Influence of Bariatric Surgery on the Use and Pharmacokinetics of Some Major Drug Classes

The purpose of this review is to evaluate the influence of bariatric surgery on the use and pharmacokinetics of some frequently used drugs. A PubMed literature search was conducted. Literature was included on influence of bariatric surgery on pharmacoepidemiology and pharmacokinetics. Drug classes to be searched for were antidepressants, antidiabetics, statins, antihypertensive agents, corticosteroids, oral contraceptives, and thyroid drugs. A reduction in the use of medication by patients after bariatric surgery has been reported for various drug classes. Very few studies have been published on the influence of bariatric surgery on the pharmacokinetics of drugs. After bariatric surgery, theoretically, reduced drug absorption may occur. Correct dosing and choosing the right dosage form for drugs used by patients after bariatric surgery are necessary for optimal pharmacotherapy. Therefore, more clinical studies are needed on the influence of bariatric surgery on the pharmacokinetics of major drugs.     

BONE-INDUCTIVE EFFICACY OF RECOMBINANT HUMAN BONE MORPHOGENETIC PROTEIN-2 EXPRESSED IN ESCHERICHIA COLI: AN EXPERIMENTAL STUDY IN RAT MANDIBULAR DEFECTS

Because to our knowledge the efficacy of prokaryotically expressed recombinant human bone morphogenetic proteins (rhBMP) to promote orthotopic osteogenesis has not previously been investigated, our aim was to test the efficacy of rhBMP-2 produced in Escherichia coli to promote bone healing in a standardised experimental bone healing model in rat mandibles. Different doses of rhBMP-2 were delivered in an absorbable collagen sponge carrier, and microporous barrier membranes were placed over half the number of defects in each treatment group, thereby making intraosseous cells the only recruitment source for new osteogenic cells. Results were evaluated by computerised image analysis after 12 and 24 days. The relative efficacy of rhBMP-2 preparations of different purity was also compared. E coli-produced rhBMP-2 stimulated bone healing, but its efficacy was estimated to be about one order of magnitude less than that of rhBMP-2 expressed in eukaryotic cells. We conclude that bacterially expressed rhBMP-2 is osteogenic in vivo, although higher doses will be required than of rhBMP-2 expressed in mammalian cell lines.     

A multiplex polymerase chain reaction assay for genus-, group- and species-specific detection of mycobacteria

We developed and evaluated a single-step, multiplex polymerase chain reaction (PCR) assay for distinguishing (1) between the Mycobacterium tuberculosis complex (MTBC) and mycobacteria other than tuberculosis (MOTT) and (2) between M. tuberculosis and M. bovis species. The assay targeted the 16S and the 23S rDNA to distinguish between MTBC and MOTT species, and the oxyR gene to distinguish between M. tuberculosis and M. bovis strains. Clinical samples and reference strains (N = 156) comprised 93 strains of M. tuberculosis, 44 of M. bovis, 1 M. africanum strain, and 18 strains representing 9 different species of MOTTs. MOTTs generated only a single PCR product of about 2.5 kilobase; however, all of the MTBC strains produced a 118 base pair (bp) fragment and an additional 270 bp fragment was obtained for M. tuberculosis and M. africanum when the primer pair oxyRTB-2.1/oxyRMT-1 was used. When oxyRTB-2.1/oxyRMB-1 primers were used, the 270 bp fragment was obtained for only M. bovis. The assay needed as little as 1 pg of purified genomic DNA to make a positive identification.     

Enhancing excitability of dopamine neurons promotes motivational behaviour through increased action initiation

Motivational deficits are a key symptom in multiple psychiatric disorders, including major depressive disorder, schizophrenia and addiction. A likely neural substrate for these motivational deficits is the brain dopamine (DA) system. In particular, DA signalling in the nucleus accumbens, which originates from DA neurons in the ventral tegmental area (VTA), has been identified as a crucial substrate for effort-related and activational aspects of motivation. Unravelling how VTA DA neuronal activity relates to motivational behaviours is required to understand how motivational deficits in psychiatry can be specifically targeted. In this study, we therefore used designer receptors exclusively activated by designer drugs (DREADD) in TH:Cre rats, in order to determine the effects of chemogenetic DA neuron activation on different aspects of motivational behaviour. We found that chemogenetic activation of DA neurons in the VTA, but not substantia nigra, significantly increased responding for sucrose under a progressive ratio schedule of reinforcement. More specifically, high effort exertion was characterized by increased initiations of reward-seeking actions. This effect was dependent on effort requirements and instrumental contingencies, but was not affected by sucrose pre-feeding. Together, these findings indicate that VTA DA neuronal activation drives motivational behaviour by facilitating action initiation. With this study, we show that enhancing excitability of VTA DA neurons is a viable strategy to improve motivational behaviour.     

