Self-expanding intestinal expansion sleeves (IES) for short gut syndrome.

PURPOSE: Many disease processes (necrotizing enterocolitis, caustic esophageal injury, malrotation with volvulus), can result in short-gut syndrome (SGS), where remnant intestinal segments may dilate axially, but rarely elongate longitudinally. Here we mechanically characterize a novel model of a self-expanding mesh prototype intestinal expanding sleeve (IES) for use in SGS. METHODS: Gut lengthening was achieved using a proprietary cylindrical layered polyethylene terephthalate IES device with helicoid trusses with isometric ends. The IES is pre-contracted by diametric expansion, deployed into the gut and anchored with bioabsorbable sutures. IES expansion to its equilibrium dimension maintained longitudinal gut tension, which may permit remodeling, increased absorptive surface area while preserving vascular and nervous supplies. We performed mechanical testing to obtain the effective force-displacement characterization achieved on these prototypes and evaluated minimal numbers of sutures needed for its anchoring. Furthermore, we deployed these devices in small and large intestines of New Zealand White rabbits, measured IES length-tension relationships and measured post-implant gut expansion ex vivo. Histology of the gut before and after implantation was also evaluated. RESULTS: Longitudinal tension using IES did not result in suture failure. Maximum IES suture mechanical loading was tested using 4-6 sutures; we found similar failure loads of 2.95 ± 0.64, 4 ± 1.9 and 3.16 ± 0.24 Newtons for 4, 6 and 8 sutures, respectively (n = 3, n.s). Pre-contracted IES tubes were deployed at 67 ± 4% of initial length (i.l.); in the large bowel these expanded significantly to 81.5 ± 3.7% of i.l. (p = 0.014, n = 4). In the small bowel, pre-contracted IES were 61 ± 3.8% of i.l.; these expanded significantly to 82.7 ± 7.4% of i.l. (p = 0.0009, n = 6). This resulted in an immediate 24 ± 7.8% and 36.2 ± 11% increase in gut length when deployed in large and small bowels, respectively, with maintained longitudinal tension. Maintained IES induced tension produced gut wall thinning; gut histopathological evaluation is currently under evaluation. CONCLUSION: IES is a versatile platform for gaining length in SGS, which may be simply deployed via feeding tubes. Our results need further validation for biocompatibility and mechanical characterization to optimize use in gut expansion.

Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis.

Progressive multifocal leukoencephalopathy (PML) is an uncommon and often fatal demyelinating disease of human central nervous system, which is caused by reactivation of the polyomavirus JC (JCV). PML generally occurs in patients with profound immunosuppression such as AIDS patients. Recently, a number of PML cases have been associated with administration of natalizumab for treatment of multiple sclerosis (MS) patients. Diagnosis and management of PML became a major concern after its occurrence in multiple sclerosis patients treated with natalizumab. Diagnosis of PML usually rests on neuroimaging in the appropriate clinical context and is further confirmed by cerebrospinal fluid polymerase chain reaction (PCR) for JCV DNA. Treatment with antiretroviral therapies in HIV-seropositive patients or discontinuing natalizumab in MS patients with PML may lead to the development of immune reconstitution inflammatory syndrome (IRIS) which presents with deterioration of the previous symptoms and may lead to death. In patients under treatment with monoclonal antibodies in routine practice, or new ones in ongoing clinical trials, differentiating PML from new MS lesions on brain MRI is critical for both the neurologists and neuroradiologists. In this review, we discuss the clinical features, neuroimaging manifestations of PML, IRIS and neuroimaging clues to differentiate new MS lesions from PML. In addition, various neuroimaging features of PML on the non-conventional MR techniques such as diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), and MR spectroscopy (MRS) are discussed.

Increasing female preponderance of multiple sclerosis in Isfahan, Iran: a population-based study.

There is an overall increase in the worldwide prevalence and incidence of multiple sclerosis (MS). Studies from several countries also demonstrated an increase of female/male ratio over time denoting an increase in the incidence of MS particularly in women. In this study we sought to assess the trends in MS incidence and prevalence in males and females over recent decades in Isfahan, Iran, which differs from other regions in terms of environmental and lifestyle changes. We determined female/male ratio by year of birth (YOB) in 1584 patients with MS registered with Isfahan Multiple Sclerosis Society (IMSS) from April 2003 to August 2007. A comparison of sex ratio of MS patients by YOB showed a significant, progressive, gradual increase, with an apparent interruption in the late 1960s. In this study year of birth is a significant predictor for sex ratio (p < 0.001, chi(2) = 17.130, Spearman's rank correlation r = 0.893). Our findings show that there is a significant increase in the incidence of MS among females for the the last decades in the Isfahan province of Iran. This rapid increase may be related to changes in environmental interactions rather than genetic factors, and among them vitamin D insufficiency, enhanced diagnosis, and lifestyle changes appear to be more plausible causative factors.

Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b.

BACKGROUND: Interferon-beta1b (IFN-beta1b), an effective treatment for multiple sclerosis (MS), lessens disease severity in MS patients. However, the mechanisms of its immunoregulatory and anti-inflammatory effects in MS remain only partially understood. Matrix metalloproteinases (MMP) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) are involved in blood brain barrier disruption and formation of MS lesions. Th1/Th17 cytokines e.g. interleukins IL-12p40, IL-17, and IL-23, are associated with MS disease activity and are significant players in pathogenesis of MS. OBJECTIVE: During a 1-year prospective study, we serially measured serum MMP-8, MMP-9, TIMP-1, IL-12p40, IL-17, and IL-23 in 24 patients with relapsing-remitting MS. We compared the results to clinical course and to brain magnetic resonance imaging. IFN-beta1b decreased serum MMP-8 and MMP-9 (not TIMP-1). RESULTS: The sustained treatment with IFN-beta1b attenuated the pro-inflammatory environment by significantly reducing the serum IL-12p40, IL-23, and showed a trend for decreasing IL-17. Decreased serum MMP-8, MMP-9, IL-12 and IL-23 levels were correlated with a decrease in the number of contrast-enhanced T2-weighted lesions. CONCLUSION: Early treatment of MS with IFN-beta1b may stabilize clinical disease by attenuating levels of inflammatory cytokines and MMPs. Serial measurement of inflammatory mediators may serve as sensitive markers to gauge therapeutic responses to IFN-beta1b during the first year of treatment.

Neurolymphatic biomarkers of brain endothelial inflammatory activation: Implications for multiple sclerosis diagnosis.

AIMS: Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults, and its diagnosis is often delayed due to the lack of diagnostic markers. Initiation of disease -modifying therapy in the early stages of MS is especially critical because currently available therapy mostly target relapsing-remitting MS, and is less effective as disease progresses into the more chronic form of secondary-progressive MS. Therefore, exploring specific and sensitive biomarkers will facilitate an expedited and more accurate diagnosis to allow currently available therapies to be more effective. MAIN METHODS: Western blotting was conducted to detect the expression of neurolymphatic proteins in human brain endothelial cells in culture. Additionally, using a cohort of 150 patients with relapsing remitting MS, 26 with secondary progressive MS, and 60 healthy control samples, neurolymphatic protein expression was detected in serum samples using dot blot analysis. KEY FINDINGS: Human brain microvascular endothelial cells express neurolymphatic markers. Neurolymphatic protein abundance increases with tumor necrosis factor (TNF)-α stimulation but decreases with interferon (IFN)- γ or combined (TNF + IFN) treatment. Circulating neurolymphatic protein levels is significantly lower in MS patients. Further, one of the markers, FOXC2, is associated with the clinical stages of MS, with significantly lower expression in secondary progressive MS compared to relapsing remitting MS. SIGNIFICANCE: Our findings describe brain endothelial expression of neurolymphatic proteins, which is altered under inflammatory stress, and provide a possibility of using a collective pool of circulating neurolymphatic proteins as a diagnostic and prognostic biomarker of MS.

MAdCAM-1 expression and regulation in murine colonic endothelial cells in vitro.

BACKGROUND: Although the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is associated with the etiology of inflammatory bowel diseases, few studies have directly examined MAdCAM-1 using microvascular endothelium derived from the colon. This study measured the expression of MAdCAM-1 in a novel colon endothelial line MJC-1, as well as MAdCAM-1 regulation and function in vitro. METHODS: We cloned microvascular endothelial cells from primary colon cultures using ImmortoMice mice (whose cells express a temperature-sensitive SV40 large T antigen, H-2Kb-tsA58 mice). Expression of MAdCAM-1 after stimulation with cytokines [tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, or interferon (IFN)-gamma] was determined by Western blotting. Signal paths regulating MAdCAM-1 expression were examined using pharmacological blockers before cytokines. We also examined lymphocyte adhesion using lymphocytes that constitutively express alpha4beta7 integrin. RESULTS: TNF-alpha induced MAdCAM-1 in a dose-dependent manner by 24 hours. MAdCAM-1 induction was protein kinase C, tyrosine kinase, p38 mitogen activated protein kinase, and nuclear-factor kappa-B/poly adenosine diphosphate ribose polymerase dependent. Lymphocyte adhesion was increased 2.6-fold after TNF-alpha stimulation and was inhibited by anti-MAdCAM-1 antibody before treatment (P < 0.05 control versus TNF-alpha). CONCLUSIONS: In vitro, MAdCAM-1 can be induced on colon endothelial cells by TNF-alpha stimulation and may represent a useful model to study microvascular injury in the large intestine.

