Links between race/ethnicity and cultural values as mediated by racial/ethnic identity and moderated by gender.
Two studies examined whether individualism (orientation toward one's own welfare), collectivism (orientation toward the welfare of one's larger community), and familism (orientation toward the welfare of one's immediate and extended family) are distinct cultural values predicted by race/ ethnicity. The 3 constructs proved to be separate dimensions, although collectivism and familism were positively correlated. In Study 1, persons of color scored higher on collectivism and familism than did Anglos. No differences emerged for individualism. Also, persons of color scored higher than Anglos on racial/ethnic identity, which in turn was a positive predictor of all 3 cultural values. In Study 2, we replicated the group differences on collectivism and familism for men but not for women.


Causes, clinical characteristics, and outcomes of high lithium levels and intoxications: Retrospective analysis of patient records.
The mood stabilizer lithium has a narrow therapeutic index with a relevant risk of intoxication. We used real-world hospital data to identify causes, treatment courses, and outcomes of high lithium levels and intoxications. Retrospective chart review of patients with a lithium concentration of ⩾1.1 mmol/L, who were treated at Charité University Medical Center Berlin. We identified 136 patients (58% women; mean age: 54.7 years) with high lithium levels or intoxication. 66.9% were chronic (stable lithium dose but changes in other variables such as co-medication). 40.4% took at least one risk medication with a relative contraindication for concurrent lithium treatment. 11.1% of the cases with a high therapeutic level showed moderate to severe intoxications. Feverish infections were significantly associated with severe intoxications. Overall, 97.1% (132/136) of patients fully recovered, two had residual but mild symptoms and two died during hospitalization (unlikely related to the intoxication). In 37.5% of patients, no psychiatrist was involved in the management of high lithium levels or intoxication. In these patients, lithium treatment was adjusted or discontinued in 37.3% of the cases compared to 64.7% when a psychiatrist was involved (χ²(1) = 9.683, p = 0.002). Patients and medical doctors should be aware of the increased risk of lithium intoxication already within the high therapeutic range and should consider alternative medications without relative contraindications for concurrent lithium use. Involving psychiatrists during or after an intoxication event is associated with more frequent adjustment of the maintenance lithium dose and should be considered in most cases.


Spin trapping of nitric oxide in aqueous solutions of cigarette smoke.
Nitric oxide, a gaseous free NO radical (.NO) generated in particulate-free gas-phase main-stream smoke of cigarettes, was observed with electrical spin resonance (ESR) using a spin trapping technique. N-Methyl-D-glucamine-dithiocarbamate (MGD)2-Fe2+ complex was used for the NO radical spin trapper in aqueous solution. The intensity of the ESR signal of the spin adduct formed by bubbling smoke from one cigarette increased gradually with time over 2 hours at about 20 degrees C and was constant for 2 days or longer. The time course of the production of the NO radical followed the rate equation y = 1520(1-e-0.018t) for the first-order reaction up to around 25 min after mixing of Fe2+ solution and then slowly approached the maximum value determined by the concentration of the spin adduct. These findings suggest that NO radical is produced slowly from NO radical donors such as amine .NO complexes, peroxinitrite (ONOO-), and other reactants such as nitrogen oxides (NOx), which are produced from the smoke of tobacco leaves, and suggest that its generation could be involved in the decomposition or cleavage of such substances.


Limitation of transthoracic echocardiography in the diagnosis of congenital heart diseases.
Nowadays, it has been widely accepted that echocardiography is the most efficient, non invasive diagnostic tool to diagnose congenital heart diseases. However, cardiac catheterization remains the gold standard to diagnose and obtain hemodynamic data prior to cardiovascular surgery. In order to find out the accuracy of transthoracic echocardiography in relation to the anatomical diagnosis of congenital heart diseases, 175 consecutive patients who underwent diagnostic cardiac catheterization during January 1999 to December 1999 were reviewed. All of them had complete echocardiographic studies prior to the procedure. The male to female ratio was 1.06:1. The median age at the time of echocardiography was 3.36 (0.01-28.8) years old. The indications of the cardiac catheterization were to demonstrate cardiovascular anatomy 64 per cent, to obtain pulmonary artery pressure and pulmonary vascular resistance 13.7 per cent, and to get both information 22.3 per cent. Tetralogy of Fallot (23.4%) was the most frequent cardiac malformation, followed by complex congenital heart diseases (22.3%), simple left to right shunt (12%), pulmonary atresia with ventricular septal defect (8.6%), tricuspid atresia (5.7%), simple d-transposition of great arteries (4%), etc. From cardiac catheterization; 49 cases (28%) revealed additional data which were surgically important, 3 cases (1.7%) resulted in different diagnoses, and 3 cases (1.7%) revealed additional information which was not surgically important. Inadequate imaging technique (36 cases, 65.5%) and limitation of technique (19 cases, 34.5%) were the reasons for missing anatomical findings of transthoracic echocardiography. Age at the time of echocardiography was not a significant factor affecting the accuracy. Persistent left superior vena cava, multiple aorto-pulmonary collateral arteries, pulmonary artery anatomy, and coronary artery anatomy were the most frequent cardiac lesions misdiagnosed by transthoracic echocardiography that were somewhat surgically important. The incorrect echocardiographic diagnoses were aorto-pulmonary window, patent ductus arteriosus, and vascular ring. Thorough and extensive echocardiographic scanning coupled with cooperative or adequately sedated patients by an experienced operator using an efficient echocardiographic machine might improve the accuracy of transthoracic echocardiography in the diagnosis of congenital heart diseases.


Performance and individual feed intake characteristics of group-housed sows fed a nonstarch polysaccharides diet ad libitum during gestation over three parities.
The objective of this experiment was to study the effects of feeding group-housed gestating sows a diet with a high level of fermentable nonstarch polysaccharides (NSP; approximately 45% sugar beet pulp as fed) ad libitum on the development in individual feed intake characteristics and reproductive performance during three successive reproduction cycles. Performance of the ad libitum-fed sows was compared to the performance of sows that were fed a conventional diet restrictedly. Feed intake characteristics during gestation were only measured in the ad libitum-fed sows. One hundred and nineteen sows were assigned to one of two gestation feeding regimens. Gestating sows were fed a conventional Dutch diet restrictedly or a diet with a high level of fermentable NSP ad libitum. During lactation, sows were given free access to a commercial lactation diet from d 6 after parturition onward. The ad libitum-fed sows ate 1.3 kg/d more during gestation than the restrictedly fed sows (P < 0.001), resulting in higher body weight and backfat gains during gestation (P < 0.05). Sows that were fed ad libitum during gestation lost more body weight and backfat during lactation (P < 0.001) than sows that were fed restrictedly during gestation. Feed intake during lactation, however, did not differ between sows that were fed restrictedly or ad libitum during gestation. The numbers of total piglets born, live-born and stillborn piglets, piglet birth weight, weaning-to-estrus interval, and percentage of sows that returned to estrus after first insemination were not affected by gestation feeding regimen. Mean daily voluntary feed intake (as-fed basis) over the three reproduction cycles in the ad libitum-fed gestating sows was 4.2 kg/d. Depending on the number of preceding reproduction cycles during which a sow was fed ad libitum, the maximum voluntary feed intake was reached in Parity 3, 4, or 5 and then remained stable in subsequent parities. Mean daily feed intake of the ad libitum-fed sows increased from wk 2 to 6 of gestation and then decreased to wk 15 of gestation. The mean number of daily visits with feed intake over the three reproduction cycles was 13.8. On average, ad libitum-fed sows spent 90 min/d on eating. This study shows that it is possible to feed gestating sows a diet with a high level of fermentable NSP ad libitum during three successive reproduction cycles without negative effects on reproductive performance.


[The Central Military Hospital of the People's Commissariat for Defence during the Great Patriotic War].
The article is devoted to activity of the Central Military Hospital of the People's Commissariat for Defence during the Great Patriotic War. The research is based on declassified orders of PCD and orders of the chef of hospital. Authors presented the role of the hospital in organization of medical aid for officers of PCD, members of their families, Red Army soldiers, junior and senior Red Army commanders; the role of the hospital in organization of medical facilities for combat army; medical supply for evacuation of family members of PCD's officers ( en route and in evacuation places); delivery of child health care to children of officers of PCD in the hospital and education in kindergartens of PCD.


Equation counting and the interpretation of sensory data.
Many problems in biological information processing require the solution to a complex system of equations in many unknown variables. An equation-counting procedure is described for determining whether such a system of equations will indeed have a unique solution, and under what conditions the solution should be interpreted as 'correct'. Three examples of the procedure are given for illustration, one from auditory signal processing and two from vision.


Use of repeated measures analysis for evaluation of genetic background of dairy cattle behavior in automatic milking systems.
Milking frequencies measured at official test days were used with repeated measurement analysis to reveal the environmental and genetic impact on the milking frequency of cows in automatic milking systems. Repeated measurements were 3 test-day observations per cow within days in milk (DIM) classes, with 1,216 cows in DIM class 1 (d 0 to 99), from 1,112 cows in DIM class 2 (d 100 to 199), and from 1,004 cows in DIM class 3 (d 200 to 299) kept in 15 farms. Selection criteria for models analyzing repeated measurements were Akaike and Schwarz Bayesian values, which favored the autoregressive [AR(1)] covariance structure over the compound symmetry model. Results from the AR(1) model indicated a significant impact of fixed herd and parity effects. Milking frequencies decreased with increasing parities and were greatest for first-parity cows. High daily milk yield was associated with higher milking frequencies. Heritabilities for milking frequency were 0.16, 0.19, and 0.22 in DIM classes 1, 2, and 3, respectively, from the AR(1) model. Higher heritabilities in the later stage of lactation were due to a substantial reduction of the residual variance. Genetic correlations between test-day milk yield and daily milking frequency were in the range of 0.46 to 0.57 for all DIM classes and between milking frequency and somatic cell score were near zero. For verification of results, milking frequencies of the same cows obtained from herd management programs were averaged within DIM classes. Heritabilities were slightly above the values from the AR(1) model. In conclusion, heritabilities for milking frequency in automatic milking systems are moderate enough to incorporate this behavioral trait in a combined breeding goal. The inevitable improvement of labor efficiency in dairy cattle farming demands such cows going easily and voluntarily in automatic milking systems.


