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PubMed1976

Histocompatibility antigens and immune responsiveness; their relevance to rheumatic diseases.

Associations between histocompatibility antigens and human diseases have been found. Some of the highest correlations are with the so-called "rheumatoid variant" disorders. Data gained from ummunogenetic studies in laboratory animals has been invoked in speculation on the significance of the high antigen associations in disease pathogenesis. While much of this data better supports theories on the aetiology of other conditions with less significant antigen associations, it is discussed here with reference to the rheumatic diseases.

Animals↗
PubMed1975

Heterogeneity of human hepatic H-acetyl-beta-D-hexosaminidose. A activity toward natural glycosphingolipid substrates.

A crude soluble preparation of human hepatic N-acetyl-beta-D-hexosaminidase was examined for its activities toward three natural glycosphingolipid substrates after fractionation by the isoelectric focusing procedure. Profiles of activities toward N-acetylgalactosaminyl-galactosyl-glucosylceramide (asialo GM2-ganglioside) and N-acetylgalactosaminyl-galactosyl-galactosyl-glucosylceramide (globoside) were always identical with that of nonspecific N-acetyl-beta-D-hexosaminidase as determined with artificial substrates. The Component A of the enzyme had the activity peak at an isoelectric point of 5.0 to 5.1. In contrast, hydrolytic activities toward N-acetylgalactosaminyl-[N-acetylneuraminyl]galactosyl- glucosylceramide (GM2-ganglioside) were associated with only the most acidic subfraction of the hexosaminidase A component. The activity to hydrolyze GM2-ganglioside had its peak at an isoelectric point of 4.8 to 4.9. These findings might provide an explanation for the GM2-ganglioside accumulation in juvenile GM2-gangliosidosis (partial deficiency of hexosaminidase A) and in the so-called AB variant of GM2-gangliosidosis (apparently normal hexosaminidase A and B activity).

Autopsy↗
PubMedDate not supplied

Histopathological atlas of renal diseases: ANCA-associated vasculitis (first part).

"ANCA-associated vasculitis" are Wegener's Granulomatosis, Micropolyarteritis and its renal-limited variant (previously called idiopathic necrotizing glomerulonephritis). According to the "Chapel Hill Consensus Conference" classification, ANCA-associated vasculitis are characterized by prevalent involvement of small-size vessels, whereas medium and large-size arteries involvement is the marker of Polyarteritis Nodosa. But the vessel size-based classification is not always powerful enough, because also in ANCA-associated vasculitis the involvement of medium and large-size arteries if frequent. The distinctive marker of ANCA-associated renal vasculitis has therefore become the presence of necrotizing extracapillary glomerulonephritis, that is always absent in Polyarteritis Nodosa.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1991

Protein engineering of novel plasminogen activators with increased thrombolytic potency in rabbits relative to activase.

Human tissue-type plasminogen activator (t-PA) is a glycoprotein used currently in thrombolytic therapy for patients with acute myocardial infarction. Due to its rapid rate of clearance from the circulation, continuous intravenous administration of approximately 100 mg over 3 h is recommended. We have previously characterized novel thrombolytic variant forms of t-PA which offer the potential of administration by bolus injection and reduced dosage due to their slower rates of clearance, relative to t-PA. This study was undertaken to quantitatively compare the pharmacokinetics, thrombolytic activity, and hemostatic effects of two of these variant forms, called delta FE1X and delta FE3X plasminogen activator (PA), with commercially available recombinant t-PA (Activase). These evaluations were performed in rabbits after bolus intravenous injection of the proteins. Following injection of 0.25 mg of protein/kg of body weight, the rates of clearance for delta FE3X and delta FE1X PA antigen were decreased approximately 9- and 18-fold, respectively, relative to Activase. Plasma plasminogen activator activity was also measured and the rates of clearance of delta FE3X and delta FE1X PA activity were similarly decreased by approximately 9- and 22-fold, respectively, relative to Activase. To quantitate thrombolytic activity we used the rabbit jugular vein thrombosis model and demonstrated that approximately 50% thrombolysis was achieved with delta FE1X and delta FE3X PA at approximately an 8.6- and 3-fold lower dose than Activase, respectively. No major differences in fibrinogen and alpha 2-antiplasmin depletion were observed among the agents at doses required to produce 50% thrombolysis, indicating similarities in fibrin specificities among these agents. These results demonstrate a reciprocal relationship between thrombolysis and rate of clearance for these thrombolytic proteins. The 8.6-fold increase in potency of delta FE1X PA relative to Activase supports the future clinical testing of this novel engineered protein as a thrombolytic agent.

