Miracle-dz/UniFAR-FTUs huggingface dataset:
Phase 1/2 Double-Blind, Placebo-Controlled, Dose Escalation, Safety, and Pharmacokinetic Study of Pagibaximab (BSYX-A110), an Antistaphylococcal Monoclonal Antibody for the Prevention of Staphylococcal Bloodstream Infections, in Very-Low-Birth-Weight Neonates

ABSTRACT Staphylococcal sepsis is a major cause of morbidity and mortality in very-low-birth-weight (VLBW) infants. A human chimeric monoclonal antibody, pagibaximab, was developed against staphylococcal lipoteichoic acid. We evaluated the safety, tolerability, and pharmacokinetics of pagibaximab in VLBW neonates. A phase 1/2, randomized, double-blind, placebo-controlled, dose escalation study was conducted in VLBW infants (700 to 1,300 g) 3 to 7 days old. Patients received two doses 14 days apart of intravenous pagibaximab (10, 30, 60, or 90 mg/kg of body weight) or placebo in a 2:1 ratio. Blood and urine samples were obtained pre- and postinfusion for analysis of safety and pharmacokinetics, and data on adverse events were gathered. Staphylococcal organisms causing sepsis were collected and evaluated. Fifty-three patients received at least one dose of pagibaximab or placebo. The average gestational age was 27.6 weeks; the average birth weight was 1,003 g. All serious adverse events were deemed unrelated or probably not drug related. Morbidity and mortality were similar across treatment groups. No evidence of immunogenicity of pagibaximab was detected. Pagibaximab pharmacokinetics was linear. The mean clearance (CL), volume of distribution, and elimination half-life of pagibaximab were independent of dose. The serum half-life was 20.5 ± 6.8 days. Pagibaximab enhanced serum opsonophagocytic activity. All staphylococci causing sepsis were opsonizable by pagibaximab. Two infusions of pagibaximab, administered 2 weeks apart to high-risk neonates appeared safe and tolerable, and pharmacokinetics were linear. Evaluation of more frequent doses, at the highest doses tested, in neonates at high-risk of staphylococcal sepsis, is warranted.
Effects of Stenting for Atherosclerotic Renal Artery Stenosis on eGFR and Predictors of Clinical Events in the CORAL Trial.

BACKGROUND AND OBJECTIVES Atherosclerotic renal artery stenosis may cause kidney function loss, but effects of stenting on eGFR and clinical events associated with CKD are uncertain. Our study objectives were to determine effects of stenting on eGFR and predictors of clinical events. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Participants (n=931) in the Cardiovascular Outcomes in Renal Artery Stenosis Trial (from May of 2005 to September of 2012) had >60% atherosclerotic renal artery stenosis and systolic hypertension on two or more antihypertensive drugs and/or stage ≥3 CKD. The intervention was stenting versus no stenting on a background of risk factor management: renin-angiotensin system inhibition, statin, antiplatelet therapy, and smoking cessation education. The effect of stenting on eGFR by the serum creatinine-cystatin C Chronic Kidney Disease Epidemiology Collaboration equation was the prespecified analysis of kidney function. Predictors of eGFR and CKD outcomes (≥30% eGFR loss, ESRD, and death) and cardiovascular disease outcomes (stroke, myocardial infarction, heart failure, and death) controlling for eGFR and albuminuria were also determined. RESULTS eGFR was 59±24 ml/min per 1.73 m(2) (mean±SD) at baseline. Over 3 years, eGFR change, assessed by generalized estimating equations, was -1.5±7.0 ml/min per 1.73 m(2) per year in the stent group versus -2.3±6.3 ml/min per 1.73 m(2) per year in the medical therapy only group (P=0.18). eGFR predictors (multiple variable generalized estimating equations) were age, albuminuria, systolic BP, and diabetes (inverse associations) as well as men, total cholesterol, and HDL cholesterol (positive associations). CKD outcomes events occurred in 19% (175 of 931), and predictors (Cox proportional hazards models) included albuminuria (positive association), systolic BP (positive association), and HDL cholesterol (inverse association). Cardiovascular disease outcomes events occurred in 22% (207 of 931), and predictors included age, albuminuria, total cholesterol, prior cardiovascular disease, and bilateral atherosclerotic renal artery stenosis (positive associations). CONCLUSIONS Stenting did not influence eGFR in participants with atherosclerotic renal artery stenosis receiving renin-angiotensin system inhibition-based therapy. Predictors of clinical events were traditional risk factors for CKD and cardiovascular disease.
A re-examination of proliferation and differentiation of type A spermatogonia in the adult rhesus monkey (Macaca mulatta).

