Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.

Biochemical and Hematological Relationship with the Evaluation of Autonomic Dysfunction by Heart Rate Recovery in Patients with Asthma and Type 2 Diabetes.

There are several methods to assess the function of the autonomic nervous system. Among them, heart rate recovery (HRR) is an accepted, easy, low-cost technique. Different pathological conditions have been related to the development of autonomic dysfunction. Our study aimed to evaluate the relationship between HRR and HRR-derived parameters in ambulatory patients with asthma or type 2 diabetes followed at the National Institutes of Health in Mexico City. A total of 78 participants, 50 women and, 28 men were enrolled; anthropometric, respiratory evaluations, and fasting blood samples were taken before participants performed a 6-min walking test (6MWT). Abnormal HRR was defined as a drop of ≤8 and ≤11 beats/min at 1 or 2 min and correlated negatively with basal oxygen saturation at 1 min. Heart rate at 1 min, correlated negatively with final oxygen saturation (p < 0.01). Statistically significant negative correlations were also observed between red cell count and white blood cell count and HOMA-IR with a p < 0.01. Since discrete hematological but significant changes correlated with HRR and HRR-derived parameters, we consider that these measures are helpful in clinical settings to identify subclinical autonomic dysfunction that permits us to prevent or anticipate chronic and fatal clinical outcomes.

Mef2 induction of the immediate early gene Hr38/Nr4a is terminated by Sirt1 to promote ethanol tolerance.

Drug naïve animals given a single dose of ethanol show changed responses to subsequent doses, including the development of ethanol tolerance and ethanol preference. These simple forms of behavioral plasticity are due in part to changes in gene expression and neuronal properties. Surprisingly little is known about how ethanol initiates changes in gene expression or what the changes do. Here we demonstrate a role in ethanol plasticity for Hr38, the sole Drosophila homolog of the mammalian Nr4a1/2/3 class of immediate early response transcription factors. Acute ethanol exposure induces transient expression of Hr38 and other immediate early neuronal activity genes. Ethanol activates the Mef2 transcriptional activator to induce Hr38, and the Sirt1 histone/protein deacetylase is required to terminate Hr38 induction. Loss of Hr38 decreases ethanol tolerance and causes precocious but short-lasting ethanol preference. Similarly, reduced Mef2 activity in all neurons or specifically in the mushroom body α/ß neurons decreases ethanol tolerance; Sirt1 promotes ethanol tolerance in these same neurons. Genetically decreasing Hr38 expression levels in Sirt1 null mutants restores ethanol tolerance, demonstrating that both induction and termination of Hr38 expression are important for behavioral plasticity to proceed. These data demonstrate that Hr38 functions as an immediate early transcription factor that promotes ethanol behavioral plasticity.

A novel method to recover DD fusion proton CR-39 data corrupted by fast ablator ions at OMEGA and the National Ignition Facility.

CR-39 detectors are used routinely in inertial confinement fusion (ICF) experiments as a part of nuclear diagnostics. CR-39 is filtered to stop fast ablator ions which have been accelerated from an ICF implosion due to electric fields caused by laser-plasma interactions. In some experiments, the filtering is insufficient to block these ions and the fusion-product signal tracks are lost in the large background of accelerated ion tracks. A technique for recovering signal in these scenarios has been developed, tested, and implemented successfully. The technique involves removing material from the surface of the CR-39 to a depth beyond the endpoint of the ablator ion tracks. The technique preserves signal magnitude (yield) as well as structure in radiograph images. The technique is effective when signal particle range is at least 10 µm deeper than the necessary bulk material removal.

[Pneumomediastinum associated with hyperemesis gravidarum: a case report]. / Neumomediastino secundario a hiperémesis gravídica: reporte de un caso.

