Miracle-dz/UniFAR-FTUs huggingface dataset:
The Effect of the Interaction of Propofol and Alfentanil on Recall, Loss of Consciousness, and the Bispectral Index

The Bispectral Index (BIS) correlates well with the level of consciousness with single anesthetic drugs.We studied the effect of the interaction of propofol with alfentanil on propofol concentration and BIS associated with 50% probability of loss of consciousness and lack of recall (Cp50 and BIS50, respectively). We studied 40 consenting volunteers at two institutions who were randomly assigned to receive stepped increases of propofol (10 subjects at each site), propofol plus alfentanil 50 ng/mL (10 subjects at Emory site), or propofol plus alfentanil 100 ng/mL (10 subjects at Duke site) by using a target-controlled infusion device. Measures of sedation, BIS, Delta BIS (absolute change of BIS after a painful stimulus), memory, and drug concentration were obtained at each target drug concentration. The relation among BIS, measured drug concentration, sedation score, and presence or absence of recall was determined by linear and logistic regression for different drug regimens, and the prediction probability (Pk) was calculated. The addition of alfentanil in increasing doses did not significantly affect the BIS50 and propofol Cp50 values for loss of consciousness and lack of recall. Delta BIS was significantly decreased by both an increase in the concentration of propofol and the presence of alfentanil. The Pk for BIS was >0.93 with all drug regimens, better than those of the target and measured propofol concentrations. We conclude that BIS correlated well with the hypnotic component of anesthesia independent of the presence of an opioid. Moreover, the level of consciousness, and, therefore, the BIS index, is affected by a painful stimulus, and this response is ablated either by opioids or increasing propofol concentration. Implications: In volunteers, the sedation and changes in memory function produced by propofol correlated well with changes in the Bispectral Index. This relationship was not altered by the addition of an analgesic (alfentanil). However, in moderately sedated patients who received a painful stimulus, the Bispectral Index increased, but this response was blocked by the analgesic or increasing propofol concentrations. (Anesth Analg 1998;87:949-55)
The impact of a faculty development program in health literacy and ethnogeriatrics.

PROBLEM A faculty development curriculum aimed at increasing health literacy and awareness of patient care issues in ethnogeriatrics is essential to address serious deficiencies in faculty and health professionals' training and to prepare future health care professionals to care for older adults. APPROACH Authors from the Stanford Geriatric Education Center developed and implemented a faculty development program in Health Literacy and Ethnogeriatrics (HLE). The goal was to enhance faculty and health professionals' knowledge, skills, and attitudes in HLE-related areas (e.g., health disparities, low health literacy, quality of care for ethnically diverse elders, patient/provider communication). The curriculum was implemented during an intensive weeklong program over a three-year period (2008-2010). The eight-module core curriculum was presented in a train-the-trainer format, supplemented by daily resource sessions. OUTCOMES Thirty-four faculty participants from 11 disciplines, including medicine, came from 19 institutions in 12 states. The curriculum positively affected participants' knowledge, skills, and attitudes related to topics in HLE. Participants rated the curriculum's usefulness highly, and they reported that over 57% of the content was new. The HLE curriculum provided a mechanism to increase the self-assessed knowledge, skills, and attitudes of participants. It also fostered local curricular change: Over 91% of the participants have either disseminated the HLE curriculum through seminars conducted at their home sites or implemented HLE-related projects in their local communities, reaching diverse patient populations. NEXT STEPS Next steps include measuring the impact on the participants' teaching skills and at their home sites through their trainees and patients.
On the evolution of morphogenetic models: mechano‐chemical interactions and an integrated view of cell differentiation, growth, pattern formation and morphogenesis

In the 1950s, embryology was conceptualized as four relatively independent problems: cell differentiation, growth, pattern formation and morphogenesis. The mechanisms underlying the first three traditionally have been viewed as being chemical in nature, whereas those underlying morphogenesis have usually been discussed in terms of mechanics. Often, morphogenesis and its mechanical processes have been regarded as subordinate to chemical ones.
"We have our protector": misperceptions of protection against HIV among participants in a microbicide efficacy trial.

