Biomedical subjects

Timothy G Lesnick

Publications and source records attributed to Timothy G Lesnick.

33 records · Page 2Linked to original sources

PubMed2004

Insulin and messenger ribonucleic acid expression of insulin receptor isoforms in ovarian follicles from nonhirsute ovulatory women and polycystic ovary syndrome patients.

Insulin action is mediated by two insulin receptor (IR) isoforms, differing in mitogenic and metabolic function. IR isoform expression might occur in human granulosa cells and could be altered in polycystic ovary syndrome (PCOS) from hyperinsulinemia. To determine the relationship between granulosa cell IR isoform expression and follicular fluid insulin concentration in individual follicles, 18 normal women and seven PCOS patients receiving gonadotropins for in vitro fertilization were studied. Glucose tolerance testing was performed before pituitary desensitization, and fasting serum insulin was measured at oocyte retrieval. Granulosa cells and fluid aspirated from the first follicle were used to determine IR isoform mRNA expression and insulin concentration, respectively. IR isoform A mRNA expression was greater than that of IR isoform B expression in normal mural granulosa and cumulus cells, without a cell type effect. Intrafollicular insulin levels increased with adiposity and serum insulin levels at oocyte-retrieval but did not predict IR mRNA expression. Total IR mRNA expression, but not intrafollicular insulin levels, was elevated in PCOS patients, whereas intrafollicular insulin levels were increased in women with impaired glucose tolerance. Granulosa cell IR heterogeneity, together with adiposity-dependent intrafollicular insulin availability, introduces a novel mechanism by which insulin may affect granulosa cell function within the follicle.

Adult↗

PubMed2004

Factors underlying scalp-EEG interictal epileptiform discharges in intractable frontal lobe epilepsy.

AIMS: Scalp-EEG interictal epileptiform discharges (IEDs) may be less predictive of the outcome of frontal lobe epilepsy surgery than of temporal lobe epilepsy surgery. We identified factors associated with the location of scalp-EEG IEDs in intractable frontal lobe epilepsy. METHODS: Ten factors were assessed in a retrospective review of 53 patients with either concordant (frontal lobe seizure focus) or discordant (generalized or outside frontal seizure focus) IED or both, who had excellent surgical outcomes. The Fisher exact test and the Wilcoxon rank sum test determined statistically significant associations. RESULTS: Thirty-six patients (68%) had concordant IED, 24 (45%) discordant IED, and 17 (32%) both. Younger age at onset was significantly associated with discordant IED (mean, 7.5 years versus 17 years for patients without discordant IED; P < 0.01), whereas duration of epilepsy was not. Seizure foci at the frontal convexity were associated with concordant IED. About 72% of patients with a convexity seizure focus had concordant IED, compared with only 33% of patients with mesial frontal foci having concordant IED (P = 0.06). CONCLUSIONS: Early seizure onset in intractable frontal lobe epilepsy is associated with IEDs discordant with seizure focus. Frontal convexity seizure foci are more likely than mesial frontal seizure foci to be associated with concordant discharges.

Adolescent↗

PubMed2003

Complex interactions in Parkinson's disease: a two-phased approach.

The identification of pathogenic mutations in the three genes alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) has elucidated the ubiquitin proteasome system (UPS) and its potential role as a causal pathway in Parkinson's disease (PD). In addition, polymorphisms of these three genes have been shown to be independently associated with PD. In a sample of 298 unrelated PD cases and 185 controls, we applied a two-phased approach of recursive partitioning and logistic regression analyses to explore complex interactions. For women only, we observed an epistatic interaction of UCHL1 and alpha-synuclein genotypes with significant effects on PD risk (odds ratio = 2.42; P = 0.003). Our findings are consistent with the hypothesis that PD is a multigenic disorder of the UPS.

Case-Control Studies↗

PubMed2003

Case-control study of the alpha-synuclein interacting protein gene and Parkinson's disease.

