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Abstract Transcription factors are key mediators of human complex disease processes. Identifying the target genes of transcription factors will increase our understanding of the biological network leading to disease risk. The prediction of transcription factor binding sites (TFBSs) is one method to identify these target genes; however, current prediction methods need improvement. We chose the transcription factor upstream stimulatory factor l (USF1) to evaluate the performance of our novel TFBS prediction method because of its known genetic association with coronary artery disease (CAD) and the recent availability of USF1 chromatin immunoprecipitation microarray (ChIP-chip) results. The specific goals of our study were to develop a novel and accurate genome-scale method for predicting USF1 binding sites and associated target genes to aid in the study of CAD. Previously published USF1 ChIP-chip data for 1 per cent of the genome were used to develop and evaluate several kernel logistic regression prediction models. A combination of genomic features (phylogenetic conservation, regulatory potential, presence of a CpG island and DNaseI hypersensitivity), as well as position weight matrix (PWM) scores, were used as variables for these models. Our most accurate predictor achieved an area under the receiver operator characteristic curve of 0.827 during cross-validation experiments, significantly outperforming standard PWM-based prediction methods. When applied to the whole human genome, we predicted 24,010 USF1 binding sites within 5 kilobases upstream of the transcription start site of 9,721 genes. These predictions included 16 of 20 genes with strong evidence of USF1 regulation. Finally, in the spirit of genomic convergence, we integrated independent experimental CAD data with these USF1 binding site prediction results to develop a prioritised set of candidate genes for future CAD studies. We have shown that our novel prediction method, which employs genomic features related to the presence of regulatory elements, enables more accurate and efficient prediction of USF1 binding sites. This method can be extended to other transcription factors identified in human disease studies to help further our understanding of the biology of complex disease.

Abstract Background Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders. Methods We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR). Results Our analysis revealed a genomic deletion containing the oxytocin receptor gene, OXTR (MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls. Conclusion Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the disorder. See the related commentary by Gurrieri and Neri: http://www.biomedcentral.com/1741-7015/7/63

Abstract Background We previously identified a 40 Mb region of linkage on chromosome 1q in our early onset coronary artery disease (CAD) genome-wide linkage scan (GENECARD) with modest evidence for linkage (n = 420, LOD 0.95). When the data are stratified by acute coronary syndrome (ACS), this modest maximum in the overall group became a well-defined LOD peak (maximum LOD of 2.17, D1S1589/D1S518). This peak overlaps a recently identified inflammatory biomarker (MCP-1) linkage region from the Framingham Heart Study (maximum LOD of 4.27, D1S1589) and a region of linkage to metabolic syndrome from the IRAS study (maximum LOD of 2.59, D1S1589/D1S518). The overlap of genetic screens in independent data sets provides evidence for the existence of a gene or genes for CAD in this region. Methods A peak-wide association screen (457 SNPs) was conducted of a region 1 LOD score down from the peak marker (168–198 Mb) in a linkage peak for acute coronary syndrome (ACS) on chromosome 1, within a family-based early onset coronary artery disease (CAD) sample (GENECARD). Results Polymorphisms were identified within the 'family with sequence similarity 5, member C' gene (FAM5C) that show genetic linkage to and are associated with myocardial infarction (MI) in GENECARD. The association was confirmed in an independent CAD case-control sample (CATHGEN) and strong association with MI was identified with single nucleotide polymorphisms (SNPs) in the 3' end of FAM5C. FAM5C genotypes were also correlated with expression of the gene in human aorta. Expression levels of FAM5C decreased with increasing passage of proliferating aortic smooth muscle cells (SMC) suggesting a role for this molecule in smooth muscle cell proliferation and senescence. Conclusion These data implicate FAM5C alleles in the risk of myocardial infarction and suggest further functional studies of FAM5C are required to identify the gene's contribution to atherosclerosis.

