Efficacy of methylprednisolone pulse therapy on neuroleptic malignant syndrome in Parkinson's disease.

BACKGROUND: Neuroleptic malignant syndrome (NMS) is a dangerous complication in patients with Parkinson's disease (PD). AIMS: To evaluate the efficacy of methylprednisolone pulse therapy compared to placebo in PD patients with NMS. METHODS: In a double blind, placebo controlled study, 20 PD patients with NMS received steroid pulse therapy for three days, and 20 PD patients received placebo. Both groups received levodopa, bromocriptine, and dantrolene. RESULTS: NMS in the steroid group healed within 10 days in 17 patients; median value of duration of illness of NMS in this group was 7 days (range 4-20). NMS in the placebo group healed within 10 days in five patients; in the remaining 15, it persisted for 12-27 days after the onset of NMS; median value of duration illness of NMS in this group was 18 days. Hyperthermia, rigidity, and consciousness improved within 10 days in many patients in the steroid group; these signs persisted more than 10 days in many patients in the placebo group. CONCLUSIONS: Steroid pulse therapy is useful in NMS for reducing the illness duration and improving symptoms.

Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency.

Significant reduction in bone mineral density (BMD) occurs in patients with Parkinson's disease (PD), correlating with immobilization and with vitamin D deficiency, and increasing the risk of hip fracture, especially in elderly women. As a biological indicator of compromised vitamin K status, an increased serum concentration of undercarboxylated osteocalcin (Oc) has been associated with reduced BMD in the hip and an increased risk of fracture in otherwise healthy elderly women. We evaluated treatment with vitamin K(2) (menatetrenone; MK-4) in maintaining BMD and reducing the incidence of nonvertebral fractures in elderly female patients with PD. In a random and prospective study of PD patients, 60 received 45 mg of MK-4 daily for 12 months, and the remaining 60 (untreated group) did not. At baseline, patients of both groups showed vitamin D and K(1) deficiencies, high serum levels of ionized calcium, and glutaminic residue (Glu) Oc, and low levels of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25-(OH)(2)D], indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1,25-(OH)(2)D and compensatory PTH secretion. BMD in the second metacarpals increased by 0.9% in the treated group and decreased by 4.3% in the untreated group (p < 0.0001). Vitamin K(2) level increased by 259.8% in the treated group. Correspondingly, significant decreases in Glu Oc and calcium were observed in the treated group, in association with an increase in both PTH and 1,25-(OH)(2)D. Ten patients sustained fractures (eight at the hip and two at other sites) in the untreated group, and one hip fracture occurred among treated patients (p = 0.0082; odds ratio = 11.5). The treatment with MK-4 can increase the BMD of vitamin D- and K-deficient bone by increasing vitamin K concentration, and it can also decrease calcium levels through inhibition of bone resorption, resulting in an increase in 1,25-(OH)(2)D concentration.

Vitamin D deficiency and risk of hip fractures among disabled elderly stroke patients.

BACKGROUND AND PURPOSE: Risk of hip fracture after stroke is 2 to 4 times that in a reference population. Osteomalacia is present in some patients with hip fractures in the absence of stroke, while disabled elderly stroke patients occasionally have severe deficiency in serum concentrations of 25-hydroxyvitamin D (25-OHD) (/=51 nmol/L (>/=21 ng/mL; sufficient group, n=72). RESULTS: Over a 2-year follow-up interval, hip fractures on the paretic side occurred in 7 patients in the deficient group and 1 patient in the insufficient group (P<0.05; hazard ratio=6.5), while no hip fractures occurred in the sufficient group. The 7 hip fracture patients in the deficient group had an osteomalacic 25-OHD level of <5 ng/mL. Higher age and severe immobilization were noted in the deficient group. Serum 25-OHD levels correlated positively with age, Barthel Index, and serum parathyroid hormone. CONCLUSIONS: Elderly disabled stroke patients with serum 25-OHD concentrations

Study on glutathionesulphonic acid as biodistribution promoter: concomitant use effect on verapamil hydrochloride and tegafur.

The effect of glutathionesulphonic acid (N-(N-gamma-L-glutamyl-L-beta-sulphoalanylglycine, GSO3H), which is one of the minor metabolites of glutathione (GSH), on the pharmacokinetics of verapamil hydrochloride (verapamil x HCl) and tegafur was investigated in rats. GSO3H was concomitantly used as sodium salt (GSO3Na). No significant change by the concomitant use of GSO3Na was recognized in the pharmacokinetics parameters of verapamil x HCl and tegafur, and plasma elimination of both substances was not affected by GSO3Na. The tissue-to-plasma concentration ratio (Kp) of verapamil x HCl in the lung 5 min after its administration under concomitant use of GSO3Na rose significantly, however, this effect disappeared 120 min after administration. No significant change was recognized in other organs. On the other hand, a significant difference of Kp of tegafur under a steady state concentration of GSO3Na was not recognized in any organs. It seemed that the elevation of a lipid solubility (oil water partition coefficient) of verapamil x HCl by the concomitant use of GSO3Na was related to the increase of the Kp value of verapamil x HCl in the lung. The partition coefficient of GSO3Na itself decreased when it was used concomitantly with verapamil x HCl.

