Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and pharmacokinetics of pantoprazole in alpacas.

BACKGROUND Despite frequent clinical use, information about the pharmacokinetics and efficacy of pantoprazole in camelids is not available. OBJECTIVES To examine the pharmacokinetics of both IV and SC pantoprazole and to determine whether pantoprazole administration would increase 3rd compartment pH in alpacas. ANIMALS Six healthy adult alpacas. METHODS Alpacas were fitted with a 3rd compartment cannula for measuring gastric pH. After recovery, alpacas received 1 mg/kg pantoprazole IV, q24h for 3 days or 2 mg/kg SC q24h for 3 days. Alpacas received both IV and SC pantoprazole, with a minimum of 3 weeks between treatments. Third compartment pH was recorded and plasma samples were taken for pharmacokinetic analysis. RESULTS Pantoprazole induced a slow but sustained increase in 3rd compartment pH when given by both the IV and SC routes. Third compartment pH was significantly increased as compared with baseline values (1.81+/-0.7; mean+/-SD) at 24 (2.47+/-0.8), 48 (3.53+/-1.0) and 72 hours (4.03+/-1.3) after daily IV administration of pantoprazole. Third compartment pH increased from 1.73+/-0.6 at baseline to 3.05+/-1.1, 4.02+/-1.4, and 3.61+/-1.6 at 24, 48, and 72 hours after SC administration, respectively. Pharmacokinetic analysis demonstrated that pantoprazole had a short elimination half-life (0.47+0.06 h) and a high clearance rate (12.2+/-2.9 mL/kg/min) after both IV and SC administration. CONCLUSIONS AND CLINICAL RELEVANCE Based on the results of this study, pantoprazole represents a safe and effective drug for increasing 3rd compartment pH in camelids. Either IV or SC administration is likely to be an effective treatment for gastric ulcers.
Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance

Significance Poly(ADP-ribose) polymerase (PARP) inhibitors have produced responses in homologous recombination (HR) repair-deficient cancers, such as those with a mutated breast cancer 1, early onset (BRCA1) gene. We have delineated a two-event mechanism of acquired resistance by using a BRCA1 BRCA C-terminal (BRCT) domain-mutated breast cancer cell line, involving heat shock protein (HSP)90-mediated stabilization of the mutant protein coupled with tumor protein p53 binding protein 1 (TP53BP1) gene mutation, which together restore DNA end resection and RAD51 filament formation, critical steps in HR. Similar events may occur in primary BRCA1-mutated ovarian cancers as cells develop resistance to platinum. The data demonstrate that, even though BRCA1 BRCT domain mutant proteins cannot promote DNA end resection, they retain partial function and can contribute to RAD51 loading and HR. Finally, HSP90 inhibition may prove useful for resensitizing resistant BRCA1-mutant cancer cells to drug treatment. Breast Cancer Type 1 Susceptibility Protein (BRCA1)-deficient cells have compromised DNA repair and are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Despite initial responses, the development of resistance limits clinical efficacy. Mutations in the BRCA C-terminal (BRCT) domain of BRCA1 frequently create protein products unable to fold that are subject to protease-mediated degradation. Here, we show HSP90-mediated stabilization of a BRCT domain mutant BRCA1 protein under PARP inhibitor selection pressure. The stabilized mutant BRCA1 protein interacted with PALB2-BRCA2-RAD51, was essential for RAD51 focus formation, and conferred PARP inhibitor as well as cisplatin resistance. Treatment of resistant cells with the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin reduced mutant BRCA1 protein levels and restored their sensitivity to PARP inhibition. Resistant cells also acquired a TP53BP1 mutation that facilitated DNA end resection in the absence of a BRCA1 protein capable of binding CtIP. Finally, concomitant increased mutant BRCA1 and decreased 53BP1 protein expression occur in clinical samples of BRCA1-mutated recurrent ovarian carcinomas that have developed resistance to platinum. These results provide evidence for a two-event mechanism by which BRCA1-mutant tumors acquire anticancer therapy resistance.
Growing Through Trade in Intermediate Goods: The Role of Foreign Growth and Domestic Tariffs

