Lower total protein and absence of neuronavigation are novel poor prognostic factors of endoscopic hematoma removal for intracerebral hemorrhage.
Endoscopic hematoma removal is widely performed for the treatment of intracerebral hemorrhage. We investigated the factors related to the prognosis of intracerebral hemorrhage after endoscopic hematoma removal. From 2013 to 2019, we retrospectively analyzed 75 consecutive patients with hypertensive intracerebral hemorrhage who underwent endoscopic hematoma removal. Their characteristics, including neurological symptoms, laboratory data, and radiological findings were investigated using univariate and multivariate analysis. Complications during hospitalization, Glasgow Coma Scale (GCS) score on day 7, and modified Rankin Scale (mRS) score at 6 months were considered as treatment outcomes. The mean age of the patients (33 women, 42 men) was 71.8 (36-95) years. Mean GCS scores at admission and on day 7 were 10.3 ± 3.2 and 11.7 ± 3.8, respectively. The mean mRS score at 6 months was 3.8 ± 1.6, and poor outcome (mRS score ranging from 3 to 6 at 6 months) in 53 patients. Rebleeding occurred in 4 patients, and other complications in 15 patients. Multivariate analysis revealed that older age, hematoma in the basal ganglia, lower total protein level, higher glucose level, and absence of neuronavigation were associated with poor outcomes. Of the 75 patients, 9 had cerebellar hemorrhages, and they had relatively favorable outcomes compared to those with supratentorial hemorrhages. Several factors were related to the prognosis of intracerebral hemorrhage after endoscopic hematoma removal. Lower total protein level at admission and absence of neuronavigation were novel factors related to poor outcomes of endoscopic hematoma removal for intracerebral hemorrhage.


Effect of an angiotensin converting enzyme inhibitor (SQ 14,225) on beta-adrenergic and angiotensin-induced thirsts.
The effect of acute administration of SQ 14,225, a new angiotensin converting enzyme inhibitor, on the drinking response of female rats administered either isoprenaline, angiotensin I, or angiotensin II was studied during 2 h after treatment. Administration of isoprenaline (25 micrograms/kg body wt) was accompanied by a significant increase in water intake when compared with saline-treated controls. Acute administration of a constant dose of isoprenaline (25 micrograms/kg body wt) and increasing doses of SQ 14,225 (5--50 mg/kg) was accompanied by a dose-related, linear decrease in water intake. Acute administration of either angiotensin I or angiotensin II (200 micrograms/kg body wt) was accompanied by a significant increase in water intake. The dipsogenic response to angiotensin II was not affected by acute administration of 35 mg SQ 14,225/kg body wt. However, at the same dose of SQ 14,225, angiotensin I-induced thirst was attenuated. Since isoprenaline-induced and angiotensin I-induced, but not angiotensin II-induced, thirsts are blocked by SQ 14,225, the results suggest that isoprenaline-induced thirst is mediated by way of the renin--angiotensin system.


Effect of iron on neonatal gut flora during the first three months of life.
To study the effect of milk supplemented with iron on neonatal gut flora, faecal specimens of ten infants receiving breast milk, six receiving a cow-milk preparation supplemented with iron (5 mg/l) and seven receiving the same product without iron supplement (iron concentration less than 0.5 mg/l) were examined during the first 12 weeks of life. In breast-fed infants bifidobacteria was predominant, counts of Escherichia coli were low, and other bacteria were rarely present. Infants receiving fortified cow-milk preparation had high counts of Escherichia coli, counts and isolation frequency of bifidobacteria were low and other bacteria were frequently isolated. In those on unfortified cow-milk preparation isolation frequency of Escherichia coli, bifidobacteria and bacteroides was comparable with that in breast-fed infants; however, counts of Escherichia coli were high. It is concluded that the faecal flora of infants fed unfortified cow-milk preparation acquires characteristics of that found in breast-fed infants.


Differential effects of modafinil on memory in naïve and memory-impaired rats.
Modafinil is a wake-promoting drug and has been approved for the treatment of excessive daytime sleepiness in narcolepsy and obstructive sleep apnea. Modafinil was shown to improve learning and memory in rodents, and to reverse memory deficits induced by sleep deprivation or stress. However, depending on the memory paradigm used, modafinil might also impair memory. We aimed to investigate the effects of modafinil on memory consolidation and retrieval for object recognition and inhibitory avoidance in naïve adult rats. We also investigated whether acute or chronic administration of modafinil would reverse memory deficits induced by iron overload, a model of memory impairment related to neurodegenerative disorders. Adult naïve rats received modafinil (0.0, 0.75, 7.5 or 75 mg/kg) either immediately after training or 1 h prior to testing in object recognition or inhibitory avoidance. Iron-treated rats received modafinil immediately after training in object recognition. In order to investigate the effects of chronic modafinil, iron-treated rats received daily injections of modafinil for 17 days, and 24 h later they were trained in object recognition or inhibitory avoidance. Acute modafinil does not affect memory consolidation or retrieval in naive rats. A single injection of modafinil at the highest dose was able to recover recognition memory in iron-treated rats. Chronic modafinil completely recovered iron-induced recognition memory and emotional memory deficits. Additional preclinical and clinical studies are necessary in order to support the applicability of modafinil in recovering memory impairment associated with neurodegenerative disorders.


Selective Targeting of Glioblastoma with EGFRvIII/EGFR Bitargeted Chimeric Antigen Receptor T Cell.
The heterogeneous expression of EGFRvIII [variant III mutant of epidermal growth factor receptor (EGFR)] in glioblastoma has significant impact on the clinical response to the treatment of EGFRvIII-specific chimeric antigen receptor-engineered T (CAR T) cells. We hypothesized that CAR T cells that could target both EGFRvIII and the form of EGFR expressed on tumor cells, but not EGFR on normal cells, would greatly improve efficacy without inducing on-target, off-tumor toxicity. Therefore, we developed a humanized single-chain antibody, M27, with a single specificity that binds to an epitope found both on wild-type EGFR- and EGFRvIII-overexpressing tumor cells, but not EGFR-expressing normal cells, including primary keratinocytes, on which wild-type EGFR is highly expressed. M27-derived CAR T cells effectively lysed EGFRvIII- or EGFR-overexpressing tumor cells, but showed no observable toxicity on normal cells. Inclusion of the CD137 (4-1BB) costimulatory intracellular domain in the M27-28BBZ CAR provided CAR T cells with higher tumor lysis activity than when not included (as in the M27-28Z CAR). The growth of established EGFR- or EGFRvIII-overexpressing glioma xenografts was suppressed by M27-28BBZ CAR T cells as well. The growth of heterogeneic xenograft tumors, created by mixing EGFR- and EGFR-overexpressing glioblastoma cells, was also effectively inhibited by M27-28BBZ CAR T cells. The survival of mice in the orthotopic models was significantly prolonged after M27-28BBZ CAR T-cell infusion. These results suggested that tumor-selective, bitargeted anti-EGFR/EGFRvIII CAR T cells may be a promising modality for the treatment of patients with EGFR/EGFRvIII-overexpressing glioblastoma. Cancer Immunol Res; 6(11); 1314-26. ©2018 AACR.


Hydroxychloroquine versus placebo in the treatment of non-hospitalised patients with COVID-19 (COPE - Coalition V): A double-blind, multicentre, randomised, controlled trial.
Previous Randomised controlled trials (RCT) evaluating chloroquine and hydroxychloroquine in non-hospitalised COVID-19 patients have found no significant difference in hospitalisation rates. However, low statistical power precluded definitive answers. We conducted a multicenter, double-blind, RCT in 56 Brazilian sites. Adults with suspected or confirmed COVID-19 presenting with mild or moderate symptoms with ≤ 07 days prior to enrollment and at least one risk factor for clinical deterioration were randomised (1:1) to receive hydroxychloroquine 400 mg twice a day (BID) in the first day, 400 mg once daily (OD) thereafter for a total of seven days, or matching placebo. The primary outcome was hospitalisation due to COVID-19 at 30 days, which was assessed by an adjudication committee masked to treatment allocation and following the intention-to-treat (ITT) principle. An additional analysis was performed only in participants with SARS-CoV-2 infection confirmed by molecular or serology testing (modified ITT [mITT] analysis). This trial was registered at ClinicalTrials.gov, NCT04466540. From May 12, 2020 to July 07, 2021, 1372 patients were randomly allocated to hydroxychloroquine or placebo. There was no significant difference in the risk of hospitalisation between hydroxychloroquine and placebo groups (44/689 [6·4%] and 57/683 [8·3%], RR 0·77 [95% CI 0·52-1·12], respectively, p=0·16), and similar results were found in the mITT analysis with 43/478 [9·0%] and 55/471 [11·7%] events, RR 0·77 [95% CI 0·53-1·12)], respectively, p=0·17. To further complement our data, we conducted a meta-analysis which suggested no significant benefit of hydroxychloroquine in reducing hospitalisation among patients with positive testing (69/1222 [5·6%], and 88/1186 [7·4%]; RR 0·77 [95% CI 0·57-1·04]). In outpatients with mild or moderate forms of COVID-19, the use of hydroxychloroquine did not reduce the risk of hospitalisation compared to the placebo control. Our findings do not support the routine use of hydroxychloroquine for treatment of COVID-19 in the outpatient setting. COALITION COVID-19 Brazil and EMS.


Isolation of five Rubrobacter strains from biodeteriorated monuments.
In the last few years, the microbial colonisation of mural paintings in ancient monuments has been attracting the attention of microbiologists and conservators. The genus Rubrobacter is commonly found in biodeteriorated monuments, where it has been reported to cause rosy discolouration. However, to date, only three species of this genus have been isolated, all from thermophilic environments. In this paper, we studied three monuments: the Servilia and Postumio tombs in the Roman Necropolis of Carmona (Spain), and Vilar de Frades church (Portugal), in search of Rubrobacter strains. In all cases, biodeterioration and the formation of efflorescences were observed, and five Rubrobacter strains were isolated. These isolates showed different physiology and migration in denaturing gradient gel electrophoresis, suggesting they might represent new species within this genus. The isolates reproduced some biodeterioration processes in the laboratory and revealed their biomediation in crystal formation.


Induction of dominant lethal mutations in male mice by fosfestrol.
Using the dominant lethal assay, the ability of fosfestrol, a diethylstilboestrol derivate, to induce mutations in male mice was tested and confirmed. Up to 300 mg/kg of fosfestrol the induction of mutations occurs exclusively in spermatozoa. A dose of 600 mg/kg of fosfestrol induces dominant lethal mutations up to 10 days posttreatment. The majority of induced dominant lethal mutations in all dose groups are expressed as loss after implantation.


