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Background: Medical training can be a challenging time for residents both professionally and personally. Resident support programs must be able to address a range of potential experiences, be accessible and easy to navigate, and consider the unique context of residency. Rigorous evaluation of resident support programs is needed to determine whether these programs are meeting these goals., Methods: The Directors of Resident Support (DRS) program, launched in January 2021 at the Cumming School of Medicine at the University of Calgary, is a near-peer support model consisting of three faculty physicians, trained in peer support, who receive contacts from residents needing support for any issue. DRS physicians provide empathetic listening, referral to existing resources, and peer support for residents. A multisource evaluation of the DRS program, including field notes, data collection forms, and surveys, was guided by the Donabedian framework., Results: There were 62 total contacts in the 2-year evaluation period which required a median 2 h to address (range 5 min to more than 40 h). The most common topic for contact was to discuss feedback or evaluation (n = 10, 24.4%) and the most common response was listening and support (n = 29, 70.7%). Residents also contacted DRS to discuss experiences of racism, physical assault, sexual harassment, and mental health crises. Residents (n = 13) rated a median score of 74 out of possible 100 for usefulness (interquartile range [IQR] 1-100, with higher scores suggesting greater usefulness). Free text survey responses suggested that residents felt validated by contact with the program though some residents felt that additional follow-up would have been helpful., Conclusion: The DRS program has been well-utilized by residents for a variety of issues. Postgraduate Medical Education offices seeking to create resident support programs may anticipate that about 3% of residents may use a similar program per year and that the typical interaction would last 2 h, with a wide range. Feedback suggested that similar programs should have a formal process for follow-up with residents to ensure their concern was addressed and that resident supporters should have diverse lived experiences., (© 2024. The Author(s).)

Genetic research into complex diseases is frequently hindered by a lack of clear biomarkers for phenotype ascertainment. Phenotypes for such diseases are often identified on the basis of clinically defined criteria; however such criteria may not be suitable for understanding the genetic composition of the diseases. Various statistical approaches have been proposed for phenotype definition; however our previous studies have shown that differences in phenotypes estimated using different approaches have substantial impact on subsequent analyses. Instead of obtaining results based upon a single model, we propose a new method, using Bayesian model averaging to overcome problems associated with phenotype definition. Although Bayesian model averaging has been used in other fields of research, this is the first study that uses Bayesian model averaging to reconcile phenotypes obtained using multiple models. We illustrate the new method by applying it to simulated genetic and phenotypic data for Kofendred personality disorder-an imaginary disease with several sub-types. Two separate statistical methods were used to identify clusters of individuals with distinct phenotypes: latent class analysis and grade of membership. Bayesian model averaging was then used to combine the two clusterings for the purpose of subsequent linkage analyses. We found that causative genetic loci for the disease produced higher LOD scores using model averaging than under either individual model separately. We attribute this improvement to consolidation of the cores of phenotype clusters identified using each individual method.

Objective: To develop, validate, and evaluate a questionnaire (Cats' Assessment Tool for Cardiac Health [CATCH] questionnaire) for assessing health-related quality of life in cats with cardiac disease., Design: Prospective study., Animals: 275 cats with cardiac disease., Procedures: The questionnaire was developed on the basis of clinical signs of cardiac disease in cats. A CATCH score was calculated by summing responses to questionnaire items; possible scores ranged from 0 to 80. For questionnaire validation, owners of 75 cats were asked to complete the questionnaire (10 owners completed the questionnaire twice). Disease severity was assessed with the International Small Animal Cardiac Health Council (ISACHC) classification for cardiac disease. Following validation, the final questionnaire was administered to owners of the remaining 200 cats., Results: Internal consistency of the questionnaire was good, and the CATCH score was significantly correlated with ISACHC classification. For owners that completed the questionnaire twice, scores were significantly correlated. During the second phase of the study, the CATCH score ranged from 0 to 74 (median, 7) and was significantly correlated with ISACHC classification., Conclusions and Clinical Relevance: Results suggested that the CATCH questionnaire is a valid and reliable method for assessing health-related quality of life in cats with cardiac disease. Further research is warranted to test the tool's sensitivity to changes in medical treatment and its potential role as a clinical and research tool.

