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Biomedical subjects

B Franklin

Publications and source records attributed to B Franklin.

At least 19 recordsLinked to original sources
PubMed2002

A hMLH1 genomic mutation and associated novel mRNA defects in a hereditary non-polyposis colorectal cancer family.

Hereditary non-polyposis colorectal cancer (HNPCC), or Lynch syndrome I, is responsible for as high as 10% of all colorectal cancers (CRCs) newly diagnosed in any given year. This disorder has an autosomal dominant inheritance pattern and is almost fully penetrant (>85%). It occurs when there is a mutation in any one of six mismatch repair genes: hMLH1, hMSH2, hPMS1, hPMS2, hMSH3 and hMSH6. Mutations in these genes allow mistakes in tumor suppressor genes and oncogenes to accumulate which eventually leads to cancer. The founder of an HNPCC family in the Creighton University Hereditary Cancer Institute database was known to produce truncated hMLH1 protein, a product of one of the aforementioned mismatch repair genes. Lymphoblasts were isolated from ten members of this HNPCC family (six affected and four unaffected) and two persons from outside this family (both unaffected controls). RNA and DNA were purified from these lymphoblasts which had been transformed by the Epstein-Barr virus (EBV). The hypothesis was that a mutation in the hMLH1 gene perpetuated defects in its mRNA and functional protein. hMLH1 RNA transcripts were detected in reverse transcriptase polymerase chain reactions (RT-PCR) whereby total poly A(+) RNA was converted to a complementary DNA (cDNA), amplified using hMLH1 specific primers, purified and cycle sequenced. Likewise, DNA was employed as template for PCR amplification of hMLH1 exons; PCR products were then directly cycle sequenced. Affected family members were found to produce hMLH1 mRNA lacking exons 6 and 7 (and wild-type mRNA). A splicing mutation at 546--2 (two bases 5' to exon 7) was located in the genomic DNA samples from the six family members with the HNPCC phenotype. This mutation caused deletion of exon 7 from the mRNA. None of the four unaffected family members or the two unaffected persons outside of this family had the above defects in their hMLH1 mRNA and DNA.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Comparison of exercise test scores and physician estimation in determining disease probability.

BACKGROUND: The recent American College of Cardiology/American Heart Association exercise testing guidelines provided equations to calculate treadmill scores and recommended their use to improve the predictive accuracy of the standard exercise test. However, if physicians can estimate the probability of coronary artery disease as well as the scores can, there would be no reason to add this complexity to test interpretation. To compare the exercise test scores with physician's estimation of disease probability, we used clinical, exercise test, and coronary angiographic data to compute the recommended scores and print patient summaries and treadmill reports. OBJECTIVE: To determine whether exercise test scores can be as effective as expert cardiologists in diagnosing coronary disease. METHODS: Five hundred ninety-nine consecutive male patients without previous myocardial infarction with a mean +/- SD age of 59 +/- 11 years were considered for this analysis. With angiographic disease defined as any coronary lumen occlusion of 50% or more, 58% had disease. The clinical/treadmill test reports were sent to expert cardiologists and to 2 other groups, including randomly selected cardiologists and internists, who classified the patients as having high, low, or intermediate probability of disease and estimated a numerical probability from 0% to 100%. RESULTS: Forty-five expert cardiologists returned estimates on 336 patients, 37 randomly chosen practicing cardiologists returned estimates on 129 patients, 29 randomly chosen practicing internists returned estimates on 106 patients, 13 academic cardiologists returned estimates on 102 patients, and 27 academic internists returned estimates on 174 patients. When probability estimates were compared, the scores were superior to all physician groups (0.76 area under the receiver operating characteristic curve to 0.70 for experts [P=.046], 0.73 to 0.58 for cardiologists [P=.003], and 0.76 to 0.61 for internists [P=.006]). Using a probability cut point of greater than 70% for abnormal, predictive accuracy was 69% for scores compared with 64% for experts, 63% to 62% for cardiologists, and 70% to 57% for internists. CONCLUSION: Although most similar to the disease estimates of the presence of clinically significant angiographic coronary artery disease provided by the expert cardiologists, the scores outperformed the nonexpert physicians.

Adult↗
PubMed2001

Low compliance with national standards for cardiovascular emergency preparedness at health clubs.

