How to manage the left subclavian artery during endovascular stenting of the thoracic aorta.

We performed a systematic review of the literature to establish whether revascularisation of the left subclavian territory is necessary when this artery is covered by a stent. We retrieved data from 99 studies incorporating 4906 patients. Incidences of left-arm ischaemia (0.0% vs 9.2%, p=0.002) and stroke (4.7% vs 7.2%, p<0.001) were significantly less following revascularisation, although mortality (10.5% vs 3.4%, p=0.032) and endoleak incidence (25.8% vs 12.6%, p=0.008) were increased. No significant differences in spinal-cord ischaemia were seen. Revascularisation may reduce downstream ischaemic complications but can cause significant risk. Indications must be carefully considered on an individual patient basis.

Hand-in-hand advances in biomedical engineering and sensorimotor restoration.

BACKGROUND: Living in a multisensory world entails the continuous sensory processing of environmental information in order to enact appropriate motor routines. The interaction between our body and our brain is the crucial factor for achieving such sensorimotor integration ability. Several clinical conditions dramatically affect the constant body-brain exchange, but the latest developments in biomedical engineering provide promising solutions for overcoming this communication breakdown. NEW METHOD: The ultimate technological developments succeeded in transforming neuronal electrical activity into computational input for robotic devices, giving birth to the era of the so-called brain-machine interfaces. Combining rehabilitation robotics and experimental neuroscience the rise of brain-machine interfaces into clinical protocols provided the technological solution for bypassing the neural disconnection and restore sensorimotor function. RESULTS: Based on these advances, the recovery of sensorimotor functionality is progressively becoming a concrete reality. However, despite the success of several recent techniques, some open issues still need to be addressed. COMPARISON WITH EXISTING METHOD(S): Typical interventions for sensorimotor deficits include pharmaceutical treatments and manual/robotic assistance in passive movements. These procedures achieve symptoms relief but their applicability to more severe disconnection pathologies is limited (e.g. spinal cord injury or amputation). CONCLUSIONS: Here we review how state-of-the-art solutions in biomedical engineering are continuously increasing expectances in sensorimotor rehabilitation, as well as the current challenges especially with regards to the translation of the signals from brain-machine interfaces into sensory feedback and the incorporation of brain-machine interfaces into daily activities.

A selective nociceptive block is not sufficient to prevent central changes after peripheral nerve injury

Background: Providing analgesia without suppressing motor or sensory function is a challenge for regional anesthesia and postoperative pain management. Resiniferatoxin (RTX), an ultrapotent agonist for transient receptor potential subtype-1 (TRPV1) can produce this selective blockade, as TRPV1 is selectively expressed on nociceptors. Futhermore, after peripheral nerve injury, spontaneous ectopic activity arises from all types of nerve fibers that can affect spinal neurons and glial cells. The goal of the present experiment is to determine whether spontaneous activity generated in C-fibers or in both A&C-fibers is required for microglia activation. Method: We applied RTX (0.01%) or bupivacaine microspheres to the sciatic nerve of rats to block the conduction of C-fibers or A&C-fibers, respectively, before spared nerve injury (SNI). Behavior was tested and all the rats were sacrificed 2 days later; immunohistochemistry was performed on their spinal cord for mitogen-activated protein kinase (MAPK) p38, bromodeoxyuridine (BrdU, marker of proliferation) and Iba1 (microglial marker). Result: At day 2 after SNI robust mechanical allodynia and p38 activation in spinal microglia were documented. There was also a substantial cell proliferation in the spinal cord, all proliferating cells (BrdU+) being microglia (Iba1+). RTX blocked heat sensitivity and produced heat hypoalgesia without affecting mechanical allodynia and motor function. Microglial proliferation and p38 activation in the spinal cord were not affected by RTX (p >0.05). In contrast, a complete sensory and motor blockade was seen with bupivacaine which also significantly inhibited p38 activation and microglial proliferation in the spinal cord (p <0.05). Conclusion: We conclude that (1) RTX can provide a selective nociceptive blockade but that (2) blocking only nociceptive fibers does not impair the development of mechanical allodynia and microglia activation. Therefore (3) if microglia activation is important for chronic pain development then specific nociceptive blockade won't be sufficient to prevent it.