The effect of zolpidem on operant behavior and its relation to pharmacokinetics after intravenous and subcutaneous administration: concentration-effect relations.
We characterized the effects of i.v. and s.c. zolpidem (1-8 mg/kg) under a differential reinforcement of low-rate schedule (i.e. DRL 45 s) in 3-hour sessions. Both behavioral and pharmacokinetic-pharmacodynamic analyses were used with the intent to compare the effects of zolpidem with those of benzodiazepines reported previously under the same behavioral paradigm. Zolpidem increased the shorter-response [inter-response times (IRTs)<45 s] rate and decreased the reinforcement rate in a dose- and time-related fashion. The behavioral profiles of zolpidem were mainly similar to those of benzodiazepines, except zolpidem produced far fewer shorter IRT responses. Pharmacokinetically, zolpidem decays biexponentially with distributional and terminal elimination half-lives of 5.2 and 42 min, respectively. The absorption rate constant and absolute bioavailability for s.c. zolpidem were 0.083/min and of 84.1%, respectively. The pharmacodynamic parameters for the reinforcement rate, an index of timing performance, were determined by integration of behavioral and pharmacokinetic profiles in a between-subject design using the effect-linked inhibitory sigmoidal E(max) model. The pharmacokinetic-pharmacodynamic analysis revealed that the potency of zolpidem (concentration required to produce 50% maximal effects, IC(50)) in disrupting the timing performance was 0.129 microg/ml. The pharmacodynamic estimates of zolpidem were compared to our previous results for benzodiazepines.


Co-induction of a glutathione-S-transferase, a glutathione transporter and an ABC transporter in maize by xenobiotics.
Glutathione conjugation reactions are one of the principal mechanisms that plants utilize to detoxify xenobiotics. The induction by four herbicides (2,4-D, atrazine, metolachlor and primisulfuron) and a herbicide safener (dichlormid) on the expression of three genes, ZmGST27, ZmGT1 and ZmMRP1, encoding respectively a glutathione-S-transferase, a glutathione transporter and an ATP-binding cassette (ABC) transporter was studied in maize. The results demonstrate that the inducing effect on gene expression varies with both chemicals and genes. The expression of ZmGST27 and ZmMRP1 was up-regulated by all five compounds, whereas that of ZmGT1 was increased by atrazine, metolachlor, primisulfuron and dichlormid, but not by 2,4-D. For all chemicals, the inducing effect was first detected on ZmGST27. The finding that ZmGT1 is activated alongside ZmGST27 and ZmMRP1 suggests that glutathione transporters are an important component in the xenobiotic detoxification system of plants.


Eosinophil hematopoietins antagonize the programmed cell death of eosinophils. Cytokine and glucocorticoid effects on eosinophils maintained by endothelial cell-conditioned medium.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) was established as the constitutive and elicited human umbilical vein endothelial cell-derived eosinophil viability-sustaining factor. Stimulation of endothelium cell monolayers with IL-1 alpha (5 U/ml) increased the 48-h elaboration of GM-CSF from a mean of 3.2 to a mean of 8.2 pM (P less than 0.05). Dexamethasone (100 nM) decreased the constitutive GM-CSF elaboration by 49% (P less than 0.001) but did not diminish production by IL-1 alpha-stimulated endothelium. However, eosinophil viability decreased by 21% in dexamethasone-pretreated IL-1 alpha-stimulated endothelial cell-conditioned medium (P less than 0.05), which suggested viability antagonism by glucocorticoids. After 24 h of culture, eosinophil viability for replicate cells in enriched medium alone or with 1 pM GM-CSF decreased from means of 43 and 75% to means of 21 and 54%, respectively, when dexamethasone was included (P less than 0.05). However, 10 pM GM-CSF, IL-3, or IL-5 protected the cells against dexamethasone and against endonuclease-specific DNA fragmentation. In this model system of eosinophil-tissue interactions, dexamethasone prevents the endothelial cells from inducing a pathobiologic phenotypic change in the eosinophil by suppression of GM-CSF elaboration to concentrations that are not cytoprotective. Cytokine priming by GM-CSF, IL-3, or IL-5 may account for the differential responsiveness of select eosinophilic disorders to glucocorticoids.


Disruption of the myocardial extracellular matrix leads to cardiac dysfunction.
MMP activity with disruption of structural collagen has been implicated in the pathophysiology of dilated cardiomyopathy. To examine the role of this enzyme in cardiac function, a transgenic mouse was created that constitutively expressed human collagenase (MMP-1) in the heart. At 6 months of age, these animals demonstrated compensatory myocyte hypertrophy with an increase in the cardiac collagen concentration due to elevated transcription of type III collagen. Chronic myocardial expression of MMP-1 produced loss of cardiac interstitial collagen coincident with a marked deterioration of systolic and diastolic function at 12 months of age. This is the first animal model demonstrating that direct disruption of the extracellular matrix in the heart reproduces the changes observed in the progression of human heart failure.


[The problem of peroxidation in radiobiology].
A hypothesis is validated concerning the products of free radical oxidation of lipids and the phenol compounds as a mediator unit of the stress-syndrome. The data are reviewed on activation of peroxidation under the effect of radiation, cytochemical agents, etc., secondarily stimulating the neurohumoral system function of homeostasis regulation. With the emotional-algesic and cold-stresses, the regulatory system stimulation is of primary, reflex, nature, but it secondarily promotes the peroxidation activation. The radiotoxins (of the quinoid and lipid nature) appearing in tissues under the effect of ionizing radiation, are similar in structure and mechanism of action to peroxidation activation products formed under the effect of other stress-agents.


Group refractive index and group velocity dispersion measurement by complex master slave interferometry.
This paper demonstrates that the complex master slave interferometry (CMSI) method used in spectral domain interferometry (SDI) can efficiently be used for accurate refractive index and group velocity dispersion measurements of optically transparent samples. For the first time, we demonstrate the relevance of the phase information delivered by CMSI for dispersion evaluations with no need to linearize data. The technique proposed here has been used to accurately measure the group refractive index and the group velocity dispersion of a strong dispersive sample (SF6 glass), and a weak dispersive one (distilled water). The robustness of the technique is demonstrated through the manipulation of several sets of experimental data.


Verbal episodic memory declines prior to diagnosis in Huntington's disease.
Previous studies of verbal episodic memory in pre-diagnostic Huntington's disease (HD) have yielded mixed results; some evidence suggests that memory decline is evident prior to the onset of pronounced neurological signs of HD, whereas other data indicate that memory function remains normal throughout the pre-diagnostic period. This study examines verbal episodic memory in a sample of CAG expanded individuals who have not yet been clinically diagnosed, and who represent a wide range of points along the continuum from health to disease. The Hopkins Verbal Learning Test-Revised (HVLT-R) was administered to 479 participants (428 with the HD CAG expansion and 51 without), and performance was compared to neurobiological indices of disease progression, including a DNA-based estimate of proximity to clinical diagnosis, magnetic resonance imaging (MRI) measures of striatal volume, and neurologist ratings of motor signs. Lower HVLT-R scores were associated with closer proximity to clinical diagnosis and smaller striatal volumes; these relationships were found even in groups with no neurological signs of HD. The CAG expanded groups, including those with only minimal neurological signs, had significantly lower HVLT-R scores than the control group, and performance was worse in sub-groups that had more neurological signs consistent with HD. These findings indicate that verbal episodic memory is affected in early pre-diagnostic HD and may decline as striatal volumes decrease and individuals approach the motor diagnostic threshold.


Hematological Oncology journal women in lymphoma special issue: Latest updates in nodal peripheral T-cell lymphoma.
In the last decade, there has been increased understanding of the pathologic features and biology of peripheral T cell lymphomas (PTCLs) through development of multi omics and molecular profiling techniques. In addition, international collaborations through multi center trials as well as prospective registry studies have improved our knowledge of host and tumor genomic factors and treatment factors affecting disease outcomes. In our review today, we aim to highlight the current epidemiology, latest advances in classification, disease biology and the evolving treatment landscape for nodal PTCLs.


Challenges in diagnosing and managing cystic duct carcinoma: A case report from Syria.
Primary cystic duct carcinoma, an uncommon and aggressive biliary cancer variant, poses a significant challenge in clinical practice. This study examines recent clinical cases, focusing on diagnostics, interventions, and implications in managing this disease, with a prevalence ranging from 0.03 % to 0.05 %, contributing to 2.6-12.6 % of extrahepatic biliary neoplasms. A 57-year-old male, a smoker with hypertension and hyperuricemia, presented symptoms of severe upper right abdominal pain, jaundice, and altered stool color. Diagnosis revealed ulcerated papillary adenocarcinoma invading all gallbladder layers (2.5 cm). Surgical resection and Roux-en-Y anastomosis were performed. Histopathological examination showed invasive tumor proliferation, preserved lymph node architecture, and severe hepatic microsteatosis. Lymph nodes were tumor-free, and a benign hepatic biopsy (0.5 cm) displayed chronic portitis. The final diagnosis confirmed cystic duct carcinoma, emphasizing the complex diagnostic and therapeutic aspects in biliary cases. The clinical discussion unveils the complexities associated with primary cystic duct carcinomas. Emphasizing the necessity of a multidisciplinary approach, this case highlights the importance of efficient management strategies-from initial diagnosis to surgical intervention-in dealing with this challenging malignancy. In conclusion, this case underscores the intricate nature of primary cystic duct carcinomas. It accentuates the essential role of a multidisciplinary approach, urging the need for continuous research endeavors to further comprehend and enhance the treatment methodologies for this rare and complex malignancy.


Subacute toxicity of a Pseudomonas vaccine prepared from outer membrane fraction of Pseudomonas aeruginosa in beagle dogs.
CFC-101, a Pseudomonas vaccine, was administered to beagle dogs by intramuscular injection for 4 weeks (5 days/week) at 0.05, 0.15 and 0.45 mg/kg/d. Clinical signs considered to be related to treatment were restricted to swelling at the injection sites, being apparent 1-2 h after treatment. There was no effect on body weight, food consumption, ophthalmoscopy, electrocardiography, hematology, biochemical and urinary parameters. The histopathological examination revealed treatment-related changes at the injection sites at all dosages, particularly in the hindlimbs where both perivascular and intramuscular aggregations of inflammatory cells were seen. Thus, the only treatment-related changes seen in this study were local reactions to the test substance at the injection sites; furthermore these changes seem to represent a pharmacological response to the test material. Because no evidence of any systemic toxicity was observed at any dosage level, it is concluded that dosages of CFC-101 up to and including 0.45 mg/kg/d were well tolerated over a period of 4 weeks in the beagle dog.


