Relationship between overnight rostral fluid shift and obstructive sleep apnea in drug-resistant hypertension.

Obstructive sleep apnea occurs frequently in patients with drug-resistant hypertension. The factors accounting for this observation, however, are unclear. Both conditions demonstrate clinical features suggestive of extracellular fluid volume overload. The aims of this study were to examine whether the spontaneous overnight fluid shift from the legs to the upper body is associated with obstructive sleep apnea in hypertensive subjects and whether its magnitude is greater in drug-resistant hypertension. Leg fluid volume and the circumference of the calf and neck were measured before and after sleep in drug-resistant hypertensive (n = 25) and controlled hypertensive (n=15) subjects undergoing overnight polysomnography. The severity of obstructive sleep apnea was greater in the drug-resistant hypertensive group than in the controlled hypertensive group (apnea-hypopnea index: 43.0 ± 5.4 versus 18.1 ± 4.2 events per hour of sleep; P = 0.02, case-mix adjusted). In both groups, the apnea-hypopnea index strongly related to the amount of leg fluid volume displaced (R² = 0.56; P < 0.0001), although the magnitude of change was greater in the drug-resistant hypertensive group (346.7 ± 24.1 versus 175.8 ± 31.3 mL; P = 0.01, propensity-score adjusted). The overnight reduction in calf circumference and increase in neck circumference were also greater in drug-resistant hypertension (both P ≤ 0.02). In hypertensive subjects, rostral fluid displacement strongly relates to the severity of obstructive sleep apnea with its magnitude being greater in drug-resistant hypertension. Our findings support the concept that fluid redistribution centrally during sleep accounts for the high prevalence of obstructive sleep apnea in drug-resistant hypertension.

Characterization of the 12q15 MDM2 and 12q13-14 CDK4 amplicons and clinical correlations in osteosarcoma.

The chromosomal region 12q13-15 is recurrently amplified in osteosarcoma (OS), but its importance in bone tumor development remains unknown. Although there are two major candidate genes (MDM2, a TP53 downregulator, and CDK4, involved in cell cycle progression) considered to be the driving genes in this region, the size of the amplicon and number of genes involved have not been determined. In this study, we used 130 classical OS and 15 parosteal OS to determine MDM2 and CDK4 amplification frequency in OS. Tumors in which these genes were amplified were used to map the 12q13-15 amplified region and to determine its correlation with clinical prognosis. The 12q13-15 amplification was more prevalent in parosteal OS (67% of cases) than in high-grade classical OS (12%). Quantitative real-time PCR of MDM2, CDK4, and 25 other genes showed that this region contains two different amplicons: one at 12q15 centered on MDM2 and one at 12q13-14 centered on CDK4. Both regions were frequently co-amplified in both types of OS, and MDM2 and CDK4 amplification was correlated with higher expression levels for both genes. Univariate and multivariate analyses of clinical data indicated that classical OS patients whose tumors exhibited MDM2 amplification were more likely to be older at diagnosis (median age 32.6 vs. 17.8 years) and female (66.7 vs. 33.3%) than those without gene amplification. There was no association with other clinical parameters. In conclusion, co-amplification of MDM2 and CDK4 in two separate amplicons occurs frequently in parosteal OS and less so in classical high-grade OS.

Dose requirement of intrathecal bupivacaine for cesarean delivery is similar in obese and normal weight women.

BACKGROUND AND OBJECTIVES: The effect of BMI on the spread of intrathecal bupivacaine is controversial. This study assessed the ED95 of intrathecal bupivacaine for elective cesarean delivery in obese and normal weight women. METHODS: We studied normal weight (BMI < 25 kg x m(-2)) and obese (BMI > 30 kg x m(-2)) women with singleton term pregnancies undergoing elective cesarean delivery. The study was conducted as a single blinded, up-down sequential allocation study (modified by the Narayana rule). All patients received a combined spinal-epidural anesthesia with a variable intrathecal dose of hyperbaric 0.75% bupivacaine, plus fentanyl 10 microg and morphine 100 microg. The first patient received 9 mg of bupivacaine. Supplemental anesthesia was provided through the epidural catheter if required. The primary outcome was successful analgesia, defined as a sensory block to at least T6, and no request for supplemental anesthesia. The ED95 for the satisfactory outcome was determined by a logistic model with non-log-transformed doses. RESULTS: Twenty-four normal weight and sixteen obese patients were enrolled. The estimated ED95 for all forty patients was 12.92 mg (95% CI: 11.49 to 34.77). The estimated ED95 for the normal weight and the obese subgroups were similar at 12.78 mg (95% CI: 10.75 to + infinity) and 11.86 mg (95%CI: 11.31 to 15.61), respectively. CONCLUSIONS: If single shot spinal anesthesia is used for cesarean delivery, obese and normal weight patients should receive similar doses of hyperbaric bupivacaine. Although in our study the effective dose 95% could not be precisely determined, it is possible to state that it is at least 11.49 mg.

