Recovery of C-starts, equilibrium and targeted feeding after whole spinal cord crush in the adult goldfish Carassius auratus.
Central nervous system neurons of many adult teleost fish are capable of regrowth across spinal cord lesions, which may result in behavioral recovery of swimming. Since there have been few, if any, studies that examine the return of behaviors other than swimming, we provide a quantitative analysis of the recovery of C-starts that occur in adult goldfish after spinal cord injury. In addition, we include a qualitative analysis of the return of targeted feeding and equilibrium. Whole spinal cord crushes near the junction of the brain and spinal cord [spinomedullary level (SML)] were made in 45 experimental fish. Eight sham-operated goldfish served as controls for the effects of the surgery procedures alone. After spinal cord crush and recovery from the anesthetic, experimental fish lay on their sides with no movement caudal to the wound. The fish were monitored for the return of behaviors for up to 190 days postoperatively. Twenty-five fish survived the course of this study. Of these fish, 12 regained equilibrium and C-starts, two regained equilibrium but not C-starts, and 11 did not regain equilibrium (one of these did display a C-start). Twenty-two of the 25 experimental fish that survived the 190 days were able to target food from the water surface. Quantitative analysis of recovered C-starts in this study revealed that the probability of eliciting the response is reduced, that latencies from stimulus to response are longer and that movement parameters (i.e. angles, distance and velocity) are reduced compared with those of sham-operated control animals for up to 190 days postoperatively. The recovery of C-starts, equilibrium and targeted feeding was due to re-growth across the wound site, since re-crushing the spinal cord at the SML resulted in the loss of these behaviors. Mauthner cells are known to initiate C-starts in goldfish. Since the majority of M-axons that regrow across a crush wound associate with an inappropriate pathway (i.e. the first ventral root), it is unlikely that these cells play a major role in the return of C-starts. We propose that regeneration of Mauthner cell homologues across the wound site is responsible for the recovery of most C-starts. The identifiability of the M-cell and its homologues provides a unique opportunity to analyze the mechanisms underlying behavioral recovery at the cellular level.


Sequential adsorption of bovine mucin and lactoperoxidase to various substrates studied with quartz crystal microbalance with dissipation.
Mucin and lactoperoxidase are both natively present in the human saliva. Mucin provides lubricating and antiadhesive function, while lactoperoxidase has antimicrobial activity. We propose that combined films of the two proteins can be used as a strategy for surface modification in biomedical applications such as implants or biosensors. In order to design and ultilize mixed protein films, it is necessary to understand the variation in adsorption behavior of the proteins onto different surfaces and how it affects their interaction. The quartz crystal microbalance with dissipation (QCM-D) technique has been used to extract information of the adsorption properties of bovine mucin (BSM) and lactoperoxidase (LPO) to gold, silica, and hydrophobized silica surfaces. The information has further been used to retrieve information of the viscoelastic properties of the adsorbed film. The adsorption and compaction of BSM were found to vary depending on the nature of the underlying bare surface, adsorbing as a thick highly hydrated film with loops and tails extending out in the bulk on gold and as a thinner film with much lower adsorbed amount on silica; and on hydrophobic surfaces, BSM adsorbs as a flat and much more compact layer. On gold and silica, the highly hydrated BSM film is cross-linked and compacted by the addition of LPO, whereas the compaction is not as pronounced on the already more compact film formed on hydrophobic surfaces. The adsorption of LPO to bare surfaces also varied depending on the type of surface. The adsorption profile of BSM onto LPO-coated surfaces mimicked the adsorption to the underlying surface, implying little interaction between the LPO and BSM. The interaction between the protein layers was interpreted as a combination of electrostatic and hydrophobic interactions, which was in turn influenced by the interaction of the proteins with the different substrates.


Albumin in decompensated cirrhosis: new concepts and perspectives.
The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.


The absence of resting-state high-gamma cross-frequency coupling in patients with tinnitus.
Tinnitus is a psychoacoustic phantom perception of currently unknown neuropathology. Despite a growing number of post-stimulus tinnitus studies, uncertainty still exists regarding the neural signature of tinnitus in the resting-state brain. In the present study, we used high-gamma cross-frequency coupling and a Granger causality analysis to evaluate resting-state electroencephalographic (EEG) data in healthy participants and patients with tinnitus. Patients with tinnitus lacked robust frontal delta-phase/central high-gamma-amplitude coupling that was otherwise clearly observed in healthy participants. Since low-frequency phase and high-frequency amplitude coupling reflects inter-regional communication during cognitive processing, and given the absence of frontal modulation in patients with tinnitus, we hypothesized that tinnitus might be related to impaired prefrontal top-down inhibitory control. A Granger causality analysis consistently showed abnormally pronounced functional connectivity of low-frequency activity in patients with tinnitus, possibly reflecting a deficiency in large-scale communication during the resting state. Moreover, different causal neurodynamics were characterized across two subgroups of patients with tinnitus; the T1 group (with higher P300 amplitudes) showed abnormal frontal-to-auditory cortical information flow, whereas the T2 group (with lower P300 amplitudes) exhibited abnormal auditory-to-frontal cortical information control. This dissociation in resting-state low-frequency causal connectivity is consistent with recent post-stimulus observations. Taken together, our findings suggest that maladaptive neuroplasticity or abnormal reorganization occurs in the auditory default mode network of patients with tinnitus. Additionally, our data highlight the utility of resting-state EEG for the quantitative diagnosis of tinnitus symptoms and the further characterization of tinnitus subtypes.


Characterization of IL-22 and antimicrobial peptide production in mice protected against pulmonary Cryptococcus neoformans infection.
Cryptococcus neoformans is a significant cause of fungal meningitis in patients with impaired T cell-mediated immunity (CMI). Experimental pulmonary infection with a C. neoformans strain engineered to produce IFN-γ, H99γ, results in the induction of Th1-type CMI, resolution of the acute infection, and protection against challenge with WT Cryptococcus. Given that individuals with suppressed CMI are highly susceptible to pulmonary C. neoformans infection, we sought to determine whether antimicrobial peptides were produced in mice inoculated with H99γ. Thus, we measured levels of antimicrobial peptides lipocalin-2, S100A8, S100A9, calprotectin (S100A8/A9 heterodimer), serum amyloid A-3 (SAA3), and their putative receptors Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE) in mice during primary and recall responses against C. neoformans infection. Results showed increased levels of IL-17A and IL-22, cytokines known to modulate antimicrobial peptide production. We also observed increased levels of lipocalin-2, S100A8, S100A9 and SAA3 as well as TLR4(+) and RAGE(+) macrophages and dendritic cells in mice inoculated with H99γ compared with WT H99. Similar results were observed in the lungs of H99γ-immunized, compared with heat-killed C. neoformans-immunized, mice following challenge with WT yeast. However, IL-22-deficient mice inoculated with H99γ demonstrated antimicrobial peptide production and no change in survival rates compared with WT mice. These studies demonstrate that protection against cryptococcosis is associated with increased production of antimicrobial peptides in the lungs of protected mice that are not solely in response to IL-17A and IL-22 production and may be coincidental rather than functional.


Atrial mechanics and their prognostic impact in Takotsubo syndrome: a cardiovascular magnetic resonance imaging study.
The exact pathophysiology of Takotsubo syndrome (TTS) remains not fully understood with most studies focussing on ventricular pathology. Since atrial involvement may have a significant role, we assessed the diagnostic and prognostic potential of atrial cardiovascular magnetic resonance feature tracking (CMR-FT) in TTS. This multicentre study recruited 152 TTS patients who underwent CMR on average within 3 days after hospitalization. Reservoir [total strain εs and peak positive strain rate (SR) SRs], conduit (passive strain εe and peak early negative SRe), and booster pump function (active strain εa and peak late negative SRa) were assessed in a core laboratory. Results were compared with 21 control patients with normal biventricular function. A total of 20 patients underwent follow-up CMR (median 3.5 months, interquartile range 3-5). All patients were approached for general follow-up. Left atrial (LA) but not right atrial (RA) reservoir and conduit function were impaired during the acute phase (εs: P = 0.043, εe: P < 0.001, SRe: P = 0.047 vs. controls) and recovered until follow-up (εs: P < 0.001, SRs: P = 0.04, εe: P = 0.001, SRe: P = 0.04). LA and RA booster pump function were increased in the acute setting (LA-εa: P = 0.045, SRa: P = 0.002 and RA-εa: P = 0.004, SRa: P = 0.002 vs. controls). LA-εs predicted mortality [hazard ratio 1.10, 95% confidence interval (CI) 1.01-1.20; P = 0.037] irrespectively of established cardiovascular risk factors (P = 0.019, multivariate analysis) including left ventricular ejection fraction (LVEF) (area under the curve 0.71, 95% CI 0.55-0.86, P = 0.048). TTS pathophysiology comprises transient impairments in LA reservoir and conduit functions and enhanced bi-atrial active booster pump functions. Atrial CMR-FT may evolve as a superior marker of adverse events over and above established parameters such as LVEF and atrial volume.


[Assessment of the effects of dipyridamole and dobutamine on coronary microcirculation using myocardial contrast echocardiography].
To evaluate the effects of dipyridamole and dobutamine on myocardial blood flow (MBF) and myocardial blood volume (MBV), and their ability to detect non-flow-limiting coronary stenoses with myocardial contrast echocardiography (MCE). Thirteen closed-chest dogs were studied at 7-10 days after placement of ameroid constrictors around proximal coronary arteries and their branches. MBF was measured with radiolabeled microspheres and myocardial plateau video intensity (VI, which indicates relative MBV) and microbubble velocity (beta) were measured with MCE at rest, after dipyridamole (0.56 mg/kg), and during peak dobutamine dose (30-40 micrograms.kg-1.min-1). The effects of both agents on MBF were similar in abnormal and normal segments. Plateau VI increased more and beta increased less with dobutamine than dipyridamole (P < 0.05), but the plateau VI ratios and beta ratios between abnormal and normal segments were almost identical during both drugs (P < NS), resulting in similar perfusion defects. Excellent linear relations were found between the plateau VI ratio or beta ratio and MBF (derived from radiolabeled microspheres) ratio from abnormal and normal beds during dipyridamole and dobutamine. Although the effect of dipyridamole and dobutamine on MBV is different, they unmask MBF reserve to a similar extent. Thus, the quantification of stenosis severity is identical using both agents with MCE.


