The optimal use of bexarotene in cutaneous T-cell lymphoma.

The management goal in cutaneous T-cell lymphomas (CTCLs) is to improve symptoms and induce remission. Early-stage disease is generally treated with skin-directed therapies. However, if these do not control the disease, systemic therapy becomes necessary. Bexarotene, a novel rexinoid, is an oral, noncytotoxic drug that has been approved in Europe for the treatment of refractory advanced-stage CTCL and in the U.S.A. for refractory CTCL. We provide guidance on the use of bexarotene in the management of CTCL, based on data from phase II/III clinical trials and the authors' clinical experience, and suggest how the potential of the drug can be maximized. The clinical trial results with bexarotene are reviewed, especially in comparison with interferon-alpha, which is the other commonly used noncytotoxic systemic therapy for CTCL. A treatment algorithm for bexarotene in refractory CTCL is suggested. As bexarotene may take time to achieve a maximum response, this algorithm recommends that therapy should be continued for a sufficient period to allow for a delayed onset of action. In addition, possible combination therapies with bexarotene are discussed. We conclude that bexarotene is effective in the management of CTCL, and has the advantage of oral administration. An on-going randomized clinical trial comparing psoralen plus ultraviolet A (PUVA) with PUVA plus bexarotene will provide valuable information about this combination regimen in early-stage disease, but further data are needed on the relative efficacies of other combination therapies with bexarotene in CTCL.

Minimizing adverse side-effects of oral bexarotene in cutaneous T-cell lymphoma: an expert opinion.

Bexarotene is an oral retinoid therapy that is effective for the treatment of early and advanced-stage cutaneous T-cell lymphoma (CTCL) in patients who have failed on other therapies. However, bexarotene treatment is associated with unavoidable side-effects, in particular hypertriglyceridaemia and hypothyroidism, which are manageable with adequate concomitant medications and are reversible on cessation of treatment. A pragmatic strategy for minimizing bexarotene-associated hypertriglyceridaemia and hypothyroidism is suggested, based on data from the studies with bexarotene in CTCL and on day-to-day experience with this agent in the clinical setting. The strategy anticipates that these common adverse events are likely to occur and recommends the early use of preventive therapy to lower triglycerides and elevate thyroid hormone levels in the blood, followed by subsequent monitoring, dose adjustment during bexarotene treatment, and titration of the daily bexarotene dose from 150 to 300 mg m(-2), which is optimal for most patients. When further information becomes available on how bexarotene interacts with lipid metabolism and thyroid function, the management approach suggested here may need to be changed.

[Recommendations for statin therapy in the elderly]. / Empfehlungen zur Statintherapie im AlterDaten und Konsensus.

Elderly patients are significantly less likely to receive statins than younger patients possibly because of doubts regarding compliance or concerns regarding the increased likelihood of adverse events and drug interactions. Poor compliance can be expected especially in patients suffering from dementia or depression as well as those whose stage of cardiovascular disease exhibits few symptoms. On the other hand, the clinical significance of CHD events is high in the elderly, and 80% of coronary deaths occur in patients aged over 65 years. The average statistical life expectancy of elderly and old patients is often underestimated. The HPS and PROSPER studies showed that statins reduce mortality and morbidity even in very elderly individuals with a high global cardiovascular risk and/or CAD. Patients up to the age of 79 years should be treated according to the same guidelines as younger patients. Statin therapy should only be considered for patients aged 80 years and older who are at a very high risk for cardiovascular events.

Vector and tensor polarization lifetimes for a stored deuteron beam.

The time dependence of the vector and tensor polarization of a 270 MeV stored deuteron beam was measured near a depolarizing resonance, which was induced by an oscillating, longitudinal magnetic field. The distance to the resonance was varied by changing the oscillation frequency. The measured ratio of the polarization lifetimes is tau(vector)/tau(tensor)=1.9+/-0.2. Assuming that the effect of the resonance is to induce transitions between magnetic substates m(I), we find that the transition rate between neighboring states (+1 and 0 or -1 and 0) is four times higher than between the states with m(I)=+1 and -1.

