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Results for “precision prevention”

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PubMed1986

Conjunctival oxygen tension and its relationship to arterial oxygen tension.

Using a miniaturized Clark electrode embedded in a polymethylmethacrylate eyepiece, we measured transconjunctival oxygen tension (PcjO2) in 5 healthy volunteer subjects at multiple levels of steady-state isocapnic hypoxia, normoxia, and hyperoxia. PcjO2 was linearly related to arterial oxygen tension (PaO2) as PaO2 ranged from 28 to 205 mm Hg (PcjO2 = 0.59 PaO2 + 0.36 mm Hg; r = 0.94; standard error of the estimate = 7.09 mm Hg). However, the relationships between PcjO2 and PaO2 varied significantly among subjects. Whereas the overall mean ratio of PcjO2 to PaO2 was 0.59, the mean ratio for subjects ranged from 0.47 to 0.79 and was significantly different among subjects (P less than 0.0001). The time response of the electrode to a step change in oxygen tension in vitro was exponential, with a 90% response time of 38 seconds after a lag of 3.7 seconds. The time responses to in vivo changes in oxygen tension were also exponential. From hypoxia to normoxia, 90% response time was 45.0 seconds after a lag of 5.1 seconds; from room air to hypoxia, 90% response time was 72.4 seconds after a lag of 30.3 seconds; from room air to hyperoxia, 90% response time was 87.2 seconds after a lag of 6.8 seconds. We conclude that, although PcjO2 measured by a miniaturized Clark electrode is linearly related to PaO2 in healthy subjects, variation in the relationship of PcjO2 to PaO2 among individuals will prevent precise estimation of PaO2 for any individual unless subject-specific calibration is performed.

Adult↗

PubMed1982

Relationship of transepithelial electrical potential to membrane potentials and conductance ratios in frog skin.

Previous studies in anuran epithelia have shown that, after clamping the transepithelial voltage in symmetrical sequences for 4-6 min there is near-constancy of the rate of active Na transport and the associated oxidative metabolism, with a near-linear potential dependence of both. Here we have investigated in frog skin the cellular electrophysiolgical events associated with voltage clamping (Vt = inside-outside potential). Increase and decrease of Vt produced converse effects, related directly to the magnitude of Vt. Hyperpolarization resulted in prompt decrease in inward transepithelial current It and increase in fractional outer membrane resistance fRo (as evaluated from small transient voltage perturbations) and in outer membrane potential Vo. Overshoot of Vo was followed by relaxation to a quasi-steady state in minutes. Changes in fRo were progressive, with half times of some 1-5 sec. Changes in transepithelial slope conductance gt were more variable, usually preventing precise evaluation of the outer and inner cell membrane conductances go and gi. Nevertheless, it was shown that go is related inversely to Vt and Vo. Presuming insensitivity of gi to Vt, the dependence of Go on Vo in the steady state much exceeds that predicted by the constant field equation. Apparent inconsistencies with earlier results of others may be attributable to differences in protocol and the complex dependence of go on Vo and/or cellular-current. In contrast to previous findings in tight epithelia at open circuit, differences in Vt were associated with substantial differences in fRo and inner membrane potential Vi. Hyperpolarization of Vt over ranges commonly employed in studies of active transport ad metabolism appears to increase significantly the electrochemical work per Na ion transported.

Animals↗

PubMed2000

Acute appendicitis in children: comparison of clinical diagnosis with ultrasound and CT imaging.

