A mutation in myotilin causes spheroid body myopathy.

BACKGROUND: Spheroid body myopathy (SBM) is a rare, autosomal dominant, neuromuscular disorder, which has only been previously reported in a single large kindred. Identification of the mutated gene in this disorder may provide insight regarding abnormal neuromuscular function. METHODS: The authors completed a detailed clinical evaluation on an extensive kindred diagnosed with SBM. Genome-wide linkage analysis was performed to localize the disease gene to a specific chromosomal region. Further marker genotyping and screening of a positional, functional candidate gene were completed to detect the disease-causing mutation. Pathologic analysis of muscle biopsy was performed on three individuals. Biochemical studies were performed on one muscle biopsy specimen from an affected individual. RESULTS: Linkage to chromosome 5q23-5q31 was detected with a lod score of 2.9. Genotyping of additional markers in a larger sample of family members produced a maximum lod score of 6.1 and narrowed the critical interval to 12.2 cM. Screening of the candidate gene titin immunoglobulin domain protein (TTID, also known as MYOT) detected a cytosine-to-thymine mutation in exon 2 of all clinically affected family members. Similar pathologic changes were present in all muscle biopsy specimens. Immunohistologic and biochemical analysis revealed that the TTID protein, also known as myotilin, is a component of the insoluble protein aggregate. CONCLUSIONS: A novel mutation in the TTID gene results in the clinical and pathologic phenotype termed "spheroid body myopathy." Mutations in this gene also cause limb-girdle muscular dystrophy 1A and are associated with myofibrillar myopathy.

Visual mechanisms of spatial disorientation in Alzheimer's disease.

Impaired optic flow perception may contribute to the visuospatial disorientation of Alzheimer's disease (AD). We find that 36% of AD patients have elevated perceptual thresholds for left/right outward radial optic flow discrimination. This impairment is related to independent visual motion processing deficits affecting the perception of left/right motion-defined boundaries and in/out radial motion. Elevated optic flow thresholds in AD are correlated with greater difficulty in the Road Map test of visuospatial function (r = -0.5) and in on-the-road driving tests (r = -0.83). When local motion cues are removed from optic flow, subjects must rely on the global pattern of motion. This reveals global pattern perceptual deficits that affect most AD patients (85%) and some normal elderly subjects (21%). This deficit might combine with impaired local motion processing to undermine the alternative perceptual strategies for visuospatial orientation. The greater prevalence of global pattern deficits suggests that it might precede local motion processing impairments, possibly relating to the sequence of early hippocampal and later posterior cortical damage that is typical of AD.

Hypomorphic phenotype in mice with pituitary-specific knockout of steroidogenic factor 1.

The bacteriophage Cre recombinase provides a powerful approach for tissue-specific gene inactivation. Using a Cre transgene driven by the common alpha subunit of glycoprotein hormones (alphaGSU-Cre), we have previously inactivated steroidogenic factor 1 (SF-1) in the anterior pituitary, causing hypogonadotropic hypogonadism with sexual infantilism, sterility, and severe gonadal hypoplasia. We now explore the molecular mechanisms underlying a hypomorphic gonadal phenotype in mice carrying two floxed SF-1 alleles (F/F) relative to mice carrying one recombined and one floxed allele (F/R). Because their Cre-mediated disruption of the locus encoding SF-1 was less efficient, alphaGSU-Cre, F/F mice retained some gonadotropin-expressing cells in the anterior pituitary, thereby stimulating some gonadal function. This novel in vivo model for exploring the effects of differing levels of gonadotropins on gonadal development highlights the need for careful genotype-phenotype comparisons in studies using Cre recombinase to produce tissue-specific knockouts.

Measuring subjective quality of life following spinal cord injury: a validation study of the assistive technology device predisposition assessment.

