Expression of human cathepsin L or human cathepsin V in mouse thymus mediates positive selection of T helper cells in cathepsin L knock-out mice

A genetic deficiency of the cysteine protease cathepsin L (Ctsl) in mice results in impaired positive selection of conventional CD4+ T helper cells as a result of an incomplete processing of the MHC class II associated invariant chain or incomplete proteolytic generation of positively selecting peptide ligands. The human genome encodes, in contrast to the mouse genome, for two cathepsin L proteases, namely cathepsin L (CTSL) and cathepsin V (CTSV; alternatively cathepsin L2). In the human thymic cortex, CTSV is the predominately expressed protease as compared to CTSL or other cysteine cathepsins. In order to analyze the functions of CTSL and CTSV in the positive selection of CD4+ T cells we employed Ctsl knock-out mice crossed either with transgenic mice expressing CTSL under the control of its genuine human promoter or with transgenic mice expressing CTSV under the control of the keratin 14 (K14) promoter, which drives expression to the cortical epithelium. Both human proteases are expressed in the thymus of the transgenic mice, and independent expression of both CTSL and CTSV rescues the reduced frequency of CD4+ T cells in Ctsl-deficient mice. Moreover, the expression of the human cathepsins does not change the number of CD4+CD25+Foxp3+ regulatory T cells, but the normalization of the frequency of conventional CD4+ T cell in the transgenic mice results in a rebalancing of conventional T cells and regulatory T cells. We conclude that the functional differences of CTSL and CTSV in vivo are not mainly determined by their inherent biochemical properties, but rather by their tissue specific expression pattern.

Scoliosis surgery: correction not correlated with instrumentation, quality of life not correlated with correction or instrumentation

The authors conducted a retrospective study on 24 consecutive adolescent scoliosis patients, 11 of whom were instrumented with hooks and 13 with hooks and screws (hybrid technique). The mean preoperative Cobb angle was 62.2 degrees (range: 48 degrees-96 degrees). The mean correction of the primary curve was 56.6% at followup after +/- 1.18 years ; there was no statistically significant difference between groups. Special attention was given to the postoperative quality of life (QOL) by means of the following scores: COMI patient self-assessment, SF-36, ODI, and VAS. Again, there was no statistical difference between groups but, interestingly, there was no correlation between QOL and degree of correction, after a follow-up period of +/- 2.1 years. Nevertheless, on the COMI patient self-assessment, there was a high level of satisfaction with treatment. Further studies should concentrate on how to achieve a high QOL, and abandon the best possible correction as a primary endpoint of success.

Dual-modality PET/CT instrumentation-today and tomorrow

Positron emission tomography (PET) has proven to be a clinically valuable imaging modality, particularly for oncology staging and therapy follow-up. The introduction of combined PET/CT imaging has helped address challenging imaging situations when anatomical information on PET-only was inadequate for accurate lesion localization. After a decade of PET/CT these combined systems have matured technically. Today, whole-body oncology staging is available with PET/CT in 15 min, or less. This review details recent developments in combined PET/CT instrumentation and points to implications for major applications in clinical oncology.

Sonographic follow-up of patients with carpal tunnel syndrome undergoing surgical or nonsurgical treatment: prospective cohort study

Purpose To compare changes in the largest cross-sectional area (CSA) of the median nerve in wrists undergoing surgical decompression with changes in wrists undergoing non-surgical treatment of carpal tunnel syndrome (CTS). Methods This study was a prospective cohort study in 55 consecutive patients with 78 wrists with established CTS, including 60 wrists treated with surgical decompression and 18 wrists with non-surgical treatment. A sonographic examination was scheduled before and 4 months after initiation of treatment. We compared changes in CSA of the median nerve between wrists with surgical treatment and wrists with non-surgical treatment using linear regression models. Results Decreases in CSA of the median nerve were more pronounced in wrists with CTS release than in wrists undergoing nonsurgical treatment (difference in means, 1.0 mm2; 95% confidence interval, 0.3–1.8 mm2). Results were robust to the adjustment for age, gender, and neurological severity at baseline. Among wrists with CTS release, those with postoperative CSA of 10 mm2 or less tended to have better clinical outcomes than those with postoperative CSA of greater than 10 mm2 (p=.055). Postoperative sonographic workup in the 3 patients with unfavorable outcome or recurrence identified likely causes for treatment failure in 2 patients. Conclusions In this observational study, surgical decompression was associated with a greater decrease in median nerve CSA than was nonsurgical treatment. Smaller postoperative CSAs may be associated with better clinical outcomes. Additional randomized trials are necessary to determine the optimal treatment strategy in different subgroups of patients with CTS. Type of study/level of evidence Therapeutic III.

