[in Japanese]

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[in Japanese]

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Atherosclerosis leading to coronary heart disease and cerebrovascular disorders is the most serious cause of death in the industrialized societies. For the last two decades, great advances have been made in understanding the pathogenesis of those disorders by studies based on molecular and cell biology. These findings have been confirmed by several randomized clinical trials. In this article, the current status of treatment and prevention of atherosclerosis will be reviewed and discussed.

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The deposition of amyloid β peptides (Aβ) in one of the pathological hallmarks of Alzheimer's disease (AD). Aβ are composed of 40-42 amino acid peptides that are proteolytically cleaved from β amyloid precursor proteins (βAPP). The deposition as diffuse plaques of a species of Aβ ending at the 42nd residue residue (Aβ42) is one of the earliest pathological changes of AD. Importantly, mutations in βAPP genes located in positions flanking the Aβ sequences have been shown to cosegregate with the clinical manifestations of AD in a subset of familial AD (FAD) pedigrees. Moreover, mutations in presenilin (PS) 1 and 2, novel polytopic membrane proteins that were identified as causative molecules for the majority of early onset FAD, also increase the secretion and deposition of Aβ42. These results support the notion that Aβ42 plays a key role in the pathogenesis of AD. Recently, it was suggested that PS1 is a coactivator of γ-cleavage of βAPP as well as γ-like cleavage of Notch protein which plays an essenitial role in morphogenesis and development. In addition, the pathogenic role of tau in neuronal death is highlighted based on the identification of mutations in tau gene in a dominantly-inherited neurode-generative dementia FTDP-17. These novel findings regarding the protein aggregates and causative genes for AD and related disorders will facilitate our understanding of the pathogenesis of AD, as well as development of therapeutic strategies against it.

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A Japanese herbal medicine termed“Kami-Umtan-To (KUT)”was first described in Japanese literature in 1626. KUT consists of 13 dfferent herbs, and it has been used for a long time in the treatment of a variety of neuropsychiatric problems including neurosis and insomnia. Recently, Yabe et al. have demonstrated that KUT increased both choline acetyltransferase (ChAT) and nerve growth factor at the protein and mRNA levels in cultured rat brain cells. Moreover, the same research group has reported that KUT improved mean latency on passive avoidance test in both basal forbrain lesioned and aged rats. KUT significantly improved the survival rate, and increased the number of ChAT-positive neurons in aged rats. Here, we report a 12-month open clinical trial of KUT and combination of estrogen, vitamin E and NSAID to aim at slowing down the progression of Alzheimer's disease (AD). Twenty AD patients (MMSE score: 18.6±5.8) received extracts from original KUT herbs, and 7AD patients (MMSE score: 21.3±2.8) were placed on the combination therapy. Rate of cognitive decline as measured by change in MMSE score per year was significantly slower (p=0.04, ANOVA) in the KUT group (1.4 points) and the combination group (0.4 points) as compared to 4.1 points in 32 control AD patients (MMSE score: 20.8±5.6) who received no medicines for AD. Any of CSF measures including tau. and Aβ_1-42 did not differ significantly after KUT theraopy. The efficacy of the KUT therapy was most obvious at 3 months. Our results suggest that traditional Japanese herbal medicine(s) may serve a new interventional strategy for AD.

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The renin-angiotensin system, composed of enzymatic and signal-transduction cascades, plays a key role in the regulation of arterial blood pressure and in the development of certain forms of experimental and human hypertension. The products of this system, angiotensin peptides, exert a wide range of physiologically important effects on many tissues, including those of the cardiovascular systems, through their actions on angiotensin receptors. Molecular genetic and transgenic studies have begun to implicate some of the genes encoding components of the renin-angiotensin system in the development of cardiovascular diseases. Here, I review new developments related to the functional role of angiotensin II, an important product of the renin-angiotensin system, by focusing on knockout approaches including cardiovascular and central nervous systems.

