A K-ras oncogene increases resistance to sulindac-induced apoptosis in rat enterocytes

BACKGROUND & AIMS: Mutations of c-K-ras occur commonly in colonic neoplasms. The aim of this study was to determine how c-K-ras mutations alter the responses to the chemopreventive agent sulindac. METHODS: The parental rat intestinal cell line IEC-18 and c-K-ras-transformed derivatives were treated with sulindac sulfide. Cell cycle distribution was determined by flow-cytometric analysis (fluorescence-activated cell sorter), apoptosis by DNA fragmentation (laddering), flow cytometry, and microscopy, and changes in gene expression by immunoblotting. RESULTS: Sulindac sulfide inhibited cell growth and induced apoptosis in a time- and dose-dependent manner more rapidly in and at lower concentrations in parental cells than ras-transformed cells. Expression of the sulindac sulfide arrested cells in G0/G1, but cells entered apoptosis throughout the cell cycle. Proapoptotic protein Bak was relatively high in untreated parental cells and increased markedly after sulindac sulfide but was low in untreated ras-transformed cells and did not increase after sulindac sulfide. Expression of other Bcl-2 family members was unchanged after sulindac sulfide. However, sulindac sulfide reduced levels of cyclin D1 protein and cyclin E- and cyclin D1- associated kinase activity. CONCLUSIONS: c-K-ras-transformed enterocytes are relatively resistant to sulindac sulfide-induced growth inhibition and apoptosis, which may result from specific reduction of bak expression. (Gastroenterology 1997 Dec;113(6):1892-900)     

Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females

Abstract. With the aim of preventing postmenopausal bone loss, a placebo-controlled double-blind trial of 2 years duration was performed. We randomized 315 healthy volunteers in their early natural menopause to seven treatment and three placebo groups: 17β-oestra-diol, oestriol and sequential norethisteron (hormones); bendroflumethiazide 5 mg/day (thiazide); hormones and thiazide; sodium fluoride 20 mg/day; vitamin D3 2000 IU/day (D₃); fluoride and D₃; and lα (OH) vitamin D3 0–25 μg/day (lαD₃). All participants were given daily calcium supplement of 500 mg. Every 3 months we measured the bone mineral content (BMC) of both forearms by photon absorptiometry and chemical quantities in blood and 48 h urinary collections. The study was completed by 264 (84%).
The combined placebo groups snowed a linear fall in BMC reaching 3-3 % after 2 years ( P < 0–001). Hormones and hormones and thiazide led to a 2–5% gain in BMC ( P < 001). Thiazide alone postponed the BMC fall for 6 months. After 2 years the thiazide group showed a BMC fall of 1–5% ( P < 0–05), less than that of the placebo group ( P < 0–05). BMC declined by 3–6%, 4–5%, 3–7% and 3–7% during the respective use of fluoride, D₃, fluoride and D₃ and lαD₃. Nevertheless, the urinary calcium excretion during lαD₃ and D₃ treatment was 1-1-5 mmol/day higher than in the placebo groups.
Apparently, there is no real alternative to oestro-gen/gestagen in the prevention of postmenopausal osteoporosis.     

Postural Fall in Blood Pressure in the Elderly in Relation to Drug Treatment and Other Lifestyle Factors

In a study of 843 independent-living men and women aged between60 and 87 in Perth, Western Australia, stepwise multiple regression,after correction for initial levels of systolic blood pressure,showed that postural fall in systolic blood pressure was positivelyrelated to alcohol intake of more than 20 ml/day, the use ofsleeping tablets and higher levels of anxiety on the Spielbergerstate-trait scale, and negatively related to body mass index.Postural fall in blood pressure was not significantly relatedto treatment for hypertension, age, sex, patterns of usual physicalactivity, tea or coffee drinking, or the diagnosis of diabetesmellitus. This analysis is the first to examine the relationshipbetween lifestyle factors and the magnitude of the fall in systolicblood pressure on standing after adjustment for the associationbetween the change in a variable and its initial level. Ouranalysis suggests the need for further study of the possiblerole of lifestyle factors such as the use of sleeping tabletsand alcohol in postural hypotension in the elderly.     