Dose de bupivacaína subaracnóidea necessária para cesariana é semelhante em mulheres obesas e com peso normal / Las dosis de bupivacaína intratecal necesarias para cesáreas en mujeres obesas son similares a las usadas en mujeres con peso normal / Dose requirement of intrathecal bupivacaine for cesarean delivery is similar in obese and normal weight women

Justificativa e objetivos: Os efeitos do IMC na dispersão subaracnóidea de bupivacaína são controversos. O presente estudo avaliou a ED95 de bupivacaína subaracnóidea em cesarianas eletivas em mulheres obesas...

Background and objectives: The effect of BMI on the spread of intrathecal bupivacaine is controversial. This study assessed the ED95 of intrathecal bupivacaine for elective cesarean delivery in obese...

Justificativa y objetivos: Los efectos del IMC en la dispersión intratecal de bupivacaína son controvertidos. El presente estudio evaluó la ED95 de bupivacaína intratecal en cesáreas de elección en mujeres obesas...

Recurrence of Crohn's disease after ileocolic resection is not affected by anastomotic type: results of a multicenter, randomized, controlled trial.

PURPOSE: This study attempts to determine whether stapled side-to-side anastomosis, compared with handsewn end-to-end anastomosis, results in decreased recurrence of Crohn's disease following ileocolic resection. METHODS: Patients with Crohn's disease who underwent an ileocolic resection were randomized to side-to-side anastomosis or end-to-end anastomosis. Colonoscopy was performed at 12 months. The primary outcome was endoscopic recurrence, while the secondary outcome was symptomatic recurrence (defined as symptoms attributable to Crohn's disease and severe enough to warrant treatment, plus endoscopic disease recurrence). RESULTS: One hundred and thirty-nine subjects were included in the efficacy analysis. After a mean follow-up of 11.9 months, the endoscopic recurrence rate was 42.5 percent in the end-to-end anastomosis group, compared with 37.9 percent in the side-to-side anastomosis group (-4.6 percent difference; 95 percent confidence interval -21.0 to 11.9 percent; P = 0.55). The symptomatic recurrence rate was 21.9 percent in the end-to-end anastomosis group, compared with 22.7 percent in the side-to-side anastomosis group (+0.8 percent difference; 95 percent confidence interval -13.2 to 15.3 percent; P = 0.92). In multivariate logistic regression analysis, previous resections were predictive of a higher risk of both endoscopic (odds ratio 1.78; 95 percent confidence interval 1.06 to 2.90; P = 0.028) and symptomatic (odds ratio 2.0; 95 percent confidence interval 1.14 to 3.60; P = 0.0016) recurrence. Compliance with postoperative maintenance therapy was predictive of a lower risk of symptomatic recurrence (odds ratio 0.13, 95 percent confidence interval 0.01 to 0.78; P = 0.021). CONCLUSION: Recurrence rates are similar whether end-to-end anastomosis or side-to-side anastomosis is performed.

Oxytocin pretreatment decreases oxytocin-induced myometrial contractions in pregnant rats in a concentration-dependent but not time-dependent manner.

