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PubMed1987

Abnormal regulation of LDL receptor activity and abnormal cellular metabolism of hypertriglyceridaemic low density lipoprotein: normalization with bezafibrate therapy.

The regulation of LDL (B,E) receptor activity and of cellular LDL protein metabolism by hypertriglyceridaemic (HTG) low density lipoprotein before and during hypolipidaemic therapy (with bezafibrate (BZ] were determined in cultured human skin fibroblasts. Defective binding and subnormal capacity to regulate LDL receptor activity was found for HTG-LDL. Binding affinity (Kd) of HTG-LDL to the receptor was 4.97 x 10(-8) M and of N-LDL, 1.74 x 10(-8) M. When assayed with normal 125I-LDL, the capacity of HTG-LDL to down-regulate receptor activity was 46-68% less than N-LDL. Both abnormalities reverted towards normal during treatment. The cellular metabolism of HTG-, BZ- and N-LDL in cells grown for 48 h with the respective lipoproteins was determined. In spite of their defective binding to the receptor, the metabolism of HTG-LDL in the regulated cells was accelerated in comparison to N-LDL, and equal to that of BZ-LDL. That observation is explained by the inefficient ability of HTG-LDL to depress LDL receptor activities in the cells.

Bezafibrate↗
PubMed2005

Chromosome abnormalities in sperm of individuals with constitutional sex chromosomal abnormalities.

The most common type of karyotype abnormality detected in infertile subjects is represented by Klinefelter's syndrome, and the most frequent non-chromosomal alteration is represented by Y chromosome long arm microdeletions. Here we report our experience and a review of the literature on sperm sex chromosome aneuploidies in these two conditions. Non mosaic 47,XXY Klinefelter patients (12 subjects) show a significantly lower percentage of normal Y-bearing sperm and slightly higher percentage of normal X-bearing sperm. Consistent with the hypothesis that 47,XXY germ cells may undergo and complete meiosis, aneuploidy rate for XX- and XY-disomies is also increased with respect to controls, whereas the percentage of YY-disomies is normal. Aneuploidy rates in men with mosaic 47,XXY/46,XY (11 subjects) are lower than those observed in men with non-mosaic Klinefelter's syndrome, and only the frequency of XY-disomic sperm is significantly higher with respect to controls. Although the great majority of children born by intracytoplasmic sperm injection from Klinefelter subjects are chromosomally normal, the risk of producing offspring with chromosome aneuploidies is significant. Men with Y chromosome microdeletions (14 subjects) showed a reduction of normal Y-bearing sperm, and an increase in nullisomic and XY-disomic sperm, suggesting an instability of the deleted Y chromosome causing its loss in germ cells, and meiotic alterations leading to XY non-disjunction. Intracytoplasmic injection of sperm from Y-deleted men will therefore transmit the deletion to male children, and therefore the spermatogenic impairment, but raises also concerns of generating 45,X and 47,XXY embryos.

Chromosome Aberrations↗
PubMedDate not supplied

Abnormal composition of hypertriglyceridemic very low density lipoprotein determines abnormal cell metabolism.

