Stoma associated complications after diverting loop ileostomy, end ileostomy or split stoma formation after right sided colectomy-a retrospective cohort study (StoComSplit Analysis).

BACKGROUND: For high-risk patients receiving right-sided colectomy, stoma formation is a safety strategy. Options are anastomosis with loop ileostomy, end ileostomy, or split stoma. The aim is to compare the outcome of these three options. METHODS: This retrospective cohort study included all patients who underwent right sided colectomy and stoma formation between January 2008 and December 2021 at two tertial referral centers in Switzerland. The primary outcome was the stoma associated complication rate within one year. RESULTS: A total of 116 patients were included. A total of 20 patients (17%) underwent primary anastomosis with loop ileostomy (PA group), 29 (25%) received an end ileostomy (ES group) and 67 (58%) received a split stoma (SS group). Stoma associated complication rate was 43% (n = 21) in PA and in ES group and 50% (n = 34) in SS group (n.s.). A total of 30% (n = 6) of patients in PA group needed reoperations, whereas 59% (n = 17) in ES and 58% (n = 39) in SS group had reoperations (P = 0.07). Wound infections occurred in 15% (n = 3) in PA, in 10% (n = 3) in ES, and in 30% (n = 20) in SS group (P = 0.08). A total of 13 patients (65%) in PA, 7 (24%) in ES, and 29 (43%) in SS group achieved stoma closure (P = 0.02). A total of 5 patients (38%) in PA group, 2 (15%) in ES, and 22 patients (67%) in SS group had a stoma-associated rehospitalization (P < 0.01). CONCLUSION: Primary anastomosis and loop ileostomy may be an option for selected patients. Patients with end ileostomies have fewer stoma-related readmissions than those with a split stoma, but they have a lower rate of stoma closure. CLINICAL TRIAL REGISTRATION: Trial not registered.

Sympathetic activity and early mobilization in patients in intensive and intermediate care with severe brain injuries: a preliminary prospective randomized study.

BACKGROUND: Patients who experience severe brain injuries are at risk of secondary brain damage, because of delayed vasospasm and edema. Traditionally, many of these patients are kept on prolonged bed rest in order to maintain adequate cerebral blood flow, especially in the case of subarachnoid hemorrhage. On the other hand, prolonged bed rest carries important morbidity. There may be a clinical benefit in early mobilization and our hypothesis is that early gradual mobilization is safe in these patients. The aim of this study was to observe and quantify the changes in sympathetic activity, mainly related to stress, and blood pressure in gradual postural changes by the verticalization robot (Erigo®) and after training by a lower body ergometer (MOTOmed-letto®), after prolonged bed rest of minimum 7 days. METHODS: Thirty patients with severe neurological injuries were randomized into 3 groups with different protocols of mobilization: Standard, MOTOmed-letto® or Erigo® protocol. We measured plasma catecholamines, metanephrines and blood pressure before, during and after mobilization. RESULTS: Blood pressure does not show any significant difference between the 3 groups. The analysis of the catecholamines suggests a significant increase in catecholamine production during Standard mobilization with physiotherapists and with MOTOmed-letto® and no changes with Erigo®. CONCLUSIONS: This preliminary prospective randomized study shows that the mobilization of patients with severe brain injuries by means of Erigo® does not increase the production of catecholamines. It means that Erigo® is a well-tolerated method of mobilization and can be considered a safe system of early mobilization of these patients. Further studies are required to validate our conclusions. TRIAL REGISTRATION: The study was registered in the ISRCTN registry with the trial registration number ISRCTN56402432 . Date of registration: 08.03.2016. Retrospectively registered.

Cell-specific modulation of monocarboxylate transporter expression contributes to the metabolic reprograming taking place following cerebral ischemia.

