Preparation of rGO/MnO2 Composites through Simultaneous Graphene Oxide Reduction by Electrophoretic Deposition.
We report the preparation of manganese dioxide (MnO2) nanoparticles and graphene oxide (GO) composites reduced by an electrophoretic deposition (EPD) process. The MnO2 nanoparticles were prepared by the electrolysis of an acidic KMnO4 solution using an alternating monopolar arrangement of a multiple-electrode system. The particles produced were γ-MnO2 with a rod-like morphology and a surface area of approximately 647.2 m2/g. The GO particles were produced by the oxidation of activated coconut shell charcoal using a modified Hummers method. The surface area of the GO produced was very high, with a value of approximately 2525.9 m2/g. Fourier transform infrared spectra indicate that a significant portion of the oxygen-containing functional groups was removed from the GO by electrochemical reduction during the EPD process after sufficient time following deposition of the GO. The composite obtained by the EPD process was composed of reduced graphene oxide (rGO) and γ-MnO2 and exhibited excellent electrocatalytic activity toward the oxygen reduction reaction following a two-electron transfer mechanism. This approach opens the possibility for assembling rGO composites in an efficient and effective manner for electrocatalysis.


Cow efficiency: modeling the biological and economic output of a Michigan beef herd.
In recent decades, beef cattle producers have selected cattle for biological traits (i.e., improved growth) to maximize revenue, leading to an increase in average cow body size. However, matching cow size to the production environment would allow producers to maximize productivity and economic returns per unit of land. This may help meet the goals of sustainable intensification, but environmental complexity and varying cow-calf production systems dictates a regional approach. The objective of this experiment was to examine the biological efficiency and economic returns of a Northern Michigan cow-calf system. We hypothesized that biological efficiency and economic returns would decrease with increasing cow body size. Data were collected from a Red Angus cow herd located at the Lake City AgBio Research Center in Lake City, MI from 2011 to 2018 on cow age, weight, and body condition score at weaning, and subsequent 205 d adjusted calf weaning weight (WW), sex, and yearling weight. Biological efficiency was defined as WW as a percentage of cow body weight (DBW). Enterprise budgeting techniques were used to calculate expected net returns from 2011 to 2018 after classifying cows into 11 BW tiers at 22.67 kg intervals beginning at 430.83 kg. Forward-looking net present value (NPV) was calculated using the same tier system, for a 10-yr production cycle with the baseline being a 200 d grazing season. Weaning weight increased with increasing DBW (P < 0.01), but the percentage of cow body weight weaned was reduced by -38.58 × Ln(DBW) (P < 0.01). This led to cows weaning 26.38 kg/ha more with every 100 kg drop in DBW. Expected net returns from 2011 to 2018 did not differ by DBW tier on a per cow basis but did on a per ha basis with a decrease in $10.27/ha with each increase in DBW tier (P < 0.01). Net present value was maximized in the baseline scenario at 453.51 kg DBW and decreased in value as DBW increased. These results suggest that for a Northern Midwestern cow-calf herd, comparatively lighter cows provide a higher economic value on a land basis.


Binding of cationic and neutral phenanthridine intercalators to a DNA oligomer is controlled by dispersion energy: quantum chemical calculations and molecular mechanics simulations.
Correlated ab initio as well as semiempirical quantum chemical calculations and molecular dynamics simulations were used to study the intercalation of cationic ethidium, cationic 5-ethyl-6-phenylphenanthridinium and uncharged 3,8-diamino-6-phenylphenanthridine to DNA. The stabilization energy of the cationic intercalators is considerably larger than that of the uncharged one. The dominant energy contribution with all intercalators is represented by dispersion energy. In the case of the cationic intercalators, the electrostatic and charge-transfer terms are also important. The DeltaG of ethidium intercalation to DNA was estimated at -4.5 kcal mol(-1) and this value agrees well with the experimental result. Of six contributions to the final free energy, the interaction energy value is crucial. The intercalation process is governed by the non-covalent stacking (including charge-transfer) interaction while the hydrogen bonding between the ethidium amino groups and the DNA backbone is less important. This is confirmed by the evaluation of the interaction energy as well as by the calculation of the free energy change. The intercalation affects the macroscopic properties of DNA in terms of its flexibility. This explains the easier entry of another intercalator molecule in the vicinity of an existing intercalation site.


Further evidence that BAT thermogenesis modulates cardiac rate in infant rats.
Previous research in infant rats suggested that brown adipose tissue (BAT), by providing warm blood to the heart during moderate cold exposure, protects cardiac rate. This protective role for BAT thermogenesis was examined further in the present study. In experiment 1, 1-wk-old rats in a warm environment were pretreated with saline or chlorisondamine (a ganglionic blocker), and then BAT thermogenesis was stimulated by injection with the beta3-agonist CL-316243. In experiment 2, pups were pretreated with chlorisondamine and injected with CL-316243, and after BAT thermogenesis was stimulated the interscapular region of the pups was cooled externally with a thermode. In both experiments, cardiac rate, oxygen consumption, and physiological temperatures were monitored. Activation of BAT thermogenesis substantially increased cardiac rate in saline- and chlorisondamine-treated pups, and focal cooling of the interscapular region was sufficient to lower cardiac rate. The results of these studies support the hypothesis that BAT thermogenesis contributes directly to the modulation of cardiac rate.


Gap junctions and chagas disease.
Gap junction channels provide intercellular communication between cells. In the heart, these channels coordinate impulse propagation along the conduction system and through the contractile musculature, thereby providing synchronous and optimal cardiac output. As in other arrhythmogenic cardiac diseases, chagasic cardiomyopathy is associated with decreased expression of the gap junction protein connexin43 (Cx43) and its gene. Our studies of cardiac myocytes infected with Trypanosoma cruzi have revealed that synchronous contraction is greatly impaired and gap junction immunoreactivity is lost in infected cells. Such changes are not seen for molecules forming tight junctions, another component of the intercalated disc in cardiac myocytes. Transcriptomic studies of hearts from mouse models of Chagas disease and from acutely infected cardiac myocytes in vitro indicate profound remodelling of gene expression patterns involving heart rhythm determinant genes, suggesting underlying mechanisms of the functional pathology. One curious feature of the altered expression of Cx43 and its gene expression is that it is limited in both extent and location, suggesting that the more global deterioration in cardiac function may result in part from spread of damage signals from more seriously compromised cells to healthier ones.


[Outcomes of ER:YAG LASER treatment of stress urinary incontinence in women].
To evaluate the effectiveness of a new method of treatment for stress urinary incontinence in women using an ER: YAG laser in SMOOTH mode and investigate pathophysiological and pathomorphological changes induced by erbium laser. This study comprised 98 women aged 37-63 years, who between 2014 and 2016 were diagnosed with SUI (type 1 and 2a, 2b) and grade 0-2 vaginal prolapse. The treatment was performed with a 2940 nm Er:YAG laser (Fotona, Slovenia) using a SMOOTH mode. Clinical assessment included PFIQ-7 and PISQ-12 questionnaires, uroflowmetry, laser Doppler flowmetry and biopsy of the anterior vaginal wall. The examination was carried out at baseline and 1-2 months after the treatment. The effectiveness of treatment was 73%. There was no deterioration after the procedure. Analysis of PFIQ-7 and PISQ-12 questionnaires showed that patients with mild incontinence had the greatest difference between pre- and posttreatment results. Uroflowmetry parameters improved in a majority of patients. Results of laser Doppler flowmetry demonstrated the improvement of blood flow in the microvascular bed. An important feature of the vaginal biopsy after laser exposure was an increase in neoangiogenesis. The findings of questionnaires and clinical evaluation of patients with SUI and vaginal prolapse before and after treatment with Er: YAG laser showed high therapeutic effectiveness of this treatment modality. Clinical effectiveness of ER: YAG laser in SMOOTH mode was 73%. Patients with type 1 and 2a SUI and mild or moderate incontinence have the best prognosis after treatment with this method.


Atherosclerosis risk factors in systemic lupus erythematosus.
Cardiovascular disease (CVD) has emerged as a leading cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Growing evidence suggests that inflammation plays a key role in the pathogenesis of atherosclerosis from initial endothelial dysfunction to rupture of atheromatous plaques. The increased frequency of atherosclerosis in SLE is likely due to a complex interplay among traditional risk factors, disease-related factors such as medications and disease activity, and inflammatory and immunogenic factors. Identification of these novel risk factors will lead to a better understanding of CVD pathogenesis and may also provide targets for potential treatment strategies. When caring for SLE patients, clinicians should be aware of the increased CVD risk and treat the known modifiable risk factors in addition to controlling disease activity and inflammation.


Computer-controlled apparatus for automated development of continuous flow methods.
An automated apparatus to assist in the development of analytical continuous flow methods is described. The system is capable of controlling and monitoring a variety of pumps, valves, and detectors through an IBM PC-AT compatible computer. System components consist of two types of peristaltic pumps (including a multiple pump unit), syringe pumps, electrically and pneumatically actuated valves, and an assortment of spectrophotometric and electrochemical detectors. Details of the interface circuitry are given where appropriate. To demonstrate the utility of the system, an automatically generated response surface is presented for the flow injection determination of iron(II) by its reaction with 1,10-phenanthroline.


F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis.
This systematic review was designed to provide more precise effect estimates of inhibitor development for the various types of F8 gene mutations in patients with severe hemophilia A. The primary outcome was inhibitor development and the secondary outcome was high-titer-inhibitor development. A systematic literature search was performed to include cohort studies published in peer-reviewed journals with data on inhibitor incidences in the various F8 gene mutation types and a mutation detection rate of at least 80%. Pooled odds ratios (ORs) of inhibitor development for different types of F8 gene mutations were calculated with intron 22 inversion as the reference. Data were included from 30 studies on 5383 patients, including 1029 inhibitor patients. The inhibitor risk in large deletions and nonsense mutations was higher than in intron 22 inversions (pooled OR = 3.6, 95% confidence interval [95% CI], 2.3-5.7 and OR = 1.4, 95% CI, 1.1-1.8, respectively), the risk in intron 1 inversions and splice-site mutations was equal (pooled OR = 0.9; 95% CI, 0.6-1.5 and OR = 1.0; 95% CI, 0.6-1.5), and the risk in small deletions/insertions and missense mutations was lower (pooled OR = 0.5; 95% CI, 0.4-0.6 and OR = 0.3; 95% CI, 0.2-0.4, respectively). The relative risks for developing high titer inhibitors were similar.


