Efficacy and safety of plasma exchange in interstitial lung diseases with anti-melanoma differentiation-associated 5 gene antibody positive clinically amyopathic dermatomyositis.

OBJECTIVE: Clinically amyopathic dermatomyositis (CADM) patients frequently develop refractory interstitial lung disease (ILD), with a poor prognosis. We aimed to verify the efficacy and safety of plasma exchange (PE) treatment for ILD in CADM. METHOD: A retrospective case-control study was conducted to compare clinical outcomes with and without PE treatment in CADM-ILD patients refractory to combination therapy of high-dose glucocorticoids, calcineurin inhibitors, and cyclophosphamide. Among 19 enrolled patients, 11 were further treated with PE. We compared survival rates and other clinical characteristics. PE consisted of either fresh-frozen plasma or albumin as a replacement solution. RESULTS: Basal clinical characteristics at diagnosis, including age, gender, serum ferritin, Krebs von den Lungen-6 (KL-6), C-reactive protein, and respiratory function tests, did not differ between the two groups. The survival rate for treatment with PE was higher than for treatment without PE (91% and 50%, respectively, p < 0.05). Among PE-treated patients, anti-melanoma differentiation-associated gene-5 (anti-MDA-5) antibody titre, ferritin, and KL-6 as serological activity markers were sustainably reduced only after initiating PE. Therapeutic intervention with PE reduced the frequency of exacerbation of ILD requiring methylprednisolone pulse therapy. The occurrence of bacterial, fungal, and cytomegalovirus infection did not differ between the groups with and without PE, and adverse events associated with PE resolved with appropriate intervention. CONCLUSION: Combination therapy with PE was associated with an improved survival rate, and may be effective for the management of refractory ILD in CADM patients. A personalized therapeutic strategy including PE could be introduced for fatal rapidly progressive ILD.

Three cases of lupus nephritis patients with serum interleukin-32γ detection.

PURPOSE: Interleukin-32 (IL-32) is an inflammatory cytokine that is associated with the pathogenesis of several connective tissue diseases. We measured serum IL-32γ concentrations of systemic lupus erythematosus (SLE) patients. METHODS: Serum samples were obtained from SLE patients (n = 51), and healthy controls (n = 15). Serum IL-32 concentrations were measured using ELISA. Clinical information was obtained from medical records. RESULTS: Serum IL-32γ was detectable in three cases of SLE patients, whereas it was not detected in any healthy controls. Case 1: a 44-year-old female with lupus nephritis (LN) (Class II) and antiphospholipid antibody syndrome. Serum IL-32γ was 5.1 pg/ml. Case 2: a 30-year-old female with a history of diffuse proliferative LN (Class IV G (A/C)) and pulmonary hemorrhage. Serum IL-32γ was 8.9 pg/ml. Case 3: a 45-year-old female with chronic LN. Serum IL-32γ was 9.1 pg/ml. All three cases of IL-32γ-detectable patients had histories of LN and one had an active disease. In the context of LN, serum IL-32γ was detectable in 18.8% (three of 16) of SLE patients with histories of LN. CONCLUSION: We suppose that IL-32γ could contribute to the pathogenesis of renal diseases in some LN patients.

Subacute cerebellar ataxia and atrophy developed in a young woman with systemic lupus erythematosus whose cerebrospinal fluid was positive for antineuronal cell antibody.

Subacute cerebellar ataxia in combination with cerebellar atrophy has rarely been reported as one of the manifestations of lupus in the central nervous system (CNS). We describe a 27-year-old woman with systemic lupus erythematosus who developed subacute cerebellar ataxia. Computed tomography and magnetic resonance imaging of her brain showed cerebellar atrophy in both hemispheres, particularly on the right side. Moreover, increased antineuronal cell antibody levels were detected in her cerebrospinal fluid. The cerebellar ataxia improved markedly following high-dose corticosteroid administration. This suggests that a relationship exists between autoantibodies and subacute atrophic processes in CNS lupus.

Selective elevation of the N1-acetylspermidine level in human colorectal adenocarcinomas.