The metabolism of very low density lipoprotein (VLDL) from normolipemic (NTG) subjects, hypertriglyceridemic (HTG) subjects, and hypertriglyceridemic subjects treated with bezafibrate (BZ) was studied in cultured human skin fibroblasts. The binding, cell association, and proteolytic degradation of 125I-labeled lipoproteins and the capacity to regulate cellular sterol synthesis was determined with and without maximal stimulation of the lipoprotein by exogenous recombinant or plasmatic apolipoprotein (apo) E-3. The VLDL was separated into three density subfractions: I, II, and III. Multiple differences between HTG and NTG lipoproteins were found, which all reverted toward normal with therapy. Even in the presence of an optimal concentration of apo E-3, HTG-VLDL demonstrated 100% to 200% higher metabolic activities, indicating a better association or a better biological expression of apo E-3 at the surface of the lipoprotein. There was a strong and linear relationship between the cholesterol ester/protein ratios of the different VLDLs and their proteolytic degradations by the cells (r = 0.95). Thus, the composition/structure alterations of VLDL appear to determine their apo E-3-dependent cellular catabolism. In addition, HTG-VLDLs not enriched with apo E-3 exhibited a capacity to down-regulate cellular sterol synthesis independently of their uptake and degradation by the cells. This abnormality appeared to reflect the ability of the VLDL to donate cholesterol to the cells and was not observed in receptor-negative cells. Thus, HTG-VLDL is much more capable than NTG-VLDL of introducing cholesterol to cells by at least two mechanisms: 1) accelerated uptake and degradation and 2) direct transfer of cholesterol to the cells. Both processes are potentially atherogenic and are reversible when triglyceride-lowering therapy is instituted.

Adult↗
PubMed2001

Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis.

BACKGROUND: We report hypertrophic cardiomyopathy (HCM) in a Spanish-American family caused by a novel alpha-tropomyosin (TPM1) mutation and examine the pathogenesis of the clinical disease by characterizing functional defects in the purified mutant protein. METHODS AND RESULTS: HCM was linked to the TPM1 gene (logarithm of the odds [LOD] score 3.17). Sequencing and restriction digestion analysis demonstrated a TPM1 mutation V95A that cosegregated with HCM. The mutation has been associated with 13 deaths in 26 affected members (11 sudden deaths and 2 related to heart failure), with a cumulative survival rate of 73+/-10% at the age of 40 years. Left ventricular wall thickness (mean 16+/-6 mm) and disease penetrance (53%) were similar to those for the ss-myosin mutations L908V and G256E previously associated with a benign prognosis. Left ventricular hypertrophy was milder than with the ss-myosin mutation R403Q, but the prognosis was similarly poor. With the use of recombinant tropomyosins, we identified several functional alterations at the protein level. The mutation caused a 40% to 50% increase in calcium affinity in regulated thin filament-myosin subfragment-1 (S1) MgATPase assays, a 20% decrease in MgATPase rates in the presence of saturating calcium, a 5% decrease in unloaded shortening velocity in in vitro motility assays, and no change in cooperative myosin S1 binding to regulated thin filaments. CONCLUSIONS: In contrast to other reported TPM1 mutations, V95A-associated HCM exhibits unusual features of mild phenotype but poor prognosis. Both myosin cycling and calcium binding to troponin are abnormal in the presence of the mutant tropomyosin. The genetic diagnosis afforded by this mutation will be valuable in the management of HCM.

Adult↗
PubMed1975

Gel electrophoretic studies on proteoglycans and collagen of abnormal human growth cartilage: proteoglycan abnormalities in pseudoachondroplasia and in Kniest's disease.

The microchemical study of growth cartilage biopsies may improve the classification and the genetic advice of some types of growth disturbances and contribute to the understanding of biochemical defects. Small tibial growth cartilage biopsies were performed during orthopedic surgery in cases with achondroplasia, pseudoachondroplasis (three cases), Kniest's disease (two cases), diastrophic dwarfism (two cases), parastrematic dwarfism, pycnodysos tosis, mucolipidosis type III, Blount's disease, and in three normal growing children. Five human fetal cartilages were also studied. The proteoglycans were extracted with 4 M guanidinium chloride. After dialysis against 8 M urea at pH 7, the proteoglycans were obtained by ion chromatography in urea on DEAE-cellulose and submitted to gel electrophoresis on polyacrylamide-agarose gels. The gel electrophoresis of the proteoglycans of growth cartilage of normal growing children gave two metachromatic bands situated close one to another. The proteoglycans extracted from fetal growth cartilage gave a single band with a slightly slower migration. An abnormal gel electrophoretic pattern was found in pseudoachondroplasia and in Kniest's disease. In pseudoachondroplasia a single wide band was found; in overcharged tubes several thin, more rapid bands appeared in addition to the main band. In Kniest's disease three bands were found. In all of the other syndromes studied two normally or almost normally situated bands were present. Small differences in the width and intensity of the bands observed in several cases were difficult to assess. In all cases except mucolipidosis III and Kniest's disease the collagen was extracted by using limited cleavage and solubilization with pepsin, purified and analyzed by polyacrylamide gel electrophoresis. A type of collagen with a single alpha band was found.