Objectives: In order to more fully understand degenerative mitral valve disease (DMVD) in the Norfolk terrier, we sought to characterize findings from the physical and echocardiographic examination; biochemical, biomarker, and nutritional profiles; and select environmental variables from a cohort of apparently healthy Norfolk terriers., Animals, Materials and Methods: Overtly healthy Norfolk terriers ≥ 6 yrs old were recruited by 3 different veterinary hospitals and underwent historical, physical, electrocardiographic (ECG), and 2D/color-flow Doppler echocardiographic examinations. Anterior mitral valve leaflet length, maximal thickness, area, and degree of prolapse were measured or calculated from two-dimensional images. Blood samples were obtained for serum biochemistry, serum serotonin, plasma NT-proBNP, amino acid profile, C-reactive protein, and cardiac troponin I., Results: Of the 48 dogs entered into the study, 23 (48%) had murmurs, 2 (4%) had mid-systolic clicks, 11 (23%) had ECG P pulmonale, and 41 (85%) were deemed to have echocardiographic evidence of DMVD, including 18 Norfolk terriers without a murmur. Seven (15%), 28 (58%), and 13 (27%) dogs were classified as normal (stage 0), International Small Animal Cardiac Health Council (ISACHC) stage 1a, and 1b, respectively. Mean indexed echocardiographic mitral leaflet thickness (P = 0.017), area (P = 0.0002), prolapse (P = 0.0004), and left atrial to aortic diameter (P = 0.01) were significantly different between ISACHC 0, 1a, and 1b., Conclusion: DMVD is relatively common in Norfolk terriers and echocardiographic changes consistent with mild DMVD can be seen in dogs without a heart murmur., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Hypothesis/objectives: To describe the therapeutic use of pimobendan in cats, describe the patient population to which it was administered, document potential side effects and report the clinical course following administration of pimobendan in conjunction with standard heart failure therapy. It is hypothesized that cats with advanced heart disease including congestive heart failure from a variety of causes will tolerate pimobendan with a minimum of side effects when used in treatment in conjunction with a variety of other medications., Animals, Materials and Methods: One hundred and seventy client owned cats with naturally occurring heart disease, one hundred and sixty four of which had congestive heart failure. Medical records were reviewed and owners and referring veterinarians were contacted for follow-up data. Data collected included pimobendan dose, other medications administered concurrently, data collected at physical examination, presence or absence of heart failure, adverse effects, classification of heart disease, echocardiographic data and survival time. The data were analyzed for significance between the initial visit and any follow-up visits., Results: All cats were treated with pimobendan. The median pimobendan dose was 0.24 mg/kg q 12 h. Pimobendan was used in combination with multiple concurrent medications including angiotensin converting enzyme inhibitors, diuretics and anti-thrombotics. Five cats (3.0%) had potential side effects associated with pimobendan. One cat (0.6%) had presumed side effects severe enough to discontinue pimobendan use. Median survival time for 164 cats with congestive heart failure after initiation of pimobendan was 151 days (range 1-870)., Conclusion: Pimobendan appears to be well tolerated in cats with advanced heart disease when used with a variety of concurrent medications. Randomized controlled studies need to be performed to accurately assess whether it is efficacious for treatment of congestive heart failure in cats., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: Since 2003, compliance with Accreditation Council on Graduate Medical Education (ACGME) work hours regulations has been required for United States residency training programs. Further work hours restrictions have been proposed by the Institute of Medicine (IOM). This study examines General Surgery residents' views of current work hours restrictions and proposed changes by the IOM., Design: An anonymous multiple-choice survey regarding work hours regulations was distributed to all US General Surgery residency program directors in 2009. Responses were compiled via an on-line survey program. Statistical analysis was performed in aggregate and by junior and senior resident responses., Results: Nine hundred sixty-five (13.1%) general surgery residents responded. Responses demonstrated that 25% of surgery residents underreported work hours, with statistically significant differences between junior (22%) and senior residents (27%), p = 0.03. Sixteen percent of residents indicated they were instructed to report their work hours inaccurately, while 8% of residents advised junior or coresidents to report their work hours inaccurately. Sixty-five percent felt that other residents underreport their work hours. Junior residents (34%) were more in favor of increased work hours regulations than senior residents (17%; p < 0.001). The majority (52%) have underreported work hours to take care of a sick patient or perform surgery. Seventy-six percent are aware of the recent IOM recommendations for further work hours restrictions, of whom the majority felt that the IOM recommendations would make surgical training worse., Conclusions: General surgery resident physicians in the US do not always record their work hours accurately and many have concerns about further work hour restrictions. The majority admitted underreporting work hours to care for a sick patient. Most US surgical residents feel further work hour restrictions would be detrimental to their training. Current work hours restrictions force surgery residents to underreport their work hours to perform the activities that they feel are necessary for their surgical training., (Copyright © 2010 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

