Helicobacter pylori risk associated with sibship size and family history of gastric diseases in Japanese adults

BACKGROUND: Data on whether long-acting somatostatin analogue octreotide causes or prevents pancreatic injury following endoscopic retrograde cholangiopancreatography (ERCP) are controversial. AIM: This multicentre, prospective trial studied the effect of octreotide on pancreatic injury in a large unselected group of patients after ERCP and endoscopic sphincterotomy. METHODS: The study was carried out in a prospective random manner on 2102 patients in 11 endoscopic centres. Patients in the study received 0.1 mg octreotide acetate and those in the control group received isotonic sodium chloride, subcutaneously before and 45 min after ERCP. Pancreatic injury was assessed by clinical symptoms such as pain, fever and abdominal tenderness. Serum amylase and blood sugar were determined prior to, and 6 and 24 h after the endoscopic procedure. RESULTS: Data from 599 patients in the study group and 600 in the control group were included in the final evaluation. When all the patients were considered, octreotide did not induce pancreatic injury as assessed by clinical symptoms, and diminished the increase of serum amylase levels following ERCP. However, when subgroups of patients were studied, the frequency of increased amylase levels decreased significantly in patients with chronic obstructive pancreatitis and in patients who underwent endoscopic sphincterotomy (P < 0.01). The peak serum glucose level was higher in the treated group when compared to the controls. CONCLUSION: The prophylactic use of long-acting somatostatin does not alter the frequency of post-ERCP pancreatic injury, but it may diminish the rate of increased serum amylase levels in patients with chronic obstructive pancreatitis and also in those with an endoscopic sphincterotomy.     

Prognostic significance of microsatellite instability in patients with gastric carcinoma

A proportion of gastric adenocarcinomas exhibit replication errors manifested as microsatellite instability. The clinicopathological and prognostic significance of this abnormality remains uncertain. This study aimed to determine the importance of microsatellite instability by analysing a large series of gastric carcinomas from an English population. Using a novel fluorescent polymerase chain reaction technique, we amplified 11 microsatellite sequences from paired normal and carcinoma DNA from 101 patients who underwent a potentially curative resection for gastric carcinoma. Overall, 21% of cases demonstrated microsatellite instability in at least one locus. At least four loci were examined in each case. A replication error positive phenotype (minimum of 29% of loci affected) was detected in 9% of cases. There was no statistically significant association between the presence of microsatellite instability or replication error positive phenotype and the patient's age, sex, tumour site, stage, node status, histological subtype or grade. Carcinomas confined to the mucosa or submucosa (T1) showed a significantly higher frequency of instability and replication error positive phenotypes than T3 lesions (P = 0.03 and P = 0.05, respectively). A larger proportion of patients who were microsatellite instability or replication error positive were alive at 5 years compared with those who were negative but this did not reach statistical significance (P = 0.15 and P = 0.16, respectively). We identified a subset of gastric carcinomas from a relatively low-risk population which showed evidence of microsatellite instability. There were no statistically significant 5-year survival advantages in cases demonstrating microsatellite instability or replication error positive phenotypes. The detection of microsatellite instability is of limited prognostic value in gastric carcinoma.     

Abnormal tryptophan metabolism in a family with a history of bladder cancer

Tryptophan metabolism was studied in a family in which a sister and brother had bladder cancer. Urinary tryptophan metabolites after administration of 2 g L-tryptophan were measured in 4 sisters and 1 brother, all free of disease when studied. One sister with and 2 without histories of bladder cancer had significantly elevated levels of kynurenine, acetylkynurenine, and 3-hydroxykynurenine. Administration of 100 mg pyridoxine hydrochloride returned the tryptophan metabolism to normal in these 3 individuals. One brother with a 1 sister without bladder cancer had normal metabolism. A repeat study 2 years later confirmed the abnormal metabolism in the 3 sisters. Two sisters with abnormal tryptophan metabolism were given 200 mg L-kynurenine sulfate orally to bypass the effects of tryptophan oxygenase activity. Both excreted elevated levels of kynurenine and 1 excreted elevated levels of 3-hydroxykynurenine.     

Vaginal cancer in a woman with a family history of ovarian cancer

The proband was referred to familial ovarian cancer surveillance because two of her sisters died of carcinoma of the ovary. Her third sister succumbed of cervical cancer and her brother had acute myeloblastic leukaemia. Her second brother is alive and healthy. None of her parents and their sibs suffered of malignant disease. The offspring of the proband's sibs are young and appear to be normal. During surveillance she developed a stage I vaginal cancer. Following preoperative brachytherapy she underwent a radical hysterectomy and bilateral salpingoophorectomy with pelvic lymphadenectomy, and she is free of disease during 2 years of follow-up. The authors are not aware of any similar case.     