Recent biomolecular studies have shown that continuous exposure of human myometrial cells to oxytocin results in a significant loss of responsiveness to subsequent oxytocin stimulation, perhaps because of desensitization of the oxytocin receptors. However, it is unclear whether this phenomenon results in a reduction of the contractile activity of the uterine muscle in humans or animals. The objective of our study was to investigate the in vitro response of the uterine muscle of pregnant rats to oxytocin, following preexposure to varying concentrations of oxytocin, for varying durations. Longitudinal myometrial strips were isolated from 16 pregnant Wistar rats at 19 to 21 days of gestation and preexposed to oxytocin 10(-10) or 10(-8) mol/L (experimental groups) or physiological salt solution (control groups) for 1- or 4-hour period. All muscle strips were then subjected to a dose-response study with oxytocin 10(-10) to 10(-5) mol/L. The area under the curve, frequency, and amplitude of contractions were recorded and compared between the groups. The area under the curve, frequency, and amplitude of the oxytocin-induced contractions were all significantly suppressed in the groups preexposed to oxytocin 10(-8) mol/L compared to either the control groups (P < .0001) or the groups preexposed to oxytocin 10(-10) mol/L (P < .0001). There was no difference in the oxytocin-induced myometrial contractions between the groups preexposed to oxytocin for either the 1- or 4-hour periods. The inhibition of the oxytocin-induced contractile response of pregnant rat myometrium is observed as early as 1 hour of preexposure to oxytocin and is dependent on the preexposed oxytocin concentration and not on the duration of its exposure.

Incidence and risk factors for cardiovascular events and death in pediatric renal transplant patients: a single center long-term outcome study.

There are considerable mortality data associated with renal transplantation in children; however, morbidity data, especially related to CV disease, are scarce. The objectives of this study were to determine incidence of non-fatal and fatal CV events and all-cause mortality in PRTx and evaluate risk factors for these conditions. Using a population-based retrospective cohort design, 274 PRTx with or without a functioning graft was followed until death or date of last contact (median follow-up 11.9 yr). Primary outcomes (time to first fatal or non-fatal CV event and all-cause mortality after first transplant) were ascertained from chart review and linkage with administrative databases of a universal health care system. During 3073 patient-years, there were 46 deaths; 13 were because of CV disease. Twenty patients had CV events that did not result in death. Post-transplant diabetes mellitus (10.5%) was associated with increased risk of death (HR: 2.79, 95% CI: 1.04-7.44) and CV events (HR: 3.90, 95% CI: 1.31-11.59). Low estimated glomerular filtration rate at one yr post-transplant was also associated with increased risk of death. The rates of developing CV disease and dying prematurely are extraordinarily high in PRTx, underscoring the need for early and aggressive intervention to reduce the burden of suffering in this patient population.

COPS3 amplification and clinical outcome in osteosarcoma.

BACKGROUND: Amplification of several genes that map to a region of chromosome 17p11.2, including COPS3, was observed in high-grade osteosarcoma. These genes were also shown to be overexpressed and may be involved in osteosarcoma tumorigenesis. COPS3 encodes a subunit of the COP9 signalosome implicated in the ubiquitination and ultimately degradation of the P53 tumor suppressor. To determine the relation between COPS3 amplification, P53 mutation, and patient outcome in osteosarcoma, tumors from a large cohort of patients with high-grade osteosarcoma and long-term clinical follow-up were examined. METHODS: Quantitative real-time polymerase chain reaction (PCR) was performed to detect copy number changes for COPS3, as well as additional genes (NCOR1, TOM1L2, and PMP22) from the 17p11.2 amplicon, in 155 osteosarcomas from a prospective collection of tumors with corresponding clinical data. Univariate and multivariate analyses were performed to assess differences in survival between groups. RESULTS: Amplification of COPS3, detected in 31% of the osteosarcomas, was strongly associated with large tumor size (P=.0009), but was not associated with age at diagnosis, site, sex, and tumor necrosis. COPS3 amplification was significantly correlated with a shorter time to metastasis with an estimated hazard ratio (HR) of 1.61 (95% confidence interval [CI], 1.02-2.55) in univariate analysis (log-rank test, P=.042). However, in an a priori multivariate Cox model including the other clinical parameters, the HR for COPS3 amplification decreased to 1.32 (95% CI, 0.82-2.13, P=.25), mainly due to the strong correlation with tumor size. COPS3 amplification and P53 mutation frequently occurred in the same tumors, suggesting that these are not mutually exclusive events in osteosarcoma. Although not statistically significant, patients whose tumors exhibited both molecular alterations tended to be more likely to develop metastasis compared with patients with either COPS3 amplification or P53 mutation alone. CONCLUSIONS: COPS3 is the likely target of the 17p11.2 amplicon. COPS3 may function as an oncogene in osteosarcoma, and an increased copy number may lead to an unfavorable prognosis.

High prevalence of masked hypertension in treated hypertensive patients with type 2 diabetes mellitus.