Longitudinal coherence of organic-based microcavity lasers.
We report on the measurement of the longitudinal coherence of organic microcavity lasers based on a conjugated polymer. By using a modified Michelson interferometer configuration enabling single-shot measurements of the coherence length, the transition from spontaneous emission to lasing is investigated. The measured coherence length grows upon increasing the pumping fluence, saturating around 45 microm above threshold. At large fluences, possible thermal and photo-oxidation processes occurring in the gain medium limit the further increase of the coherence length. Our results are important for understanding lasing emission in organic microcavities and optimizing the device design and performances.


Normalisation of the dexamethasone suppression test: a correlate of clinical improvement in primary depressives.
Thirty-six patients with a primary depressive illness, admitted consecutively to hospital, were studied. All patients had a pre-treatment DST, followed by weekly DSTs during a six-week treatment period. Three categories of DST response were identified, on the basis of the serial DSTs. All three groups showed improvement with treatment: the two non-suppressor groups showed normalisation of the DST over the treatment period, but only the normalising nonsuppressors showed a significant correlation between DST normalisation and clinical improvement.


Classifying dogs' (Canis familiaris) facial expressions from photographs.
Humans accurately read other humans' emotional facial expressions. Little research was found examining human ability to read dogs' expressions. Cross-species research extended facial expression research to chimpanzees, and there is much research on dogs' auditory signaling to humans. To explore humans' ability to identify dogs' facial displays, photographs of a dog's face were taken under behaviorally defined conditions expected to elicit specific emotions. Dog experts consistently rated these photographs. The photographs rated as best by experts were used as stimuli for people experienced and inexperienced with dogs. Both groups were able to read the dog's emotions. Paradoxically, experienced people were less accurate reading aggressiveness. Experienced people were better identifying behaviorally defined situations. Research using behaviorally anchored, standardized photographs is recommended.


Fortification of bakery and corn masa-based foods in Mexico and dietary intake of folic acid and folate in Mexican national survey data.
In Mexico, wheat and corn flour fortification with folic acid (FA) was implemented in 2001 and mandated in 2008, but without direct enforcement. Current Mexican nutrient-content tables do not account for FA contained in bakery bread and corn masa-based foods, which are dietary staples in Mexico. The objective of this study was to examine the impact of FA fortification of dietary staples on the proportion of the population consuming below the Estimated Average Requirement (EAR) for folate or above the Tolerable Upper Intake Level (UL) for FA. We measured FA and folate content in dietary staples (bakery bread and tortillas) using microbial assays and MS, and we recalculated FA intake from 24-h recall dietary intake data collected in the 2012 Mexican National Health and Nutrition Survey (Encuesta Nacional de Salud y Nutrición) utilizing estimates from our food measurements, using nutrient concentrations from tortillas to approximate nutrient content of other corn masa-derived foods. The revised FA intake estimates were used to examine population-level intake of FA and dietary folate equivalent (DFE) accounting for geographic differences in FA content with statistical models. FA content in dietary staples was variable, whereas use of FA-fortified flour in corn masa tortillas increased with population size in place of residence. Accounting for dietary staples' FA fortification increased population estimates for FA and DFE intake, resulting in a lower proportion with intake below the EAR and a higher proportion with intake above the UL. Despite accounting for FA-fortified staple foods, 9-33% of women of childbearing age still have intake below the EAR, whereas up to 12% of younger children have intake above the UL. Unregulated FA fortification of dietary staples leads to unpredictable total folate intake without adequately impacting the intended target. Our findings suggest that monitoring, evaluation, and enforcement of mandatory fortification policies are needed. Without these, alternate strategies may be needed in order to reach women of childbearing age while avoiding overexposing children.


Partial characterization of lysyl oxidase from several human tissues.
Lysyl oxidase activity was assayed in urea extracts of a number of human tissues, proving to be highest in skin. Antibodies to human placental lysyl oxidase completely inhibited the activity of crude lysyl oxidase from all the human tissues studied, with no significant differences in the amounts of antiserum required for 50% inhibition. By contrast, marked differences were found in this value between skin tissue samples from different species. The Mr of lysyl oxidase in crude extracts of human skin and in the medium of cultured human skin fibroblasts was 30 000 by gel filtration, no active species with a higher Mr being detectable. Four forms of lysyl oxidase activity were seen in DEAE-cellulose chromatography of urea extract from human skin, all having Mr 30 000. Antibodies to human placental lysyl oxidase stained a 30 000-Mr protein in urea extracts of all the human tissues studied and in the medium of cultured human skin fibroblasts when examined by immunoblotting after sodium dodecyl sulphate/polyacrylamide-slab-gel electrophoresis, but they also stained high-Mr material. The findings suggest that there are no immunologically distinct lysyl oxidase isoenzymes in the various human tissues and that the true Mr of lysyl oxidase in crude urea extracts is 30 000.


Oral fluid drug testing of chronic pain patients. I. Positive prevalence rates of licit and illicit drugs.
Oral fluid compliance monitoring of chronic pain patients is an analytical challenge because of the limited specimen volume and the number of drugs that require detection. This study evaluated oral fluid for monitoring pain patients and compared results to urine studies of similar populations. Oral fluid specimens were analyzed from 6441 pain patients from 231 pain clinics in 20 states. Specimens were screened with 14 ELISA assays and non-negative specimens were confirmed by LC-MS-MS for 40 licit and illicit drugs and metabolites. There was an 83.9% positive screening rate (n=5401) of which 98.7% (n=5329) were confirmed at ≥ LOQ concentrations for at least one analyte. The prevalence of confirmed positive drug groups was as follows: opiates > oxycodone > benzodiazepines > methadone ≈ carisoprodol > fentanyl > cannabinoids ≈ tramadol > cocaine > amphetamines ≈ propoxyphene ≈ buprenorphine > barbiturates > methamphetamine. Approximately 11.5% of the study population of pain patients apparently used one or more illicit drugs (cannabis, cocaine, methamphetamine and/or MDMA). Overall, the pattern of licit and illicit drugs and metabolites observed in oral fluid paralleled results reported earlier for urine, indicating that oral fluid is a viable option for use in compliance monitoring programs of chronic pain patients.


Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers.
Early-onset gastric cancer, which develops in patients younger than most gastric cancers, is usually detected at advanced stages, has diffuse histologic features, and occurs more frequently in women. We investigated somatic genomic alterations associated with the unique characteristics of sporadic diffuse gastric cancers (DGCs) from younger patients. We conducted whole exome and RNA sequence analyses of 80 resected DGC samples from patients 45 years old or younger in Korea. Patients with pathogenic germline mutations in CDH1, TP53, and ATM were excluded from the onset of this analysis, given our focus on somatic alterations. We used MutSig2CV to evaluate the significance of mutated genes. We recruited 29 additional early-onset Korean DGC samples and performed SNP6.0 array and targeted sequencing analyses of these 109 early-onset DGC samples (54.1% female, median age, 38 years). We compared the SNP6.0 array and targeted sequencing data of the 109 early-onset DGC samples with those from diffuse-type stomach tumor samples collected from 115 patients in Korea who were 46 years or older (late onset) at the time of diagnosis (controls; 29.6% female, median age, 67 years). We compared patient survival times among tumors from different subgroups and with different somatic mutations. We performed gene silencing of RHOA or CDH1 in DGC cells with small interfering RNAs for cell-based assays. We identified somatic mutations in the following genes in a significant number of early-onset DGCs: the cadherin 1 gene (CDH1), TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. None of 109 early-onset DGC cases had pathogenic germline CDH1 mutations. A higher proportion of early-onset DGCs had mutations in CDH1 (42.2%) or TGFBR1 (7.3%) compared with control DGCs (17.4% and 0.9%, respectively) (P < .001 and P = .014 for CDH1 and TGFBR1, respectively). In contrast, a smaller proportion of early-onset DGCs contained mutations in RHOA (9.2%) than control DGCs (19.1%) (P = .033). Late-onset DGCs in The Cancer Genome Atlas also contained less frequent mutations in CDH1 and TGFBR1 and more frequent RHOA mutations, compared with early-onset DGCs. Early-onset DGCs from women contained significantly more mutations in CDH1 or TGFBR1 than early-onset DGCs from men. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times in patients with early-onset DGCs (hazard ratio, 3.4; 95% confidence interval, 1.5-7.7). RHOA activity was reduced by an R5W substitution-the RHOA mutation most frequently detected in early-onset DGCs. Silencing of CDH1, but not RHOA, increased migratory activity of DGC cells. In an integrative genomic analysis, we found higher proportions of early-onset DGCs to contain somatic mutations in CDH1 or TGFBR1 compared with late-onset DGCs. However, a smaller proportion of early-onset DGCs contained somatic mutations in RHOA than late-onset DGCs. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times of patients, which might account for the aggressive clinical course of early-onset gastric cancer. Female predominance in early-onset gastric cancer may be related to relatively high rates of somatic CDH1 and TGFBR1 mutations in this population.


The Possible Role of Brain-derived Neurotrophic Factor in Epilepsy.
Epilepsy is a neurological disease characterized by repeated seizures. Despite of that the brain-derived neurotrophic factor (BDNF) is implicated in the pathogenesis of epileptogenesis and epilepsy, BDNF may have a neuroprotective effect against epilepsy. Thus, the goal of the present review was to highlight the protective and detrimental roles of BDNF in epilepsy. In this review, we also try to find the relation of BDNF with other signaling pathways and cellular processes including autophagy, mTOR pathway, progranulin (PGN), and α-Synuclein (α-Syn) which negatively and positively regulate BDNF/tyrosine kinase receptor B (TrkB) signaling pathway. Therefore, the assessment of BDNF levels in epilepsy should be related to other neuronal signaling pathways and types of epilepsy in both preclinical and clinical studies. In conclusion, there is a strong controversy concerning the potential role of BDNF in epilepsy. Therefore, preclinical, molecular, and clinical studies are warranted in this regard.


