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At least 73 records · Page 4Linked to original sources
PubMed1977

Unexplained hyperinsulinemia in normal and "prediabetic" Pima Indians compared with normal Caucasians. An example of racial differences in insulin secretion.

The pattern of insulin response to oral and/or intravenous glucose has been claimed to be characteristic of diabetes and even prediabetes. To determine if differences in insluin secretion might explain the exceptionally high prevalence of diabetes in the Pima Indians, 26 genetically normal Pimas (nondiabetic offspring of nondiabetic parents), 32 genetically prediabetic Pimas (nondiabetic offspring of diabetic parents), 10 diabetic Pimas, and 29 normal Caucasians were studied. All subjects received an intravenous glucose tolerance test (IVGTT) to examine the acute-phase insulin response, and all nondiabetic subjects received an oral glucose tolerance test (OGTT) and arginine infusion (AI). The prediabetics also received a cortisone-primed oral glucose tolerance test (CGTT) and were classified by the result of this test. While acute-phase insulin release during the IVGTT was absent in the diabetics, there was a rapid response in all nondiabetics. Prediabetic Pimas with normal or abnormal CGTT had insulin levels similar to normal Indians during the IVGTT, OGTT, and AI. Thus, no evidence of impairment of acute- or late-phase insulin release was found. The normal and prediabetic Indians had fasting and stimulated insulin levels during all the tests two-to-threefold greater than the Caucasians. Differences in insulin levels between the two races could not be explained by differences in glucose level, age, or obesity.

Adolescent↗
PubMedDate not supplied

Immunohistochemical evidence that angiotensins I and II are formed by intracellular mechanism in juxtaglomerular cells.

The existence of angiotensin II (AII) immunoreactivity in juxtaglomerular (JG) cells of rat kidney, which has been demonstrated previously by immunohistochemical studies, can be explained either as the product of intracellular synthesis or by the internalization of receptor-bound AII originating in plasma. To resolve these two alternative mechanisms, attempts were made to identify AI in JG cells of rat kidney by immunohistochemical staining using specific antibodies to AI. Although AI-like immunoreactivity was not detected in normal rat kidney, rats treated with the angiotensin-converting enzyme inhibitors, MK-421 or captopril, showed AI-like immunoreactivity in JG cells. The presence of renin and AII-like immunoreactivity was demonstrated in the same cells by specific antibodies to respective antigens used on adjacent serial sections. These findings support an intracellular mechanism of the formation of AII and suggest an intracellular renin angiotensin system, presumably separate from the extracellular system.

Angiotensin I↗
PubMed1985

Changes in human high density lipoproteins in patients with extra-hepatic biliary obstruction.

Plasma high density lipoproteins (HDL) from patients with obstruction of the common bile duct were studied by crossed immunoelectrophoresis and isoelectric focusing. All cholestatic HDL fractions were rich in phospholipids (51.5 +/- 9%) with high proportions of free cholesterol (13.8 +/- 1.5%). Moreover, crossed immunoelectrophoresis of sera against anti-Apo A revealed the presence of multiple immunoprecipitates sharply contrasting with the pattern formed by normal sera. Tandem crossed immunoelectrophoresis against anti-Apo A and anti-Apo B was performed with whole serum and with the HDL fraction from various cholestatic subjects. Crossed identity was observed for two of these precipitates, which could be explained by the decrease in HDL stability due to the detergent effect of bile salts. The most noteworthy changes found in cholestatic patients appeared to be the apolipoprotein pattern of HDL. Both Apo AI (48%) and Apo AII (5.5%) were greatly diminished and Apo E was present in remarkably high amounts (39%) with two additional isoforms (Apo E'1 and Apo E'2).

Apolipoproteins A↗
PubMed1982

Manipulation of thrombus formation in the hamster cheek pouch with drugs that interact with PGI2 in vitro.

