The glutamate receptor subunit delta2 is capable of gating its intrinsic ion channel as revealed by ligand binding domain transplantation.
The family of ionotropic glutamate receptors includes 2 subunits, delta1 and delta2, the physiological relevance of which remains poorly understood. Both are nonfunctional in heterologous expression systems, although the isolated, crystallized ligand binding domain (LBD) of delta2 is capable of binding D-serine. To investigate these seemingly contradictory observations we tested whether delta receptors can be ligand gated at all. We used a strategy that replaced the native LBD of delta2 by a proven glutamate-binding LBD. Test transplantations between alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA) and kainate receptors (GluR1 and GluR6, respectively) showed that this approach can produce functional chimeras even if only one part of the bipartite LBD is swapped. Upon outfitting delta2 with the LBD of GluR6, the chimera formed glutamate-gated ion channels with low Ca(2+) permeability and unique rectification properties. Ligand-induced conformational changes can thus gate delta2, suggesting that the LBD of this receptor works fundamentally differently from that of other ionotropic glutamate receptors.


Scattering and absorption in dense discrete random media of irregular particles.
We present an approximate numerical solution for the multiple scattering problem involving densely packed arbitrarily shaped small particles. We define incoherent volume elements that describe the statistics of the random medium and formulate an order-of-scattering solution for the entire random medium. We apply the T-matrix formalism to compute the incoherent interactions of irregular particles in the sequence of scattering events in the Monte Carlo radiative transfer algorithm. The T-matrices for the volume elements of arbitrarily shaped particles are computed by the volume-integral-equation (VIE)-based T-matrix method. We show that the approximate solution is in agreement with the numerically exact VIE solution for a small spherical random medium. Finally, we demonstrate the importance of applying irregular particle shape models in the analysis of multiple scattering by a large random medium of non-spherical particles.


[Estimation of anticholinesterase activity in reversible inhibitors of cholinesterase hydrolysis].
The kinetic analysis of cholinesterase interaction with reversible inhibitors was carried out. It has shown that the existing methods for definition of the type of reversible inhibition of enzyme reactions are not reliable. For example, mixed inhibition with the correlation between the competitive inhibition constant (Kl) and noncompetitive inhibition constant (K'i) less than 0.04, is identified as competitive inhibition. Apparently the ideal competitive inhibition with Ki/Ki = 0 does not exist in reality, because it is unlikely for a reversible inhibitor to decrease the process of the substrate sorption on a catalytical centre of cholinesterase not affecting the deacetylation rate. For objective evaluation of efficiency of reversible inhibitors it is suggested to determine the generalized inhibitory constant Ki at the cholinesterase hydrolysis in acetylcholine or acetylthiocholine. The data about anticholinesterase activity of carbonic and sulfoesters of lupinin are adduced.


Selected mouse lines, alcohol and behavior.
The technique of selective breeding has been employed to develop a number of mouse lines differing in genetic sensitivity to specific effects of ethanol. Genetic animal models for sensitivity to the hypnotic, thermoregulatory, excitatory, and dependence-producing effects of alcohol have been developed. These genetic animal models have been utilized in numerous studies to assess the bases for those genetic differences, and to determine the specific neurochemical and neurophysiological bases for ethanol's actions. Work with these lines has challenged some long-held beliefs about ethanol's mechanisms of action. For example, lines genetically sensitive to one effect of ethanol are not necessarily sensitive to others, which demonstrates that no single set of genes modulates all ethanol effects. LS mice, selected for sensitivity to ethanol anesthesia, are not similarly sensitive to all anesthetic drugs, which demonstrates that all such drugs cannot have a common mechanism of action. On the other hand, WSP mice, genetically susceptible to the development of severe ethanol withdrawal, show a similar predisposition to diazepam and phenobarbital withdrawal, which suggests that there may be a common set of genes underlying drug dependencies. Studies with these models have also revealed important new directions for future mechanism-oriented research. Several studies implicate brain gamma-aminobutyric acid and dopamine systems as potentially important mediators of susceptibility to alcohol intoxication. The stability of the genetic animal models across laboratories and generations will continue to increase their power as analytic tools.


Assessment of the Albuscreen microalbuminuria kit in diabetic outpatients.
Diabetic patients who have albumin excretion rates of greater than 30 micrograms/min (30 mg/L at normal urine volumes) are at increased risk of the development of diabetic nephropathy. The Albuscreen microalbuminuria kit detects albuminuria at concentrations of 30 mg/L and above by an agglutination-inhibition reaction. One hundred and ninety-five random urine samples from diabetic outpatients were assessed by Albuscreen and Albustix testing for albuminuria and the results were correlated with those of a sensitive radioimmunoassay technique. Albuscreen testing was simple, easy to use and had a sensitivity of 96%, with a specificity of 88%. Albustix testing at a detection level of 50 mg/L revealed a sensitivity of 100% and a specificity of 68% (43 samples, false-positive "trace" readings), while, at 30 mg/L, the sensitivity and specificity were 90% and 71%, respectively. Therefore, Albuscreen testing is well suited as a screening test for the presence of microalbuminuria in a diabetic outpatient setting. However, the role of Albustix in screening for microalbuminuria is less well defined, especially at the 30 mg/L level of detection, and requires further investigation.


Semiconductor quantum dots for biosensing and in vivo imaging.
Semiconductor quantum dots (QDs) have captivated researchers in the biomedical field over the last decade. Compared to organic dyes and fluorescent proteins, QDs have unique optical properties such as tunable emission spectra, improved brightness, superior photostability, and simultaneous excitation of multiple fluorescence colors. Since the first successful reports on the biological use of QDs a decade ago, QDs and their bioconjugates have been successfully applied to various imaging applications including fixed cell labeling, live-cell imaging, in situ tissue profiling, fluorescence detection and sensing, and in vivo animal imaging. In this review, we will briefly survey the optical properties of QDs, the biofunctionalization strategies, and focus on their biosensing and in vivo imaging applications. We conclude with a discussion on the issues and perspectives on QDs as biosensing probes and in vivo imaging agents.


Pituitary volume, stress reactivity and genetic risk for psychotic disorder.
Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, associated with increased pituitary volume, may mediate observed alterations in stress reactivity in patients with psychotic disorder. We examined the association between pituitary volume, real-life stress reactivity and genetic liability for psychotic disorder. Pituitary volumes were derived from magnetic resonance imaging (MRI) scans of 20 patients with psychotic disorder, 37 non-psychotic siblings of these patients, and 32 controls. The Experience Sampling Method (ESM) was used to measure emotional stress reactivity [changes in negative affect (NA) associated with daily life stress] in the three groups, and biological stress reactivity (changes in cortisol associated with daily life stress) in siblings and controls. Interactions between group, stress and pituitary volume in models of NA and cortisol were examined. Groups did not differ in pituitary volume. Patients showed significantly higher emotional stress reactivity than siblings and controls. In addition, emotional stress reactivity increased with increasing pituitary volume to a greater degree in patients than in controls and siblings. Siblings had higher cortisol levels than controls but did not show increased cortisol reactivity to stress. There was no interaction between pituitary volume, stress and group in the model of cortisol. Higher pituitary volume was associated with increased emotional stress reactivity in patients with psychotic disorder, siblings and controls. The association was significantly stronger in the patient group, suggesting a process of progressive sensitization mediating clinical outcome.


The effect of strategic memory training in older adults: who benefits most?
ABSTRACTBackground:Previous research has suggested that there is a degree of variability among older adults' response to memory training, such that some individuals benefit more than others. The aim of the present study was to identify the profile of older adults who were likely to benefit most from a strategic memory training program that has previously proved to be effective in improving memory in healthy older adults. In total, 44 older adults (60-83 years) participated in a strategic memory training. We examined memory training benefits by measuring changes in memory practiced (word list learning) and non-practiced tasks (grocery list and associative learning). In addition, a battery of cognitive measures was administered in order to assess crystallized and fluid abilities, short-term memory, working memory, and processing speed. Results confirmed the efficacy of the training in improving performance in both practiced and non-practiced memory tasks. For the practiced memory tasks, results showed that memory baseline performance and crystallized ability predicted training gains. For the non-practiced memory tasks, analyses showed that memory baseline performance was a significant predictor of gain in the grocery list learning task. For the associative learning task, the significant predictors were memory baseline performance, processing speed, and marginally the age. Our results indicate that older adults with a higher baseline memory capacity and with more efficient cognitive resources were those who tended to benefit most from the training. The present study provides new avenues in designing personalized intervention according to the older adults' cognitive profile.


Death on transport: a follow-up program.
St. Louis Children's Hospital has a self-contained, designated neonatal and pediatric transport team. In 1990, this team initiated a formalized death follow-up program. Its purposes are to provide feedback to referring hospitals, conduct an internal review, meet quality improvement guidelines, and educate transport team members. The program differs from the traditional morbidity and mortality conference, which provides an educational and review forum only. Death follow-up meetings are held quarterly, and 61 follow-ups were done between January 1990 and December 1993. (Follow-up was done on all deaths occurring during transport as well as those occurring within 24 hours of transport).


Changes in Nursing Students' Attitudes and Perceptions After Receipt of Enhanced Substance Use-Related Curricular Content.
Negative attitudes toward persons who use alcohol and other drugs contribute to suboptimal care. Nurses are in key roles to address the needs of this population, yet they lack the education needed to identify persons who may be at risk because of substance use and intervene accordingly. The purpose of this study was to evaluate the impact of a substance-use-related curriculum on nursing students' attitudes and therapeutic commitment for working with patients with alcohol- and drug-use-related problems. Data were collected for four cohorts of 169 nursing students enrolled in a Master's Entry into Nursing program. Questionnaires included the Person-Centered Alcohol and Alcohol Problems Perception Questionnaire and the Drug and Drug Problems Perception Questionnaire, completed before and after completing the curriculum. Paired samples t test were used to examine pre/post differences for each measure's subscale. Four of the seven Person-Centered Alcohol and Alcohol Problems Perception Questionnaire subscales showing significant increases were role adequacy, role support, role legitimacy, and general perceptions. Four of the five Drug and Drug Problems Perception Questionnaire subscales showing significant increases were role adequacy, role support, job satisfaction, and role legitimacy; there was a significant change in role-related self-esteem, however, in a negative direction. This study adds to the growing evidence of the positive impact of providing evidence-based information and skill development, which enhance alcohol- and drug-related knowledge and competence for nurses entering professional practice.