Tissue-specific expression and in vivo regulation of zebrafish orthologues of mammalian genes related to symptomatic hypomagnesemia.
Introduction of zebrafish as a model for human diseases with symptomatic hypomagnesemia urges to identify the regulatory transport genes involved in zebrafish Mg(2+) physiology. In humans, mutations related to hypomagnesemia are located in the genes TRPM6 and CNNM2, encoding for a Mg(2+) channel and transporter, respectively; EGF (epidermal growth factor); SLC12A3, which encodes for the Na(+)-Cl(-) co-transporter NCC; KCNA1 and KCNJ10, encoding for the K(+) channels Kv1.1 and Kir4.1, respectively; and FXYD2, which encodes for the γ-subunit of the Na(+),K(+)-ATPase. Orthologues of these genes were found in the zebrafish genome. For cnnm2, kcna1 and kcnj10, two conserved paralogues were retrieved. Except for fxyd2, kcna1b and kcnj10 duplicates, transcripts of orthologues were detected in ionoregulatory organs such as the gills, kidney and gut. Gene expression analyses in zebrafish acclimated to a Mg(2+)-deficient (0 mM Mg(2+)) or a Mg(2+)-enriched (2 mM Mg(2+)) water showed that branchial trpm6, gut cnnm2b and renal slc12a3 responded to ambient Mg(2+). When changing the Mg(2+) composition of the diet (the main source for Mg(2+) in fish) to a Mg(2+)-deficient (0.01 % (w/w) Mg) or a Mg(2+)-enriched diet (0.7 % (w/w) Mg), mRNA expression of branchial trpm6, gut trpm6 and cnnm2 duplicates, and renal trpm6, egf, cnnm2a and slc12a3 was the highest in fish fed the Mg(2+)-deficient diet. The gene regulation patterns were in line with compensatory mechanisms to cope with Mg(2+)-deficiency or surplus. Our findings suggest that trpm6, egf, cnnm2 paralogues and slc12a3 are involved in the in vivo regulation of Mg(2+) transport in ionoregulatory organs of the zebrafish model.


Gastric and extragastric actions of the histamine antagonist ranitidine during posttraumatic sepsis.
Histamine H2 antagonists (e.g., ranitidine) are generally thought to specifically reduce gastric acid secretion and are commonly used for stress ulcer prophylaxis in critically ill patients because of their efficacy and safety profile. A few reports suggest that ranitidine might also bind to extragastric sites and/or act as an immunomodulator. The potential effects on posttraumatic sepsis are unknown. Mongrel pigs (n = 24) were anesthetized with fentanyl, injured by a 10 kg steel bar dropped from a height of 1 m onto the fleshy portion of the posterior thigh, and then 35% of their blood volume was drained through the arterial catheter. All the shed blood plus two times the hemorrhage volume as lactated Ringer's solution was infused after a 1-hour shock period. Either vehicle or ranitidine (1.5 mg/kg) was intravenously administered at the time of resuscitation and every 12 hours thereafter in a blinded fashion. After 72 hours a septic challenge was administered (15 micrograms/kg Escherichia coli lipopolysaccharide [LPS] x 30 min). Serial gastroscopy, gastric pH, hemodynamics, leukocyte counts, cortisol, and tumor necrosis factor were recorded for 180 minutes after LPS. Immediately before LPS all hemodynamic variables were identical between treatments, but gastric pH was slightly higher and stress gastritis was marginally lower with ranitidine. LPS caused profound leukopenia and a hyperdynamic circulatory response (i.e., tachycardia, increased cardiac output, and decreased peripheral vascular resistance at relatively constant blood pressure); these changes were not altered by ranitidine. Gastric pH remained elevated after LPS with ranitidine, but LPS-induced gastritis was not modified. Ranitidine delayed the LPS-induced ventilation-perfusion imbalance and attenuated the peak increase in the proinflammatory cytokine, tumor necrosis factor, without altering its antiinflammatory opponent, cortisol. Similar changes were observed in four additional animals treated with cimetidine. The proportion of circulating neutrophils and lymphocytes was slightly altered 180 minutes after LPS, but there was no obvious effect on T lymphocytes in vivo, and no effect on the LPS-induced increase in neutrophil CD18 expression in vitro was seen. (1) Ranitidine increased gastric pH, which blunted the stress gastritis caused by trauma but not that caused by LPS; (2) ranitidine delayed the early LPS-evoked pulmonary changes and reduced the tumor necrosis factor spike, which is consistent with a favorable immunomodulatory action that has been reported in patients who are critically ill or are undergoing an elective abdominal surgical procedure; (3) the mechanism is probably related to H2 receptor antagonism rather than to a nonspecific side effect of ranitidine, which suggests that histamine may have a previously unrecognized role in posttraumatic septic responses; and (4) the site of action is probably not in the heart or peripheral resistance vessels, but salutary effects on circulating lymphocytes or neutrophils cannot be excluded.


A cartridge based sensor array platform for multiple coagulation measurements from plasma.
This paper proposes a MEMS-based sensor array enabling multiple clot-time tests for plasma in one disposable microfluidic cartridge. The versatile LoC (Lab-on-Chip) platform technology is demonstrated here for real-time coagulation tests (activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT)). The system has a reader unit and a disposable cartridge. The reader has no electrical connections to the cartridge. This enables simple and low-cost cartridge designs and avoids reliability problems associated with electrical connections. The cartridge consists of microfluidic channels and MEMS microcantilevers placed in each channel. The microcantilevers are made of electroplated nickel. They are actuated remotely using an external electro-coil and the read-out is also conducted remotely using a laser. The phase difference between the cantilever oscillation and the coil drive is monitored in real time. During coagulation, the viscosity of the blood plasma increases resulting in a change in the phase read-out. The proposed assay was tested on human and control plasma samples for PT and aPTT measurements. PT and aPTT measurements from control plasma samples are comparable with the manufacturer's datasheet and the commercial reference device. The measurement system has an overall 7.28% and 6.33% CV for PT and aPTT, respectively. For further implementation, the microfluidic channels of the cartridge were functionalized for PT and aPTT tests by drying specific reagents in each channel. Since simultaneous PT and aPTT measurements are needed in order to properly evaluate the coagulation system, one of the most prominent features of the proposed assay is enabling parallel measurement of different coagulation parameters. Additionally, the design of the cartridge and the read-out system as well as the obtained reproducible results with 10 μl of the plasma samples suggest an opportunity for a possible point-of-care application.


Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis after hematopoietic stem-cell transplantation.
Oral mucositis following high-dose chemotherapy may result in systemic infection and airway compromise, and the severity of oral mucositis may be dose-limiting. Here we investigate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF), which significantly shortens duration of neutropenia after hematopoietic stem-cell transplantation (HSCT) on oral mucositis. Thirteen children undergoing HSCT were prepared with etoposide (VP-16), thiotepa (TT), and total-body irradiation (TBI), and 13 with VP-16, TT, and cyclophosphamide (CPM). Following transplantation, 14 patients received GM-CSF at a dose of 125 micrograms/m2/d by continuous intravenous infusion (six prepared with VP-16, TT, and TBI, and eight prepared with VP-16, TT, and CPM), and 12 patients received no growth factor. Mucositis was more severe and persisted longer in patients prepared with the TBI-containing regimen. For this regimen, the duration of severe oral mucositis was shortened by the administration of GM-CSF, although the severity of mucositis was unaffected. No statistically significant effect of GM-CSF could be shown in patients who received VP-16, TT, and CPM. The incidence of positive fungal oral or blood cultures did not appear different whether patients received GM-CSF or not. For patients undergoing stomatotoxic HSCT regimens, GM-CSF may reduce the duration of oral mucositis, but is unlikely to effect the severity of oral mucositis or risk of airway compromise, and the severity of mucositis is likely to remain dose-limiting.


Effect of structural stability on endolysosomal degradation and T-cell reactivity of major shrimp allergen tropomyosin.
Tropomyosins are highly conserved proteins, an attribute that forms the molecular basis for their IgE antibody cross-reactivity. Despite sequence similarities, their allergenicity varies greatly between ingested and inhaled invertebrate sources. In this study, we investigated the relationship between the structural stability of different tropomyosins, their endolysosomal degradation patterns, and T-cell reactivity. We investigated the differences between four tropomyosins-the major shrimp allergen Pen m 1 and the minor allergens Der p 10 (dust mite), Bla g 7 (cockroach), and Ani s 3 (fish parasite)-in terms of IgE binding, structural stability, endolysosomal degradation and subsequent peptide generation, and T-cell cross-reactivity in a BALB/c murine model. Tropomyosins displayed different melting temperatures, which did not correlate with amino acid sequence similarities. Endolysosomal degradation experiments demonstrated differential proteolytic digestion, as a function of thermal stability, generating different peptide repertoires. Pen m 1 (Tm 42°C) and Der p 10 (Tm 44°C) elicited similar patterns of endolysosomal degradation, but not Bla g 7 (Tm 63°C) or Ani s 3 (Tm 33°C). Pen m 1-specific T-cell clones, with specificity for regions highly conserved in all four tropomyosins, proliferated weakly to Der p 10, but did not proliferate to Bla g 7 and Ani s 3, indicating lack of T-cell epitope cross-reactivity. Tropomyosin T-cell cross-reactivity, unlike IgE cross-reactivity, is dependent on structural stability rather than amino acid sequence similarity. These findings contribute to our understanding of cross-sensitization among different invertebrates and design of suitable T-cell peptide-based immunotherapies for shrimp and related allergies.


Effects of Electrical Stimulation on Risk Factors for Developing Pressure Ulcers in People with a Spinal Cord Injury: A Focused Review of Literature.
Pressure ulcers (PUs) are a common and serious problem for wheelchair users, such as individuals with a spinal cord injury (SCI), resulting in great discomfort, loss of quality of life, and significant medical care costs. Therefore, it is of utmost importance to prevent PUs. In this literature overview, the effects of electrical stimulation (ES) on the risk factors for developing PUs in people with an SCI are examined and synthesized from January 1980 to January 2015. Thirty-four relevant studies of PU prevention in SCI were identified. Four were randomized clinical trials, 24 were case series, 6 had other designs. Three types of ES modalities were identified. The methodological quality varied from poor to fairly strong, with a large variety in used ES parameters. Twenty-three studies were identified describing short-term effects of ES on interface pressure, oxygenation, and/or blood flow, and 24 studies described the long-term effects of ES on muscle volume, muscle strength, and histology. Whereas there is a lack of controlled studies on the effects of ES on PU incidence, which disallows definite conclusions, there is moderate evidence to suggest that ES-induced muscle activation has a positive influence on several risk factors for developing PUs in people with an SCI.


