Mild cognitive impairment: potential pharmacological treatment options

Both mild cognitive impairment and age-associated memory impairment are terms used to describe memory decline in otherwise healthy, intellectually intact individuals aged older than 50 years. It is estimated that up to 38% of the middle-aged and older population fulfill diagnostic criteria for this condition. Although the memory deficits observed in these individuals are fairly mild, they can interfere with day-to-day functioning. This article presents a review of the types of memory decline observed in older people, the diagnostic criteria used to define memory decline, the physiological and morphological brain changes that accompany aging, and the potential pharmacological treatment options, focusing on agents that have been evaluated in mildly cognitively impaired or normal older populations.     

Ticagrelor and the Prevention of Microvascular Complications in Diabetes Patients with Lower Extremity Arterial Disease; Rationale and Design of the Hema-Kinesis Trial

Background

Lower extremity arterial disease (LEAD) occurs more common in patients with diabetes than without diabetes. Microvascular complications of diabetes contribute to higher rates of adverse limb events in patients with LEAD. Blood flow in the macrocirculation and microcirculation is reduced with increasing low-shear and high-shear blood viscosity. We hypothesize that the adenosine enhancing properties of ticagrelor will reduce low-shear blood viscosity and improve microcirculatory flow in the dorsum of the feet of patients with type 2 diabetes. Ticagrelor is a P2Y12 receptor antagonist with evidence of cardiovascular event reduction in patients with acute coronary syndromes and those with a previous myocardial infarction. In a large multicenter trial of patients with symptomatic LEAD and a history of limb revascularization, ticagrelor was no more effective than clopidogrel in reducing cardiovascular disease events; however, this trial was not designed to investigate microvascular complications of diabetes.

Design

Hema-kinesis will evaluate whether ticagrelor monotherapy or ticagrelor combined with aspirin as compared with aspirin monotherapy can reduce blood viscosity-dependent blood flow in the feet of type 2 diabetes patients with LEAD. Eligible study participants will be randomized into a three-arm double-dummy crossover trial design. All subjects will have baseline blood viscosity measurements and determinations of microvascular flow using laser Doppler flowmetry.

Summary

If the results of Hema-kinesis are positive, ticagrelor should be considered as treatment to reduce microvascular complications of LEAD in patients with type 2 diabetes.

     

Prevention of autoimmune diabetes by immunogene therapy using recombinant vaccinia virus expressing glutamic acid decarboxylase

AIMS/HYPOTHESES: Type I (insulin-dependent) diabetes mellitus results from T-cell-mediated autoimmune destruction of pancreatic beta cells. Among the beta-cell autoantigens that have been implicated in triggering of beta-cell-specific autoimmunity, glutamic acid decarboxylase (GAD) is a strong candidate in both humans and the NOD mouse. We aimed to determine whether treatment with a recombinant vaccinia virus expressing GAD (rVV-GAD65) could prevent the development of diabetes in NOD mice. METHODS: Three-eight-to-nine-week-old female NOD mice were injected with various doses of rVV-GAD65 or rVV-MJ601as a control. We then examined the incidence of diabetes, T-cell proliferative response to GAD, amounts of anti-GAD IgGs, cytokine production and generation of regulatory cell populations. RESULTS: Administration of rVV-GAD65 to NOD mice prevented diabetes in an age-dependent and dose-dependent manner. Splenic T cells from rVV-GAD65-treated mice did not proliferate in response to GAD65. The amount of IgG1 was increased, whereas IgG2a amounts did not change in rVV-GAD65-treated NOD mice. The production of interleukin-4 increased, whereas the production of interferon-gamma decreased in rVV-GAD65-treated mice after stimulation with GAD. Furthermore, splenocytes from rVV-GAD65-treated NOD mice prevented the transfer of diabetes by splenocytes from acutely diabetic NOD mice in NOD. scid recipients. CONCLUSION/INTERPRETATION: Immunogene therapy using a recombinant vaccinia virus expressing GAD results in the prevention of autoimmune diabetes in NOD mice by the induction of immunological tolerance through active suppression of effector T cells, and this treatment might have therapeutic value for the prevention of Type I diabetes.     