The hamster polyomavirus--a brief review of recent knowledge.
The hamster polyomavirus (HaPV) was first described in 1967 as a virus associated with skin epithelioma of the Syrian hamster. The tumors appear spontaneously in a hamster colony bred in Berlin-Buch (HaB). Virus particles isolated from skin epitheliomas cause lymphoma and leukemia when injected into newborn hamsters from a distinct colony bred in Potsdam, Germany (HaP). The viral genome has been totally sequenced and the overall genetic organization establishes HaPV as a member of the polyomaviruses. HaPV is a second example of an middle T (MT) antigen encoding polyomavirus and nucleotide sequence homologies designates the mouse polyomavirus (Py) as the closest relative. Lymphomas induced by HaPV in HaP hamsters do not contain virus particles but instead accumulate different amounts of nonrandomly deleted free and/or integrated viral genomes. Transgenic mice produced by microinjection of HaPV DNA into the pronucleus of fertilized eggs of Gat: NMRI mice developed both, epitheliomas and lymphomas. Both tumor types contain extrachromosomal DNA. HaPV DNA was found to replicate in hamster lymphoid and fibroblast cell lines. Fully reproductive cycles could be detected only in GD36 lymphoblastic leukemia cells. HaPV carries the full transforming properties of a polyomavirus in vitro. Immortalization of primary rat cells is essentially carried out by the HaPV large T (LT) antigen and coexpression of HaPV MT and HaPV small T (ST) antigen is required for full transformation of rat fibroblasts. The preferential binding of HaPV MT to c-Fyn, a Src family kinase, has been proposed as a mechanism leading to lymphoid malignancies. Heterologous expression of HaPV-VP1 allowed the formation of virus like particles (VLPs) resembling HaPV particles. The high flexibility of HaPV-VP1 for insertion of foreign peptides offers a broad range of potential applications, especially in vaccine development.


Lysergic acid diethylamide: radioimmunoassay.
A radioimmnunoassay for d-lysergic acid diethylamide (LSD) is described. Antibodies to LSD were obtained by immunizing rabbits with a conjugate of LSD and human serum albumin. The specificity of the antibody was shown by competitive binding studies. The method has been used to detect the presence of LSD in human urines. Picogram amounts can be measured by this assay.


[Quantitative determination and reversible modification of sulfhydryl groups in low and high molecular weight compounds using a biradical spin marker].
A new method for quantitation of sulfhydryl groups of low and high molecular weight compounds is proposed. The method is based on the use of a biradical spin label carrying a disulfide bond, RS-SR, where R is the imidazoline radical. It was found that this biradical is involved in the reaction of thiol-disulfide exchange with thiols; the EPR spectra of the original biradical and monoradical products differ essentially. This circumstance made it possible to determine the bimolecular rate constant for the biradical interaction with cysteamine, cysteine, glutathione and human serum albumin. The method was used for measuring glutathione and cysteine levels in murine and rat blood and for assaying the insect acetylcholine esterase activity and reversible inhibition of NADPH-cytochrome P-450 reductase. The method is marked for a high sensitivity (10(-6)-10(-7) M) towards sulfhydryl groups and allows the determination of thiol groups in coloured and nontransparent solutions.


Leucobacter komagatae gen. nov., sp. nov., a new aerobic gram-positive, nonsporulating rod with 2,4-diaminobutyric acid in the cell wall.
A new aerobic, gram-positive, nonsporulating rod-shaped organism is described: Strain IFO 15245T (T = type strain) has the following characteristics: the menaquinone contains a side chain with 11 isoprenyl units; the guanine-plus-cytosine content of the DNA is 66.2 mol%; 2,4-diaminobutyric acid, glutamic acid, alanine, glycine, and gamma-aminobutyric acid are present in the cell wall at a molar ratio of ca. 1:1:2:1:1; and glucose and galactose are also present in the cell wall. A comparison of partial 16S rRNA sequences revealed that IFO 15245T represents a distinct line of descent within the gram-positive bacteria with high guanine-plus-cytosine contents. The taxonomic characteristics of this organism are different from those of previously described aerobic, gram-positive, nonsporulating, rod-shaped bacteria. The name Leucobacter komagatae gen. nov., sp. nov., is proposed for this organism. The type strain is strain IFO 15245.


CXCL6 promotes the progression of NAFLD through regulation of PPARα.
An increasing number of studies have shown that Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity, insulin resistance, dyslipidemia, hypertension and metabolic syndrome, but its specific pathogenesis remains unclear. By analyzing GEO database, we found CXCL6 was upregulated in liver tissues of patients with NAFLD. We also confirmed with qPCR that CXCL6 is highly expressed in serum of patients with NAFLD. To identify the underlying impact of CXCL6 on NAFLD, we established animal and cell models of NAFLD. Similarly, we confirmed by qPCR and Western blot that CXCL6 was upregulated in the NAFLD model in vitro and vivo. After transfecting NAFLD cells with siRNA targeting CXCL6 (si-CXCL6), a series of functional experiments were carried out, and these data indicated that the inhibition of CXCL6 reduced intracellular lipid deposition, decreased AST, ALT and TG level, facilitate cell proliferation and suppress their apoptosis. Furthermore, western blot and qPCR analyses displayed that the suppression of CXCL6 could raise the PPARα expression, but PPAR α inhibitor, GW6471 could partially counteract this effect. What's more, Oil Red O staining, biochemical analyzer and TG detection kit revealed that GW6471 could reverse the inhibitory effect of si-CXCL6 on NAFLD. In summary, we provide convincing evidence that CXCL6 is markedly elevated in NAFLD, and the CXCL6/PPARα regulatory network mediates disease progression of NAFLD.


Effect of re-irradiation for painful bone metastases on urinary markers of osteoclast activity (NCIC CTG SC.20U).
The NCIC CTG Symptom Control.20 randomized trial (SC.20) confirmed the effectiveness of re-irradiation to painful bone metastases. This companion study correlates urinary markers of osteoclast activity with response to re-irradiation, survival and skeletal related events (SREs). Pain response was assessed using the International Consensus Endpoints. Urinary markers of bone turnover-pyridinoline (PYD), deoxypyridinoline (DPD), N-telopeptide (NTX), Alpha and Beta cross-laps of C-telopeptide (CTX)-before and 1month after re-irradiation were correlated to response to re-irradiation and then to both, either or none of the initial and re-irradiation: frequent responders (response to both); eventual responders (response to re-irradiation only); eventual non-responders (response to initial radiation only), and absolute non-responders (no response to both). Significant differences between 40 responders and 69 non-responders to re-irradiation existed for PYD (p=0.03) and DPD (p=0.04) at baseline. When patients were categorized as frequent responders (N=34), eventual responders (6), eventual non-responders (59) and absolute non-responders (10), the mean values of all markers in the absolute non-responders at baseline and the follow-up were about double those for the other three groups with statistically significant difference for DPD (p=0.03) at baseline. Absolute non-responders had the worst survival. The few occurrences of the SREs did not allow meaningful comparisons among the groups. There were significant differences between responders and non-responders to re-irradiation for PYD and DPD at baseline. The urinary markers in the absolute non-responders were markedly elevated at both baseline and follow-up with a statistically significant difference for DPD at baseline.


Carnegie Mellon University's MMM program: management education for 21st-century physicians.
The number and types of executive and graduate-level management programs for physicians have exploded in recent years. These programs take on a variety of formats, ranging from executive seminars to master's-level degree programs. Options for physicians obtaining the master's degree tend to be either regionally based programs in traditional evening classes or nationally based programs that combine executive education formats with distance education. This paper examines a nationally based program - the Master of Medical Management (MMM) - from the perspectives of an administrator and a graduate of the program. It offers reasons for the growth of similar programs and data from students enrolled in the Carnegie Mellon University MMM program. The paper also examines educational outcomes in the form of behavioral competencies that the physicians acquired in the program. It concludes with reflections on the future of the MMM and related programs for physician executives in the 21st century.


The Ethical Implications of Big Data Research in Public Health: "Big Data Ethics by Design" in the UK-REACH Study.
In this article, we analyze legal and ethical issues raised in Big Data health research projects in the Covid-19 era and consider how these issues might be addressed in ways that advance positive values (e.g., furtherance of respect for persons and accordance with relevant legal frameworks) while mitigating or eliminating any negative aspects (e.g., exacerbation of social inequality and injustice). We apply this analysis specifically to UK-REACH (The United Kingdom Research Study into Ethnicity and Covid-19 Outcomes in Healthcare Workers), a project with which we are involved. We argue that Big Data projects like UK-REACH can be conducted in an ethically robust manner and that funders and sponsors ought to encourage similar projects to drive better evidence-based public policy in public health. As part of this, we advocate that a Big Data ethics-by-design approach be undertaken when such projects are constructed. This principle extends the work of those who advocate ethics by design by addressing prominent issues in Big Data health research projects; it holds that ethical values and principles in Big Data health research projects are best adhered to when they are already integrated into the project aims and methods at the design stage. In advocating this principle, we present a unique perspective regarding pressing ethical problems around large-scale, data-driven Covid-19 research, as well as legal issues associated with processing ostensibly anonymized health data.


Corneal iron lines after refractive keratoplasty.
Twenty-three of 55 patients who underwent refractive keratoplasty for the correction of aphakia were found to have a pigmented corneal epithelial line similar to the Fleischer ring. In 21 of 23 cases, the pigmented ring was adjacent to the superficial keratectomy scar that resulted from the keratorefractive operation. In two cases, the pigmented line was located central to the lamellar keratectomy scar. Histopathologic study demonstrated that the line was due to iron in the form of ferritin particles deposited within basal corneal epithelial cells. We believe that the steep anterior corneal curvature (average, 51.45 diopters) and changes in corneal topography at or central to the margin of the lamellar keratoplasty may lead to malapposition of the eyelid to the cornea and cause disturbances in the precorneal tear film. Iron from the tears may then be deposited in the corneal epithelium in areas of tear pooling.


