Baseline Prostate Atrophy is Associated with Reduced Risk of Prostate Cancer in Men Undergoing Repeat Prostate Biopsy.
We evaluated whether the presence and severity of baseline prostate atrophy in men with initial biopsy negative for prostate cancer was associated the risk of subsequent prostate cancer detection in a clinical trial with scheduled study mandated biopsies. We retrospectively analyzed the records of 3,084 men 50 to 75 years old with prostate specific antigen between 2.5 and 10 ng/ml, and a prior negative biopsy in the placebo arm of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study who completed at least 1 per-protocol biopsy. Prostate cancer (defined as present or absent) and prostate atrophy (graded as absent, mild or moderate/marked) was assessed by central pathology review. The association of baseline atrophy with positive 2 and 4-year repeat biopsies was evaluated with logistic regression, controlling for baseline covariates. Baseline prostate atrophy was detected in 2,143 men (70%) and graded as mild and moderate/marked in 1,843 (60%) and 300 (10%) baseline biopsies, respectively. Patients with atrophy were older and had a larger prostate, and more acute and chronic prostate inflammation. At 2-year biopsy the prostate cancer incidence was 17% (508 cases). Baseline atrophy was significantly associated with lower prostate cancer risk (univariable and multivariable OR 0.60, 95% CI 0.50-0.74 and OR 0.67, 95% CI 0.54-0.83, p <0.001, respectively) at the 2-year biopsy. These results were similar at the 4-year biopsy (univariable and multivariable OR 0.70, 95% CI 0.53-0.93 and OR 0.72, 95% CI 0.53-0.97, p = 0.03, respectively). Relative to no atrophy the prostate cancer risk at the 2-year repeat biopsy was lower for mild atrophy (OR 0.69, 95% CI 0.55-0.86) and moderate/marked atrophy (OR 0.51, 95% CI 0.34-0.76, each p <0.001). Baseline prostate atrophy in men with a prostate biopsy negative for prostate cancer was independently associated with subsequent lower prostate cancer detection.


Lysozyme is an inducible marker of macrophage activation in murine tissues as demonstrated by in situ hybridization.
This study demonstrates the induction of lysozyme mRNA expression in situ in tissue macrophages (M phi) of mice following in vivo stimulation. The resting resident tissue M phi of most tissues do not contain enough lysozyme mRNA to be detected by in situ hybridization using 35S-labeled RNA probes. Following Bacille Calmette Guerin or Plasmodium yoelli infection, however, M phi recruited to liver and spleen hybridize strongly to the lysozyme probe. Within 24 h of infection, cells found in the marginal zone of the spleen begin to produce lysozyme mRNA. This response is also evoked by a noninfectious agent (intravenously injected sheep erythrocytes), and is possibly the result of an early phagocytic interaction. Later in the infection, other cells in the red and white pulp of the spleen, and cells in granulomas in the liver, become lysozyme-positive. Kupffer cells are rarely lysozyme-positive. Lysozyme mRNA levels in liver granulomas remain relatively constant during the infection, and lysozyme is produced by most granuloma cells. This contrasts with tumor necrosis factor alpha (TNF alpha) mRNA, which is produced by fewer cells in the granuloma, and which can be massively induced by lipopolysaccharide administration. The production of lysozyme, previously considered a constitutive function of M phi, is therefore an indicator of M phi activation in vivo, where immunologically specific and nonspecific stimuli both stimulate lysozyme production at high levels in subpopulations of cells occupying discrete anatomical locations.


An investigation of motor function in schizophrenia using transcranial magnetic stimulation of the motor cortex.
In this first investigation of motor function in schizophrenia using transcranial magnetic stimulation (TMS), the general hypothesis tested was that this methodology could be used to investigate the disruption of corticospinal inhibitory processes suggested by cognitive and psychophysiological paradigms. Nine drug-free DSM-IV schizophrenic patients were compared with nine age- and sex-matched normal subjects. Electromyographic (EMG) recordings were made from the thenar muscles of the dominant hand during sustained, weak voluntary contraction. TMS over a particular threshold applied to the motor cortex would elicit a compound motor evoked potential (cMEP) followed by a period of suppression of EMG. The latency of cMEPs following TMS was significantly shorter in the schizophrenic patients. The two groups did not differ significantly with respect to mean latency of suppression of EMG activity, or stimulus thresholds for either cMEPs or EMG suppression. These findings could be the result of a relative lack of corticospinal inhibition of motor responses; a change in the site of TMS activation; or an abnormality of peripheral nervous function in schizophrenia. Drug effects were unlikely since seven of the patients were drug-naive.


Appendicular lean mass index changes in patients with Duchenne muscular dystrophy and Becker muscular dystrophy.
Mutations in the 79 exons of the dystrophin gene result in muscle wasting and weakness of varying clinical severity, ranging from severe/typical Duchenne muscular dystrophy (DMD) to intermediate DMD and mild Becker muscular dystrophy (BMD), depending on the frameshift of the mutation. We previously reported that males with DMD have progressively declining appendicular lean mass (ALM) and ALM index (ALMI) with age and worsening functional motor ability compared with healthy controls. These indices have not been studied in patients with intermediate DMD and BMD phenotypes and across DMD genotypes. In this study, we compared age-related trajectories of ALM and ALMI of patients who had (1) BMD without functional mobility deficits with patients who had DMD at different stages of disease and healthy controls; (2) a DMD intermediate phenotype with patients who had a typical DMD phenotype; and (3) DMD categorized by genotype. We conducted a retrospective review of ALM and ALMI data from 499 patients (ages 5-23 years) with DMD (466 typical and 33 intermediate) and 46 patients (ages 5-21 years) with BMD (without functional mobility deficits and functional mobility score of 1). Patients were grouped according to age reflecting disease stage (ages 5 to <7, 7 to <10, 10 to <14, and 14 to <20 years) and genotype (mutations in exons 1-30, 31-44, 45-62, and 63-79). ALM and ALMI trajectories of patients with BMD paralleled those of healthy controls until adolescence, in contrast to patients with DMD. ALMI Z-scores of patients with BMD remained within ±2 SD without decline while those of patients with DMD fell below -2 SD around age 12 years. Patients with BMD had increasing ALM and ALMI with age, with peak accrual between ages 10 to <14 years. ALMI declined after age 14 years for those with intermediate DMD compared with 10 years for patients with typical DMD. Patients with mutations in exons 63-79 had a greater decline in ALMI as compared with those with other genotypes after age 10 years. Age-related changes in ALMI in patients with BMD and intermediate DMD differ from those with typical DMD, reflecting their clinical phenotypes. ALM and ALMI should be further studied in patients with BMD and DMD subtypes for their potential value as surrogate markers to characterize the severity of BMD and DMD and inform clinical care decisions and clinical trial designs.


Short stem shoulder replacement.
It is agreed that it is important to anatomically reproduce the proximal humeral anatomy when performing a prosthetic shoulder replacement. This can be difficult with a long stemmed prosthesis, in particular if there is little relationship of the metaphysis to the humeral shaft. The 'short stem' prosthesis can deal with this problem. A prospective study assessed the results of total shoulder arthroplasty using a short stem humeral prosthesis, a ceramic humeral head, and a pegged cemented polyethylene glenoid. Patients with primary shoulder osteoarthritis were recruited into this prospective trial and pre-operatively had the ASES, Constant, SPADI, and DASH scores recorded. The patients were clinically reviewed at the two weeks, eight weeks, one year, and two year mark with completion of a data form. Radiological evaluation was at the eight week, one year and two year follow-up. At the one and two year follow-up the satisfaction rating, the range of passive and active motion, Constant, ASES, SPADI, DASH and pain results were recorded and analysed with SPPS 20. During the study period 97 short stem, ceramic head total shoulder replacements were carried out. At the time of follow-up 12 were two years from operation and 38 one year from operation. Active elevation was overall mean 160 degrees. Constant scores were 76 at 1 year, and 86 at 2 years, ASES 88 and 93, and satisfaction 96% and 98% respectively at one and 2 year follow up. There were no problems during insertion of the humeral prosthesis, or any radiolucent lines or movement of the prosthesis on later radiographs. The short stem prosthesis had no complications, and on follow up radiographs good bone fixation. These fairly short term clinical results were overall good.


Interleukin-22 is frequently expressed in small- and large-cell lung cancer and promotes growth in chemotherapy-resistant cancer cells.
In lung cancer, interleukin-22 (IL-22) expression within primary tissue has been demonstrated, but the frequency and the functional consequence of IL-22 signaling have not been addressed. This study aims at analyzing the cellular effects of IL-22 on lung carcinoma cell lines and the prognostic impact of IL-22 tissue expression in lung cancer patients. Biological effects of IL-22 signaling were investigated in seven lung cancer cell lines by Western blot, flow cytometry, real-time polymerase chain reaction, and proliferation assays. Tumor tissue specimens of two cohorts with a total of 2300 lung cancer patients were tested for IL-22 expression by immunohistochemistry. IL-22 serum concentrations were analyzed in 103 additional patients by enzyme-linked immunosorbent assay. We found the IL-22 receptor 1 (IL-22-R1) to be expressed in six of seven lung cancer cell lines. However IL-22 signaling was functional in only four cell lines, where IL-22 induced signal transducer activator of transcription 3 phosphorylation and increased cell proliferation. Furthermore, IL-22 induced the expression of antiapoptotic B-cell lymphoma 2, but did not rescue tumor cells from carboplatin-induced apoptosis. Cisplatin-resistant cell lines showed a significant up-regulation of IL-22-R1 along with a stronger proliferative response to IL-22 stimulation. IL-22 was preferentially expressed in small- and large-cell lung carcinoma (58% and 46% of cases, respectively). However, no correlation between IL-22 expression by immunohistochemistry and prognosis was observed. IL-22 is frequently expressed in lung cancer tissue. Enhanced IL-22-R1 expression and signaling in chemotherapy-refractory cell lines are indicative of a protumorigenic function of IL-22 and may contribute to a more aggressive phenotype.


Astrocytes are required for the oscillatory activity in cultured hippocampal neurons.
Synchronous oscillations of intracellular calcium concentration ([Ca2+]i) and of membrane potential occurred in a limited population of glutamatergic hippocampal neurons grown in primary cultures. The oscillatory activity occurred in synaptically connected cells only when they were in the presence of astrocytes. Microcultures containing only one or a few neurons also displayed oscillatory activity, provided that glial cells participated in the network. The glutamate-transporter inhibitors L-trans-pyrrolidine-2, 4-dicarboxylic acid (PDC) and dihydrokainate, which produce an accumulation of glutamate in the synaptic microenvironment, impaired the oscillatory activity. Moreover, in neurons not spontaneously oscillating, though in the presence of astrocytes, oscillations were induced by exogenous L-glutamate, but not by the stereoisomer D-glutamate, which is not taken up by glutamate transporters. These data demonstrate that astrocytes are essential for neuronal oscillatory activity and provide evidence that removal of glutamate from the synaptic environment is one of the major mechanisms by which glial cells allow the repetitive excitation of the postsynaptic cell.