We conducted a case-control study of the alpha-synuclein-interacting protein gene (SNCAIP, also known as synphilin-1) and Parkinson's disease (PD). A total of 319 PD cases and 195 controls were genotyped for four SNCAIP variants, including a microsatellite repeat in intron 4 and three restriction fragment length polymorphisms (RFLP) proximal to the 5' terminal of exons 1, 4, and 6. None of the variants were found associated with PD overall. Global score statistics were not significant for four, three, and two loci haplotypes. All four loci were in linkage disequilibrium for cases, controls, or both groups combined (P < 0.0001). Recursive partitioning showed no interactions between variants of the SNCAIP gene and variants of the alpha-synuclein gene (SNCA) or the parkin (PARK2) gene.

Adult↗

PubMed2003

Parkin variants in North American Parkinson's disease: cases and controls.

We report on an evaluation of coding variants within the parkin gene to assess their frequency in a North American clinical series of 313 Parkinson's disease (PD) cases and 192 unrelated controls. We hypothesized that the carrier frequency of parkin coding mutations, exon deletions, or duplications may be greater in PD cases. However, point mutations and exonic deletions/duplications, reported previously as pathogenic in homozygous or compound heterozygous individuals, occurred in both cases and controls with similar frequencies (3.8% in cases, 3.1% in controls). Furthermore, only stratified subanalyses detected any genetic association between the V380L common coding polymorphism and PD. We discuss the implication of parkin mutations for Parkinson's disease from this population perspective.

Adult↗

PubMed2003

Molecular and histopathologic predictors of distant failure in endometrial cancer.

A case-cohort study was designed to correlate various histopathologic and molecular variables with distant failure in endometrial cancer by analyzing phenotypic and molecular indices in hysterectomy specimens. From an overall population of 283 patients with endometrial cancer, we selected a cohort including all 49 patients who experienced any recurrence and 76 randomly chosen patients without recurrence. Expression of nuclear proliferating cell nuclear antigen (PCNA), MIB-1 (a marker of cell proliferation), and p53 was determined with digital image analysis, and cell membrane HER-2/neu and bcl-2 were quantitated visually. Ploidy and DNA indices were determined with flow cytometry. Overall, 6 immunohistochemical and 11 flow cytometric cases were eliminated because of technical inadequacies. Distant failures were defined as primary recurrences that developed outside the pelvis or vagina. Median follow-up was 91 months. Distant failures occurred in 13% of the patients. Cervical stromal invasion, positive adnexae, myometrial invasion >50%, positive lymph nodes, positive peritoneal cytology, lymphovascular invasion, grade 3 histology, nonendometrioid subtype, p53 >33%, strong HER-2/neu membranous staining, aneuploidy, S-phase fraction > or =9%, proliferative index > or =14%, and DNA index > or =1.5 significantly (P<0.05) predicted distant failures. However, a logistic regression model identified only p53 (OR=43.73; P<0.005), lymphovascular invasion (OR=11.59; P<0.001), and cervical stromal invasion (OR=11.29; P=0.001) as cogent predictors of distant failures. Only 3% of patients without any of these three predictors developed distant failures compared with 36% of those with at least one of the three (P<0.01). Thus, locoregional therapy may be insufficient when at least one of these predictors is present.

Adult↗

PubMed2003

McIndoe procedure for vaginal agenesis: long-term outcome and effect on quality of life.

OBJECTIVE: The purpose of this study was to evaluate quality of life, sexual function, and long-term outcome in women after undergoing the McIndoe procedure for vaginal agenesis. STUDY DESIGN: This was a retrospective descriptive study of patients who were treated with the McIndoe procedure for vaginal agenesis. Participants answered a structured questionnaire to describe self-reported outcomes in quality of life, sexual function and satisfaction, and body image after the McIndoe procedure. Patient characteristics along with short- and long-term findings were abstracted from the medical record. RESULTS: Eighty-six patients responded to the questionnaire. Average age (+/-SD) at surgery was 21+/-6 years (range, 12-49 years). The mean number of years (+/-SD) since surgery was 23+/-12 (range, 2-50 years). Seventy-nine percent of the respondents stated that the McIndoe procedure improved their quality of life. Ninety-one percent of the respondents were sexually active, with 75% able to achieve orgasm. Reported self-image was improved in 55% of the women. CONCLUSION: The McIndoe procedure improves quality of life and sexual satisfaction and provides a functional vagina with minimal complications.