The Accreditation Council for Graduate Medical Education (ACGME) uses the resident/fellow survey to assess residency programs compliance with ACGME work hours regulations. Survey results can have significant consequences for residency programs including ACGME letters of warning, shortened program accreditation cycle, immediate full program and institutional site visits, or administrative withdrawal of a program's accreditation. Survey validity was assessed by direct query of general surgery residents who answer the survey each year. A multiple-choice survey was created to assess all US general surgery residents' interpretation and understanding of the ACGME survey. The survey was distributed to all surgery residency program directors in the US in 2009. Responses were compiled via an online survey program. Statistical analysis was performed in aggregate and between junior and senior residents. Nine hundred sixty-five (13.2%) general surgical residents responded with 961 (99.6%) completing all questions. All responding residents had taken the ACGME survey at least once with 634 (66%) having taken it more than once. Nineteen percent of residents had difficulty understanding the questions with senior residents (23%) reporting difficulty more than junior residents (14%), p < 0.001. Thirty-five percent of residents had discussed the survey with their faculty or program director prior to taking it, while 17% were instructed on how to answer the survey. One hundred thirty-three residents (14%) admitted to not answering the questions truthfully while 352 (37%) of residents felt that the survey did not provide an accurate evaluation of their work hours in residency training. An evaluation tool in which 1 in 7 residents admit to answering the questions falsely and 1 in 5 residents had difficulty interpreting the questions may not be a valid method to evaluate compliance with work hours regulations. Evaluation of work hours regulations compliance should be based on actual work hours data rather than an anonymous survey., (Copyright © 2010 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established., Methods: We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention., Results: At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P=0.97) or between the insulin-sensitization group (88.2%) and the insulin-provision group (87.9%, P=0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P=0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P=0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P=0.01; P=0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P=0.003)., Conclusions: Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision. (ClinicalTrials.gov number, NCT00006305.), (2009 Massachusetts Medical Society)

Background: Peritoneal carcinomatosis has a typical natural history of bowel obstruction and death. Significant evidence suggests that cytoreduction with heated intraperitoneal chemotherapy (HIPEC) improves long-term survival for these tumors., Methods: A retrospective case series of patients who underwent initial HIPEC treatment was performed at 2 moderate-volume centers. Clinicopathologic data were reviewed and univariate analyses performed to determine predictors of periprocedural complications., Results: Twenty-eight patients underwent HIPEC procedures. The most common pathologies were colonic adenocarcinoma and pseudomyxoma peritonei. The median preoperative peritoneal cancer index was 9.5. Thirteen patients had 34 complications, with no postoperative deaths. Pleural effusion and wound infection were the most common complications. Preoperative performance status and the extent of disease were predictive of complications., Conclusions: Cytoreduction and HIPEC can be done at moderate-volume centers with morbidity and mortality rates comparable with published results from large-volume centers. Preoperative performance status and the extent of disease predict postoperative complications.