The impact of different doses of estrogen and progestin on mood and sexual behavior in postmenopausal women.

This study investigated the effects of various doses of estrogen and progestin on psychological functioning and sexual behavior of 48 healthy, naturally menopausal women. Subjects were tested before treatment and then randomly assigned to 1 of 4 cyclic sequential hormone regimens for 1 yr. Groups A and C received 0.625 or 1.25 mg conjugated equine estrogen (CEE), respectively, for days 1-25 and 5 mg medroxyprogesterone acetate from days 15-25. Groups B and D were given 0.625 or 1.25 mg CEE, respectively, from days 1-25 and placebo from days 15-25. The higher dose of CEE induced supraphysiological levels of plasma estrone. Plasma testosterone levels were lower in group A when blood was sampled during days 18-20 at a time when they were ingesting both 0.625 mg CEE and 5 mg medroxyprogesterone acetate (P less than 0.05), although these decreases were perhaps too trivial to have affected sexual behavior as was hypothesized. Women in group A also had more negative moods and more psychological symptomatology during treatment compared to those in group D who were receiving 1.25 mg CEE and placebo (P less than 0.01). Regardless of group, sexual desire and arousal were higher during the first 2 weeks of the treatment cycle than during week 4 when no hormones were being ingested (P less than 0.05). These findings demonstrate that the effects of progestin on the central nervous system are reflected by an increase in psychological, exclusive of sexual, symptomatology and are attenuated by a higher estrogen/progestin dose ratio.     

Platelets, but not erythrocytes, significantly affect cytokine release and scaffold contraction in a provisional scaffold model

Platelets and erythrocytes are major components of wound provisional scaffolding. In this study, we hypothesized that the concentration of platelets and erythrocytes would significantly affect fibroblast‐mediated contraction of three‐dimensional scaffolds or the release of cytokines from the scaffold. To test this hypothesis, human anterior cruciate ligament fibroblasts were cultured in one of four scaffolds: a collagen matrix, a collagen‐fibrin matrix containing the same concentration of platelets as whole blood, a collagen‐fibrin matrix containing a high platelet concentration, and a collagen–fibrin matrix containing a high platelet concentration and red blood cells. Cytokine release from the four groups of gels and gel contraction were measured over a 10‐day period. The results of these assays supported greater cytokine release, fibroblast proliferation, and gel contraction in scaffolds with higher platelet concentration. In contrast, the addition of erythrocytes did not significantly stimulate or suppress scaffold contraction or growth factor release from the provisional scaffolds. We concluded that while platelet concentration can significantly impact cytokine release and scaffold retraction in a provisional scaffold, the inclusion of erythrocytes does not have a significant effect on these same behaviors. Therefore, while platelets may be an important regulator of repair processes after injury, it is less likely that erythrocytes have a similar function.     

Phase II study of recombinant interferon-gamma in patients with disseminated malignant melanoma

Twenty-eight patients with disseminated malignant melanoma received daily im therapy with recombinant interferon-gamma. The dose was 0.25 mg/m2 on Days 1-7 followed by a daily dose of 0.5 mg/m2 if tolerated. Among 27 patients, we observed three objective partial regressions (8.3, 3.7, and 3.9+ months). The median leukocyte count nadir was 2.5 X 10(3)/mm3 (range, 1.4-5.1). Constitutional symptoms included moderate to severe fever greater than 37 degrees C (100%), fatigue (59%), chills (37%), and mild to moderate myalgias (64%). Recombinant interferon-gamma produces manageable side effects but limited efficacy as employed in this study.     

Latex condom deterioration accelerated by environmental factors: I. Ozone

Commercial non-lubricated latex condoms were unpackaged and exposed in an environmental chamber to ozone levels (0.3 ppm) commonly present in urban smog conditions. Deterioration was observed by scanning electron microscopy after 18 hours exposure. Loss of mechanical strength was quantitated by measurement of the air pressures necessary to burst the condom and volumes at burst. After 24 hours exposure to ozone the latex surface was covered with craters and after 48 hours the pressure required to burst the condom was 44% that of control samples. Data suggest the need for study of the effectiveness of lubrication and packaging in protecting condoms from environmental factors which may accelerate deterioration.