Building polymer-like clusters from colloidal particles with isotropic interactions, in aqueous solution.
Colloidal particles that interact via a long-ranged repulsive barrier in combination with a very short-ranged attractive minimum can "polymerize" to form highly anisotropic structures. Motivated by previous experimental achievements in non-aqueous solvents, and recent theoretical predictions, we hypothesize that it is possible to construct clusters that resemble linear or branched polymers, in aqueous solution. If these clusters are not too large, they may even remain dispersed, but even if they grow large enough to sediment, they may be collected and used in future applications. In this work, we specifically synthesize poly (ethylene glycol) (PEG) chains, grafted onto poly (styrene) (PS) particles in aqueous solution, and adjust the conditions so that strongly anisotropic and isolated polymer-like clusters are formed. These conditions include a very low ionic strength (the particles are weakly charged), a relatively high temperature, and a low particle concentration. An important criterion is that the particle size is large enough to admit structural analyses via confocal laser scanning microscopy (CLSM). We have furthermore utilized Metropolis Monte Carlo (MC) simulation to generate theoretical predictions of these cluster formations. We have conducted such simulations of 3D as well as 2D systems, where the latter is also relevant, given that the clusters sometimes deposit onto the glass surfaces upon imaging. A simplistic particle-particle potential of mean force is adopted for the simulations, but we also invoke a more elaborate theoretical model, to demonstrate that similar interactions can be obtained when the grafted chains are treated explicitly. According to our Zeta potential measurements, the particles indeed carry a weak negative charge, presumably due to ion specific adsorption. Furthermore, by ensuring that the ionic strength is very low, with a Debye length similar to the particle size, we could use temperature to control the hydrophobicity of the grafted PEG layer, and thus the strength of the short-ranged attraction. We were indeed able to establish highly anisotropic structures, that resemble linear or branched polymers, which we could image by CLSM. The average degree of polymerization could be adjusted by a variation of the particle concentration.


Subregion-specific down-regulation of 5-HT3 immunoreactivity in the nucleus accumbens shell during the induction of cocaine sensitization.
Repeated exposure to psychostimulants such as cocaine and amphetamine can result in behavioral sensitization, which is believed to model the onset of drug addiction, as well as neural adaptations that occur after repeated drug abuse that lead to addictive behaviors. Dopamine (DA) in the nucleus accumbens (NAc) has been shown to play an integral role in this phenomenon. However, cocaine also acts on the serotonin (5-HT) system, which has been shown to modulate psychostimulant-induced increases in motor behavior and DA release in the NAc. Recently, it has been demonstrated that the shell portion of the NAc can no longer be considered a homogeneous structure and can be subdivided into at least five separate regions. The present study examines 5-HT(3) receptors in the subdivisions of the NAc in cocaine-sensitized rats. Rats received a sensitization-inducing regimen of cocaine (twice-daily injections of 15 mg/kg ip for five consecutive days). Two or 14 days following the last injection, rats were given a challenge injection of cocaine (15 mg/kg ip) and sacrificed 2 h later. Sections of the NAc were processed for 5-HT(3) immunoreactivity (5-HT(3)-IR), and the number of puncta was quantified in each of the subregions of the shell, as well as the core of the accumbens. Repeated cocaine administration resulted in robust sensitization that correlated with a transient decrease in the density of 5-HT(3) immunoreactive puncta in the intermediate zone of the accumbens shell. After a 2-week withdrawal period, sensitized animals no longer showed any differences in any of the areas examined. These data suggest a possible role for 5-HT(3) receptors in the intermediate zone during the induction of cocaine sensitization.


Preconception blood pressure and risk of preterm birth: a large historical cohort study in a Chinese rural population.
To examine the relationship between preconception blood pressure (BP) and the risk of preterm birth (PTB) using a historical cohort of reproductive-aged women and girls from a Chinese rural population. A historical cohort study established between 2010 and 2013 in People's Republic of China. Local family-planning service agencies and maternal-child care service centers. A total of 367,425 reproductive-aged women and girls who participated in the National Free Pre-pregnancy Checkups in 2010-2012 and subsequently had a live birth before October 2013. None. Incidence rates of PTB in reproductive-aged women and girls across preconception BP levels. Preterm births were defined as babies born alive at 28 to 37 weeks of pregnancy. Compared with the participants with a systolic BP of <120 mm Hg, the multivariable-adjusted odds ratio (OR) for PTB was 0.99 (95% confidence interval [CI]: 0.95-1.03]), 1.21 (95% CI: 1.11-1.32), 1.47 (95% CI: 1.22-1.77), 1.80 (95% CI: 1.25-2.59), and 1.81 (95% CI: 1.20-2.73) for the participants with systolic BP of 120-129, 130-139, 140-149, 150-159, and ≥160 mm Hg, respectively. When the participants with normal BP were used as the reference, the adjusted OR for PTB was 1.04 (95% CI: 1.01-1.08), 1.38 (95% CI: 1.25-1.53), and 1.54 (95% CI: 1.21-1.97) for the participants with prehypertension, stage-1 hypertension, and stage-2 hypertension, respectively. In addition, isolated systolic and diastolic hypertension increased the risk of PTB by 55% and 30%, respectively. Our results indicated a strong linear and independent relationship between BP levels and the risk of PTB in Chinese reproductive-aged women and girls. Maternal hypertension before pregnancy can significantly increase the risk of PTB.


Overall survival analysis in patients with metastatic breast cancer and liver or lung metastases treated with eribulin, gemcitabine, or capecitabine.
The purpose of this study was to estimate the overall survival (OS) in real-world clinical practice in patients with metastatic breast cancer (MBC) and visceral metastases (liver or lung) treated in the third-line setting with eribulin, gemcitabine or capecitabine overall and in the major clinical categories of MBC (TNBC, HR+/HER2-, and HER2+). A retrospective, observational study was conducted with de-identified patient electronic health records from the Cancer Treatment Centers of America (CTCA). Patients with a diagnosis of metastatic breast with lung or liver metastases, and treated with eribulin, gemcitabine, or capecitabine as third-line therapy were included in the analysis. Landmark survival was calculated as percentage of patients alive at 6, 12, 24, and 36 months. Overall survival was compared between treatment arms within TNBC and HR+/HER2- using log-rank analysis. Cox regression analyses was performed to estimate hazard ratios for comparison of treatments within TNBC and HR+/HER2- subtype. 443 patients with liver or lung metastases received third-line therapy with eribulin (n = 229), gemcitabine (n = 134), or capecitabine (n = 80). Eribulin patients had a higher percentage of patients alive at all landmark timepoints vs. gemcitabine, and a higher percentage of patients alive until 36 months vs. capecitabine. Median survival times showed that overall, and within the TNBC and HR+/HER2- subtype, patients receiving eribulin had a numerically higher median overall survival. This real-world evidence study is consistent with randomized clinical trial data and demonstrates consistency of eribulin effectiveness in MBC patients with lung or liver metastases overall and in TNBC and HR+/HER2- disease.


Nomophobia and its relationship with depression, anxiety, and quality of life in adolescents.
Nomophobia is a portmanteau for "no mobile phone" and phobia or mobile phone addiction. Nomophobia refers to discomfort, anxiety, nervousness, or anguish caused by being out of contact with a mobile phone. There is a paucity of literature from India on this emerging mental health condition. The objectives of this study were to assess the prevalence of nomophobia and its relationship with depression, anxiety, and quality of life among adolescent students. A cross-sectional study was carried out in 1386 high school students aged between 14 and 17 years. The Nomophobia Questionnaire (NMP-Q) was used to assess nomophobia. Beck's Depression Inventory (BDI), Beck's Anxiety Inventory (BAI), and Short Form-36 (SF-36) were used to measure depression, anxiety, and quality of life, respectively. Out of 1386 adolescents, 569 (41.05%), 303 (21.86%), and 82 (5.1%) have mild, moderate, and severe nomophobia, respectively. There were significantly more males with nomophobia. There was a statistically significant relationship between NMP-Q score and BDI, BAI, and SF-36 scores. A significant positive correlation was observed between NMP-Q score and scores on BDI and BAI and a significant negative correlation between SF-36 score. The results of the study indicate that nomophobia is an emerging mental health condition, especially in male adolescents. Nomophobia is significantly associated with depression, anxiety, and poor quality of life. Multicentric studies are needed to better understand this disorder.


Human monoclonal antibodies to cytokeratins associated with squamous cell carcinoma.
Human lymphocytes from a lymph node draining the tumor-bearing area of a patient with a large primary squamous cell carcinoma of the oral mucosa were fused with the nonproducer mouse myeloma, NS-1, to produce interspecies hybridomas. Of 95 hybridoma culture supernatants tested, 23 contained from 0.5 to 50 micrograms/ml of human IgM or IgG. Six supernatant fluids containing greater than 15 micrograms/ml of Ig were tested by indirect immunoperoxidase and immunofluorescence against sections of the autologous carcinoma. Five IgM (lambda) monoclonal antibodies stained the cytoplasm of autologous and allogeneic squamous carcinoma cells. All five monoclonal antibodies stained all layers of normal epidermis but each antibody stained the superficial keratin layer most intensely. Two of the five hybridoma antibodies were further tested. Both antibodies stained all types of normal epithelium; a network of fibers characteristic of intermediate filaments in cultured squamous carcinoma cells and cultured fibroblasts; Z lines in skeletal muscle; and axons in peripheral nerve fibers. We conclude that all five IgM monoclonal antibodies recognize cytokeratins associated with the autologous squamous cell carcinoma. Two of the five hybridoma antibodies recognize an antigenic determinant common to all types of intermediate filament proteins. These data indicate that cytokeratins released by squamous carcinoma cells induced an antibody response in this patient.


Single-Versus Multiple-Dose Antimicrobial Prophylaxis in Peroral Endoscopic Myotomy: A Randomized Controlled Study (SMAPP Trial).
Infections are uncommon after peroral endoscopic myotomy (POEM) procedure. However, prophylactic antibiotics are routinely administered for variable duration during peri-operative period. In this study, we aimed to determine the difference in the rate of infections between single (SD-A) and multiple doses (MD-A) antibiotic prophylaxis groups. The study was a prospective, randomized, non-inferiority trial conducted at a single tertiary care centre from Dec 2018 to Feb 2020. Eligible patients undergoing POEM were randomized into SD-A and MD-A groups. SD-A group received one dose of antibiotic (IIIrd gen cephalosporin) within 30-min of POEM. In the MD-A group, the same antibiotic was administered for a total of three days. Primary aim of the study was to determine the incidence of infections in the two groups. Secondary outcomes included incidence of fever (> 100 °F), inflammatory markers [erythrocyte sedimentation rate (ESR), c-reactive protein(CRP)], serum procalcitonin and adverse events related to antibiotics. (NCT03784365). 114 patients were randomized to SD-A (57) and MD-A (57) antibiotic groups. Mean post-POEM CRP (0.8 ± 0.9 vs 1.5 ± 1.6), ESR (15.8 ± 7.8 20.6 ± 11.7) and procalcitonin (0.05 ± 0.04 0.29 ± 0.58) were significantly higher after POEM (p = 0.001). Post-POEM inflammatory markers (ESR, CRP and procalcitonin) were similar in both the groups. Fever on day-0 (10.5% vs 14%) and day-1 (1.7% vs 3.5%) was detected in similar proportion of patients. Post-POEM infections were recorded in 3.5% (1.7% vs 5.3%, p = 0.618). Single dose of antibiotic is non-inferior to multiple dose antibiotic prophylaxis. Elevation of inflammatory markers and fever after POEM represents inflammation and does not predict infection after POEM.


