Miracle-dz/UniFAR-FTUs huggingface dataset:
pH modulation of the kinetics of a Ca2(+)‐sensitive cross‐bridge state transition in mammalian single skeletal muscle fibres.

1. The rate constant of tension redevelopment (ktr) following a rapid release and subsequent re‐extension of muscle length has been demonstrated to be Ca2+ sensitive and is thought to reflect the rate‐limiting step in the cross‐bridge cycle leading to the formation of the strongly bound, force‐bearing state. The kinetics of this cross‐bridge state transition were investigated at 15 degrees C over a wide range of Ca2+ concentrations while varying pH from 7.00 to 6.20 in rat slow‐twitch soleus, rat fast‐twitch superficial vastus lateralis (SVL) and rabbit fast‐twitch psoas skinned single fibres. 2. At maximal levels of Ca2+ activation, ktr was unaffected by changes in pH from 7.00 to 6.20 while isometric tension was depressed to 0.60 +/‐ 0.02 P0 (mean +/‐ S.E.M.) at the low pH in fast‐twitch fibres and to 0.78 +/‐ 0.01 P0 in slow‐twitch fibres (P0 is the maximum isometric tension obtained at pH 7.00). 3. At reduced levels of Ca2+ activation, corresponding to pCa (‐log [Ca2+]) greater than 5.0, ktr was markedly depressed in all fibre types when pH was lowered. The Ca2+ sensitivity of steady‐state isometric tension was also reduced in all fibres at pH 6.20 compared to pH 7.00. 4. The results suggest that pH has a modulatory effect upon an apparent rate constant which is rate limiting in terms of the formation of the strongly bound, force‐bearing cross‐bridge state. This effect of altered pH may in part account for the reduction in the Ca2+ sensitivity of isometric force at low pH as well as the depression of the rate of rise of tension in living fibres during fatiguing stimulation.
Phase I Clinical Trial of STA-4783 in Combination with Paclitaxel in Patients with Refractory Solid Tumors

Purpose: STA-4783 is a new compound that markedly enhances the therapeutic index of paclitaxel against human tumor xenograft models. A phase I clinical trial was undertaken to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of STA-4783 in combination with paclitaxel. Experimental Design: Adults with refractory solid tumors concurrently received STA-4783 and paclitaxel as a 3-h i.v. infusion at starting doses of 44 and 135 mg/m2, respectively. After increasing paclitaxel to 175 mg/m2, the STA-4783 dose was escalated as permitted by dose-limiting toxicity during the first 21-day cycle. Results: Thirty-five patients were treated with eight dose levels of STA-4783/paclitaxel. In patients receiving 175 mg/m2 paclitaxel, the incidence of severe toxicity increased with escalation of the STA-4783 dose above 263 mg/m2, and 438 mg/m2 was the maximum tolerated dose. All toxicities were typical of paclitaxel, with neutropenia, mucositis, and myalgia/arthralgia being dose limiting. Partial responses were achieved in one patient with Kaposi's sarcoma and another with ovarian cancer that progressed during prior treatment with paclitaxel. STA-4783 exhibited linear pharmacokinetics characterized by rapid elimination from plasma (biological half-life, 1.06 ± 0.24 h) and a low steady-state apparent volume of distribution (25.1 ± 8.1 L/m2). The total body clearance of paclitaxel decreased significantly with escalation of the STA-4783 dose. Conclusions: The STA-4783/paclitaxel combination was well tolerated with a toxicity profile similar to single-agent paclitaxel. Enhanced systemic exposure to paclitaxel resulting from a dose-dependent interaction with STA-4783 was associated with increased toxicity. Objective responses in two heavily pretreated patients, both with taxane exposure, have encouraged further clinical evaluation of this regimen.
An uncooked vegan diet shifts the profile of human fecal microflora: computerized analysis of direct stool sample gas-liquid chromatography profiles of bacterial cellular fatty acids

