Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacological Properties of NAI-603, a Well-Tolerated Semisynthetic Derivative of Ramoplanin

ABSTRACT NAI-603 is a ramoplanin derivative designed to overcome the tolerability issues of the parent drug as a systemic agent. NAI-603 is highly active against aerobic and anaerobic Gram-positive bacteria, with MICs ranging from 0.008 to 8 μg/ml. MICs were not significantly affected by pH (range, 6 to 8), by inoculum up to 108 CFU/ml, or by addition of 50% human serum. Against staphylococci and enterococci, NAI-603 was rapidly bactericidal, with minimum bactericidal concentration (MBC)/MIC ratios never exceeding 4. The frequency of spontaneous resistance was low at 2× to 4× MIC (≤1 × 10−6 to ≤1 × 10−8) and below the detection limit (about ≤1 × 10−9) at 8× MIC. Serial subcultures at 0.5× MIC yielded at most an 8-fold increase in MICs. In a systemic infection induced by methicillin-resistant Staphylococcus aureus (MRSA), the 50% effective dose (ED50) of intravenous (i.v.) NAI-603 was 0.4 mg/kg, lower than that of oral (p.o.) linezolid (1.4 mg/kg) and subcutaneous (s.c.) teicoplanin (1.4 mg/kg) or vancomycin (0.6 mg/kg). In neutropenic mice infected with vancomycin-resistant enterococci (VRE), the ED50s for NAI-603 were 1.1 to 1.6 mg/kg i.v. , compared to 0.5 mg/kg i.v. of ramoplanin. The bactericidal activity was confirmed in vivo in the rat granuloma pouch model induced by MRSA, where NAI-603, at 40 mg/kg i.v. , induced about a 2- to 3-log10-reduction in viable bacteria in the exudates, which persisted for more than 72 h. The pharmacokinetic (PK) profiles of NAI-603 and ramoplanin at 20 mg/kg show similar half-lives (3.27 and 3.80 h, respectively) with the maximum concentration (Cmax) markedly higher for NAI-603 (207 μg/ml versus 79 μg/ml). The favorable pharmacological profile of NAI-603, coupled with the absence of local tolerability issues, supports further investigation.
Validity of goniometric joint measurements in cats.

OBJECTIVE To compare and validate goniometric joint measurements obtained from nonsedated and sedated cats with measurements from radiographic evaluation. ANIMALS 20 adult cats with no evidence of joint disease. PROCEDURES Measurements of flexion and extension of the carpus, elbow, shoulder, tarsus, stifle, and hip joints and of carpal and tarsal joints during varus and valgus angulation were made by a single investigator before and after sedation of cats. Measurements were made by use of a goniometer with a masked dial. Joint angle measurements were compared between nonsedated and sedated cats and also with measurements from radiographs made while cats were sedated. Each series of measurements was repeated 4 times. To evaluate repeatability, Cronbach alpha values were calculated for repeated measure results of goniometric joint measurements of nonsedated and sedated cats. An intraclass correlation was calculated to determine reliability among the 3 measurement types (ie, measurements from nonsedated and sedated cats and on radiographic evaluation). RESULTS Joint measurements did not differ significantly by measurement type, when comparing radiographic measurements with goniometric measurements in sedated and nonsedated cats. Cronbach alpha values were > 0.99 for goniometric joint measurements within individual nonsedated and sedated cats and also for comparison of mean measurements obtained from sedated cats versus nonsedated cats versus radiographs. An intraclass correlation of 0.999 revealed high reliability among measurement types. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that goniometric joint measurements in nonsedated and sedated cats are repeatable and valid.
Standardized reaction times used to describe the mechanism of enzyme-induced gelation in whey protein systems