Infliximab maintains durable response and facilitates catch-up growth in luminal pediatric Crohn's disease.
Infliximab induces and maintains clinical remission in children with Crohn's disease (CD), but specifically pediatric long-term data remain sparse. Patients (N = 195) who received infliximab ± immunomodulator for luminal CD were retrospectively reviewed. Outcomes included clinical response, linear growth, and mucosal healing. Durability of response was assessed using Cox proportional hazards models. Levels of infliximab and antibodies (antibodies to infliximab) were measured when response was lost. Among 195 patients (median age, 13.9 yr; median CD duration, 1.6 yr), 81% experienced complete response (judged by physician global assessment and pediatric Crohn's disease activity index ≤10). Longer duration of diagnosed CD and female gender were associated with lower response. During first year of follow-up, 35% of subjects had regimen individualized through dose escalation/interval shortening. Despite regimen optimization, 16/157 complete responders experienced loss of response at a rate of 2% to 6% per year over 5 years, associated with development of antibodies to infliximab. Concurrent immunomodulation for ≥30 weeks significantly decreased loss of response (hazard ratio = 0.25, 95% confidence interval, 0.08-0.76; P = 0.014). Follow-up endoscopic examination was performed in 40 responders, of whom 22 (73%) demonstrated complete resolution of mucosal ulceration. Patients with growth potential (Tanner 1/2 at induction) demonstrated significant improvements in mean height z-score from induction to years 1 and 2 of follow-up (P < 0.001). With infliximab initiation within the first 18 months after diagnosis, mean height z-score normalized to 0 after 3 years. These data demonstrate sustained effectiveness of infliximab in children and adolescents with luminal CD. Durability of response is increased by concomitant immunomodulation. Clinical response is associated with enhanced linear growth, particularly when therapy is initiated early.


Location of the right boundary of the virulence region on Agrobacterium tumefaciens plasmid pTiC58 and a host-specifying gene next to the boundary.
The right boundary of the virulence (Vir) region of the nopaline plasmid pTiC58 of Agrobacterium tumefaciens was determined by transposon insertion, cartridge emplacement, and deletion mutagenesis. Genetic complementation with mutant and wild-type alleles led to the identification of the virE locus at the right boundary, which was located about 6 kilobases from the left border of the segment of DNA that is transferred into the plant genome. virE is 2.0 kilobases long and encodes at least one protein of 69 kilodaltons. Various mutations in virE resulted in different truncated lengths of the 69-kilodalton protein. As this protein was increasingly truncated from the carboxy terminus, the host range of A. tumefaciens and the frequency of tumor formation diminished concomitantly. Thus, as one of its functions, the 69-kilodalton protein of virE is probably involved in some aspect of the host range specificity of A. tumefaciens and in infection efficiency.


The thyroid receptor modulator KB3495 reduces atherosclerosis independently of total cholesterol in the circulation in ApoE deficient mice.
Thyroid hormones (TH) regulate cholesterol metabolism but their use as lipid-lowering drugs is restricted due to negative cardiac effects. TH mimetic compounds modulating TH receptor β (THRβ) have been designed as potential drugs, reducing serum cholesterol levels while avoiding apparent deleterious cardiac effects. Using ApoE deficient mice, we examined whether KB3495, a TH mimetic compound, reduces atherosclerosis and if there is a synergistic effect with atorvastatin. The effect of KB3495 was investigated after 10 and 25 weeks. KB3495 treatment reduced atherosclerotic plaque formation in aorta and decreased the cholesteryl ester (CE) content by 57%. Treatment with KB3495 was also associated with a reduction of macrophage content in the atherosclerotic plaques and reduced serum levels of IL-1β, TNFalpha, IL-6, Interferon γ, MCP-1 and M-CSF. Serum lipoprotein analysis showed no change in total cholesterol levels in ApoB-containing lipoproteins. KB3495 alone increased fecal BA excretion by 90%. The excretion of neutral sterols increased in all groups, with the largest increase in the combination group (350%). After 25 weeks, the animals treated with KB3495 showed 50% lower CE levels in the skin and even further reductions were observed in the combination group where the CE levels were reduced by almost 95% as compared to controls. KB3495 treatment reduced atherosclerosis independently of total cholesterol levels in ApoB-containing lipoproteins likely by stimulation of sterol excretion from the body and by inhibition of the inflammatory response.


A robotic molecular method for in situ detection of marine invertebrate larvae.
Knowledge of the temporal and spatial abundance of invertebrate larvae is critical to understanding the dispersal capabilities and recruitment potential of marine and aquatic organisms. Traditional microscopic analyses are time-consuming and difficult given the diversity of larval species and a frequent lack of discriminating morphological characteristics. Here, we describe a sensitive rRNA targeted sandwich hybridization assay (SHA) that uses oligonucleotide probes to detect and enumerate the larvae of invasive green crabs (Carcinus maenas), native blue mussels (Mytilus), native barnacles (Balanus) and polychaetes (Osedax and Ophelia) that occur in the Monterey Bay National Marine Sanctuary, California. Laboratory-based assays demonstrate specificity, high sensitivity, and a quantitative response to cultured samples from three of the target organisms. Oligonucleotide probes were then printed in arrays on nitrocellulose membranes and deployed in our robotic Environmental Sample Processor (ESP) to detect larvae in situ and autonomously. We demonstrate that the SHA-detection method and ESP robot can be used for near real-time, in situ detection of larval species in the marine environment.


Resurrection of Ancestral Malate Dehydrogenases Reveals the Evolutionary History of Halobacterial Proteins: Deciphering Gene Trajectories and Changes in Biochemical Properties.
Extreme halophilic Archaea thrive in high salt, where, through proteomic adaptation, they cope with the strong osmolarity and extreme ionic conditions of their environment. In spite of wide fundamental interest, however, studies providing insights into this adaptation are scarce, because of practical difficulties inherent to the purification and characterization of halophilic enzymes. In this work, we describe the evolutionary history of malate dehydrogenases (MalDH) within Halobacteria (a class of the Euryarchaeota phylum). We resurrected nine ancestors along the inferred halobacterial MalDH phylogeny, including the Last Common Ancestral MalDH of Halobacteria (LCAHa) and compared their biochemical properties with those of five modern halobacterial MalDHs. We monitored the stability of these various MalDHs, their oligomeric states and enzymatic properties, as a function of concentration for different salts in the solvent. We found that a variety of evolutionary processes, such as amino acid replacement, gene duplication, loss of MalDH gene and replacement owing to horizontal transfer resulted in significant differences in solubility, stability and catalytic properties between these enzymes in the three Halobacteriales, Haloferacales, and Natrialbales orders since the LCAHa MalDH. We also showed how a stability trade-off might favor the emergence of new properties during adaptation to diverse environmental conditions. Altogether, our results suggest a new view of halophilic protein adaptation in Archaea.


Ras-mediated activation of mTORC2 promotes breast epithelial cell migration and invasion.
We previously identified the mechanistic target of rapamycin complex 2 (mTORC2) as an effector of Ras for the control of directed cell migration in Dictyostelium. Recently, the Ras-mediated regulation of mTORC2 was found to be conserved in mammalian cells, and mTORC2 was shown to be an effector of oncogenic Ras. Interestingly, mTORC2 has been linked to cancer cell migration, and particularly in breast cancer. Here, we investigated the role of Ras in promoting the migration and invasion of breast cancer cells through mTORC2. We observed that both Ras and mTORC2 promote the migration of different breast cancer cells and breast cancer cell models. Using HER2 and oncogenic Ras-transformed breast epithelial MCF10A cells, we found that both wild-type Ras and oncogenic Ras promote mTORC2 activation and an mTORC2-dependent migration and invasion in these breast cancer models. We further observed that, whereas oncogenic Ras-transformed MCF10A cells display uncontrolled cell proliferation and invasion, disruption of mTORC2 leads to loss of invasiveness only. Together, our findings suggest that, whereas the Ras-mediated activation of mTORC2 is expected to play a minor role in breast tumor formation, the Ras-mTORC2 pathway plays an important role in promoting the migration and invasion of breast cancer cells.


Mutualist-mediated effects on species' range limits across large geographic scales.
Understanding the processes determining species range limits is central to predicting species distributions under climate change. Projected future ranges are extrapolated from distribution models based on climate layers, and few models incorporate the effects of biotic interactions on species' distributions. Here, we show that a positive species interaction ameliorates abiotic stress, and has a profound effect on a species' range limits. Combining field surveys of 92 populations, 10 common garden experiments throughout the range, species distribution models and greenhouse experiments, we show that mutualistic fungal endophytes ameliorate drought stress and broaden the geographic range of their native grass host Bromus laevipes by thousands of square kilometres (~ 20% larger) into drier habitats. Range differentiation between fungal-associated and fungal-free grasses was comparable to species-level range divergence of congeners, indicating large impacts on range limits. Positive biotic interactions may be underappreciated in determining species' ranges and species' responses to future climates across large geographic scales.


Venous Thrombo-Embolism in Hospitalized SARS-CoV-2 Patients Treated with Three Different Anticoagulation Protocols: Prospective Observational Study.
The purpose of this study is to assess thrombotic risk in CoViD-19/pneumonia patients with acute respiratory failure and to compare populations treated with three different antithrombotic prophylaxis protocols. The primary outcome is to analyze the prevalence of thrombotic events in hospitalized patients, while the secondary outcome is to analyze the correlation between different anticoagulation targets with thrombotic events. All patients referred to our hospital for acute respiratory failure due to COVID-19 pneumonia between 18 and 31 May 2020 were included. Seventy-four patients were enrolled (44 men and 30 women, average age 68.6). Diagnosis of venous thromboembolism was made in 21 cases (28.4%) and thrombotic events were associated with positive pressure ventilation support (p = 0.024) and hospitalization in ICU (p < 0.0001). These patients presented higher levels of D-dimer (p < 0.0001) and their hospital length of stay was >16 days longer. Forty-seven out of 74 patients (63.5%) received intermediate or therapeutic dose of anticoagulation, while twenty-seven patients (34.5%) received standard antithrombotic prophylaxis. The analysis showed that an intermediate or therapeutic dose of anticoagulation did not decrease the prevalence of thrombotic events. On the other hand, six patients reported severe hemorrhagic complications. Despite intermediate or therapeutic-dose of anticoagulation, a high number of patients with acute respiratory failure secondary to COVID-19 developed thrombotic complications.


Health and living arrangements among older Americans: does marriage matter?
This research examines how physical and mental health influence living arrangements among older Americans and whether these effects differ for married and unmarried persons. Data came from the Asset and Health Dynamics Among the Oldest Old study. These two intervals were pooled, and hierarchical multinomial logistic regressions were used to analyze pooled time lags. Functional status and cognitive functioning are significantly associated with living arrangements among those not married. Health conditions exert no significant effects among those married. Given the same functional status, unmarried elders are significantly more likely than their married counterparts to reside with their children or with others. These results underscore the critical role of the spouse in influencing living arrangements, providing new evidence supporting the assertion that a spouse is the greatest guarantee of support in old age and the importance of the marriage institution.