Adolescent↗

PubMed2003

Hepatic resection for metachronous metastases from ovarian carcinoma.

OBJECTIVE: Hepatic resection for recurrent ovarian carcinoma is controversial because of the paucity of relevant published data. The principles of cytoreduction before chemotherapy suggest that resection of measurable liver lesions in properly selected patients would be beneficial. To determine the effect of resection of metachronous liver metastases on morbidity and survival, we reviewed our experience with this treatment. METHODS: Medical records were reviewed retrospectively for all patients who had anatomic hepatic resection for metachronous parenchymal liver metastases from ovarian carcinoma (epithelial or malignant mixed Müllerian tumors) at Mayo Clinic from 1976 to 1999. RESULTS: We identified 26 patients (median age at hepatic resection, 62 years; range, 39-75 years) who had hepatic resection requiring complete segmentectomies or more extensive hepatic surgery for recurrent ovarian carcinoma. Cytoreduction was optimal (extrahepatic and hepatic residual disease <or=1 cm) in 21 patients and suboptimal in 5. No intraoperative or postoperative deaths occurred. Aside from blood loss requiring transfusion of more than 4 units of erythrocytes in 4 patients, only two complications were noted: one superficial wound infection and one small-bowel perforation that required reoperation. The overall median disease-related survival was 26.3 months after hepatic resection; 18 patients (69%) died of disease at a median of 14.6 months (range, 5.0-41.3 months). However, 8 patients (31%) were alive at median follow-up of 33.2 months (range, 3.6-49.6 months). Factors significantly associated with improved disease-related survival were consistent with known prognostic factors associated with cytoreductive surgery, including more than 12 months since original diagnosis (27.3 vs 5.7 months, P = 0.004) and less than or equal to 1 cm of residual disease after hepatic resection (27.3 vs 8.6 months, P = 0.031). CONCLUSIONS: We present evidence that hepatic resection can be performed with minimal surgical morbidity and mortality by surgical teams trained in the procedures. Because of the disease-related survival advantage afforded women by optimal cytoreductive surgery, parenchymal liver metastases should not preclude secondary cytoreductive surgical efforts.

Adult↗

PubMed2002

Case-control study of dopamine transporter-1, monoamine oxidase-B, and catechol-O-methyl transferase polymorphisms in Parkinson's disease.

We investigated the association of Parkinson's disease (PD) with dopamine transporter-1 (DAT1), monoamine oxidase-B (MAO-B), and catechol-O-methyltransferase (COMT) gene polymorphisms. Overall, we observed no significant association of PD with the DAT1-3'-variable numbers of tandem repeats, the MAO-B-(GT)(n), and the COMT-Val108Met gene polymorphisms in a sample of 319 unrelated PD cases and 196 control subjects. Analyses stratified by sex, age at examination, family history of PD, and ethnic origin also yielded negative findings, with three exceptions. We found statistically significant associations of PD with MAO-B polymorphisms in older patients and with a COMT polymorphism in younger subjects and in women. These significant differences at the two-tailed alpha level of 0.05 and restricted to subgroup analyses may have a biological basis or may be chance findings.

Adult↗

PubMed2002

Surgical stage I endometrial cancer: predictors of distant failure and death.