Monocarboxylate transporters (MCTs) are involved in lactate trafficking and utilization by brain cells. As lactate is not only overproduced during ischemia but its utilization was shown to be essential upon recovery, we analyzed the expression of the main cerebral MCTs at 1 and 24h after an ischemic insult induced by a transient occlusion of the left middle cerebral artery (MCAO) in CD1 mice (n=5, 7 and 10 for control, 1 and 24h groups, respectively). After 1h of reperfusion, an upregulation of the three MCTs was observed in the striatum (MCT1 ipsilateral 2.73 ± 0.2 and contralateral 2.01 ± 0.4; MCT2 ipsilateral 2.1 ± 0.1; MCT4 ipsilateral 1.65 ± 0.1) and in the surrounding cortex of both the ipsilateral (MCT1 2.4 ± 0.4; MCT2 1.62 ± 0.2; MCT4 1.31 ± 0.1) and contralateral (MCT1 2.78 ± 0.4; MCT2 1.76 ± 0.2) hemispheres, compared to the corresponding sham hemispheres. An increase of MCT1 (ipsilateral 2.1 ± 0.2) and MCT2 (contralateral 1.9 ± 0.1) expression was also observed in the hippocampus, while no effect was observed for MCT4. At 24h of reperfusion, total MCT2 and MCT4 expressions were decreased in the striatum (MCT2 ipsilateral 0.32 ± 0.1 and contralateral 0.63 ± 0.1; MCT4 ipsilateral 0.59 ± 0.1) and the surrounding cortex (MCT4 ipsilateral 0.67 ± 0.1), compared to the sham. At the cellular level, neurons which usually express only MCT2 strongly expressed MCT1 at both time points. Surprisingly, staining for MCT4 appeared on neurons and was strong at 24h post-insult, in the striatum and the cortex of both hemispheres. A similar expression pattern was observed also in the ipsilateral hemisphere of the sham operated animals at 24h. Overall, our study indicates that cell-specific changes in MCT expression induced by an ischemic insult may participate to the metabolic adaptations taking place in the brain after a transient ischemic episode.

Density gradients at hydrogel interfaces for enhanced cell penetration.

We report that stiffness gradients facilitate infiltration of cells through otherwise cell-impermeable hydrogel interfaces. By enabling the separation of hydrogel manufacturing and cell seeding, and by improving cell colonization of additively manufactured hydrogel elements, interfacial density gradients present a promising strategy to progress in the creation of 3D tissue models.

[Giant cell arteritis: guidelines of the University Hospital of Lausanne]. / Artérite de Horton: recommandations Lausannoises de prise en charge.

Giant cell arteritis (GCA) is a subacute/chronic vasculitis and represents the most common form of systemic vasculitis in people over the age of 50 years. The absence of clear and specific diagnostic criteria with the highly variable clinical presentation is a diagnostic challenge requesting a multidisciplinary approach. Yet, GCA is an emergency and the treatment must be initiated very rapidly due to the risk of blindness. This article presents a review of GCA as well as the diagnostic and therapeutic institutional guidelines of the University Hospital of Lausanne.

[Neurology]. / Neurologie.

In 2011, new oral anticoagulants for atrial fibrillation are available and the ABCD3-I score predicting stroke after TIA updates the ABCD2 score. New McDonald criteria allow faster MS diagnosis and the first oral treatment (fingolimod) for MS can be prescribed. A new anti-antiepileptic drug (retigabine) is available and sodium valproate has long term neurological adverse effects after in utero exposure. Among Parkinson disease treatments, deep brain stimulation is extending applications and dopamine agonists with extended release are as efficient and well tolerated as standard forms at long term scale. Monoclonal antibodies and immunosuppressant agents are proposed as good alternatives in the treatment of chronic dysimmune polyneuropathies. Gene therapy for the treatment of genetic myopathies is progressing.

[Therapeutic advances in neurology]. / Neurologie.

This article summarizes the main therapeutic advances of 2010 in the field of neurology. It focuses on aspects that are likely to change the care of patients in clinical practice. Among these, we discuss the new oral treatments that have proved to be effective in multiple sclerosis, the results of two large studies comparing endarterectomy and stenting in carotid stenosis, novel therapeutic approaches for the treatment of non-motor symptoms in Parkinson's disease as well as the results of several pharmacological studies in the field of epilepsy.

Nitric oxide is involved in ischemia-induced apoptosis in brain: a study in neuronal nitric oxide synthase null mice.