OBJECTIVES We examined perceptions of the effectiveness and acceptability of a candidate microbicide among 94 South African female sex workers who had participated in a phase 3 microbicide trial for HIV prevention. METHODS Sixteen focus groups were conducted in 2001, 12 to 15 months after participants were informed that the candidate microbicide had been determined to be ineffective in preventing HIV and other sexually transmitted infections (STIs). RESULTS Participants clearly indicated that they understood the experimental nature of the candidate microbicide, and they recognized that they had been informed after the trial that the product was ineffective. Nevertheless, most continued to believe that the candidate microbicide helped prevent HIV and other STIs, alleviated reproductive tract pain and STI symptoms, and helped to clean the vagina. CONCLUSIONS These findings underscore the importance of understanding women's perceptions of the efficacy of candidate microbicides and the rationale for these beliefs. These issues need to be addressed in counseling throughout microbicide trials for HIV prevention. These results also demonstrate how desperate many women at high risk of HIV infection may be for new HIV prevention technologies.
Regulation of Gephyrin Assembly and Glycine Receptor Synaptic Stability*

Gephyrin is required for the formation of clusters of the glycine receptor (GlyR) in the neuronal postsynaptic membrane. It can make trimers and dimers through its N- and C-terminal G and E domains, respectively. Gephyrin oligomerization could thus create a submembrane lattice providing GlyR-binding sites. We investigated the relationships between the stability of cell surface GlyR and the ability of gephyrin splice variants to form oligomers. Using truncated and full-length gephyrins we found that the 13-amino acid sequence (cassette 5) prevents G domain trimerization. Moreover, E domain dimerization is inhibited by the gephyrin central L domain. All of the gephyrin variants bind GlyR β subunit cytoplasmic loop with high affinity regardless of their cassette composition. Coexpression experiments in COS-7 cells demonstrated that GlyR bound to gephyrin harboring cassette 5 cannot be stabilized at the cell surface. This gephyrin variant was found to deplete synapses from both GlyR and gephyrin in transfected neurons. These data suggest that the relative expression level of cellular variants influence the overall oligomerization pattern of gephyrin and thus the turnover of synaptic GlyR.
MORPHOLOGICAL DESCRIPTION OF THE DEVELOPING OSTRICH EMBRYO: A TOOL FOR EMBRYONIC AGE ESTIMATION

The ostrich (Struthio camelus), the largest living bird, is farmed intensively worldwide. However, despite the importance of understanding embryonic development in the ostrich for successful egg incubation practice, little is known about it. Using the chicken model for scaling is currently a common practice in estimating age in ostrich embryos. The aim of this study was to compare the embryonic morphological development of the ostrich to that of the chicken, as both physiological and morphological differences in the embryonic development of the two species have been reported recently. Ostrich eggs were incubated at 36.5 °C and 25% relative humidity. The embryos were inspected on alternate days from day 4 through day 40 of incubation. The study showed that the temporal appearance of structures in the first half of the embryonic development of the ostrich resembles that of the chicken. However, differences in the temporal appearance of grooves between toes and digits, nictitating membrane, eyelid covering of the eyeball, and the appearance of scales on the legs appear to exist between the two species, but their confirmation will require the use of larger egg samples. The second half of the development was described by changes in the beak, wing, and leg lengths, as well as by that of the embryo’s wet mass. Since the growth patterns of the ostrich and the chicken differ, embryonic age estimation of one species cannot be inferred from relative changes in linear dimensions of the other. We offer equations for estimating the embryonic age of the ostrich during the second half of incubation using morphometric measurements of the above parameters.
Statins and myositis: the role of anti-HMGCR antibodies