BACKGROUND: Anemia is a reduction in the oxygen-carrying capacity of red blood cells that results in a variety of symptoms, including dyspnea, headaches, light-headedness, and fatigue. Although anemia has been associated with reduced health-related quality of life (HRQoL), its treatment has not yet been consistently shown to improve HRQoL. OBJECTIVE: This systematic review of the literature was conducted to determine whether the treatment of anemia improves HRQoL domains, regardless of the type of underlying disease. METHODS: Data for this review were drawn from the clinical trial databases from 2 previous systematic literature reviews of erythropoiesis-stimulating protein treatment for renal insufficiency- and cancer-related anemia, both spanning the period January 1, 1980, through December 31, 2001. MEDLINE, Cancerlit, and Current Contents/Clinical Medicine were searched using the combined terms erythropoietin, kidney failure, neoplasms, and anemia. The reference lists of all identified articles were searched manually for additional relevant papers. The review included prospective studies that reported both HRQoL and hematocrit (Hct) in patients with cancer or renal insufficiency who received treatment for anemia with an erythropoiesis-stimulating protein. HRQoL was categorized by domain (overall, energy/fatigue, physical, activity); changes in HRQoL domains were expressed as effect sizes and meta-analyzed, as were correlation coefficients. The effects on HRQoL of dropout rate, study duration, baseline Hct, and change in Hct were examined in meta-regression analyses. RESULTS: Sixteen studies each were identified in patients with renal insufficiency (N = 2253) and patients with cancer (N = 10,695). The treated groups included 11,710 patients, and the control groups included 1238 patients. The baseline Hct in all treated groups averaged 26.0%: 28.3% in the group with cancer and 24.4% in the group with renal insufficiency. The mean improvement in Hct from baseline to the end of treatment was 8.3% (range, 1.0%-16.5%) in treated patients and 1.0% (range, 0.0%-3.3%) in controls. The Hct changes were similar in treated patients with cancer and treated patients with renal insufficiency, as was the HRQoL effect size (0.43). Dropout rate and study duration were not significant predictors of HRQoL changes, but change in Hct was a significant predictor in both conditions. Meta-analysis of the correlation coefficients, adjusting for HRQoL domains, showed a consistent and significant positive correlation between change in Hct and change in HRQoL (P < 0.001). CONCLUSION: The consistency in both direction and magnitude of effect across many studies and thousands of patients supports the hypothesis that treatment of anemia with erythropoiesis-stimulating protein improves selected HRQoL domains in patients with renal insufficiency- or cancer-related anemia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Systolic hypertension is the most common form of hypertension, particularly in people aged >60 years. Caused by decreased compliance of large arteries, systolic hypertension is an independent risk factor for cardiovascular disease. Recent studies have demonstrated that it is more important to control systolic blood pressure (SBP) than diastolic blood pressure (DBP). OBJECTIVE: The objective of this study was to perform a systematic literature review to examine the effectiveness of amlodipine in lowering SBP in a variety of patient subgroups and clinical settings. METHODS: The literature review methodology included identifying, selecting, appraising, extracting, and synthesizing primary research studies. Following an a priori protocol, published literature was searched from 1980 to 2001 using 3 electronic databases. A manual review of the reference lists of recent review articles and all accepted studies was performed. Parallel-group, randomized, controlled trials that included at least 10 adults with baseline hypertension (SBP>or=140 mm Hg, DBP>or=90 mm Hg, or both), included at least 1 arm randomized to initial treatment with amlodipine monotherapy, had a minimum treatment duration of 8 weeks, and reported baseline and end-point blood pressure were included. RESULTS: Of 696 citations identified, 85 primary studies met all inclusion criteria. Comparable treatment arms were pooled, and weightd mean SBP was calculated. In the amlodipine monotherapy arms, which included >5000 patients, SBP decreased by a mean of 17.5 mm Hg from baseline. The effect of amlodipine in reducing SBP was greater in elderly patients (age>or=60 years) and patients with author-defined isolated systolic hypertension. The dose was titrated to achieve the target blood pressure in 73 of 89 amlodipine treatment arms, whereas 16 treatment arms reported fixed doses. The median daily dose was 5 mg (range, 1.25-15 mg) in both the fixed-dose and dose-titration groups. CONCLUSIONS: In this review of the published literature, amlodipine monotherapy was effective in reducing SBP. Antihypertensive agents such as amlodipine warrant consideration for the management of patients with inadequately controlled SBP. [ABSTRACT FROM AUTHOR]

Background/objective: National guidelines do not recommend the routine use of antimicrobial prophylaxis in patients with solid tumors, yet prophylactic agents are still sometimes prescribed for head and neck cancer patients. The purpose of this study is to determine the effect of prophylactic antimicrobials on the incidence of infection in patients undergoing chemoradiation for head and neck cancer., Methods: Between 2013 and 2016, patients receiving chemoradiation for head and neck cancer at three outpatient oncology clinics were identified by retrospective review. Cohorts were based on administration or absence of prophylactic antimicrobials. The primary outcome of this study was incidence of infection. Secondary outcomes included incidence of hospitalization and length of hospital stay., Results: Seventy-seven patients were analyzed, 47% (n = 36) were not prescribed antimicrobial prophylaxis and 53% (n = 41) were prescribed prophylaxis. Infection occurred in 31 patients in the no prophylaxis cohort and in 34 patients in the prophylaxis cohort (86.1% vs. 82.9%, p  = 0.945). Twenty patients in the no prophylaxis cohort were hospitalized versus 16 patients in the prophylaxis cohort ( p  = 0.222). The average length of hospital stay was 6 days in the no prophylaxis cohort and 10.6 days in the prophylaxis cohort ( p  = 0.007)., Conclusion: The use of antimicrobial prophylaxis did not significantly impact the incidence of infection when compared to patients who were not prescribed prophylaxis. There was no difference in the incidence of hospitalization, however, the patients in the prescribed prophylactic group had longer length of hospital stay.