The association of N1-acetylspermidine with human colorectal adenocarcinomas has been evaluated in this study. Free polyamines and their monoacetylated forms in adenocarcinomas, adenomas, and apparently healthy mucosae were determined using high-performance ion-exchange chromatography. The N1-acetylspermidine levels in well- and moderately differentiated adenocarcinomas were 27.30 +/- 3.13 (S.E.) (n = 99) and 22.86 +/- 3.60 (n = 22) nmol/g, wet weight, respectively. These values were significantly higher than those of benign adenomas (5.38 +/- 0.85 nmol/g, n = 31) and of control mucosae. The N1-acetylspermidine levels in control mucosae on the oral and anal side of adenocarcinomas were 5.84 +/- 1.44 (n = 57) and 7.92 +/- 2.89 (n = 50) nmol/g, respectively; no significant difference was observed between control mucosae and adenomas. The mean levels of three polyamines, putrescine, spermidine, and spermine in both adenomas and adenocarcinomas were about twice as high as those of control mucosae. The molar ratios of spermidine to spermine were significantly greater in both adenomas and adenocarcinomas than in control tissues. There was no obvious correlation between the free polyamine concentrations and the degree of malignancy of the colorectal tumors. These results suggest that the metabolism of N1-acetylspermidine in colorectal adenocarcinomas is quite different from that in adenomas and in nonneoplastic mucosae and that N1-acetylspermidine can be a promising biochemical marker of cancer in the human large intestine.

Inhibitory effects of tenilsetam on the Maillard reaction.

It has been hypothesized that advanced Maillard reaction in vivo could explain some of the age- and diabetes-related changes. Furthermore, involvement of the Maillard reaction with Alzheimer's disease has also been suggested, as advanced glycation end products, such as pyrraline and pentosidine, were demonstrated to localize in lesions of the disease. Although aminoguanidine has been studied extensively and established as an inhibitor of the Maillard reaction, other candidates have not been investigated thoroughly. In the present study, we examined the inhibitory effect of tenilsetam [(+/-)-3-(2-thienyl)-2-piperazinone], an antidementia drug, on the Maillard reaction. Tenilsetam inhibited glucose- and fructose-induced polymerization of lysozyme in a concentration-dependent manner in vitro. Reduced enzymatic digestibility of collagen incubated with 100 mM glucose for 4 weeks was also restored to a control level by coincubation with 100 mM tenilsetam. To determine whether tenilsetam inhibits the Maillard reaction in vivo, streptozotocin-induced diabetic rats were treated with tenilsetam (50 mg/kg x day). Elevated levels of advanced glycation end-product-derived fluorescence and pyrraline in renal cortex and aorta of diabetic rats were suppressed by the administration of tenilsetam for 16 weeks. These inhibitory effects of this agent on advanced glycation in diabetic rats suggested its potential therapeutic role in controlling diabetic complications.

[Management of pulmonary tuberculosis patients complicated with diabetes mellitus before diagnosis as pulmonary tuberculosis and feasibility of chemoprophylaxis].

We studied whether diabetics who are one of the high risk groups of developing pulmonary tuberculosis had undergone chest X-ray examination periodically. The feasibility of chemoprophylaxis in diabetics was also studied by investigating whether fibrotic lesions of tuberculosis can be found on previous chest X-ray films of these patients. Of the pulmonary tuberculosis patients admitted to our hospital for treatment, 78 patients complicated with diabetes mellitus were enrolled in this study. As to the mode of detection, the majority, 63 cases, are discovered, by undergoing medical examination because of respiratory symptoms, followed by 8 patients in whom pulmonary tuberculosis was found by health examination and only 1 patient was found by the periodic observation of diabetes mellitus. Of the 57 patients receiving the original treatment for pulmonary tuberculosis preceded by the discovery of diabetes mellitus, only 15 (26%) had undergone chest X-ray examination periodically. This fact shows that physicians treating diabetes mellitus have only a little concern on tuberculosis, thus the re-training of physicians dealing with diabetics on tuberculosis is considered to be necessary. According to chest X-ray films of 21 patients who had undergone chest X-ray examination and in whom the previous films were available, there were 6 patients without any lesion of pulmonary tuberculosis, 8 patients with fibrotic lesions and 7 patients with active lesions. The 8 patients showing fibrotic lesions have developed pulmonary tuberculosis on the average 15 years after they were diagnosed with diabetes mellitus, and the fact suggests that the prevention of the development of pulmonary tuberculosis among diabetics could be possible by chemoprophylaxis.