Objective: To describe the disposition of and pharmacodynamic response to atenolol when administered as a novel transdermal gel formulation to healthy cats., Animals: 7 healthy neutered male client-owned cats., Procedures: Atenolol was administered either orally as a quarter of a 25-mg tablet or as an equal dose by transdermal gel. Following 1 week of treatment, an ECG and blood pressure measurements were performed and blood samples were collected for determination of plasma atenolol concentration at 2 and 12 hours after administration., Results: 2 hours after oral administration, 6 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 579 +/- 212 ng/mL. Two hours following transdermal administration, only 2 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 177 +/- 123 ng/mL. The difference in concentration between treatments was significant. Trough plasma atenolol concentrations of 258 +/- 142 ng/mL and 62.4 +/- 17 ng/mL were achieved 12 hours after oral and transdermal administration, respectively. A negative correlation was found between heart rate and plasma atenolol concentration., Conclusions and Clinical Relevance: Oral administration of atenolol at a median dose of 1.1 mg/kg every 12 hours (range, 0.8 to 1.5 mg/kg) in cats induced effective plasma concentrations at 2 hours after treatment in most cats. Transdermal administration provided lower and inconsistent plasma atenolol concentrations. Further studies are needed to find an effective formulation and dosing scheme for transdermal administration of atenolol.

The Steiner Minimal Tree (SMT) problem determines the minimal length network for connecting a given set of vertices in three-dimensional space. SMTs have been shown to be useful in the geometric modeling and characterization of proteins. Even though the SMT problem is an NP-Hard Optimization problem, one can define planes within the amino acids that have a surprising regularity property for the twist angles of the planes. This angular property is quantified for all amino acids through the Steiner tree topology structure. The twist angle properties and other associated geometric properties unique for the remaining amino acids are documented in this paper. We also examine the relationship between the Steiner ratio rho and the torsion energy in amino acids with respect to the side chain torsion angle chi(1). The rho value is shown to be inversely proportional to the torsion energy. Hence, it should be a useful approximation to the potential energy function. Finally, the Steiner ratio is used to evaluate folded and misfolded protein structures. We examine all the native proteins and their decoys at http://dd.stanford.edu. and compare their Steiner ratio values. Because these decoy structures have been delicately misfolded, they look even more favorable than the native proteins from the potential energy viewpoint. However, the rho value of a decoy folded protein is shown to be much closer to the average value of an empirical Steiner ratio for each residue involved than that of the corresponding native one, so that we recognize the native folded structure more easily. The inverse relationship between the Steiner ratio and the energy level in the protein is shown to be a significant measure to distinguish native and decoy structures. These properties should be ultimately useful in the ab initio protein folding prediction., ((c) 2006 Wiley-Liss, Inc.)

A 4-month-old West Highland White Terrier was evaluated for dyspnea. Severe cardiac silhouette enlargement was present radiographically. Severe right ventricular hypertrophy and dilation with a dilated pulmonary trunk and a stenosis of the right pulmonary artery were diagnosed via echocardiography. Additional areas of peripheral pulmonary artery stenosis were diagnosed with nonselective computed tomography (CT) angiography and selective fluoroscopic angiography. Balloon dilation therapy was unsuccessful and the imaging findings were confirmed at necropsy.

Background: The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial, a National Heart, Lung, and Blood Institute-sponsored study in type 2 diabetic patients with coronary artery disease, completed patient recruitment in March 2005. This trial had a nuclear substudy in addition to many other substudies., Methods and Results: After patient enrollment, adenosine gated single photon emission computed tomography perfusion imaging is performed at years 1 and 3. The images are interpreted at the core laboratory. Among the objectives of the nuclear substudy are (1) to determine the impact of the mode of therapy on left ventricular function, extent of ischemia, and scar; (2) to determine the impact of therapy on the progression/regression of ischemia/scar and changes in left ventricular function between years 1 and 3; and (3) to determine the independent and incremental prognostic value of ischemia, scar, and left ventricular function on the primary and secondary endpoints of the trial in the entire patient population and specified subgroups such as women, elderly patients, and minorities., Conclusions: This article describes the methodology and the initial experience of the nuclear core laboratory in this large multicenter trial and provides a summary of variables that are available for future analysis by the working group.

