Sulfation of 4-hydroxy toremifene: individual variability, isoform specificity, and contribution to toremifene pharmacogenomics

Toremifene (TOR) is a selective estrogen receptor modulator used in adjuvant therapy for breast cancer and in clinical trials for prostate cancer prevention. The chemical structure of TOR differs from that of tamoxifen (TAM) by the presence of a chlorine atom in the ethyl side chain, resulting in a more favorable toxicity spectrum with TOR. In addition, some patients who fail on TAM therapy benefit from high-dose TOR therapy. Several studies have indicated that functional genetic variants in the TAM metabolic pathway influence response to therapy, but pharmacogenomic studies of patients treated with TOR are lacking. In this study, we examined individual variability in sulfation of 4-hydroxy TOR (4-OH TOR) (the active metabolite of TOR) in human liver cytosols from 104 subjects and found approximately 30-fold variation in activity. 4-OH TOR sulfation was significantly correlated (r = 0.98, P < 0.0001) with β-naphthol sulfation (diagnostic for SULT1A1) but not with 17β estradiol sulfation, a diagnostic substrate for SULT1E1(r = 0.09, P = 0.34). Examination of recombinant sulfotransferases (SULTs) revealed that SULT1A1 and SULT1E1 catalyzed 4-OH TOR sulfation, with apparent Km values of 2.6 and 6.4 μM and Vmax values of 8.5 and 5.5 nmol x min(-1) x mg protein(-1), respectively. 4-OH TOR sulfation was inhibited by 2,6-dichloro-4-nitrophenol (IC50 = 2.34 ± 0.19 μM), a specific inhibitor of SULT1A1. There was also a significant association between SULT1A1 genotypes and copy number and 4-OH TOR sulfation in human liver cytosols. These results indicate that variability in sulfation could contribute to response to TOR in the treatment of breast and prostate cancer.     

Resolving diagnostic uncertainty in initially poorly localizable fevers: a prospective study

AIMS: Prospective, observational data collection of fever patients with regard to aetiology and means of detecting it particularly noting the factors, which quickly helped resolve diagnostic uncertainty. METHODS: Prospective follow-up of patients with clinically non-localizable fever admitted to Manipal Teaching Hospital, Pokhara, Nepal, documenting their temperature response, clinical and lab findings and diagnoses with their response to treatment. RESULTS: Enteric fever 56.8% (25), urinary tract infection 15.9% (7), malaria 9% (4), TB (pulmonary) 4% (2), abscess 4% (2) and hydatid cyst 4% (2). Remaining 4% were due to some other systemic causes. Culture positive: Salmonella typhi positive 32% (8), S. paratyphi positive 20% (5) and culture negative 48%. Response to treatment: enteric fever--(i) first-line drugs (ampicillin/cotrimoxazole) 16% (4), (ii) second-line drugs (ciprofloxacin) 20% (5) and (iii) ceftriaxone 44% (11). CONCLUSIONS: Fever charting as a means to localize Salmonella vs other fevers is still an invaluable clinical tool in adult patients in Nepal. If used judiciously, it can be used as an effective means to diagnose and treat patients of initially non-localizable fevers. Patience must be exercised in starting antibiotics, not until the fever pattern of 2 days suggests enteric, and also while waiting for a response to first-line drugs for Salmonella before one switches over to costlier second-line drugs, with the possible exception of quinolones which may even be used first line owing to their reduced costs (at the danger of wielding a double-edged sword).     

Patterns and trends of pancreatic cancer mortality rates in Arkansas, 1969-2002: a comparison with the US population.

Little is known about trends in pancreatic cancer mortality in individual states of the US and its whole population. This study aimed to describe the patterns and trends of pancreatic cancer mortality in Arkansas, 1969-2002, using the US national rates as a reference. Joinpoint regression analyses were performed to evaluate trends in age-standardized mortality rates of pancreatic cancer by age group, sex, and race, using data obtained from the National Center for Health Statistics. Throughout the period examined, mortality decreased in young and middle-aged people (<60 years) and men but increased in old people (>/=60 years) and women. A continuous fall in mortality occurred among whites except for a transient rise in the late 1970s. For blacks, mortality rates did not cease to increase until 1995. Unlike in Arkansas, a monotonic upward or downward trend in mortality by age group and sex was not observed in the US. A decline of mortality stopped in 1997 for US whites. Recent decreasing trends were more pronounced in Arkansas blacks than in US blacks. Changes of pancreatic cancer mortality in the last three decades in Arkansas remarkably differed by age, sex, and race and were different in patterns from those of the US population.     

