Effects of metal-containing drugs taken simultaneously with clioquinol upon clinical features of SMON

In order to explore the effects of metals upon the subsequent onset of several clinical events in SMON, a retrospective cohort study was attempted. Study subjects were 216 "exposed" patients and 149 "unexposed" patients. "Exposure" was defined as the simultaneous ingestion of metal-containing drugs with clioquinol before the onset of neurological disorders. These two cohorts were identified from 531 patients among 832 patients, collected by the nationwide survey in 1975 and 1976. Effects provoked by ingestion of five metals (alminum, calcium, magnesium, copper and bismuth) were evaluated by relative risks with and without adjustment of the total amount of clioquinol ingested. Adjusted relative risks were estimated by maximum likelihood method. Significance of relative risk was determined by its 95% confidence interval. Following major findings emerged from the present analysis. (1) Simultaneous ingestion of Al-, Ca-, Mg-, Cu- or Bi-containing drugs with clioquinol significantly reduced the risk of developing motor disturbances. (2) Risk of developing visual disturbances were favorably modified by Al-containing drugs. (3) Clinical severity was significantly reduced by ingestion of Al-, Ca-, Mg- or Bi-containing drugs. (4) About 2-fold increase in risk of unfavorable clinical course was demonstrated by Al-containing drugs. (5) Onset of both green-fur on the tongue and relapse appeared unrelated to the metal-containing drugs ingested. (6) Combined ingestion of two kinds of metal-containing drugs with clioquinol appeared to yield more favorable effects than single ingestion of metal-containing drugs. (7) Al- or Bi-containing drugs demonstrated the strongest association with clinical features of SMON, followed by the drugs containing Mg or Ca. Cu-containing drugs had little association.     

Habitual Dietary Intake Affects the Altered Pattern of Gut Microbiome by Acarbose in Patients with Type 2 Diabetes

The aim of this research was to reveal the characteristics of gut microbiome altered by acarbose intervention in Japanese patients with type 2 diabetes (T2D) and its possible association with habitual dietary intake. Eighteen patients with T2D were administered acarbose for four weeks. The abundances of two major phyla, namely Actinobacteria and Bacteroidetes, were reciprocally changed accompanied by the acarbose intervention. There were also significant changes in the abundances of ten genera, including the greater abundance of Bifidobacterium, Eubacterium, and Lactobacillus and the lower abundance of Bacteroides in the group after the intervention than that before the intervention. Hierarchical clustering of habitual dietary intake was performed based on the pattern of changes in the gut microbiota and were classified into distinct three clusters. Cluster I consisted of sucrose, cluster II mainly included fat intake, and cluster III mainly included carbohydrate intake. Moreover, the amount of change in Faecalibacterium was positively correlated with the intake of rice, but negatively correlated with the intake of bread. The intake of potato was negatively correlated with the amount of change in Akkermansia and Subdoligranulum. Acarbose altered the composition of gut microbiome in Japanese patients with T2D, which might be linked to the habitual dietary intake.     

Variable region gene analysis of 2 human monoclonal-antibodies to gd3

We analyzed the genetic origins of anti-GD3 antibodies by comparing nucleotide sequences of the variable regions from the human monoclonal antibody (mAb), 27-26 (mu, k), established from a patient with leukemia, and another human anti-GD3 mAb, HJM-1 (mu, lambda) derived from a patient with melanoma. The variable regions of 27-26 and HJM-1 were remarkably similar to the germ-line genes. The mAb 27-26 was thought to be derived from germ-line repertoire expanded throughout our experiment. HJM-1 was derived from lymphocytes stimulated by GD3 abundantly expressed on melanoma cells.     

p53 status and prognosis in stage I-IIIa non-small cell lung cancer

To investigate the role of p53 abnormalities in predicting the survival of patients with non-small cell lung cancer (NSCLC), polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and immunohistochemical analyses were performed on 74 and 67 tumor samples, respectively, from patients with pathological stage I-IIIa NSCLC. An abnormally migrating SSCP band was observed in 21 of 74 (28%) tumor specimens. DNA sequence analysis revealed 23 intragenic mutations including 3 small deletions and 20 point mutations. Immunohistochemical analysis using the DO-7 monoclonal antibody showed abnormal expression of p53 in 27 of 67 (40%) patients. The concordance rate between immunohistochemical and PCRSSCP analyses was 73% (49/67) in this study. Univariate and multivariate analyses demonstrated that abnormal expression of p53 may be associated with prolonged survival (p=0.0997 and 0.0099, respectively). In contrast, no relationship was observed between p53 mutation and overall survival (0.6968). These results suggest that p53 status and the survival outcome changes between immunohistochemical and mutational analyses in stage I-IIIa NSCLC.     