Impact of non-steroidal anti-inflammatory drugs (NSAIDs) on cardiovascular outcomes in patients with stable atherothrombosis or multiple risk factors

We aimed to assess whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of cardiovascular (CV) events in stable patients with established atherothrombosis or multiple risk factors.

Narcolepsy: autoimmunity, effector T cell activation due to infection, or T cell independent, major histocompatibility complex class II induced neuronal loss?

Human narcolepsy with cataplexy is a neurological disorder, which develops due to a deficiency in hypocretin producing neurons in the hypothalamus. There is a strong association with human leucocyte antigens HLA-DR2 and HLA-DQB1*0602. The disease typically starts in adolescence. Recent developments in narcolepsy research support the hypothesis of narcolepsy being an immune-mediated disease. Narcolepsy is associated with polymorphisms of the genes encoding T cell receptor alpha chain, tumour necrosis factor alpha and tumour necrosis factor receptor II. Moreover the rate of streptococcal infection is increased at onset of narcolepsy. The hallmarks of anti-self reactions in the tissue--namely upregulation of major histocompatibility antigens and lymphocyte infiltrates--are missing in the hypothalamus. These findings are questionable because they were obtained by analyses performed many years after onset of disease. In some patients with narcolepsy autoantibodies to Tribbles homolog 2, which is expressed by hypocretin neurons, have been detected recently. Immune-mediated destruction of hypocretin producing neurons may be mediated by microglia/macrophages that become activated either by autoantigen specific CD4(+) T cells or superantigen stimulated CD8(+) T cells, or independent of T cells by activation of DQB1*0602 signalling. Activation of microglia and macrophages may lead to the release of neurotoxic molecules such as quinolinic acid, which has been shown to cause selective destruction of hypocretin neurons in the hypothalamus.

Clinical outcome of high-risk patients with severe aortic stenosis and reduced left ventricular ejection fraction undergoing medical treatment or TAVI

Introduction Reduced left ventricular function in patients with severe symptomatic valvular aortic stenosis is associated with impaired clinical outcome in patients undergoing surgical aortic valve replacement (SAVR). Transcatheter Aortic Valve Implantation (TAVI) has been shown non-inferior to SAVR in high-risk patients with respect to mortality and may result in faster left ventricular recovery. Methods We investigated clinical outcomes of high-risk patients with severe aortic stenosis undergoing medical treatment (n = 71) or TAVI (n = 256) stratified by left ventricular ejection fraction (LVEF) in a prospective single center registry. Results Twenty-five patients (35%) among the medical cohort were found to have an LVEF≤30% (mean 26.7±4.1%) and 37 patients (14%) among the TAVI patients (mean 25.2±4.4%). Estimated peri-interventional risk as assessed by logistic EuroSCORE was significantly higher in patients with severely impaired LVEF as compared to patients with LVEF>30% (medical/TAVI 38.5±13.8%/40.6±16.4% versus medical/TAVI 22.5±10.8%/22.1±12.8%, p <0.001). In patients undergoing TAVI, there was no significant difference in the combined endpoint of death, myocardial infarction, major stroke, life-threatening bleeding, major access-site complications, valvular re-intervention, or renal failure at 30 days between the two groups (21.0% versus 27.0%, p = 0.40). After TAVI, patients with LVEF≤30% experienced a rapid improvement in LVEF (from 25±4% to 34±10% at discharge, p = 0.002) associated with improved NYHA functional class at 30 days (decrease ≥1 NYHA class in 95%). During long-term follow-up no difference in survival was observed in patients undergoing TAVI irrespective of baseline LVEF (p = 0.29), whereas there was a significantly higher mortality in medically treated patients with severely reduced LVEF (log rank p = 0.001). Conclusion TAVI in patients with severely reduced left ventricular function may be performed safely and is associated with rapid recovery of systolic left ventricular function and heart failure symptoms.

Transcatheter aortic valve implantation or surgical aortic valve replacement as redo procedure after prior coronary artery bypass grafting

The perioperative risk for redo surgical aortic valve replacement (S-AVR) in patients with severe aortic stenosis and prior coronary artery bypass grafting (CABG) is increased. Transcatheter aortic valve implantation (TAVI) represents an alternative. We assessed the perioperative and mid-term clinical outcome of patients undergoing S-AVR or TAVI.