Lifestyle intervention in overweight individuals with a family history of diabetes

OBJECTIVE: To assess the effect of lifestyle intervention over 2 years on changes in weight, coronary heart disease (CHD) risk factors, and incidence of diabetes in overweight individuals with a parental history of diabetes. RESEARCH DESIGN AND METHODS: Participants (n = 154), who were 30-100% over ideal body weight, had one or both parents with diabetes, and were currently nondiabetic, were randomly assigned to 2-year treatments focused on diet (decreasing calories and fat intake), exercise (goal of 1,500 kcal/week of moderate activity), or the combination of diet plus exercise or to a no-treatment control group. Subjects were reassessed at 6 months, 1 year, and 2 years. RESULTS: At 6 months, the groups differed significantly on measures of eating, exercise, and fitness; weight losses in the diet and diet-plus-exercise groups were significantly greater than in the exercise and control conditions. Weight losses were associated with positive changes in CHD risk factors. After 6 months, there was gradual deterioration of behavioral and physiological changes, so that at 2 years, almost no between-group differences were maintained. Differences between groups in risk of developing diabetes were of borderline significance (P = 0.08). Strongest predictors were impaired glucose tolerance at baseline, which was positively related to risk of developing diabetes, and weight loss from baseline to 2 years, which was negatively related; in all treatment groups, a modest weight loss of 4.5 kg reduced the risk of type 2 diabetes by approximately 30% compared with no weight loss. CONCLUSIONS: Although initially successful, the interventions studied here were not effective in producing long-term changes in behavior, weight, or physiological parameters. However, weight loss from 0 to 2 years reduced the risk of developing type 2 diabetes. Since modest weight loss significantly reduced risk of type 2 diabetes, further research is needed to determine how best to increase the percentage of subjects achieving at least a modest weight loss.     

Validity of the family history method in relatives of gerontopsychiatric patients

It was the aim of the present study to evaluate the validity of the family history method in relatives of a sample of elderly subjects. A total of 201 relatives of patients and 89 relatives of control subjects were interviewed directly using the Composite International Diagnostic Interview and the Structured Interview for the Diagnosis of Dementia of the Alzheimer Type, Multi-infarct Dementia and Dementias of other Etiology. At least one relevant other could provide family history information on a respective subject. Family history information for psychiatric disorders including dementia (DSM-III-R) was neither accurate, nor sensitive (10 to 40%), but highly specific (> 95%). The sensitivity of the family history for dementia and depression increased in relation to the severity of the disorder. Relatives of patients were better informants than relatives of controls (at least for the presence of any psychiatric disorder). The use of several informants only slightly improved the sensitivity of the family history, without reducing the specificity to a significant extent. The combination of different sources of information may serve to reduce information biases. The evaluation of possible biases in future family studies is required to draw adequate conclusions from differences in familial loads.     

The results of diagnostic studies for thrombophilia in a large group of patients with a personal or family history of thrombosis

The range of tests used in the evaluation of thrombophilia has been altered by the recent recognition of common genetic defects predisposing to thrombosis such as factor VLeiden (FVR506Q), enzyme deficiencies causing hyperhomocysteinemia, and improvement in the sensitivity and utilization of assays for antiphospholipid antibodies. In this study, the outcomes of laboratory evaluation of 402 patients with thrombophilia were reviewed and correlated with clinical data. A predisposing factor was present (positive diagnosis, group A) in 110 patients (27%), the test results of 111 patients (28%) could not be definitively interpreted (equivocal results, group B), and the test results of 181 (45%) were normal (group C). The median age of the group A patients was 48 years (range, 3.7-88 years), suggesting that evaluation of patients over the age of 50 is worthwhile. Of the 110 patients in group A, 84% had single defects and 16% had combined defects. The most common defect was factor VLeiden (44 patients). Equal numbers of patients presenting with arterial and venous thromboses were evaluated. Patients with arterial events were less likely to have a definable laboratory defect (33 of 132 [25%]) than were those with venous events (50 of 136 [37%]). Factor VLeiden was the most frequent finding in patients with venous events, and lupus anticoagulant or anticardiolipin antibodies were the most frequent findings in patients with arterial events. Positive diagnoses were made in patients on anticoagulants, indicating that this should not preclude investigation. Our study confirms the need for thorough evaluation to assess thrombotic risk, and it reflects the impact of newly identified thrombophilic disorders on the expected outcome of laboratory evaluation for thrombophilia.     