Intravenous adrenomedullin in myocardial function and energy metabolism in patients after myocardial infarction.
This study investigated the effects of adrenomedullin on left ventricular myocardial contraction and relaxation, coronary blood flow, and myocardial oxygen consumption in comparison with those of atrial natriuretic peptide (ANP). Fourteen patients who had had myocardial infarctions were randomly assigned to receive IV infusion of adrenomedullin (0.05 microg/kg/min) or ANP (0.05 microg/kg/min). Both adrenomedullin and ANP significantly decreased left ventricular systolic pressure (-17 mm Hg, -13 mm Hg, respectively, both p < 0.05). The increase in cardiac index by adrenomedullin (+31%) was significantly greater than that by ANP (+16%). Adrenomedullin significantly increased an index of myocardial contractility, Emax (2.5 +/- 0.3 mm Hg-3.7 +/- 0.3 mm Hg/ml, p < 0.05) and shortened an index of myocardial relaxation, Tau (52 +/- 5 ms-48 +/- 4 ms, p < 0.05). In contrast, ANP did not significantly alter either parameter. In addition, adrenomedullin, but not ANP, significantly increased coronary sinus blood flow (73 +/- 10 ml/min-86 +/- 10 ml/min, p < 0.05). Adrenomedullin did not increase myocardial oxygen consumption. Unlike ANP, IV administration of adrenomedullin enhanced left ventricular myocardial contraction and improved left ventricular relaxation without increasing myocardial oxygen consumption in patients who had had a myocardial infarction.


Kidney disease is an independent risk factor for adverse fetal and maternal outcomes in pregnancy.
Kidney disease has long been recognized to adversely affect fetal and maternal outcomes during pregnancy. The goal of this study is to better describe the population of women with kidney disease and provide a contemporary assessment of their risk for adverse events caused by kidney disease after adjustment for other contributing factors. We used Colorado birth and death certificate data for 1989 to 2001. Of 747,368 births during this period, 911 births from women with kidney disease were identified, and 4,606 births from women without kidney disease were randomly selected for comparison. Adverse fetal outcomes included fetal prematurity, low birth weight, or neonatal death, whereas adverse maternal outcomes included preeclampsia, eclampsia, or abruptio placenta. Women with kidney disease were more likely to have comorbid illnesses, including chronic hypertension, anemia, diabetes, and lung and cardiac disease. Women with kidney disease had a greater frequency of adverse fetal (18.2% versus 9.5%) and maternal outcomes (13.7% versus 4.3%) compared with women without kidney disease (P < 0.0001). The presence of kidney disease independently increased the likelihood of adverse fetal outcomes (adjusted odds ratio [OR], 1.76; 95% confidence interval [CI], 1.40 to 2.21) and occurrence of adverse maternal outcomes, especially in the middle 1990s, among nulliparous women (adjusted OR, 4.07; 95% CI, 2.17 to 7.66). This analysis shows that independent of other risk factors, kidney disease significantly increases the likelihood of unfavorable pregnancy outcomes for both mother and child.


Epidemiological trends of severely immunosuppressed people living with HIV at time of starting antiretroviral treatment in China during 2005-2018.
High HIV-related mortality is mainly associated with severe immunosuppression (CD4 count < 50 cells/μL) in people living with HIV (PLWH). This study intended to explore the trends in epidemic and early mortality among PLWH with severe immunosuppression for further targeted intervention. We extracted the data of treatment-naïve PLWH with severe immunosuppression from China's National Free Antiretroviral Treatment (ART) Program database. Early mortality (within 6 or 12 months after initiating ART) and spatial, temporal, and population distribution were analyzed during 2005-2018. Of 748,066 treatment-naïve PLWH, 105,785 (14.1%) were severely immunosuppressed PLWH aged more than 15-year-old. The proportion of severely immunosuppressed PLWH peaked at 31.4% and then decreased with time, leveling off at approximately 11-12% from 2015 onward. Early mortality rates of these PLWH declined significantly (from 17.0% to 8.1% after 6 months of initiating ART; 20.4% to 10.6% after 12 months; both p values < 0.01) from 2005-2007 to 2016-2018. In the South-central and Southwest, the number of these PLWH was larger than that in the other regions during 2005-2018, and it increased to 4780 (37.1%) and 3370 (26.2%) in 2018. The proportion of PLWH aged 30-44 years among all treatment-naïve severely immunosuppressed PLWH in each region was higher than that of other age groups during 2005-2018. After the proportion decreased during 2005-2007, the proportion of PLWH aged 45-59 years in Southwest and South-central were increased steadily from 11% (69/626) and 16.7% (358/2140) in 2007 to 33.8% (1138/3370) and 34.0% (1626/4780) in 2018, respectively; the proportion of PLWH aged ≥60 years showed an increasing trend during 2005-2018; while changes in the proportion of those age groups were less pronounced in North and Northeast. The proportion of PLWH infected by heterosexual contact was high at 83% (2798/3370) in Southwest, and 75.1% (3588/4780) in South-central in 2018; conversely, proportion of PLWH infected by homosexual contacts was largest in North (57.8% [500/865]) and Northeast (59.9% [561/936]). The persistent burden of treatment-naïve PLWH with severe immunosuppression remains challenging. Our results provide evidence for policy-makers to allocate resources and establish targeting strategies to identify early infection of PLWH.


Relative efficacy and safety of tofacitinib for treating psoriasis: A Bayesian network meta-analysis of randomized controlled trials.
To assess the relative efficacy and safety of tofacitinib administration (5 and 10 mg) twice daily in psoriasis patients. Randomized controlled trials (RCTs) examining the efficacy and safety of tofacitinib in psoriasis patients were included in this network meta-analysis. A Bayesian network meta-analysis was performed to combine the direct and indirect evidence from the RCTs. Five RCTs, including 3,265 patients, met the inclusion criteria. The 75% or more reduction in Psoriasis Area and Severity Index (PASI75) response rate was significantly higher in the 10-mg tofacitinib group than in the placebo group (OR, 20.53; 95% credible interval (CrI), 13.98 - 32.69). Similarly, the PASI75 response rate was significantly higher in the 50-mg etanercept and 5-mg tofacitinib groups than in the placebo group (OR, 18.39; 95% CrI, 10.19 - 36.97 and OR, 8.87; 95% CrI, 6.02 - 13.55, respectively). However, 10 mg tofacitinib tended to be more efficacious than 50 mg etanercept and 5 mg tofacitinib. Ranking probability based on Surface under the cumulative ranking curve (SUCRA) indicated that 10 mg tofacitinib had the highest probability of being the best treatment for achieving the PASI75 response rate, followed by 50 mg etanercept, 5 mg tofacitinib, and placebo. The Physician's Global Assessment (PGA) and PASI75 response rates showed similar distribution patterns. In contrast, the number of patients with serious adverse events (SAEs) or withdrawals due to AEs did not differ significantly among the 4 treatment options. Tofacitinib (10 mg) showed the highest efficacy for the intervention for psoriasis, followed by 50 mg etanercept and 5 mg tofacitinib, and was not associated with a significant risk for SAEs or AE-induced withdrawals.


Outcome of treatment of implant-retained overdenture in patients with extreme mandibular bone resorption treated with bone grafts using a modified tent pole technique.
To evaluate the outcome (prosthetic maintenance, survival of implants, patient satisfaction, and quality of life) of prosthetic treatment using an implant-retained overdenture and a modified tent pole procedure for severe mandibular resorption. Seventeen edentulous patients (mean age, 68 yr; range, 54 to 77 yr) with severely resorbed mandibles were treated with autogenous bone grafts using a modified tent pole technique and implant overdentures. A bar was used to splint the implants and the final prostheses with implant connection were completed approximately 7 months after surgery. The mean follow-up time was 5 years (1.5 to 7.4 yr). Patients filled out the Oral Health Impact Profile-14 questionnaire concerning their oral health-related quality of life, and then panoramic radiographs were taken during clinical examination. The stability of the overdenture was good in 58.8% of cases and retention was good in 64.7%. The most usual prosthetic complication was loosening of the attachment component, which occurred in 7 cases (41.2%). The amount of plaque and bleeding was more remarkable on the lingual surface of the implants and less remarkable on the buccal surface. Pocket depth around the implants seemed to correspond to intraoral implantation. The radiographs depicted excellent grafted bone survival. The patients' oral health-related quality of life was found to be good after treatment. Implant placement with bone grafting using a modified tent pole technique enables the achievement of a good prosthetic solution and the rehabilitation of occlusion, thereby improving the functionality of the prostheses and quality of life.


Right aortic arch with left descending aorta (circumflex aorta). Roentgenographic diagnosis.
Right aortic arch with retroesophageal segment is a rare anomaly with distinctive roentgenographic features. We present 2 patients, who on the barium oesophogram had an additional finding which has not previously been described. The typical features include an indentation on the right upper barium filled oesophagus (in the antero-posterior view), an oblique indentation descending from right to left (caused by the retroesophageal segment) and the left descending aorta. The oblique identation has not previously been described. The embryology and incidence of the lesion are briefly discussed.


Thoracolithiasis: a case report.
We present a rare case of incidentally found mobile thoracolithiasis in a 76-year-old cirrhotic patient on serial computed tomography scans performed before and after transarterial chemoembolization for hepatocellular carcinoma. Mobility and calcification are the important clue to diagnosing this benign condition and avoiding unnecessary surgery.


Looking back or looking all around: comparing two spell checking strategies for documents edition in an electronic patient record.
We report on the comparison of two systems for correcting spelling errors resulting in non-existent words (i.e. not listed in any lexicon). Both systems aim at improving edition of medical reports. Unlike traditional systems, based on word language models, both semantic and syntactic contexts are considered here. Both systems share the same string-to-string edit distance module, and the same contextual disambiguation principles. The differences between the two systems are located at the user interaction level: while the first system is using exclusively the left context, simulating the underlining of every mis-spelling at the end of every word typing, the second system uses the left as well as the right context and simulate a post-edition correction, when asked by the author. Our conclusion shows the improvements brought by the second approach.


