Evidence of patient beliefs, values, and preferences is not provided in osteoporosis clinical practice guidelines.

We examined how patient beliefs, values, and preferences (BVPs) were included and conceptualized in international osteoporosis guidelines. The majority of guidelines did not mention BVPs. When mentioned, BVPs were conceptualized as preference for one medication over another. A broader conceptualization and inclusion of BVPs should be incorporated in osteoporosis guidelines. INTRODUCTION: Our objectives were to determine (1) the extent to which osteoporosis guidelines reflected patients' beliefs, values, and preferences (BVPs); (2) how BVPs were conceptualized; and (3) the methods used to elicit BVPs in the references cited by the guidelines. METHODS: We conducted a document analysis of English-language international osteoporosis guidelines based on the International Osteoporosis Foundation website. We examined each guideline and extracted all instances of statements pertaining to BVPs. The statements were reviewed by two independent researchers. Discrepancies in data extraction were resolved by the first author. We developed categories based on five common elements that represented the BVP statements. RESULTS: Twenty-seven of 70 (39%) guidelines included 95 statements about patient BVPs. Of the 95 statements, 32 statements (14 guidelines) were classified under BVP related to the choice of pharmacotherapy or general treatment, 10 (7 guidelines) under BVP related to adherence to pharmacotherapy or treatment in general, 5 (5 guidelines) under BVP related to financial costs and benefits, 43 (19 guidelines) under other BVP mentioned but not supported by a reference to a primary study or systematic review, and 5 (3 guidelines) under other BVP mentioned and supported by at least one reference to a primary study or systematic review. Twenty-nine references were cited to reflect the BVPs mentioned, including an editorial and quantitative studies. CONCLUSIONS: Twenty-seven (39%) of the guidelines included mention of patients' BVPs. In 19 guidelines, the importance of BVPs was mentioned but these statements were not supported by references to a primary study or systematic review. BVPs were most often (14 guidelines) conceptualized as preference for one medication over another. We suggest that qualitative data be included as evidence of BVPs in guidelines.

Impact of a centralized osteoporosis coordinator on post-fracture osteoporosis management: a cluster randomized trial.

UNLABELLED: We conducted a cluster randomized trial evaluating the effect of a centralized coordinator who identifies and follows up with fracture patients and their primary care physicians about osteoporosis. Compared with controls, intervention patients were five times more likely to receive BMD testing and two times more likely to receive appropriate management. INTRODUCTION: To determine if a centralized coordinator who follows up with fracture patients and their primary care physicians by telephone and mail (intervention) will increase the proportion of patients who receive appropriate post-fracture osteoporosis management, compared to simple fall prevention advice (attention control). METHODS: A cluster randomized controlled trial was conducted in small community hospitals in the province of Ontario, Canada. Hospitals that treated between 60 and 340 fracture patients per year were eligible. Patients 40 years and older presenting with a low trauma fracture were identified from Emergency Department records and enrolled in the trial. The primary outcome was 'appropriate' management, defined as a normal bone mineral density (BMD) test or taking osteoporosis medications. RESULTS: Thirty-six hospitals were randomized to either intervention or control and 130 intervention and 137 control subjects completed the study. The mean age of participants was 65 ± 12 years and 69% were female. The intervention increased the proportion of patients who received appropriate management within 6 months of fracture; 45% in the intervention group compared with 26% in the control group (absolute difference of 19%; adjusted OR, 2.3; 95% CI, 1.3-4.1). The proportion who had a BMD test scheduled or performed was much higher with 57% of intervention patients compared with 21% of controls (absolute difference of 36%; adjusted OR, 4.8; 95% CI, 3.0-7.0). CONCLUSIONS: A centralized osteoporosis coordinator is effective in improving the quality of osteoporosis care in smaller communities that do not have on-site coordinators or direct access to osteoporosis specialists.

The class I antigen-processing pathway for the membrane protein tyrosinase involves translation in the endoplasmic reticulum and processing in the cytosol.

