Isolation of di-N-2-propylpentyl phthalate from human urine

Summary A higher percentage of di-N-2 propylpentyl phthalate isolated from the urine of the normals and a lower quantity in the patients suffering from Eales' disease accompanied with the occurrence in patients of another compound which is also most likely a phthalate ester has been correlated with the Eales' disease.Acknowledgement. This work was supported by grants from the Indian Council of Medical Research, New Delhi, India.     

Ferritin synthesis by splenic tumor tissue of Hodgkin's disease.

Increased ferritin synthesis by Hodgkin's disease splenic tumor tissue was demonstrated by incorporation of 14C-leucine and radioautography. This suggests that elevated tumor and serum ferritin concentrations found in patients with Hodgkin's disease is derived from tumor tissue per se.     

Cerebrospinal fluid immune complexes in multiple sclerosis.

Using a C1q binding test, immune complexes have been detected in one half of cerebrospinal fluid samples from patients with multiple sclerosis. These results provide additional evidence for the participation of an immune reaction in the disease process.     

Cerebrospinal fluid immune complexes in multiple sclerosis

Summary Using a C 1q binding test, immune complexes have been detected in one half of cerebrospinal fluid samples from patients with multiple sclerosis. These results provide additional evidence for the participation of an immune reaction in the disease process.     

Erythrophagocytosis by cultured skin fibroblasts from patients with hereditary metabolic disorders

Phagocytosis of native allogenic red blood cells was observed in cultures of skin fibroblasts obtained from patients with neuronal ceroid-lipofuscinosis, Niemann-Pick disease type C and morbus Fabry. Occasional phagocytizing cells were observed in 9 other syndromes. Cells from three normal donors did not phagocytize.     

The TSH receptor and its role in thyroid disease

The thyrotropin (TSH) receptor plays a preeminent role in thyroid physiology and disease. TSH, acting through the TSH receptor, is the major stimulator of thyroid cell growth, differentiation and function. In Graves' disease, the TSH receptor is the target of stimulating antibodies that cause hyperthyroidism. Although still a topic of debate, the TSH receptor has been implicated in the pathogenesis of the endocrine ophthalmopathy associated with Graves' disease. Blocking antibodies against the TSH receptor are involved in the development of hypothyroidism in a subset of patients with autoimmune hypothyroidism. Transplacental passage of stimulating or blocking TSH receptor antibodies from a mother with autoimmune thyroid disease may result in transient hyper- or hypothyroidism in early infancy. During pregnancy, the placental hormone human choriogonadotropin (hCG) can cause gestational hyperthyroidism through cross-reaction with the TSH receptor. Gestational hyperthyroidism may also be involved in the pathogenesis of hyperemesis gravidarum. Trophoblast tumors secreting hCG are a rare cause of hyperthyroidism. Somatic activating mutations of the TSH receptor have been identified as a molecular cause of toxic adenomas, whereas activating mutations in the germline give rise to nonautoimmune familial hyperthyroidism or sporadic congenital hyperthyroidism. These gain-of-function mutations are dominant, and one mutated allele is sufficient to result in disease. Inactivating germline mutations of both TSH receptor alleles lead to variable degrees of resistance to TSH, encompassing a spectrum ranging from euthyroid hyperthyrotropinemia to overt hypothyroidism with thyroid hypoplasia. Received 31 January 2001; received after revision 3 April 2001; accepted 3 April 2001     

Detection of human cytomegalovirus (HCMV) DNA from cell-free plasma of immunosuppressed patients by nested PCR: influence of nucleic acid extraction method

Conclusions Blood cells and plasma preparations from HCMV-seropositive healthy blood donors were all nPCR negative. Detection of HCMV DNA from PBMC and granulocytes (DNAemia) of immunosuppressed patients by nPCR did not correlate with the isolation of infectious virus from these cell populations in cell culture (viremia). However HCMV could be isolated in 60% of cases from other materials of the same patient. HCMV DNA detected in blood cells persisted for up to one year in an asymptomatically infected individual after NTX. The sensitivity of HCMV DNA detection in cell-free plasma (up to 5 fg) depended on the method used for DNA isolation. The rate of HCMV DNA detection in plasma was lower than in leukocytes. In all cases of positive plasma PCR infectious virus could be isolated from any other material of the symptomatically infected patients. Therefore HCMV DNA PCR from plasma of immunosuppressed patients seems to be a suitable and easy alternative to HCMV RT/PCR for routine diagnosis of HCMV disease.     

