The Influence of Prebiotics on Neurobiology and Behavior.

Manipulating the intestinal microbiota for the benefit of the brain is a concept that has become widely acknowledged. Prebiotics are nondigestible nutrients (i.e., fibers, carbohydrates, or various saccharides) that proliferate intrinsic, beneficial gut bacteria, and so provide an alternative strategy for effectively altering the enteric ecosystem, and thence brain function. Rodent studies demonstrating neurobiological changes following prebiotic intake are slowly emerging, and have thus far revealed significant benefits in disease models, including antiinflammatory and neuroprotective actions. There are also compelling data showing the robust and favorable effects of prebiotics on several behavioral paradigms including, anxiety, learning, and memory. At present, studies in humans are limited, though there is strong evidence for prebiotics modulating emotional processes and the neuroendocrine stress response that may underlie the pathophysiology of anxiety. While the mechanistic details linking the enteric microbiota to the central nervous system remain to be elucidated, there are a number of considerations that can guide future studies. These include the modulation of intestinal endocrine systems and inflammatory cascades, as well as direct interaction with the enteric nervous system and gut mucosa. Our knowledge of gut microbiome-brain communication is steadily progressing, and thorough investigations validating the use of prebiotics in the treatment of neuropsychiatric disorders would be highly valued and are encouraged.

Methylenetetrahydrofolate reductase gene variants and antipsychotic-induced weight gain and metabolic disturbances.

Weight gain and metabolic disturbances represent serious side-effects in antipsychotic (AP) treatment, particularly with clozapine and olanzapine. The methylenetetrahydrofolate reductase (MTHFR) gene is a key determinant in the folate metabolism and previous studies reported a significant effect on AP-induced weight gain and related metabolic abnormalities. Thus, we investigated MTHFR gene variants and changes in several important metabolic parameters in AP-treated patients. In this study, two functional MTHFR polymorphisms, rs1801133 (C677T) and rs1801131 (A1298C), were investigated for changes in weight and metabolic parameters. Genotypic associations were evaluated in a large population (n = 347 including 66 first episode psychosis, FEP patients) treated mostly with clozapine and olanzapine. We did not detect any genotypic association with weight changes (p > 0.05) in our total sample and in the sample refined for ancestry and medication. In our allelic analyses, we observed a trend for the 677-C allele to be associated with weight gain in the total sample (p = 0.03). This effect appeared to be driven by the FEP patients where those carrying the C-allele gained, on average, twice as much weight. Exploratory analyses revealed a significant association between the C677T and the A1298C polymorphism with HDL cholesterol serum levels in patients (p = 0.031). Overall we did not detect a major effect of two functional MTHFR gene variants and AP-induced weight gain. However, our findings suggest an effect of the C677T polymorphism in FEP patients and changes in weight and cholesterol levels. Further investigations in a larger sample are required.

Ventricular arrhythmia in the X-linked cardiomyopathy Barth syndrome.

Barth syndrome is an X-linked disorder characterized by dilated cardiomyopathy, cyclic neutropenia, skeletal myopathy, abnormal mitochondria, and growth deficiency. The primary defect is a mutation in the TAZ gene on the X chromosome at Xq28, resulting in abnormal phospholipid biosynthesis and cardiolipin deficiency. To date, there has been no systematic evaluation of the cardiac phenotype. We report five cases of cardiac arrest and/or placement of an internal cardiac defibrillator with documented ventricular arrhythmia. We suggest that ventricular arrhythmia is part of the primary phenotype of the disorder and that patients should be screened accordingly.

Physician incentives and disclosure of payment methods to patients.

