Coumarins and carbazoles from Clausena excavata exhibited antimycobacterial and antifungal activities

Four known coumarins, dentatin (1), nor-dentatin (2), clausenidin (3) and xanthoxyletin (5), and six known carbazole derivatives, 3-formylcarbazole (6), mukonal (7), 3-methoxycarbonylcarbazole (8), murrayanine (9), 2-hydroxy-3-formyl-7-methoxycarbazole (10) and clauszoline J (11) were isolated from Clausena excavata. Compounds 1 and 6 were first isolated from the crude chloroform extract of the rhizomes. Compounds 1, 2, 3, 6, 7, 8, 10 and 11 showed antimycobacterial activity at a minimum inhibitory concentration (MIC) of 50, 100, 200, 100, 200, 50, 100 and 100 microg/mL, respectively. O-Methylated clausenidin ( 4), prepared from 3, exhibited antimycobacterial activity at MIC 50 microg/mL. Compounds 6, 7, 8 and 10 showed antifungal activity with IC 50 values of 13.6, 29.3, 9.5 and 2.8 microg/mL, respectively. All compounds demonstrated no cytotoxicity against KB and BC-1 cell lines.     

Physical check-up and blood data analysis in the Thai elderly of Chaingmai Province, Thailand

Introduction:   Chiangmai is one of the provinces in Northern Thailand. The Aging population has increased rapidly since family planning commenced in 1972. For the surveillance of aging, we started a health investigation of the elderly over 60 years of age in the suburban area of Chiangmai since 1997 with the Nippon Medical School Team.
Materials and Method:   Medical examination was carried out for the elderly (male = 34, female = 73) at Department of Family Medicine, Chiangmai University, Chiangmai Thailand in August 2002. Chula Mental Test (CMT) was used for cognitive function and Geriatric Depression Scale was used for evaluation of depressive condition.
Results:   The major health problems of this group of elderly in Chiangmai Province were visual acuity abnormality (98.1%), anemia (66.4%), hypertension (37.4%), dental caries (29%), bone and joint disease (23.4%), cardiovascular disease (11.2%), gingivitis (11.2%), diabetes mellitus (9.3%), digestive system disease (8.4%), and presbycrusis (8.4%). The prevalence of cognitive impairment and depression were 0.9 and 2.8%, respectively. The prevalence of high cholesterol, triglyceride, and LDL cholesterol were 43.9, 29.0, and 15.9%, respectively. The prevalence of high BUN, creatinine, and uric acid were 17.8, 11.2, and 29.9%, respectively. The prevalence of high GOT, GPT, gamma GT, ZTT, and TTT were 4.7, 1.9, 53.3, 35.5, and 21.5%, respectively. The prevalence of low hemoglobin was 66.4%.
Conclusion:   There was a high prevalence of anemia and hyperlipidemia in this group of elderly in Chiangmai Province. The analysis of background factors and further investigation should be carried out continuously.     

Biochemical markers of bone turnover and response of bone mineral density to intervention in early postmenopausal women: an experience in a clinical laboratory

BACKGROUND: Markers of bone formation and resorption may be useful as early indicators of response to therapy. Our aim in this study was to investigate the use of bone markers for monitoring of intervention for bone loss in early postmenopausal women and to assess the relationships between these markers and changes in bone mineral density (BMD). METHODS: Subjects were randomly assigned to the following groups: a control group; a group receiving calcium alone; groups receiving calcium plus low or conventional doses of conjugated equine estrogen; and groups receiving calcium plus low or conventional doses of calcitriol. At baseline and at 1 and 3 months after intervention, we measured serum intact osteocalcin, serum N-terminal midfragment osteocalcin, serum C-terminal telopeptide of type I collagen (CTx), urinary deoxypyridinoline cross-links, and urinary CTX: The BMD of the lumbar spine and the femoral neck was measured at baseline and after 1 and 2 years of intervention. RESULTS: No marker changed significantly in the control group except urinary CTx, which increased at 3 months. Serum CTx decreased in all regimens at 1 or 3 months of intervention. In addition, the changes of all markers at 3 months were inversely associated with the change in the BMD of the lumbar spine at 1 or 2 years (r = -0.144 to -0.314), whereas only the changes of bone resorption markers at 3 months were inversely correlated with the changes in femoral BMD at 1 or 2 years (r = -0.143 to -0.366). CONCLUSIONS: Biochemical markers of bone turnover appear to be of use in assessing early response to therapy. Bone resorption markers, especially serum CTx, are better indicators than bone formation markers for estimating the response to intervention in early postmenopausal women. However, the early changes in bone markers were weakly related to the later changes in BMD.     

