Association between liver fibrosis and cognition in a nationally representative sample of older adults.

BACKGROUND AND PURPOSE: Liver fibrosis, a common yet often subclinical manifestation of chronic liver disease, may have an unrecognized role in cognitive impairment. We evaluated the association between a validated liver fibrosis index and cognitive measures among older adults. METHODS: We examined the association between liver fibrosis and cognitive performance among participants aged 60 years and older in the US National Health and Nutrition Examination Survey. Liver fibrosis was measured with the validated Fibrosis-4 (FIB-4) liver fibrosis score. The outcomes were performance on four standardized cognitive tests of immediate and delayed verbal learning, verbal fluency, and attention/concentration. We used linear regression to evaluate the association between FIB-4 score and performance on cognitive tests while adjusting for potential confounders. In sensitivity analyses, we examined this association in participants without known liver disease. RESULTS: Among 3217 adult participants, the mean age was 69 years, and 54% were women. Standard liver chemistries were largely in the normal range. However, 5.0% [95% confidence interval (CI) 4.0-6.0] had liver fibrosis based on a validated cut-off. In adjusted linear regression models, higher liver fibrosis scores were associated with worse immediate recall (ß -0.39; 95% CI -0.58, -0.21), language fluency (ß -0.46; 95% CI -0.72, -0.21), and attention/concentration (ß -1.34; 95% CI -2.25, -0.43), but not delayed recall (ß -0.10; 95% CI -0.20, 0.01). Results were similar when limiting the study population to participants without known clinical liver disease. CONCLUSION: Liver fibrosis, including subclinical liver fibrosis, may be an independent risk factor for cognitive impairment among older adults.

Efficacy and safety results of patients with HCV genotype 2 or 3 infection treated with ombitasvir/paritaprevir/ritonavir and sofosbuvir with or without ribavirin (QUARTZ II-III).

The efficacy and safety of an investigational combination of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) plus sofosbuvir (SOF) ± ribavirin (RBV) in patients with HCV genotype 2 or 3 infection with or without cirrhosis was evaluated. Patients with HCV genotype 3 infection without cirrhosis were randomized to receive OBV/PTV/r + SOF ± RBV for 12 weeks; OBV/PTV/r + SOF + RBV was administered to genotype 3-infected patients with cirrhosis for 12 weeks and to genotype 2-infected patients without cirrhosis for either 6 or 8 weeks. Efficacy was assessed by sustained virologic response [HCV RNA <25 IU/mL] 12 weeks post-treatment (SVR12). Safety was assessed in all treated patients. In patients with genotype 3 infection with or without cirrhosis treated with 12 weeks of OBV/PTV/r + SOF ± RBV, the overall SVR12 rate was 98% (50/51), with no virologic failures. Patients with genotype 2 infection treated with OBV/PTV/r + SOF + RBV had SVR12 rates of 90% (9/10) and 44% (4/9) following 8- and 6-week treatment durations, respectively; failure to achieve SVR12 for these patients was due to relapse without baseline or treatment-emergent resistance-associated substitutions. Thus, the investigational combination of OBV/PTV/r with SOF ± RBV was well tolerated and achieved high SVR rates with no virologic failures in patients with genotype 3 infection. Combining direct-acting antivirals with complementary mechanisms of action and different viral targets may be an effective treatment strategy that may allow for shorter durations of therapy.

Serum miR-122 may serve as a biomarker for response to direct acting antivirals: effect of paritaprevir/R with dasabuvir or ombitasvir on miR-122 in HCV-infected subjects.

Circulating microRNAs (miRNA) have been intensely investigated as biomarkers in disease and therapy. Several studies have identified miR-122 as an important regulator of HCV replication. The effect of new therapies that directly target the HCV replication life cycle on circulating microRNA levels has not been elucidated. We performed expression profiling of circulating miRNA in serum in subjects treated with HCV direct-acting antiviral agents (DAAs). Serum miRNA levels were evaluated from two studies in HCV GT1-infected treatment-naïve subjects and prior nonresponders to pegylated interferon (pegIFN) and ribavirin (RBV) who received paritaprevir/ritonavir + dasabuvir + RBV for 12 weeks, and in treatment-naïve genotype (GT)1-3-infected subjects who received paritaprevir/ritonavir + ombitasvir ± RBV for 12 weeks. Over 100 different miRNA species were detected in serum. Of these, levels of miR-122 showed the most consistent change in response to treatment across all HCV genotypes. In all subjects, miR-122 showed an average four-fold reduction between baseline and week 2, and remained below baseline through post-treatment week 12 in subjects who achieved sustained virological response. In contrast, in subjects who did not achieve SVR, miR-122 levels began to return to baseline levels after the second week of treatment. The change in miR-122 levels was similar across genotypes, and was comparable with or without RBV. This is the first report comparing expression levels of circulating miRNA in HCV GT1-3 subjects treated with IFN-free combinations of DAAs. The results suggest that serum levels of miR-122 are reduced following treatment in subjects who achieve SVR, and correlate with HCV RNA levels across genotypes.