Formation of major histocompatibility complex class I-associated peptides from membrane proteins has not been thoroughly investigated. We examined the processing of an HLA-A*0201-associated epitope, YMDGTMSQV, that is derived from the membrane protein tyrosinase by posttranslational conversion of the sequence YMNGTMSQV. Only YMDGTMSQV and not YMNGTMSQV was presented by HLA-A*0201 on cells expressing full-length tyrosinase, although both peptides have similar affinities for HLA-A*0201 and are transported by TAP. In contrast, translation of YMNGTMSQV in the cytosol, as a minigene or a larger fragment of tyrosinase, led to the presentation of the unconverted YMNGTMSQV. This was not due to overexpression leading to saturation of the processing/conversion machinery, since presentation of the converted peptide, YMDGTMSQV, was low or undetectable. Thus, presentation of unconverted peptide was associated with translation in the cytosol, suggesting that processing of the full-length tyrosinase occurs after translation in the endoplasmic reticulum. Nevertheless, presentation of YMDGTMSQV in cells expressing full-length tyrosinase was TAP (transporter associated with antigen processing) and proteasome dependent. After inhibition of proteasome activity, tyrosinase species could be detected in the cytosol. We propose that processing of tyrosinase involves translation in the endoplasmic reticulum, export of full-length tyrosinase to the cytosol, and retransport of converted peptides by TAP for association with HLA-A*0201.

Cognitive speed of processing and functional declines in older cancer survivors: an analysis of data from the ACTIVE trial.

It has been suggested that chemotherapy treatment for cancer may contribute to cognitive decline in older cancer survivors. This issue is particularly important given that subtle cognitive impairment, particularly in cognitive processing speed, can affect functional status and quality of life for older adults. Multivariate regression of data from a longitudinal randomized controlled trial of older adults revealed a trend towards decreased performance after cancer treatment with chemotherapy on several functional measures associated with processing speed (as compared with matched individuals who did not have cancer). Additional analyses revealed that a subset of the chemotherapy-treated adults demonstrated a reliable negative change on several measures of processing speed. While inconclusive, this hypothesis generating work suggests that cognitive dysfunction following cancer treatment may contribute to disability observed in older cancer survivors. Further research is needed to determine the significance of the relationship between cognitive and functional impairment in older cancer survivors.

The minor histocompatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism.

The minor histocompatibility antigen (mHag) HA-1 is the only known mHag for which mismatching is correlated with the development of severe graft versus host disease (GvHD) after human leukocyte antigen-identical bone marrow transplantation. HA-1 was found to be a nonapeptide derived from an allele of the KIAA0223 gene. The HA-1-negative allelic counterpart encoded by KIAA0223 had one amino acid difference from HA-1. Family analysis with HA-1 allele-specific polymerase chain reaction showed an exact correlation between this allelic polymorphism and the HA-1 phenotype. HA-1 allele typing of donor and recipient should improve donor selection and allow the determination of bone marrow transplantation recipients with high risk for HA-1-induced GvHD development.

Human H-Y: a male-specific histocompatibility antigen derived from the SMCY protein.

H-Y is a transplantation antigen that can lead to rejection of male organ and bone marrow grafts by female recipients, even if the donor and recipient match at the major histocompatibility locus of humans, the HLA (human leukocyte antigen) locus. However, the origin and function of H-Y antigens has eluded researchers for 40 years. One human H-Y antigen presented by HLA-B7 was identified as an 11-residue peptide derived from SMCY, an evolutionarily conserved protein encoded on the Y chromosome. The protein from the homologous gene on the X chromosome, SMCX, differs by two amino acid residues in the same region. The identification of H-Y may aid in transplantation prognosis, prenatal diagnosis, and fertilization strategies.

Abnormalitieis of monocyte chemotaxis in patients with melanoma: effects of immunotherapy and tumor removal.

The chemotactic responsiveness of peripheral blood monocytes was studied before and after immunotherapy was administered to 56 patients with melanoma. Abnormal chemotaxis was found in 36 patients (64%) prior to treatment; this abnormality correlated with severity of disease and prognosis. Immunotherapy with BCG and sensitized autologous lymphocytes and X-irradiated melanoma cells or surgical removal of the neoplasm both reduced the percentage of patients with abnormal chemotactic responses. The best prognosis was found for those patients who had normal chemotaxis prior to therapy. The data support the hypothesis that abnormalities of monocyte function might render the host less likely to destroy developing neoplasms and that malignant tumors themselves might affect monocyte function.

