Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia

OBJECTIVE: Clinical trials in patients with stable angina show that drugs that partially inhibit myocardial fatty acid oxidation reduce the symptoms of demand-induced ischemia, presumably by reducing lactate production and improving regional systolic function. We tested the hypothesis that partial inhibition of fatty acid oxidation with oxfenicine (a carnitine palmitoyl transferase-I inhibitor) reduces lactate production and increases regional myocardial power during demand-induced ischemia. METHODS: Demand-induced ischemia was produced in anesthetized open-chest swine by reducing flow by 20% in the left anterior descending coronary artery and increasing heart rate and contractility with dobutamine (15 microg kg(-1) min(-1) i.v.) for 20 min. Glucose and fatty acid oxidation were measured with an intracoronary infusion of [U-14C] glucose and [9,10-3H] oleate, and hearts were treated with oxfenicine (2 mmol l(-1); n=7) or vehicle (n=7). Regional anterior wall power was assessed from the left ventricular pressure-anterior free wall segment length loops. RESULTS: During demand-induced ischemia, the oxfenicine group had a higher rate of glucose oxidation (6.9+/-1.1 vs. 4. 7+/-0.8 micromol min(-1); P<0.05), significantly lower fatty acid uptake, but no change in total or active PDH activity. The oxfenicine group had significantly lower lactate output integrals (1.11+/-0.23 vs. 0.60+/-0.11 mmol) and glycogen depletion (66+/-6 vs. 43+/-8%), and higher anterior wall power index (0.95+/-0.17 vs. 1.30+/-0.11%) and anterior wall energy efficiency index (91+/-17 vs. 129+/-10%). CONCLUSIONS: Partial inhibition of fatty acid oxidation reduced non-oxidative glycolysis and improved regional contractile power and efficiency during demand-induced ischemia.     

Outcomes of patients with Kaposi's sarcoma who start antiretroviral therapy under routine programme conditions in Malawi

AIDS-associated Kaposi's sarcoma (KS) is the most common AIDS-related malignancy in sub-Saharan Africa, with a generally unfavourable prognosis. We report on six-month and 12-month cohort treatment outcomes of human immunodeficiency virus (HIV)-positive KS patients and HIV-positive non-KS patients treated with antiretroviral therapy (ART) in public sector facilities in Malawi. Data were collected from standardized antiretroviral (ARV) patient master cards and ARV patient registers. Between July and September 2005, 7905 patients started ART-488 (6%) with a diagnosis of KS and 7417 with a non-KS diagnosis. Between January and March 2005, 4580 patients started ART-326 (7%) with a diagnosis of KS and 4254 with a non-KS diagnosis. At six-months and 12-months, significantly fewer KS patients were alive and significantly more had died or defaulted compared to non-KS patients. HIV-positive KS patients on ART in Malawi have worse outcomes than other patients on ART. Methods designed to improve these outcomes must be found.     

Complexity of work and risk of Alzheimer's disease: a population-based study of Swedish twins

We examined the association between risk of dementia or Alzheimer's disease (AD) and occupation by using measures of complexity of work with data, people, and things. The study included 10,079 members of the population-based Swedish Twin Registry who were participants in the HARMONY study. We diagnosed dementia by means of a two-stage procedure--cognitive impairment screening followed by full clinical evaluation. We analyzed data with case-control and cotwin control designs. The cotwin control design provides control over genetic and familial factors. In the case-control study, controlling for age, gender, and level of education, we found that more complex work with people was associated with reduced risk of AD. Greater complexity of work with people and data was protective in twin pairs discordant for AD. Findings suggest that greater complexity of work, and particularly complex work with people, may reduce the risk of AD.     