Elucidating how serine/threonine phosphatases regulate kinase function and bacterial virulence is critical for our ability to combat these infections. Group B streptococci (GBS) are β-hemolytic Gram-positive bacteria that cause invasive infections in humans. To adapt to environmental changes, GBS encodes signaling mechanisms comprising two component systems and eukaryotic-like enzymes. We have previously described the importance of the serine/threonine kinase Stk1 to GBS pathogenesis. However, how the presence or absence of the cognate serine/threonine phosphatase Stp1 affects Stk1 function and GBS virulence is not known. Here, we show that GBS deficient only in Stp1 expression are markedly reduced for their ability to cause systemic infections, exhibit decreased β-hemolysin/cytolysin activity, and show increased sensitivity to autolysis. Although transcription of genes important for β-hemolysin/cytolysin expression and export is similar to the wild type (WT), 294 genes (excluding stp1) showed altered expression in the stp1 mutant and included autolysin genes. Furthermore, phosphopeptide enrichment analysis identified that 35 serine/threonine phosphopeptides, corresponding to 27 proteins, were unique to the stp1 mutant. This included phosphorylation of ATP synthase, DNA and RNA helicases, and proteins important for cell division and protein synthesis. Collectively, our results indicate that Stp1 is important for appropriate regulation of Stk1 function, hemolysin activity, autolysis, and GBS virulence.

Group B Streptococcus (GBS) is an important cause of invasive infections in humans. The pathogen encodes a number of virulence factors including the pluripotent beta-haemolysin/cytolysin (beta-H/C). As GBS has the disposition of both a commensal organism and an invasive pathogen, it is important for the organism to appropriately regulate beta-H/C and other virulence factors in response to the environment. GBS can repress transcription of beta-H/C using the two-component system, CovR/CovS. Recently, we described that the serine/threonine kinase Stk1 can phosphorylate CovR at threonine 65 to relieve repression of beta-H/C. In this study, we show that infection with CovR-deficient GBS strains resulted in increased sepsis. Although CovR-deficient GBS showed decreased ability to invade the brain endothelium in vitro, they were more proficient in induction of permeability and pro-inflammatory signalling pathways in brain endothelium and penetration of the blood-brain barrier (BBB) in vivo. Microarray analysis revealed that CovR positively regulates its own expression and regulates the expression of 153 genes. Collectively, our results suggest that the positive feedback loop which regulates CovR transcription modulates host cell interaction and immune defence and may facilitate the transition of GBS from a commensal organism to a virulent meningeal pathogen.

Exotoxins, including the hemolysins known as the alpha (alpha) and beta (beta) toxins, play an important role in the pathogenesis of Staphylococcus aureus infections. A random transposon library was screened for S. aureus mutants exhibiting altered hemolysin expression compared to wild type. Transposon insertions in 72 genes resulting in increased or decreased hemolysin expression were identified. Mutations inactivating a putative cyclic di-GMP synthetase and a serine/threonine phosphatase (Stp1) were found to reduce hemolysin expression, and mutations in genes encoding a two component regulator PhoR, LysR family transcriptional regulator, purine biosynthetic enzymes and a serine/threonine kinase (Stk1) increased expression. Transcription of the hla gene encoding alpha toxin was decreased in a Deltastp1 mutant strain and increased in a Deltastk1 strain. Microarray analysis of a Deltastk1 mutant revealed increased transcription of additional exotoxins. A Deltastp1 strain is severely attenuated for virulence in mice and elicits less inflammation and IL-6 production than the Deltastk1 strain. In vivo phosphopeptide enrichment and mass spectrometric analysis revealed that threonine phosphorylated peptides corresponding to Stk1, DNA binding histone like protein (HU), serine-aspartate rich fibrinogen/bone sialoprotein binding protein (SdrE) and a hypothetical protein (NWMN&#95;1123) were present in the wild type and not in the Deltastk1 mutant. Collectively, these studies suggest that Stk1 mediated phosphorylation of HU, SrdE and NWMN&#95;1123 affects S. aureus gene expression and virulence.

Suffering is frequent among patients, and it is common for physicians to attempt to avoid contact with individuals who are dying, debilitated, or in pain. Both patients and physicians are harmed when this happens: patients feel abandoned, resulting in unnecessary suffering, and physicians miss moments of meaning and renewal through direct connection. Ernest Gaines's novel A Lesson Before Dying is not a medical story, yet one character, Grant Wiggins, behaves like a physician when he tries to avoid direct, personal contact with Miss Emma, a community member who is suffering. This novel illuminates the tendency of human beings (including physicians) to try to avoid suffering, and the realization of this tendency can provide opportunities for ongoing medical education to help students, residents, and faculty members recognize their discomfort about suffering and learn to address it appropriately.