Molecular targets of non-steroidal anti-inflammatory drugs in neurodegenerative diseases

During the last decade, interest has grown in the beneficial effects of non-steroidal anti-inflammatory drugs (NSAIDs) in neurodegeneration, particularly in pathologies such as Alzheimer’s (AD) and Parkinson’s (PD) disease. Evidence from epidemiological studies has indicated a decreased risk for AD and PD in patients with a history of chronic NSAID use. However, clinical trials with NSAIDs in AD patients have yielded conflicting results, suggesting that these drugs may be beneficial only when used as preventive therapy or in early stages of the disease. NSAIDs may also have salutary effects in other neurodegenerative diseases with an inflammatory component, such as multiple sclerosis and amyotrophic lateral sclerosis. In this review we analyze the molecular (cyclooxygenases, secretases, NF-κB, PPAR, or Rho-GTPasas) and cellular (neurons, microglia, astrocytes or endothelial cells) targets of NSAIDs that may mediate the therapeutic function of these drugs in neurodegeneration. Received 4 December 2006; received after revision 24 January 2007; accepted 23 February 2007     

Deficiency of kallikrein-like enzyme activities in cerebral tissue of patients with Alzheimer's disease.

We examined the changes in the intracerebral activities, at the time of postmortem autopsy, in patients with Alzheimer's disease. When compared with the control group, the activity of kallikrein-like enzyme was significantly decreased, while prolyl endopeptidase activity increased, in the patients group. Aprotinin inhibited 50% of the activity of the former enzyme at 2 x 10(-7) M. Taken together with the results of a multivariate study, the above findings may indicate that intracerebral kallikrein deficiency plays an important role in the pathogenesis of Alzheimer's disease.     

Cross-reactivity of autoantibodies from patients with epidermolysis bullosa acquisita with murine collagen VII

The pathomechanism of antibody-mediated tissue damage in autoimmune diseases can be best studied in experimental models by passively transferring specific autoantibodies into animals. The reproduction of the disease in animals depends on several factors, including the cross-reactivity of patient autoantibodies with the animal tissue. Here, we show that autoantibodies from patients with epidermolysis bullosa acquisita (EBA), a subepidermal autoimmune blistering disease, recognize multiple epitopes on murine collagen VII. Indirect immunofluorescence microscopy revealed that EBA patients’ IgG cross-reacts with mouse skin. Overlapping, recombinant fragments of murine collagen VII were used to characterize the reactivity of EBA sera and to map the epitopes on the murine antigen by ELISA and immunoblotting. The patients’ autoantibody binding to murine collagen VII triggered pathogenic events as demonstrated by a complement fixing and an ex vivo granulocyte-dependent dermal–epidermal separation assay. These findings should greatly facilitate the development of improved disease models and novel therapeutic strategies.     

Periostin in kidney diseases

Chronic kidney disease is an incurable to date pathology, with renal replacement therapy through dialysis or transplantation being the only available option for end-stage patients. A deeper understanding of the molecular mechanisms governing the progression of kidney diseases will permit the identification of unknown mediators and potential novel markers or targets of therapy which promise more efficient diagnostic and therapeutic applications. Over the last years, periostin was established by several studies as a novel key player in the progression of renal disease. Periostin is de novo expressed focally by the injured kidney cells during the development of renal disease. In diverse cohorts of renal disease patients, the expression levels of periostin in the kidney and urine were highly correlated with the stage of the pathology and the decline of renal function. Subsequent studies in animal models demonstrated that periostin is centrally involved in mediating renal inflammation and fibrosis, contributing to the deterioration of renal structure and function. Genetic or pharmaco-genetic inhibition of periostin in animal models of renal disease was efficient in arresting the progression of the pathology. This review will summarize the recent advances on periostin in the field of kidney diseases and will discuss its utility of as a novel target of therapy for chronic kidney disease.     

Genetic susceptibility to hypertensive renal disease

Hypertensive renal disease occurs at increased frequency among the relatives of patients with this disease compared to individuals who lack a family history of disease. This suggests a heritable risk in which genetic variation may play a role. These observations have motivated a search for genetic variation contributing to this risk in both experimental animal models and in human populations. Studies of animal models indicate the capacity of natural genetic variants to contribute to disease risk and have produced a few insights into the disease mechanism. In its current phase, human population genetic studies have sought to associate genetic variation with disease in large populations by testing genotypes at a large number of common genetic variations in the genome, expecting that common genetic variants contributing to renal disease risk will be identified. These genome-wide association studies (GWAS) have been productive and are a clear technical success; they have also identified narrowly defined loci and genes containing variation contributing to disease risk. Further extension and refinement of these GWAS are likely to extend this success. However, it is also clear that few additional variants with substantial effects accounting for the greatest part of heritability will be uncovered by GWAS. This raises an interesting biological question regarding where the remaining unaccounted heritable risk may be located. At present, much consideration is being given to this question and to the challenge of testing hypotheses that lead from the various alternative mechanisms under consideration. One result of the progress of GWAS is likely to be a renewed interest in mechanisms by which related individuals can share and transmit traits independently of Mendelian inheritance. This paper reviews the current progress in this area and considers other mechanisms by which familial aggregation of risk for renal disease may arise.     