The effect of an uncooked extreme vegan diet on fecal microflora was studied by direct stool sample gas-liquid chromatography (GLC) of bacterial cellular fatty acids and by quantitative bacterial culture by using classical microbiological techniques of isolation, identification, and enumeration of different bacterial species. Eighteen volunteers were divided randomly into two groups. The test group received an uncooked vegan diet for 1 month and a conventional diet of mixed Western type for the other month of the study. The control group consumed a conventional diet throughout the study period. Stool samples were collected. Bacterial cellular fatty acids were extracted directly from the stool samples and measured by GLC. Computerized analysis of the resulting fatty acid profiles was performed. Such a profile represents all bacterial cellular fatty acids in a sample and thus reflects its microflora and can be used to detect changes, differences, or similarities of bacterial flora between individual samples or sample groups. GLC profiles changed significantly in the test group after the induction and discontinuation of the vegan diet but not in the control group at any time, whereas quantitative bacterial culture did not detect any significant change in fecal bacteriology in either of the groups. The results suggest that an uncooked extreme vegan diet alters the fecal bacterial flora significantly when it is measured by direct stool sample GLC of bacterial fatty acids.
Distinct Regulation of Osmoprotective Genes in Yeast and Mammals

In yeast glycerol-3-phosphate dehydrogenase 1 is essential for synthesis of the osmoprotectant glycerol and is osmotically regulated via the high osmolarity glycerol (HOG1) kinase pathway. Homologous protein kinases, p38, and stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) are hyperosmotically activated in some mammalian cell lines and complement HOG1 in yeast. In the present study we asked whether p38 or SAPK/JNK signal synthesis of the osmoprotectant sorbitol in rabbit renal medullary cells (PAP-HT25), analogous to the glycerol system in yeast. Sorbitol synthesis is catalyzed by aldose reductase (AR). Hyperosmolality increasesAR transcription through an osmotic response element (ORE) in the 5′-flanking region of the AR gene, resulting in elevated sorbitol. We tested if AR-ORE is targeted by p38 or SAPK/JNK pathways in PAP-HT25 cells. Hyperosmolality (adding 150 mmNaCl) strongly induces phosphorylation of p38 and of c-Jun, a specific target of SAPK/JNK. Transient lipofection of a dominant negative mutant of SAPK kinase, SEK1-AL, into PAP-HT25 cells specifically inhibits hyperosmotically induced c-Jun phosphorylation. Transient lipofection of a dominant negative p38 kinase mutant, MKK3-AL, into PAP-HT25 cells specifically suppresses hyperosmotic induction of p38 phosphorylation. We cotransfected either one of these mutants or their empty vector with an AR-ORE luciferase reporter construct and compared the hyperosmotically induced increase in luciferase activity with that in cells lipofected with only the AR-ORE luciferase construct. Hyperosmolality increased luciferase activity equally (5–7-fold) under all conditions. We conclude that hyperosmolality induces p38 and SAPK/JNK cascades in mammalian renal cells, analogous to inducing the HOG1 cascade in yeast. However, activation of p38 or SAPK/JNK pathways is not necessary for transcriptional regulation of ARthrough the ORE. This finding stands in contrast to the requirement for the HOG1 pathway for hyperosmotically induced activation of yeastGPD1.
Role of motor center activity for hormonal changes and substrate mobilization in humans.

The study evaluated the hypothesis that during exercise autonomic neuroendocrine activity and, in turn, substrate mobilization, is subjected to feed-forward stimulation from motor centers. Eight young healthy men bicycled for two 20-min periods without (control, C) as well as during partial neuromuscular blockade with tubocurarine (Cu). 3-[3H]glucose was infused, and arterialized hand vein blood was sampled. In period 1 O2 consumption (VO2) (56% VO2 max), heart rate, and blood lactate were identical in Cu compared with C experiments, whereas hand grip strength was lower and perceived exertion [14.0 +/- 1.5 vs. 9.1 +/- 1.2 (SE) points, P less than 0.01] higher in Cu experiments, indicating higher motor center activity. Concentrations of norepinephrine [7.39 +/- 1.18 (Cu) vs. 5.14 +/- 1.06 (C) nmol/l], epinephrine (1.69 +/- 0.33 vs 0.87 +/- 0.16 nmol/l), growth hormone (25.9 +/- 7.3 vs. 11.5 +/- 4.7 mU/l), and adrenocorticotropin hormone (11.3 +/- 1.3 vs. 5.5 +/- 0.7 pmol/l) attained higher values in Cu than in C experiments (P less than 0.05). The initial increase in glucose production was enhanced in Cu (8.1 +/- 1.6 mumol.min-1.kg-1) compared with C experiments (3.9 +/- 1.9, P less than 0.05), and plasma glucose only increased in Cu experiments. Free fatty acid (P less than 0.05) and glycerol (P less than 0.1) concentrations were higher in Cu than in C experiments. In period 2 identical perceived exertion was achieved in the two experiments by reducing work load in Cu experiments. In this period hormonal responses were similar in the two experiments. (ABSTRACT TRUNCATED AT 250 WORDS)
Sleep Quality in Postpartum Women: Exploring Correlation With Childbirth Experience and Household Work