Achondroplasia↗
PubMed2003

A higher prevalence of abnormal regional cerebral blood flow in patients with syndrome X and abnormal myocardial perfusion.

To test the hypothesis that syndrome X is a systemic vascular disorder, technetium-99m ethyl cysteinate dimer (Tc-99m ECD) brain single photon emission computed tomography (SPECT) was used to detect abnormal regional cerebral blood flow (rCBF) in 30 patients with syndrome X. These patients were separated into group 1, 20 patients with definite myocardial perfusion defects diagnosed by thallium-201 (Tl-201) myocardial perfusion SPECT; and group 2, 10 patients without any myocardial perfusion defects. Tc-99m ECD brain SPECT demonstrated hypoperfusion brain lesions in 95% (19/20) and 20% (2/10) of patients in groups 1 and 2, respectively. This difference in the cidence between the two groups was significant. In group 1 and 2 patients, parietal lobes were the most common hypoperfusion areas, while the cerebellum was the least common hypoperfusion area of the brain. Syndrome X is a systemic vascular disorder with a high incidence of hypoperfusion lesions of the brain based on the findings of Tc-99m ECD brain SPECT, and is usually coincident with myocardial defects based on the Tl-201 myocardial perfusion SPECT findings.

Adult↗
PubMed1999

[Congenital abnormalities of the vessels of the base of the heart: "ring" and "sling" vascular abnormalities. Case report].

We present a case of double aortic arch corrected by surgical interruption and full mobilization of the trachea and the esophagus. The vascular malformations of the supraaortic trunks, which form more or less complete vascular rings encircling the esophagus and the trachea, are reviewed. The different presentations of double aortic arch, aberrant subclavian arteries, and abnormal development of the pulmonary arteries are discussed.

Aorta, Thoracic↗
PubMed2004

Abnormal aneurysmal dilatation of the internal carotid artery on angiography without abnormal finding at surgery: a case report.

After trauma, the next most common cause of subarachnoid hemorrhage (SAH) is aneurysm rupture. Aneurysms can be of any size and shape and most commonly are found at the anterior or posterior communicating cerebral arteries. Although magnetic resonance angiography is improving in diagnostic accuracy, routine catheter angiography is still considered the "gold standard" for diagnosis. We report a case in which an abnormal dilatation of the supraclinoid internal carotid artery was diagnosed as an aneurysm following catheter angiography; at surgery this area appeared normal.

Aneurysm↗
PubMed1990

Evidence that an abnormality in the glycoprotein Ib alpha gene is not the cause of abnormal platelet function in a family with classic Bernard-Soulier disease.

The underlying molecular basis for Bernard-Soulier Disease (BSD) is currently unknown. Platelets from patients with this autosomal recessive bleeding disorder have multiple abnormalities, including a markedly reduced von Willebrand factor-dependent adhesiveness due to a deficiency of the platelet membrane glycoprotein (GP) Ib/IX complex. In the present studies, we have used an intragenic restriction fragment length polymorphism (RFLP) for Taq I in the GPIb alpha gene to study linkage between this gene and the inheritance of BSD in a family with two affected siblings. Whereas the proband was heterozygous, showing both the 0.7 and 4.0 kb bands of this polymorphism (A/B), her affected brother was homozygous for the 0.7 kb band (A/A). Accordingly, these siblings did not inherit the same pair of GPIb alpha alleles from their parents. Additionally, one child of the proband was A/A, while the second studied child was A/B, with neither showing any evidence of BSD. No construct of heterozygosity or homozygosity for GPIb alpha alleles in this family is consistent with a model in which one or more defective GPIb alpha alleles could produce BSD. RFLP analysis with BamHI or HindIII showed entirely normal patterns in the patients, indicating the absence of any gross deletion of the GPIb alpha gene. GPIb alpha mRNA from patient platelets was reverse transcribed and subsequently amplified by the polymerase chain reaction, demonstrating the presence of GPIb alpha transcript. Furthermore, trace amounts of GPIb could be shown on the surface of patient platelets. Based on these results, a defect in the GPIb alpha gene is unlikely to be the cause of BSD in this family.

