Genetic effects of demographic bottleneck and recovery in Kinkazan Island and mainland populations of Japanese macaques (Macaca fuscata).

Populations of Japanese macaques were significantly reduced in most areas from the 1900s to the 1960s and then recovered mainly in the northeastern part of Honshu. A drastic reduction in population size reduces genetic variability through a bottleneck effect. Demographic expansion after the reduction that accumulates new mutations can reduce the bottleneck effects or drive the recovery of genetic variability. We examined the genetic status of a small island population (Kinkazan Island) and a larger mainland population (southern Tohoku) of Japanese macaques that experienced recent demographic bottlenecks and recovery using eight microsatellite loci. The two populations were significantly genetically different from each other. The Kinkazan population exhibited lower genetic variability, remarkable evidence of bottleneck (i.e., significant heterozygosity excess and lower frequency of rare alleles), and a considerably smaller effective population size based on genetic data than based on the current census size. These results indicate that the genetic status has not completely recovered from the demographic bottleneck despite a full recovery in census size on Kinkazan Island. New mutations might rarely have accumulated because of the small carrying capacity of the island. Therefore, the genetic variability of the population would have been restrained by the severe bottleneck size, small carrying capacity, and long-term isolation. On the other hand, the bottleneck effect seems to be limited in the southern Tohoku population considering higher genetic variability, non-significant heterozygosity excess in many mutation conditions, and the highest frequency of rare alleles.

Prolonged heart rate recovery time after 6-minute walk test is an independent risk factor for cardiac events in heart failure: a prospective cohort study

OBJECTIVES: To determine whether the time for peak exercise heart rate to return to resting heart rate after the 6-minute walk test (6MWT) can predict cardiac events in patients with heart failure (HF) within 2 years. DESIGN: Prospective cohort study. SETTING: HF outpatient facility at a tertiary teaching hospital. PARTICIPANTS: Seventy-six patients with HF, New York Heart Association functional classification II and III, and left ventricular ejection fraction <50% MAIN OUTCOME MEASURES: Patients used a heart rate monitor to measure the time for peak exercise heart rate to return to resting heart rate after the 6MWT. Data were analysed using Polar Pro-Trainer 5 software (Kempele, Finland). Patients were followed for >2 years for cardiac events (hospitalisations and death). RESULTS: Thirty-four patients had cardiac events during the 2-year follow-up period. There was a significant difference in time to return to resting heart rate between the groups with and without cardiac events {with 3.6 [standard deviation (SD) A] vs without 2.8 (SD B) minutes; mean difference C; 95% confidence interval (CI) of the difference D to E; P=0.003}. No significant differences between patients with and without cardiac events were found for mean walking distance, mean heart rate recovery at 1 minute and mean heart rate recovery at 2 minutes. The receiver operating curve discriminated between patients with and without cardiac events (área under the curve 0.71, 95% CI 0.61 to 0.81; P< 0.001). Using logistic regression analysis, prolonged time to return to resting heart rate (≥3 minutes) independently increased the risk for cardiac events 6.9-fold (95% CI 2.34 to 20.12; P< 0.001). The Kaplan­Meier curve showed more cardiac events in patients with prolonged time to return to resting heart rate (P=0.028). CONCLUSIONS: Prolonged time to return to resting heart rate (≥3 minutes) after the 6MWT was an independent predictor of cardiac events in patients with HF.

Prolonged heart rate recovery time after 6-minute walk test is an independent risk factor for cardiac events in heart failure: A prospective cohort study.