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To elucidate the clinical characteristics of disability due to various basic disease groups, by using Japanese Minimum Data Set (MDS), Nishimura's mental scale (NM) and activity of daily living scale (N-ADL), cognitive function and basic activity of daily living (ADL) together with the grading scale of nursing care (freedom-grade of daily living: N₁, frequency of bedside visits by a nurse: N₂) and nutritional function (serum albumin: SA) were assessed in 926 elderly disabled inpatients in April 1998 in our long-stay chronic care hospital. Basic diseases were divided into five groups: cerebrovascular (C), senile dementia (D), bone and joint (B), Parkinson's disease (P) and other diseases (O). (1) In all patients, women were 2.9 years significantly older than men. Mean age in disease groups was significantly greater in the following decreasing order, B>D>C>P. (2) In all patients and patients with C, significant negative correlations were found between age and the scores of various scales (NM, N-ADL, N₁, SA). In patients with D and B, significant negative correlations were found only between age and N-ADL and N1, but not NM or SA. In patients with P, no correlations were found between age and the various scales. (3) The cognitive function score decreased significantly as follows, B>C>P>D and the score of ADL decreased significantly as follows, B>D>C>P. (4) In patients with C and P, significant positive correlations were found between 3 scores (Cognition, ADL, SA). In patients with D, significant positive correlation was found between only two scores (ADL, SA) and in patients with B, no correlations were found between SA and other scores. (5) Because in all patients and in patients with all disease groups, significant positive correlations were found between the scores of cognition, ADL by MDS and the scores of NM, N-ADL respectively, the scales of cognition and ADL evaluated by MDS were validated for us to assess cognitive function and ADL and are probably suitable tools for evaluating elderly disabled patients. The other various functional states should also be assessed in elderly disabled patients where the quality of life of the patients must take priority over other considerations in decision making for medical interventions, including care. We should discuss care in detail and continue more medical studies to improve the quality of care.

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We investigated the effects of breeding conditions on neurochemical markers, muscarinic receptor (mAChR), β-adrenoreceptor (β-AdrR), imipramine binding sites (IMBS), choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and monoamine oxidase (MAO) activity in aged rat brains. An increase of affinity (Kd) and the decrease in the number (Vmax) of mAChR were found in the individual aged rats. Concerning IMBS, Kd and Vmax values increased in the individual aged rats. However, no significant changes were observed in the β-AdrR. The increases of ChAT and MAO activity were found in the aggregated aged rats to compare with in the individual aged rats, while AChE activity decreased in the aggregated aged rats. These changes were also particularly seen in the forebrain of aged rats. These results indicate that the functions of the central nervous system may be reduced in the individual aged rats to compare with in the aggregated aged rats under the breeding conditions.

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To clarify carotid arterial changes in female patients with arteriosclerosis obliterans (ASO) and aortic aneurysm (AA), ultrasonographic (US) findings of the extra-cranial carotid arteries were studied in 26 patients with ASO (ASO group), and 31 patients with AA (AA group), compared to 38 controls (control group) with neither ASO nor AA. ASO was diagnosed with an ankle pressure index less than 0.9, while AA was done with computed tomography or angiography. Half of the patients with ASO were in stage II of the Fontaine clinical staging, and angiography, performed in 12, showed femoral arterial obstruction in 10. Most AA patients were abdominal aortic aneurysm. Using a high-resolution, real-time, B-mode US instrument, the diameter and wall thickness of the common carotids were measured bilaterally in the end-diastolic phase, and occlusive changes and plaque were estimated. As a risk factor for arteriosclerosis, hypertension, diabetes, hyperlipidemia, and cigarette smoking were assessed, in addition to the age, body height and weight. Mean ages of each group were 73 to 76.3 year-old. There was no significant difference between them in body height and weight. Diabetes, cigarette smoking, and cerebrovascular disease were frequent in the ASO group, whereas ischemic heart disease was frequent in the AA group. US findings revealed that carotid lesions were mostly plaque, and bilateral carotid lesions were significantly more frequent in the ASO and AA groups. The mean wall thickness of the carotids was greater in the AA and ASO groups, although dilated carotid arteries, namely arteriomegaly, was more frequent in the AA group than in the ASO and control groups. Stepwise regression analyses demonstrated that strong correlations were seen between carotid lesion and two variables [vessel diseases (ASO/AA) and cigarette smoking], between carotid diameter and three variables (age, AA, and wall thickness), and between the wall thickness and three variables (age, vessel diseases and diameter). These findings showed that atherosclerosis was not only frequent in female patients with ASO and AA, but arteriomegaly was characteristc in female patients with AA. Therefore, it suggested that circulatory disturbance in whole organs due to arteriosclerosis should be paid attention even in female patients with ASO and AA as well as male patients. Furthermore, it is considered that systemic fragility of the arterial media and ectasia could be present extensively in patients with AA.