Protocol of a feasibility study of a virtual personalized (N-of-1) trial for increasing low-intensity physical activity in older adults via habit formation.
Personalized interventions that can be delivered remotely are needed to increase physical activity (PA) in older adults to reduce risk of CV disease and mortality. Prior research indicates that Behavioral Change Techniques (BCTs) (e.g., goal setting, self-monitoring, behavioral repetition) can instill a habit for increasing daily walking. However, past interventions relied on between-subject randomized clinical trials, which can only only be informative about response of the hypothetical average person. Personalized trial designs can identify the benefits of an intervention for a specific individual although extended periods are required for collecting frequent measurements within-subject. Advances in remote, virtual technologies (e.g., text messaging, activity trackers), integrated with automatic platforms, can meet these requirements because they capacitate delivery of BCT interventions, and collection of data during daily life without personal contact. This Stage I-b trial is designed test whether a virtual, personalized intervention is feasible and acceptable to older adults, can elicit participant adherence and exhibit preliminary evidence for efficacy. A series of up to 60 single-arm, personalized trials, involving no personal contact, will recruit adults, 45-75 years of age, to wear an activity tracker during a 2-week baseline and a 10-week intervention. Five BCT prompts to execute a walking plan will be delivered on a daily basis during the intervention phase. Participants will rate satisfaction with personalized trial components and whether automaticity of the walking plan can be achieved. Step-counts, adherence to the walking plan and self-monitoring of step-count will also be recorded.


Intracellular studies of the convergence of sensory input on caudate neurons of cat.
Quantitative analyses of the intracellular responses to peripheral stimuli were made in a 172 neurons recorded in the head of the caudate nucleus (Cd) of cat. Responsiveness of Cd neurons was tested using auditory and somatosensory stimuli which were presented unilaterally. We found that most cells (99%) responded to both auditory and somatosensory stimuli. Excitation followed by inhibition (i.e. E-I response) was the primary pattern of intracellular response occurring approximately 75% of the time. Qualitative and quantitative analyses revealed marked similarities in the amplitudes and time courses of the intracellular responses following supramaximal stimulation of the peripheral stimuli studied. Similarly, analyses of 40 pairs of simultaneously recorded neurons revealed a marked homogeneity in the intracellular responses to the same stimulus even though the recordings were made several mm apart. The most striking feature of the simultaneous recordings was that the peaks of the initial E-I response and the afterpotentials often occurred in register after a peripheral stimulus. Furthermore, changes in the responses of pairs of simultaneously recorded neurons co-varied. Because the striatum typically demonstrates spontaneous rhythmic activity, these data suggest that a peripheral stimulus has the potential of briefly synchronizing Cd's neuronal activity.


Synthesis, radiolabeling and evaluation of [99mTc][Tc-HYNIC/EDDA]-Met(O) as a early agent for amino acid metabolic imaging in C6 glioblastoma tumor.
Amino acid metabolism is recognized as a target for medical imaging due to its increase in malignant cells. Several radiotracers with primary achievement and possible subsequent chances have been designed and tested to image amino acid metabolism. Here, we report a new amino acid conjugate, with the purpose of extending [99mTc][Tc-HYNIC/EDDA]-Met(O) for single photon emission tomography (SPECT) imaging. The S-oxo-l-methionine (Met(O)) amino acid hydrazinonicotinamide (HYNIC) chelator conjugate (HYNIC-Met(O)) was prepared, using Fmoc solid-phase synthesis, and was radiolabeled with [99mTc]technetium pertechnetate, using tricine and ethylenediamine-N,N-diacetic acid (EDDA) as co-ligands. In vitro cellular uptake profile and saturation binding of radiotracer were determined on C6 glioma cells. Biodistribution and imaging studies were carried out on rat bearing C6 tumor tissue grafts. [99mTc][Tc-HYNIC/EDDA]-Met(O) was prepared in high yield and radiochemical purity (>98 %). The partition coefficient result showed that radioconjugate was very hydrophilic. The radioconjugate indicated both high cell uptake and in vitro internalization. Low nanomolar dissociation constant (66.02 nM) in C6 glioma cells was obtained for it as well. [99mTc][Tc-HYNIC/EDDA]-Met(O) revealed magnificent tumor uptake at early time points, with 1.98 ± 0.33 % injected activity per gram tumor (% IA/g) at 30 min post injection. The tumor uptake continued for 1 and 2 h and was 0.45 ± 0.33 % IA/g at 4 h. The uptake in other organs decreased much more rapidly causing high tumor to normal organ ratios so that the highest ratio of 13.25 of tumor-to-muscle at 60 min after injection was obtained with high contrast in gamma imaging. These results point out a very favorable [99mTc]Tc-labeled amino acid for targeting amino acid metabolism through target system L amino acid transporter (LAT1) in malignant cells especially C6 glioma cells. [99mTc][Tc-HYNIC/EDDA]-Met(O) manifests extremely good distribution, excretion and imaging attributes. So it seems to be an appropriate nominate for clinical imaging.


Immobilization of horseradish peroxidase on amidoximated acrylic polymer activated by cyanuric chloride.
Horseradish peroxidase (HRP) was immobilized on amidoximated acrylic fabric after being activated with cyanuric chloride. FT-IR spectroscopy and scanning electron microscopy were used to characterize fabrics. The maximum immobilization efficiency of HRP (70%) was detected at 4% cyanuric chloride and pH 7.0. The immobilized enzyme retained 45% of its initial activity after ten reuses. The immobilization of enzyme on the carrier is saturated after 6h of incubation time. The pH was shifted from 7.0 for soluble HRP to 7.5-8.0 for the immobilized enzyme. The soluble HRP and immobilized HRP had the same optimum activity at 40°C. The immobilized HRP is more thermal stable than soluble HRP. Substrate analogues were oxidized by immobilized HRP with higher efficiencies than those of soluble HRP. Km values of the soluble HRP and the immobilized HRP were 31 and 37mM for guiacol and 5.0 and 7.8mM for H2O2, respectively. The immobilized HRP had higher efficiency for removal of phenol than that of soluble HRP. The immobilized HRP had higher resistance toward heavy metal ions compared to the soluble enzyme. The immobilized HRP was more stable against high concentration of urea, Triton X-100 and isopropanol. The immobilized HRP exhibited high resistance to proteolysis by trypsin than soluble enzyme. In conclusion, the immobilized HRP could be used as a potential efficient catalyst for the removal of aromatic pollutants from wastewater.


The corticopontocerebellar pathway to crus I in the cat as studied with anterograde and retrograde transport of horseradish peroxidase.
In 13 cats injections of horseradish peroxidase (HRP) in various parts of the cerebral cortex were combined with injections of HRP in the cerebellar crus I in the same animal in order to study the cortical regions which may influence the crus I via the pontine nuclei. In the pons terminal regions anterogradely labeled from the cerebral cortex and cell groups retrogradely labeled from crus I were carefully plotted. Overlap between sites of ending of cortical fibers and sites of origin of fibers to crus I was relatively modest in all experiments. On the other hand, partial overlap was usually found at multiple sites. The largest single input to crus I appears to come from the parietal region, particularly the anterior part of the suprasylvian gyrus, while the sensorimotor region contributes much less. Area 6, the second somatosensory cortex and the orbital gyrus, all seem able to influence pontine cells projecting to crus I. Least overlap is found after injections of the visual cortex. The size and orientation of the dendritic fields of pontine cells were studied in Golgi-impregnated material. The dendritic fields average 187 X 339 microns in the transverse plane and are so small that they will only moderately increase the overlap. It is concluded that small subgroups of neurons projecting to crus I receive somewhat different sets of cortical afferents. The input to crus I must originate in wide areas of the cerebral cortex, and probably exhibits a high degree of spatial order, with an intricate pattern of specific divergence and convergence. The present results are compatible with previous physiological evidence from micromapping studies of a precise and complicated mosaic pattern of connections to the cerebellar hemispheres.


Postless Tape Augmentation for Posterior Cruciate Ligament Reconstruction.
Many techniques have been described for posterior cruciate ligament (PCL) reconstruction, but residual laxity remains an ongoing challenge. Suture or tape augmentation during ligament reconstruction has become a popular option to prevent graft elongation but comes at the expense of additional costs due to implants for augment fixation, and concern for stress shielding of the graft if the augment and graft are not equally tensioned. We introduce a technique for postless tape augmentation during allograft PCL reconstruction that allows for equal tensioning of graft and augment through the use of a sheath and screw construct without the need for additional implants for augment fixation.


Cognitive and motor functioning in a patient with selective infarction of the left basal ganglia: evidence for decreased non-routine response selection and performance.
Focal damage to the basal ganglia is relatively rare, and little is known about the cognitive effects of damage to specific basal ganglia structures. A 28-year-old, highly educated male (patient RI) sustained a unilateral left ischemic infarction involving primarily the putamen and secondarily the head of the caudate and the anterior internal capsule. Two detailed neuropsychological assessments, at 3 and 16 months post-infarction, revealed that a majority of cognitive abilities were spared. RI's general intelligence, simple attention, concept formation, cognitive flexibility, and explicit memory were unaffected. Select cognitive abilities were affected, and these appeared to be related to direct involvement of the putamen and/or to indirect disruption of circuits between the basal ganglia and frontal lobes. Consistent with involvement of the left putamen, RI showed micrographia with his right hand. Interestingly, his micrographia was context-dependent, appearing only when verbal expression was involved (e.g., present when writing spontaneously, but not when copying sentences or when drawing). Evidence of disruption to frontal systems included variably decreased sustained attention, mildly decreased ability to generate words and to generate ideas, and significantly impaired abstraction ability in both verbal and visual modalities. Although there are several possible interpretations for these findings, this pattern of cognitive and motor functioning is consistent with neuroimaging research suggesting that the frontal/subcortical circuit between the putamen and frontal motor areas plays a role in non-routine response selection and performance.


Mating pattern variability among western toad (Bufo boreas) populations.
Breeding ecology and mating patterns of the western toad, Bufo boreas, were examined in three large explosively breeding populations in the Oregon Cascade Mountains. Two mating patterns occurred variably within and among the three populations. First, a large male mating advantage was observed in two of the three populations when data from all the days of data collection were combined. When each day of breeding was analyzed separately, there was a large male mating advantage on 3 of 5 days at one population, and mating was random on all days at the two other populations. The second mating pattern, positive assortative mating by size, was observed at two of the three populations. This pattern was found on separate days of breeding as well as when data from all days were combined at one population, and on only one day of breeding at the second population.In a survey of anuran amphibian mating patterns, intraspecific variation was found in 13 of 15 species, including the present study of the western toad. Intrapopulation variation in mating patterns among breeding years has been observed in 5 of 8 anurans, whereas within-site, within-year mating pattern variation has only been reported for the western toad. These results strongly suggest that anuran mating patterns are frequently neither species-specific nor population-specific attributes. Variable mating patterns were most commonly observed in explosively-breeding anurans. Explosive breeders may be susceptible to variable mating patterns because they may be more sensitive to fluctuations in environmental conditions, demographic parameters, and the intensities of intrasexual competition and mate choice.


