Neurohormonal response to left ventricular reconstruction surgery in ischemic cardiomyopathy

OBJECTIVES: Activation of the neuroendocrine axis in congestive heart failure is of prognostic significance, and neurohumoral blocking therapy prolongs survival. The hypothesis that surgical reduction of left ventricular size and function decreases neuroendocrine activation is less established. We evaluated the neurohormonal response to left ventricular reconstruction surgery in ischemic cardiomyopathy. METHODS: Norepinephrine, plasma renin activity, and angiotensin II were measured in 10 patients before and 12 months after left ventricular reconstruction. In an additional 5 patients, brain natriuretric peptide was measured before and 3 months postoperatively. Three-dimensional cardiovascular imaging was used to assess ejection fraction and left ventricular end-diastolic volume index. RESULTS: Concurrent with improvements of New York Heart Association functional class (2.9 +/- 0.5 preoperatively vs 2.0 +/- 0.4 postoperatively, P <.001), ejection fraction (23.9% +/- 6.6% vs 36.2% +/- 6.2%, P <.01), and left ventricular end-diastolic volume index (140.8 +/- 33.8 mL/m(2) vs 90.6 +/- 18.3 mL/m(2), P <.01), considerable reductions were observed for median plasma profiles of norepinephrine (562.0 pg/mL vs 319.0 pg/mL, P <.05), plasma renin activity (5.75 microg/L/h vs 3.45 microg/L/h, P <.05), angiotensin II (41.0 ng/mL vs 23.0 ng/mL, P =.051), and brain natriuretric peptide (771.0 pg/mL vs 266.0 pg/mL, P <.05). The more plasma renin activity or angiotensin II decreased after left ventricular reconstruction, the higher was the increase in ejection fraction (R = -.745, P <.05 [plasma renin activity]; R = -.808, P <.05 [angiotensin II]). CONCLUSIONS: Surgical improvements of ejection fraction and left ventricular end-diastolic volume index by left ventricular reconstruction were accompanied by improvement of both the neuroendocrine activity and the functional status in patients with congestive heart failure. Whether this favorable neurohormonal response is predictive of an improved survival requires further evaluation.     

Attitudes Towards Bariatric Surgery in the General Public

Background

Prevalence rates of obesity are still rising. Weight loss surgery (WLS) is the most invasive but also most effective treatment option when behavioral modification has failed. Research indicates that health care professionals hold ambivalent views on bariatric surgery, while views of the general public have not yet been investigated.

Methods

In a German representative sample of n?=?3,003 respondents in a computer-assisted telephone interview, n?=?1,008 persons were interviewed on their views of the effectiveness of bariatric surgery and other interventions for obesity. Also, willingness to recommend a treatment was assessed.

Results

Lifestyle-based interventions were viewed as most effective in terms of weight loss. About 50 % of the population stated that WLS is “very effective” while still a quarter of respondents did not ascribe effectiveness to WLS. Higher age was associated with lower expectations of effectiveness while higher stigmatizing attitudes and genetic attributes for obesity were associated with higher expectations of effectiveness. Seventy-two percent would not recommend WLS or undergo it, if applicable, themselves. Higher educated respondents and those that viewed WLS as effective were more likely to recommend WLS.

Conclusions

The German general public seems to be rather cautious regarding bariatric surgery. It may be assumed that false beliefs on the effectiveness and risk patterns of bariatric surgery are still very common, despite rising surgery numbers. Our results further emphasize the need for providing evidence-based information on bariatric surgery to the general public.     

Exome Sequence Data From Multigenerational Families Implicate AMPA Receptor Trafficking in Neurocognitive Impairment and Schizophrenia Risk