OBJECTIVES: To determine whether the time for peak exercise heart rate to return to resting heart rate after the 6-minute walk test (6MWT) can predict cardiac events in patients with heart failure (HF) within 2 years. DESIGN: Prospective cohort study. SETTING: HF outpatient facility at a tertiary teaching hospital. PARTICIPANTS: Seventy-six patients with HF, New York Heart Association functional classification II and III, and left ventricular ejection fraction <50%. MAIN OUTCOME MEASURES: Patients used a heart rate monitor to measure the time for peak exercise heart rate to return to resting heart rate after the 6MWT. Data were analysed using Polar Pro-Trainer 5 software (Kempele, Finland). Patients were followed for >2 years for cardiac events (hospitalisations and death). RESULTS: Thirty-four patients had cardiac events during the 2-year follow-up period. However, there was a significant difference in the time to return to resting heart rate between the groups with and without cardiac events {with 3.6 (SD 1.1) vs without 2.8 (SD 1.1) minutes; mean difference of 0.79 (95% confidence interval (CI) of the difference 0.28 to 1.28; P=0.003}. No significant differences between patients with and without cardiac events were found for mean walking distance, mean heart rate recovery at 1minute and mean heart rate recovery at 2minutes. The receiver operating curve discriminated between patients with and without cardiac events (área under the curve 0.71, 95% CI 0.61 to 0.81; P<0.001). Using logistic regression analysis, prolonged time to return to resting heart rate (≥3minutes) independently increased the risk for cardiac events 6.9-fold (95% CI 2.34 to 20.12; P<0.001). The Kaplan-Meier curve showed more cardiac events in patients with prolonged time to return to resting heart rate (P=0.028). CONCLUSIONS: Prolonged time to return to resting heart rate (≥3minutes) after the 6MWT was an independent predictor of cardiac events in patients with HF.

Tempo de recuperação da frequência cardíaca como marcador prognóstico de eventos cardíacos / Heart rate recovery time as a prognostic marker of cardiac events

INTRODUÇÃO: O teste de caminhada de 6 minutos (TC6M) é um teste funcional amplamente utilizado em pacientes com insuficiência cardíaca crônica (IC). A distância percorrida no teste, bem como o delta de frequência cardíaca entre o repouso e a recuperação no 1° minuto (HRR1) e o delta de frequência cardíaca entre o repouso e a recuperação no 2° minuto (HRR2) têm sido propostos como marcadores prognósticos de eventos cardíacos em pacientes com IC. Nós hipotetizamos que a variação do tempo em minutos (denominado THRR) entre o pico da frequência cardíaca e o retorno à frequência cardíaca no repouso possa ser um marcador simples e de fácil obtenção no contexto clínico para estimar eventos cardíacos em pacientes com IC. OBJETIVOS: Nós investigamos se o THRR pode ser usado para estimar hospitalizações e morte ao longo de 2 anos de acompanhamento em pacientes com IC. MÉTODOS: Setenta e seis pacientes (média de idade 57 anos, NYHA II e III, IMC 25.5kg/m2, média FEVE de 33%) foram incluídos nesse estudo e divididos em Com eventos e Sem eventos. RESULTADOS: Trinta e quatro pacientes do grupo Com eventos e 42 pacientes do grupo Sem eventos tiveram, respectivamente as seguintes médias: THRR= 3.6 vs 2.8 min (p=0,003), distância percorrida= 463 vs 465 metros (p=0,930), HRR1=12 bpm para ambos grupos (p=0,952) e HRR2= 23 vs 22 bpm (p=0,723). A área sob a curva ROC para discriminar eventos e não eventos foi de 0,70 (IC95%: 0,58-0,82 e p=0,001). Usando a análise de regressão logística, o THRR ≥ 3 minutos dobrou o risco para eventos cardíacos (p=0,003). CONCLUSÃO: A variação de tempo entre o pico do exercício no TC6M e a recuperação da frequência cardíaca de repouso ≥ 3 minutos é um eficiente marcador clínico preditor de hospitalizações e morte em 2 anos para pacientes com IC. (AU)

Schizophrenia-like phenotypes in mice with NMDA receptor ablation in intralaminar thalamic nucleus cells and gene therapy-based reversal in adults.