Multiple schwannomatosis caused by the recently described INI1 gene--molecular pathology, and implications for prognosis.
The most common genetic predisposition to multiple schwannoma growth is mutation of the neurofibromatosis type 2 gene. We describe a patient with multiple schwannomas and mutation in the recently described INI1 gene, which also predisposes to the disease. We explore the implications for prognosis and outcome.


Sources and preservation of organic matter in soils of the wetlands in the Liaohe (Liao River) Delta, North China.
Total organic carbon, total nitrogen, δ(13)Corg, δ(15)N, and aliphatic and polyaromatic hydrocarbons of fifty-five soil samples collected from the coastal wetlands of the Liaohe Delta were measured, in order to determine the sources and possible preservation of organic matter (OM). The δ(15)N and δ(13)Corg values in the samples ranged from 3.0‰ to 9.4‰ and from -30.4‰ to -20.3‰, respectively, implying that the OM in the soils is predominantly derived from C3 plant. The long-chain n-alkanes had a strong odd-over-even carbon number predominance, suggesting a significant contribution from waxes of higher plants. The ubiquitous presence of unresolved complex mixture, alkylated polycylic aromatic hydrocarbons and typical biomarkers of petroleum hydrocarbons (pristane, phytane, hopanes and steranes) indicates that there is a contribution of petroleum hydrocarbons to the organic carbon pool in the wetland soils. P. australis-vegetated wetlands have strong potentials for the preservation of organic carbon in the wetlands.


Retrograde percutaneous nephrostolithotomy: an acceptable alternative to antegrade techniques.
Retrograde percutaneous nephrostolithotomy was attempted by the urology service in 28 patients. Renal access was achieved with the standard Lawson retrograde nephrostomy set. Tract dilation was performed over the 0.017-inch puncture wire. Successful renal access was achieved in 28 of 30 kidneys (93 per cent) and in 1 session the targeted stone was removed in 26 (87 per cent). Two patients failed the retrograde technique and underwent successful antegrade stone removal under the same anesthesia. Two patients required open stone removal. No patient required a second percutaneous procedure for incomplete stone removal, no major bleeding episodes occurred and no complications requiring surgical intervention were encountered. The technique of retrograde percutaneous nephrostolithotomy is a safe and reliable means to achieve precise, atraumatic intrarenal access. It is easy to learn and does not require the expertise of a trained radiologist.


The significance of 123I-BMIPP delayed scintigraphic imaging in cardiac patients.
Earlier studies have not fully investigated the significance of radionuclide planar imaging in cardiac patients using the fatty acid analogue 123I-beta-methyl-iodophenylpentadecanoic acid (123I-BMIPP). This study was to clarify the effectiveness of 123I-BMIPP in assessing the heart-to-mediastinum ratio (H/M) and myocardial washout rate (WR) in patients with heart disease. Myocardial 123I-BMIPP imaging was performed in 33 patients (20 with chronic heart failure [CHF] and 13 with stable angina pectoris [AP]) and 11 control subjects. Myocardial 123I-BMIPP planner images were obtained 30 min (early image) and 4 h (delayed image) after tracer injection. The left ventricular ejection fraction (LVEF) was measured by quantitative gated single photon emission computed tomography. The concentration of plasma brain natriuretic peptide (BNP) was measured before the scintigraphic study. (1) Delayed H/M was much lower in CHF than in AP (1.93 +/- 0.37 vs. 2.21 +/- 0.38, p < 0.05) and controls (vs. 2.47 +/- 0.38, p < 0.001). (2) The WR in CHF and AP were higher than the WR in controls (39.8 +/- 12.7% and 38.7 +/- 11.1 vs. 27.9 +/- 10.2%, p < 0.01 and p < 0.05, respectively). (3) In all subjects, LVEF was correlated with delayed H/M (r = 0.39, p < 0.01). And, the BNP was correlated with both the WR (r = 0.36, p < 0.05) and delayed H/M (r = - 0.29, p = 0.05). These data strongly suggest that the delayed H/M and myocardial WR of 123I-BMIPP enhances the assessment of the myocardial fatty acid metabolism disorders in patients with heart disease in both masked and unmasked conditions.


Physiologic considerations in radionuclide imaging of the extrahepatic biliary tract.
Scintigraphy of the biliary system using 99mTc-labeled radiopharmaceuticals enables the clinician to assess kinetics of bile flow through the gallbladder, common bile duct, and sphincter of Oddi. We review some aspects of biliary tract physiology and imaging which may be of interest to the physicians ordering and performing these studies.


Use of thromboelastography to assess the combined role of pregnancy and obesity on coagulation: a prospective study.
Thromboelastography (TEG®) is a point of care monitor of whole blood coagulation and has previously demonstrated hypercoagulability in both pregnant and obese populations. However, the individual and combined contribution of pregnancy and obesity on coagulation status has not been defined. We carried out a study to assess the effect of both pregnancy and body mass index (BMI) on blood coagulation using laboratory tests of coagulation and thromboelastography. This was a prospective study of 96 women divided into four equal groups; non-pregnant lean (NPL) BMI <25kg/m(2), pregnant lean (PL) BMI <25kg/m(2), non-pregnant obese (NPO) BMI >35kg/m(2) and pregnant obese (PO) BMI >35kg/m(2). Women were of either >36weeks of gestation presenting for elective caesarean delivery; non-pregnant women with BMI >35kg/m(2) presenting for bariatric surgery; or non-pregnant volunteers with BMI <25kg/m(2). Eligible women were then allocated to a group based on BMI and pregnancy status. TEG® analysis, full blood count and coagulation profiles were performed on all patients. The main outcome measures were TEG® profile (including r time, k time, α angle, maximum amplitude and coagulation index), platelet count, activated partial thromboplastin time, prothrombin time, and fibrinogen levels. The coagulation index was significantly higher in the obese patient groups compared with the lean groups (NPL -4.5 vs. NPO 1.9, P<0.001; PL -4.3 vs. PO 2.5, P<0.001). However, comparisons between the pregnant and non-pregnant groups when matched for BMI demonstrated no significant difference in coagulation. The combined effect of pregnancy and obesity on coagulation has not previously been investigated. Thromboelastographic comparison of pregnant and non-pregnant females separated into low or high BMI cohorts in the current study suggests that obesity correlates more with a hypercoagulable state than with pregnancy, particularly in pregnant patients at the extremes of low and high body weight.


Positive inotropic effects of Tityus cambridgei and T. serrulatus scorpion venoms on skeletal muscle.
Toxins that block voltage-dependent K+ channels and those that modify Na+ channel gating exhibit positive inotropic effect on skeletal muscle. We compared the effect of the venom of Tityus cambridgei (Tc) and Tityus serrulatus (Ts) scorpions on mouse diaphragm force, in vitro. In indirect and direct (using D-tubocurarine 7.3 microM) stimulation, Tc, 10microg/mL, increased the contractile force, an effect prevented by tetrodotoxin (TTX) while Ts, 0.5 microg/mL, potentiated only indirectly stimulated diaphragm, thus indicating its activity is mainly mediated through acetylcholine release from nerve terminal. This effect is prevented by TTX and attenuated by the K+ channel opener cromakalim. In conclusion, our data show that while the positive inotropic effect of both venoms appears associated to the activity of Na+ and K+ channels, only Tc venom acts also directly on skeletal muscle. This finding call for further studies on Tc venom to identify the toxin responsible for its direct inotropic activity as it may have clinical applications.


Analysis of the proteoglycans synthesized by human bone cells in vitro.
Proteoglycans were isolated by ion-exchange chromatography from the extracted cell layer and culture medium of human bone cell cultures following incubation in the presence of [35S]sulfate and [3H]leucine. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), the synthesized proteoglycans consisted of at least five polydisperse species having median apparent Mr = 600,000, 400,000, 270,000, 135,000 and 40,000. When chromatographed further on octyl-Sepharose CL-4B, the proteoglycans of the cell layer resolved into three peaks. The unbound fraction (peak cell layer-I) contained a 40,000 species consisting of a single glycosaminoglycan chain with or without peptide. Peak cell layer-II contained three sulfated species on electrophoresis: a 600,000 species uniformly distributed across the peak, a 135,000 species enriched in the ascending limb (similar to bone PG-I as described previously), and a 270,000 species (similar to bone PG-I) enriched in the descending limb. Peak cell layer-III, eluting at 0.2% Triton X-100, was highly enriched in a 400,000 proteoglycan component. When media proteoglycans were chromatographed on octyl-Sepharose, two labeled peaks were found. Peak medium-I (unbound) contained a species exhibiting electrophoretic mobility similar to that of the 400,000 species present in peak cell layer-III. Peak II of the culture medium (medium-II) was apparently identical to that of peak cell layer-II, containing the 600,000, 270,000 and 135,000 species. No appreciable 40,000 species was observed in the medium. Treatment of the 600,000 species with either chondroitinase ABC or ACII generated a core protein preparation with bands of 390,000 and 340,000 on SDS gels. Neither the intact nor the chondroitinase ABC-treated 600,000 species was immunoprecipitated by a purified, polyclonal antiserum raised against the core protein of the large chondroitin sulfate proteoglycan of human articular cartilage. Treatment of the 270,000 and 135,000 proteoglycans with chondroitinase ABC, but not ACII, generated a core protein preparation with bands of 52,000 and 49,000 on SDS gels, indicating that they were dermatan sulfate-containing species. The 400,000 species contained both heparan sulfate and chondroitin sulfate, in approximately a 3:1 labeling ratio. This species changed in electrophoretic mobility following treatment with chondroitinase ABC, heparatinase, or both enzymes in combination, which suggested that it may be a hybrid proteoglycan (i.e. both types of glycosaminoglycan chain on the same core protein).(ABSTRACT TRUNCATED AT 400 WORDS)


A Low-Cost Ultrasound Phantom for Peritonsillar Abscess Drainage Training.
Peritonsillar abscesses (PTAs) are encountered routinely in clinical practice. Ultrasound-guided aspiration has been proven both safe and effective in treating this condition. However, to date, there are no easily produced, low-cost models that enable the practice of point-of-care ultrasound-guided PTA aspiration and PTA diagnosis. The objective was to create a low-cost, easy-to-produce, ultrasound phantom to train emergency physicians on ultrasound-guided PTA drainage. We improved on previous work with ultrasound phantoms by creating a refillable phantom that approximates the oral cavity. This enabled learners to gain the manual dexterity necessary to operate an intraoral ultrasound probe while also aspirating a PTA. We have created a low-cost ultrasound phantom that is amenable to repeated ultrasound-guided aspirations for the purpose of training both resident- and attending-level physicians. With minimal lead time and readily available equipment, we successfully created a low-cost ultrasound phantom for the purpose of PTA identification and drainage.


