Analytic power calculation for QTL linkage analysis of small pedigrees

Power calculation for QTL linkage analysis can be performed via simple algebraic formulas for small pedigrees, but requires intensive computation for large pedigrees, in order to evaluate the expectation of the test statistic over all possible inheritance vectors at the test position. In this report, we show that the non-centrality parameter for an arbitrary pedigree can be approximated by the sum of the variances of the correlations between all pairs of relatives, each variance being weighted by a factor that is determined by the mean correlation of the pair. We show that this approximation is sufficiently accurate for practical purposes in small to moderately large pedigrees, and that large sibships are more efficient than other family structures under a range of genetic models.     

5-fluorouracil,adriamycin, and mitomycin-C (FAM) chemotherapy in advanced adenocarcinoma of the lung: comparison of two dosage schedules

Summary Fifty patients with inoperable adenocarcinoma of the lung were randomized in a prospective study to receive either standard doses or high doses of 5-fluorouracil, adriamycin, and mitomycin-C (FAM versus Hi-FAM). The response/stabilization rate was 32% for FAM and 34% for Hi-FAM (P>0.05), and the median survival was 27 weeks for FAM group and 24 weeks for Hi-FAM group (P>0.05). Myelotoxicity was mild in FAM, but moderate to severe in Hi-FAM. It is concluded that Hi-FAM did not yield a higher response rate or median survival compared with FAM, but caused significantly more severe myelotoxicity.     

The prevalence of osteoporosis in the Hong Kong Chinese female population

Objectives: This paper aims to present population-based age-related bone mass values in the Hong Kong Chinese female population, and to assess the number and proportion of Chinese women considered osteoporotic according to the WHO diagnostic guidelines. Methods: A total of 769 community-based female subjects were recruited. Social demographic characteristics of these subjects were similar to the Hong Kong general population. All bone mass measurements were performed by means of a dual energy X-ray densitometry (Norland XR 26) at two sites: lumbar vertebrae L2–L4 and left hip. These values were expressed as T-scores, with reference to the mean bone mineral density (BMD) values of the group aged 21–40 years. Results: The study revealed that, in women aged 60 years and above, their mean BMD values are 30% lower than the young normal mean. The prevalence of osteoporosis at the spine increased dramatically from about 10% in the age group 50–59 to 45% in the group aged 60–69. In women aged 70 onwards, over half have osteoporosis at the hip. The prevalence of osteoporosis at the spine is relatively stable in the age groups above 60, while that for osteoporosis at the hip increased exponentially with age. Conclusions: The prevalence of osteoporosis in Hong Kong women is comparable to that found in Caucasian populations. Prevention of osteoporosis, involving both immediate and long-term measures, and targeting at different age groups, are required to combat this serious public health problem in Hong Kong.     

An association study of ADSS gene polymorphisms with schizophrenia

Background  

Adenylosuccinate synthase (ADSS) catalyzes the first committed step of AMP synthesis. It was suggested that the blood-derived RNA of ADSS was down-regulated in schizophrenia (SZ) and one of the eight putative biomarker genes to discriminate SZ from normal controls. However, it remains unclear whether the reduction of ADSS RNA is due to the polymorphisms of the gene or not.     

Beneficial intervention of experimental colitis by passive cigarette smoking through the modulation of cytokines in rats.