Application of 4-hydroxyantipyrine and acetaminophen O-sulfate as biodistribution promoter.

The effects of 4-hydroxyantipyrine (4-OH), a major metabolite of antipyrine and its sulfate, 4-hydroxyantipyrine O-sulfate (4-S), on the pharmacokinetics of citicoline and thiopental sodium were investigated in rats. The concomitant use of 4-OH increased significantly the tissue-to-plasma concentration ratio (Kp) of citicoline in the brain and liver and that of thiopental sodium in the brain, liver, and heart, while 4-S did not affect them. The permeability clearance of blood-brain barrier (BBB) (Kin) and the total distribution volume (Vdbr) of citicoline were not affected by either 4-OH or 4-S. However, those of thiopental sodium were significantly increased by not only 4-OH but also by 4-S. On the other hand, the plasma concentration of antipyrine was significantly decreased by the intravenous bolus coadministration of N-acetyl-p-aminophenyl O-sulfate (APAPS) at steady-state plasma concentration of antipyrine. A similar reduction was not observed with the intravenous coadministration of acetaminophen (APAP). The Kp value of antipyrine was significantly increased in the brain by the coadministration of APAPS, but was not affected by APAP. The increment in the drug distribution to the brain with the concomitant use of 4-OH (or APAPS) observed in this study is useful information for the application of drug combinations as biodistribution promoters.

Beneficial effect of intermittent cyclical etidronate therapy in hemiplegic patients following an acute stroke.

Significant decreases in bone mineral density (BMD) occur on the hemiplegic side in chronic stroke patients, which correlate with the degree of paralysis and hypovitaminosis D. In this double-blind, randomized, and prospective study of 98 patients with hemiplegia involving both an upper and lower extremity (55 males and 53 females; mean age, 71.4 +/- 0.6 years) after an acute stroke, 49 were given etidronate for 56 weeks and 49 received a placebo. The BMD was measured by computed X-ray densitometry (CXD) of the second metacarpal bone bilaterally. Forty age-matched control subjects were followed for 56 weeks. At baseline, both groups had 25-hydroxyvitamin D [25(OH)D] insufficiency, increased serum ionized calcium and pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), and low serum concentrations of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D], suggesting immobilization-induced hypercalcemia and inhibition of renal synthesis of 1,25(OH)2D. The BMD on the hemiplegic side decreased by 2.3% and 4.8% in the etidronate and placebo groups, respectively (p = 0.0003). After treatment, the serum 1,25(OH)2D concentration increased by 62.2% in the etidronate group and decreased by 12.4% in the placebo group. The etidronate group had significant decreases in the serum ionized calcium and ICTP and increases in PTH and bone Gla protein (BGP), whereas the placebo group had higher serum calcium and ICTP concentrations but stable PTH. These results suggest that etidronate can prevent decreases in the BMD in hemiplegic stroke patients because it decreases the serum calcium through inhibition of bone resorption and causes a subsequent increase in the serum 1,25(OH)2D concentration.

Effect of immobilization on vitamin D status and bone mass in chronically hospitalized disabled stroke patients.

OBJECTIVE: To assess the influence of immobilization upon vitamin D status and bone mass in chronically hospitalized, disabled, elderly patients following stroke. DESIGN: cross-sectional study. SETTING: Department of geriatric neurology in a Japanese hospital. SUBJECTS: 129 chronically hospitalized, disabled, elderly stroke patients and 28 age-matched controls. RESULTS: We observed a deficiency of both 1,25-dihydroxyvitamin D (1,25-[OH]2D; 24.3 pg/ml) and 25-hydroxyvitamin D concentrations (25-OHD; 11.7 ng/ml) in stroke patients compared with controls. A high serum ionized calcium (mean; 2.648 mEq/l) was an independent determinant of the Barthel index (66) and 1,25-[OH]2D. When the patients were categorized into three groups by 25-OHD level (deficient, insufficient and sufficient), there was no difference in the mean 1,25-[OH]2D levels. Parathyroid hormone levels were normal or low and did not correlate with 25-OHD. Serum bone turnover variables and bone mineral density (BMD) of the second metacarpal in patients were significantly decreased compared to control subjects. Independent determinants of BMD included Barthel index, 25-OHD and 1,25-[OH]2D. CONCLUSIONS: 1,25-[OH]2D deficiency in immobilized stroke patients is not caused by substrate (25-OHD) deficiency but by hypercalcaemia. Immobilization-induced hypercalcaemia may inhibit parathyroid hormone secretion and thus 1,25-[OH]2D production, resulting in decreased BMD. Immobilization itself also may be responsible for decreased BMD. Exogenous 1,25-[OH]2D (calcitriol) rather than dietary vitamin D supplementation may be required in disabled elderly stroke patients who have a deficiency of 1,25-[OH]2D in order to prevent hip fractures, which frequently occur in this population.