Association between rs267196 and rs267201 of BMP6 gene and osteonecrosis among sickle cell aneamia patients.
The skeletal manifestations of sickle cell disease are the result of changes in bone and bone marrow caused by chronic tissue hypoxia that is exacerbated by episodic occlusion of the microcirculation by the abnormal sickle cells. Furthermore, the occurrence of osteonecrosis is under the control of some modifier gene. BMP6 (Bone morphogenetic protein) has been reported as associated with osteonecrosis in sickle cell anemia (SCA). Herein, we intend to study the impact of rs267196, rs267201, rs408505 and rs449853 of BMP6 gene in the occurrence of osteonecrosis among sickle cell patients in Tunisia. Our study involved 100 SCA patients among whom 19 have osteonecrosis of the head of the femur. The latter polymorphisms of BMP6 gene were analyzed for all subjects by PCR/sequencing. To test for trait association with the candidate SNPs, genotype and allele frequencies between cases (osteonecrosis group) and controls (non-osteonecrosis group) were compared using Pearson's chi_square test with a significance threshold of P<0.05 (compare 2, version 1.02). Our findings showed that the patients carried genotype TA of rs 267196 and genotype AG of rs267201 present a high risk factor for developing osteonecrosis RR=1.317 and RR=1.3 respectively. The results showed a significant association between the alleles A of rs 267196 and G of rs267201 and osteonecrosis P=0.0023; RR=2.42 and P=0.041; RR=2.24 respectively. Interestingly, SCA patients with the combined genotype TA/AG were found to be at higher risk of developing osteonecrosis (P=0.009). As for rs408505 and rs449853 of BMP6 gene no significant association was found among SCA patients.


Dermatoses of the Caribbean: Burden of skin disease and associated socioeconomic status in the Caribbean.
Dermatologic disease represents a significant burden worldwide, but the regional effect of skin disease in the Caribbean and how it relates to socioeconomic status remain unknown. This study aims to measure the burden of skin disease in the Caribbean from epidemiologic and socioeconomic standpoints. We selected Global Burden of Disease Study data sets to analyze disability-adjusted life-years (DALYs) and the annual rate of change of dermatoses between 1990 and 2017 in 18 Caribbean countries and the United States. The principal country-level economic factor used was gross domestic product per capita from the World Bank. Countries with lower gross domestic product per capita had higher DALYs for dermatology-related infectious diseases, urticaria, asthma, and atopic dermatitis. Countries with higher gross domestic product per capita had higher DALYs of cutaneous neoplasms, contact dermatitis, psoriasis, and pruritus. Several Caribbean countries were among the top worldwide for annual increase in DALYs for melanoma, nonmelanoma skin cancers, bacterial skin disease, and total skin and subcutaneous diseases. Despite promising ongoing interventions in skin disease, better support is needed in both resource-rich and -poor areas of the Caribbean. DALYs can serve as a purposeful measure for directing resources and care to improve the burden of skin disease in the Caribbean.


Suicide by Fire Extinguisher Powder Ingestion: A Case Report.
A 51-year-old man committed suicide by swallowing the contents of a fire extinguisher. A few hours after his suicide attempt, he was referred to the medical center for poisoning. At the time of admission, the patient was conscious with stable vital signs. The patient complained of burning lips and mouth, mentioning diarrhea. Initial treatments included gastric lavage with activated charcoal, while paraclinical measures were requested. The patient had undergone hypernatremia (Na: 152 mEq/l) and metabolic alkalosis. Treatment focused on the adjustment of sodium level and alkalosis. On the first day of hospitalization, the patient experienced recurrent episodes of tonic-clonic seizure along with the loss of consciousness. On the third day of hospitalization, the patient developed respiratory arrest followed by cardiac arrest and death.


Cell reprogramming requires silencing of a core subset of polycomb targets.
Transcription factor (TF)-induced reprogramming of somatic cells into induced pluripotent stem cells (iPSC) is associated with genome-wide changes in chromatin modifications. Polycomb-mediated histone H3 lysine-27 trimethylation (H3K27me3) has been proposed as a defining mark that distinguishes the somatic from the iPSC epigenome. Here, we dissected the functional role of H3K27me3 in TF-induced reprogramming through the inactivation of the H3K27 methylase EZH2 at the onset of reprogramming. Our results demonstrate that surprisingly the establishment of functional iPSC proceeds despite global loss of H3K27me3. iPSC lacking EZH2 efficiently silenced the somatic transcriptome and differentiated into tissues derived from the three germ layers. Remarkably, the genome-wide analysis of H3K27me3 in Ezh2 mutant iPSC cells revealed the retention of this mark on a highly selected group of Polycomb targets enriched for developmental regulators controlling the expression of lineage specific genes. Erasure of H3K27me3 from these targets led to a striking impairment in TF-induced reprogramming. These results indicate that PRC2-mediated H3K27 trimethylation is required on a highly selective core of Polycomb targets whose repression enables TF-dependent cell reprogramming.


Pulsed wave tissue Doppler imaging for the quantification of contractile reserve in stunned, hibernating, and scarred myocardium.
To assess whether quantification of myocardial systolic velocities by pulsed wave tissue Doppler imaging can differentiate between stunned, hibernating, and scarred myocardium. Observational study. Tertiary referral centre. 70 patients with reduced left ventricular function caused by chronic coronary artery disease. Pulsed wave tissue Doppler imaging was done close to the mitral annulus at rest and during low dose dobutamine; systolic ejection velocity (Vs) and the difference in Vs between low dose dobutamine and the resting value (DeltaVs) were assessed using a six segment model. Assessment of perfusion (with Tc-99m-tetrofosmin SPECT) and glucose utilisation (by 18F-fluorodeoxyglucose SPECT) was used to classify dysfunctional regions (by resting cross sectional echocardiography) as stunned, hibernating, or scarred. 253 of 420 regions (60%) were dysfunctional. Of these, 132 (52%) were classified as stunned, 25 (10%) as hibernating, and 96 (38%) as scarred. At rest, Vs in stunned, hibernating, and scar tissue was, respectively, 6.3 (1.8), 6.6 (2.2), and 5.5 (1.5) cm/s (p = 0.001 by ANOVA). There was a gradual decline in Vs during low dose dobutamine infusion between stunned, hibernating, and scar tissue (8.3 (2.6) v 7.8 (1.5) v 6.8 (1.9) cm/s, p < 0.001 by ANOVA). DeltaVs was higher in stunned (2.1 (1.9) cm/s) than in hibernating (1.2 (1.4) cm/s, p < 0.05) or scarred regions (1.3 (1.2) cm/s, p = 0.001). Quantitative tissue Doppler imaging showed a gradual reduction in regional velocities between stunned, hibernating, and scarred myocardium. Dobutamine induced contractile reserve was higher in stunned regions than in hibernating and scarred myocardium, reflecting different severities of myocardial damage.


Effects of a 12-month exercise program on cardiorespiratory health indicators of Vietnam War veterans resident in the tropics.
To measure the effect of a combined aerobic and resistance exercise program on key cardiovascular disease risk factors (i.e. body composition or anthropometry and cardiorespiratory function) of Australian male, Vietnam War veterans living in the tropics. Twelve-month exercise program with assessments at commencement, 3, 6 and 12 months. North Queensland regional centre. Australian male, Vietnam War veterans (n = 164) resident in north Queensland. Measurement of heart rate, blood pressure, skinfold and girth measurements, exercise heart rate response and estimated aerobic capacity to determine whether the implementation of a simple aerobic and resistance exercise program could positively change selected cardiovascular disease risk factors in Vietnam Veterans. Significant improvements were reported for systolic blood pressure (131.1 (SD 15.7) reduced to 122.7 (12.4) mmHg), diastolic blood pressure (82.7 (9.1) reduced to 76.3 (10.3) mmHg), resting heart rate (73 (11) reduced to 69 (11) bpm), sum of skinfolds (127.5 (40.3) reduced to 99.5 (32.1) mm), waist girth (103.2 (12.0) reduced to 100.5 (12.1) cm), hip girth (105.3 (9.6) reduced to 103.7 (10.4) cm) and aerobic capacity (2.17 (0.39) increased to 2.36 (0.34) L min(-1)). Participation in a combined aerobic and resistance training program elicited significant anthropometric and cardiorespiratory benefits that might lead to a decreased risk of developing cardiovascular disease for male Vietnam War veterans resident in rural and regional areas.


Profile and functional properties of seed proteins from six pea (Pisum sativum) genotypes.
Extractability, extractable protein compositions, technological-functional properties of pea (Pisum sativum) proteins from six genotypes grown in Serbia were investigated. Also, the relationship between these characteristics was presented. Investigated genotypes showed significant differences in storage protein content, composition and extractability. The ratio of vicilin:legumin concentrations, as well as the ratio of vicilin + convicilin: Legumin concentrations were positively correlated with extractability. Our data suggest that the higher level of vicilin and/or a lower level of legumin have a positive influence on protein extractability. The emulsion activity index (EAI) was strongly and positively correlated with the solubility, while no significant correlation was found between emulsion stability (ESI) and solubility, nor between foaming properties and solubility. No association was evident between ESI and EAI. A moderate positive correlation between emulsion stability and foam capacity was observed. Proteins from the investigated genotypes expressed significantly different emulsifying properties and foam capacity at different pH values, whereas low foam stability was detected. It appears that genotype has considerable influence on content, composition and technological-functional properties of pea bean proteins. This fact can be very useful for food scientists in efforts to improve the quality of peas and pea protein products.