Structure and organization of the human theta-class glutathione S-transferase and D-dopachrome tautomerase gene complex.
The structure and organization of the human Theta-class glutathione S-transferase (GST) genes have been determined. GSTT1 and GSTT2 are separated by approx. 50 kb. They have a similar structure, being composed of five exons with identical exon/intron boundaries. GSTT1 is 8.1 kb in length, while GSTT2 is only 3.7 kb. The GSTT2 gene lies head-to-head with a gene encoding d-dopachrome tautomerase (DDCT), which extends over 8.5 kb and contains four exons. The sequence between GSTT2 and DDCT may contain a bidirectional promoter. The GSTT2 and DDCT genes have been duplicated in an inverted repeat. Sequence analysis of the duplicated GSTT2 gene has identified an exon 2/intron 2 splice site abnormality and a premature translation stop signal at codon 196. These changes suggest that the duplicate gene is a pseudogene, and it has been named GSTT2P.


Ultrasonography of Quadriceps Femoris Muscle and Subcutaneous Fat Tissue and Body Composition by BIVA in Chronic Dialysis Patients.
Protein Energy Wasting (PEW) in hemodialysis (HD) patients is a multifactorial condition due to specific pathology-related pathogenetic mechanisms, leading to loss of skeletal muscle mass in HD patients. Computed Tomography and Magnetic Resonance Imaging still represent the gold standard techniques for body composition assessment. However, their widespread application in clinical practice is difficult and body composition evaluation in HD patients is mainly based on conventional anthropometric nutritional indexes and bioelectrical impedance vector analysis (BIVA). Little data is currently available on ultrasound (US)-based measurements of muscle mass and fat tissue in this clinical setting. The purpose of our study is to ascertain: (1) if there are differences between quadriceps rectus femoris muscle (QRFM) thickness and abdominal/thigh subcutaneous fat tissue (SFT) measured by US between HD patients and healthy subjects; (2) if there is any correlation between QRFM and abdominal/thigh SFT thickness by US, and BIVA/conventional nutritional indexes in HD patients. We enrolled 65 consecutive HD patients and 33 healthy subjects. Demographic and laboratory were collected. The malnutrition inflammation score (MIS) was calculated. Using B-mode US system, the QRFM and SFT thicknesses were measured at the level of three landmarks in both thighs (superior anterior iliac spine, upper pole of the patella, the midpoint of the tract included between the previous points). SFT was also measured at the level of the periumbilical point. The mono frequency (50 KHz) BIVA was conducted using bioelectrical measurements (Rz, resistance; Xc, reactance; adjusted for height, Rz/H and Xc/H; PA, phase angle). 58.5% were men and the mean age was 69 (SD 13.7) years. QRFM and thigh SFT thicknesses were reduced in HD patients as compared to healthy subjects (p < 0.01). Similarly, also BIVA parameters, expression of lean body mass, were lower (p < 0.001), except for Rz and Rz/H in HD patients. The average QRFM thickness of both thighs at top, mid, lower landmarks were positively correlated with PA and body cell mass (BCM) by BIVA, while negatively correlated with Rz/H (p < 0.05). Abdominal SFT was positively correlated with PA, BCM and basal metabolic rate (BMR) (p < 0.05). Our study shows that ultrasound QRFM and thigh SFT thicknesses were reduced in HD patients and that muscle ultrasound measurements were significantly correlated with BIVA parameters.


Dietary sodium and cardiovascular disease.
Although an essential nutrient, higher sodium intake is associated with increasing blood pressure (BP), forming the basis for current population-wide sodium restriction guidelines. While short-term clinical trials have achieved low intake (<2.0 g/day), this has not been reproduced in long-term trials (>6 months). Guidelines assume that low sodium intake will reduce BP and reduce cardiovascular disease (CVD), compared to moderate intake. However, current observational evidence suggests a J-shaped association between sodium intake and CVD; the lowest risks observed with 3-5 g/day but higher risk with <3 g/day. Importantly, these observational data also confirm the association between higher intake (>5 g/day) and increased risk of CVD. Although lower intake may reduce BP, this may be offset by marked increases in neurohormones and other adverse effects which may paradoxically be adverse. Large randomised clinical trials with sufficient follow-up are required to provide robust data on the long-term effects of sodium reduction on CVD incidence. Until such trials are completed, current evidence suggests that moderate sodium intake for the general population (3-5 g/day) is likely the optimum range for CVD prevention.


Interaction of central Ang II and NO on the cardiac sympathetic afferent reflex in dogs.
The aim of this study was to test the hypothesis that the central angiotensin II (Ang II) and nitric oxide (NO) systems interact to modulate the cardiac sympathetic afferent reflex (CSAR). All dogs were anesthetized with alpha-chloralose (100 mg/kg, iv). They were sino-aortic baroreceptor denervated and vagotomized throughout the experiment renal sympathetic nerve activity responses to cardiac sympathetic afferent stimulation and the central gain of the CSAR were measured. Three protocols were performed: (1) intracerebroventricular injection (icv, 3 microg/h or 6 microg/h) of Ang II with and without N(omega)-nitro-L-arginine methyl ester (L-NAME) (icv, 1 mg/kg), (2) L-NAME (icv) with and without Ang II (icv, 6 microg/h), and (3) administration of the specific neural NO synthase (nNOS) inhibitor, S-Methyl-L-thiocitrulline (MeTC) (icv, 0.1 or 1 mM, 0.5 ml in 5 min) with and without pretreatment with the angiotensin type 1 receptor antagonist, losartan (icv, 0.125 mg/kg). The primary findings were (1) Ang II alone did not significantly affect the central sensitivity of the CSAR. However, Ang II with L-NAME enhanced this reflex, (2) even though L-NAME alone augmented the CSAR, this excitatory effect was further potentiated in the presence of Ang II and (3) MeTC significantly enhanced the central sensitivity of the CSAR. However, this enhancement did not occur after pretreatment with losartan. These data suggest that Ang II interacts with NO in the brain to modulate the CSAR and that inhibition of NO is required for facilitation of the CSAR by Ang II.


A cautionary note regarding hydroxyurea in sickle cell disease.
Hydroxyurea can increase fetal hemoglobin (HbF) and improve the clinical course of sickle cell disease (SCD) patients. However, several issues of hydroxyurea therapy remain unresolved, including differences in patients' drug clearance, predictability of drug response, reversibility of sickle cell disease-related organ damage by hydroxyurea, and the efficacy of elevated HbF. We treated two patients with hydroxyurea for periods of 1 to 4 years, monitoring clinical course and laboratory parameters at regular intervals. The first patient (patient A) had a history of chronic pain and extensive hospitalizations. The second patient (patient B) had a history of stroke and refused to continue with chronic transfusion therapy and chelation. Both patients showed a fivefold to tenfold increase in HbF (5% to 25%, 3% to 31%). However, patient A developed an acute chest syndrome, despite an HbF level of 20%. After red blood cell transfusions for hypoxia, the HbF level decreased to 5%. When hydroxyurea dosage was increased, pancytopenia developed and was not resolved until 2 months after hydroxyurea was discontinued; Patient B developed a cerebral hemorrhage on hydroxyurea; he died shortly thereafter. His HbF level was 21% before death. We noted an increase in HbF and a general improvement in the two patients. However, both experienced major SCD-related complications despite HbF levels over 20%. Our findings also suggest that the progressive vascular changes associated with SCD are unlikely to be dramatically affected by increased HbF levels. Because neither the efficacy nor the toxicity of hydroxyurea have been thoroughly investigated, physicians should be cautious in prescribing hydroxyurea for patients with SCD before completion of the National Clinical Trial.


Simultaneous biogas upgrading and medium-chain fatty acids production using a dual membrane biofilm reactor.
Utilizing H2-assisted ex-situ biogas upgrading and acetate recovery holds great promise for achieving high value utilization of biogas. However, it faces a significant challenge due to acetate's high solubility and limited economic value. To address this challenge, we propose an innovative strategy for simultaneous upgrading of biogas and the production of medium-chain fatty acids (MCFAs). A series of batch tests evaluated the strategy's efficiency under varying initial gas ratios (v/v) of H2, CH4, CO2, along with varying ethanol concentrations. The results identified the optimal conditions as initial gas ratios of 3H2:3CH4:2CO2 and an ethanol concentration of 241.2 mmol L-1, leading to maximum CH4 purity (97.2 %), MCFAs yield (54.2 ± 2.1 mmol L-1), and MCFAs carbon-flow distribution (62.3 %). Additionally, an analysis of the microbial community's response to varying conditions highlighted the crucial roles played by microorganisms such as Clostridium, Proteiniphilum, Sporanaerobacter, and Bacteroides in synergistically assimilating H2 and CO2 for MCFAs production. Furthermore, a 160-day continuous operation using a dual-membrane aerated biofilm reactor (dMBfR) was conducted. Remarkable achievements were made at a hydraulic retention time of 2 days, including an upgraded CH4 content of 96.4 ± 0.3 %, ethanol utilization ratio (URethanol) of 95.7 %, MCFAs production rate of 28.8 ± 0.3 mmol L-1 d-1, and MCFAs carbon-flow distribution of 70 ± 0.8 %. This enhancement is proved to be an efficient in biogas upgrading and MCFAs production. These results lay the foundation for maximizing the value of biogas, reducing CO2 emissions, and providing valuable insights into resource recovery.


Molecular diagnosis of leukemia.
The diagnosis of leukemia relies upon a multiparametric approach involving a number of different pathology disciplines. Molecular methods are increasingly employed to help refine diagnosis, establish prognosis and determine the most appropriate treatment, including rational therapies targeting the underlying genetic lesion. This review aims to highlight some of the molecular techniques commonly used in the diagnosis of leukemia using relevant examples. The focus is on procedures in current use and technologies showing promise in the research setting that are likely to enter clinical use in the near future. The list is not exhaustive, and this article concentrates on diagnosis of leukemia; techniques used to monitor response to therapy and molecular residual disease are mentioned but have not been covered extensively.


Rapid propagation of membrane tension at retinal bipolar neuron presynaptic terminals.
Many cellular activities, such as cell migration, cell division, phagocytosis, and exo-endocytosis, generate and are regulated by membrane tension gradients. Membrane tension gradients drive membrane flows, but there is controversy over how rapidly plasma membrane flow can relax tension gradients. Here, we show that membrane tension can propagate rapidly or slowly, spanning orders of magnitude in speed, depending on the cell type. In a neuronal terminal specialized for rapid synaptic vesicle turnover, membrane tension equilibrates within seconds. By contrast, membrane tension does not propagate in neuroendocrine adrenal chromaffin cells secreting catecholamines. Stimulation of exocytosis causes a rapid, global decrease in the synaptic terminal membrane tension, which recovers slowly due to endocytosis. Thus, membrane flow and tension equilibration may be adapted to distinct membrane recycling requirements.


