The contribution of inner and outer retinal photoreceptors to infra‐slow oscillations in the rat olivary pretectal nucleus

A subpopulation of olivary pretectal nucleus (OPN) neurons discharges action potentials in an oscillatory manner, with a period of approximately two minutes. This ‘infra‐slow’ oscillatory activity depends on synaptic excitation originating in the retina. Signals from rod‐cone photoreceptors reach the OPN via the axons of either classic retinal ganglion cells or intrinsically photosensitive retinal ganglion cells (ipRGCs), which use melanopsin for photon capturing. Although both cell types convey light information, their physiological functions differ considerably. The aim of the present study was to disentangle how rod‐cone and melanopsin photoresponses contribute to generation of oscillatory activity. Pharmacological manipulations of specific phototransduction cascades were used whilst recording extracellular single‐unit activity in the OPN of anaesthetized rats. The results show that under photopic conditions (bright light), ipRGCs play a major role in driving infra‐slow oscillations, as blocking melanopsin phototransmission abolishes or transiently disturbs oscillatory firing of the OPN neurons. On the other hand, blocking rod‐cone phototransmission does not change firing patterns in photopic conditions. However, under mesopic conditions (moderate light), when melanopsin phototransmission is absent, blocking rod‐cone signalling causes disturbances or even the disappearance of oscillations implying that classic photoreceptors are of greater importance under moderate light. Evidence is provided that all photoreceptors are required for the generation of oscillations in the OPN, although their roles in driving the rhythm are determined by the lighting conditions, consistent with their relative sensitivities. The results further suggest that maintained retinal activity is crucial to observe infra‐slow oscillatory activity in the OPN.     

A novel <Emphasis Type="Italic">KCNA1</Emphasis> mutation in a family with episodic ataxia and malignant hyperthermia

Episodic ataxia type 1 (EA1) is an autosomal dominant channelopathy caused by mutations in KCNA1, which encodes the voltage-gated potassium channel, Kv1.1. Eleven members of an EA family were evaluated with molecular and functional studies. A novel c.746T>G (p.Phe249Cys) missense mutation of KCNA1 segregated in the family members with episodic ataxia, myokymia, and malignant hyperthermia susceptibility. No mutations were found in the known malignant hyperthermia genes RYR1 or CACNA1S. The Phe249Cys-Kv1.1 channels did not show any currents upon functional expression, confirming a pathogenic role of the mutation. Malignant hyperthermia may be a presentation of KCNA1 mutations, which has significant implications for the clinical care of these patients and illustrates the phenotypic heterogeneity of KCNA1 mutations.     

Elevated plasma levels of TIMP-1 in patients with rotator cuff tear

Background and purpose

Extracellular matrix remodeling is altered in rotator cuff tears, partly due to altered expression of matrix metalloproteinases (MMPs) and their inhibitors. It is unclear whether this altered expression can be traced as changes in plasma protein levels. We measured the plasma levels of MMPs and their tissue inhibitors (TIMPs) in patients with rotator cuff tears and related changes in the pattern of MMP and TIMP levels to the extent of the rotator cuff tear.

Methods

Blood samples were collected from 17 patients, median age 61 (39–77) years, with sonographically verified rotator cuff tears (partial- or full-thickness). These were compared with 16 age- and sex-matched control individuals with sonographically intact rotator cuffs. Plasma levels of MMPs and TIMPs were measured simultaneously using Luminex technology and ELISA.

Results

The plasma levels of TIMP-1 were elevated in patients with rotator cuff tears, especially in those with full-thickness tears. The levels of TIMP-1, TIMP-3, and MMP-9 were higher in patients with full-thickness tears than in those with partial-thickness tears, but only the TIMP-1 levels were significantly different from those in the controls.

Interpretation

The observed elevation of TIMP-1 in plasma might reflect local pathological processes in or around the rotator cuff, or a genetic predisposition in these patients. That the levels of TIMP-1 and of certain MMPs were found to differ significantly between partial and full-thickness tears may reflect the extent of the lesion or different etiology and pathomechanisms.The subacromial pain syndrome includes a range of disorders from reversible inflammation to massive rotator cuff tearing (Shindle et al. 2011). The etiology appears to be multifactorial, and several anatomic structures may be involved. Repetitive damage of the supraspinatus tendon by mechanical wear from the coraco-acromial ligament and the anterior acromion was described by Neer 1972, and for a long time it was considered the major cause of cuff tearing (Neer 1983). Others have reported age-related tendon degeneration, associated with alterations in extracellular matrix remodeling as a contributing factor (Lo et al. 2004, Millar et al. 2009, Pasternak and Aspenberg 2009, Shindle et al. 2011). Histopathological changes associated with rotator cuff tendinosis have been documented, but it is unclear whether they are a result of a subacromial impingement or an endogenous process, and whether tendinosis might predispose to tendon tears (Lo et al. 2004).Regardless of whether mechanical or degenerative factors initiates tearing, there are alterations in the cellular and extracellular matrix (Gwilym et al. 2009). It has been suggested that genetic factors may influence apoptosis or regeneration (Gwilym et al. 2009, Shindle et al. 2011). Still, the molecular changes associated with rotator cuff tearing are largely unknown (Lo et al. 2004, Garofalo et al. 2011). Turnover of the extracellular matrix (ECM) is mediated by matrix metalloproteinases (MMPs), a family of at least 24 zinc-dependent endopeptidases. The MMPs are classified according to their main degradative activity, into for example collagenases, gelatinases, and stromelysins (Pasternak and Aspenberg 2009). Their activity is regulated by endogenous inhibitors: tissue inhibitors of metalloproteinases (TIMPs). There are 4 known TIMPs, which reversibly inhibit all MMPs by 1:1 interaction with the zinc-binding site (Lo et al. 2004, Pasternak and Aspenberg 2009). MMP production is induced by factors such as cytokines and tumor necrosis factor-α. MMPs are secreted by connective tissue and inflammatory cells and then activated in the extracellular space (Garofalo et al. 2011). The composition of the ECM is dependent on the balance between MMPs and TIMPs (Lo et al. 2004, Pasternak and Aspenberg 2009, Garofalo et al. 2011). Levels of MMP mRNA and TIMP mRNA were found to be altered in biopsies from torn rotator cuff tendon (Lo et al. 2004). It is not known, however, whether these changes are causative or whether they are secondary to tendon tearing.Studies on MMP and TIMP levels in patients with rotator cuff syndrome and cuff tears have used samples collected at surgery from the subacromial bursa, synovial fluid, or the tendons (Lo et al. 2004, Lakemeier et al. 2010, Shindle et al. 2011). To date, there have been no data on systemic levels. Alterations in MMP and TIMP levels in systemic blood samples have been identified in other musculoskeletal diseases such as Dupuytren’s disease, ankylosing spondylitis, and fracture non-union, suggesting that alterations associated with rotator cuff disease may also be measurable systemically (Ulrich et al. 2003, Henle et al. 2005, Pasternak and Aspenberg 2009). In osteoarthritis, circulating MMP-3 has been suggested to be a marker of disease severity and has been used as a prognostic tool (Lohmander et al. 2005).We measured plasma levels of MMPs and TIMPs in patients with rotator cuff tears and compared partial- and full-thickness tears, in order to find disease-associated changes in the expression patterns of MMP and TIMP.     

NextStitch: double-stranded suture chain,a tool to optimize approximation of sutures in valve surgery with echocardiographic correlation

Suture technique for valve replacement surgery has often focused on decreasing the soft tissue injury that leads to pseudoaneurysm formation and associated latent infection. There is universal recognition that precise suture placement is essential for avoiding adverse sequelae while allowing flexibility during the implantation of the prosthesis. The use of a continuous chain of linked horizontal mattress sutures (NextStitch) has allowed maximal precision in the approximation of sutures within the valve annulus. The product was used in a series of consecutive mitral and aortic valve replacements, and typical echocardiographic images from each type of implantation are presented. Postoperative echocardiography images revealed that no perivalvular leaks occurred and that NextStitch did not obscure detailed interrogation or assessment of the valve prosthesis.     

Acute and subacute toxicity associated with concurrent adjuvant radiation therapy and paclitaxel in primary breast cancer therapy