BACKGROUND: There is strong evidence that imaging with ultrasound and CT can be of substantial diagnostic value in the diagnosis of acute appendicitis in children, but there is limited information of the impact of imaging on the management of these patients and its possible effect on surgical findings. OBJECTIVE: We studied the impact of imaging in the management of acute appendicitis, in particular its effect on the rate of negative appendectomies and perforations. PATIENTS AND METHODS: We reviewed retrospectively the clinical records and imaging findings of 633 consecutive children and adolescents seen on an emergency basis with clinical suspicion of acute appendicitis. Two hundred seventy patients were operated upon on clinical evidence alone, while 360 were referred for US or CT, and occasionally both, because of doubtful clinical findings. RESULTS: Acute appendicitis was found in 237 of those on clinical grounds alone, 68 of whom had perforation and related complications. Thus the rate of negative exploration and the rate of perforation were13 % and 29 %, respectively. One hundred eighty-two patients had preoperative US (sensitivity 74 %, specificity 94 %), 119 had CT (sensitivity 84 %, specificity 99 %), and 59 had both US and CT (sensitivity 75 %, specificity 100 %, but often with interpretation at variance with each other). The rate of negative appendectomy and perforation was 8 % and 23 %, respectively, for US, 5 % and 54 % for CT, and 9 % and 71 % when both examinations were performed. There is no statistical significance between the rates of diagnostic performance of US, CT, or their combination, nor between the negative appendectomy rates of each group, but the rate of perforation was significantly higher when CT was performed, alone or after US. CONCLUSION: The retrospective nature of the study prevents precise definition of the clinical characteristics and selection criteria for diagnostic examinations that may contribute to the management of children with suspected acute appendicitis. It was designed, however, to reflect the diagnostic approach and management of these patients, under the care of many decision makers and interpreters of imaging examinations, prevalent today in most hospital-based clinical practices. It is suggested that imaging increases diagnostic accuracy in difficult cases, but it might be one of the factors increasing the rate of perforations.

Acute Disease↗

PubMed2026

A genetic signal at 8q12.3 modulates GGT levels via the Runx1-CYP7B1 axis in female ethnic minorities from Guizhou.

Gamma-glutamyl transferase (GGT) regarded as a biomarker of liver dysfunction or excessive alcohol consumption; however, existing genome-wide association studies (GWAS) have been conducted predominantly in European populations and East Asian populations from Japan and the Taiwan region, with limited investigation in ethnic minorities from Guizhou Province. Previous genetic studies have demonstrated that Guizhou ethnic minorities share an East Asian genetic background while exhibiting specific genetic structures, a pattern that is also confirmed by our principal component analysis (PCA) results. We therefore performed a GWAS in this population and identified a genome-wide significant signal at 8q12.3 in female ethnic minorities from Guizhou. Fine-mapping and functional annotation analyses suggest that a regulatory pathway involving Runt-related transcription factor 1 (Runx1)-Cytochrome P450 family 7 subfamily B member 1 (CYP7B1)-cholesterol-reactive oxygen species (ROS)-glutathione (GSH) may contribute to the regulation of GGT levels. Mendelian randomization (MR) analyses further supported a causal relationship between GGT levels and autoimmune hepatitis (AIH). These findings uncover a genetic mechanism underlying GGT variation at 8q12.3 in female ethnic minorities from Guizhou, implicating a pathway linked to cholesterol metabolism and oxidative stress, and providing potential targets and insights for precision prevention and treatment of related diseases.

Female↗

PubMed1999

Intrahepatic cholangiocarcinoma in Taiwan.

We report our experience of the surgical treatment of intrahepatic cholangiocarcinoma (ICC) in Taiwanese patients. A total of 162 patients with histologically proven ICC were treated of whom 106 (65. 4%) had associated hepatolithiasis. Patients with hepatolithiasis were in earlier stages than those without hepatolithiasis. Two-thirds of the patients with hepatolithiasis presented with acute cholangitis, and two-thirds of those without hepatolithiasis presented with hepatomegaly. The rate of hepatic resection was 29.6% (48 of 162), and these rates were 31.1% and 26.8% for the patients with and without hepatolithiasis, respectively. Ninety-three percent of the patients with hepatolithiasis underwent common bile duct exploration, compared with 18% of those without hepatolithiasis. The surgical mortality rates were 3.7% (6/162), for all patients, and 3. 8% and 3.6% for patients with and without hepatolithiasis, respectively. The morbidity rate was much higher in the patients with hepatolithiasis (37.7% vs 16.1%). The 1-, 3-, and 5-year survival rates were 35.5%, 20.5%, and 16.5% in the patients with hepatolithiasis and 27.2%, 8.8%, and 7.8% in those without hepatolithiasis. Concomitant hepatolithiasis prevented precise diagnosis preoperatively and precipitated biliary sepsis, which affected resectability and increased postoperative morbidity. Hepatolithiasis per se did not influence long-term survival.

Adult↗

PubMedDate not supplied

Developmental neurotoxicity of anticonvulsants: human and animal evidence on phenytoin.