A Single-Center Prospective Study of 116 Women with Osteoporosis Treated with Zoledronic Acid Monitored by Electrocardiography for the Development of Cardiac Arrhythmia During the Acute Phase in China.
BACKGROUND Concerns have been raised among clinicians and patients about the cardiovascular risks of bisphosphonates used in the treatment of osteoporosis. The goal of this study was to investigate the acute effect of zoledronic acid (ZA) infusion on arrhythmia development using an electrocardiograph (ECG). MATERIAL AND METHODS This prospective study was a self-controlled case series study that recruited 116 female patients with osteoporosis. The patients underwent standard 12-lead electrocardiography before and 1 day after zoledronic acid intravenous infusion to evaluate cardiac adverse effects and the change in ECG parameters after the infusion. Heart rhythm, atrial and ventricular premature contractions, atrial fibrillation, P wave, and QTc parameters were measured using an ECG. A blood biochemical examination was performed for all patients before the ZA infusion. Body temperature was measured twice per day. RESULTS Before ZA administration, ECG findings were normal in 47 patients and abnormal in 69 patients. After ZA administration, ECG findings were normal in 35 patients and abnormal in 81 patients. New onsets of premature atrial contractions and atrial fibrillation were observed in 1 patient each, and new onsets of premature ventricular contractions were observed in 2 patients. The heart rate was obviously higher, and the QT interval was obviously shorter after ZA administration, compared with before administration. No significant differences in P wave and QTc parameters were found between the 2 ECG measurements. CONCLUSIONS During the acute phase, 116 women with osteoporosis who were treated with zoledronic acid infusion did not develop significantly abnormal ECG changes.


Angiotensin converting enzyme 2 activator (DIZE) modulates metabolic profiles in mice, decreasing lipogenesis.
Recent studies have shown that angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang) -(1-7)/Mas axis activation is able to improve the metabolic profile, enhance glucose tolerance and insulin sensitivity, improve metabolic parameters, and counteract deleterious effects of Ang II. The effects of endogenous ACE 2 activation on the metabolic profile of mice are poorly studied. In this study, 12 weeks old male mice were treated with the ACE 2 activator (diminazene aceturate, DIZE, 1 mg/kg/day, gavage) or saline (control) for 30 days followed by glucose tolerance tests, insulin sensitivity tests, and blood analysis. Epididymal ACE2, ACE, angiotensinogen, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) were measured by quantitative RT-PCR. ACE 2 activation treatment lowered body weight (DIZE vs control) (28.69 vs 30.28g, P < 0.001), serum cholesterol (140,0 vs 177.5; P < .05), and serum triglycerides (75,00 vs 165,0; P < .05) as well as epididymal (0.008 vs 0.016; P < .05) and retroperitoneal (0.0024 vs. 0.0068; P < .01) adipose tissue weights. These effects were associated with significantly increased epididymal ACE 2 and decreased ACE and angiotensinogen (AGT) expression. Additionally, DIZE decreased adipogenesis-related gene transcription, such as ACC and FAS mRNA. In conclusion, these results indicate that activation of ACE2 by oral DIZE treatment improves the metabolic profile and reduces fat deposition in mice. These results, along with the reduction of lipogenesis markers open a new perspective for metabolic disorder pharmacotherapy.


Resolution of fluent dysphasia following excision of metastatic carcinoma from the arcuate fasciculus.
The effect of therapy on aphasic syndromes in patients with brain tumours is poorly documented. A case in which resection of a metastatic lesion led to resolution of a fluent dysphasia that had not responded to corticosteroid therapy is presented. As well as surgical and neurolinguistic interest this case demonstrates that CT diagnosis of malignant glioma can be erroneous and may lead to sub-optimal treatment.


Novel Linkage of Individual and Geographic Data to Study Firearm Violence.
Firearm violence is the end result of a causative web of individual-level and geographic risk factors. Few, if any, studies of firearm violence have been able to simultaneously determine the population-based relative risks that individuals experience as a result of what they were doing at a specific point in time and where they were, geographically, at a specific point in time. This paper describes the linkage of individual and geographic data that was undertaken as part of a population-based case-control study of firearm violence in Philadelphia. New methods and applications of these linked data relevant to researchers and policymakers interested in firearm violence are also discussed.


Effects of prenatal alcohol exposure at school age. I. Physical and cognitive development.
Alcohol is a potent teratogen associated with dysmorphology, growth retardation, and neurological damage in children with the full fetal alcohol syndrome (FAS); alcohol is also associated with growth retardation and behavioral alterations in neonates prenatally exposed to various dosages. Questions remain about the long-term consequences of prenatal alcohol exposure. This study reports on the follow-up of a subsample of 68 children, the majority of whom were low income and black (mean age: 5 years, 10 months) who were first evaluated as neonates. Physical and cognitive outcomes of 25 children of women who drank throughout pregnancy [absolute alcohol (AA)/week: mean = 11.80 oz), even after receiving an educational intervention to stop drinking, were compared with outcomes of children in two contrast groups: a) women (n = 22) who stopped drinking (AA/week: mean = 11.46 oz) in the second trimester after an educational intervention but resumed postpartum; and b) women who did not drink during pregnancy and who drank little postnatally (n = 21). Children were compared for alcohol-related birth defects (ARBDs), growth (height, weight, and head circumference), and cognitive, academic, and adaptive measures. Neonatal and current physical measures were correlated to determine predictability of neonatal status. When the effects of age and gender were controlled, children in the continued-to-drink group showed significantly more ARBDs and had smaller head circumferences than those in the other two groups. When current drinking reported by caretakers was controlled, the children who were exposed throughout pregnancy also showed significant and consistent deficits in several areas of intellectual functioning including sequential processing (short-term memory and encoding) and overall mental processing. Alcohol-exposed children displayed significant deficits in preacademic skills when compared with children of nondrinkers, with both alcohol groups deficient in premath and reading skills. There were no differences in adaptive behavior at follow-up. These data suggest that alcohol exposure throughout pregnancy is correlated with persistent physical differences as well as identifiable deficits in sequential memory processes and specific academic skills. However, even when alcohol use is limited to the first part of pregnancy, significant deficits in academic skills and growth parameters are measurable.


Preleukemia in long-term plasmacytoma-regressor mice.
Our previous results have indicated that mice whose plasmacytoma regressed following curative melphalan chemotherapy manifested various persistent immunohematological abnormalities including immunosuppression, myeloproliferation, as well as excessive production of and response to growth factors. Mice not bearing plasmacytoma treated with an identical dose of melphalan chemotherapy did not exhibit such abnormalities. In the present study we show that plasmacytoma-regressor mice (PRM) contain preleukemic cells which do not progress to leukemia in these mice. However, adoptive transfer of splenocytes originating in PRM to preirradiated but otherwise untreated syngeneic recipients resulted in the development of overt leukemia in these recipients. The presence of leukemia in the primary recipient mice was ascertained by blood counts as well as by spleen histology. Furthermore, splenocytes from the irradiated primary recipients adoptively transferred to non-irradiated secondary recipients caused leukemia formation in 100% of the secondary recipients. Sex chromosome analysis of the leukemic cells in the irradiated primary recipients clearly showed that they originated in the PRM donors. Two leukemic lines were established from leukemias developing in the secondary recipients and both expressed surface markers of hematopoietic progenitor cells as well as markers of T cells. We suggest that PRM could serve as an animal model to investigate development of chemotherapy-related leukemia in humans.


Residency training--the profession's forge for leadership development.
The concept of leadership may be the most widely studied and least understood topic in the domain of social services. Leadership has been described as a major force in the profession's transition to pharmaceutical care and effective program development. Pharmacy practice residency programs are a major means of developing and sustaining leadership for the growth of the profession. Three concepts that are explored include: (1) some insight into noncognitive elements of residency training that are critical to the development of professional practice, (2) analysis of leadership perceived to be critical for pharmacists, and (3) a definition of how residency training can develop professional leaders to meet the challenges for pharmacy.


Secretion from corticotropes after avidin-fluorescein stains for biotinylated ligands (CRF or AVP).
Viable pituitary target cells were identified with biotin-labeled corticotropin-releasing factor (1-Bio-CRF) or arginine vasopressin (Bio-AVP) and avidin-fluorescein (cell sorter grade). Stain was reduced from 8-10% of pituitary cells to less than 3% if nonbiotinylated ligands were added to compete with their respective biotinylated ligand for specific binding sites. However, AVP did not decrease the stain for 1-Bio-CRF nor did CRF decrease the Bio-AVP stain. Media adrenocorticotropin (ACTH) levels increased 4-18 times when 1-Bio-CRF or Bio-AVP were added during the staining process. One hour after staining, the cells secreted ACTH at levels identical to prestain basal levels. When challenged with CRF or AVP after this hour, the cells responded again with increases not different from those seen during staining. Tests of stained cell populations also showed that the cells were fully responsive 24 h after staining. The reverse hemolytic plaque assay for ACTH, which was used to study secretion from individual stained cells, showed that approximately 80% of plaques contained a stained cell and that plaque numbers and areas were like those of unstained populations. These data show that corticotropes are not chronically desensitized during exposure to low doses of biotinylated ligands (50-500 pM).


Rhizobium Radiobacter Infection in a 27-Year-Old African American Woman With Munchausen Syndrome.
Rhizobium radiobacter is an opportunistic, usually saprophytic, gram-negative bacillus found in agricultural soil. Isolation from blood has been reported most often in hospitalized patients harboring malignant neoplasms or human immunodeficiency virus (HIV) associated immunosuppression, who have catheter or medical device-related febrile neutropenia; treatment involves removal of the catheter or implanted medical device.(1)Herein, we report a case of a 27-year-old African American woman with sickle cell anemia who sought treatment of generalized body pain, shaking, chills, dyspnea, and fever, suggestive of sickle cell crisis. As part of her work up, routine blood cultures were drawn, revealing the presence of a Gram negative bacillus that was identified as the nonfermenter bacillus R. radiobacter The patient displayed a unique infection with R. radiobacter sepsis in a patient secondary to self-injection of organic material into a peripheral line during hospitalization. The growth of an unusual organism in the blood of a patient, without the usual risk factors of R. radiobacter, raised suspicion of a factitious psychiatric disorder known as Munchausen syndrome, which was confirmed when we discovered self-injection of feces and dirt into a central intravenous (IV) line.