Cloning, tissue-specific expression, gene structure and chromosomal localization of human phosphatidylcholine transfer protein.

Phosphatidylcholine transfer protein (PC-TP) is a cytosolic protein that catalyzes intermembrane transfer of phosphatidylcholines in vitro. We have cloned a cDNA encoding the human ortholog of PC-TP and have determined its tissue-specific expression as well as genomic organization. Radiation hybrid mapping localized the human gene, PCTP, to chromosome 17q21-22 and PCR-based single strand conformation polymorphism analysis of an interspecific backcross assigned mouse Pctp to the region of syntenic conservation on chromosome 11.

Cloning and characterization of a cDNA encoding the specific phosphatidylcholine transfer protein from bovine liver.

A 1917-bp cDNA clone encoding phosphatidylcholine transfer protein (PC-TP) was identified by screening a bovine liver library. Northern blot analysis demonstrated a 2-kb mRNA transcript in bovine liver, and Southern blotting was consistent with a single bovine PC-TP gene which was shown to be present in a diverse group of vertebrates, but not in yeast. Database comparisons revealed the nucleotide sequence of the clone to be unique and unrelated to other cytosolic lipid TP.

Cloning and gene structure of rat phosphatidylcholine transfer protein, Pctp.

Phosphatidylcholine transfer protein (PC-TP) is a cytosolic lipid transfer protein that promotes intermembrane transfer of phosphatidylcholines but no other phospholipids. Although its physiological function remains unknown, phosphatidylcholine transfer protein is enriched in liver and evidence from model systems suggests a role in hepatocellular selection and transport of biliary phospholipids. To facilitate in vivo studies, a cDNA encoding rat PC-TP was cloned by library screening and 5'-rapid amplification of cDNA ends. Genomic cloning demonstrated the rat Pctp gene spans 10. 8kb and is comprised of six exons. The putative transcription initiation site was identified 50bp upstream of the translation initiation site. Nucleotide sequence analysis of the 5'-flanking region revealed a CAAT- but no TATA-box. Transient transfection of a series of 5'-deleted Pctp-promoter-firefly luciferase constructs into Reuber H35 rat hepatoma cells, which express Pctp mRNA, and Gunn rat fibroblasts, which do not, suggest that cis-acting elements in a 637bp promoter region contribute to enhanced expression of PC-TP in liver.

Experience of an interdisciplinary pediatric pain service.

This article is a report of our experience with an interdisciplinary pain service in a large tertiary care pediatric hospital. During the first 2 years of operation, we received 869 consultations and referrals from more than 19 hospital divisions. Postoperative pain was the most frequent reason for consultation (56% of patients). Patients with pain related to cancer and sickle cell disease comprised 25% of the consultations. The remaining patients had a wide variety of primary diagnoses and causes of pain. We calculated the time spent by pain service physicians in direct patient care. The majority (63%) of physician time was spent with a small number of patients (17%). Most of these patients had pain that was unrelated to surgery, cancer, or sickle cell disease, and many posed dilemmas in diagnosis and treatment. Physician time was correlated directly to the use of psychologic and physical therapies for the pain, involving multiple team members. This experience supports the demand for an interdisciplinary pain service in a tertiary care children's hospital. A significant amount of physician time is necessary to provide patient care and to maintain a team approach, however, and pediatricians and other health care professionals who aim to implement such services should be cognizant of the time required.

Effect of intraoperative intervention on neurological outcome based on electroencephalographic monitoring during cardiopulmonary bypass.

Neurological complications of cardiopulmonary bypass procedures are well documented. The present two-part study was undertaken to (1) determine if on-line computerized electroencephalographic changes correlated with neurological outcome and (2) compare neurological outcome with that of a second group of patients who received intraoperative interventions based on electroencephalographic data. Part 1 consisted of monitoring 50 patients. A power drop index was developed that correlated with new global neurological deficits. New global deficits occurred in 44% of the patients. In part 2, this information was used to design intervention criteria. Treatment protocols used previously accepted methods of increasing cerebral blood flow, ie, increasing pump flow, raising mean arterial pressure, and increasing CO2 content in the ventilator blend. Global neurological deficits were reduced to 5% in a group of 41 clinically similar patients (p less than 0.001). Cerebral perfusion pressures were similar in both groups. The single correlating factor was the power drop index as identified by computerized EEG. Our conclusion is that simple intervention guided by computerized EEG can reduce global neurological deficits in patients having cardiopulmonary bypass procedures.