Potentiation by alpha and inhibition by beta-adrenergic stimulations of rat platelet aggregation. A comparative study with human and rabbit platelets.
Epinephrine, known to potentiate and elicit aggregation of human platelets, was shown to inhibit thrombin-induced aggregation of rat platelets, delaying the onset of aggregation from 2 to 12 times. Incubation of rat platelet suspensions with propranolol (1.25--30 micrometer), inactive by itself, totally prevented the inhibitory effect of epinephrine and also permitted a potentiation effect to show up. On the contrary, phentolamine (1.25--30 micrometer) potentiated the inhibitory effect of epinephrine on rat platelets and unmasked an inhibitory effect on human platelets. Finally, isoproterenol (0.25--9 micrometer) produced a marked inhibition of aggregation induced by thrombin, ADP and collagen in the three species studied, but most particularly in the rat. From these results, we conclude that stimulation of the platelet adrenergic receptors may either result in promotion (alpha-stimulation) or inhibition (beta-stimulation) of platelet aggregation. Furthermore, differences in the ratios or responses of alpha/beta receptors may account for species variations in the platelet aggregation response to catecholamine challenge.


Recurring challenges from a necrotrophic fungal plant pathogen: a case study with Leptosphaeria maculans (causal agent of blackleg disease in brassicas) in Western Australia.
Blackleg disease of Brassica napus, caused by the necrotrophic fungus Leptosphaeria maculans, causes severe yield losses in Australia, Europe and Canada. In Western Australia, it nearly destroyed the oilseed rape industry in 1972 when host genotypes and conducive environmental conditions favoured severe epidemics. The introduction of cultivars with polygenic resistance and the adoption of sound cultural practices two decades later helped to manage the disease. These were abandoned by many farmers in recent years in favour of the effective but ephemeral resistance conferred by the single dominant gene-based resistance derived from B. rapa ssp. sylvestris. Recently, several cultivars carrying this gene have collapsed widely within a period of 3 years after their commercial release. An environment conducive to the disease and the association of the pathogen with susceptible hosts in Western Australia for over 80 years together have led to the proliferation of L. maculans races, amounting to half of all races delineated to date from Europe, including the United Kingdom, Canada and Australia. This review demonstrates the problems that emerge when traditional cultural practices employed, along with cultivars containing polygenic resistance to a serious necrotrophic pathogen, are discarded in preference to the exclusive deployment of effective but ephemeral single dominant gene-based resistance to the disease across Southern Australia. Single dominant gene-based resistance currently available, on its own, will not confer durable resistance to blackleg disease in oilseed rape. Return to earlier management practices, including reliance upon polygenic resistance and induced resistance, may be the best currently available options to maintain production in regions across Southern Australia predisposed to severe epidemics.


Association of simian immunodeficiency virus Nef with the T-cell receptor (TCR) zeta chain leads to TCR down-modulation.
The Nef protein of simian immunodeficiency virus (SIV) is dispensable for replication in established T-cell lines but essential for high level virus replication in the adult host, though the mechanism by which Nef contributes to this has remained unclear. We demonstrate here that SIV Nef binds to the zeta chain of the T-cell receptor (TCR). SIV Nef proteins that interact with TCR zeta in a yeast two-hybrid system also reduce T-cell surface expression levels of TCR alphabeta, CD3 and CD4. These findings are the first demonstration that Nef can bind directly to a component of the TCR-CD3 complex and modulate its surface expression.


Protein Arp and protein H from group A streptococci. Ig binding and dimerization are regulated by temperature.
Cell surface proteins that bind to the Fc part of Ig are expressed by many strains of group A streptococci, an important human pathogen. Two such bacterial strains, AP4 and AP1, were shown to bind IgA and IgG, respectively, in a temperature-dependent manner. The binding of radiolabeled Ig to the bacterial cells was lower at 37 degrees C than at 22 and 4 degrees C. Similarly, protein Arp, the IgA-binding protein isolated from strain AP4, and protein H, the IgG-binding protein isolated from strain AP1, displayed a strong Ig-binding at 22 degrees C and lower temperatures, and virtually no binding at all at 37 degrees C. The effect was reversible: lowering of the temperature restored the binding and vice versa. A gradual shift between binding and nonbinding took place between 27 and 37 degrees C. Gel chromatography and velocity sedimentation centrifugation showed that protein Arp and protein H appeared as noncovalently associated dimers at 10 and 22 degrees C, and as monomers at 37 degrees C. These results strongly suggest that the dimerization of protein Arp and protein H, rather than the low temperature itself, yielded the strong Ig-binding of the proteins at 10 and 22 degrees C. Indeed, after covalent cross-linking of the dimers at 10 degrees C by incubation with low concentrations of glutaraldehyde, full Ig-binding was achieved even at 37 degrees C. A carboxyl-terminal proteolytic fragment of protein Arp, which completely lacked the IgA-binding capacity at any temperature, showed the same temperature-dependent dimerization as intact protein Arp, suggesting that the Ig-binding part of the protein is not required for dimerization. The implications of these results for the function of Ig-binding group A streptococcal proteins, and their role in the host-parasite relationship are discussed.


Comparison of infectious complications with synthetic mesh in ventral hernia repair.
Infection can be a devastating complication associated with prosthetic incisional hernia repair. It is unclear whether the type of mesh used affects the risk of infection. A retrospective review was performed of all patients who underwent elective incisional hernia repair with permanent prosthetic mesh between January 1, 2000, and August 1, 2007. A total of 176 patients underwent elective incisional hernia repair with mesh. The overall infection rate with the use of goretex (Flagstaff, AZ, USA) was 12 of 86 (14%) and 2 of 90 (2.2%) in cases in which nongoretex material was used (P = .016). In the goretex group, infection rates were significantly higher in open versus laparoscopic cases (26.5% vs 5.8%, P = .030). Methicillin-resistant Staphylococcus aureus was the most common organism recovered. The risk of mesh infection with the use of goretex was found to be higher than with the use of nongoretex mesh. Laparoscopic placement of goretex reduces this risk of infection. No significant differences in recurrence rates were found.


Synthesis of guggulsterone derivatives as potential anti-austerity agents against PANC-1 human pancreatic cancer cells.
E- and Z-guggulsterones and nine guggulsterone derivatives (GSDs) were synthesized and evaluated for their preferential cytotoxicity against human PANC-1 cell in nutrient deprived medium utilizing antiausterity strategy. Among the synthesized compounds, GSD-1 and GSD-7 showed potent cytotoxicity against PANC-1 cells under nutrient-deprived conditions in a concentration dependent manner, with a PC50 value of 1.6 μM and 3.2 μM, respectively. The effect of GSD-1 and GSD-7 was further evaluated in a real time using live cell imaging. Both of these compounds altered PANC-1 cell morphology, leading to cell death at sub micromolar concentration range. GSD-1 and GSD-7 also inhibited PANC-1 cell colony formation in a concentration-dependent manner. GSD-1 and GSD-7 are lead structure for the anti-austerity drug development.


Comparison of Hodgkin's Lymphoma in Children and Adolescents. A Twenty Year Experience with MH'96 and LH2004 AIEOP (Italian Association of Pediatric Hematology and Oncology) Protocols.
Adolescents and young adults (AYAs) represent a distinct group of patients. The objectives of this study were: To compare adolescent prognosis to that of younger children; to compare the results achieved with the two consecutive protocols in both age groups; to analyze clinical characteristics of children and adolescents. Between 1996 and 2017, 1759 patients aged <18 years were evaluable for the study. Five hundred and sixty patients were treated with the MH'96 protocol and 1199 with the LH2004 protocol. Four hundred and eighty-two were adolescents aged ≥15 years. Patients in both age groups showed very favorable prognoses. In particular, OS improved with the LH2004 protocol, especially in the adolescent group and in the low risk group, where radiation therapy was spared. Adolescent characteristics differed significantly from the children's according to sex, histology, and the presence of symptoms. Remarkable is the decrease both in mixed cellularity in the children and in low stages in both age groups in the LH2004 protocol with respect to MH'96 protocol. Based on our experience, adopting pediatric protocols for AYA does not compromise patient outcomes.


Differences in Delirium Evaluation and Pharmacologic Management in Children With Developmental Delay: A Retrospective Case-Control Study.
Delirium is associated with increased mortality and cost, decreased neurocognition, and decreased quality of life in the pediatric intensive care unit (PICU) population. The Cornell Assessment for Pediatric Delirium (CAPD) is used in PICUs for delirium screening but lacks specificity in children with developmental delay (DD). Within a cohort of children receiving pharmacologic treatment for intensive care unit (ICU) delirium, we compared delirium scoring and medication management between children with and without DD. We hypothesized that CAPD scores and treatment decisions would differ between DD and neurotypical (NT) patients. In this retrospective case-control study, we queried the medical record of patients admitted to our PICU with respiratory failure from June 2018 to March 2022 who received antipsychotics typically used for ICU delirium. Antipsychotics prescribed for home use were excluded. Nonparametric statistics compared demographics, CAPD scores, medication choice, dosing (mg/kg), and medication continuation after discharge between those with and without DD based on the ICD-10 codes. Twenty-one DD admissions and 59 NT admissions were included. Groups did not significantly differ by demographics, LOS, drug, or initial dosage. DD patients had higher median CAPD scores at admission (17 vs 13; P = .02) and treatment initiation (18 vs 16.5; P = .05). Providers more frequently escalated doses in DD patients (13/21 vs 21/59; P = .04) and discharged them home on new antipsychotics (7/21 vs 5/59; P = .01). DD patients experience delirium screening and management differently than NT counterparts. Providers should be aware of baseline elevated scores in DD patients and carefully attend to indications for dosage escalation. Further work is needed to understand if prolonged duration, even after hospital discharge, benefits patients, or represents potential disparity in care.