Antibiotic Prophylaxis for Thyroid and Parathyroid Surgery: A Systematic Review and Meta-analysis.
Although thyroid and parathyroid surgery is considered a clean procedure with a low incidence of surgical site infections (SSIs), a great number of endocrine surgeons use antibiotic prophylaxis (AP). The aim of this study was to assess whether AP is significantly effective in reducing the incidence of SSIs in this kind of surgery. A systematic literature search was performed with PubMed, Scopus, and ISI-Web of Science. Studies addressing the efficacy of AP in reducing the incidence of SSIs in thyroid and parathyroid surgery were included in the systematic review and meta-analysis. The random effects model was assumed to account for different sources of variation among studies. The overall effect size was computed through the inverse variance method. Heterogeneity across studies, possible outlier studies, and publication bias were evaluated. A total of 6 studies with 4428 patients were included in the quantitative analysis. The incidence of SSI was 0.6% in the case group and 0.4% in the control group (odds ratio, 1.07; 95% CI, 0.3-3.81; P = .915). There was no evidence of heterogeneity among the studies (Q = 8.36, P = .138; I2 = 40.17). The analysis of several continuous moderators, including age, use of drain, and duration of surgery, did not generate any significant result. AP is not effective in reducing the incidence of SSI in thyroid and parathyroid surgery and should be avoided, notwithstanding the negative impact on social costs and the risk of development of antibiotic resistance.


["What choice do people have other than us?": The role of doctors' offices adjacent to private pharmacies in the Covid-19 pandemic].
With the arrival of coronavirus in Mexico, doctors' offices adjacent to private pharmacies (DAPPs) played a major role in the diagnosis, care, and prevention of Covid-19, providing treatment for 11.7% to 23% of people with Covid-19 symptoms according to national surveys. Therefore, this article seeks to identify the role of DAPPs as a private health system providing care for patients with Covid-19 symptoms in the city of Oaxaca, and to describe and analyze the factors that influenced their utilization. Using a qualitative methodology, twelve physicians were interviewed and 59 users responded to a questionnaire at doctors' offices adjacent to pharmacies in the municipality of Oaxaca de Juárez between September 2020 and August 2022. Secondary data were also collected. Among the findings, the function of these offices at the front line of care for Covid-19 and other health needs that emerged with the public health crisis is described, and the determining factors in care trajectories of users that sought care there are analyzed, such as the increase in perception of risk and mistrust towards public services or strategies implemented by the federal government.


Cleavage at both Arg306 and Arg506 is required and sufficient for timely and efficient inactivation of factor Va by activated protein C.
Activated protein C (APC) inactivates membrane-bound factor Va following cleavages of the heavy chain at Arg, Arg, and Arg. The objective of this study is to examine which cleavage is most important for inactivation. The recombinant factor V molecules were constructed as follows: factor V (mutations R→Q), factor V (mutations R→Q), and factor V (mutations R→Q and R→Q). The recombinant molecules were expressed in mammalian cells, purified, and assayed prior and after incubation with APC and lipids for 30 min (factor Vai) in clotting assays and in an assay using purified reagents and saturating concentrations of factor Va. Clotting assays demonstrated that wild-type factor Vai (Vai), factor Vai, and factor Vai were devoid of activity, whereas factor Vai maintained approximately 70% activity following a 30 min incubation with APC. Prothrombinase assembled with all mutant cofactor molecules before and after treatment with APC had kinetic constant (Km) values similar to values found with prothrombinase assembled with factor Va. Prothrombinase assembled with factor Vai demonstrated a 20-fold reduction in kcat, whereas prothrombinase assembled with factor Vai had a two-fold reduction in kcat as compared with prothrombinase assembled with factor Va. In contrast, factor Vai and factor Vai did not show any loss in kcat under similar experimental conditions. In conclusion, our data demonstrate that the activity of an APC-treated factor Va molecule bearing a single mutation at Arg or Arg depends on the assay used; and regardless of the assay employed, in the absence of the APC-cleavage sites at Arg and Arg, the active cofactor is unable to be significantly inactivated by APC in the presence of a membrane surface.


In silico identification of potent small molecule inhibitors targeting epidermal growth factor receptor 1.
The receptor tyrosine kinase of the epidermal growth factor receptor (EGFR, ErbB) family played an important role in multisignaling pathways, which controlled numerous biological activities including proliferation, differentiation, apoptosis, etc. EGFR abnormalities have been associated with a variety of human tumors, which was a well-characterized target for cancer treatment. It was known to all that drug repositioning has been considered as a useful tool to accelerate the process of drug development. Herein, a total of 1408 small molecule drugs approved by the Food and Drug Administration (FDA) were employed to identify potential EGFR inhibitors by a series of bioinformatics approaches, including virtual screening and molecular dynamics (MD) simulations. According to the docking score, five small molecules were chosed for further MD simulations. Following the 5 ns MD simulations, ZINC03830276 (Benzonatate) were finally recognized as "new use" of FDA-approved EGFR-targeting drug. Our findings suggested that the small molecule ZINC03830276 (Benzonatate) could be a promising EGFR inhibitor candidate and may also provide new ideas for designing more potent EGFR inhibitors for the future study.


Akkermansia muciniphila Ameliorates Alcoholic Liver Disease in Experimental Mice by Regulating Serum Metabolism and Improving Gut Dysbiosis.
Alcoholic liver disease (ALD) represents a significant global health concern, yet the available treatment options remain limited. Numerous studies have shown that gut microbiota is a critical target for the treatment of ALD. Additionally, there is increasing evidence that host metabolism also plays a crucial role in the development of ALD. Akkermansia muciniphila has been demonstrated to ameliorate experimental ALD through its modulatory effects on the intestinal vascular barrier, enhancement of mucus layer thickness, and promotion of intestinal tight junction proteins. Nevertheless, there is a dearth of studies investigating the impact of A. muciniphila on host metabolism and gut microbiota. Here, C57BL/6 mice were utilized to establish a modified NIAAA model in order to investigate the impact of the oral administration of A. muciniphila during the development of ALD. Furthermore, we employed targeted metabolomics to analyze the serum metabolomic profiles of the mice and 2bRAD-M sequencing to comprehensively examine the underlying mechanisms of the efficacy of A. muciniphila on ALD. Our results illustrated that the oral administration of A. muciniphila alleviated alcohol-induced liver injury in conjunction with encouraged serum levels of ornithine and diminished the elevation of oxalic acid levels induced by alcohol intake. In addition, A. muciniphila also inhibited the proliferation of harmful bacteria, such as Escherichia coli and Helicobacter hepaticus, induced by alcohol consumption while promoting the growth of butyrate-producing and commensal bacteria, including Paramuribaculum intestinale and Bacteroides ovatus. In conclusion, this study suggests that A. muciniphila restores ALD by regulating the gut microbiota, and this corrective effect is associated with alterations in the serum metabolism. Our research supplies a theoretical basis for developing A. muciniphila as an innovative generation of probiotic for preventing and managing ALD.


The impact of body weight management in chronic kidney disease patients with obesity.
Chronic kidney disease (CKD) and obesity are important public health concerns. Because obesity may initiate and/or accelerate kidney damage, weight control may benefit CKD patients. We examined the influence of dietary management and physical exercise in 38 obese CKD patients with or without target reduction of body weight 3% or more from baseline. After a 2-month lifestyle intervention program, those with target body weight control had significant improvement of blood pressure control, as well as reduced lipid profiles, serum creatinine level (1.1 ± 0.3 vs. 0.8 ± 0.3; P < .001), estimated glomerular filtration rate (75.9 ± 21.2 vs. 104.9 ± 38.1; P < .001), and proteinuria (76.3% vs. 50.0%; P = .02). They had greater improvement in cardiorespiratory endurance in an 800-m running test (375.1 ± 64.7 vs. 327.1 ± 84.0 seconds; P = .001), better abdominal muscle strength and endurance in a timed sit-up test (13.6 ± 9.1 vs. 19.9 ± 9.2 number/minute; P = .005), and greater flexibility in a sit-and-reach test (18.8 ± 10.9 vs. 27.8 ± 10.9 cm; P < .001) comparing baseline and postintervention values. A combination of dietary management and exercise were associated with improvements in health-related physical fitness, cardiovascular risk factors (blood pressure and lipid control), and renal profiles in obese CKD patients. Supportive individualized programs for lifestyle change could exert beneficial effects, but long-term research with a larger patient population is needed to elucidate the optimal effective combination of dietary management and exercise.


Targeted drug delivery systems mediated by a novel Peptide in breast cancer therapy and imaging.
Targeted delivery of drugs to tumors represents a significant advance in cancer diagnosis and therapy. Therefore, development of novel tumor-specific ligands or pharmaceutical nanocarriers is highly desirable. In this study, we utilized phage display to identify a new targeting peptide, SP90, which specifically binds to breast cancer cells, and recognizes tumor tissues from breast cancer patients. We used confocal and electron microscopy to reveal that conjugation of SP90 with liposomes enables efficient delivery of drugs into cancer cells through endocytosis. Furthermore, in vivo fluorescent imaging demonstrated that SP90-conjugated quantum dots possess tumor-targeting properties. In tumor xenograft and orthotopic models, SP90-conjugated liposomal doxorubicin was found to improve the therapeutic index of the chemotherapeutic drug by selectively increasing its accumulation in tumors. We conclude that the targeting peptide SP90 has significant potential in improving the clinical benefits of chemotherapy in the treatment and the diagnosis of breast cancer.