Allergic contact and photoallergic contact dermatitis to plant and pesticide allergens.

BACKGROUND: The panel of patch test allergens used for the evaluation of patients with suspected photoallergy typically does not include plant and pesticide allergens. The prevalence of allergic contact dermatitis and photoallergic contact dermatitis to plant and pesticide allergens was determined for this subgroup of patients. OBSERVATION: Positive reactions were detected in 12 of 26 patients who were tested with our photoallergen series: 5 with allergic contact dermatitis, 5 with photoallergic contact dermatitis, and 2 with both. Four of the 12 patients had positive patch and photo-patch test reactions to plant allergens, pesticide allergens, or both. The positive patch test reactions were to the plants Taraxacum officinale (dandelion) and Tanacetum vulgare (tansy) and to the pesticides folpet and captafol. Positive photo-patch test reactions were to the pesticides folpet and captan. The histories of the patients suggested that 2 or 3 of the 4 patients had clinically relevant reactions. In the other 8 patients, positive reactions to the patch and photo-patch tests included fragrances, sunscreens, and antibacterial agents. CONCLUSION: Plant and pesticide allergens should be included in the patch and photo-patch test series used for the evaluation of patients with suspected photoallergy.

Patient-controlled analgesia for sickle-cell-related pain.

To delineate dose ranges, utilization patterns, and the frequency and types of problems encountered, we retrospectively reviewed the medical records of 46 patients with sickle hemoglobinopathies who used patient-controlled analgesia (PCA) a total of 92 times for the management of vasooclusive pain. Patients varied widely in the drug administered, use of basal infusion, individual dose, and total amount of drug received. On the day of heaviest use, the average maximum hourly dose was equivalent to 0.09 mg/kg of morphine. In this study, 11 patients and two families disliked PCA, one patient had respiratory compromise, and one patient tampered with the machine. Patient satisfaction with PCA probably reflects interactions among the psychosocial impact of chronic illness and chronic pain, individual psychological and temperamental factors, environmental contingencies, and the expectations and beliefs of the family and the health-care professionals. Based on this experience, recommendations can be proposed for the use of PCA in this condition.

Is outpatient tonsillectomy appropriate for young children?

The current literature suggests that outpatient tonsillectomy is a safe, cost-effective procedure. These reports have based their conclusions on the low rates of postoperative bleeding and dehydration. Generally, they have not examined other factors that may influence the postoperative course or identified groups of patients in whom outpatient management may not be appropriate. The literature regarding tonsillectomy in young children is conflicting. A retrospective analysis of the records of 223 children, 36 months of age and younger who had tonsillectomies, was performed. Postoperative airway complications including oxygen desaturation and airway obstruction developed in 115 patients. Seventeen (7.6%) children required postoperative care in an intensive care unit while an additional 117 (52.5%) patients received more than standard management. Preoperative apnea, an age of less than 12 months, and the presence of accompanying medical conditions were associated with a higher incidence of postoperative airway complications. It is recommended that tonsillectomy in patients under 36 months of age be planned as an inpatient procedure.

What is new in clinical research in contact dermatitis.

The field of cutaneous allergy has enjoyed dynamic research advances in epidemiology and clinical contact dermatitis. Studies regarding outcomes analysis, validity, predictive value, and sensitivity have allowed clinicians to better understand the importance of patch test results. In the clinical arena, new and clinically relevant allergens are being discovered, such as corticosteroids, metals, preservatives, surfactants, and glues. Continued epidemiologic surveillance of new allergens will enable manufacturers to develop safer products for patients to use.

Treatment of minors without parental consent: the law in Oklahoma.

Many Oklahoma physicians face the problem of treating minors without parental consent. For them, this review of current Oklahoma law should prove especially useful.

MicroRNAs in metabolism and metabolic diseases.