Nitric oxide can promote or inhibit apoptosis depending on the cell type and coexisting metabolic or experimental conditions. We examined the impact of nitric oxide on development of apoptosis 6, 24, and 72 h after permanent middle cerebral artery occlusion in mutant mice that lack the ability to generate nitric oxide from neuronal nitric oxide synthase. Adjacent coronal sections passing through the anterior commissure were stained with hematoxylin and eosin or terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Immunoblotting was used to identify changes in the anti- and proapoptotic proteins Bcl-2 and Bax, respectively. Activation of caspases was assessed by appearance of actin cleavage products using a novel antiserum directed against 32-kDa actin fragment (fractin). In the neuronal nitric oxide synthase mutant mouse, infarct size and TUNEL positive apoptotic neurons were reduced compared to the wild-type controls. At 6 h, Bcl-2 levels in the ischemic hemisphere were increased in mutants but decreased in the wild-type strain. Bax levels did not change significantly. Caspase-mediated actin cleavage appeared in the ischemic hemisphere at this time point, and was significantly less in mutant brains at 72 h compared to the wild-type. The reduction in the number of TUNEL and fractin positive apoptotic cells appears far greater than anticipated based on the smaller lesion size in mutant mice.Hence, from these data we suggest that a deficiency in neuronal nitric oxide production slows the development of apoptotic cell death after ischemic injury and is associated with preserved Bcl-2 levels and delayed activation of effector caspases.

Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death.

After mild ischemic insults, many neurons undergo delayed neuronal death. Aberrant activation of the cell cycle machinery is thought to contribute to apoptosis in various conditions including ischemia. We demonstrate that loss of endogenous cyclin-dependent kinase (Cdk) inhibitor p16(INK4a) is an early and reliable indicator of delayed neuronal death in striatal neurons after mild cerebral ischemia in vivo. Loss of p27(Kip1), another Cdk inhibitor, precedes cell death in neocortical neurons subjected to oxygen-glucose deprivation in vitro. The loss of Cdk inhibitors is followed by upregulation of cyclin D1, activation of Cdk2, and subsequent cytoskeletal disintegration. Most neurons undergo cell death before entering S-phase, albeit a small number ( approximately 1%) do progress to the S-phase before their death. Treatment with Cdk inhibitors significantly reduces cell death in vitro. These results show that alteration of cell cycle regulatory mechanisms is a prelude to delayed neuronal death in focal cerebral ischemia and that pharmacological interventions aimed at neuroprotection may be usefully directed at cell cycle regulatory mechanisms.

Astrocyte-specific expression of aquaporin-9 in mouse brain is increased after transient focal cerebral ischemia.

Aquaporin-9 (AQP9) is a new member of the aquaporin family of water-selective channels mainly expressed in liver and testis, presenting the characteristic of also being permeable to various solutes, particularly lactate. Recent data have shown the presence of AQP9 on tanycytes in the rat brain. In the current study, the authors show the expression of AQP9 in astrocytes in the mouse brain and changes in its expression after cerebral ischemia. Indeed, in control mouse, the AQP9 immunolabeling is present on astrocytic processes bordering the subarachnoid space and ventricles. The labeling also is observed on astrocytes in the white matter, hippocampus, hypothalamus, and lateral septum. After focal transient ischemia, an increase of the immunolabeling is detected on astrocytes in periinfarct areas. This AQP9 distribution study in mouse brain suggests a role of AQP9 in water homeostasis in the central nervous system. Furthermore, the overexpression of AQP9 on astrocytes surrounding an ischemic lesion suggests that AQP9 may also play a role in the regulation of postischemia edema and, in view of its permeability to monocarboxylates, in the clearance of lactate from the ischemic focus.

Synergistic protective effect of caspase inhibitors and bFGF against brain injury induced by transient focal ischaemia.

We tested the hypothesis that combined use of trophic factors and caspase inhibitors increases brain resistance to ischaemia in mice. Intracerebroventricular administration of bFGF (>10 ng) 30 min after MCA occlusion decreased infarct size and neurological deficit in a dose-dependent manner following 2 h ischemia and reperfusion (20 h). Combined administration of the subthreshold doses of bFGF (3 ng) and caspase inhibitors (z-VAD.FMK, 27 ng or z-DEVD.FMK, 80 mg) reduced infarct volume by 60%, and reduced neurological deficit. Treatment with a subthreshold dose of bFGF (3 ng) extended the therapeutic window for z-DEVD.FMK (480 ng) from 1 to 3 h after reperfusion. Caspase-3 activity in the ischaemic brain was increased 30 min and 2 h after reperfusion but, was significantly reduced in bFGF-treated animals by 29 and 16%, respectively. Caspase-3 activity was not reduced by a direct bFGF effect because addition of bFGF (10 nM - 2 microM) did not decrease recombinant caspase-3 activity, in vitro. Our data show that combining caspase inhibitors and bFGF lengthens the treatment window for the second treatment, plus lowers the dosage requirements for neuroprotection. These findings are important because low doses of caspase inhibitors or bFGF reduce the possibility of side effects plus extend the short treatment window for ischaemic stroke.