Most epileptic women delivering children each year take anticonvulsants throughout pregnancy. The teratogenic potential of anticonvulsants is most notable for phenytoin, trimethadione, valproic acid, and carbamazepine. This review focuses on the human and animal evidence for the teratogenicity of phenytoin, with emphasis on neurobehavioral end points. The Fetal Hydantoin Syndrome (FHS) consists of craniofacial defects and any two of the following: pre/postnatal growth deficiency, limb defects, major malformations, and mental deficiency. Available data suggest a prevalence of FHS of 10-30% in infants of women ingesting 100-800 mg/kg of phenytoin during the first trimester or beyond. Unfortunately, data on neurobehavioral development in FHS children is limited. Animal models of FHS have been developed and those focusing on neurobehavioral effects are reviewed. Phenytoin produces multiple behavioral dysfunctions in rat offspring at subteratogenic and nongrowth retarding doses. These behaviorally teratogenic doses produce maternal serum phenytoin concentrations in rats comparable to those found in humans. The dysfunctions in rats are dose-dependent and exposure-period-dependent, but independent of nutritional, maternal rearing, or seizure disorder confounds. Effects include vestibular dysfunction, hyperactivity and deficits in learning and memory. General comparability between the human and animal findings for phenytoin are apparent, however, difficulties with existing studies prevent precise comparisons. Animal studies have not dealt satisfactorily with the potential contribution of epileptic disease state to the FHS, with fetal brain drug concentration determinations, a complete dose-effect range, effects in multiple species (although limited nonhuman primate data exist), site of CNS injury, and the comparability of end points assessed. Human studies have not dealt satisfactorily with issues of the need for prospective study designs, separation of the effects of different anticonvulsants, or adequate long-term follow-up of cases, especially with attention to neuropsychological assessment.

Abnormalities, Drug-Induced↗

PubMed2026

Genome-wide interactions with cadmium exposure in dysglycemia: Populational effects and molecular insights.

Dysglycemia is a complex metabolic disorder governed by the interplay between environmental exposures and genetic factors, yet the precise molecular mechanisms driving these gene-environment (G×E) interactions remains poorly understood. Here, we characterized the population-level landscape and molecular causality underlying the interactions between cadmium (Cd), a widespread environmental toxicant, and genetic susceptibility loci in dysglycemia. By conducting a Genome-wide Environmental Interaction (GWEI) study within a sub-cohort of the China National Human Biomonitoring (CNHBM) cohort (N = 1298), we identified 29 genetic risk loci that significantly interact with Cd burden to exacerbate elevated fasting plasma glucose levels. Functional enrichment integrated with metabolomic profiling unmasked a profound multi-omics convergence, positioning epigenetic modifications (e.g. H3K27me3) and zinc-finger transcription factors (e.g. OVOL2, KLFs) as central regulatory hubs that disrupt metabolic homeostasis. To establish causality, we demonstrated that the rs11743277 A>T variant at the lead G×E locus functions as a Cd-responsive enhancer element, facilitating recruitment of TEAD3 and upregulating TICAM2 expression in CRISPR/Cas9-edited HepG2 cells, especially upon Cd exposure. This initiates a TICAM2-mediated inflammatory response, with elevated pro-inflammatory cytokines (IFN-β, TNF-α, IL-6) impairing downstream insulin signaling and glucose utilization. Collectively, these findings establish a robust paradigm for G×E interactions in complex metabolic disorders, revealing how environmental stressors reprogram genetic susceptibilities through molecular checkpoints and paving the way for tailored, precision-prevention strategies in environmental health.

CRISPR/Cas9 editing↗

PubMed1983

Threshold for retinal damage associated with the use of high-power neodymium-YAG lasers in the vitreous.

Ultrashort, Q-switched or mode-locked, neodymium-YAG laser pulses focused within 2 mm of the retina caused reproducible retinal damage in four eyes of two monkeys and in four eyes of three rabbits. The distance of the laser focus from the retina for clinically observed threshold retinal damage was characterized for pulse energies up to 9 mJ. For the 2- to 6-mJ pulse energies necessary to rupture vitreal membranes in clear media in rabbits, the high-power laser pulses could not be focused within 2 mm of the retina without substantial risk of damaging the underlying retina. These laser pulses did not rupture vitreal membranes in hazy ocular media that prevented precise focusing. The retinal damage was somewhat greater than expected for retinal absorption of 1.06-micron laser energy, suggesting that secondary effects such as self-focusing and shock waves emanating from the focus may be important.