Heart rate variability in patients with systemic lupus erythematosus: a systematic review and methodological considerations.
Aim The aim of this review was to summarize current knowledge about the scientific findings and potential clinical utility of heart rate variability measures in patients with systemic lupus erythematosus. Methods PubMed, Embase and Scopus databases were searched for the terms associated with systemic lupus erythematosus and heart rate variability, including controlled vocabulary, when appropriate. Articles published in English and available in full text were considered. Finally, 11 publications were selected, according to the systematic review protocol and were analyzed. Results In general, heart rate variability, measured in the time and frequency domains, was reported to be decreased in patients with systemic lupus erythematosus compared with controls. In some systemic lupus erythematosus studies, heart rate variability was found to correlate with inflammatory markers and albumin levels. A novel heart rate variability measure, heart rate turbulence onset, was shown to be increased, while heart rate turbulence slope was decreased in systemic lupus erythematosus patients. Reports of associations of changes in heart rate variability parameters with increasing systemic lupus erythematosus activity were inconsistent, showing decreasing heart rate variability or no relationship. However, the low/high frequency ratio was, in some studies, reported to increase with increasing disease activity or to be inversely correlated with albumin levels. Conclusions Patients with systemic lupus erythematosus have abnormal heart rate variability, which reflects cardiac autonomic dysfunction and may be related to inflammatory cytokines but not necessarily to disease activity. Thus measurement of heart rate variability could be a useful clinical tool for monitoring autonomic dysfunction in systemic lupus erythematosus, and may potentially provide prognostic information.


Diagnosis and Management of Ovarian Cancer.
Ovarian cancer is the most lethal gynecologic cancer. Less than one-half of patients survive for more than five years after diagnosis. Ovarian cancer affects women of all ages but is most commonly diagnosed after menopause. More than 75% of affected women are diagnosed at an advanced stage because early-stage disease is usually asymptomatic and symptoms of late-stage disease are nonspecific. The strongest risk factors are advancing age and family history of ovarian and breast cancer. Women who have symptoms concerning for ovarian cancer should undergo a physical examination, transvaginal ultrasonography, and measurement of biomarkers such as cancer antigen 125. If results are suspicious for ovarian cancer, the patient should be referred to a gynecologic oncologist. Despite the low rate of early diagnosis, guidelines recommend against routine screening for ovarian cancer in average-risk women because screening, including routine pelvic examinations, is ineffective and associated with harm. However, a recent trial found a potential benefit of annual screening using an algorithm based on serial cancer antigen 125 measurements followed by transvaginal ultrasonography for women at increased risk, as determined by the algorithm. Women with an increased-risk family history should be referred for genetic counseling and, if genetic mutations (e.g., BRCA mutations) are identified, bilateral salpingo-oophorectomy can be considered for risk reduction. In both average- and high-risk women, long-term hormonal contraceptive use reduces risk by about 50%. The treatment of ovarian cancer usually involves surgery, with or without intraperitoneal and intravenous chemotherapy. Primary care physicians have important roles in posttreatment surveillance and end-of-life care.


Serglycin expression in CD2+ and CD14+ cells from patients with various rheumatic diseases.
The objective of the study was to look at the in vivo expression of serglycin in cells taken from patients with an inflammatory disease. The mRNA expression of the small proteoglycan serglycin was investigated in macrophages/monocytes and T-cells derived from the synovial fluid and blood of six patients with various rheumatic diseases and from the blood of two control subjects. Our results demonstrate higher Levels of expression in CD14+ cetts taken from patients with chronic inflammatory diseases than in control subjects. This suggests that serglycin may play a role during the inflammatory process.


Different perception of musical stimuli in patients with monolateral and bilateral cochlear implants.
The aim of the present study is to measure the perceived pleasantness during the observation of a musical video clip in a group of cochlear implanted adult patients when compared to a group of normal hearing subjects. This comparison was performed by using the imbalance of the EEG power spectra in alpha band over frontal areas as a metric for the perceived pleasantness. Subjects were asked to watch a musical video clip in three different experimental conditions: with the original audio included (Norm), with a distorted version of the audio (Dist), and without the audio (Mute). The frontal EEG imbalance between the estimated power spectra for the left and right prefrontal areas has been calculated to investigate the differences among the two populations. Results suggested that the perceived pleasantness of the musical video clip in the normal hearing population and in the bilateral cochlear implanted populations has similar range of variation across the different stimulations (Norm, Dist, and Mute), when compared to the range of variation of video clip's pleasantness for the monolateral cochlear implanted population. A similarity exists in the trends of the perceived pleasantness across the different experimental conditions in the mono- and bilaterally cochlear implanted patients.


Platelets influence vascularized organ transplants from start to finish.
This review relates the basic functions of platelets to specific aspects of organ allograft rejection. Platelet activation can occur in the donor or recipient before transplantation as well as during antibody- and cell-mediated rejection. Biopsies taken during organ procurement from cadaver donors have documented that activated platelets are attached to vascular endothelial cells or leukocytes. In addition, many patients waiting for transplants have activated platelets due to the diseases that lead to organ failure or as a result of interventions used to support patients before and during transplantation. The contribution of platelets to hyperacute rejection of both allografts and xenografts is well recognized. Intravascular aggregates of platelets can also be prominent in experimental and clinical transplants that undergo acute antibody or cell-mediated rejection. In acute rejection, platelets can recruit mononuclear cells by secretion of chemokines. After contact, monocytes, macrophages and T cells interact with platelets through receptor/ligand pairs, including P-selectin/PSGL-1 and CD40/CD154. There is a potential for therapy to inhibit platelet mediated immune stimulation, but it is counterbalanced by the need to maintain coagulation in the perioperative period.


Topical transforming growth factor-beta3 in the prevention or alleviation of chemotherapy-induced oral mucositis in patients with lymphomas or solid tumors.
Transforming growth factor (TGF)-beta3 has been hypothesized to prevent or alleviate oral mucositis (OM) in cancer patients receiving high-dose chemotherapy (CT). Two double-blind, placebo-controlled, multicenter, phase II studies of TGF-beta3 were initiated in the United States, Europe, and Argentina in patients with lymphomas or solid tumors who were receiving highly stomatotoxic CT regimens. Patients were to apply 10-mL mouthwash applications of TGF-beta3 (25 microg/mL) or placebo four times daily (or twice daily) 1 day before and all days during CT. The patients were subsequently evaluated for OM incidence, severity, and duration using National Institute of Cancer Common Toxicity Criteria (NCI-CTC) criteria and an objective scoring system (1). After the start of the trials, negative results from new preclinical studies suggesting suboptimal formulation and/or dosing led to an interim analysis of the ongoing clinical trials. One hundred fifty-two patients from the combined studies were included in the interim analysis, with 116 patients on the TGF-beta3 four times daily and placebo arms. Most (72%) patients had breast cancer, 22% had lymphomas, and 6% had other solid tumors. Although 98% (149 of 152) of patients experienced adverse events, only 14% (22 of 152) experienced events that were judged as possibly or probably related to the study drug (primarily gastrointestinal symptoms). No clinically relevant differences were seen between the treatment and placebo arms regarding safety, nor was there evidence for systemic absorption of TGF-beta3. Finally, there was no advantage of TGF-beta3 treatment regarding the incidence (TGF-beta3 four times daily versus placebo [46% versus 47%]), onset, or duration of NCI-CTC grade 3 or 4 OM. For this dose, formulation, regimen. and patient population, TGF-beta3 was not effective in the prevention or alleviation of CT-induced OM.


Safety, pharmacokinetics, and pharmacodynamics of intravenous ferric carboxymaltose in children with iron deficiency anemia.
Iron deficiency is the primary cause of anemia in children. Intravenous (IV) iron formulations circumvent malabsorption and rapidly restore hemoglobin. This Phase 2, non-randomized, multicenter study characterized the safety profile and determined appropriate dosing of ferric carboxymaltose (FCM) in children with iron deficiency anemia. Patients aged 1-17 years with hemoglobin <11 g/dL and transferrin saturation <20% received single IV doses of undiluted FCM 7.5 mg/kg (n = 16) or 15 mg/kg (n = 19). The most common drug-related treatment-emergent adverse event was urticaria (in three recipients of FCM 15 mg/kg). Systemic exposure to iron increased in a dose-proportional manner with approximate doubling of mean baseline-corrected maximum serum iron concentration (157 µg/mL with FCM 7.5 mg/kg; and 310 µg/mL with FCM 15 mg/kg) and area under the serum concentration-time curve (1901 and 4851 h·µg/mL, respectively). Baseline hemoglobin was 9.2 and 9.5 g/dL in the FCM 7.5 and 15 mg/kg groups, respectively, with mean maximum changes in hemoglobin of 2.2 and 3.0 g/dL, respectively. In conclusion, FCM was well tolerated by pediatric patients. Improvements in hemoglobin were greater with the higher dose, supporting use of the FCM 15 mg/kg dose in pediatric patients (Clinicaltrials.gov NCT02410213). This study provided information on the pharmacokinetics and safety of intravenous ferric carboxymaltose for treatment of iron deficiency anemia in children and adolescents. In children aged 1-17 years with iron deficiency anemia, single intravenous doses of ferric carboxymaltose 7.5 or 15 mg/kg increased systemic exposure to iron in a dose-proportional manner, with clinically meaningful increases in hemoglobin. The most common drug-related treatment-emergent adverse event was urticaria. The findings suggest that iron deficiency anemia in children can be corrected with a single intravenous dose of ferric carboxymaltose and support use of a 15 mg/kg dose.