All living organisms respond to changes in their internal and external environment for their survival and existence. Signaling is primarily achieved through reversible phosphorylation of proteins in both prokaryotes and eukaryotes. A change in the phosphorylation state of a protein alters its function to enable the control of cellular responses. A number of serine/threonine kinases regulate the cellular responses of eukaryotes. Although common in eukaryotes, serine/threonine kinases have only recently been identified in prokaryotes. We have described that the human pathogen Group B Streptococcus (GBS, Streptococcus agalactiae) encodes a single membrane-associated, serine/threonine kinase (Stk1) that is important for virulence of this bacterium. In this study, we used a combination of phosphopeptide enrichment and mass spectrometry to enrich and identify serine (S) and threonine (T) phosphopeptides of GBS. A comparison of S/T phosphopeptides identified from the Stk1 expressing strains to the isogenic stk1 mutant indicates that 10 proteins are potential substrates of the GBS Stk1 enzyme. Some of these proteins are phosphorylated by Stk1 in vitro and a site-directed substitution of the phosphorylated threonine to an alanine abolished phosphorylation of an Stk1 substrate. Collectively, these studies provide a novel approach to identify serine/threonine kinase substrates for insight into their signaling in human pathogens like GBS.

All living organisms communicate with the external environment for their survival and existence. In prokaryotes, communication is achieved by two-component systems (TCS) comprising histidine kinases and response regulators. In eukaryotes, signalling is accomplished by serine/threonine and tyrosine kinases. Although TCS and serine/threonine kinases coexist in prokaryotes, direct cross-talk between these families was first described in Group B Streptococcus (GBS). A serine/threonine kinase (Stk1) and a TCS (CovR/CovS) co-regulate toxin expression in GBS. Typically, promoter binding of regulators like CovR is controlled by phosphorylation of the conserved active site aspartate (D53). In this study, we show that Stk1 phosphorylates CovR at threonine 65. The functional consequence of threonine phosphorylation of CovR in GBS was evaluated using phosphomimetic and silencing substitutions. GBS encoding the phosphomimetic T65E allele are deficient for CovR regulation unlike strains encoding the non-phosphorylated T65A allele. Further, compared with wild-type or T65A CovR, the T65E CovR is unable to bind promoter DNA and is decreased for phosphorylation at D53, similar to Stk1-phosphorylated CovR. Collectively, we provide evidence for a novel mechanism of response regulator control that enables GBS (and possibly other prokaryotes) to fine-tune gene expression for environmental adaptation.

Narrative is ever present in medicine and is an integral aspect of the doctor and patient relationship. Although theoretical discussions of narrative medicine and narrative ethics are important, they may serve to reify the patient's story, to make it a specific entity. In practice, the patient's story unfolds in the moment of communication depending on the individuals and the circumstances; the story is not an "object." Patients' narratives heard in clinical settings are often limited by physician behaviors, especially the tendency of physicians to control the interaction with the patient. To develop individual narratives effectively and competently, physicians must be able to help the patient tell the story that is most important, meaningful, and descriptive of the situation. If the patient's narrative is not heard fully, the possibility of diagnostic and therapeutic error increases, the likelihood of personal connections resulting from a shared experience diminishes, empathic opportunities are missed, and patients may not feel understood or cared for. The practice of mindfulness--moment-to-moment, nonjudgmental awareness--opens a doorway into the patient's story as it unfolds. Such mindful practice develops the physician's focus of attention and offers the possibility for a meaningful and important narrative to arise between patient and physician.

Bisphosphonate drugs for treating osteoporosis are excreted by the kidney. However, many of the major trials on efficacy and safety of the bisphophonates for treating osteoporosis excluded patients with significant renal compromise. Since both osteoporosis and renal insufficiency become more prevalent with age, it seems prudent for physicians to be aware of the prevalence of renal dysfunction in patients with osteoporosis who are candidates for treatment with bisphosphonates. Data on 13,831 men and women aged 20+ from the Third National Health and Nutrition Examination Survey, 1988-1994 (NHANES III) were used to study the occurrence of compromise in renal clearance function in men and women with osteopenia and osteoporosis. To estimate creatinine clearance (CCr), a measure of renal function, serum creatinine (sCr), weight and age were inserted into the Cockcoft-Gault (C-G) formula. The World Health Organization gender specific bone mineral density (BMD) cut-offs were used to define the populations with osteopenia and osteoporosis. For women ages 20-80+ with osteoporosis, the percent prevalence (95% CI) for mild to moderate compromise of CCr