[Immediate and late results of surgical treatment of gastric cancer].
Under analysis were results of surgical treatment of 145 patients with gastric cancer by original author's method of reflux esophago-gastro-intestinal anastomoses. Gastrectomy was performed in 66.9% of patients. Postoperative lethality was 3.4%. In remote terms after operation mild degree of reflux-esophagitis developed in 3 out of 83 patients observed after gastrectomy and 1 of 12 patients after proximal resection of the stomach. Five-year survival made up 21.4%.


Wastewater Surveillance for SARS-CoV-2 at Long-Term Care Facilities: Mixed Methods Evaluation.
Wastewater surveillance provided early indication of COVID-19 in US municipalities. Residents of long-term care facilities (LTCFs) experienced disproportionate morbidity and mortality early in the COVID-19 pandemic. We implemented LTCF building-level wastewater surveillance for SARS-CoV-2 at 6 facilities in Kentucky to provide early warning of SARS-CoV-2 in populations considered vulnerable. This study aims to evaluate the performance of wastewater surveillance for SARS-CoV-2 at LTCFs in Kentucky. We conducted a mixed methods evaluation of wastewater surveillance following Centers for Disease Control and Prevention (CDC) guidelines for evaluating public health surveillance systems. Evaluation steps in the CDC guidelines were engaging stakeholders, describing the surveillance system, focusing the evaluation design, gathering credible evidence, and generating conclusions and recommendations. We purposively recruited stakeholders for semistructured interviews and undertook thematic content analysis of interview data. We integrated wastewater, clinical testing, and process data to characterize or calculate 7 surveillance system performance attributes (simplicity, flexibility, data quality, sensitivity and positive predictive value [PPV], timeliness, representativeness, and stability). We conducted 8 stakeholder interviews. The surveillance system collected wastewater samples (N=811) 2 to 4 times weekly at 6 LTCFs in Kentucky from March 2021 to February 2022. Synthesis of credible evidence indicated variable surveillance performance. Regarding simplicity, surveillance implementation required moderate human resource and technical capacity. Regarding flexibility, the system efficiently adjusted surveillance frequency and demonstrated the ability to detect additional pathogens of interest. Regarding data quality, software identified errors in wastewater sample metadata entry (110/3120, 3.53% of fields), technicians identified polymerase chain reaction data issues (140/7734, 1.81% of reactions), and staff entered all data corrections into a log. Regarding sensitivity and PPV, using routine LTCF SARS-CoV-2 clinical testing results as the gold standard, a wastewater SARS-CoV-2 signal of >0 RNA copies/mL was 30.6% (95% CI 24.4%-36.8%) sensitive and 79.7% (95% CI 76.4%-82.9%) specific for a positive clinical test at the LTCF. The PPV of the wastewater signal was 34.8% (95% CI 27.9%-41.7%) at >0 RNA copies/mL and increased to 75% (95% CI 60%-90%) at >250 copies/mL. Regarding timeliness, stakeholders received surveillance data 24 to 72 hours after sample collection, with delayed reporting because of the lack of weekend laboratory staff. Regarding representativeness, stakeholders identified challenges delineating the population contributing to LTCF wastewater because of visitors, unknown staff toileting habits, and the use of adult briefs by some residents preventing their waste from entering the sewer system. Regarding stability, the reoccurring cost to conduct 1 day of wastewater surveillance at 1 facility was approximately US $144.50, which included transportation, labor, and materials expenses. The LTCF wastewater surveillance system demonstrated mixed performance per CDC criteria. Stakeholders found surveillance feasible and expressed optimism regarding its potential while also recognizing challenges in interpreting and acting on surveillance data.


Quantitative studies of single-cell properties in monkey striate cortex. I. Spatiotemporal organization of receptive fields.
1. The properties of single cells in striate cortex of the rhesus monkey, representing the visual field 2 degrees -5 degrees from the fovea, were examined quantitatively with stationary and moving stimuli. Three distinct classes of cells were identified: S type, CX type, and T type. 2. S-type cells were defined as those oriented cells which to the optimal direction of movement in their receptive fields exhibited one or more spatially separate subfields within each of which a response was obtained to either a light or dark edge, but not to both. Several different types of S-cells were distinguished: a) S1-type cells for which moving edges revealed a single excitatory area within which a response was elicited by either a light or a dark edge but not by both. Most of these cells were unidirectional. b) S2-type cells for which moving edges revealed two spatially separate response areas, one of which was excited by a light edge and the other by a dark edge. Both regions responded to the same direction of movement. c) S3-type cells which had two response areas, one of which was excited by a stimulus moving in one direction (at right angles to the axis of orientation) and the other, of opposite contrast, which responded in the opposite direction, d) S4-type cells which to one direction of movement showed two spatially separate regions sensitive to a light and dark edge and which in the other direction of movement had only one responsive area (either light or dark). e) Cells which had multiple spatially separate subfields (S5-7 types). 3. CX-type cells were defined as those oriented cells which in their receptive fields exhibited no spatial separation for light- and dark-edge responses; they discharged to both edges in the same direction of movement and in the same spatial area. Flashing stimuli elicited both on and off responses throughout the receptive field. CX-type cells were predominantly of two types: those which were selective for direction of stimulus movement and those which were not. 4. A third class of cells (T-type) were those which were excited by only one sign of contrast change and responded in a sustained fashion even when there was no contour within the receptive field. These cells were poorly or not at all oriented; some of them were selective to wavelength. 5. Quantitative comparisons showed the following differences between S-type and CX-type cells: a) S-type cells had smaller receptive fields than CX-type cells but the populations over-lapped considerably. Receptive-field size was smallest in layer 4c. In all other layers S-type cells had the same size fields. CX-type cells, by contrast, tended to have larger fields in layer 5-6 than 2-3. b) The spatial separation between light and dark response areas was the best criterion for distinguishing S-type and CX-type cells. The distribution of this measure disclosed two populations of cells with relatively limited overlap. c) In layers 2 and 3, both S-type and CX-type cells had low spontaneous activity...


Perioperative Use of Anticoagulant and Platelet-inhibiting Medications for Elective Spine Surgery: Results of a Nationwide Survey.
Perioperative use of anticoagulant and platelet-inhibiting agents by patients undergoing spine surgery poses the dilemma of increased risk of hemorrhage. We examined the standards of use for these medications and expert opinions through a nationwide survey. An online-based survey was conducted by invitation. A personal token to access the survey was sent to one representative of each neurosurgical and orthopaedic unit performing spine surgery and to all other active members of the Swiss Society of Neurosurgery and the Swiss Society of Spinal Surgery. A total of 97 e-mail invitations were sent to 19 representatives of neurosurgical or orthopaedic units and 78 registered neurosurgeons and orthopaedic surgeons who potentially perform spine surgery. From February to April 2016, 40 surgeons (26 neurosurgeons, 14 orthopaedic surgeons) completed the survey (41%). Among the respondents, 55% prescribed prophylactic heparin preoperatively; depending on the procedure, 83 to 95% prescribed heparin postoperatively. Depending on the type of surgery, 23 to 48% discontinued acetylic acid preoperatively, and 80 to 87% always discontinued clopidogrel preoperatively. On average, platelet inhibition was resumed 4 ± 2.5 days postoperatively. Orthopaedic surgeons recommenced platelet inhibition earlier than neurosurgeons (p = 0.013). Anticoagulation with rivaroxaban was discontinued 3 ± 2 days before surgery. Depending on the indication, 72 to 98% of respondents temporarily replaced traditional anticoagulation therapy (vitamin K antagonists) with heparin perioperatively. Administration and discontinuation of anticoagulant and platelet-inhibiting medications in the perioperative setting of spinal surgery differ vastly between different units and surgeons. Recommendations from the spine surgeon societies may be helpful to develop nationwide guidelines.


Blood organochlorine pesticide levels in Virginia residents.
This study attempts to establish 1972 baseline levels for 31 organochlorine pesticides and industrial chemicals in postmortem human whole blood in Virginia. These pesticides and industrial chemicals have been detected previously in other parts of the food chain and environment. In the present study DDT and its metabolites, DDE and TDE, were detected most frequently and at highest levels. DDT and DDE tended to appear more frequently as people grew older although TDE levels remained constant. Dieldrin and lindane showed peak levels in the middle age group. Analyzing distribution of pesticides in blood by sex showed that females had higher levels of lindane and dieldrin and males had higher levels of DDT, DDE, and TDE. Analyzing racial distribution showed blacks with higher levels of DDT, TDE, and DDE and indicated little difference from whites for lindane and dieldrin. Higher levels were found in Richmond and Norfolk than in the Fairfax and Roanoke regions.


Developmental refinement of hair cell synapses tightens the coupling of Ca2+ influx to exocytosis.
Cochlear inner hair cells (IHCs) develop from pre-sensory pacemaker to sound transducer. Here, we report that this involves changes in structure and function of the ribbon synapses between IHCs and spiral ganglion neurons (SGNs) around hearing onset in mice. As synapses matured they changed from holding several small presynaptic active zones (AZs) and apposed postsynaptic densities (PSDs) to one large AZ/PSD complex per SGN bouton. After the onset of hearing (i) IHCs had fewer and larger ribbons; (ii) CaV1.3 channels formed stripe-like clusters rather than the smaller and round clusters at immature AZs; (iii) extrasynaptic CaV1.3-channels were selectively reduced, (iv) the intrinsic Ca(2)(+) dependence of fast exocytosis probed by Ca(2)(+) uncaging remained unchanged but (v) the apparent Ca(2)(+) dependence of exocytosis linearized, when assessed by progressive dihydropyridine block of Ca(2)(+) influx. Biophysical modeling of exocytosis at mature and immature AZ topographies suggests that Ca(2)(+) influx through an individual channel dominates the [Ca(2)(+)] driving exocytosis at each mature release site. We conclude that IHC synapses undergo major developmental refinements, resulting in tighter spatial coupling between Ca(2)(+) influx and exocytosis.