Tim62, a Novel Mitochondrial Protein in Trypanosoma brucei, Is Essential for Assembly and Stability of the TbTim17 Protein Complex.
Trypanosoma brucei, the causative agent of human African trypanosomiasis, possesses non-canonical mitochondrial protein import machinery. Previously, we characterized the essential translocase of the mitochondrial inner membrane (TIM) consisting of Tim17 in T. brucei. TbTim17 is associated with TbTim62. Here we show that TbTim62, a novel protein, is localized in the mitochondrial inner membrane, and its import into mitochondria depends on TbTim17. Knockdown (KD) of TbTim62 decreased the steady-state levels of TbTim17 post-transcriptionally. Further analysis showed that import of TbTim17 into mitochondria was not inhibited, but its half-life was reduced >4-fold due to TbTim62 KD. Blue-native gel electrophoresis revealed that TbTim62 is present primarily in ∼150-kDa and also in ∼1100-kDa protein complexes, whereas TbTim17 is present in multiple complexes within the range of ∼300 to ∼1100 kDa. TbTim62 KD reduced the levels of both TbTim62 as well as TbTim17 protein complexes. Interestingly, TbTim17 was accumulated as lower molecular mass complexes in TbTim62 KD mitochondria. Furthermore, depletion of TbTim62 hampered the assembly of the ectopically expressed TbTim17-2X-myc into TbTim17 protein complex. Co-immunoprecipitation analysis revealed that association of TbTim17 with mHSP70 was markedly reduced in TbTim62 KD mitochondria. All together our results demonstrate that TbTim62, a unique mitochondrial protein in T. brucei, is required for the formation of a stable TbTim17 protein complex. TbTim62 KD destabilizes this complex, and unassembled TbTim17 degrades. Therefore, TbTim62 acts as a novel regulatory factor to maintain the levels of TIM in T. brucei mitochondria.


Gender role influences on Turkish adolescents' self-identity.
This study investigated gender role influences on Turkish adolescents' self-identity process as part of the International Self-Identity Research Project. A total of 154 male and 119 female adolescents ages 14 through 17 from urban and rural areas of Turkey were surveyed through a questionnaire. The results indicated that "family" was the dominant source of belongingness for both males and females, followed by "friendships" and "school." Friendships and education were valued more by females than by males. Symbolic items (e.g., relationships, happiness) influenced females' self-identity more than they did males, while males tended to place greater importance on material items (e.g., home, TV, sports equipment). Athletic activities were highly important in males' self-validation process while females were oriented more toward the artistic and creative. General affective attributes (e.g., honesty, respect, thoughtfulness) were similarly valued by males and females as important criteria for self-evaluation. Finally, males were more religious, patriotic, and felt stronger ties to ancestors while females appeared to be more altruistic and placed high importance on social relations.


Use of surfactant in the prevention and treatment of neonatal respiratory distress syndrome.
The rationale for surfactant therapy in premature infants is presented, along with a discussion of the characteristics of surfactant and a review of clinical trials of surfactant for the prevention and treatment of neonatal respiratory distress syndrome (RDS). RDS is a major complication of prematurity, affecting up to 40,000 infants in the United States and Canada annually. Poor lung compliance due to a functional or quantitative deficiency of surfactant causes progressive collapse of the lungs. Surfactant, a mixture of phospholipids, neutral lipids, and proteins synthesized by pneumocytes during gestation, reduces surface tension and stabilizes alveoli, which increases lung compliance and decreases the work of breathing. Mammalian, human, and artificial surfactants are being investigated for use in premature infants. Several controlled trials of exogenous surfactant therapy have demonstrated reductions in mortality and pulmonary air-leak phenomena and improved gas exchange, but these results are not seen consistently, and no significant reductions in bronchopulmonary dysplasia have been observed. Surfactant has no appreciable toxicity, although the potential for immunogenicity exists. Typical doses range from 60 mg to 200 mg/kg administered endotracheally either before the first breath or after development of RDS. Surfactant is a safe investigational agent that appears promising for the prevention and treatment of neonatal RDS, although additional clinical trials with long-term follow-up are needed to determine its true efficacy.


Malignant peripheral nerve sheath tumor: A rare malignancy.
Malignant peripheral nerve sheath tumor (MPNST) is also termed as spindle cell malignancy of the peripheral nerve Schwann cell. It is a rare and highly aggressive, soft-tissue sarcoma of ectomesenchymal origin that accounts for 10% of all sarcomas and only 10%-12% of all lesions occur in the head-and-neck region, thus making it a rare entity. It arises de novo or from the preexisting benign neurofibroma. The diagnosis of MPNST is one of the most elusive among the soft-tissue tumors because of its greater variability in overall presentation both clinically and histologically. This difficulty can be overcome by the use of immunohistochemistry. This article presents a rare case of MPNST of the oral cavity in a 40-year-old female patient with a brief review of the current literature.


Study of plasma neuropeptide Y (NPY) and catecholamines levels during spinal anesthesia.
Plasma levels of neuropeptide Y (NPY) and catecholamines were investigated during spinal anesthesia. Ten ASA physical status I-II patients were studied after obtaining institutional approval and informed contents. All patients were free from endocrine and metabolic disease underwent elective low risk operation. No premedication was given before operation. Spinal anesthesia was performed on lateral position from L3-4 interspace with 15 mg tetracaine without added epinephrine. The analgesic level was about at T6 dermatone. Blood samples were obtained from radial artery catheter, 15 minutes before spinal anesthesia and 5', 15', 30', 60', 120', during operative period and 30' after operation in postanesthesia recovery room. The results showed that there were significant elevation in plasma level of NPY during spinal anesthesia compared with the level before anesthesia. However, no statistically significant changes of plasma catecholamines were found.


Heparan sulfate proteoglycan modulation of Wnt5A signal transduction in metastatic melanoma cells.
Heparan sulfate proteoglycans (HSPGs) are important modulators for optimizing signal transduction of many pathways, including the Wnt pathways. We demonstrate that HSPG glycosaminoglycan levels increased with increasing metastatic potential of melanoma cells. Previous studies have demonstrated that Wnt5A increases the invasiveness of melanoma cells. We further demonstrate that HSPGs potentiate Wnt5A signaling, since enzymatic removal of the HSPG backbone resulted in a decrease in cellular Wnt5A levels, an increase in secreted Wnt5A in cell media, a decrease in downstream signaling, and ultimately, a decrease in invasiveness. Specifically, syndecan 1 and syndecan 4 expression correlated to Wnt5A expression and melanoma malignancy. Knockdown of syndecan 1 or 4 caused decreases in cell invasion, which could be restored by treating the cells with recombinant Wnt5A. These data indicate that syndecan 1 and 4 correlate to increased metastatic potential in melanoma patients and are an important component of the Wnt5A autocrine signaling loop, the activation of which leads to increased metastasis of melanoma.


Laparoscopic diagnosis of tuberculous ascites.
We report 14 patients with tuberculous peritonitis presenting as persistent and exudative ascites. We found a primary site of tuberculous infection in only 10% of the patients. PPD test was positive in 9 patients. Ascitic fluid showed a protein content in excess of 3.5 g/dl. and more than 300 cells/mm3, mainly lymphocytes, in all patients, Ziehl stain and the culture for Tb. bacilli were negative in all cases. The confirmatory diagnosis was made by laparoscopy and peritoneal biopsy. Good views were obtained on all occasions, and there was no morbidity. Appearances were similar in all cases. Multiple white tubercles were scattered over the parietal and visceral peritoneum. filmy adhesions were present. Four patients had cirrhotic liver disease confirmed by laparoscopy. The biopsy specimen showed caseating granulomata, and the auramine stain was positive in four cases. We conclude that laparoscopy and biopsy is a safe and effective method of obtaining an early diagnosis in patients with tuberculous ascites, especially if they also have cirrhosis.


[Etiology of hemolytic anemia].
When hemolytic anemia is diagnosed the etiology of most cases can be determined by simple methods: familial and personal history, physical examination and search for erythrocyte morphologic anomalies (spontaneous or induced). These latter are often typical of a particular mechanism of hemolysis. The antihuman globulin test and the screening test for G-6-PD deficiency and sickle cell anemia are included in the routine tests. More specialized tests should be performed only in doubtful cases. For example, the determination of erythrocyte survival by an isotopic method may confirm suspected mild hemolysis. Measurement of several enzyme activities may detect an enzymatic deficiency. Hemoglobin electrophoresis may reveal hemoglobinopathy.


NMR shielding constants of CuX, AgX, and AuX (X = F, Cl, Br, and I) investigated by density functional theory based on the Douglas-Kroll-Hess Hamiltonian.
Two-component relativistic density functional theory (DFT) with the second-order Douglas-Kroll-Hess (DKH2) one-electron Hamiltonian was applied to the calculation of nuclear magnetic resonance (NMR) shielding constant. Large basis set dependence was observed in the shielding constant of Xe atom. The DKH2-DFT-calculated shielding constants of I and Xe in HI, I2, CuI, AgI, and XeF2 agree well with those obtained by the four-component relativistic theory and experiments. The Au NMR shielding constant in AuF is extremely more positive than in AuCl, AuBr, and AuI, as reported recently. This extremely positive shielding constant arises from the much larger Fermi contact (FC) term of AuF than in others. Interestingly, the absolute values of the paramagnetic and the FC terms are considerably larger in CuF and AuF than in others. The large paramagnetic term of AuF arises from the large d-components in the Au dπ -F pπ and Au sdσ-F pσ molecular orbitals (MOs). The large FC term in AuF arises from the small energy difference between the Au sdσ + F pσ and Au sdσ-F pσ MOs. The second-order magnetically relativistic effect, which is the effect of DKH2 magnetic operator, is important even in CuF. This effect considerably improves the overestimation of the spin-orbit effect calculated by the Breit-Pauli magnetic operator.


Comprehensive quality evaluation of corn steep liquor in 2-keto-L-gulonic acid fermentation.
Corn steep liquor (CSL) is one of the main raw materials in 2-keto-L-gulonic acid (2-KLG) fermentation by Ketogulonicigenium vulgare and Bacillus megaterium . Due to its natural origin and variations in the manufacturing process, unpredicted and uncontrolled variability of CSL has a great influence on 2-KLG production; however, conventional quality specifications are not enough to ensure stability of fermentation behaviors. A process analytical technology (PAT) could be considered to explore the relationship between CSL quality and 2-KLG production comprehensively. The compositions of CSL from six manufacturers were profiled by gas chromatography with time-of-flight mass spectrometry (GC-TOFMS) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES), combined with orthogonal partial least-squares discriminant analysis (OPLS-DA). Seventeen components were identified as the most discriminant marker compounds related to 2-KLG production. Results revealed that they were responsible for providing nutrients and protecting osmotic pressure. Furthermore, nine amino acids were verified as potential group markers by addition to the medium and demonstration of the correlation to 2-KLG production. The comprehensive approach provided an important platform to explore CSL marker compounds for quality evaluation in 2-KLG fermentation.


