at the underlying movement deficits in those people likely to respond. To compare the movement characteristics of successful and failed StS movements in people early after stroke and identify which characteristics change in people recovering their ability to perform this movement independently following rehabilitation. Muscle activity and kinematic (including center of mass, CoM) data were recorded from 91 participants (mean 35 days after stroke) performing the StS movement before (baseline), immediately after (outcome), and 3 months after (follow-up) rehabilitation. Three subgroups (never-able [n = 19], always-able [n = 51], and able-after-baseline [n = 21]) were compared at baseline with the able-after-baseline subgroup compared before and after rehabilitation. The subgroups differed at baseline for quadriceps onset time ( P = .009) and forward body position when quadriceps peaked ( P = .038). Following rehabilitation, the able-after-baseline subgroup increased their forward position ( P < .001), decreased the time difference between bilateral quadriceps peaks ( P < .001) and between quadriceps and hamstrings peaks on the nonhemiplegic side ( P = .007). An improved performance in the always-able subgroup was associated with a number of baseline factors, including forward positioning ( P = .002) and time difference between peak activity of bilateral quadriceps ( P = .001). This neuromechanical study of StS before and after rehabilitation in a sample of people early after stroke identified the importance of temporal coupling between forward trunk movement and quadriceps and hamstrings' activity. These findings advance the science of stroke rehabilitation by providing evidence-based therapy targets to promote recovery of the StS movement.


High level of urokinase-type plasminogen activator is a new prognostic marker in patients with gastric carcinoma.
Prognosis of gastric carcinoma is related to invasion and metastasis. Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membrane. The serine protease urokinase-type plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), appear to have a major function in these processes. Recent reports have demonstrated that expression of these proteolytic enzymes is elevated in breast and colon carcinoma and that it can be associated with invasiveness and poor prognosis. Therefore, the authors evaluated whether the expression and activation of uPA and PAI-1 might be of clinical value as a tumor/biologically defined risk factor in patients with gastric carcinoma. Enzyme-linked immunoadsorbent assays were used to test for uPA antigens and PAI-1 in tissue extracts of normal and cancerous tissue from 160 gastric carcinoma patients who were enrolled in the Yonsei Cancer Center Study Group. Both uPA and PAI-1 levels were significantly higher in cancerous tissues than in normal tissues (uPA: 9.4 +/- 8.7 vs. 5.3 +/- 3.1 ng/mg protein cytosol; PAI-1: 10.9 +/- 9.1 vs. 5.8 +/- 2.9 ng/mg protein cytosol), (P < 0.001, respectively). Both high uPA and PAI-1 levels were associated with differentiation of the tumor (P = 0.04 and P = 0.004, respectively), and a high PAI-1 level was associated with lymph node metastasis at an advanced stage (P = 0.003 and P = 0.04, respectively). There was a correlation between the levels of uPA and PAI-1 expression in cancerous tissues (correlation coefficient = 0.57). In univariate analysis, a high level of uPA or PAI-1 was associated with a short relapse free survival, but in multivariate analysis only a high level of uPA was an independent prognostic parameter for a short relapse free survival for gastric carcinoma patients. These data indicate that uPA is a new independent variable for the identification of high risk gastric carcinoma patients. Therefore, therapy targeting uPA can be applied as a new biologic treatment modality for these individuals.


Sagittal MR of multiple sclerosis in the spinal cord: fast versus conventional spin-echo imaging.
We compared conventional spin-echo (CSE) with fast spin-echo (FSE) dual-echo MR images to determine which of these sequences was better able to depict spinal cord abnormalities in patients with multiple sclerosis (MS). CSE and FSE dual-echo MR images were obtained in 37 patients with MS and in six healthy control subjects, all of whom were examined on a 1.0-T MR unit with a phased-array coil and cardiac triggering. Two blinded interpreters graded the MR studies, first separately and then by consensus. Images were scored for presence of artifacts, number of focal lesions, and presence of a diffuse increase in signal intensity. No abnormalities were seen in the volunteers. The CSE sequences were significantly less hindered by MR imaging artifacts than were the FSE sequences. Interobserver agreement was slightly higher for the CSE than the FSE sequences. After reaching a consensus, the observers found that both CSE and FSE techniques enabled detection of approximately the same number of focal lesions; however, in three patients, small single lesions seen on the CSE images were missed on the FSE images. Also, depiction of a diffuse increase in signal intensity was better on the CSE images. As a result, more patients had abnormal findings on the CSE sequences than on the FSE sequences (35 versus 31). Cardiac-triggered dual-echo FSE sequences are almost as good as CSE sequences for depicting spinal MS lesions. Therefore, in cases of established spinal MS, FSE techniques may be as effective as CSE techniques. Because sensitivity for subtle abnormalities is lower with FSE imaging, CSE remains the preferred technique for patients with suspected MS of the spinal cord.


Impaired Arterial Elastic Properties and Endothelial Glycocalyx in Patients with Embolic Stroke of Undetermined Source.
Cardioembolism is a postulated mechanism of embolic stroke of undetermined source (ESUS). We investigated endothelial glycocalyx, aortic elastic properties, oxidative stress, and their association with left atrial (LA) function in ESUS and healthy individuals. In 90 ESUS patients (age 50.4 ± 13.2) and 90 controls with similar risk factors, we measured: (1) perfused boundary region (PBR) of the sublingual arterial microvessels (range 5-25 µm), a marker inversely related with glycocalyx thickness, (2) pulse wave velocity (PWV), central systolic blood pressure (cSBP), and augmentation index (AIx), (3) LA volume and strain using speckle-tracking imaging, and (4) malondialdehyde (MDA) and protein carbonyls (PCs), as oxidative stress markers. Compared with controls, ESUS had higher PWV, PBR, MDA, and PC levels as well as higher LA volume and reduced reservoir LA strain (p < 0.05). PBR > 1.2 μm of microvessel ranging from 5 to 9 μm and PWV > 10.2 m/s were associated with ESUS on multivariable analysis (odds ratio: 2.374 and 5.429, p < 0.05, respectively) and increased the c-statistic of the initial model from 0.54 to 0.71. In ESUS, glycocalyx damage (increased PBR) was related with increased PWV (p < 0.01) which was linked with LA reservoir strain after controlling for age, sex, and risk factors (p = 0.03). Increased MDA and PC were related with glycocalyx damage, increased PWV (r = 0.67 and r = 0.52), AIx, cSBP, and aortic atheroma (p < 0.01). Arterial function and endothelial glycocalyx are severely impaired in ESUS and are linked to LA dysfunction suggesting their contribution to ESUS pathogenesis. URL-http://www.clinicaltrials.gov. Unique identifier: NCT03609437.


Delivery of ceramide phosphoethanolamine lipids to the cleavage furrow through the endocytic pathway is essential for male meiotic cytokinesis.
Cell division, wherein 1 cell divides into 2 daughter cells, is fundamental to all living organisms. Cytokinesis, the final step in cell division, begins with the formation of an actomyosin contractile ring, positioned midway between the segregated chromosomes. Constriction of the ring with concomitant membrane deposition in a specified spatiotemporal manner generates a cleavage furrow that physically separates the cytoplasm. Unique lipids with specific biophysical properties have been shown to localize to intercellular bridges (also called midbody) connecting the 2 dividing cells; however, their biological roles and delivery mechanisms remain largely unknown. In this study, we show that ceramide phosphoethanolamine (CPE), the structural analog of sphingomyelin, has unique acyl chain anchors in Drosophila spermatocytes and is essential for meiotic cytokinesis. The head group of CPE is also important for spermatogenesis. We find that aberrant central spindle and contractile ring behavior but not mislocalization of phosphatidylinositol phosphates (PIPs) at the plasma membrane is responsible for the male meiotic cytokinesis defect in CPE-deficient animals. Further, we demonstrate the enrichment of CPE in multivesicular bodies marked by Rab7, which in turn localize to cleavage furrow. Volume electron microscopy analysis using correlative light and focused ion beam scanning electron microscopy shows that CPE-enriched Rab7 positive endosomes are juxtaposed on contractile ring material. Correlative light and transmission electron microscopy reveal Rab7 positive endosomes as a multivesicular body-like organelle that releases its intraluminal vesicles in the vicinity of ingressing furrows. Genetic ablation of Rab7 or Rab35 or expression of dominant negative Rab11 results in significant meiotic cytokinesis defects. Further, we show that Rab11 function is required for localization of CPE positive endosomes to the cleavage furrow. Our results imply that endosomal delivery of CPE to ingressing membranes is crucial for meiotic cytokinesis.