Abnormal monocyte chemotaxis in patients with breast cancer: evidence for a tumor-mediated effect.

The chemotactic responsiveness of peripheral blood monocytes was measured in 194 individuals: 37 patients with breast cancer, 17 patients with a history of breast cancer but clinically free of disease after surgery, 42 patients with benign breast masses, and 98 normal controls. Monocyte chemotactic responsiveness (MCR) in vitro was not significantly different from normal [mean = 72.8 migrating monocytes/oil immersion field, +/- 9.3 (1 SD)] in 2 groups of patients: a) those with benign breast masses (mean = 72.6 +/- 15.1; P greater than 0.3) and b) those previously having breast cancer resected and remaining clinically free of disease (mean = 69.0 +/- 12.5; P greater than 0.4). However, MCR was significantly depressed in the group of patients with active breast cancer (mean = 57.2 +/- 20.7; P less than 0.0025). Resection of malignant breast masses resulted in a significant change in MCR (P less than 0.0025), whereas resection of benign lesions did not (P greater than 0.4). MCR was abnormal in all clinical stages of breast cancer, including breast cancer without evidence of metastasis to regional lymph nodes. These data supported the hypothesis that neoplasms adversely affect monocyte function and may thereby hinder immunologically mediated destruction of malignant cells.

Sodium channels as macromolecular complexes: implications for inherited arrhythmia syndromes.

Mutations in cardiac ion channels and their auxiliary subunits can lead to life-threatening cardiac arrhythmias. In recent years it has become apparent that ion channels are part of large, multi-protein complexes, comprising not only the ion channels and their auxiliary subunits, but also components of the cytoskeleton, regulatory kinases and phosphatases, trafficking proteins, extracellular matrix proteins, and possibly even other ion channels. Disruption of any member of a particular ion channel complex has the potential to disrupt the function of the associated channels, resulting in paroxysmal disease. Understanding the molecular composition of individual ion channel signaling complexes in heart may yield important insights into the molecular basis of cardiac arrhythmias and may suggest novel therapeutic approaches to treatment of these life-threatening conditions.

Cardiac-gated computed tomography angiography in three alpacas with complex congenital heart disease.

BACKGROUND: The prevalence of congenital heart disease is higher in camelids than in other domestic species and complex defects, often involving the great vessels, are more frequently encountered in llamas and alpacas than in other species. Some of these complex defects can be difficult to accurately characterize via echocardiography, the most commonly used diagnostic imaging technique to evaluate the heart in veterinary patients. Contrast-enhanced, electrocardiogram (ECG)-gated computed tomography (CT) has proven utility for the evaluation of human patients with certain congenital heart defects, including those with conotruncal septation defects and other abnormalities involving the formation of the great vessels. METHODS: Three alpaca crias, 4 days, 5 weeks and 14 months of age were clinically evaluated and subjected to a complete color-flow Doppler echocardiogram and a contrast-enhanced ECG-gated CT. RESULTS: These alpacas exhibited a variety of clinical findings including lethargy, failure to thrive, exercise intolerance, heart murmur, and/or respiratory difficulty. All three crias were subsequently diagnosed with complex cardiac defects including pulmonary atresia with a ventricular septal defect (VSD), a truncus arteriosus with a large VSD, and a double outlet right ventricle with a large VSD and aortic hypoplasia. In each case, the diagnosis was confirmed by postmortem examination. CONCLUSION: Color flow echocardiographic evaluation identified all of the intra-cardiac lesions and associated flow anomalies but contrast-enhanced ECG-gated CT permitted more accurate assessment of the morphology of the extracardiac structures and permitted a more precise determination of the exact nature and anatomy of the great vessels.

Does Dynorphin Play a Role in the Onset of Puberty in Female Sheep?