Animals↗
PubMedDate not supplied

[Electrophoretic and kinetic properties of the erythrocyte glucose-6-phosphate dehydrogenase of patients with hemolytic anemia related to a deficit in the activity of that enzyme].

Partially purified glucose-6-phosphate dehydrogenase (G6PD) was studied in erythrocytes of patients with hereditary hemolytic anemia. Kinetic and electrophoretic properties of G6PD distinctly varied both in patients--homozygotes and in maternal heterozygotes. All the enzymes studied together with the decreased activity possessed the reduced Km value for NADP and G6P. Anomalous enzymes were shown to differ from normal ones by several patterns (pH-dependency, thermostability, % of the substrate analogues utilization, electrophoretic mobility etc). The mutant variant of G6PD was not described earlier. The anomalies variant was called "Kremenchug" to indicate the place of proband origination.

Chemical Phenomena↗
PubMedDate not supplied

[Pharmacologic treatment of constitutional short stature].

The term constitutional short stature is used to describe clinical situations characterized by low stature, assessed using special growth nomograms, but which are not due to specific endocrine alterations, nor to genetic causes or skeletal dysmorphisms, nor secondary to specific organ pathologies or chronic diseases. On the basis of this definition, our paper also includes the so-called normal variants of short stature (familial short stature and constitutional delay of growth) and intrauterine growth retardation. The endocrine and auxological features of constitutional short stature are described in the literature and provide an adequate basis for the use of therapies which include, in addition to growth hormone, substances capable of stimulating the endogenous secretion of the hormone (L-dopa, bromocriptine, clonidine, GHRH, pyridostigmine), or anabolic hormones. Biosynthetic growth hormone therapy is without doubt the most widely used, both on account of the extensive clinical experience and due to the easy availability of the drug made possible by the use of the biosynthetic molecule. Many subjects affected by constitutional short stature show a good response to hGH therapy, whereas others do not benefit by this treatment. New therapies using GHRH and neurodrugs, which are certainly easier to handle and less expensive, represent a new approach to the therapy of constitutional short stature but this condition still requires further investigation.

Dwarfism↗
PubMed1989

[Current aspects of nephrosclerosis].

The most frequent form of nephrosclerosis in human kidneys is the so-called benign variant. It may develop subsequent to even short-lasting hypertensive episodes. The interlobular arteries may be primarily affected, occasionally accompanied by glomerular and tubulointerstitial lesions. Consequently, progressive renal damage may occur potentially aggravating renal diseases of different origin. Malignant nephrosclerosis became a rare disease. Experimentally, it was impossible to induce its early intimal changes exclusively by high blood pressure values. Therefore, it was assumed that previous adaptive vascular changes, in addition to further advancing hypertension, may also be prerequisites for the development of malignant nephrosclerosis.

Humans↗
PubMed1987

[Acanthosis nigricans maligna and Leser-Trélat sign in double malignancy of the breast and stomach].

A female patient with primary cancer of the breast and the stomach developed acanthosis nigricans maligna and Leser-Trélat's sign. Acanthosis nigricans maligna is a well-known cutaneous marker of internal malignancy. It may be intensified by radiotherapy. A variant is called florid cutaneous papillomatosis. Leser-Trélat's sign is a rare cutaneous marker of internal neoplasms. According to the literature, we present 46 patients showing Leser-Trélat's sign. Neither Leser nor Trélat described this sign.

Acanthosis Nigricans↗
PubMed1983

[Taxonomic and medical status of isoenzyme strains of Trypanosoma cruzi. Considerations of the systematic and immunologic values of various isoenzymes].

The genetic distance calculations for 45 Bolivian stocks of Trypanosoma cruzi show the lack of continuum among them and allow to distinguish two main groups, which origin is perhaps a passed speciation. The presence of some heterogeneity within each group leads us to propose a temporary terminology: each isozymic variant is called "zymostrain" without prejudging its medical or taxonomic importance. The relationships between biochemical Taxonomy and medical data are discussed. The taxonomic value of the different isoenzymes is examined. The possible immunogenic properties of some of them (particularly Glutamate deshydrogenase) is discussed.

Alleles↗
PubMed1997

Post-traumatic stress disorder after childbirth: the phenomenon of traumatic birth.