[The complication with tuberculosis of the central nervous system in patients with miliary tuberculosis].

The complication with tuberculosis of the central nervous system (CNS) were studied in 16 patients with miliary tuberculosis who were admitted to our hospital during a period of two years from April, 1997 to March, 1999, and were examined by head MRI. Twelve cases (75%) were diagnosed as having tuberculosis of CNS. Six cases had tuberculosis of CNS which was found during the screening of miliary tuberculosis cases, and all had only cerebral tuberculoma. Meningeal irritative symptoms led to the discovery of tuberculosis of CNS in the remaining six cases, in which cerebral tuberculoma was complicated with tuberculous meningitis. Of these cases of meningitis, three cases showing disturbance of consciousness died, but no cases of death was found in cases by the screening. The length of time from the onset of symptoms to the diagnosis of tuberculosis was long in many of the cases complicated with tuberculosis of CNS compared with the cases without such a complication. In the cases of miliary tuberculosis, the rate of complication with tuberculosis of CNS is high, and the possibility of patients developing serious symptoms suddenly even when they were asymptomatic at the time of diagnosis and the paradoxical expansion that becomes intensified after initiation of treatment have been reported. Therefore, it is necessary to make a close checkup of CNS when the diagnosis of miliary tuberculosis has been made.

[Frequency of complication of diabetes mellitus in pulmonary tuberculosis].

The frequency of complication of diabetes mellitus in patients with pulmonary tuberculosis is high, and the presence of diabetes mellitus plays an important role in the development of pulmonary tuberculosis. We studied the frequency of complication of diabetes mellitus by year, sex and age among patients with pulmonary tuberculosis who were discharged from our hospital during a period of 12 years from 1987 to 1998. The number of diabetic cases in patients with pulmonary tuberculosis was 588, namely 14.1% out of 4169 patients during the 12 years from 1987 to 1998. The frequency of complication of diabetes in every four years period showed an increasing trend; 144 cases (11.8%) out of 1225 cases from 1987 to 1990, 208 cases (14.5%) out of 1434 cases from 1991 to 1994, and 236 cases (15.6%) out of 1510 cases from 1995 to 1998. By sex, the frequency of complication with diabetes mellitus in male was about twice that of female, with 501 cases (16.0%) out of 3127 cases in male and 87 cases (8.3%) out of 1042 cases in female. By age, the frequency of complication of diabetes mellitus showed a peak in the 40s and 50s in male, being 21.3% and 23.4% respectively. In female, it showed a peak in the 60s, being 18.5%. In conclusion, in the 12 years the frequency of complication of diabetes mellitus in tuberculosis cases has been increasing, and the presence of diabetes mellitus has been playing more important role in the development of pulmonary tuberculosis.

[A clinical study in the collagen disease patients developed pulmonary tuberculosis during corticosteroid administration].

The study subjects consisted of 14 pulmonary tuberculosis (PTB) patients with collagen disease. They are under corticosteroid treatment and the mean age is 56.4 years. The length of time from the development of collagen disease to the development of PTB averaged 4.1 years. The breakdown of collagen disease are SLE (6 patients), MCTD (3 patients), PN (2 patients), and PSS, PM, Sjogren syndrome (1 case, each). Thirteen cases were bacilli positive by the sputum examination on admission to our hospital. Chest X-ray findings on admission revealed cavitation in 3 cases and non-cavitation in 11 cases, of which 5 cases had miliary tuberculosis. Corticosteroid preparation had been administered to all of the 14 cases for more than one year. The mean dose of corticosteroid preparation administered when PTB developed was 13.9 mg (prednisolone) and it was more than 20 mg in 8 cases. The median duration from the start of the respiratory symptoms to diagnosis was 39.2 days. The delay in the discovery exceeding 1 month were seen in 9 cases. In the cases of collagen disease, when the disease course extends over a long period of time, and even when the dose of corticosteroid preparations are decreased, there is a need to be note on the risk of developing PTB. There are many non-cavitary cases with sputum smear positive. The fact suggested that an appropriate diagnosis is need so that the discovery of PTB should not be delayed.