Muscle toxicity is a recognized adverse effect of statin use. Recently, a new myositis syndrome was described in association with antibodies directed against the pharmacologic target of statins, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR antibody). The patient’s genetic background, characteristic histologic patterns (immune-mediated necrotizing myopathy), and presence of anti-HMGCR antibodies define the syndrome. In most patients, statin discontinuation is insufficient to reverse the myositis symptoms, and immunosuppressive therapy is needed. The mechanisms by which these antibodies may lead to disease are not fully elucidated. Several important questions remain unsolved and warrant further research.
Significant improvement of bone mineral density by denosumab without bisphosphonate pre-treatment in glucocorticoid-induced osteoporosis

Abstract Objective: The aim of this study was to evaluate differences in outcomes of denosumab for a year with or without bisphosphonate (BP) pre-treatment in patients with glucocorticoid-induced osteoporosis (GIO). Methods: Forty-eight female patients with GIO and low bone mineral density (BMD) (T score of BMD; less than −3.0 SD) were, retrospectively, enrolled and classified into the following two groups: (1) GIO with BP pre-treatment (BP pre-treated group; n = 24) and (2) GIO without BP treatment (BP pre-untreated group; n = 24). We measured serum bone alkaline phosphatase (BAP), N-terminal propeptide of type 1 procollagen (P1NP), and tartrate-resistant acid phosphatase (TRACP)-5b at baseline, and at 3, 6, and 12 months. We also assessed BMD of the lumbar 1–4 vertebrae BMD (L-BMD) and bilateral hip BMD (H-BMD) at baseline, and at 6 and 12 months. Results: TRACP-5b was significantly inhibited at 3 months in both groups and at 6 and 12 months in the BP pre-untreated group compared with pre-treatment levels. Both BAP and P1NP were significantly suppressed at 3, 6, and 12 months in both groups compared with baseline values. L-BMD and H-BMD were significantly increased at 6 (4.2% and 3.4%, respectively) and 12 months (4.7% and 4.7%, respectively) in the BP pre-untreated group over pre-treatment levels. There were no significant differences between the groups during the observational period. Conclusion: Denosumab significantly improved both L-BMD and H-BMD in the BP pre-untreated group, but not in the BP pre-treated group, suggesting it to be a good option for GIO patients without BP pre-treatment.
Solution conformation of the (+)-cis-anti-[BP]dG adduct opposite a deletion site in a DNA duplex: intercalation of the covalently attached benzo[a]pyrene into the helix with base displacement of the modified deoxyguanosine into the minor groove.

We have applied a combined NMR-molecular mechanics approach to determine the solution structure of the (+)-cis-anti-[BP]dG adduct positioned opposite a deletion site in the sequence d(C5-[BP]G6-C7). d(G16-G17) at the DNA oligomer duplex level. Our structural studies establish that the benzo[a]pyrene ring intercalates into the helix opposite the deletion site while the modified deoxyguanosine is displaced into the minor groove with its plane parallel to the helix axis. The intercalation site is wedge-shaped with the benzo[a]pyrene ring stacked over intact flanking Watson-Crick dG.dC base pairs. The modified deoxyguanosine stacks over the minor groove face of the sugar ring of the 5'-flanking dC5 residue. The structure at the lesion site is consistent with the observed intermolecular NOEs which served as input restraints to guide the molecular mechanics calculations, and, in addition, the various stacking interactions explain the observed large ring current shifts associated with adduct formation. The solution structure of the (+)-cis-anti-[BP]dG adduct positioned opposite a deletion site reported in this study is similar to the corresponding structure of the same adduct positioned opposite dC reported previously [Cosman, M. , de los Santos, C. , Fiala, R. , Hingerty, B. E. , Luna, E. , Harvey, R. G. , Geacintov, N. E. , Broyde, S. , & Patel, D. J. (1993) Biochemistry 32, 4145-4155]. This is not surprising since the dC opposite the lesion site was looped out of the helix and it can be readily replaced by a deletion site through minor changes associated with buckling of the intercalation site. By contrast, the solution structures of the (+)-trans-anti-[BP]dG and (+)-cis-anti-[BP]dG adducts positioned opposite deletion sites in the same sequence context exhibit distinct surface topologies in the grooves of the DNA helix. Thus, even though the benzo[a]pyrene intercalates into the helix opposite the deletion site in both cases, the modified deoxyguanosine is displaced into the major groove for the (+)-trans-anti-[BP]dG adduct while it is displaced into the minor groove for the (+)-cis-anti-[BP]dG stereoisomer. The orientational differences reflect the chiral characteristics of the two [BP]-dG stereoisomeric adducts with the different alignments of the bulky DNA lesion opposite the deletion site likely to influence interactions with the cellular repair machinery.
Alcohol and gastrointestinal cancer: pathogenic mechanisms