We show that pure Ricardian trade can account for the empirical evidence that domestic growth is more affected by foreign growth than by trade openness. To do this, we develop a two‐country model involving a backward economy that exchanges intermediate goods with a faster growing country. We obtain three main results regarding growth and welfare of the backward economy: (i) the growth‐enhancing comparative advantage is facilitated by faster foreign growth; (ii) the growth rate may be negatively affected or unaffected by a domestic tariff, while it is always positively impacted by foreign growth; and (iii) a domestic tariff could be welfare‐improving.
Detection of human papilloma virus in potentially malignant and malignant lesions of the oral cavity and a study of associated risk factors

Abstract Background: Squamous cell carcinoma of the head and neck is the 6 th most frequently occurring cancer worldwide, with over 400,000 cases projected annually. Multiple factors such as tobacco, alcohol, irradiation, virus, and chronic irritants are involved in the development of oral squamous cell carcinomas (OSCCs). The most important risk factors are chronic exposure to tobacco and alcohol. Although the evidence that implicates virus is increasing, particularly (human papillomavirus [HPV]), in the carcinogenesis process, the role of virus is not well established. Aim and Objective: This study is designed to assess the presence of HPV in potentially malignant and malignant lesions of the oral cavity as well as to correlate the presence of HPV with addictive habits and histopathological grading of the disease. Materials and Methods: Biopsy samples of OSCC and potentially malignant lesions were obtained and 3, 5 μm thickness sections were cut using a microtome. The sections were collected using a sterile brush and transferred to an Eppendorf tube. DNA extraction and polymerase chain reaction for the detection of HPV were done. Results and Conclusion: The association between histopathological grading and presence of HPV was assessed using Chi-square test and the values thus obtained were found to be statistically significant. HPV was more predominantly seen in well-differentiated carcinomas and moderately differentiated carcinomas as compared to poorly differentiated carcinomas.
Sequential Cervical Specimens and the Isolation of Chlamydia trachomatis: Factors Affecting Detection

For 260 consecutive patient visits by women to a clinic for sexually transmitted diseases, four cervical specimens were cultured in duplicate for detection of Chlamydia trachomatis. Sixty-one positive results were detected by at least one of the four specimens; the first two specimens detected 67-69% and the last two 80-82% of the 61 positives. The difference in these isolation rates is statistically significant (P = 0.003). Duplicate cultures of the same specimen did not significantly increase detection rates. A combination of two specimens could increase the number detected by 44.7% beyond the results of a single-specimen culture. Contamination rates were higher for the first two specimens. Routine cleaning of the cervical canal with a swab before the taking of specimens should reduce contamination and increase the probability of obtaining infected cells when they are present.
Specifying the relationship between alcohol use and cognitive loss: the effects of frequency of consumption and psychological distress.

Previous research has found a relationship between increased quantity of alcohol usually consumed per drinking occasion and decreased sober cognitive performance. It has been suggested that the effects of quantity of alcohol consumed may be conditional upon the frequency of alcohol use and that decreased performance in social drinkers may be a consequence of psychological distress (i.e., anxiety and depression). An analysis of data from a representative sample of employed men and women in metropolitan Detroit indicates that the relation between quantity of alcohol consumed per occasion and abstraction performance is conditional upon the frequency of alcohol use but that the relationship cannot be accounted for by psychological distress.
Patterns of Selective Neuronal Damage in Methamphetamine-User AIDS Patients

The risk for HIV infection attributable to methamphetamine (METH) use continues to increase. The combined effect of HIV and METH in the pathogenesis of HIV encephalitis (HIVE) is unclear, however. To better understand the neuropathology associated with HIV and METH use, the patterns of neurodegeneration were assessed in HIV-positive METH users and in HIV-positive non-METH users. Patients in the study met criteria for inclusion and received neuromedical and postmortem neuropathologic examinations. Immunocytochemical and polymerase chain reaction analyses were performed to determine brain HIV levels and to exclude the presence of other viruses. METH-using patients with HIVE showed significantly lower gp41 scores and less severe forms of encephalitis but a higher frequency of ischemic events, a more pronounced loss of synaptophysin immunoreactivity, and a more severe microglial reaction than HIVE non-METH users. Furthermore, in METH-using patients with HIVE, extensive loss of calbindin (CB)-immunoreactive interneurons displaying phylopodial neuritic processes suggestive of aberrant sprouting was observed. Taken together, these studies indicate that the combined effects of METH and HIV selectively damage CB immunoreactive nonpyramidal neurons. In combination, METH and HIV may increase neuronal cell injury and death, thereby enhancing brain metabolic disturbances observed in clinical populations of HIV-positive METH abusers.
Atrial Fibrillation Is Associated with Decreased Cardiac Sympathetic Response to Isometric Exercise in CHF in Comparison to Sinus Rhythm