Background: New mothers commonly report sleep deprivation and sleep disturbances during the first 3 postpartum months. A better understanding of factors related to postpartum sleep quality is necessary to develop interventions to improve sleep quality in postpartum women. Purpose: This study explored the impact of specific demographic and obstetric factors on the subjective sleep quality of postpartum women. Methods: We used a cross-sectional, correlational study design. A convenience sample of 202 women in their fourth to sixth postpartum week was recruited from two hospitals in southern Taiwan. A demographic data form and the Postpartum Sleep Quality Scale were used to collect data. Results: The mean Postpartum Sleep Quality Scale score of participants was 22.82 (SD = 8.16), indicating a mild level of sleep disturbance. We found that better sleep quality correlated positively with a satisfactory childbirth experience and correlated negatively with daily time spent on household work. Pain, discomfort, and fear were the main dimensions associated with unsatisfactory childbirth experiences. Conclusions/Implications for Practice: Study results recommend that health professionals should improve current protocols to help women better confront and manage childbirth-related pain, discomfort, and fear. Evidence-based postnatal education for parents should highlight the positive relationship between reduced daily household workloads and sleep quality for new mothers.
Role of sodium ions in the vitrification process: Glass matrix modification, slag structure depolymerization, and influence of metal immobilization

This study investigates the role of Na ions, a common flux, in the vitrification process. Artificial glass systems composed of Al2O3, CaO, and SiO2 with various Na concentrations were melted at 1450 °C. The specimens were cooled by air cooling and water quenching and the metal mobility was evaluated using a sequential extraction procedure. The X-ray diffraction analysis and scanning electron microscopy observations showed that Na ions governed the air-cooled slag’s structure. Na ions initially depolymerized CaSiO3-linked chains into CaSiO3 chains, and further cut them into shorter and nonuniform ones, making the slag structure amorphous. With even more Na ions, CaSiO3 chains were divided into single SiO4 tetrahedrons and formed Na-related crystals (Na2Ca3Si2O8 and NaAlSiO4). The phase distributions of Al, Cr, Cu Mn, and Ni showed that Na has a positive effect on the immobilization of heavy metals at suitable concentrations, but a negative effect when in excess amounts. Implications: Vitrification has been widely used to treat hazardous materials. The Na-bearing additives were often used as a flux to improve the melting process. This study described the role of Na played in the vitrification process. The Na ions acted as glass modifier and depolymerize the chain structure of slag. With adequate addition amount of Na ions, the immobilization of heavy metals was improved. The results provided much information about the crystalline phase variation, metal mobility, and surface characteristics while Na serves as a flux.
PTH(1-34) for Surgical Hypoparathyroidism: A Prospective, Open-Label Investigation of Efficacy and Quality of Life.

CONTEXT Conventional therapy for hypoparathyroidism consists of calcium and calcitriol, but sometimes normal serum calcium cannot be maintained, and/or this approach might lead to nephrocalcinosis, nephrolithiasis, or renal insufficiency. OBJECTIVE The objective of the study was to investigate the effects of 6 months of PTH(1-34) treatment in adult subjects with postoperative hypoparathyroidism and to evaluate quality-of-life changes. DESIGN This was a 2-year prospective, open-label study. At baseline and after 6 months of PTH(1-34) treatment, calcium and vitamin D supplementation requirements, serum calcium, phosphate, creatinine, alkaline phosphatase, uric acid, and 24-hour urinary calcium excretion were evaluated. Quality of life was evaluated by the Rand 36-Item Short Form Health Survey covering eight domains of physical and mental health. SETTING This was an Italian multicentric study. PARTICIPANTS Participants included 42 subjects with surgical hypoparathyroidism (90% females, age range 34-77 y). INTERVENTION The intervention included a twice-daily PTH(1-34) 20 μg sc injection. RESULTS The mean serum calcium levels significantly increased from baseline to 15 days (7.6 ± 0.6 vs 9.1 ± 0.9 mg/dL, P < .001) and remained stable until the end of the observational period, despite a significant reduction in calcium and vitamin D supplementation. Phosphate levels gradually decreased from baseline to the sixth month (P = .005 for the trend), whereas the alkaline phosphatase increased (P < .001). Data from the Rand 36-Item Short Form Health Survey showed a significant improvement in the mean scores of all eight domains (P < .001). CONCLUSION This is the largest study that demonstrates the effectiveness of PTH(1-34) in the treatment of adult patients with postsurgical hypoparathyroidism, and it shows that PTH(1-34) may improve the mental and physical health in hypoparathyroid subjects.
Myocardial Impairment in Chronic Hypoxia is Abolished by Short Aeration Episodes: Involvement of K+ATP Channels