There is heightened concern that older adults and individuals with occult or known heart disease are exercising at fitness facilities that do not provide adequate cardiovascular screening and emergency procedures, as outlined in contemporary recommendations. To evaluate adherence to these standards, we surveyed 122 randomly chosen fitness clubs in Ohio (53% response rate; n = 65) that included > 110,000 total members. Special programs for older adults, cardiac patients, or both, were offered at 52% of these clubs. More than one fourth of the clubs (28%) failed to employ pre-entry screening to identify members with signs, symptoms, or history of cardiovascular disease, even though 17% reported one or more cardiovascular emergencies (ie, acute myocardial infarction, sudden cardiac death, or both) in their facility during the past 5 years. Moreover, a majority of the clubs (53%) had no written emergency response plan and 92% failed to conduct emergency response drills as described in published national standards. Only 3% of the centers reported having automated external defibrillators. These findings indicate that staff at public fitness facilities must work to identify members with signs, symptoms, or history of cardiovascular disease and prepare for prompt and appropriate responses to cardiovascular emergencies as described in contemporary national recommendations. Such risk management procedures may reduce exercise-related cardiovascular events among the escalating number of moderate-to-high-risk adults who are being mainstreamed into health and fitness facilities.

Cardiovascular Diseases↗
PubMed1999

Microsatellite instability and expression of MLH1 and MSH2 in normal and malignant endometrial and ovarian epithelium in hereditary nonpolyposis colorectal cancer family members.

Mismatch repair deficiency is a characteristic molecular finding in hereditary nonpolyposis colorectal cancer (HNPCC), and has been demonstrated in both colorectal cancers and benign adenomas. Endometrial and ovarian cancers are common extracolonic tumors in this syndrome; however, few studies have investigated whether genetic changes occur in histologically normal endometrial and ovarian epithelia from HNPCC family members. If early genetic changes exist, they might be used as molecular markers to detect susceptibility to endometrial and ovarian cancers. In this study, we analyzed microsatellite instability (MSI) and MLH1 and MSH2 immunohistochemical expression in 20 histologically normal epithelia (12 endometrial and 8 ovarian) and 8 cancers (4 endometrial and 4 ovarian) obtained from 20 individuals representing 7 unrelated HNPCC families. While MSI was observed in endometrial (75%) and ovarian (100%) cancers, no case was determined to exhibit MSI in histologically normal epithelia of the endometrium or ovary. Similarly, in immunohistochemical expressions for MLH1 and MSH2, histologically normal epithelia had no genetic changes predisposing to malignancy. In cancer cases, a correlation existed between the expression of MLH1 and MSH2, the presence of germline mutations in the hMLH1 and hMSH2 genes, and the presence of tumor MSI. These data suggest that MSI and MLH1 and MSH2 expression are not useful biomarkers for the early detection of endometrial and ovarian malignancy in cancer-unaffected HNPCC germline mutation carriers. Further studies of other genetic changes in normal and premalignant precursor lesions are needed.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome.

A male member of a large HNPCC kindred, affected by primary malignancies of the breast and colon, was identified. This individual was found to harbor a germline mutation of the MLH1 mismatch repair gene previously shown to segregate with disease in this kindred. The breast tumor exhibited somatic reduction to homozygosity for the MLH1 mutation, and microsatellite instability was evident in the breast tumor. We conclude that hereditary male breast cancer can occur as an integral tumor in the HNPCC syndrome.

Aged↗
PubMed1999

When the earth stops shaking: earthquake sequelae among children diagnosed for pre-earthquake psychopathology.

OBJECTIVE: To examine risk and protective processes for posttraumatic stress reactions and negative sequelae following the Northridge earthquake (EQ) among youths diagnosed for pre-EQ psychopathology. METHOD: Symptoms of posttraumatic stress disorder (PTSD), depression, general anxiety, and social impairment were evaluated using telephone interviews among 66 children participating in a family-genetic study of childhood-onset depression at the time of the EQ. RESULTS: Significant predictors of PTSD symptoms 1 year after the EQ included perceived stress and resource loss associated with the EQ, a pre-EQ anxiety disorder, and more frequent use of cognitive and avoidance coping strategies. PTSD symptoms were associated with high rates of concurrent general anxiety symptoms, depressive symptoms, and social adjustment problems with friends. The only significant correlation between sibling scores was on measures of sibling reports of objective exposure. CONCLUSIONS: Preexisting anxiety disorders represent a risk factor for postdisaster PTSD reactions. Postdisaster services need to attend to the needs of these youths as well as those of youths experiencing high levels of subjective stress, resource loss, and/or high exposure. That children within families show significant variation in postdisaster reactions underscores the need for attention to individual child characteristics and unshared environmental attributes.