Fas receptor and neuronal cell death after spinal cord ischemia.

Cell death from spinal cord injury is mediated in part by apoptotic mechanisms involving downstream caspases (e.g., caspase-3). Upstream mechanisms may involve other caspases such as procaspase-8, a 55 kDa apical caspase, which we found constitutively expressed within spinal cord neurons along with Fas. As early as 1.5 hr after transient ischemia, activated caspase-8 (p18) and caspase-8 mRNA appeared within neurons in intermediate gray matter and in medial ventral horn. We also detected evidence for an increase in death receptor complex by co-immunoprecipitation using Fas and anti-procaspase-8 after ischemia. At early time points, Fas and p18 were co-expressed within individual neurons, as were activated caspase-8 and caspase-3. Moreover, we detected p18 in cells before procaspase-3 cleavage product (p20), suggesting sequential activation. The appearance of cytosolic cytochrome c and gelsolin cleavage after ischemia was consistent with mitochondrial release and caspase-3 activation, respectively. Numerous terminal deoxynucleotidyl transferase-mediated DNA nick end-labeling-positive neurons contained p18 or p20 (65 and 80%, respectively), thereby supporting the idea that cells undergoing cell death contain both processed caspases. Our data are consistent with the idea that transient spinal cord ischemia induces the formation of a death-inducing signaling complex, which may participate in caspase-8 activation and sequential caspase-3 cleavage. Death receptors as well as downstream caspases may be useful therapeutic targets for limiting the death of cells in spinal cord.

Ischemic brain damage in mice after selectively modifying BDNF or NT4 gene expression.

The neurotrophins and the tyrosine kinase (Trk) B receptor may play a protective role in the pathophysiology of cerebral ischemia. In this study, the authors investigated whether reducing endogenous expression of TrkB-binding neurotrophins modifies the susceptibility to ischemic injury after 1-hour middle cerebral artery occlusion followed by 23 hours of reperfusion in a filament middle cerebral artery occlusion model. Mice lacking both alleles for neurotrophin-4 (nt4-/-) or deficient in a single allele for brain-derived neurotrophic factor (bdnf+/-) exhibited larger cerebral infarcts compared to wild-type inbred 129/SVjae mice (68% and 91%, respectively, compared to controls). Moreover, lesions were larger (21%) in nt4-/- mice after permanent middle cerebral artery occlusion. Hence, expression of both NT4 and BDNF, and by inference the TrkB receptor, confers resistance to ischemic injury.

Spinal cord ischemia. Development of a model in the mouse.