Urinary excretion of platinum (Pt) following skin and respiratory exposure to soluble Pt at South African precious metals refineries

Adverse respiratory and skin health effects have been associated with occupational exposure to soluble platinum (Pt). However, the relationship between skin exposure and urinary Pt excretion has not yet been investigated. In this study we examined the relationship between skin and respiratory exposure to soluble Pt and urinary Pt excretion at two South African precious metals refineries.The skin and respiratory exposure to soluble Pt as well as the urinary Pt excretion of forty precious metals refinery workers was assessed simultaneously using Ghostwipes?, Methods for the Determination of Hazardous Substances method 46/2 and spot urine tests, respectively.The geometric mean for skin exposure to soluble Pt on four anatomical positions (palm, wrist, neck and forehead) was 0.008?μg/cm² [95% confidence interval (CI): 0.005-0.013?μg/cm²], while the geometric mean for respiratory exposure was 0.301?μg/m³ (95%CI: 0.151-0.601?μg/m³) and the geometric mean for urinary Pt excretion was 0.212?μg/g creatinine (95%CI: 0.169-0.265?μg/g creatinine). Partial correlations identified significant positive correlations between skin exposure, respiratory exposure and urinary Pt excretion (r?=?0.580 to 0.754).Skin and respiratory exposures to soluble Pt were both positively correlated with urinary Pt excretion, and both exposure routes should be considered when investigating occupational exposure to soluble Pt.     

Activation of the cortical pain network by soft tactile stimulation after injection of sumatriptan

The anti-migraine drug sumatriptan often induces unpleasant somatosensory side effects, including a dislike of being touched. With a double-blind cross-over design, we studied the effects of sumatriptan and saline on perception (visual analogue scale) and cortical processing (functional magnetic resonance imaging) of tactile stimulation in healthy subjects. Soft brush stroking on the calf (n=6) was less pleasant (p<0.04) and evoked less activation of posterior insular cortex in the sumatriptan compared to the saline condition. Soft brushing activated pain processing regions (anterior insular, lateral orbitofrontal, and anterior cingulate cortices, and medial thalamus) only in the sumatriptan condition, whereas activation of somatosensory cortices was similar in both conditions. Soft brush stroking on the palm (n=6) was equally pleasant in both conditions. One possible mechanism for the activation of pain processing regions by brush stroking is sensitization of nociceptors by sumatriptan. Another possibility is inhibition of a recently discovered system of low-threshold unmyelinated tactile (CT) afferents that are present in hairy skin only, project to posterior insular cortex, and serve affective aspects of tactile sensation. An inhibition of impulse transmission in the CT system by sumatriptan could disinhibit nociceptive signalling and make light touch less pleasant. This latter alternative is consistent with the observed reduction in posterior insular cortex activation and the selective effects of stimulation on hairy compared to glabrous skin, which are not explained by the nociceptor sensitization account.     

人肝、肾ABO血型抗原表达差异的初步研究

目的比较人肝、肾ABO血型抗原表达的差异,探索ABO血型抗原在血型抗体介导排斥反应中的作用。 方法ABO血型为A型和B型血的公民逝世后器官捐献供者各4例,O型血对照2例。获取供者肝脏和双肾后,留取肾动脉、肾静脉、肾组织、肝动脉、肝静脉、门静脉和肝组织标本,运用蛋白质印迹法(WB)和免疫组织化学法检测ABO血型抗原的含量和分布。 结果WB检测结果显示,同一供者不同部位ABO血型抗原含量并不一致。在同一个体内,A型抗原在肾组织和门静脉含量最高,在肾动脉含量最低;B型抗原在肝静脉及肾组织含量最高,在肾动脉、肾静脉及肝组织含量最低。不同个体之间,同一部位血型抗原含量差别也较大。通过免疫组织化学法检测,进一步发现血型抗原在肝、肾组织和血管中的分布与WB结果基本一致。 结论ABO血型抗原在不同血型、个体和器官之间均存在不同程度差异,这种差异也可能会影响ABO血型不相容器官移植的结局。     

N-Linked Glycosylation on Anthrax Toxin Receptor 1 Is Essential for Seneca Valley Virus Infection

Seneca Valley virus (SVV) is a picornavirus with potency in selectively infecting and lysing cancerous cells. The cellular receptor for SVV mediating the selective tropism for tumors is anthrax toxin receptor 1 (ANTXR1), a type I transmembrane protein expressed in tumors. Similar to other mammalian receptors, ANTXR1 has been shown to harbor N-linked glycosylation sites in its extracellular vWA domain. However, the exact role of ANTXR1 glycosylation on SVV attachment and cellular entry was unknown. Here we show that N-linked glycosylation in the ANTXR1 vWA domain is necessary for SVV attachment and entry. In our study, tandem mass spectrometry analysis of recombinant ANTXR1-Fc revealed the presence of complex glycans at N166, N184 in the vWA domain, and N81 in the Fc domain. Symmetry-expanded cryo-EM reconstruction of SVV-ANTXR1-Fc further validated the presence of N166 and N184 in the vWA domain. Cell blocking, co-immunoprecipitation, and plaque formation assays confirmed that deglycosylation of ANTXR1 prevents SVV attachment and subsequent entry. Overall, our results identified N-glycosylation in ANTXR1 as a necessary post-translational modification for establishing stable interactions with SVV. We anticipate our findings will aid in selecting patients for future cancer therapeutics, where screening for both ANTXR1 and its glycosylation could lead to an improved outcome from SVV therapy.