Disseminated histiocytosis X complicated by diffuse erythrophagocytosis: report of two cases.
Two children with the clinical and histopathological features of disseminated histiocytosis X became refractory to chemotherapy and a diffuse erythrophagocytic process developed. No cause of the erythrophagocytosis could be found. Pancytopenia and marked erythrophagocytosis persisted until death ensued. The relationship of this disorder to familial erythrophagocytosis is discussed.


Curvature domains in V4 of macaque monkey.
An important aspect of visual object recognition is the ability to perceive object shape. Two basic components of complex shapes are straight and curved contours. A large body of evidence suggests a modular hierarchy for shape representation progressing from simple and complex orientation in early areas V1 and V2, to increasingly complex stages of curvature representation in V4, TEO, and TE. Here, we reinforce and extend the concept of modular representation. Using intrinsic signal optical imaging in Macaque area V4, we find sub-millimeter sized modules for curvature representation that are organized from low to high curvatures as well as domains with complex curvature preference. We propose a possible 'curvature hypercolumn' within V4. In combination with previous studies, we suggest that the key emergent functions at each stage of cortical processing are represented in systematic, modular maps.


Intra-crystalline protein diagenesis (IcPD) in Patella vulgata. Part I: Isolation and testing of the closed system.
This study successfully isolates a fraction of intra-crystalline proteins from shells of the marine gastropod Patella vulgata and assesses the suitability of these proteins for IcPD (Intra-crystalline Protein Diagenesis) geochronology. We discuss the mineralogical composition of this gastropod, investigated for the first time by X-ray diffraction mapping, and use the results to inform our sampling strategy. The potential of the calcitic rim and of a bulk sample (containing both apex and rim) of the shell to act as stable repositories for the intra-crystalline proteins during diagenesis is examined. The composition and the diagenetic behaviour of the intra-crystalline proteins isolated from different locations within the shell are compared, highlighting the necessity of targeting consistent sampling positions. We induced artificial diagenesis of both intra-crystalline and whole-shell proteins by conducting high-temperature experiments in hydrous environment; this allowed us to quantify the loss of amino acids by leaching and therefore evaluate the open- or closed-system behaviour of the different fractions of proteins. The results obtained provide further confirmation that patterns of diagenesis vary according to the protein sequence, structure, and location within or outside the intra-crystalline fraction. As Patella is frequently found in the fossil record, both in archaeological and geological contexts, the application of IcPD geochronology to this biomineral opens up the possibility to obtain reliable age information from a range of sites in different areas of the world.


WEAK SEED DORMANCY 1, an aminotransferase protein, regulates seed dormancy in rice through the GA and ABA pathways.
Seed dormancy is a critical trait that enhances plant survival by preventing seed germination at the wrong time or under unsuitable conditions. Lack of seed dormancy in rice can lead to pre-harvest sprouting on mother plants leading to reduced yield and seed quality. Although some genes have been identified, knowledge of regulation of seed dormancy is limited. Here, we characterized a weak seed dormancy mutant named weak seed dormancy 1 (wsd1) that showed a higher seed germination percentage than the wild-type following the harvest ripeness. We cloned the WSD1 encoding an aminotransferase protein using a MutMap approach. WSD1 was stably expressed after imbibition and its protein was localized in the endoplasm reticulum. A widely targeted metabolomics assay and amino acid analysis showed that WSD1 had a role in regulating homeostasis of amino acids. PAC treatment and RNA-seq analysis showed that WSD1 regulates seed dormancy by involvement in the GA biosynthesis pathway. GA1 content and expression of GA biosynthesis-related genes were increased in the wsd1 mutant compared with the wild-type. The wsd1 mutant had reduced sensitivity to ABA. Our overall results indicated that WSD1 regulates seed dormancy by balancing the ABA and GA pathways.


Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer's disease.
The drivers of sporadic Alzheimer's disease (AD) remain incompletely understood. Utilizing directly converted induced neurons (iNs) from AD-patient-derived fibroblasts, we identified a metabolic switch to aerobic glycolysis in AD iNs. Pathological isoform switching of the glycolytic enzyme pyruvate kinase M (PKM) toward the cancer-associated PKM2 isoform conferred metabolic and transcriptional changes in AD iNs. These alterations occurred via PKM2's lack of metabolic activity and via nuclear translocation and association with STAT3 and HIF1α to promote neuronal fate loss and vulnerability. Chemical modulation of PKM2 prevented nuclear translocation, restored a mature neuronal metabolism, reversed AD-specific gene expression changes, and re-activated neuronal resilience against cell death.


Improved local control and survival for surgically staged patients with locally advanced prostate cancer treated with up-front low dose rate iridium-192 prostate implantation and external beam irradiation.
In an effort to improve upon the historically poor local control and survival rates for locally advanced prostate carcinoma, a prospective multidisciplinary clinical trial was initiated using low dose rate Iridium-192 prostate implantation and external beam irradiation. Between January 1983 and September 1989, 57 patients with newly diagnosed bulky prostatic carcinoma (5 Stage B2, 52 Stage C) were treated at the Mayo Clinic (34 patients) and William Beaumont Hospital (23 patients) with (a) 5 Gy delivered preoperatively in one fraction, (b) pelvic lymphadenectomy with interstitial implantation of the prostate using Iridium-192 seeds via a perineal template to 30-35 Gy, and (c) 30.6 Gy external irradiation to prostate only in 17 fractions. After lymphadenectomy, 30/57 (53%) patients had pathologically confirmed positive lymph nodes or "D1" disease. Thirty-four patients (60%) had Gleason scores > or = 7. Mean age at diagnosis was 63.3 years. Median overall follow-up was 72 months. The 5-year actuarial survival rate was 85% and disease-free survival was 63%. The 5-year survival for patients with negative nodes was 93% and with positive nodes was 79%. The corresponding survival for patients with Gleason scores < or = 6 was 96% and > or = 7 was 78%. Multivariate analysis demonstrated that of all covariates considered, only Gleason score had prognostic significance for disease-free survival (p < 0.05) and no covariates were statistically significant for overall survival. Thirty-nine of the 57 patients had a prostatic re-biopsy performed at 18 months. Pathologically confirmed local control was ultimately achieved in 31/39 (79.5%). There was no difference in survival in patients with positive re-biopsies vs. those with negative results. The 5-year actuarial rate of clinical local control was 94%. Three patients clinically failed locally and 21 demonstrated distant progression. The median time to progression was 34 months. Nineteen percent received some form of hormonal manipulation at the time of their treatment course and an additional 42% were treated with hormones during their follow-up period, primarily after distant failure. The grade 4 rectal ulceration rate decreased to 4.5% with modification of the brachytherapy technique. Three patients experienced grade 4 urinary incontinence and three patients experienced grades 3 or 4 chronic perineal pain. These results indicate that bulky prostate carcinoma can be successfully controlled locally by this novel and aggressive approach with moderate toxicity and improved survival.


Functional mapping of the A2 domain from human factor VIII.
Coagulation factor VIII (FVIII) is a multidomain glycoprotein in which the FVIII A2 domain is a key structural element. We aimed at identifying residues within FVIII A2 domain that are crucial for the maintenance of the cofactor function. A high number (n=206) of mutants were generated by substituting original residues with alanine. The mutants were expressed in COS-1 cells and their antigen levels and procoagulant activities were measured. The residues were classified in three categories: those with a non-detrimental alteration of their activities (activity >50 % of control FVIII; n=98), those with a moderate alteration (15 %<activity<50%; n=45) and those that were severely affected (activity<15%; n=63). The mutants sensitive to mutation were retrieved in the HAMSTeRS database with a higher percentage than those that were not affected (58.8% vs. 9.2%). The results revealed the existence of clusters of residues that are sensitive (Arg418-Phe436, Thr459-Ile475, Ser535-Gly549, Asn618-Ala635) or not (Leu398-Arg418, Pro485-Asp500, Gly506-Gly520, Pro596-Asp605) to mutations. The stretches of residues sensitive to mutations were buried within the molecule suggesting that these amino acids participate in the maintenance of the A2 domain structure. In contrast, residues resistant to mutations formed external loops without well- defined structures suggesting that these loops were not crucial for the process of factor X activation. This study provided a detailed map of the FVIII A2 domain between residues 371 and 649, identifying residues crucial for maintaining FVIII function and residues that can be mutated without jeopardising the coagulant activity.


Ventricular haemorrhages and hypoxic-ischaemic lesions in preterm infants: neurodevelopmental outcome at 3 1/2 years.
The association of cerebral ultrasound images and developmental outcome at age 3 1/2 years was studied in 50 preterm infants (mean gestational age 31 weeks, mean birthweight 1450 g). 25 children had normal neonatal scans and 25 had abnormal neonatal scans; 11 without and 14 with ventricular dilatation. At one year a repeat scan was done and neurodevelopmental outcome was assessed. Follow-up results at 3 1/2 years stress the importance of long-term follow-up: at one year four of the 50 children had developmental deficits, at 3 1/2 years 13 had such deficits. At 3 1/2 years the risk of neurodevelopmental deficits was extremely high for children with persistent haemorrhagic and/or atrophic ventricular dilatation. There was significant over-representation of children with developmental deficits in the group with abnormal scans, both neonatally and at one year. The incidence of cerebral palsy was high in the group with large haemorrhages extending into the parenchyma and/or periventricular leucomalacia. In the group with periventricular leucomalacia there was also a greater risk of mental retardation with severe behavioural problems. Follow-up at a later age than 3 1/2 years will be necessary to determine the effects on the motor, intellectual and emotional development of these children.