CHILDBIRTH CAN BE A VERY PAINFUL EXPERIENCE, often associated with feelings of being out of control. It should not, therefore, be surprising that childbirth may be traumatic for some women. Most women recover quickly post partum; others appear to have a more difficult time. The author asserts that post-traumatic stress disorder (PTSD) may occur after childbirth. He calls this variant of PTSD a "traumatic birth experience." There is very little literature on this topic. The evidence available is from case series, qualitative research and studies of women seeking elective cesarean section for psychologic reasons. Elective cesarean section exemplifies the avoidance behaviour typical of PTSD. There are many ways that health care professionals, including physicians, obstetric nurses, midwives, psychologists, psychiatrists and social workers, can address this phenomenon. These include taking a careful history to determine whether a woman has experienced trauma that could place her at risk for a traumatic birth experience; providing excellent pain control during childbirth and careful postpartum care that includes understanding the woman's birth experience; and ruling out postpartum depression. Much more research is needed in this area.

Cesarean Section↗
PubMedDate not supplied

Histopathologic findings in the lymphoid and reticuloendothelial system in pediatric HIV infection: a postmortem study.

The present report describes the histopathological features of lymphoreticular tissues in 29 pediatric autopsies of human immunodeficiency virus (HIV)-infected patients. Mean age for the whole group was 1.77 years; 68.9% and 62% of the cases were 2 years old or less and 1 year old or less at the time of death, respectively. Twenty-one cases were categorized as acquired immunodeficiency syndrome (AIDS) and the rest included seven HIV-positive newborns and infants and two infants belonging to a high-risk group. The thymus (24 cases) showed severe lymphoid depletion (atrophy) in 16 (66.6%) cases, microcystic transformation of Hassall's corpuscles (HCs) in 4, calcified HCs in 3, absence of HCs in 3, and plasmacytic infiltrates and Warthin-Finkeldey-type multinucleated giant cells (also found in lymph nodes and bowel lymphoid aggregates in the same case) in 1. Lymph nodes (25 cases) revealed extensive lymphocyte depletion (68%); selective follicular (2 cases) or paracortical (3 cases) atrophy; hemophagocytosis (44%); some type of hyperplasia (plasmacytosis, enlarged follicles) in 5 cases; some type of lymphadenitis (12 cases), 5 cases of which were due to opportunistic infections (cytomegalovirus, 2; histoplasmosis, cryptococcosis, Mycobacterium avium-intracellulare, 1 each). Main findings in the spleen (28 cases) were extensive lymphocyte depletion (10 cases), limited to the white pulp in 4 and including the red pulp in 7; some type of lymphoid hyperplasia (limited to white pulp in 6 cases and involving the red pulp in 5); hemophagocytosis (7 cases); and foci exhibiting a peculiar arrangement of spindle-shaped cells combined with capillaries, plasma cells, and occasionally siderophages in 11. These we have termed kaposiform areas due to the resemblance to the so-called inflammatory variant of Kaposi's sarcoma. This pattern was also recognized in lymph nodes of two cases. Although atrophy was the main theme, cases with hyperplasia were also noticed. The possible relationship, if it exists at all, between kaposiform areas and Kaposi's sarcoma remains to be established. No tumor was found in this series. No specific histopathologic pattern of lymphoid tissues atributable to HIV emerged form this study aside from kaposiform areas, a microscopic feature not previously reported in this circumstance in pediatrics.

AIDS-Related Opportunistic Infections↗
PubMed1994

The combination of Pit-1 and Pit-1T have a synergistic stimulatory effect on the thyrotropin beta-subunit promoter but not the growth hormone or prolactin promoters.