Aberrant cholesterol/lipid homeostasis is linked to a number of diseases prevalent in the developed world, including metabolic syndrome, type II diabetes, and cardiovascular disease. We have previously uncovered gene regulatory mechanisms of the sterol regulatory element-binding protein (SREBP) family of transcription factors, which control the expression of genes involved in cholesterol and lipid biosynthesis and uptake. Intriguingly, we recently discovered conserved microRNAs (miR-33a/b) embedded within intronic sequences of the human SREBF genes that act in a concerted manner with their host gene products to regulate cholesterol/lipid homeostasis. Indeed, miR-33a/b control the levels of ATP-binding cassette (ABC) transporter ABCA1, a cholesterol efflux pump critical for high-density lipoprotein (HDL) synthesis and reverse cholesterol transport from peripheral tissues. Importantly, antisense inhibition of miR-33 in mice results in elevated HDL and decreased atherosclerosis. Interestingly, miR-33a/b also act in the fatty acid/lipid homeostasis pathway by controlling the fatty acid ß-oxidation genes carnitine O-octanoyltransferase (CROT), hydroxyacyl-coenzyme A-dehydrogenase (HADHB), and carnitine palmitoyltransferase 1A (CPT1A), as well as the energy sensor AMP-activated protein kinase (AMPKα1), the NAD(+)-dependent sirtuin SIRT6, and the insulin signaling intermediate IRS2, key regulators of glucose and lipid metabolism. These results have revealed a highly integrated microRNA (miRNA)-host gene circuit governing cholesterol/lipid metabolism and energy homeostasis in mammals that may have important therapeutic implications for the treatment of cardiometabolic disorders.

Hepatocellular transport and secretion of biliary phospholipids.

Recent progress has begun to elucidate molecular and cellular mechanisms whereby bile salts stimulate hepatocellular selection, transport, and biliary secretion of phospholipids, which are enriched (up to 95%) in phosphatidylcholines. This article first summarizes classical observations concerning the molecular structures of biliary phospholipids, as well as the role of bile salts in promoting their secretion into bile. New data are then reviewed and synthesized into a working model for biliary phospholipid secretion. An important feature is that this model is selective for biliary phospholipids and necessitates a largely independent pathway for cholesterol secretion into bile.

Hepatocellular transport and secretion of biliary lipids.

Bile is the route for elimination of cholesterol from the body. Recent studies have begun to elucidate hepatocellular, molecular and physical-chemical mechanisms whereby bile salts stimulate biliary secretion of cholesterol together with phospholipids, which are enriched (up to 95%) in phosphatidylcholines. Active translocation of bile salts and phosphatidylcholines across the hepatocyte's canalicular plasma membrane provides the driving force for biliary lipid secretion. This facilitates physical-chemical interactions between detergent-like bile salt molecules and the ectoplasmic leaflet of the canalicular membrane, which result in biliary secretion of cholesterol and phosphatidylcholines as vesicles. Within the hepatocyte, separate molecular pathways function to resupply bile salts, phosphatidylcholines and cholesterol to the canalicular membrane for ongoing biliary lipid secretion.

Acyl chain unsaturation modulates distribution of lecithin molecular species between mixed micelles and vesicles in model bile. Implications for particle structure and metastable cholesterol solubilities.

We determined the distribution of lecithin molecular species between vesicles and mixed micelles in cholesterol super-saturated model biles (molar taurocholate-lecithin-cholesterol ratio 67:23:10, 3 g/dl, 0.15 M NaCl, pH approximately 6-7) that contained equimolar synthetic lecithin mixtures or egg yolk or soybean lecithins. After apparent equilibration (48 h), biles were fractionated by Superose 6 gel filtration chromatography at 20 degrees C, and lecithin molecular species in the vesicle and mixed micellar fractions were quantified as benzoyl diacylglycerides by high performance liquid chromatography. With binary lecithin mixtures, vesicles were enriched with lecithins containing the most saturated sn-1 or sn-2 chains by as much as 2.4-fold whereas mixed micelles were enriched in the more unsaturated lecithins. Vesicles isolated from model biles composed of egg yolk (primarily sn-1 16:0 and 18:0 acyl chains) or soy bean (mixed saturated and unsaturated sn-1 acyl chains) lecithins were selectively enriched (6.5-76%) in lecithins with saturated sn-1 acyl chains whereas mixed micelles were enriched with lecithins composed of either sn-1 18:1, 18:2, and 18:3 unsaturated or sn-2 20:4, 22:4, and 22:6 polyunsaturated chains. Gel filtration, lipid analysis, and quasielastic light scattering revealed that apparent micellar cholesterol solubilities and metastable vesicle cholesterol/lecithin molar ratios were as much as 60% and 100% higher, respectively, in biles composed of unsaturated lecithins. Acyl chain packing constraints imposed by distinctly different particle geometries most likely explain the asymmetric distribution of lecithin molecular species between vesicles and mixed micelles in model bile as well as the variations in apparent micellar cholesterol solubilities and vesicle cholesterol/lecithin molar ratios.(ABSTRACT TRUNCATED AT 250 WORDS)