Whey protein isolate (WPI), either untreated or pretreated at 80 °C for 30 min, was incubated with a proteinase from Bacillus licheniformis until a gel was formed. Standardized reaction times, directly linked to the degree of hydrolysis, were obtained from plots of the relative amount of peptides released v. reaction time obtained under different conditions (enzyme concentration, temperature, pH, NaCl addition). This provided a connection between the gelation profile and the degree of hydrolysis. In the case of untreated WPI, gelation occurred at lower degrees of proteolysis when the enzyme concentration was decreased, demonstrating that a rate-limiting aggregation process occurred at the same time as the proteolysis in a manner similar to the renneting of milk. This was not the case for preheated WPI, when gelation was found to take place at a constant degree of proteolysis, independent of the enzyme concentration. In this case, the mechanism could be described by assuming the thermally induced aggregates present in this substrate had progressively more stabilizing peptide segments shaved off, resulting in increased attraction between individual aggregates that ultimately led to gelation. Results obtained at 40–60 °C supported this, as we found no effect of temperature on the degree of proteolysis at gelation for the untreated WPI, whereas the degree of proteolysis decreased with increasing temperature when heated WPI was hydrolysed. The effect of pH and NaCl addition on the process was to reduce repulsion between the aggregating species so that gelation was induced at a decreased degree of proteolysis.
Recombinant human microplasmin: production and potential therapeutic properties

Summary. The effect of recombinant human microplasmin was studied in ischemic stroke models in mice and in an extracorporeal loop thrombosis model in rabbits. Human microplasminogen (µPlg), which lacks the five ‘kringle’ domains of plasminogen was expressed with high yield in Pichia pastoris. It was purified, converted to microplasmin (µPli) and equilibrated with 5 mmol L−1 citrate, pH 3.1, yielding a stable preparation. In mice with middle cerebral artery (MCA) ligation, an intravenous (i.v.) bolus of 5.0 mg kg−1µPli reduced infarct size at 24 h from 27 (26–30) to 25 (21–28) mm3 (median and range, n= 16 each, P= 0.0001), whereas 4.0 mg kg−1 rt‐PA and 40 mg kg−1µPlg had no effect. Infarct reduction was observed with administration at 4 h after occlusion. In mice with MCA, infarct size at 24 h was reduced from 20 (14–30) to 9.1 (3.1–25) mm3 with 5.0 mg kg−1µPli (n = 15 each, P < 0.002) and to 11 (5.2–27) mm3 with 4.0 mg kg−1 rt‐PA (n = 6; P= 0.02). Infarct reduction was still observed at 10 h after occlusion with µPli but not with t‐PA. In rabbits with radiolabeled clots in an extracorporeal arteriovenous loop, local infusion of 2.5 mg kg−1µPli over 2 h, induced 51 ± 15% lysis (mean ± SD, n= 11) vs. a control value of 23 ± 5.5%. µPli did not prolong template bleeding times, whereas equipotent doses of rt‐PA were associated with extensive rebleeding. The potency of µPli in both models was similar to that of intact plasmin. These findings indicate that recombinant µPli may be useful for treatment of ischemic stroke and arterial thrombosis.
p38 MAPK and MAPK kinase 3/6 mRNA and activities are increased in early diabetic glomeruli.

BACKGROUND The p38 mitogen-activated protein kinase (MAPK) pathway is activated by several stress factors, potentially leading to cellular apoptosis and growth. Little is known about the pattern of glomerular p38 MAPK pathway activation during the course of diabetic nephropathy (DN). We examined the activity and expression of the p38 MAPK pathway members, p38 MAPK, MKK3/6, cAMP-responsive element binding protein (CREB), and MAPK phosphatase-1 (MKP-1), in experimental DN in rats over the course of four months. METHODS Control (C; N = 16) and diabetic (DM; N = 16) rats were studied. Four rats from each group were sacrificed monthly, and competitive reverse transcription-polymerase chain reaction and Western blot were performed with microdissected and sieved glomeruli, respectively. RESULTS Glomerular p38 MAPK mRNA expression was significantly higher in DM than C (P < 0.01) throughout the four-month period. Western blot revealed an average 3.1-fold increase in p38 MAPK protein throughout the study period (P < 0.05). However, p38 MAPK activity was significantly increased only in one- and two-month diabetic glomeruli. Glomerular MKK3/6 and CREB mRNA as well as activity were significantly increased only in one- and two-month DM compared with C. MKP-1 mRNA showed a similar pattern. CONCLUSIONS Glomerular p38 MAPK activity was increased in early DN. Parallel to this, we also showed, to our knowledge for the first time, that there were increased MKK3/6 and CREB activities and mRNA expression. This activated p38 MAPK pathway in diabetic glomeruli may, in part, play a role in the pathogenesis of early hypertrophy and extracellular matrix accumulation.
Blocking angiotensin II ameliorates proteinuria and glomerular lesions in progressive mesangioproliferative glomerulonephritis.