Efficacy of short-term Yoga therapy program on quality of life in patients with psychosomatic ailments.
The aim was to study the effect of short-term Yoga therapy program on quality of life in patients suffering from psychosomatic ailments. Sample size and Study period: All the subjects coming to SVYASA AROGYADHAMA in month of July 2011 for Yoga therapy for various psychosomatic ailments and were free of any primary psychiatric illness and volunteering to participate were enrolled in the study after taking informed consent. Their physical condition was healthy enough to practice Yoga as judged clinically. All subjects (n = 94) who were enrolled in the study underwent Integrated Approach to Yoga Therapy, which included Asanas, Pranayamas, meditation, Kriyas and lectures on practice of Yoga and derived special techniques in their respective sections. The quality of life was assessed by SF-12 questionnaire and thereby calculating Physical and Mental Composite Scores (PCS and MCS) before and after 1 week of Yoga therapy. Data thus obtained was analyzed using paired t-test. A significant improvement (P < 0.001) was seen in the study group in both PCS (from mean ± SD of 37.50 ± 9.58 to 43.7 ± 8.73) and MCS (from 45.87 ± 9.57 to 53.35 ± 7.9.) with minor variations in patients of various departments. A short-term Yoga therapy program leads to a remarkable improvement in the quality of life of the subjects and can contribute favorably in the management of psychosomatic disorders.


The incidence of rotavirus infection in children from two selected study areas in Zimbabwe.
Five hundred and twenty faecal samples or rectal swabs, collected over one year from children mainly under 24 months, were tested for the presence of human rotavirus (HRV) in enzyme linked immunosorbent assays (ELISA). Fifty-three (23.6 pc) of 225 diarrhoea samples and 25 (8.5 pc) of 295 control samples were HRV positive. The association between diarrhoea and detection of HRV in stools was statistically significant with an overall odds ratio of diarrhoea patients of 3.32 (0.001 greater than p). No significant difference in the incidence of HRV infection between populations at a communal farming location and a high density suburb community was proved. The highest HRV incidence was found during the dry cool season in diarrhoea patients between four and 24 months of age. Overall proportions of 16.7 pc and 28.6 pc HRV positive in groups of 0-3 and 4-6 months old diarrhoea patients respectively was remarkably high, suggesting influence of close human contact, crowding in residences and insufficient sanitary facilities on the transmission of the HRV. Approximately 10 pc of 4-18 months old control patients were HRV positive.


Two distinct categories of warm autoantibody reactivity with age-fractionated red cells.
Using age-fractionated erythrocytes, warm autoantibodies can be classified into two distinct categories, depending on their reactivity with reticulocyte-enriched (younger) or reticulocyte-poor (older) red cell fractions. The strength of the direct antiglobulin test (DAT) on the age-fractionated red cells of 24 patients indicated that 19 (79%) had an IgG warm autoantibody that reacted preferentially with older red blood cells. In 7 of these 19 patients (37%), the DAT was negative using reticulocyte-enriched red cell fractions. We have termed this preferential reactivity of warm autoantibodies with older red cells as type I. Five of the 24 patients studied (21%) had an IgG warm autoantibody that demonstrated no preference for young or older red cells. We have termed this pattern of warm autoantibody reactivity as type II. All 5 patients having type II warm autoantibodies had severe anemia. In contrast, 6 of 19 patients having type I warm autoantibody did not have clinical evidence of anemia when tested, and 11 of the 19 had only slight to moderate anemia. Additionally, our results using type I warm autoantibody raise questions regarding the blood group specificity of warm autoantibodies. The antigen recognized by type I warm autoantibody may be a cryptantigen. Rh specificity or relative Rh specificity, often associated with warm autoantibodies, may simply be a coincidental finding.


Multi-Response Optimisation of Automotive Door Using Grey Relational Analysis with Entropy Weights.
Tail-welded blanks (TWBs) are widely used in automotive bodies to improve the structural performance and reduce weight. The stiffness and modal lightweight design optimisation of TWBs for automotive doors was performed in this study. The finite element model was validated through physical experiments. An L27 (312) Taguchi orthogonal array was used to collect the sample points. The multi-objective optimisation problem was transformed into a single-objective optimisation problem based on the grey relational degree. The optimal combination of structural design parameters was obtained for a tail-welded door using the proposed method, and the weight of the door structure was reduced by 2.83 kg. The proposed optimisation method has fewer iterations and a lower computational cost, enabling the design of lightweight TWBs.


Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial.
Therapeutic dendritic cell (DC) vaccination against cancer is a strategy aimed at activating the immune system to recognize and destroy tumor cells. In this nonrandomized phase 1/2 trial, we investigated the safety, feasibility, induction of T-cell response, and clinical response after treatment with a DC-based vaccine in patients with metastatic renal cell carcinoma. Twenty-seven patients with progressive cytokine-refractory metastatic renal cell carcinoma were vaccinated with DCs loaded with either a cocktail of survivin and telomerase peptides or tumor lysate depending on their HLA-A2 haplotype, and low-dose IL-2 was administered concomitantly. Tumor response, immune response, and serum IL-6 and YKL-40 were measured during treatment. Vaccine generation was successful in all patients and no serious adverse events were observed. None of the patients had an objective response but 13/27 patients obtained disease stabilization (SD) for more than 8 weeks. An antigen-specific immune response was demonstrated in 6/6 patients tested. Furthermore, significant alterations in serum YKL-40 and IL-6 were found during treatment. In conclusion, DC vaccination in our setting is feasible and without severe toxicity. Almost half of the patients obtained SD, and in more than 1/3 of the patients, SD persisted for more than 6 months. However, the evaluation of SD is difficult to interpret in the absence of a randomized trial and, therefore, these results should be interpreted with caution. Antigen-specific immune responses were observed in a subset of the treated patients.


Socio-Demographics, Pain Characteristics, Quality of Life and Treatment Values Before and After Specialized Interdisciplinary Pain Treatment: Results from the Danish Clinical Pain Registry (PainData).
PainData is an electronic internet-based clinical pain registry established to improve the understanding and treatment of high-impact chronic pain. The primary aim of this paper is to describe socio-demographics, pain characteristics, quality of life, and treatment values at baseline and follow-up in individuals referred to public and private interdisciplinary pain centers in Denmark between 2018 and 2020. Self-reported patient-reported outcomes collected through PainData before (n=12,257) and after (n=4,111) treatment across 13 public and private interdisciplinary specialized pain centers in Denmark (87% of all pain centers in Denmark) are described. Mean duration of pain was 10 years, and one in three patients reported chronic widespread pain. More than 40% reported opioid use, and 50% had tried four or more different treatment modalities prior to referral. More than 60% reported poor sleep, severe fatigue, and memory and/or concentration deficits. Mean scores on pain catastrophizing, fear of movement, and pain-related disability were high, whereas scores on pain acceptance and self-efficacy were low. Physical and mental health were rated as poor and fair, respectively. One in four patients reported being very much improved or much improved after treatment. Items commonly reported after treatment were increased knowledge about pain, emotions and mood (66.5%), being better at accepting life with chronic pain (63.1%), and improved activity pacing (60.6%). The PainData registry, containing data from a large cohort of individuals, can help to improve the understanding and treatment of high-impact chronic pain, and collaborations with other researchers are welcome.


Peritoneovenous shunt for refractory ascites: operative complications and long-term results.
We studied the clinical course of 35 patients with refractory ascites who underwent 51 peritoneovenous shunts. Nine of them had hepatorenal syndrome (HRS). Operative complications included shunt malfunction, shunt infection, ascitic leak, fluid overload, and disseminated intravascular coagulation. Two of the patients without HRS died postoperatively. The survival rate in this group was 67% at one year and 43% at two years. Ascites was completely controlled in 83% of the survivors at two months and 50% at two years. Neither survival nor shunt patency were predictable. The shunt reversed HRS in three patients, but failed to do so in the other six. Late complications included shunt malfunction and infection. During the first two years of follow-up, five patients bled from esophageal varices. Liver failure was the sole cause of late death. Peritoneovenous shunt should be reserved for patients with truly refractory ascites, for whom it provides excellent palliation.


Synthesis of 8-hydroxy-2-iminochromene derivatives as selective and potent inhibitors of human carbonyl reductase 1.
Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces anthracycline anticancer drugs to their less potent anticancer C-13 hydroxy metabolites, which are linked with pathogenesis of cardiotoxicity, a side effect of the drugs. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with a twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity. In order to search for new potential inhibitors of CBR1, we synthesized a series of des-methoxyphenyl derivatives of (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) that was developed previously as a potent inhibitor of aldo-keto reductase (AKR) 1B10 and AKR1B1. Among the newly synthesized inhibitors, 8-hydroxy-2-imino-2H-chromene-3-carboxylic acid (2-chlorophenyl)amide (13h) was the most potent competitive inhibitor of CBR1, showing a Ki value of 15 nM. 13h also showed high selectivity to CBR1 over its isozyme CBR3 and other enzymes with CBR activity (AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C4, DXCR and DHRS4). Furthermore, 13h inhibited the cellular metabolism by CBR1 at its concentration of 4 μM. The structure-activity relationship of the derivatives, site-directed mutagenesis of putative binding residues (Met141 and Trp229) and molecular docking of 13h in CBR1 revealed that the interactions of 13h with the substrate-binding residues (Ser139, Met141, Tyr193 and Trp229) are important for the tight binding.