Background: The hyperemesis gravidarum is a severe illness of nauseas and vomit that is present in the first trimester of the pregnancy, it has an incidence of 0.3 to 2%, it has been associated to weight loss, electrolytic disturbances, ketonuria, dehydration and in very seldom cases spontaneous pneumomediastinum. Clinical case: A 21 years old female patient, primigest, in the first trimester of gestation, she started her disease with nauseas and vomiting more than 15 times during 6 hours period, odynophagia, dysphonia and pain in the cervical region, loss of 5 kilograms in the last month. The physical examination showed the patient in bad conditions, dehydration, neck with volume increased and emphysema subcutaneus, crakles until torax. Laboratory findings with hypokalemia, leukocytosis, acute kidney failure, and elevation of hepatic enzymes. The initial treatment was with intravenous fluids resuscitation, hydroelectrolytic balance restoration, antiemetic treatment and rest, it was taken TC of neck and torax, and was exclude any laryngeal and esophageal injury and perforation, but it showed air in the mediastinum. Conservative management with favorable evolution and completed resolution in 7 days. Conclusion: It is very important that the medical doctor must keep in mind the different diagnosis of and take an opportune decision in case of present those complications potentially fatal to the mother.

Molecular Profile of Mitochondrial Dysfunction in Kidney Transplant Biopsies Is Associated With Poor Allograft Outcome.

BACKGROUND: In kidney transplantation (KT), progression of chronic histological damage with subclinical inflammation is associated with poor long-term allograft survival. The role of nonimmunological pathways in chronic allograft injury has not been fully assessed. METHODS: We analyzed a public microarray dataset that used 1-year protocol kidney transplant biopsy specimens to investigate whether nonimmunological genes and pathways might influence long-term allograft outcome. The selected microarray dataset included 3 patient/sample groups based on their histological findings: normal histology (n = 25), interstitial fibrosis alone (IF alone, n = 24), and interstitial fibrosis with inflammation (IF+i, n = 16). The IF+i group had lower death-censored graft survival and renal function in patients with a mean follow-up of 4 years. We performed statistical analysis comparing gene expression patterns in the 3 group samples. RESULTS: Gene cluster enrichment and group-specific expression patterns demonstrated a divergent pattern between mitochondrial and immune response genes, with downregulation of mitochondrial genes in the IF+i group. Gene ontological analysis of the downregulated mitochondrial genes identified generation of precursor metabolite and energy, and response to oxidative stress as the most significant biological processes. The transcription regulation pathway analysis of downregulated gene cluster demonstrated transcription factors involved in mitochondrial biogenesis. CONCLUSIONS: The molecular signature of mitochondrial dysfunction reflects mitochondrial energetic insufficiency, and inadequate antioxidant response involved in mitochondria biogenesis pathways is associated with IF+i and worse long-term allograft survival. Thus, mitochondria function impairment appears to be an important nonimmune factor involved in chronic allograft injury.

Impact of x-ray dose on the response of CR-39 to 1-5.5 MeV alphas.

The CR-39 nuclear track detector is used in many nuclear diagnostics fielded at inertial confinement fusion (ICF) facilities. Large x-ray fluences generated by ICF experiments may impact the CR-39 response to incident charged particles. To determine the impact of x-ray exposure on the CR-39 response to alpha particles, a thick-target bremsstrahlung x-ray generator was used to expose CR-39 to various doses of 8 keV Cu-Kα and Kß x-rays. The CR-39 detectors were then exposed to 1-5.5 MeV alphas from an Am-241 source. The regions of the CR-39 exposed to x-rays showed a smaller track diameter than those not exposed to x-rays: for example, a dose of 3.0 ± 0.1 Gy causes a decrease of (19 ± 2)% in the track diameter of a 5.5 MeV alpha particle, while a dose of 60.0 ± 1.3 Gy results in a decrease of (45 ± 5)% in the track diameter. The reduced track diameters were found to be predominantly caused by a comparable reduction in the bulk etch rate of the CR-39 with x-ray dose. A residual effect depending on alpha particle energy is characterized using an empirical formula.

Empirical assessment of the detection efficiency of CR-39 at high proton fluence and a compact, proton detector for high-fluence applications.