BACKGROUND Companion studies using an experimental non-human primate paradigm known as a testicular clamp indicated that the behavior of undifferentiated type A spermatogonia did not conform fully to earlier classical models. This issue was therefore re-examined in normal monkeys. METHODS Adult male rhesus monkeys (n = 4) received an i.v. bolus of 5-bromo-2'-deoxyuridine (BrdU): one testis (first) was removed 3 h later and the remaining testis (second) was removed after 11 days and 3 h. Tissue was fixed in Bouin's solution, and numbers of A dark (Ad), small A pale (Aps) and large A pale spermatogonia, differentiating B spermatogonia, S-phase-labeled and degenerating cells were enumerated. Data are given as mean +/- SEM. RESULTS During the early stages of the seminiferous epithelial cycle in the first testis, Ap spermatogonia (1.3 cells/cross section) were predominantly Aps (nuclear dia., 7.1 +/- 0.1 microm). Aps were never S-phase labeled. Apl (nuclear dia., 8.8 +/- 0.5 microm) appeared in Stages IV-VI and were maximal in Stages VII-X when S-phase labeling of this phenotype at 3 h was greatest. The first generation of B spermatogonia appeared in Stages XI-XII (0.84 cells/cross section). Using cells/cross section, the ratio of Ap (Stages I-V):B1:B2:B3:B4:preleptotene spermatocyte was 1:0.7:1.4:2.8:5.6:11.2. In the second testis, labeled Aps (and Apl) were observed. Ad were not BrdU labeled, and degenerating cells were rarely observed. CONCLUSIONS The results are not entirely consistent with earlier models of spermatogonial proliferation and differentiation in the monkey. Most notably, our findings suggest that in any one cycle of the seminiferous epithelium only a fraction of Ap spermatogonia is mitotically active.
Fear does not correspond to higher costs of rape among married women

Abstract Thornhill and Thornhill posited that sexual assault inflicts greater fitness costs on women in committed long-term heterosexual relationships than on women not in such relationships because the former face the added risk of decreased investment by their partners. In a series of papers (1990a, 1990b, 1990c, and 1991), Thornhill and Thornhill reported support for what we term the Relationship Status Hypothesis (RSH) using data on the psychological sequelae of rape. Here, we reexamine the RSH in light of Thornhill and Thornhill's original findings and the relevant literature. Identifying limitations of the original work and finding little support for the RSH in other published work, we then test the RSH in two studies using prospective fear of rape as a dependent measure; again, we find no support for the hypothesis. We conclude that, although marital discord following rape is an important issue warranting further study, the Relationship Status Hypothesis has limited empirical support at present.
Splenic Atrophy in Experimental Stroke Is Accompanied by Increased Regulatory T Cells and Circulating Macrophages1

Induction of stroke not only produces local ischemia and brain damage, but also has profound effects on peripheral immune responses. In the current study, we evaluated effects on spleen and blood cells 4 days after stroke induction. Surprisingly, there was a less inflammatory cytokine profile in the middle cerebral artery occlusion-affected right brain hemisphere at 96 h compared with earlier time points. Moreover, our results demonstrate that stroke leads to splenic atrophy characterized by a reduction in organ size, a drastic loss of splenocyte numbers, and induction of annexin V+ and TUNEL+ cells within the spleen that are in the late stages of apoptosis. The consequence of this process was to reduce T cell proliferation responses and secretion of inflammatory cytokines, resulting in a state of profound immunosuppression. These changes produced a drastic reduction in B cell numbers in spleen and blood, and a novel increase in CD4+FoxP3+ regulatory T cells. Moreover, we detected a striking increase in the percentage of nonapoptotic CD11b+ VLA-4-negative macrophages/monocytes in blood. Immunosuppression in response to brain injury may account for the reduction of inflammatory factors in the stroke-affected brain, but also potentially could curtail protective immune responses in the periphery. These findings provide new evidence to support the contention that damage to the brain caused by cerebral ischemia provides a powerful negative signal to the peripheral immune system that ultimately induces a drastic state of immunosuppression caused by cell death as well as an increased presence of CD4+FoxP3+ regulatory T cells.
O‐linked mucin‐type glycoproteins in normal and malignant colon mucosa: Lack of T‐antigen expression and accumulation of tn and sialosyl‐Tn antigens in carcinomas