Estrogen receptor (ER)-positive MCF-7 breast cancer cell lines can be used both in vitro and in vivo to create anti-hormone resistance. Estrogen withdrawal in vitro results in spontaneous growth of MCF-7 cells. Similarly, culture in the selective ER modulators (SERMs) tamoxifen and raloxifene, can result in SERM resistance. This form of anti-hormone resistance is evidenced by SERM-stimulated tumor growth in athymic mice. These tumors are transplantable into successive generations of overiectomized SERM treated mice. However, there is an evolution of drug resistance to anti-hormones. This is evidenced by a change in sensitivity to estrogen. The natural hormone no longer stimulated tumor growth but causes apoptosis and tumor regression.

Objective: To determine clinical characteristics and clinicopathologic findings, including results of pericardial fluid analysis, and determine the outcome associated with pericardial effusion caused by cardiac lymphoma in dogs., Design: Retrospective case series., Animals: 12 dogs., Procedure: Medical records of affected dogs were reviewed for echocardiographic findings, radiographic findings, results of pericardial fluid analysis, clinicopathologic findings, treatment protocols, and outcomes., Results: Pericardial effusion was detected by echocardiography in all 12 dogs, and lymphoma was detected by cytologic examination of the effusion (11/12 dogs) or histologic examination of pericardium (3/12). Large-breed dogs were overrepresented; median weight was 40.5 kg (89.1 lb). Most hematologic and biochemical changes were mild and non-specific. Survival time for dogs treated with combination chemotherapeutic agents was 157 days and for dogs that did not receive chemotherapy survival time was 22 days. This difference was not significant, but several dogs had long-term survival., Conclusions and Clinical Relevance: Cardiac lymphoma is an uncommon cause of pericardial effusion, and results suggest that cardiac lymphoma does not always warrant the poor prognosis of other stage V, substage b lymphomas.

We report a case of primary cardiac lymphoma in a cat, causing pericardial effusion. A 13-year-old castrated male Himalayan cat was evaluated for chronic weight loss and radiographic finding of cardiomegaly. Pericardial effusion and a heart mass were detected via echocardiography. Pericardiocentesis and ultrasound-guided fine needle aspirate of the heart mass were performed under sedation. Antemortem diagnosis of cardiac lymphoma was made based on cytology of pericardial fluid. Based on physical examination, laboratory tests and abdominal radiographs, primary cardiac lymphoma was established as the presumptive clinical diagnosis. Treatment with chemotherapeutic agents was initiated.

The oestrogen receptor (ER) has proven to be an extraordinarily successful target for breast cancer treatment and prevention. The clinical use of tamoxifen, a nonsteroidal antioestrogen, demonstrated (1) that the strategic use of adjuvant tamoxifen in ER-positive patients could save lives and (2) that a selective ER modulator (SERM) could reduce the incidence of breast cancer in high-risk women. The ER is now the target for new and safer therapies such as the aromatase inhibitors and the pure antioestrogens that either block oestrogen synthesis or destroy the ER. However, the use of raloxifene, a SERM to prevent osteoporosis with the potential to prevent breast cancer has introduced a new dimension into preventive oncology. The widespread use of endocrine modulators (SERMs, aromatase inhibitors, and pure antioestrogens) raised the question of drug resistance. It is now clear that endocrine resistance can evolve through stages. Once a breast tumour becomes resistant to SERMs, the growth is stimulated by either the SERM or oestrogen. This is why an aromatase inhibitor is effective following SERM resistance and withdrawal. However, the extended use of repeated endocrine therapies now supersensitized the cells to oestrogen that causes apoptosis through the ER. We suggest that future clinical treatment strategies incorporate an 'oestrogen purge' to both enhance the actions of chemotherapy or completely reverse endocrine resistance and restore endocrine sensitivity. These new data build on the idea that breast cancer can be controlled as a chronic disease and will permit patients to live long and productive lives during targeted maintenance treatment.