Puberty onset involves increased gonadotrophin-release (GnRH) release as a result of decreased sensitivity to oestrogen (E2 )-negative feedback. Because GnRH neurones lack E2 receptor α, this pathway must contain interneurones. One likely candidate is KNDy neurones (kisspeptin, neurokinin B, dynorphin). The overarching hypothesis of the present study was that the prepubertal hiatus in luteinising hormone (LH) release involves reduced kisspeptin and/or heightened dynorphin input. We first tested the specific hypothesis that E2 would reduce kisspeptin-immunopositive cell numbers and increase dynorphin-immunopositive cell numbers. We found that kisspeptin cell numbers were higher in ovariectomised (OVX) lambs than OVX lambs treated with E2 (OVX+ E2 ) or those left ovary-intact. Very few arcuate dynorphin cells were identified in any group. Next, we hypothesised that central blockade of κ-opioid receptor (KOR) would increase LH secretion at a prepubertal (6 months) but not postpubertal (10 months) age. Luteinising hormone pulse frequency and mean LH increased during infusion of a KOR antagonist, norbinaltorphimine, in OVX + E2 lambs at the prepubertal age but not in the same lambs at the postpubertal age. We next hypothesised that E2 would increase KOR expression in GnRH neurones or alter synaptic input to KNDy neurones in prepubertal ewes. Oestrogen treatment decreased the percentage of GnRH neurones coexpressing KOR (approximately 68%) compared to OVX alone (approximately 78%). No significant differences in synaptic contacts per cell between OVX and OVX + E2 groups were observed. Although these initial data are consistent with dynorphin inhibiting pulsatile LH release prepubertally, additional work will be necessary to define the source and mechanisms of this inhibition.

Analysis of Drosophila salivary gland, epidermis and CNS development suggests an additional function of brinker in anterior-posterior cell fate specification.

Salivary glands are simple structured organs which can serve as a model system in the study of organogenesis. Following a large EMS mutagenesis we have identified a number of genes required for normal salivary gland development. Mutations in the locus small salivary glands-1 (ssg-1) lead to a drastic reduction in the size of the salivary glands. The gene ssg-1 was cloned and subsequent sequence and genetic analysis showed identity to the recently published gene brinker. The salivary gland placode in brinker mutants appears reduced along both the anterior-posterior and dorso-ventral axis. Analysis of the brinker cuticle phenotype revealed a similar loss of anterior-posterior as well as lateral cell fates. The abdominal ventral denticle belts show a reduced number of setae in the first denticle row. Furthermore, we observed a preferential loss of lateral neuroblasts in the anterior parasegment. Together, these phenotypes suggest that brinker not only plays a role in dorso-ventral but also in anterior-posterior axis patterning.

alpha-Interferon and 5-fluorouracil: possible mechanisms of antitumor action.

We have treated 17 patients with 5-fluorouracil (5-FU, 300 mg/m2/d by continuous ambulatory infusion for 8 weeks) and interferon alfa-2b (escalating doses to cohorts of three to five patients, given subcutaneously on a daily schedule at 2.0, 3.5, 5.0, and 10.0 x 10(6) IU/m2). The two major toxicities observed were mucositis, which occurred in 10 patients at 2 weeks and required interruption of therapy and 5-FU dose reduction, and chronic fatigue syndrome, which required reduction of the dose of interferon alfa-2b. Other toxicities seen included elevation in BUN/creatinine, elevation in liver function tests, alopecia, diarrhea, confusion, and myelosuppression. No toxic deaths occurred. Five responses were observed: two complete responses, two partial responses, and one minor response, all in patients with gastrointestinal malignancy; three of the responding patients had previously failed 5-FU-containing regimens. When we measured 5-FU plasma levels in nine of our patients, they were at or below 1 ng/mL in most patients; however, within 1 hour of administration of interferon alfa-2b, plasma levels rose 16-fold. This elevation of 5-FU levels persisted for at least 24 hours, and could not be accounted for on the basis of altered interleukin-6 levels. When the regimen was tested in eight patients with metastatic renal cell carcinoma as part of a pilot study, three partial responses were observed, and no patient developed disease progression while on treatment. The combination of 5-FU, given by continuous infusion, and interferon alfa-2b, given daily, appears worthy of advancement to phase II trials.