Schizophrenia is a mental disorder characterized by impairments in behavior, thought, and neurocognitive performance. We searched for susceptibility loci at a quantitative trait locus (QTL) previously reported for abstraction and mental flexibility (ABF), a cognitive function often compromised in schizophrenia patients and their unaffected relatives. Exome sequences were determined for 134 samples in 8 European American families from the original linkage study, including 25 individuals with schizophrenia or schizoaffective disorder. At chromosome 5q32–35.3, we analyzed 407 protein-altering variants for association with ABF and schizophrenia status. For replication, significant, Bonferroni-corrected findings were tested against cognitive traits in Mexican American families (n = 959), as well as interrogated for schizophrenia risk using GWAS results from the Psychiatric Genomics Consortium (PGC). From the gene SYNPO, rs6579797 (MAF = 0.032) shows significant associations with ABF (P = .015) and schizophrenia (P = .040), as well as jointly (P = .0027). In the Mexican American pedigrees, rs6579797 exhibits significant associations with IQ (P = .011), indicating more global effects on neurocognition. From the PGC results, other SYNPO variants were identified with near significant effects on schizophrenia risk, with a local linkage disequilibrium block displaying signatures of positive selection. A second missense variant within the QTL, rs17551608 (MAF = 0.19) in the gene WWC1, also displays a significant effect on schizophrenia in our exome sequences (P = .038). Remarkably, the protein products of SYNPO and WWC1 are interaction partners involved in AMPA receptor trafficking, a brain process implicated in synaptic plasticity. Our study reveals variants in these genes with significant effects on neurocognition and schizophrenia risk, identifying a potential pathogenic mechanism for schizophrenia spectrum disorders.Key words: schizophrenia, cognition, SYNPO, WWC1, synaptic plasticity     

Student–Teacher Relationships for Young Children with Autism Spectrum Disorder: Risk and Protective Factors

The quality of early student–teacher relationships (STRs) has been shown to predict children’s school adjustment, and children with autism spectrum disorder (ASD) are at risk for poor quality STRs. The present study examined 162 children with ASD (ages 4–7) and their teachers to evaluate student, teacher, and classroom characteristics that predicted concurrent and prospective STR quality across one school year. Child oppositional behavior, autism severity and teacher degree predicted changes in student–teacher conflict over a 1-year period, while child social skills and IQ positively predicted change in student–teacher closeness. Teacher preparedness, trainings in ASD, and classroom setting were unrelated to STR quality. Implications for intervention are discussed.     

Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington County, Maryland

Chronic kidney disease (CKD) is an increasing cause of morbidity and mortality in the United States. Prospective data on risk factors for CKD are limited to men, and few studies examine the importance of smoking. The authors performed a community-based, prospective observational study of 20-yr duration to examine the association between hypertension and smoking on the future risk of CKD in 23,534 men and women in Washington County, Maryland. CKD was identified as end-stage renal disease in the Health Care Financing Administration database or kidney disease listed on the death certificate. All cases were confirmed as CKD by medical chart review. Adjusted relative hazards of CKD were modeled using Cox proportional hazards regression including age as the time variable and baseline BP, cigarette smoking, gender, and diabetes status as risk factors. The adjusted hazard ratio (95% confidence interval) of developing CKD among women was 2.5 (0.05 to 12.0) for normal BP, 3.0 (0.6 to 14.4) for high-normal BP, 3.8 (0.8 to 17.2) for stage 1 hypertension, 6.3 (1.3 to 29.0) for stage 2 hypertension, and 8.8 (1.8 to 43.0) for stages 3 or 4 hypertension compared with individuals with optimal BP. In men, the relationship was similar but somewhat weaker than in women, with corresponding hazard ratios of 1.4 (0.2 to 12.1), 3.3 (0.4 to 25.6), 3.0 (0.4 to 22.2), 5.7 (0.8 to 43.0), and 9.7 (1.2 to 75.6), respectively. Current cigarette smoking was also significantly associated with risk of CKD in both men and women (hazard ratio in women 2.9 [1.7 to 5.0] and in men 2.4 [1.5 to 4.0]). A large proportion of the attributable risk of CKD in this population was associated with stage 1 hypertension (23%) and cigarette smoking (31%). In conclusion, CKD risk shows strong graded relationships to the sixth report of the Joint National Committee (JNC-VI) on Prevention, Detection Evaluation and Treatment of High BP criteria for BP, to diabetes, and to current cigarette smoking that are at least as strong in women as in men.     