Synchronized shift of oral, faecal and urinary microbiotas in bats and natural infection dynamics during seasonal reproduction.
Seasonal reproduction is a period of extreme physiological and behavioural changes, yet we know little about how it may affect host microbial communities (i.e. microbiota) and pathogen transmission. Here, we investigated shifts of the bacterial microbiota in saliva, urine and faeces during the seasonal reproduction of bats in South Africa, and test for an interaction in shedding patterns of both bacterial (Leptospira) and viral (adeno- and herpesviruses) agents. Based on a comparative approach in two cave-dwelling bat species and high-throughput sequencing of the 16S rRNA gene, we demonstrated a clear signature in microbiota changes over the reproduction season, consistent across the multiple body habitats investigated, and associated with the sex, age and reproductive condition of bats. We observed in parallel highly dynamic shedding patterns for both bacteria and viruses, but did not find a significant association between viral shedding and bacterial microbiota composition. Indeed, only Leptospira shedding was associated with alterations in both the diversity and composition of the urinary microbiota. These results illustrate how seasonal reproduction in bats substantially affects microbiota composition and infection dynamics, and have broad implications for the understanding of disease ecology in important reservoir hosts, such as bats.


Fulminant liver failure secondary to submassive hepatic necrosis in a patient treated with Orlistat. A case report.
Orlistat is an intestinal lipase inhibitor drug that is recommended in obese patients along with a hypocaloric diet. Although the most frequent secondary effect is steatorrhea, fulminant liver failure has also been associated with this drug, which has required liver transplantation in 3 patients. We present the case of a 42-year-old obese male.


Tuberculosis Phenotypic and Genotypic Drug Susceptibility Testing and Immunodiagnostics: A Review.
Tuberculosis (TB), considered an ancient disease, is still killing one person every 21 seconds. Diagnosis of Mycobacterium tuberculosis (M.tb) still has many challenges, especially in low and middle-income countries with high burden disease rates. Over the last two decades, the amount of drug-resistant (DR)-TB cases has been increasing, from mono-resistant (mainly for isoniazid or rifampicin resistance) to extremely drug resistant TB. DR-TB is problematic to diagnose and treat, and thus, needs more resources to manage it. Together with+ TB clinical symptoms, phenotypic and genotypic diagnosis of TB includes a series of tests that can be used on different specimens to determine if a person has TB, as well as if the M.tb strain+ causing the disease is drug susceptible or resistant. Here, we review and discuss advantages and disadvantages of phenotypic vs. genotypic drug susceptibility testing for DR-TB, advances in TB immunodiagnostics, and propose a call to improve deployable and low-cost TB diagnostic tests to control the DR-TB burden, especially in light of the increase of the global burden of bacterial antimicrobial resistance, and the potentially long term impact of the coronavirus disease 2019 (COVID-19) disruption on TB programs.


Correlations in Joint Spectral and Polarization Imaging.
Recent imaging techniques enable the joint capture of spectral and polarization image data. In order to permit the design of computational imaging techniques and future processing of this information, it is interesting to describe the related image statistics. In particular, in this article, we present observations for different correlations between spectropolarimetric channels. The analysis is performed on several publicly available databases that are unified for joint processing. We perform global investigation and analysis on several specific clusters of materials or reflection types. We observe that polarization channels generally have more inter-channel correlation than the spectral channels.


Managing risk for silicone tubing applications.
Quality must be designed into medical devices, including into their raw materials and components. Operating according to the critical principles of medical device good manufacturing practices ensures that the silicone tubing incorporated into devices has the highest standards of quality and safety.


Permissive zones for the centromere-binding protein ParB on the Caulobacter crescentus chromosome.
Proper chromosome segregation is essential in all living organisms. In Caulobacter crescentus, the ParA-ParB-parS system is required for proper chromosome segregation and cell viability. The bacterial centromere-like parS DNA locus is the first to be segregated following chromosome replication. parS is bound by ParB protein, which in turn interacts with ParA to partition the ParB-parS nucleoprotein complex to each daughter cell. Here, we investigated the genome-wide distribution of ParB on the Caulobacter chromosome using a combination of in vivo chromatin immunoprecipitation (ChIP-seq) and in vitro DNA affinity purification with deep sequencing (IDAP-seq). We confirmed two previously identified parS sites and discovered at least three more sites that cluster ∼8 kb from the origin of replication. We showed that Caulobacter ParB nucleates at parS sites and associates non-specifically with ∼10 kb flanking DNA to form a high-order nucleoprotein complex on the left chromosomal arm. Lastly, using transposon mutagenesis coupled with deep sequencing (Tn-seq), we identified a ∼500 kb region surrounding the native parS cluster that is tolerable to the insertion of a second parS cluster without severely affecting cell viability. Our results demonstrate that the genomic distribution of parS sites is highly restricted and is crucial for chromosome segregation in Caulobacter.


Not so Shocking: Electromyography in Pediatrics Remains Feasible and Diagnostically Useful.
Electrodiagnostic testing, including nerve conduction studies (NCS) and electromyography (EMG), assists with localizing lesions within the peripheral nervous system. NCS/EMG in children can be technically challenging and its relevance has been questioned in the era of affordable genetic testing. NCS/EMG provides information that may not be available in the examination of a young or developmentally delayed child. Our goal was to review the volume and referral sources of NCS/EMG studies and evaluate its feasibility and diagnostic yield at a pediatric tertiary care hospital. Retrospective chart review of NCS/EMG studies done in pediatric patients at one center from 2014 to 2019. A total of 725 studies were performed, with a median age of 13.2 years (range 0-18 years). The annual number of studies remained constant throughout the study period. Neurologists and surgeons were the most common referral sources, but an increased number of referrals from geneticists was observed. Most (94.5%) NCS/EMG were done on awake patients, with only 5.5% of studies being terminated early due to tolerability of the patient. Of all studies, 326/725 (44%) demonstrated a neuromuscular abnormality, of which 63.5% (207/326) were acquired conditions. Mononeuropathies and polyneuropathies were the most common electrophysiologic diagnoses. Our study indicates that NCS/EMG remains a useful diagnostic tool, both for the diagnosis of acquired neuromuscular conditions but also as an adjunct for interpreting genetic results, as indicated by the recent increase in referrals from geneticists. Overall NCS/EMG is well tolerated and able to be performed without sedation in children of all ages.


Beauty, brains or health: trends in ovum recipient preferences.
What do ovum donation (OD) recipients request most from their ideal donor: beauty, brains, health or physical self-resemblance? Previous data have shown recipients primarily requested "similar appearance or gene pool." We consider the possibility that these criteria may have changed due to a positive social shift towards OD participation and have evaluated recipients' requests for donor criteria over a span of 5 years. Donor trait preferences of OD recipients (n=438) enrolled in a private, academic OD program from 2008-2012 were assessed in this retrospective cohort analysis. Requests were categorized by appearance, ethnicity, intellect, ability, and mental health. Statistical analyses were conducted by Cochran-Armitage trend tests with significance at p<0.05. The percentage of requests for "health" increased steadily from 2008 (50%) to 2012 (72%) (p<0.05). The percentage of requests for "intelligence" were highest in 2012 (55%), increasing from 2008 (18%) (p<0.05). Requests for "athletic ability" rose from 2008 (1%) to 2012 (17%) (p<0.05). Recipients requested a "similar gene pool" most in 2009 (40%) and least in 2012 (25%), though this trend did not reach statistical significance. Our study demonstrates an increase in the percentage of OD recipients' requests for health, athleticism, and intelligence over our 5-year analysis. It appears that the current recipient is more likely to request a donor with practical traits that would serve their offspring overall quality of life rather than self-reflective traits such as physical resemblance or their genetic composition. We believe that improved awareness and acceptance of OD as a treatment of infertility will continue to inform practical considerations and approaches toward donor recruitment and the donor-recipient matching process.


Ultracompact autocorrelator for multiphoton microscopy.
Pulse temporal characterization is a fundamental task when operating a Ti:Sapphire ultrafast laser system for multiphoton microscopy applications. In the present report, an ultracompact autocorrelator setup and a simple procedure is reported to perform pulse width measurements at the focal plane of the microscope objective without the need of any further instrumentation, aside from a few optical elements, since the confocal microscope, detection, data acquisition, processing, and displaying capabilities are used.


Infection with agents of human granulocytic ehrlichiosis, lyme disease, and babesiosis in wild white-footed mice (Peromyscus leucopus) in Connecticut.
White-footed mice, Peromyscus leucopus, were captured in southern Connecticut during 1997 and 1998 to determine the prevalence of infections caused by granulocytic Ehrlichia sp., Borrelia burgdorferi, and Babesia microti. Of the 50 mice captured and recaptured, 25 of 47 (53.2%) and 23 of 48 (47.9%) contained antibodies to the BDS or NCH-1 Ehrlichia strains, respectively, as determined by indirect fluorescent antibody (IFA) staining methods. The majority (83.3%) of 48 mice also contained antibodies to B. burgdorferi, as determined by enzyme-linked immunosorbent assay. Moreover, 20 of 26 (76.9%) contained antibodies to B. microti by IFA staining methods. In nested PCR tests using the 16S rRNA gene, the DNA of the human granulocytic ehrlichiosis (HGE) agent was detected in 17 of 47 mice (36.2%), but only 4 (23.5%) of these 17 mice were PCR positive at each capture. Antibody-positive reactions to granulocytic Ehrlichia sp. organisms were detected in 17 of 23 (73. 9%) of the PCR-positive mice. The sequences from PCR products from nine positive blood samples were identical to the HGE agent. Ehrlichia spp. were cultured from three of five mice captured in April 1998, including one that was PCR positive in April 1997. In addition, 2 of 14 larval Ixodes scapularis pools, which were attached to two PCR-positive mice, contained DNA of the HGE agent. A high percentage of white-footed mice are infected or have been infected naturally by the HGE agent with low-level persistent infection or frequent reinfection in some individual mice. However, the changes noted in the presence of DNA and antibodies in repeated blood and serum samples from individual mice over several months of field collection suggests that infection with granulocytic Ehrlichia is transient in most wild P. leucopus.


