A possible mechanism for Inv22‐related F8 large deletions in severe hemophilia A patients with high responding factor VIII inhibitors

Summary. Background: Intron 22 inversion (Inv22) of the coagulation factor (F)VIII gene (F8) is a frequent cause of severe hemophilia A. In addition to Inv22, a variety of F8 mutations (1492 unique mutations) causing hemophilia A have been reported, of which 171 involve deletions of over 50 bp (HAMSTeRs database; http://hadb.org.uk/ ). However, only 10% of these large deletions have been fully characterized at the nucleotide level. Patients and methods: We investigated gene abnormalities in three unrelated severe hemophilia A patients with high titer FVIII inhibitors. They had previously been shown to carry large deletions of the F8, but the precise gene abnormalities remain to be elucidated. Results: Inverse shifting‐PCR (IS‐PCR) Inv22 diagnostic tests revealed that these patients carried either type I or II Inv22. However, they showed a wild‐type (WT) pattern in the IS‐PCR Inv22 complementary tests. We further analyzed their X chromosomes to account for the puzzling results, and found that they had different centromeric breakpoints in the Inv22 X chromosomes, adjacent to the palindromic regions containing int22h‐2 or ‐3, and their spacer region, respectively. The connections appeared to be shifted towards the telomere of the WT F8 Xq28, resulting in a new telomere with an additional intact int22h copy. Conclusions: These gene rearrangements might result from double‐strand breaks in the most distal regions of the long arms of the Inv22 X chromosomes, followed by DNA restorations using the WT F8 Xq28 by non‐homologous end joining or break‐induced replication; thus leading to large F8 deletions in severe hemophilia A patients.     

The dark side of sniffing: Paint colour affects intoxication experiences among adolescent inhalant users

Introduction and Aims. Inhalant abuse among adolescents is a significant health concern in many countries; however, limited research has explored whether the intoxication experience differs between commonly used inhalants. The aim of the present study was to examine how exposure to different types of paints (chrome vs. non‐chrome) were experienced by adolescent users. Design and Methods. Sixteen adolescent (aged 15–19 years) regular inhalant users completed a semistructured questionnaire enquiring about their inhalant use. Participants were divided into two groups based on paint colour preference [chrome paints (n = 10) and non‐chrome paints (n = 6)] and were compared using appropriate statistical tests. Results. Relative to non‐chrome users, the chrome‐using group were more likely to report deliberately inhaling to experience altered perceptions (such as visual and auditory hallucinations). In addition, a significantly greater proportion of chrome users reported that the perceptual alterations they experienced after sniffing paint differed between paint colours, with chrome colours being associated with more vivid hallucinations. Discussion and Conclusion. While both chrome and non‐chrome users reported a comparable level of pleasure from paint sniffing, chrome paint users were more likely to be motivated by the potential to hallucinate. Our findings suggest that the type of inhalant used is an important consideration that may have relevance to clinical treatment.[Takagi MJ, Yücel M, Lubman DI. The dark side of sniffing: Paint colour affects intoxication experiences among adolescent inhalant users. Drug Alcohol Rev 2010]     

Direct effects of protein S in ameliorating acute lung injury

Summary. Objective: Protein S may exert an anticoagulant activity by enhancing the anticoagulant activity of activated protein C and/or by directly inhibiting the prothrombinase complex. Protein S itself may also directly regulate inflammatory responses and apoptosis. The role of protein S in acute lung injury (ALI) was unknown. This study evaluated the effect of protein S on ALI in the mouse. Methods: Animal ALI was induced in C57/BL6 mice by intratracheal instillation of lipopolysaccharide (LPS). Mice were treated with protein S or saline by intraperitoneal injection 1 h before LPS instillation. Results: Activated protein or protein S alone and combined activated protein C + protein S therapy decreased inflammatory markers and cytokines in mice with acute lung injury. In LPS‐treated mice compared with controls ALI was induced as shown by significantly increased levels of total protein, tumor necrosis factor‐α, interleukin‐6 and monocyte chemoattractant protein‐1 in the bronchoalveolar lavage fluid. Mice with ALI treated with protein S had significantly decreased concentrations of tumor necrosis factor‐α and interleukin‐6 in the lung compared with untreated animals. Thrombin‐antithrombin III, a marker of the activity of the coagulation cascade, was unchanged. Protein S inhibited the expression of cytokines in vitro and increased activation of the Axl tyrosine kinase pathway in A549 epithelial cells. Conclusion: Protein S protects against LPS‐induced ALI, possibly by directly inhibiting the local expression of inflammatory cytokines without affecting coagulation.     