Colorectal cancer genomics: evidence for multiple genotypes which influence survival.

Colorectal cancer (CRC) is a leading cause of cancer death and the mechanism for variable outcome in this disease is not yet fully understood. It is hypothesized that differences in the genetic make-up of tumours may be partially responsible for the differences observed in survival among same staged individuals for this disease. In this study the tumour genomes of 29 consecutive patients undergoing surgery for Dukes' C CRC were assessed by comparative genomic hybridization (CGH). In addition, the CGH profiles from the tumours were compared with those from eight colorectal cell lines. Great variation in genetic grade (all detectable aberrations i.e., loss + gain) was observed in 29 Dukes' C colorectal tumours by CGH (median four aberrations per tumour, range 0-20). Gain was found in 76% and loss in 41% of tumours. The most frequently observed regions of gain were 13q (27.6%), 20q (27.6%), 7p (24.1%), 8q (24.1%), and 1q (20.7%) and loss were 18q (31%), 4q (20.7%), 17p (20.7%), 18p (20.7%), and 15q (20.1%). None of these specific genomic aberrations were associated with patient survival. However, patients with more than two aberrations had a better survival than patients with fewer regions of loss and gain (P = 0.02). CRC cell lines had similar regions of loss or gain as the tumours. However, the frequency of genomic aberrations was much greater in the CRC cell lines. Although genomic change in CRC is relevant to the survival of patients with Dukes' C CRC, careful analysis is required to identify cell lines which are representative models of CRC genomics.     

Elevated vitamin D status in postmenopausal women on thiazolidinediones for type 2 diabetes

Thiazolidenediones (TZD) have been reported to lead to non-vertebral bone loss in postmenopausal women with diabetes, but the true incidence of vertebral fractures has been under-detected because two-thirds of vertebral fractures are silent. TZD is also related to increased adiposity, with a consequently greater risk of vitamin D deficiency-both of which seem to aggravate the untoward effect of TZD on bone. The aim of this study is to determine whether TZD use is associated with prevalence of vertebral fractures and low vitamin D status in postmenopausal women with type 2 diabetes. A group of 102 postmenopausal women with type 2 diabetes, 52 TZD users for at least 12 months, and 50 non-TZD users were enrolled in the study. Any data regarding diabetes, age at menopause, co-morbidities, and drug use were recorded. Blood sampling and thoraco-lumbar radiography were performed. Bone mineral density (BMD) of L2-L4 and the femur were measured by dual-energy X-ray absorptiometry (DXA). The occurrence of vertebral fractures at one level or more in subjects on TZD was higher than those not on TZD, but did not reach statistical significance (19.2 vs. 14.0%, P = 0.5). Total hip BMD in subjects on TZD was significantly lower than those not on TZD (0.96 ± 0.15 vs. 1.02 ± 0.11; P < 0.05). Levels of 25(OH)D in TZD users were significantly higher (35.3 ± 1.5 vs. 25.9 ± 1.2 ng/dl; P < 0.001). The prevalence of vitamin D deficiency was 75.5% in subjects not on TZD compared to 34.6% in those on TZD (OR 6.4, 95% CI 2.6-15.6). Higher circulating 25(OH)D was observed in TZD users. TZD use was associated with lower total hip BMD but not with vertebral fracture.     

Association of genetic variations near P2 promoter of the hepatocyte nuclear factor-4α gene and insulin secretion index in Thais

This study was aimed to assess the association of the two single nucleotide polymorphisms (SNPs) near P2 promoter (rs1884614 and rs2144908) of hepatocyte nuclear factor-4α (HNF4A) with insulin secretion index and type 2 diabetes in Thais. Participants were categorized into three groups; unrelated type 2 diabetes (N = 219), prediabetes subjects (N = 228), and normal glucose tolerant controls (N = 203). Homeostasis model assessment was calculated for individual insulin secretion and insulin sensitivity index. Genotyping of both SNPs was done by allele-specific PCR technique. Difference of SNP allele frequencies between groups were computed using the χ ²-statistic. Multivariate regression analysis was performed to determine the effect of SNPs on insulin secretion index. The clinical features of all groups were similar. We demonstrated genotype TT at rs1884614, BMI, and waist circumference were significantly associated with insulin secretion index (P = 0.023) but not with diabetes phenotype.     

Association of a T262C transition in exon 1 of estrogen-receptor-alpha gene with skeletal responsiveness to estrogen in post-menopausal women.

