Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Background and purpose:

Thrombus formation is commonly associated with pulmonary arterial hypertension (PAH). Thrombin may thus play an important role in the pathogenesis and pathophysiology of PAH. Hence, we investigated the contractile effects of thrombin and its mechanism in pulmonary artery.

Experimental approach:

The cytosolic Ca²⁺ concentrations ([Ca²⁺]_i), 20 kDa myosin light chain (MLC20) phosphorylation and tension development were evaluated using the isolated porcine pulmonary artery.

Key results:

Thrombin induced a sustained contraction in endothelium-denuded strips obtained from different sites of a pulmonary artery, ranging from the main pulmonary artery to the intrapulmonary artery. In the presence of endothelium, thrombin induced a transient relaxation. The contractile effect of thrombin was abolished by either a protease inhibitor or a proteinase-activated receptor 1 (PAR₁) antagonist, while it was mimicked by PAR₁-activating peptide (PAR₁AP), but not PAR₄AP. The thrombin-induced contraction was associated with a small elevation of [Ca²⁺]_i and an increase in MLC20 phosphorylation. Thrombin and PAR₁AP induced a greater increase in tension for a given [Ca²⁺]_i elevation than that obtained with high K⁺-depolarization. They also induced a contraction at a fixed Ca²⁺ concentration in α-toxin-permeabilized preparations.

Conclusions and implications:

The present study revealed a unique property of the pulmonary artery. In contrast to normal arteries of the systemic circulation, thrombin induces a sustained contraction in the normal pulmonary artery, by activating PAR₁ and thereby increasing the sensitivity of the myofilament to Ca²⁺. This responsiveness of the pulmonary artery to thrombin may therefore contribute to the pathogenesis and pathophysiology of PAH.     

IQ and Posttraumatic Stress Symptoms in Children Exposed to Interpersonal Violence

Background: The literature is mixed as to the relationship between intelligence quotient (IQ) and Posttraumatic Stress Disorder (PTSD) symptomatology in adult populations. Even less is known about the relationship in children who have been traumatized. Methods: Fifty-nine children and adolescents (mean age = 10.6) with a history of interpersonal violence were evaluated with respect to PTSD symptomatology, number of traumas, and estimated Verbal, Performance and Full scale IQ scores. PTSD symptomatology included symptom levels for cluster B (re-experiencing), cluster C (avoidance and numbing), and cluster D (Hypervigilance) and criterion F, functional impairment. Results: Results indicated that Full scale and Verbal IQ were significantly associated with the number of traumas, re-experiencing symptoms, and impairment. Performance IQ was only associated with impairment. Regression analyses suggested that together PTSD symptomatology predicted Full scale and Verbal IQ but nor Performance IQ and impairment was the single best predictor of IQ generally. Conclusions: Findings provide support for an association between PTSD symptoms and IQ, particularly verbal IQ. Two possible reasons for this relationship are that higher levels of Verbal IQ may serve as a premorbid protective factor against the development of re-experiencing symptoms, or performance on post-trauma Verbal IQ measures may be negatively impacted by expression of PTSD symptoms. Longitudinal studies are needed to clarify which of these two possibilities explains the association     

The relation between identity status and romantic attachment style in middle and late adolescence

This study examined the linkages between identity formation and romantic attachment in an ethnically diverse sample of high school (n=189) and college students (n=324). Individuals in the foreclosed identity status group had significantly lower relationship avoidance scores than the diffused identity status group, and the foreclosed group had significantly lower relationship anxiety scores than both the achieved identity and moratorium groups. Identity status and romantic attachment style were significantly related among the college sample, but not among the high school sample. Some ethnic differences in attachment style were noted. Developmental implications are discussed.     