Distribution, contamination status and source of trace elements in the soil around brick kilns.
This study reports the distribution, contamination level, and possible sources of 54 metal (oid)s in the soils found around brick kilns in south-western Bangladesh. In total, 40 soil samples were collected from the vicinity of five brick kilns in four directions at 250 m intervals. This study reveals that the mean respective concentrations of caesium (Cs), beryllium (Be), lead (Pb), cerium (Ce), praseodymium (Pr), neodymium (Nd), samarium (Sm), europium (Eu), dysprosium (Dy), holmium (Ho), terbium (Tb), erbium (Er), thulium (Tm), ytterbium (Yb), thorium (Th), germanium (Ge), yttrium (Y), zirconium (Zr), niobium (Nb), silver (Ag), hafnium (Hf), tantalum (Ta), and tungsten (W), were 7.83, 3.19, 22.93, 85.93, 9.61, 36.86, 7.30, 1.23, 5.76, 1.13, 0.99, 3.14, 0.45, 2.91, 17.72, 3.04, 30.07, 185.13, 13.99, 0.30, 5.34, 1.26, and 2.61 μg g-1. Furthermore, those amounts exceeded their respective shale values. The pollution evaluation indices indicated a moderate level of contamination by Cs, Pb, Th, Ag, Hf, Ta, W, and lanthanides but excluding lanthanum (La) and lutetium (Lu). The pollution load index revealed pollution at two brickfields. Multivariate statistics reported that coal combustion in the brick kilns is the primary source of lanthanides, actinides, Y, Zr, and Hf in the soil, while other elements derived mostly from natural sources. A portion originated from coal combustion in brick kilns and agricultural activities. Changes in metal (oid)s concentrations were non-linear with the distance between the kilns and sampling points. Consequently, further studies are required and should consider meteorological factors and severity of human impact in the study area.


Localized operable soft tissue sarcoma of the upper extremity. Presentation, management, and factors affecting local recurrence in 108 patients.
Radical ablative surgery for upper extremity sarcoma often results in significant loss of function. With the recent emphasis on limb preservation, function-sparing excision has been combined with adjuvant radiation and chemotherapy in an increasing number of patients. To assess the effect of changing management on local recurrence rates and identify factors governing local failure, the records of 108 patients with operable, nonmetastatic soft tissue sarcoma of the upper extremity, treated at the Memorial Sloan-Kettering Cancer Center between 1968 and 1978, were reviewed. Median follow-up care was 8.2 years. One third of the patients presented with locally recurrent tumors after initial treatment elsewhere. Over half of the lesions were above the elbow and 62% were high grade. Seventy-three patients (68%) had limb-sparing surgery (LSS), but margins were considered adequate in less than half. Local recurrence was directly related to the adequacy of the surgical margins and was significantly higher in the LSS patients (p = 0.008). Other factors associated with an increased risk of local failure included: presentation with local recurrence, superficial location, and invasion of vital structures (LSS only). Local failure varied significantly with histologic type and was highest in patients with embryonal rhabdomyosarcoma and angiosarcoma. When the data were subjected to multivariate analysis, the following variables emerged as independent predictors of local failure: presentation with local recurrence, surgery by LSS, inadequate margins, angiosarcoma, and invasion of vital structures. These risk factors should be carefully weighed when selecting local treatment for patients with upper extremity soft tissue sarcomas.


Two novel phenylacetoxylated p-terphenyls from Thelephora ganbajun Zang.
Two novel phenylacetoxylated p-terphenyl derivatives, namely ganbajunin F (6'-methoxy-2'-phenylacetoxy-3', 4, 4", 5'-tetrahydroxy- p-terphenyl), and ganbajunin G (5'-methoxy-2'-phenylacetoxy-3', 4, 4", 6'-tetrahydroxy-p-terphenyl), together with a known compound cycloleucomelone were isolated from the fruiting bodies of Thelephora ganbajun Zang. Their structures were established on the basis of spectral (MS, IR, NMR, HMBC, HMQC measurement) and chemical evidence.


Gut dysbiosis, endotoxemia and clotting activation: A dangerous trio for portal vein thrombosis in cirrhosis.
Liver cirrhosis (LC) is associated with portal venous thrombosis (PVT) in roughly 20% of cirrhotic patients but the underlying mechanism is still unclear. Low-grade endotoxemia by lipopolysaccharides (LPS), a component of outer gut microbiota membrane, is detectable in the portal circulation of LC and could predispose to PVT. LPS may translocate into systemic circulation upon microbiota dysbiosis-induced gut barrier dysfunction, that is a prerequisite for enhanced gut permeability and ensuing endotoxemia. Experimental and clinical studies provided evidence that LPS behaves a pro-thrombotic molecule so promoting clotting and platelet activation. Experiments conducted in the portal circulation of cirrhotic patients showed the existence of LPS-related enhanced thrombin generation as well as endothelial dysfunction, venous stasis, and platelet activation. The review will analyze 1) the pro-thrombotic role of endotoxemia in the context of LC 2) the biological plausibility linking endotoxemia with PVT and 3) the potentially interventional tools to lower endotoxemia and eventually hypercoagulation.


New insights on Schwann cell development.
In the peripheral nervous system, Schwann cells are glial cells that are in intimate contact with axons throughout development. Schwann cells generate the insulating myelin sheath and provide vital trophic support to the neurons that they ensheathe. Schwann cell precursors arise from neural crest progenitor cells, and a highly ordered developmental sequence controls the progression of these cells to become mature myelinating or nonmyelinating Schwann cells. Here, we discuss both seminal discoveries and recent advances in our understanding of the molecular mechanisms that drive Schwann cell development and myelination with a focus on cell-cell and cell-matrix signaling events.


[Experimental use of dentin bonding agents and a cavity varnish to reduce marginal microleakage in high copper amalgam restorations].
The effects of a cavity varnish and two bonding agents on marginal microleakage at the interface of amalgam restorations and cavity walls in extracted teeth is investigated with a dye penetration technique. Marginal microleakage associated with amalgam restorations can be greatly reduced by paintings a bonding agent on the inner wall of the cavity.


Partial denture framework design for bone-grafted mandibles restored with osseointegrated implants.
Unilateral osseous reconstruction of a dentate mandible after tumor ablation may be restored with implants and a removable partial denture. Often the remaining dentition is in a "straight line" that does not allow cross-arch stabilization of the framework. Framework design incorporating existing unilateral lingual or buccal retention in the natural dentition and unilateral implant attachments affords a stable, retentive definitive prosthesis for this patient population.


Carpal tunnel release using the MANOS CTR system: preliminary results in 52 patients.
To describe a carpal tunnel release technique using the MANOS Carpal Tunnel Release device, with preliminary results in 52 patients. The MANOS Carpal Tunnel Release device is a blade that divides the transverse carpal ligament using wrist and palm skin punctures. The awake patient provides feedback as the surgeon navigates a 2.1-mm-diameter blunt probe across the undersurface of the ligament from a wrist incision with standard disposable nerve stimulator monitoring. The leading tip of the blunt probe is uninsulated and conducts 2 mA. The surgeon converts the blunt insulated probe into an uninsulated blade by advancing a 0.9-mm needle through the palm with a thumb-activated deployment feature. The surgeon saws the ligament through the 2 skin punctures. We used a validated outcome questionnaire to assess postoperative symptoms at 3 months. Symptom severity and functional status scores compare favorably with literature controls for open and endoscopic surgery at 3 months. One patient required reoperation for incomplete release. There were no tendon or nerve injuries. Preliminary results suggest the MANOS Carpal Tunnel Release device to be safe and effective. Therapeutic IV.


Learning musculoskeletal anatomy through new technologies: a randomized clinical trial.
to investigate the influence of the application of new methodologies on learning and the motivation of students of the Anatomy discipline. randomized, longitudinal, prospective, intervention study. Sixty-two students were recruited to assess the impact of different methodologies. The sample was randomized to compare the results of teaching with a 3D atlas, ultrasound and the traditional method. The parameters were assessed through a satisfaction evaluation questionnaire and anatomical charts. Repeated measures ANOVA was used to determine statistical significance. in terms of the usefulness of the seminars, 98.1% of the students considered them to be very positive or positive, stating that they had stimulated their interest in anatomy. The students who learned with the 3D atlas improved their understanding of anatomy (p=0.040). In general, the students improved their grades by around 20%. the traditional method combined with new technologies increases the interest of students in human anatomy and enables them to acquire skills and competencies during the learning process.


[The place of total aerodigestive upper endoscopy in oncology].
The epidemiology of upper digestive and bronchogenic carcinoma shows a large overlap between the high risk groups. Thus, a candidate for bronchogenic carcinoma is also a possible candidate for upper digestive cancer. Furthermore, the high frequency of multiple carcinoma in the upper aero-digestive tract, the esophagus and the tracheo-bronchial tree warrants a pan-endoscopic (buccal-pharyngo-esophagoscopy and laryngo-tracheo-bronchoscopy) approach to the problem. Using this type of endoscopy, 16 multiple carcinomas have so far been simultaneously discovered among 200 pan-endoscopies.


An indication for "granny glasses".
A young woman with a large astigmatic refractive error obtained no visual improvement with glasses. Repeated manifest refractions revealed persistent variations in the apparent cylinder axis. A suitable choice of spectacle frames facilitated a satisfactory outcome. The pitfalls inherent in the clinical specification of cylinder axis, and the potential visual consequences, are discussed.


[Xerostomia].
A great many conditions may lead to dry mouth; indeed, xerostomy is a very frequent clinical finding that occasionally does not receive the attention deserved. A review of this condition is carried out, providing a practical perspective for the general stomatologist regarding the physiopatological mechanisms involved, the clinical manifestations, diagnostic procedures and current therapeutic approaches.


The correction of alpha7 nicotinic acetylcholine receptor concentration-response relationships in Xenopus oocytes.
The rapid desensitization of alpha7 nicotinic acetylcholine receptors (nAChR) has presented a serious problem for the characterization of this receptor subtype, potentially confounding the interpretation of concentration-response relationships. However, the consistency of cell geometry and solution flow in oocyte recordings permits estimations of instantaneous concentrations to be made in this system. Results interpreted with predicted instantaneous concentrations suggest that estimates of EC50 derived from conventional analysis may overestimate the actual EC50 values by a factor of 10 and underestimate Hill slopes by a factor of 2-3. If the limiting desensitization process of alpha7 receptors is driven by the agonist concentration itself rather than by time-dependent processes, then similar dependencies may exist between the response and instantaneous agonist concentration in other systems.


Multimodality molecular imaging: Gaining insights into the mechanisms linking chronic stress to cardiovascular disease.
Positron emission tomography (PET) imaging can yield unique mechanistic insights into the pathophysiology of atherosclerosis. 18F-fluorodeoxyglucose (18F-FDG), a radiolabeled glucose analog, is retained by cells in proportion to their glycolytic activity. While 18F-FDG accumulates within several cell types in the arterial wall, its retention correlates with macrophage content, providing an index of arterial inflammation (ArtI) which predicts subsequent cardiovascular disease (CVD) events. Furthermore, 18F-FDG-PET imaging allows the simultaneous assessment of metabolic activity in several tissues (e.g., brain, bone marrow) and is performed in conjunction with cross-sectional imaging that enables multi-organ structural assessments. Accordingly, 18F-FDG-PET/computed tomography (CT) imaging facilitates evaluation of disease pathways that span multiple organ systems. Within this paradigm, 18F-FDG-PET/CT imaging has been implemented to study the mechanism linking chronic stress to CVD. To evaluate this, stress-associated neural activity can be quantified (as metabolic activity of the amygdala (AmygA)), while leukopoietic activity, ArtI, and coronary plaque burden are assessed concurrently. Such simultaneous quantification of tissue structures and activities enables the evaluation of multi-organ pathways with the aid of mediation analysis. Using this approach, multi-system 18F-FDG-PET/CT imaging studies have demonstrated that chronically heightened stress-associated neurobiological activity promotes leukopoietic activity and systemic inflammation. This in turn fuels more ArtI and greater non-calcified coronary plaque burden, which result in more CVD events. Subsequent studies have revealed that common stressors, such as chronic noise exposure and income disparities, drive the front end of this pathway to increase CVD risk. Hence, multi-tissue multimodality imaging serves as a powerful tool to uncover complex disease mechanisms.