CR-39 solid-state nuclear track detectors are widely used in physics and in many inertial confinement fusion (ICF) experiments, and under ideal conditions these detectors have 100% detection efficiency for ∼0.5-8 MeV protons. When the fluence of incident particles becomes too high, overlap of particle tracks leads to under-counting at typical processing conditions (5 h etch in 6N NaOH at 80 °C). Short etch times required to avoid overlap can cause under-counting as well, as tracks are not fully developed. Experiments have determined the minimum etch times for 100% detection of 1.7-4.3-MeV protons and established that for 2.4-MeV protons, relevant for detection of DD protons, the maximum fluence that can be detected using normal processing techniques is ≲3 × 10(6) cm(-2). A CR-39-based proton detector has been developed to mitigate issues related to high particle fluences on ICF facilities. Using a pinhole and scattering foil several mm in front of the CR-39, proton fluences at the CR-39 are reduced by more than a factor of ∼50, increasing the operating yield upper limit by a comparable amount.

Hypoglycaemia and somnambulism: a case report.

Sleepwalking (somnambulism) is a sleep disorder classified as a parasomnia. Sleepwalkers develop motor activities that may be simple or complex: they can get out of bed, walk, urinate and even leave the house while remaining unconscious and unable to communicate. It is difficult to wake a sleepwalker, but it is not dangerous - as many people think. Sleepwalking cases have been caused by jet lag, the consumption of narcotics, sedatives and alcohol, cardiac problems such as arrhythmias, and other medical conditions, including epilepsy, asthma and apnoea. In a quick search of the literature, only one case due to hypoglycaemia has been reported, describing a patient with type 1 diabetes whose sleepwalking was triggered by nocturnal hypoglycaemia. Our present case was similar, and our report also describes how it occurred and how the condition was remedied.

Incidence and risk factors associated with urinary tract infection in diabetic patients with and without asymptomatic bacteriuria.

In order to compare the incidence of symptomatic urinary tract infection (UTI) in diabetic patients with and without asymptomatic bacteriuria (ASB), and to identify other risk factors for these infections, 289 females and 168 males were studied over a 12-month period. Symptomatic UTI occurred in 69.2% of patients with ASB (67.6% female and 76.5% male) versus 9.8% without ASB (14.9% female and 2.6% male). ASB and urinary incontinence were associated with symptomatic UTI in both women and men. Other risk factors included previous antimicrobial treatment and macrovascular complications in women and obesity and prostatic syndrome in men. The presence of ASB was found to be the major risk factor for developing symptomatic urinary tract infection. Further prospective randomized clinical trials of diabetic patients with risk factors for UTI who are receiving or not receiving treatment may be considered.

[Evaluation of the efficacy of a comprehensive programme of secondary prevention of cardiovascular disease in primary care: the PREseAP Study]. / Evaluación de la eficacia de un programa integral de prevención secundaria de la enfermedad cardiovascular en atención primaria: estudio PREseAP.

OBJECTIVES: To assess the efficacy of a comprehensive secondary prevention programme to reduce morbidity and mortality in patients who have suffered a cardiovascular (CV) event; to control CV risk factors and prophylactic treatment in order to prevent recurrence; and to improve the quality of life of patients with cardiovascular disease. DESIGN: Randomised, pragmatic, open clinical trial in primary care. SETTING: A total of 42 primary care centres of 8 different areas in Spain. PARTICIPANTS: Men and women below 86 years old, diagnosed with coronary disease and/or stroke and/or peripheral vascular disease in the preceding year, and who have no serious or terminal disease. INTERVENTION: Primary care centres will be randomised to following usual care (control group), or to following a comprehensive programme of secondary prevention (intervention group). MAIN MEASUREMENTS: Cardiovascular fatal events, cardiovascular non-fatal events, total mortality and health-related quality of life (SF-36).

Multifactorial approach and adherence to prescribed oral medications in patients with type 2 diabetes.

The aims of this study were to assess adherence to oral hypoglycaemic/cardiovascular drugs and determine non-adherence predictors in type 2 diabetes patients. It was designed as a population-based cross-sectional study in which 90 patients from a primary care setting were studied. Pill count and self-report methods were used to measure adherence. Logistic regression analysis was performed to predict factors related to non-adherence. Adequate adherence to all drugs was found in 29 patients (35.4%; 95% confidence interval (CI) 25.0-45.7). Variables associated with non-adherence were HbA1c odds ratio (OR) 2.32 (95% CI: 1.09-4.95), systolic blood pressure OR 1.68 (95% CI: 1.08-2.62), total cholesterol OR 1.34 (95% CI: 1.08-1.66), number of pills OR 1.80 (95% CI: 1.26-2.55) and duration of disease OR 0.44 (CI 95%: 0.24-0.83). In conclusion, one in three patients had adequate adherence. Factors associated with non-adherence were duration of disease, complexity of drug regimen and inadequate control of cardiovascular risk factors.