Compensatory and decompensatory alterations in cardiomyocyte Ca2+ dynamics in hearts with diastolic dysfunction following aortic banding.
At the cellular level cardiac hypertrophy causes remodelling, leading to changes in ionic channel, pump and exchanger densities and kinetics. Previous studies have focused on quantifying changes in channels, pumps and exchangers without quantitatively linking these changes with emergent cellular scale functionality. Two biophysical cardiac cell models were created, parameterized and validated and are able to simulate electrophysiology and calcium dynamics in myocytes from control sham operated rats and aortic-banded rats exhibiting diastolic dysfunction. The contribution of each ionic pathway to the calcium kinetics was calculated, identifying the L-type Ca2+ channel and sarco/endoplasmic reticulum Ca2+ ATPase as the principal regulators of systolic and diastolic Ca2+ , respectively. Results show that the ability to dynamically change systolic Ca2+ , through changes in expression of key Ca2+ modelling protein densities, is drastically reduced following the aortic banding procedure; however the cells are able to compensate Ca2+ homeostasis in an efficient way to minimize systolic dysfunction. Elevated left ventricular afterload leads to myocardial hypertrophy, diastolic dysfunction, cellular remodelling and compromised calcium dynamics. At the cellular scale this remodelling of the ionic channels, pumps and exchangers gives rise to changes in the Ca2+ transient. However, the relative roles of the underlying subcellular processes and the positive or negative impact of each remodelling mechanism are not fully understood. Biophysical cardiac cell models were created to simulate electrophysiology and calcium dynamics in myocytes from control rats (SHAM) and aortic-banded rats exhibiting diastolic dysfunction. The model parameters and framework were validated and the fitted parameters demonstrated to be unique for explaining our experimental data. The contribution of each ionic pathway to the calcium kinetics was calculated, identifying the L-type Ca2+ channel (LCC) and the sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA) as the principal regulators of systolic and diastolic Ca2+ , respectively. In the aortic banding model, the sensitivity of systolic Ca2+ to LCC density and diastolic Ca2+ to SERCA density decreased by 16-fold and increased by 23%, respectively, relative to the SHAM model. The energy cost of ionic homeostasis is maintained across the two models. The models predict that changes in ionic pathway densities in compensated aortic banding rats maintain Ca2+ function and efficiency. The ability to dynamically alter systolic function is significantly diminished, while the capacity to maintain diastolic Ca2+ is moderately increased.


Effects of practice combined with somatosensory or motor stimulation on hand function in persons with spinal cord injury.
Individuals with chronic tetraplegia prioritize recovery of hand function as an important factor in improving their quality of life. Interventions that may improve hand function and increase corticomotor excitability are functional electrical stimulation (FES), somatosensory stimulation (SS), and task-oriented training. We compared functional and corticomotor outcomes in a control condition to changes associated with FES (triggered via electromygraphic signals) and with SS (constant trains), each combined with either unimanual or bimanual training. Using a randomized, clinical trial design, comparisons were made to a delayed intervention control group. Participants (n = 24) had chronic tetraplegia, with the ability to activate thenar muscles, and were randomly assigned to either the immediate intervention (intervention) or control/ delayed intervention groups. Primary analyses compared intervention (FES or SS) to control/delayed intervention. Secondary analyses compared subgroups of FES versus SS (regardless of uni- or bilateral training) and uni- versus bimanual training (regardless of stimulation type). Outcomes were assessed before and after the control and the intervention period. Compared to control/delayed intervention, the intervention group had greater changes in unimanual function and corticomotor area, regardless of whether practice was combined with FES or with SS. Irrespective of stimulation type, the bimanual subgroups improved to a greater extent than the unimanual subgroups on the bimanual hand function test. Hand training combined with either SS or FES was associated with improved hand use and corticomotor activity in persons with chronic tetraplegia. Both interventions appear to be equally effective.


Cranberry use among pediatric nephrology patients.
Recurrent urinary tract infections are common in children, and the use of complementary therapies is common in other children with recurrent illnesses. However, little is known about the use of cranberry products by children with renal disease. We hypothesized that, because cranberry is often used to prevent urinary tract infections (UTI) in adult women, many parents would give it to their children, particularly to children prone to recurrent UTI (rUTI). Anonymous, cross-sectional, self-administered survey of parents of children seen in the pediatric nephrology clinic at Brenner Children's Hospital between June 1, 2004, and August 13, 2004. Of the 117 parents surveyed, the patients' average age was 10.3 years, and 15% reported rUTI as a problem. Overall, 29% of surveyed parents gave cranberry products therapeutically; as expected, use was higher among those with rUTI (65%) than among those with other renal conditions (23%); odds ratio = 6.1 (2.0, 18.4, P < .001); many parents gave cranberry to treat as well as prevent diverse renal problems. Most felt it was beneficial and only 1 parent reported a side effect (nausea). Only 23% of those who used it had discussed cranberry use with their physician. Cranberry is commonly used therapeutically among patients seen in a pediatric nephrology clinic and is perceived as useful by parents, though uncommonly discussed with physicians. Randomized controlled trials are needed to determine the effectiveness of cranberry juice therapy for rUTI in children.


Characterization and quantitative analysis of DNA adducts formed from lower chlorinated PCB-derived quinones.
Polychlorinated biphenyls are wide pollutants readily detected in environmental and human specimens. DNA adduction occurs through the corresponding quinones. Polychlorinated biphenyls are first metabolized to arene oxides, which can be further oxidized to dihydroxy metabolites by microsomal cytochrome p450s. The catechol and hydroquinone products are further oxidized by peroxidases to quinones, which are electrophilic and capable of reacting with DNA to form adducts. DNA adduction is initiated by Michael addition preferentially to guanosine followed by stabilization through enolization. Another nucleophilic attack forms a five-membered ring, which aromatizes by dehydration to form the final adduct. This report describes the characterization and quantitative study of DNA adducts formed from lower chlorinated PCB-derived quinones. Quantitative study by HPLC/ESI-MS/MS and (32)P-postlabeling-HPLC gave the adduct levels in the range of 3-1200 adducts per 10(8) nucleotides. These results demonstrate that increasing chlorine substitution is associated with lower yields of DNA adduct. Although (32)P-postlabeling is more sensitive than HPLC/ESI-MS/MS for the quantitative analysis of DNA adducts, modification levels were severely underestimated by the (32)P-postlabeling assay as compared to the HPLC/ESI-MS/MS assay.


The occurrence and antimicrobial susceptibility of salmonellae isolated from commercially available canine raw food diets in three Canadian cities.
The purpose of the present study was to evaluate the prevalence and antimicrobial resistance patterns of Salmonella isolated from commercially available canine raw food diets in Canada. A total of 166 commercial frozen raw food diet samples were purchased from randomly selected local pet stores in three Canadian cities for a period of 8 months. All samples were evaluated for the presence of Salmonella, serotyped and tested for antimicrobial susceptibility. There was an overall Salmonella prevalence of 21%; chicken was an ingredient for 67% of the Salmonella-positive diets. Eighteen different Salmonella serotypes were recovered, and resistance was observed to 12 of the 16 antimicrobials tested, with the majority of Ontario isolates exhibiting resistance to ampicillin and Calgary isolates to tetracycline. This study demonstrates the potential risk of raw food diets, especially for immunocompromised individuals, and stresses the need for implementing regulatory guidelines for the production of these diets in order to help control and ideally eliminate the bacterial risks associated with their use and consumption.


Proton NMR of aequorin. Structural changes concomitant with calcium-independent light emission.
Aequorin, a Ca(II)-sensitive bioluminescent protein from jellyfish, emits light at 469 nm from an excited state of a substituted pyrazine (oxyluciferin) which results from the oxidation of a chromophore molecule that is noncovalently bound to the protein. The chromophore is oxidized when Ca(II) or other activating metal ions are bound by aequorin. In the absence of Ca(II), spontaneous emission of light, referred to as Ca(II)-independent light emission, occurs at a rate less than 10(-6) of that for Ca(II)-induced emission. Proton nuclear magnetic resonance (NMR), circular dichroism (CD), and fluorescence were used to study structural changes of aequorin accompanying Ca(II)-independent light emission. Time course studies by 1H NMR and CD demonstrate that as a result of Ca(II)-independent light emission, aequorin progressively changes from a rigid, fully active form showing little segmental mobility to a practically unfolded, discharged (i.e., inactive) form in which a number of amino acid residues are significantly mobile. This slow discharged protein (SDP) is distinct in nature and conformation from aequorin which has been discharged by Ca(II), i.e., the blue fluorescent protein. The rate of Ca(II)-independent discharge of aequorin is substantially reduced in the presence of excess Mg(II); the time constant for inactivation at 5 degrees C is 30 days with no Mg(II) present and 70 days with Mg(II) present. The NMR spectra are nearly identical at a given stage of inactivation whether or not Mg(II) is present. Oxyluciferin remains bound to SDP. If it is removed, however, by column chromatography, the resulting apo-SDP partially refolds, and the segmental mobility acquired in the formation of SDP is significantly attenuated particularly for some of the aromatic amino acid residues.


Time course of neuroprotection induced by in vivo normobaric hyperoxia preconditioning and angiogenesis factors.
Every year, a large number of people lose their lives due to stroke. Stroke is the second leading cause of death worldwide. Surprisingly, recent studies have shown that preconditioning with hyperoxia (HO) increases tissue tolerance to ischemia, ultimately reducing damages caused by stroke. Addressed in this study are beneficial contributions from HO preconditioning into reduced harm to be incurred by the attack, as well as its effect on the expression levels of vascular endothelial growth factor (VEGF) and endostatin. A set of experiments was conducted where a number of rats were divided into three groups. The animals in the first group received 90% oxygen for 4 hr a day, for 6 days. The second group was housed in room air and the third group was a sham (surgical stress). After 60 min of ischemia, 24 hr blood flow, neurological deficit score (NDS) and infarct volume (IV) in the group MCAO (Middle Cerebral Artery Occlusion) were investigated. Immediately following a 48 hr HO pre-treatment, sampling was performed to measure the expression levels of VEGF and endostatin. Preconditioning with alternating HO led to reduced infarct volume and NDS. Moreover, pre-treatment with HO resulted in increased VEGF expression while decreasing endostatin. Although further studies are deemed necessary to clarify the mechanisms of ischemic tolerance, apparently, somewhat intermittent hyperoxia can be associated with positive impacts by increasing VEGF and decreasing expression of endostatin.