The expression of carbohydrate core‐structures on O‐linked glycoproteins was examined in fetal (n = 6), infantile (n = 2), normal adult (n = 15), and malignant (n = 22) colorectal tissue by means of monoclonal antibodies (MAbs) specific for Tn (Ga1NAcα1‐O‐R), sialosyl‐Tn (NeuAcα2‐6Ga1NAcα1‐O‐R), and T (Ga1β‐3GalNAcα1‐O‐R) antigens. Immunolabelling of solubilized malignant tissue, separated by SDS‐PAGE, showed expression of Tn and sialosyl‐Tn antigens on 3 molecules of similar mw (230, 210, and 170 kDa), whereas no T antigens could be detected. Immunohistochemical techniques showed that fetal colon mucosa expressed Tn antigens but no sialosyl‐Tn antigens. Infantile colon mucosa, however, expressed Tn as well as sialosyl‐Tn antigens, and normal adult colon mucosa cells expressed no Tn antigens but sialosyl‐Tn in 2 out of 6 biopsies from cecum, which indicates occurrence post partum of α‐6‐NeuAc‐transferase. Endothelium in normal adult mucosa showed expression of both Tn and sialosyl‐Tn antigens; 82% of carcinoma tissue sections expressed Tn antigens, and 73% expressed sialosyl‐Tn antigens in mucin or cytoplasm, or on luminal cell membranes. T antigens could be detected neither in normal mucosa cells at any stage of development, nor in carcinomas. The possibility exists that this could be due to masking of T antigen. Mucin‐type blood‐group A antigens which contain an internal T‐disaccharide were demonstrated in 4 out of 4 A1 tumors by means of MAb HH5. However, urea‐containing SDS‐PAGE analysis demonstrated an HH5 binding to molecules different from those binding anti‐Tn. In remote morphologically normal and abnormal crypts in colons from carcinoma patients, both Tn and sialosyl‐Tn antigens were expressed in secreted mucin in 40% of the cases. The data indicate an expression of O‐linked Tn and sialosyl‐Tn core structures in fetal and infantile colon and in colorectal carcinomas.
Invasive Shigella flexneri Activates NF-κB Through a Lipopolysaccharide-Dependent Innate Intracellular Response and Leads to IL-8 Expression in Epithelial Cells1

The pathogenesis of Shigella flexneri infection centers on the ability of this organism to invade epithelial cells and initiate an intense inflammatory reaction. Because NF-κB is an important transcriptional regulator of genes involved in inflammation, we investigated the role of this transcription factor during S. flexneri infection of epithelial cells. Infection of HeLa cells with invasive S. flexneri induced NF-κB DNA-binding activity; noninvasive S. flexneri strains did not lead to this activation. The pathway leading to NF-κB activation by invasive S. flexneri involved the kinases, NF-κB-inducing kinase, IκB kinase-1, and IκB kinase-2. NF-κB activation was linked to inflammation, because invasive S. flexneri activated an IL-8 promoter-driven reporter gene, and the κB site within this promoter was indispensable for its induction. Microinjection of bacterial culture supernatants into HeLa cells suggested that LPS is responsible for NF-κB activation by S. flexneri infection. In conclusion, the eukaryotic transcription factor NF-κB was activated during S. flexneri infection of epithelial cells, which suggests a role for this transcriptional regulator in modulating the immune response during infection in vivo.
The association of multiple visual impairments with self-reported visual disability: SEE project.