OBJECTIVE: There is increasing public discussion of the value of disclosing how physicians are paid. However, little is known about patients' awareness of and interest in physician payment information or its potential impact on patients' evaluation of their care. DESIGN: Cross-sectional survey SETTING: Managed care and indemnity plans of a large, national health insurer. PARTICIPANTS: Telephone interviews were conducted with 2,086 adult patients in Atlanta, Ga; Baltimore, Md/Washington DC; and Orlando, Fla (response rate, 54%). MEASUREMENTS AND MAIN RESULTS: Patients were interviewed to assess perceptions of their physicians' payment method, preference for disclosure, and perceived effect of different financial incentives on quality of care. Non-managed fee-for-service patients (44%) were more likely to correctly identify how their physicians were paid than those with salaried (32%) or capitated (16%) physicians. Just over half (54%) wanted to be informed about their physicians' payment METHOD: Patients of capitated and salaried physicians were as likely to want disclosure as patients of fee-for-service physicians. College graduates were more likely to prefer disclosure than other patients. Many patients (76%) thought a bonus paid for ordering fewer than the average number of tests would adversely affect the quality of their care. About half of the patients (53%) thought a particular type of withhold would adversely affect the quality of their care. White patients, college graduates, and those who had higher incomes were more likely to think that these types of bonuses and withholds would have a negative impact on their care. Among patients who believed that these types of bonuses adversely affected care, those with non-managed fee-for-service insurance and college graduates were more willing to pay a higher deductible or co-payment in order to get tests that they thought were necessary. CONCLUSIONS: Most patients were unaware of how their physicians are paid, and only about half wanted to know. Most believed that bonuses or withholds designed to reduce the use of services would adversely affect the quality of their care. Lack of knowledge combined with strong attitudes about various financial incentives suggest that improved patient education could clarify patient understanding of the nature and rationale for different types of incentives. More public discussion of this important topic is warranted.

Validation of dizziness as a possible geriatric syndrome.

OBJECTIVE: While dizziness has traditionally been considered solely as a symptom of discrete diseases, recent findings from population-based studies of older persons suggest that it may often be a geriatric syndrome with multiple predisposing risk factors, representing impairments in diverse systems. To validate these findings, we identified predisposing risk factors for dizziness in a clinic-based population. DESIGN: Cross-sectional study. SETTING: Geriatric assessment center. PARTICIPANTS: 262 consecutive, eligible patients. MEASUREMENTS: Medical history and physical examination data were ascertained and characteristics of patients with and without a report of dizziness were compared. RESULTS: Seven factors were independently associated with a report of dizziness, namely depressive symptoms, cataracts, abnormal balance or gait, postural hypotension, diabetes, past myocardial infarction, and the use of three or more medications. Of patients with none of these risk factors, none reported dizziness. This proportion rose from 6% among patients with one factor, to 12%, 26%, and 51% among patients with two, three, and four or more factors, respectively. CONCLUSIONS: The finding of similar factors associated with dizziness in previous community-based cohorts and the present clinic-based cohort supports the possibility of a multifactorial etiology of dizziness in many older persons. A multifactorial intervention targeting the factors identified in these studies may be effective at reducing the frequency or severity of dizziness in older patients.

The relationship between method of physician payment and patient trust.

CONTEXT: Trust is the cornerstone of the patient-physician relationship. Payment methods that place physicians at financial risk have raised concerns about patients' trust in physicians to act in patients' best interests. OBJECTIVE: To evaluate the extent to which methods of physician payment are related to patient trust. DESIGN: Cross-sectional telephone interview survey done between January and June 1997. SETTING: Health plans of a large national insurer in Atlanta, Ga, the Baltimore, Md-Washington, DC, area, and Orlando, Fla. PARTICIPANTS: A total of 2086 adult managed care and indemnity patients. MAIN OUTCOME MEASURE: A 10-item scale (alpha = .94) assessing patients' trust in physicians. RESULTS: More fee-for-service (FFS) indemnity patients (94%) completely or mostly trust their physicians to "put their health and well-being above keeping down the health plan's costs" than salary (77%), capitated (83%), or FFS managed care patients (85%) (P<.001 for pairwise comparisons). In multivariate analyses that adjusted for potentially confounding factors, FFS indemnity patients also had higher scores on the 10-item trust scale than salary (P<.001), capitated (P<.001), or FFS managed care patients (P<.01). The effects of payment method on patient trust were reduced when a measure based on patients' reports about physician behavior (eg, Does your physician take enough time to answer your questions?) was included in the regression analyses, but the differences remained statistically significant, except for the comparison between FFS managed care and FFS indemnity patients (P=.08). Patients' perceptions of how their physicians were paid were not independently associated with trust, but the 37.7% who said they did not know how their physicians were paid had higher levels of trust than other patients (P<.01). A total of 30.2% of patients were incorrect about their physicians' method of payment. CONCLUSIONS: Most patients trusted their physicians, but FFS indemnity patients have higher levels of trust than salary, capitated, or FFS managed care patients. Patients' reports of physician behavior accounted for part of the variation in patients' trust in physicians who are paid differently. The impact of payment methods on patient trust may be mediated partly by physician behavior.

