Short-term treatment with 17-beta estradiol enhances spontaneous [3H] dopamine release from cultured rat tuberoinfundibular neurons

The effects of 17-beta estradiol (E2) on spontaneous [3H] dopamine ([3H]DA) release was investigated using primary cultured cells from the tuberoinfundibular region of rat hypothalamus, which includes DA neurons. [3H] DA uptake by the neurons in the presence of E2 at 10(-8) mol/l was similar to that by control cells. Pretreatment with E2 at 10(-9) mol/l or more resulted in dose-dependent increase in spontaneous [3H] DA release from the cultured hypothalamic cells. The spontaneous [3H] DA release reached almost a plateau on pretreatment with E2 at 10(-9) mol/l for 6 hours. Pretreatment with 1 nM E2 also enhanced DA release induced by 10 microM ionophore A23187. These results indicate that estrogen stimulates tuberoinfundibular DA neuronal activity.     

Experience with percutaneous transhepatic cholangiography using the Japanese needle

Percutaneous transhepatic cholangiography using a very thin needle has been performed in 885 patients with a variety of underlying hepatic, biliary, and pancreatic disorders. The procedure was successful in 99% of the patients with dilated intrahepatic bile ducts and in 85% of those with non-dilated ducts. Complications which required surgical intervention occurred only in two cases (0.2%). In patients with obstructive jaundice, external bile drainage was performed immediately after visualization of the bile duct. Percutaneous transhepatic cholangiography is an extremely useful and safe method for investigating disorders of the biliary tract, for localizing the cause of obstructive jaundice, and for reducing the degree of jaundice and improving the general status of patients with obstructive jaundice.     

Upregulation of CD80 on glomerular podocytes plays an important role in development of proteinuria following pig‐to‐baboon xeno‐renal transplantation – an experimental study

We have previously reported that co‐transplantation of the kidney with vascularized donor thymus from α‐1,3‐galactosyltransferase gene knockout pigs with an anti‐CD154 with rituximab‐based regimen led to improved xenograft survival in baboons with donor‐specific unresponsiveness. However, nephrotic syndrome emerged as a complication in which the glomeruli showed mild mesangial expansion with similarities to minimal change disease (MCD) in humans. Since MCD is associated with CD80 expression in glomeruli and elevated urinary excretion, we evaluated a potential role for CD80 in xenograft nephropathy. Study 1 confirmed high urinary CD80 excretion in nephrotic animals with renal xenografts showing CD80 expression in glomeruli. In Study 2, baboons receiving xenografts received CTLA4‐Ig once a week from the second postoperative week or no CTLA4‐Ig. The non‐CTLA4‐Ig group developed severe proteinuria with modest mesangial expansion with high urinary excretion of CD80 and documented CD80 expression in glomerular podocytes. All of the recipients in non‐CTLA4‐Ig groups had to be euthanized before POD 60. In contrast, CTLA4‐Ig group showed a marked reduction in proteinuria and survived significantly longer, up to 193 days. These results demonstrate that anti‐CD80 targeted therapy represents a promising strategy for reduction of proteinuria following renal xeno‐transplantation with improved survival.     

Antigen-specific immunotherapy for autoimmune diseases

The status of autoimmune disease therapies is not satisfactory. Antigen-specific immunotherapy has potential as a future therapy that could deliver maximal efficacy with minimal adverse effects. Several trials of antigen-specific immunotherapy have been performed, but so far no clear directions have been established. With regard to antigen-specificity in the immune system, T cells are essential components. However, at present, we do not have a sufficient range of strategies for manipulating antigen-specific T cells. In this review, the authors propose that T cell receptor gene transfer could be used for antigen-specific immunotherapy. In the proposed technique, important disease-related and, thus, antigen-specific T cells in patients would first be identified, and then a pair of cDNAs encoding alpha and beta T cell receptors would be isolated from these single T cells. These genes would then be transferred into self lymphocytes. These engineered antigen-specific cells can also be manipulated to express appropriate functional genes that could then be applied to specific immunotherapy.     

Relationship between genetic polymorphisms of alcohol-metabolizing enzymes and changes in risk factors for coronary heart disease associated with alcohol consumption

BACKGROUND: There are large individual variations in the responses of risk factors for coronary heart disease to alcohol consumption. To clarify the factors responsible for these individual variations, we studied the relationship between blood pressure, serum lipids, and uric acid and the genetic polymorphisms of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 in alcohol drinkers. METHODS: We examined 133 male workers who drank >300 g of alcohol per week. Information regarding lifestyle habits was obtained by questionnaire. The ADH2 genotype was determined by PCR and subsequent digestion with MaeIII. The ALDH2 genotype was determined based on amplified product length polymorphisms. RESULTS: When the workers were divided into three groups: the ADH2(1)/2(1), ADH2(1)/2(2), and ADH2(2)/2(2) groups, the mean triglycerides and gamma-glutamyl transpeptidase concentrations were significantly higher in the ADH2(2)/2(2) group than in the ADH2(1)/2(1) group. In addition, multiple logistic regression analysis showed that the frequencies of individuals whose systolic blood pressure, triglycerides, and uric acid values were in the highest one third were significantly higher in the ADH2(2)/2(2) group than in the ADH2(1)/2(1) group. In contrast, no difference was observed between the ALDH2(1)/2(1) and (ALDH2(1)/2(2) + ALDH2(2)/2(2)) groups with regard to the mean value of any variable and to the frequency of individuals with any variable value in the highest one third. CONCLUSION: Individuals with the ADH2(1)/2(1) genotype might suffer fewer negative effects of drinking.     