Multimodal biomarker discovery for active Onchocerca volvulus infection.
The neglected tropical disease onchocerciasis, or river blindness, is caused by infection with the filarial nematode Onchocerca volvulus. Current estimates indicate that 17 million people are infected worldwide, the majority of them living in Africa. Today there are no non-invasive tests available that can detect ongoing infection, and that can be used for effective monitoring of elimination programs. In addition, to enable pharmacodynamic studies with novel macrofilaricide drug candidates, surrogate endpoints and efficacy biomarkers are needed but are non-existent. We describe the use of a multimodal untargeted mass spectrometry-based approach (metabolomics and lipidomics) to identify onchocerciasis-associated metabolites in urine and plasma, and of specific lipid features in plasma of infected individuals (O. volvulus infected cases: 68 individuals with palpable nodules; lymphatic filariasis cases: 8 individuals; non-endemic controls: 20 individuals). This work resulted in the identification of elevated concentrations of the plasma metabolites inosine and hypoxanthine as biomarkers for filarial infection, and of the urine metabolite cis-cinnamoylglycine (CCG) as biomarker for O. volvulus. During the targeted validation study, metabolite-specific cutoffs were determined (inosine: 34.2 ng/ml; hypoxanthine: 1380 ng/ml; CCG: 29.7 ng/ml) and sensitivity and specificity profiles were established. Subsequent evaluation of these biomarkers in a non-endemic population from a different geographical region invalidated the urine metabolite CCG as biomarker for O. volvulus. The plasma metabolites inosine and hypoxanthine were confirmed as biomarkers for filarial infection. With the availability of targeted LC-MS procedures, the full potential of these 2 biomarkers in macrofilaricide clinical trials, MDA efficacy surveys, and epidemiological transmission studies can be investigated.


Forty month follow-up of persistent and difficultly controlled acromegalic patients treated with depot long acting somatostatin analog octreotide.
The objective of the present study was to investigate the effects of octreotide long acting release (S-LAR) preparation on GH and IGF-1 serum concentrations and pituitary tumor size in patients with persistent and difficultly controlled acromegaly even after adjuvant irradiation and/or dopamine agonists. Thirty-three patients with active acromegaly (26 female and 7 male, mean age; 43.94 +/- 14.01 SD years) were included in this study. Patients were evaluated at baseline and at 6, 12, 30 and 40 months for GH, IGF-1, and GH response to OGTT and biliary ultrasonography. Sella MRI was performed at initial and at 40 months. All patients received 20 mg S-LAR. Afterwards, the dosage was titrated to improve individual GH response and reduction of IGF-1 into normal ranges. Basal serum IGF-1 levels decreased from median: 530 microg/l [IQR: 420-600] to 340 microg/l [IQR: 230-460] at 6 months (p = 0.01), to 400 microg/l [IQR: 222.4-600] at 12 months (p = 0.48), to 396 microg/l [IQR: 318-468] at 30 months (p = 0.49), to 482 microg/l [308-580] at 40 months (p = 0.47). Nadir GH levels in OGTT fell from 2.70 ng/ml [IQR: 1.35-6.90] to 1.60 ng/ml [IQR: 0.36-4.10] at 6 months (p = 0.03), to 0.31 ng/ml [IQR: 0.18-0.65] at 12 months (p<0.0001), to 1.50 ng/ml [IQR: 0.83-4.00] at 30 months (p = 0.398) and to 0.89 ng/ml [IQR: 0.58-1.35] at 40 months (p<0.0001). Initially, pituitary adenoma volume was median: 1.18 ml [IQR: 0.08-3.50] and it shrank to 0.21 ml [IQR: 0-2.1] at 40 months (p = 0.08). Gallstones were detected in 12 patients and six of them underwent cholecystectomy. S-LAR is an effective treatment regimen in reducing GH and IGF-1 concentrations and as well as in shrinking tumor volume in persistent and difficultly controlled acromegalic patients.


Membrane-associated diacylglycerol kinase activity is increased by noradrenaline, but not by angiotensin II, in arterial smooth muscle.
In rat small arteries, noradrenaline stimulates the sustained production of arachidonoyl-phosphatidic acid, whereas there is only a slight and transient increase with angiotensin II [Ohanian, Ollerenshaw, Collins and Heagerty (1990) J. Biol. Chem. 265, 8921-8928]. Diacylglycerol kinase (DGK) is the enzyme responsible for generating phosphatidic acid from 1,2-diacylglycerol (DAG). To investigate whether agonists influence DGK activity, we have studied this enzyme in both particulate and soluble fractions prepared from rat small arteries. Soluble DGK activity was inhibited by octyl glucoside. Therefore a deoxycholate assay was used for this fraction, whereas an octyl glucoside mixed-micelle assay was used to examine particulate fractions. Particulate DGK selectively phosphorylated long-chain DAG at a rate 2.5-3-fold higher than that for the synthetic substrate dioctanoylglycerol. In contrast, the substrate preference of the soluble isoenzyme(s) was: dioctanoylglycerol > arachidonoyl-DAG= dioleoylglycerol. Stimulation of intact arteries with noradrenaline (15 microM) increased membrane-associated DGK activity 3-fold, transiently. Angiotensin II (100 nM) stimulation did not alter the DGK activity of this fraction. The activity of the soluble DGK was increased by both agonists, but only transiently. These results demonstrate that rat small arteries contain a membrane-associated DGK which metabolizes arachidonoyl-containing substrate. Also, the activity of this enzyme is regulated differentially by vasoconstrictor hormones. It is concluded that modulation of DGK activity may represent one point at which agonists using the same signal-transduction pathway may tailor the cellular response.


Recovery Programs for People With Mental Illness in Taiwan: A Feasibility Study.
Most recovery programs have been developed in Western countries. This study explores the cultural adaptation of a recovery program to a non-Western country. To test the feasibility of a recovery group developed for people with mental illness in Taiwan. Mixed-methods feasibility study. Community psychiatric rehabilitation center in southern Taiwan. Twenty-four people with mental illness living in the community. The authors designed a recovery group based on the Pathways to Recovery program and the mental health recovery literature. The curriculum included two phases: recovery profile and recovery plan. The group gathered for a 1-hr session once a week for 18 wk. Outcomes were assessed preintervention, mid-intervention, and postintervention. Data collected included Stages of Recovery Scale (SRS) scores, course assessments, and course discussions. Most participants were satisfied with the recovery program and its implementation. Scores on the Social Functioning/Role Performance subscale of the SRS showed a medium to large effect size (r = .36) for the Recovery Stage 1-3 subsample (n = 16). This study affirmed the feasibility of a recovery group for people with mental illness in Taiwan. Prospective randomized controlled trials should be used to verify recovery groups' effectiveness. Recovery programs tailored to people with mental illness in non-Western countries may need more examples and longer sessions to enable participants to fully understand and implement the concepts of recovery.


High-frequency transformation of yeast: autonomous replication of hybrid DNA molecules.
A set of vector DNAs (Y vectors) useful for the cloning of DNA fragments in Saccharomyces cerevisiae (yeast) and in Escherichia coli are characterized. With these vectors, three modes of yeast transformation are defined. (i) Vectors containing yeast chromosomal DNA sequences (YIp1, YIp5) transform yeast cells at low frequency (1--10 colonies per microgram) and integrate into the genome by homologous recombination; this recombination is reversible. (ii) Hybrids containing endogenous yeast plasmid DNA sequences (YEp2, YEp6) transform yeast cells at much higher frequency (5000--20,000 colonies per microgram). Such molecules replicate autonomously with an average copy number of 5--10 covalently closed circles per yeast cell and also replicate as a chromosomally integrated structure. This DNA may be physically isolated in intact form from either yeast or E. coli and used to transform either organism at high frequency. (iii) Vectors containing a 1.4-kilobase yeast DNA fragment that includes the centromere linked trp1 gene (YRp7) transform yeast with an efficiency of 500--5000 colonies per microgram; such molecules behave as minichromosomes because they replicate autonomously but do not integrate into the genome. The uses of Y vectors for the following genetic manipulations in yeast are discussed: isolation of genes; construction of haploid strains that are merodiploid for a particular DNA sequence; and directed alterations of the yeast genome. General methods for the selection and the analysis of these events are presented.


How much will linked deformable registrations decrease the quality of multi-atlas segmentation fusions?
Multi-atlas segmentation can yield better results than single atlas segmentation, but practical applications are limited by long calculation times for deformable registration. To shorten the calculation time pre-calculated registrations of atlases could be linked via a single atlas registered in runtime to the current patient. The primary purpose of this work is to investigate and quantify segmentation quality changes introduced by such linked registrations. We also determine the optimal parameters for fusing linked multi-atlas labels using probabilistic weighted fusion. Computed tomography images of 10 head and neck cancer patients were used as atlases, with parotid glands, submandibular glands, the mandible and lymph node levels II-IV segmented by an experienced radiation oncologist following published consensus guidelines. The change in segmentation quality scored by Dice similarity coefficient (DSC) for linking free-form deformable registrations, modeled by B-splines, was investigated for both single- and multi-atlas label fusion by using a leave-one-out approach. The median decrease of the DSC was in the range 2.8% to 8.4% compared to direct registrations for all structures while reducing the computer calculation time to that of a single deformable registration. Linking several registrations showed a DSC decrease almost linear to the number of links, suggesting that extrapolation to zero links provides an observer independent measure of the inherent precision with which the segmentation guidelines can be applied. Linking pre-made registrations of multiple atlases via a runtime registration of a single atlas provides a feasible method for reducing computation time in multi-atlas registration.


Genome-wide screen identifies host loci that modulate M. tuberculosis fitness in immunodivergent mice.
Genetic differences among mammalian hosts and Mycobacterium tuberculosis ( Mtb ) strains determine diverse tuberculosis (TB) patient outcomes. The advent of recombinant inbred mouse panels and next-generation transposon mutagenesis and sequencing approaches has enabled dissection of complex host- pathogen interactions. To identify host and pathogen genetic determinants of Mtb pathogenesis, we infected members of the BXD family of mouse strains with a comprehensive library of Mtb transposon mutants (TnSeq). Members of the BXD family segregate for Mtb -resistant C57BL/6J (B6 or B ) and Mtb -susceptible DBA/2J (D2 or D ) haplotypes. The survival of each bacterial mutant was quantified within each BXD host, and we identified those bacterial genes that were differentially required for Mtb fitness across BXD genotypes. Mutants that varied in survival among the host family of strains were leveraged as reporters for "endophenotypes", each bacterial fitness profile directly probing specific components of the infection microenvironment. We conducted QTL mapping of these bacterial fitness endophenotypes and identified 140 h ost- p athogen quantitative trait loci ( hp QTL). We identified a QTL hotspot on chromosome 6 (75.97-88.58 Mb) associated with the genetic requirement of multiple Mtb genes; Rv0127 ( mak ), Rv0359 ( rip2 ), Rv0955 ( perM ), and Rv3849 ( espR ). Together, this screen reinforces the utility of bacterial mutant libraries as precise reporters of the host immunological microenvironment during infection and highlights specific host-pathogen genetic interactions for further investigation. To enable downstream follow-up for both bacterial and mammalian genetic research communities, all bacterial fitness profiles have been deposited into GeneNetwork.org and added into the comprehensive collection of TnSeq libraries in MtbTnDB.


