Development, trafficking, and function of memory T-cell subsets

Summary: The precise mechanisms that govern memory T‐cell lineage commitment during an immune response continue to be the subject of intense scrutiny. The existence of memory T‐cell subsets defined by location, function, and phenotype adds an additional layer of complexity to the overall memory T‐cell population. In this review, the integration of memory subset development and migration and the functional consequences of specific tissue localization are discussed.     

Neuro-ototoxicity in andean adults with chronic lead and noise exposure.

Brainstem auditory evoked responses and audiological thresholds were used as biomarkers for neuro-ototoxicity in adults with chronic lead (Pb) intoxication from long-term Pb exposure in ceramic-glazing work. Venous blood samples collected from 30 adults (15 men and 15 women) indicated a mean blood Pb level of 45.1 micrograms/dL (SD, 19.5; range, 11.2 to 80.0 micrograms/dL) and in excess of the World Health Organization health-based biological limits (men, 46.2 micrograms/dL; SD, 19.6; range, 18.3 to 80.0 micrograms/dL; women, 44.0 micrograms/dL; SD, 20.1; range, 11.2 to 74.2 micrograms/dL). Mean auditory thresholds at frequencies susceptible to ototoxicity (2.0, 3.0, 4.0, 6.0, and 8.0 kHz) revealed sensory-neural hearing loss in men, which may be attributable to occupational noise exposure in combination with Pb intoxication. Bilateral brainstem auditory evoked response tests on participants with elevated blood Pb levels (mean, 47.0 micrograms/dL) showed delayed wave latencies consistent with sensory-neural hearing impairment. The results suggest that environmental noise exposure must be considered an important factor in determining sensory-neural hearing status in occupationally Pb-exposed adults.     

Endometrial cancer: our experience

The Authors have referred to their experience based on 293 endometrial cancer patients operated at the II University Gynecological Clinic in Catania, between 1975 and 1989. Many prognostic indicators such as stage, histologic grade, myometrial invasion depth, lymph-node metastasis, non-neoplastic endometrium histology, tumor size and histology were studied; the Authors affirm the validity of two risk factors such as tumor size and the histology of the non-neoplastic endometrium, readily observable by hysteroscopy during the preoperative assessment and which are well correlated with the depth of myometrial invasion and lymph node methastasis.     

Compensating conduction times as a mechanism for alternation during reciprocating tachycardia

This paper reflects a hitherto undescribed mechanism for alternation of conduction time during supraventricular reciprocating tachycardia. Delayed anterograde conduction through an A-V nodal pathway effectively delays conduction of the reciprocal impulse to its retrograde course and hence to its intrajunctional reciprocal point: the point where it begins anterograde conduction once again. This section of the A-V nodal pathway consequently has a longer recovery time. The ensuing anterograde conduction is therefore faster and the ensuing cycle therefore shorter. The shorter ensuing cycle, in turn, means that the returning impulse reaches its intrajunctional reciprocal point earlier. There is consequently less time for recovery for the anterograde A-V nodal pathway. Hence the ensuing delay and longer cycle. This establishes a sequel of long and short cycles due to alternation of conduction.     

Membrane pathways for drug/ion channel interactions: Molecular basis for pharmacokinetic properties

This review focuses on the interactions of certain classes of drugs that are known to bind to membrane-bound ion channel/receptors. The concepts described here have broad applications to various ion channels as well as membrane bound receptors that are not ion channels such as the superfamily of G protein coupled receptors. Since data spanning from the molecular to the clinical field currently exists for drugs that bind to the voltage gated calcium channel, this review will highlight this rather narrow scope. It is to be appreciated that the concepts, as described, may have applicability to other membrane-bound receptors. The focus will be on the calcium channel antagonist drugs of the 1,4 dihydropyridine type that bind to the L type calcium channel. Clearly an evolution in their molecular design has been brought to a point where these molecules are not only amphiphilic but increasingly lipophilic. Simply stated, this means that these drugs can readily transport across cell membranes accessing both hydrophilic and hydrophobic environments, although they have also become more soluble in the membrane bilayer. From an equilibrium point of view these molecules prefer to reside in the lipid bilayer hydrocarbon core; from a kinetic point of view they spend more time, on average, solvated within membranes than outside membranes, but their rates of entry into and exit from membranes do not appear to be related solely to their intramembranal equilibrium concentration. This biophysical understanding appears not only to define the molecular pathways for drug binding to the calcium channel receptor, but also to explain differences in the overall clinical pharmacokinetics observed for different drugs in this class. The potency of calcium antagonists is primarily related to their binding affinity to the calcium channel with a variable degree of dependency on the solvation of the drug in the membrane. The pharmacokinetic profile of calcium antagonists, although influenced to some degree by interactions with the target receptor, appears to be largely dictated by their interactions with the cell membranes at the molecular level. These interactions are distinctly different for each calcium antagonist but they can be classified into a few subgroups to explain drug onset and duration of action. © 1994 Wiley-Liss, Inc.     

The role of coenzyme Q10 in statin-associated myopathy: a systematic review.

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are currently the most effective medications for reducing low-density lipoprotein cholesterol concentrations. Although generally safe, they have been associated with a variety of myopathic complaints. Statins block production of farnesyl pyrophosphate, an intermediate in the synthesis of ubiquinone or coenzyme Q10 (CoQ10). This fact, plus the role of CoQ10 in mitochondrial energy production, has prompted the hypothesis that statin-induced CoQ10 deficiency is involved in the pathogenesis of statin myopathy. We identified English language articles relating statin treatment and CoQ10 levels via a PubMed search through August 2006. Abstracts were reviewed and articles addressing the relationship between statin treatment and CoQ10 levels were examined in detail. Statin treatment reduces circulating levels of CoQ10. The effect of statin therapy on intramuscular levels of CoQ10 is not clear, and data on intramuscular CoQ10 levels in symptomatic patients with statin-associated myopathy are scarce. Mitochondrial function may be impaired by statin therapy, and this effect may be exacerbated by exercise. Supplementation can raise the circulating levels of CoQ10, but data on the effect of CoQ10 supplementation on myopathic symptoms are scarce and contradictory. We conclude that there is insufficient evidence to prove the etiologic role of CoQ10 deficiency in statin-associated myopathy and that large, well-designed clinical trials are required to address this issue. The routine use of CoQ10 cannot be recommended in statin-treated patients. Nevertheless, there are no known risks to this supplement and there is some anecdotal and preliminary trial evidence of its effectiveness. Consequently, CoQ10 can be tested in patients requiring statin treatment, who develop statin myalgia, and who cannot be satisfactorily treated with other agents. Some patients may respond, if only via a placebo effect.