Estimability and estimation in case-referent studies.

The concepts that case-referent studies provide for the estimation of "relative risk" only if the illness is "rare", and that the rates and risks themselves are inestimable, are overly superficial and restrictve. The ratio of incidence densities (forces of morbidity)-and thereby the instantaneous risk-ratio-is estimable without any rarity-assumption. Long-term risk-ratio can be computed through the coupling of case-referent data on exposure rates for various age-categories with estimates, possibly from the study itself, or the corresponding age-specific incidence-densities for the exposed and nonexposed combined-but again, no rarity-assumption is involved. Such data also provide for the assessment of exposure-specific absolute incidence-rates and risks. Point estimation of the various parameters can be based on simple relationships among them, and in interval estimation it is sufficient simply to couple the point estimate with the value of the chi square statistic used in significance testing.     

High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumors (GISTs) represent a distinctive (but histologically heterogeneous) group of neoplasms, the malignant potential of which is often uncertain. To determine the prognostic relevance of p16INK4 alterations in GISTs, we investigated a larger group of GISTs and correlated the genetic findings with clinicopathological factors and patient survival. MATERIAL AND METHODS: We evaluated the methylation status of the promotor by methylation-specific polymerase chain reaction (PCR), the presence of mutations by PCR-SSCP-sequencing, the loss of heterozygosity at the p16INK4 locus (using the c5.1 marker), and the immunohistochemical expression of p16INK4 protein in 43 GISTs in 39 patients. RESULTS: p16INK4 alterations were found in 25 of 43 GISTs (58.1%), with benign, borderline, or malignant GISTs showing no differences in the type and frequency of alteration. p16INK4 alterations were correlated with a loss of p16INK4 protein expression (P <.01). Patients who had tumors with p16INK4 alterations had a poorer prognosis than patients with tumors without such alterations (P =.02). There was a high predictive value for p16INK4 alterations only in the group of benign and borderline GISTs (P <.01) with regard to clinical outcome. Univariate Cox's proportional hazard regression analysis revealed a strong correlation between p16INK4 alterations, tumor size, mitotic index, and overall survival (P <.02), whereas multivariate Cox's analysis confirmed only p16INK4 alterations as an independent prognostic factor. CONCLUSION: We believe that the evaluation of p16INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.     

Introducing a new component of the metabolic syndrome: low cholesterol absorption

BACKGROUND: Weight reduction is the recommended treatment of obese type 2 diabetes, but the effects of weight reduction on cholesterol metabolism are poorly understood. OBJECTIVE: We investigated glucose, cholesterol, and lipoprotein metabolism at baseline and 2 y after weight reduction in obese patients with type 2 diabetes consuming an isoenergetic diet. DESIGN: Sixteen subjects were randomly chosen to consume a very-low-energy or low-energy diet for 3 mo, after which they consumed a weight-maintenance diet for up to 2 y. Cholesterol absorption and metabolism, LDL and HDL kinetics, and variables of glucose metabolism were studied at baseline and 2 y. RESULTS: Baseline serum sex hormone binding globulin (SHBG) was significantly related to cholesterol absorption efficiency, and serum glucose and insulin concentrations were associated with cholesterol synthesis. After 2 y, body weight was reduced by 6 +/- 1 kg (P < 0.01), body mass index by 6% (P < 0.05), and blood glucose by 14% (P < 0.01); the ratio of serum SHBG to insulin increased by 66% (P < 0.05). Serum and VLDL, LDL, and HDL triacylglycerol were significantly reduced by 13-24%. Despite unchanged serum concentrations of cholesterol, cholesterol absorption efficiency and the ratio of serum plant sterols to cholesterol-indicators of cholesterol absorption-increased by 28% (P < 0.01) and 20-31% (P < 0. 05 for both), respectively; the fractional removal of LDL apolipoprotein B decreased. Fecal excretion of cholesterol as neutral sterols decreased significantly by 11%. Changes in body weight were significantly negatively correlated with changes in ratios of cholesterol to serum plant sterols and cholestanol. CONCLUSIONS: Baseline cholesterol absorption and synthesis were related to respective serum SHBG, glucose, and insulin values. Weight reduction increased cholesterol absorption and improved variables of glucose metabolism. These results suggest that low cholesterol absorption and high synthesis may be part of the insulin resistance syndrome.     

X-radiation induces 8-hydroxy-2'-deoxyguanosine formation in vivo in rat mammary gland DNA

Ionizing radiation is a carcinogen that induces oxidative DNA damage. 8- Hydroxy-2'-deoxyguanosine (8-OHdG) is a relatively abundant, mutagenic lesion that is widely regarded as a reliable index of oxidative DNA damage. The purpose of this study was to examine the effects of X- radiation on levels of 8-OHdG in the context of an experimental model for breast cancer in which chronic radiation exposure has been shown to be carcinogenic in Sprague-Dawley rats. A secondary objective of this study was to determine if the use of phenol during DNA isolation affected the concentration of 8-OHdG subsequently measured. Our results indicate that a profoundly carcinogenic dose of radiation induced a small but significant increase in 8-OHdG concentration in mammary gland DNA, and that the use of a phenol-based versus a salt-based method of DNA isolation had no significant impact on the levels of 8-OHdG detected in either control or irradiated tissue.      