The authors wanted to determine whether adding interferon-alpha (IFN-alpha) to chemotherapy regimens, in either induction or maintenance settings, provides additional survival benefits in follicular non-Hodgkin's lymphoma (NHL). A meta-analysis was performed based on published data from randomized controlled clinical trials involving nine separate study populations. Patients receiving IFN-alpha (in either induction or maintenance therapy) had significantly increased 5-year and progression-free survival rates at 3 and 5 years compared with concurrent controls. The advantages of IFN-alpha therapy were most marked in studies using anthracycline-containing induction chemotherapy; in these studies, patients who received IFN-alpha had approximately 20% increased progression-free survival rates compared with controls and a lesser survival advantage. The available literature did not allow a determination of the relative benefit of IFN-alpha in induction or maintenance treatments for NHL or a determination of the optimum duration of IFN-alpha treatment. Although questions remain about its optimal use. IFN-alpha appears to prolong survival time in patients with follicular NHL.

Objective: To explore characteristics of patients who are physically healthy but who perceive poor health by investigating the hypothesis that mental health problems, financial strain, and deficiencies in social support underlie why these patients are "worried sick.", Methods: Three hundred forty-eight continuity patients in 2 rural primary care practices were administered the PRIME-MD, the MOS SF-36, a health-related worry (1-item, 5-point) scale, the MOS social support survey, and perceived economic strain instruments. The patient's physician rated physical health on a 10-point scale. Health care utilization was defined as the number of office visits and total office and laboratory charges for 6 months before and after the interview date., Results: Two hundred thirty-seven patients (group A) scored in the upper and middle terciles on the MOS health perceptions scale. One hundred eleven patients scored in the lower tercile on health perceptions: 59 (group B) were rated as having good physical health (physical health rating > 6) and 52 (group C) as having poor health (rating < or = 6). The "worried sick" patients (group B) resembled Group A with regard to physical health, but resembled the sick (group C) with regard to all MOS functional scales, prevalence of mental health diagnoses, and worry. Social support was similar across groups. Only 1 of 3 measures of economic strain was less in group A than B and C., Conclusions: Our measures of mental health problems, financial strain, and deficiencies in social support accounted only in part for the differences among the three groups. Other explanations of why some are "worried sick" require study, such as other life stressors and personality traits.

To establish the evidence base for the diagnosis of sleep apnea (SA) in adult patients, a systematic review of the literature from 1980 through November 1, 1997 was performed. Diagnostic studies were included if they reported results of any test to establish or support a diagnosis of SA, in comparison to a diagnosis from a full polysomnogram (PSG). Test results were meta-analyzed using fixed effects models and summary receiver operating characteristic curves (ROCs) to examine consistency of tests within and between diagnostics vs. the "gold standard" of PSG. From a total of 937 studies, 249 fit the broad eligibility criteria for inclusion in the clinical trial database and its data were extracted from these reports; useable data for statistical analyses were reported in 71 studies (7,572 patients). The sensitivity and specificity of partial channel and partial time PSGs appeared most promising as replacements for full PSG in patients suspected of obstructive SA. Clinical prediction rules (multivariate models) were also promising. Studies of portable sleep monitors, radiologic or morphologic features, and focused questionnaires were too heterogeneous to be meta-analyzed. In general, the diversity of study designs and objectives were very high and the methodological rigor of these studies as assessments of diagnostic tests was very low. Thus, we are still not in a position to recommend standardization of diagnostic methodology for sleep apnea. Instead, our recommendations for future research include standardization of terms and diagnostic criteria, and consistently reported statistics to enhance the utility of this literature.

We performed a literature search for all clinical studies reporting outcomes in patients with the acquired immunodeficiency syndrome (AIDS) receiving granulocyte-macrophage colony-stimulating factor (GM-CSF) for any indication. Safety outcomes included human immunodeficiency virus replication, immune status, and frequency of opportunistic infections and neoplasms. Data were synthesized qualitatively. We identified 22 studies (274 patients): 12 addressed AIDS neutropenia, 8 AIDS cancer therapy, and 2 opportunistic infections. Viral burden was assessed by serum p24Ag in 15 studies. Nine reported no change in levels, three net decreases, and three net increases. All studies showing net increases involved patients receiving GM-CSF without a concurrent antiretroviral. The CD4 counts were unchanged in 5 studies, increased in 3, and not reported in 14. The incidence of neoplasms or new opportunistic infections was low. The literature suggests no increased risk of viral replication or clinical deterioration in patients with AIDS who take GM-CSF concurrently with zidovudine.