BACKGROUND The renin-angiotensin system is thought to be involved in the progression of glomerulonephritis (GN) into end-stage renal failure (ESRF) because of the observed renoprotective effects of angiotensin-converting enzyme inhibitors (ACEIs). However, ACEIs have pharmacological effects other than ACE inhibition that may help lower blood pressure and preserve glomerular structure. We previously reported a new animal model of progressive glomerulosclerosis induced by a single intravenous injection of an anti-Thy-1 monoclonal antibody, MoAb 1-22-3, in uninephrectomized rats. Using this new model of progressive GN, we examined the hypothesis that ACEIs prevent the progression to ESRF by modulating the effects of angiotensin II (Ang II) on the production of transforming growth factor-beta (TGF-beta) and extracellular matrix components. METHODS We studied the effect of an ACEI (cilazapril) and an Ang II type 1 receptor antagonist (candesartan) on the clinical features and morphological lesions in the rat model previously reported. After 10 weeks of treatment with equihypotensive doses of cilazapril, cilazapril plus Hoe 140 (a bradykinin receptor B2 antagonist), candesartan, and hydralazine, we examined systolic blood pressure, urinary protein excretion, creatinine clearance, the glomerulosclerosis index, and the tubulointerstitial lesion index. We performed a semiquantitative evaluation of glomerular immunostaining for TGF-beta and collagen types I and III by immunofluorescence study and of these cortical mRNA levels by Northern blot analysis. RESULTS Untreated rats developed massive proteinuria, renal dysfunction, and severe glomerular and tubulointerstitial injury, whereas uninephrectomized control rats did not. There was a significant increase in the levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III in untreated rats. Cilazapril and candesartan prevented massive proteinuria, increased creatinine clearance, and ameliorated glomerular and tubulointerstitial injury. These drugs also reduced levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III. Hoe 140 failed to blunt the renoprotective effect of cilazapril. Hydralazine did not exhibit a renoprotective effect. CONCLUSION These results indicate that ACEIs prevent the progression to ESRF by modulating the effects of Ang II via Ang II type 1 receptor on the production of TGF-beta and collagen types I and III, as well as on intrarenal hemodynamics, but not by either increasing bradykinin activity or reducing blood pressure in this rat model of mesangial proliferative GN.
Sequential Evaluation of Dogs Naturally Infected withEhrlichia canis, Ehrlichia chaffeensis,Ehrlichia equi, Ehrlichia ewingii, orBartonella vinsonii

ABSTRACT Historically, disease manifestations in dogs seroreactive toEhrlichia canis antigens by indirect immunofluorescent antibody testing have been attributed to infection with eitherE. canis or Ehrlichia ewingii. A 1996 study by Dawson and colleagues provided PCR evidence that healthy dogs from southeastern Virginia could be naturally infected withEhrlichia chaffeensis. This observation stimulated us to determine which Ehrlichia spp. infected sick dogs that were referred to our hospital from the same region. Based upon PCR amplification with species-specific primers, sick dogs seroreactive toE. canis antigens were determined to be infected with four Ehrlichia species: E. canis,E. chaffeensis, E. equi, andE. ewingii. Coinfection with threeEhrlichia species (E. canis,E. ewingii, and E. equi) was documented for one dog. An additional canine pathogen presumed to be tick transmitted, Bartonella vinsonii subsp.berkhoffii, was identified in 7 of 12 dogs. Importantly, our results indicate that in naturally infected dogs, E. chaffeensis can cause severe disease manifestations that are clinically and serologically indistinguishable from disease manifestations of E. canis or E. ewingii. In addition, our findings support the efficacy of doxycycline for treatment of E. canis, E. equi, and E. ewingii infections but indicate that, based upon the persistence of E. chaffeensis DNA for 1 year following treatment, E. chaffeensisinfection in dogs may be more refractory to doxycycline treatment. Undetected coinfection with Bartonella may also complicate the evaluation of treatment efficacy while resulting in disease manifestations that mimic ehrlichiosis.
The Pathology of the Spinal Cord in Progressive Supranuclear Palsy

