A Clinical Report Utilizing the VITOM 3D Microvideoscope for Cleft Palate Repair.

Cleft palate surgery has traditionally presented numerous problems for cleft surgeons including ergonomics, limited visual fields restricting the opportunity for demonstration and teaching. Additionally, the move toward online teaching means the ability to record or livestream video is paramount. The following report of eight cleft palate repairs highlights the novel use of the Vitom 3D microvideoscope as an innovative technique for cleft palate repair with our early experience demonstrating significant ergonomic and teaching benefits.

Differential cellular expression of organic anion transporting peptides OATP1A2 and OATP2B1 in the human retina and brain: implications for carrier-mediated transport of neuropeptides and neurosteriods in the CNS.

Organic anion transporting polypeptides (OATPs) are polyspecific organic anion transporters, which are expressed in the blood-brain barrier, the choroid plexus, and other organs. The physiologic function of OATPs in extrahepatic tissues remains ambiguous. In rat retina, members of the OATP family are expressed.

Pharmacogenetics of drug transporters in the enterohepatic circulation.

This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice.

Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired cholestasis has recently made considerable progress by the identification of canalicular ATP-binding cassette (ABC) transporters as likely targets for these forms of cholestasis. Cholestasis of pregnancy is linked to estrogen and progesterone metabolites.

ABC-transporters are localized in caveolin-1-positive and reggie-1-negative and reggie-2-negative microdomains of the canalicular membrane in rat hepatocytes.

Unlabelled: The canalicular plasma membrane is constantly exposed to bile acids acting as detergents. Bile acids are essential to mediate release of biliary lipids from the canalicular membrane. Membrane microdomains (previously called lipid rafts) are biochemically defined by their resistance to detergent solubilization at cold temperature.

Mechanisms of pH-gradient driven transport mediated by organic anion polypeptide transporters.

Organic anion transporting polypeptides (humans OATPs, rodents Oatps) are expressed in most mammalian tissues and mediate cellular uptake of a wide variety of amphipathic organic compounds such as bile salts, steroid conjugates, oligopeptides, and a large list of drugs, probably by acting as anion exchangers. In the present study we aimed to investigate the role of the extracellular pH on the transport activity of nine human and four rat OATPs/Oatps. Furthermore, we aimed to test the concept that OATP/Oatp transport activity is accompanied by extrusion of bicarbonate.

Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump.

Aim: To study the association of three common ABCB11 and ABCC2 polymorphisms (ABCB11: 1331T>C --> V444A; ABCC2: 3563T>A --> V1188E and 4544G>A --> C1515Y) with intrahepatic cholestasis of pregnancy (ICP) and contraceptive-induced cholestasis (CIC).

Methods: ABCB11 and ABCC2 genotyping data were available from four CIC patients and from 42 and 33 ICP patients, respectively. Allele-frequencies of the studied polymorphisms were compared with those in healthy pregnant controls and Caucasian individuals.

Hepatocyte transplantation: potential of hepatocyte progenitor cells and bone marrow derived stem cells.

The liver has a large regenerative capacity in response to injury. However, in severe cases of liver injury, its regenerative capacity may prove insufficent and the liver injury may progress to liver failure, and in such situations liver transplantation is the only treatment option. An alternative, less invasive approach may be transplantation of hepatocytes or hepatocyte precursor cells.

Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury.

Objectives: Increasing evidence suggests that a genetically determined functional impairment of the hepatocellular efflux transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) play a pathophysiological role in the development of drug-induced liver injury. The aim of this study was therefore to describe the extent of genetic variability in ABCB11 and ABCB4 in patients with drug-induced liver injury and to in vitro functionally characterize newly detected ABCB11 mutations and polymorphisms.

Methods: ABCB11 and ABCB4 were sequenced in 23 patients with drug-induced cholestasis and 13 patients with drug-induced hepatocellular injury.

Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy.

Unlabelled: Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus and elevated bile acid serum concentrations in late pregnancy. Splicing mutations have been described in the multidrug resistance p-glycoprotein 3 (MDR3, ABCB4) gene in up to 20% of ICP women. Pedigrees studied were not large enough for linkage analysis.

The bile salt export pump.

Canalicular secretion of bile salts mediated by the bile salt export pump Bsep constitutes the major driving force for the generation of bile flow. Bsep is a member of the B-family of the super family of ATP-binding cassette transporters and is classified as ABCB11. Bsep has a narrow substrate specificity, which is largely restricted to bile salts.

Hepatocyte transplantation: potential of hepatocyte progenitor cells and bone marrow derived stem cells.

The liver has a large regenerative capacity in response to injury. However, in severe cases of liver injury, its regenerative capacity may prove insufficent and the liver injury may progress to liver failure, and in such situations liver transplantation is the only treatment option. An alternative, less invasive approach may be transplantation of hepatocytes or hepatocyte precursor cells.

Hepatobiliary transporters and drug-induced cholestasis.

Drug-induced liver injury is an important clinical problem with significant morbidity and mortality. Whereas for most hepatocellular forms of drug-induced hepatic injury the underlying pathophysiological mechanism is poorly understood, there is increasing evidence that cholestatic forms of drug-induced liver damage result from a drug- or metabolite-mediated inhibition of hepatobiliary transporter systems. In addition to their key role in determining hepatic drug exposure and clearance, the coordinated action of these transport systems is essential for bile formation and the biliary secretion of cholephilic compounds and xenobiotics.