We conducted a systematic review of all published randomized, controlled trials to assess the risk of cancer or death in patients receiving verapamil for hypertension, angina pectoris, or cardiac arrhythmias. Meta-analysis comparing the risk of new cancers, cancer deaths, and all deaths was performed. Thirty-nine trials comprising 11,201 patients were eligible. Study durations ranged from 8 days-6 years (mean 29.5 wks). Nine trials (6507 patients) were 24 weeks in duration or longer. For cancer and cancer death, OR was 1.20 (95% CI = 0.60-2.42) for verapamil versus active controls and 0.73 (95% CI = 0.39-1.39) for verapamil versus placebo. For all deaths, OR was 1.13 (95% CI = 0.70-1.82) for verapamil versus active controls and 0.85 (95% CI = 0.71-1.00) for verapamil versus placebo. Sensitivity analysis for the 9 trials 24 weeks' duration or longer gave similar results. There is no statistically significant increased risk of cancer or deaths with verapamil compared with active controls or placebo.

Objective: To determine the prevalence of mental disorders in rural primary care office practice., Design: Patient interview; chart review., Setting: Two rural primary care office practices., Patients: Three hundred-fifty scheduled or walk-in patients age 18 years or older., Measurements: Medical Outcomes Study 36-Item Short-Form Health Survey (MOS SF-36), the Primary Care Evaluation of Mental Disorders (PRIME-MD), physical health using Greenfield's index of coexistent disease (ICED), and health care utilization using the number of office visits and total office and laboratory charges six months before until six months after the interview., Results: Of these patients 34% met criteria for one or more of the 18 mental disorders evaluated by the PRIME-MD; 19% met criteria for specific disorders according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R). Mood disorders were most common (21.7%), followed by anxiety disorders (12.3%), somatoform disorders (11.1%), probable alcohol abuse or dependence (6.0%), and eating disorders (2.0%). By logistic regression, there was an association of age, sex, race (black), and education with lower prevalence of various mental disorder categories. Even after adjustment for demographic variables and physical health (ICED score), those with PRIME-MD diagnoses had significantly lower function as measured by the eight MOS SF-36 scales and higher utilization of office services (p < .001)., Conclusions: The prevalence of mental disorders in rural primary care office practice is as high as in urban office practice.

Introduced to U.S. medical schools in 1972, the field of literature and medicine contributes methods and texts that help physicians develop skills in the human dimensions of medical practice. Five broad goals are met by including the study of literature in medical education: 1) Literary accounts of illness can teach physicians concrete and powerful lessons about the lives of sick people; 2) great works of fiction about medicine enable physicians to recognize the power and implications of what they do; 3) through the study of narrative, the physician can better understand patients' stories of sickness and his or her own personal stake in medical practice; 4) literary study contributes to physicians' expertise in narrative ethics; and 5) literary theory offers new perspectives on the work and the genres of medicine. Particular texts and methods have been found to be well suited to the fulfillment of each of these goals. Chosen from the traditional literary canon and from among the works of contemporary and culturally diverse writers, novels, short stories, poetry, and drama can convey both the concrete particularity and the metaphorical richness of the predicaments of sick people and the challenges and rewards offered to their physicians. In more than 20 years of teaching literature to medical students and physicians, practitioners of literature and medicine have clarified its conceptual frameworks and have identified the means by which its studies strengthen the human competencies of doctoring, which are a central feature of the art of medicine.

Objective: To describe the clinical features of home visits and their role in continuity of care, costs, and benefits in a rural office practice., Design: Prospective study of all home visits performed during a 26-month period., Setting: A general medicine teaching office practice located in rural Virginia., Patients: All persons to whom home visits were made during the study period., Main Results: 138 home visits were made to 47 patients who had a mean age of 73.2 years. Home visits accounted for 1.4% of patient encounters in the practice, required a mean of 7.1 miles of one-way travel and a mean of 48 minutes, including travel time, to complete, and generated $36 in income per visit. Most patients (27 of 47) were not permanently homebound. Reasons for patients' being homebound were grouped into six categories (acute illness, frail elderly, terminal illness, advanced chronic disease, neurologic problem, and miscellaneous reasons). The reasons for visits were grouped into four categories (acute self-limited illness, exacerbation of chronic disease, routine follow-up of chronic disease, and psychosocial problem). Physicians judged that 80% of home visits represented appropriate use of their services. In addition, 46% of home visits made an emergency room visit unnecessary, and 9% made a hospital admission unnecessary. At the time of 75% of home visits, physicians reported personal benefits of making the visit., Conclusions: Home visits have an important role in the care of ambulatory as well as permanently homebound patients. While physicians judged most home visits to be appropriate and personally beneficial, these visits required more time and generated less revenue than did office visits for comparable problems. Because home visits generated as well as prevented the use of medical services, their impact on the overall cost of medical care in this setting is unclear.