High prevalence of vitamin D deficiency and reduced bone mass in elderly women with Alzheimer's disease.

Patients with Alzheimer's disease (AD) are at increased risk for falls and hip fractures. To better understand causes and prevention, we measured bone mineral density (BMD) in the second metacarpals of 46 ambulatory elderly women with AD and analyzed its relation to serum biochemical indices, sunlight exposure, and vitamin D intake. BMD was significantly less than in age-matched controls. In 26% of AD patients, the serum 25-hydroxyvitamin D (25-OHD) concentration was at a deficient level (5-10 ng/mL), and in 54% it was at an osteomalacic level (<5 ng/mL). Concentrations of ionized calcium were significantly lower in patients. Conversely, concentrations of serum bone Gla-protein and urinary hydroxyproline in patients were significantly higher than in controls. BMD correlated positively with 25-OHD concentration (p = 0.0041) and negatively with parathyroid hormone (PTH) concentration (p = 0.0022). PTH was higher in patients than in controls, and correlated negatively with 25-OHD (p < 0.0001). Many AD patients were sunlight-deprived and consumed less than 100 IU of vitamin D per day. We concluded that vitamin D deficiency due to sunlight deprivation and malnutrition, together with compensatory hyperparathyroidism, contributes significantly to reduced BMD in AD patients. Low BMD increases risk of hip fractures in patients with AD, but may be improved by vitamin D supplementation.

Cerebrospinal fluid atypical lymphocytes in Japanese encephalitis.

Among atypical lymphocytes (AL) examined morphologically and immunohistochemically in the cerebrospinal fluid (CSF) of adult patients with encephalitis, we distinguished a CD4+ 'type I' AL, with a multilobulated nucleus resembling those of the abnormal cells in adult T-cell leukemia (ATL), from a CD8+ 'type II' AL, a large lymphocyte with basophilic cytoplasm and a nucleus containing coarse chromatin. Type I AL were detected in 7 of 8 patients with Japanese encephalitis (JE), but in none of 11 patients with herpes simplex encephalitis (HSE) and none of 19 patients with unspecified acute viral encephalitis. Type II AL were seen frequently in all three groups. The observation of type I AL in CSF strongly suggests JE, which warrants careful follow-up without antiherpetic drugs. In identifying type I AL, which presumably are virally transformed lymphocytes, care must be taken to distinguish them from leukemic involvement by ATL cells, which frequently includes the meninges. Both type I and type II AL also must be differentiated from lymphoma cells.

Rectal carcinoid tumor associated with the Peutz-Jeghers syndrome.

A 16-year-old man who had been diagnosed with the Peutz-Jeghers syndrome at the age of 8 years presented with crampy abdominal pain. Thorough examinations revealed a large jejunal polyp causing intussusception, as well as multiple polyps in the small and large intestines. Preoperative proctoscopy demonstrated the coexistence of a submucosal tumor in the rectum. Proctoscopic mucosal resection was performed and histological and immunohistochemical examinations led to a diagnosis of carcinoid tumor. Additional transanal resection of the rectal wall showed no residual tumor and the patient has been well for 2 years to date. Although malignant tumors are increasingly reported in association with the Peutz-Jeghers syndrome, to our knowledge, there have been no previous reports of such an association in the English-language and Japanese literature.

Increased bone resorption during the first year after stroke.