Patients' trust in their physicians: effects of choice, continuity, and payment method.

OBJECTIVE: To evaluate the extent to which physician choice, length of patient-physician relationship, and perceived physician payment method predict patients' trust in their physician. DESIGN: Survey of patients of physicians in Atlanta, Georgia. PATIENTS: Subjects were 292 patients aged 18 years and older. MEASUREMENTS AND MAIN RESULTS: Scale of patients' trust in their physician was the main outcome measure. Most patients completely trusted their physicians "to put their needs above all other considerations" (69%). Patients who reported having enough choice of physician (p < .05), a longer relationship with the physician (p < .001), and who trusted their managed care organization (p < .001) were more likely to trust their physician. Approximately two thirds of all respondents did not know the method by which their physician was paid. The majority of patients believed paying a physician each time a test is done rather than a fixed monthly amount would not affect their care (72.4%). However, 40.5% of all respondents believed paying a physician more for ordering fewer than the average number of tests would make their care worse. Of these patients, 53.3% would accept higher copayments to obtain necessary medical tests. CONCLUSIONS: Patients' trust in their physician is related to having a choice of physicians, having a longer relationship with their physician, and trusting their managed care organization. Most patients are unaware of their physician's payment method, but many are concerned about payment methods that might discourage medical use.

Allograft diastolic dysfunction and chronotropic incompetence limit cardiac output response to exercise two to six years after heart transplantation.

BACKGROUND: Because prolonged survival of heart transplant recipients is expected with the current immunosuppressive treatment, the functional capacity of these long-term survivors is of interest. Previous exercise studies showed no objective improvement in exercise tolerance several years after transplantation, but the extent to which chronotropic incompetence and allograft diastolic dysfunction observed early after transplantation may improve over time has not been defined. METHODS: Thirteen untrained heart transplant recipients without symptoms, between 27 and 70 months after transplantation, and 13 age-matched sedentary normal controls underwent maximal upright bicycle exercise testing with simultaneous hemodynamic, radionuclide, and expired gas measurements. RESULTS: Systolic function as measured by ejection fraction was supranormal at rest in the transplant group and normalized with exercise. Despite their maximal exercise effort, transplant recipients had a 60% reduction in their exercise capacity compared with nontransplant recipients. Peak oxygen consumption was similarly reduced by 52%. Cardiac output response to exercise was 43% lower in the transplant group because of a 78% reduction in heart rate reserve and an 18% reduction in maximal stroke volume. Ventricular volumes were similarly reduced after transplantation, but filling pressures remained normal, indicating allograft diastolic dysfunction. Despite the significantly reduced maximal cardiac output, maximal arteriovenous oxygen difference was 25% lower in the transplant recipients, suggesting a peripheral deficit in oxygen handling. CONCLUSIONS: Therefore, patients, 2 to 6 years after transplantation, continue to have a significant reduction in exercise tolerance as a result of a combination of severe chronotropic incompetence, limited stroke volume reserve caused by a reduced ventricular size and allograft diastolic dysfunction, and an abnormality in peripheral oxygen delivery or use. Efforts aimed at improving these factors may further enhance the functional capacity of these long-term survivors of heart transplantation.

Central and peripheral limitations to upright exercise in untrained cardiac transplant recipients.