Generalized microsporum audoninii infection and depressed cellular immunity associated with a missing plasma factor required for lymphocyte blastogenesis.

Described herein is a 15 year old girl with a generalized, possibly systemic Microsporum audouinni infectin associated with anergy and defective lymphocyte transformation as a consequence of a deficiency of an uncharacterized plasma factor. Intravenous administration of plasma, obtained from normal donors, has produced consistent although incomplete clinical improvement. Defective lymphocyte transformation to M. audiouinii antigen cultured in autologous plasma became normal after infusions of normal plasma were instituted. Systemic administrations of griseofulvin, clotrimazole and miconazole produced transient and incomplete clinical improvement. Clearing of the cutaneous infection and stabillization of the neurologic status was finally achieved with plasma infusions combined with parenterally administered amphotericin B.

Deficiency of the fifth component of complement in human subjects. Clinical, genetic and immunologic studies in a large kindred.

The discovery of a large kindred with a heritable deficiency of the fifth component of complement (C5) has permitted the accumulation of new clinical, genetic and immunologic data concerning the role of C5 in human subjects. The proband, who has had nine episodes of disseminated gonococcal infection, has a hemolytic C5 level of approximately 0.5 per cent of normal. No C5 protein was detectable, but low levels of functional C5 activity could be found using a sensitive bactericidal assay. The proband's twin as well as another sister also had extremely low levels of hemolytic C5(approximately 0.5 per cent normal), but both these subjects have been healthy. Hemolytic complement and bacteriolytic activity could be restored by the addition of purified C5. No chemotactic activity for polymorphonuclear leukocytes could be generated in the C5-deficient serums upon activation of either the classic or alternative pathways, again demonstrating the importance of C5 in human subjects for the production of chemotactic factors. The chemotactic responsiveness of the patients' polymorphonuclear leukocytes and monocytes to preformed chemotactic factors was not depressed. Twenty-two of 32 other family members from three generations had depressed whole hemolytic complement levels. In 19 of 30 family members, levels of hemolytic C5 ranged from 13 to 64 per cent of normal. No linkage for C5 deficiency and the A or B loci of the major histocompatibility complex could be found. These data suggest an autosomal codominant mode of inheritance of C5 deficiency. Deficiency of C5 is compatible with good health, but it can be associated with repeated disseminated gonococcal infection.

Functional modulation of human brain Nav1.3 sodium channels, expressed in mammalian cells, by auxiliary beta 1, beta 2 and beta 3 subunits.

Voltage-gated sodium channels consist of a pore-forming alpha subunit and two auxiliary beta subunits. Excitable cells express multiple alpha subtypes, designated Na(v)1.1-Na(v)1.9, and three beta subunits, designated beta1, beta2 and beta3. Understanding how the different alpha subtypes, in combination with the various beta subunits, determine sodium channel behavior is important for elucidating the molecular basis of sodium channel functional diversity. In this study, we used whole-cell electrophysiological recording to examine the properties of the human Na(v)1.3 alpha subtype, stably expressed in Chinese hamster ovary cells, and to investigate modulation of Na(v)1.3 function by beta1, beta2 and beta3 subunits. In the absence of beta subunits, human Na(v)1.3 formed channels that inactivated rapidly (tau(inactivation) approximately equals 0.5 ms at 0 mV) and almost completely by the end of 190-ms-long depolarizations. Using an intracellular solution with aspartate as the main anion, the midpoint for channel activation was approximately -12 mV. The midpoint for inactivation, determined using 100-ms conditioning pulses, was approximately -47 mV. The time constant for repriming of inactivated channels at -80 mV was approximately 6 ms. Coexpression of beta1 or beta3 did not affect inactivation time course or the voltage dependence of activation, but shifted the inactivation curve approximately 10 mV negative, and slowed the repriming rate ca. three-fold. beta2 did not affect channel properties, either by itself or in combination with beta1 or beta3. Na(v)1.3 expression is increased in damaged nociceptive peripheral afferents. This change in channel expression levels is correlated with the emergence of a rapidly inactivating and rapidly repriming sodium current, which has been proposed to contribute to the pathophysiology of neuropathic pain. The results of this study support the hypothesis that Na(v)1.3 may mediate this fast sodium current.