A single platelet thrombus was formed in an arteriole of the hamster cheek pouch by electrical stimulation followed by topical application of ADP. The sizes of the thrombi were continuously recorded with a photocell placed on a TV monitor screen and quantified by areas on the record. Repeated application of small doses of ADP (5-15 nmole/10 microliters) resulted in very reproducible formation of the thrombi, and the size of the thrombi was reduced dose-dependently by topical application of PGI2. Three drugs were tested in this model. Cyclooxygenase inhibitor (indomethacin 10 mg/kg, i.p.) increased the formation of thrombi, while a smaller dose (3 mg/kg) did not have any significant effect. This could be explained by inhibition of the generation of endogenous PGI2, since aggregation of hamster platelets by ADP was not inhibited by indomethacin in vitro. EG-626 (phthalazinol, a phosphodiesterase inhibitor) (300 mg/kg, i.p.) decreased the size of thrombus. AI-122 (1.0 mg/kg, i.p.), which has been proven to enhance PGI2 biosynthesis from isolated rat aortae, also decreased the formation. Thus, drugs such as EG-626 or AI-122 are quite promising as anti-thrombotic drugs.

Adenosine Diphosphate↗
PubMed1992

The von Rosen splint compared with the Frejka pillow. A study of 408 neonatally unstable hips.

101 children in Tromsö, Norway, treated with the Frejka pillow for 4.5 months because of neonatal hip instability (NHI) were compared with 307 children in Malmö, Sweden, treated with the von Rosen splint for 3 months. The pelvic radiographs, taken when the treatment was terminated, were assessed by the acetabular index (AI) and the cases of failure were evaluated. The AI showed no difference between the two groups. The Frejka group had 4 patients who received further treatment because of remaining acetabular dysplasia and/or subluxation while the von Rosen group had none. The difference in risk of failure might partly be explained by different criteria for failure.

Female↗
PubMed1992

Plasma lipid changes in psoriatic children.

Plasma lipid, lipoprotein and apoprotein concentrations were determined in psoriatic children and in healthy controls. The plasma total cholesterol (TC) was higher than in controls (p = 0.03). The higher cholesterol levels were explained by an almost significant increase in cholesterol associated with high-density lipoproteins and by the tendency towards higher values of cholesterol associated with low-density lipoproteins and very-low-density lipoproteins. No significant changes of plasma triglycerides were observed. Levels of apoproteins (apo) AI and apo B were not significantly different in psoriatic children; however, the levels of apo B were correlated differently with plasma TC in psoriatic children, and the ratio TC/apo B was significantly increased in patients with respect to the controls, suggesting some differences of plasma lipoprotein lipid/apoprotein relationship in psoriasis.

Adolescent↗
PubMed1984

Adult erotosexual status and fetal hormonal masculinization and demasculinization: 46,XX congenital virilizing adrenal hyperplasia and 46,XY androgen-insensitivity syndrome compared.

Among 30 young women with a history of the treated adrenogenital syndrome (CVAH), 11 (37%) rated themselves as bisexual or homosexual. Among a control group consisting of 15 women with the 46,XY androgen-insensitivity syndrome (AIS) plus 12 with the Rokitansky syndrome (MRKS), the corresponding figure was 2 (7%), both bisexual. Chi-square was significant beyond the 0.01 level. In Kinsey's 1953 sample 15% of women experienced homoerotic arousal imagery by age 20, and 10% had had homoerotic partner contact. The most likely hypothesis to explain the CVAH findings is that of a prenatal and/or neonatal masculinizing effect on sexual dimorphism of the brain in interaction with other developmental variables.

Adrenal Hyperplasia, Congenital↗
PubMed1985

Apolipoprotein AIMilano. Accelerated binding and dissociation from lipids of a human apolipoprotein variant.

The lipid binding properties of apolipoprotein (apo) AIMilano, a molecular variant of human apolipoprotein AI, characterized by the Arg173----Cys substitution, was investigated by the use of dimyristoylphosphatidylcholine liposomes. Both the variant AIMilano and normal AI are incorporated to the same extent in stable complexes isolated by gel filtration, showing similar dimensions and stoichiometries. A higher affinity of apo-AIMilano for dimyristoylphosphatidylcholine is suggested by the faster association rate of the variant apoprotein compared to normal AI; similarly, apo-AIMilano is more readily displaced by guanidine hydrochloride from the isolated dimyristoylphosphatidylcholine-apoprotein complexes. When the secondary structure of apo-AIMilano was investigated by spectrofluoroscopy and circular dichroism, a higher fluorescence peak wavelength and a lower alpha-helical content were detected in the variant apoprotein compared to normal AI. The substitution Arg173----Cys in the AIMilano dramatically alters the amphipathic nature of the modified alpha-helical fragment of apoprotein AI. The association rate with lipids is accelerated by an increased exposure of hydrophobic residues. The reduced stability of the lipid-apoprotein particles is possibly mediated by a reduction in the number of helical segments involved in lipid association. The high flexibility of the AIMilano apolipoprotein in the interaction with lipids may explain its accelerated catabolism and the possibly improved uptake capacities for tissue lipids.