Pit-1 is a pituitary-specific transcription factor with protein expression limited to thyrotrope, somatotrope, and lactotrope cells of the anterior pituitary gland. We have recently described a thyrotrope-specific variant isoform of Pit-1, called Pit-1T, which contains an additional 14 amino acids in the activation domain generated by an alternate 3'-splicing choice. Pit-1T, in the presence of Pit-1, stimulates the thyrotropin beta-subunit (TSH beta) promoter in a thyrotrope-derived cell that lacks all Pit-1 isoform proteins. Three laboratories have identified another Pit-1 splice variant, called Pit-1 beta, which contains an additional 26 amino acids in the activation domain that is generated by a similar 3'-alternate splice choice. Pit-1 beta has been shown to stimulate the GH promoter, but not the PRL or TSH beta promoters. In this report, we evaluate the effect of the three Pit-1 isoforms (Pit-1, Pit-1T, and Pit-1 beta) on the GH, PRL, and TSH beta promoters when introduced into different cell types. The combination of Pit-1 and Pit-1T had a synergistic stimulatory effect on the TSH beta promoter, but not on the PRL or GH promoters in a thyrotrope-derived cell line that lacks all Pit-1 protein isoforms (alpha TSH cells). When added to GH3 cells, which lack only the Pit-1T isoform, Pit-1T selectively stimulated the TSH beta promoter and not the GH or PRL promoters, suggesting that the thyrotrope-specific Pit-1T exhibits a promoter-specific effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Alternative Splicing↗
PubMed2002

A novel variant of the immunoglobulin fold in surface adhesins of Staphylococcus aureus: crystal structure of the fibrinogen-binding MSCRAMM, clumping factor A.

We report here the crystal structure of the minimal ligand-binding segment of the Staphylococcus aureus MSCRAMM, clumping factor A. This fibrinogen-binding segment contains two similarly folded domains. The fold observed is a new variant of the immunoglobulin motif that we have called DE-variant or the DEv-IgG fold. This subgroup includes the ligand-binding domain of the collagen-binding S.aureus MSCRAMM CNA, and many other structures previously classified as jelly rolls. Structure predictions suggest that the four fibrinogen-binding S.aureus MSCRAMMs identified so far would also contain the same DEv-IgG fold. A systematic docking search using the C-terminal region of the fibrinogen gamma-chain as a probe suggested that a hydrophobic pocket formed between the two DEv-IgG domains of the clumping factor as the ligand-binding site. Mutagenic substitution of residues Tyr256, Pro336, Tyr338 and Lys389 in the clumping factor, which are proposed to contact the terminal residues (408)AGDV(411) of the gamma-chain, resulted in proteins with no or markedly reduced affinity for fibrinogen.

Adhesins, Bacterial↗
PubMed1989

Haplotype analysis of familial amyloidotic polyneuropathy. Evidence for multiple origins of the Val----Met mutation most common to the disease.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant genetic disease characterized by systemic accumulation of amyloid fibrils. A major component of FAP amyloid has been identified as variant transthyretin (TTR, also called prealbumin). In particular, a variant with the substitution 30Val----Met has been commonly found in FAP of various ethnic groups. To understand the origin and spread of the Val----Met mutation, we analyzed DNA polymorphisms associated with the TTR gene in six Japanese FAP families and several Portuguese FAP patients. Three distinct haplotypes associated with the Val----Met mutation were identified in Japanese FAP families, one of which was also found in Portuguese patients. On the other hand, it was found that the Val----Met mutation can be explained by a C-T transition at the CpG dinucleotide sequence of a mutation hot spot. Thus, our findings indicate that the Val----Met mutation has probably recurred in the human population, to generate FAP families of independent origin.

Haplotypes↗
PubMed2000

Structure of the human serotonin 5-HT4 receptor gene and cloning of a novel 5-HT4 splice variant.

Several variants of the serotonin 5-HT4 receptor are known to be produced by alternative splicing. To survey the existence and usage of exons in humans, we cloned the human 5-HT4 gene. Based on sequence analysis seven C-terminal variants (a-g) and one internal splice variant (h) were found. We concentrated in this study on the functional characterization of the novel splice variant h, which leads to the insertion of 14 amino acids into the second extracellular loop of the receptor. The h variant was cloned as a splice combination with the C-terminal b variant; therefore, we call this receptor 5-HT4(hb). This novel receptor variant was expressed transiently in COS-7 cells, and its pharmacological profile was compared with those of the previously cloned 5-HT4(a) and 5-HT4(b) isoforms, with the latter being the primary reference for the h variant. In competition binding experiments using reference 5-HT4 ligands, no significant differences were detected. However, the broadly used 5-HT4 antagonist GR113808 discriminated functionally among the receptor variants investigated. As expected, it was an antagonist on the 5-HT4(a) and 5-HT4(b) variant but showed partial agonistic activity on the 5-HT4(hb) variant. These data emphasize the importance of variations introduced by splicing for receptor pharmacology and may help in the understanding of conflicting results seen with 5-HT4 ligands in different model systems.

Amino Acid Sequence↗