Succinylcholine-induced cardiac arrest in unsuspected becker muscular dystrophy--a case report.
A five year-old boy undergoing elective tonsillectomy sustained cardiac arrest following the administration of a single dose of succinylcholine during induction of anesthesia. With a 10-minute cardiopulmonary resuscitation (CPR) during which intravenous calcium gluconate, epinephrine, and sodium bicarbonate were given and DC counter shock applied, we were successful to restore cardiac activity without neurological sequelae. The cause of cardiac arrest we speculated was hyperkalemia, possibly secondary to succinylcholine-induced rhabdomyolysis. It is suggested that succinylcholine should not be used in patients with known or suspected muscular dystrophy.


Acute Renal Failure due to Rhabdomyolysis Following Human Stampede.
Acute renal failure (ARF) following rhabdomyolysis is a well known entity. In this paper, we present an unusual cause for trauma that resulted in rhabdomyolysis associated with renal failure. Rhabdomyolysis resulted from human stampede that occurred in a mountain tunnel on the occasion of The Pilgrimage to Makkah in 1990. To the best of our knowledge, human stampede as a cause of rhabdomyolysis has not been reported in the literature. A total of eight patients were referred to our center. Laboratory investigations revealed rhabdomyolysis as well as evidence of moderate to severe renal impairment in all patients. They were treated with forced alkaline diuresis, but three required hemodialysis. All patients recovered. Treatment with forced alkaline diuresis was found to be useful in the treatment of these patients and instituting such treatment is worthwhile even in those cases where renal failure is established.


Early-onset mild cognitive impairment in Parkinson's disease: Altered corticopetal cholinergic network.
Degeneration of the substantia innominata (SI) is significantly correlated with cognitive performance in Parkinson's disease (PD). We examined functional and structural patterns of SI degeneration in drug-naïve PD patients according to the duration of parkinsonism before mild cognitive impairment (MCI) diagnosis. Twenty PD patients with a shorter duration (PD-MCI-SD, <1 year), 18 patients with a longer duration (PD-MCI-LD, ≥1 year), and 29 patients with intact cognition (PD-IC) were included. Seed-based resting-state functional connectivity (rsFC) analysis using bilateral SI seed and region-of-interest-based volumetric analysis were performed. Compared to PD-IC, the collapsed PD-MCI group showed altered rsFC in the right frontal and bilateral parietal areas. PD-MCI-SD showed rsFC alteration in broader frontal and parietal areas compared to the other groups. Decreased rsFC in the right frontal area was also significantly correlated with shorter disease duration. No significant SI volume change was found between the groups. Altered rsFC between the SI and the frontal and parietal areas might be relevant to cognitive dysfunction in PD. Decreased rsFC between the SI and frontal area might be associated with early-onset MCI, suggesting that cholinergic deficits in the frontal brain areas might play an important role in the acceleration of cognitive decline in PD.


Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century.
The mainstay of diagnosis for Treponema pallidum infections is based on nontreponemal and treponemal serologic tests. Many new diagnostic methods for syphilis have been developed, using specific treponemal antigens and novel formats, including rapid point-of-care tests, enzyme immunoassays, and chemiluminescence assays. Although most of these newer tests are not yet cleared for use in the United States by the Food and Drug Administration, their performance and ease of automation have promoted their application for syphilis screening. Both sensitive and specific, new screening tests detect antitreponemal IgM and IgG antibodies by use of wild-type or recombinant T. pallidum antigens. However, these tests cannot distinguish between recent and remote or treated versus untreated infections. In addition, the screening tests require confirmation with nontreponemal tests. This use of treponemal tests for screening and nontreponemal serologic tests as confirmatory tests is a reversal of long-held practice. Clinicians need to understand the science behind these tests to use them properly in syphilis management.


Post-traumatic stress disorders in women who experienced childhood incest.
Symptoms exhibited in a clinical population of 17 women who had experienced childhood or adolescent incest appear to fit the features of a chronic and/or delayed post-traumatic stress disorder. These women, entering individual therapy an average of 17 years after the abuse had ended, ranged in age from 24 to 44. All regarded their incest experience as the most damaging event of their lives, and had manifested, in adulthood, such symptoms as intrusive imagery of the incest, feelings of detachment or constricted affect, sleep disturbance, guilt, and intensification of symptoms when exposed to events resembling the incest trauma. Treatment included establishment of trust, expression of feelings, guilt reduction through an understanding of family dynamics and acquisition of new, adaptive behaviors.


The role of peroxidases in the pathogenesis of atherosclerosis.
Reactive oxygen species (ROS), which include superoxide anions and peroxides, induce oxidative stress, contributing to the initiation and progression of cardiovascular diseases involving atherosclerosis. The endogenous and exogenous factors hypercholesterolemia, hyperglycemia, hypertension, and shear stress induce various enzyme systems such as nicotinamide adenine dinucleotide (phosphate) oxidase, xanthine oxidase, and lipoxygenase in vascular and immune cells, which generate ROS. Besides inducing oxidative stress, ROS mediate signaling pathways involved in monocyte adhesion and infiltration, platelet activation, and smooth muscle cell migration. A number of antioxidant enzymes (e.g., superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins) regulate ROS in vascular and immune cells. Atherosclerosis results from a local imbalance between ROS production and these antioxidant enzymes. In this review, we will discuss 1) oxidative stress and atherosclerosis, 2) ROS-dependent atherogenic signaling in endothelial cells, macrophages, and vascular smooth muscle cells, 3) roles of peroxidases in atherosclerosis, and 4) antioxidant drugs and therapeutic perspectives.


Nursing home case-mix classification and residents suffering from cognitive impairment: RUG-II and cognition in the Texas case-mix data base.
Case-mix reimbursement systems for nursing home care are now in use or under consideration in over 20 states. Though many in the long-term care field still debate the relative merits of the various systems, those systems based on the Resource Utilization Groups-II (RUG-II) system used in New York seem to be increasingly popular. However, one of the more serious questions raised concerning RUG-like systems is whether they fully acknowledge the role played by cognitive deficits in determining nursing home residents' care needs. The results of this research indicate: 1) that resource provision and cognitive status are correlated, 2) that residents with higher levels of cognitive impairment appear most frequently in RUG-II categories that have higher case-mix weights, 3) that simply adding some measure of cognitive function does not significantly increase the power of these models, and 4) that the RUG-II model predicts the level of care resources provided to the cognitively intact much better than it predicts those provided to residents suffering from relatively severe disorientation. These results imply that such classification systems may create disincentives for the admission of the most cognitively impaired residents and that the care of these individuals, more than others, may be dependent on facility-to-facility variation.


Subtyping of juvenile idiopathic arthritis using latent class analysis. British Paediatric Rheumatology Group.
To use statistical techniques to identify underlying subtypes of juvenile idiopathic arthritis (JIA) that best explain the observed relationships of clinical and laboratory variables, and to compare the statistically derived subtypes with those defined by the International League of Associations for Rheumatology (ILAR) criteria and examine them for HLA associations. Information on 572 patients diagnosed as having JIA was summarized by 10 clinical and laboratory categorical variables (age at onset, large joint involvement, small joint involvement, polyarthritis, symmetric arthritis, spinal pain, fever, psoriasis, antinuclear antibodies [ANA], and rheumatoid factor). Latent class analysis (LCA) was used to identify underlying ("latent") classes that explained the relationships among the observed variables. Statistical models incorporating 5-8 latent classes were applied to the data. The 7-class model was the most appropriate. Patterns of joint involvement and the presence of ANA were influential in determining latent classes. There was some correspondence between the latent classes and the ILAR categories, but they did not coincide completely. Significant differences between the latent classes were seen for 3 HLA haplotypes (DRB1*04-DQA1*03-DQB1*03, DRB1*13-DQA1*01-DQB1*06, and DRB1*08-DQA1*0401-DQB1*0402). LCA provides a novel approach to the task of identifying homogeneous subtypes within the umbrella of JIA. In further work, the identified latent classes will be examined for associations with other candidate genes and for differences in outcome.


Recent advances in fluorescent and colorimetric chemosensors for the detection of chemical warfare agents: a legacy of the 21st century.
Chemical warfare agents (CWAs) are among the most prominent threats to the human population, our peace, and social stability. Therefore, their detection and quantification are of utmost importance to ensure the security and protection of mankind. In recent years, significant developments have been made in supramolecular chemistry, analytical chemistry, and molecular sensors, which have improved our capability to detect CWAs. Fluorescent and colorimetric chemosensors are attractive tools that allow the selective, sensitive, cheap, portable, and real-time analysis of the potential presence of CWAs, where suitable combinations of selective recognition and transduction can be integrated. In this review, we provide a detailed discussion on recently reported molecular sensors with a specific focus on the sensing of each class of CWAs such as nerve agents, blister agents, blood agents, and other toxicants. We will also discuss the current technology used by military forces, and these discussions will include the type of instrumentation and established protocols. Finally, we will conclude this review with our outlook on the limitations and challenges in the area and summarize the potential of promising avenues for this field.


Genomic approaches to accelerate cancer interception.
Although major advances have been reported in the last decade in the treatment of late-stage cancer with targeted and immune-based therapies, there is a crucial unmet need to develop new approaches to improve the prevention and early detection of cancer. Advances in genomics and computational biology offer unprecedented opportunities to understand the earliest molecular events associated with carcinogenesis, enabling novel strategies to intercept the development of invasive cancers. This Series paper will highlight emerging big data genomic approaches with the potential to accelerate advances in cancer prevention, screening, and early detection across various tumour types, and the challenges inherent in the development of these tools for clinical use. Through coordinated multicentre consortia, these genomic approaches are likely to transform the landscape of cancer interception in the coming years.


High-yield halide-assisted synthesis of metal-organic framework UiO-based nanocarriers.
The synthesis of nanosized metal-organic frameworks (NMOFs) is requisite for their application as injectable drug delivery systems (DDSs) and other biorelevant purposes. Herein, we have critically examined the role of different synthetic parameters leading to the production of UiO-66 crystals smaller than 100 nm. Of note, we demonstrate the co-modulator role conferred by halide ions, not only to produce NMOFs with precise morphology and size, but also to significantly improve the reaction yield. The resulting NMOFs are highly crystalline and exhibit sustained colloidal stability in different biologically relevant media. As a proof of concept, these NMOFs were loaded with Rhodamine 6G (R6G), which remained trapped in most common biologically relevant media. When incubated with living mammalian cells, the R6G-loaded NMOFs were efficiently internalized and did not impair cell viability even at relatively high doses.