Benign and malignant myoepithelioma of salivary-gland - an immunohistochemical evaluation

Three myoepitheliomas (MEOs) derived from the salivary glands were examined immunohistochemically. Proliferating cell nuclear antigen (PCNA)-positive cells were very rare (less than 2% of all tumor cells) in localized tumors of case 1 (epithelioid) (E-oid) cells) and case 2 (plasmacytoid) (P-toid) cells with a small number of spindle-shaped cells), but the percentage of PCNA-positive cells was high (21.8%) in case 3 (clear cells) exhibiting bone destruction. Strong c-myc expression was detected in all the tumors, but p53 or c-erbB-2 protein was not detected in any of the cases. More than half of the clear cells were positive for epidermal growth factor (EGF), while fewer tumor cells in cases 1 and 2 expressed EGF. A few tumor cells in cases 2 and 3 were positive for EGF-receptor (R). Keratin was most prominent in the E-oid cells, The P-toid cells were most strongly positive for S-100 protein followed by the E-oid and clear cells. More than half of the spindle-shaped cells and one-third of the E-oid cells were positive for alpha-smooth muscle actin (alpha-SMA), but less than 5% of the clear cells and none of the P-toid cells were positive for alpha-SMA. These results suggest that tumor cells in MEO are heterogenous and have different proliferation activities.     

A study on how a 6-month aerobic exercise program can modify coronary risk factors depending on their severity in middle-aged sedentary women

It is well known that physical exercise can reduce coronary risk factors. But how an aerobic exercise modifies coronary risk factors in relation to severity and physical fitness is still controversial. Fifty-four middle-aged women (mean age, 55 years) completed a 6-month on-site and home-based anaerobic threshold-level exercise program. The changes in coronary risk factor profiles were observed during the pre-intervention and intervention periods. Before the intervention (during control period), most coronary risk factors showed a rather unfavorable trend. After the program, their mean body weight decreased from 56.7 to 55.7 kg (p>0.05) and the proportion of body fat from 30.9 to 27.9% (p>0.05) without any reduction in lean body mass. Systolic blood pressure (SBP) decreased from 129.0 to 125.0 mm Hg (p>0.05) and diastolic blood pressure from 79.5 to 76.6 mm Hg (p>0.05). Fasting plasma glucose (FPG) declined from 109.6 to 103.4 mg/dl (p>0.05). Changes in SBP and FPG were most remarkable in their respective worst tertile. Serum lipids improved only modestly. Maximum oxygen uptake increased from 23.6 to 26.1 ml/kg/min (p>0.01). However, no significant correlations were found between changes in coronary risk factors and those in physical fitness. We conclude that the 6-month aerobic exercise program would modify women’s coronary risk factors depending on their initial values, probably independently of the changes in physical fitness.     

Changes in liver regenerative factors in a case of living-related liver transplantation

Liver regeneration in a patient with fulminant hepatic failure (FHF) who underwent living-related partial liver transplantation (LRLT) was investigated regarding hepatic growth factors. The patient was a 16-yr-old Japanese male who developed severe subacute FHF. LRLT was performed using an extended left lobe of the ABO matched patient's mother. In the recipient, the pre-transplant levels of both plasma hepatocyte growth factor (HGF) and transforming growth factor (TGF)-beta were extremely high and rapidly decreased following the liver replacement. The liver volume evaluated using a CAT scan increased 195% after 2 wk in graft liver and 110% after 2 wk in the hepatectomized donor. The explanted liver (FHF liver), the liver from donor (normal liver), and the graft liver [the 3rd post-transplant day (POD 3)] were all investigated immunohistochemically. FHF liver: No liver regeneration was observed [proliferative cell nuclear antigen (PCNA) labeling index (L.I.): 0%]. In the liver, both HGF in the hepatocytes and c-met on the membrane of the hepatocytes were positive. TGF-beta was positive in the hepatocytes and no apoptosis was detected by the TUNEL method. Donor liver (POD 0): Few PCNA stained hepatocytes were detected. No HGF was detected but c-met was clearly detected on the cell membrane of the hepatocytes. Neither TGF-beta nor apoptosis was detected. Graft liver (POD 3): The PCNA L.I. was conspicuous at 40%. HGF was positive in non-parenchymal cells and c-met was positive in the cytoplasm of the hepatocytes. TGF-beta was negative while apoptosis was positive in the zone 3 hepatocytes. In conclusion, these findings suggested that the liver of the patient with FHF did not respond to liver regenerative stimulus, in part, through involvement of inhibitor TGF-beta. On POD 3, the transplanted graft was in a vigorous regenerative status in comparison to that in the hepatectomized donor. The HGF/c-met system is thought to be involved in the mechanism of regeneration. Intrahepatic apoptosis was detected in the graft on the 3rd post-transplant day probably due to transient ischemia in the liver, which was not related to the Fas/Fas-ligand system.     