In understanding the mechanism of schizophrenia pathogenesis, a significant finding is that drug abuse of phencyclidine or its analog ketamine causes symptoms similar to schizophrenia. Such drug effects are triggered even by administration at post-adolescent stages. Both drugs are N-methyl-d-aspartate receptor (NMDAR) antagonists, leading to a major hypothesis that glutamate hypofunction underlies schizophrenia pathogenesis. The precise region that depends on NMDAR function, however, is unclear. Here, we developed a mouse strain in which NMDARs in the intralaminar thalamic nuclei (ILN) were selectively disrupted. The mutant mice exhibited various schizophrenia-like phenotypes, including deficits in working memory, long-term spatial memory, and attention, as well as impulsivity, impaired prepulse inhibition, hyperlocomotion and hyperarousal. The electroencephalography analysis revealed that the mutant mice had a significantly reduced power in a wide range of frequencies including the alpha, beta and gamma bands, both during wake and rapid eye movement (REM) sleep, and a modest decrease of gamma power during non-REM sleep. Notably, restoring NMDARs in the adult ILN rescued some of the behavioral abnormalities. These findings suggest that NMDAR dysfunction in the ILN contributes to the pathophysiology of schizophrenia-related disorders. Furthermore, the reversal of inherent schizophrenia-like phenotypes in the adult mutant mice supports that ILN is a potential target site for a therapeutic strategy.

Late Graft Rejection in Association With T-Large Granular Lymphocyte Expansion of Recipient Origin After Human Leukocyte Antigen-Haploidentical Stem Cell Transplantation: A Case Report.

BACKGROUND: Large granular lymphocyte (LGL) expansion occasionally occurs after allogeneic stem cell transplantation (allo-SCT), and is thought to be a good prognostic sign that is associated with a lower relapse rate. However, there have been no reports of late graft failure (LGF) due to graft rejection in association with oligoclonal LGL expansion. We herein report a case of LGF associated with the transient expansion of recipient-derived T-LGL after allo-SCT. CASE REPORT: A 65-year-old man underwent peripheral blood stem cell transplantation (PBSCT) from his human leukocyte antigen (HLA)-haploidentical son for the treatment of acute myeloid leukemia, which had evolved from a myelodysplastic syndrome (MDS). Neutrophil engraftment occurred on day 20. A chimerism analysis on day 29 showed both granulocytes and mononuclear cells in the peripheral blood to be completely of donor origin. However, his neutrophil count gradually decreased and a chimerism analysis on day 61 showed that 84% of the patient's T cells were of recipient origin while the granulocytes were 100% donor-derived. His LGLs rapidly increased to 4.01 × 109/L on day 113 and decreased thereafter. The percentage of donor cells in his granulocytes gradually decreased, and the patient's leukocytes were completely replaced by recipient cells on day 177. CONCLUSIONS: The clinical course suggests that the expansion of recipient-derived T-LGLs after allo-SCT can be a sign of graft rejection. Early intervention may be needed if the LGL expansion is recipient-derived.

Triphos derivatives and diphosphines as ligands in the ruthenium-catalysed alcohol amination with NH3.

The ruthenium-triphos and diphosphine-catalysed amination of alcohols with ammonia is reported. Various types of triphos derivatives with electron-donating functional group were synthesized and used as ligands in the Ru-catalysed alcohol amination with NH3. The triphos derivatives are effective for the formation of primary amines. On the other hand, if hemilabile diphosphines as tridentate ligands are used, mixtures of secondary-along with primary amines are obtained. It was found that even simple diphosphines can be used as ligands for the selective formation of the secondary amines. The diphosphine system allows a new entry to the Ru-catalysed formation of secondary amines.

Cord blood transplantation is associated with rapid B-cell neogenesis compared with BM transplantation.

Hematopoietic cell transplantation (HCT) is used for treatment of hematopoietic diseases. Assessment of T- and B-cell reconstitution after HCT is crucial because poor immune recovery has a major effect on the clinical course. In this study, we retrospectively analyzed T-cell receptor excision circles (TRECs) as well as signal and coding joint kappa-deleting recombination excision circles (sjKRECs and cjKRECs, respectively) as markers of newly produced lymphocytes in 133 patients (56 primary immunodeficient and 77 malignant cases, median (range): 12 (0-62) years old). We analyzed the kinetics of TREC and KREC recovery and determined the factors that contributed to better immune recovery. KRECs became positive earlier than TRECs and increased thereafter. Younger recipient age had a favorable effect on recovery of sjKRECs and cjKRECs. Compared with BM and peripheral blood, our data suggested that cord blood (CB) provided rapid B-cell recovery. CB also provided better B-cell neogenesis in adult HCT recipients. Chronic GVHD was associated with low TRECs, but not increased sjKRECs/cjKRECs. Finally, positive sjKRECs 1 month after HCT were associated with fewer infectious episodes. Monitoring of TRECs and KRECs may serve as a useful tool for assessment of immune reconstitution post HCT.