This study was undertaken to determine whether self-measured home blood pressure (BP) readings were comparable to clinic visit BP readings in hypertensive type II diabetic patients. We measured the BP of 27 hypertensive patients at home and during the clinic visits over a three week period. The BP readings were analyzed using a mixed linear model with mean daytime ambulatory measure as a covariate. We found that, although there was no significant difference in the mean systolic BP between home and clinic readings (0.6 mm Hg), the mean home BP readings were significantly higher (difference = 6.8 mm p < 0.0006). The proportion of masked hypertension, defined as elevated home systolic or diastolic BP (or both) values despite normal clinic visit BP values, was 40.7%. Three diastolic and one systolic BP measurement at home achieved a reliability coefficient of 0.8. Self-measurement of BP gave highly reliable readings when they were compared with blind readings taken by a trained professional using a mercury sphygmomanometer. We conclude that self-measured BP at home identifies a high prevalence of masked hypertension in treated hypertensive type 2 diabetic patients and that it represents a valuable management adjunct to ensure maximum benefit from antihypertensive drug therapy.

TP53 mutations and outcome in osteosarcoma: a prospective, multicenter study.

PURPOSE: Mutations of the TP53 gene have been associated with resistance to chemotherapy as well as poor prognosis in many different malignancies. This is the first prospective study of the prognostic value of somatic TP53 mutations in patients with newly diagnosed extremity osteosarcoma. PATIENTS AND METHODS: One hundred ninety-six patients with high-grade, nonmetastatic osteosarcoma of the extremities were enrolled from seven tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 44 months). All patients received neoadjuvant or adjuvant chemotherapy and surgery. Tumors were analyzed for the presence of TP53 mutations by polymerase chain reaction single-strand conformation polymorphism analysis and direct DNA sequencing. The association of the status of the TP53 gene with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Patient age was the only factor that varied with TP53 gene status (P = .05). No relationship was identified between TP53 status and systemic relapse (relative risk, 1.24; P = .41). Analyses based on missense or nonsense mutations gave similar results (P > .10). In multivariate analysis, large (> 9 cm) tumor size (relative risk, 1.9; P = .006) and poor histologic response (< or = 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. CONCLUSION: We found no evidence that TP53 mutations predict for development of metastases in patients with high-grade osteosarcoma. Identification of other genes that influence chemotherapy response and clinical outcome in osteosarcoma is needed to facilitate further improvements in patient outcomes.

Invasive lobular carcinoma: to grade or not to grade.

Grading of invasive ductal carcinoma of no special type using the Nottingham combined histologic grading system provides independent prognostic information. The prognostic utility of grading invasive lobular carcinomas, however, has not been fully elucidated. In addition, the relationship between grade in invasive lobular carcinomas and expression of predictive biomarkers is less certain. The purpose of this study was to correlate histologic grade in invasive lobular carcinoma with known prognostic and predictive markers. All primary resections for invasive mammary carcinomas diagnosed in Mount Sinai Hospital, Toronto, between the years 1996 and 2002 were reviewed (n=1053). Of these cases, 50 were pure invasive lobular carcinoma (incidence 4.7%). The median age at diagnosis was 64 years. These tumors were graded using the Nottingham combined histologic grading system and analyzed for estrogen receptor, progesterone receptor, HER2/neu and E-cadherin expression. Tumor grade was correlated with tumor size (P=0.03), and the American Joint Committee on Cancer nodal status (P=0.05). Assessment of the individual components of grade showed that the mitotic score was highly correlated with tumor size (P=0.02), lymph node positivity (P=0.02) and overall American Joint Committee on Cancer stage (P=0.01). Estrogen receptor and progesterone receptor were highly expressed irrespective of the grade of tumor. HER2/neu protein overexpression and E-cadherin protein expression was absent in all invasive lobular carcinomas studied. We conclude that pure invasive lobular carcinoma is uncommon and occurs predominantly in postmenopausal women. Increasing tumor grade is correlated with median tumor size and the American Joint Committee on Cancer nodal stage, but not correlated with the expression of estrogen receptor, progesterone receptor, E-cadherin or HER2/neu protein overexpression.

A clinicobiological model predicting survival in medulloblastoma.