PURPOSE This report examines the relationship between psychophysical measures of visual impairment and self-reported difficulty with everyday visual tasks in a population-based sample of individuals 65 years of age and older. METHODS Community-dwelling residents (n = 2520) of Salisbury, MD, between the ages of 65 and 84 were recruited for the study. Visual acuity under normal and low luminance, contrast and glare sensitivity, stereoacuity, and visual fields were measured. Subjective physical disability was assessed with the Activities of Daily Vision Scale (ADVS). RESULTS In multiple regression analyses adjusted for demographic factors, cognitive status, depression, and number of comorbid medical conditions, each of the vision tests except low luminance acuity was independently associated with lower ADVS scores. The analyses indicate that a factor of 2 reduction in visual acuity or contrast sensitivity, comparable with that observed in mild to moderate lens opacity, was associated with a three- to fivefold odds of reporting difficulty with daily tasks. Although age alone was a significant risk factor for disability, it was not associated with overall ADVS score, once visual impairment and other chronic medical conditions were taken into account. CONCLUSIONS Visual acuity, contrast and glare sensitivity, stereoacuity, and visual fields are significant independent risk factors for self-reported visual disability in an older population. Visual impairment defined by acuity alone is not the only dimension of the association with subjective disability. Additional vision measures are required to understand the impact of vision loss on everyday life.
Surveillance of Dairy Production Holdings Supplying Raw Milk to the Farmhouse Cheese Sector for Escherichia coli O157, O26 and O111

Clinically healthy domestic animals can harbour Escherichia coli O157 and other verocytotoxigenic E. coli (VTEC) strains in their faeces. Milk filters can be used to microbiologically monitor direct milk secretion and environmental contamination for these pathogens. The aim of this study was to establish baseline data on the prevalence and characteristics of VTEC organisms in lactating animals (bovine, ovine and caprine) supplying milk to the farmhouse cheese sector, with particular emphasis on serogroups O157, O111 and O26. Fifty‐six bovine, 13 caprine and 5 ovine herds/flocks, the majority of which supplying milk for farmhouse cheese production, were surveyed from May 2004 to July 2005. Milk filters were analysed by immunomagnetic separation followed by PCR, on a serogroup‐specific basis for E. coli O157, O26 and O111. Positive isolates were examined using a multiplex PCR protocol, for their potential to produce verocytotoxins (vt1/vt2), the haemolysin‐encoding gene (hlyA) and the gene encoding attaching and effacement (eae). Five verocytotoxigenic and 22 non‐virulent E. coli O157 isolates were detected. Seventeen E. coli O26 isolates were also detected, four of which were verocytotoxigenic, seven isolates contained the eae gene only and six isolates were devoid of any of the virulence factors. The VTEC O157 and O26 isolates contained the hlyA and eae genes along with the verocytotoxin genes. No E. coli O111 isolates were detected. Some of the herds were positive on more than one occasion and multiple E. coli serogroups were isolated from the same milk filter sample. Although all food products tested were VTEC negative, routine surveillance for such pathogens in raw milk/raw milk products is of public health importance. Herd‐level surveillance along with subsequent risk management action may be a cost‐effective component of risk reduction strategies for food production, drinking water supplies and the protection of public health.
Per-unit-length parameters of 1-D CPW metamaterials with simultaneously series-C and shunt-L loading

CPW transmission line metamaterials with simultaneous loading of series-C and shunt-L lumped elements in periodical intervals are thoroughly investigated using a self-calibrated method of moments (MoM). Two effective per-unit-length parameters, i.e., propagation constant and characteristic impedance, are numerically extracted to demonstrate the complete guided-wave characteristics of these 1-D artificial metamaterials in a wide frequency range, covering the LH stopband, LH passband, LH/RH stopband, RH passband and so on. In the LH passband, the phase constant with negative sign rises up to zero with the frequency while the characteristic impedance with only non-zero real part goes up from zero and then falls down beyond peak. Under perfect impedance matching in two terminals, finite-length CPW structures are consequently modeled to showcase the transmission performance across these 1-D metamaterials with varied lengths. Finally, a 9-unit cell CPW metamaterial fed by two 50-12 CPW feeding lines is designed, fabricated and measured to validate our reported effective per-unit-length parameters in experiment.
The Role of Early Maternal Responsiveness in Supporting School-Aged Cognitive Development for Children Who Vary in Birth Status