Background: The presence of atrial fibrillation (AF) in congestive heart failure (CHF) is accompanied by increased mortality, although the exact mechanism is unclear. In previous studies, we have demonstrated cardiac baroreceptor abnormalities in association with AF and CHF. In this study, we sought to examine the effect of cardiac rhythm on the cardiac sympathetic response to exercise in CHF.
JAK/STAT but Not ERK1/ERK2 Pathway Mediates Interleukin (IL)-6/Soluble IL-6R Down-regulation of Type II Collagen, Aggrecan Core, and Link Protein Transcription in Articular Chondrocytes

Signal transducers and activators of transcription (STAT) factors are cytoplasmic proteins that can be activated by Janus kinases (JAK) and that modulate gene expression in response to cytokine receptor stimulation. STAT proteins dimerize, translocate into the nucleus, and activate specific target genes. In the present study, we show for the first time that interleukin-6 (IL), in the presence of its soluble receptor (sIL-6R), induces activation of JAK1, JAK2, and STAT1/STAT3 proteins in bovine articular chondrocytes. Western blotting and mobility shift assays demonstrated that this effect is accompanied by the DNA binding of the STAT proteins. The mitogen-activated protein kinase pathway was also activated in response to IL-6/sIL-6R association, as reflected by phosphorylation of ERK1 and ERK2 proteins. In these conditions, the expression of cartilage-specific matrix genes, type II collagen, aggrecan core, and link proteins was found to be markedly down-regulated. This negative effect was abolished by addition of parthenolide, an inhibitor of the STAT activation, whereas blockade of the MAP kinases with PD098059 was without significant effect. Thus, activation of the STAT signaling pathways, but not ERK-dependent pathways, is essential for down-regulation of the major cartilage-specific matrix genes by IL-6. In addition, a parallel reduction of Sox9 expression, a key factor of chondrocyte phenotype, was found in these experimental conditions. These IL-6 effects might contribute to the phenotype loss of chondrocytes in joint diseases and the alteration of articular cartilage associated with this pathology.
Frequency of M-Cadherin-stained Satellite Cells Declines in Human Muscles During Aging

To answer the question of whether the satellite cell pool in human muscle is reduced during aging, we detected satellite cells in 30-μm-thick transverse sections under the confocal microscope by binding of M-cadherin antibody. The basal lamina was detected with laminin. Nuclei were stained with bisbenzimide or propidium iodide. Satellite cells were counted by applying the disector method and unbiased sampling design. To determine if there are age-related differences in muscle fiber types, morphometric characteristics of muscle fibers were examined on thin sections stained for myofibrillar ATPase. Autopsy samples of vastus lateralis muscle from six young (28.7 ± 2.3 years) and six old (70.8 ± 1.3 years) persons who had suffered sudden death were analyzed. Numbers of satellite cells per fiber length (Nsc/Lfib) and number of satellite cells per total number of nuclei (satellite cell nuclei + myonuclei) (Nsc/Nnucl) were significantly lower in the old group (p<0.05). We demonstrate the importance of proper sampling and counting in estimation of sparsely distributed structures such as satellite cells. Our results support the hypothesis that the satellite cell fraction declines during aging.
Normal complement of motor units in asymptomatic familial (SOD1 mutation) amyotrophic lateral sclerosis carriers