In vivo exposure to chronic hypoxia is considered to be a cause of myocardial dysfunction, thereby representing a deleterious condition, but repeated aeration episodes may exert some cardioprotection. We investigated the possible role of ATP-sensitive potassium channels in these mechanisms. First, rats (n = 8/group) were exposed for 14 days to either chronic hypoxia (CH; 10% O2) or chronic hypoxia with one episode/day of 1-hr normoxic aeration (CH+A), with normoxia (N) as the control. Second, isolated hearts were Langendorff perfused under hypoxia (10% O2, 30 min) and reoxygenated (94% O2, 30 min) with or without 3 μM glibenclamide (nonselective K+ATP channel-blocker) or 100 μM diazoxide (selective mitochondrial K+ATP channel-opener). Blood gasses, hemoglobin concentration, and plasma malondialdehyde were similar in CH and CH+A and in both different from normoxic (P < 0.01), body weight gain and plasma nitrate/nitrite were higher in CH+A than CH (P < 0.01), whereas apoptosis (number of TUNEL-positive nuclei) was less in CH+A than CH (P < 0.05). During in vitro hypoxia, the efficiency (ratio of ATP production/pressure x rate product) was the same in all groups and diazoxide had no measurable effects on myocardial performance, whereas glibenclamide increased end-diastolic pressure more in N and CH than in CH+A hearts (P < 0.05). During reoxgenation, efficiency was markedly less in CH with respect to N and CH+A (P < 0.0001), and rate x pressure product remained lower in CH than N and CH+A hearts (P < 0.001), but glibenclamide or diazoxide abolished this difference. Glibenclamide, but not diazoxide, decreased vascular resistance in N and CH (P < 0.005 and < 0.001) without changes in CH+A. We hypothesize that cardioprotection in chronically hypoxic hearts derive from cell depolarization by sarcolemmal K+ATP blockade or from preservation of oxidative phosphorylation efficiency (ATP turnover/myocardial performance) by mitochondrial K+ATP opening. Therefore K+ATP channels are involved in the deleterious effects of chronic hypoxia and in the cardioprotection elicited when chronic hypoxia is interrupted with short normoxic aeration episodes.
Memoirs of a Bystander: A Life in Diplomacy

The skirmish in the Rann of Kutch and the 1965 war with India, the Tashkent Conference, Bhutto's walk-out from the Security Council, Bhutto's rise and fall, and the nuclear deal with France - the author writes of these as a witness, and tells the inside story in this book. Blending description, analysis and anecdote, Iqbal Akhund's account casts a fresh light on these critical and still controversial events in Pakistan's history. There are perspective pen-pictures of the eminent personalities whom he met or had to deal with - Ayub and Shustri, Bhutto and Ziaul Haq, Nasser of Egypt and Tito of Yugoslavia. The book begins in the declining heyday of Britain's Indian Empire and describes the way things were under what the author calls the "Brown Raj". It outlines the author's personal reaction to the concept of Pakistan. It ends in Lebanon, in the midst of the civil war and Israeli invasion, drawing a thought-provoking parallel with Pakistan.
Antitumor Activity and Underlying Mechanisms of Ganopoly, The Refined Polysaccharides Extracted from Ganoderma Lucidum, in Mice