OBJECTIVES: The objective was to analyze the effect of various histopathologic characteristics on prognosis in surgical stage I (node-negative) endometrial carcinoma. METHODS: During a 10-year period, 229 patients with stage I epithelial (all subtypes) endometrial cancer had hysterectomy and node dissection. Mean number of nodes harvested was 16.2 pelvic and 5.7 paraaortic. Median follow-up was 83 months. Sixty-seven patients (29%) received adjuvant radiotherapy. RESULTS: Five-year disease-related survival (DRS) was 95%, and 5-year relapse-free survival (RFS) 91%. We observed 7 (3%) isolated vaginal recurrences, 14 (6%) distant failures, and 1 (0.4%) simultaneous recurrence at both regional (pelvic sidewall) and distant sites. Only 1 of 7 patients (14%) with vaginal failure died of the disease (median follow-up of censored patients after failure was 110 months), compared with 10 of the 15 patients (67%) with distant failure. By univariate analysis, myometrial invasion (MI) >or= 66%, nonendometrioid histology, lymphovascular invasion, absence of associated hyperplasia, and tumor diameter >2 cm were significant predictors of poor prognosis with distant failure (P or= 66% as the only independent predictor of DRS (P < 0.001, relative risk [RR] = 12.44), RFS (P < 0.001, RR = 8.67), and distant failure (P < 0.001, RR = 24.89). Only 2% of patients with MI < 66% had distant failure and died of the disease at 5 years, compared with a 29% 5-year distant failure rate and a 22% 5-year death rate among patients with MI >or= 66%. CONCLUSION: Stage I (negative nodes) endometrial cancer patients with MI >or= 66% are at significant risk for distant failure and death and should be considered candidates for new randomized trials of adjuvant systemic therapy.

Adult↗

PubMed2002

Genetic determinants of lung cancer short-term survival: the role of glutathione-related genes.

PURPOSE: Survival of lung cancer patients has been dismal. Glutathione enzymes are directly involved in the metabolism of platinum compounds, a group of important chemotherapeutic drugs in cancer treatment. We tested the hypothesis that genes encoding glutathione enzymes may predict lung cancer short-term survival. METHODS: We studied DNA polymorphisms of 250 primary lung cancer patients at four glutathione-related loci: GSTP1, GSTM1, GSTT1 and gamma-GCS that encode glutathione-S-transferase-pi, glutathione-S-transferase-mu, glutathione-S-transferase-theta, and gamma-glutamylcysteine synthetase, respectively. Pearson's chi(2)-square tests, Kaplan-Meier survival curves, log rank tests, and Cox regression models were applied in the analysis. RESULTS: There were 150 (60%) men and 100 (40%) women in this study. Seventeen percent of the patients had never smoked cigarettes, and 61% had stopped smoking at least 6 months prior to their lung cancer diagnosis. Among never smokers, those with null (N) or low (L) genotype experienced a better 1-year-survival rate than those with a positive (P) or high (H) genotype. Patients with P or H at two loci (PP or PH) were compared with patients with N or L at one or both loci (other). Among never smokers, 1-year-survival rates were 60-78% for patients with PP or PH genotypes compared with 89-100% for other types. The survival advantage was greater among advanced-stage patients who were NL or NN than low-stage patients. Similar results were not observed among smokers. CONCLUSIONS: Glutathione-related genes may determine lung cancer survival. Our results, if confirmed, would suggest new directions to enhance cancer treatment, and provide easily measurable markers for clinicians to plan patient-specific therapy.

Female↗

PubMed2002

Factors that are associated with clinically overt postpartum urinary retention after vaginal delivery.

OBJECTIVE: This study was undertaken to determine the incidence of clinically overt postpartum urinary retention after vaginal delivery and to examine what maternal, fetal, and obstetric factors are associated with this problem. STUDY DESIGN: This was a retrospective case-controlled study of women who had overt postpartum urinary retention after vaginal delivery from August 1992 through April 2000. RESULTS: Fifty-one of 11,332 (0.45%) vaginal deliveries were complicated by clinically overt postpartum urinary retention. In most cases (80.4%), the problem had resolved before hospital dismissal. Persons with urinary retention were more likely than control subjects to be primiparous (66.7% vs 40.0%; P <.001), to have had an instrument-assisted delivery (47.1% vs 12.4%; P <.001), to have received regional analgesia (98.0% vs 68.8%; P <.001), and to have had a mediolateral episiotomy (39.2% vs 12.5%; P <.001). On multivariate logistic regression analysis, of these 4 variables, only instrument-assisted delivery and regional analgesia were significant independent risk factors. CONCLUSION: Clinically overt postpartum urinary retention complicates approximately 1 in 200 vaginal deliveries, with most resolving before hospital dismissal. Factors that are independently associated with its occurrence include instrument-assisted delivery and regional analgesia.

Adult↗

PubMed2002

Myeloperoxidase -463 (G-->A) polymorphism associated with lower risk of lung cancer.