First spin flipping of a stored spin-1 polarized beam.

We recently studied spin flipping of a 270 MeV vertically polarized deuteron beam stored in the Indiana University Cyclotron Facility Cooler Ring. We adiabatically swept an rf solenoid's frequency through an rf-induced spin resonance and observed its effect on the deuterons' vector and tensor polarizations. After optimizing the resonance crossing rate and maximizing the solenoid's voltage, we measured a vector spin-flip efficiency of 94.2%+/-0.3%. We also found striking behavior of the spin-1 tensor polarization.

Effect of atorvastatin on lipid parameters, LDL subtype distribution, hemorrheological parameters and adhesion molecule concentrations in patients with hypertriglyceridemia.

BACKGROUND AND AIM: Hypertriglyceridemia is a risk factor for atherosclerosis that is typically associated with high concentrations of adhesion molecules, impaired hemorrheology and an unfavourable low-density lipoprotein (LDL) subtype distribution. We hypothesised that some of these risk markers might be beneficially influenced by lipid-lowering therapy with atorvastatin in hypertriglyceridemic patients. METHODS AND RESULTS: Nineteen patents with primary hypertriglyceridemia were given 10 mg of atorvastatin per day for four weeks. Their cholesterol, triglyceride, LDL and high-density lipoprotein cholesterol (HDL-C) levels, LDL subtype profile, hemorrheological parameters and E-selectin, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 concentrations were measured before and at the end of atorvastatin therapy. The levels of total and LDL cholesterol respectively decreased by 25% and 24% (both p < 0.001). Furthermore, cholesterol was reduced by 8-29% in all seven LDL subfractions (density range: 1.020-1.066 g/mL) (p < 0.05). The reduction in triglyceride concentrations was of marginal significance (9%, p = 0.1), but its degree positively correlated with the reduction of small-dense LDL (r = 0.5, p < 0.025). Plasma viscosity and blood viscosity at low shear rates were respectively reduced by 2% and 16% (both p < 0.05). The effect of the treatment on the concentrations of HDL-C, fibrinogen and adhesion molecules was not significant. CONCLUSIONS: Atorvastatin (10 mg/day) not only reduced the plasma concentrations of atherogenic lipoproteins but also improved the LDL-subtype profile and reduced plasma and blood viscosity in patients with hypertriglyceridemia; however, it failed to significantly lower triglyceride concentrations.

The importance of reaching lipid targets: statins and the prevention of atherosclerosis.

To help prevent the development of coronary heart disease (CHD), the European and NCEP guidelines have recommended target cholesterol levels for all individuals. Lifestyle changes are advocated for individuals not achieving these targets. Intervention with lipid-modifying agents may be required for patients at high risk of a cardiovascular event and statins are generally recognised as first-line therapy. Unfortunately, large numbers of patients at risk of cardiovascular events are not being treated to the guideline targets. Primary care physicians are in a good position to improve lipid management by assessing risk factors, implementing lipid management strategies, monitoring whether targets are being reached and amending treatment appropriately. Furthermore, by educating and motivating patients,primary care physicians may improve compliance with lifestyle changes and medication. These approaches may help more patients to achieve recommended lipid levels and prevent the development of cardiovascular disease.

Influence of simvastatin on LDL-subtypes in patients with heterozygous familial hypercholesterolemia and in patients with diabetes mellitus and mixed hyperlipoproteinemia.