The p21-activated kinase PAK3 forms heterodimers with PAK1 in brain implementing trans-regulation of PAK3 activity.
p21-activated kinase 1 (PAK1) and PAK3 belong to group I of the PAK family and control cell movement and division. They also regulate dendritic spine formation and maturation in the brain, and play a role in synaptic transmission and synaptic plasticity. PAK3, in particular, is known for its implication in X-linked intellectual disability. The pak3 gene is expressed in neurons as a GTPase-regulated PAK3a protein and also as three splice variants which display constitutive kinase activity. PAK1 regulation is based on its homodimerization, forming an inactive complex. Here, we analyze the PAK3 capacity to dimerize and show that although PAK3a is able to homodimerize, it is more likely to form heterodimeric complexes with PAK1. We further show that two intellectual disability mutations impair dimerization with PAK1. The b and c inserts present in the regulatory domain of PAK3 splice variants decrease the dimerization but retain the capacity to form heterodimers with PAK1. PAK1 and PAK3 are co-expressed in neurons, are colocalized within dendritic spines, co-purify with post-synaptic densities, and co-immunoprecipitate in brain lysates. Using kinase assays, we demonstrate that PAK1 inhibits the activity of PAK3a but not of the splice variant PAK3b in a trans-regulatory manner. Altogether, these results show that PAK3 and PAK1 signaling may be coordinated by heterodimerization.


Upper extremity swelling and hyperpigmentation due to onchocerciasis in an American.
An American woman who had lived in Equatorial Guinea was seen in the United States with intermittent swelling, pruritus, hyperpigmentation, and mild cutaneous atrophy of the right arm. Filarial diseases were considered in the differential diagnosis; skin snips subsequently revealed Onchocerca volvulus microfilariae. There was no evidence of ocular involvement. The case illustrates the importance of obtaining a history of international travel, the need to consider "exotic" parasitic diseases in travelers returning from the tropics, and several of the presenting features of onchocerciasis. In the past, onchocerciasis was treated with diethylcarbamazine and suramin, both of which have appreciable toxicity. A major recent advance has been the introduction of ivermectin, which appears to be more effective and less toxic, and is currently undergoing clinical evaluation in the United States and abroad.


Can caregivers trust information technology in the care of their patients? A systematic review.
The Health Insurance Portability and Accountability Act of 1996 (HIPAA) requires that healthcare providers allow patients to engage in their healthcare by allowing access to their health records. Often patients need informal caregivers including family members or others to help them with their care. This paper explores whether trust is a key factor for informal caregivers' decision to use health information technologies (HIT) including electronic health records (EHR), patient portals, mobile apps, or other devices to care for their patient. Six reviewers conducted a comprehensive search of four literature databases using terms that pertained to a caregiver and trust to investigate the role trust plays when caregivers use HIT. While trust is a key factor for the use of HIT, it the researchers only identified ten articles that met the research question thresholds. Four main topics of trust surfaced including perceived confidentiality, perceived security, technological malfunction, and trustworthiness of the information. Trust is a critical factor for informal caregivers when using HIT to assist in the care of their patient (child, loved one, parent, or acquaintance). Based on the findings, it is clear that more research on the use of HIT by caregivers is needed.


Digestive involvement in a patient with Lambert-Eaton syndrome.
We present the case of a 50-year-old male diagnosed with myasthenia gravis, secondary to thymoma or Lambert-Eaton syndrome during the study of repeated vomiting. Gastrointestinal symptoms persisted despite the treatment of the thymoma. He suffered from sigma volvulus that required sigmoidectomy 9 years after diagnosis. Neuromuscular junction disorders are not characterized by gastrointestinal involvement, as in our case. They have previously sporadically been related to intestinal motility dysfunction.


The Association of Class I and II Human Leukocyte Antigen Serotypes With End-Stage Kidney Disease Due to Membranoproliferative Glomerulonephritis and Dense Deposit Disease.
Membranoproliferative glomerulonephritis (MPGN), encompassing several distinct diseases, is a rare but significant cause of kidney failure in the United States. The potential etiologies of MPGN are unclear, but prior studies have suggested dysregulation of the alternative complement pathway and, recently, autoimmunity as potential mechanisms driving MPGN pathogenesis. In this study, we examined HLA associations with end-stage kidney disease (ESKD) due to MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse US-based cohort. Case-control study. Using US Renal Data System (USRDS) and United Network for Organ Sharing (UNOS) data, we identified 3,424 patients with kidney failure due to MPGN and 263 due to DDD. We matched patients to kidney donor controls on designated race and ethnicity in a 1:15 ratio. 58 class I and II HLA serotypes. Case-control status. For each disease cohort, univariable and multivariable logistic regression analyses were used to investigate associations between the disease and 58 HLA serotypes. In subgroup analyses, we investigated HLA associations in White and Black patients. We also studied antiglomerular basement membrane (anti-GBM) nephritis as a positive-control outcome. We applied a Bonferroni correction to account for multiple comparisons. Eighteen serotypes were significantly associated with the odds of having MPGN in univariable analyses, with DR17 having the strongest association (odds ratio [OR], 1.55 [95% CI, 1.44-1.68], P=4.33e-28). No significant associations were found between any HLA serotype and DDD. Designated race-specific analyses showed comparable findings. We recapitulated known HLA associations in anti-GBM nephritis. Reliance on HLA serotypes (rather than genotype), lack of biopsy-confirmed diagnoses. HLA-DR17 is associated with ESKD due to MPGN in a racially and ethnically diverse cohort. The strength of association was similar in White and Black patients, suggesting a role in the pathogenesis of MPGN. No HLA associations were observed in patients with DDD. Prior studies have suggested dysregulation of the alternative complement pathway as a potential etiology of membranoproliferative glomerulonephritis (MPGN), but recent evidence from a British White population has implicated an autoimmune mechanism in MPGN pathogenesis. We investigated HLA associations between MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse cohort of patients. We found that HLA-DR17 is associated with end-stage kidney disease (ESKD) due to MPGN in both White and Black patients. By contrast, no significant HLA associations with ESKD due to DDD were identified. These results suggest a role for autoimmunity in some cases of MPGN and highlight differences in the disease etiology of MPGN compared with DDD.


Development of new cytogenetic markers for Thinopyrum ponticum (Podp.) Z.-W. Liu & R.-C. Wang.
Thinopyrum ponticum (Podpěra, 1902) Z.-W. Liu & R.-C.Wang, 1993 is an important polyploid wild perennial Triticeae species that is widely used as a source of valuable genes for wheat but its genomic constitution has long been debated. For its chromosome identification, only a limited set of FISH probes has been used. The development of new cytogenetic markers for Th. ponticum chromosomes is of great importance both for cytogenetic characterization of wheat-wheatgrass hybrids and for fundamental comparative studies of phylogenetic relationships between species. Here, we report on the development of five cytogenetic markers for Th. ponticum based on repetitive satellite DNA of which sequences were selected from the whole genome sequence of Aegilops tauschii Cosson, 1849. Using real-time quantitative PCR we estimated the abundance of the found repeats: P720 and P427 had the highest abundance and P132, P332 and P170 had lower quantity in Th. ponticum genome. Using fluorescence in situ hybridization (FISH) we localized five repeats to different regions of the chromosomes of Th. ponticum. Using reprobing multicolor FISH we colocalized the probes between each other. The distribution of these found repeats in the Triticeae genomes and its usability as cytogenetic markers for chromosomes of Th. ponticum are discussed.


Asymmetry of interhemispheric interaction in left-handed subjects.
In right-handed subjects the execution of a simple finger-tapping task is associated with an asymmetry of interhemispheric interaction, probably suggesting that the dominant left hemisphere inhibits the right one. The present study investigated the left-handed subjects in order to elucidate whether this asymmetry is related to handedness. Nineteen healthy subjects performed unimanual left, right, and bimanual auditorily paced finger-tapping tasks while neuromagnetic activity was recorded with a 122-channel whole-head neuromagnetometer (MEG). Simultaneously, we recorded activity of the first dorsal interosseus (FDI) muscle of both hands. By using the analysis tool dynamic imaging of coherent sources (DICS), oscillatory activity at alpha as well as at beta frequency within the primary sensorimotor (S1/M1) and premotor (PMC) cortex was localized. As expected, we observed oscillatory coupling between S1/M1 and PMC contralateral to the moving hand. Furthermore, coupling between left PMC and bilateral S1/M1 occurred in each movement condition, suggesting that the left PMC modulates neural activity in bilateral primary sensorimotor cortices independent of the moving hand. Coupling between bilateral S1/M1 occurred more frequently and significantly stronger during the right hand condition. This result demonstrates the same interhemispheric coupling pattern as in right-handed subjects, suggesting that the asymmetry of this interaction is not due to hand dominance. A specialization of the left premotor cortex either for superior motor control per se or for the execution of sequential tasks might account for these results.


[A case of neuromyelitis optica associated with pulmonary Mycobacterium avium complex disease].
A 62-year-old woman suffering from pulmonary Mycobacterium avium complex (MAC) disease was admitted to our hospital with fever, visual impairment, and lower limb weakness. MRI detected lesions in the optic chiasm and spinal cord extending the length of 6 vertebrae. The anti-aquaporin 4 (AQP4) antibody titer determined by ELISA was elevated to 8.3 IU/l. On the basis of these findings, the patient was diagnosed as having neuromyelitis optica (NMO), when chest CT also demonstrated exacerbation of pulmonary lesions. Methylprednisolone pulse therapy and double-filtered plasma exchange ameliorated the symptoms, and the EDSS score improved from 8.5 to 6.5. Six months later, visual impairment recurred, although ELISA showed that the anti-AQP4 antibody titer had become undetectable. Also, the CSF interleukin-6 (IL-6) level was elevated to 34.8 pg/ml. There have been few reports of NMO associated with pulmonary MAC disease. An increase of IL-6 is considered to exacerbate the clinical picture of NMO, whereas it may suppress progression of the pulmonary MAC disease. Exacerbation of the pulmonary MAC disease and the following internal counteraction with IL-6 may have resulted in a NMO relapse. The present patient was therefore administered eculizumab but not satralizumab, a humanized anti-IL-6 receptor antibody, for prevention of NMO recurrence.


Role of a cell surface-associated protein in adherence and dental caries.
Insertional inactivation of the Streptococcus mutans spaP gene was used to construct an isogenic mutant (834) of strain NG8 (serotype c) which lacked the major cell surface-associated protein referred to as P1 (15). Results of several studies suggest that P1 is involved in the adherence of S. mutans to saliva-coated apatite surfaces. With an in vitro model system of hydroxyapatite (HA) beads coated with parotid saliva (PS) and additional HA surfaces coated with PS and in situ-formed glucan, it was observed that mutant 834 adhered poorly to the PS/HA surfaces. In contrast, both parent and mutant strains bound to the PS-glucan/HA surface. Groups of intact and desalivated rats were infected with each strain to determine relative capacities to induce dental caries. Rats were fed a highly cariogenic diet containing 56% sucrose for 3 to 5 weeks. Each strain colonized the rodent model and caused similar levels of smooth-surface caries under these dietary conditions. It was concluded that P1 influences the ability of organisms to adhere to saliva-coated surfaces and possibly affects primary colonization of the oral cavity in the absence of a glucan surface but has no effect on glucan-mediated adherence in vitro or in vivo.