[Outpatient rehabilitation of alcohol dependent patients in a day clinic: initial results of a comparative follow-up study of day clinic and inpatient treatment].
This article describes the development of an outpatient concept for the day-clinic withdrawal treatment of alcohol dependent persons in a Hamburg institution for addiction aid. It reports the initial, selected results of a comparative follow-up study of patients discharged during the years 1998-2000, who either receive ambulatory treatment in the day clinic (n = 270) or inpatient treatment in the institution's special clinic (n = 462). Assessable questionnaires are available from 131 outpatients of the day-clinic treatment and 173 patients of the inpatient treatment form. The response rate - with reference to the group of those who were reachable - was 57.2 % for patients of the day clinic and 53.2 % for patients of the special clinic. The results of the study arrive at the conclusion that both treatment forms can be seen as thoroughly comparable with regard to primary outcome measurements (for example reduction of psychological stress, abstinence rates, reintegration into occupational life). Rehabilitants treated in the inpatient setting more frequently report that they had already contacted centres for further treatment and self-help groups during the rehabilitation phase, which however doesn't lead to a change of participation behaviour following the rehabilitation phase. This serves to confirm the assumption that an additional offer of a day-clinic service in the area of addiction rehabilitation provides a further, effective treatment concept that sensibly supplements the otherwise inpatient-oriented treatment landscape. The results indicate the quality of the work performed in the day clinic studied (as well as in the inpatient clinic) and should encourage the funding agencies and employees of other day clinic institutions in the field of addiction rehabilitation to participate in evaluation and quality assurance measures, thus continuing to bridge the gap between the (theoretical) state of knowledge concerning outpatient rehabilitation and the degree to which it can be successfully realized.


Practice on Metered Dose Inhaler Techniques and Its Associated Factors among Asthmatic Patients at Debre Markos Comprehensive Specialized Hospital, East Gojjam, Ethiopia: A Prospective Study.
Asthma stands 16th among the leading causes of years lived with disability and 28th among the leading causes of disease in the world. A metered-dose inhaler remains the principal route for drug administration, and it has greater advantages over systemic treatment. In routine use, however, a majority of patients make inhalation errors. Suboptimal inhaler technique worsens health outcomes, with poor disease control, and increases the risk of hospitalization. This study aimed to assess practice metered-dose inhalation techniques and associated factors among asthmatic patients at Debre Markos Comprehensive Specialized Hospital, East Gojjam, Amhara region, Ethiopia. Prospective cross-sectional study was conducted from July 15 to August 30, 2020. Data were collected through a semistructured questionnaire. The data were analyzed using SPSS version 25. Associations between dependent and independent variables were assessed by using binary and multiple logistic regressions. P values less than 0.05 were considered to be statistically significant in all cases. Results are presented in tables, figures, numbers, and percentages. A total of 166 patients had involved in the study, of which 52.4% were females. One hundred and eleven (66.9%) participants had good knowledge of asthma and inhalational techniques, while the rest of them had poor knowledge. One hundred and eight (65.1%) patients had effective practice on metered-dose inhaler use techniques. Participant's knowledge regarding asthma and meter dose inhaler and marital status has a significant association with their practice of metered-dose inhaler techniques with P value 0.001 and 0.006, respectively. In this study, most participants are suffering from asthma for a long duration and they have repeated exacerbation. Around two-thirds of patients had good knowledge regarding asthma and metered-dose inhaler and practice on metered-dose inhaler techniques. Participants with poor knowledge had poor practice on metered-dose inhaler techniques, and single patients were less likely to have poor practice on metered-dose inhaler techniques. Health education and counseling services should be consistently provided to the clients regarding the proper steps of inhalers use.


Development of program-controlled portable insulin delivery devices.
Various alternatives for program-controlled insulin delivery systems, on which we have been working since 1972, are described. Fixed-programmable and demand-programmable devices, both in two parts comprising separate control and delivery units, have been miniaturized and technically improved to the extent that they can now be used for the ambulant, long-term treatment of diabetic patients. The electronic drive systems, including control and safety circuits, that are discussed using the demand-type system as an example have been conventionally designed, using CMOS technology. The mechanical components of the insulin-delivery devices, in particular the roller pump driven by a stepping motor, have been developed in such a way that they can also be employed in implantable devices, without any essential modifications. Particular attention was thus paid to the features of miniaturization, high insulin concentration, low energy consumption, and a high degree of safety and reliability. The experience obtained from broad-based clinical trials of the devices is summarized briefly.


Phenotypic modifications in ovarian cancer stem cells following Paclitaxel treatment.
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite initial responsiveness, 80% of EOC patients recur and present with chemoresistant and a more aggressive disease. This suggests an underlying biology that results in a modified recurrent disease, which is distinct from the primary tumor. Unfortunately, the management of recurrent EOC is similar to primary disease and does not parallel the molecular changes that may have occurred during the process of rebuilding the tumor. We describe the characterization of unique in vitro and in vivo ovarian cancer models to study the process of recurrence. The in vitro model consists of GFP+/CD44+/MyD88+ EOC stem cells and mCherry+/CD44-/MyD88- EOC cells. The in vivo model consists of mCherry+/CD44+/MyD88+ EOC cells injected intraperitoneally. Animals received four doses of Paclitaxel and response to treatment was monitored by in vivo imaging. Phenotype of primary and recurrent disease was characterized by quantitative polymerase chain reaction (qPCR) and Western blot analysis. Using the in vivo and in vitro models, we confirmed that chemotherapy enriched for CD44+/MyD88+ EOC stem cells. However, we observed that the surviving CD44+/MyD88+ EOC stem cells acquire a more aggressive phenotype characterized by chemoresistance and migratory potential. Our results highlight the mechanisms that may explain the phenotypic heterogeneity of recurrent EOC and emphasize the significant plasticity of ovarian cancer stem cells. The significance of our findings is the possibility of developing new venues to target the surviving CD44+/MyD88+ EOC stem cells as part of maintenance therapy and therefore preventing recurrence and metastasis, which are the main causes of mortality in patients with ovarian cancer.


Medical informatics specialists: what are their job profiles? Results of a study on the first 1024 medical informatics graduates of the Universities of Heidelberg and Heilbronn.
Since 1972, the University of Heidelberg and the University of Applied Sciences Heilbronn have jointly been running a medical informatics program. To continuously provide high quality education, the curriculum is regularly evaluated among its graduates. The objectives of this study were to assess the job situation of the graduates and to evaluate the curriculum from their viewpoint. Anonymous inquiry of all medical informatics graduates, having finished their studies before March 31, 2001 (n=1024) using a structured questionnaire. The questionnaire was answered by 446 (compliance: 45.5%) graduates. About one third (146 of 444 valid cases) are working in software/hardware companies. 179 (43.0% of 416 valid cases) graduates are working within medical informatics, 214 (51.4%) are working outside of medical informatics, but within other informatics. 23 (5.5%) graduates are working neither in medical nor in other informatics. 15 percent of the responding graduates have received a doctor's degree. Software engineering, database and information systems are regarded as most important parts of the education. The majority of the graduates are satisfied with their education as well as with their personal career. The variety of jobs, the job profiles, and the high level of our graduates' satisfaction with their education indicate the relevance of specialized medical informatics programs with a curricular profile like the one in Heidelberg/Heilbronn. Investigations like this can help to adjust the contents of the curriculum to professional needs.


Polyphenol-rich Indian ginger cultivars ameliorate GLUT4 activity in C2C12 cells, inhibit diabetes-related enzymes and LPS-induced inflammation: An in vitro study.
Diabetes is a chronic metabolic disorder that results in distorted insulin signaling and microvascular complications. Current antidiabetic drugs possess harmful long term side effects, necessitating the need for alternate or compliment therapy with lesser issues. Medicinal plants such as ginger have been reported to possess several beneficial activities including antidiabetic activity. The antidiabetic efficacy of microwave-assisted polyphenolic extracts of Indian ginger cultivars from Odisha (MPO) and Tamil Nadu (MPT) is reported here. MPT and MPO showed insulin stimulated glucose uptake of 1.74 ± 0.25 and 1.47 ± 0.15 fold at 6.25 µg/ml of concentrations in C2C12 cells respectively when compared to control. MPT possessed α-amylase, α-glucosidase inhibitory and anti-glycation properties. It also showed DPPH radical scavenging activity (7.69 ± 0.001%), inhibited LPS-induced nitric oxide production (1.06 ± 0.004 fold) than the latter and increased the GLUT4 protein expression by 1.4 fold. Major active compounds such as shogaol and gingerol derivatives, curcumene, zingiberone were identified through GC-ESI/MS analysis and D-pinitol (cyclitol) was identified through HPLC analysis in this variety. This is the first paper to report the presence of an antidiabetic compound, D-pinitol, in the ginger variety. Polyphenol rich, biologically potent ginger extracts can be a good food and nutraceutical supplement to address diabetes and related complications. PRACTICAL APPLICATIONS: Ginger is a native spice of South Asian Countries including India. Ginger extracts possess several medicinal properties such as anti-inflammatory, antidiabetic and antioxidant activities. It is used to treat nausea, vomiting and commonly used as a food flavouring agent and dietary food supplement. Our study shows the antidiabetic, anti-glycation and antioxidant efficacy of polyphenol rich Indian ginger cultivars grown in different geographical regions. Variations in the biological activities between the MPT and MPO ginger variety was observed. Different environmental conditions and their corresponding metabolite accumulation can be correlated with the better activity shown by MPT variety. It showed an increased GLUT4 expression even at a lower dose of 6.25 µg/ml. Ginger cultivar, especially MPT variety can be used as an adjuvant therapy for treating diabetes. Therefore, our study indicates that polyphenols rich ginger cultivar has major application in functional food product development.