Haematuria in Nigerians: a prospective study.
One hundred and ninety Nigerians who presented with haematuria at an out-patient department were fully investigated and treated. There were 135 males and 55 females of mean age 37.8 years. Fifty-eight per cent of them presented over 3 months after onset of symptoms. Haematuria was severe in 27%, painless in 50%, intermittent in 26%. Infection accounted for 22.6%, neoplasms 17.4%, schistosomiasis, 14.2%, trauma 13.7%, benign prostatic hyperplasia 7.9%, calculous disease 7.9% and haemoglobinopathy 2.6%. There was no case of haematuria due to Hb type AS. Aetiology was unknown in 1.6%. Urethrocystoscopy and intravenous urography were the most rewarding investigations. All patients with carcinoma of the bladder presented very late and none survived more than 1 year after diagnosis. Eighty-six per cent of the cases were of non-schistosomal origin and the need for early and thorough investigation of haematuria is stressed.


Analysis of fibrinolytic shutdown in trauma patients with traumatic brain injury.
Coagulation profiles following major trauma vary depending on injury pattern and degree of shock. The physiologic mechanisms involved in coagulation function at any given time are varied and remain poorly understood. Thromboelastography (TEG) has been used evaluate coagulation profiles in the trauma population with some reports demonstrating a spectrum of fibrinolysis to fibrinolytic shutdown on initial presentation. The objective of this study was to evaluate the fibrinolytic profile of patients with TBI using thromboelastography (TEG). We hypothesized that patients with TBI would demonstrate low fibrinolytic activity. All trauma activations at an ACS-verified level 1 trauma center received a TEG analysis upon arrival from December 2019 to June 2021. A retrospective review of the results and outcomes was conducted, and TBI patients were compared to patients without TBI. Linear regression was used to evaluate the effect of patient and injury factors on fibrinolysis. Hyperfibrinolysis was defined as LY30 > 7.7%, physiologic fibrinolysis as LY30 0.6-7.7%, and fibrinolytic shutdown as LY30 < 0.6%. A total of 1369 patients received an admission TEG analysis. Patients with TBI had a significantly higher median ISS (16 vs. 8, p < 0.001), lower median admission Glasgow Coma Scale (14 vs. 15, p < 0.001), longer intensive care unit length of stay (3 vs. 2 days, p < 0.0001), increased ventilator days (216 vs. 183, p < 0.001), higher mortality (14.6% vs. 5.1%, p < 0.001), but lower shock index (0.6 vs. 0.7, p < 0.0001) compared to those without TBI. Median LY30 was found to be decreased in the TBI group (0.1 vs. 0.2, p = 0.0006). Patients with TBI were found to have a higher rate of fibrinolytic shutdown compared those without TBI (68.7% vs. 63.5%, p = 0.054). ISS, sex, and shock index were found to be predictive of LY30 on linear regression, but TBI was not (Β: 0.09, SE: 0.277, p = 0.745). The rate of DVT/PE did not appear to be elevated in patients with TBI (0.8%) and without TBI (1.2%). Trauma patients with and without TBI were found to have high rates of fibrinolytic shutdown. Although there was a high incidence of fibrinolytic shutdown, it did not appear to have an impact on the rate of thrombotic complications. The clinical significance of these results is unclear and differs significantly from recent reports which demonstrated that TBI is associated with a 25% rate of fibrinolytic shutdown. Further investigation is needed to better define the fibrinolytic pathway in patients with trauma and TBI to develop optimal treatment algorithms.


Changes in arsenic fractionation, bioaccessibility and speciation in organo-arsenical pesticide amended soils as a function of soil aging.
Although organoarsenical pesticides are being phased out, sites with high concentrations of organic arsenical residues still exist due to the long-term application of these pesticides. The biotic and abiotic speciation of dimethylarsinic acid (DMA) can result in the formation of inorganic arsenic (As) species. Oxidation state, retention, and thereby persistence, varies according to temporal changes, influencing the availability and toxicity of contaminants. The current greenhouse study aimed at evaluating temporal changes in the oxidation state of As, geochemical partitioning, and bioaccessibility. Four soils with varying physiochemical properties were contaminated with DMA at two concentrations (675 and 1,500 mg kg(-1) of As). Rice plants were grown for a 6 months period, following which, the soils were allowed to age. The operationally defined forms of As and its bioaccessibility was analyzed at 0, 6 months, 1 year, and 3 years. Changes in oxidation state of As were evaluated immediately after spiking and after 3 years of soil-pesticide equilibration. Results show that geochemical partitioning of As was affected significantly (P<0.05) by soil type, loading rates, and equilibration time. Arsenic was bound mainly to the poorly-crystalline Fe/Al-oxyhydroxides in the soil. However, these interactions did not affect As bioaccessibility, presumably due to the dissolution of the bound fractions of As in the acidic stomach. While 74-94% of the total bioaccessible As was transformed to As(V), 4-19% was transformed to the more toxic As(III). This study indicates that although aging affected the geochemical partitioning of As in the soil, bioaccesibility was controlled by the gastric pH.


[Current principles in the use of diagnostic coronary angiography].
The paper presents current principles in designing diagnostic coronary angiography by taking into account of fundamental achievements in endovascular medicine in diagnosing and treating various heart diseases. Analyzing the world and Russian experience gained, the authors present basic qualitative and quantitative requirements for X-ray contrast study of cardiac vessels to enhance the information value of coronary angiography. They consider necessary diagnostic criteria to be achieved during the study to choose a surgical or endovascular treatment: a type and number of diagnostic film projections, X-ray anatomy of coronary vessels. The present-day accumulated data on X-ray anatomic features of coronary vessels in coronary heart disease are classified. Current classifications of coronary circulation, principles in the development of collateral blood supply, main sources of collaterals, and the specific features of the coronary bed in patients with coronary heart disease are also given.


[Electrophysiological correspondence between Kv4.2 current and transient outward potassium current in the cultured rat hippocampal neuron].
The present study was carried out to determine the functional properties of Kv4.2 expressed in mammalian cells in comparison with native transient potassium outward current (I(A)) in the hippocampal neurons. Transient transfection, cell culture and whole cell voltage clamp techniques were used. The results showed that I(A) in cultured rat hippocampal neurons and Kv4.2 expressed in HEK293 cells both displayed "A"-type current properties. The activation curves of I(A) and Kv4.2 were better fitted by simple Boltzmann function with V(1/2) 10.0+/-3.3 mV, k 13.9+/-2.6 mV for I(A) and V1/2 -9.7+/-4.1 mV, k 15.8+/-5.7 mV for Kv4.2, respectively. The steady-state inactivation curves of I(A) had a midpoint of -93.0+/-11.4 mV and a slope of 9.0+/-1.5 mV. The voltage-dependence of inactivation for Kv4.2 exhibited midpoint and slope values of -59.4+/-12.2 mV and 8.0+/-3.1 mV, respectively. The time constants (tau) of recovery from inactivation of I(A) and Kv4.2 were 27.9+/-14.1 ms and 172.8+/-10.0 ms, respectively. These results suggest that Kv4.2 is probably a major isoform contributing to I(A) in hippocampus neurons.


Case report congenital LQTS--an electrocardiographic and genotype correlation.
The congenital Long QT Syndrome (LQTS) is characterized by abnormally prolonged ventricular repolarization due to inherited defect in cardiac sodium and potassium channels, which predisposes the patients to syncope, ventricular arrhythmias, and sudden cardiac death. Early diagnosis and preventive treatment are instrumental to prevent sudden cardiac death in patients with the congenital LQTS. The diagnostic criteria for congenital LQTS are based on certain electrocardiographic findings and clinical history. Recently genotype specific electrocardiographic pattern in the congenital LQTS has also been described. Recent studies suggest feasibility of genotype specific treatment of LQTS and in near future, mutation specific treatment will probably become a novel approach to this potentially fatal syndrome. We describe two cases that fulfilled the electrocardiographic and historical diagnostic criteria with morphology on electrocardiogram (ECG) suggestive of LQT1 genotype.


Overexpression of CST4 promotes gastric cancer aggressiveness by activating the ELFN2 signaling pathway.
Gastric cancer is one of the most lethal malignancies of gastrointestinal cancer and its prognosis remains dismal because of the paucity of effective therapeutic targets. Here, we show that cystatin 4 (CST4) is markedly upregulated in gastric cancer cell lines and clinical tissues. Ectopic expression of CST4 in gastric cancer cells promoted proliferation, migration, and invasion of gastric cancer cells in vitro. Furthermore, CST4 overexpression significantly promoted the tumorigenicity of gastric cancer cells in vivo, whereas silencing endogenous CST4 caused an opposite outcome. In addition, extracellular leucine rich repeat and fibronectin type III domain containing 2 (ELFN2) was identified as a downstream target of CST4 in gastric cancer cells and was positively correlated with ELFN2 expression in gastric cancer tissues. Finally, we demonstrated that CST4 enhanced gastric cancer aggressiveness by regulating ELFN2 signaling. Together, our results provide new evidence that CST4 overexpression promotes the progression of gastric cancer and might represent a novel therapeutic target for its treatment.


Role of User Benefit Awareness in Health Coverage Utilization among the Poor in Cambodia.
The objective of this study was to understand the steps to health coverage benefit utilization in Cambodia toward improving access to health care and financial risk protection for the poor. We particularly examine the role of user awareness in the pathway to care seeking and benefit utilization with respect to the Health Equity Funds (HEF). Using 2016 survey data that were nationally representative of households with children under two years of age, we used a series of logistic regression models to evaluate associations between respondents' awareness of benefits, public health care seeking behaviors, coverage benefit claims, and out-of-pocket expenditures. Beneficiaries were generally aware of their entitlements, although their awareness of specific benefits, such as transport reimbursement, was relatively lower. Awareness of free services at public health centers was associated with twice the odds of having ever visited a public provider for outpatient care, while awareness of free services at public hospitals was associated with higher odds of always seeking inpatient care in the public sector. Study findings point to the decision of where to seek care as the critical point in the pathway to HEF utilization. If the decision had already been made to go to a public provider, it was likely that HEF benefits were claimed. Interventions that prompt appropriate care seeking in the public sector may do the most to improve HEF utilization and subsequently improve access to care through sufficient financial risk protection.