Blood circulating microparticle species in relapsing-remitting and secondary progressive multiple sclerosis. A case-control, cross sectional study with conventional MRI and advanced iron content imaging outcomes.

BACKGROUND: Although multiple sclerosis (MS) is thought to represent an excessive and inappropriate immune response to several central nervous system (CNS) autoantigens, increasing evidence also suggests that MS may also be a neurovascular inflammatory disease, characterized by endothelial activation and shedding of cell membrane microdomains known as 'microparticles' into the circulation. OBJECTIVE: To investigate the relationships between these endothelial biomarkers and MS. METHODS: We examined the relative abundance of CD31(+)/PECAM-1, CD51(+)CD61(+) (αV-ß3) and CD54(+) (ICAM-1) bearing microparticles in sera of healthy individuals, patients with relapsing-remitting MS, and secondary-progressive MS. We also investigated the correlation among circulating levels of different microparticle species in MS with conventional MRI (T2- and T1-lesion volumes and brain atrophy), as well as novel MR modalities [assessment of iron content on susceptibility-weighted imaging (SWI)-filtered phase]. RESULTS: Differences in circulating microparticle levels were found among MS groups, and several microparticle species (CD31(+)/CD51(+)/CD61(+)/CD54(+)) were found to correlate with conventional MRI and SWI features of MS. CONCLUSION: These results indicate that circulating microparticles' profiles in MS may support mechanistic roles for microvascular stress and injury which is an underlying contributor not only to MS initiation and progression, but also to pro-inflammatory responses.

Glossopharyngeal neuralgia and MS.

Glossopharyngeal neuralgia (GPN) is characterized by a severe lancing pain in the posterior pharynx, tonsillar fossa, and base of the tongue. It is induced frequently by swallowing and yawning. GPN has not been described previously in MS patients. The authors report four MS patients with GPN. Three responded to carbamazepine and one resolved during treatment with adrenocorticotrophin hormone (ACTH) and cyclophosphamide. Withdrawal of carbamazepine after 1 week in one patient resulted in recurrence of pain. GPN may be associated with MS and responds to carbamazepine.

Cerebral ventricles are smaller in Hispanic than non-Hispanic patients with Alzheimer's disease.

MRI scans were compared between 71 Hispanic and 73 white non-Hispanic patients with National Institute of Neurological Disorders and Stroke probable AD. Analysis of covariance controlled for age, sex, education, and Mini-Mental State Examination scores indicated that ventricular size was smaller in Hispanic than white non-Hispanic patients (p = 0.0003). There was no difference in cortical atrophy and T2-weighted white matter hyperintense signals between groups.

Bilateral infarction in the territory of the anterior cerebral arteries.

An elderly hypertensive man had extensive bilateral infarction in the distribution of the anterior cerebral arteries. The circle of Willis was fully formed, but occlusion of the dominant anterior cerebral artery, aggravated and perhaps caused by postlaparotomy hypotension, produced the dramatic lesions, causing akinetic mutism. This stroke pattern occurs in various settings and does not require an anomalous azygous unilateral supply to both anterior cerebral arteries.

Perverted head-shaking nystagmus: a possible mechanism.

The authors describe a patient with acute MS who developed vertigo (tumbling) and downbeat nystagmus upon horizontal head oscillation (perverted head-shaking nystagmus). The only abnormality on brain MRI was a hyperintense signal in the caudal medulla that contains the nucleus Roller and nucleus intercalatus. These nuclei project to structures involved in the velocity storage system for horizontal vestibulocular reflex (VOR) and vertical VOR, and also to the vestibular cerebellum. The authors offer possible mechanisms for perverted nystagmus in this patient.

Pramipexole in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder with no effective treatment. Dopaminergic agents occasionally produce transient symptomatic improvement. The authors report the results of pramipexole treatment (4.5 mg daily) in six patients with PSP (average disease duration, 4.4 years). Patients were treated for 2 months. Patients were evaluated with the Unified Parkinson's Disease Rating Scale, Hoehn and Yahr stage, and Schwab and England Activities of Daily Living Scale at baseline and 2 months. Pramipexole was not efficacious for the symptoms of PSP.

Amantadine-induced peripheral neuropathy.