Adolescent↗
PubMed1999

Colorectal cancer and the Muir-Torre syndrome in a Gypsy family: a review.

OBJECTIVES: The Muir-Torre syndrome (MTS) is characterized by an autosomal dominant predilection to sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas, in concert with the cancer phenotype of hereditary nonpolyposis colorectal cancer (HNPCC). Proof that patients showing a familial aggregation of MTS's cutaneous signs in combination with a specific pattern of visceral cancers which are consonant with an HNPCC diagnosis has been buttressed by the discovery of hMSH2 and hMLH1 germ-line mutations in such families. Our purpose in this investigation was to determine the germ-line mutation in a Gypsy family with MTS in concert with HNPCC cancer features, and to provide genetic counseling. An added objective for this paper is to review the literature on MTS. METHODS: We describe a Gypsy family with MTS in concert with HNPCC cancer features, as well as the molecular genetic and genetic counseling procedures used in the interest of improved compliance with cancer control recommendations. We review the clinical phenotype, natural history, and molecular genetics involved in the MTS variant HNPCC. RESULTS: An hMSH2 germ-line mutation was identified as the culprit germ-line mutation in this family. CONCLUSIONS: The presence of the hMSH2 germ-line mutation in this family provides powerful predictability of colorectal and other HNPCC integral cancers. The gastroenterologist must assume an important role in the diagnosis and management of MTS.

Adult↗
PubMed1999

Research on physical activity and health among people with disabilities: a consensus statement.

Research is required to advance the understanding of issues related to the effect of physical activity on health and disease prevention among people with disabilities. This report is the result of a consensus process using selected experts in health and exercise. The purpose of the consensus conference was to identify research priorities for physical activity and health among people with disabilities. Priorities were established by 30 participants, who were selected by the principal investigators to achieve balance in the areas of engineering, epidemiology, medicine, nutrition, exercise physiology, and psychology. Experts summarized relevant data from their research and from comprehensive review of the scientific literature on the topic areas chosen for the conference. Public commentary was provided by participants in the 1996 Paralympic Congress. Panel members discussed openly all material presented to them in executive session. Commentary from open discussion periods were recorded and transcribed. Selected panelists prepared first drafts of the consensus statements for each research priority question. All of these drafts were distributed to the panelists and pertinent experts. The documents were edited by the drafting committee to obtain consensus. This research priority setting process revealed that greater emphasis must be placed on determining the risks and benefits of exercise among people with disabilities. Exercise must be studied from the perspective of disease prevention while mitigating risk for injury. Five areas were identified as focal points for future work: epidemiological studies; effects of nutrition on health and ability to exercise; cardiovascular and pulmonary health; children with disabilities; and accessibility and safety of exercise programs. As people with disabilities live longer, the need for addressing long-term health issues and risk for secondary disability must receive greater attention. As a consequence of the consensus process, specific recommendations for future research regarding the impact of exercise on the health and quality of life of persons with disabilities were defined.

Cardiovascular Diseases↗
PubMed1998

Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members.

BACKGROUND: Patients with hereditary nonpolyposis colorectal carcinoma (HNPCC) reportedly have better prognoses than sporadic colorectal carcinoma (CRC) patients, but it has been unclear whether this could be due to differences in stage at diagnosis. The current study compared stage and survival in a retrospective cohort of HNPCC family members who developed CRC with the same factors in an unselected hospital series of patients with sporadic CRC. METHODS: This retrospective cohort study compared HNPCC cases (274 cases from 98 HNPCC families) with an unselected hospital series comprising 820 consecutive CRC cases. All patients were staged according to the TNM system of the American Joint Committee on Cancer and the International Union Against Cancer. Median follow-up among living patients was > 10 years and 8.5 years, respectively, for the two cohorts. Cox regression was used to compare survival in stage-stratified analyses of time from diagnosis to death. RESULTS: Compared with the unselected series, the HNPCC cases had lower stage disease (P < 0.001), and fewer had distant metastases at diagnosis (P < 0.001 in an analysis stratified by T classification). In stage-stratified survival analysis, the HNPCC cases had a significant overall survival advantage regardless of adjustment for their younger age. A conservative estimate of the hazard ratio (of HNPCC cases to the unselected series) was 0.67 (P < 0.0012). CONCLUSIONS: HNPCC patients had lower stage disease at diagnosis than the unselected CRC cases, mainly due to rarer distant metastases at diagnosis. They survived longer than unselected CRC patients with tumors of the same stage. The estimated death rate for the HNPCC cases, adjusted for stage and age differences, was at most two-thirds of the rate for the hospital series.