Hereditary C2 deficiency associated with cutaneous lupus erythematosus: clinical, laboratory, and genetic studies.

Selective congenital deficiency in the second component of complement has been described in association with lupus erythematosus (LE) and other connective tissue disorders. We identified a 59-year-old woman with a 13-year history of cutaneous LE and no detectable serum C2. The patient's photosensitivity, large polycyclic erosive cutaneous lesions, lack of renal disease, paucity of serological findings, and high incidence of bacterial infection is consistent with previously described patients with this association. Uniquely, the patient demonstrated secondary infection with Staphylococcus aureus and Trichophyton rubrum in the skin lesions themselves. Immunologic studies disclosed depression in both humoral and cellular immunity. Moderation in her clinical disease and immunologic measurements has been observed after treatment with levamisole hydrochloride. Immunogenetic studies of the patient's four-generation kindred was consistent with an autosomal recessive inheritance of C2 deficiency genetically linked to HLA, segregating with the B18 allele. Mixed lymphocyte culture determinations reinforce evidence for linkage between the HLA-D locus and the trait for C2 deficiency.

Factors that mediate and moderate the link between partner abuse and suicidal behavior in African American women.

Findings from a study comparing partner abuse in African American women suicide attempters (n = 148) and nonattempters (n = 137) revealed higher rates of physical and nonphysical partner abuse among attempters than their demographically similar nonsuicidal counterparts. The partner abuse--suicidal behavior link was mediated by psychological distress, hopelessness, and drug use and moderated by social support. Results also revealed that nonphysical partner abuse accounted for unique variance in the prediction of suicide attempt status beyond that attributable to childhood maltreatment. Implications of the findings for assessing both suicidal and abused women are discussed, and recommendations for preventive interventions for women at risk for suicidal behavior are provided.

Testing for predictive validity in health care education research: a critical review.

BACKGROUND: The assessment of predictive validity is the essential core from which a sound model of prediction is built. METHOD: Three methods for assessing predictive validity in health care education research were reviewed: longitudinal profile development, cross-validation, and inspection of the adjusted R2. A total of 47 articles published between 1973 and 1993 in nine health care disciplines were critically reviewed to determine whether the studies tested for predictive validity by using these methods. RESULTS: Very few of the 47 studies used at least one of the three methods for assessing predictive validity. Furthermore, the proportion of variance explained that is reported in the articles is typically small even before assessment of predictive validity. It is sobering to note that these small values may be inflated, since shrinkage is likely to occur when assessing predictive validity on a second, or cross-validation, sample. CONCLUSION: The scarcity of testing of predictive validity in the studies reviewed highlights the necessity of future research to establish the degree of predictive validity, if improvements in predicting success in health care education research are to be realized.

Immigrant women's health.

The immigration process entails many changes in the lives of those who emigrate including establishing oneself in a new country. There is continuing interest in what happens to the health of those who undergo this process. This qualitative study investigated the perceived health and health-related experiences of a sample of mid-life immigrant women and explored relationships between determinants of health and their experiences connected to immigration. Forty-two women participated in the study. While respondents were relatively well educated, their current socioeconomic status was relatively low. While women defined their health in a holistic manner. personal health focused on their physical health and their ability to function. This functionality was closely related to women's roles as resources for their families' well-being. Several health-related themes were identified that related to their change in homelands as adults: immigration and health, adapting to immigration and rebuilding their lives. Women are unlikely to talk about non-physical aspects of health unless asked about the general context of their lives. The family-centredness of immigrant women's well-being is a mediating factor in all aspects of their health; it is the health of the family unit that is the final point of adjudication for women. Spirituality and religious practices were identified as important resources for health. In addition, the process of immigration needs to be recognized as a determinant of health in and of itself. An understanding of these conceptualizations and health beliefs is an important component of the knowledge to be brought to formulating health promotion strategies and health services delivery that are relevant to and appropriate for this population of mid-life women.