Repolarization dispersion in patients with systemic sclerosis.
Systemic sclerosis (SSc) is associated with increased cardiac morbidity and mortality. Whether some electrocardiographic markers of arrhythmias predispose to early cardiogenic death in SSc remains controversial. This study evaluated the occurrence of previously reported as well as unstudied markers of repolarization in patients with SSc and assessed their prognostic implications. A total of 21 patients with SSc and 31 unaffected controls were included in this prospective study. Electrocardiograms were conducted under strict standards. Repolarization and dispersion parameters and markers of late ventricular potentials were determined using designated computer software. Results of multiple beats were averaged. There were no significant differences between the SSc and control groups in average QT intervals, average corrected QT intervals, average QT interval dispersion (QTd), average QT corrected dispersion (QTcd), and QT dispersion ratio. However, average QT apex dispersion, average JT dispersion, average JT corrected dispersion, and Tpeak-Tend corrected were significantly higher in patients with SSc than in controls. Late ventricular potentials were not found in patients with SSc or in controls. Increased QTd and QTcd were recorded in 1 patient who experienced ventricular arrhythmia before inclusion in the study. None of the remaining patients with SSc or the controls developed arrhythmia during the 9-year follow-up. Abnormal repolarization parameters may be observed in patients with SSc. However, their prognostic significance with regard to increased risk for repolarization-associated ventricular arrhythmias and increased cardiac death could not be determined in this study. Our findings endorse additional studies on this matter.


The intersection of school corporal punishment and associated factors: Baseline results from a randomized controlled trial in Pakistan.
Violence against youth is a global issue; one form of youth victimization is school corporal punishment. We use baseline assessments from a cluster randomized controlled trial to examine the prevalence of school corporal punishment, by gender, and the relationship to levels of peer violence at school, parent corporal punishment, youth food security and youth academic performance and school attendance in Pakistan. Forty homogenous public schools in the urban city of Hyderabad, Pakistan were chosen for randomization into the trial evaluating a youth violence prevention intervention. 1752 6th graders, age 11-14 years, were selected as the target population. Since schools are segregated by gender in Pakistan, data are from interviews in 20 boys' schools and 20 girls' schools. Overall, 91.4% of boys and 60.9% of girls reported corporal punishment at school in the previous 4 weeks and 60.3% of boys had been physically punished at home in the past 4 weeks compared to 37.1% of girls. Structural equation modeling revealed one direct pathway for both boys and girls from food insecurity to corporal punishment at school while indirect pathways were mediated by depression, the number of days missed from school and school performance and for boys also by engagement in peer violence. Exposure to corporal punishment in school and from parents differs by gender, but in both boys and girls poverty in the form of food insecurity was an important risk factor, with the result that poorer children are victimized more by adults.


[The diagnostic and treatment characteristics of cardiac arrhythmias in patients with the premature ventricular excitation syndrome].
Studied were 24 patients with the syndrome of premature excitation of the ventricles. In 18 of them transesophageal electrophysiological examination was carried out. Reciprocal paroxysmal tachycardia was revealed in 16 patients (orthodromic form--in 14, antidromic--in 2 patients). Cardiac fibrillation with a cardiac contraction rate of 320-340 per minute was noted in 2 patients. Difficulties are noted in the differential diagnosis of antidromic form with ventricular paroxysmal tachycardia and risk of development of ventricular fibrillation in auricular fibrillation. The authors propose a method of diagnosis of latent forms of the syndrome of premature excitation of the ventricles using short-term pharmacological block of atrioventricular conduction in intravenous administration of ATP.


Endoscopic full-thickness plication for the treatment of GERD: a multicenter trial.
A novel endoscopic full-thickness plication device has been designed to inhibit gastroesophageal reflux by placing a transmural plication near the gastroesophageal junction under direct endoscopic visualization. This study assessed the safety and efficacy of endoscopic full-thickness plication in the treatment of patients with symptoms caused by GERD. Patients with chronic heartburn requiring maintenance therapy with antisecretory medication were recruited. Exclusion criteria were the following: hiatal hernia (>2 cm), grade III and IV esophagitis, and Barrett's esophagus. The following were assessed over a follow-up period of 6 months: GERD-Health-Related Quality of Life, Gastrointestinal Symptom Rating Scale, and SF-36 Health Survey, medication use, 24-hour esophageal pH monitoring and esophageal manometry. Patients underwent a single, full-thickness plication in the gastric cardia just distal to the gastroesophageal junction. Re-treatment was not permitted. A total of 64 patients (mean age 46.3 years, range 23-71 years) underwent endoscopic full-thickness plication (mean procedure time 17.2 minutes). At 6 months after plication, proton pump inhibitor therapy had been eliminated in 74% of previously medication-dependent patients. Median GERD-Health-Related Quality of Life scores improved 67% (19.0 vs. 5.0; p<0.001). Improvements also were observed in median Gastrointestinal Symptom Rating Scale and SF-36 Health Survey mental and physical composite scores. Median esophageal acid exposure improved significantly (10 vs. 8; p<0.008) with normalization of pH noted in 30% of patients. No significant change in esophageal manometry was noted. One gastric perforation occurred and was managed conservatively without sequelae. In this study, a single full-thickness plication placed at the gastroesophageal junction reduced symptoms, medication use, and esophageal acid exposure associated with GERD.


Seroprevalence of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) antibodies among healthcare personnel in the Midwestern United States, September 2020-April 2021.
To determine the prevalence of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) IgG nucleocapsid (N) antibodies among healthcare personnel (HCP) with no prior history of COVID-19 and to identify factors associated with seropositivity. Prospective cohort study. An academic, tertiary-care hospital in St. Louis, Missouri. The study included 400 HCP aged ≥18 years who potentially worked with coronavirus disease 2019 (COVID-19) patients and had no known history of COVID-19; 309 of these HCP also completed a follow-up visit 70-160 days after enrollment. Enrollment visits took place between September and December 2020. Follow-up visits took place between December 2020 and April 2021. At each study visit, participants underwent SARS-CoV-2 IgG N-antibody testing using the Abbott SARS-CoV-2 IgG assay and completed a survey providing information about demographics, job characteristics, comorbidities, symptoms, and potential SARS-CoV-2 exposures. Participants were predominately women (64%) and white (79%), with median age of 34.5 years (interquartile range [IQR], 30-45). Among the 400 HCP, 18 (4.5%) were seropositive for IgG N-antibodies at enrollment. Also, 34 (11.0%) of 309 were seropositive at follow-up. HCP who reported having a household contact with COVID-19 had greater likelihood of seropositivity at both enrollment and at follow-up. In this cohort of HCP during the first wave of the COVID-19 pandemic, ∼1 in 20 had serological evidence of prior, undocumented SARS-CoV-2 infection at enrollment. Having a household contact with COVID-19 was associated with seropositivity.


Relationship of Choroidal Microvasculature Dropout and Beta Zone Parapapillary Area With Visual Field Changes in Glaucoma.
To evaluate the association between rates of choroidal microvasculature dropout (MvD) change, beta zone parapapillary atrophy (β-PPA) area change, and visual field (VF) changes in eyes with primary open-angle glaucoma (POAG). Retrospective, observational cohort study. In a tertiary glaucoma clinic, we included 76 eyes from 58 patients with POAG with and without localized MvD, who had ≥2 years of follow-up with a minimum of 4 visits with optical coherence tomography angiography and optical coherence tomography scans. β-PPA area was evaluated using scanning laser ophthalmoscopy-like images and compared with the area of MvD on an en face choroidal vessel density map during the follow-up period. Joint longitudinal mixed effects models were used to estimate the rates of change in β-PPA area or MvD area and VF mean deviation (MD). Mean rates of change in β-PPA and MvD area were 0.037 mm2 (95% confidence interval [CI] 0.030-0.043 mm2) per year and 0.039 mm2 (95% CI 0.029-0.048 mm2) per year, respectively, over the mean follow-up of 4.1 years. In multivariable models, MvD area enlargement was significantly associated with faster rates of VF MD loss (0.03 mm2 [95% CI 0.02-0.04 mm2] per 1-dB worse, P < .001) but not β-PPA area enlargement (0.04 mm2 [95% CI 0.03-0.05 mm2] per 1-dB worse, P = .252). MvD area rates, but not β-PPA area rates, were associated with VF MD loss changes in eyes with POAG. Assessment of MvD is useful for the detection of patients with glaucoma who are at an increased risk of faster VF loss.


The role of meat in foodborne disease: Is there a coming revolution in risk assessment and management?
Meat has featured prominently as a source of foodborne disease and a public health concern. For about the past 20 years the risk management paradigm has dominated international thinking about food safety. Control through the supply chain is supported by risk management concepts, as the public health risk at the point of consumption becomes the accepted outcome based measure. Foodborne pathogens can be detected at several points in the supply chain and determining the source of where these pathogens arise and how they behave throughout meat production and processing are important parts of risk based approaches. Recent improvements in molecular and genetic based technologies and data analysis for investigating source attribution and pathogen behaviour have enabled greater insights into how foodborne outbreaks occur and where controls can be implemented. These new approaches will improve our understanding of the role of meat in foodborne disease and are expected to have a significant impact on our understanding in the coming years.


Breast cancer: An overview of published Indian data.
The Incidence of breast cancer has been steadily increasing in the last two decades, more so in urban areas of the sub-continent. Cancer ceters across the country have large numbers of patients being treated with multiple publications in this field. Inspite of paucity of prospective data and randomised clinical trials from India, there are large number of retrospective publications on various aspects of the disease including pathology, radiology, surgery, chemotherapy, radiation, palliative care and alternatitive treatment modalities. These published data provide an insight into the trends of breast cancer in the country and this comprehensive data review of Indian data will provide a basis for designing trials relevant to our population and planning health care.