Protective effect of Plantago major L. Pectin polysaccharide against systemic Streptococcus pneumoniae infection in mice.
The antibacterial effect of a soluble pectin polysaccharide, PMII, isolated from the leaves of Plantago major, was examined in inbred NIH/OlaHsd and Fox Chase SCID mice experimentally infected with Streptococcus pneumoniae serotype 6B. Serotype 6B is known to give a more protracted infection when injected intraperitoneally into susceptible mice than more virulent serotypes like type 4. PMII was administered i.p. either once 3 days before challenge or once to thrice from 3 to 48 h after challenge. The number of bacteria in blood and the mouse survival rate were recorded. Pre-challenge administration of PMII and also lipopolysaccharide (LPS), included as a control, gave a dose-dependent protective effect against S. pneumoniae type 6B infection. However, injection of PMII after establishment of the infection in NIH/OlaHsd mice had no effect. The data demonstrate that, firstly, the polysaccharide fraction PMII from P. major protects against pneumococcal infection in mice when administered systemically prechallenge, and secondly that the protective effect is owing to stimulation of the innate and not the adaptive immune system.


Mutation in S6 domain of HCN4 channel in patient with suspected Brugada syndrome modifies channel function.
Diseases such as the sick sinus and the Brugada syndrome are cardiac abnormalities, which can be caused by a number of genetic aberrances. Among them are mutations in HCN4, a gene, which encodes the hyperpolarization-activated, cyclic nucleotide-gated ion channel 4; this pacemaker channel is responsible for the spontaneous activity of the sinoatrial node. The present genetic screening of patients with suspected or diagnosed Brugada or sick sinus syndrome identified in 1 out of 62 samples the novel mutation V492F. It is located in a highly conserved site of hyperpolarization-activated cyclic nucleotide-gated (HCN)4 channel downstream of the filter at the start of the last transmembrane domain S6. Functional expression of mutant channels in HEK293 cells uncovered a profoundly reduced channel function but no appreciable impact on channel synthesis and trafficking compared to the wild type. The inward rectifying HCN4 current could be partially rescued by an expression of heteromeric channels comprising wt and mutant monomers. These heteromeric channels were responsive to cAMP but they required a more negative voltage for activation and they exhibited a lower current density than the wt channel. This suggests a dominant negative effect of the mutation in patients, which carry this heterozygous mutation. Such a modulation of HCN4 activity could be the cause of the diagnosed cardiac abnormality.


Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.
Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown. We generated mice with deficient myocardial mTORC1 activity by targeted ablation of raptor, which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and β-myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding-induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed. Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy.


Ex Vivo Conjunctival Retention and Transconjunctival Transport of Poorly Soluble Drugs Using Polymeric Micelles.
This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a vehicle for the ocular delivery of dexamethasone, cyclosporine, and econazole nitrate. The research steps were: (1) characterize polymeric micelles by dynamic light scattering (DLS) and X-ray scattering; (2) evaluate the solubility increase of the three drugs; (3) measure the in vitro transport and conjunctiva retention, in comparison to conventional vehicles; (4) investigate the mechanisms of enhancement, by studying drug release from the micelles and transconjunctival permeation of TPGS; and (5) study the effect of micelles application on the histology of conjunctiva. The data obtained demonstrate the application potential of polymeric micelles in ocular delivery, due to their ability to increase the solubility of lipophilic drugs and enhance transport in and across the conjunctival epithelium. The best-performing formulation was the one made of TPGS alone (micelles size ≈ 12 nm), probably because of the higher mobility of these micelles, an enhanced interaction with the conjunctival epithelium, and, possibly, the penetration of intact micelles.


Preparation and characterization of 6-mercaptopurine-coated magnetite nanoparticles as a drug delivery system.
Iron oxide nanoparticles are of considerable interest because of their use in magnetic recording tape, ferrofluid, magnetic resonance imaging, drug delivery, and treatment of cancer. The specific morphology of nanoparticles confers an ability to load, carry, and release different types of drugs. We synthesized superparamagnetic nanoparticles containing pure iron oxide with a cubic inverse spinal structure. Fourier transform infrared spectra confirmed that these Fe3O4 nanoparticles could be successfully coated with active drug, and thermogravimetric and differential thermogravimetric analyses showed that the thermal stability of iron oxide nanoparticles coated with chitosan and 6-mercaptopurine (FCMP) was markedly enhanced. The synthesized Fe3O4 nanoparticles and the FCMP nanocomposite were generally spherical, with an average diameter of 9 nm and 19 nm, respectively. The release of 6-mercaptopurine from the FCMP nanocomposite was found to be sustained and governed by pseudo-second order kinetics. In order to improve drug loading and release behavior, we prepared a novel nanocomposite (FCMP-D), ie, Fe3O4 nanoparticles containing the same amounts of chitosan and 6-mercaptopurine but using a different solvent for the drug. The results for FCMP-D did not demonstrate "burst release" and the maximum percentage release of 6-mercaptopurine from the FCMP-D nanocomposite reached about 97.7% and 55.4% within approximately 2,500 and 6,300 minutes when exposed to pH 4.8 and pH 7.4 solutions, respectively. By MTT assay, the FCMP nanocomposite was shown not to be toxic to a normal mouse fibroblast cell line. Iron oxide coated with chitosan containing 6-mercaptopurine prepared using a coprecipitation method has the potential to be used as a controlled-release formulation. These nanoparticles may serve as an alternative drug delivery system for the treatment of cancer, with the added advantage of sparing healthy surrounding cells and tissue.


"Clinical trials are space travel": Factors of psychological response to recurrence among oncologists enrolling patients in treatment optimization trials.
Cancer recurrence after treatment is a concern for patients and oncologists alike. The movement towards treatment optimization, with trials testing less than the current standard of care (SoC), complicates this experience. Our objective was to assess oncologists' psychological response to patient recurrence on optimization-focused trials and identify factors that influence those experiences. Clinical oncologists participated in a semi-structured interview regarding patient enrollment in treatment optimization trials. We identified factors that influence the degree of psychological response that the oncologist may feel after patient recurrence. Residual agreement analysis was used to identify whether differences in reported psychological response was associated with alternative emphases on identified factors. Thirty-six oncologists identified 20 factors spanning five major themes that affected their psychological response to patient recurrence. All oncologists expressed willingness to enroll patients in treatment optimization clinical trials; however, half indicated that they were more likely to experience a negative psychological response after a treatment optimization trial than after a traditional intensification trial, and a quarter reported that patient recurrence on an optimization trial would impact their recommendations for future trial enrollment. Oncologists who reported more negative psychological responses to patient recurrence after participation in an optimization trial were more likely to emphasize introspective factors, while those who reported no difference in response emphasized patient- and process-focused factors. Although most oncologists recognize the importance of treatment optimization trials, a significant proportion indicated a greater potential for psychological distress following patient recurrence in such trials and offered insight into how trial design and the process of patient enrollment can be improved to minimize those negative psychological responses.


Stress-induced DNA damage biomarkers: applications and limitations.
A variety of environmental stresses like chemicals, UV and ionizing radiation and organism's endogenous processes such as replication stress and metabolism can lead to the generation of reactive oxygen and nitrogen species (ROS/RNS) that can attack cellular vital components like DNA, proteins and lipid membranes. Among them, much attention has been focused on DNA since DNA damage plays a role in several biological disorders and aging processes. Thus, DNA damage can be used as a biomarker in a reliable and accurate way to quantify for example radiation exposure and can indicate its possible long term effects and cancer risk. Based on the type of DNA lesions detected one can hypothesize on the most probable mechanisms involved in the formation of these lesions for example in the case of UV and ionizing radiation (e.g., X- or α-, γ-rays, energetic ions, neutrons). In this review we describe the most accepted chemical pathways for DNA damage induction and the different types of DNA lesions, i.e., single, complex DNA lesions etc. that can be used as DNA damage biomarkers. We critically compare DNA damage detection methods and their limitations. In addition, we suggest the use of DNA repair gene products as biomarkes for identification of different types of stresses i.e., radiation, oxidative, or replication stress, based on bioinformatic approaches and meta-analysis of literature data.


Comparison of non-magnetic and magnetic beads multiplex assay for assessment of Plasmodium falciparum antibodies.
New reagents have emerged allowing researchers to assess a growing number of vaccine-associated immune parameters. Multiplex immunoassay(s) are emerging as efficient high-throughput assays in malaria serology. Currently, commercial vendors market several bead reagents for cytometric bead assays (CBA) but relative performances are not well published. We have compared two types of bead-based multiplex assays to measure relative antibody levels to malarial antigens. Assays for the measurement of antibodies to five Plasmodium falciparum vaccine candidates using non-magnetic and magnetic fluorescent microspheres were compared for their performances with a Bio-Plex200 instrument. Mean fluorescence intensity (MFI) was determined from individuals from western Kenya and compared to known positive and negative control plasma samples. P. falciparum recombinant antigens were successfully coupled to both non-magnetic and magnetic beads in multiplex assays. MFIs between the two bead types were comparable for all antigens tested. Bead recovery was superior with magnetic beads for all antigens. MFI values of stored non-magnetic coupled beads did not differ from freshly coupled beads, though they showed higher levels of bead aggregation. Magnetic and non-magnetic beads performed similarly in P. falciparum antibody assays. Magnetic beads were more expensive, but had higher bead recovery, were more convenient to use, and provided rapid and easy protocol manipulation. Magnetic beads are a suitable alternative to non-magnetic beads in malarial antibody serology.