Adult↗
PubMed1997

Etiology, natural history, management and molecular genetics of hereditary nonpolyposis colorectal cancer (Lynch syndromes): genetic counseling implications.

We estimate that 5-10% of virtually all forms of cancer are due to a primary hereditary etiology. However, a hereditary cancer diagnosis is often missed because the family history of cancer is given short shrift in medical practice. Hereditary nonpolyposis colorectal cancer (HNPCC) certainly fits this estimate, although some studies suggest that a minimum of 2% with a range as high as 10% of the total colorectal cancer burden is due to HNPCC. Mutations in one of the four mismatch repair genes, i.e., hMSH2, hMLH1, hPMS1, and hPMS2, account for about 70% of HNPCC kindreds. Other germ-line mutations are likely to be identified to account for the remainder of HNPCC patients. By far the most common HNPCC mutations involve hMSH2 and hMLH1, with hPMS1 and hPMS2 accounting for only about 3% of such families. Prior to these molecular genetic discoveries, the genetic counselor could only provide the patient with an estimate of a 50% likelihood of manifesting HNPCC based on the counselee having one or more first-degree relatives manifesting syndrome cancers in their direct genetic lineage. Because DNA testing has become available in families with known mutations, we have provided pretest group education in the form of a family information service with intensive education about the natural history, genetic risk, surveillance, and options for management of HNPCC, as well as discussion of the potential for fear, anxiety, apprehension, and insurance or employer discrimination that might impact on this DNA testing. Following informed consent, these relatives were then counseled on a one-to-one basis. Using DNA-based genetic counseling involving hMSH2 or hMLH1, we have provided this service to four extended HNPCC kindreds. Details of this genetic counseling experience on these four kindreds will be discussed.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Genetic counseling in hereditary nonpolyposis colorectal cancer: an extended family with MSH2 mutation.

OBJECTIVES: Molecular genetic advances have increased the demand for DNA testing. We describe DNA based genetic counseling in a hereditary nonpolyposis colorectal cancer (HNPCC) family. METHODS: This extended HNPCC family was found to harbor the MSH2 germline mutation. Family history, medical, and pathology documents enabled us to secure a high degree of verification that the kindred qualified as HNPCC. DNA testing revealed the MSH2 germline mutation that was verified independently in two laboratories. Genetic counseling was provided before DNA testing and disclosure of MSH2 findings. RESULTS: Genetic counseling revealed a variety of findings characterized by emotional stress in MSH2 germline mutation carriers. Concerns centered around reproductive issues, potential transmission of the deleterious gene to their progeny, and discrimination by insurance carriers and employers. More than one-half of the patients found to harbor the MSH2 mutation considered the option of prophylactic subtotal colectomy. CONCLUSION: DNA testing should be restricted to well-verified candidate families in which genetic counseling should be mandatory. HNPCC family members sought genetic risk assessment for their own health and that of their children. Contrasting emotional responses took place when told of their gene testing status and this required a sensitive empathetic listening ear. Patients have many concerns about their lifetime cancer destiny when told that they harbor the culprit MSH2 germline mutation.

Adult↗
PubMed1992

Double mosaic aneuploidy: 45,X/47,XY,+8 in a male infant.

We report on a 13-month-old boy with abnormalities consistent with mosaic trisomy 8 syndrome and male genitalia with partial penoscrotal transposition without hypospadias, a retractile left testis in inguinal canal, and an absent right testis. A voiding cystourethrogram showed an outpouching close to the lower right side of the bladder (utriculum) and bilateral hydronephrosis secondary to vesicoureteral reflux. Peripheral blood karyotype was 45,X/47,XY,+8. The karyotype of cultured skin fibroblasts was 47,XY,+8 with no 45,X cells detected among 20 cells counted. Tissues removed during surgery documented a 45,X/47,XY,+8 complement in the left testicle and utriculum, but only a 45,X line among 20 cells counted from vas deferens tissue. A possible mechanism for the origin of this previously unreported mosaicism might be an abnormal zygote with a 47,XY,+8 complement with subsequent simultaneous loss of chromosome Y and 8 in a cell at a very early embryonic stage.

