Miracle-dz/UniFAR-FTUs huggingface dataset:
Human pharmacology of the opioid neuropeptide dynorphin A(1-13).

We evaluated the human pharmacology of dynorphin A(1-13) and determined whether this peptide can modulate naloxone-precipitated withdrawal effects. Such information could help determine its receptor mechanism of action and whether dynorphin is useful for treating opioid dependence. Six opioid-experienced subjects participated in a within-subject, placebo-controlled design. There were two phases, each with four test sessions. In phase 1, volunteers who were not physically dependent were administered 0, 0.1, 0.32 and 1 mg/kg dynorphin (15-min i.v. infusion) in ascending order, and subjective, observer-rated and physiological effects were monitored. Dynorphin produced brief, dose-related increases in drug effect ratings with both good and bad drug effects reported by different subjects. There were no significant changes in pupil size, respiratory rate, skin temperature, heart rate or blood pressure, These data are consistent with preclinical findings that dynorphin has a short duration of action and does not primarily exert its direct effects through mu-opioid receptors. In four separate sessions of phase 2, acute morphine pretreatment (45 mg/70 kg i.m.) was followed 15 or 18 hr later by dynorphin (0 vs. 1 mg/kg, 15-min i.v.) and then naloxone (1 or 3 vs. 10 mg/70 kg, 5-min i.v.). Under these conditions, dynorphin weakly potentiated naloxone-precipitated withdrawal. These data contrast with those of previous preclinical studies showing dependence-attenuating effects of dynorphin and fail to support its use as an antiwithdrawal agent in humans.
The histopathology of prolymphocytic leukaemia with particular reference to the spleen: a comparison with chronic lymphocytic leukaemia

The histological features of prolymphocytic leukaemia are described in spleen, lymph nodes, liver and bone marrow from nine cases. Eight patients had B‐PLL one had T‐PLL. These features were compared with those of six cases of B chronic lymphocytic leukaemia (B‐CLL) with massive splenomegaly. Both PLL and B‐CLL showed enlargement of the white pulp with nodule formation and diffuse infiltration of the red pulp. In both PLL and CLL larger cells were found in the white pulp nodules often concentrated on the periphery producing a bizonal appearance. The extent of involvement of the white pulp was greater in PLL than in uncomplicated CLL. However, this was not so in two cases of B‐CLL in prolymphocytoid transformation in which the heavy replacement of the white pulp by large cells without a bizonal arrangement had effaced the red pulp. The cytological differences between PLL and CLL were best appreciated in splenic red pulp. The cells of CLL were small lymphocytes with clumped chromatin, those of PLL were larger with bigger nuclei, often indented in some cases, and distinct nucleoli. The pattern of infiltration in the bone marrow, liver and lymph nodes was similar in PLL and CLL. In conclusion, PLL can be distinguished from CLL by morphological and immunological features. The distinction is important clinically, because the survival of PLL is shorter than that of CLL.
A comparison of the United Kingdom Clinical Aptitude Test (UK-CAT) with a traditional admission selection process

Background: The United Kingdom Clinical Aptitude Test (UK-CAT) was introduced for the purpose of student selection by a consortium of 23 UK University Medical and Dental Schools, including the University of Aberdeen in 2006. Aim: To compare candidate performance on UK-CAT with local medical student selection outcome. Method: We compared the outcomes of all applicants to Medicine, University of Aberdeen (UoA), in 2006 who undertook the UK-CAT. The candidates were selected into one of five outcomes (academic reject, reject following assessment, reject following interview, reserve list or offer). The candidate performance in the UK-CAT was compared to candidate performance on the UoA selection. Results: Data are reported on 1307 (85.0%) students who applied to UoA in 2006 and undertook the UK-CAT. Total UK-CAT scores were significantly correlated with local selection scores. However, of 314 students offered a place following the conventional selection process, only 101 were also in the highest scoring 318 on the UK-CAT. Conclusions: Results from this study indicate that UK-CAT scores show weak correlation with success in our medical admissions process. It appears therefore that the UK-CAT examines different traits compared to our selection process. Further work is required to establish which better predicts success as an undergraduate or as a doctor.
Paramyxovirus replication and pathogenesis. Reverse genetics transforms understanding