Role of Protein Ubiquitination in NFH-LacZ mice

In neurodegenerative diseases, one can observe deposits of degradation products that represent hallmark structures. Actually, the underlying mechanisms are not well understood, but some hypotheses claim that the ubiquitin-proteasome system is perturbed in neurodegenerative diseases. Some of the influencing factors are aging, oxidation and the formation of free radicals, as well as genetic mutations which affect the function of proteins and result in an accumulation and formation of aggresomes. The amyotrophic lateral sclerosis, in which a malfunction of the sodium dismutase perturbs the redox system, is characterized by the accumulation of elements of the cytoskeleton in motor neurons and a progressive neuronal death. We suppose that in these diseases the ubiquitin- proteasome system is deregulated and try to demonstrate this hypothesis by comparing the ubiquitination of different neurofilaments in brain and spinal cord of transgenic and control mice. These NFH-LacZ mice with a truncated NF-H protein and a ß-galactosidase marker protein induce an accumulation of NF-proteins and neurofilaments are no longer transported into axons or dendrites. The accumulation of such aggregates resembles the phenotype of amyotrophic lateral sclerosis. Beside the ubiquitination the neurofilament expression and phosphorylation state was investigated. The results cannot demonstrate a perturbation of the ubiquitin-proteasome system of neurofilaments in transgenic mice. In contrast, in accordance with the mechanism of the NFH-LacZ mice a decrease of high and medium density neurofilaments and a hypophosphorylation were found. In conclusion, to elicit the pathological mechanism of amyotrophic lateral sclerosis and to develop focused treatments, we have to review the pathological mechanism of the transgenic mice and repeat the experiments with other animal models or with human material. Other possibilities would be to focus on other degradation mechanisms, such as the endosome/lysosome system, and to define their role in the amyotrophic lateral sclerosis more clearly.

Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis

Background Multiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors of demyelination and neurodegeneration, by secreting cytokines and others neurotoxic agents. Previous studies have demonstrated that microglia expresses ATP-sensitive potassium (KATP) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of KATP channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Methods Anti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNy)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice were orally treated daily with diazoxide or vehicle for 15 days from the day of EAE symptom onset. Treatment starting at the same time as immunization was also assayed. Clinical signs of EAE were monitored and histological studies were performed to analyze tissue damage, demyelination, glial reactivity, axonal loss, neuronal preservation and lymphocyte infiltration. Results Diazoxide inhibited in vitro nitric oxide (NO), tumor necrosis factor alpha (TNF-¿) and interleukin-6 (IL-6) production and inducible nitric oxide synthase (iNOS) expression by activated microglia without affecting cyclooxygenase-2 (COX-2) expression and phagocytosis. Oral treatment of mice with diazoxide ameliorated EAE clinical signs but did not prevent disease. Histological analysis demonstrated that diazoxide elicited a significant reduction in myelin and axonal loss accompanied by a decrease in glial activation and neuronal damage. Diazoxide did not affect the number of infiltrating lymphocytes positive for CD3 and CD20 in the spinal cord. Conclusion Taken together, these results demonstrate novel actions of diazoxide as an anti-inflammatory agent, which might contribute to its beneficial effects on EAE through neuroprotection. Treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention in ameliorating MS disease.

Comparative modular analysis of gene expression in vertebrate organs.

ABSTRACT: BACKGROUND: The degree of conservation of gene expression between homologous organs largely remains an open question. Several recent studies reported some evidence in favor of such conservation. Most studies compute organs' similarity across all orthologous genes, whereas the expression level of many genes are not informative about organ specificity. RESULTS: Here, we use a modularization algorithm to overcome this limitation through the identification of inter-species co-modules of organs and genes. We identify such co-modules using mouse and human microarray expression data. They are functionally coherent both in terms of genes and of organs from both organisms. We show that a large proportion of genes belonging to the same co-module are orthologous between mouse and human. Moreover, their zebrafish orthologs also tend to be expressed in the corresponding homologous organs. Notable exceptions to the general pattern of conservation are the testis and the olfactory bulb. Interestingly, some co-modules consist of single organs, while others combine several functionally related organs. For instance, amygdala, cerebral cortex, hypothalamus and spinal cord form a clearly discernible unit of expression, both in mouse and human. CONCLUSIONS: Our study provides a new framework for comparative analysis which will be applicable also to other sets of large-scale phenotypic data collected across different species.