Absorption↗

PubMedDate not supplied

Linkage mapping of a new syndromic form of X-linked mental retardation, MRXS7, associated with obesity.

A new syndromic form of X-linked mental retardation associated to obesity, MRXS7, has been localised to Xp11.3-Xq23 in a large Pakistani family. The ten affected males show clinical manifestations of mental retardation, obesity and hypogonadism. The family was genotyped by a set of microsatellite markers spaced at approximately 10 cM intervals on the X chromosome. Linkage to five adjacent microsatellite markers, mapping in the pericentromeric area, was established and a maximum two-point lod score of 3.86 was reached at zero recombination with marker DXS1106. Reduced recombination events around the centromere prevented precise mapping of the gene.

Adolescent↗

PubMed2001

Palliation of malignant gastric outlet obstruction after oesophagectomy by percutaneous transthoracic placement of an expanding metal stent.

Self-expanding stents can be used in the palliative management of strictures in the oesophagus, gastric outlet, bile duct and lower gastrointentinal tract [1-4]. Successful stent deployment depends on satisfactory positioning of the assembly device across the stricture. Previous reconstructive surgery may prevent precise endoscopic stent placement. This case report describes percutaneous transthoracic stenting of gastric outlet obstruction due to malignant external compression three years after oesophagectomy. Lyburn, I. (2001). Clinical Radiology56, 82-83.

Esophageal Neoplasms↗

PubMed2001

Location, size and morphological characteristics of left atrial thrombi as assessed by echocardiography in patients with rheumatic mitral valve disease.

AIMS: This study aimed to assess the use of transthoracic and transoesophageal echocardiography in diagnosing the thrombi located in the left atrium and/or left atrial appendage in patients with rheumatic mitral valve disease, and to investigate the characteristics of thrombi in comparison to intraoperative findings. METHODS AND RESULTS: The study group was comprised of 474 patients who underwent transthoracic and transoesophageal echocardiography prior to mitral valve surgery. Location, thickness and morphological characteristics of thrombi were determined by transoesophageal echocardiography. Intraoperative assessment disclosed left atrial thrombi in 105 patients. Thickness of thrombi < or = 1cm, and thrombi confined to left atrial appendage were associated with false-negative results by transthoracic echocardiography. However, diameter and morphological characteristics of thrombi, left atrial and left atrial appendage size, and the presence of the spontaneous echo contrast were not associated with the diagnosis of thrombi by transthoracic echocardiography. For overall left atrial thrombi, sensitivity and specificity of transthoracic echocardiography were 32%, and 94%, respectively. Sensitivity and specificity of transoesophageal echocardiography for thrombi in the left atrial appendage were 98%, and 98%, for thrombi in the main left atrial cavity were 81%, and 99%, and for thrombi located in both left atrium and appendage cavities were 100%, and 100%, respectively. CONCLUSION: In patients with rheumatic mitral valve disease, detection of left atrial thrombi by transthoracic echocardiography seems to be determined by thickness and location of thrombi. The multilobed structure of the left atrial appendage and artifacts over posterior wall of the left atrium may still prevent precise diagnosis even with transoesophageal echocardiography.

Adult↗

PubMed1999

Heart rate variability in the neonate and infant: analytical methods, physiological and clinical observations.

Naturally occurring oscillations in heart rate have long been considered to reflect the modulating influences of the autonomic nervous system. Individual reports of heart rate variability in healthy and sick neonates and infants have provided valuable information as to pathophysiological changes in autonomic cardiovascular control. It is evident that prematurity and poor health are reflected in attenuated heart rate variability. However, at present, there are few standard criteria for the analysis of heart rate variability, preventing precise comparisons among the various studies. Until recommendations for standardized analytical methods are made, clinical application of heart rate variability in neonatal and infant prognosis and therapy remains premature.

Asphyxia Neonatorum↗

PubMed2025

Sex as a modifier of genetic risk for type 1 diabetes.