OBJECTIVE To understand the mechanisms causing neuronal death in amyotrophic lateral sclerosis (ALS), an electrophysiological technique of motor unit number estimation (MUNE) was used to examine the pattern of motor neuron loss in amyotrophic lateral sclerosis. The aim was to determine whether gradual lifelong loss of motor units precedes clinical disease or whether sudden, catastrophic loss of motor units occurs at the onset of the disease. METHOD Using the statistical technique of motor unit number estimation, a cross sectional study was performed on a group of asymptomatic carriers of the Cu, Zn superoxide dimutase 1 (SOD1) gene. MUNE results were compared with those from age and sex matched family controls who did not carry the SOD1 mutation. A total of 87 subjects (45 men and 42 women) with an age range from 16–73 years of age were studied. RESULTS There was no detectable difference in the number of motor units in SOD1 mutation carriers compared with SOD1 negative family controls or population controls. Symptomatic subjects showed a definite loss of motor units. The test-retest reproducibility of this technique yielded an average difference between MUNE results on separate occasions on the same subject of ±5%. CONCLUSION The finding that presymptomatic SOD1 mutation carriers have a full complement of motor neurons indicates that mutation carriers must have normal survival of motor neurons until rapid and widespread cell death of these neurons occurs, coinciding with the onset of clinical features. This implies that symptomatic ALS is not the end result of a slow attrition of motor neurons.
Voices from the pipeline: high school completion among rural Latinos.

Although significant strides have been made in increasing the numbers and proportions of minorities in nursing, at 2.0% of the RN population (MinorityNurse.com, 2001), Latinos continue to lag far behind other minorities (Buerhaus & Auerback, 1999). As the fastest growing minority group in the United States--an increase from 9% of the population in 1990 to 11.9% in 2000 and projections of 14.6% by 2001 and 17% by 2020 (U.S. Census, 2001)--Latinos' under-representation in all fields of health care is expected to continue unless concerted efforts are taken to recruit and educate more students. This paper presents an analysis of narratives of high school completion as articulated by Latino adolescents in group interviews. Narrative inquiry of the focus group data found three major categories of supports and challenges: peers, family, and schools. The paper concludes with a discussion of how these findings can be used to develop community based interventions to increase high school completion and thus increase the pool of applicants for nursing and other health careers.
Excess body iron and the risk of type 2 diabetes mellitus: a nested case–control in the PREDIMED (PREvention with MEDiterranean Diet) study

A prospective nested case–control study within the PREvention with MEDiterranean Diet (PREDIMED) was conducted to evaluate the relationship between excess body Fe (measured as serum ferritin (SF), soluble transferrin receptor (sTfR) and sTfR:ferritin ratio) and the risk of type 2 diabetes mellitus (T2DM) in a Mediterranean population at a high risk of CVD, without T2DM at the start of the study. The study contained 459 subjects, 153 with incident T2DM (cases) and 306 without incident T2DM (controls). The follow-up period was for 6·0 (interquartile range 3·9–6·5) years. For each incident diabetic subject, two subjects were selected as controls who were matched broadly for age as well as for sex, intervention group and BMI. We observed a relationship between SF values >257 μg/l in males and >139 μg/l in females and the risk of T2DM, following adjustment in the conditional logistic regression model for high-sensitivity C-reactive protein, fasting glucose and other components of the metabolic syndrome (OR 3·62, 95 % CI 1·32, 19·95; P= 0·022). We also found an association between low sTfR:ferritin ratio levels and the incidence of T2DM (OR 3·02, 95 % CI 1·09, 8·39; P= 0·042), but no association with sTfR (OR 1·29, 95 % CI 0·51, 3·23; P= 0·722). Oxidative stress has been hypothesised to contribute to the development of insulin resistance and β-cell dysfunction, the two key events in the clinical development of T2DM. Following adjustment for other risk factors for T2DM, excess body Fe (measured as SF and sTfR:ferritin ratio) was associated with an increased risk of developing T2DM in a Mediterranean population at a high risk of CVD.
Prospective evaluation of environmental contamination by Clostridium difficile in isolation side rooms.

We determined prospectively the frequency, persistence and molecular epidemiology of Clostridium difficile environmental contamination after detergent-based cleaning in side rooms used to isolate patients with C. difficile diarrhoea. Approximately one-quarter of all environmental sites in side rooms sampled over four-week periods were contaminated with C. difficile. The overall side room prevalence of environmental C. difficile declined from 35% initially, to 24% in week 2, 18% in week 3, and 16% in week 4. The bed frame was the most common site from which C. difficile was recovered, although the floor was the most contaminated site in terms of total numbers of colonies. C. difficile was recovered significantly more frequently from swabs plated directly on to C. difficile selective media containing lysozyme than from enrichment broth (P< 0.001), emphasizing the benefit of lysozyme supplementation. The great majority of C. difficile isolates (87% of all isolates, 84% of patient isolates) was indistinguishable from the UK epidemic strain (PCR ribotype 1). It thus could not be determined whether environmental contamination was a cause or a consequence of diarrhoea. Our findings highlight the need for improved approaches to hospital environmental hygiene, and call into question current UK guidelines that recommend detergent-based cleaning to remove environmental C. difficile. In particular, improved cleaning of frequently touched sites in the immediate bed space area is required.
Financial Market Contagion and the Sovereign Debt Crisis: A Smooth Transition Approach