PURPOSE: Assesses the validity of a subset of items of the Assistive Technology Device Predisposition Assessment (ATD PA) as a measure of quality of life (QOL) for persons with new spinal cord injury. METHOD: Subjects completed the ATD PA QOL subset, Satisfaction with Life Scale (SWLS), and Brief Symptom Inventory (BSI) while in acute rehabilitation. The internal reliability of the QOL subset of the ATD PA was assessed. Concurrent validity of the ATD PA's QOL subset with the SWLS and construct validity with the BSI depression subscale was assessed using Spearman correlations. Subjects were recruited while acute rehabilitation inpatients in a general hospital and consisted of twenty persons with newly acquired SCI (10 males and 10 females). RESULTS: Significant positive correlations between the ATD PA's QOL subset and SWLS (and significant negative correlations with the BSI depression subscale) suggest the QOL subset has concurrent and construct validity. CONCLUSIONS: The ATD PA's QOL subset appears to be a valid measure and, thus, it can be useful both in identifying subjective quality of life and predispositions to AT use early in rehabilitation.

Persistent Prop1 expression delays gonadotrope differentiation and enhances pituitary tumor susceptibility.

The 'paired'-like homeodomain transcription factor Prop1 is essential for the expansion of the pituitary primordia and for the differentiation and/or function of the hormone-producing cells of the anterior pituitary gland. Prop1 expression is normally extinguished before transcription of most differentiation markers is initiated. We report that constitutive expression of Prop1 interferes with anterior pituitary cell differentiation and increases the susceptibility for pituitary tumors. The terminal differentiation of pituitary gonadotropes is delayed, resulting in transient hypogonadism and a delay in the onset of puberty. Thyrotrope differentiation occurs normally, but thyrotrope function is impaired resulting in mild hypothyroidism. Aged mice exhibit defects consistent with misregulation of pituitary cell proliferation, including adenomatous hyperplasia with the formation of Rathke's cleft cysts and tumors. Thus, silencing Prop1 is important for normal pituitary development and function. These data suggest that gain-of-function mutations in PROP1 could contribute to the most common human pituitary endocrinopathies and tumors.

Prostate carcinoma knowledge, attitudes, and screening behavior among African-American men in Central Harlem, New York City.

BACKGROUND: Although the benefits of prostate carcinoma screening in reducing mortality rates have not been proven or shown to be cost-effective, screening, particularly using prostate specific antigen (PSA) tests, is widespread. A better understanding of screening behavior, knowledge of prostate carcinoma risk, and attitudes toward screening among men at high risk, such as African-American men, would be valuable. METHODS: A prevalence survey was conducted using 2 samples of African-American men, aged 50-74 years: a clinic sample drawn from all clinics in Central Harlem (n = 404) and a random-digit dial sample from the same geographic region (n = 319). The prevalence of self-reported PSA screening was estimated using a cognitive survey methodology based on the internal consistency of answers to four different questions. Prevalence estimates were adjusted to take into account the high proportion of nontelephone residences. RESULTS: The clinic sample, representing a poorer, more ill population (as determined by MOS Physical Function Scores, was less likely to report PSA screening than the community sample (11.1% in clinic sample vs. 25.5% in community). The prevalence of PSA testing in Central Harlem overall in this age group by using two different techniques was estimated to be 24%. In multiple logistic models, self-reported PSA screening was associated with age, education, favorable attitudes toward screening, and knowing someone who had prostate carcinoma. However, the association between these factors and the likelihood of self-reported PSA screening differed between clinic and community samples. CONCLUSIONS: The prevalence of self-reported PSA screening in Central Harlem was lower than that reported for other populations. These findings may be useful in the design of health education campaigns and for counseling innercity, low-income African-American patients appropriately about the disease.

Steroidogenic factor 1 (SF1) is essential for pituitary gonadotrope function.