Tlymphocyte subsets in homosexual men from Copenhagen

Abstract. Screening of sixty-six asymptomatic homosexual men from Copenhagen revealed significantly lower Leu-3a/Leu-2a ratios as compared to controls. Ten (15%) of the homosexuals had a ratio ≤ 1·0. The low Leu-3a/Leu-2a ratios were the result of an increase in the absolute number of Leu-2a cells. Homosexuals with many partners and those who had been sexual partners of patients with the acquired immuno-deficiency syndrome (AIDS) had significantly lower ratios than those without these features. Cytomegalovirus was isolated from urine and/or sputum of 15% and this was associated with a Leu-3a/Leu-2a ratio ≤ 1·0. The observed immunological abnormalities could either represent latent infection with the putative AIDS agent or alternatively be caused by repeated infections and/or exposure to allogenic spermatocytes or lymphocytes.     

De novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features

Mutations in genes involved in Ras signalling cause Noonan syndrome and other disorders characterised by growth disturbances and variable neuro-cardio-facio-cutaneous features. We describe two sisters, 46 and 31 years old, who presented with dysmorphic features, hypotonia, feeding difficulties, retarded growth and psychomotor retardation early in life. The patients were initially diagnosed with Costello syndrome, and autosomal recessive inheritance was assumed. Remarkably, however, we identified a germline HRAS mutation (G12A) in one sister and a germline KRAS mutation (F156L) in her sibling. Both mutations had arisen de novo. The F156L mutant K-Ras protein accumulated in the active, guanosine triphosphate-bound conformation and affected downstream signalling. The patient harbouring this mutation was followed for three decades, and her cardiac hypertrophy gradually normalised. However, she developed severe epilepsy with hippocampal sclerosis and atrophy. The occurrence of distinct de novo mutations adds to variable expressivity and gonadal mosaicism as possible explanations of how an autosomal dominant disease may manifest as an apparently recessive condition.     

Difficulty swallowing and lack of receipt of highly active antiretroviral therapy predict acute weight loss in human immunodeficiency virus disease

In human immunodeficiency virus (HIV) disease, symptoms of underlying illness may promote weight loss through decreased caloric intake, increased metabolic needs, or nutrient malabsorption. We evaluated disease symptoms as predictors of acute weight loss (i.e., loss of > or =5% of weight). HIV-infected men and women (n=415) were telephoned every 5 weeks to obtain information about weight and recent symptoms. Weight change between each pair of consecutive calls (telephone intervals, 2814) was calculated. Acute weight loss occurred across 4.5% of intervals and among 24% of individuals. Patients reported > or =1 symptom before 58% of telephone intervals. The most common symptoms or symptom complexes before intervals were diarrhea (21% of patients), anorexia (17%), upper respiratory symptoms (16%), skin symptoms (12%), and abdominal pain (12%). Trouble swallowing (6%) and oral symptoms (7%) were less common. Risk of acute weight loss was significantly increased when oral symptoms or trouble swallowing were present, and it was decreased when highly active antiretroviral therapy (HAART) was used or when diarrhea was not present. Even when HAART is being administered, clinicians should remain vigilant regarding weight loss, oral symptoms, and trouble swallowing.     

Antineutrophil cytoplasmic antibody–associated vasculitides: Could geographic patterns be explained by ambient ultraviolet radiation?

Objective

This ecological study describes and quantifies the association between ambient ultraviolet (UV) radiation levels, including daily winter vitamin D effective UV radiation levels and the incidence of the 3 antineutrophil cytoplasmic antibody–associated vasculitides (AAVs): Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), and Churg‐Strauss syndrome (CSS). Latitudinal variation in occurrence of the AAVs, especially WG, has been previously reported. For other autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus, inverse associations with latitude are hypothesized to indicate a causative role for low UV radiation exposure, possibly acting via vitamin D status.