Amino Acid Sequence↗
PubMed1987

Rebinding and relaxation in the myoglobin pocket.

The infrared stretching bands of carboxymyoglobin (MbCO) and the rebinding of CO to Mb after photodissociation have been studied in the temperature range 10-300 K in a variety of solvents. Four stretching bands imply that MbCO can exist in four substates, A0-A3. The temperature dependences of the intensities of the four bands yield the relative binding enthalpies and and entropies. The integrated absorbances and pH dependences of the bands permit identification of the substates with the conformations observed in the X-ray data (Kuriyan et al., J. Mol. Biol. 192 (1986) 133). At low pH, A0 is hydrogen-bonded to His E7. The substates A0-A3 interconvert above about 180 K in a 75% glycerol/water solvent and above 270 K in buffered water. No major interconversion is seen at any temperature if MbCO is embedded in a solid polyvinyl alcohol matrix. The dependence of the transition on solvent characteristics is explained as a slaved glass transition. After photodissociation at low temperature the CO is in the heme pocket B. The resulting CO stretching bands which are identified as B substates are blue-shifted from those of the A substates. At 40 K, rebinding after flash photolysis has been studied in the Soret, the near-infrared, and the integrated A and B substates. All data lie on the same rebinding curve and demonstrate that rebinding is nonexponential in time from at least 100 ns to 100 ks. No evidence for discrete exponentials is found. Flash photolysis with monitoring in the infrared region shows four different pathways within the pocket B to the bound substates Ai. Rebinding in each of the four pathways B----A is nonexponential in time to at least 10 ks and the four pathways have different kinetics below 180 K. From the time and temperature dependence of the rebinding, activation enthalpy distributions g(HBA) and preexponentials ABA are extracted. No pumping from one A substate to another, or one B substate to another, is observed below the transition temperature of about 180 K. If MbCO is exposed to intense white light for 10-10(3) s before being fully photolyzed by a laser flash, the amplitude of the long-lived states increases. The effect is explained in terms of a hierarchy of substates and substate symmetry breaking. The characteristics of the CO stretching bands and of the rebinding processes in the heme pocket depend strongly on the external parameters of solvent, pH and pressure. This sensitivity suggests possible control mechanisms for protein reactions.

Carbon Monoxide↗
PubMed2026

Postzygotic biallelic inactivation of FDFT1 underlies solitary lesion formation in porokeratosis of Mibelli.

BACKGROUND: Porokeratosis reflects clonal expansion of keratinocytes with biallelic inactivation of mevalonate-cholesterol biosynthesis pathway genes. In disseminated porokeratosis (DP), lesions arise through independent somatic second hits in carriers of heterozygous germline pathogenic variants, whereas porokeratosis of Mibelli (PM) is usually solitary, and its molecular basis remains incompletely defined. OBJECTIVE: To elucidate the molecular basis of solitary PM. METHODS: We analyzed blood and lesional epidermis from seven patients with solitary PM within a 156-patient porokeratosis cohort using deep sequencing, copy-number/SNP profiling, and methylation analysis. RESULTS: Solitary PM plaques were larger and more irregular than the annular DP lesions. No pathogenic germline variants were detected in MVK, PMVK, MVD, FDPS, or FDFT1. Three patients had somatic biallelic genetic inactivation of FDFT1 through putative deleterious variants and/or focal microdeletions. The remaining four showed FDFT1 promoter hypermethylation with loss of heterozygosity (LOH) at the FDFT1 locus due to copy-neutral LOH or a monoallelic 8p deletion, consistent with early monoallelic epigenetic silencing, followed by genetic loss of the remaining active allele. In one patient, part of the plaque expanded centrifugally over 7.5 years. CONCLUSION: Solitary PM can be driven by postzygotic, lesion-restricted, biallelic inactivation of FDFT1 through genetic or epigenetic mechanisms within a single epidermal clone, promoting clonal expansion. This model may explain the tendency toward solitary PM lesions. The low probability of acquiring postzygotic biallelic inactivation without germline predisposition may underlie solitary PM and suggest a low recurrence risk for offspring, unlike DP driven by germline heterozygosity.