[A study of patient's and doctor's delay in patients with pulmonary tuberculosis discovered by visiting doctors with symptoms in particular on doctor's delay].

Epidemiological trend of tuberculosis in Japan has reversed recently. The incidence of pulmonary tuberculosis (PTB) patients has increased again in Japan, and many outbreaks of PTB including nosocomial outbreaks in health-care facilities have been reported. The purpose of this study is to investigate patient's delay (interval between onset of the disease and first visit to a doctor) and doctor's delay (interval between first visit to a doctor and diagnosis as TB) in patients with PTB discovered by visiting doctors with symptoms, and especially, to investigate causes of doctor's delay in details. Of 236 PTB patients who were admitted to our hospital for treatment in 1997, 118 patients (85 males, 33 females) who were detected by their symptomatic visits were enrolled in to this study. 97 were initial treatment cases and the others were re-treatment cases. Among 34 initial treatment cases who were first seen at a general hospital and diagnosed as PTB by a close medical checkup after admission to our hospital, the 50 percentile of patient's delay was 17.0 days, and the 80 percentile was 36.4 days. The 50 percentile doctor's delay was 19.6 days, and the 80 percentile was 64.2 days. The average hospital stay was 16.2 days, the 50 percentile hospital stay was 7.8 days, and 80 percentile hospital stay was 23.5 days. On the sputum test for acid fast bacilli (AFB) performed on admission to our hospital, 26(76%) out of 34 cases were positive for tubercle bacilli, with 18 cases were positive for smear and 8 cases positive for culture. Therefore, risk of nosocomial infection was suspected. Doctor's delay had been attributed mainly to insufficient medical checkup. Among 25 initial treatment cases in whom doctor's delay as more than 4 weeks, 11 cases (44%) showed delay in chest X-ray examination and 8 cases (32%) ordered no sputum examination in spite of recognition of abnormal shadows on chest X-ray. On the sputum test for AFB on admission to our hospital, 22 (88%) out of 25 cases were positive for tubercle bacilli. Therefore, it is assumed that the delay in the adequate medical checkup was accountable for the doctor's delay. Shortening of the doctor's delay could be possible if hospitals perform the sputum examination for AFB and chest X-ray examinations properly for patients with respiratory symptoms.

[An outbreak of Mycobacterium tuberculosis infection among young adults in close contact].

We experienced an outbreak of tuberculosis among young adults in close contact. The index case (case 1) was 22-year-old builder and was symptomatic for 9 months before diagnosis as pulmonary tuberculosis (PTB). His sputum smear was positive for tubercle bacilli. On immediate family contacts examination carried out at our hospital, his brother and sister (case 3, case 4) were detected as having PTB. His mother (case 5) and father (case 6) were later detected as having PTB by their symptomatic visits after some months, as tuberculin test as not done at first examination. Case 7 was 19-year-old-man, and was undiagnosed for 5 months. His sputum smear was positive. Immediately, contacts examination for case 7 as carried out at our hospital, and his colleague (case 8) was detected as having PTB. By interview with the case 7, it was found that the case 1 and the case 7 were close friends and spent long time together. Case 10 was 30-year-old builder, and he was accidentally referred to our hospital and was diagnosed as PTB. By the interview with the case 10, it was found that the case 1 and case 10 were members of builders group. This fact was informed to the F health center, and contacts examination for other members of the group were carried out by the F health center, and two young men were detected as having PTB. Analysis of restriction fragment length polymorphism (RFLP) showed that the case 1, the case 5, the case 7, and the case 10 were caused by the same strain of M. tuberculosis. Based on these findings, it is highly suspected that this outbreak was origined from the case 1, and 13 developed tuberculosis and 13 were primarily infected among contacts. The characteristics of this outbreak was that the family and contacts examination were enforced and most of the cases were detected at our hospital. If the outbreak of tuberculosis highly suspected, physicians should actively cooperate with health centers for contacts examination.