Methods

Published epidemiologic studies provided data on incident cases, total population of study regions, age‐specific incidence rates, and study location. From these data and online age‐specific population data, we calculated crude incidence rates, the expected number of cases (to control for possible age confounding), and measures of ambient UV radiation. Negative binomial regression models were used to calculate the incidence rate ratio (IRR) for a 1,000 joules/m² increase in ambient UV radiation.

Results

The incidence of WG and CSS increased with increasing latitude and decreasing ambient UV radiation, with a stronger and more consistent effect across different UV radiation measures for WG, e.g., for average daily ambient clear sky erythemal UV radiation (WG: IRR 0.64 [95% confidence interval (95% CI) 0.44–0.94], P = 0.02; CSS: IRR 0.67 [95% CI 0.43–1.05], P = 0.08; MPA: IRR 1.16 [95% CI 0.92–1.47], P = 0.22). There was no apparent latitudinal variation in MPA incidence.

Conclusion

Our findings are consistent with a protective immunomodulatory effect of ambient UV radiation on the onset of WG and CSS. We discuss possible mechanisms, including the effect of vitamin D on the immune system.     

Aetiological factors and development in subjects with obstructive sleep apnoea

OBJECTIVE: To examine whether maternal pregnancy complications, adverse birth events, respiratory illnesses, or developmental difficulty were increased in neurologically normal children with obstructive sleep apnoea (OSA) and whether severity of OSA adversely affects the child's development and temperament. METHODOLOGY: Maternal report of perinatal events, respiratory illness and developmental difficulty in 37 children with OSA was contrasted with a comparison group (n = 67). Children with OSA were assessed developmentally (Griffiths Scales), had a parental rating of temperament (Australian Temperament Scale) and attended an overnight polysomnographic sleep study. RESULTS: Children with OSA had an increased prevalence of adverse maternal pregnancy and perinatal events, respiratory disease and developmental concerns. Limited associations were found between the severity of OSA and development or temperament difficulty. CONCLUSIONS: This study suggests a relationship between OSA, though not its severity, and pre/perinatal adversity and child development. Polysomnographic and detailed developmental assessment of community-based samples of children with OSA and control children are necessary to confirm these findings.     

Validity of Clinical Symptoms in Benign Esophageal Disease,Assessed by Questionnaire

ABSTRACT. A questionnaire designed to test the value of questions identifying benign esophageal disease was sent to patients representing four well-defined entities: angina pectoris (n=30), benign esophageal disease (n=25), gastroduodenal ulcer or former gallstones (n=27) and normal subjects (n=38). By means of logistic regression, three key-questions were selected. A combination of an affirmative answer to “difficulty in swallowing solid food” and to “pain in the chest” or “heartburn at night” or both did not occur in the group of normal subjects, while occurring in 68% of the patients with esophageal diseases. The combination occurred in only 10% of the patients with angina pectoris and 15% of those suffering from gastroduodenal ulcer or gallstones. The predictive accuracy of the combination of the three questions is estimated for various hypothetic prevalences of esophageal disease. These questions appear to identify approximately two-thirds of individuals with esophageal disease with acceptable false-positive rates and can therefore be used in epidemiological studies.     

Palpable solid breast masses: retrospective single- and multimodality evaluation of 201 lesions

The diagnostic virtues and limitations of single- and multimodality testing in the evaluation of solid palpable breast masses were studied. Two hundred one consecutive patients who had a solid palpable breast mass and who underwent biopsy between September 1982 and July 1986 were included for blinded retrospective analysis of their physical examination, mammographic, ultrasonographic (US), thermographic, and pathologic characteristics. Benign breast disease was diagnosed histologically in 106 women, while carcinoma was established in 95. The sensitivities of physical examination, mammography, US, and thermography were 0.88, 0.94, 0.78, and 0.49, respectively. US alone had the highest sensitivity in correct diagnosis of a benign solid breast mass and had the highest accuracy (0.84). Use of four modalities increased the preoperative diagnostic true-positive rate to 0.97, with some decline in specificity. Multimodality testing seems particularly beneficial in pre- and perimenopausal patients.