In this paper, we investigate the timing and extent of sovereign debt contagion across nine Eurozone countries using daily returns on 10-year government bonds from 2007 until 2017. The novelty lies in modelling bond return correlations using a multivariate GARCH model with a multiplicative decomposition of the variance and time-varying conditional correlations. The model introduces flexibility by allowing the individual unconditional variances to be time-dependent and the correlations to change smoothly between two extreme states according to time and observable financial variables. The main results provide no evidence of asymmetric response of comovements to negative shocks, as opposed to the size of innovations from the periphery which is expected to affect the dynamics of correlations. Our findings further indicate the presence of long-run contagion effects across peripheral countries following the more acute phase of the sovereign crisis. Interestingly, periods of high turbulence in the European stock market do not seem to drive financial contagion.
Expression of a constitutive NF-kappa B-like activity is essential for proliferation of cultured bovine vascular smooth muscle cells.

We have recently discovered bovine and human vascular smooth muscle cells (SMCs) express a novel constitutive Nuclear Factor-kappa B (NF-kappa B)/Rel-like activity (Lawrence, R., L.-J. Chang, U. Siebenlist, P. Bressler, and G.E. Sonenshein. 1994. J. Biol. Chem. 269:28913-28918), here termed SMC-Rel. Since cytomegalovirus (CMV) infection of human vascular SMCs has been implicated in aberrant SMC proliferation during post-angioplasty restenosis, we tested the role of NF-kappa B/Rel activity in transactivation of the CMV immediate early (ie) promoter. The basal CMV ie promoter linked to three wild-type, but not mutant, copies of its NF-kappa B element was active in bovine aortic SMCs. The anti-oxidants N-acetyl cysteine (NAC) or pentoxifylline (PTX), which are used clinically to reduce NF-kappa B/Rel activity, inhibited NF-kappa B driven promoter transactivation, and SMC-Rel binding activity. Treatment with either NAC or PTX was observed to slow the growth of the SMCs in a dose dependent fashion. Microinjection of either purified I kappa B-alpha, a naturally occurring specific inhibitor of NF-kappa B/Rel activity, or double-stranded oligonucleotides harboring wild type, but not non-binding mutants of NF-kappa B elements selectively inhibited SMC proliferation. Thus constitutive NF-kappa B/Rel activity appears essential for proliferation of vascular SMCs and might be a novel target for therapeutic intervention for restenosis.
The effect of endodontic procedures on apical crack initiation and propagation ex vivo.

AIM To evaluate the potential effects of endodontic procedures (instrumentation and filling) on crack initiation and propagation in apical dentine. METHODOLOGY Forty extracted single-rooted premolars with two canals were selected, 1.5 mm of the apex was ground perpendicular to the long axis of the tooth and the surface polished. The specimens were divided into 4 groups. The buccal canals of groups A, B and C were enlarged to size 40 with manual K-files. Group A was filled with gutta-percha using lateral condensation and vertical compaction without sealer. Group B was filled with the same method as group A except only lateral condensation was used. Group C was left unfilled, while group D was left unprepared and unfilled. Images of the resected surface were taken after resection (baseline), after canal preparation, after filling and after 4-week storage. The images were then inspected for cracks originating from the canal. RESULTS A significant effect of preparation on crack initiation (P < 0.05) and no significant effect of filling (P > 0.05) or 4-week storage on crack initiation (P > 0.05) was found (logistic regression). Fisher's exact test revealed a significant effect of filling on crack propagation (P < 0.05) and no effect of 4-week storage on crack propagation (P > 0.05). CONCLUSIONS Root canal procedures can potentially initiate and propagate cracks from within the root canal in the apical region.