[Patients' opinions about the reasons for their heart attacks in the context of their health belief models--a preliminary report].
The importance of psychological factors in Myocardial Infarction (MI) is well documented. The aim of the study was to define a relationship between the perception of the reasons for MI and real health activity of the sufferers, in order to prepare an adequate psychological intervention. 30 patients after acute MI hospitalized in the Cardiology Department were included to the study. They were questioned in directed interviews. The modified form of Shalit's Circle was used to infer the model of health activity. Perceived reasons for the heart attack (first in 67% cases) appeared as a manifold area, which was divided into eight categories: stressful situations and occurrences (66.67%), an individual's character (40%), lifestyle (36.67%), connected illnesses 36.67%), genetics (20%), age (13.33%), weather (10%), "spontaneous" heart attack (6.67%). The results indicated exterior attribution of MI (e.g. political and economic crisis, innate predisposition, loss of relatives). Similar tendency in the planning of changes after heart attack was observed. For instance 43.33% patients just said they planed to restrict or give up their previous sickness-promoting behaviour, 33.33% talked laconically about "the increase of caution" or "slowing down" and only 26.67% intended to undertake new forms of activity. These opinions illustrate the general model of health beliefs (in declarations and realization), which seems to be of very limited use (or even disadvantageous) with regard to the future. Moreover, the contemporary clinical conditions are conducive to such model. Modern medical methods of treatment reduce the time spent by patients in hospital, thereby reducing the hospitalization stress. On the other hand it limits or even eliminates the most important part of treatment--the "doctor-patient" relationship. Because of the limited number of subjects a further research is needed to combine the psychological intervention aimed at health behaviour change with the high standard of cardiology treatment those patients are being given now. The psychological program should tackle emotional and social costs of heart attack and strive to change patients' health belief system.


[An express-method for predicting fibrinous iridocyclitis in the early postoperative period in artiphakia].
The authors investigated the possibility of using the level of preoperative blood monocytosis as an express method for predicting fibrinous iridocyclitis in planned artiphakia. Extracapsular cataract extraction with intraocular correction (B. N. Alexeev's design) was carried out in 372 patients, 287 of these without non-insulin-dependent diabetes mellitus (NIDDM) (group 1) and 85 with NIDDM (group 2). The patients were divided into 3 subgroups depending on the absolute blood monocyte counts before operation: 1) up to 200 monocytes, 2) 200-400, and 3) more than 400. The incidence of fibrinous iridocyclitis was significantly higher (p < 0.01, 17-18-fold on average) in both subgroups 3 (more than 400 monocytes) in comparison with subgroups 1 (less than 200 monocytes), the treatment strategy being the same in all patients. In NIDDM group the total number of fibrinous iridocyclitis cases was 2 times higher in all 3 subgroups than in group 1. Hence, the level of preoperative blood monocytosis can be used as an express method for predicting fibrinous iridocyclitis in planned artiphakia choosing the treatment strategy during the immediate postoperative period, including that for patients with NIDDM.


Pros and cons of feeding the septic intensive care unit patient.
Sepsis is a common disease seen in critically ill patients. Many patients with sepsis are unable to provide nutrition for themselves, and therefore initiating artificial nutrition has become part of routine care for these patients. However, studies investigating the optimal route, composition, volume, and duration of nutrition in critically ill patients with sepsis are lacking. The best recommendations have to be extrapolated from studies in heterogeneous populations of critically ill patients or in those with syndromes such as acute lung injury or acute respiratory distress syndrome (ARDS) where sepsis is a common predisposing etiology. In this review, we summarize pertinent studies that inform clinical practice on providing artificial nutrition to critically ill patients with severe sepsis and make recommendations as to how these studies influence clinical care of these patients.


Piracetam in the management of spasticity in cerebral palsy.
This article is a preliminary report of a new indication for the drug piracetam (Nootropil; UCB). It was found that piracetam was useful for the control of spasticity in 8 out of 16 patients with cerebral palsy. Side-effects were minimal.


Therapy outcome related to adalimumab trough levels in pediatric patients with inflammatory bowel disease.
We evaluated the relationship between serum concentration and efficacy of adalimumab (ADA), an anti-tumor necrosis factor-alpha agent, in pediatric patients with inflammatory bowel disease (PIBD). This retrospective cross-sectional study traced 75 patients with PIBD (Crohn's disease, n = 57) treated with ADA at two tertiary centers in Finland in 2012-2018. Drug levels and drug antibody titers were chart-reviewed, and the treatment continuation rate of ADA therapy was evaluated. We also assessed the impact of trough levels in the first 3 months on the continuation of ADA within one year of therapy. ADA was introduced at a median age of 13.4 years, and the median disease duration was 2.7 years. During the first year, 22 patients (29%) discontinued ADA due to either loss of response (20%, n = 15) or anti-drug antibody formation (5.3%, n = 4). Regarding trough levels in the first 3 months, 9/16 patients (56%) with trough levels <5 mg/L and 12/20 (60%) with trough levels <7.5 mg/L at 3 months discontinued the therapy by the end of the first year. In comparison, only 8/32 patients (25%) with trough levels >7.5 mg/L at 3 months discontinued treatment during the first year (p = .005). At the last follow-up (median 1.5 years), 52% of the 75 patients were on maintenance therapy and had a median trough level of 8.8 mg/L. Higher trough levels in the first 3 months of adalimumab treatment are associated with lower rates of discontinuation due to loss of response during the first year.


Transcription, DNA damage and beyond: the roles of histone ubiquitination and deubiquitination.
Myriad covalent post-translational modifications of histones have been demonstrated to play crucial roles in regulating gene transcription, gene repression, DNA damage and repair, and beyond. It has been long known that these modifications are often dynamic, such as histone ubiquitination and deubiquitination, and the processes through adding and/or removing these modified marks catalyzed by various classes of enzymes commonly influence many important physiological functions. In recent few years, studies on histone ubiquitination re-garners much attention arising from lots of new exciting findings emerged. Several important histone ubiquitination sites have been mapped in different organisms. In addition, the identification and characterization of numerous ubiquitin modifying enzymes, especially ligases and deubiquitinases, have facilitated the progress in understanding the roles of histone ubiquitination/deubiquitination events. Of particular interest, histone ubiquitination interplays with many other chromatin modifications, namely "crosstalk", which contributes to a variety of cellular events. In this review, I summarize the enzymes and factors involved in regulating the attachment and removal of ubiquitin from histones, and focus on what essential roles this modification plays. I also present new evidence that links histone ubiquitination with other histone modifications, which comprises an intricate crosstalk network.


Overlapping community detection in networks based on link partitioning and partitioning around medoids.
In this paper, we present a new method for detecting overlapping communities in networks with a predefined number of clusters called LPAM (Link Partitioning Around Medoids). The overlapping communities in the graph are obtained by detecting the disjoint communities in the associated line graph employing link partitioning and partitioning around medoids which are done through the use of a distance function defined on the set of nodes. We consider both the commute distance and amplified commute distance as distance functions. The performance of the LPAM method is evaluated with computational experiments on real life instances, as well as synthetic network benchmarks. For small and medium-size networks, the exact solution was found, while for large networks we found solutions with a heuristic version of the LPAM method.


Why APIs? Anticipated value, barriers, and opportunities for standards-based application programming interfaces in healthcare: perspectives of US thought leaders.
Improving health data interoperability through application programming interfaces (APIs) is a focus of US policy initiatives and could have tremendous impact on many aspects of care delivery, such as innovation, operational efficiency, and patient-centered care. To better understand the landscape of API use cases, we interviewed US thought leaders involved in developing and implementing standard-based APIs. We conducted semi-structured virtual interviews with US subject matter experts (SMEs) on APIs. SMEs were asked to describe API use cases along with value and barriers for each use case. Written summaries were checked by the SME and analyzed by the study team to identify findings and themes. We interviewed 12 SMEs representing diverse sectors of the US healthcare system, including academia, industry, public health agencies, electronic health record vendors, government, and standards organizations. Use cases for standards-based APIs fell into six categories: patient-facing, clinician-facing, population health and value-based care, public health, administrative, and social services. The value across use cases was viewed as unrealized to date, and barriers to the use of APIs varied by use case. SMEs identified a diverse set of API use cases where standard-based APIs had the potential to generate value. As policy efforts seek to increase API adoption, our work provides an early look at the landscape of API use cases, value propositions, and barriers. Additional effort is needed to better understand the barriers and how to overcome them to create value, such as through demonstration projects and rigorous evaluations for specific use cases.