Chronic granulomatous disease: two decades of experience from a tertiary care centre in North West India.

Chronic granulomatous disease (CGD) results from an inherited defect in the phagocytic cells of the immune system. It is a genetically heterogenous disease caused by defects in one of the five major subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. There is a paucity of data from India on CGD. We herein describe the clinical features in 17 children with CGD from a single tertiary referral center in India. A detailed analysis of the clinical features, laboratory investigations and outcome of 17 children 7 with X-linked (XL) and 10 with autosomal recessive (AR) form was performed. Diagnosis of CGD was based on an abnormal granulocyte oxidative burst evaluated by either Nitroblue Tetrazolium (NBT) test or flow cytometry based Dihyrorhodamine 123 assay or both. The molecular diagnosis was confirmed by genetic mutation analysis in 13 cases. The mean age at diagnosis and the age at onset of symptoms was significantly lower in children diagnosed with XL- CGD compared those with AR disease. Mutations were detected in CYBB gene in 6 patients with XL-CGD and NCF-1 gene mutations were observed in 7 cases of AR- CGD. The course and outcome of the disease was much worse in children diagnosed with X-linked form of disease compared to AR forms of the disease; 4/7 (57%) children with X-CGD were dead at the time of data analysis. This is one of the largest series on chronic granulomatous disease from any developing country.

Spatiotemporal classification of environmental monitoring data in the Yeongsan River basin, Korea, using self-organizing maps.

Environmental monitoring data for planning, implementing and evaluating the Total Maximum Daily Loads (TMDL) management system have been measured at about 8-day intervals in a number of rivers in Korea since 2004. In the present study, water quality parameters such as Suspended Solids (SS), Biochemical Oxygen Demand (BOD), Dissolved Oxygen (DO), Total Nitrogen (TN), and Total Phosphorus (TP) and the corresponding runoff were collected from six stations in the Yeongsan River basin for six years and transformed into monthly mean values. With the primary objective to understand spatiotemporal characteristics of the data, a methodologically systematic application of a Self-Organizing Map (SOM) was made. The SOM application classified the environmental monitoring data into nine clusters showing exclusively distinguishable patterns. Data frequency at each station on a monthly basis identified the spatiotemporal distribution for the first time in the study area. Consequently, the SOM application provided useful information that the sub-basin containing a metropolitan city is associated with deteriorating water quality and should be monitored and managed carefully during spring and summer for water quality improvement in the river basin.

Ataxia-telangiectasia in a patient presenting with hyper-immunoglobulin M syndrome.

Ataxia-telangiectasia (AT) and hyper-immunoglobulin M (HIGM) syndrome are both primary immunodeficiency diseases caused by different genetic defects. While a small proportion of AT patients have increased serum immunoglobulin (Ig) M concentrations during the course of a disease, a high level of IgM at onset is rare. We report the case of an 8-year-old girl who had experienced recurrent respiratory infection, cutaneous abscesses, and hepatosplenomegaly since the age of 2 years. She was diagnosed with HIGM based on the results of immunological studies, including low IgG and IgA levels and raised serum IgM concentrations. However, at the age of 4 years, a neurological examination revealed gait disturbance and telangiectatic lesions on the conjunctiva; therefore, a diagnosis of AT was suggested. In spite of regular intravenous immunoglobulin infusions and antimicrobial prophylaxis, the patient experienced several episodes of respiratory infection and eventually died of respiratory failure at the age of 8 years. Further molecular analysis revealed a novel homozygous missense mutation in exon 53 (c.8250C>T, p.2622Ala>Val) of the ATM gene. Patients with AT and the HIGM phenotype may not develop clinical characteristics of AT for some time. While patients with AT and increased serum IgM levels could have a considerably more severe disease course and a shorter survival, IgM levels could be considered a prognostic factor.

Hyper IgM syndrome and complement Clq deficiency in an individual with systemic lupus erythematosus-like disease.