A recent breakthrough in the field of nonsegmented negative strand RNA viruses (Mono‐ negavirales), including paramyxoviruses, is the establishment of a system to recover an infectious virus entirely from complementary DNA and hence allow reverse genetics. Mutations can now be introduced into viral genomes at will and the resulting phenotypes studied as long as the introduced mutations are not lethal. This technology is being successfully applied to answer outstanding questions regarding the roles of viral components in replication and their contribution to pathogenicity, which are difficult to address using conventional virology. For instance, how the paramyxovirus accessory proteins V and C contribute to actual viral replication and pathogenesis has remained unanswered since their first description more than 20 years ago. Using Sendai virus, which causes fatal pneumonia in mice, it has been shown that the V protein is completely dispensable for viral replication in cell cultures but encodes a luxury function required for pathogenesis in vivo. The Sendai virus C proteins were also defined to be nonessential gene products which greatly contributed to replication both in vitro and in vivo. It is also now possible to design live vaccines by introducing predetermined or plausible attenuating mutations. In addition, the use of paramyxoviruses to express foreign genes has also become feasible. Paramyxovirus reverse genetics is thus renovating our understanding of viral replication and pathogenesis and will further mark an era in recombinant technology for disease prevention and gene therapy. Copyright © 1999 John Wiley & Sons, Ltd.
IDEal: efficient and precise alias-aware dataflow analysis

Program analyses frequently track objects throughout a program, which requires reasoning about aliases. Most dataflow analysis frameworks, however, delegate the task of handling aliases to the analysis clients, which causes a number of problems. For instance, custom-made extensions for alias analysis are complex and cannot easily be reused. On the other hand, due to the complex interfaces involved, off-the-shelf alias analyses are hard to integrate precisely into clients. Lastly, for precision many clients require strong updates, and alias abstractions supporting strong updates are often relatively inefficient. In this paper, we present IDEal, an alias-aware extension to the framework for Interprocedural Distributive Environment (IDE) problems. IDEal relieves static-analysis authors completely of the burden of handling aliases by automatically resolving alias queries on-demand, both efficiently and precisely. IDEal supports a highly precise analysis using strong updates by resorting to an on-demand, flow-sensitive, and context-sensitive all-alias analysis. Yet, it achieves previously unseen efficiency by propagating aliases individually, creating highly reusable per-pointer summaries. We empirically evaluate IDEal by comparing TSf, a state-of-the-art typestate analysis, to TSal, an IDEal-based typestate analysis. Our experiments show that the individual propagation of aliases within IDEal enables TSal to propagate 10.4x fewer dataflow facts and analyze 10.3x fewer methods when compared to TSf. On the DaCapo benchmark suite, TSal is able to efficiently compute precise results.
Can salivary composition and high flow rate explain the low caries rate in children with familial dysautonomia?

PURPOSE Extremely low caries rate and increased major salivary gland flow rare have been previously reported in children with familial dysautonomia (FD). The purpose of this study was to explore the possibility that, in addition to increased salivary flow, children with FD have alterations in their salivary components, which may suggest an explanauon to their low caries rate. METHODS Whole unstimulated and stimulated saliva samples were collected from 13 children with FD who were found to be caries free, and from 28 age- and ethnic-matched healthy children, 15 caries-free children and 13 caries-affected children. The electrolyte and protein content of the unstimulated saliva and the microbial count and buffering capacity of the stimulated saliva were determined. RESULTS Children with FD had the highest salivary flow rate and the lowest levels of mutans streptococci and lactobacilli, as well as the lowest concentration of chloride, magnesium, total protein and IgA. Healthy caries-affected children displayed the highest mutans streptococci and lactobacilli levels and lysozyme concentration, concomitantly with the lowest potassium and calcium concentrations. CONCLUSIONS The results of this investigation suggest that the caries-free state in FD may be associated with high salivary flow rate, while in healthy children, low caries rate may be associated with high salivary calcium concentration.
Pharmacokinetics and Efficacies of Liposomal and Conventional Formulations of Tobramycin after Intratracheal Administration in Rats with Pulmonary Burkholderia cepacia Infection