Potent mitogenic effects of parathyroid hormone (PTH) on embryonic chick and rabbit chondrocytes. Differential effects of age on growth, proteoglycan, and cyclic AMP responses of chondrocytes to PTH.

The effect of PTH on chondrocyte proliferation as a function of cartilage age was examined. PTH[1-34] induced a 12- to 15-fold increase in the efficiency of colony formation in soft agar by chondrocytes from embryonic 13- to 19-d-old chickens and fetal 25-d-old rabbits with a 10-fold increase in their DNA content. It also caused a 2.5-fold increase in [3H]thymidine incorporation into DNA in fetal 25-d-old rabbit chondrocytes. No mitogenic responses to PTH were observed, however, in postnatal 7- to 21-d-old chick chondrocytes or postnatal 21-d-old rabbit chondrocytes. This age dependency was observed only with PTH: fibroblast growth factor, epidermal growth factor, and insulin stimulated chondrocyte proliferation irrespective of cartilage age. The absence of a mitogenic effect in postnatal chondrocytes was not due to a decrease in number or a reduction in affinity of receptors for PTH. PTH also increased [35S]sulfate incorporation into proteoglycans and the cyclic AMP level in fetal and postnatal chondrocytes, but at 100-fold higher concentrations (10(-8)-10(-7) M) than those (10(-10)-10(-9) M) required for the stimulation of cell division. These results suggest that PTH is a potent mitogen for embryonic chondrocytes, and that its mitogenic effect disappears selectively after birth.     

Significance of serum IgA levels and serum IgA/C3 ratio in diagnostic analysis of patients with IgA nephropathy

Diagnostic analysis of clinical markers including serum IgA levels and serum IgA/C3 ratio in patients with IgA nephropathy is described. One hundred patients with IgA nephropathy (IgA nephropathy group) and 100 patients with other primary glomerular diseases (non-IgA nephropathy group) were examined. The analysis was performed to distinguish between these two groups using four clinical markers: 1) more than five red blood cells in urinary sediments, 2) persistent proteinuria (urinary protein of more than 0.3 g/day), 3) serum IgA levels of more than 315 mg/dl, and 4) a serum IgA/C3 ratio of more than 3.01. Patients with three or four clinical markers were easily diagnosed as having IgA nephropathy in this study. Furthermore, there was a significant difference in these clinical markers between the good prognosis and relatively good prognosis groups (Groups I and II) and the relatively poor prognosis and poor prognosis groups (Groups III and IV) of IgA nephropathy patients. It appears that the presence of microscopic hematuria and/or persistent proteinuria, high serum IgA levels, and the serum IgA/C3 ratio are useful for distinguishing IgA nephropathy from other primary renal diseases. It is postulated that these clinical markers are also useful for diagnosis of IgA nephropathy without renal biopsy.     

Antiphospholipid antibodies in arterial thrombosis

The high correlation between the IgG isotype of anticardiolipin antibodies (aCLs) and clinical thrombosis was first documented in 1983, and this observation was confirmed in subsequent studies. In addition, the frequency of fetal loss and thrombocytopenia was increased in this group of patients. These findings were termed the antiphospholipid syndrome (APS). This syndrome was mostly seen in patients with systemic lupus erythematosus (SLE), but it soon became clear that also other patients not suffering from defined SLE might exhibit features of APS. aCL in APS patients are detected in immunoassays by using solid phase cardiolipin as a putative antigen. However, antibodies directed against phospholipid-binding plasma or serum proteins, beta2-glycoprotein I (beta2-GPI), in particular, are also detected. Many recent studies have indicated that one of predominant antibodies that has been identified as aCL in APS patients is against beta2-GPI rather than any of the negatively charged phospholipids. The epitopes recognized by anti-beta2-GPI antibodies raised in APS patients are composed of discontinuous amino acid sequences from the IV domain of human beta2-GPI. These epitopes are cryptic when beta2-GPI does not interact with anionic phospholipids. An early event in atherosclerosis is the accumulation of cholesterol-laden foam cells, which originate mainly from monocyte-macrophage cells by their uptake of chemically modified low-density lipoprotein (LDL). We found that beta2-GPI binds directly to oxLDL, and that the complex of oxLDL and beta2-GPI is subsequently recognized by aCL (anti-beta2-GPI) to be taken up by macrophages. While the pathogenesis of this accelerated atherosclerosis is likely to be multifactorial, it is possible that antiphospholipid antibodies, including aCL (anti-beta2-GPI antibodies), may have contributed to the formation of atherosclerotic lesion.