General dermatology↗
PubMedDate not supplied

The number and sizes of reconstructed peripheral autonomic, sensory and motor neurons in a case or dysautonomia.

Motor, spinal ganglion, intermediolateral and sympathetic trunk neurons were reconstructed by morphometric sampling of their cell bodies at L5 and T7 segments and at various levels of spinal roots and peripheral nerves in a 31-year-old patient with dysautonomia and compared to reference cases. The patient had strikingly fewer intermediate motoneuron column neurons and intermediate ventral root axons (probably gamma motoneurons), spinal ganglion neurons, preganglionic autonomic neurons and sympathetic trunk neurons that did controls (approximately 10--30% of reference values). The striking agreement between selective absence of intermediate-diameter cytons (Ci) and of intermediate diameter myelinated fibers (Ai), which are thought to be gamma efferent, of L5 motoneuron columns provides further confirmation to our previous suggestion that the Ci peak of motoneuron columns are somas of gamma efferent neurons. The number and size of alpha motoneuron cell bodies and their proximal axons were like those of controls but their distal axons were probably atrophic. This finding probably explains the small reduction in maximum conduction velocity of motor nerve fibers found in this disorder. The brunt of the pathologic process in this disorder has been borne by intermediate and small neurons preferentially.

Adult↗
PubMed1983

Quantitative structure--activity relationship of double alkyl chain drugs.

The quantitative structure--activity relationship of double alkyl chain drugs, including alkanols, aliphatic esters, ketones, barbiturates, amphetamines, butyrylcholinesterase inhibitors, antimalarials, and rifamycin amides, is investigated. A series of double-chain homologues, CnH2n+1XCmH2m+1, in which n changes, keeping m constant, is classified into three types: in type IIL, n greater than m; in type IIE, n = m; in type IIS, n less than m. When a linear relationship, vis., log (1/C) = an + b, holds, the slope a depends on the type; aI greater than or equal to aIIL greater than aIIE greater than aIIS. Here aI means the slope for single-chain homologues. The same order is observed for the equation, log hydrophobicity = an + b, where the hydrophobicity of drug denotes the water solubility, the critical micelle concentration, and the partition coefficient for the 1-octanol--water phases. Therefore, decreased biological activity of a double-chain drug relative to that of a single-chain isomer can be explained by a decreased hydrophobicity of the double-chain drug, due to the intramolecular association of these chains in water. When a parabolic relationship between log (1/C) and n holds, the optimum n depends on the type: nopI less than nopIIL less than nopIIE. This order is also explicable on the basis of a decreased hydrophobicity of double-chain drug. The N-dealklation rate of amphetamines in vivo appears to be affected by the steric factor as well as the hydrophobic factor. A decreased hydrophobicity of double-chain compounds should be taken into consideration for estimating their partition coefficients.

Alkylation↗
PubMed2026

Artificial Intelligence-Driven Multi-Omics Analysis Reveals Hydroxytyrosol Targeting of the TXNIP-NLRP3 Inflammasome Axis in Traumatic Brain Injury.