ABSTRACT The objective of the present study was to determine the pharmacokinetics and efficacies of liposomal and conventional formulations of tobramycin against Burkholderia cepacia in a model of chronic lung infection. Male Sprague-Dawley rats were inoculated intratracheally with 106 CFU of a very resistant strain of B. cepacia (strain BC 1368; MIC, 128 μg/ml) to establish lung infection. A 1,200-μg dose of tobramycin was administered intratracheally as a liposomal formulation and as a conventional formulation. Rats were anesthetized and exsanguinated by cardiac puncture at different times over 24 h to assess pulmonary tobramycin concentrations and the number of residual CFU. Pharmacokinetic parameters were calculated by using a two-compartment model with NONMEM. The mean half-life at the β phase (t1/2β) and the pulmonary exposure (the area under the concentration-time curve [AUC]) of liposomal tobramycin were 19.7 h (coefficient of variation [CV], 24.2%) and 6,811 μg · h/lungs (CV, 19.7%), respectively. The pharmacokinetics of conventional tobramycin were statistically different, with a t1/2β and AUC of 12.9 h (CV, 31.4%) and 821 μg · h/lungs (CV, 15.0%), respectively. Pearson chi-square analyses were performed on residual CFU data distributed in the following categories: <103, 103 to 105, and >105. Differences in CFU data between formulations showed a statistical trend (P < 0.10) when data from all time points were used, and statistically significant differences were found after 12 h (P < 0.05), with greater eradication achieved with the liposomal formulation. In conclusion, intratracheal administration of tobramycin in liposomes was associated with marked changes in the pharmacokinetics of the drug in the lung and an apparent trend for a prolonged efficacy against B. cepacia. These results support the hypothesis that inhalation of liposomal tobramycin may improve the management of chronic pulmonary infections caused by resistant bacteria in patients with cystic fibrosis.
Centrosymmetric bilayers in the 0.75 å resolution structure of a designed alpha‐helical peptide, D, L‐Alpha‐1

We report the 0.75 Å crystal structure of a racemic mixture of the 12‐residue designed peptide “Alpha‐1” (Acetyl‐ELLKKLLEELKG), the L‐enantiomer of which is described in the accompanying paper. Equivalent solutions of the centrosymmetric bilayers were determined by two direct phasing programs in space groups P1 and P1. The unit cell contains two L‐alpha‐helices and two D‐alpha‐helices. The columnar‐sheet bilayer motif seen in L‐Alpha‐1 is maintained in the D, L‐Alpha‐1 structure except that each sheet of head‐to‐tail helices is composed of one enantiomer and is related to its neighboring sheets by inversion symmetry. Comparison to the L‐Alpha‐1 structure provides further insight into peptide design. The high resolution and small asymmetric unit allowed building an intricate model (R = 13.1%, Rfree = 14.5%) that incorporates much of the discrete disorder of peptide and solvent. Ethanolamine and 2‐methyl‐2, 4‐pentanediol (MPD) molecules bind near helix termini. Rigid body analysis identifies sites of restricted displacements and torsions. Side‐chain discrete disorder propagates into the backbone of one helix but not the other. Although no side chain in Alpha‐1 is rigid, the environments in the crystal restrict some of them to no or only one active torsion.
High Prevalence of Antimicrobial Resistance among Shigella Isolates in the United States Tested by the National Antimicrobial Resistance Monitoring System from 1999 to 2002

ABSTRACT Shigella spp. infect approximately 450,000 persons annually in the United States, resulting in over 6,000 hospitalizations. Since 1999, the National Antimicrobial Resistance Monitoring System (NARMS) for Enteric Bacteria has tested every 10th Shigella isolate from 16 state or local public health laboratories for susceptibility to 15 antimicrobial agents. From 1999 to 2002, NARMS tested 1,604 isolates. Among 1,598 isolates identified to species level, 1,278 (80%) were Shigella sonnei, 295 (18%) were Shigella flexneri, 18 (1%) were Shigella boydii, and 7 (0.4%) were Shigella dysenteriae. Overall, 1,251 (78%) were resistant to ampicillin and 744 (46%) were resistant to trimethoprim-sulfamethoxazole (TMP-SMX). Prevalence of TMP-SMX- or ampicillin- and TMP-SMX-resistant Shigella sonnei isolates varied by geographic region, with lower rates in the South and Midwest regions (TMP-SMX resistance, 27% and 30%, respectively; ampicillin and TMP-SMX resistance, 25% and 22%, respectively) and higher rates in the East and West regions (TMP-SMX resistance, 66% and 80%, respectively; ampicillin and TMP-SMX resistance, 54% and 65%, respectively). Nineteen isolates (1%) were resistant to nalidixic acid (1% of S. sonnei and 2% of S. flexneri isolates); 12 (63%) of these isolates had decreased susceptibility to ciprofloxacin. One S. flexneri isolate was resistant to ciprofloxacin. All isolates were susceptible to ceftriaxone. Since 1986, resistance to ampicillin and TMP-SMX has dramatically increased. Shigella isolates in the United States remain susceptible to ciprofloxacin and ceftriaxone.
The Antagonistic Actions of Endogenous Interleukin-1β and 15-Deoxy-Δ12,14-prostaglandin J2 Regulate the Temporal Synthesis of Matrix Metalloproteinase-9 in Sheared Chondrocytes*