This study evaluates the influence of simvastatin on lipid concentrations and on LDL-subtype distribution in patients with heterozygous familial hypercholesterolemia and in patients with type 2 diabetes and mixed hyperlipoproteinemia. Nine patients with familial hypercholesterolemia (LDL-cholesterol: 7.1 +/- 1.1 mmol/L, triglycerides: 1.3 +/- 0.4 mmol/L) and 8 patients with type 2 diabetes mellitus and mixed hyperlipoproteinemia (HbA1c 6.8 +/- 1.1%, LDL-cholesterol: 4.8 +/- 0.7 mmol/L, triglycerides: 2.5 +/- 1.1 mmol/L) were examined. Cholesterol concentration was determined in 7 LDL-subfractions isolated by density gradient ultracentrifugation before and during simvastatin treatment (10-20 mg/d, 4 weeks). Simvastatin decreased LDL-cholesterol (-34%/-30%, all p < 0.05) and triglycerides (-2%, n.s./-25%, p < 0.05), but had little effect on HDL-cholesterol (+7%/+2%, n.s.) in patients with familial hypercholesterolemia and diabetes mellitus, respectively. In both groups a significant reduction of cholesterol in each LDL-subfraction was observed. Large-buoyant (LDL-1, LDL-2) and intermediate-dense (LDL-3, LDL-4) LDL were reduced more than small-dense (LDL-5-LDL-7) LDL-subtypes (-36%/-38%/-23%, respectively) in patients with familial hypercholesterolemia, while in diabetic patients cholesterol reduction was uniform in all LDL-subtypes (-29%/-27%/-31%, respectively). Simvastatin decreases cholesterol concentration in all LDL-subfractions in patients with familial hypercholesterolemia and in patients with diabetes mellitus with mixed hyperlipoproteinemia. However, the relative reduction of individual LDL-subtypes differed between both groups. This suggests that the effect of simvastatin on LDL-subtype distribution depends on the type of underlying hyperlipoproteinemia.

99.6% spin-flip efficiency in the presence of a strong Siberian snake.

We recently studied the spin-flipping efficiency of an rf-dipole magnet using a 120-MeV horizontally polarized proton beam stored in the Indiana University Cyclotron Facility Cooler Ring, which contained a nearly full Siberian snake. We flipped the spin by ramping the rf dipole's frequency through an rf-induced depolarizing resonance. By adiabatically turning on the rf dipole, we minimized the beam loss. After optimizing the frequency ramp parameters, we used 100 multiple spin flips to measure a spin-flip efficiency of 99.63+/-0.05%. This result indicates that spin flipping should be possible in very-high-energy polarized storage rings, where Siberian snakes are certainly needed and only dipole rf-flipper magnets are practical.

Cholesterol, essential fatty acids, and suicide.

Epidemiological and clinical studies have described an association between lower serum cholesterol concentrations and increased suicide risk that is not entirely attributable to depression-related malnutrition and weight loss. Recent epidemiological studies with greater samples and longer follow-up periods, however, have even shown a positive correlation between cholesterol concentrations and suicide risk after controlling for potential confounding variables. A meta-analysis of earlier intervention trials suggested that cholesterol lowering could cause or worsen depressive symptoms and increase the risk of suicide. Large trials of statins (simvastatin, lovastatin, and pravastatin) did not show an increase of suicide mortality. The aim of this selective review is to critically discuss the current evidence for a potential link between cholesterol, essential fatty acids, depression, suicide, impulsivity, and aggression. Preclinical data support the hypothesis that cholesterol reduction may contribute to the serotonergic abnormalities that have been postulated in suicidal subjects. Recently, it was hypothesised that a decreased consumption of polyunsaturated fatty acids, especially omega-3 fatty acids, may be a risk factor for depression and suicide. Currently, we do not have sufficient evidence that cholesterol-lowering therapies increase the risk of depression and suicide. Increasing the dietary intake of omega-3 fatty acids may increase central serotonergic activity and reduce impulsive and aggressive behaviours.

Standardized ultrasound as a new method to induce platelet aggregation: evaluation, influence of lipoproteins and of glycoprotein IIb/IIIa antagonist tirofiban.