The effect of written information on adherence to antibiotic treatment in acute sore throat.

A randomised clinical trial was conducted to establish whether written instructions, in addition to verbal ones, significantly improve adherence to antibiotic treatment for acute sore throat in comparison with verbal instructions only. Patients were selected by consecutive sampling at seven primary healthcare surgeries. The pill count average was 87.4+/-25.2% and it was higher in the intervention group (93.7+/-24.5%) than in the control group (81.1+/-24.5%) (P < 0.05). Absolute risk reduction was 14% (95% confidence interval (CI), -3.77 to 26.56); relative risk reduction was 24.9% (95% CI, -11.04 to 58.28); the number needed to treat was 8.77. Written instructions, in addition to verbal ones, significantly improve compliance with antibiotic treatment in tonsillitis of acute sore throat in comparison with verbal instructions only.

Expresión de proteínas del choque térmico HSP72 y HSP73 en casos colombianos de Linfoma de Hodgkin positivos y negativos para virus de Epstein Barr / Expression of heat shock proteins HSP72 and HSP73 in Epstein-Barr positive or negative Hodgkin lymphoma

Background: The expression of heat shock proteins (HSP70) in tumor cells or virus infected cells is important for the induction of specific cellular immune response. They are implicated in transport of immunodominants peptides in the endoplasmic reticulum, activation of antigen presenting cells and cross priming of CD8 T cells. Aim: To analyze the expression of HSP70 protein in its constitutive (HSP73) and inducible forms (HSP72) in Hodgkin's lymphoma (HL), infected or not by Epstein Barr virus (EBV) and to assess its relationship with pathological subtype, clinical stages and treatment response. Material and methods: The analysis of HSP73 and HSP72 was done by immunoperoxidase on routinely processed paraffin sections with prior antigen retrieval. Results: Sixty seven cases were studied. The expression of HSP73 and HSP72 was detected in 19.4 and 17.9% of samples respectively. The infiltrating lymphocytes expressed HSP72 in 58% of cases. The pathological subtypes with the higher expression in lymphocytes were mixed cellularity and nodular sclerosis. No differences in HSP70 expression were observed, according to clinical stage, treatment response or the presence of EBV. Conclusions: The expression of HSP72 on lymphocytes suggests that this protein plays an important role in the induction and amplification of anti-tumor immune response (Rev Méd Chile 2003; 131: 1375-81).

[Identification of variables influencing waiting times for specialized care]. / Identificación de las variables de influencia en los tiempos de espera en atención especializada.

OBJECTIVE: To identify the variables influencing waiting time for specialized care (waiting lists) through multiple regression analysis and to analyze the health districts with long waiting times according to these variables. DESIGN: Descriptive, cross sectional and retrospective study of waiting times for access to specialized care between 1997 and 1998. SETTING: Area 20 of the Health Department of the Autonomous Community of Valencia (Spain) consisting of 12 health districts with 204,424 inhabitants. INTERVENTIONS: The following variables were gathered: variables influencing demand: type of municipality, aging and indexes of dependent population, and percentage of pensioners; variables influencing supply: age, sex, training and professional stability of the doctor, and size of the patient list; variables influencing resource consumption: percentage of referrals to specialized care per thousand inhabitants, mean WT for access to specialized care (in natural days) by district and year, number of consultations, and workload. A multiple regression model was constructed through (backward) elimination, taking the mean WT as the dependent variable and the remaining variables as independent variables. The resulting equation enabled calculation of the expected WT per health district and the deviation of the real WT from the expected WT. A district was considered to have a high WT when its deviation was above the mean plus one standard deviation of the distribution. RESULTS: The mean WT for access to specialized care was 37 days in 1997 and 34 days in 1998. A significant correlation (p < 0.005) was found between WT and the percentage of the population aged less than 14 years (r = 0.693), the percentage of the population aged between 14-65 years (r = 0.517), the number of consultations (r = 0.689), and coastal population (r = 0.470). Our final model included: percentage of the population aged less than 14 years, number of consultations, and coastal population (F = 41.803; p < 0.000; r = 0.945; r2 = 0.893). Three districts (37.5%) with high WTs were identified. CONCLUSIONS: The number of consultations, the percentage of the pediatric population, and proximity to the coast were closely correlated with WT for specialized care, with a consequent influence on waiting lists.