Multiple roles of mouse Numb in tuning developmental cell fates.

BACKGROUND: Notch signaling regulates multiple differentiation processes and cell fate decisions during both invertebrate and vertebrate development. Numb encodes an intracellular protein that was shown in Drosophila to antagonize Notch signaling at binary cell fate decisions of certain cell lineages. Although overexpression experiments suggested that Numb might also antagonize some Notch activity in vertebrates, the developmental processes in which Numb is involved remained elusive. RESULTS: We generated mice with a homozygous inactivation of Numb. These mice died before embryonic day E11.5, probably because of defects in angiogenic remodeling and placental dysfunction. Mutant embryos had an open anterior neural tube and impaired neuronal differentiation within the developing cranial central nervous system (CNS). In the developing spinal cord, the number of differentiated motoneurons was reduced. Within the peripheral nervous system (PNS), ganglia of cranial sensory neurons were formed. Trunk neural crest cells migrated and differentiated into sympathetic neurons. In contrast, a selective differentiation anomaly was observed in dorsal root ganglia, where neural crest--derived progenitor cells had migrated normally to form ganglionic structures, but failed to differentiate into sensory neurons. CONCLUSIONS: Mouse Numb is involved in multiple developmental processes and required for cell fate tuning in a variety of lineages. In the nervous system, Numb is required for the generation of a large subset of neuronal lineages. The restricted requirement of Numb during neural development in the mouse suggests that in some neuronal lineages, Notch signaling may be regulated independently of Numb.

Myélite transverse et neuromyélite optique chez l'enfant. A propos de trois observations [Transverse myelitis and optic neuromyelitis in children. Apropos of 3 case reports]

We report on three children with acute transverse myelitis. One of them also had optic neuritis. In connection with these three cases, we discuss etiology, diagnosis and outcome of transverse myelitis in childhood and possible involvement of the optic nerve. Our observations show the variability of spinal cord deficit and the fact that there can be a good prognosis, despite severe initial neurological deficits and massive elevation of basic myelin protein in children with ATM.

Peripheral neuropathy is linked to a severe form of myotonic dystrophy in transgenic mice.

Myotonic dystrophy type 1 (DM1) is a multisystem disorder with a variable phenotype. The involvement of peripheral nerves in DM1 disease is controversial. The DM1 animal model DM300 transgenic mice that carry 350 to 500 CTG repeats express a mild DM1 phenotype but do not exhibit motor or sensory pathology. Here, we investigated the presence or absence of peripheral neuropathy in transgenic mice (DMSXL) that carry more than 1,300 CTG repeats and display a severe form of DM1. Electrophysiologic, histologic, and morphometric methods were used to investigate the structure and function of peripheral nerves. We observed lower compound muscle action potentials recorded from hind limb muscles and slowing of sciatic nerve conduction velocity in DMSXL versus control mice. Morphometric analyses showed an axonopathy and neuronopathy in the DMSXL mice characterized by a decrease in numbers of myelinatedmotor axons in sciatic nerve and in spinal cord motor neurons. Pathologic alterations in the structure of hind limb neuromuscular junctions were also detected in the DMSXL mice. These results suggest that peripheral neuropathy can be linked to a large CTG expansion and a severe form of DM1.