We describe the results of a study of the spinal cord of 5 patients with progressive supranuclear palsy (PSP). Examination of the 6th cervical, 7th thoracic, and 5th lumbar segments revealed variable degree of gliosis and density of neuropil threads (NTs), nerve cell loss, and tau-positive cytoplasmic staining of neurons, some of which was reminiscent of neurofibrillary tangles (NFT). Tau-positive neurons were seen at each spinal level and in the 3 zones in which each level was subdivided. Cells with the appearance of NFT predominated in the intermediate zone. Morphometric study revealed 47%, 52%, and 32% decrease in cell numbers in the motor area (lamina IX) at the 3 spinal levels, respectively, and 39% in the intermedio-lateral column. This is the first report describing severe neuronal loss throughout the whole spinal cord in patients with PSP and its results are in keeping with a previous study of the nucleus of Onufrowicz. The reasons why cell loss fails to produce clinical symptoms are analyzed and the clinico-pathological correlations between anatomical changes and dystonia are considered. On the basis of existing data, we conclude that previous suggestions implicating spinal interneurons in the pathogenesis of neck dystonia should not be supported.
Factor V Leiden does not have a role in cryptogenic ischemic stroke among Iranian young adults

Background: Different risk factors have been suggested for ischemic stroke in young adults. In a group of these patients despite of extensive diagnostic work-up, the primary cause remains unknown. Coagulation tendency is accounted as a possible cause in these patients. Previous studies on factor V Leiden (FVL) as the main cause of inherited thrombophilia for clarifying the role of FVL in stroke have resulted in controversial findings. The current study investigates the role of this factor in ischemic stroke among Iranians. Materials and Methods: This case-control study was performed between September 2007 and December 2008 in Isfahan, Iran. The case group comprised of 22 patients of which 15 were males and 7 were females with age range of ≤50 years, diagnosed as ischemic stroke without classic risk factors and the control group consisted of 54 healthy young adults. After filling consent form, venous blood samples were obtained and sent to the laboratory for genetic examination. Results: No FVL mutation was found in the case group. There was one carrier of the mutation as heterozygous in the control group (relative frequency = 1.85%). Conclusions: Based on our study, FVL might not be considered as an independent risk factor for ischemic stroke in Iranian individuals who are not suffering from other risk factors of ischemic stroke.
Impact of de novo donor‐specific HLA antibodies detected by Luminex solid‐phase assay after transplantation in a group of 88 consecutive living‐donor renal transplantations

De novo donor‐specific HLA antibodies (DSA) after renal transplantation are known to be correlated with poor graft outcome and the development of acute and chronic rejection. Currently, data for the influence of de novo DSA in patient cohorts including only living‐donor renal transplantations (LDRT) are limited. A consecutive cohort of 88 LDRT was tested for the occurrence of de novo DSA by utilizing the highly sensitive Luminex solid‐phase assay for antibody detection. Data were analyzed for risk factors for de novo DSA development and correlated with acute rejection (AR) and graft function. Patients with de novo DSA [31 (35%)] showed a trend for inferior graft function [mean creatinine change (mg/dL/year) after the first year: 0.15 DSA (+) vs. 0.02 DSA (−) (P = 0.10)] and a higher rate of AR episodes, especially in case of de novo DSA of both class I and II [6 (55%), (P = 0.05)]. Antibody‐mediated rejection (AMR) appeared in five patients and was significantly correlated with de novo DSA (P = 0.05). Monitoring for de novo DSA after LDRT may help to identify patients at risk of declining renal function. Especially patients with simultaneous presence of de novo DSA class I and class II are at a high risk to suffer AR episodes.
Measuring Temporal Resolution (Release of Masking) with a Hughson-Westlake Up-Down Instead of a Békèsy-Tracking Procedure.

BACKGROUND A temporal resolution test in addition to the pure-tone audiogram may be of great clinical interest because of its relevance in speech perception and expected relevance in hearing aid fitting. Larsby and Arlinger developed an appropriate clinical test, but this test uses a Békèsy-tracking procedure for estimating masked thresholds in stationary and interrupted noise to assess release of masking (RoM) for temporal resolution. Generally the Hughson-Westlake up-down procedure is used in the clinic to measure the pure-tone thresholds in quiet. A uniform approach will facilitate clinical application and might be appropriate for RoM measurements as well. Because there is no golden standard for measuring the RoM in the clinic, we examine in the present study the Hughson-Westlake up-down procedure to measure the RoM and compare the results with the Békèsy-tracking procedure. PURPOSE The purpose of the current study was to examine the differences between a Békèsy-tracking procedure and the Hughson-Westlake up-down procedure for estimating masked thresholds in stationary and interrupted noise to assess RoM. RESEARCH DESIGN RoM is assessed in eight normal-hearing (NH) and ten hearing-impaired (HI) listeners through both methods. Results from both methods are compared with each other and with predicted thresholds from a model. DATA ANALYSIS Wilcoxon signed-rank tests, paired t tests. RESULTS Some differences between the two methods were found. We used a model to quantify the results of the two measurement procedures. The results of the Hughson-Westlake procedure were clearly better in agreement with the model than the results of the Békèsy-tracking procedure. Furthermore, the Békèsy-tracking procedure showed more spread in the results of the NH listeners than the Hughson-Westlake procedure. CONCLUSIONS The Hughson-Westlake procedure seems to be an applicable alternative for measuring RoM for temporal resolution in the clinical audiological practice.
Environmental and genetic determinants of neural migration and postmigratory survival *