BACKGROUND: Epidemiologic observations have indicated that cigarette smoking decreases the risk of ulcerative colitis, but the modes of action remain anonymous. The present study aimed to investigate the beneficial effects of passive cigarette smoking using an animal colitis model. We hypothesized that the underlying mechanisms may involve immunoregulation of cytokines. METHODS: Experimental colitis was induced in rats by enema administration of 2,4-dinitrobenzene sulfonic acid (DNBS). Passive cigarette smoking by rats was performed for 1 hour once daily, from 3 days before DNBS enema until they were sacrificed on day 8. Other groups of DNBS-treated rats received therapeutic treatment of cyclosporin A or pentoxifylline, a tumor necrosis factor (TNF)-alpha inhibitor. Macroscopic and histologic damage were graded, and the colonic levels of different cytokines and the levels/activities of parameters related to neutrophil activation were also measured. RESULTS: DNBS-induced colonic damage was improved in passive-cigarette-smoking rats. This was accompanied by attenuation of the elevated colonic myeloperoxidase and inducible nitric oxide synthase activities and leukotriene B4 level. Likewise, the augmentation in colonic levels of TNF-alpha, interleukin (IL)-1 beta, and IL-6 in colitis rats was also alleviated by passive cigarette smoking. In contrast, the deprivation of colonic IL-10 during colitis was preserved in cigarette-smoking rats. These effects were similarly accomplished by pentoxifylline and, to some degree, by cyclosporin A. CONCLUSIONS: The results support the idea that the beneficial effects of passive cigarette smoking in experimental colitis involved immunoregulation of cytokines in colonic tissues.     

Assessing the risk of nasopharyngeal carcinoma on the basis of EBV antibody spectrum.

We have evaluated the performance of 3 new EBV ELISA for the diagnosis of nasopharyngeal carcinoma (NPC). The tests were specific for EBNA 1 IgA, EBNA 1 IgG and zta IgG, respectively. Their distinct antigenic specificity permits these assays to be used in concert in an approach that differentiates patients and apparently healthy subjects on the basis of their antibody spectrum. By so exploiting a distinguishing feature of NPC first described by Lloyd Olds and his group (Olds et al., Proc Nat Acad Sci 1966;56:1699-1704) [corrected] that the patients sustain high levels of a broad spectrum of serum EBV antibodies, this approach achieved a sensitivity of 92% and a specificity of 93%, surpassing the performance of each of these assays individually. The enhanced performance is especially useful in population screening. It was shown that relative risk of NPC sustained by apparently healthy subjects residing in a high incidence area for NPC in the Pearl River estuary in Southern China may vary according to EBV antibody spectrum. The risk of the cancer was markedly reduced with odds ratios of 0.009 for 59% of those who had low level of all 3 antibodies. The risk was increased as antibody spectrum broadens and the risk was the highest with an odds ratio of 138 for 0.4% of those who had high levels of all 3 antibodies. Thus, EBV antibody spectrum may serve to guide follow-up measures for early detection of the cancer and/or risk counseling according to level of the risk of the cancer sustained by the screened individuals.     

Is the P300 wave an endophenotype for schizophrenia? A meta-analysis and a family study

INTRODUCTION: We assessed the usefulness of the P300 wave as endophenotype for schizophrenia by means of a meta-analysis of the literature as well as our own family study. METHOD: Meta-analysis: We conducted a systematic search for articles published between 1983 and 2003 that reported P300 measures in non-psychotic relatives of schizophrenic patients and in healthy controls. Meta-regression analyses were performed using a random effects procedure. The pooled standardized effect size (PSES) was calculated as the difference between the means of the two groups divided by the common standard deviation. Local study: We examined the P300 wave with a standard two-tone oddball paradigm in 30 patients with schizophrenia, 40 non-psychotic relatives, and 40 controls using linear mixed models. RESULTS: Meta-analysis: We pooled 472 relatives and 513 controls. The P300 amplitude was significantly reduced in relatives (PSES = 0.61; 95% CI: 0.30 to 0.91; P < 0.001). The P300 latency was significantly delayed in relatives (PSES of -0.50; 95% CI: -0.88 to -0.13; P = 0.009]. Local study: The patients showed a trend for amplitude reductions (P = 0.06) and significant latency delays (P < 0.01). The relatives displayed normal amplitude but had significant latency delays (P = 0.01). The P300 amplitude and especially the P300 latency are promising alternative phenotypes for genetic research into schizophrenia.     