Grade progression and regression in recurrent urothelial cancer

PURPOSE: Recurrent urothelial cancers are reported to have characteristics similar to those of the primary tumor, with 10% to 25% of low grade tumors recurring as high grade disease. We determined how often grade progression and regression occur and whether abnormalities in p53 protein expression in original tumors are preserved in recurrences. MATERIALS AND METHODS: Two groups of patients treated for recurrent stages Ta/T1 urothelial bladder cancers with at least 1 tumor-free examination between the index and recurrent tumors were reviewed. Group 1 included 115 patients in whom the first available tumor was compared with the last recurrence and group 2 included 42 in whom the initial tumor was compared with the first recurrence. Immunohistochemical analysis of p53 expression was performed on a subset of 34 tumor pairs. RESULTS: In group 1, 33 grade 3 tumors (45%) recurred as grade 1 or 2 tumors, while 9 of 82 grades 1 and 2 tumors (11%) recurred as grade 3 tumors. Five of 7 group 2 grade 3 tumors (71%) recurred as grade 1 or 2 disease, while 1 of 35 grades 1 and 2 tumors (3%) recurred as grade 3 disease. In the 34 pairs studied immunohistochemically 6 of 14 grade 3 tumors recurred at lower grades. Nuclear p53 over expression occurred in 21 index tumors (12 of 14 grade 3, 8 of 17 grade 2 and 1 of 3 grade 1) and in 9 recurrences (6 of 10 grade 3, 2 of 17 grade 2 and 1 of 7 grade 1). Only 7 of 21 p53 positive and 2 of 12 p53 negative index tumors were p53 positive on recurrence. CONCLUSIONS: While progression from low to high grade occurred in less than 15% of patients, grade regression was observed in almost 50%. The loss of p53 positivity in regressing tumors indicates that these recurrences are molecularly distinct from the corresponding initial tumor.     

First demonstration of leukemia imaging with the proliferation marker 18F-fluorodeoxythymidine

Acute myeloid leukemia (AML) is a neoplasm of hematopoietic stem cells with partial or complete loss of the ability to differentiate but with preserved proliferation capacity. The aim of our study was to evaluate if the in vivo proliferation marker 3'-deoxy-3'-18F-fluorothymidine (FLT) is suitable for visualizing leukemia manifestation sites and if 18F-FLT is a surrogate marker for disease activity. METHODS: In this pilot study, 10 patients with AML underwent pretherapeutic imaging with 18F-FLT PET or 18F-FLT PET/CT. The biodistribution of 18F-FLT was assessed 60 min after intravenous injection of the radiotracer. Standardized uptake values were calculated for reference segments of bone marrow, spleen, and normal organs. 18F-FLT PET in 10 patients with benign pulmonary nodules and the absence of malignant or inflammatory disease served as controls. RESULTS: Retention of 18F-FLT was observed predominantly in bone marrow and spleen and was significantly higher in AML patients than in controls (mean 18F-FLT SUV in bone marrow, 11.5 and 6.6, P < 0.05; mean 18F-FLT SUV in spleen, 6.1 and 1.8, P < 0.05). Outside bone marrow, focal 18F-FLT uptake showed extramedullary manifestation sites of leukemia in 4 patients (meningeal disease, pericardial, abdominal, testicular, and lymph node), proven by other diagnostic procedures. CONCLUSION: This pilot study indicated that PET using 18F-FLT is able to visualize extramedullary manifestation sites of AML and reflects disease activity. Because 18F-FLT uptake in bone marrow is caused by a combination of both neoplastic and normal hematopoietic cells, the correlation of 18F-FLT uptake in bone marrow and leukemic blast infiltration did not reach statistical significance.     

Quantification of locomotor recovery following spinal cord contusion in adult rats

Injury to the spinal cord not only disrupts the functioning of spinal circuits at the site of the impact, but also limits sensorimotor function caudal to the level of the lesion. Ratings of gross locomotor skill are generally used to quantify locomotor recovery following spinal cord injury (SCI). The purpose of this study was to assess behavioral recovery following SCI with three tasks: (1) BBB ratings, (2) walking on a horizontal ladder, and (3) footprint analyses. Behavioral testing was conducted for 6 postoperative weeks, and then the spinal cords were processed for the amount of white matter spared. As expected, BBB ratings dramatically decreased and then improved during recovery. The number of hindlimb foot-faults on the horizontal ladder increased after injury and remained elevated during the recovery period. Footprint analyses revealed that sham-control rats used several different gaits to cross the runway. In contrast, the locomotor function of rats with a SCI was impaired throughout the postoperative period. Some locomotor parameters of the injured rats improved slightly (velocity, stride length, stride duration, stance duration), some did not change (interlimb coordination, swing duration, forelimb base of support, hindpaw angle), and others declined (hindlimb base of support) during the recovery period. Together, these results show that gross locomotor skill improved after SCI, while recovery of fine locomotor function was more limited. Multiple tests should be included in future experiments in order to assess gross and fine changes in sensorimotor function following SCI.     

Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice

Background

Epithelial sodium channel (ENaC, Scnn1) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease.