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PubMed1993

Kinetic models for unfolding and refolding of ribonuclease T1 with substitution of cis-proline 39 by alanine.

The replacement of cis proline 39 of ribonuclease T1 by an alanine residue leads to a decrease in stability by about 20 kJ/mol and to major changes in the folding kinetics that are not easily explained by the proline model for protein folding. In particular, a novel very slow reaction is observed in the refolding of the Pro39Ala variant. Here the unfolding and refolding kinetics of this protein are further investigated. We show that the very slow reaction is not a prolyl isomerization. It is not created by a slow isomerization of the unfolded protein, nor is it catalyzed by prolyl isomerase, and all molecules have to undergo this reaction during refolding. Most of the unfolded Pro39Ala molecules contain an incorrect trans isomer at the remaining cis Pro55. They use a sequential pathway for refolding, in which trans to cis isomerization at Pro55 precedes the very slow reaction. The refolding of the minor fraction of unfolded Pro39Ala molecules with a correct cis isomer at proline 55 is a single first-order reaction that is limited in rate by the very slow step. The folding mechanism of wild-type ribonuclease T1 cannot be used to explain these results and independent mechanisms are proposed to model the unfolding and refolding of the Pro39Ala variant. The molecular interpretation of the changes in the folding mechanism is tied to the question, as to whether the cis character of the peptide bond at position 38-39 is maintained after the substitution of Pro39 by alanine. A possible explanation could be that the novel very slow folding reaction involves the trans to cis isomerization of the Tyr38-Ala39 bond. Such a reaction is probably slow, since the activation energy is high and since tight coupling with the formation of structure is required to stabilize the cis form of a non-prolyl peptide bond. Alternatively, the strong decrease in folding rate could be correlated with the general destabilization of ribonuclease T1 by the Pro39Ala mutation.

Alanine↗

PubMed1976

[Sphingolipid storage disease as an example of a molecular neuropathology (author's transl)].

A short survey on the sphingolipid storage diseases is presented. The chemical nature of the accumulated substances is related to the genetically induced enzymic blocks on their biodegradation. Two disorders are stressed with alter the nervous system: metachromatic leukodystrophy and familiar infantile amaurotic idiocy (GM2-gangliosidosis). The difficulties in the causal interpretation of three variants of the latter disease due to the involvement of isoenzymes are dealt with. The relationship between the enzyme defect in these disorders and their time of clinical onset is discussed. Finally, the diagnostic possibilities are presented which are a prerequisite for preventing a further dissemination of these therapy-resistent inborn errors of metabolism.

Child, Preschool↗

PubMed1979

Studies on 1-beta-D-arabinofuranosyl cytosine-resistant mutants of Chinese hamster fibroblasts: III. Joint resistance to arabinofuranosyl cytosine and to excess thymidine--a semidominant manifestation of deoxycytidine triphosphate pool expansion.

Variants isolated from mutagenized Chinese hamster fibroblasts by a single cycle of exposure to ara-C distributed into two classes: (1) deoxycytidine (dC) kinase deficient clones with a high level of resistance, this phenotype was recessive in hybrids; and (2) clones exhibiting joint resistance to thymidine (dT) and to "low" ara-C concentration, this phenotype was accounted for by an increased dCTP pool. The incorporation of exogenous dC into macromolecules was markedly altered in these variants. In hybrids, the phenotype of joint resistance to dT and ara-C was semidominant. Through a second selection step, variants cumulating recessive high resistance to ara-C and semidominant dT resistance were recovered. The identification of these two classes of ara-C-resistant variants suggests an interpretation of the known phenotypes of ara-C resistance as manifestations of chromosomal gene mutations. Dominant resistance mutations might contribute to the survival of cancer cells during prolonged ara-C chemotherapy.

Animals↗

PubMed1988

Angiosarcoma of the thyroid: a light, electron microscopic and histoimmunological study.

A histologic, histoimmunological, and ultrastructural study of a primary angiosarcoma of the thyroid gland is reported. The occurrence of neoplastic cells positive for Factor VIII-related antigen and Ulex Europaeus Agglutinin-I and the presence in their cytoplasms of Weibel-Palade bodies are consistent with this diagnosis. These findings further support the view that primary angiosarcoma of the thyroid is a distinct pathological entity and should no longer be interpreted as a variant of a poorly differentiated carcinoma.

Aged↗

PubMed1999

Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA.

BACKGROUND: Prostate cancer is a very common disease in more-developed countries, but its cause is largely unknown. It is an androgen-dependent cancer, and androgens have been proposed as having a substantial role in predisposition to the disease. Thus, variations in androgen metabolism genes may affect risk of this disease. METHODS: We screened 216 African-American and 172 Hispanic men with prostate cancer, and 261 African-American and 200 Hispanic healthy men (controls), from a large prospective cohort study (the Hawaii-Los Angeles Multiethnic Cohort Study) for a mis-sense substitution in the human prostatic (or type II) steroid 5alpha-reductase (SRD5A2) gene, the product of which controls metabolic activation of testosterone to dihydrotestosterone. This mis-sense substitution results in an alanine residue at codon 49 being replaced with threonine (A49T). We also reconstructed this mutation in the SRD5A2 cDNA, and overexpressed the enzyme in mammalian tissue culture cells. FINDINGS: The A49T aminoacid substitution in the SRD5A2 gene increased the risk of clinically significant disease 7.2-fold in African-American men (95% CI=2.17-27.91; p=0.001) and 3.6-fold in Hispanic men (1.09-12.27; p=0.04). The mutant enzyme had a higher in-vitro Vmax than the normal enzyme (9.9 vs 1.9 nmol min(-1) mg(-1)). INTERPRETATION: The A49T variant of the SRD5A2 gene may be a significant contributor to the incidence of prostate cancer in African-American and Hispanic men in Los Angeles. We estimate that the population attributable risk due to this aminoacid substitution for clinically significant disease is about 8% in both populations. Increased conversion of testosterone to dihydrotestosterone catalysed by this variant steroid 5alpha-reductase enzyme may be the cause of the increased risk.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1996

Unusual variants of the tributaries of the main pancreatic duct revealed by postmortem and endoscopic pancreatography.

Analysis of 97 human postmortem pancreatograms and 103 endoscopic pancreatograms revealed a total of 3 cases (1.5%) with isolated variants in the branches of the main pancreatic duct. In the first one, tortuous branches were present in the upper head-body region. The second case involved joint tributaries bridging over an unstenosed segment of the main pancreatic duct. In the third case, we found three branches from the uncinate process running down to the main duct. In all of these cases no pathological substrate was found, and they should be considered as anatomical variants observed during interpretation of a radiogram.

Adult↗

PubMed1984

Factor VIII-related antigen in malignant hemangioendothelioma of the thyroid: additional evidence for the endothelial origin of this tumor.

Malignant hemangioendothelioma of the thyroid gland, which most often originates in a hemorrhagic nodule, is a well-known entity in European alpine regions with endemic goiter. In other parts of the world it very rarely has been diagnosed. This tumor may display considerable morphologic variation and often has been interpreted as a variant of undifferentiated carcinoma. In 13 out of 20 thyroid tumors, classified by light microscopy as malignant hemangioendothelioma, Factor VIII-related antigen, a marker for endothelial cells, was demonstrated in neoplastic cells with the help of immunohistochemical technics applied to conventional paraffin sections. In one case, in which material suitable for electron microscopy was available, Weibel-Palade bodies were found in tumor cells. These findings add strong support to the notion of an endothelial origin of this neoplasm.

Aged↗

PubMed1979

Pulmonary metastases (with admixed epithelial elements) from smooth muscle neoplasms. Report of nine cases, including three males.

This study pertains to an entity characterized by the presence of multiple intrapulmonary nodules, which consist of an admixture of bundles of well-differentiated smooth muscle cells and epithelial-lined spaces. These lesions have been frequently interpreted as a variant of hamartomas. However, in this review of the literature, and careful analysis of nine cases of this entity, we concluded that they should be considered metastases from smooth muscle tumors which incorporate some structures of mature lung parenchyma as they slowly expand. We affirm that the designation "fibroeliomyomatous hamartoma" should be discarded. Our cases occurred in six female and three male patients. In all but one female the primary source for lung metastases was uterus, while the male patients had primary lesions in the saphenous vein, diaphragm, and soft tissues. These lung lesions increase in size and number and are potentially fatal, though this may take many years. Even though the smooth muscle cells of the lung nodules appear bland on light microscopy, we were always able to demonstrate mitotic activity; electron microscopy indicated immaturity of the cells. For these reasons, we believe the tumors to represent metastatic leiomyosarcomas.

Adult↗

PubMed1989

Morphological nature of the atrioventricular valves in hearts with double inlet left ventricle.

The rudimentary right ventricle in hearts with double inlet to a dominant left ventricle can exist either to the right or the left side of the ventricular mass. These variants have been interpreted to imply differences in ventricular topology. If correct, they also imply that differences should exist in the morphology of the atrioventricular valves, previously thought to be indistinguishable one from the other. To test this possibility, we examined 15 hearts with double inlet to a morphologically left ventricle and 10 normal hearts. The distinguishing features of normal valves were evaluated for their consistency, and the most reliable were employed for interpreting the valves in the abnormal hearts. As shown by previous echocardiographic studies, insertion of valvar tension apparatus to the interventricular septum was unique to the morphologically tricuspid valve. Ten of the abnormal hearts had one valve showing this feature, it being absent in the other valve. The attachment, consistently on the same side as the rudimentary right ventricle, could be of diagnostic value in determining ventricular topology. In our small study, nonetheless, this approach still leaves one third of the hearts in which topology cannot be ascertained with certainty and in which it is not possible to distinguish the morphological nature of the atrioventricular valves.

Echocardiography↗

PubMed2026

Systematic common and rare variant association testing in 392,030 whole genomes in All of Us.

Large-scale genome-wide association studies (GWAS) and rare variant association studies (RVAS) from population biobanks provide valuable resources for gene discovery in complex human traits. We present an analysis of the All of Us Research Program v8 release, which includes whole genome sequencing data and harmonized phenotypic information of 392,030 participants after quality control, enabling a unified investigation of rare and common variants across a spectrum of human traits and diseases. We build an extensive phenome- and genome-wide ("All by All") computational framework to perform GWAS and RVAS on 3,602 phenotypes and identify 49,863 approximately independent, high-quality single-variant and gene-level associations. Meta-analyses of All of Us and UK Biobank, with sample sizes as large as 786,871 participants, further enhance statistical power and find 193 pLoF gene-phenotype associations that are not significant in either cohort alone, including 22 associations not highlighted by previous studies. We also present a public interactive browser that integrates association results for common and rare variants to facilitate interpretation and rapid querying of summary statistics, along with supporting documentation, and a Featured Workspace in the All of Us Researcher Workbench. Our framework will apply to iterative data releases as All of Us grows, empowering researchers worldwide to uncover insights into the functional effects of genetic components on complex traits and diseases.

Journal Article↗

PubMed1991

[Increased risk of death from coronary heart disease in men with low blood concentration of total cholesterol and low density lipoprotein cholesterol according to data from a prospective epidemiologic study in Moscow and Leningrad within the framework of Soviet-American cooperation].

The authors provide the results of a prospective study carried out for almost 10 years among men who underwent screenings in 1975-1977 at an age of 40-59 years in Moscow and Leningrad (overall 6431 persons) with a purpose of analyzing potential causes of high risk of death from coronary heart disease in a group of subjects with hypocholesterolemia. Based on a mathematical-statistical analysis, variants of the interpretations of the indicated fact are presented.

Adult↗

PubMed1989

A lineage switch in acute monocytic leukemia. A case report.

A case of congenital monocytic leukemia that underwent a lineage switch to acute lymphocytic leukemia (ALL) is described. The original leukemia had typical monocytic features, as evidenced by morphology (FAB M5), cytochemistry (nonspecific esterase) and immunophenotype (My4 positive). Cytogenetic study showed a pseudodiploid clone t(9;11)(p22;q21) that could be interpreted as a variant of the t(9;11)(p22;q23) reported in patients with the M5 type of leukemia. After successful remission induction with single-agent chemotherapy (VM-26) and subsequent sustained remission for 12 months with alternating VM-26 and VP-16-213, lineage switch to ALL (FAB L1) occurred. The presence of both lymphoid and myeloid markers on leukemic cells at lineage switch suggested the biphenotypic character of the patient's ALL. Our observation indicates that a lineage switch can occur from monocytic leukemia to ALL, although most of the cases previously reported have been in the reverse direction. This case emphasizes again the need to carry out careful and comprehensive marker studies to gain insight into the possible prognostic significance and the application of appropriate therapy.

Bone Marrow↗

PubMed1986

[Hereditary factors and their causative role in anatomic variation].

As demonstrate the literature data and the authors' observations on the composition of the anatomical structures of the extremities at the popliteal pterigyum syndrome of Smith-Lemley-Optis, as well as at some other monogenic syndromes, the manifestation of the anatomical changeability in humans is defined, to an essential degree, by hereditary factors. A suggestion is made that investigation of the anatomical changeability in connection with genetic peculiarities of the organism makes it possible to approach the causal interpretation of the variants and the developmental anomalies and comprehend the sources of multiplicity of forms and structure of the human organs and systems.

Chromosome Aberrations↗

PubMed1988

[Biology of glucose-6-phosphate dehydrogenase deficiency].