"Health in the Mirror": An Unconventional Approach to Unmet Psychological Needs in Oncology.
Background: The introduction of aesthetic care programs for cancer patients inside hospitals could help patients cope with the side effects of both disease and treatment. The specific objective of this study is to evaluate whether a complementary and supportive program, called "Health in the Mirror," has a positive effect on participants by analyzing certain psychological variables. Methods: Eighty-eight female cancer patients were included in this analysis. The support program is composed of three group aesthetic interventions that address both physical and psychological aspects that accompany cancer and its treatment. Patients were asked to complete a battery of tests in order to measure the impact of the program on certain psychological variables including anxiety, depression, body image, self-esteem, and quality of life. Outcome variables were measured at three different time-points: prior to participation, on the last day of the program, and after a 3-month follow-up. Results: Participating in the psychosocial support program "Health in the Mirror" determines an improvement in the psychological variables measured. Results revealed a significant reduction in depressive symptoms, anxiety and body image issues, as well as an improvement in self-esteem levels; this suggests that participating in this program could facilitate better adjustment to disease and treatment. Discussion: This study legitimizes the importance of implementing supportive and complementary therapies together with conventional therapies; the therapeutic approach to cancer cannot be restricted solely to medical care, but it must consider the patient as a whole person with needs that are not only physical or medical, but also psychological, social, and existential.


High Seebeck Coefficient Inorganic Ge15Ga10Te75 Core/Polymer Cladding Fibers for Respiration and Body Temperature Monitoring.
Wearable thermal sensors based on thermoelectric (TE) materials with high sensitivity and temperature resolution are extensively used in medical diagnosis, human-machine interfaces, and advanced artificial intelligence. However, their development is greatly limited by the lack of materials with both a high Seebeck coefficient and superior anticrystallization ability. Here, a new inorganic amorphous TE material, Ge15Ga10Te75, with a high Seebeck coefficient of 1109 μV/K is reported. Owing to the large difference between the glass-transition temperature and initial crystallization temperature, Ge15Ga10Te75 strongly inhibits crystallization during fiber fabrication by thermally codrawing a precast rod comprising a Ge15Ga10Te75 core and PP polymer cladding. The temperature difference can be effectively transduced into electrical signals to achieve TE fiber thermal sensing with an accurate temperature resolution of 0.03 K and a fast response time of 4 s. It is important to note that after the 1.5 and 5.5 K temperatures changed repeatedly, the TE properties of the fiber demonstrated high stability. Based on the Seebeck effect and superior flexibility of the fibers, they can be integrated into a mask and wearable fabric for human respiration and body temperature monitoring. The superior thermal sensing performance of the TE fibers together with their natural flexibility and scalable fabrication endow them with promising applications in health-monitoring and intelligent medical systems.


Impact of nutrient overload on metabolic homeostasis.
Nutrient overload occurs worldwide as a consequence of the modern diet pattern and the physical inactivity that sometimes accompanies it. Cells initiate multiple protective mechanisms to adapt to elevated intracellular metabolites and restore metabolic homeostasis, but irreversible injury to the cells can occur in the event of prolonged nutrient overload. Many studies have advanced the understanding of the different detrimental effects of nutrient overload; however, few reports have made connections and given the full picture of the impact of nutrient overload on cellular metabolism. In this review, detailed changes in metabolic and energy homeostasis caused by chronic nutrient overload, as well as their associations with the development of metabolic disorders, are discussed. Overnutrition-induced changes in key organelles and sensors rewire cellular bioenergetic pathways and facilitate the shift of the metabolic state toward biosynthesis, thereby leading to the onset of various metabolic disorders, which are essentially the downstream manifestations of a misbalanced metabolic equilibrium. Based on these mechanisms, potential therapeutic targets for metabolic disorders and new research directions are proposed.


Estimated number of reported vaccine-preventable disease cases averted following the introduction of routine vaccination programs in Sweden, 1910-2019.
Routine childhood vaccination programs have had enormous positive public health impacts worldwide. However, in some areas, these benefits may be impeded by vaccine hesitancy and undervaccination. We estimated the number of reported cases of measles, pertussis, mumps and poliomyelitis averted in Sweden after the introduction of routine childhood vaccination programs. We used annual national data on population size and the number of reported cases of measles (1911-2019), pertussis (1911-2019), mumps (1914-2019) and poliomyelitis (1910-2019) for Sweden. For each disease, we calculated the median and 95% confidence interval of the annual pre-vaccination incidence to estimate the number of counterfactual cases; that is, the estimated number of cases that would have been observed in the post-vaccination period had no vaccine been introduced (median incidence × average annual population). For the post-vaccination periods, we calculated reported cases averted and assumed all decreases were due to vaccines. In total, for all four diseases combined, over 2.1 million cases were reported over the respective surveillance periods. Since the introduction of vaccinations, we estimate that over 1.5 million reported cases of these four diseases combined have been averted: measles (633 091), pertussis (608 670), mumps (262 951) and poliomyelitis (58 240). However, due to underreporting, especially during pre-vaccination years, these are likely underestimates. Since the introduction of these routine childhood vaccination programs in Sweden, a substantial number of reported cases of vaccine-preventable diseases have been averted. Vigilance against both failure to vaccinate and undervaccination is necessary to prevent future increases of these vaccine-preventable diseases.


Persistent Use of Extended Fractionation Palliative Radiotherapy for Medicare Beneficiaries With Metastatic Breast Cancer, 2011 to 2014.
With no evidence to support extended radiation courses for the palliation of bone metastases, multiple guidelines were issued discouraging its use. We assessed contemporary use and cost of prolonged palliative radiotherapy in Medicare beneficiaries with bone metastases from breast cancer. We conducted a retrospective, longitudinal study of palliative radiotherapy use among fee-for-service Medicare beneficiaries with bone metastasis from breast cancer who underwent palliative radiotherapy during 2011 to 2014. Patients were categorized according to the number of days (fractions) on which they received palliative radiotherapy: 1, 2 to 10, 11 to 19, or 20 to 30. We examined the association of clinical, demographic, and provider characteristics with the use of extended (≥11 fractions) or very extended (≥20 fractions) fractionation with logistic regression models. We also compared the cost of different fractionation schemes from the payer perspective. Of the 7547 patients in the sample (mean age, 71 y), 3084 (40.8%) received extended fractionation. The proportion of patients receiving 11 to 19 (34.7% in 2011 and 28.1% in 2014, trend P<0.001) and 20 to 30 treatments (10.3% in 2011 to 9.0% in 2014, trend P=0.07) decreased modestly over time. Patients with comorbidities were less likely to undergo extended fractionation (34.4% for ≥3 comorbidities vs. 44.9% for 0 comorbidities; adjusted odds ratio 0.67 [95% confidence interval, 0.58-0.76]). Patients treated at free-standing practices were more likely to undergo extended fractionation (47.9%) compared with those treated at hospital-based practices (37.3%, P<0.001; adjusted odds ratio, 1.49 [95% confidence interval, 1.35-1.65]). The mean cost of treatment varied from $633 (SD $240) for single-fraction treatment, to $3566 (SD $1349) for 11 to 19 fractions, to $6597 (SD $2893) for 20 to 30 fractions. The use of prolonged courses of palliative radiotherapy among Medicare beneficiaries with breast cancer remained high in 2011 to 2014. The association between free-standing facility status and use of extended fractionation suggests that provider financial incentives may impact choice of treatment.


Infections during pregnancy and after birth, and the risk of autism spectrum disorders: a register-based study utilizing a Danish historic birth cohort.
Mounting evidence suggests that immune dysfunction may play a crucial role in the pathophysiology of autism spectrum disorders (ASD). In addition, several studies have reported that congenital and postnatal infections may contribute to the neurobiological basis of ASD. This study aimed to investigate the relationship between infections during pregnancy and after birth, and ASD. A case-control study design was adopted. Both cases and controls were retrieved from a historic birth cohort (HBC) maintained at Statens Serum Institute in Copenhagen/Denmark and were followed up retrospectively during pregnancy and after birth over four pre-defined periods. Study subjects were followed-up utilizing Danish nation-wide health registers for outpatient and hospital admissions due to infections. Associations between infections and ASD were analyzed using Mantel-Haenszel estimate of the odds ratio (OR) and logistic regression models. In total, 414 ASD cases and 820 controls were followed-up during pregnancy and a mean 16.3 years after birth. Crude, but not adjusted estimates showed that ASD cases had an increased risk of hospital admission due to infection at the end of the first year of life (OR = 1.48 [range: 1.07-2.05], P = 0.02) and at the end of the follow-up period (OR = 1.30 [range: 1.02-1.64], P = 0.03). The present findings indicate that infections have a potential role in the pathophysiology of ASD; however, further studies are necessary to determine if infections etiologically contribute to ASD or if they act as an epiphenomenon due to distorted immunity in children with ASD.


Autonomic nervous system and inflammation interaction in endometriosis-associated pain.
Endometriosis is a chronic inflammatory disease. Pain is the most common symptom in endometriosis. Endometriosis-associated pain is caused by inflammation, and is related to aberrant innervation. Although the specific mechanism between endometriosis-associated pain and the interaction of aberrant innervation and inflammation remains unclear, many studies have confirmed certain correlations between them. In addition, we found that some chronic inflammatory autoimmune diseases (AIDs) such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) share similar characteristics: the changes in dysregulation of inflammatory factors as well as the function and innervation of the autonomic nervous system (ANS). The mechanisms underlying the interaction between the ANS and inflammation have provided new advances among these disorders. Therefore, the purpose of this review is to compare the changes in inflammation and ANS in endometriosis, IBD, and RA; and to explore the role and possible mechanism of sympathetic and parasympathetic nerves in endometriosis-associated inflammation by referring to IBD and RA studies to provide some reference for further endometriosis research and treatment.