Sex differences influence the pathogenesis of type 1 diabetes (T1D), yet most genetic studies have treated sex as a control covariate rather than a dynamic effect modifier. Sex influences immune cell behaviour, including CD4+ and CD8+ T cell activation, regulatory T cell stability, B cell autoantibody production, dendritic cell priming and monocyte/macrophage inflammation. Underlying mechanisms include hormone-responsive enhancers, X-escape gene dosage and sex-biassed chromatin states, intersecting with T1D-associated variants to produce sex-specific immune phenotypes. These insights help explain regional variation in sex ratios of T1D incidence, such as male predominance in high-risk populations and female excess in low-risk populations. Biological sex shapes T1D risk across multiple layers, including polygenic load; environmental exposures such as vitamin D deficiency and enteroviral infection; and sex-specific hormonal, chromosomal and epigenetic influences. An integrative G × E × S (genetic × environmental × sex-specific) liability-threshold framework is thus supported. Clinical and translational implications include developing sex-specific polygenic risk scores, biomarker panels and interventional strategies targeting pathways such as hormone signalling, vitamin D metabolism and the microbiome. Future multi-omic, longitudinal studies are warranted to test genotype-sex interactions, integrate sex as a core effect modifier and enable precision prevention and treatment of T1D in both males and females.

Humans↗

PubMed2026

Unveiling the BMI Risk Threshold for Osteoarthritis: Multi-Database Causal and Nonlinear Evidence.

OBJECTIVE: To characterize the nonlinear relationship between BMI and osteoarthritis (OA), and to identify BMI thresholds that inform precise prevention strategies. METHODS: This multi-database study integrated Global burden of disease 2021, National Health and Nutrition Examination Survey 2007-2018, and Genome-Wide Association Studies. A generalized additive model was performed to visualize the BMI-OA relationship, adjusting for multiple confounders. We applied segmented logistic regression models to identify potential threshold effects and used Mendelian randomization to estimate the causal effects of BMI on OA subtypes. RESULTS: From 1990 to 2021, the age-standardized prevalence and years lived with disability rates for OA were highest in regions with high SDI. OA prevalence rose nonlinearly with BMI, with breakpoints at 24.00 and 41.58 kg/m2. Each unit increase in BMI was associated with higher odds of OA between 24.00 and 41.58 kg/m2 (OR = 1.022, 95% CI: 1.003-1.041) and above 41.58 kg/m2 (OR = 1.055, 95% CI: 1.022-1.090). Women and individuals aged ≥ 45 years exhibited a higher susceptibility to knee osteoarthritis. BMI was causally associated with knee osteoarthritis (OR = 1.63, 95% CI 1.50-1.77) and hip osteoarthritis (OR = 1.54, 95% CI 1.40-1.70). CONCLUSIONS: These findings suggest that OA risk awareness and weight-management strategies should begin before BMI reaches the high range, particularly among individuals with BMI exceeding 24.00 kg/m2.

Humans↗

PubMed1991

Modified PCR-RFLP method for HLA-DPB1 and -DQA1 genotyping.

We previously developed a new technique for HLA class II genotyping by digestion of polymerase chain reaction-amplified genes with restriction endonucleases (PCR-RFLP method). This PCR-RFLP method is an efficient and convenient typing technique for class II alleles. However, small fragments or bands located close to each other on polyacrylamide gels sometimes prevent precise analysis of the RFLP bands. Furthermore, the restriction enzymes we have reported in the previous papers are not sufficient to identify the genotypes of all heterozygous individuals. Here, we report an improved PCR-RFLP method using some informative restriction enzymes which have either a single cleavage site or, alternatively, no cleavage site in the amplified DNA region, depending on the HLA alleles, making reading of RFLP band patterns much easier. Each second exon of the HLA-DQA1 or -DPB1 gene was selectively amplified from genomic DNAs of 70 HLA-homozygous B-cell lines and 100 healthy Japanese by PCR. Amplified DNAs were digested with restriction endonucleases and then subjected to electrophoresis assaying simply for cutting, or no cutting, of the DNA. ApaLI, HphI, BsaJI, FokI, MboII and Mn1I can discriminate eight alleles of the DQA1 gene. Similarly 19 alleles of the DPB1 gene can be discriminated with Bsp1286I, FokI, DdeI, BsaJI, BssHII, Cfr13I, RsaI, EcoNI, and AvaII enzymes. This modified PCR-RFLP method can be successfully applied to heterozygotes. Thus, the method is technically simpler and more practical for routine HLA typing work than our previous PCR-RFLP method.