Sampling issues of cerebrospinal fluid and plasma monoamines: Investigation of the circadian rhythm and rostrocaudal concentration gradient.
Biomarkers for neurodegenerative dementias offer interesting prospects regarding diagnosis and disease monitoring. Monoamines such as dopamine, (nor)adrenaline, serotonin (5-hydroxytryptamine or 5-HT), and their respective metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA), were shown to be altered in dementia, including Alzheimer's disease (AD). Biomarker research is hampered by potential confounds including the influence of time of day and volume of cerebrospinal fluid (CSF) collected. Therefore, the possibility of a circadian rhythm in CSF and plasma, and the presence of a rostrocaudal concentration gradient (RCG) in CSF for aforementioned monoamines/metabolites, were investigated. Circadian rhythmicity was assessed using reversed-phase ultra-high performance liquid chromatography with electrochemical detection (RP-UHPLC-ECD) to measure monoamine/metabolite concentrations in 271 paired CSF and plasma samples, successively collected over a period of 30 h and derived from eight healthy subjects. Plasma samples were also analyzed for melatonin, serving as positive control analyte, using ELISA. The RCG examination entailed RP-UHPLC-ECD analyses on five consecutive CSF samples derived from 10 patients with AD and 10 non-AD/control subjects. Besides a diurnal rhythm for melatonin, we found a similar rhythmicity for plasma HVA, with acrophases occurring between 02:00 and 06:00 h, in four out of seven subjects. Three and two subjects showed a circadian rhythm for CSF HVA and 5-HIAA, respectively. No rhythmicity was observed in any other compound. We found that only CSF MHPG, HVA and 5-HIAA levels differed across CSF fractions, and that these changes in 5-HIAA levels varied in the AD versus non-AD/control group. Positive correlations between CSF volume and HVA and 5-HIAA levels, indicative of a RCG, were also observed. Such a RCG could not be detected for the other monoamines/metabolites. Our results stress the importance of standardizing sampling procedures of biological fluids with respect to time of day, volume and number of samples.


VIETHERB: A Database for Vietnamese Herbal Species.
Vietnam carries a highly diverse practice of traditional medicine in which various combinations of herbs have been widely used as remedies for many types of diseases. Poor hand-written records and current text-based databases, however, perplex the process of conventionalizing and evaluating canonical therapeutic effects. In efforts to reorganize the valuable information, we provide the VIETHERB database ( http://vietherb.com.vn/ ) for herbs documented in Vietnamese traditional medicines. This database is constructed with confidence to provide users with information on herbs and other side information including metabolites, diseases, morphologies, and geographical locations for each individual species. Our data in this release consist of 2,881 species, 10,887 metabolites, 458 geographical locations, and 8,046 therapeutic effects. The numbers of species-metabolite, species-therapeutic effect, species-morphology, and species-distribution binary relationships are 17,602, 2,718, 11,943, and 16,089, respectively. The information on Vietnamese herbal species can be easily accessed or queried using their scientific names. Searching for species sharing side information can be simply done by clicking on the data. The database primarily serves as an open source facilitating users in studies of modernizing traditional medicine, computer-aided drug design, conservation of endangered plants, and other relevant experimental sciences.


Medical specialist examinations: item format types and minimising error.
Examinations such as those within anaesthesia and intensive care are used to identify candidates who are able to progress through their training programs or onto specialist practice. Examinations that are valid, reliable, fair, practical and generalisable are useful tools for determining the underlying anaesthesia and intensive care related abilities of candidates. However, medical specialty examinations are only indirect indicators of candidate competency or mastery. It is possible for error to enter examination decision making and to adversely affect examination processes and results. This article presents an effective method for viewing examination content, procedures and processes for the purposes of minimising error. The article also describes the six question (or item) formats currently utilised within the examinations used by the Australian and New Zealand College of Anaesthetists and/or the Joint Faculty of Intensive Care Medicine. The article includes summaries of the advantages and disadvantages of each of these formats.


Survival following lung transplantation for silicosis and other occupational lung diseases.
Information is scant assessing outcomes in lung transplantation (LT) in advanced occupational lung diseases (OLD). To analyse survival after LT for OLD. Using data from the US Organ Procurement and Transplantation Network Registry (OPTN-R), we identified subjects aged ≥ 18 years transplanted for OLD from 2005 to 2010. OPTN-R selected referents of corresponding age, sex and body mass index (BMI) who underwent LT for other diagnoses were also identified. Post-LT survival time was estimated with Cox proportional hazard models. Baseline age, BMI, forced expiratory volume in 1 s, creatinine, lung allocation score, donor age, donor lung ischaemic time and transplant type (single versus bilateral) were included as covariates. Time-dependent covariates were used to model differences in relative risk over time. Thirty-seven males underwent LT for silicosis (n = 19) or other OLD (n = 18) during the analytic period (0.5% of all LTs). For non-silicotic OLD, 6-month and 1- and 3-year survival estimates were 66, 55 and 55%, compared with the silicotic group (86, 86 and 76%) and referent group (89, 84 and 67%). During the first year post-transplant, those with OLD (silicosis and others combined) manifested an overall 2-fold increased mortality risk [hazard ratio (HR) 2.3, 95% CI 1.3-4.4; P < 0.05] compared to referents. In stratified analysis, this increased risk of death was restricted to those with non-silicotic OLD (HR 3.1, 95% CI 1.5-6.6; P < 0.01). Poorer survival was limited to the first year post-LT. Subjects undergoing LT for OLD other than silicosis may be at increased risk of death in the first year post-transplantation.


Promigratory activity of oxytocin on umbilical cord blood-derived mesenchymal stem cells.
Recent studies show that oxytocin has various effects on cellular behaviors. Oxytocin is reported to stimulate cardiomyogenesis of embryonic stem cells and endothelial cell proliferation. Mesenchymal stem cells (MSCs) are widely used for cardiac repair, and we elucidated the effect of oxytocin on umbilical cord derived-MSCs (UCB-MSCs). UCB-MSCs were pretreated with oxytocin (100 nM) and washed with saline prior to experiments. To evaluate their angiogenic potential and migration activity, tube formation assay and Boyden chamber assay were performed. For in vivo study, ischemia-reperfusion was induced in rats, and UCB-MSCs with or without oxytocin pretreatment were injected into the infarcted myocardium to evaluate the engraftment of injected cells. Histological and hemodynamic studies were performed. Oxytocin-treated UCB-MSCs showed a decrease in tube formation but a drastic increase in transwell migration activity. The transcription level of matrix metalloproteinase (MMP)-2 was increased in oxytocin-treated UCB-MSCs. Knock-down of MMP-2 by use of siRNA restored the tube formation, while reducing transmigration activity. In rats injected with oxytocin-treated UCB-MSCs, cardiac fibrosis and CD68 infiltration in the peri-infarct zone were reduced, whereas cell engraftment and connexin43 expression were greater than in rats injected with untreated UCB-MSCs. By contrast, angiogenesis did not differ significantly between the two groups. Cardiac contractility was higher in the group injected with oxytocin-treated UCB-MSCs than in the group injected with phosphate-buffered saline alone. Collectively, oxytocin is an effective priming reagent for stem cells for application to damaged heart tissue.


Investigating speech and language impairments in delirium: A preliminary case-control study.
Language impairment is recognized as as part of the delirium syndrome, yet there is little neuropsychological research on the nature of this dysfunction. Here we hypothesized that patients with delirium show impairments in language formation, coherence and comprehension. This was a case-control study in 45 hospitalized patients (aged 65-97 years) with delirium, dementia without delirium, or no cognitive impairment (N = 15 per group). DSM-5 criteria were used for delirium. Speech was elicited during (1) structured conversational questioning, and (2) the "Cookie Theft" picture description task. Language comprehension was assessed through standardized verbal and written commands. Interviews were audio-recorded and transcribed. Delirium and dementia groups scored lower on the conversational assessment than the control group (p<0.01, moderate effect sizes (r) of 0.48 and 0.51, resp.). In the Cookie Theft task, the average length of utterances (i.e. unit of speech), indicating language productivity and fluency, distinguished patients with delirium from those with dementia (p<0.01, r = 0.50) and no cognitive impairment (p<0.01, r = 0.55). Patients with delirium performed worse on written comprehension tests compared to cognitively unimpaired patients (p<0.01, r = 0.63), but not compared to the dementia group. Production of spontaneous speech, word quantity, speech content and verbal and written language comprehension are impaired in delirious patients compared to cognitively unimpaired patients. Additionally, patients with delirium produced significantly less fluent speech than those with dementia. These findings have implications for how speech and language are evaluated in delirium assessments, and also for communication with patients with delirium. A study limitation was that the delirium group included patients with co-morbid dementia, which precludes drawing conclusions about the specific language profile of delirium.