We report a 48-year-old woman with a 17-year history of PD who developed a peripheral sensory-motor neuropathy secondary to chronic administration (8 years) of amantadine. Discontinuation of amantadine resulted in resolution of trophic skin ulcers, paresthesias, and distal weakness. Amantadine may be hazardous to patients with severe and chronic livedo reticularis.

Elevated plasma endothelial microparticles in multiple sclerosis.

OBJECTIVE: To assess endothelial dysfunction in patients with MS and to investigate whether plasma from patients with MS induces endothelial cell dysfunction in vitro. BACKGROUND: Endothelial cell dysfunction may contribute to the pathogenesis of MS. Elevations of soluble adhesion molecules intracellular adhesion molecule, vascular cell adhesion molecule, and platelet-endothelial cell adhesion molecule-1 (CD31) have been reported as markers of blood-brain barrier (BBB) damage in MS, but direct assay of endothelium has been difficult. Endothelial cells release microparticles < approximately 1.5 microm (EMP) during activation or apoptosis. The authors developed a flow cytometric assay of EMP and studied EMP as markers of endothelial damage in MS. METHODS: Platelet-poor plasma (PPP) from 50 patients with MS (30 in exacerbation and 20 in remission) and 48 controls were labeled with fluorescein isothiocyanate (FITC)-conjugated anti-CD31 and anti-CD51 (vitronectin receptor) antibodies, and two classes of EMP (CD31+ and CD51+) were assayed by flow cytometry. For in vitro studies, patients' plasma was added to the microvascular endothelial cell (MVEC) culture and release of CD31+ and CD51+ EMP were measured in the supernatant. RESULTS: Plasma from patients in exacerbation had 2.85-fold elevation of CD31+ EMP as compared with healthy controls, returning to near control value during remission. The CD31+ EMP concentration showed a positive association with gadolinium enhancement in patients with MS. In contrast, CD51+ EMP remained elevated in both exacerbation and remission. This suggests that CD31+ EMP is a marker of acute injury, whereas CD51+ EMP reflects chronic injury of endothelium. MS plasma induced release of both CD31+ and CD51+ EMP from MVEC culture in vitro. CONCLUSION: Endothelial dysfunction is evident during exacerbation of MS, evidenced by shedding of EMP expressing PECAM-1 (CD31). The in vitro data indicate contribution of one or more plasma factors in endothelial dysfunction of MS.

Analytic approaches to differential gene expression in AIDS versus control brains.

We previously showed that specific strains of human immunodeficiency virus (HIV)-1 infect the brain and contribute to Neuropathology, Cognitive Distress, and Neuropsychiatric Disease. To study further brain disease that results from HIV-1 infection, we commenced analysis of changes in gene expression in brain. We analyzed RNA purified from Frontal Cortex of 5 HIV-1 infected and 4 HIV-1 negative control subjects RNA was amplified and Affymetrix technology was used to analyze gene expression using the 12,585 gene Affymetrix Human Genome U95A chip. The expressed genes showed highly significant Pearsons correlations with each other within the two groups. Expression intensities were transferred to Microsoft Excel and Spotfire was used to analyze the results. Twenty-group K-means cluster analysis was done for HIV+ and HIV- subjects. Genes that were expressed in the same cluster numbers in the two groups were removed from further analysis. Analysis of Gene expression in the top 13 HIV+ clusters showed expression in the 40 gene categories designated in our prior studies. Genes from several categories occurred in more than one K-means cluster. Genes identified in these lists included several genes that have been previously studied: MBP, Myelin-PLP, NMDA receptor, MAG, astrocytic protein, Notch 3, APP, Senescence, proteasome, Ferritin, signaling, cell cycle, iNOS, Chemokine, splicing, synapse, protein tags, and ribosomal proteins. The first (primary significant) axis of both Principal Component Analyses ordered the genes in the same patient groups as the K-means cluster analysis for the respective patient groups. PCA was thus not more informative than K-Means cluster analysis. Ratios of HIV+ to HIV- intensities were calculated for all the averaged gene expression intensities. The ratio range was 0.14 to 9.26. The genes at the extremes (ad extrema) did not correspond to the gene order by K-means clustering (or PCA). The genes in the top 13 K-means clusters showed low-level changes by expression ratio. Genes ad extrema by ratio were in clusters with very large memberships. Mann-Whitney analysis confirmed expression ratio results. Several inferences result from our preliminary study. First, study design will be different in future studies involving additional replicates. Second, ratios inform us of the extent of changes in gene expression quantitatively. Third, Cluster methodology provides us with more subtle information, how bunches (clusters) of genes behave in terms of their centroids (attractors). Fourth, genes that change extensively by ratio tend to be in the larger k-Means clusters. We conclude that ranking gene expression with the use of expression ratio or by K-means clustering, yield different representations of the data.