Effects of dietary fat and a vegetable-fruit mixture on the development of intestinal neoplasia in the ApcMin mouse

The variation in colorectal cancer (CRC) incidence worldwide strongly suggests a role for dietary influences. Based on epidemiological data, protective effects of vegetables and fruit intake on CRC are widely claimed, while other data indicate a possible increased CRC risk from (higher) dietary fat intake. Therefore, we have investigated single and interactive effects of dietary fat and a vegetable-fruit mixture (VFM) in the ApcMin mouse, a mouse model for multiple intestinal neoplasia. In this study, four different diets (A-D) were compared, which were either low in fat (20% energy diets A/B) or high in fat (40% energy diets C/D). In addition, 19.5% (wt/wt) of the carbohydrates in diets B and D were replaced by a freeze-dried VFM. The diets were balanced so that they only differed among each other in fat/carbohydrate content and the presence of specific plant-constituents. Because the initiation of intestinal tumors in ApcMin mice occurs relatively early in life, exposure to the diets was started in utero. Without the addition of VFM, mice maintained at a high-fat diet did not develop significantly higher numbers of small or large intestinal adenomas than mice maintained at a low-fat diet. VFM added to a low-fat diet significantly lowered multiplicity of small intestinal polyps (from 16.2 to 10.2/mouse, 15 animals/group), but not of colon tumors in male ApcMin mice only. Strikingly, addition of VFM to female mice maintained on a low-fat diet and to both sexes maintained on a high-fat diet significantly enhanced intestinal polyp multiplicity (from 16.5 to 26.7 polyps/mouse). In conclusion, our results indicate that neither a lower fat intake nor consumption of VFM included in a high-fat diet decreases the development of polyps in mice genetically predisposed to intestinal tumor development.      

1-取代吡唑烷酮类抗惊构效关系的研究

1-正癸基吡唑烷-3-酮(Ⅱ结构式见表1)是欧洲专利报道的一种新型减肥剂。White等报道该化合物可通过血脑屏障,并对γ-氨基丁酸氨基转移酶(GABA-T)有强烈的抑制活性,但对谷氨酸脱羧酶的抑制作用较弱,因此可引起脑内γ-氨基丁酸(GABA)水平的升高,故我们相信应有抗惊活性。经我们合成后,发现Ⅱ确有良好的抗癲痫活性,抗小鼠最大电     

Preschool behavior disorders: their prevalence in relation to determinants

The occurrence of behavior disorders was investigated in a prospectively followed 3-year-old birth cohort. Of 1116 eligible children, the parents of 918 were successfully contacted. All agreed to complete a telephone interview and were mailed a Childhood Behavior Checklist (CBCL) standardized for 2- to 3-year-old children; 756 (82%) returned the CBCL. The prevalence of one or more of the deviant behavior syndromes identified by the CBCL was 11.1%. From a number of subject characteristics recorded throughout infancy, age-specific determinants for the occurrence of these deviant behaviors were identified. Characteristics most consistently associated with preschool psychopathology included the mother's ill health and lack of social support, the presence of chronic illness in the child, and the frequent use of hospital emergency services. These and other determinant (risk) indicators were entered into logistic regression (LR) models to derived adjusted relative risk estimates for the occurrence of a behavior disorder. The derived LR equations emphasize the important role of both the mother as well and the father and the health of the child.     

Gastrointestinal stromal tumors in patients with neurofibromatosis: imaging features with clinicopathologic correlation

OBJECTIVE: The purpose of this study was to evaluate the clinical, pathologic, and imaging features of gastrointestinal stromal tumors that occur in patients with neurofibromatosis. CONCLUSION: Gastrointestinal stromal tumors that occur in patients with neurofibromatosis commonly originate from the proximal small intestine and are often multiple. The cross-sectional imaging appearance of gastrointestinal stromal tumors that occur in patients with neurofibromatosis is similar to that of gastrointestinal stromal tumors that occur in the general population.     

Acute tubulointerstitial nephritis,treatment with steroid and impact on renal outcomes

Background: The use and timing of steroids in the management of acute tubulointerstitial nephritis (ATIN) remains debatable. Aims: To determine the incidence and aetiology of ATIN in our unit, and to examine trends in the use of steroids and their impact on renal outcomes. Methods: Patients with a histological diagnosis of ATIN over a 9‐year period were identified and divided into steroid‐treated (StG) and steroid‐naïve groups (SnG). Mean change in estimated glomerular filtration rate (eGFR) was determined. Results: Forty‐nine patients had ATIN as their main diagnosis, 67% of cases were drug‐induced, and proton pump inhibitors (PPI) were the second commonest implicated drug category. Majority (75%) of patients received steroids, and eGFR improved to a significantly greater degree in these steroid‐treated patients (3.4‐fold improvement vs 2.0‐fold in SnG; P < 0.05, unpaired t‐test). Despite comparable eGFR at presentation (StG: 11.7; SnG: 15.4), steroid‐treated patients were less likely to receive dialysis, although not significantly so (OR 0.27; 95% CI 0.06–1.15, P = 0.066, chi‐squared test). However, there was no significant relation between the degree of eGFR improvement and delay in starting steroids (Pearson r = ?0.25, P > 0.45), and no difference in eGFR at the time of last follow‐up (StG: 33 ± 3; SnG: 32 ± 7; P > 0.9, unpaired t‐test). Conclusion: StG patients had a greater degree of improvement in renal function, but with no correlation between degree of improvement in eGFR and delay in starting steroids, and similar eGFR values at final follow‐up. PPI were the second commonest drug category among drug‐induced cases.