G-6-PD deficiency is predominant in the entire history of haemolytic anemias secondary to enzyme deficiency, since its represents, by far, the most frequent erythro-enzymopathy; it is also the most studied and the best known from the clinical as well as biological standpoints. Because of the ethnic groups particularly affected, this deficiency is essentially, in France, an imported pathology, even if there are a few true european cases. The biological diagnosis of the deficient patient is simple and well codified, but the interpretation of numerous variants of the enzyme remains quite complex. The recent cloning of the gene should provide a decisive progress in understanding these various deficiencies.

Anemia, Hemolytic↗

PubMedDate not supplied

[Somatotropic function of the hypophysis in the hypothalamic puberty syndrome].

The STH level was studied in the blood of 105 patients with the hypothalamic pubertal syndrome (HPS). A tendency toward STH hyperproduction was revealed. A comparison of the STH level in the blood and the degree of obesity of the HPS patients showed a clear decrease of the growth hormone in Stage IV obesity. The STH level was almost the same in Stages I, II, III obesity. The STH secretion in the HPS patients correlated with age. The period of disease did not influence hypophysial somatotropic function in the HPS patients. No interrelationship between the content of hydrocortisone and STH in the blood was established. In most of the patients with the HPS, the growth hormone secretion in response to hypoglycemia was undisturbed. Preliminary results obtained with parlodel tests showed an opposite reaction in the HPS patients as compared to healthy ones. Our results confirmed once more that the HPS should not be interpreted as a variant of Icenko-Cushing's syndrome or constitutional obesity in which STH production was lowered.

Adolescent↗

PubMed1985

[Double-outlet right ventricle with intact interventricular septum. Case report, review of the literature and proposed pathogenetic interpretation].

Double Outlet Right Ventricle with intact ventricular septum is an extremely rare malformation. Only nine cases are recorded in the known world literature. A new case is reported, concerning a female infant six months old when first seen, and still alive after atrial septectomy. The anatomical studies in Double Outlet Right Ventricle suggest that only the Ventricular Septal Defect in the outlet septum is an integral part of the malformation and can be defined as "typical". In more than 10% of cases the Ventricular Septal Defect opens into the inlet or trabecular-muscular portions of the septum: these latter locations of the defect should therefore be considered as "associated". Double Outlet Right Ventricle with intact ventricular septum can be interpreted as the variant lacking both typical and associated Ventricular Septal Defect. From the analysis of anatomical descriptions of the ten known specimens of Double Outlet Right Ventricle with intact Ventricular septum, the Authors word out the hypothesis that ventricular septum closure could be referred to a well developed bulbo-ventricular fold (bulbo-ventricular fold synonimous of cono-ventricular flange and bulbo-atrio-ventricular ledge), as a consequence of missed or defective conal absorption. They conceive a range including on one hand the Subarterial Ventricular Septal defect (bulbo-ventricular fold poorly developed due to effective conal absorption), on the other hand the Restrictive Ventricular Septal Defect and Intact Ventricular Septum (bulbo-ventricular fold well developed due to defective conal absorption).

Female↗

PubMed1979

[Impetigo herpetiformis and PUVA-treatment (author's transl)].

Report on a 20 years old pregnant woman, who fulfilled the criteria of the impetigo herpetiformis as well as later those of the pustular psoriasis Zumbusch in her clinical course. The impetigo herpetiformis is interpreted as a variant of the pustular psoriasis occurring during the pregnancy with lowered calcium-level, which increases the endogeneous eruption pressure. After negative attempts of treatment with Prednisolon, antibiotics, and later with Methotrexat an excellent therapeutic effect could be achieved by oral PUVA-treatment.

Administration, Oral↗

PubMed1980

[Delusional psychopathology of the paranoid stage of paranoid schizophrenia].

The psychopathological traits of paranoial delusions were studied in 65 patients with paranoial schizophrenia. Of these patients, 16 had hypochondriacal delusions, 13 delusions of jealousy and 36 delusions of reference and persecution. All cases were studied from the standpoint of structural-dynamic aspects of the development of systematized interpretative delusions. Two variants of the development of such delusions were distinguished: paranoic and mixed. The paranoic variant by its nature appeared to be catathymic (4 cases), in a mixed variant separate elements of sensorial and imaginative delusions were interspersed with a catathymic development of delusions. Such states were mainly expressed in the form of delusions of significance and special significance. An assumption is made that there is a reciprocal transition of catathymic delusions, delusions of significance and special significance in compliance to the development of the morbid process.

Adolescent↗