Traumatic brain injury (TBI) induces secondary neuroinflammation driven by oxidative stress, inflammasome activation, and immune remodeling, yet specific mechanism-guided pharmacological interventions remain limited. This study established an artificial intelligence (AI)-integrated network pharmacology and multi-omics framework to evaluate whether hydroxytyrosol (HT), an olive-derived natural polyphenol, may regulate TBI-related neuroinflammatory targets centered on the TXNIP/NLRP3 inflammasome axis. Starting from the SMILES structure of HT, potential targets were predicted using PharmMapper, SwissTargetPrediction, and the Similarity Ensemble Approach and were standardized to UniProt identifiers. TBI-associated genes were integrated from GeneCards, DisGeNET, OMIM, and the Therapeutic Target Database. The overlapping target set was analyzed using STRING-based protein-protein interaction (PPI) networks, MCODE, CytoHubba, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Public GEO transcriptomic datasets (GSE123831 and GSE104687) were used for cross-platform expression validation, differential expression analysis, and exploratory CIBERSORT-based immune infiltration estimation. Random forest (RF), multilayer perceptron (MLP), graph convolutional network (GCN), graph attention network (GAT), SHAP/LIME explainability analysis, LASSO inflammatory-risk scoring, and two-sample Mendelian randomization (MR) were further applied for target prioritization, immune phenotype mapping, and genetic association analysis. Seventy-three overlapping HT-TBI targets were identified. PPI and topology analyses prioritized TXNIP, NLRP3, CASP1, MAPK1, and TP53 as key hubs enriched in inflammasome activation, oxidative stress, apoptosis, and NOD-like receptor signaling. TXNIP, NLRP3, and CASP1 were consistently upregulated in both TBI transcriptomic datasets. LM22-based immune deconvolution suggested increased pro-inflammatory immune signatures and a positive TXNIP-M1 macrophage association (r&#x202f;=&#x202f;0.63, p < 0.001), which should be interpreted as a transcriptome-derived hypothesis rather than validated murine immune-cell proportions. AI-based models consistently ranked TXNIP/NLRP3 as high-contribution features under internal validation, and removal of these targets reduced model performance. A five-gene inflammatory score achieved an internally evaluated AUC of 0.87, while two-sample MR supported positive genetic associations involving TXNIP expression, TBI risk, NLRP3 and IL-1&#x3b2; expression. Collectively, these findings prioritize the TXNIP/NLRP3/CASP1 module as a computationally supported candidate mechanism through which HT may influence oxidative stress-inflammasome-immune coupling in TBI. This study provides an interpretable drug-target-pathway-phenotype framework and identifies TXNIP, NLRP3, and CASP1 as priority nodes for future experimental validation.

Artificial Intelligence↗
PubMed1992

Patterns of association between genetic variability in apolipoprotein (apo) B, apo AI-CIII-AIV, and cholesterol ester transfer protein gene regions and quantitative variation in lipid and lipoprotein traits: influence of gender and exogenous hormones.

Patterns of RFLP association were studied, to identify gene regions influencing quantitative variation in lipid and lipoprotein traits (coronary artery disease [CAD] risk factors or metabolically related traits). Subjects (118 female and 229 male; age 20-59 years) were selected for health. Multiple RFLPs were used to sample variability in regions around genes for apolipoprotein (apo) B (restriction enzymes HincII, PvuII, EcoRI, and XbaI), apo AI-CIII-AIV (BamHI, XmnI, TaqI, PstI, SstI, and PvuII) and cholesterol ester transfer protein (TaqI). Separate analyses were done by gender. The sample was truncated at mean +/- 4 SD, to remove extreme outliers. There was no significant gender difference in RFLP genotype frequency distribution. After trait-level adjustment to maximize removal of concomitant variability, analysis of variance was used to estimate the percentage trait phenotypic variance explained by measured variability in the gene regions studied. Fewer gene regions were involved in men, with less influence on quantitative trait variation than in women, in whom hormone use affected association patterns. Gender differences imply that pooling genders or adjusting data for gender effects removes genetic information and should be avoided. The association patterns show that variability around the candidate genes modulates trait levels: the genes are contributors to the genetics of CAD risk variables in a healthy sample.

Adult↗
PubMed1992

Effect of simvastatin on high density lipoprotein subfractions and apolipoproteins in type IIa hypercholesterolemia.