Background: Metalloproteinase-9 (MMP-9) is detected at the early but not late stages of osteoarthritis. Results: Application of high fluid shear to chondrocytes recapitulates the temporal regulation of MMP-9 expression. Conclusion: The antagonistic actions of shear-induced IL-1β and 15d-PGJ2 regulate the temporal pattern of MMP-9 synthesis. Significance: Reconstructing the signaling network of shear-mediated MMP-9 synthesis in chondrocytes is crucial for developing strategies to treat osteoarthritis. Mechanical overloading of articular cartilage producing hydrostatic stress, tensile strain, and fluid flow results in irreversible cartilage erosion and osteoarthritis (OA). Application of high fluid shear to chondrocytes recapitulates the earmarks of OA as evidenced by the induction of proinflammatory cytokines and prostaglandins, which are capable of inducing the expression of matrix-degrading enzymes. Matrix metalloproteinase-9 (MMP-9) synthesis is detected at early but not late stages of OA. However, the underlying mechanism(s) of the MMP-9 temporal regulation remains unknown. Using the T/C-28a2 chondrocyte cell line as a model system, we demonstrated that high fluid shear induces a marked increase in MMP-9 expression at short shear exposure times (3–6 h), which falls below basal levels after prolonged shear exposure (12–48 h). High fluid shear stress induced the rapid and sustained synthesis of IL-1β, activating PI3K, ERK1/2, and JNK, which are in turn responsible for MMP-9 expression. Prolonged shear exposure (>12 h) induced 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) synthesis, which exerted an antagonistic effect on IL-1β-mediated PI3K-, ERK1/2-, and JNK-dependent NF-κB activation, thereby suppressing MMP-9 expression in human chondrocytes. Reconstructing the signaling network that regulates shear-mediated MMP-9 expression in human chondrocytes may provide insights for developing strategies to treat arthritic disorders.
Immediate rehabilitation of the edentulous mandible with a definitive prosthesis supported by an intraorally welded titanium bar.

PURPOSE The aim of this prospective study was to evaluate the suitability of intraoral welding of implant frameworks to allow placement of the definitive restoration on the same day of surgery. MATERIALS AND METHODS Forty patients with an edentulous mandible were planned to be treated with a fixed restoration supported by an intraoral welded titanium bar. Definitive abutments were to be connected to the implants and then welded to a titanium bar using an intraoral welding unit. This framework was to be used as support for the definitive restoration, which was to be placed on the same day as the implants. Mean marginal bone loss and radiographically detectable alterations of the welded framework were to be assessed using periapical radiographs immediately after surgery, and at 6-, 12-, and 24-month follow-up examinations. RESULTS Twenty men and 20 women, with a mean age of 47.8 years (+/- 13.9), were consecutively treated with 160 immediately loaded implants. All implants osseointegrated. No fractures or radiographically detectable alterations of the welded frameworks were present. All implants were clinically stable at the 24-month follow-up. Mean marginal bone loss (n = 160 at all time points), assessed using 640 periapical radiographs, was 0.59 +/- 0.12 mm at 6 months, 0.21 +/- 0.051 mm at 12 months, and 0.11 +/- 0.036 mm at 24 months. The accumulated mean marginal bone loss was 0.91 +/- 0.21 mm. CONCLUSIONS It is possible to successfully rehabilitate the edentulous mandible on the same day as implant placement surgery with a fixed definitive prosthesis supported by an intraorally welded titanium framework.
Identification of a novel microRNA, miR-4449, as a potential blood based marker in multiple myeloma