The purpose of this study was to describe the toxicity of concurrent standard dose adjuvant radiation therapy (RT) and paclitaxel in a series of patients receiving primary breast cancer therapy. From June 1998 to April 1999, 20 patients with breast cancer received concurrent adjuvant radiation and paclitaxel. There were 16 patients (80%) with American Joint Committee on Cancer (AJCC) stage II disease and 4 with stage III disease. Eighteen patients, 12 postmastectomy and 6 breast conservation, were treated with definitive surgery followed by concurrent RT and paclitaxel. Two received concurrent neoadjuvant radiation and paclitaxel. All patients received a doxorubicin-containing combination prior to radiation and paclitaxel. RT was delivered concurrently with paclitaxel after the completion of all doxorubicin therapy, with all patients receiving at least two cycles of paclitaxel (175 mg/m ²) every 3 weeks during RT. Toxicity was graded weekly according to Radiation Therapy Oncology Group criteria. Thirteen patients (65%) developed grade 2 or higher cutaneous toxicity. In the postmastectomy group, 6 of 12 patients (50%) developed grade 2 cutaneous toxicity, and 4 of 12 patients (33%) developed grade 3. RT was discontinued in 1 and placed on hold in 3 of these patients. In the breast-conservation group, 2 of 6 patients (33%) developed grade 3 toxicity. In the neoadjuvant group, 1 of 2 patients (50%) developed grade 3 toxicity. Four patients (20%) developed radiation pneumonitis, 2 of 12 (17%) in the postmastectomy group and 2 of 6 (33%) in the breast conservation group, with 2 requiring hospitalization and 1 a diagnostic open-lung biopsy. In this group of patients, standard dose concurrent radiation and paclitaxel resulted in a high incidence of cutaneous and pulmonary toxicity. Concurrent radiation and paclitaxel with these doses and schedule should be approached cautiously until further studies documenting its safety are completed.     

New onset postoperative atrial fibrillation and early anticoagulation after cardiac surgery

Objectives. New onset postoperative atrial fibrillation (POAF) after cardiac surgery is associated with increased risk for thromboembolic complications. Compliance with anticoagulation treatment is prerequisite for successful outcome after POAF. We hypothesized that a disciplined anticoagulation protocol initiated instantly after POAF secures a long-term outcome. Design. A total of 519 consecutive patients undergoing cardiac surgery were retrospectively analyzed. Patients received anticoagulation using warfarin whenever POAF lasted longer than five min. Postoperative outcome including mortality, myocardial infarction and stroke were compared with patients on sinus rhythm (non-POAF). Results. Mean age of the study cohort was 64.3?±?9.0 years and median follow-up time was 76 months. There were 177 (34%) POAF and 342 (66%) non-POAF patients. At discharge, 144 (81%) POAF patients complied with warfarin, while 82 (24%) non-POAF patients received warfarin for non-rhythm causes (p?p?=?.03). After adjustment for comorbidities, major adverse clinical events (MACE)- including a combination of late cardiovascular mortality, myocardial infarction, stroke and late atrial fibrillation- was independently associated with POAF (OR 2.73, 95%CI 1.69-4.45, p?Conclusions. POAF after cardiac surgery was associated with high risk of MACE. Early anticoagulation may be justified in POAF patients to secure a long-term outcome after cardiac surgery.     

Laparoscopic repair of hiatus hernia: Does mesh type influence outcome? A meta-analysis and European survey study

Background

Synthetic mesh (SM) has been used in the laparoscopic repair of hiatus hernia but remains controversial due to reports of complications, most notably esophageal erosion. Biological mesh (BM) has been proposed as an alternative to mitigate this risk. The aim of this study is to establish the incidence of complications, recurrence and revision surgery in patients following suture (SR), SM or BM repair and undertake a survey of surgeons to establish a perspective of current practice.

Methods

An electronic search of EMBASE, MEDLINE and Cochrane database was performed. Pooled odds ratios (PORs) were calculated for discrete variables. To survey current practice an online questionnaire was sent to emails registered to the European Association for Endoscopic Surgery.

Results

Nine studies were included, comprising 676 patients (310 with SR, 214 with SM and 152 with BM). There was no significant difference in the incidence of complications with mesh compared to SR (P = 0.993). Mesh significantly reduced overall recurrence rates compared to SR [14.5 vs. 24.5 %; POR = 0.36 (95 % CI 0.17–0.77); P = 0.009]. Overall recurrence rates were reduced in the SM compared to BM groups (12.6 vs. 17.1 %), and similarly compared to the SR group, the POR for recurrence was lower in the SM group than the BM group [0.30 (95 % CI 0.12–0.73); P = 0.008 vs. 0.69 (95 % CI 0.26–1.83); P = 0.457]. Regarding surgical technique 503 survey responses were included. Mesh reinforcement of the crura was undertaken by 67 % of surgeons in all or selected cases with 67 % of these preferring synthetic mesh to absorbable mesh. One-fifth of the respondents had encountered mesh erosion in their career.

Conclusions

Both SM and BM reduce rates of recurrence compared to SR, with SM proving most effective. Surgical practice is varied, and there remains insufficient evidence regarding the optimum technique for the repair of hiatal hernia.