Most of the published studies concerning platelet aggregation were performed with chemical stimulation procedures, however, mechanical stimulation might be a better simulation of physiological activation of platelets. In order to evaluate the influence of ultrasound on platelet aggregation in vitro, we developed an ultrasound device in a standardized set-up, and we evaluated the influence of lipoproteins and the glycoprotein IIb/IIIa inhibitor tirofiban on ultrasound induced platelet aggregation. A cylindrical shaped plastic test tube with 1 ml of platelet-rich plasma was placed in an ultrasound bath (35 kHz) for 5 s. The ultrasound energy transfer into the sample (Delta W=3.77 J) was calculated using the average temperature increase (averaged by 0.935 degrees C) of the sample. Platelet aggregation was quantified immediately after stimulation with ultrasound or adenosine diphosphate (ADP 2.1 and 4.2 microM) by the Myrenne Aggregometer PA2 at low (40 s(-1)) and afterwards at high (2500 s(-1)) shear. To evaluate the influence of lipoproteins, seven healthy male volunteers were investigated before and after a fat load (50 g fat per m(2) body surface), and 11 patients suffering from hypercholesterolemia and atherosclerotic disease before and after a single low-density lipoprotein (LDL) apheresis. Platelet aggregation after ultrasound stimulation was well correlated with platelet aggregation after ADP (r between 0.50 and 0.95). However, when exposed to high shear, the low shear-induced platelet aggregates were more stable after ultrasound stimulation compared with ADP stimulation either with or without tirofiban. After the fat load triglyceride concentration increased from 0.86+/-0.39 to 2.10+/-1.10 mmol l(-1) (P<0.05) resulting in a reduced formation of platelet aggregates after weak (ADP 2.1 microM) but not after strong (ADP 4.2 microM or ultrasound) stimuli. After a single LDL apheresis LDL cholesterol dropped from 3.99+/-0.90 to 1.06+/-0.55 mmol l(-1) (P<0.005). No changes in platelet aggregation were observed with the exception of a lower aggregation when exposed to high shear after stimulation with 2.1 microM ADP. In conclusion, we found the ultrasound stimulation of platelet-rich plasma easy to perform. The platelet aggregation after ultrasound stimulation correlated well with stimulation after ADP. While a reduction in LDL cholesterol concentration had only slight effects on platelet aggregation, an increase in triglyceride concentration resulted in a reduced formation of platelet aggregates after weak stimulation.

[Cholesterol, omega-3 fatty acids, and suicide risk: empirical evidence and pathophysiological hypotheses]. / Cholesterin, Omega-3-Fettsäuren und Suizidrisiko - Empirische Evidenz und pathophysiologische Hypothesen

Studies in psychiatric patients described an association between lower serum cholesterol concentrations, suicidality, depression, impulsivity, and aggression which is not entirely attributable to depression-related malnutrition and weight-loss. Several lines of evidence suggest that a serotonergic deficit in the prefrontal cortex may predispose vulnerable subjects to impulsive, autoaggressive, and suicidal behaviour in stressful life-events. In-vitro studies, animal experiments, and human in-vivo studies support the hypothesis that cholesterol reduction may contribute to the serotonergic abnormalities which have been postulated in suicidal subjects. Recently it was hypothesized that decreased consumption of polyunsaturated fatty acids, especially omega-3 fatty acids, may be a risk factor for depression and suicide. Data from human studies in healthy volunteers suggest that increasing the dietary intake of omega-3 fatty acids may increase central serotonergic activity and reduce impulsive and aggressive behaviours. Earlier epidemiological studies showed an association between low cholesterol concentrations and increased suicide risk. Recent epidemiological studies with greater samples and longer follow-up periods, however, even showed a positive correlation between cholesterol concentrations and suicide risk after controlling for potential confounding variables. Large trials of statins (simvastatin, lovastatin, pravastatin) did not show an increase of suicide mortality.