BACKGROUND AND PURPOSE: Significant bone mineral density (BMD) reduction occurs in stroke patients on the hemiplegic side compared with the intact side. To elucidate the pathogenesis of hip fractures in this population, we measured serum markers of bone metabolism and BMD in the stroke patients within 1 year (early group) and between 1 and 2 years after onset of hemiplegia (long-term group). METHODS: Sera were collected from 51 patients from the early group and 93 patients from the long-term group. All patients had hemiplegia. Sera were assayed for pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP; a bone resorption marker) and bone Gla protein (a bone formation marker). The z score of BMD was determined in both second metacarpals. RESULTS: Serum ICTP concentrations (ng/mL) were higher in the early group (15.4+/-4.1) than in the long-term group (6.7+/-4.4). Bone Gla protein was normal or low in both groups. Multiple regression analysis identified Barthel Index, degree of hemiplegia, and illness duration as independent determinants of ICTP in the early group, whereas Barthel Index, degree of hemiplegia, and serum calcium were determinants of ICTP in the long-term group. There were statistically significant correlations between the z score of the hemiplegic side and age, Barthel Index, degree of hemiplegia, illness duration, 25-hydroxyvitamin D (25-OHD), and ICTP in the early group and between the z score and degree of hemiplegia and 25-OHD level in the long-term group. CONCLUSIONS: The pathogenesis of reduced BMD differed between the early and long-term stroke groups. These results suggest that in the early group, increased bone resorption caused by immobilization was responsible for osteopenia on the hemiplegic side, whereas the degree of hemiplegia and 25-OHD level were the determinants of osteopenia in the long-term group.

Cerebrospinal fluid ferritin in glioblastoma: evidence for tumor synthesis.

Ferritin concentrations in cerebrospinal fluid (CSF) of 16 patients with glioblastoma were found to be very high (mean, 103.0 ng/mL) relative to 29 patients with viral meningitis and 20 patients with headache (mean concentrations, 5.4 and 4.3 ng/mL respectively). Simultaneous measurement of ferritin in CSF and serum revealed CSF concentrations exceeding those in serum in 11 of 16 patients with glioblastoma (CSF vs. serum ratio, 132.6%), contrasting with very low ratios in patients with meningitis (7.9%) or headache (4.9%). Ferritin was detected immunocytochemically in tumor cell cytoplasm in a resected glioblastoma. Thus, ferritin in CSF appears to be produced by glioblastoma cells, with a biologic significance requiring further investigation.

Morphologic and histochemical evaluation of muscle in patients with chronic pulmonary emphysema manifesting generalized emaciation.

Twelve severely emaciated patients with emphysema and 4 control patients with mild emaciation were studied. Arterial blood gas analysis, pulmonary function tests, and muscle biopsy were performed. According to the percentage of ideal body weight (%IBW), patients were divided into two groups of 6 patients each; one with %IBW values greater than 70.0 (group 1) and the other with %IBW values less than 70.0 (group 2), and 4 control patients with emphysema whose %IBW values were greater than 85.5. %FEV1.0, PaO2 and Hugh-Jones scores in group 2 patients were consistent with significantly greater deterioration as compared with those in group 1 patients and controls. In the muscle fibers of 11 patients and 4 controls, nicotinamide and adenosine dinucleotide tetrazolium reductase activity was studded with spots. Nemalin rods were detected in 3 specimens in group 2 and in 1 specimen each in both group 1 and controls. These changes probably result from chronic hypoxemia. Fiber type grouping accompanied by type II dominant fiber atrophy was demonstrated in 5 patients of group 2, whereas type II fiber atrophy was shown in 2 specimens from patients of group 1. Diameters of both types I and II fibers in group 2 were smaller than those in group 1 and controls. Significant correlations were observed between fiber diameters and %IBW, %FEV1.0 and %IBW, and PaO2 and %IBW. Neurogenic and disuse muscular atrophy due to both hypoxic axonal disorder and disuse is likely to be the cause of the emaciation, and a 'vicious circle' between muscular atrophy, respiratory function and hypoxemia probably exists in group 2. Since mild or moderate emaciation was observed in controls and group 1 in spite of the lack of fiber atrophy, involvement of fat and connective tissue should also be taken into consideration to determine the cause of emaciation.

The feasibility of epidural anesthesia without endotracheal intubation for abdominal surgery in patients with collagen diseases.

BACKGROUND/AIMS: Patients with collagen diseases are generally regarded as high-risk surgical candidates. MATERIAL AND METHODS: To evaluate the feasibility of epidural anesthesia and to determine the risk factors in abdominal surgery for patients with collagen diseases, 20 patients with collagen diseases who underwent elective abdominal surgery were examined for their surgical outcomes and clinical characteristics. Among the 20 cases, 12 received epidural anesthesia alone without endotracheal intubation, 3 received general anesthesia only, 4 received general anesthesia with epidural anesthesia and one received lumbar anesthesia. RESULTS: Only one patient receiving epidural anesthesia died after operation. The mortality in patients receiving epidural anesthesia was 8.3% (1/12) while the overall mortality was 5.0% (1/20). No significant difference was observed either in the mortality or incidence of postoperative complications among the 4 groups according to the method of anesthesia. Patients with a dysfunction of the vital organs more often had postoperative complications than those without a dysfunction of the vital organs (p = 0.043). CONCLUSIONS: Although only a small number of patients were included in this study, these results suggested that 1) elective abdominal surgery can be as safely performed under epidural anesthesia alone as with general anesthesia even for patients with collagen diseases, and 2) the patients with collagen diseases, who preoperatively showed a dysfunction of the vital organs, might be at a higher risk for abdominal surgery.