Psychiatric family history in adolescents with severe asthma

OBJECTIVE: To examine the hypothesis that an association exists between severe asthma and familial affective and anxiety disorders. METHOD: A parent, usually the mother, of 62 adolescents admitted to a tertiary care asthma center was administered the Family History-Research Diagnostic Criteria Interview. Lifetime prevalence rates of psychiatric disorders in first-degree relatives were compared with previously reported rates. RESULTS: In relatives of asthmatic adolescents, rates for depression, mania (females only), substance abuse (males only), and antisocial personality disorder were significantly higher than the rates in the non-ill comparison sample. Rates for substance abuse (males only) and antisocial personality disorder were higher than the rates for relatives of the depressed comparison sample. Rates for anxiety disorders were not higher than rates in epidemiological samples. Rates of attention-deficit hyperactivity disorder (females only) and posttraumatic stress disorder in relatives were higher than in community samples. CONCLUSIONS: These results support the presence of a link between severe asthma and familial affective disorders, posttraumatic stress disorder, antisocial personality disorder, and substance abuse. Whether these disorders are genetically associated with asthma or represent an association with severe asthma because of environmental effects on the growing child is discussed.     

Baroreceptor reflex function in young normotensive men with a family history of hypertension

The purpose of this study is to evaluate the baroreflex function using lower body negative pressure (LBNP) and neck suction in young normotensive men with or without a family history of hypertension. Twenty-two young normotensive men with a family history of hypertension (FH+) and eight young normotensive men who had no family history of hypertension (FH-) were studied. FH(+) consisted of men who had a family history of hypertension within second degree relatives. We studied cardiopulmonary baroreflex function using LBNP and carotid sinus baroreflex function using neck suction and evaluated the reflex function under stimulated conditions using both LBNP and neck suction at the same time. Systolic arterial pressure (SAP)(F = 5.42, p < 0.0001) and pulse pressure (PP)(F = 15.57, p < 0.0001) decreased similarly in both groups in response to LBNP. SAP and PP responses to LBNP were not significantly affected by the family history of hypertension. Diastolic arterial pressure (DAP) increased (F = 2.89, p < 0.005) in both groups. There was a relationship between the LBNP level and family history of hypertension (F = 2.53, p < 0.013), and the increment in DAP during LBNP -30, -40 mmHg was larger in the FH(+) group. Through mean arterial pressure (MAP) was not effected by LBNP, there LBNP level was related to the family history of hypertension (F = 2.23, p < 0.02). Heart rate increased progressively (F = 25.7, p < 0.0001) with increasing levels of LBNP; however, these changes did not differ significantly in either group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Multifocal renal cell carcinoma: evidence for a common clonal origin

The reported incidence of satellite tumor lesions in kidneys resected by radical nephrectomy for renal cell carcinoma (RCC) is 7-25%; however, genetic analyses of satellite tumors in comparison with those of main tumor lesions have not been performed well. In the present study, we investigated the incidence of loss of heterozygosity (LOH) at chromosome arms 3p, 6q, 8p, 9p, 9q, and 14q using 18 microsatellite markers in 10 nonpapillary RCCs of 50 mm or less in diameter and the accompanying satellite tumor lesions to evaluate the genetic alterations in main and satellite tumors. LOH was detected in 10, 3, 5, 3, 2, and 3 cases at chromosome arms 3p, 6q, 8p, 9p, 9q, and 14q, respectively. In addition, primary and satellite tumor lesions in 8 of 10 cases exhibited identical patterns of LOH on the 18 loci examined. In the remaining two cases, both main and satellite tumors demonstrated LOH on the common seven and three loci, respectively, whereas for another locus, LOH was observed only in the satellite tumor lesions. The similarity of LOH patterns detected in main and satellite tumor lesions indicates that the presence of satellite tumors might be the result of intrarenal metastasis from the main tumor lesion. These findings strongly suggest that even in case of small nonpapillary RCC, nephron-sparing surgery might carry the risk of failing to prevent postoperative local recurrence due to the incomplete resection of unrecognized satellite tumors with genetic alterations similar to those of the main tumor.     

Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer

BACKGROUND: Options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic mastectomy. The data on the outcomes for surveillance and prophylactic mastectomy are incomplete. METHODS: We conducted a retrospective study of all women with a family history of breast cancer who underwent bilateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. The women were divided into two groups - high risk and moderate risk - on the basis of family history. A control study of the sisters of the high-risk probands and the Gail model were used to predict the number of breast cancers expected in these two groups in the absence of prophylactic mastectomy. RESULTS: We identified 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy: 214 at high risk and 425 at moderate risk. The median length of follow-up was 14 years. The median age at prophylactic mastectomy was 42 years. According to the Gall model, 37.4 breast cancers were expected in the moderate-risk group; 4 breast cancers occurred (reduction in risk, 89.5 percent; P<0.001). We compared the numbers of breast cancers among the 214 high-risk probands with the numbers among their 403 sisters who had not undergone prophylactic mastectomy. Of these sisters, 38.7 percent (156) had been given a diagnosis of breast cancer (115 cases were diagnosed before the respective proband's prophylactic mastectomy, 38 were diagnosed afterward, and the time of the diagnosis was unknown in 3 cases). By contrast, breast cancer was diagnosed in 1.4 percent (3 of 214) of the probands. Thus, prophylactic mastectomy was associated with a reduction in the incidence of breast cancer of at least 90 percent. CONCLUSIONS: In women with a high risk of breast cancer on the basis of family history, prophylactic mastectomy can significantly reduce the incidence of breast cancer.     

Risk factors for breast cancer in women with a breast cancer family history

For the study of the relationship of the pelviureteric system of one kidney to that of the contralateral one, bilateral cutaneous ureterostomy was performed in 14 dogs. The renal pelvis (RP) and ureter (U) of one side were distended separately with a balloon filled with saline in increments of 1 and 0.25 ml, respectively, and the pressure response of the contralateral RP and U was recorded. The test was repeated after anesthetization of the RP and U. RP distension with 1 ml of saline effected a pressure rise (P < 0.05) in the ipsilateral RP but no pressure response in the ipsilateral U or the contralateral RP or U (P > 0.05). RP distension with 2, 3, and 4 ml of saline induced a significant pressure rise in the ipsi- and contralateral RP but not in the ureters. Ureteric distension produced a pressure elevation (P < 0.05) on the ipsilateral U but had no effect on the contralateral U (P > 0.05) or on either of the renal pelves (P > 0.05). Distension of the anesthetized RP or U effected no pressure response in any of the ipsi- or contralateral RPs or Us. In conclusion, distension of the RP with large volumes led to an increase in pressure in the contralateral RP but not in the U. A reflex relationship is postulated to exist between the two renal pelves and to be mediated through a reflex we call the reno-renal pelvic reflex. It seems that this reflex acts to allow either of the kidneys to share an extra load of the other one by increasing the contractile activity of the RP, thus assumedly assisting the regulation of urine flow.     

Recent advances in surgical treatment have improved the survival of patients with gastric carcinoma

BACKGROUND: Mortality resulting from gastric carcinoma is decreasing. This is mainly due to vigorous endoscopic screening and the consequent higher incidence of early detection of the disease. In this study, to evaluate the effect of surgical treatment on the prognoses of patients with gastric carcinoma, the survival of 1579 patients who underwent gastrectomy between 1970 and 1994 was retrospectively analyzed. METHODS: The patients were divided into 5 groups at 5-year intervals. Postoperative survival was compared among the groups. RESULTS: Postoperative survival was significantly improved in the later groups for patients with Stage I, II, III, and IV disease. A multivariate analysis of prognostic factors revealed that the time period during which the gastrectomy was performed was an independent predictor of survival. CONCLUSIONS: It was concluded that survival has been improved by recent advances in the surgical approach to gastric carcinoma.     

BRCA2 germ-line mutations are frequent in male breast cancer patients without a family history of the disease

Breast cancer is a rare disease in men, affecting less than 0.1% of the male population. Two heritable gene defects have been associated with a predisposition to male breast cancer development, ie., germ-line mutations in the breast cancer susceptibility gene BRCA2 and the androgen receptor (AR) gene. In this study, the entire coding regions of BRCA2 and AR were screened for mutations in 34 consecutive male breast cancer patients. Five different truncating BRCA2 mutations were identified in 7 (21%) of the 34 cases, with all mutations being of germ-line origin. Three of the mutated cases carried the same mutation (4186delG), which has been found earlier in two Swedish families with multiple female breast cancer cases. Haplotype analysis supported a common ancestry of 4186delG. One mutation, 6503delTT, was found in a male carrying also a previously identified COOH-terminal polymorphic stop codon (Lys3326ter). No differences were seen between mutation carriers and noncarriers with respect to clinical stage and estrogen or progesterone receptor status. Mutation carriers tended to be younger at diagnosis. No germ-line AR mutations were found in the present material, but the number of AR polyglutamine repeats tended to be lower among mutation carriers. Most surprisingly, only one of the seven BRCA2 mutation carriers had a positive family history of breast cancer, suggesting a lower penetrance of some BRCA2 mutations or an influence of modifying factors for disease development in males and females. The present study implies that approximately one-fifth of all male breast cancer cases in the Swedish population are due to germ-line BRCA2 mutations.     