PURPOSE: The purpose of this study was to determine the relative contributions of biological and clinical predictors of survival in patients with medulloblastoma (MB). EXPERIMENTAL DESIGN: Clinical presentation and survival information were obtained for 119 patients who had undergone surgery for MB at the Hospital for Sick Children (Toronto, Ontario, Canada) between 1985 and 2001. A tissue microarray was constructed from the tumor samples. The arrays were assayed for immunohistochemical expression of MYC, p53, platelet-derived growth factor receptor-alpha, ErbB2, MIB-1, and TrkC and for apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling). Both univariable and multivariable analyses were conducted to characterize the association between survival and both clinical and biological markers. For the strongest predictors of survival, a weighted predictive score was calculated based on their hazard ratios (HRs). The sum of these scores was then used to give an overall prediction of survival using a nomogram. RESULTS: The four strongest predictors of survival in the final multivariable model were the presence of metastatic disease at presentation (HR, 2.02; P=0.01) and p53 (HR, 2.29; P=0.02), TrkC (HR, 0.65; P=0.14), and ErbB2 (HR, 1.51; P=0.21) immunopositivity. A linear prognostic index was derived, with coefficients equal to the logarithm of these HRs. The 5-year survival rate for patients at the 10th, 50th, and 90th percentiles of the score distribution was 80.0%, 71.0%, and 35.7%, respectively, with radiation therapy and 70.5%, 58.5%, and 20.0%, respectively, without radiation therapy. CONCLUSIONS: In this study, we demonstrate an approach to combining both clinical and biological markers to quantify risk in MB patients. This provides further prognostic information than can be obtained when either clinical factors or biological markers are studied separately and establishes a framework for comparing prognostic markers in future clinical studies.

Amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples.

Recent clinical trials have suggested that patients whose breast tumors overexpress HER2 may derive particular benefit from anthracycline-containing chemotherapy compared to that without anthracycline. It has been proposed that the HER2 gene amplification reported in these tumors might mask an underlying TOP2A gene amplification that occurs frequently and concurrently with HER2 amplification. Topoisomerase II alpha, encoded by TOP2A, is a direct molecular target of anthracycline drug action and is potentially useful as a predictive marker of response to anthracycline therapy for breast cancer. In this study, we examined whether TOP2A gene amplification is an appropriate marker for identifying breast tumors expressing high levels of topoisomerase II alpha. We determined topoisomerase II alpha protein expression by immunohistochemistry in 81 human breast tumors in relation to HER2 and TOP2A gene copy numbers analyzed by fluorescence in situ hybridization, histologic grade, cell proliferation fraction measured by MIB-1 expression, and HER2 protein expression determined by immunohistochemistry. The results showed no correlation between TOP2A gene copy number and topoisomerase II alpha protein expression levels in breast tumors, in contrast to the analogous situation for HER2 gene amplification and HER2 immunohistochemistry. Our results suggest that TOP2A gene amplification in breast tumors does not predict high expression of topoisomerase II alpha protein.

Developmental changes in left and right ventricular diastolic filling patterns in mice.

Developmental changes in left and right ventricular diastolic filling patterns were determined noninvasively in isoflurane-anesthetized outbred ICR mice. Blood velocities in the mitral and tricuspid orifices were recorded in 16 embryos at days 14.5 (E14.5) and 17.5 of gestation (E17.5) using an ultrasound biomicroscope and also serially in three groups of postnatal mice aged 1-7 days (n = 23), 1-4 wk (n = 18), and 4-12 wk (n = 27) using 20-MHz pulsed Doppler. Postnatal body weight increased rapidly to 8 wk. Heart rate increased rapidly from approximately 180 beats/min at E14.5 to approximately 380 beats/min at 1 wk after birth and then more gradually to plateau at approximately 450 beats/min after 4 wk. Ventricular filling was quantified using the ratio of peak velocity of early ventricular filling due to active relaxation (E wave) to that of the late ventricular filling caused by atrial contraction (A wave) (peak E/A ratio) and the ratio of the peak E velocity to total time-velocity integral of E and A waves (peak E/total TVI ratio). Both ventricles had similar diastolic filling patterns in embryos (peak E/A ratio of 0.28 +/- 0.02 for mitral flow and 0.27 +/- 0.02 for tricuspid flow at E14.5). After birth, mitral peak E/A increased to >1 between the third and fifth day, continued to increase to 2.25 +/- 0.25 at approximately 3 wk, and then remained stable. The tricuspid peak E/A ratio increased much less but stabilized at the same age (increased to 0.79 +/- 0.03 at 3 wk). The peak E/total TVI ratio showed similar left-right differences and changes with development. Age-related changes were largely due to increases in peak E velocity. The results suggest that diastolic function matures approximately 3 wk postnatally, presumably in association with maturation of ventricular recoil and relaxation mechanisms.