Aneuploidy↗
PubMed1991

Gestational diabetes mellitus: evidence for autoimmunity against the pancreatic beta cells.

Diabetes mellitus is a frequent transient or rare permanent complication of pregnancy. The role of autoimmune phenomena in this gestational form of diabetes is incompletely understood. We have examined sera from 312 pregnant women who had abnormal glucose tolerance (based on a screening examination during the second trimester) for the presence of islet cell surface antibodies or insulin autoantibodies. Fifty-eight of these women were lost to follow-up. Of the remaining subjects, 144 (57.1%) had gestational diabetes diagnosed by formal glucose tolerance testing and the others (42.9%) were normal. Sixty percent of the women with gestational diabetes eventually required insulin to control their blood glucose during pregnancy. One serum from the non-diabetic women was positive for insulin antibodies (0.9%); 8 of the sera from the patients with gestational diabetes were positive (5.6%). Subsequent analysis revealed that all nine of the women whose sera were positive for insulin autoantibodies had been treated with insulin previously. Islet cell surface antibodies were strongly correlated with gestational diabetes. Forty-five of 144 gestational diabetic sera were positive (31.3%) whereas only 9 of 108 suspect control sera (8.3%) and 7 of 60 unknown sera (11.7%) were positive. These data suggest that a high percentage of pregnant women who screen positive for glucose intolerance have serological evidence of an autoimmune response against the pancreatic islets, in spite of the state of relative immune tolerance during pregnancy. These data suggest that autoimmune phenomena may play a role in gestational diabetes and that the presence of islet cell antibodies can predict insulin-requiring gestational diabetes.

Autoantibodies↗
PubMed1991

Role of gram-negative and gram-positive gastrointestinal flora in temperature regulation of mice.

An earlier study showed that the presence of gut flora elevates body temperature of mice and rats. In these experiments, we questioned whether the signal coming from the gut was endotoxin from gram-negative (Gm-) bacteria or some signal derived from gram-positive (Gm+) microorganisms. To test the idea that endotoxin is responsible for the effects of flora, we compared the temperature of the endotoxin-resistant mouse (C3H/HeJ) with that of endotoxin-sensitive strains of mice (C3H/SnJ and C3H/HeN). Temperature of C3H/HeJ was not different from that of C3H/SnJ or C3H/HeN during the light period but was significantly lower during the later hours of the dark period. We speculated that, if endotoxin leaking across the gut wall were responsible for elevating temperature, then reduction of gut flora with nonabsorbable antibiotics would depress the temperature of the endotoxin-sensitive mice more than that of the endotoxin-resistant mice. Because antibiotics lowered the temperature of both strains of mice to the same extent, the signal coming from the gut is unlikely to be endotoxin. To test whether Gm+ flora can be responsible for elevating temperature, we inoculated one group of germfree mice with Gm+ organisms. Their mean temperature was significantly higher than that of mice that remained germfree. Cecectomy had no effect on temperature, indicating that the special properties of the germfree cecum were not involved in lowering the temperature of germfree mice. These data support the hypotheses that Gm+ organisms are a major source of the stimulatory effect of flora on normal body temperature and that the presence of Gm- organisms is unnecessary.

Animals↗
PubMed1990

Validity of arm ergometer blood pressures immediately after exercise.

It is not possible to assess blood pressure (BP) by the standard cuff method during exercise primarily involving the arms. Consequently, such measurements are often taken immediately after (within 15 seconds) exercise. To assess the validity of this practice, 18 healthy men (mean age 32 years) who completed 3 progressive 3-minute workloads were studied during arm-crank ergometry. Ankle systolic BP was measured at the dorsalis pedis artery at seated rest, 15 seconds before completion of each exercise stage and immediately after each workload, using a Doppler stethoscope; simultaneous postexercise brachial systolic BPs were determined by auscultation. Brachial systolic BP during armcrank ergometry was estimated by the formula: (resting brachial systolic BP) + (exercise ankle systolic BP - resting ankle systolic BP). Brachial systolic BPs, obtained immediately after arm-crank ergometry, were significantly lower than those estimated during exercise (p less than 0.001), with corresponding mean values of 141 versus 153, 144 versus 173 and 151 versus 182 mm Hg at 150, 300, and 450 kg.m.min-1, respectively. The difference between measured (postexercise) and estimated pressures increased with progressive workloads. These findings indicate that systolic BPs taken by the standard cuff method immediately after arm-crank ergometry are likely to underestimate "true" physiologic responses.

Adult↗