Hypovitaminosis D and decreased bone mineral density in amyotrophic lateral sclerosis.

To assess the bone health of patients with amyotrophic lateral sclerosis (ALS), we evaluated the bone density and serum biochemical indices of bone metabolism in 11 ALS patients. The serum concentration of 25-hydroxyvitamin D (25-OHD) was significantly lower in patients (14.0 +/- 3.7 ng/ml) than in controls (25.2 +/- 4.0 ng/ml), at deficient levels (< 10 ng/ml) in 2, and at insufficient levels (10-20 ng/ml) in 9 patients. Serum levels of parathyroid hormone (PTH) and ionized calcium were elevated in 8 and 6 patients, respectively. Dietary intake of vitamin D was below the recommended level (100 IU) in 10 patients, and 10 patients were in a sunlight-deprived state. The metacarpal bone density (MBD) and the metacarpal index (MCI) of the second metacarpal bone were measured by computed X-ray densitometry. Z scores of the MBD and the MCI were negative in 7 and 6 patients, respectively. The serum concentration of 25-OHD was positively correlated with the Z score of the MBD (p < 0.05, r = 0.727) and negatively with the PTH level (p < 0.05, r = -0.410). The degree of dysfunction of hand grip also correlated with the Z score of the MBD (p < 0.05, r = 0.749). These data underscore the importance of hypovitaminosis D and compensatory hyperparathyroidism in the development of osteopenia in patients with ALS.

Development of osteopenia in the hemiplegic finger in patients with stroke.

Previous studies have demonstrated that hip fractures in stroke patients occurred almost exclusively on the hemiplegic side. We examined the bone changes in the second metacarpal of the hemiplegic side in terms of microdensitometric indices in 93 stroke patients with hemiplegia. All six indices indicated a significant decrease in bone mass on the hemiplegic side compared with the contralateral side. Differences in the indices between the hemiplegic and contralateral sides were correlated well with the duration of the illness and Brunstrom's stage for finger, arm, and leg. The same degree of osteopenia occurred in both small capsular and large hemispheric lesions. The same osteopenia was demonstrated in paralyzed and immobilized patients with myopathy. Thus a combination of weakness and immobilization is thought to be responsible for the osteopenia in the hemiplegic metacarpal bone. The osteopenia noted in the second metacarpal in the affected limb may account for the fact that hip fractures in stroke patients occur almost exclusively on the hemiplegic side.

Immunohistochemical features of HLA-DR antigen expression and lymphoid infiltrates in gastric carcinoma after low-dose interleukin-2 and mitomycin C.

We immunohistochemically evaluated lymphoid cell infiltration and HLA-DR antigen expression in gastric tumor tissue obtained from advanced gastric cancer patients 1 day after the completion of the treatment with mitomycin C (MMC) 12 mg/m2 i.v. on day 1 and recombinant interleukin-2 (IL-2) i.v. every 12 h from day 4 through day 8. Then the results were compared with those in 11 patients pretreated with MMC alone, 5 treated with IL-2 alone, and 24 untreated patients. Widespread lymphoid infiltration was observed in 17% of untreated tumors, 27% of MMC-pretreated tumors, and 40% of tumors treated with IL-2 alone. However, 71% of carcinomas pretreated with MMC plus IL-2 exhibited widespread infiltration. The frequency of cases with high-grade infiltration of CD4+ cells was significantly higher in either group of patients treated with MMC alone or MMC plus IL-2. Because the CD8+ cell infiltration was not significantly altered, the ratio of CD4+ to CD8+ cells estimated as being > 1 was more frequently noted in patients given MMC alone or MMC plus IL-2, as compared with untreated control. Furthermore, 86% of tumors pretreated with MMC plus IL-2 exhibited positive HLA-DR antigen expression, whereas 29% of untreated carcinomas did so. MMC or IL-2 alone did not significantly increase HLA-DR expression. These results indicate that the combination of low-dose of IL-2 with MMC enhances the intensity of lymphoid cell infiltration in tumors, with the predominance of CD4+ cells, and HLA-DR antigen expression on tumor cells in patients with advanced gastric carcinoma.