Ganopoly is an aqueous polysaccharide fraction extracted from G. lucidum by patented biochemical technique and has been marketed as an over-the-counter product for chronic diseases including cancer and hepatopathy in many Asian countries. This study was undertaken to explore the anti-tumour effect and the underlying mechanisms of Ganopoly in mice and human tumor cell lines. The maximum tolerateddose (MTD) of Ganopoly in mice was estimated to be 100 mg/kg from a pilot study. Treatment of mice with oral Ganopoly for 10 days significantly reduced the tumour weight of sarcoma-180 in a dose-dependent manner, with inhibition rates of 32.3, 48.2 and 84.9% and growth delays of 1.5, 3.5, and 13.1 days at 20, 50, and 100 mg/kg, respectively. Incubation of Ganopoly at 0.05–1.0 mg/ml for 48 hours showed little or negligible cytotoxicity against human tumor CaSki, SiHa, Hep3B, HepG2, HCT116, HT29, and MCF7 cells in vitro. In contrast, 10 mg/ml of Ganopoly caused significant cytotoxicity in all tumour cells tested except MCF7, with marked apoptotic effects observed in CaSki, HepG2, and HCT116 cells, as indicated by nuclear staining and DNA fragmentation. In addition, Ganopoly enhanced concanavalin A-stimulated proliferation of murine splenocytes by 35.3% at 10 mg/ml, and stimulated the production of nitric oxide in thioglycollate-primed murine peritoneal macrophages in a concentration-dependent manner over 0.05–10 mg/ml. Addition of Ganopoly at 1 mg/ml to murine peritoneal macrophages also potentiated lipopolysaccharide-induced nitric oxide production by 64.2%. Treatment of healthy mice or mice bearing sarsoma-180 with oral Ganopoly over 20–100 mg/kg for 7 day significantly increased the expression of both TNF-α and IFN-γ (at both mRNA and protein levels) in splenocytes in a dose-dependent manner. Moreover, treatment of Ganopoly over 20–100 mg/kg significantly increased cytotoxic T lymphocyte cytotoxicity and NK activity in mice. The overall findings indicated that Ganopoly had antitumor activity with a broad spectrum of immuno-modulating activities and may represent a novel promising immunotherapeutic agent in cancer treatment.
The impact of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) on prescribing practices: an analysis of data from a large midwestern state.

BACKGROUND The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) was a series of effectiveness trials. The results of these trials began publication in September 2005. Among other findings, these studies were interpreted to suggest that (1) second-generation antipsychotics might have fewer advantages over first-generation antipsychotics than had been generally thought; (2) among the agents assessed, olanzapine had the best efficacy outcome; and (3) after treatment failure with a second-generation antipsychotic, the most efficacious second-line medication is clozapine. To examine the actual impact on practice of these publications, we looked at change in physician prescribing behavior based on these 3 conclusions before and after publication of CATIE. METHOD Rates of antipsychotic medication prescriptions to 51,459 patients with an ICD-9 code of 295 for schizophrenia were extracted from a Missouri Medicaid claims database. χ² Tests were used to compare the rates of prescribing antipsychotic medications before and after each of 3 key CATIE publications (time 1 was September 2005, time 2 was December 2006, and time 3 was April 2006). RESULTS At all time points, we demonstrated a decrease in prescriptions by all prescribers for olanzapine (P < .0001). One year after time 1, we found an increase in prescriptions by all prescribers for aripiprazole (P < .0001). No statistically significant increases in clozapine prescribing were observed. Also, a small but statistically significant increase was seen in prescriptions of perphenazine (P < .02 at time 3). However, this increase occurred only for prescriptions written by psychiatrists and not other prescribers. CONCLUSIONS We found some evidence in our sample that the publication of the results from CATIE had a small but statistically significant effect on prescribing habits of psychiatrists but not other physicians in our sample population. However, larger changes occurred in prescribing behavior that were largely unrelated to the CATIE trial. We propose a hypothesis to explain the direction of observed changes.
HPV‐mediated cervical carcinogenesis: concepts and clinical implications

Persistent infection with a high‐risk human papillomavirus (hrHPV) is generally accepted as a necessary cause of cervical cancer. However, cervical cancer is a rare complication of an hrHPV infection since most such infections are transient, not even giving rise to cervical lesions. On average, it takes 12–15 years before a persistent hrHPV infection may ultimately, via consecutive premalignant stages (ie CIN lesions), lead to an overt cervical carcinoma. This argues that HPV‐induced cervical carcinogenesis is multi‐step in nature. In this review, the data from hrHPV‐mediated in vitro transformation studies and those obtained from analysis of clinical specimens have been merged into a cervical cancer progression model. According to this model, a crucial decision maker in the early stages following infection involves individual susceptibility for certain HPV types depending on the genetic make‐up of immune surveillance determinants. Once a CIN lesion has developed, altered transcriptional regulation of the viral E6/E7 oncogenes, resulting in genomic instability and distinguishing the process of cell transformation from a productive viral infection, probably provides the subsequent important step towards malignancy. The additional (epi)genetic alterations that subsequently accumulate in high‐grade CIN lesions may result in overt malignancy via immortality and growth conditions that gradually become less sensitive to growth‐modulating influences mediated by cytokines and cell–cell and cell–matrix adhesions. The potential implications of hrHPV testing and some other biomarkers deduced from this model for cervical screening and the clinical management of CIN disease are also discussed. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.