Modulation of cystic fibrosis lung disease by variants in interleukin-8

Cystic fibrosis pulmonary disease is characterized by excessive and prolonged inflammation. CF Pulmonary disease severity exhibits considerable variation that, to some extent, appears to be due to the presence of modifier genes. Several components of the inflammatory response are known to have altered regulation in the CF lung. Genetic variants in 52 inflammatory genes were tested for associations with lung disease indices in a CF patient population (n=737) homozygous for the DeltaF508 cystic fibrosis transmembrane conductance regulator mutation. Variants in three inflammatory genes showed significant genotypic associations with CF lung disease severity, including IL8 and previously reported TGFbeta1 (P< or =0.05). When analyzed by gender, it was apparent that IL8 variant associations were predominantly due to males. The IL8 variants were tested in an additional CF population (n=385) and the association in males verified (P< or =0.01). The IL8 variants were in strong linkage disequilibrium with each other (R2> or =0.82), while variants in neighboring genes CXCL6, RASSF6 and PF4V1 did not associate (P> or =0.26) and were in weaker LD with each other and with the IL8 variants (0.01< or =R2< or =0.49). Studies revealed differential expression between the IL8 promoter variant alleles (P<0.001). These results suggest that IL8 variants modify CF lung disease severity and have functional consequences.     

Secondary ureteropelvic junction stricture: percutaneous dilation

Percutaneous incision and balloon catheter dilation of the ureteropelvic junction (UPJ) was performed in nine patients with secondary UPJ strictures. In all patients, the UPJ was successfully dilated, and no immediate complications were encountered. After a postoperative follow-up period of 4-27 months, six patients showed marked improvement on excretory urograms. Three patients had recurrent obstruction after 3-18 months. The 66% success rate of percutaneous balloon dilation with or without endopyelotomy compares favorably with the success rate of open surgical repair of secondary UPJ strictures in adults.     

The Urological Association of Asia clinical guideline for urinary stone disease

The Urological Association of Asia, consisting of 25 member associations and one affiliated member since its foundation in 1990, has planned to develop Asian guidelines for all urological fields. The field of stone diseases is the third of its guideline projects. Because of the different climates, and social, economic and ethnic environments, the clinical practice for urinary stone diseases widely varies among the Asian countries. The committee members of the Urological Association of Asia on the clinical guidelines for urinary stone disease carried out a surveillance study to better understand the diversity of the treatment strategy among different regions and subsequent systematic literature review through PubMed and MEDLINE database between 1966 and 2017. Levels of evidence and grades of recommendation for each management were decided according to the relevant strategy. Each clinical question and answer were thoroughly reviewed and discussed by all committee members and their colleagues, with suggestions from expert representatives of the American Urological Association and European Association of Urology. However, we focused on the pragmatic care of patients and our own evidence throughout Asia, which included recent surgical trends, such as miniaturized percutaneous nephrolithotomy and endoscopic combined intrarenal surgery. This guideline covers all fields of stone diseases, from etiology to recurrence prevention. Here, we present a short summary of the first version of the guideline – consisting 43 clinical questions – and overview its key practical issues.     

A phase II study of irofulven in women with recurrent and heavily pretreated ovarian cancer

OBJECTIVE: To determine the safety and efficacy of a novel illudin S derivative, irofulven (MGI-114), in patients with recurrent ovarian cancer who had received extensive prior chemotherapy. METHODS: The trial was an open label phase II study. Patients initially enrolled in this study were treated every 14 days with a dose of 24 mg/m2. Unexpected retinal toxicity associated with this dose and schedule lead to modification of the dosing to 0.55 mg/kg on the same schedule with a maximum individual dose of 50 mg. Dose reductions were permitted based on both hematologic and non-hematologic toxicities. RESULTS: Seventy-four women were accrued and stratified into two cohorts including 58 women with platinum-resistant disease and 16 with platinum-sensitive disease. Non-hematologic toxicities included nausea, vomiting, and fatigue. Thirty-one women had between one and six visual symptoms, most were Grade 1 and 2 in nature. The majority of visual toxicities resolved either during treatment or post-treatment with irofulven. There was one partial response in each cohort with 19 (33%) and 8 (50%) of women having stable disease in the platinum-resistant and platinum-sensitive cohorts, respectively. CONCLUSIONS: Irofulven at 24 mg/m2 on every 14-day schedule is associated with significant retinal toxicity in this patient population. Dosing at 0.55 mg/kg has persistent retinal toxicity, yet demonstrated only limited anti-tumor activity in a population of women who had received extensive prior chemotherapy.