Commentary on "Abiraterone in metastatic prostate cancer without previous chemotherapy." Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators, Genitourinary Medical Oncology Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA. N Engl J Med 2013;368(2):138-48 [Epub 2012 Dec 10]; N Engl J Med 2013;368(6):584.
Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy. In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival. The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone-prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P = 0.01) but did not cross the efficacy boundary. Abiraterone-prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone-prednisone. Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer.


Anticipatory anxiety of seizures is associated with ictal emotional distress and amygdala onset seizures.
Anxiety disorders are a frequent psychiatric condition in patients with epilepsy. Anticipatory anxiety of seizures (AAS) is described as a daily persistent fear or excessive worry of having a seizure. AAS seems to be related to "subjective ictal anxiety" reported by patients. The current study aimed to assess the association between objective ictal features and the presence of AAS. Ninety-one patients with drug-resistant focal epilepsy underwent a standardized psychiatric assessment, specific for epilepsy, and presurgical long-term video-electroencephalography (EEG) or stereo-EEG (SEEG). We compared seizure semiology and epilepsy features of patients with AAS (n = 41) to those of patients without AAS (n = 50). We analyzed emotional and motor behavior ictal signs as well as ictal consciousness. We further assessed amygdala ictal involvement in seizures recorded with SEEG (n = 28). AAS was significantly associated with the presence of ictal emotional distress; negative emotional behavior (p < .01) and negative emotion were explicitly reported to the examiner during recording (p = .015), regardless of the ictal level of consciousness. Among the patients recorded with SEEG, we found a significant involvement of amygdala within the seizure onset zone (p < .01) for patients with AAS. Higher risk of developing AAS is associated with seizures expressing negative emotional symptoms, independently of ictal consciousness level. Persistent interictal fear of seizures might be viewed as the consequence of a reinforcement of the emotional networks secondary to amygdala involvement in seizures of temporal origin. Physicians should screen for AAS not only to assess the impact of epilepsy on daily life, but also as an interictal biomarker of ictal semiology and emotional network involvement at seizure onset.


Molecular and genetic immunoprobes for biotechnology.
Recent advances concerning immunoprobes are described and their biotechnologic potential is emphasized. Selected examples of immunoprobes discussed include interleukin 7, genetically engineered vaccines using live bacterial carriers, and applications of monoclonal antibodies (MAb's) for understanding and controlling blood cell malignancies as well as for analysis of prokaryotic cells. The fundamental and practical interconnections of these research areas are highlighted to show, for instance, that definition of lymphoid-cell lineages and identification of their various subsets are aided by MAb's and interleukins. On the other hand, understanding interleukins requires isolation of cell subsets. Likewise, designing vaccines presupposes a knowledge of lymphocyte subsets and of the antigenic mosaics of the pathogens against which the vaccines are directed. Dissection of antigens in cells and in infectious agents depends to a great extent on MAb's, which are also instrumental for cloning the genes encoding antigens for vaccine preparation and those encoding interleukins for large scale production of these molecules that are promising as immunotherapeutic and vaccine adjuvants. Last, brief mention is made of the uses of MAb's in prokaryotic cell biology to illustrate the long-range impact on these immunoprobes and, consequently, how they are opening new avenues for biotechnology.


Impact of the COVID-19 pandemic on acute coronary syndromes.
To assess the impact of the first wave of the COVID-19 pandemic on acute coronary syndromes and on the delay from symptom onset to first medical contact among patients presenting with ST-segment elevation myocardial infarction (STEMI), as well as to investigate whether there were patient-related reasons related to COVID-19 for delaying first medical contact. All patients undergoing percutaneous coronary intervention (PCI) at the Geneva University Hospitals for acute coronary syndromes (ACS) during the first COVID-19 wave were compared with a control group consisting of all ACS patients who underwent PCI during the same period in 2019 and those treated in the period immediately preceding the pandemic. The primary outcome measure was the difference in the delay from symptom onset to first medical contact in the setting of STEMI between the COVID-19 period and the control period. Secondary outcome measures were the difference in ACS incidence and the impact of the COVID-19 pandemic on patients' decisions to call the emergency services, assessed using a questionnaire. Delay from symptom onset to first medical contact was longer among patients suffering from STEMI in the COVID-19 period compared with the control period (112 min vs 60 min, p = 0.049). The incidence rate of ACS was lower during the COVID-19 period (incidence rate ratio 0.6, 95% confidence interval [CI] 0.449–0.905). ACS patients delayed their call to the emergency services mainly because of fear of contracting or spreading COVID-19 following hospital admission, as well as of adding burden to the healthcare system. We observed prolonged delays from symptom onset to first medical contact and a decline in overall ACS incidence during the first wave of the COVID-19 pandemic, with a higher threshold to call for help among ACS patients.


Influence of diet and calorie restriction on the initiation and promotion of skin carcinogenesis in the SENCAR mouse model.
Diets were restricted to 60% of the intake of the control mice by feeding less diet (total diet restriction, TDR) or by feeding fewer calories from fat and carbohydrate (calorie restriction, CR) during the initiation or promotion phases of skin tumorigenesis in female SENCAR mice. Skin cancer was initiated by topical treatment with 10 nmol of 7,12-dimethylbenzanthracene in acetone and promoted by twice weekly treatments with 12-O-tetradecanoylphorbol-13-acetate in acetone for 20 wk. Dietary restriction preceding and during 7,12-dimethylbenzanthracene treatment did not influence skin papilloma or carcinoma yield. Papilloma incidence and the number of papillomas per effective mouse were reduced in mice restricted by both TDR and CR protocols during and following promotion with 12-O-tetradecanoylphorbol-13-acetate. Papilloma size was reduced at experimental wk 16 and 20 in both TDR and CR groups fed these diet regimens during promotion. However, by wk 28 and 32, papilloma sizes were similar in the control and TDR groups, and smaller papillomas were observed only in the CR group. The average carcinoma latency was extended by 26% in the groups restricted during promotion, and incidence was reduced in both groups. The reduction, however, was statistically significant only in the CR group. Body weight gain was reduced during the times when dietary restriction was enforced, and in a short-term study, both restricted diet treatments reduced the percentage of carcass protein.


Observed ozone response to variations in solar ultraviolet radiation.
During the winter of 1979, the solar ultraviolet irradiance varied with a period of 13.5 days and an amplitude of 1 percent. The zonal mean ozone values in the tropics varied with the solar irradiance, with an amplitude of 0.25 to 0.60 percent. This observation agrees with earlier calculations, although the response may be overestimated. These results imply changes in ozone at an altitude of 48 kilometers of up to 12 percent over an 11-year solar cycle. Interpretation of ozone changes in the upper stratosphere will require measurements of solar ultraviolet radiation at wavelengths near 200 nanometers.


Critical occurrence of verotoxgenic E.coli and non-typhoidal salmonella in some heat treated dairy products.
Pathogenic strains of E.coli and Salmonella are common causes of foodborne illness and have been frequently isolated from inadequately heat-treated milk products in Mansoura city. The current study was performed to explore the prevalence of E.coli and Salmonella spp. in heattreated milk products intended for consumption in Mansoura university hospitals and hostels, as well as, to investigate their serotypes and virulence potential. Seventyfive samples of heat-treated milk products (Soft cheese, yoghurt, and processed cheese, 25 of each) were randomly gathered and directed to further investigation using conventional and molecular microbiology. Result revealed that 3(12%) of soft cheese samples harbored E.coli O146:H21, O26:H11 and O128:H2 serotypes and 2(8%) of yoghurt samples were contaminated with O128:H2 and O121:H7 serotypes while 3(12%) of processed cheese samples were positive for non-typhoidal Salmonella (NTS) serovars (Salmonella Typhimurium, Salmonella Infantis and Salmonella Essen). Virulence gene profiling reported that all E.coli isolates harbored eaeA gene and only E.coli O26:H11 and O121:H7 encoded stx2 (verotoxin) gene. Further, all Salmonella isolates harbored invA and stn genes, while only Salmonella Typhimurium and Salmonella Infantis encoded spvC gene. This study confirmed the existence of highly pathogenic verotoxogenic E.coli (VTEC) and NTS in investigated milk products which could be hazardous for public health and resident in Mansoura hospitals and hostels. Hence, the implementation of good hygienic practices together with hazard analysis, and risk-based preventive control measures are rigorously required in the process of HACCP plan to eliminate the risk of contamination that may occur during the manufacturing process.


Immunohistochemical analysis of beta-catenin expression: a probable prognostic marker and potential therapeutic target in renal cell carcinoma.
Renal cell carcinoma (RCC) seems to be the most aggressive type of genitourinary neoplasm. Down regulation of normal beta-catenin expression contributes to development of RCC, reflecting the role of beta-catenin/Wnt signaling pathway in pathogenesis. This study aims to evaluate the significance of beta-catenin expression and its correlation with the prognostic parameters. A cross-sectional observational study was carried out in a tertiary care center on 58 RCC cases using variables like histological grade and type, tumor stage, necrosis. Formalin fixed, paraffin-embedded blocks were evaluated for beta-catenin expression by immunohistochemistry using scoring system. Data were analyzed by mean ± SD, χ2 test, Pearson's correlation test. Membranous score (MS) had a strong negative correlation with tumor stage (r=-0.407, p=0.044) and grade (r=-0.787, p=<0.001). Mean membranous score difference between low (Stage 1 and 2) vs. high stage (Stage 3 and 4) and low (Grade 1 and 2) vs. high grade (Grade 3 and 4) was statistically significant (p<0.001). Cytoplasmic score (CS) had positive correlation with tumor stage (r=0.586; p=0.002). No significant correlation was evident between cytoplasmic scores and tumor grade, however the mean cytoplasmic score difference between low grade vs. high grade was statistically significant (p < 0.001). Beta-catenin may play a crucial role in the pathogenesis of RCC and has a positive correlation with the biological behavior of this tumor. The important role of beta-catenin as a prognostic parameter and probably a critical evaluator of targeted chemotherapy cannot be overemphasized.