Screening women aged less than 50 years with a family history of breast cancer

Family history is an important breast cancer risk factor and is a common reason for referral to specialist breast clinics for consideration of breast screening. The aims of this study were to determine cancer detection rates and prognostic features of breast cancers identified in women aged less than 50 years at increased risk of breast cancer who attend a Family History Breast Screening Clinic (FHC). Between January 1988 and December 1995, 1371 asymptomatic women aged less than 50 years underwent annual clinical breast examination and biennial mammography due to a family history of breast cancer. A total of 29 cancers (23 invasive and 6 in situ) were detected or presented as interval cancer during a mean follow-up of 22 months (range 0-96 months). This gave a relative risk for invasive breast cancer in this high-risk group of 5 when compared with an age-matched female population in the U.K. The cancer screening detection rates were similar to those of women aged 50 years or over undergoing population screening in the NHS Breast Screening Programme (NHSBSP)--FHC prevalent screen 8 per 1000 screening visits versus NHSBSP 6.5 per 1000, FHC incident screen 3.3 per 1000 screening visits versus NHSBSP 3.8 per 1000. A higher proportion of in situ cancers were detected in the FHC screened group compared with cancers identified in symptomatic patients from an age-matched risk group (21% versus 4%). No differences were demonstrated for invasive tumour size, grade or lymph node stage between symptomatic and screened women. The early results of this study suggests that young women at risk of breast cancer due to a family history may benefit from regular breast screening due to the early detection of in situ lesions.     

Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease

BACKGROUND: A family history of premature coronary artery disease (CAD) in a first-degree relative is an independent risk factor for coronary disease. Both genetic and environmental influences are likely to be responsible and may interact, but their relative importance is unclear. METHODS AND RESULTS: We studied endothelial function in 50 first-degree relatives (31 men, 19 women; mean age, 25+/-8 years) of patients (men < or = 45 years, women < or = 55 years) with proven CAD. All subjects were well, lifelong nonsmokers, not diabetic, and not hypertensive and took no medications. Using high-resolution external vascular ultrasound, we measured brachial artery diameter at rest and in response to reactive hyperemia (with increased flow causing an endothelium-dependent vasodilatation) and to sublingual glyceryltrinitrate (GTN, an endothelium-independent dilator). Vascular responses were compared with those of 50 healthy control subjects matched for age and sex. Flow-mediated dilatation (FMD) was impaired in the family history group (4.9+/-4.6% versus 8.3+/-3.5% in control subjects, P<.005). In contrast, GTN caused dilatation in all subjects (family history, 17.1+/-8.8%; control subjects, 19.0+/-6.3%; P=NS), suggesting that reduced FMD was due to endothelial dysfunction. When the family history subjects were subdivided, those found to have a serum cholesterol > 4.2 mmol/L (group A, n=10) had mildly impaired FMD compared with control subjects (5.5+/-5.1% versus 8.3+/-3.5%). In others whose affected relative had coronary risk factors (group B, n=24), FMD was also only slightly reduced (6.2+/-4.8% versus 8.3+/-3.5%). In contrast, subjects with no risk factors and whose affected relative had a normal cardiovascular risk factor profile (group C, n=16) had markedly impaired FMD (2.9+/-3.7% versus 8.3+/-3.5%). Although ANOVA of the three family history subgroups did not reach statistical significance (F=2.55, P=.09), pairwise analysis showed that FMD in group C was significantly impaired compared with group B (P=.026). CONCLUSIONS: Healthy young adults with a family history of premature coronary disease may have impaired endothelium-dependent dilatation, even in the absence of other cardiovascular risk factors. Those subjects, who were free of risk factors and whose affected first-degree relative was free of risk factors, had the most impaired endothelial function, suggesting a genetic influence on early arterial physiology that may be relevant to later clinical disease.