Many immunedeficiency syndromes are associated with autoimmune disorders. We here report on a girl with a systemic lupus erythematosus-like disease who suffered from both hyperimmunoglobulin M syndrome (HIGMS) and C1q deficiency. Despite severe central nervous system-lupus like disease, probably due to C1q deficiency, kidney function was relatively spared. IgM autoantibody might play a protective role against lupus-glomerulonephritis.

Subchronic effects of nasally instilled diesel exhaust particulates on the nasal and airway epithelia in mice.

Diesel exhaust is the major source of ultrafine particles released during traffic-related pollution. Subjects with chronic respiratory diseases are at greater risk for exacerbations during exposure to air pollution. This study evaluated the effects of subchronic exposure to a low-dose of diesel exhaust particles (DEP). Sixty male BALB/c mice were divided into two groups: (a) Saline: nasal instillation of saline (n = 30); and (b) DEP: nasal instillation of 30 microg of DEP/10 microl of saline (n = 30). Nasal instillations were performed 5 days a week, over 30 and 60 days. Animals were anesthetized with pentobarbital sodium (50 mg/kg intraperitoneal [i.p.]) and sacrificed by exsanguination. Bronchoalveolar lavage (BAL) fluid was performed to evaluate the inflammatory cell count and the concentrations of the interleukin (IL)-4, IL-10, and IL-13 by enzyme-linked immunosorbent assay (ELISA). The gene expression of oligomeric mucus/gel-forming (Muc5ac) was evaluated by real-time polymerase chain reaction (PCR). Histological analysis in the nasal septum and bronchioles was used to evaluate the bronchial and nasal epithelium thickness as well as the acidic and neutral nasal mucus content. The saline group (30 and 60 days) did not show any changes in any of the parameters. However, the instillation of DEP over 60 days increased the expression of Muc5ac in the lungs and the acid mucus content in the nose compared with the 30-day treatment, and it increased the total leukocytes in the BAL and the nasal epithelium thickness compared with saline for 60 days. Cytokines concentrations in the BAL were detectable, with no differences among the groups. Our data suggest that a low-dose of DEP over 60 days induces respiratory tract inflammation.

Physical function is weakly associated with angiotensin-converting enzyme gene I/D polymorphism in elderly Japanese subjects.

BACKGROUND: The turning point in the deterioration of physical function seems to occur between the ages of 70 and 80 years. In particular, muscle strength may decline even more in subjects older than 75. A recent study found that the angiotensin-converting enzyme (ACE) genotype also affects physiological left ventricular hypertrophy. A very limited number of papers have examined genetic differences in resistance and endurance forms of a single sporting discipline. OBJECTIVE: The purpose of this study was to evaluate the relationship between ACE genotype and physical function by controlling the known confounding factors including dental status. METHODS: We selected 431 subjects who were aged 76 years and did not require special care for their daily activities. We conducted a medical examination, followed by 5 physical function tests, as follows: (1) maximum hand grip strength, (2) maximal isometric knee extensor strength, (3) maximal stepping rate for 10 s, (4) one-leg standing time with eyes open and (5) 10-meter maximum walking speed. Subjects were genotyped for the ACE intron 16 Alu insertion. In addition, serum concentrations of total cholesterol, total protein, IgA and IgG were measured at a commercial laboratory. The Eichner index was used as an indicator of occlusal condition. Multiple linear regression analysis was performed to evaluate the relationship between the ACE gene insertion/deletion (I/D) polymorphism and physical function considering confounding factors. RESULTS: The ACE gene I/D polymorphism was positively associated with hand grip strength and 10-meter maximum walking speed. Betas of hand grip strength were 0.09 for I/D (p = 0.022) and 0.12 for insertion/insertion (I/I; p = 0.004). Betas of 10-meter walking speed were -0.11 for I/D (p = 0.093) and -0.14 for I/I (p = 0.039). Dental status such as Eichner index class C was significantly associated with one-leg standing time with eyes open (beta -0.11; p = 0.028). CONCLUSION: This study suggests that there is a significant relationship between ACE genotype and physical function. In particular, subjects with the ACE deletion/deletion genotype were associated with upper extremities.