A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma.
Chronic infection with hepatitis Delta virus (HDV) is a risk factor for cirrhosis and hepatocellular carcinoma (HCC); predictors of disease outcome are, however, poorly defined. We tracked the course of HDV infection in 299 patients over a mean period of 233 months. We analyzed data from patients who had been HDV positive for at least 6 months (230 males; mean age, 30 years) admitted from 1978 to 2006 to Maggiore Hospital, Milan. HDV infection was defined by the presence of HDV antigen in liver tissue or serum HDV RNA in anti-HDV/hepatitis B surface antigen seropositive patients. At enrollment, 7 patients had acute hepatitis, 101 had mild-moderate chronic hepatitis, 76 had severe chronic hepatitis, and 104 had histologic or clinical cirrhosis. Ninety patients were treated with interferon, 62 with corticosteroids, and 12 with nucleoside analogues; 135 received no therapy. Over a mean period of 233 months, 82 patients developed cirrhosis. Among the 186 total patients with cirrhosis, 46 developed HCC, 43 ascites, 44 jaundice, and 1 encephalopathy. Female sex, alcohol abuse, and HDV replication were associated with liver decompensation; HBV replication and interferon were associated with HCC development. By the end of the study, 186 patients were still alive, 63 had died, and 29 had received liver transplants. The main cause of death was liver failure (n = 37, 59%); HDV replication was the only independent predictor of mortality. Persistent HDV replication leads to cirrhosis and HCC at annual rates of 4% and 2.8%, respectively, and is the only predictor of liver-related mortality.


Estimating the cost of health care-associated infections: mind your p's and q's.
Monetary valuations of the economic cost of health care-associated infections (HAIs) are important for decision making and should be estimated accurately. Erroneously high estimates of costs, designed to jolt decision makers into action, may do more harm than good in the struggle to attract funding for infection control. Expectations among policy makers might be raised, and then they are disappointed when the reduction in the number of HAIs does not yield the anticipated cost saving. For this article, we critically review the field and discuss 3 questions. Why measure the cost of an HAI? What outcome should be used to measure the cost of an HAI? What is the best method for making this measurement? The aim is to encourage researchers to collect and then disseminate information that accurately guides decisions about the economic value of expanding or changing current infection control activities.


Partnering for the future clinic: A multidisciplinary perinatal substance use program.
The current model of obstetric care does not integrate multiple subspecialty services for high-risk pregnancies with substance use disorder (SUD), resulting in fragmented care. We describe the framework of our multidisciplinary and integrated perinatal substance use clinic and provide recent clinical outcomes. We detail the Partnering for the Future (PFF) clinic, which integrates numerous subspecialty and support services for patients with SUDs and complex mental health needs. Additionally, a retrospective chart review of patients receiving care in the PFF clinic from 2017 to 2021 was completed. Seven integrated services are detailed with a focus on reducing stigma, providing trauma-informed care and mitigating harm. During the study period, 182 patients received care in PFF clinic, with opioid use disorder the most common indication for care. Co-occurring mental illness was common (81%). NICU admissions and severe NOWS diagnosis declined after the implementation of Eat-Sleep-Console. Social services identified care coordination, transportation assistance and adjustment counseling as the most common needs. A novel virtual behavioral health consultation service was successfully launched. Our integrated care model supports the holistic care of pregnant people with SUD and mental health disease. Patient-centered care and co-located services have improved perinatal outcomes, particularly for opioid-exposed pregnancies.


[Status of muscle tone in rheumatoid arthritis patients].
Muscle tonus in patients with rheumatoid arthritis (RA) was collated with the activity of the pathological process and functional articular insufficiency (FAI) in different variants of polyneuropathy (P). Hetero- or unidirectional hypotension of muscles was the most characteristic sign in RA. In cases of the sensory variant of P, patients with an early period of the disease and 1-0 degree FAI showed severe damage to the central motor neuron, linked with a dissociated type of muscular dystonia (predominantly hypotension of the flexory group of legs) and a peculiar dystonic phenomenon (a vestibular-cerebellar positioning of the wrist). This kind of wrist positioning was directly correlated with the side of the predominant damage to the central motor neuron. In cases of sensory-motor forms of P, patients with degree II-III FAI, in whom lesions to the peripheral motor neuron were predominant, developed unidirectional muscle hypotension. EMG findings served as an adequate reflection of the nature of changes in the muscle tonus.


Endovascular and surgical treatment of unruptured cerebral aneurysms: comparison of risks.
Unruptured cerebral aneurysms are commonly treated by surgical clipping, but endovascular coil embolization is increasingly employed as an alternative. In a blinded review of unruptured aneurysms treated at our institution since 1990, we identified patients whose aneurysms were judged to be treatable by both neurosurgeons and neurointerventional radiologists. A change in Rankin Scale score of 2 or more from hospital admission to discharge, indicating a new moderate disability or worse, was predefined as the primary outcome measure. Long-term follow-up was obtained by mailed questionnaire and telephone interview. Length of stay and hospital charges were totaled for all hospitalizations, including follow-up. Sixty-eight patients treated surgically and 62 patients treated with endovascular coil embolization were considered candidates for either procedure on blinded review, and overall anticipated procedure risk was rated as identical. A larger proportion of patients in the surgical group developed a change in Rankin Scale score of 2 or more (25% of surgical patients vs 8% of endovascular patients). Total length of stay was longer (mean days: 7.7 for surgical patients vs 5.0 for endovascular patients) and hospital charges were greater (mean, $38,000 for surgical patients vs $33,400 for endovascular patients) for the surgical patients. At follow-up, an average of 3.9 years after the procedure, surgical patients were more likely to report persistent new symptoms or disability since treatment (34% of surgical patients vs 8% of endovascular patients) and a longer period for recovery to normal (50% returning to normal in 1 year for surgery and in 27 days for coil embolization). Coil embolization of unruptured cerebral aneurysms seems to be associated with significantly fewer complications than surgical clipping. More long-term data on aneurysm rupture rates are required to confirm efficacy.


"It happens to clinicians too": an Australian prevalence study of intimate partner and family violence against health professionals.
The purpose of this study was to measure the prevalence of intimate partner and family violence amongst a population of Australian female nurses, doctors and allied health professionals. We conducted a descriptive, cross-sectional survey in a large Australian tertiary maternity hospital with 471 participating female health professionals (45.0% response rate). The primary outcome measures were 12 month and lifetime prevalence of intimate partner violence (Composite Abuse Scale) and family violence. In the last 12 months, one in ten (43, 11.5%) participants reported intimate partner violence: 4.2% (16) combined physical, emotional and/or sexual abuse; 6.7% (25) emotional abuse and/or harassment; 5.1% (22) were afraid of their partner; and 1.7% (7) had been raped by their partner. Since the age of sixteen, one third (125, 29.7%) of participants reported intimate partner violence: 18.3% (77) had experienced combined physical, emotional and/or sexual abuse; 8.1% (34) emotional abuse and/or harassment; 25.6% (111) had been afraid of their partner; and 12.1% (51) had been raped by their partner. Overall, 45.2% (212) of participants reported violence by a partner and/or family member during their lifetime, with 12.8% (60) reporting both. Intimate partner and family violence may be common traumas in the lives of female health professionals, and this should be considered in health workplace policies and protocols, as health professionals are increasingly urged to work with patients who have experienced intimate partner and family violence. Implications include the need for workplace manager training, special leave provision, counselling services and other resources for staff.


Performance of Genotype MTBDRsl V2.0 over the Genotype MTBDRsl V1 for detection of second line drug resistance: An Indian perspective.
Genotype MTBDRsl Version 1 (V1.0) was recommended as an initial test for rapid detection of pre-extensively drug resistant (pre-XDR) and extensively drug resistant tuberculosis (XDR-TB). However, in recent years a number of novel mutations are identified that confer resistance. Thus, Genotype MTBDRsl V2.0 was endorsed by WHO. Though, Genotype MTBDRsl V2.0 has been rolled out in national TB programme in 2018, there is dearth of data from India on its performance for second line drug susceptibility testing (DST). For this, performance of new version was evaluated on 113 MDR-TB isolates. The results showed that 39 (34.5%) of these isolates were resistant to FQ and 7 (6.2%) were XDR by Genotype MTBDRsl V2.0. Amongst the FQ resistant isolates most prevalent mutation was ΔWT3-D94G (17; 38.6%) and N538D (12; 85.7%). Among the AG/CP and KAN resistant isolates most common mutation in the rrs region was ΔWT1-A1401G (5; 71.4%) and C-14T (2; 28.5%) in eis gene. Second line Bactec MGIT-960 detected 40 (35.4%) isolates as resistant to FQ and 6 (5.3%) as XDR isolates, whereas Genotype MTBDRsl V1.0 also detected 39 (34.5%) as resistant to FQ but missed 2 isolates in correctly identifying as XDR (5; 4.4%). Thus, concordance of second line Bactec MGIT-960 with Genotype MTBDRsl V2.0 was similar (100%) for FQ detection but it has improvised the diagnostic sensitivity for correctly identifying XDR isolates. Nevertheless, the cost of Genotype MTBDRsl V2.0 remains an issue for screening of second line drug (SLDs) resistance from countries with high burden of MDR-TB.


Femoral Artery Thrombosis After Pediatric Cardiac Catheterization.
Femoral artery thrombosis (FAT) is an adverse event post-catheterization. We decided to study the incidence and risk factors of FAT before and after initiation of a pulse loss monitoring program. All cardiac catheterization cases performed using femoral arterial vascular access were retrospectively reviewed. The study period was divided into two eras: before (era 1), and after the initiation of the protocol (era 2). The primary outcome was FAT requiring therapy. Univariable and multivariable logistic regression models were used to identify factors associated with FAT. Receiver operating characteristic curve were generated to predict FAT. Our cohort consisted of 2,388 cases including 467 (19.6%) infants weighing < 10 kg. The overall incidence of FAT was 1.7% (n = 41). The incidence of FAT was 3.5 times higher in era 2 (p < 0.001). Multivariable model showed that era, weight, sheath exchange, and coarctation intervention were significantly associated with FAT. Infants younger than 7.7 months and less than 6.7 kg were found to be at highest risk for FAT. Our study shows that the incidence of FAT may be underestimated without a monitoring program. Small infants and coarctation interventions requiring larger sheaths or sheath exchanges are at highest risk for FAT.


Electrophysiological studies in healthy subjects involving caffeine.
We review the electrophysiological studies concerning the effects of caffeine on muscle, lower and upper motor neuron excitability and cognition. Several different methods have been used, such as electromyography, recruitment analysis, H-reflex, transcranial magnetic stimulation (TMS), electroencephalography and event-related potentials. The positive effect of caffeine on vigilance, attention, speed of reaction, information processing and arousal is supported by a number of electrophysiological studies. The evidence in favor of an increased muscle fiber resistance is not definitive, but higher or lower motor neuron excitability can occur as a consequence of a greater excitation of the descending input from the brainstem and upper motor neurons. TMS can address the influence of caffeine on the upper motor neuron. Previous studies showed that cortico-motor threshold and intracortical excitatory and inhibitory pathways are not influenced by caffeine. Nonetheless, our results indicate that cortical silent period (CSP) is reduced in resting muscles after caffeine consumption, when stimulating the motor cortex with intensities slightly above threshold. We present new data demonstrating that this effect is also observed in fatigued muscle. We conclude that CSP can be considered a surrogate marker of the effect of caffeine in the brain, in particular of its central ergogenic effect.


Cross-bispectrum connectivity of intracranial EEG: A novel approach to seizure onset zone localization.
Connectivity analyses of intracranial electroencephalography (iEEG) could guide surgical planning for epilepsy surgery by improving the delineation of the seizure onset zone. Traditional approaches fail to quantify important interactions between frequency components. To assess if effective connectivity based on cross-bispectrum -a measure of nonlinear multivariate cross-frequency coupling- can quantitatively identify generators of seizure activity, cross-bispectrum connectivity between channels was computed from iEEG recordings of 5 patients (34 seizures) with good postsurgical outcome. Personalized thresholds of 50% and 80% of the maximum coupling values were used to identify generating electrode channels. In all patients, outflow coupling between α (8-15 Hz) and β (16-31 Hz) frequencies identified at least one electrode inside the resected seizure onset zone. With the 50% and 80% thresholds respectively, an average of 5 (44.7%; specificity = 82.6%) and 2 (22.5%; specificity = 99.0%) resected electrodes were correctly identified. Results show promise for the automatic identification of the seizure onset zone based on cross-bispectrum connectivity analysis.


An intact Raf zinc finger is required for optimal binding to processed Ras and for ras-dependent Raf activation in situ.
The function of the c-Raf-1 zinc finger domain in the activation of the Raf kinase was examined by the creation of variant zinc finger structures. Mutation of Raf Cys 165 and Cys 168 to Ser strongly inhibits the Ras-dependent activation of c-Raf-1 by epidermal growth factor (EGF). Deletion of the Raf zinc finger and replacement with a homologous zinc finger from protein kinase C gamma (PKC gamma) (to give gamma/Raf) also abrogates EGF-induced activation but enables a vigorous phorbol myristate acetate (PMA)-induced activation. PMA activation of gamma/Raf does not require endogenous Ras or PKCs and probably occurs through a PMA-induced recruitment of gamma/Raf to the plasma membrane. The impaired ability of EGF to activate the Raf zinc finger variants in situ is attributable, at least in part, to a major decrement in their binding to Ras-GTP; both Raf zinc finger variants exhibit decreased association with Ras (V12) in situ upon coexpression in COS cells, as well as diminished binding in vitro to immobilized, processed COS recombinant Ras(V12)-GTP. In contrast, Raf binding to unprocessed COS or prokaryotic recombinant Ras-GTP is unaffected by Raf zinc finger mutation. Thus, the Raf zinc finger contributes an important component to the overall binding to Ras-GTP in situ, through an interaction between the zinc finger and an epitope on Ras, distinct from the effector loop, that is present only on prenylated Ras.


Investigation of FoxO3 dynamics during erythroblast development in β-thalassemia major.
The FoxO3 transcription factor is a key regulator of oxidative stress and erythroid maturation during erythropoiesis. In this study, we explored the involvement of FoxO3 in severe β-thalassemia. Using primary CD34+ hematopoietic progenitor cells from patients with β-thalassemia major, we successfully developed an in vitro model of ineffective erythropoiesis. Based on this model, FoxO3 activity was quantified in single cells using high throughput imaging flow cytometry. This study revealed a significant reduction of FoxO3 activity during the late stage of erythroblast differentiation in β-thalassemia, in contrast to erythropoiesis in normal cells that maintain persistent activation of FoxO3. In agreement with the decreased FoxO3 activity in β-thalassemia, the expression of FoxO3 target genes was also found to decrease, concurrent with elevated phosphorylation of AKT, most clearly at the late stage of erythroid differentiation. Our findings provide further evidence for the involvement of FoxO3 during terminal erythropoiesis and confirm the modulation of the PI3K/AKT pathway as a potential therapeutic strategy for β-thalassemia.


Post-stroke depression, obstructive sleep apnea, and cognitive impairment: Rationale for, and barriers to, routine screening.
Stroke can cause neurological impairment ranging from mild to severe, but the impact of stroke extends beyond the initial brain injury to include a complex interplay of devastating comorbidities including: post-stroke depression, obstructive sleep apnea, and cognitive impairment ("DOC"). We reviewed the frequency, impact, and treatment options for each DOC condition. We then used the Ottawa Model of Research Use to examine gaps in care, understand the barriers to knowledge translation, identification, and addressing these important post-stroke comorbidities. Each of the DOC conditions is common and result in poorer recovery, greater functional impairment, increased stroke recurrence and mortality, even after accounting for traditional vascular risk factors. Despite the strong relationships between DOC comorbidities and these negative outcomes as well as recommendations for screening based on best practice recommendations from several countries, they are frequently not assessed. Barriers related to the nature of the screening tools (e.g., time consuming in high-volume clinics), practice environment (e.g., lack of human resources or space), as well as potential adopters (e.g., equipoise surrounding the benefits of treatment for these conditions) pose challenges to routine screening implementation. Simple, feasible approaches to routine screening coupled with appropriate, evidence-based treatment protocols are required to better identify and manage depression, obstructive sleep apnea, and cognitive impairment symptoms in stroke prevention clinic patients to reduce the impact of these important post-stroke comorbidities. These tools may in turn facilitate large-scale randomized controlled treatment trials of interventions for DOC conditions that may help to improve cardiovascular outcomes after stroke or TIA.


Bone morphogenetic protein 2 (BMP-2) induces sequential changes of Id gene expression in the breast cancer cell line MCF-7.
Bone morphogenetic proteins (BMPs) are involved in the development of various organs including the mammary gland. They are well-regulated and act in a time-, concentration- and cell-type-specific manner. We found that BMP-2 is expressed in primary breast tumor tissue samples and in breast cancer cell lines. Hybridization of labeled cDNA, obtained from the breast cancer cell line MCF-7, against the Atlas human cDNA expression array revealed differential gene expression depending on BMP-2 treatment. The most prominent changes were observed for the helix-loop-helix proteins Id-1, Id-2 and Id-3. Id-1 expression had increased severalfold after 4 h and was even higher after 24 h. Id-2 and Id-3 were more strongly induced after 4 h and showed no further significant change after 24 h. Analysis of cell-cycle distribution revealed a marked increase of the sub-G1 phase after 48 h in serum-deprived cells. In the presence of BMP-2 no change was observed over 48 h indicating that BMP-2 does not induce apoptosis. In addition, expression of caspase-3 was reduced in BMP-2-treated cells after 24 h. In summary, our results clearly indicate that BMP-2 is a susceptibility factor keeping the cells ready for the integration of various other signals for cell progression.


Lipoprotein(a) concentration is not associated with venous thromboembolism in a case control study.
Lipoprotein(a) is an LDL-like particle displaying strong athero-thrombotic properties. Although Lp(a) plays a pivotal role in the genesis and progression of thrombosis in the arterial district, its role in promoting thrombosis in the venous district is still unclear. To give further insight into the thrombotic potential of Lp(a), 100 potentially eligible consecutive outpatients who had suffered from previous episodes of venous thrombosis (deep vein thrombosis with or without pulmonary embolism) were enrolled into the study. Thirty-six of these patients who did not fulfil the entry criteria were then excluded from the study. The concentration of Lp(a) was thus measured in 64 patients, and compared to that of 64 control subjects, matched for sex (p=0.46), age (p=0.25) and pharmacological treatment; no subject belonging to the control group had a familial or personal history of venous thromboembolism. Exclusion criteria for both groups included: diabetes mellitus, liver or kidney diseases and malignancy, as established by both laboratory analysis and physical examination. To rule out false elevations of Lp(a) due to the presence of a concurrent acute phase response, C reactive protein (CRP) was measured in both groups using a commercial immunonephelometric assay. No statistically significant differences were observed in the median Lp(a) concentration between patients and controls (median: 69 vs 83 mg/L, respectively; p=0.34). Neither were any significant differences found between patients who had suffered from deep venous thrombosis with (n=18) or without (n=46) pulmonary embolism (median: 73 vs 69 mg/L, respectively; p=0. 83). The concentration of CRP did not differ significantly between cases and controls (median: 1.8 vs 2.3 g/L, respectively; p=0.37). Although there are several plausible biological mechanisms to explain the strong thrombogenicity of Lp(a) in vitro, we failed to demonstrate a convincing association between Lp(a) and thrombosis in the venous district. Besides the proven prothrombotic role of Lp(a) in some selected clinical settings, it is thus conceivable that the contribution of Lp(a) to genesis and progression of the venous thrombosis might be marginal or efficiently counterbalanced in vivo. The clinical usefulness of including the measurement of Lp(a) among the screening tests for thrombophilic patients, therefore, remains questionable.


Ovarian cancer: interplay of vitamin D signaling and miRNA action.
Increasing attention is being devoted to the mechanisms by which cells receive signals and then translate these into decisions for growth, death, or migration. Recent findings have presented significant breakthroughs in developing a deeper understanding of the activation or repression of target genes and proteins in response to various stimuli and of how they are assembled during signal transduction in cancer cells. Detailed mechanistic insights have unveiled new maps of linear and integrated signal transduction cascades, but the multifaceted nature of the pathways remains unclear. Although new layers of information are being added regarding mechanisms underlying ovarian cancer and how polymorphisms in VDR gene influence its development, the findings of this research must be sequentially collected and re-interpreted. We divide this multi-component review into different segments: how vitamin D modulates molecular network in ovarian cancer cells, how ovarian cancer is controlled by tumor suppressors and oncogenic miRNAs and finally how vitamin D signaling regulates miRNA expression. Intra/inter-population variability is insufficiently studied and a better understanding of genetics of population will be helpful in getting a step closer to personalized medicine.


[Assessment of persistent potential dominant pathogens of acute intestinal infections].
To determine the prevalence,and etiological structure of acute intestinal infections, to investigate the dominant agents' persistence factors. According with materials of statistical reports we did the retrospective epidemiological analysis of acute intestinal infections incidence in Sumy region from 2006 till 2011. Biological properties of 40 strains of Klebsiella pneumonia, 40 strains of Enterobacter cloacae and 50 strains of Staphylococcus aureus were investigated. Moderate trend of acute intestinal infections incidence increase was indicated. Bacteria of genera Klebsiella, Enterobacter, Staphylococcus were predominated in etiological structure. Incidence of acute diarrheal infections caused by Klebsiella and Enterobacter was reached the maximum in the spring-summer period. The incidence of staphylococcal etiology was discrete. The strains of Klebsiella pneumonia, Staphylococcus aureus and Enterobacter cloacae were remarkable for different frequency and intensity of persistence factors. Аnti-interferon activity was detected in 100% of clinical isolates of microorganisms, anti-lysozym activity was detected in 87.3 ± 2.9% of clinical isolates of microorganisms, anti-complementary activity was detected in 72.3 ± 3.9% of clinical isolates of microorganisms. Biological properties of opportunistic pathogens that cause acute intestinal infections can be used as epidemiological factors for differentiation of microorganisms pathogenicity.


Preclinical Rodent Toxicity Studies for Long Term Use of Ceftriaxone.
A 6-month rodent toxicology and pharmacokinetic (PK) study was performed to provide supportive safety data for long-term use of intravenous ceftriaxone in a clinical trial in patients with amyotrophic lateral sclerosis (ALS). Ceftriaxone was administered by subcutaneous injection at up to 2 g/kg/day to Sprague-Dawley Crl:CD (SD) rats. Ceftriaxone was found to be safe and well tolerated. Specifically, no significant differences in body weight and food consumption were observed between the treatment and control groups. With the exception of in red cell parameters decrease, there were no ceftriaxone-related changes in hematology, coagulation, clinical chemistry and urinalysis parameters. Injection site trauma and associated reversible anemia, likely due to chronic blood loss at the injection site, were all attributable to subcutaneous route of administration. Cecum dilatation and some skin changes were reversible after recovery period, while bile duct dilatation, observed only in a few animals, persisted. Changes in the non-glandular stomach do not have a human correlate. The no-observed-adverse-effect dose level (NOAEL) was 0.5 g/kg/day ceftriaxone in both sexes. Ceftriaxone showed rapid absorption with half-life values ranging between 1 and 1.5 hours. Additionally, there was no evidence of accumulation and a virtually complete elimination by 16 hours after the last dose. Overall there were no toxicologically meaningful drug-related animal findings associated with the long-term administration (6 months) of ceftriaxone. These results support safety of long-term use of ceftriaxone in human clinical trials.


Displaced Tibia Fractures in Adolescents: Closed Reduction and Casting Versus Flexible Intramedullary Nails.
Although there has been a recent trend towards the operative intervention of pediatric diaphyseal tibial fractures, there is sparse literature that supports this trend. This study compares the outcomes in children between 10 and 18 years of age with diaphyseal tibial fractures who undergo nonoperative treatment with closed reduction and casting (CRC) to those who undergo operative treatment with flexible intramedullary nailing. A retrospective chart review was performed of all patients between 10 and 18 years of age who underwent treatment for tibia fractures at the authors home institution between 2005 and 2018. Radiographs and medical records were reviewed for the duration of immobilization, time to fracture healing and complications including delayed union, malunion, nonunion, and surgical site infection. All statistical analysis was performed using an αof 0.05. One hundred forty one patients (81.8% males) were included in the final analysis. Patients treated with flexible nailing took an average of 7 weeks ( P <0.001) longer than patients treated with CRC to achieve radiographic healing. The average time to full weight-bearing activities was longer by 1 week in the patients treated nonoperatively with CRC ( P =0.001). There was no statistically significant difference in the malunion rates between the 2 groups ( P =0.067), but delayed union and nonunion were exclusively seen in the flexible nailing group. There was a total of 40 complications among 33 (23.4%) patients, most of whom were in the CRC cohort (60.6%, n=20), but there was no statistically significant difference in complication rates between the 2 cohorts. Most adolescents presenting with closed diaphyseal tibial fractures of moderate severity can be successfully treated both nonoperatively with CRC and operatively with flexible intramedullary nailing. However, we recommend an initial attempt at nonoperative treatment be performed in these patients due to the association of more severe complications with flexible nailing. Level III.


Dual-functional carbon dots-silver@zinc oxide nanocomposite: in vitro evaluation of cellular uptake and induction of apoptosis.
Carbon dots (CDs) are novel bioimaging tools with fascinating fluorescence properties. We report here the development of novel CDs decorated on a silver-zinc oxide (CD-Ag@ZnO) nanocomposite (NC) consisting of highly fluorescent CDs and Ag@ZnO. The CD-Ag@ZnO NC was characterized by various analytical techniques. Our work provides an insight into the application of this CD-Ag@ZnO NC in monitoring cellular uptake and mediating apoptotic effects in MCF-7 and A549 cancer cell lines. By monitoring the simultaneous green fluorescence emission of the CDs, the distribution of the CD-Ag@ZnO NC could be followed, eliminating the need to use fluorescent organic dyes. Fluorescence microscopy and atomic absorption spectrometry were used for the qualitative and quantitative assessment of cellular uptake. In vitro studies of cancer cells treated with CD-Ag@ZnO NC revealed concentration-dependent cytotoxic effects via the induction of apoptosis. Fluorescence and scanning electron microscopy were used to study the characteristic nuclear and morphological changes during apoptosis. We used flow cytometry to quantify the reactive oxygen species and the reverse transcriptase polymerase chain reaction to study apoptotic gene expression. The role of reactive oxygen species in eliciting the apoptotic gene cascade was also studied. Intriguingly, the multifunctional CD-Ag@ZnO NC has a tendency to evoke apoptosis while allowing real-time intracellular trafficking, which may be of huge relevance in cancer theranostic applications.


"Doctors' Lounge" podcast to teach clinical reasoning to first-year medical students.
This article was migrated. The article was marked as recommended. In the first year of medical school, our students have a comprehensive course in history taking, physical examination skills, clinical reasoning, and patient-centered care. We have observed that first year students struggle to conduct a focused history and perform a focused physical examination on a given chief complaint. We developed an innovative program to address this concern in our Essentials of Medicine- Physical Diagnosis course. We created an online outline and audio podcast for students to review illustrating the key elements of the history of presenting illness, review of systems, other historical patient information, and focused physical examination for 3 specific chief complaints to assist them in their approach to these patients. This resource also included the discussion of the work up and treatment plans and was created in collaboration of Internal, Family, and Emergency Medicine to account for the various approaches to the same chief complaint within the various specialites of medicine. Students completed a brief pre- and post-session survey to assess their utilization of the resource, quality of the content, and delivery of the session materials. The preceptor's were also surveyed regarding the students' ability to conduct a patient encounter and discuss their assessment and plan comparing current students to those in previous years who did not use this resource. We also asked for feedback on how these resources might be improved for future use. The resource was highly effective for first-year medical students in preparation for focused history taking and physical examination of a patient with a specific chief complaint. Students were more engaged in the critical reasoning discussion of the case assessment and plan after using this resource and preceptors were in agreement. We believe this model we called the "Doctors' Lounge" developed for the chief complaints of sore throat, chest pain, and abdominal pain can be replicated at any medical school desiring to introduce or enhance teaching of clinical reasoning skills to their preclinical students.


Alpha phase dynamics predict age-related visual working memory decline.
Alpha oscillations (7-14Hz) are modulated in response to visual temporal and spatial cues. However, the neural response to alerting cues is less explored, as is how this response is affected by healthy aging. Using scalp EEG, we examined how visual cortical alpha activity relates to working memory performance. Younger (20-30 years) and older (60-70 years) participants were presented with a visual alerting cue uninformative of the position or size of a lateralized working memory array. Older adults showed longer response times overall and reduced accuracy when memory load was high. Older adults had less consistent cue-evoked alpha phase resetting than younger adults, which predicted worse performance. Alpha phase prior to memory array presentation predicted response time, but the relationship between phase and response time was weaker in older adults. These results suggest that changes in alpha phase dynamics, especially prior to presentation of task-relevant stimuli, potentially contribute to age-related cognitive decline.


Multifocused Ultrasound Therapy for Controlled Microvascular Permeabilization and Improved Drug Delivery.
Focused ultrasound (FUS) exposure of micro-bubble (MB) contrast agents can transiently increase microvascular permeability allowing anticancer drugs to extravasate into a targeted tumor tissue. Either fixed or mechanically steered in space, most studies to date have used a single element focused transducer to deliver the ultrasound (US) energy. The goal of this study was to investigate various multi-FUS strategies implemented on a programmable US scanner (Vantage 256, Verasonics Inc.) equipped with a linear array for image guidance and a 128-element therapy transducer (HIFUPlex-06, Sonic Concepts). The multi-FUS strategies include multi-FUS with sequential excitation (multi-FUS-SE) and multi-FUS with temporal sequential excitation (multi-FUS-TSE) and were compared to single-FUS and sham treatment. This study was performed using athymic mice implanted with breast cancer cells ( N = 20 ). FUS therapy experiments were performed for 10 min after a solution containing MBs (Definity, Lantheus Medical Imaging Inc.) and near-infrared (NIR, surrogate drug) dye were injected via the tail vein. The fluorescent signal was monitored using an in vivo optical imaging system (Pearl Trilogy, LI-COR) to quantify intratumoral dye accumulation at baseline and again at 0.1, 24, and 48 h after receiving US therapy. Animals were then euthanized for ex vivo dye extraction analysis. At 48 h, fluorescent tracer accumulation within the tumor space for the multi-FUS-TSE therapy group animals was found to be 67.3%, 50.3%, and 36.2% higher when compared to sham, single-FUS, and multi-FUS-SE therapy group measures, respectively. Also, dye extraction and fluorescence measurements from excised tumor tissue found increases of 243.2%, 163.1%, and 68.1% for the multi-FUS-TSE group compared to sham, single-FUS, and multi-FUS-SE therapy group measures, respectively. In summary, experimental results revealed that for a multi-FUS sequence, increased microvascular permeability was considerably influenced by both the spatial and temporal aspects of the applied US therapy.