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Congenital factor V deficiency is a very rare hereditary coagulation disorder. Total gastrectomy in a patient with factor V deficiency has not been reported in Japan.
A 71-year-old woman visited our hospital because of gastric cancer and gallbladder stone. A preoperative screening examination revealed severe anemia, prolonged prothrombin time (35.1 sec.) and activated partial thromboplastin time (109.8 sec.) The value of factor V was 8%. Her parents had a consanguineous marriage. The level of factor V in her two children and a grandchild were lower than the normal limit. We transfused fresh blood and fresh frozen plasma (FFP) preoperatively in order to improve anemia and prothrombin time and activated thromboplastin time.
Operating carefully with transfused FFP and fresh blood, we performed total gastrectomy with cholecystectomy successfully. There was no serious tendency to hemorrhage during the operation and the postoperative period.
Enough FFP should be transfused during the pre-and postoperative period, paying attention to pulmonary or cardiac failure in elderly patients. Postoperatively, during FFP should be used for 3-10day with under careful observation of wound bleeding.

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An 82-year old man was admitted with dyspnea, productive cough and wheezing. In addtion to antibiotics (meropenem trihydrate 0.5g/day), glucocorticoids (hydrocortisone 1, 250mg, methylpredonisolone 4, 250mg) were administered for the severe bronchospasms. Since his respiratory condition deteriorated, he underwent mechanical ventilation using a muscle relaxant (vecuronium bromide, total dose 776mg) in combination with high dose glucocorticoid.
As his pneumonia improved on the 10th hospital day, we started weaning him from the ventilator. However, we were unable to complete weaning from the ventilator because of prolonged quadriplegia and paralysis of the respiratory muscles. A few days later, myoglobinuria appeared. Electrophysiological examinations suggested the involvement of both neuromuscular junctions and muscles. Muscle biopsy showed rhabdomyolysis. Acute necrotizing myopathy was diagnosed due to high doses of glucocorticoid, muscle relaxant, or both. He required about 3 months to be weaned from the mechanical ventilation, and another 3 months to leave the hospital.
Based on our experience, we should consider acute myopathy as an adverse effect of glucocorticoids, muscle relaxants or both in elderly patients who require mechanical ventilation.

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A 70-year-old woman began to experience gait disturbance in 1995, followed by the appearance of action tremor of the left hand in 1996. This tremor was subsequently noted in the right hand. Her doctor initially diagnosed Parkinson's disease and administered amantadine and levodopa. The gait disturbance and tremor improved. However, she stopped taking the medication and her symptoms worsened in April, 1998. She was admitted to our hospital, and showed rigidity and action tremor predominantly on the left side, frozen gait, postural reflex disturbance and orthostatic hypotension. Following levodopa administration, her UPDRS score improved from 61.3±1.2 (mean±SD) to 41.7±5.4. However, she experienced a greater decrease in systolic blood pressure following administration upon standing, from 12.5±5.8mmHg to 17.8±9.2mmHg. Thus, although levodopa administration led to an improvement in rigidity, tremor and akinesia, her orthostatic hypotension worsened. Based on the present results clinicians should be aware of the potential of worsened orthostatic hypotension when prescribing levodopa to treat Parkinson's disease.

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