In 1989 the authors surveyed faculty who were teaching medical ethics in residencies in order to obtain information concerning the goals, formats, topics, and settings of such teaching, as well as the difficulties encountered. Of 163 teachers contacted, 94 (58%) responded and 63 (39%), representing 50 institutions, reported participation in formal ethics teaching programs for residents. The 63 teachers reported using a variety of formats, including ethics rounds, lectures, and incorporating ethics teaching into weekly case-management conferences. Frequently mentioned goals of ethics teaching included improving the residents' skills in reasoning about ethical decisions and improving the residents' understanding of the language and concepts of ethics. Thirty-four of the 63 teachers (54%) taught ethics in hospital settings exclusively and 21 (33%) taught both in hospitals and in outpatient clinics or offices. The teachers identified a number of barriers encountered in carrying out such teaching, most of which can be grouped in six categories: (1) time constraints due to residents' heavy schedules; (2) attitudes of residents that pose obstacles; (3) logistical problems associated with teaching in the clinical setting; (4) time demands placed on teachers; (5) lack of reinforcement for teaching ethics from other faculty; and (6) shortcomings in the background and training of faculty for teaching ethics in the clinical setting. The authors conclude that difficulties are commonly encountered and discuss ways to overcome the principal barriers to effective teaching of ethics in the residency years.

Skin necrosis is a well-known yet rare complication of oral anticoagulant therapy. We report the unusual recurrence of lesions typical of warfarin skin necrosis in the absence of anticoagulant therapy. A 59-year-old woman developed skin necrosis while receiving prophylactic warfarin following the detection of a large left ventricular thrombus. The warfarin was discontinued and the lesions improved. One month later new areas of skin necrosis developed although the patient had received no further warfarin. Progressive congestive heart failure, poor nutrition, and prolonged oral antibiotic therapy preceded the recurrence. Vitamin K deficiency was present on admission. The potential role of vitamin K-dependent coagulation factors in the pathogenesis of anticoagulant-associated skin necrosis is discussed.

Objective: To determine what proportion of patients who have poor health perceptions are physically healthy and to explore why some patients perceive a healthy state while others perceive illness., Design: A prospective consecutive series of office patients completed the Rand Corporation's General Health Perceptions Questionnaire, and their physicians rated their physical health. Their use of health care services was determined for the following 12 months., Setting: A rural teaching office practice., Patients: Of 243 adult patients asked to complete the questionnaire, 32 were excluded, for dementia (8), illiteracy (4), illness (8), incomplete questionnaires (6), and other reasons (6). 208 patients (86%) formed the final study group., Measurements and Main Results: 62 of 208 patients had poor health perception scores. 39 of the 62 were rated by physicians as physically healthy and were not statistically different in physical health ratings or numbers of prescribed medications from the 146 patients who had higher health perception scores. However, these 39 patients had significantly more health-related worry, acute pain, and depression than did the other 146 patients. They also made more office visits and telephone calls and had higher total primary care charges., Conclusions: This study suggests that 21% of adult primary care patients (39 of 208) have health perceptions lower than expected for their levels of physical health. These low health perceptions are correlated with increased emotional distress and higher utilization of health care resources. Strategies to identify these patients and interventions to improve their views of their health could reduce utilization.

Emotions play a central role in our daily lives. They influence our behavior as well as the development and direction of our relationships. Clinically, emotions may signal the presence of ethical conflicts between patients, physicians, and others involved in the patients' care. Emotions need to be recognized as physicians work toward empathic interactions, while both reason and emotion need to be integrated into the process of ethical decision making to ensure balanced outcomes.

Medical residents require an experience beyond the tertiary care hospital to understand many aspects of contemporary medical practice and to make informed career choices. To provide this balanced training, the University of Virginia has operated for 10 years an internal medicine teaching office practice to provide an outpatient experience similar to private practice. It allows residents to work closely with general internal medicine faculty and introduces them to the knowledge and skills necessary to establish and manage a successful practice. The curriculum of the 10 week rotation includes patient care in the office and by telephone, nursing home and home visits, tutorials and seminars on primary care and office management topics, and training in the use of microcomputers. A survey of 46 (92%) of the first 50 residents completing the rotation revealed that the content of the rotation was valuable, the rotation substantially influenced career choices, and the rotation helped provide a balanced view of internal medicine practice.

This prospective study was conducted to determine the influence of primary care patients' health perceptions on their utilization of health care services. Patients' health perceptions were measured using the RAND Corporation's General Health Perceptions Questionnaire. Physicians provided scores of how they thought the patients perceived their health and of actual physical and emotional health. Utilization data (number of office visits, number of telephone calls to the physician, and ambulatory charges) were evaluated for a 12-month period after completion of the questionnaire. Of 208 patients, 62 (30%) patients with health perceptions scores less than 50 had greater degrees of anxiety (P less than .001), depression (P less than .001), health-related worry (P less than .001), and felt less able to resist illness (P less than .001) than patients with higher health perception scores. Analysis of covariance was used to control for differences in physical health among groups of patients with varying health perceptions. These analyses revealed that patients with low health perceptions made more office visits (P = .002), more telephone calls to the physician (P = .01), and had more office charges (P = .05) than patients with higher scores. Physicians accurately predicted the patients' health perceptions in 49% of the cases. In 37%, they thought patients would score their health perceptions higher than they did; in 14% they thought patients would score their health perceptions lower. Health perceptions are an important factor contributing to the use of health care by primary care patients, regardless of the patient's actual physical health. Persons with low health perceptions account for approximately 5% of office visits, a clinically important fraction, especially when compared to the 9% of office visits for hypertension, the most common disease treated in the medical office.