OBJECTIVE: To study the association of the myeloperoxidase (MPO) -463 (G-->A) polymorphism with lung cancer risk. PATIENTS AND METHODS: We performed a paired case-control analysis of 307 patients with primary lung cancer and an equal number of age-, sex-, and ethnicity-matched controls to evaluate the effect of the MPO -463 (G-->4A) polymorphism on disease susceptibility. We also performed conditional logistic regression analyses to evaluate the effect of the polymorphism adjusted for smoking status and chronic obstructive pulmonary disease, 2 established risk factors. We used 2 models for these analyses: one to compare homozygous (AA) genotypes with wild type (GG) and heterozygous (GA) genotypes and one to compare carriers (heterozygotes and AA homozygotes) with GG genotypes. Finally, we combined the results from the published studies of this putative association and performed a stratified analysis. RESULTS: The AA genotype was inversely associated with susceptibility to lung cancer (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.15-1.00). There was no association in heterozygotes. However, in the stratified analysis, we found an association between patients with the AA (OR, 0.44; 95% CI, 0.27-0.68) and GA (OR, 0.77; 95% CI, 0.64-0.93) genotypes vs the GG genotype. CONCLUSION: Our results are consistent with previous reports and show that homozygotes of the less common A allele of MPO -463 polymorphism have a 2.6-fold lower risk of lung cancer.

Adult↗

PubMedDate not supplied

HER-2/neu overexpression and hormone dependency in endometrial cancer: analysis of cohort and review of literature.

BACKGROUND: Overexpression of HER-2/neu (HER) is associated with unfavorable prognoses in both endometrial and breast cancer. MATERIALS AND METHODS: To determine whether an association exists between HER expression and markers of hormone dependency in endometrial cancers, we subjected hysterectomy specimens from 125 patients to immunohistochemical staining for HER. HER was visually interpreted as negative/weakly positive (HER-) versus strongly positive (HER+). Estrogen receptor (ER) and progesterone receptor (PR) levels were quantitated on fresh tissue using a dextran-coated charcoal assay. RESULTS: HER+ was observed in 12% of endometrioid tumors and 22% of nonendometrioid tumors (p = 0.07). Mean ER and PR levels were 255 fmol/mg and 457 fmol/mg in endometrioid tumors, compared with 74 and 104 in nonendometrioid tumors (p < 0.01). Hyperplasia associated with the tumor was related to high levels of both ER and PR (p < 0.05), but not with HER expression. Age was significantly related to high levels of ER (p = 0.007). Both recurrence and death rates were significantly associated with low levels of ER and PR (p < 0.01). Mean ER and PR levels were 270 and 466 fmol/mg, respectively, in HER-tumors, compared with 95 (p = 0.14) and 138 fmol/mg (p = 0.02) in HER+ tumors. CONCLUSION: HER overexpression may be an important step in hormone-independent growth and proliferation in a subgroup of endometrial cancers.

Adult↗

PubMedDate not supplied

Role of bcl-2 in endometrioid corpus cancer: an experimental study.

BACKGROUND: Bcl-2 expression appears to be under hormonal control in normal endometrium and to correlate with hormone receptor status in endometrial cancer. The aim of this study was to assess bcl-2 expression in endometrial cancer. MATERIALS AND METHODS: Hysterectomy specimens from 125 patients with endometrial cancer were stained for bcl-2. Estrogen receptor (ER) and progesterone receptor (PR) levels were quantified with a dextran-coated charcoal assay. RESULTS: Bcl-2 expression correlated significantly with endometrioid histology and high levels of ER and PR (p < 0.05). For the entire population, bcl-2 expression was not significantly associated with the presence of extrauterine disease. However, when only patients with grade 1 or 2 endometrioid histology were considered, tumors with bcl-2 expression were significantly (p < 0.05) more likely to present with extrauterine disease than those not expressing bcl-2. CONCLUSION: Bcl-2-mediated inhibition of apoptosis may be important in the acquisition of molecular alterations and development of metastases in a subset of hormone-dependent endometrial cancers.

Carcinoma, Endometrioid↗