Abstract Background: miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis, suggesting their role in cancer. Methods: We examined the miRNAs perturbed in CD138+ primary multiple myeloma (MM) cells, using microarray analysis and real-time quantitative PCR (RT-qPCR). Serum miR-4449 expression levels were detected from 71 primary MM patients and 46 healthy controls by RT-qPCR. Results: Our analysis revealed up-regulation of 54 and down-regulation of 28 miRNAs in MM subjects compared to healthy controls. miR-4449 has not been reported in MM. It was found that the relative expression of bone marrow miR-4449 in MM patients (2.14±1.42) was higher than that in healthy controls (0.815±0.165) (U=8, p=0.0093). The relative expression of serum miR-4449 in MM patients (2.11±2.10) was significantly higher than that in healthy controls (0.357±0.235) (U=374, p<0.0001) and was significantly correlated with β2M, λ light and κ light chain concentration (r=0.480, p=0.0003; r=0.560, p<0.0001; r=0.560, p<0.0001), but not correlated with the lactate dehydrogenase (LDH) concentration (r=0.247, p=0.0611). The area under the curve (AUC) of the receiver-operating characteristics (ROC) curve of serum miR-4449 was 0.885 (95% CI, 0.826–0.945), which is higher than for other markers. Combining miR-4449, λ light chain, and β2M together, the sensitivity was highest compared with λ light chain or β2M alone, or combined. Conclusions: The expression levels of serum miR-4449 in MM patients were significantly higher than in healthy controls, suggesting that it may prove to be useful in the auxiliary diagnosis of MM.
A comparative analysis of pretrained and transfer-learning model for automatic diagnosis of glaucoma

In the recent years, glaucoma is the most generally spotted eye disease in the human that suddenly leads to loss of vision. The glaucoma occurs due to the intraocular pressure in the optic nerve, which averts the transmission of information from the optic nerve to brain. In the current scenario, the medical field has achieved the rapid changes due to the advancement of Artificial Intelligence (AI) technology. Deep Learning (DL) is one of the subfamily of AI, which assists to diagnose the disease in the short interval of time with better accuracy results. The Computer Aided Diagnosis (CAD) is a very effective tool, which helps the physician to diagnose and analyze the disease in an easier manner. In the proposed work, a transfer-learning model designed to diagnose the intra ocular pressure in the optic nerve. This model provides the better validation accuracy of 91.2% with minimized loss function. The training data are obtained from publicly available datasets such as DRIVE, ORIGA and RIM ONE. Using the transfer learning model, the overall training time has been reduced considerably because they are already trained in the millions of images and the inter observability error is minimized.
Oral Toxicity and Bacterial Mutagenicity Studies with a Spunbond Polyethylene and Polyethylene Terephthalate Polymer Fabric

Spunbond, nonwoven fabrics consisting of polyethylene and polyethylene terephthalate, which meet food contact requirements, may be used as pouch materials for products containing food and/or flavor ingredients that are held in the mouth. In these situations ingestion may occur, resulting in exposure to the fabric and potentially antimony, a catalyst used in polyethylene terephthalate. To assess potential adverse effects when such a material is ingested, a 13week dietary study in Sprague-Dawley CD rats and a Salmonella reverse mutation assay were conducted. Ground fabric was dosed at target concentrations of 0.5%, 2.5%, and 5% in the dietary study. Antimony trioxide in the polyethylene terephthalate was used to determine the test material concentration in the diet and was also assessed for bioavailability. Detectable levels of antimony were found in 2/20 blood samples of control rats, and in 20/20 high-dose group rats. No toxicologically relevant treatment related effects were observed in any of end points evaluated in the feeding study. In the mutagenicity assay, ground fabric was extracted in phosphate buffered saline or dimethysulfoxide and tested in Salmonella strains TA98, TA100, TA102, TA1535, and TA1537 with and without S9 activation. No mutagenic response was observed at any dose level tested. These results demonstrate that repeated daily ingestion of a spunbond, nonwoven polymer fabric consisting of polyethylene and polyethylene terephthalate for up to 13 weeks is well tolerated in rats, with no apparent target-organ toxicity at dietary levels up to 5%, and that fabric extracts are not mutagenic in a bacterial reverse mutation assay.