Bowel function remains subjectively unchanged after ileal resection for construction of continent ileal reservoirs

Construction of a continent catheterizable urinary reservoir or an orthotopic bladder substitute requires substantial bowel resection, which can cause changes in bowel transit time. The reported incidence of chronic diarrhea after ileocecal resection is about 20%. Studies assessing bowel function after resection of 55-60 cm of ileum without compromising the ileocecal valve are scarce, and long-term results have not been reported.

Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials

Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α(2)-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.

Influence of V5/6-His Tag on the Properties of Gap Junction Channels Composed of Connexin43, Connexin40 or Connexin45

HeLa cells expressing wild-type connexin43, connexin40 or connexin45 and connexins fused with a V5/6-His tag to the carboxyl terminus (CT) domain (Cx43-tag, Cx40-tag, Cx45-tag) were used to study connexin expression and the electrical properties of gap junction channels. Immunoblots and immunolabeling indicated that tagged connexins are synthesized and targeted to gap junctions in a similar manner to their wild-type counterparts. Voltage-clamp experiments on cell pairs revealed that tagged connexins form functional channels. Comparison of multichannel and single-channel conductances indicates that tagging reduces the number of operational channels, implying interference with hemichannel trafficking, docking and/or channel opening. Tagging provoked connexin-specific effects on multichannel and single-channel properties. The Cx43-tag was most affected and the Cx45-tag, least. The modifications included (1) V j-sensitive gating of I j (V j, gap junction voltage; I j, gap junction current), (2) contribution and (3) kinetics of I j deactivation and (4) single-channel conductance. The first three reflect alterations of fast V j gating. Hence, they may be caused by structural and/or electrical changes on the CT that interact with domains of the amino terminus and cytoplasmic loop. The fourth reflects alterations of the ion-conducting pathway. Conceivably, mutations at sites remote from the channel pore, e.g., 6-His-tagged CT, affect protein conformation and thus modify channel properties indirectly. Hence, V5/6-His tagging of connexins is a useful tool for expression studies in vivo. However, it should not be ignored that it introduces connexin-dependent changes in both expression level and electrophysiological properties.

Comparison of titanium-nitride-oxide-coated stents with zotarolimus-eluting stents for coronary revascularization a randomized controlled trial

Objectives This study sought to compare the efficacy of passive stent coating with titanium-nitride-oxide (TiNO) with drug-eluting stents releasing zotarolimus (ZES) (Endeavor, Medtronic, Minneapolis, Minnesota). Background Stent coating with TiNO has been shown to reduce restenosis compared with bare-metal stents in experimental and clinical studies. Methods In an assessor-blind noninferiority study, 302 patients undergoing percutaneous coronary intervention were randomized to treatment with TiNO or ZES. The primary endpoint was in-stent late loss at 6 to 8 months, and analysis was by intention to treat. Results Both groups were well balanced with respect to baseline clinical and angiographic characteristics. The TiNO group failed to reach the pre-specified noninferiority margin for the primary endpoint (in-stent late loss: 0.64 ± 0.61 mm vs. 0.47 ± 0.48 mm, difference: 0.16, upper 1-sided 95% confidence interval [CI]: 0.26; pnoninferiority = 0.54), and subsequent superiority testing was in favor of ZES (psuperiority = 0.02). In-segment binary restenosis was lower with ZES (11.1%) than with TiNO (20.5%; psuperiority = 0.04). A stratified analysis of the primary endpoint found particularly pronounced differences between stents among diabetic versus nondiabetic patients (0.90 ± 0.69 mm vs. 0.39 ± 0.38 mm; pinteraction = 0.04). Clinical outcomes showed a similar rate of death (0.7% vs. 0.7%; p = 1.00), myocardial infarction (5.3% vs. 6.7%; p = 0.60), and major adverse cardiac events (21.1% vs. 18.0%, hazard ratio: 1.19, 95% CI: 0.71 to 2.00; p = 0.50) at 1 year. There were no differences in rates of definite or probable stent thrombosis (0.7% vs. 0%; p = 0.51) at 1 year. Conclusions Compared with TiNO, ZES was superior with regard to late loss and binary restenosis. The concept of passive stent coating with TiNO remains inferior to drug-eluting stent technology in reducing restenosis. ([TIDE] Randomized Trial Comparing Titan Stent With Zotarolimus-Eluting Stent: NCT00492908)