Drug resistance to tamoxifen (Tam) is a significant clinical problem but the mechanism through which this occurs remains elusive. We have developed a number of xenograft models of Tam-stimulated growth that model breast cancer progression using estrogen receptor positive MCF-7 or T47D breast cancer cells. When estrogen-stimulated T47D:E2 tumors are treated long term with Tam, Tam-stimulated tumors develop (T47D:Tam) that are stimulated by both estrogen and Tam. When HER-2/neu status is determined, it is clear that the T47D:Tam tumors express significantly higher levels of HER-2/neu protein by immunohistochemistry and mRNA as measured by real-time RT-PCR. The T47D:Tam tumors also express higher levels of estrogen receptor and progesterone receptor protein than their estrogen-stimulated T47D:E2 counterparts. We compared out results to the MCF-7 model of Tam-stimulated growth. The MCF-7:Tam ST (estrogen- and Tam-stimulated) and MCF-7:Tam LT (estrogen-inhibited, Tam-stimulated) were bilaterally transplanted to account for any mouse to mouse variation and characteristic growth patterns were observed. TUNEL staining was performed on MCF-7:Tam LT treated with either estrogen or Tam and it was concluded that estrogen-inhibited tumor growth was a result of increased apoptosis. Three phases of tumor progression are described that involve increases in HER-2/neu expression, de-regulation of estrogen receptor expression and increases in apoptosis which in concert determine the phenotype of drug resistance to Tam.

Objective: Tamoxifen has mixed agonist/antagonist activities, leading to tissue-specific estrogen-like actions and endometrial cancer. The purpose of this study was to evaluate the effects of antiestrogens on the growth of estrogen receptor (ER)-positive ECC-1 endometrial cancer cells in vitro and in vivo., Methods: We performed growth studies and luciferase assays using ERE-tK and AP-1 reporters. ERalpha protein expression was measured by Western blot after antiestrogen treatments. We investigated the actions of antiestrogens on the transcription of the pS2 gene in situ measured by Northern blot and the actions of antiestrogens on the VEGF protein secreted by ELISA. ERalpha, ERbeta, EGFR, and HER2/neu mRNAs were determined by RT-PCR. Last, ECC-1 tumors were developed by inoculation of cells into ovariectomized athymic mice and treated with estradiol (E2), tamoxifen, raloxifene, and a combination., Results: E2 induced cell proliferation while antiestrogens did not. E2 and raloxifene down regulated ERalpha protein; in contrast, 4OHT did not. ICI182,780 completely degraded the receptor. ECC-1 cells express ERbeta at insignificant levels. Luciferase assays did not show any induction in ERE- nor AP-1-mediated transcription by antiestrogens. E2 caused a concentration-dependent increase in pS2 mRNA but antiestrogens did not. E2 increased VEGF expression in a dose-dependent manner and antiestrogens blocked E2 action. E2 down regulated HER2/neu while 4OHT and raloxifene did not change HER2/neu levels compared to control. In addition, EGFR mRNA was down regulated by E2 but raloxifene did not change it. Tamoxifen and raloxifene did not promote tumor growth in vivo. However, raloxifene (1.5 mg daily) only partially blocked E2-stimulated growth., Conclusion: Tamoxifen and raloxifene are antiproliferative agents and antiestrogens in ECC-1 endometrial cells in vitro and in vivo. The observation that selective estrogen-receptor modulators do not down regulate EGFR and HER2/neu mRNA may provide a potential role for these oncogenes in the development of raloxifene- or tamoxifen-stimulated endometrial cancer. The ECC-1 cell line could provide important new clues about the evolution of drug resistance to tamoxifen and raloxifene.

Amino acid Asp-351 in the ligand binding domain of estrogen receptor alpha (ERalpha) plays an important role in regulating the estrogen-like activity of selective estrogen receptor modulator-ERalpha complexes. 4-Hydroxytamoxifen is a full agonist at a transforming growth factor alpha target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with the wild-type ERalpha. In contrast, raloxifene (Ral), which is also a selective estrogen receptor modulator, is a complete antiestrogen in this system. Because D351G ERalpha allosterically silences activation function-1 activity in the 4-hydroxytamoxifen-ERalpha complex with the complete loss of estrogen-like activity, we examined the converse interaction of amino acid 351 and the piperidine ring of the antiestrogen side chain of raloxifene to enhance estrogen-like action. MDA-MB-231 cells were either transiently or stably transfected with Asp-351 (the wild type), D351E, D351Y, or D351F ERalpha expression vectors. Profound differences in the agonist and antagonist actions of Ralcenter dotERalpha complexes were noted only in stable transfectants. The agonist activity of the Ralcenter dotERalpha complex was enhanced with D351E and D351Y ERalpha, but raloxifene lost its agonist activity with D351F ERalpha. The distance between the piperidine nitrogen of raloxifene and the negative charge of amino acid 351 was critical for estrogen-like actions. The role of the piperidine ring in neutralizing Asp-351 was addressed using compound R1h, a raloxifene derivative replacing the nitrogen on its piperidine ring with a carbon to form cyclohexane. The derivative was a potent agonist with wild type ERalpha. These results support the concept that the side chain of raloxifene shields and neutralizes the Asp-351 to produce an antiestrogenic ERalpha complex. Alteration of either the side chain or its relationship with the negative charge at amino acid 351 controls the estrogen-like action at activating function 2b of the selective estrogen receptor modulator ERalpha complex.