Specific Characteristics of Patients with Advanced Genitourinary Cancer Receiving Specialized Inpatient Palliative Care.
The aim of this study was to compare the characteristics for genitourinary cancer (GUC) patients receiving specialized inpatient palliative care (SIPC) with those of a general cohort. We retrospectively evaluated 151 GUC patients receiving SIPC from 2008 to 2014 regarding symptoms, problems, treatment, and outcome. These characteristics were compared with a general cohort of 1,285 patients with various diseases who received SIPC (German Hospice and Palliative care investigation: HOPE). Patients suffering from advanced prostate cancer (n = 59), renal cell cancer (n = 37), urothelial cancer (n = 36), urothelial accompanied by prostate cancer (n = 11), germ cell cancer (n = 7), and penile squamous cell cancer (n = 1) were included in the study. Most frequent symptoms and problems at admission were weakness (93%), the need for assistance with activities of daily living (85%), loss of appetite (81%), and organization of care (80%). Symptoms were more frequent in the GUC than in the general cohort during treatment, in particular with regards to pain (p < 0.001), tension (p < 0.001), nausea (p = 0.001), and vomiting (p < 0.001). GUC patients received significantly more opioids with 89% compared to the general cohort with 72% (p < 0.001). Symptom burden of GUC patients, in particular pain, tension, and nausea was higher compared to the general cohort, and analgesic treatment played an important role in achieving control of symptoms.


Quasars, blazars, and gamma rays.
Before the launch of the Compton Gamma Ray Observatory (CGRO), the only source of >100-megaelectron volt (MeV) gamma radiation known outside our galaxy was the quasar 3C 273. After less than a year of observing, 13 other extragalactic sources have been discovered with the Energetic Gamma Ray Experiment Telescope (EGRET) on CGRO, and it is expected that many more will be found before the full sky survey is complete. All 14 sources show evidence of blazar properties at other wavelengths; these properties include high optical polarization, extreme optical variability, flat-spectrum radio emission associated with a compact core, and apparent superluminal motion. Such properties are thought to be produced by those few, rare extragalactic radio galaxies and quasars that are favorably aligned to permit us to look almost directly down a relativistically outflowing jet of matter expelled from a supermassive black hole. Although the origin of the gamma rays from radio jets is a subject of much controversy, the gamma-ray window probed by CGRO is providing a wealth of knowledge about the central engines of active galactic nuclei and the most energetic processes occurring in nature.


Physiological Changes as a Measure of Crustacean Welfare under Different Standardized Stunning Techniques: Cooling and Electroshock.
Stunning of edible crustaceans to reduce sensory perception prior and during slaughter is an important topic in animal welfare. The purpose of this project was to determine how neural circuits were affected during stunning by examining the physiological function of neural circuits. The central nervous system circuit to a cardiac or skeletal muscle response was examined. Three commercially important crustacean species were utilized for stunning by immersion in an ice slurry below 4 °C and by electrocution; both practices are used in the seafood industry. The blue crab (Callinectes sapidus), the red swamp crayfish (Procambarus clarkii), and the whiteleg shrimp (Litopenaeus vannamei) responded differently to stunning by cold and electric shock. Immersion in ice slurry induced sedation within seconds in crayfish and shrimp but not crabs and cardiac function was reduced fastest in shrimp. However, crabs could retain a functional neural circuit over the same time when shrimp and crayfish were nonresponsive. An electroshock of 10 s paralyzed all three species and subsequently decreased heart rate within 1 min and then heart rate increased but resulted in irregularity over time. Further research is needed to study a state of responsiveness by these methods.


Quantifying the clinical and economic burden of desquamating dermatological conditions: Implications for a supraregional burns centre.
This study aimed to identify the spectrum of desquamating skin diseases referred for tertiary burns care and quantify the care requirements and expenses associated with caring for these patients within the burns service. Patient records were identified with nonburn-induced skin loss between 2016 and 2022. Data was extracted from inpatient records, operative notes, and dressing clinic records. A cost analysis was conducted using figures from the National Schedule of National Health Service Costs and our own unit-specific costs. Twenty patients were identified, with a median age of 46.5 and a median total body surface area of 30%. The mean length of stay was 21.2 days, with 8/20 patients requiring intensive care. Overall mortality was 30%, rising to 50% if patients required intensive treatment unit (ITU) admission. Patients had a mean of 1.5 procedures under general anaesthesia and a mean operative time of 169 min per patient. Postoperatively, a mean of 8.3 dressing changes was required per patient (range 1-21). Of 75% of patients referred as suspected toxic epidermal necrolysis syndrome (TENS), only 32% of patients histologically had TENS (32%), with linear IgA disease, pemphigus vulgaris and bullous lupus comprising the other diagnoses. Cost analysis predicted a total cost to the unit of £1,422,106. Desquamating dermatological diseases are life-threatening conditions with exhaustive care requirements. Our experiences highlight the importance of awareness of the range of desquamating skin conditions beyond TENS to enable optimum management and the need to ensure adequate financial provisions to accommodate the care requirements mandated by these patients.


Extrahepatic manifestations and healthcare expenditures of non-alcoholic fatty liver disease in the Medicare population.
Non-alcoholic fatty liver disease (NAFLD) is a very common liver disease which has been associated with a number of the extrahepatic manifestations (EHMs) and healthcare expenditures. Our aim was to assess the presence and impact of these EHMs of NAFLD on mortality and healthcare expenditures. Medicare beneficiaries (2005-2016) were included. ICD-9 and ICD-10 codes were used to identify patients with NAFLD and EHMs which included cardiovascular disease (CVD), hypertension (HTN), diabetes (DM), hyperlipidemia (HL), non-hepatocellular carcinoma (HCC) cancers, and others. Temporal trends among different groups were analyzed by join point regression model. Independent predictors of outcomes were evaluated in multiple generalized linear or logistic regression models. Among 30,908,679 Medicare beneficiaries (5% sample of Medicare data from 2005-2016), 1,980,950 (6.4%) had NAFLD diagnosis. From 2005 to 2016, the prevalence of NAFLD in the Medicare population increased at an average annual increase of 3.1%. The most common diseases associated with NAFLD were DM (86.3%), followed by HTN (85.2%), HL (79.8%), and CVD (35.8%). One-year mortality rate in NAFLD patients increased from 3.55 to 6.33 per 1000 from 2005 to 2016. One-year mortality was independently associated with diagnosis of HCC, cirrhosis, DM (outpatient), depression, dementia, lung disease, renal failure, thyroid disorder (inpatient), neurological disorder as well as non-HCC cancers. NAFLD is associated with a number of EHMs that increases its mortality and increased healthcare expenditure.


[Changes in autonomic homeostasis during anesthesia induction in patients operated on for congenital cleft palate].
Variation pulsometry was used to study vegetative homeostasis changes over the course of induction anesthesia and tracheal intubation in children operated on for palatal clefts. The same premedication scheme was employed in all the patients. The same neuroleptic doses were administered in induction anesthesia. Induction anesthesia parallel with electroanalgesia with an Electronarcol-1 apparatus helped reduce the promedol dose necessary for adequate anesthesiologic protection from 1.2-1.4. to 0.2-0.4 mg/kg. This was associated with the minimal changes in autonomic nervous system functioning, evidencing the efficacy of electroanalgesia in induction anesthesia for this patient population.


Tocilizumab challenge: A series of cytokine storm therapy experiences in hospitalized COVID-19 pneumonia patients.
To recognize the period of exaggerated cytokine response in patients with coronavirus disease 2019 (COVID-19) pneumonia, and to describe the clinical outcomes of using tocilizumab as a treatment option. The data of 12 adult COVID-19 pneumonia patients who were followed in the inpatient clinics of Biruni University Medical Faculty Hospital (Istanbul, Turkey) were retrospectively analyzed. Diagnostic tests, laboratory examinations, clinical findings, and computed tomography of the thorax imaging results were evaluated. A dramatic laboratory and clinical improvement was observed in 83% (10 out of 12) of patients after tocilizumab. In 17% (2 out of 12) of our patients, short-term ventilator support was required in the intensive care unit. The longest hospital stay was 18 days. However, in the end, all of our patients were discharged home with good health. Although arterial oxygen saturations (87.58 ± 3.12%) dropped in room air in the pre-tocilizumab period, post-tocilizumab they normalized in all patients (94.42 ± 1%). None of them had fever after tocilizumab treatment and the levels of C-reactive protein (13.08 ± 12.89) were almost within normal limits. Eosinophil values were quite low at the time of diagnosis (10 ± 17.06), but increased significantly post-tocilizumab (155.33 ± 192.69). There is currently no proven treatment for COVID-19 induced by novel coronavirus SARS-CoV-2. Based on our experience with twelve adult COVID-19 pneumonia patients, we can say that tocilizumab, an IL-6 inhibitor, is more beneficial in preventing the damage caused by excessive cytokine response in the body if administered at the right time and provides clinical and radiological recovery.