Characterization of two splice variants of human organic anion transporting polypeptide 3A1 isolated from human brain.

In the present study we isolated two splice variants of organic anion transporting polypeptide 3A1 (OATP3A1_v1 and OATP3A1_v2) from human brain. OATP3A1_v2 lacks 18 amino acids (aa) at the COOH-terminal end (692 aa) but is otherwise similar in sequence to OATP3A1_v1 (710 aa). OATP3A1_v1 exhibits a wide tissue distribution, with expression in testis, various brain regions, heart, lung, spleen, peripheral blood leukocytes, and thyroid gland, whereas OATP3A1_v2 is predominantly expressed in testis and brain.

Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver.

Interindividual variability in hepatic canalicular transporter expression might predispose to the development of hepatic disorders such as acquired forms of intrahepatic cholestasis. We therefore investigated expression patterns of bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4), multidrug resistance associated protein 2 (MRP2, ABCC2) and multidrug resistance protein 1 (MDR1, ABCB1) in healthy liver tissue of a white population. Protein expression levels were correlated with specific single nucleotide polymorphisms (SNPs) in the corresponding transporter genes.

Functional analysis of the extracellular cysteine residues in the human organic anion transporting polypeptide, OATP2B1.

Organic anion transporting polypeptide (OATP) superfamily member 2B1 (OATP2B1) mediates the uptake of steroid hormone precursors and selected drugs in the placenta, liver, mammary gland, brain, and intestine. This action is modulated by sulfhydryl reagents. Common to all OATPs is a large extracellular loop between transmembrane domains IX and X with 10 conserved cysteines.

Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis.

Background/aims: Inherited dysfunction of the bile salt export pump BSEP (ABCB11) causes a progressive and a benign form of familial intrahepatic cholestasis, denominated as PFIC2 and BRIC2, respectively. We functionally characterized novel ABCB11 mutations encountered in two patients with a PFIC2 and a BRIC2 phenotype, respectively.

Methods: BSEP expression was determined in liver biopsies by immunohistochemistry.

Magnetic resonance imaging with hepatospecific contrast agents in cirrhotic rat livers.

Objective: During biliary cirrhosis in rats, organic anion-transporting peptides (Oatps) and ATP-dependent multidrug resistance-associated protein 2 (Mrp2) that are likely to transport the contrast agent Gd-BOPTA through hepatocytes are down-regulated. However, the consequences of such down-regulation on the signal intensity (SI) enhancement are unknown. Consequently, the aim of our study was to measure the hepatic SI enhancement during Gd-BOPTA perfusion as well as the Oatp and Mrp2 expression in normal and cirrhotic livers.

Hepatocellular transporters and cholestasis.

The secretion of bile is the result of active hepatocellular transport processes, most of which occur across the canalicular membrane of liver cells. Disturbance of the function and/or expression of these transporters leads to the intracellular accumulation of toxic bile acids, thereby promoting cholestatic liver cell injury. Genetically determined alterations of hepatobiliary transporter function are increasingly recognized as important risk factors for an individual's susceptibility to develop cholestasis.

Incidence of drug-induced liver injury in medical inpatients.

Objectives: Drug-induced liver injury (DILI) is a common concern. However, data on DILI epidemiology in inpatients are sparse.

Methods: To investigate the incidence of DILI, we screened all patients in the pharmacoepidemiological inpatient database according to the CIOMS (Council for International Organisation of Medical Science) criteria, which consist of the evaluation of some clinical chemistry laboratory liver parameters (CIOMS laboratory criteria) and the exclusion of any disease-related causes for the liver injury.

The human organic anion transporter 2 gene is transactivated by hepatocyte nuclear factor-4 alpha and suppressed by bile acids.

The human organic anion transporter 2 (hOAT2, SLC22A7) mediates the sodium-independent uptake of numerous drugs, including cephalosporins, salicylates, dicarboxylates, and prostaglandins, and is mainly expressed in hepatocytes. Because the regulation of hOAT2 expression is poorly understood, we characterized cis-acting elements in the 5'-flanking region that regulate hOAT2 transcription. A consensus binding motif for the hepatocyte nuclear factor-4 alpha (HNF-4 alpha), arranged as a direct repeat (DR)-1, is located at nucleotides -329/-317 relative to the transcription initiation site.

Localization of organic anion transporting polypeptides in the rat and human ciliary body epithelium.

Purpose: To identify and localize the expression of multispecific organic anion transporting polypeptides (Oatps/OATPs) in the ciliary body epithelium and to investigate their possible involvement in the transport of the antiglaucoma agent unoprostone.

Methods: Oatps/OATPs were detected by immunoblot analysis and by immunofluorescence microscopy in homogenized and fixed rat and human ciliary body samples using specific polyclonal antibodies. Transport of 3H-labelled unoprostone was measured in Oatp/OATP expressing Xenopus laevis oocytes.

Adverse drug events caused by medication errors in medical inpatients.

Principles: In view of growing concern in recent years regarding medication errors as causes of adverse drug events (ADEs), we explore the frequency and characteristics of error-associated ADEs in medical inpatients.

Methods: All patients with ADEs or ADErelated hospital admission in a cohort of medical inpatients identified by "event monitoring" (SAS/CHDM database, Br J Clin Pharmacol 2000:49:158-67) were evaluated independently by two experienced physicians. ADEs were first divided into ADEs occurring during cohort stay (incident ADE) and ADE present prior to/at admission.