Objectives: To determine whether a Traffic Sign Recognition Test (TSRT) can identify older drivers who recently had a motor vehicle crash (MVC)., Design: Retrospective, matched, case-control study., Setting: Licensed drivers in Galveston, Texas., Participants: 60 crash and 60 control subjects matched for age and gender. Cases were identified from accident records. Controls were selected from a randomized list of licensed drivers in Galveston., Measurements: Folstein Mini-Mental State Examination (MMSE) and the TSRT., Results: A TSRT significantly distinguished between case and control groups (P = .01). The MMSE did not (P = .61). A TSRT predicted MVC in a multivariate analysis controlling for education, MMSE score, race/ethnicity, and mileage driven/year (odds ratio = 0.88, 95% confidence interval = 0.77-1.00)., Conclusion: A TSRT successfully identifies older drivers with a recent MVC, but the test lacks sensitivity and specificity. A prospective study is needed to further delineate the TSRT's usefulness in predicting crash risk in older drivers.

Lead dislodgement is one of the most common complications of endocardial pacing lead implantation in dogs. Incidence of lead displacement appears to be higher in large-breed, compared with small-breed, dogs, suggesting that excessive neck movements may be a contributing factor. To avoid introducing pacing leads through a vein in the neck, we developed a technique for implantation of endocardial pacing leads through the right costocervical vein. A right second intercostal space thoracotomy was performed to expose the vein, and the pacing generator was placed in the musculature over the lateral aspect of the thorax. The technique was performed in 6 dogs, 5 of which had had an endocardial pacing lead dislodge. None of the dogs had problems with lead dislodgement during follow-up periods of 15 to 20 months. Implantation of endocardial pacing leads through the costocervical vein should not be considered a replacement for implantation through the jugular vein. However, we believe that this technique is indicated for large dogs in which endocardial pacing leads implanted through the jugular vein have dislodged.

AN analysis has been made of the family histories of a survey of 1280 cases of IDDM entering Children's Hospital of Pittsburgh between December 31, 1964 and January 1, 1981, discharged on insulin and initial age of onset under 17 yr. Family histories revealed an increased occurrence of IDDM among relatives in the affected families. The risk to siblings was estimated by age-corrected proband exclusion (3.3%) by age 20 and by the Li-Mantel segregation ratio estimator (6.0%). The comparison of these risk measures is discussed. The occurrence of IDDM among the parents is 2.6% and of NIDDM among the parents is 2.4%. A comparison of risk to relatives (parents, sibs, uncles, half-sibs) observed in the Pittsburgh Study to those of six other studies reveal essentially equivalent rates. There is no increased risk to siblings of a diabetic who had an early age of onset. There is an increased risk to siblings of a diabetic (10.5%) in families where at least one parent has insulin-dependent diabetes mellitus (IDDM) and also an increased risk to siblings of a diabetic (8.8%) when at least one parent has non-insulin-dependent diabetes (NIDDM). The average age of onset for second cases in a family is significantly older than age of onset in single case families.

The results of a national investigation to determine the prevalence of Huntington's chorea in South Africa are presented. A total of 481 persons who have died from or are presently suffering from the disorder have been identified. The prevalence rate of 0,1 per million in the South African Negro population is much less than the estimate of 22 per million in the White and Coloured groups. It is apparent that the great variation in the ethnic distribution of the disease is a reflection of the diverse origins of the different population groups of South Africa.