Polymorphic genetic markers of estrogen-receptor-alpha (ERalpha) gene studied so far in osteoporosis reside in non-coding region with uncertain functional significance. The purpose of the present study was to search for nucleotides changes in the exon 1 and 5' regulatory region of ERalpha gene, to study the nature of their linkages to the previously reported Pvull polymorphism in intron 1 and their functional significance in postmenopausal osteoporosis. Direct sequencing of exon 1 and promotor region of ERalpha gene revealed a synonymous nucleotide substitution from T to C at position 262, 29 nucleotides downstream from the putative start codon. No nucleotide change was found in the promotor region. Linkage disequilibrium between the T262C polymorphism and the Pvull polymorphism in intron 1 of ERalpha gene was demonstrated in 129 post-menopausal women (p<0.001). After treating 96 post-menopausal with 0.3 mg or 0.625 mg conjugated equine estrogen (CEE) for 2 yr, vertebral bone mineral density (BMD) increased regardless of the T262C genotype. However, with regard to femoral neck BMD, only those subjects that were homozygous for the T262C polymorphism had an increase in femoral BMD (+5.9+/-1.4%, mean+/-SE; p<0.0001). Using analysis of covariance to assess the effects of the T262C polymorphism, the intronic Pvull polymorphism, doses of CEE and the corresponding baseline BMD on the changes in vertebral or femoral BMD after treatments, it was found that the change in vertebral BMD was related only to the baseline BMD (p<0.05). The change in femoral BMD was independently related to the T262C polymorphism (p<0.01) and the baseline femoral BMD (p<0.01). No effect of the Pvull polymorphism or the doses of CEE on femoral BMD was demonstrated. We concluded that the previously described intronic Pvull polymorphism of ERalpha gene is in linkage disequilibrium with a T262C polymorphism in exon 1. This T262C polymorphism appears to be more directly related to the skeletal response after long-term treatment with estrogen.     

Shorter sleep duration is associated with poorer glycemic control in type 2 diabetes patients with untreated sleep-disordered breathing

Purpose

The purpose of this study is to explore the impact of sleep duration on glycemic control in type 2 diabetes patients with untreated sleep-disordered breathing (SDB).

Methods

Ninety type 2 diabetes patients participated in the study. SDB was diagnosed using an overnight in-home monitoring device (WatchPAT200). Sleep duration was recorded by wrist actigraphy for 7 days. Medical records were reviewed for hemoglobin A1c (HbA1c) values.

Results

Seventy-one patients (78.8 %) were diagnosed with SDB [apnea-hypopnea index (AHI) ≥ 5]. In patients with SDB, there was no significant relationship between AHI and glycemic control. In addition, oxygen desaturation index, minimum oxygen saturation, and time spent below oxygen saturation of 90 % were not significantly correlated with glycemic control. Sleep duration, however, was inversely correlated with HbA1c (r = ?0.264, p 0.026). Multiple regression analysis adjusting for age, sex, body mass index, insulin use, diabetes duration, and AHI revealed that sleep duration was significantly associated with HbA1c (p = 0.005). Each hour reduction in sleep duration was associated with a 4.8 % increase in HbA1c of its original value (95 % CI 1.5–8.0).

Conclusion

In type 2 diabetes patients with untreated SDB, shorter sleep duration was independently associated with poorer glycemic control. Sleep duration optimization may lead to improved glycemic control in this population.

     

Differences in insulin sensitivity, pancreatic beta cell function and circulating adiponectin across glucose tolerance status in Thai obese and non-obese women

Although adiponectin levels are associated with obesity and insulin insensitivity, the role of adiponectin in the progression to diabetes in non-obese subjects is unclear. Therefore, 289 women aged 50–80 years without previous history of diabetes or impaired glucose tolerance (IGT) were studied. They were classified as normal glucose tolerance (NGT), IGT or diabetes based on WHO criteria. Insulin sensitivity (S) and beta cell function (B) indices were calculated using homeostasis model assessment (HOMA). In obese women with BMI ≥ 25 kg/m² (n = 161), there were declines in HOMA-%S (P < 0.001), HOMA-%B (P < 0.05) and circulating adiponectin (P < 0.001) across glucose tolerance status. In non-obese women with BMI < 25 kg/m² (n = 128), there was no significant change in HOMA-%S in women with IGT and diabetes as compared to women with NGT. However, HOMA-%B (P < 0.05) and serum adiponectin levels (P < 0.001) were significantly decreased across glucose tolerance. Serum adiponectin levels were correlated to HOMA-%S in both obese and non-obese women while negative correlations between circulating adiponectin and HOMA-%B were demonstrated only in obese women. We have demonstrated in the present study the predominant role of beta cell dysfunction as compared to that of insulin resistance in the deterioration of glucose tolerance in non-obese women. Circulating adiponectin appears to be inversely related to beta cell dysfunction in addition to insulin resistance only in obese women.