Knockout mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF1) exhibit a complex endocrine phenotype that includes adrenal and gonadal agenesis, impaired expression of pituitary gonadotropins, and absence of the ventromedial hypothalamic nucleus (VMH). These multiple defects complicate efforts to delineate primary versus secondary effects of SF1 deficiency in different tissues, such that its direct role in gonadotropes remains uncertain. To define this role, we have expressed Cre recombinase driven by the promoter region of the common alpha subunit of glycoprotein hormones (alpha GSU), thereby inactivating a loxP-modified SF1 locus in the anterior pituitary gland. Although pituitary-specific SF1 knockout mice were fully viable, they were sterile and failed to develop normal secondary sexual characteristics. Their adrenal glands and VMH appeared normal histologically, but their testes and ovaries were severely hypoplastic. alpha GSU-Cre, loxP mice had normal levels of most pituitary hormones, but had markedly decreased expression of LH and FSH. Treatment with exogenous gonadotropins stimulated gonadal steroidogenesis, inducing germ cell maturation in males and follicular and uterine maturation in females--establishing that the gonads can respond to gonadotropins. The pituitary-specific SF1 knockout mice are a novel genetic model of hypogonadotropic hypogonadism that establishes essential role(s) of SF1 in pituitary gonadotropes.

Challenge of managing interventional cardiology patients over a decade.

Using an outcomes management approach, St. Luke's Episcopal Hospital has achieved positive outcomes in the interventional cardiology patient population. In this article the authors describe a decade of experiences related to the processes they implemented and the outcomes achieved in this patient population.

Use of complementary and alternative medicine among women in New York City: a pilot study.

OBJECTIVE: This study documents the use of complementary and alternative medicine (CAM), among White, African American, and Hispanic/Latina women living in New York City. A pilot to a national survey of CAM use among American women, this study explores women's use of categories of CAM and various CAM practitioners, racial and ethnic differences in CAM use, and women's perceptions regarding the effectiveness of CAM. DESIGN AND LOCATION: Data were collected from women residing in New York City using random digit dialing/computer-assisted telephone interviewing (CATI). The sample of 300 had equal numbers of women (n = 100) who self-identified as White, Hispanic/Latina, and African American, equally stratified by age (below and above age 40). SUBJECTS: Eligibility requirements included self-identification as Anglo/white, African American, or Hispanic/Latina and between ages 18 and 80. MEASURES: Three distinct categories of CAM were explored: (1) medicinal teas, homeopathic remedies, herbs, vitamins; (2) yoga, meditation, spiritual practices; and (3) manual therapies including chiropractic, massage, acupressure. Health concerns of interest were those frequently described in prior focus groups, and included reproductive health issues (e.g., pregnancy, menstruation, menopause) as well as other common women's health problems (e.g., heart disease, high blood pressure, headaches). RESULTS: More than half the sample has used a CAM treatment or remedy, and 40% have visited a CAM practitioner. Among users, half have used only one of the CAM categories, approximately one third have used two, and 16% used all three. The category of CAM used most often was medicinal tea/herbs/vitamins; the practitioners visited most frequently were chiropractors (18%) and nutritionists (17%). Racial and ethnic differences in CAM use were minimal, and approximately one third of all treatments used were rated "very effective" by users. CONCLUSIONS: Substantial utilization of CAM remedies and treatments for a variety of women's health concerns is observed. Further inquiry with larger samples of women is recommended.

Cre-mediated recombination in the pituitary gland.

Organ-specific expression of a cre recombinase transgene allows for the analysis of gene function in a particular tissue or cell type. Using a 4.6 kb promoter from the mouse glycoprotein hormone alpha-subunit (alphaGSU or Cga) gene, we have generated and characterized a line of transgenic mice that express cre recombinase in the anterior and intermediate lobes of the pituitary gland. Utilizing a cre-responsive reporter transgene, alphaGSU-cre transgene expression was detected in the pituitary primordium and in all five cell types of the adult anterior pituitary. alphaGSU-cre transgene activity was also detected in the cardiac and skeletal muscle. Little or no activity was evident in the gonads, adrenal glands, brain, ventromedial hypothalamus, or kidneys. The alphaGSU-cre transgenic mice characterized here will be a valuable tool for examining gene function in the pituitary gland.

Use of complementary and alternative medicine among Dominican emergency department patients.