OBJECTIVES. To examine the relation between the pattern of maternal responsiveness that children experienced in the infancy, preschool, and school-age periods and growth in cognitive skills across 3–10 years of age and determine whether the relation differs by birth status. METHODS. In 1990–1992, 360 children varying in birth status (very low birthweight [VLBW]; demographically matched controls) were recruited to examine parenting and birth status influences on development. This report includes children with observations of parenting at 6, 12, and 24 months and 3, 4, 6, 8, and 10 years and cognitive skills evaluated at 3, 4, 6, 8, and 10 years of age (71% of original cohort). RESULTS. Four groups of mothers varying in the pattern of responsiveness displayed across the infancy and the preschool period were found. When controlling for school-age parenting and economic status, children parented with higher levels of responsiveness across both developmental periods, irrespective of birth status, showed higher levels in development than those who experienced responsiveness in only 1 development period or minimal responsiveness. Greater benefit was found for consistency in responsiveness for children born VLBW with less, versus more, severe neonatal complications. Inspection of the means showed that higher risk birth status combined with minimal responsiveness resulted in cognitive scores, on average, 14 points lower than when parented with consistently higher responsiveness. CONCLUSIONS. Cognitive development for children born at VLBW, particularly those with less severe complications, are supported by consistently responsive parenting across early childhood in similar ways to those born at term. This effect persisted through 10 years of age even after school-age parenting and economic level. These findings have important implications for the timing (across early childhood) and content (responsive interactive behaviors) of early intervention to enhance the outcomes for children born at VLBW.
pH Nanoenvironment at the Surface of Single Melanoma Cells

Extracellular pH and the Na+/H+ exchanger (NHE1) modulate tumor cell migration. Yet, the pH nanoenvironment at the outer surface of the cell membrane (pHem) where cell/matrix interaction occurs and matrix metalloproteinases work was never measured. We present a method to measure this pH nanoenvironment using proton-sensitive dyes to label the outer leaflet of the plasma membrane or the glycocalyx of human melanoma cells. Polarized cells generate an extracellular proton gradient at their surface that increases from the rear end to the leading edge of the lamellipodium along the direction of movement. This gradient collapses upon NHE1 inhibition by HOE642. NHE1 stimulation by intracellular acidification increases the difference in pHem between the tips of lamellipodia and the cell body in a Na+ dependent way. Thus, cells create a pH nanoenvironment that promotes cell migration by facilitating cell adhesion at their front and the release of cell/matrix contacts at their rear part.
An increased MRP8/14 expression and adhesion, but a decreased migration towards proinflammatory chemokines of type 1 diabetes monocytes

In the early development of type 1 diabetes macrophages and dendritic cells accumulate around the islets of Langerhans at sites of fibronectin expression. It is thought that these macrophages and dendritic cells are derived from blood monocytes. Previously, we showed an increased serum level of MRP8/14 in type 1 diabetes patients that induced healthy monocytes to adhere more strongly to fibronectin (FN). Here we show that MRP8/14 is expressed and produced at a higher level by type 1 diabetes monocytes, particularly after adhesion to FN, creating a positive feedback mechanism for a high fibronectin‐adhesive capacity. Also adhesion to endothelial cells was increased in type 1 diabetes monocytes. Despite this increased adhesion the transendothelial migration of monocytes of type 1 diabetes patients was decreased towards the proinflammatory chemokines CCL2 and CCL3. Because non‐obese diabetic (NOD) mouse monocytes show a similar defective proinflammatory migration, we argue that an impaired monocyte migration towards proinflammatory chemokines might be a hallmark of autoimmune diabetes. This hampered monocyte response to proinflammatory chemokines questions whether the early macrophage and dendritic cell accumulation in the diabetic pancreas originates from an inflammatory‐driven influx of monocytes. We also show that the migration of type 1 diabetes monocytes towards the lymphoid tissue‐related CCL19 was increased and correlated with an increased CCR7 surface expression on the monocytes. Because NOD mice show a high expression of these lymphoid tissue‐related chemokines in the early pancreas it is more likely that the early macrophage and dendritic cell accumulation in the diabetic pancreas is related to an aberrant high expression of lymphoid tissue‐related chemokines in the pancreas.