Effects of Interfacial Layers on the Open Circuit Voltage of Polymer/Fullerene Bulk Heterojunction Devices Studied by Charge Extraction Techniques.
Interfacial layers are frequently used in organic solar cells performing various functions, including blocking surface recombination, improving selectivity of charge carrier extraction, modification of the work function of the contact materials, and enhancing light absorption within the photoactive layer through an optical cavity effect. The aim of this work is to investigate the origin of performance enhancement of bulk heterojunction solar cells using various electron and hole interfacial layers, with a particular focus on separating the contributions of work function modification and reduced recombination to the improvement of the open circuit voltage ( Voc). Solar cells using poly[ N-9'-hepta-decanyl-2,7-carbazole- alt-5,5-(4',7'-di-2-thienyl-2',1',3'-benzothiadiazole)]:[6,6]-phenyl C70-butyric acid methyl ester (1:4) active layers were prepared with a combination of polymeric, metal oxide, and polyelectrolyte electron and/or hole interfacial layers. Four device structures with (i) no interfacial layers (reference); (ii) only hole; (iii) only electron; (iv) both electron and hole interfacial layers were fabricated and compared using current-voltage, transient photovoltage, and charge extraction measurements. The voltage gains (Δ Voc) at matched charge density attributed to work function modification (Δ Voch or Δ Voce) are distinguished from the increase in Voc arising from increased charge carrier density. At the hole contact, Δ Voch was 0.21 V by using a poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) hole interfacial layer, whereas Δ Voce was 0.29 V on the electron contact using a polyethoxylate imine-TiO x interfacial layer compared to reference devices. The electron lifetime also improved by orders of magnitude with the use of either electron or hole contact layers, contributing to a further 0.35-0.38 V increase in the open circuit voltage (Δ Vocrec) because of increased charge density. The increased charge carrier lifetime is proposed to originate from the larger spatial separation of the electrons and holes in the device because of the increased internal field. Using both an electron and a hole interfacial layer did not significantly increase the charge carrier lifetime compared to single interfacial layer devices; therefore, the Voc did not increase significantly. The findings presented clarify the role of interfacial layers in organic solar cells and provide new insights into using time-resolved charge extraction techniques to understand the influence of interfacial layers on the open circuit voltage.


[Seasonal changes in cardiovascular indices and monoamine content in the brain of rabbits].
In our previous studies a rather substantial difference between the initial values of the cerebral blood flow was found. On the other hand the brain monoamine content varies in different months of the year when studied. Comparative analysis of these parameters in rabbit brain was the aim of this paper. The content of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in cortical and subcortical structures and the local cerebral blood flow (ICBF), the systemic arterial pressure (SAP) and pulse rate (PR) were studied. There were found seasonal variations in all parameters. A certain LCBF retardation in subcortical structures and cortex and the weakest effect of the stimulation was observed in May. There was a drop in SAP and some PR increase in the spring (April-May). Brain NA and 5-HT content showed seasonal changes with the lowest values near the winter months and reaching maximum in May as the PR does. Content of DA was low in May. So it seams possible that the ion ICBF in May can be explained by the decrease of brain DA at that time. The ICBF and the reactivity of cerebral microvessels seem to depend on the monoamine content and show seasonal variability.


Improving Iron and Folic Acid Supplementation Among Pregnant Women: An Implementation Science Approach in East-Central Uganda.
To address maternal iron-deficiency anemia and low uptake of iron and folic acid supplementation (IFAS) among antenatal care (ANC) clinic attendees in East-Central Uganda, the Anemia Implementation Science Initiative embedded enhanced quality improvement (QI) activities into an integrated health project utilizing QI methodologies. To address 2 bottlenecks of stock-outs and inadequate health education for pregnant women during ANC, an enhanced QI intervention was implemented from July 2019 to September 2020 in 2 districts. We conducted a mixed-methods effectiveness quasi-experimental study to assess whether the intervention increased the availability of IFAS in the intervention districts. We used longitudinal facility-level data from 2 treatment districts and 1 comparison district for the quantitative results. Difference-in-difference estimation was used to measure the impact of the intervention on IFAS health education and IFA availability at the health facility. We used logistic regression modeling to control for factors associated with IFAS uptake and potential differences in baseline values. Researchers conducted exit interviews with ANC clients and in-depth interviews with providers and district managers for greater insights into the implementation process. The intervention increased the probability, at a statistically significant level, of pregnant women both receiving IFAS and receiving health education on IFAS during ANC. According to inter-viewees, the intervention approach improved stakeholder engagement and buy-in, which brought about change at all levels of the health system. The intervention successfully addressed the 2 main bottlenecks to availability of IFAS for pregnant women attending ANC-inadequate provision of IFAS education and a weak drug quantification process. Even without additional funds to purchase commodities, this approach improved district capacity to advocate for and manage IFAS commodities. It could also be used to strengthen overall ANC quality.


Musculoskeletal manifestations of Lyme disease in children.
Lyme disease, caused by a tick-transmitted spirochete, has significant musculoskeletal manifestations in children as well as in adults. A series of 23 children with Lyme disease is examined. Acute arthritis was present in five cases, with the knee being involved in three of these cases. Twelve cases (52%) presented with arthralgias, and 10 cases (43%) presented with myalgias. Neurological manifestations were present in 39% of the cases. Five cases have demonstrated recurrent polyarthralgias. Lyme disease should be considered in the differential diagnosis of arthralgias and arthritis in children.


Molecular cloning of cDNA encoding gp68 of adult T-cell leukaemia-associated antigen: evidence for expression of the pX IV region of human T-cell leukaemia virus.
A 2.3 kb cDNA was cloned from human T-cell leukaemia virus [HTLV(MT-2)] virion RNA using a vector system, as plasmid pHTLV 707. The restriction endonuclease map of pHTLV 707 revealed that the insert contained the 5' half of the env gene and a portion of the pX region of HTLV, corresponding to the subgenomic RNA derived from 32S defective HTLV. Nucleotide sequence analysis of pHTLV 707 indicated that the clone contained an open reading frame for a 60K mol. wt. protein including the upstream and entire pX IV region. A rabbit antibody raised against a synthetic decapeptide deduced from the nucleotide sequence at the carboxyl terminus of the pX IV region immunoprecipitated gp68, and also 80K and 40K proteins.


A possible mechanism of basic fibroblast growth factor-promoted scarless wound healing: the induction of myofibroblast apoptosis.
Although recent clinical reports have indicated that recombinant basic fibroblast growth factor (bFGF) promotes scarless wound healing, the mechanism remains unclear. The present study was carried out to elucidate the mechanisms. The protein levels of cellular α-smooth muscle actin increased at 2-4 days after TGFβ treatment alone and at 4 to 6 days after a costimulation of bFGF and TGFβ. A spontaneous contraction of stressed myofibroblast-collagen matrix was cancelled by bFGF, which was restored under the presence of C3 exotransferase or Y27632. bFGF stimulation of myofibroblasts as well as fibroblasts elicited a transient Rac and Rho activation. bFGF promoted apoptosis of the myofibroblasts but not of the fibroblasts, even in the presence of two different inhibitors, either LY294002 or an Akt inhibitor. The present study suggests that the phosphatidylinositol-3-kinase to Akt as well as the Rho to Rho kinase signaling pathway is involved in bFGF-promoted myofibroblast apoptosis, and bFGF can promote the scarless wound healing upon the induction of apoptosis of myofibroblasts, but not fibroblasts.


Validation of human microRNA target pathways enables evaluation of target prediction tools.
MicroRNAs are regulators of gene expression. A wide-spread, yet not validated, assumption is that the targetome of miRNAs is non-randomly distributed across the transcriptome and that targets share functional pathways. We developed a computational and experimental strategy termed high-throughput miRNA interaction reporter assay (HiTmIR) to facilitate the validation of target pathways. First, targets and target pathways are predicted and prioritized by computational means to increase the specificity and positive predictive value. Second, the novel webtool miRTaH facilitates guided designs of reporter assay constructs at scale. Third, automated and standardized reporter assays are performed. We evaluated HiTmIR using miR-34a-5p, for which TNF- and TGFB-signaling, and Parkinson's Disease (PD)-related categories were identified and repeated the pipeline for miR-7-5p. HiTmIR validated 58.9% of the target genes for miR-34a-5p and 46.7% for miR-7-5p. We confirmed the targeting by measuring the endogenous protein levels of targets in a neuronal cell model. The standardized positive and negative targets are collected in the new miRATBase database, representing a resource for training, or benchmarking new target predictors. Applied to 88 target predictors with different confidence scores, TargetScan 7.2 and miRanda outperformed other tools. Our experiments demonstrate the efficiency of HiTmIR and provide evidence for an orchestrated miRNA-gene targeting.


The use, cost, and economic burden of nursing-home care in 1985.
Nursing-home expenses constitute one of the greatest financial risks for elderly Americans. This study, based largely on the 1985 National Nursing-Home Survey, examines the economic burden posed by nursing-home care during 1985. The results indicate that nursing-home expenses constitute by far the largest out-of-pocket burden of all health care services. It was found that nursing-home care expenses constituted 82.5% of the out-of-pocket expenditures among the elderly who incurred $3,000 or more in such expenditures during 1985. Surprisingly, though, it was found that the frequency in which those in nursing homes "spend-down" their assets and income, thus becoming eligible for Medicaid, is much lower than others have calculated. This may be due in part to the fact that a large proportion of the elderly are already eligible for Medicaid when they begin their nursing-home stays.