Dental amalgam--what are the alternatives?
Alternatives to amalgam include glass ionomer cements, direct placement composites, composite inlays, and ceramic inlays. Glass ionomer cements are suitable only in minimally stress-bearing areas but have the advantages of reliable adhesion and fluoride release. For the larger cavity, resin inlays offer a viable alternative to direct placement composites because of better control of contour and contact areas, and management of polymerisation shrinkage. However, there are reservations regarding the long-term marginal quality in view of possible wear of the cement lute. Ceramic inlays offer maximum aesthetics, but similar cement lute concerns have been expressed. The cost of the restoration to the patient is in the order direct resin < resin inlay < ceramic inlay. Tooth-coloured resin or ceramic alternatives to amalgam are indicated for aesthetic restoration of moderate lesions, in patients with good oral hygiene. Contraindications include high caries rate, inability to obtain perfect moisture control, heavy occlusal stress, and poor or absent marginal enamel.


Mitochondrial diversity of Iñupiat people from the Alaskan North Slope provides evidence for the origins of the Paleo- and Neo-Eskimo peoples.
All modern Iñupiaq speakers share a common origin, the result of a recent (∼800 YBP) and rapid trans-Arctic migration by the Neo-Eskimo Thule, who replaced the previous Paleo-Eskimo inhabitants of the region. Reduced mitochondrial haplogroup diversity in the eastern Arctic supports the archaeological hypothesis that the migration occurred in an eastward direction. We tested the hypothesis that the Alaskan North Slope served as the origin of the Neo- and Paleo-Eskimo populations further east. We sequenced HVR I and HVR II of the mitochondrial D-loop from 151 individuals in eight Alaska North Slope communities, and compared genetic diversity and phylogenetic relationships between the North Slope Inupiat and other Arctic populations from Siberia, the Aleutian Islands, Canada, and Greenland. Mitochondrial lineages from the North Slope villages had a low frequency (2%) of non-Arctic maternal admixture, and all haplogroups (A2, A2a, A2b, D2a, and D4b1a-formerly known as D3) found in previously sequenced Neo- and Paleo-Eskimos and living Inuit and Eskimo peoples from across the North American Arctic. Lineages basal for each haplogroup were present in the North Slope. We also found the first occurrence of two haplogroups in contemporary North American Arctic populations: D2a, previously identified only in Aleuts and Paleo-Eskimos, and the pan-American C4. Our results yield insight into the maternal population history of the Alaskan North Slope and support the hypothesis that this region served as an ancestral pool for eastward movements to Canada and Greenland, for both the Paleo-Eskimo and Neo-Eskimo populations.


Rapid and practical detection of beta-globin mutations causing beta-thalassemia by fluorescence-based PCR-single-stranded conformation polymorphism analysis.
We report a useful method for daily clinical examination for the diagnosis of thalassemia. We applied a fluorescence-based image analyser to a non-radioisotopic PCR-single-stranded conformation polymorphism (SSCP) analysis to detect mutations in the beta-globin gene. PCR primers were labelled with rhodamine X and the amplified fragments from the beta-globin gene were resolved by non-denaturing polyacrylamide gel electrophoresis. After loading, the glass plate was set in the image analyser and scanned with a green laser. We detected four common mutations in exon I and two major mutations in intron 1 of the beta-globin gene isolated from patients with beta-thalassemia. Moreover, to discriminate mutations and natural polymorphisms, we used primers including one base mismatch at the polymorphic site, which can substitute the polymorphic site by a constant base in the PCR amplified fragment. This fluorescence-based system was simple to operate and results were obtained rapidly as clear image data. Therefore, once the optimal conditions of the electrophoresis are determined, this system will be suitable for daily clinical use, especially for screening of molecular defects and for the prenatal diagnosis of genetic disorders.


In silico investigation of riboswitches in fungi: structural and dynamical insights into TPP riboswitches in Aspergillus oryzae.
Riboswitches are RNA sensors affecting post-transcriptional processes through their ability to bind to small molecules. Thiamine pyrophosphate (TPP) riboswitch plays a crucial role in regulating genes involved in synthesizing or transporting thiamine and phosphorylated derivatives in bacteria, archaea, plants, and fungi. Although TPP riboswitch is reasonably well known in bacteria, there is a gap in the knowledge of the fungal TPP riboswitches structure and dynamics, involving mainly sequence variation and TPP interaction with the aptamers. On the other hand, the increase of fungal infections and antifungal resistance raises the need for new antifungal therapies. In this work, we used computational approaches to build three-dimensional models for the three TPP riboswitches identified in Aspergillus oryzae, in which we studied their structure, dynamics, and binding free energy change (ΔGbind) with TPP. Interaction patterns between the TPP and the surrounding nucleotides were conserved among the three models, evidencing high structural conservation. Furthermore, we show that the TPP riboswitch from the A. oryzae NMT1 gene behaves similarly to the E. coli thiA gene concerning the ΔGbind. In contrast, mutations in the fungal TPP riboswitches from THI4 and the nucleoside transporter genes led to structural differences, affecting the binding-site volume, hydrogen bond occupancy, and ΔGbind. Besides, the number of water molecules surrounding TPP influenced the ΔGbind considerably. Notably, our ΔGbind estimation agreed with previous experimental data, reinforcing the relationship between sequence conservation and TPP interaction.


Survival analysis on aggregate data to assess time to sero-conversion after experimental infection with Bovine Leukemia virus.
Bovine Leukemia virus (BLV) is a ubiquitous retrovirus that affects mainly cattle. Knowledge of the precise moment of infection is fundamental for identification and evaluation of factors related to BLV transmission. Systematic reviews and meta-analyses provide good evidence on the effects of medical interventions. The objectives were to estimate time to sero-conversion after experimental infection using data from retrieved literature and to detect factors that may influence the length of that interval using survival analysis on pooled data. An analysis using aggregate data from 36 studies totalling 438 observations was performed. From this, four sets were created and analysed by interval-censored accelerated failure time models (AFT) with different distributions (exponential, Weibull, log-logistic, lognormal and generalized gamma), and some variants of the Cox model (Andersen-Gill, smoothing splines) with and without a frailty effect. The AFT gamma model fit best and the estimated median time to sero-conversion in the null model was 57 days (95% confidence interval (CI): 49; 75) using all data and 47 days (95% CI: 39; 55) when only studies using experimental inoculation were considered. Some factors were consistently associated with time to sero-conversion. These included exposure by animal-to-animal contact (resulting in a seven-fold increase in time to sero-conversion compared to direct inoculation), diagnostic method to detect sero-conversion (time to sero-conversion was 1.4 times shorter when AGID was used compared to ELISA), and transmission by insect bites (biological media) delayed sero-conversion 2.3 times compared transmission via needles or other inanimate media. After fitting a frailty Cox model, results showed that sero-conversion in susceptible animals after infection using donors, in which presence of virus before the experiment started was confirmed, increased the hazard of sero-conversion two times in comparison with donors in which virus presence was not confirmed before start of the experiment. Inoculation with blood decreased the hazard 2.5 times in comparison with lymphocyte suspensions. Heterogeneity due to different research groups was also present. Finally, a Cox model with smoothing splines contained three variables: research group, route of inoculation and a non-linear spline for infective dose. In conclusion, it can be stated some factors that influence the time to sero-conversion were identified and quantified and that a moderate influence of research centre existed. These results may contribute to the estimation of the most probable times of infection in field conditions and in a better evaluation of control measures.


Progressive Mitochondrial SOD1G93A Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis.
In recent years, the "non-autonomous motor neuron death" hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since patients die of sudden death when they become unable to compensate for cardiorespiratory arrest. Mitochondria are thought to play a fundamental role in the physiopathology of ALS, as they are compromised in multiple ALS models in different cell types, and it also occurs in other neurodegenerative diseases. Our study aimed to uncover mitochondrial alterations in the sympathoadrenal system of a mouse model of ALS, from a structural, bioenergetic and functional perspective during disease instauration. We studied the adrenal chromaffin cell from mutant SOD1G93A mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1G93A protein and the down-regulation of optic atrophy protein-1 (OPA1) provoke mitochondrial ultrastructure alterations prior to the onset of clinical symptoms. These changes affect mitochondrial fusion dynamics, triggering mitochondrial maturation impairment and cristae swelling, with increased size of cristae junctions. The functional consequences are a loss of mitochondrial membrane potential and changes in the bioenergetics profile, with reduced maximal respiration and spare respiratory capacity of mitochondria, as well as enhanced production of reactive oxygen species. This study identifies mitochondrial dynamics regulator OPA1 as an interesting therapeutic target in ALS. Additionally, our findings in the adrenal medulla gland from presymptomatic stages highlight the relevance of sympathetic impairment in this disease. Specifically, we show new SOD1G93A toxicity pathways affecting cellular energy metabolism in non-motor neurons, which offer a possible link between cell specific metabolic phenotype and the progression of ALS.


[The hematocrit and cerebrovascular accidents].
That an elevated haemoglobin or haematocrit is a risk factor in stroke is suggested by the prospective epidemiological evidence from Framingham. Our own study of a series of patients with transient ischaemic attacks revealed that even when due allowance was made for interaction between haematocrit, hypertension and smoking, there was still evidence that both male and female patients had a higher haematocrit than age and sex matched controls. Toghi's autopsy study further shows that cerebral infarction is more frequently found in the elderly population in subjects with a high haematocrit, the effect being most obvious in the presence of severe cerebral atherosclerosis. Cerebral blood flow is inversely related to haematocrit, reflecting the physiological maintenance of oxygen supply according to the metabolic demands of cerebral tissue. When oxygen carriage is enhanced at high haematocrit, flow falls. This could however, predispose in the face of atheroma to thrombosis, a suggestion given some support by the finding that amongst TIA patients the greatest proportion with a haematocrit over 50 were found among those with thrombotic carotid occlusion. The effect of haematocrit on flow might become limiting when considering collateral flow, and flow in a maximally dilated vascular bed in the territory of recent infarction. This hypothesis is supported by the finding that the size of the cerebral infarct accompanying carotid occlusion is greater in patients with an elevated haematocrit.(ABSTRACT TRUNCATED AT 250 WORDS)


Presence of a small plasmid in clinical isolates of Streptococcus pneumoniae.
We have detected the presence of a small (2.95 kb) plasmid in a clinical isolate of Streptococcus pneumoniae. A restriction map was constructed for this plasmid and for pDP1 (the only previously reported pneumococcal plasmid); no apparent differences were observed and the two plasmids hybridized strongly to each other. Portions of pDP1 were then cloned into Escherichia coli K-12, using the vector pUC19, and the pneumococcal DNA insert was used as a probe to screen 500 clinical isolates of S. pneumoniae for pDP1 sequences. The plasmid was detected in a total of 8 isolates. These were of various serotypes and no correlation could be found between the presence of the plasmid and the geographical location from which it came, the type of infection, or with resistance to antibacterial drugs. Although no function has yet been assigned to pDP1, it may form the basis of a useful vector for cloning in S. pneumoniae, as it contains at least seven unique restriction sites.