Balloon angioplasty or medical therapy for hypertensive patients with atherosclerotic renal artery stenosis? A meta-analysis of randomized controlled trials.

PURPOSE: The optimal treatment for hypertensive patients with atherosclerotic renal artery stenosis is controversial. We performed a meta-analysis comparing the effects of balloon angioplasty and medical therapy in these patients. METHODS: We searched MEDLINE, EMBASE, the Science Citation Index, the Cochrane Controlled Trials Registry, and reference lists. Authors of published trials were contacted. RESULTS: We identified three trials involving a total of 210 patients with moderate-to-severe (> or = 50%) unilateral or bilateral atherosclerotic renal artery stenosis and poorly controlled hypertension who were followed for at least 3 months after intervention. Balloon angioplasty was significantly more effective in reducing blood pressure than was medical therapy; the weighted mean difference between the two treatments was -7 mm Hg (95% confidence interval [CI]: -12 to -1 mm Hg) for systolic blood pressure and -3 mm Hg (95% CI: -6 to -1 mm Hg) for diastolic blood pressure. There was no consistent difference in changes in renal function. Patients treated with balloon angioplasty were more likely to have patent renal arteries after 12 months (52% vs. 19%; odds ratio [OR] = 4.2; 95% CI: 1.8 to 9.8), used fewer antihypertensive medications, and appeared to have fewer major cardiovascular and renovascular complications (OR = 0.27; 95% CI: 0.06 to 1.23; P = 0.09). CONCLUSION: Balloon angioplasty has a modest but significant effect on blood pressure and should be considered for patients with atherosclerotic renal artery stenosis and poorly controlled hypertension. There is no evidence supporting its use in improving or preserving renal function, although none of the trials were designed to address this issue.

Angiotensinogen M235T genotype predicts progression in chronic renal allograft dysfunction.

BACKGROUND: Genotypes of the renin-angiotensin system have been implicated in essential hypertension and in progression of native kidney diseases, but gene effects on progression in chronic renal allograft dysfunction are unclear. METHODS: To examine gene effects on long-term renal allograft function, we conducted a prospective cohort study of 210 nondiabetic renal allograft recipients younger than 36 years of age who underwent transplantation between 1980 and 1993 and were followed up through 1999. All grafts survived more than 1 year and all subjects received cyclosporine-based immunosuppression. DNA was analyzed by polymerase chain reaction for the angiotensin-converting enzyme insertion/deletion and angiotensinogen (AGT) M235T polymorphisms. Linear regression multivariate modeling of the slope of the inverse creatinine-versus-time, survival analyses for time-to-sustained doubling of baseline serum creatinine, time-to-graft loss, and a composite endpoint including patient death were performed. RESULTS: Mean follow-up time was 8.4+/-3 years. Genotype frequencies for each marker system did not deviate significantly from the Hardy-Weinberg equilibrium. The slope of the inverse creatinine-versus-time for AGT 235T/T and M/T was significantly increased compared with M/M ( <0.0001). The AGT 235T/T genotype was also associated with a shorter time-to-sustained doubling of serum creatinine ( =0.001). When subjects were divided into quartiles based on slope magnitude, the frequency of the AGT 235T/T genotype was overrepresented in the fastest progressing group compared with the slowest ( =0.001). The AGT 235T/T genotype was also associated with shorter time-to-graft loss ( =0.007) and the composite endpoint ( =0.001). CONCLUSION: The AGT 235 T allele independently influences long-term decline in renal allograft function.

HER-2/neu status and tumor morphology of invasive breast carcinomas in Ashkenazi women with known BRCA1 mutation status in the Ontario Familial Breast Cancer Registry.