Carotid sparing in definitive irradiation of T1N0 squamous cell larnyx cancer using helical tomotherapy

Objective: To implement a carotid sparing protocol using helical Tomotherapy(HT) in T1N0 squamous-cell laryngeal carcinoma.Materials/Methods: Between July and August 2010, 7 men with stage T1N0 laryngeal carcinoma were included in this study. Age ranged from 47-74 years. Staging included endoscopic examination, CT-scan and MRI when indicated.Planned irradiation dose was 70 Gy in 35 fractions over 7 weeks. A simple treatment planning algorithm for carotidsparing was used: maximum point dose to the carotids 35 Gy, to the spinal cord 30 Gy, and 100% PTV volume to becovered with 95% of the prescribed dose. Carotid volume of interest extended to 1 cm above and below of the PTV.Doses to the carotid arteries, critical organs, and planned target volume (PTV) with our standard laryngealirradiation protocol was compared. Daily megavoltage scans were obtained before each fraction. When necessary, thePlanned Adaptive? software (TomoTherapy Inc., Madison, WI) was used to evaluate the need for a re-planning,which has never been indicated. Dose data were extracted using the VelocityAI software (Atlanta, GA), and datanormalization and dosevolume histogram (DVH) interpolation were realized using the Igor Pro software (Portland,OR).Results: A significant (p < 0.05) carotid dose sparing compared to our standard protocol with an average maximum point dose of 38.3 Gy (standard devaition [SD] 4.05 Gy), average mean dose of 18.59 Gy (SD 0.83 Gy) was achieved.In all patients, 95% of the carotid volume received less than 28.4 Gy (SD 0.98 Gy). The average maximum point doseto the spinal cord was 25.8 Gy (SD 3.24 Gy). PTV was fully covered with more than 95% of the prescribed dose forall patients with an average maximum point dose of 74.1 Gy and the absolute maximum dose in a single patient of75.2 Gy. To date, the clinical outcomes have been excellent. Three patients (42%) developed stage 1 mucositis that was conservatively managed, and all the patients presented a mild to moderate dysphonia. All adverse effectsresolved spontaneously in the month following the end of treatment. Early local control rate is 100% considering a 4-5months post treatment follow-up.Conclusions: HT allows a clinically significant decrease of carotid irradiation dose compared tostandard irradiation protocols with an acceptable spinal cord dose tradeoff. Moreover, this technique allows the PTV to be homogenously covered with a curative irradiation dose. Daily control imaging brings added security marginsespecially when working with high dose gradients. Further investigations and follow-up are underway to better evaluatethe late clinical outcomes especially the local control rate, late laryngeal and vascular toxicity, and expected potentialimpact on cerebrovascular events.

Brain Injuries In Iowa, September 2001

Under Iowa law, hospitals treating persons with a brain or spinal cord injury which results in a hospital admission, patient transfer, or death must report that injury to the Central Registry for Brain and Spinal Cord Injuries of the Iowa Department of Public Health.

The BH4 domain of Bcl-X(L) rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals.

Collective evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is non-cell-autonomous and requires the interaction with the neighboring astrocytes. Recently, we reported that a subpopulation of spinal cord astrocytes degenerates in the microenvironment of motor neurons in the hSOD1(G93A) mouse model of ALS. Mechanistic studies in vitro identified a role for the excitatory amino acid glutamate in the gliodegenerative process via the activation of its inositol 1,4,5-triphosphate (IP(3))-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP(3) can prompt IP(3) receptor (IP(3)R)-mediated Ca(2+) release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca(2+) signaling that occurs downstream of mGluR5 in hSOD1(G93A)-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca(2+) concentrations ([Ca(2+)](i)) in the absence of spontaneous oscillations. The interaction of IP(3)Rs with the anti-apoptotic protein Bcl-X(L) was previously described to prevent cell death by modulating intracellular Ca(2+) signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-X(L), fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca(2+) oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1(G93A) mice with the TAT-BH4 peptide reduces focal degeneration of astrocytes, slightly delays the onset of the disease and improves both motor performance and animal lifespan. Our results point at TAT-BH4 as a novel glioprotective agent with a therapeutic potential for ALS.

Supracerebellar arachnoid cyst - A rare cause of acquired Chiari I malformation.

Chiari I malformation (CM) associated with a cervico-thoracic syrinx due to supracerebellar arachnoid cyst has not been reported in the literature. We report such a case, managed by fenestration of the arachnoid cyst and foramen magnum decompression (FMD), aiming to reduce the inferiorly directed pressure on the cerebellum and eliminate the craniospinal pressure dissociation respectively. Imaging done post-operatively showed upward displacement of the cerebellar tonsils with a decompressed craniovertebral junction and disappearance of the syrinx.