Negative affectivity in children: Development and validation of a self-statement questionnaire

A questionnaire, the NASSQ (Negative Affect Self-Statement Questionnaire), was developed to assess self-statements associated with negative affect in children and young adolescents. Male and female 7- to 15-year-olds recalled representative self-statements (items) which were then administered to a sample along with a battery of measures used to identify criterion groups. Items discriminating between anxious/nonanxious and depressed/nondepressed criterion groups in separate 7- to 10- and 11- to 15-year-old samples were identified. Each inventory was then cross-validated on new samples. Anxious and depressive self-statement inventories were combined (separately for the age groups) to form the NASSQ. Both the 7- to 10- and the 11- to 15-year-old samples on NASSQ were found to be internally reliable and temporally stable. Additional analyses supported concurrent and construct validity. The NASSQ was found to be sensitive, and relatively specific, to an anxiety treatment, particularly with treated 11- to 15-year-olds. The NASSQ appears to be a useful measure to assess self-talk reflecting negative affectivity.     

Cerebrospinal fluid and plasma (1-->3)-beta-D-glucan as surrogate markers for detection and monitoring of therapeutic response in experimental hematogenous Candida meningoencephalitis

The treatment, diagnosis and therapeutic monitoring of hematogenous Candida meningoencephalitis (HCME) are not well understood. We therefore studied the expression of (1-->3)-beta-D-glucan (beta-glucan) in cerebrospinal fluid (CSF) and plasma in a nonneutropenic rabbit model of experimental HCME treated with micafungin and amphotericin B. Groups studied consisted of micafungin (0.5 to 32 mg/kg) and amphotericin B (1 mg/kg) treatment groups and the untreated controls (UC). Despite well-established infection in the cerebrum, cerebellum, choroid, vitreous humor (10(2) to 10(3) CFU/ml), spinal cord, and meninges (10 to 10(2) CFU/g), only 8.1% of UC CSF cultures were positive. By comparison, all 25 UC CSF samples tested for beta-glucan were positive (755 to 7,750 pg/ml) (P < 0.001). The therapeutic response in CNS tissue was site dependent, with significant decreases of the fungal burden in the cerebrum and cerebellum starting at 8 mg/kg, in the meninges at 2 mg/kg, and in the vitreous humor at 4 mg/kg. A dosage of 24 mg/kg was required to achieve a significant effect in the spinal cord and choroid. Clearance of Candida albicans from blood cultures was not predictive of eradication of organisms from the CNS; conversely, beta-glucan levels in CSF were predictive of the therapeutic response. A significant decrease of beta-glucan concentrations in CSF, in comparison to that for UC, started at 0.5 mg/kg (P < 0.001). Levels of plasma beta-glucan were lower than levels in simultaneously obtained CSF (P < 0.05). CSF beta-glucan levels correlated in a dose-dependent pattern with therapeutic responses and with Candida infection in cerebral tissue (r = 0.842). Micafungin demonstrated dose-dependent and site-dependent activity against HCME. CSF beta-glucan may be a useful biomarker for detection and monitoring of therapeutic response in HCME.     

A multicenter,open-label,randomized comparison of levofloxacin and azithromycin plus ceftriaxone in hospitalized adults with moderate to severe community-acquired pneumonia

BACKGROUND: Changing etiologic patterns and the growing problem of antimicrobial resistance, particularly an increase in macrolide-resistant pneumococcal bacteremia, are causing physicians to adopt new approaches to the treatment of community-acquired pneumonia (CAP). OBJECTIVE: The relative efficacy and tolerability of levofloxacin monotherapy and azithromycin and ceftriaxone combination therapy were assessed in hospitalized adults with moderate to severe CAP. METHODS: This Phase IV, multicenter, open-label, randomized trial compared 2 treatment regimens: (1) levofloxacin 500 mg PO or IV q24h, and (2) azithromycin 500 mg IV q24h for > or = 2 days plus ceftriaxone 1 g IV q24h for 2 days, followed by an optional transition to azithromycin 500 mg PO q24h at the investigator's discretion. The total duration of therapy was to be a minimum of 10 days in both treatment groups. Ceftriaxone was included in the initial azithromycin regimen to ensure coverage against pneumococcal bacteremia. RESULTS: Of 236 patients in the intent-to-treat population, completion or withdrawal information was available for 110 patients in the levofloxacin group and 114 in the azithromycin group. Baseline demographic and disease characteristics were comparable between groups. At the end of treatment, the clinical success rate (cured + improved) in clinically evaluable patients was 94.1% in the levofloxacin group and 92.3% in the azithromycin group. The respective posttherapy microbiologic eradication rates were 89.5% and 92.3%. Levofloxacin was as well tolerated as azithromycin, with an incidence of drug-related adverse events (AEs) for all body systems of 5.3% and 9.3%, respectively. None of the drug-related AEs were considered serious [corrected]. CONCLUSIONS: In this study in hospitalized patients with moderate to severe CAP, levofloxacin monotherapy was at least as effective as a combination regimen of azithromycin and ceftriaxone in providing coverage against the current causative pathogens in CAP. In addition, levofloxacin was as well tolerated as the combination of azithromycin and ceftriaxone.     