Effect of intra-abdominal pressure on respiratory mechanics.
There has been an exponentially increasing interest in intra-abdominal hypertension (IAH). The intra-abdominal pressure (IAP) markedly affects the function of the respiratory system. This review will focus on the available literature from the past few years. A Medline and Pubmed search was performed in order to find an answer to the question "What is the impact of increased IAP on respiratory function in the critically ill?". In particular, increased IAP increases chest wall elastance (or decreases compliance) and promotes cranial shift of the diaphragm, with consequent reduction in lung volume and atelectasis formation. Compression of the lung parenchyma also triggers pulmonary infection. During general anaesthesia, in normal subjects, IAP does not affect the chest wall mechanics, but plays a relevant role in the caudal-cranial displacement of the abdominal content, the diaphragm and consequent changes in lung mechanics and function. In obese patients, the increased IAP is the major determinant of the reduction in lung volume, atelectasis formation and alterations in chest wall mechanics. In ARDS patients the measurement of IAP and chest wall mechanics is important for a better interpretation of respiratory mechanics, hemodynamics and appropriate setting of the ventilator. Furthermore, increased IAP promotes lung oedema, ventilator induced lung injury and reduced lymphatic flow in normal and diseased lungs. Increased IAP markedly affects respiratory function in such a way that it has an impact on daily clinical practise.


[Endocrine apparatus of the epithelium of small intestinal mucosa of Rana temporaria].
By methods of light and electron microscopy and histochemistry endocrinocytes of mucosal epithelium of small intestine were studied in Rana temporaria in June. Middle part of small intestine contains maximum number of endocrinocytes per 1 mm of mucosa. Electron microscopic study revealed 7 types of endocrinocytes, EC cells being the most numerous one. In the aspect of endocrinocyte identification endocrine apparatus of rana temporaria small intestine epithelium can be compared with that of mammals despite peculiarities of the epithelial layer structural organization.


Differences in HPRT mutant frequency among middle-aged Flemish women in association with area of residence and blood lead levels.
Biomarkers were measured in residents of Wilrijk and Hoboken, industrial suburbs of the city of Antwerp, and of Peer, a rural municipality in Flanders, Belgium. Persons with known occupational exposures to toxic compounds or commuting over long distances were excluded. Here, we report the hypoxanthine phosphoribosyltransferase gene (HPRT) variant frequencies for 99 non-smoking women aged 50-65 years. HPRT values above the detection limit (V(fpos) values) were observed for 43 subjects (21 from Peer, 22 from Antwerp). The median (10th to 90th percentiles) HPRT variant frequency (V(fpos)) in peripheral lymphocytes was 9.59 (3.44-56.99) for Peer and 3.57 (1.57-13.96) for Antwerp. The V(fpos) value was significantly higher in Peer than in Antwerp, both in terms of crude data (p=0.011) and after correction for age, level of education, smoking status, serum level of selenium and body mass index through analysis of covariance (p=0.011). For the total study population, serum lead concentration showed a non-significant positive correlation with lnV(fpos). In addition, subjects with a blood lead concentration above the median tended to have higher V(fpos) values (9.45x10(-6) for 'high' group versus 5.21x10(-6) for 'low' group; p=0.077 after correction for confounding). Subjects with a serum selenium level above the median tended to have lower V(fpos) values (4.99x10(-6) for 'high' group versus 9.83x10(-6) for 'low' group; p=0.051 after correction for confounding). These data are consistent with an indirect genotoxic effect of lead and with an antimutagenic effect of selenium.


Chiral vanadium(V) complexes with 2-aminoglucose Schiff-base ligands and their solution configurations: synthesis, structures, and DFT calculations.
The sugar-modified Schiff-base ligands derived from benzyl 2-deoxy-2-salicylideneamino-α-D-glucopyranoside (H2L(5-Br) and H2L(3-OMe)) were used to prepare the chiral oxidovanadium(V) complexes [VO(L(5-Br))(OMe)] (1) and [VO(L(3-OMe))(OMe)] (2) which can be isolated from a methanol solution as the six-coordinate complexes with an additional methanol ligand [VO(L(5-Br))(OMe)(MeOH)] (1-MeOH) and [VO(L(3-OMe))(OMe) (MeOH)] (2-MeOH). Both complexes crystallize in the orthorhombic space group P2(1)2(1)2(1) together with two solvent molecules of methanol as 1-MeOH·2MeOH and 1-MeOH·2MeOH. In both crystal structures, only diastereomers with A configuration at the chiral vanadium centre (OC-6-24-A) are observed which corresponds to an cis configuration of the oxido group at the vanadium centre and the benzyl group at the anomeric carbon of the sugar backbone. Upon recrystallization of 2-MeOH from chloroform, the five-coordinate complex 2 was obtained which crystallizes in the monoclinic space group P2(1) with one co-crystallized chloroform molecule (2·CHCl3). For the chiral vanadium centre in 2·CHCl3, a C configuration (SPY-5-43-C) is observed which corresponds to an trans structure as far as the orientations of the oxido and benzyl groups are concerned. (1)H and (51)V NMR spectra of 1 and 2 indicate the presence of two diastereomers in solution. Their absolute configurations can be assigned based on the magnetic anisotropy effect of the oxidovanadium group. This effect leads to significant differences for the (1)H NMR chemical shifts of the H-2 (1.1 ppm) and H-3 protons (0.3 ppm) of the glucose backbone of the two diastereomers, with the downfield shift observed for the H-2 proton of the C-configured and the H-3 proton of the A-configured diastereomer at the vanadium centre. For 1 and 2 the difference between the (51)V NMR chemical shifts of the two diastereomers is 30 and 28 ppm, respectively. Also in the (13)C NMR significant chemical shift differences between the two diastereomers are observed for the carbon atoms C2 (2 ppm) and C3 (4 ppm). DFT calculations of the NMR chemical shift parameters have been performed which are in good agreement with the experimental data. Moreover, the isomerization mechanism between the diastereomers is analysed on the basis of DFT calculations which indicate the required presence of methanol molecules as protic donors.


Free and conjugated catecholamines and serotonin in canine thoracic duct lymph: effects of feeding.
The source and fate of sulfoconjugated catecholamines present in plasma are not known. Sulfated norepinephrine has been shown to overflow together with free norepinephrine from a typical peripheral neuroeffector junction. Some released free norepinephrine is removed via the lymphatic system, but it is not known whether sulfated catecholamines are removed similarly. Serotonin, another biogenic amine, is released from the enterochromaffin cells into portal blood. The aims of the present study were to determine whether conjugated catecholamines and serotonin could be detected in thoracic duct lymph of dogs and to compare concentrations in lymph with those in samples of portal blood collected before and after the dogs were fed. A method is described for the extraction and purification of free and conjugated catecholamines and serotonin from lymph. In lymph and in plasma, there were similar concentrations of free (0.2-0.4 ng/ml) and conjugated (0.1-0.2 ng/ml) norepinephrine and of conjugated dopamine (0.2-1.0 ng/ml). The concentrations of free serotonin were much lower in lymph (0.1-0.2 ng/ml) than in portal blood (100-200 ng/ml). Small amounts of conjugated serotonin (0.1-0.4 ng/ml) were detected in lymph but were not detected in plasma. Feeding caused increases in concentration of conjugated dopamine in lymph and in plasma and small increases in the output of free norepinephrine and free and conjugated serotonin in lymph.


Transdiagnostic Dimensions of Psychiatric Comorbidity in Individuals at Clinical High Risk for Psychosis: A Preliminary Study Informed by HiTOP.
Background: Although psychiatric comorbidity is the norm among individuals at clinical high risk for psychotic disorders (CHR), research has yet to examine transdiagnostic dimensional models of comorbidity in this critical population. Methods: This study analyzed quantitative measures of eleven psychiatric syndromes in a group at CHR (n = 71) and a matched healthy comparison group (n = 73) to determine these syndromes' dimensional structure and relationships to cognition, functioning, and risk of conversion to psychotic disorders. Results: Relative to the comparison group, the CHR group was elevated on all eleven psychiatric syndromes. Exploratory factor analysis found three psychopathology dimensions: internalizing, negative symptoms, and positive symptoms. Depression cross-loaded onto the internalizing and negative symptom dimensions. Hypomania loaded positively on positive symptoms but negatively on negative symptoms. The negative symptom factor was associated with poorer cognition and functioning and a higher risk of conversion to psychosis. Conclusions: These dimensions align with internalizing, detachment, and thought disorder, three of the five spectra in higher-order models such as the Hierarchical Taxonomy of Psychopathology (HiTOP). In the CHR state, detachment appears to be particularly insidious and predictive of psychosis. Further research is required to distinguish depression and hypomania from attenuated psychotic symptoms in this population.


UCHL3 inhibits ferroptosis by stabilizing β-catenin and maintains stem-like properties of hepatocellular carcinoma cells.
Hepatocellular carcinoma (HCC) is the most common type of primary hepatic liver cancer. Dysregulated Wnt/β-catenin activation is closely related to the progression of cancer. Nevertheless, the mechanism that sustains the abnormal expression of β-catenin in HCC has yet to be identified. In this study, we find that UCHL3 is overexpressed in HCC tissues and correlated with β-catenin protein level. High expression of UCHL3 is associated with poor prognosis. UCHL3 knockdown markedly reduces the protein level of β-catenin in HCC cells. TOP-luciferase activity and β-catenin target genes expression are also decreased upon UCHL3 depletion. We find that the ARM domain of β-catenin is required for the interaction with UCHL3. UCHL3 increases β-catenin protein stability via removing K48-specific poly-ubiquitin chains from β-catenin protein. Furthermore, the depletion of UCHL3 induces ferroptosis and hinders the growth, invasion, and stem cell properties of HCC cells. These impacts could be restored by the overexpression of β-catenin. In addition, the UCHL3 inhibitor TCID inhibits the aggressive phenotype of HCC through the degradation of β-catenin. In general, our results indicates that UCHL3 increases the stability of β-catenin, which in turn facilitates tumorigenesis of HCC, suggesting that targeting UCHL3 may be a promising approach for the treatment of HCC.