Ethnic differences in past hysterectomy for benign conditions.

BACKGROUND: Hysterectomy for a benign condition is common, particularly in the underserved. The objective was to determine if ethnic differences could be explained by known risk factors. METHODS: A phone survey was conducted at random on 15,160 women, ages 40-55, from seven US cities. Subjects were 49.9% Caucasian, 28.1% African American, 12.3% Hispanic, and 9.8% Asian American. RESULTS: Ethnicity was associated with past hysterectomy (odds ratio [OR]: Caucasian = 1.0, African American = 1.66; confidence interval [CI] = 1.46-1.88, Hispanic = 1.64, CI = 1.29-2.07; Asian American = 0.44, CI = 0.34-0.56), after adjustment for age, education, fibroids, body mass index, marital status, smoking, geographic site, and country of education. CONCLUSION: Because the highest rates occurred in the disadvantaged African American and Hispanic subgroups, and could not be explained by known risk factors, disparity in the form of overuse in these disadvantaged groups may exist.     

Suicidal and self-injurious behavior in personality disorder: Controversies and treatment directions

Contrary to common clinical perceptions, individuals with personality disorders attempt and commit suicide at nearly the same rate as individuals with major depression. In particular, those with borderline personality disorder are at high risk for suicidal behavior and nonsuicidal self-injury. Yet there is significant controversy surrounding the diagnosis of borderline personality disorder in terms of its existence, its definition and symptom structure, its Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) axis location, and its importance as a contributing factor to suicidality and nonsuicidal self-injury. Furthermore, both suicidal and nonsuicidal self-harm is prominent in borderline personality disorder. There is often confusion between suicidal and nonsuicidal self-injury with one sometimes mistaken for the other. Nonsuicidal self-injury is sometimes met with hospitalization, because it is viewed as life threatening. Alternately, the potential lethality of suicidal behavior is underestimated, because it occurs in the context of multiple low lethality self-harm behaviors. It is possible to view these behaviors as distinct yet on a spectrum in borderline personality-disordered patients. With respect to treatment of self-injury in personality disorders, some recent pharmacotherapy trials have been conducted, though efficacy is often unclear. Findings with respect to psychotherapy, particularly dialectical behavior therapy, a form of cognitive behavioral treatment, are promising.     

The relationship of circulating dehydroepiandrosterone,testosterone, and estradiol to stages of the menopausal transition and ethnicity

In this report, 3029 women between the ages of 42 and 54 yr from five ethnic groups were studied for 2 yr. Log circulating dehydroepiandrosterone sulfate (DHEAS) concentrations were highest among Chinese and Japanese and lowest among African Americans and Hispanics, and this pattern persisted after adjustment for age, smoking, and log body mass index (BMI). With the exception of Japanese women, log BMI was negatively related to log circulating DHEAS. The magnitude of this association varied by ethnic group, and the decline in log circulating DHEAS levels with higher log BMI was steepest for Chinese and least steep for Hispanics. The relationship between log DHEAS and log BMI was positive for Japanese. DHEAS levels did not decline at a steady rate during the menopausal transition and transiently increased in some women and increased, on average, during the transition to late perimenopause. These increases tended to be larger for Chinese, Hispanic, and Japanese than for African Americans and Caucasians, although the interactions were not statistically significant. Changes in circulating testosterone and, to a lesser extent, estradiol were correlated to changes in DHEAS. These data have importance in understanding the endocrinology of the menopausal transition, defining the relationship of adrenal steroid production during declining ovarian function and determining a rationale regarding DHEAS supplementation for older women.     

Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules

Temozolomide, an oral DNA methylator that inactivates the DNA repair enzyme O(6)-alkylguanine-DNA alkyltransferase (AGAT), has demonstrated anticancer activity on protracted schedules. Protracted schedules may lead to an 'autoenhancement' of temozolomide's inherent cytotoxic potential by cumulative reduction of the cell's capacity for AGAT-mediated DNA repair and resistance. This study was undertaken to characterise AGAT inactivation and regeneration in the peripheral blood mononuclear cells (PBMCs) of patients treated on two protracted temozolomide schedules. O(6)-alkyl guanine-DNA alkyltransferase activity was measured in the PBMCs of patients treated on two phase I protracted temozolomide studies. Patients were treated daily for either 7 days every 2 weeks (Schedule A) or 21 days every 4 weeks (Schedule B). The effects of various temozolomide doses (75-175 mg m(-2)), treatment duration (7-21 days), and temozolomide plasma levels on AGAT inactivation and regeneration, as well as the relation between AGAT inactivation and toxicity, were studied. O(6)-alkyl guanine-DNA alkyltransferase activity in PBMCs was measured serially in 52 patients. Marked inactivation of AGAT occurred following 7 days of temozolomide treatment, with mean AGAT activity decreasing by 72% (P<0.0001). Similarly, mean AGAT activity decreased by 63 and 73% after 14 and 21 days of treatment, respectively (P<0.001 for both comparisons). O(6)-alkyl guanine-DNA alkyltransferase inactivation was greater after 7 days of treatment with higher doses of temozolomide than lower doses and remained markedly reduced 7 days post-treatment. However, AGAT inactivation following temozolomide treatment for 14 and 21 days was similar at all doses. On the continuous 21-day schedule, AGAT inactivation was significantly greater in patients who experienced severe thrombocytopenia than those who did not (90.3+/-5.5 vs 72.5+/-16.1%, P<0.045). In conclusion, protracted administration of temozolomide, even at relatively low daily doses, leads to significant and prolonged depletion of AGAT activity, which may enhance the antitumour activity of the agent.     