Enhanced expression of lmb gene encoding laminin-binding protein in Streptococcus agalactiae strains harboring IS1548 in scpB-lmb intergenic region.
Group B streptococcus (GBS) is the main cause of neonatal sepsis and meningitis. Bacterial surface proteins play a major role in GBS binding to and invasion of different host surfaces. The scpB and lmb genes, coding for fibronectin-binding and laminin-binding surface proteins, are present in almost all human GBS isolates. The scpB-lmb intergenic region is a hot spot for integration of two mobile genetic elements (MGEs): the insertion element IS1548 or the group II intron GBSi1. We studied the structure of scpB-lmb intergenic region in 111 GBS isolates belonging to the intraspecies major clonal complexes (CCs). IS1548 was mostly found (72.2%) in CC19 serotype III strains recovered more specifically (92.3%) from neonatal meningitis. GBSi1 was principally found (70.6%) in CC17 strains, mostly (94.4%) of serotype III, but also (15.7%) in CC19 strains, mostly (87.5%) of serotype II. No MGE was found in most strains of the other CCs (76.0%), notably CC23, CC10 and CC1. Twenty-six strains representing these three genetic configurations were selected to investigate the transcription and expression levels of scpB and lmb genes. Quantitative RT-PCR showed that lmb transcripts were 5.0- to 9.6-fold higher in the group of strains with IS1548 than in the other two groups of strains (P<0.001). Accordingly, the binding ability to laminin was 3.8- to 6.6-fold higher in these strains (P< or =0.001). Moreover, Lmb amount expressed on the cell surface was 2.4- to 2.7-fold greater in these strains (P<0.001). By contrast, scpB transcript levels and fibronectin binding ability were similar in the three groups of strains. Deletion of the IS1548 sequence between scpB and lmb genes in a CC19 serotype III GBS strain substantially reduced the transcription of lmb gene (13.5-fold), the binding ability to laminin (6.2-fold), and the expression of Lmb protein (5.0-fold). These data highlight the importance of MGEs in bacterial virulence and demonstrate the up-regulation of lmb gene by IS1548; the increased lmb gene expression observed in CC19 serotype III strains with IS1548 may play a role in their ability to cause neonatal meningitis and endocarditis.


Multidigit control of contact forces during transport of handheld objects.
When an object is lifted vertically, the normal force increases and decreases in tandem with tangential (load) force to safely avoid slips. For horizontal object transport, horizontal forces at the contact surfaces can be decomposed into manipulation forces (producing acceleration/deceleration) and grasping forces. Although the grasping forces must satisfy equilibrium constraints, it is not clear what determines their modulation across time, nor the extent to which they result from active muscle contraction or mechanical interactions of the digits with the moving object. Grasping force was found to increase in an experimental condition where the center of mass was below the contact plane, compared with when it was in the contact plane. This increase may be aimed at stabilizing object orientation during translation. In another experimental condition, more complex moments were introduced by allowing the low center of mass to swing around a pivot point. Electromyographic (EMG) activity recorded from several intrinsic and extrinsic hand muscles failed to reveal active feedback regulation of contact force in this situation. Instead, in all experimental conditions, EMG data revealed a strategy of feedforward stiffness modulation. Multiple regression analysis revealed that muscle activity at remote digits (e.g., the index and ring fingers) was highly correlated with the contact force measured at another digit (e.g., the thumb). The data suggest that to maintain grasp stability during horizontal translation, predictable as well as somewhat unpredictable inertial forces are compensated for by controlling the stiffness of the hand through cocontraction and modulation of hand muscle activity.


Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer.
Mutations in genes that constitute the phosphatidylinositol 3-kinase (PI3K) pathway occur in >70% of breast cancers. Clinical and experimental evidence suggest that PI3K pathway activation promotes resistance to some of the current breast cancer therapies. PI3K is a major signaling hub downstream of human epidermal growth factor receptor (HER)2 and other receptor tyrosine kinases. PI3K activates AKT, serum/glucocorticoid regulated kinase (SGK), phosphoinositide-dependent kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and several other molecules involved in cell cycle progression and survival. In estrogen receptor (ER)+ breast cancer cells, PI3K activation promotes estrogen-dependent and -independent ER transcriptional activity, which, in turn, may contribute to anti-estrogen resistance. Activation of this pathway also confers resistance to HER2-targeted therapies. In experimental models of resistance to anti-estrogens and HER2 inhibitors, pharmacological inhibition of PI3K/AKT/mTOR has been shown to overcome drug resistance. Early clinical data suggest that combined inhibition of either HER2 or ER plus inhibition of the PI3K pathway might be an effective strategy for treatment of respective HER2+ and ER+ breast cancers resistant to standard therapies. Here, we review alterations in the PI3K pathway in breast cancer, their association with therapeutic resistance, and the state of clinical development of PI3K pathway inhibitors.


Occupations at risk of developing contact allergy to isothiazolinones in Danish contact dermatitis patients: results from a Danish multicentre study (2009-2012).
In recent years, the prevalence of contact allergy to isothiazolinones has reached epidemic levels. Few studies have presented data on occupations at risk of developing contact allergy to isothiazolinones. To present demographics and examine risk factors for sensitization to methylisothiazolinone (MI), methylchloroisothiazolinone (MCI) in combination with MI and benzisothiazolinone (BIT) in Danish dermatitis patients. A retrospective epidemiological analysis of data from three Danish hospitals departments was conducted. All patients consecutively patch tested with MI, MCI/MI and BIT between 2009 and 2013 were included. MI contact allergy showed a significantly increased trend in prevalence from 1.8% in 2009 to 4.2% in 2012 (p < 0.001). Females with facial dermatitis mainly drove the increase in 2012. Adjusted logistic regression analysis showed that MI sensitization was significantly associated with occupational exposures, hand and facial dermatitis, age > 40 years, and the occupational groups of tile setters/terrazzo workers, machine operators, and painters. MCI/MI contact allergy was significantly associated with the following high-risk occupations: painting, welding (blacksmiths), machine operating, and cosmetology. The occupational group of painting was frequent in the group of patients with BIT contact allergy. Several high-risk occupations for sensitization to isothiazolinones exist. Regulation on the allowed concentration of isothiazolinones, and especially MI, in both consumer products and industrial products is needed.


Chromatic aberration measurement for transmission interferometric testing.
A method of chromatic aberration measurement is described based on the transmitted wavefront of an optical element obtained from a Mach-Zehnder interferometer. The chromatic aberration is derived from transmitted wavefronts measured at five different wavelengths. Reverse ray tracing is used to remove induced aberrations associated with the interferometer from the measurement. In the interferometer, the wavefront transmitted through the sample is tested against a plano reference, allowing for the absolute determination of the wavefront radius of curvature. The chromatic aberrations of a singlet and a doublet have been measured.


Food and chemicals as environmental incitants.
Susceptibility to environmental incitants such as air, food and water components is becoming an increasingly recognized health problem. These sensitivities and reactions can induce a spectrum of symptoms affecting smooth muscle, mucous membranes and collagen in the respiratory, gastrointestinal, genitourinary and vascular systems. These reactions may be mistaken for hypochondriasis, but actually are due to reactions to foods and chemicals found in the patient's home and work environments. Careful clinical histories should alert the nurse and physician, who can confirm suspicions by eliminating and challenging the patient with potentially offending agents under controlled circumstances.


Proteomic analysis of the crayfish gastrolith chitinous extracellular matrix reveals putative protein complexes and a central role for GAP 65.
Chitin is a major component of arthropod cuticles, where it forms a three-dimensional network that constitutes the scaffold upon which cuticles form. The chitin fibers that form this network are closely associated with specific structural proteins, while the cuticular matrix contains many additional structural, enzymatic and other proteins. We study the crayfish gastrolith as a simple model for the assembly of calcified cuticular structures, with particular focus on the proteins involved in this process. The present study integrates a gastrolith-forming epithelium transcriptomic library with data from mass spectrometry analysis of proteins extracted from the gastrolith matrix to obtain a near-complete picture of gastrolith protein content. Using native protein separation we identified 24 matrix proteins, of which 14 are novel. Further analysis led to discovery of three putative protein complexes, all containing GAP 65 the most abundant gastrolith structural protein. Using immunological methods we further studied the role of GAP 65 in the gastrolith matrix and forming epithelium, as well as in the newly identified protein complexes. We propose that gastrolith matrix construction is a sequential process in which protein complexes are dynamically assembled and disassembled around GAP 65, thus changing their functional properties to perform each step in the construction process. The scientific interest on which this study is based arises from three main features of gastroliths: (1) Gastroliths possess partial analogy to cuticles both in structural and molecular properties, and may be regarded, with the appropriate reservations (see Introduction), as simple models for cuticle assembly. At the same time, gastroliths are terminally assembled during a well-defined period, which can be controlled in the laboratory, making them significantly easier to study than cuticles. (2) Gastroliths, like the crayfish exoskeleton, contain stable amorphous calcium carbonate (ACC) rather than crystalline calcite. The biological mechanism for the stabilization of a naturally unstable, but at the same time biologically highly available, calcium carbonate polymorph is of great interest from the pharmaceutical point of view. (3) The gastrolith organic matrix is based on a highly structured chitin network that interacts with a variety of substances. This biologically manipulated, biodegradable structure is in itself of biotechnological and pharmaceutical potential. A growing body of evidence indicates that proteins play central roles in all above aspects of gastrolith construction. This study offers the first comprehensive screening of gastrolith proteins, and we believe that the analysis presented in this work can not only help reveal basic biological questions regarding assembly of mineralized and non-mineralized cuticular structures, but may also serve as basis for applied research in the fields of agriculture (e.g. cuticle-based pest management), health (e.g. bioavailable calcium supplements and biodegradable drug carriers) and materials science (e.g. non-toxic scaffolds for water purification).


Errors in medicine.
The medical profession has been reminded of the problem of errors occurring in the practice of medicine by some recent local and overseas studies. These studies provide data on the incidence and demographics of these errors, and they provide a starting point for improving the situation. A body of research is developing on the subject of human error, and it is suggested that the medical profession take advantage of the knowledge derived from this research. In particular, attention should be directed towards developing an atmosphere of reporting errors without fear of blame, developing back-up systems, standardizing processes, monitoring processes extensively, and recertifying operators. Some of these suggestions are already being adopted in this country.