This small, pilot study examined presenting complaint, brief health history, use of complementary and alternative medicine (CAM), and sociodemographic characteristics, among patients attending the emergency department (ED) of a large urban hospital. The sample (n = 50) was primarily Dominican and of low socioeconomic status. Almost half had used CAM for their presenting complaint or another health problem during the past year, most commonly in the form of medicinal plants made into herbal teas. CAM users were more likely to be female, longer-term residents of the United States, and to have also used religious practices for health problems. Subjects who had used CAM for any problem other than the presenting complaint during the past year rated its effectiveness higher than subjects who had used CAM for their presenting complaint. In conclusion, it is likely that a significant proportion of Dominican ED patients use CAM, suggesting that they should be asked about their CAM use during triage.

Predicting satisfaction with assistive technology for a sample of adults with new spinal cord injuries.

To assess the validity of the Assistive Technology Device Predisposition Assessment-Consumer Form for persons with a new spinal cord injury, 10 men and 10 women completed the scale and the Satisfaction with Life Scale and the Brief Symptom Inventory while in acute rehabilitation. One month postdischarge, subjects completed the Perceived Needs Inventory and rated their satisfaction with assistive technology. Significant positive correlations between items of the Assistive Technology Device Predisposition Assessment and Satisfaction with Life Scale (and their significant negative correlations with scores on the Brief Symptom Inventory-Depression) suggest the selected Assistive Technology Device Predisposition Assessment items measure quality of life (concurrent validity). Only Assistive Technology Device Predisposition Assessment scores predicted satisfied use 1-mo. postdischarge as measured by the Perceived Needs Inventory.

Use of complementary and alternative medicine among African-American and Hispanic women in New York City: a pilot study.

OBJECTIVE: To explore the use of complementary and alternative medicine (CAM) among African-American and Hispanic women residing in New York City, including use of specific treatments and practitioners, perceived effectiveness of CAM, and culturally specific words or expressions for CAM. METHODS: Focus groups were conducted with two groups of African-American and two groups of Hispanic women (age 18-40 and 41-80) as preparation for the development of a quantitative instrument to assess the prevalence and determinants of CAM use among women of various ethnic backgrounds. Participants were recruited using a standard random digit dial procedure. RESULTS: The most commonly used CAM remedies were teas and herbs, vitamins and nutritional supplements, prayer and spiritual healing, meditation and relaxation techniques. Practitioners most frequently seen were chiropractors, herbalists, and acupuncturists. Use of alternative remedies and practitioners, particularly the latter, was most common among older women in both groups. Younger Hispanic women reported the most skepticism toward CAM, especially when it was used by relatives as a substitute for conventional medical care. Overall, these African-American and Hispanic women used CAM for a wide range of health conditions and for prevention. Few racial and ethnic differences emerged in patterns of CAM use for either self-care or treatment by practitioners, but there was a distinct age variation, especially in attitudes toward CAM.

Potential barriers to the removal of Norplant among family planning clinic patients.

OBJECTIVES: This study examined the prevalence and effects of potential barriers to removal of levonorgestrel implants (Norplant) among low-income women. METHODS: A sample of 687 women who received Norplant at hospital-based family planning clinics were interviewed before Norplant insertion and 6 months after Norplant insertion (or at Norplant removal if removal occurred earlier). Those who continued to use Norplant were reinterviewed at 2 years or at removal. RESULTS: In a multivariate analysis, only 1 of the 4 potential barriers--cost--significantly impeded Norplant discontinuation. CONCLUSIONS: Family planning clinics need to make clear that they follow a policy of Norplant removal on demand, regardless of the patient's ability to pay.

Condom use among women choosing long-term hormonal contraception.