Drug metabolites in safety testing

This report summarizes the deliberations of a multidisciplinary committee, sponsored by the Pharmaceutical Research and Manufacturers of America, on current "best practices" within the U.S. pharmaceutical industry in assessing the role of drug metabolites as potential mediators of the toxicity of new drug products. Input to the document was obtained from numerous sources, including members of the pharmaceutical industry, academic investigators, and representatives of regulatory agencies who attended a workshop on the subject in November 2000. The overall goal of the paper is to define practical and scientifically based approaches to the use of metabolite data that address contemporary issues in the safety evaluation of drug candidates. Although there remains a lack of consensus on how best to deal with several aspects of this complex subject, this paper raises a number of points to consider, which emphasize the need to treat drug metabolite issues on a case-by-case basis. It is hoped that the discussion will promote continued dialog among industrial scientists and regulators charged with ensuring the clinical safety of new therapeutic agents.     

SHORT COMMUNICATION: The relationship between megacolon and carcinoma of the colon: an experimental approach

‘Carcinoma of the colon does not occur in cases of megacolon’is an axiom held by Brazilian physicians working in endemicareas for Chagas' disease. The objective of the present studywas to test this axiom experimentally by submitting rats withexperimental megacolon to a carcinogen which causes carcinomaof the colon. Eighty young male Wistar rats received serosalapplication of either saline (0.9% NaCl) or 2 mM benzalkoniumchloride (BAC) to the distal colon. Ten months later randomlychosen saline and BAC rats were injected weekly with dimethylhydrazine(DMH) for 20 weeks. Non-DMH-treated rats from both originalgroups were maintained, for a total of four experimental groups.Three months after the injections all surviving rats were killed.At autopsy the presence or absence of carcinomas along the colonwas recorded. The induction of megacolon was evaluated by morphometryof the wall from the distal colon and myenteric denervationwas assessed by neuron counts. An increase of at least 2-foldin distal colon wall thickness confirmed the induction of megacolonin BAC-treated rats. Neuronal counts from BAC and control ratsnot treated with DMH showed an average denervation of 63%. Thenumber of distal colon carcinomas in BAC+ DMH-treated rats wassignificantly lower than that in DMH-treated rats. These findingsappear to contradict the traditional concept of carcinogenesisof the colon. The clinical axiom was reproduced experimentally.     

Asymptomatic congenital cytomegalovirus infection. Audiologic, neuroradiologic, and neurodevelopmental abnormalities during the first year

Twenty-eight infants with asymptomatic congenital cytomegalovirus infection and 13 control infants were followed up prospectively. Congenital sensorineural hearing loss was documented by auditory brain-stem responses in four infected infants (two had mild bilateral loss, one had mild unilateral loss, and one had extreme unilateral loss) but in no controls. Four infected infants had diffuse periventricular radiolucencies on computed tomographic scan; none had calcifications or ventriculomegaly. No differences between groups were noted on neurologic examination results or on the Bayley Mental Developmental Index; however, one infected infant had a severely delayed Bayley Psychomotor Developmental Index score. In addition, the mean Mental Developmental Index score of the four infected infants with diffuse periventricular radiolucencies was significantly below that of the remaining infected infants (93 +/- 8 vs 109 +/- 13). These data suggest that asymptomatic congenital cytomegalovirus infection may be associated with a broad range of audiologic, subtle neuroradiologic, and neurodevelopmental differences in early infancy.     