BACKGROUND AND PURPOSE: Spinal cord ischemia with resulting paraplegia is a devastating complication of thoracoabdominal aortic surgery. Experimental models of spinal cord ischemia have been developed in primate, dog, pig, rabbit, and rat with variable reproducibility, but none has been developed in mouse. Because genetically engineered mice have become important to examine the impact of specific genes in ischemic pathophysiology, we sought to develop a reproducible mouse model of spinal cord ischemia. METHODS: C57BL/6NCrlBR mice were subjected to cross-clamping of the aortic arch, left subclavian artery, and internal mammary artery for 9 minutes (group A; n=8) or 11 minutes (group B; n=29) followed by reperfusion for 24 or 48 hours. Mean distal arterial blood pressure (left femoral artery) and lumbar (L1) spinal cord blood flow (laser-Doppler flowmetry) were measured for the duration of the procedure. The arterial blood supply of the spinal cord was visualized by intravascular perfusion of carbon black ink. We evaluated motor function in the hind limbs at 0, 1, 3, 6, and 24 hours after reperfusion using a rating scale of 0 (normal function) to 6 (total absence of movement). Spinal cord histopathology was evaluated after 24 and 48 hours of reperfusion by Luxol fast blue-hematoxylin and eosin. RESULTS: The vascular anatomy of the mouse and human spinal cord appeared similar in that blood was supplied by 1 anterior and 2 posterior spinal arteries and heterosegmental radicular arteries. During combined occlusion of aortic arch and left subclavian artery, mean distal arterial blood pressure dropped to 10+/-5 mm Hg, and spinal cord blood flow at the L1 level decreased to 27+/-7% of baseline. All animals recovered from anesthesia with acute paraplegia. Animals in the 9-minute group (group A) showed steady recovery of hind limb function over the ensuing 24 hours, whereas the majority (80%) in the 11-minute group (group B) remained paralyzed with maximum deficit throughout the postoperative period. Mortality was 0% and 21% in groups A and B, respectively. Maximal ischemic damage was observed at the lower thoracic and higher lumbar spinal levels in both groups. In group A (9 minutes), tissue damage was mild, affecting predominantly dorsal horns and intermediate gray matter, whereas ventral horns were minimally involved. All mice in group B (11 minutes) showed extensive gray matter lesions particularly involving dorsal horns and intermediate areas; in ventral horns, >50% of motor neurons died. White matter lesions were present in the most severely damaged cords only. CONCLUSIONS: Spinal cord ischemia caused by aortic arch plus left subclavian artery cross-clamping provides a mouse model useful for the study of spinal cord injury and of potential relevance to the complications following thoracoabdominal aortic surgery in humans.

Sniff nasal pressure: a sensitive respiratory test to assess progression of amyotrophic lateral sclerosis.

Impairment of pulmonary function is a major prognostic indicator in amyotrophic lateral sclerosis (ALS). Forced vital capacity (FVC) and maximal voluntary ventilation (MVV) decline linearly and are commonly used to assess disease progression. The aim of this study was to evaluate the usefulness of testing respiratory muscle strength in ALS with a novel test, sniff nasal pressure (Pn(sn)), in parallel with more classic tests such as maximal inspiratory pressure (PI(max)) and maximal expiratory pressure (PE(max)). Sixteen patients with ALS were examined monthly over a period of 18 +/- 10 months. At the time of inclusion in the study, values were normal for FVC (107% of predicted value) and MVV (87% of predicted value) but abnormally low for Pn(sn) (67% of predicted value), PI(max) (69% of predicted value), and PE(max) (54% of predicted value). Late in the course of ALS, all patients could perform Pn(sn) whereas 6 could not perform PI(max) and 7 could not perform PE(max). The rate of deterioration was most often linear and similar for FVC (-4.1% of predicted value per month), MVV (-4.3% of predicted value per month), and Pn(sn) (-4.2% of predicted value per month). We conclude that Pn(sn) was the single respiratory test combining linear decline, sensitivity in mild disease, and feasibility in advanced disease. Being easy to perform and inexpensive, Pn(sn) appears well suited to assess the decline of respiratory muscle strength in ALS.

[Ocular mitochondrial myopathies: a spectrum of clinical presentations]. / Myopathies mitochondriales oculaires: un éventail de présentations cliniques.

PURPOSE: To determine the spectrum of clinical presentations of patients with chronic progressive external ophthalmoplegia (CPEO). METHODS: Retrospective study of 13 cases with CPEO. RESULTS: Eight patients presented an isolated CPEO, three patients had an associated retinopathy (Kearns-Sayre syndrome), one case suffered from retinopathy, deafness, diabetes mellitus and dysphagia, and one patient had an associated dysphagia. Mitochondrial DNA deletions were found in two cases. CONCLUSIONS: Our cases illustrate the wide spectrum of mitochondrial ocular myopathies. As patients present mostly with ptosis and ophthalmoplegia, ophthalmologists should be aware of these rare conditions.

Ragged-red fibers and complex I deficiency in a neonate with arthrogryposis congenita.

We describe a neonate with hypotonia, weakness, early death owing to respiratory failure, and a severe form of arthrogryposis multiplex congenita. Postmortem studies revealed numerous ragged-red fibers and central nervous system abnormalities consistent with a mitochondrial disease. No NADH:ubiquinone-1 oxidoreductase (complex I) activity could be detected in skeletal muscle. These findings suggest that mitochondrial cytopathies can be associated with arthrogryposis multiplex congenita and should therefore be sought in neonates presenting with severe arthrogryposis.