Loss of adaptability of horizontal optokinetic response eye movements in mGluR1 knockout mice.
Metabotropic glutamate receptor subtype 1 (mGluR1) plays an essential role in the cerebellar long-term depression (LTD). We examined the dynamic characteristics and adaptability of horizontal vestibulo-ocular reflex (HVOR) and optokinetic response (HOKR) eye movements in mGluR1 knockout mice. A mild difference was seen in the HOKR/HVOR dynamics between the wild-type and mGluR1(-/-) mice. Exposure to 1 h of sustained screen oscillation, which induced HOKR adaptation in wild-type mice, induced no change in mutant mice. These results suggest that the mGluR1 plays an essential role in the adaptation of HOKR, and LTD underlies the adaptation of ocular reflexes.


Okadaic acid-sensitive protein phosphatases dephosphorylate MARCKS, a major protein kinase C substrate.
The myristoylated alanine-rich C kinase substrate (MARCKS) undergoes a rapid and, in certain circumstances, transient increase in phosphorylation in response to stimuli that activate protein kinase C. We have investigated the protein-serine/threonine phosphatase activity responsible for reversing the phosphorylation of MARCKS. In cell-free assays, protein phosphatases 1, 2A and 2C (PP1, PP2A and PP2C) all dephosphorylate recombinant MARCKS or a synthetic peptide based on its phosphorylation site domain. In intact Swiss 3T3 cells, okadaic acid, a specific inhibitor of PP1 and PP2A, had little effect on MARCKS phosphorylation on its own, but largely prevented the dephosphorylation of MARCKS that occurred following activation of protein kinase C by bombesin with subsequent receptor blockade. These results indicate that although the dephosphorylation of MARCKS can be mediated by PP2C in vitro, this protein is dephosphorylated by okadaic acid-sensitive phosphatases in the intact cell.


PINK1 and Parkin regulate IP3R-mediated ER calcium release.
Although defects in intracellular calcium homeostasis are known to play a role in the pathogenesis of Parkinson's disease (PD), the underlying molecular mechanisms remain unclear. Here, we show that loss of PTEN-induced kinase 1 (PINK1) and Parkin leads to dysregulation of inositol 1,4,5-trisphosphate receptor (IP3R) activity, robustly increasing ER calcium release. In addition, we identify that CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) functions downstream of Parkin to directly control IP3R. Both genetic and pharmacologic suppression of CISD1 and its Drosophila homolog CISD (also known as Dosmit) restore the increased ER calcium release in PINK1 and Parkin null mammalian cells and flies, respectively, demonstrating the evolutionarily conserved regulatory mechanism of intracellular calcium homeostasis by the PINK1-Parkin pathway. More importantly, suppression of CISD in PINK1 and Parkin null flies rescues PD-related phenotypes including defective locomotor activity and dopaminergic neuronal degeneration. Based on these data, we propose that the regulation of ER calcium release by PINK1 and Parkin through CISD1 and IP3R is a feasible target for treating PD pathogenesis.


Temporal changes in metabolites of prostanoids in milk of heifers after intramammary infusion of Escherichia coli organisms.
A study was conducted to characterize the changes in the concentrations of three metabolites of prostanoids in the milk of a) heifers (n = 14; control) inoculated with Escherichia coli (E. coli) organisms into the udder and b) in heifers (n = 10; treatment) vaccinated with E. coli bacterin and treated similar to control heifers. Milk samples were obtained from the challenged quarter and analyzed for the concentrations of stable metabolites of thromboxane A2 (TXB2), prostacyclin (PCM) and prostaglandin E2 (PGEM) using radioimmunoassays. In control heifers milk TXB2 concentrations were significantly higher (P = 0.03) compared to treated heifers. Milk PCM concentrations increased significantly (P = 0.02) in control and treated heifers after the respective treatments, however, differences between the two groups were not significant. Milk PGEM concentrations also increased significantly (P = 0.02) in control and treated heifers after the respective treatments, and there were no differences between the two groups. Results of the present study suggest that, the prostanoids have a role in the pathophysiologic process of coliform mastitis.


Results of a two-center, before and after study of piperacillin-tazobactam versus ampicillin and gentamicin as empiric therapy for suspected sepsis at birth in neonates ≤ 1500 g.
We changed from ampicillin and gentamicin (AG) to piperacillin-tazobactam (PT) for routine treatment of suspected early-onset sepsis. The rationale for this change included ototoxic and renal toxic effects of gentamicin, resistance to gentamicin in late-onset infections and emergence of ampicillin resistant Escherichia coli. A before and after study was designed before the start of PT administration to monitor whether PT was associated with altered outcomes within the 501 to 1500 g birth weight (Very Low Birth Weight) population. Both unmatched and matched comparisons of AG (2007 to 2009) and PT (2010 to 2011) exposed infants are reported. Cohorts were evaluated for initial effectiveness for congenital infections, subsequent morbidities and mortality. Data from 714 patients were collected (499 AG and 215 PT in the unmatched and 301 AG and 183 PT in the matched cohorts). No significant differences in demographics or initial Apgar scores were noted in the unmatched or matched comparisons. There were significant differences in many of the outcomes of interest in both the matched and unmatched comparisons including less necrotizing enterocolitis (NEC) and less diaper rash with PT versus AG. The only adverse finding with PT was a small, but statistically significant elevation in alkaline phosphatase. Use of PT as the initial empiric antibiotic for very low birth weight infants was not associated with adverse microbiological outcomes. There was no increase in major morbidities. Although outcomes were superior in ≤ 1500 g infants treated with PT when compared with AG, the study design does not allow us to conclude that others will see a reduction in NEC or diaper rash if they implement this alternative.


Occupational health and safety surveillance and research using workers' compensation data.
Examine uses of US workers' compensation (WC) data for occupational safety and health purposes. This article is a summary of the proceedings from an invitational workshop held in September 2009 to discuss the use of WC data for occupational safety and health prevention purposes. Workers' compensation data systems, although limited in many ways, contain information such as medical treatments, their costs and outcomes, and disability causes that are unavailable from national occupational surveillance sources. Despite their limitations, WC records are collected in a manner consistent with many occupational health and safety surveillance needs. Reports are available on the use of WC data for surveillance and research purposes such as estimating the frequency, magnitude, severity, and cost of compensated injuries. Inconsistencies in WC data can limit generalization of research results.


Effects of season and area on ectoparasites of white-tailed deer (Odocoileus virginianus) in Mississippi.
Nine species of ectoparasites (4 Acari, 2 Mallophaga, 1 Anoplura, 1 Diptera, and 1 Siphonaptera) were recovered from 126 white-tailed deer collected in northern, central, and southern Mississippi. Intensity and prevalence of adults of Ixodes scapularis and larvae, nymphs, and adults of Amblyomma americanum varied significantly over collection periods, but not between host sexes. Lipoptena mazamae occurred on deer from only one study area. Although individual deer were heavily parasitized by Tricholipeurus parallelus and T. lipeuroides, their prevalence was limited. Hoplopsyllus sp., Solenopotes sp., Amblyomma maculatum, and Dermacentor albipictus had prevalences of less than 10% and were not tested for area, host sex, and seasonal effects. The potential pathogenicity of these ectoparasite species are related to white-tailed deer in Mississippi.


[The content of gonadotropic hormones in commercial immunoglobulin preparations].
The authors carried out a comparative quantitative and biological determination of gonadotropins in 32 batches of immunoglobulin preparations made of the abortive, placental, and donor blood sera. The maximal amounts of gonadotropins were contained in preparations obtained from the abortive blood serum. It was shown that purification by Kohn's method (variant B) led only to the partial purification of immunoglobulins from the gonadotropin admixtures.


Contraction intensity and sex differences in knee-extensor fatigability.
Females are less fatigable than males during isometric contractions across various muscles and intensities. However, sex differences in knee-extensor fatigability remain relatively unexplored. To determine the sex difference in performance fatigability for intermittent, isometric contractions of the knee-extensor muscles. Eighteen participants (10 males, 8 females) performed intermittent, isometric, knee-extensor contractions at 30% of their maximal voluntary force (MVC) for 30min and in a separate session at 50% MVC until task-failure. During both fatiguing protocols a MVC was performed every 60s and electromyography (EMG) was recorded during all contractions. At task completion males had a larger reduction in MVC force for the 30% MVC task (-32±15% vs. -15±16%, P=0.042) and the 50% MVC task (-34±8% vs. -24±1%, P=0.045). Furthermore, for the 50% MVC task, females had a longer task duration (937±525svs. 397±153s, P=0.007). The rise in EMG activity and force fluctuations were more rapid for the males than females (P<0.05). When participants were matched for strength post hoc (n=10), a sex difference in fatigability for both tasks was still evident. Females were less fatigable than males during intermittent, isometric, knee-extensor contractions at moderate relative forces and this difference was independent of strength.


Metronidazole.
Metronidazole is a highly effective therapy for anaerobic infections and a variety of protozoal and parasitic diseases. Its pharmacokinetics, toxicities, and unique mode of action are reviewed in detail. Indications for use and respective dosages are suggested.


The pattern-evoked electroretinogram (PERG): age-related alterations and changes in glaucoma.
Pattern-onset electroretinograms (PERGs) were studied in 147 normal subjects of different ages (14-79 years) and in 110 eyes of 65 patients with glaucoma or ocular hypertension. The responses showed an increase (P less than 0.001) in peak latency with increasing age and a decrease (P less than 0.001) in amplitude which approximately parallels the loss of ganglion cells estimated by other authors. Many glaucoma eyes showed a loss of the normally present spatial tuning. In the age group above 50 years 50% of the onset responses were significantly diminished and the peak latencies were not significantly different. A negative correlation (P less than 0.001) was found between the size of the PERG and the cup/disc ratio and a positive correlation (P less than 0.001) with the area of the neuroretinal rim of the optic disc. The PERG decreased (P less than 0.01) with increasing visual field losses.