[Experimental teratological studies on facial anomalies induced in mice by bis(dichloroacetyl)diamine. II. Pathogenesis of bis(dichloroacetyl)diamine-induced median cleft face syndrome in mice].
The present study was performed to clarify the pathogenesis of bis(dichloroacetyl)diamine (abbreviated as bisdiamine hereafter)-induced median cleft face syndrome in mice. Bisdiamine was administered by oral intubation to pregnant Jcl: ICR mice at a dosage of 3,200 mg/kg/day at days 7.5 and 8.5 of gestation (VP = day 0). Embryos were recovered at 4, 12, 24, 48, 72 and 96 hr after bisdiamine treatment at day 8.5 of gestation and morphological differences between the bisdiamine-treated and control embryos at the specific time intervals were quantitatively examined by the light and scanning electron microscopy. First, bisdiamine caused extensive death of cranial, mainly prosencephalic and mesencephalic, neural crest cells and neuroepithelial cells. Second, the former damage resulted in reduced numbers of mesenchymal cells in the frontonasal prominences and the latter resulted in dorsolateral deviation of the nasal placodes. Consequently, the medial nasal prominences were abnormally widely spaced and then, the median cleft face syndrome was induced. In addition, the findings suggesting that bisdiamine might cause aberrant movement of neural crest cells and/or mesenchymal cells were observed.


Genetic variation in human stromelysin gene promoter and common carotid geometry in healthy male subjects.
A common variant in the promoter of the human stromelysin gene, causing reduced enzyme expression, has been associated with the progression of coronary atherosclerosis. On the other hand, increased stromelysin activity may promote plaque rupture. The present study was undertaken to investigate the relationship between the genetic variation in the human stromelysin gene promoter and common carotid geometry. Forty-two healthy male subjects without major coronary heart disease risk factors were investigated. The polymorphism in the stromelysin gene promoter was studied through polymerase chain reaction amplification with the use of mutagenic primers. Age, blood pressure, lipids, glucose, viscosity, and body mass index were similar in homozygotes for the 5A allele (5A/5A), heterozygotes (5A/6A), and homozygotes for the 6A allele (6A/6A). Serum matrix metalloproteinase-3 levels did not differ significantly among genotypes. Common carotid diameters and intima-media thickness, measured by noninvasive ultrasonography, were significantly larger in 6A/6A subjects (for respective 6A/6A, 5A/6A, and 5A/5A subjects, diameter at the R wave was 0.63+/-0.09, 0.55+/-0.06, and 0.53+/-0.04 cm [mean+/-SD], P<0.005 by ANOVA; intima-media thickness was 765+/-116, 670+/-116, and 630+/-92 microm [mean+/-SD], P<0.05 by ANOVA). Wall shear stress, calculated as blood velocityxblood viscosity/internal diameter, was significantly lower in 6A/6A subjects (for respective 6A/6A, 5A/6A, and 5A/5A subjects, mean wall shear stress was 10.4+/-2.9, 13.5+/-3.5, and 12.6+/-1.9 dyne/cm(2) [mean+/-SD], P<0.05 by ANOVA). The results demonstrate that the gene polymorphism in the promoter region of stromelysin is associated with structural and functional characteristics of the common carotid artery in healthy male subjects without major risk factors for atherosclerosis. Individuals with the 6A/6A genotype (associated with lower enzyme activity) show a triad of events, namely, increased wall thickness, enlarged arterial lumen, and local reduction of wall shear stress, which might predispose them to atherosclerotic plaque localization.


Nicotinamide prevents the development of diabetes in the cyclophosphamide-induced NOD mouse model by reducing beta-cell apoptosis.
The development of diabetes in non-obese diabetic (NOD) mice, which normally takes between 3 and 7 months, can be accelerated by cyclophosphamide (CY) injections, with rapid progression to diabetes within only 2-3 weeks. This insulin-dependent diabetes mellitus (IDDM) can be prevented or delayed in CY-treated NOD mice by nicotinamide (NA). The present study was undertaken to determine the mode of cell death responsible for the development of IDDM in CY-treated male NOD mice and to investigate the effect of NA on beta-cell death. Apoptotic beta cells were present within the islets of Langerhans in haematoxylin and eosin-stained sections of the pancreata harvested from 3- and 12-week-old male NOD mice, from 8 h until 14 days after a single intraperitoneal injection of CY (150 mg/kg body weight). The maximum amount of beta-cell apoptosis in 3-week-old animals occurred 1-2 days after CY treatment (20 apoptotic cells per 100 islets), after which time levels of apoptosis declined steadily throughout the 14-day period studied. The incidence of beta-cell apoptosis in 12-week-old male NOD mice occurred in two peaks; the first was recorded 8-24 h after CY treatment (30 apoptotic cells/100 islets), while the second, at 7 days (36 apoptotic cells per 100 islets), coincided with increased insulitis. Administration of NA 15 min before CY treatment, and thereafter daily, substantially reduced the amount of apoptosis and effectively eliminated (4 apoptotic cells per 100 islets) the second wave of beta-cell apoptosis seen at day 7 in 12-week-old animals given CY alone. These results show that apoptosis is the mode of beta-cell death responsible for the development of CY-induced IDDM and that prevention of IDDM by NA is associated with a reduction in beta-cell apoptosis.


Psychometric properties of the feedback orientation scale among South African salespersons.
Feedback to employees is an important management tool, and the literature demonstrates that it has a positive effect on learning, motivation, and job performance. This study investigates in a non-U.S. context the psychometric properties of the Feedback Orientation Scale. Data were gathered from a sample of 202 salespersons from a large South African firm within the industrial fuels and lubricants sector. Confirmatory Factor Analysis provided evidence for the intended dimensionality, reliability, and convergent and discriminant validity of the scale.


[Semen quality and fertility in a population-based follow-up study].
Little is known about the importance of semen quality in male infertility. We followed 430 first pregnancy planners with no previous reproductive experience recruited among more than 50,000 cohabiting trade-union members. The couples were consecutively enrolled into the study as they discontinued contraception and were followed up for six month menstrual cycles or until a pregnancy was verified. Each man provided a semen sample at enrollment. Women kept daily record of vaginal bleeding and sexual activity. The probability of conception increased with increasing sperm concentration up to 40 x 10(6)/ml, but any higher sperm density was not associated with additional likelihood of pregnancy. The proportion of sperm with normal morphology was strongly related to likelihood of pregnancy, independently of sperm concentration. In conclusion, sperm concentration and morphology are valuable biological markers of male fecundity. Reference values for semen quality based on biological knowledge can be established.


State- and conformer-selected beams of aligned and oriented molecules for ultrafast diffraction studies.
The manipulation of the motion of neutral molecules with electric or magnetic fields has seen tremendous progress over the last decade. Recently, these techniques have been extended to the manipulation of large and complex molecules. In this article we introduce experimental approaches to the manipulation of large molecules, i.e., the deflection, focusing and deceleration using electric fields. We detail how these methods can be exploited to spatially separate quantum states and how to select individual conformers of complex molecules. We briefly describe mixed-field orientation experiments made possible by the quantum-state selection. Moreover, we provide an outlook on ultrafast diffraction experiments using these highly controlled samples.


Impact of the new UK licensing law on emergency hospital attendances: a cohort study.
To assess the effect of the new UK alcohol licensing law on overnight attendances to the emergency department. A retrospective cohort study at the emergency department of St Thomas' Hospital, London over 2 months, one before and one after the introduction of the new legislation. All people over the age of 16 years who attended the emergency department between 21:00 and 09:00 during the two study periods (March 2005 and March 2006) were included. An alcohol-related attendance was defined as having occurred if there was documentation of alcohol consumption before attendance, or of alcohol intoxication in relation to the patient's physical examination or final diagnosis. The primary outcome measure was change in the number and percentage of alcohol related attendances to the emergency department between the two study periods. Secondary outcome measures, compared between the two study periods, were number and percentage of alcohol-related attendances as a consequence of assault, and of injury; and number and percentage of alcohol-related attendances resulting in admission to hospital. In March 2005 there were 2736 overnight attendances to the ED, of which 79 (2.9%) were classified as alcohol related. In comparison, in March 2006 there were a total of 3135 overnight attendances, of which 250 (8%) were alcohol related, representing a significant increase (p<0.001). There were also significant increases in percentage of alcohol related attendances as a consequence of injury (p<0.001) and assault (p = 0.002); and in admission rates for alcohol related attendances (p<0.001) between the two study periods. Overnight alcohol related emergency attendances to St Thomas' hospital increased after the introduction of new alcohol licensing legislation. If reproduced over longer time periods and across the UK as a whole, the additional burden on emergency care could be substantial.


[X-ray differential diagnosis of focal tuberculosis and peripheral lung cancer].
The paper deals with the differential diagnosis of focal tuberculosis and peripheral lung cancer. It presents data on 25 patients of whom 24 were misdiagnosed as having focal tuberculosis. The main reason for misdiagnoses was the similarity of early X-ray symptoms of the two diseases, namely, upper lobar site, increased and thickened lung pattern and focal shadows against this background. The most important differentially diagnostic criteria for the above diseases are varying optic densities of pulmonary structures at the site of involvement and different patterns of vascular changes in the lung portion with a pathological process.


Interaction between canine platelets and adult heartworms: platelet recognition of heartworm surfaces.
An interaction between blood platelets and adult heartworms was examined in vitro. Surfaces of glutaraldehyde-fixed heartworms, which were taken from infected dogs washed, and incubated in platelet-rich plasma (PRP), were evaluated by scanning electron microscopy. Adherence of platelets to heartworms occurred only with PRP from infected dogs. Aggregation to epinephrine and adenosine diphosphate of PRP incubated with heartworms was monitored. Seemingly, platelet activation to heartworm membranes occurs in dogs with heartworm disease. The increased platelet reactivity was also observed in dogs with occult heartworm disease, indicating that the presence of circulating microfilaria was not important for this process. The ability to transfer the reactivity to heartworm-negative platelets by suspending them in heartworm-positive plasma indicated that this reactivity resided in the plasma. The processes leading to platelet activation may be responsible for the platelet-associated vascular disorders of canine heartworm disease.


Hyperpolarizing GABAergic transmission depends on KCC2 function and membrane potential.
KCC2 comprises the major Cl(-) extruding mechanism in most adult neurons. Hyperpolarizing GABAergic transmission depends on KCC2 function. We recently demonstrated that glutamate reduces KCC2 function by a phosphorylation-dependent mechanism that leads to excitatory GABA responses. Here we investigated the methods by which to estimate changes in E(GABA), as well as the processes that lead to depolarizing GABA responses and their effects on neuronal excitability. We demonstrated that current-clamp recordings of membrane potential responses to GABA can determine upper and lower limits of E(GABA). We also further characterized depolarizing GABA responses, which both excited and inhibited neurons. Our analyses revealed that persistently active GABA(A) receptors contributed to loading Cl(-) during the glutamate exposure, indicating that tonic inhibition can facilitate the development of depolarizing GABA responses and increase excitability after pathophysiological insults. Finally, we demonstrated that hyperpolarizing GABA responses could temporarily switch to depolarizing responses when they coincided with an afterhyperpolarization.