Effective treatment of acute otitis externa: a comparison of steroid antibiotic versus 10% ichthammol glycerine pack

To compare the efficacy of treatment between steroid-antibiotic and 10% Ichthammol glycerine packs (IG packs) in acute otitis externa. A prospective, randomized clinical trial between steroid-antibiotic and 10% IG pack which was performed in department of ENT-HNS, Kathmandu University Hospital, Dhulikhel from July 2009 to December 2009 on 82 patients. Pain was assessed by Numerical Rating Scale (NRS) and edema was assessed by dividing the external auditory canal in four quadrant giving score of 25% for each on the day of presentation and subsequent visits till tragal tenderness and edema subsided. Age group among studied patients ranged from 10 to 60?years, with mean of 23.5?years. Out of which 42 (51.2%) were females and 40 (48.8%) were males. Average number of visits in 10% IG pack group (n?=?41) was 5.4?days (2-5 visits) while in steroid-antibiotic group (n?=?41) it was 3.5?days (2-5 visits). There was statistically significant decrease in the number of visits in steroid group (P?相似文献   

Effect of feeding grape pomace on selected metabolic parameters associated with high fructose feeding in growing Sprague-Dawley rats

The effect of feeding grape pomace on certain metabolic parameters associated with high fructose (HF) feeding was studied. Forty male growing Sprague-Dawley rats were randomly assigned into groups: (1) control; (2) HF; (3) HF with low-level (1.5% of diet) grape pomace (HF+LP), and (4) HF with high-level (5.0% of diet) grape pomace (HF+HP). The HF+LP and HF+HP diets provided 115 and 218 mg of procyanidins/kg, respectively. Compared with the controls, HF-fed animals consumed less and were smaller, whereas animals in the HF+LP and HF+HP groups were in between. A similar trend was observed for abdominal fat and abdominal fat as a percentage of body weight. No change in heart or kidney weight occurred. Liver weight as a percentage of body weight was higher for animals when fructose was included in the diet compared with those on control diet, and inclusion of grape pomace had no effect. Fasting plasma glucose, insulin, and triglyceride levels tended to be higher in animals fed HF diet, and grape pomace reduced their levels to values similar to the control animals. Compared with control animals, HF-fed animals had higher weekly postprandial plasma triglycerides, which were reduced by feeding grape pomace, but no change in plasma cholesterol was observed. Glucose intolerance was observed in animals fed HF diet and was accompanied by a 25% increase in homeostatic model assessment (HOMA) of insulin resistance. Inclusion of grape pomace increased glucose tolerance and insulin sensitivity. No significant change (P>.1) in HOMA of β-cell function or Quantitative Insulin-Sensitivity Check Index was observed. Overall, HF diet did not produce as strong a response of metabolic syndrome as has been shown in the literature. The inclusion of grape pomace in the diet was effective in modulating some aspects of metabolic parameters associated with metabolic syndrome, and the higher level of grape pomace in the diet produced a slightly better response than the lower level.     

Effects of lateral ligament sectioning on the stability of the ankle and subtalar joint

Patients with subtalar joint instability are often diagnosed with ankle instability. Only after a prolonged period of time in which a patient does not improve after treatment for ankle instability is subtalar joint instability considered. To develop a clinically relevant method to diagnose subtalar joint instability, the kinematics of the simulated unstable subtalar joint were examined. A 6 degree‐of‐freedom positioning and loading device was developed. Plantarflexion/dorsiflexion, inversion/eversion, and internal/external rotation were applied individually or as coupled motions along with an anterior/posterior drawer. Kinematic data were collected from sensors attached to the calcaneus, talus, and tibia by keeping all the ligaments intact, and by serially sectioning anterior talofibular ligament (ATFL), calcaneofibular ligament (CFL), cervical ligament, and talocalceneal interosseous ligament. Kinematic results were reported using Euler angles. The ATFL and CFL contributed talocrural instability, similar to previous studies. The interosseous ligament was the greatest contributor to subtalar joint stability. The hindfoot motion (calcaneus relative to tibia) showed significant increases in motion when the ankle and/or subtalar joint was made to be unstable. Therefore, it is difficult to diagnose subtalar joint instability on physical examination alone. © 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29: 1459–1464, 2011