Revaccination after Autologous Hematopoietic Stem Cell Transplantation Is Safe and Effective in Patients with Multiple Myeloma Receiving Lenalidomide Maintenance

Guidelines recommend vaccination starting 12 months after autologous hematopoietic stem cell transplant (aHCT), but there is varying practice for patients on maintenance therapy, with some centers not immunizing at all. Because of decreased vaccine rates among the general population causing loss of herd immunity, we aimed to establish the safety and efficacy of revaccinating multiple myeloma patients on lenalidomide maintenance (LM). Of the 122 patients who were vaccinated after aHCT between 2010 and 2014 at Memorial Sloan Kettering Cancer Center, 91 (75%) were on LM. Vaccine responses were defined by increases between pre- and postvaccination titers. Reponses varied by vaccine type with 76% responding to pertussis, 70% diphtheria, 60% tetanus, 71% Haemophilus influenzae, and 58% pneumococcal. All patients retained minimal levels of polio immunity, but 27% responded with increased titers. Fewer patients received hepatitis A and B, but of those who did, 30% responded to hepatitis A and 40% to hepatitis B. No differences were seen in rates of response for those on LM at time of vaccination compared with those who were not. There were no vaccine-related adverse effects. Reimmunization with inactivated vaccines in patients on LM is therefore both safe and effective, offering this population immunity to vaccine-preventable diseases.     

An ad libitum schedule for conversion of morphine to methadone in advanced cancer patients: an open uncontrolled prospective study in a Chinese population

Methadone has been used as an alternative strong opioid to morphine in the management of cancer pain. The conversion of morphine to methadone is not straightforward because of the high individual variability and unpredictability in the pharmacokinetics of methadone. An ad libitum schedule for conversion of morphine to methadone was used in 37 cancer patients who had intolerable morphine-related side effects or had pain not satisfactorily controlled by morphine. Oral morphine was discontinued on the day of conversion. Methadone was given at a dose calculated as one-twelfth of the total daily dose of morphine, up to a maximum of 30 mg/dose. Methadone was administered at patient-controlled intervals not more frequent than three hours, the need of which was indicated by the presence of pain of moderate intensity or above as rated by a verbal rating scale. When the demand for methadone was stabilized, the total daily dose was given regularly in divided doses. Pain control on day 7 was taken as the primary endpoint. Twenty-seven patients completed the study. Twenty-four patients (88.9%) were in good pain control on day 7, and all reached good pain control by day 11. The median time required to achieve good pain control was three days (range 1-11 days). A majority (88.6%) of morphine-related adverse effects improved or resolved after conversion to methadone. This ad libitum schedule is effective in conversion of morphine to methadone in these patients.     

Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease

BACKGROUND: Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of ganglion cells in the nerve plexuses of the lower digestive tract. HSCR has a complex pattern of inheritance and is sometimes associated with mutations in genes of the receptor tyrosine kinase (RET) and endothelin receptor B (EDNRB) signaling pathways, which are crucial for development of the enteric nervous system. METHODS: Using PCR amplification and direct sequencing, we screened for mutations and polymorphisms in the coding regions and intron/exon boundaries of the RET, GDNF, EDNRB, and EDN3 genes of 84 HSCR patients and 96 ethnically matched controls. RESULTS: We identified 10 novel and 2 previously described mutations in RET, and 4 and 2 novel mutations in EDNRB and in EDN3, respectively. Potential disease-causing mutations were detected in 24% of the patients. The overall mutation rate was 41% in females and 19% in males (P = 0.06). RET mutations occurred in 19% of the patients. R114H in RET was the most prevalent mutation, representing 7% of the patients or 37% of the patients with RET mutations. To date, such a high frequency of a single mutation has never been reported in unrelated HSCR patients. Mutations in EDNRB, EDN3, and GDNF were found in four, two, and none of the patients, respectively. Two patients with mutations in genes of the EDNRB pathway also harbored a mutation in RET. Three novel and three reported polymorphisms were found in EDNRB, EDN3, and GDNF. CONCLUSION: This study identifies additional HSCR disease-causing mutations, some peculiar to the Chinese population, and represents the first comprehensive genetic analysis of sporadic HSCR disease in Chinese.