Alleles↗

PubMed1971

Effects of brief separation from mother on rhesus monkeys.

To summarize, data on the course of development of mother-infant relations in rhesus monkeys have been presented; a method for teasing apart the relative roles of mother and infant in causing changes or differences in the interaction described; and the complexity of the social nexus, within which the relationship is set, stressed. When the mother is removed for a few days, the infant calls a great deal at first and then shows depressed locomotor and play activity. These symptoms may last for a month after the mother's return. Simple tests given 6 months and even 2 years later strongly suggest that the differences (between infants that have had such a separation experience and infants that have not) are persistent. Are these data relevant to the human case? The rhesus monkey has no verbal language and a much less complex social development than man. Furthermore, its social environment is quite different from that found in any human culture. Parallels between monkey and man must therefore be scrutinized carefully before being used as a basis for generalization. But the facts show that a brief separation experience produces in rhesus monkey infants symptoms that are very similar (except for the apparent absence of a "phase of detachment" on reunion) to those in human infants (25). While age of separation, within the rather narrow limits used here, was a variable of minor importance, the effects of the separation varied, as in the human case, with the length of the separation experience and the sex of the infant. Differences in the techniques of experimenters, as well as differences in the species, prevent precise comparisons of the roles of the mother-infant relationships; nevertheless, the nature of the relationship appears to be an important variable in both monkey and man. There would seem, therefore, to be strong reasons for thinking that we are dealing with comparable phenomena. If that is the case, the fact that monkeys function at a simpler conceptual level than man limits the complexity of the explanatory hypotheses necessary in the human case. In addition, the finding that such a brief separation experience, involving removal of the mother but no exposure to a strange environment, can produce effects lasting for months or years in rhesus monkeys strengthens the evidence that long-term effects may occur also in man. Finally, this analysis provides bases for attempts to predict individual differences in the effects of a period of separation on rhesus infants, and the parallels with man suggest that examination of the same variables in the human case would be worthwhile.

Animals↗

PubMed1979

Heart muscle mechanics.

The goal implicit in the research reviewed above is to describe the contractile behavior of heart muscle in terms of crossbridge and filament behavior. It is necessary to elucidate these details in cardiac muscle because of the distinct biochemical differences between skeletal and cardiac myosin. As is evident in this review, significant advances have been made toward describing unique mechanical properties of cardiac muscle crossbridges. Several major problems now require attention: (a) Activation parameters are labile, making mechanical measurements sensitive to measurement perturbation; (b) significant structural inhomogeneities at the cellular and sarcomere level prevent precise assignment of externally measured force to internal structures (force generators, passive elements) within whole cardiac muscle and individual cells; (c) high resting stiffness and forces of poorly understood origin and properties confound attempts to interpret force measurements and dynamics. The differences between heart and skeletal muscle myosin may provide the means for identifying structural counterparts of the Huxley-Simmons model (33); they may also be useful in evaluating the electrostatic and quantum-mechanical models.

Adenosine Triphosphatases↗

PubMed1994

The role of drug treatment in variceal bleeding.

Pharmacological management of acute variceal hemorrhage appears to be effective in patients with liver cirrhosis. Somatostatin and presumably its longer-acting analog, octreotide, are more efficient and safer than other vasoconstrictors like vasopressin, terlipressin or their combination with nitroglycerin. Drug treatment, however, usually represents only a valuable adjunct to other measures to stop bleeding such as endoscopic variceal sclerotherapy. Prophylaxis of first bleeding by beta-blockade appears justified in patients at a high risk of bleeding which still has to be defined more precisely. Prevention of recurrent hemorrhage can be effective in some but not in all of the patients with liver cirrhosis and a first bleeding episode. Treatment of patients with good liver function under direct control of the wedged hepatic vein pressure gradient presumably will reduce the failure rate of prophylaxis with beta-blockade.

Esophageal and Gastric Varices↗