Abstract Chronic heavy alcohol consumption leads to a significantly increased risk of cancer in the oropharynx, larynx and the oesophagus. In the liver, chronic alcohol abuse results in cirrhosis, a precursor of hepatocellular cancer. More recentepidemiologic studies also demonstrate that regular alcohol consumption, even in low amounts, has an enhanced risk for rectal cancer and cancer of the breast. Alcohol by itself is not a carcinogen. However, alcohol can increase the susceptibility of various organs to chemical carcinogens by a variety of mechanisms. Among these, increased activation of procarcinogens through microsomal enzyme induction, a change in the metabolism and/or distribution of carcinogens, interference with the system that repairs carcinogen‐induced DNA alkylations, direct mucosal tissue damage with consecutive stimulation of cellular regeneration and alcohol‐mediated malnutrition may be of importance. In the upper gastrointestinal tract the production of acetaldehyde and free radicals via cytochrome P450 2E1 and via alcohol dehydrogenase may lead to tissue damage and to secondary hyper‐regeneration. In addition, local mechanisms may also be involved in the co‐carcinogenic process. In the rectal mucosa acetaldehyde seems to be an important factor in carcinogenesis and may be predominantly produced by faecal bacteria.
Cells surviving infection by human immunodeficiency virus type 1: vif or vpu mutants produce non-infectious or markedly less cytopathic viruses.

Under conditions in which a clonal cell line (M10) isolated from a human T cell lymphotrophic virus type I-transformed MT-4 cell line was completely killed by infection with wild-type human immunodeficiency virus type 1 (HIV-1), equivalent M10 cells survived infection with HIV-1 vif, vpr or vpu mutant virus after transient cytopathic effects. Several cell clones, which were isolated from the proliferating M10 cells after infection with vif and vpu mutant viruses (M10/vif- and M10/vpu-), had heterogeneous HIV-1 phenotypes in terms of HIV-1 antigen expression, their syncytium forming capacity, reverse transcriptase activity and the infectivity of HIV-1 particles produced. When the replication kinetics of the HIV-1 particles produced were assayed in M10 cells, the clones could be classified into three types, i.e. type I producing non-infectious HIV-1, type II producing infectious HIV-1 with low replicative ability and type III producing infectious HIV-1 with a replicative ability similar to that of wild-type HIV-1. HIV-1 major viral cell proteins and virus particle fractions were almost typical in types II and III but not in type I. Electron microscopic examination of particles released by I, II and III clones revealed rare defective, predominantly defective and essentially normal virions, respectively. Northern and Southern blot analyses revealed no apparent deletion in the proviral DNA and mRNA prepared from these clones, except in the case of type I and II clones isolated from M10/vpu- which contained large deletions in the mRNAs for gag and gag-pol proteins. Thus, M10 cells surviving infection with HIV-1 vif or vpu mutants are heterogeneous, persistently expressing HIV-1 antigens and producing non-infectious or less cytopathic virus.
The Immediate Impact and Persistent Effect of FX Purchases on the Exchange Rate