Towards realistic benchmarks for multiple alignments of non-coding sequences.
With the continued development of new computational tools for multiple sequence alignment, it is necessary today to develop benchmarks that aid the selection of the most effective tools. Simulation-based benchmarks have been proposed to meet this necessity, especially for non-coding sequences. However, it is not clear if such benchmarks truly represent real sequence data from any given group of species, in terms of the difficulty of alignment tasks. We find that the conventional simulation approach, which relies on empirically estimated values for various parameters such as substitution rate or insertion/deletion rates, is unable to generate synthetic sequences reflecting the broad genomic variation in conservation levels. We tackle this problem with a new method for simulating non-coding sequence evolution, by relying on genome-wide distributions of evolutionary parameters rather than their averages. We then generate synthetic data sets to mimic orthologous sequences from the Drosophila group of species, and show that these data sets truly represent the variability observed in genomic data in terms of the difficulty of the alignment task. This allows us to make significant progress towards estimating the alignment accuracy of current tools in an absolute sense, going beyond only a relative assessment of different tools. We evaluate six widely used multiple alignment tools in the context of Drosophila non-coding sequences, and find the accuracy to be significantly different from previously reported values. Interestingly, the performance of most tools degrades more rapidly when there are more insertions than deletions in the data set, suggesting an asymmetric handling of insertions and deletions, even though none of the evaluated tools explicitly distinguishes these two types of events. We also examine the accuracy of two existing tools for annotating insertions versus deletions, and find their performance to be close to optimal in Drosophila non-coding sequences if provided with the true alignments. We have developed a method to generate benchmarks for multiple alignments of Drosophila non-coding sequences, and shown it to be more realistic than traditional benchmarks. Apart from helping to select the most effective tools, these benchmarks will help practitioners of comparative genomics deal with the effects of alignment errors, by providing accurate estimates of the extent of these errors.


Monoubiquitylation of H2A.Z distinguishes its association with euchromatin or facultative heterochromatin.
H2A.Z is a histone H2A variant that is essential for viability in organisms such as Tetrahymena thermophila, Drosophila melanogaster, and mice. In Saccharomyces cerevisiae, loss of H2A.Z is tolerated, but proper regulation of gene expression is affected. Genetics and genome-wide localization studies show that yeast H2A.Z physically localizes to the promoters of genes and functions in part to protect active genes in euchromatin from being silenced by heterochromatin spreading. To date, the function of H2A.Z in mammalian cells is less clear, and evidence so far suggests that it has a role in chromatin compaction and heterochromatin silencing. In this study, we found that the bulk of H2A.Z is excluded from constitutive heterochromatin in differentiated human and mouse cells. Consistent with this observation, analyses of H2A.Z- or H2A-containing mononucleosomes show that the H3 associated with H2A.Z has lower levels of K9 methylation but higher levels of K4 methylation than those associated with H2A. We also found that a fraction of mammalian H2A.Z is monoubiquitylated and that, on the inactive X chromosomes of female cells, the majority of this histone variant is modified by ubiquitin. Finally, ubiquitylation of H2A.Z is mediated by the RING1b E3 ligase of the human polycomb complex, further supporting a silencing role of ubiquitylated H2A.Z. These new findings suggest that mammalian H2A.Z is associated with both euchromatin and facultative heterochromatin and that monoubiquitylation is a specific mark that distinguishes the H2A.Z associated with these different chromatin states.


Recurrence patterns after radical gastrectomy for gastric cancer: prognostic factors and implications for postoperative adjuvant therapy.
A recent Intergroup trial demonstrated a significant survival advantage of postgastrectomy chemoradiation in gastric cancer patients, primarily because of a reduction of a relative locoregional recurrence (LRR) rate exceeding 70% in control patients. Radical gastrectomy with extended lymphadenectomy may reduce LRR, possibly affecting adjuvant treatment strategies. Information on patients undergoing gastrectomy for potentially curable gastric cancer between 1990 and 2000 was reviewed. Patterns of first disease recurrence, survival, and disease-free survival were calculated, and predictors were identified. Gastrectomies were performed in 73 patients, with R0 resections in 82%. The median lymph node count was 24; positive nodes were found in 64% of patients. The median actuarial survival was 27 months, with a 5-year survival of 37%. Disease recurred in 35 patients (48%) after a median interval of 7 months (range,.5-67). Recurrent disease patterns included distant only (37%), peritoneal only (23%), peritoneal/locoregional (17%), all sites combined (14%), locoregional only (6%), and distant/locoregional (3%). Recurrence predictors were N3 category for distant recurrence (hazard ratio [HR], 10.2; P =.005), T3/4 category for peritoneal recurrence (HR, 4.8; P =.008), peritoneal relapse (HR, 40; P =.002), and a prior abdominal operation for LRR (HR, 3.2; P =.01). N2 disease had a distant failure risk similar to N1 status and an intraperitoneal failure risk similar to an N3 category. Isolated LRR of gastric cancer after gastrectomy and extended lymphadenectomy is rare in this series. Most recurrences appeared diffusely at distant or peritoneal sites, and most LRRs occurred in conjunction with relapse at extraregional sites. Pathologic predictors of intraperitoneal (T3/4) or systemic failure (>N1) could be used to guide individualized, risk-oriented, adjuvant treatment.


Evidence for foliar endophytic nitrogen fixation in a widely distributed subalpine conifer.
Coniferous forest nitrogen (N) budgets indicate unknown sources of N. A consistent association between limber pine (Pinus flexilis) and potential N2 -fixing acetic acid bacteria (AAB) indicates that native foliar endophytes may supply subalpine forests with N. To assess whether the P. flexilis-AAB association is consistent across years, we re-sampled P. flexilis twigs at Niwot Ridge, CO and characterized needle endophyte communities via 16S rRNA Illumina sequencing. To investigate whether endophytes have access to foliar N2 , we incubated twigs with (13) N2 -enriched air and imaged radioisotope distribution in needles, the first experiment of its kind using (13) N. We used the acetylene reduction assay to test for nitrogenase activity within P. flexilis twigs four times from June to September. We found evidence for N2 fixation in P. flexilis foliage. N2 diffused readily into needles and nitrogenase activity was positive across sampling dates. We estimate that this association could provide 6.8-13.6 μg N m(-2) d(-1) to P. flexilis stands. AAB dominated the P. flexilis needle endophyte community. We propose that foliar endophytes represent a low-cost, evolutionarily stable N2 -fixing strategy for long-lived conifers. This novel source of biological N2 fixation has fundamental implications for understanding forest N budgets.


High performance work systems and employee well-being: a two stage study of a rural Australian hospital.
This paper aims to explore the attitudes of managers and employees to high performance work practices (HPWS) in a medium sized rural Australian hospital. The study consists of two stages. Stage one involved a qualitative investigation consisting of interviews and focus group sessions with senior, middle and line management at the hospital. Bowen and Ostroffs framework was used to examine how strategic HRM was understood, interpreted and operationalised across the management hierarchy. Stage one investigates the views of managers concerning the implementation of strategic HRM/HPWS. Stage two consisted of a questionnaire administered to all hospital employees. The mediation effects of social identification on the relationship between high performance work systems and affective commitment and job satisfaction are examined. The purpose of stage two was to investigate the views and effects of SHRM/HPWS on employees. It should be noted that HPWS and strategic HRM are used inter-changeably in this paper. At the management level the importance of distinctiveness, consistency and consensus in the interpretation of strategic HRM/HPWS practices across the organization was discovered. Findings indicate that social identification mediates the relationship between HPWS and affective commitment and also mediates the relationship between HPWS and job satisfaction. High performance work systems may play a crucial role facilitating social identification at the unit level. Such practices and management support is likely to provide benefits in terms of high performing committed employees. The paper argues that team leaders and managers play a key role in building social identification within the team and that organizations need to understand this role and provide recognition, reward, education and support to their middle and lower managers.