Human neuroepithelial cells express NMDA receptors.

L-glutamate, an excitatory neurotransmitter, binds to both ionotropic and metabotropic glutamate receptors. In certain parts of the brain the BBB contains two normally impermeable barriers: 1) cerebral endothelial barrier and 2) cerebral epithelial barrier. Human cerebral endothelial cells express NMDA receptors; however, to date, human cerebral epithelial cells (neuroepithelial cells) have not been shown to express NMDA receptor message or protein. In this study, human hypothalamic sections were examined for NMDA receptors (NMDAR) expression via immunohistochemistry and murine neuroepithelial cell line (V1) were examined for NMDAR via RT-PCR and Western analysis. We found that human cerebral epithelium express protein and cultured mouse neuroepithelial cells express both mRNA and protein for the NMDA receptor. These findings may have important consequences for neuroepithelial responses during excitotoxicity and in disease.

Interferon (IFN)-beta 1a and IFN-beta 1b block IFN-gamma-induced disintegration of endothelial junction integrity and barrier.

Recent clinical trials indicate the efficacy of interferon (IFN)-beta 1b in reducing relapse rate in relapsing-remitting multiple sclerosis (MS), whereas a surge of IFN-gamma precedes and provokes acute relapses. Disruption of the cerebral endothelial barrier and transendothelial migration of inflammatory cell migration into the brain play a significant role in pathogenesis of MS and may be driven by this surge in IFN-gamma. However, the molecular mechanisms underlying the beneficial effects of IFN-beta 1b against the deleterious effects of IFN-gamma on the barrier formed by the junctional proteins remain to be characterized. The authors investigated the effects of IFN-beta 1b, IFN-beta 1a, and IFN-gamma on the integrity of two endothelial junctional proteins, occludin and vascular endothelial-cadherin (VE-cadherin). Human umbilical vein endothelial cell (HUVEC) layers were treated with IFN-beta 1b, IFN-beta 1a, IFN-gamma, IFN-beta 1b plus IFN-gamma, or IFN-beta 1a plus IFN-gamma. IFN-beta 1b, IFN-beta 1a, and IFN-gamma effects on occludin and VE-cadherin integrity and electrical resistance were assessed by Western blotting and immunofluorescence. IFN-gamma significantly reduced occludin expression and produced gaps in endothelial monolayers. VE-cadherin expression was decreased to a lesser extent in endothelial cells exposed to IFN-gamma. IFN-beta 1b significantly attenuated the IFN-gamma-induced decrease in occludin and VE-cadherin expression. The protective effects of IFN-beta 1a on IFN-gamma-treated endothelial cells were similar to those of IFN-beta 1b. IFN-gamma also significantly reduced endothelial monolayer electrical resistance; this effect was blocked by either IFN-beta 1a or IFN-beta 1b. IFN-beta 1a and IFN-beta 1b effectively prevent the IFN-gamma-induced disintegration of the endothelial tight junctions and sustain barrier against the effects of IFN-gamma. The protective effects of IFN-beta on occludin and VE-cadherin stability appear to represent molecular mechanisms for the therapeutic effects of the IFN-beta on blood brain barrier in MS.

Liposuction and ischemic optic neuropathy. Case report and review of literature.

Ischemic optic neuropathy occurred in a patient following liposuction. Perioperative anemia and hypotension may be the cause of this complication. Correction of anemia with transfusion improved the hemoglobin and hematocrit but the right eye remained blind. Liposuction should be added to the list of the surgical procedures that may produce ischemic optic neuropathy as an isolated complication.

Persisting aphasia as the sole manifestation of partial status epilepticus.

OBJECTIVES: Persisting aphasia presenting as an isolated inability to vocalize is an uncommon presentation of simple partial status epilepticus and only eight such cases have been reported over the past 40 years. METHODS: We studied a patient with a 5-year history of recurrent episodes of inability to talk, without any other motor or cognitive impairments. Episodes lasted as long as 24 h, interictal EEGs were normal and she was diagnosed as a conversion disorder. RESULTS: EEG recordings during one of the episodes showed continuous discharges in the right frontal and parasagital areas demonstrating the ictal nature of the deficits. During the episode the patient had no deficits of strength, or in her ability to perform skilled movements to command, imitation or manipulation of objects. Comprehension of complex verbal commands was preserved and she would make attempts to articulate words and correctly answered questions with head nodding or monosyllables, yes or no. She could hum but had no other vocalizations. CONCLUSIONS: This is the first case of aphasic status epilepticus secondary to epileptogenic discharges of the right hemisphere. The case is also unique for the isolated involvement of production of language during the seizure.