CONTEXT: Women who rely on long-term hormonal contraception may neglect to use condoms, and thus increase their risk of contracting sexually transmitted diseases, including AIDS. METHODS: Data from a prospective, multisite study were collected to examine the probability of condom use among 1,073 new users of either the contraceptive implant or injectable; users were interviewed when they accepted their method and again six months to one year later. Multivariate logistic regression analyses identified factors that significantly predicted the likelihood of dual method use. RESULTS: Condom use dropped markedly among women who adopted long-term hormonal contraception. The proportion who always used condoms in the previous three months fell from 21% at the time of adoption to 11% at follow-up. Among women with one sexual partner, this decrease was from 20% to 10%; however, among those with more than one partner, use increased from 25% to 31%. The factors significantly predicting dual method use included previous condom use (odds ratio of 2.5), receipt of AIDS-specific counseling (odds ratio of 1.6), the perception of being at some risk of AIDS at baseline (odds ratio of 1.4) and having had more than one sexual partner over the study period (odds ratio of 5.4). In addition, injectable users, teenagers and black women were more likely than other women to use condoms with their hormonal method. CONCLUSIONS: Although condom use among all women declined markedly once they initiated long-term hormonal contraception, frequency of condom use varied by subgroup and was associated with several factors. Most importantly, women with more than one sexual partner and those who received a message during counseling on the need to continue using condoms were more likely than others to use condoms in conjunction with the implant or injectable.

PIP: Concerns have been raised that women who use long-term hormonal contraceptive methods to prevent pregnancy will fail to protect themselves from sexually transmitted diseases (STDs), including AIDS, through concomitant condom use. This possibility was investigated in a prospective (1993-94), multi-site US (Pittsburgh, Pennsylvania; Dallas, Texas; and New York, New York) study of 1073 new users of either contraceptive implants or Depo-Provera. The mean age of study participants was 23 years; 63% were Hispanic, 24% Black, and 13% White. Overall, the proportion of women who always used condoms in the previous 3 months dropped from 21% at the time of method initiation to 11% at follow-up 6-12 months after enrollment. However, use increased from 25% to 31% among women with more than 1 sexual partner. Significant predictors of dual method use included previous condom use (odds ratio (OR), 2.5); receipt of AIDS-specific counseling (OR, 1.6); the perception, at baseline, of being at some risk of AIDS (OR, 1.4); and more than 1 sexual partner during the study period (OR, 5.4). In addition, injectable users, teenagers, and Black women were more likely than other women to use condoms with their hormonal method. These findings have important implications for family planning programs, especially the need for counseling on the continued importance of condom use for STD prevention when pregnancy is prevented by non-barrier methods.

Depressive symptoms and Depo-Provera.

Women enrolled in a multicenter prospective study were evaluated to identify any possible relationship between depressive symptoms and the use of contraceptives. Women choosing Depo-Provera (n = 495) were evaluated before starting these contraceptives and were reinterviewed 1 year later. Women who continued the method had lower depressive symptom scores at baseline than did the women who discontinued the method or who were lost to follow-up. Among the continuing Depo-Provera users, the depressive symptom scores improved slightly at 1 year (7.4 vs 6.7). Those subjects with the highest (i.e., worst) scores at enrollment demonstrated improved scores at follow-up.

PIP: The product labeling for Depo-Provera cites depression as an infrequent side effect. Previous research on this topic has documented self-reported depression or mood changes in 1-5% of Depo-Provera users. These studies were limited, however, by a lack of measurement of baseline depression. In the present study, 495 new acceptors of Depo-Provera enrolled in a broader prospective cohort study conducted at three US hospitals (Texas, Pennsylvania, New York) were interviewed at enrollment and again after 12 months of use. Included in both the initial and follow-up questionnaires were six questions on depressive symptoms in the past month taken from the Mental Health Inventory. At 12 months, 172 women were still using Depo-Provera, 221 had discontinued the method, and 102 were lost to follow-up. Women who were still using Depo-Provera at 12 months had lower depressive symptom scores at baseline than women who discontinued use or were lost to follow-up. Between baseline and the 12-month follow-up, the mean depression score dropped from 7.4 to 6.7 among continuing users and remained steady at 8.0 among discontinuers. The mean depression score in the quintile of women with the highest depression scores at baseline also decreased after 12 months of use, from 15.4 to 9.5. These results suggest that Depo-Provera use is not likely to exacerbate symptoms in women with pre-existing depression.