Ellis type 4 coronary artery perforation during percutaneous coronary intervention: Case series and review.
Ellis type 4 coronary artery perforation (CAP4), also referred to as Ellis type 3 cavity-spilling perforation, is a rare but life-threatening complication of percutaneous coronary intervention characterized by extravasation of blood into a cardiac chamber, anatomic cavity, or coronary sinus or vessel. CAP4 is uncommon, accounting for 1.9% to 3.0% of all CAP. Only 11 cases of CAP4 have been reported in detail; we report an additional two cases and review prior reports of this rare complication. Our first case highlights a patient with chronic anginal symptoms due to a 75% concentric stenotic lesion in the mid-LAD. Revascularization was complicated by perforation during pre-dilation with robust contrast extravasation into the left ventricle. Successful postperforation hemostasis was achieved with heparin reversal and covered stent placement. The second case demonstrates another major mechanism of CAP4: wire perforation. During intervention, the absence of blood flow distal to the lesion in the setting of an ST segment elevation myocardial infarction obscured the course of the nonhydrophilic floppy wire leading to perforation that was managed conservatively. In our scoping review, we found that the majority of CAP4 occurred in the LAD. The most frequently involved cavity was the left ventricle-other cavities involved were the right ventricle and coronary veins. Common etiologies of CAP4 included guidewire perforation (62%) and balloon dilation (31%). Perforation was managed with reversal of anticoagulation in 46% of cases, prolonged balloon inflation in 54% of cases, and covered stent deployment in 15% of cases. No patients required surgical repair or pericardiocentesis and perforations were successfully sealed in all cases. In-hospital mortality was 0%.


Time-resolved metabolomics reveals metabolic modulation in rice foliage.
To elucidate the interaction of dynamics among modules that constitute biological systems, comprehensive datasets obtained from "omics" technologies have been used. In recent plant metabolomics approaches, the reconstruction of metabolic correlation networks has been attempted using statistical techniques. However, the results were unsatisfactory and effective data-mining techniques that apply appropriate comprehensive datasets are needed. Using capillary electrophoresis mass spectrometry (CE-MS) and capillary electrophoresis diode-array detection (CE-DAD), we analyzed the dynamic changes in the level of 56 basic metabolites in plant foliage (Oryza sativa L. ssp. japonica) at hourly intervals over a 24-hr period. Unsupervised clustering of comprehensive metabolic profiles using Kohonen's self-organizing map (SOM) allowed classification of the biochemical pathways activated by the light and dark cycle. The carbon and nitrogen (C/N) metabolism in both periods was also visualized as a phenotypic linkage map that connects network modules on the basis of traditional metabolic pathways rather than pairwise correlations among metabolites. The regulatory networks of C/N assimilation/dissimilation at each time point were consistent with previous works on plant metabolism. In response to environmental stress, glutathione and spermidine fluctuated synchronously with their regulatory targets. Adenine nucleosides and nicotinamide coenzymes were regulated by phosphorylation and dephosphorylation. We also demonstrated that SOM analysis was applicable to the estimation of unidentifiable metabolites in metabolome analysis. Hierarchical clustering of a correlation coefficient matrix could help identify the bottleneck enzymes that regulate metabolic networks. Our results showed that our SOM analysis with appropriate metabolic time-courses effectively revealed the synchronous dynamics among metabolic modules and elucidated the underlying biochemical functions. The application of discrimination of unidentified metabolites and the identification of bottleneck enzymatic steps even to non-targeted comprehensive analysis promise to facilitate an understanding of large-scale interactions among components in biological systems.


Correlation of Fourier domain optical coherence tomography retinal nerve fiber layer maps with visual fields in nonarteritic ischemic optic neuropathy.
To correlate peripapillary retinal nerve fiber layer (NFL) loss and visual field defects in nonarteritic ischemic optic neuropathy (NAION). Patients with NAION and control subjects were enrolled in a case-control study. Participants were scanned with a Fourier domain optical coherence tomography (OCT) system. Peripapillary NFL thickness was averaged in hemispheric, quadrant, and octant divisions. Standard achromatic static perimetry was used to assess visual fields. The reproducibility of peripapillary NFL parameters was excellent in both the healthy and NAION groups. Eyes in the NAION group showed a significant decrease of peripapillary NFL thickness in terms of the overall average, all quadrant averages, and all octants. There were statistically significant correlations between the peripapillary NFL and visual fields in terms of both overall averages and superior-inferior differences. In NAION, the visual field and peripapillary NFL losses are correlated in both severity and location. Fourier domain OCT provides reproducible measurement of the peripapillary NFL and may be useful in the assessment of NAION.


Widely distributed noncoding purifying selection in the human genome.
It is widely assumed that human noncoding sequences comprise a substantial reservoir for functional variants impacting gene regulation and other chromosomal processes. Evolutionarily conserved noncoding sequences (CNSs) in the human genome have attracted considerable attention for their potential to simplify the search for functional elements and phenotypically important human alleles. A major outstanding question is whether functionally significant human noncoding variation is concentrated in CNSs or distributed more broadly across the genome. Here, we combine whole genome sequence data from four nonhuman species (chimp, dog, mouse, and rat) with recently available comprehensive human polymorphism data to analyze selection at single-nucleotide resolution. We show that a substantial fraction of active purifying selection in human noncoding sequences occurs outside of CNSs and is diffusely distributed across the genome. This finding suggests the existence of a large complement of human noncoding variants that may impact gene expression and phenotypic traits, the majority of which will escape detection with current approaches to genome analysis.


Are circulating metabolites important in pharmacokinetic drug-drug interactions? A retroanalysis of clinical data.
Pharmacokinetic (PK) drug-drug interactions (DDIs) give rise to adverse events and/or reduced efficacy. Comprehensive, systematic and mechanistic approaches have been applied in the evaluation, propagation and management of the interaction potential of a new drug during its development and clinical use. However, the role of drug metabolite(s) in DDIs was not extensively investigated. Recently, regulatory bodies have proposed that metabolites at ≥25% of the parent drug's area under the time-concentration curve (AUC) and/or >10% of the total drug-related exposure should be investigated in vitro for DDI potential. This review aimed to identify the drugs and their metabolites meeting the official guidance's criteria for DDI studies, and to assess whether the eligible drugs caused significant clinical PK DDIs and furthermore whether the metabolites contributed to the observed PK DDIs. Eighty seven drugs were eligible and nearly 45% (39/87) drugs were not reported with clinical PK DDIs. About 78% (68/87) drugs demonstrated inhibitory and/or inducible effects on drug-metabolizing enzymes and/or drug transporters; while the remaining 19 (22%) parent drugs showed no such effects. For 8 drugs (~9%), their metabolites were able to inhibit and/or induce the drug-metabolizing enzymes and drug transporters. Three drugmetabolite pairs were found to be the perpetrators of the complex PK DDIs. Our retrospective analysis suggested that the PK DDI risks caused by metabolites alone might not be high, which is somewhat different from the conclusions from some other studies on this topic. However, circulating drugs often work as perpetrators of PK DDIs suggesting a need for more efforts to characterize the roles of their metabolites. Our study should be of value in stimulating discussions among the scientific community on this important topic.


Severe duodenal injuries. Treatment with pyloric exclusion and gastrojejunostomy.
During a 12-year period, 313 patients with duodenal injuries were treated. Primary repair, pyloric exclusion, and gastrojejunostomy were used in 128 patients (41%) with severe duodenal and pancreaticoduodenal injuries, to reduce "duodenal" morbidity and mortality. The duodenal fistula rate was 2.2% overall, and 5.5% in the patients undergoing exclusion. Only two deaths were due to fistulas. Forty-two patients underwent upper gastrointestinal tract examinations after operation. In patients examined 21 days or more after operation, 94% had a patent pylorus. Marginal ulceration was infrequent (four patients), as were complications associated with the procedure (3%). Pyloric exclusion with gastrojejunostomy is a quick and simple procedure that allows return of pyloric patency and is associated with a low incidence of duodenal fistulas. When fistulas do develop, they are usually easily controlled and are associated with a low mortality. We believe pyloric exclusion with gastrojejunostomy to be the procedure of choice in patients with severe duodenal and pancreaticoduodenal trauma.