The Web-based worksheet: an opportunity for prompt,consistent, and expert feedback in a community-based hospice experience

We faced a challenge in providing a consistent high-quality learning experience in hospice care, especially because our community-based medical school has students rotating in hospices in six separated communities and the number of faculty with expertise in palliative care is limited. To address these concerns, a Web-based worksheet with interaction with a central campus faculty member was designed for use in a hospice module in a family practice clerkship.     

AUTORADIOGRAPHIC ANALYSIS OF LYMPHOPOIESIS AND LYMPHOCYTE MIGRATION IN MICE BEARING MULTIPLE THYMUS GRAFTS

Lymphopoiesis was studied in 3-month-old normal C57Bl mice and in 3-month-old C57Bl mice carrying from 12 to 48 C57Bl thymus grafts using tritiated thymidine labeling. Thymus graft lymphopoiesis was found to be identical with that of normal thymus tissue and the presence of thymus grafts was found to have no influence on host thymus lymphopoiesis. No evidence was found that the massive amounts of thymus graft tissue in the mice affected any parameter of host lymph node lymphopoiesis nor was any evidence detected for the migration of thymic lymphocytes from these massive deposits of thymus graft tissue either to host lymph nodes and blood or to other organs in the host animal. It is concluded that the majority of small lymphocytes produced in the thymus and thymus graft tissue do not migrate from these tissues but die locally at the end of their intrathymic life span of 3 to 4 days.     

γA-BLOOD GROUP ANTIBODIES

The serological characteristics of γA-anti-A and anti-B were studied using, as a source, either colostrum, or fractions relatively rich in γA obtained from selected potent antisera. γA-anti-A and anti-B were never hemolytic nor did they sensitize red cells to agglutination by anticomplement globulin sera. γA-anti-A, like γG-anti-A and unlike γM-anti-A was unaffected by heating at 56°C for 3 hr. On the other hand in the following three characteristics the behavior of γA fell between that of γG- or γM-anti-A: sensitivity to inactivation by 2-mercaptoethanol, ease of neutralization by A substance and degree of enhancement of agglutination in a medium of serum rather than saline. The agglutination produced by γA-anti-A was regularly enhanced by addition of anti-γA-globulin serum. In searching for γA-blood group antibodies of other specificities the following sera were tested: anti-D (32 examples); anti-c (2 examples); anti-Le^a or -Le^b (3 examples); anti-K (3 examples); anti-Fy^a (3 examples), and anti-Jk^a (3 examples). Only 3 sera, all containing anti-D, sensitized red cells to agglutination by anti-γA. There were no discrepancies between results obtained with four different anti-γA-globulin sera. Approximately half the sera were fractionated on DEAE-cellulose, and the fractions rich in γA tested for their ability to sensitize red cells to agglutination by anti-γA; no additional examples of γA-antibodies were detected. One of the three examples of γA-anti-D appeared in the serum of a woman during the course of deliberate reimmunization. γA-anti-D appeared only after three intravenous injections of red cells although the γG-anti-D titer rose considerably after a single injection. 3 yr after a fourth injection of Rh-positive cells γA-anti-D, as well as γG-anti-D, was still present in the serum.