Depressive symptoms and Norplant contraceptive implants.

Women enrolled in a multicenter prospective study were evaluated to identify any possible relationship between depressive symptoms and the use of contraceptive implants. Women choosing Norplant implants (n = 910) were evaluated before starting this contraceptive and were reinterviewed at 6 months and 2 years. Women who continued the method had lower depressive symptom scores before initiating Norplant implants than did the women who discontinued the method or who were lost to follow up. Among the continuing Norplant implant users, the mean scores were similar before starting Norplant and at 6 months (7.9 vs 7.7). The strongest overall predictor of the depressive symptom score was relationship satisfaction. At 24 months, the subgroup of continuing users with decreased relationship satisfaction had an increase in depressive symptom score, but those with stable or improved relationships had stable depressive symptom scores. The subjects with the highest (i.e., worst) scores at enrollment demonstrated improved scores during follow-up. These results are reassuring for women who are concerned that Norplant use may adversely affect their mood.

PIP: Although depression is cited in the Norplant contraceptive implant product labeling as a rare side effect, previous evaluations of this association have not included baseline measurement of mood. To assess this association more systematically, the present study followed a cohort of 910 new Norplant acceptors recruited from three urban hospitals in the US (Texas, Pennsylvania, New York) for 24 months. Included in both the initial and follow-up questionnaires were six questions drawn from the Mental Health Inventory on depressive symptoms in the past month. At the end of the study period, 293 women were still using Norplant, 295 had discontinued use, and 138 were lost to follow-up. Women who continued with Norplant for 2 years had significantly lower depression scores at baseline than women who discontinued use or were lost to follow-up. Among continuing Norplant users, mean depressive symptom scores were similar before starting Norplant and after 6 months of use (7.9 and 7.7, respectively). The strongest overall predictor of the depression score was relationship satisfaction. At 24 months, the subgroup of continuing users with decreased relationship satisfaction had an increase in depression score, while those with no change or improved relationships had stable scores. The mean depression score of the quintile of women most depressed at enrollment improved during the study period from 15.4 to 11.0, dispelling concerns that Norplant exacerbates pre-existing depression. Only 4.4% of discontinuers cited mood changes as a reason for terminating Norplant use and there were no cases of psychiatric hospitalization. These findings suggest that concern about possible mood changes is not a reason to withhold Norplant.

Injectable contraceptive discontinuation and subsequent unintended pregnancy among low-income women.

OBJECTIVES: This study investigated rates of discontinuation of the recently introduced injectable contraceptive depot medroxyprogesterone acetate (DMPA) and postdiscontinuation rates of unprotected intercourse and unintended pregnancy. METHODS: A sample of 402 low-income, urban, minority women were interviewed when they initiated DMPA use and 12 months later. RESULTS: The 12-month life-table discontinuation rate was 58%, with half of the discontinuers stopping after only one injection. Menstrual changes and other side effects were the most frequently cited reasons for discontinuation. Approximately half of the discontinuers at risk for unintended pregnancy either did not make the transition to another contraceptive or used contraception only sporadically. The cumulative unintended pregnancy rate by 9 months postdiscontinuation was 20%. CONCLUSIONS: DMPA initiators were at substantial risk for unintended pregnancy because most quickly discontinued use and did not make the transition to consistent use of another contraceptive.

Interventional recovery outside the walls of an intensive care environment.

St. Luke's Episcopal Hospital in Houston, Texas, created a cardiology collaborative practice team to review patient flow, to develop and implement process redesign, and to evaluate the effectiveness of the redesign project. The team focused on the recovery of interventional patients outside the critical care or intensive care unit environment. In December 1993, the team opened an interventional cardiology recovery unit on a cardiovascular telemetry floor. One thousand forty-five patients were recovered in this unit in the first year. Complication rates did not change significantly for low-risk patients; patient and family satisfaction scores improved, and the cost per case was reduced by $1,746. The success of the pilot project has become the standard for implementing new programs within the cardiology services.