[Antiviral therapy of hepatitis C].
Hepatitis C is one of the world's leading infectious diseases. The interferon-ribavirin combination therapy is the new standard for the treatment of hepatitis C in naive and relapse patients. Virological sustained response rates can be more than doubled by the IFN-ribavirin combination therapy compared to IFN-monotherapy and treatment duration can be reduced to six months in many cases. The IFN-ribavirin combination therapy has a high relative benefit in patients with unfavorable predictive parameters like high viral load, HCV genotype-1 infection and compensated liver cirrhosis. Anemia is the most important side effect of the guanosin analogue ribavirin. There are no official therapeutic recommendations for non-responder patients at present. These patients should be treated within controlled clinical trials. Monotherapy with PEG(pegylated)-interferons and combination therapies with PEG-interferons and ribavirin are the most promising future therapeutic options.


Effect of parathyroid hormone on jejunal electrolyte and water transport and cyclic nucleotide formation in the rat.
The effect of parathyroid hormone (PTH) on jejunal sodium, calcium, and water transport in situ was studied in thyroparathyroidectomized rats using the ligated loop instillation model. The acute administration of bovine PTH to the animals induced a significant increase in net sodium and water secretion when compared to animals receiving the vehicle only. This effect was due to an increase in unidirectional mucosa-to-lumen sodium flux. However, no change of calcium fluxes was observed. This acute in vivo effect on PTH could not be explained by an action via the adenyl or guanyl cyclase systems since bPTH failed to induce changes of cAMP or cGMP formation in isolated jejunal cells. Thus, other so far not elucidated mechanisms of action must be involved.


Phosphoinositide 3-OH kinase/protein kinase B inhibits apoptotic cell death induced by reactive oxygen species in Saccharomyces cerevisiae.
Apoptosis is a common mode of programmed cell death in multicellular organisms. However, the recent observation of yeast cell death displaying the morphology of apoptosis has suggested the presence of an ancestral cell death machinery. Here we examined apoptotic features induced by reactive oxygen species (ROS) in yeast. Saccharomyces cerevisiae show typical apoptotic features upon exposure to ROS: membrane staining with annexin V and DNA fragmentation by the TUNEL assay. The detection of apoptotic features in yeast strongly support the existence of molecular machinery performing the basic pathways of apoptosis. The phosphoinositide 3-OH kinase (PI3K)/protein kinase B (PKB) signaling pathway has been shown to prevent apoptosis in a variety of cells. It is therefore of interest to determine whether the PI3K/PKB signaling pathway is capable of protecting yeast from apoptosis induced by ROS. We determined that PI3K/PKB is capable of significantly inhibiting ROS-evoked apoptosis in yeast. These results suggest that yeast may provide a suitable model system in which to study the apoptotic signaling pathway elicited by a variety of stimuli.


Methods of pharmacoeconomic evaluation of psychopharmacologic therapies for patients with schizophrenia.
The pharmacoeconomic evaluation of psychopharmacologic treatments for patients with schizophrenia requires attention to the clinical and quality of life effects of the therapy, as well as its impact on the use and cost of medical services. The results of pharmacoeconomic studies help clinicians and health care decision makers determine treatments that provide the most benefit to patient functioning and well-being at the most acceptable medical cost. Various research designs and methods have been used to evaluate the cost-effectiveness of antipsychotic drugs, including retrospective studies, prospective studies, and clinical decision analysis models. This article summarizes these research designs and their strengths and weaknesses in the evaluation of antipsychotic drugs for treating schizophrenia.


Promises of anionic calix[n]arenes in life science: State of the art in 2023.
Because they hold together molecules by means of non-covalent interactions - relatively weak and thus, potentially reversible - the anionic calixarenes have become an interesting tool for efficiently binding a large range of ligands - from gases to large organic molecules. Being highly water soluble and conveniently biocompatible, they showed growing interest for many interdisciplinary fields, particularly in biology and medicine. Thanks to their intrinsic conical shape, they provide suitable platforms, from vesicles to bilayers. This is a valuable characteristic, as so they mimic the biologically functional architectures. The anionic calixarenes propose efficient alternatives for overcoming the limitations linked to drug delivery and bioavailability, as well as drug resistance along with limiting the undesirable side effects. Moreover, the dynamic non-covalent binding with the drugs enables predictable and on demand drug release, controlled by the stimuli present in the targeted environment. This particular feature instigated the use of these versatile, stimuli-responsive compounds for sensing biomarkers of diverse pathologies. The present review describes the recent achievements of the anionic calixarenes in the field of life science, from drug carriers to biomedical engineering, with a particular outlook on their applications for the diagnosis and treatment of different pathologies.


Validation of a Spanish version of the practice environment scale of the nursing work index in the Colombian context.
The literature supports that organizations that create working conditions with positive practice environments improve nurses' job satisfaction and reduce turnover in hospital settings (Havens & Johnston, 2004; International Council of Nurses [ICN], 2007). Positive practice environments promote quality nursing care and better patient outcomes. However, in South America, there are no instruments to measure the nursing practice environment in a hospital setting. The purpose of this research was to examine the validity and reliability of a Spanish translation of the Practice Environment Scale of the Nursing Work Index (PES-NWI; Lake, 2002) in the Colombian clinical context. An instrument validation study using expert panel review, content validity indexing techniques, and a factor analysis of survey responses from 144 nurses was used. The scale-level content validity evaluation achieved high levels of acceptability, with values above 0.90. Construct validity results suggest that the instrument consists of 5 factors as prescribed by original instrument. The overall internal consistency value was a Cronbach's alpha level of 0.89. This is the first instrument to measure the work environment of nursing practice in South America, now validated in the Colombian context.


Nanoscale conducting oxide PlasMOStor.
We experimentally demonstrate an ultracompact PlasMOStor, a plasmon slot waveguide field-effect modulator based on a transparent conducting oxide active region. By electrically modulating the conducting oxide material deposited into the gaps of highly confined plasmonic slot waveguides, we demonstrate field-effect dynamics giving rise to modulation with high dynamic range (2.71 dB/μm) and low waveguide loss (∼0.45 dB/μm). The large modulation strength is due to the large change in complex dielectric function when the signal wavelength approaches the surface plasmon resonance in the voltage-tuned conducting oxide accumulation layer. The results provide insight about the design of ultracompact, nanoscale modulators for future integrated nanophotonic circuits.


Wide geographic distribution of bacteriophages that lyse the same indigenous freshwater isolate (Sphingomonas sp. strain B18).
An indigenous freshwater bacterium (Sphingomonas sp. strain B18) from Lake Plubetasee (Schleswig-Holstein, Germany) was used to isolate 44 phages from 13 very different freshwater and brackish habitats in distant geographic areas. This bacterial strain was very sensitive to a broad spectrum of phages from different aquatic environments. Phages isolated from geographically distant aquatic habitats, but also those from the same sample, were diverse with respect to morphology and restriction pattern. Some phages were widely distributed, while different types coexisted in the same sample. It was concluded that phages could be a major factor in shaping the structure of bacterial communities and maintaining a high bacterial diversity.


Characterization of somatomedin/insulin-like growth factor receptors and correlation with biologic action in cultured neonatal rat astroglial cells.
The role of somatomedin/insulin-like growth factors (Sm/IGFs) in neural growth and development is not clearly defined. To characterize Sm/IGF receptors and to correlate binding with the biologic actions of Sm/IGFs in a homogeneous population of neural cells, we isolated and studied a nearly pure population of cultured astroglial monolayers derived from cerebral cortices of neonatal rats. Binding of radiolabeled Sm/IGFs was specific, saturable, and reversible, with 90% of the binding occurring within 6 hr of incubation at 4 degrees C. Competitive binding studies with Sm-C/IGF I yielded curvilinear Scatchard plots, while studies with IGF II and multiplication stimulating activity (MSA) yielded linear plots, suggesting that 125I-Sm-C/IGF I binds to more than 1 receptor species, and 125I-IGF II and 125I-MSA bind to one only. These findings were supported by affinity-labeling studies with radiolabeled Sm/IGFs using disuccinimidyl suberate as a cross-linking agent. Sm-C/IGF I appeared to bind to both type I and II Sm/IGF receptors, because cross-linked 125I-Sm-C/IGF I-receptor complexes with molecular weight (Mr) of greater than 300,000 (300K) and 130K (type I receptor) were observed under nonreducing and reducing conditions, respectively, as were 220 and 260K complexes (type II receptor) under the same respective conditions. 125I-IGF II and 125I-MSA, however, bound only to the Mr 220 and 260K moieties under nonreducing and reducing conditions, respectively, suggesting that these peptides bind only to the type II receptor. Competitive binding studies of the cross-linked moieties were consistent with this interpretation. In contrast, 125I-insulin bound poorly to astroglia (less than 0.5% specific binding), and cross-linking studies could not definitely distinguish among low-affinity binding to the type I Sm/IGF receptor, binding to a paucity of insulin receptors, or both. In addition, by combining autoradiography to localize 125I-Sm/IGFs binding on astroglial cells and immunocytochemistry with anti-glial fibrillary acidic protein to identify the cell type, we have demonstrated cell-surface binding and apparent internalization of radiolabeled Sm/IGFs. Concurrent studies of Sm/IGF stimulation of 3H-thymidine incorporation revealed that these cells were most sensitive to Sm-C/IGF I, followed by IGF II and MSA, and insulin. MSA and IGF II, however, were the most potent followed by Sm-C/IGF I and then insulin. Half-maximal stimulations of 3H-thymidine incorporation corresponded closely with half-maximal binding displacement for Sm-C/IGF I and less so for IGF II and MSA.(ABSTRACT TRUNCATED AT 400 WORDS)