Base Sequence↗
PubMed1990

[Abnormal hormone values: do drugs play a role? Abnormal prolactin, TSH and thyroid hormone values].

Whenever abnormal hormone values are found in a patient, it is necessary to inquire whether medicaments may be implicated. Some of the mechanisms of drug induced hormonal alterations are presented, and drugs which affect and alter prolactin, TSH, thyroid hormones and (in brief) GH and ACTH are summarized and discussed for the non-specialist. Hyperprolactinemia is caused by estrogens, neuroleptics and other dopaminantagonists, antidepressants, opioids, reserpine, a-methyl-dopa, H2-receptor blockers, etc. Serum TSH is decreased by glucocorticoids, somatostatin, dopaminergic agents, a-adrenergic blockers, etc., and increased by neuroleptics and other dopamin antagonists, cimetidine, clomiphene, spironolactone, etc. Thyroid hormones are altered by agents which inhibit thyroid hormone synthesis or secretion (thionamides, some sulfonamides; lithium), which increase (estrogens, methadon) or decrease (androgens, glucocorticoids) the concentration of TBG (thyroxine binding globulin), which competitively inhibit thyroid hormone binding to TBG (salicylates, phenytoin, etc.), and which inhibit the conversion of T4 to T3 (beta-adrenergic blockers, amiodarone, glucocorticoids) or stimulate degradation or fecal excretion of thyroid hormones (rifampicin, phenytoin, carbamazepine). For some drugs, in particular those with multiple effects on one or several endocrine systems, the only safe test which definitely allows drug-induced hormonal disturbances to be confirmed or ruled out is withdrawal of the drug and repetition of the hormone measurement.

Adrenocorticotropic Hormone↗
PubMed1994

[Inherited abnormality of thyroxine-binding globulin: its gene abnormality and pathogenesis].

Inherited TBG abnormalities manifest complete deficiency (CD), partial deficiency (PD) or excess in blood. Analysis of the TBG gene revealed that all cases with CD and PD studied so far had mutations within the exon. A nucleotide substitution was found in each case of PD and one of three cases of CD. In two other cases of CD, there was a nucleotide deletion. By the transfection study, it was revealed that TBG-CD secretion was completely blocked due to an impaired transport from rough endoplasmic reticulum to Golgi apparatus. The cause of PD is also explained by a partial impairment of TBG secretion. However, a pathogenesis of TBG excess has not been clarified yet.

Humans↗
PubMed1992

[Maxillofacial and dental abnormalities in some multiple abnormality syndromes. "Cri du chat" syndrome, Wilms' tumor-aniridia syndrome; Sotos syndrome; Goldenhar syndrome].

The paper describes the maxillo-facial and dental anomalies observed in some chromosome and non-chromosome poly-malformative syndromes ("Cri du chat" syndrome; Wilms' tumour; Sotos' syndrome; Goldenhar's syndrome). The Authors emphasise the possibility of diagnosing these multiple deformity syndromes from maxillo-facial alterations in early infancy; anomalous tooth position and structure cal also be successfully treated immediately after the first appearance of teeth. This is a particularly promising field of pediatrics and preventive pediatric medicine.

Abnormalities, Multiple↗