Changes in plasma concentrations of high density lipoproteins (HDL) and triglycerides may partly explain the ability of cholesterol-lowering drugs to decrease the incidence of coronary heart disease. We measured the response of fasting plasma lipids, lipoproteins, and apolipoproteins in 46 subjects with Type IIa hypercholesterolemia treated with simvastatin for 3 months. The initial dose of simvastatin (10 mg/day) was subsequently increased up to 40 mg/day if the plasma cholesterol concentration had not fallen below 5.2 mmol/l. Plasma concentrations of HDL cholesterol and of the apolipoproteins AI and AII were increased by simvastatin. The increase in HDL cholesterol (9%) was due to increases in both subfractions (HDL2 17%; HDL3 7%), changes that would be consistent with a beneficial effect on cardiovascular risk. Simvastatin decreased plasma triglyceride concentrations by 25%. Plasma total cholesterol concentrations fell by 35% after 3 months of treatment; this fall was proportional to the initial concentration and was due almost entirely to a 45% fall in low density lipoprotein cholesterol. In contrast, plasma concentrations of lipoprotein Lp(a) were not affected by simvastatin.

Anticholesteremic Agents↗
PubMed1986

Biochemical markers in a porcine model of adult respiratory distress syndrome induced by endotoxemia.

To evaluate the influence of a continuous endotoxin infusion on different hematological and biochemical variables which might underlie endotoxin-induced ARDS we investigated 2 groups of pigs, one with and one without endotoxin. Complement activation - both via the classical and alternative pathways -- antithrombin III, (AI-III) factor VIII-related antigen and fibronectin levels could not precisely predict the development of ARDS in the individual animal. It was found, however, that the animals which reacted with a severe endotoxin-induced pulmonary dysfunction (pulmonary responders) had significantly higher levels of complement of both the classical and alternative pathways, greater concentrations of AT-III and factor VIII-related antigen and higher fibronectin levels. These findings might probably be explained by a greater reactivity, i.e. synthesis and release, of these biochemical components in the animals which responded with a severe pulmonary reaction, a phenomenon which probably concealed the consumption. A greater "reactivity" regarding the drop in polymorphonuclear cell count was found in pulmonary responders; a phenomenon which, however, was not compensated for by increased production. A finding of presumably great clinical importance was that animals surviving the observation period had significantly higher levels of fibronectin already at baseline and throughout the observation period.

Animals↗
PubMed1981

[The detection of apolipoproteins AI and B in the liver of patients with and without hyperlipoproteinemia (author's transl)].

Liver sections as well as isolated liver cells from 5 patients with a normal liver and normal serum lipids and patients with familial hyperlipoproteinemia type IIa (n=6), type IIb (n=11), type IV (n=13) and type V (n=2) were studied for the presence of apolipoprotein (apo) AI and B by immunofluorescence technique. At the time of liver biopsy the actual serum concentrations of HDL- and LDL-cholesterol and triglycerides were determined. In patients without metabolic disturbances apo AI was detectable in hepatocytes in 2 out of 5 cases. Apo B was not found in the liver of these patients. The non-parenchymal liver cells did not show depositions of apoproteins. In the group of 32 patients with hyperlipoproteinemia 6 cases showed in the liver apo AI and 2 cases apo B. The apoproteins exhibited a granular fluorescence pattern in the cytoplasm of hepatocytes. There was no correlation between the apoproteins in the liver and the degree of fat depositions in hepatocytes or the concentrations of serum lipids. The results indicate that the fat droplets in hepatocytes of patients with hyperlipoproteinemia represent lipid particles free of apoproteins. The lack of apoproteins in the liver with elevation of lipids in serum can be explained with a disturbed hepatic clearance function for lipoproteins.

Adult↗
PubMedDate not supplied

SMR (simulating medical reasoning): an expert shell for non-AI experts.

SMR is an expert system shell designed to put the tools for knowledge acquisition directly into the hands of the domain expert. Since the knowledge base is represented as free text within a simplified syntactic structure, it is intelligible to anyone familiar with medical terminology. The knowledge base includes the rules for inference making as well as data groupings and protocols to facilitate case recording. In this paper, SMR is presented from the expert's point of view, describing the rule syntax and procedures for formulating the required diagnostic or therapeutic knowledge in the chosen domain. Similarly, the end-user's application of the system to patient data and the provisions for exploring and explaining the system's conclusions and reasoning processes are detailed. Avoiding tedious and often inane dialog, the user enters all that is known about the patient and receives a report of the system's conclusions and recommendations followed by a list of observations to be made in patient follow-up. An expert system for evaluating the diabetic patient is used to illustrate system operations.

Computer Simulation↗