BACKGROUND: Functional capacity and quality of life are subjectively improved after cardiac transplantation. However, the objective improvement in exercise tolerance after transplantation has been disappointing. The extent to which allograft diastolic dysfunction contributes to this exercise intolerance has not been defined. METHODS AND RESULTS: Thirty cardiac transplant recipients between 3 and 16 months after transplantation and 30 age-matched normal control subjects underwent maximal symptom-limited graded upright bicycle exercise testing with simultaneous radionuclide angiography, invasive hemodynamic monitoring, and breath-by-breath gas analysis. Mean blood pressure was higher in the transplant group at supine rest (112.1 versus 97.7 mm Hg), normalized with upright posture, and became lower than normal at peak exercise (121.1 versus 133.2 mm Hg). Systolic function as measured by ejection fraction was normal in both groups. However, the cardiac transplant recipients had significantly lower exercise tolerance, achieving a mean maximal work rate of 390 kilopond-meters per minute (kpm/min), compared with 825 kpm/min in the normal subjects. Peak oxygen consumption was 12.3 mL.min-1.kg-1 in the transplant group, 46% lower than the normal group's value of 22.9 mL.min-1.kg-1. The transplant patients had a resting tachycardia (94 beats per minute) and a 79% reduction in exercise heart rate reserve compared with normal. Despite this chronotropic incompetence, stroke index response to exercise was consistently lower after transplantation, accounting for a 41% reduction in cardiac index at maximal exercise. The lower stroke index was accompanied by a 32% lower end-diastolic volume index at rest and a 14% lower end-diastolic volume index at peak exercise. Despite the smaller ventricular volumes after transplantation, pulmonary capillary wedge pressure was 35% higher than normal at supine rest and 50% higher at maximal exercise. Right atrial and mean pulmonary arterial pressures were similarly elevated. The ratio of pulmonary capillary wedge pressure to end-diastolic volume index was significantly higher during the postural change and exercise, suggesting allograft diastolic dysfunction. Arteriovenous oxygen difference was similar between groups at rest and with submaximal exercise but was 24% lower at maximal exercise in the transplant group, suggesting an abnormality in peripheral oxygen uptake or utilization. CONCLUSIONS: Exercise tolerance is severely limited during the first 16 months after cardiac transplantation despite preservation of allograft left ventricular systolic function. This intolerance is due to an inadequate cardiac index response from a combination of chronotropic incompetence and diastolic dysfunction limiting the appropriate compensatory use of the Starling mechanism. In addition, there is a peripheral abnormality in oxygen transport or utilization that may partially reflect the effects of deconditioning.

Mitogen stimulation of Na+-H+ exchange: differential involvement of protein kinase C.

The mitogen-induced activation of Na+-H+ exchange was investigated in two cultured human fibroblast strains (HSWP and WI-38 cells) that, based on previous studies, differed in their response to the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) (L. M. Vincentini and M. L. Villereal, Proc. Natl. Acad. Sci. USA 82: 8053-8056, 1985). The role of protein kinase C in the activation of Na+-H+ exchange was investigated by comparing the effects of TPA on Na+ influx, in vitro phosphorylation, and in vivo phosphorylation in both cell types. Although both cell types have significant quantities of protein kinase C activity that can be activated by TPA in intact cells, the addition of TPA to intact cells stimulates Na+ influx in WI-38 cells but not in HSWP cells, indicating that in HSWP cells the stimulation of protein kinase C is not sufficient to activate the Na+-H+ exchanger. Cells were then depleted of protein kinase C activity by chronic treatment with high doses of TPA. Both HSWP and WI-38 cells were rendered protein kinase C deficient by this treatment as determined by in vitro and in vivo phosphorylation studies. Protein kinase C-deficient HSWP cells lose the ability for TPA to inhibit the serum-induced activation of Na+-H+ exchange, but there is no reduction in the stimulation of Na+ influx by serum, bradykinin, vasopressin, melittin, or vanadate, indicating that protein kinase C activity is not necessary for the mitogen-induced activation of Na+-H+ exchange in HSWP cells by agents known to stimulate phosphatidylinositol turnover (G. A. Jamieson and M. Villereal. Arch. Biochem. Biophys. 252: 478-486, 1987). In contrast, depletion of protein kinase C activity in WI-38 cells significantly reduces both the TPA- and the serum-induced activation of the Na+-H+ exchange system, suggesting that protein kinase C activity is necessary for at least a portion of the mitogen-induced activation of the Na+-H+ exchanger in WI-38 cells. These results indicate that the mechanisms for regulating Na+-H+ exchange can differ dramatically between different types of fibroblasts.