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Background: Activities of daily living (ADL) in aged hemodialysis patients decrease by many factors as hemodialysis therapy, various disease-related complications and underlying disease for rehabilitation. But the correlation between low ADL and mortality remains unclear. We assessed the levels of ADL and effects of rehabilitation in hemodialysis patients with low ADL. Moreover, the association between the baseline functional independence measure (FIM) or rehabilitation treatment effects and all-cause mortality were investigated., Methods: This prospective cohort study included 182 inpatients on maintenance hemodialysis, who underwent rehabilitation for a decline in ADL. Before and after initiating rehabilitation, ADL were assessed using FIM., Results: The total baseline FIM was 65.1±26.9 (motor items: 39.5±18.7; cognitive items: 25.6±10.7). After rehabilitation, the total FIM increased to 77.1±33.1 (motor items: 50.9±24.4; cognitive items: 26.1±10.8). The baseline FIM, presence or absence of FIM increase, and albumin were significantly associated with mortality. Moreover, the mortality hazard ratio in patients with FIM ≤67 and no FIM increase was 20-fold significantly higher than that in patients with FIM ≥68 and FIM increase. The cognitive items and albumin were significantly associated with the rehabilitation effects in multivariate analysis., Conclusions: Although the FIM decreased by half in hemodialysis patients, rehabilitation improved their FIM (particularly the motor items). The FIM was a novel predictive marker of 3-year mortality in these patients, and an increased FIM after rehabilitation resulted in better prognosis. Moreover, the effectiveness of rehabilitation may depend on maintaining cognitive functions.

In Japan, fifteen drugs, including tricyclic and non-tricyclic antidepressants or an MAO inhibitor, are clinically available for treatment of depression. However, the pharmacological mechanism(s) of their antidepressive effect remain uncertain. "Receptor hypothesis" that functional changes of monoamine receptors after chronic treatment, such as down-regulation of beta-adrenoceptor or 5-HT2 receptor, bring about a therapeutic effect, seems to be unsatisfactory. Recent studies focus on interaction between antidepressants and intracellular signal transduction pathways. For effective and safe uses of antidepressants, especially in aged patients or those with hepatic and renal diseases, pharmacokinetics such as distribution, protein binding and metabolism must be well understood. In this paper, pharmacokinetic characteristics of antidepressants are also reviewed.

We observed under light and electron microscopes morphological changes in the brains of rats in a thiamine deficient state as induced by an oxythiamine, pyrithiamine and thiamine deficient diet (OT, PT and TDD). We simultaneously determined thiamine levels in the whole brain of rats. The rats were separated into six groups-normal control, OT or PT treated rats (OT or PT group), OT or PT treated rats fed a TDD (OTD or PTD group), rats fed a TDD (TDD group)-. Microscopically, there were symmetrically distributed lesions containing spongy reticulation mainly in the vestibular nucleus. Electron microscopically, we found more advanced lesions in the OTD and PTD groups than in the TDD group. These ultrastructural changes were seen in the vicinity of capillaries and such consisted of abnormal endothelial cells and pericytes, excrescence of microglias, swelling or vacuolation of astrocytes, nerve cells containing distorted organelle and myelin degeneration, besides extracellular edema. The thiamine level in the TDD group decreased to 56% that of control. No effect of OT on the thiamine level was observed either in case of ingestion of a regular diet or when TDD was given. On the other hand, the thiamine level decreased to 43% in the PT group and to 17-23 in PTD. These results suggest that encephalopathy caused by the OT or PT-induced thiamine deficiency has the same selective vulnerable site as does the TDD-induced deficiency, however cellular sensitivity may differ slightly with the various ultrastructural changes.

The effect of pyrithiamin on thiamin deficient mice was studied clinically and pathologically. Thiamin deficiency was produced in the mice fed with a thiamin deficient diet by a single injection of pyrithiamin (10 mg/kg, s.c.) on day 0 to produce a mild illness and on day 14 to produce a severe disorder. Clinically, the mild illness showed only Wooley-White sign and histologically, it was characterized by edema in the thalamus, mammillary bodies, and pontine tegmentum. The severe illness showed convulsion and multiple hemorrhages in the same area. This pyrithiamin-induced thiamin deficient animal model can also be useful for research on thiamin deficient encephalopathy.