Comparison of a self-inflating bulb syringe and a colorimetric CO2 indicator with capnography and radiography to detect the misdirection of naso/orogastric tubes into the airway of critically ill adult patients.
The objective of this study was to develop a mechanism of discovering misdirection into the airway of naso/orogastric (NG) tubes before they reach their full depth of placement in adults. A prospective, observational study was performed in humans, evaluating both the self-inflating bulb syringe (SIBS) and a colorimetric CO2 detector. A prospective convenience sample of 257 NG tube placements was studied in 199 patients in medical ICUs of a tertiary care medical center. Findings were compared to a "standard" (ie, end tidal CO2 results of a capnograph and the results of a chest radiograph performed at the completion of the tube placement). On the first tube placement attempt in any patient, the SIBS had a sensitivity of 91.5% and a specificity of 87.0% in detecting nonesophageal placement, while the colorimetric device exhibited 99.4% sensitivity and 91.3% specificity. On subsequent insertions, the SIBS showed 95.7% sensitivity and 100% specificity, while the colorimetric device exhibited 97.8% sensitivity and 100% specificity. The colorimetric device was eight times more expensive than the SIBS. The SIBS and the colorimetric CO2 detector are very good at detecting NG tube malpositioning into the airway, although the colorimetric device is slightly more sensitive and specific. Neither method adds substantial time or difficulty to the insertion process. The colorimetric device is substantially more expensive. The decision as to which method to use may be based on local institutional factors, such as expense.


Multiphasic Regulation of Systemic and Peripheral Organ Metabolic Responses to Cardiac Hypertrophy.
Reduced fat oxidation in hypertrophied hearts coincides with a shift of carnitine palmitoyl transferase I from muscle to increased liver isoforms. Acutely increased carnitine palmitoyl transferase I in normal rodent hearts has been shown to recapitulate the reduced fat oxidation and elevated atrial natriuretic peptide message of cardiac hypertrophy. Because of the potential for reduced fat oxidation to affect cardiac atrial natriuretic peptide, and thus, induce adipose lipolysis, we studied peripheral and systemic metabolism in male C57BL/6 mice model of transverse aortic constriction in which left ventricular hypertrophy occurred by 2 weeks without functional decline until 16 weeks (ejection fraction, -45.6%; fractional shortening, -22.6%). We report the first evidence for initially improved glucose tolerance and insulin sensitivity in response to 2 weeks transverse aortic constriction versus sham, linked to enhanced insulin signaling in liver and visceral adipose tissue (epididymal white adipose tissue [WAT]), reduced WAT inflammation, elevated adiponectin, mulitilocular subcutaneous adipose tissue (inguinal WAT) with upregulated oxidative/thermogenic gene expression, and downregulated lipolysis and lipogenesis genes in epididymal WAT. By 6 weeks transverse aortic constriction, the metabolic profile reversed with impaired insulin sensitivity and glucose tolerance, reduced insulin signaling in liver, epididymal WAT and heart, and downregulation of oxidative enzymes in brown adipose tissue and oxidative and lipogenic genes in inguinal WAT. Changes in insulin signaling, circulating natriuretic peptides and adipokines, and varied expression of adipose genes associated with altered insulin response/glucose handling and thermogenesis occurred prior to any functional decline in transverse aortic constriction hearts. The findings demonstrate multiphasic responses in extracardiac metabolism to pathogenic cardiac stress, with early iWAT browning providing potential metabolic benefits.


First phase of glucose-stimulated insulin secretion from MIN 6 cells does not always require extracellular calcium influx.
To demonstrate an involvement of ATP-sensitive potassium (K(ATP)) channel-independent pathways in the first phase of glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells, the time course of GSIS from MIN6 cells was analyzed at 30-s sample intervals. GSIS was biphasic with the first phase being observed 120 to 390 s after glucose addition, peaking at 180 s, and with a shoulder at 240 to 330 s. Both 10 microM diazoxide and 3 microM verapamil completely inhibited tolbutamide- or glibenclamide-induced insulin secretion and suppressed the peak of the first phase of GSIS, but did not result in complete suppression. The shoulder following the peak was suppressed by 1 muM dantrolene. The peak, but not shoulder, disappeared under the extracellular Ca2+-free condition. A significant amount of insulin secretion remained even in the combined presence of verapamil and dantrolene. The Na+ channel blocker tetrodotoxin (30 nM) nearly completely inhibited the first phase release. These results suggest that the first phase of GSIS from MIN6 cells depends on both Ca2+-dependent and -independent mechanisms. The former mechanism includes the extracellular Ca2+ influx via L-type voltage-dependent calcium channel and intracellular Ca2+ release from endoplasmic reticulum via ryanodine receptors, and the latter mechanism involves the pathways associated with Na+ channels.


Transmission of tuberculosis in San Francisco and its association with immigration and ethnicity.
To determine tuberculosis transmission dynamics in San Francisco and its association with country of birth and ethnicity. Restriction fragment length polymorphism (RFLP) typing was performed on Mycobacterium tuberculosis isolates from culture-positive pulmonary tuberculosis patients in San Francisco (1991 through 1996), using IS6110 as a probe. Patients were assigned to clusters based on mycobacterial isolates with identical DNA fingerprints. Clusters were assumed to have arisen from recent transmission. A transmission index was defined as the average number of culture-positive pulmonary tuberculosis cases generated by a single source case and calculated for subgroups. The transmission index was higher in US-born (0.59) than in foreign-born groups (0.21), and was highest in blacks, in particular those aged under 35 years. The increased transmission index among blacks was not explained by smear-positivity, human immunodeficiency virus infection, or increased susceptibility to disease progression. US-born tuberculosis cases generated more secondary cases than immigrants. Young blacks appear to be a high-risk group for tuberculosis transmission. These results suggest the need to develop interventions targeted towards this risk group.


Protein kinases in chondrocyte signaling and osteoarthritis.
Protein kinases, particularly mitogen-activated protein kinases and receptor-tyrosine kinases play crucial roles in mammalian cellular metabolism by regulating intracellular signaling pathways that control proliferation, differentiation, cytokine gene induction and cytokine responsiveness, matrix metalloproteinase gene expression, mechanical transduction, as well as programmed cell death (apoptosis). Many of these pathways are also important components of cartilage homeostasis because alterations in intracellular signaling pathways appear to play a prominent role in chondrocyte dysfunction that is part of osteoarthritis pathogenesis and disease progression. Several mitogen-activated protein kinases and receptor-tyrosine kinases have been characterized as participating in chondrocyte signaling pathways. They are c-Jun-amino-terminal protein kinase, p38 kinase, extracellular signal-regulated protein kinase, and Ror2. Janus kinases and signal transducers and activators of transcription factors (Janus kinase/signal transducers and activators of transcription pathway) are also implicated in modulating the chondrogenic phenotype. Mitogen-activated protein kinase activation is required for their role as phosphorylating enzymes. Activation results from mitogen-activated protein kinase phosphorylation carried out by at least seven upstream kinases known as mitogen-activated protein kinase kinases. Additional upstream kinases (for example, MKKKKs and MKKKs) often require low molecular weight GTP-binding proteins to mediate the mitogen-activated protein-kinase kinases cascade. Identifying the functions of mitogen-activated protein kinases in normal and aging cartilage and the extent to which mitogen-activated protein kinases may be altered in osteoarthritis cartilage and synovium will be critical for developing novel therapies for osteoarthritis management.


RISE: Promoting Diversity Among Public Health Professionals.
Public health education and research training of underrepresented populations is an important component of a comprehensive approach to promote health equity. To describe student outcomes following participation in an innovative public health training cooperative agreement program funded by the Centers of Disease Control and Prevention. Sixty-six graduate, professional, and recent baccalaureate degree students participated in the Research Initiatives for Student Enhancement program. The majority of the students were from underrepresented populations (95%) and female (80%). The Research Initiatives for Student Enhancement program, a collaboration between a university-affiliated Institute and Historically Black Colleges and Universities, provided public health educational and research experiences during the summer and academic year. Student presentations at national meetings, publications, and completion of degree programs. The acceptance rate for student presentations at national scientific meetings was 89%. Almost 14 percent of the students were authors of peer-reviewed articles. More than one-third of the students (36%) completed their master's degree and 33% completed doctoral degrees during the 5 years of the program. Students used their Research Initiatives for Student Enhancement program research to complete master's theses, practicum requirements, and dissertations. Ninety-five percent of the students pursued education or careers in public health and health care.


Elastic fibers define embryonic tissue stiffness to enable buckling morphogenesis of the small intestine.
During embryonic development, tissues must possess precise material properties to ensure that cell-generated forces give rise to the stereotyped morphologies of developing organs. However, the question of how material properties are established and regulated during development remains understudied. Here, we aim to address these broader questions through the study of intestinal looping, a process by which the initially straight intestinal tube buckles into loops, permitting ordered packing within the body cavity. Looping results from elongation of the tube against the constraint of an attached tissue, the dorsal mesentery, which is elastically stretched by the elongating tube to nearly triple its length. This elastic energy storage allows the mesentery to provide stable compressive forces that ultimately buckle the tube into loops. Beginning with a transcriptomic analysis of the mesentery, we identified widespread upregulation of extracellular matrix related genes during looping, including genes related to elastic fiber deposition. Combining molecular and mechanical analyses, we conclude that elastin confers tensile stiffness to the mesentery, enabling its mechanical role in organizing the developing small intestine. These results shed light on the role of elastin as a driver of morphogenesis that extends beyond its more established role in resisting cyclic deformation in adult tissues.


The diagnostic challenge of Divry van Bogaert and Sneddon Syndrome: Report of three cases and literature review.
Divry van Bogaert Syndrome (DBS) is a familial juvenile-onset disorder characterized by livedo racemosa, white matter disease, dementia, epilepsy and angiographic finding of "cerebral angiomatosis". A similar syndrome including livedo racemosa and cerebrovascular disease, often associated with anticardiolipin antibodies, has been described as Sneddon Syndrome (SS) highlighting the question whether these two conditions have to be considered different entities or indeed different features of a unique syndrome. Herein, we report the clinical, neuroradiological, histopathological findings and follow up of three cases diagnosed as Divry-van Bogaert Syndrome, including an updated review of literature of both DBS and SS cases. Our findings support the assumption that DBS and SS are different disease entities. DBS is characterized by the typical angiographic feature of angiomatosis, a hereditary trait and a juvenile onset of cognitive impairment and leukoaraiosis, whereas SS has less severe manifestations of cerebrovascular disease associated with livedo racemosa but without the characteristic cerebral angiography. The report of our cases and the literature review underline the necessity of a detailed work-up and the collection of larger series to better clarify the DBS and SS phenotype and course.