Clinical study of an outbreak of Legionnaire's disease in Alcoy, Southeastern Spain.

The aim of this study was to identify the clinical features of Legionnaires' disease, sudden outbreaks of which demand a quick and flexible clinical approach, particularly with regard to diagnosis and therapy. A prospective and comparative study based on a clinical protocol was performed during an outbreak of Legionnaires' disease in Alcoy, Spain. The outbreak was environmental in origin, linked to cooling towers. Data about epidemiological and clinical features, blood chemistry values, radiological and microbiological findings, and characteristics related to the clinical course of Legionnaires' disease were obtained for 357 patients admitted to hospital with community-acquired pneumonia (177 with Legionella pneumonia). Patients with Legionnaires' disease were younger (mean age, 65.3+/-16.5 years) and more likely to be smokers compared with patients with other types of pneumonia (28.8% vs. 11.1%; P<0.01). Moreover, they had not been admitted to any hospital because of pneumonia in the previous year. Patients with Legionnaires' disease had higher fever, more severe headache, and less expectoration as well as lower sodium blood levels (mean, 132.6+/-4.8 mmol/l vs. 135.7 mmol/l; P<0.01). Radiological studies also showed that fewer patients with Legionnaires' disease had pleural effusion (9% vs. 19.4% of those with non- Legionella pneumonia). The presence of headache, high fever, hyponatremia, scanty or null expectoration, and current cigarette smoking provides physicians with important clues for a high suspicion of Legionella pneumonia before the results of confirmatory laboratory tests are available.

Los genotipos de helicobacter pylori en gastritis no atrófica difieren de los encontrados en úlcera péptica, lesiones premalignas y cáncer gástrico en Colombia / Helicobacter pylori genotypes in non atrophic gastritis, peptic ulcer disease, premalignant lesions and gastric cancer in Colombia

Background: Helicobacter pylori is recognized as an etiologic agent of several gastric diseases. Bacterial genotypes have been related to clinical outcome in several populations. Aim: To compare cagA, vacA and iceA genotypes of Colombian isolates from patients with several gastrointestinal diseases, including gastric cancer. Material and methods: We used polymerase chain reactions to amplify vacA, cagA and iceA genes of 137 H pylori isolates coming from 26 patients with gastric cancer (GC), 34 with peptic ulcer (PU), 19 with intestinal metaplasia (IM), 23 with atrophic gastritis (AG) and 35 with non atrophic gastritis (NAG). Results: vacA s1-m1, cagA+, iceA+ were the most frequently found genotypes. vacA s1 and m1 subtypes were found in 92 (67 percent) and 82 (60 percent) cases respectively. Sixty three percent were cagA+ and 85 percent were iceA+. There was a lower prevalence of s1 allele in cases of NAG (43 percent), compared with GC, PU and IM (81 percent, 77 percent and 81 percent prevalence, respectively, p <0.01). Isolates from NAG also showed a low frequency of vacA m1 subtype (40 percent) compared with GC or IM (81 percent and 84 percent respectively, p <0.01). The prevalence of cagA+ strains was significantly higher in GC patients (80 percent) than in NAG patients (51.4 percent, p <0.01). No differences in the frequency of vacA s1a, s1b and iceA subtypes, were observed. Conclusions: A lower frequency of cytotoxic H pylori genotypes such as cagA and vacA s1m1 and a higher frequency of non cytotoxic genotypes, was observed in patients with NAG, when compared to patients with GC or PU. These results suggest that even in Colombia, vacA and cagA could be used as markers of increased virulence