Molecular targets of glioma invasion

Glioblastoma multiforme is the most common and lethal primary malignant brain tumor. Although considerable progress has been made in technical proficiencies of surgical and radiation treatment for brain tumor patients, the impact of these advances on clinical outcome has been disappointing, with median survival time not exceeding 15 months. Over the last 30 years, no significant increase in survival of patients suffering from this disease has been achieved. A fundamental source of the management challenge presented in glioma patients is the insidious propensity of tumor invasion into distant brain tissue. Invasive tumor cells escape surgical removal and geographically dodge lethal radiation exposure and chemotherapy. Recent improved understanding of biochemical and molecular determinants of glioma cell invasion provide valuable insight into the underlying biological features of the disease, as well as illuminating possible new therapeutic targets. These findings are moving forward to translational research and clinical trials as novel antiglioma therapies. Received 25 July 2006; received after revision 27 October 2006; accepted 22 November 2006     

Overexpression of copper-zinc superoxide dismutase in trisomy 21

Down's syndrome (DS), the most frequent of congenital birth defects, results from the trisomy of chromosome 21 in all cells of affected patients. This disease is characterized by developmental anomalies, mental retardation and features of rapid aging, particularly in the brain, where the occurrence of Alzheimer's disease is observed in trisomy 21 patients over the age of 35. Copper-zinc superoxide dismutase (CuZnSOD) is one of the proteins encoded by chromosome 21 (21q22.1). As a consequence of gene dosage excess, CuZnSOD activity is increased by 50% in all DS tissues. This work reports the SOD activity of a population of DS patients with complete trisomy 21, partial trisomy 21, translocations and mosaicism, in order to confirm the gene dosage effect of SOD on the clinical features of DS, and to help to establish which is the critical region of chromosome 21 in DS. CuZnSOD was measured in red blood cells using the Minami and Yoshikawa method. In the population with complete trisomy 21, SOD activity was increased by 42%; in the population with partial trisomy 21, translocations and mosaicism, SOD activity was normal. In the population diagnosed as DS, but not karyotyped, SOD activity was increased by 28%. No differences between sexes or among ages were found. We conclude that the 21q22.1 segment is not the critical region responsible for DS, as we have found normal SOD activity in patients with the clinical features of DS.     

Deficiency of kallikrein-like enzyme activities in cerebral tissue of patients with alzheimer's disease

Summary We examined the changes in the intracerebral activities, at the time of postmortem autopsy, in patients with Alzheimer's disease. When compared with the control group, the activity of kallikrein-like enzyme was significantly decreased, while prolyl endopeptidase activity increased, in the patients group. Aprotinin inhibited 50% of the activity of the former enzyme at 2×10^–7M. Taken together with the results of a multivariate study, the above findings may indicate that intracerebral kallikrein deficiency plays an important role in the pathogenesis of Alzheimer's disease.     

Serodiagnosis of viral hepatitis A: rise in antibody titre and evaluation of three methods for detecting early and late antibodies

A serological investigation was made on patients with viral hepatitis A and individuals with a past history of this disease. Titration of antibody in sequential samples was found to be of no help in diagnosis. Separation of early (IgM) from late (IgG) antibodies by protein A or by 2-mercaptoethanol did not prove to be convenient for the serodiagnosis. A chromatographic separation of late and early antibody was found to be satisfactory, and equivalent to a radioimmunoassay for IgM-antibodies.     

Phytanic acid: production from phytol, its breakdown and role in human disease

Phytanic acid is a branched-chain fatty acid that accumulates in a variety of metabolic disorders. High levels of phytanic acid found in patients can exceed the millimolar range and lead to severe symptoms. Degradation of phytanic acid takes place by α-oxidation inside the peroxisome. A deficiency of its breakdown, leading to elevated levels, can result from either a general peroxisomal dysfunction or from a defect in one of the enzymes involved in α-oxidation. Research on Refsum disease, belonging to the latter group of disorders and characterized by a deficiency of the first enzyme of α-oxidation, has extended our knowledge of phytanic acid metabolism and pathology of the disease greatly over the past few decades. This review will centre on this research on phytanic acid: its origin, the mechanism by which its α-oxidation takes place, its role in human disease and the way it is produced from phytol. Received 4 October 2005; received after revision 24 February 2006; accepted 26 April 2006     

Ein Sensibilisator der therapeutischen Digitaliswirkung

Summary Complexes of bivalent tin with polyoxybenzene-polysulfonic acids have a diuretic effect, when injected subcutaneously in dogs or rabbits. The same compounds also sensibilize the cardiotonic effect of digitalis-substances on the isolated heart or on fragments of the isolated heart as usually employed for testing digitalis-substances.In a small number of patients suffering from heart disease, a rapid increase of their till then lowered diuresis was induced through subcutaneous injections of a solution of the above mentioned tin complex.