Evidence for regulation of myelin protein synthesis by contact between adjacent Schwann cell plasma membranes

The spontaneously immortalized S16 Schwann cell line expresses higher levels of myelin-associated glycoprotein (MAG) and PO glycoprotein and their messenger RNAs when grown at high density than at low density [Sasagasako et al: J Neurochem 1996;66:1432-1439]. This up-regulation of myelin protein expression at high density is not associated with decreased cellular proliferation and may be caused by direct cell-to-cell contact. To investigate the hypothesis that increased mRNA levels for myelin proteins are caused by contact between Schwann cells, sparse S16 cell cultures were treated for 48 h with plasma-membrane-enriched fractions isolated from dense S16 cells. The treatment had no effect on the proliferation of the cells, but MAG and PO mRNAs were elevated 2- and 1.3-fold, respectively, in comparison to untreated cells. These effects on levels of myelin protein mRNAs were eliminated by pretreatment of the membrane fraction with heat or trypsin and were not caused by plasma membrane fractions from NIH 3T3 cells. These data support the hypothesis that homotypic contact between Schwann cells up-regulates expression of myelin proteins and suggest the possibility of autotypic contact-mediated regulation of myelinogenesis by adjacent spiraled membranes of individual Schwann cells.     

Blocking angiotensin II ameliorates proteinuria and glomerular lesions in progressive mesangioproliferative glomerulonephritis

BACKGROUND: The renin-angiotensin system is thought to be involved in the progression of glomerulonephritis (GN) into end-stage renal failure (ESRF) because of the observed renoprotective effects of angiotensin-converting enzyme inhibitors (ACEIs). However, ACEIs have pharmacological effects other than ACE inhibition that may help lower blood pressure and preserve glomerular structure. We previously reported a new animal model of progressive glomerulosclerosis induced by a single intravenous injection of an anti-Thy-1 monoclonal antibody, MoAb 1-22-3, in uninephrectomized rats. Using this new model of progressive GN, we examined the hypothesis that ACEIs prevent the progression to ESRF by modulating the effects of angiotensin II (Ang II) on the production of transforming growth factor-beta (TGF-beta) and extracellular matrix components. METHODS: We studied the effect of an ACEI (cilazapril) and an Ang II type 1 receptor antagonist (candesartan) on the clinical features and morphological lesions in the rat model previously reported. After 10 weeks of treatment with equihypotensive doses of cilazapril, cilazapril plus Hoe 140 (a bradykinin receptor B2 antagonist), candesartan, and hydralazine, we examined systolic blood pressure, urinary protein excretion, creatinine clearance, the glomerulosclerosis index, and the tubulointerstitial lesion index. We performed a semiquantitative evaluation of glomerular immunostaining for TGF-beta and collagen types I and III by immunofluorescence study and of these cortical mRNA levels by Northern blot analysis. RESULTS: Untreated rats developed massive proteinuria, renal dysfunction, and severe glomerular and tubulointerstitial injury, whereas uninephrectomized control rats did not. There was a significant increase in the levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III in untreated rats. Cilazapril and candesartan prevented massive proteinuria, increased creatinine clearance, and ameliorated glomerular and tubulointerstitial injury. These drugs also reduced levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III. Hoe 140 failed to blunt the renoprotective effect of cilazapril. Hydralazine did not exhibit a renoprotective effect. CONCLUSION: These results indicate that ACEIs prevent the progression to ESRF by modulating the effects of Ang II via Ang II type 1 receptor on the production of TGF-beta and collagen types I and III, as well as on intrarenal hemodynamics, but not by either increasing bradykinin activity or reducing blood pressure in this rat model of mesangial proliferative GN.     

Bone marrow transplantation attenuates murine IgA nephropathy: role of a stem cell disorder

BACKGROUND: The pathogenesis of IgA nephropathy is still obscure. The aim of this study was to investigate whether the fundamental pathogenesis of IgA nephropathy lies in bone marrow stem cells (BMCs). METHODS: We used donors of two different strains for bone marrow transplantation (BMT) into mice with a high content of serum IgA (ddY strain, HIGA mice), a murine model of IgA nephropathy. One group (B6-->HIGA, N = 5) received BMCs of C57BL/6j (B6) mice, and the other (HIGA-->HIGA, N = 8) were reconstituted with BMCs of HIGA mice. RESULTS: Twenty-six weeks after BMT, in B6-->HIGA mice, mesangial deposits of IgA and C3 were statistically milder than those in HIGA-->HIGA mice. Light microscopic observations disclosed that glomerular sclerosis and mesangial matrix expansion in B6-->HIGA mice were decreased compared with those in HIGA-->HIGA mice. These B6-->HIGA mice also excreted less urinary albumin than HIGA-->HIGA mice. Furthermore, serum levels of IgA in B6-->HIGA mice were markedly lower than those in HIGA-->HIGA mice. Size analysis of serum IgA revealed that macromolecular IgA were notably lower in B6-->HIGA mice than in HIGA-->HIGA mice. CONCLUSIONS: Our results suggest that qualitative and quantitative changes of serum IgA are determined at the level of stem cells, and that BMT from normal donors can attenuate glomerular lesions in HIGA mice. This approach may offer a new avenue to study the pathogenesis of IgA nephropathy.