In recent years, Forex (FX) interventions have been routinely used by the Bank of Israel as well as by other central banks as an additional monetary instrument, with the objective of moderating appreciation trends of the domestic currency. This paper analyzes the immediate effect of the Bank of Israel’s FX interventions on the exchange rate and the persistence of this effect over time. To identify this effect, we first measure the intraday impact of FX intervention using a novel high-frequency, minute-by-minute dataset of interventions between 2009 and 2017. Next, we use our intraday measure to estimate the persistence of FX intervention shocks over longer horizons (in trading days), where we base our empirical approach on the potential outcome framework and the Local Projections method. We find that FX intervention shocks – that is, unexpected FX purchases – cause, on impact USDILS exchange rate depreciation in over 90 percent of the cases. We also find that this effect has a persistent impact on the nominal effective exchange rate for about 40­–60 trading days, which are equivalent to between 2 and 3 calendar months. Based on this finding we infer that between 2013 and 2017 interventions caused the level of the exchange rate to depreciate by about 2–3 percent on average, where the effect of each intervention varied with its intensity. We stress that these results reflect the contribution of unexpected FX purchases given the fact that the discretionary intervention regime was in place throughout the investigated period, and not the effect of the presence of the regime itself. ​
Role of Hedgehog signalling at the transition from double-positive to single-positive thymocyte

In the thymus, developing T cells receive signals that determine lineage choice, specificity, MHC restriction and tolerance to self‐antigen. One way in which thymocytes receive instruction is by secretion of Sonic hedgehog (Shh) from thymic epithelial cells. We have previously shown that Hedgehog (Hh) signalling in the thymus decreases the CD4:CD8 single‐positive (SP) thymocyte ratio. Here, we present data indicating that double‐positive (DP) thymocytes are Hh‐responsive and that thymocyte‐intrinsic Hh signalling plays a role in modulating the production of CD4+ (SP4), CD8+ (SP8) and unconventional T‐cell subsets. Repression of physiological Hh signalling in thymocytes altered the proportions of DP and SP4 cells. Thymocyte‐intrinsic Hh‐dependent transcription also attenuated both the production of mature SP4 and SP8 cells, and the establishment of peripheral T‐cell compartments in TCR‐transgenic mice. Additionally, stimulation or withdrawal of Hh signals in the WT foetal thymus impaired or enhanced upregulation of the CD4 lineage‐specific transcription factor Gata3 respectively. These data together suggest that Hh signalling may play a role in influencing the later stages of thymocyte development.
Antioxidant Effects of Zinc Supplementation in Tunisians with Type 2 Diabetes Mellitus

Objective: To determine the effects of zinc (Zn) supplementation on oxidative stress in persons with type 2 diabetes mellitus (type 2 DM). Design: Tunisian adult subjects with HbA1c >7.5% were supplemented for six months with 30 mg/day of Zn as Zn gluconate or placebo. The effects of supplementation on plasma zinc (Zn), copper (Cu), urinary Zn, plasma thiobarbituric acid reactive substances (TBARS), Cu-Zn superoxide dismutase (SOD) and glutathione peroxidase activities (GPX) in red blood cells, blood lipids and lipoproteins, HbA1c and fasting glucose were measured at the beginning of the study and after three and six months. Results: At the beginning of the study, more than 30% of the subjects exhibited plasma Zn values less than the normal minimum of 10.7 μmol/L, whereas levels of plasma Cu and antioxidant RBC Cu-Zn SOD and GPx enzyme activities were in the normal ranges. Oxidative stress, monitored by plasma TBARS, was increased in individuals with diabetes compared with healthy Tunisian subjects (3.32 ± 0.05 μmol/L vs. 2.08 ± 0.04 μmol/L) and an inverse correlation was found between Zn plasma levels and plasma TBARS. After three and six months of Zn supplementation, all of the subjects exhibited plasma Zn values greater than 10.7 μmol/L. There was a decrease of plasma TBARS in Zn supplemented group after six months (15%) with no significant changes in the placebo group. Supplementation did not alter significantly HbA1c nor glucose homeostasis. No adverse effects of Zn supplementation were observed on Cu status or HDL cholesterol. Conclusions: These data suggest the potential beneficial antioxidant effects of Zn supplementation in persons with type 2 DM. These results are particularly important in light of the deleterious consequences of oxidative stress in persons with diabetes.