We observed under light and electron microscopes morphological changes in the rat sciatic nerve during the early stages of a thiamine deficient state as induced by a pyrithiamine (PT: 50 microgram/100g X 6 days) and thiamine deficient diet (TDD). We simultaneously determined thiamine levels in the whole sciatic nerve of rats. Experiments were undertaken with normal control, TDD (rats fed a TDD), PT (PT treated rats) and PTD (PT treated rats fed a TDD) groups. Microscopically, there were numerous shrunken myelinated axons with myelin ovoids of folds in the PT group and many swollen ones in the PTD group. Electron microscopically, we found more advanced lesions in the PTD group than in the other groups. These ultrastructural changes were swelling of Schwann cells, enlarged rough-surfaced endoplasmic reticulum, axonal degeneration with shrinkage, loss of organelle or abnormal myelin sheath, and proliferation of fibroblasts. The thiamine level in the PTD group decreased to 18 approximately 30% that of control in proportion to the morphological changes. On the other hand, the thiamine level in the PT group (55 approximately 61%) decreased slightly more than that of the TDD group (50 approximately 56%), but changes in morphology were vice versa. These results suggest that the morphological changes in the sciatic nerve caused by PT-induced thiamine deficiency differs from changes seen in cases of dying-back neuropathy caused by TDD-induced deficiency, and that PT itself directly affects the nervous system

We studied biochemical changes in the rat liver in a thiamine (T) deficient state as induced by oxythiamine (OT), pyrithiamine (PT) and thiamine deficient diet (TDD) and simultaneously observed morphological changes under light and electron microscope. Severe loss of weight was observed in the OT treated rats fed on TDD (OTD) and such was frequently accompanied by a complete loss of righting reflex. Biochemical changes commonly found in T deficient groups were decrease in serum total protein, alkaline phosphatase activity and liver lipids, and increase in serum total cholesterol and transaminase activity. Microscopically, most of the liver cells were atrophied and necrosis was observed in the OTD group. Electron microscopically, ultrastructural changes revealed active Kupffer cells, microvilli and Golgi apparatus, and decrease in rough endoplasmic reticulum (rER) associated with increasing detached ribosomes and smooth ER. Abnormal nucleus and mitochondria were found in the OTD group. These results suggest that a T deficiency occurs readily and easily within a short time when a T antagonist, particularly OT, is used together with the TDD, while a much longer time is required to produce a T deficiency with only the TDD.

We observed under light and electron microscopes morphological changes in the rat sciatic nerve during the last stages of a thiamine deficient state as induced by pyrithiamine (PT: 50 microgram/100g X 11 days) and thiamine deficient diet (TDD), in which rats experienced severe tetanic convulsions. Experiments were undertaken with normal control, PT (PT treated rats) and PTD (PT treated rats fed a TDD) groups. Grossly, 4 out of 9 rats in the PTD group had severe tetanic convulsions on the 12th day and there were no neurologic signs in the PT group. Microscopically, many of the myelinated axons in the animals in the PT group showed shrinkage with myelin ovoids and folds, but in the PTD group, there was swelling as well as shrinkage. Despite the difference in general-symptoms between the PT and the PTD groups, axonal degeneration in the both groups, as determined electron microscopically was almost to the same degree and the convulsed rats in the PTD group showed the severest changes in the myelin sheath. These ultrastructural changes included swelling or vacuolation of Schwann cells, axonal degeneration with the appearance of a myelin like structure, collection of neuro-tubules or vacuoles, invasion of Schwann cell or/and myelin fragments into the periaxonal space, and active phagocytosis by the macrophages. These results suggest that PT directly affects the nervous system and that the dysfunction of the sciatic nerve following PT-induced thiamine deficiency originates from the central nervous system.