Involvement of cytochrome P4502E1 in the toxicity of dichloropropanol to rat hepatocyte cultures.
Hepatocytes were isolated and cultured from untreated rats and rats treated with isoniazid to induce cytochrome P4502E1. Isoniazid selectively increased p-nitrophenol hydroxylase activity in 2-h cultures, and increased the toxicity of both 1,3- and 2,3-dichloropropanol. Isoniazid also increased the rate and extent of glutathione depletion by the dichloropropanols. There was no effect of isoniazid on the toxicity of 1,3-dichloroacetone, precocene II or allyl alcohol. In addition, diethyldithiocarbamate selectively inhibited p-nitrophenol hydroxylase in 2-h cultures from untreated and isoniazid-treated rats, as well as abolishing toxicity of the dichloropropanols. In 24-h cultures from isoniazid-treated rats diethyldithiocarbamate inhibited high affinity MCOD activity by 55% and there was also a small but significant inhibition of precocene II toxicity. These results indicate that isoniazid-inducible P4502E1 can mediate the toxicity of dichloropropanol.


Autonomy in Depressive Patients Undergoing DBS-Treatment: Informed Consent, Freedom of Will and DBS' Potential to Restore It.
According to the World Health Organization, depression is one of the most common and most disabling psychiatric disorders, affecting at any given time approximately 325 million people worldwide. As there is strong evidence that depressive disorders are associated with a dynamic dysregulation of neural circuits involved in emotional processing, recently several attempts have been made to intervene directly in these circuits via deep brain stimulation (DBS) in patients with treatment-resistant major depressive disorder (MDD). Given the promising results of most of these studies, the rising medical interest in this new treatment correlates with a growing sensitivity to ethical questions. One of the most crucial concerns is that DBS might interfere with patients' ability to make autonomous decisions. Thus, the goal of this article is to evaluate the impact DBS presumably has on the capacity to decide and act autonomously in patients with MDD in the light of the autonomy-undermining effects depression has itself. Following the chronological order of the procedure, special attention will first be paid to depression's effects on patients' capacity to make use of their free will in giving valid Informed Consent. We suggest that while the majority of patients with MDD appear capable of autonomous choices, as it is required for Informed Consent, they might still be unable to effectively act according to their own will whenever acting includes significant personal effort. In reducing disabling depressive symptoms like anhedonia and decrease of energy, DBS for treatment resistant MDD thus rather seems to be an opportunity to substantially increase autonomy than a threat to it.


Ketamine alters neural processing of facial emotion recognition in healthy men: an fMRI study.
Disruption of facial emotion perception occurs in neuropsychiatric disorders where the expression of emotion is dulled or blunted, for example depersonalization disorder and schizophrenia. It has been suggested that, in the clinical context of emotional blunting, there is a shift in the relative contribution of brain regions subserving cognitive and emotional processing. The non-competitive glutamate receptor antagonist ketamine produces such emotional blunting in healthy subjects. Therefore, we hypothesised that in healthy subjects ketamine would elicit neural responses to emotional stimuli which mimicked those reported in depersonalization disorder and schizophrenia. Thus, we predicted that ketamine would produce reduced activity in limbic and visual brain regions involved in emotion processing, and increased activity in dorsal regions of the prefrontal cortex and cingulate gyrus, both associated with cognitive processing and, putatively, with emotion regulation. Measuring BOLD signal change in fMRI, we examined the neural correlates of ketamine-induced emotional blunting in eight young right-handed healthy men receiving an infusion of ketamine or saline placebo while viewing alternating 30 s blocks of faces displaying fear versus neutral expressions. The normal pattern of neural response occurred in limbic and visual cortex to fearful faces during the placebo infusion. Ketamine abolished this: significant BOLD signal change was demonstrated only in left visual cortex. However, with ketamine, neural responses were demonstrated to neutral expressions in visual cortex, cerebellum and left posterior cingulate gyrus. Emotional blunting may be associated with reduced limbic responses to emotional stimuli and a relative increase in the visual cortical response to neutral stimuli.


Tributyltin contamination of bivalves in coastal areas around northern Kyushu, Japan.
We determined tributyltin (TBT) concentrations in bivalve samples of blue mussel (Myitlus edulis), Manila clam (Ruditapes philippinarum) and pen shell (Atrina pectinata) collected from coastal areas around northern Kyushu in 1998 and 2001. TBT was detected in all bivalve samples collected, ranging in concentration from 0.008 to 0.135 microg/g wet wt. In Hakata Port, which is an industrial area, high TBT concentrations were detected in bivalves (blue mussel, maximum concentration of 0.135 microg/g wet wt). In the Ariake Sea, which is an important bivalve habitat, TBT concentrations in Manila clams ranged from 0.062 to 0.125 microg/g wet wt in 1998 and from 0.008 to 0.033 microg/g wet wt in 2001. In addition, concentrations of TBT in pen shells collected from the Ariake Sea in 2001 ranged from 0.009 to 0.095 microg/g wet wt. These results clearly demonstrate that, despite the regulation of TBT usage since 1990 in Japan, contamination of bivalves by TBT has persisted in coastal areas around northern Kyushu.


Sodium chloride-induced hypergastrinaemia in rats.
In this study the effect of Nac1 on plasma immunoreactive gastrin was investigated. I.P. administration of sodium chloride (0.9%) in a dose of 1 ml/kg.b.w. for 7 days in rats, produced a significant rise in level of sodium ion in plasma. This hypernatraemia was also accompanied by significant rise in values of plasma immunoreactive gastrin. The mechanism(s) of this sodium chloride-induced release of gastrin is discussed.


Role of adhesion molecules in the mechanism of non-MHC (major histocompatibility complex) restricted cell-mediated cytotoxicity.
Adhesion molecules involved in the interaction between immune system effector cells and tumor targets are surface molecules which contribute to the formation of cell-to-cell contacts and belong to the integrin family. In this paper, the role played by the adhesion molecules in the process of cell-mediated cytotoxicity is reviewed. Furthermore, the contact area between effector and target cells has been analyzed by scanning electron microscopy. This region, termed "closed chamber", seems to contribute to killing efficiency by creating an intimate contact region in which cytotoxic factors can easily induce lethal hit in target cell. Thus, the extension of the closed chamber seems to be positively related to effector cell killing potential as well as to target cell sensitivity and, in this context, the adhesion molecules prove to play a pivotal role. In fact, a receptor-ligand interaction occurs between CD11a/CD18 (LFA-1) and CD2 molecules, expressed on the effector cells, and the respective counterparts on target cells, i.e., ICAM-1, ICAM-2, or LFA-3. Treatment with antibodies against such molecules strongly modifies closed chamber formation without inhibiting cell-to-cell binding. Nevertheless, in these conditions, the killing ability of different effector cells toward tumor targets appears to be strongly impaired. Hence, the adhesion molecules seem to be strongly involved in the formation of the closed chamber as well as in the activation of effector cell killing machinery.


Recommendations and Best Practices for Standardizing the Pre-Analytical Processing of Blood and Urine Samples in Metabolomics.
Metabolomics can be significantly influenced by a range of pre-analytical factors, such as sample collection, pre-processing, aliquoting, transport, storage and thawing. This therefore shows the crucial need for standardizing the pre-analytical phase with the aim of minimizing the inter-sample variability driven by these technical issues, as well as for maintaining the metabolic integrity of biological samples to ensure that metabolomic profiles are a direct expression of the in vivo biochemical status. This review article provides an updated literature revision of the most important factors related to sample handling and pre-processing that may affect metabolomics results, particularly focusing on the most commonly investigated biofluids in metabolomics, namely blood plasma/serum and urine. Finally, we also provide some general recommendations and best practices aimed to standardize and accurately report all these pre-analytical aspects in metabolomics research.


Neurobiological Clusters Are Associated With Trajectories of Overall Psychopathology in Youth.
Integrating multiple neuroimaging modalities to identify clusters of individuals and then associating these clusters with psychopathology is a promising approach for understanding neurobiological mechanisms that underlie psychopathology and the extent to which these features are associated with clinical symptoms. We leveraged neuroimaging data from T1-weighted, diffusion-weighted, and resting-state functional magnetic resonance images from the Adolescent Brain Cognitive Development (ABCD) Study (N = 8035) and used similarity network fusion and spectral clustering to identify subgroups of participants. We examined neuroimaging measures as a function of clustering profiles using 1, 2, or 3 imaging modalities (i.e., data combinations), calculated the stability of the clustering assignment in each respective data combination, and compared the consistency of clusters across different data combinations. We then compared the extent to which clusters were associated with overall psychopathology at the baseline assessment and at 2 yearly follow-up visits. Each data combination resulted in optimal clusters ranging from 2 to 4 subgroups for each data combination. Clusters were stable across subsampling of the ABCD Study cohort. Widespread structural measures (surface area, fractional anisotropy, and mean diffusivity) were important features contributing to clustering across different data combinations. Five of the seven data combinations were associated with overall psychopathology, both at baseline and over time (d = 0.08-0.41). Generally, lower global cortical volume and surface area, widespread reduced fractional anisotropy, and increased radial diffusivity were associated with increased overall psychopathology. Profiles constructed from neuroimaging data combinations are associated with concurrent and future psychopathology trajectories.


[High school and professional education in nursing: some reflections].
Analyzing the politics of professional education and questioning the changes that have been introduced in the Brazilian high school system are the main objectives of this study. In general, the approved legislation expresses the interests of the neo-liberal policies, of multilateral organisms, and of the implications of the worldwide productive reorganization and of the reduction of State participation in social policies. It also mirrors the manner in which Brazil inserts itself in the globalization process, in a dependent role, more as a knowledge consumer than a producer of it, thus missing the opportunity for achieving its autonomy, including in the area of professional formation. Based on the possibilities that these laws offer for curricular organization, this article defends that professional teaching in Nursing should take up a technical perspective integrated to a general education and be provided in a single space, thus reducing the risk of a minimalist, superficial training.


Outbreaks of salmonella infection in hospitals in England and Wales 1978-87.
A total of 248 outbreaks of salmonella infection in hospital affecting over 3000 patients and 110 associated deaths were ascertained in England and Wales in 1978-87, compared with 522 outbreaks of salmonella in 1968-77. The largest reduction was found in outbreaks from children's units and maternity units. Fifty seven (24%) outbreaks were considered to be due to foodborne salmonellosis, and 70 (30%) were reported as person to person spread of the infection. The psychiatric hospital was the type of hospital in which foodborne outbreaks most often occurred, but the risk of being affected in an outbreak not due to food seemed to be highest in maternity units. Better control of infection and better surveillance should lead to earlier investigation and control of outbreaks.