Five hundred sixty-two consecutive patient visits to a medical office were prospectively evaluated for the presence of ethical problems. During 23 (4.0%) visits, patients refused recommended medical intervention. Refusal was defined as the rejection of preventive health measures, diagnostic evaluation, hospitalization, and other office procedures. Preventive health measures, vaccinations, and cancer screening were the most common types of intervention refused (n = 10). Diagnostic studies, such as roentgenograms, biopsies, and cardiac stress testing were also commonly refused (n = 9). The reasons for the refusal included psychologic factors, such as fear and anxiety, previous "bad" experiences with the recommended intervention, distrust of physicians, and problems of communication. Fourteen patients suffered no major consequences from their refusal, five of whom were seen twice during the study. Five patients had a delayed diagnosis and one patient died of a myocardial infarction after refusing hospitalization for unstable angina.

When patients request checkups, physicians may assume it is for detection of asymptomatic disease. However, such patients may have other, covert reasons for seeking medical care which might not be addressed by a periodic health examination. The authors interviewed 38 consecutive patients who requested a new appointment at an academic, hospital-based general medical practice, and said the appointment was for a checkup and not an acute problem. Health screening was the principal reason for requesting evaluation of only 24% of patients. Fifty-two per cent had two or more reasons: psychosocial problems, health concerns, or symptoms. Psychosocial problems, with and without other problems, were the reason 45% of patients requested checkups. Physicians should be alert to the various reasons why patients request checkups, and not assume that a periodic health examination alone is an appropriate response.

The majority of health care in this country is provided to patients in the office setting. This study, conducted in an internal medicine office practice, describes the ethical problems encountered in medical offices. Two hundred eighty consecutive patients, a total of 562 office visits, were prospectively evaluated. Ethical problems were defined as being present when specific ethical issues came into conflict with the physician's moral obligation to benefit the patient. The majority of the patients studied were white (214) and were women (212). The mean age of the patients was 49 years, with a range from 17 to 98 years. Ethical problems were present in 84 (30%) of the patients and in 119 (21%) of the office visits. The most common ethical problems for the patients were costs of care (11.1%), psychological factors that influence preferences (9.6%), competence and capacity to choose (7.1%), refusal of treatment (6.4%), informed consent (5.7%), and confidentiality (3.2%). Ethical problems were more common in patients over 60 years of age. This study establishes an educational as well as a research base for a broad study of biomedical ethics that looks beyond the problems encountered in the hospital.

A quantitative fluid-phase radioassay for autoantibodies reacting with insulin (competitive insulin autoantibody assay, CIAA) was developed. The assay's features include 1) use of a physiologic amount of 125I-labeled insulin, 2) parallel incubations with supraphysiologic cold insulin (competitive), and 3) an incubation time of 7 days and a single-step multiple-wash polyethylene glycol separation. Mean +/- SE CIAA levels in 50 controls were 8 +/- 1.4 nU/ml (range -16-33.3). In 36 cytoplasmic islet cell antibody (ICA)-positive nondiabetic first-degree relatives of type I (insulin-dependent) patients less than 30 yr of age, CIAA levels exceeded the normal range in 20 (55.6%) of 36 (mean 86.8 +/- 17.1 nU/ml). In 26 ICA-positive relatives greater than 30 yr of age, only 5 (19.2%) of 26 exceeded the normal range (mean 26.1 +/- 9.4 nU/ml); P less than .001 compared with younger ICA-positive relatives). Six ICA-negative HLA-identical siblings of type I diabetic patients had normal CIAA levels (mean 3.6 +/- 5.8 nU/ml), and only 2 of 13 ICA-negative identical twins discordant for diabetes (mean 15.4 +/- 6.6 nU/ml) exceeded the normal range. Nine (50%) of 18 ICA-positive schoolchildren exceeded the normal range (mean 105.3 +/- 36.7 nU/ml). Genetically susceptible subjects negative for CIAA (with only 3 exceptions) remained negative for CIAA on multiple determinations (3 conversions observed), and CIAA levels of positive subjects were relatively stable. Linear regression of the first CIAA level versus last (interval between sampling 1 mo to 10 yr) in genetically susceptible individuals showed a highly significant correlation (r = .95, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)