BACKGROUND: The prevalence of BRCA1 germline mutations is greater in the Ashkenazi Jewish population than in the general North American population. The Ontario Familial Breast Cancer Registry collects clinical and family history data in familial breast carcinoma cases, and unselected Ashkenazi breast carcinomas, and acts as a tumor tissue repository. METHODS: Using this resource, we examined the tumor morphology, hormone receptor status, and HER-2/neu protein overexpression in Canadian Ashkenazi breast carcinoma patients whose germline BRCA1 mutation status is known. RESULTS: Thirty-eight tumors from 32 BRCA1 carriers and 354 tumors from 334 noncarriers were analyzed. The tumors in BRCA1 mutation carriers were more likely to be high grade (P < 0.0001) and estrogen receptor negative (P < 0.004). There was an increased frequency of typical medullary carcinomas in mutation carriers when all tumors were analyzed. However, this difference did not remain statistically significant when only the first tumor diagnosed in each patient was included in the analysis. There was no difference in HER-2/neu protein overexpression between the two groups overall (P = 0.07). However, when the analysis was restricted to Grade III tumors, there were significantly fewer HER-2/neu-positive tumors in the mutation carriers versus noncarriers (3.1% vs. 21.5%, P = 0.012). No significant differences were found in the incidence of lymph node status, progesterone receptor status, lymphatic vessel invasion, degree of lymphocytic infiltration, or in the presence of ductal carcinoma in situ associated with the invasive tumors. CONCLUSIONS: Increasing awareness of the morphologic and immunophenotypic features more commonly found in BRCA1-associated breast carcinomas may lead to a wider use of these characteristics in genetic screening programs and provide further clues to their pathogenesis.

Reconstructive surgery for failed ileal pouch-anal anastomosis: a viable surgical option with acceptable results.

PURPOSE: Salvage procedures for failed ileal pouch-anal anastomoses frequently require total reconstruction with a combined abdominal and perineal approach. The aim of this study was to determine the indications for surgery and the outcomes in this group of patients. METHODS: All patients who underwent combined abdominal and perineal ileal pouch-anal anastomosis reconstruction at the Mount Sinai Hospital between 1982 and 2000 were reviewed. Data were collected prospectively in the inflammatory bowel disease database. RESULTS: Sixty-three reconstructive procedures were performed in 57 patients, with a mean age of 33.9 (+/-10.4) years at the time of reconstruction. There were 14 males. The mean follow-up was 69.1 months. The initial indication for ileal pouch-anal anastomosis was ulcerative colitis in 98 percent. The primary indication for reconstruction was pouch-vaginal fistula in 21 patients, long outlet in 14, pelvic sepsis in 14, ileoanal anastomotic stricture in 5, pouch-perineal fistula in 2, and chronic pouchitis in 1. The mean operative time was four hours (+/-1.1), the average blood loss was 500 mL (+/-400), and the average length of stay was 10.3 days (+/-4.6). All patients had a diverting ileostomy. Forty-two (73.6 percent) of the patients have a functioning pouch. Seven (12.3 percent) patients have had their pouch excised. The ileostomy has not yet been closed in 8 (14 percent) patients; 3 of these patients are awaiting closure, whereas the remaining 5 have a permanently defunctioning ileostomy. Eighty-nine percent have ten or fewer bowel movements per day. No patients are incontinent of stool during the day, whereas two patients are incontinent at night. Seventeen percent complain of frequent urgency. Despite this, more than 80 percent rate their physical and psychological health as good to excellent. CONCLUSION: Reconstructive pouch surgery has a high success rate in experienced hands. The functional results in those whose pouch is in use are good.

Risk factors for low bone density in Crohn's disease.

Osteopenia and osteoporosis are prevalent in patients with Crohn's disease (CD). We conducted a cross-sectional study on consecutive patients with CD to assess the prevalence and factors associated with low bone mass density (BMD). One hundred sixty-eight patients with CD were evaluated. Baseline demographics, medical and surgical history, calcium intake, physical activity, steroid use, Harvey Bradshaw Index, blood and urine tests, and dual-energy X-ray absorptiometry were obtained. Sixty-seven (40%) and seventy-five (45%) patients had osteopenia of the femur and spine, respectively. Ten to 11% of patients had osteoporosis. Of the 40 patients who never used steroids, 19 (48%) had osteopenia of the femur and 12 (30%) of the spine. Significant associations were found between BMD and age, body mass index, and serum magnesium. Lifetime steroid use was a weaker predictor of bone loss. Duration of disease did not correlate with BMD when adjusted for age. At follow-up at a mean of 2 years, BMD declined in the femur but not the spine. However, those with ongoing steroid use had lower spine BMD. A significant number of patients with CD have osteopenia. Age was the most important predictor of bone loss. Significant proportion of steroid naive patients had osteopenia, which implies that mechanisms other than steroid use are also involved in bone loss in CD. Disease activity, systemic inflammation, and hormonal and genetic factors may all be important determinants of bone loss in CD.