Immunological features of patients with primary biliary cirrhosis (PBC) overlapping systemic sclerosis: A comparison with patients with PBC alone

To characterize the immunological features of patients with primary biliary cirrhosis (PBC) overlapping systemic sclerosis (SSc), 26 patients with PBC were classified according to the presence of scleroderma-related features (Raynaud's phenomenon, sclerodactyly etc.). The patients were classified into 10 patients with PBC overlapping SSc (PBC-SSc), four patients with some scleroderma-related features although not meeting the criteria of SSc (PBC-SSc spectrum) and 12 patients with PBC alone. Sera from PBC-SSc showed a significantly higher positivity to anti-centromere antibody (P < 0.01) and to E1β of pyruvate dehydrogenase complex (P < 0.005) than those from patients with PBC alone. The same tendency was observed in PBC-SSc spectrum patients. Patients with PBC exhibiting scleroderma-related features, in both the PBC-SSc and PBC-SSc spectrum, may comprise a subset in PBC, not only clinically, but also immunologically.     

Assessment of Efficacy and Safety of Combining “Paclitaxel” Eluting Balloon and “Limus” Eluting Stent in the Same Lesion

Objectives

To assess the safety and efficacy of combining drug‐eluting balloon (DEB) and drug‐eluting stents (DES) in the same coronary lesion.

Background

Use of DEB may not always produce optimal results or even result in dissection, compelling the operators to consider bailout stenting with bare metal stents (BMS). However, BMS may not be ideal in patients who have significant risk‐profile for restenosis. We have opted for DES over BMS in such situations and present our follow‐up data.

Methods

Between 2009 and 2011, 46 patients (57 lesions) requiring bailout stenting following DEB use were treated with second‐generation DES. All patients had at‐least one or more risk‐factors that made them vulnerable for restenosis (diabetes, chronic kidney disease, previous in‐stent restenosis [ISR], and/or long diffuse lesions ≥30 mm).

Results

Of the 57 lesions, 34 (60%) were previous ISR. The mean length of the DEB was: 36.2 ± 5.6 mm. All patients had TIMI‐3 flow post PCI with no in‐lab complications. At median follow‐up of 12.3 months (interquartile range [IQR]: 7.5–18.1), the rates target lesion revascularization (TLR) and target vessel revascularization (TVR) were 3 (5.3%) and 4 (7%), respectively. One patient had died 3 months following treatment. There were no episodes of myocardial infarction, definite or probable stent thrombosis. The major adverse cardiovascular events (MACE) rate defined as cardiac‐death, MI, and TVR occurred in 11% of patients.

Conclusion

The results from this novel strategy of combining “Paclitaxel” eluting balloon and “Limus” eluting stent in a same lesion are encouraging. Dual drug‐elution acting on two different pathways may provide potential synergy that may explain the favorable outcome. (J Interven Cardiol 2013;26:259–263)

     

Effects of vaso-active agents on hepatic function and blood gases in patients with cirrhosis: A study of vasopressin and nitroglycerin

The effects of vaso-active agents on hepatic function and splanchnic oxygenation were studied in 17 patients with cirrhosis and portal hypertension. Eight patients received vasopressin (0.3 iu/min) and nine patients received nitroglycerin (50 micrograms/min). Both drugs caused a significant reduction in the portal venous pressure gradient. Vasopressin infusion significantly decreased intrinsic clearance of indocyanine green (-23%, P less than 0.01). This may be due to a decreased hepatic perfusion (-28%, P less than 0.01) and portal venous oxygenation (-15% in portal venous oxygen tension, P less than 0.05). In contrast, no changes in hepatic perfusion and portal venous oxygenation were observed after nitroglycerin infusion. Nitroglycerin did not decrease intrinsic clearance of indocyanine green. These results suggest that vasodilators, rather than vasoconstrictors, might be welcome in the treatment of patients with cirrhosis and portal hypertension.