Adversity in childhood/adolescence and premorbid tobacco, alcohol, and cannabis use among first-episode psychosis patients.
Premorbid substance use is widely recognized as a crucial factor in early psychosis. We explored the effects of childhood/adolescent adversity on premorbid tobacco, alcohol, and cannabis use. We hypothesized that adversity in childhood would be associated with an increased likelihood of use, and amount of intake, of tobacco, alcohol, and cannabis. We analysed which domains of adversity have the greatest impact. First-episode psychosis patients were enrolled from six inpatient psychiatric units in Atlanta, Georgia and Washington, D.C. Premorbid substance use was thoroughly measured, and childhood/adolescent adversity was rated using 14 scales/subscales. Factor analysis was used to reduce these scales/subscales to the three domains of adversity (termed Violence and Environmental Adversity, Interpersonal Abuse, and Neglect and Lack of Connectedness). Regression analyses determined associations between adversity domains and premorbid substance use. Our sample (n = 247) primarily consisted of African Americans (86.2%) and males (74.5%). Violence and Environmental Adversity was significantly associated with five of six substance use variables and marginally associated with the sixth. Interpersonal Abuse was unassociated with substance use, and Neglect and Lack of Connectedness was associated only with a lower likelihood cannabis use. When Violence and Environmental Adversity results were stratified by gender, effects on tobacco use and amount of tobacco use were stronger among females. Childhood/adolescent trauma and adversity have meaningful associations with premorbid substance use in first-episode psychosis patients. First-episode psychosis and clinical high-risk treatment settings may benefit from expanding the assessment of childhood/adolescent adversity to include factors pertaining to violence exposure and adversities beyond abuse and neglect.


Acute cocaine induced deficits in cognitive performance in rhesus macaque monkeys treated with baclofen.
Acute and/or chronic exposure to cocaine can affect cognitive performance, which may influence rate of recovery during treatment. Effects of the GABA-B receptor agonist baclofen were assessed for potency to reverse the negative influence of acute, pre-session, intravenous (IV) injection of cocaine on cognitive performance in Macaca mulatta nonhuman primates. Animals were trained to perform a modified delayed match to sample (DMS) task incorporating two types of trials with varying degrees of cognitive load that had different decision requirements in order to correctly utilize information retained over the delay interval. The effects of cocaine (0.2, 0.4, and 0.6 mg/kg, IV) alone and in combination with baclofen (0.29 and 0.40 mg/kg, IV) were examined with respect to sustained performance levels. Brain metabolic activity during performance of the task was assessed using PET imaged uptake of [(18) F]-fluorodeoxyglucose. Acute cocaine injections produced a dose-dependent decline in DMS performance selective for trials of high cognitive load. The GABA-receptor agonist baclofen, co-administered with cocaine, reversed task performance back to nondrug (saline IV) control levels. Simultaneous assessment of PET-imaged brain metabolic activity in prefrontal cortex (PFC) showed alterations by cocaine compared to PFC metabolic activation in nondrug (saline, IV) control DMS sessions, but like performance, PFC activation was returned to control levels by baclofen (0.40 mg/kg, IV) injected with cocaine. The results show that baclofen, administered at a relatively high dose, reversed the cognitive deficits produced by acute cocaine intoxication that may have implications for use in chronic drug exposure.


Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome.
Subcutaneous (SC) octreotide acetate effectively relieves the diarrhea and flushing associated with carcinoid syndrome but requires long-term multiple injections daily. A microencapsulated long-acting formulation (LAR) of octreotide acetate has been developed for once-monthly intramuscular dosing. A randomized trial compared double-blinded octreotide LAR at 10, 20, and 30 mg every 4 weeks with open-label SC octreotide every 8 hours for the treatment of carcinoid syndrome. Seventy-nine patients controlled with treatment of SC octreotide 0.3 to 0.9 mg/d whose symptoms returned during a washout period and who returned for at least the week 20 evaluation constituted the efficacy-assessable population. Complete or partial treatment success was comparable in each of the four arms of the study (SC, 58.3%; 10 mg, 66.7%; 20 mg, 71.4%; 30 mg, 61.9%; P> or =.72 for all pairwise comparisons). Control of stool frequency was similar in all treatment groups. Flushing episodes were best controlled in the 20-mg LAR and SC groups; the 10-mg LAR treatment was least effective in the control of flushing. Treatment was well tolerated by patients in all four groups. Once octreotide steady-state concentrations are achieved, octreotide LAR controls the symptoms of carcinoid syndrome at least as well as SC octreotide. A starting dose of 20 mg of octreotide LAR is recommended. Supplemental SC octreotide is needed for approximately 2 weeks after initiation of octreotide LAR treatment. Occasional rescue SC injections may be required for possibly 2 to 3 months until steady-state octreotide levels from the LAR formulation are achieved.


Contracting with children and helmet distribution in the emergency department to improve bicycle helmet use.
To determine whether injury prevention counseling and behavioral counseling delivered in the emergency department (ED) could result in increases in self-reported bicycle helmet use. The authors undertook a trial of counseling in 222 children recruited in an urban ED between August 2000 and October 2001. All consenting patients in the ED aged 5 to 15 years who did not have life-threatening conditions were eligible. One hundred nine children were assigned to the control group on the basis of attendance on an odd-numbered day, and they received a photocopied photograph of the hospital. One hundred thirteen children were assigned to the intervention group, and they received a personal counseling session and signed a contract promising to wear their bicycle helmets. In addition, 57 of the intervention children were assigned (based on having an even-numbered birthday) to be fitted with helmets if they did not already own them. Parents were telephoned four weeks after the ED encounter for follow-up. Follow-up data were obtained for 148 children (67% follow-up rate), of whom only 69 reported riding a bicycle in the four weeks after their ED visit. Of the final sample of 69 children, 38 belonged to one of the intervention groups, and 25 of these (66%) reported always wearing a helmet while cycling during the four weeks after their ED visit, versus 13 of 31 (42%) in the control group (odds ratio, 2.66; p < 0.05). The effect of the intervention was independent of whether the children owned a helmet at baseline. Injury prevention counseling in the ED using "The Injury Prevention Program" (TIPP) sheet, behavioral contracting, and helmet distribution may have a significant effect on reports of subsequent bike helmet use.


The fundamental role of ecological feedback mechanisms for the adaptive management of seagrass ecosystems - a review.
Seagrass meadows are vital ecosystems in coastal zones worldwide, but are also under global threat. One of the major hurdles restricting the success of seagrass conservation and restoration is our limited understanding of ecological feedback mechanisms. In these ecosystems, multiple, self-reinforcing feedbacks can undermine conservation efforts by masking environmental impacts until the decline is precipitous, or alternatively they can inhibit seagrass recovery in spite of restoration efforts. However, no clear framework yet exists for identifying or dealing with feedbacks to improve the management of seagrass ecosystems. Here we review the causes and consequences of multiple feedbacks between seagrass and biotic and/or abiotic processes. We demonstrate how feedbacks have the potential to impose or reinforce regimes of either seagrass dominance or unvegetated substrate, and how the strength and importance of these feedbacks vary across environmental gradients. Although a myriad of feedbacks have now been identified, the co-occurrence and likely interaction among feedbacks has largely been overlooked to date due to difficulties in analysis and detection. Here we take a fundamental step forward by modelling the interactions among two distinct above- and belowground feedbacks to demonstrate that interacting feedbacks are likely to be important for ecosystem resilience. On this basis, we propose a five-step adaptive management plan to address feedback dynamics for effective conservation and restoration strategies. The management plan provides guidance to aid in the identification and prioritisation of likely feedbacks in different seagrass ecosystems.