The study of genetic/epigenetic/environmental factors underlies all therapeutic and preventive approaches in fetal, perinatal and paediatric neurology, including rehabilitation (3). In this paper, we selected a few targets of environmental determinants of brain development leading to underlying priorities for protection of the developing brain. Preparation of the neural germinative epithelium has to be protected against noxious pharmacological agents. New tools have been developed to improve early neural teratology, including the whole‐embryo culture method. The neopallial astrocytic precursors have a dual origin. Astrocytes of the white matter and deep neocortical layers derive from transformed radial glial cells, whereas astrocytes of the upper neocortical layers derive from astrocytic precursors that migrate from the late germinative zone after the end of neuronal migration. Among numerous factors able to interfere with these gliogenetic events are the control factors of the lysosomal and autophagic functions, interfering with radial glial cell transformation into astrocytes. All lesions interrupting the migratory corridors of late astroglial migration can produce cytoarchitectonic disturbances of the neocortical supragranular layers, with long‐term consequences. The developing brain is weltering in a complex mixture including newly recognized excitotoxic substances, cytokines and growth factors. These substances are sometimes environmental friends like maternal vasointestinal peptide, which prevents brain intrauterine growth retardation. They are sometimes excellent endogenous friends like neurotrophic excitatory agents in physiological conditions. They become often dangerous killers triggered by environmental signals like hypoxias/ischaemias and toxins produced by intrauterine infections, launching the excitotoxic cascade. In this paper, we reviewed mainly environmental determinants interfering with neural cytogenesis and histogenesis during the embryonic, fetal and neonatal span of early life.
The novel 2016 WHO Neisseria gonorrhoeae reference strains for global quality assurance of laboratory investigations: phenotypic, genetic and reference genome characterization.

OBJECTIVES Gonorrhoea and MDR Neisseria gonorrhoeae remain public health concerns globally. Enhanced, quality-assured, gonococcal antimicrobial resistance (AMR) surveillance is essential worldwide. The WHO global Gonococcal Antimicrobial Surveillance Programme (GASP) was relaunched in 2009. We describe the phenotypic, genetic and reference genome characteristics of the 2016 WHO gonococcal reference strains intended for quality assurance in the WHO global GASP, other GASPs, diagnostics and research worldwide. METHODS The 2016 WHO reference strains (n = 14) constitute the eight 2008 WHO reference strains and six novel strains. The novel strains represent low-level to high-level cephalosporin resistance, high-level azithromycin resistance and a porA mutant. All strains were comprehensively characterized for antibiogram (n = 23), serovar, prolyliminopeptidase, plasmid types, molecular AMR determinants, N. gonorrhoeae multiantigen sequence typing STs and MLST STs. Complete reference genomes were produced using single-molecule PacBio sequencing. RESULTS The reference strains represented all available phenotypes, susceptible and resistant, to antimicrobials previously and currently used or considered for future use in gonorrhoea treatment. All corresponding resistance genotypes and molecular epidemiological types were described. Fully characterized, annotated and finished references genomes (n = 14) were presented. CONCLUSIONS The 2016 WHO gonococcal reference strains are intended for internal and external quality assurance and quality control in laboratory investigations, particularly in the WHO global GASP and other GASPs, but also in phenotypic (e.g. culture, species determination) and molecular diagnostics, molecular AMR detection, molecular epidemiology and as fully characterized, annotated and finished reference genomes in WGS analysis, transcriptomics, proteomics and other molecular technologies and data analysis.