Pap test in a high-risk population comparison of conventional and liquid-base cytology

Liquid‐based cytology (LBC) is believed to have better sensitivity than conventional smears (CSs) and offers the possibility to perform molecular assay. The goal of this work was to study the performance of CS and LBC in a high‐risk population and to compare the results with the hybrid capture (HC) II for high‐risk human papillomavirus (HPV). Samples were collected from selected women with clinical suspicions of low genital tract lesion at Pérola Biygnton Hospital (São Paulo, Brazil). After CS preparation, the brush was introduced in the endocervix and a new sample was collected and rinsed in the preservative medium of the system. The residual material was used to HC2. From 925 cases, LBC was unsatisfactory in 4 (1.51%) cases and CS was unsatisfactory in 100 cases (10.81%); among theses cases HC2⁺ reactions was observed in 54 (54%) CSs and 3 (21.4%) LBCs. Considering cases with atypia of undetermined significance (squamous and glandular), 85 (77.27%) cases from LBC and 44 (86.4%) from CS were positive for HC2 assay for high‐risk DNA‐HPV. The difference among the methods was not significant (P < 0.38). The diagnosis improvement of LBC in comparison with CS was 86% in satisfactory samples, 92.76% in undetermined atypical lesions (including glandular), 83% in positive low‐grade squamous intraepithelial lesions (LSIL⁺), and 86.84% in high‐grade SIL⁺ (HSIL⁺). HC2⁺ reactions were observed in 144 CS cases and 266 LBC cases with abnormalities. Our results have showed that LBC was superior to CS in a high‐risk population to detect lesions with high concordance with HC2⁺ reactions; CSs also exhibit a high concordance with HC2 assay but with inferior performance to detect lesions. Diagn. Cytopathol. 2004;31:169–172. © 2004 Wiley‐Liss, Inc.     

Recreational injuries among older Americans, 2001

OBJECTIVE: To describe the epidemiology of non-fatal recreational injuries among older adults treated in United States emergency departments including national estimates of the number of injuries, types of recreational activities, and diagnoses. METHODS: Injury data were provided by the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP), a nationally representative subsample of 66 out of 100 NEISS hospitals. Potential cases were identified using the NEISS-AIP definition of a sport and recreation injury. The authors then reviewed the two line narrative to identify injuries related to participation in a sport or recreational activity among men and women more than 64 years old. RESULTS: In 2001, an estimated 62 164 (95% confidence interval 35 570 to 88 758) persons >/=65 years old were treated in emergency departments for injuries sustained while participating in sport or recreational activities. The overall injury rate was 177.3/100 000 population with higher rates for men (242.5/100 000) than for women (151.3/100 000). Exercising caused 30% of injuries among women and bicycling caused 17% of injuries among men. Twenty seven percent of all treated injuries were fractures and women (34%) were more likely than men (21%) to suffer fractures. CONCLUSIONS: Recreational activities were a frequent cause of injuries among older adults. Fractures were common. Many of these injuries are potentially preventable. As more persons engage in recreational activities, applying known injury prevention strategies will help to reduce the incidence of these injuries.     

Characterization of MLH1 and MSH2 DNA mismatch repair proteins in cell lines of the NCI anticancer drug screen

Purpose and methods: The lack of a functional DNA mismatch repair (MMR) pathway has been recognized as a common characteristic of several different types of human cancers due to mutation affecting one of the MMR genes or due to promoter methylation gene silencing. These MMR-deficient cancers are frequently resistant to alkylating agent chemotherapy such as DNA-methylating or platinum-containing compounds. To correlate drug resistance with MMR status in a large panel of human tumor cell lines, we evaluated by Western blot the cellular levels of the two MMR proteins most commonly mutated in human cancers, MLH1 and MSH2, in the NCI human tumor cell line panel. This panel consists of 60 cell lines distributed among nine different neoplastic diseases. Results: We found that in most of these cell lines both MLH1 and MSH2 were expressed, although at variable levels. Five cell lines (leukemia CCRF-CEM, colon HCT 116 and KM12 and ovarian cancers SK-OV-3 and IGROV-1) showed complete deficiency in MLH1 protein. MSH2 protein was detected in all 57 cell lines studied. Absence of MLH1 protein was always linked to resistance to the methylating chemotherapeutic agent temozolomide. This resistance was independent of cellular levels of O⁶-alkylguanine DNA alkyltransferase. Based on data available for review in the NCI COMPARE database, cellular levels of MLH1 and MSH2 did not correlate significantly with sensitivity to any standard anticancer drug or with any characterized molecular target already tested against the same panel of cell lines. Conclusion: Based on evaluation of 60 tumor cell lines in the NCI anticancer drug screen, MLH1 deficiency was more common than MSH2 deficiency and was always associated with a high degree of temozolomide resistance. These data will enable correlations with other drug sensitivities and molecular targets in the COMPARE database to evaluate linked processes in tumor drug resistance. Received: 13 December 1999 / Accepted: 27 July 2000