Specificities of Meningitis and Meningo-Encephalitis After Kidney Transplantation: A French Retrospective Cohort Study.

Kidney transplant recipients develop atypical infections in their epidemiology, presentation and outcome. Among these, meningitis and meningoencephalitis require urgent and adapted anti-infectious therapy, but published data is scarce in KTRs. The aim of this study was to describe their epidemiology, presentation and outcome, in order to improve their diagnostic and management. We performed a retrospective, multicentric cohort study in 15 French hospitals that included all 199 cases of M/ME in KTRs between 2007 and 2018 (0.9 case per 1,000 KTRs annually). Epidemiology was different from that in the general population: 20% were due to Cryptococcus neoformans, 13.5% to varicella-zoster virus, 5.5% to Mycobacterium tuberculosis, and 4.5% to Enterobacteria (half of which produced extended spectrum beta-lactamases), and 5% were Post Transplant Lymphoproliferative Disorders. Microorganisms causing M/ME in the general population were infrequent (2%, for Streptococcus pneumoniae) or absent (Neisseria meningitidis). M/ME caused by Enterobacteria, Staphylococci or filamentous fungi were associated with high and early mortality (50%-70% at 1 year). Graft survival was not associated with the etiology of M/ME, nor was impacted by immunosuppression reduction. Based on these results, we suggest international studies to adapt guidelines in order to improve the diagnosis and the probabilistic treatment of M/ME in SOTRs.

Transatlantic Crossings: Early neurological exchanges between USA and France.

Transnational exchanges have existed for centuries, with both economic and cultural effects. At the end of the 18th century, in the aftermath of the French Revolution, medical education in France underwent radical innovations, prefiguring the training system now almost universally accepted. This paper presents 19th and early 20th century neurology-related exchanges between the United States (US) and Europe, particularly, Paris, which had become a major medical center and where many US neurologists were trained. We discuss some of the intense neurology-related exchanges between the USA and Europe, notably the role of US neurology founders William Alexander Hammond, Silas Weir Mitchell, Edward Seguin as well as Mauritius-born Charles Edouard Brown-Séquard and a few others. We emphasize the mutual benefits that resulted from such exchanges. In later years, the trend reversed with many foreigners, particularly Europeans coming to improve their knowledge in the US. More recently, a shared pattern of travel and enrichment is occurring despite current threats caused by isolationism and undue stress on local identity.

The Cell Biology of Cytomegalovirus: Implications for Transplantation.

Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and γδ T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.

Easier Control of Late-Onset Cytomegalovirus Disease Following Universal Prophylaxis Through an Early Antiviral Immune Response in Donor-Positive, Recipient-Negative Kidney Transplants.

Universal prophylaxis for cytomegalovirus (CMV) prevention is viable but, compared with a preemptive strategy, leads to higher incidence of late-onset disease (LOD) associated with poor patient and graft survival. The purpose of this study was to compare LOD with early onset disease (EOD), with a focus on the highest risk kidney transplant recipients (KTRs): CMV seronegative recipients transplanted from seropositive donors (D+R-). Since CMV control depends on both antiviral treatment and specific immune response, we also compared Vδ2-negative (Vδ2(neg) ) γδ T cell expansion involved in CMV infection resolution. EOD was defined as occurring <3 mo and LOD as occurring >3 mo after transplantation. Depending on the period, universal prophylaxis or preemptive treatment was used. Overall, 168 D+R- KTRs were included between 2003 and 2011. LOD was associated with a lower peak DNAemia (p = 0.04), fewer recurrences (odds ratio 0.16; 95% confidence interval 0.05-0.55; p = 0.01) and shorter anti-CMV curative treatment (40 vs. 60 days, p < 0.0001). As a corollary, we found that Vδ2(neg) γδ T cell expansion was faster in LOD than in EOD (31 vs. 168 days after the beginning of CMV disease, p < 0.0001). In D+R- KTRs, universal prophylaxis is associated with more LOD, which had better infection management and a faster immune response. These results support the use of universal prophylaxis over a preemptive strategy and reappraise outcomes of LOD.

GR gene polymorphism is associated with inter-subject variability in response to glucocorticoids in patients with myasthenia gravis.

BACKGROUND AND PURPOSE: Glucocorticoids (GCs) are the mainstay treatment of myasthenia gravis (MG). However, wide inter-individual variability exists in the response to GCs. METHODS: A Chinese cohort of 257 MG patients treated with GCs was evaluated for the association between 19 single nucleotide polymorphisms in the GR gene and clinical response to the initial 3 month GC therapy. A quantitative MG score decreasing by ≥3 units or becoming zero was defined as sensitivity to GCs. RESULTS: The rs17209237* G allele was less frequent in the GC insensitive group compared with the GC sensitive group [P = 0.013, odds ratio (OR) 0.119]. The rs9324921* A allele was more frequent in the GC insensitive group than in the GC sensitive group (P = 0.046, OR 1.94). Carriers of the rs17209237 G allele were less frequent in the GC insensitive group than in the GC sensitive group (dominant model, P = 0.009). Carriers of the rs9324921 A allele were more frequent in the GC insensitive group than in the GC sensitive group (dominant model, P = 0.037). Multivariate logistic regression revealed that the rs17209237 G allele carrier (P = 0.037, OR 0.12) and disease duration before GC treatment (P = 0.011, OR 3.45) were independent factors that contributed to GC efficacy. CONCLUSION: rs17209237 in the GR gene was identified as an independent factor that contributes to GC efficacy in MG patients. The genetic variations of the GR gene may play a role in predicting response to GC treatment.

Cytomegalovirus DNAemia Requiring (Val)Ganciclovir Treatment for More Than 8 Weeks Is a Key Factor in the Development of Antiviral Drug Resistance.

Background: Prolonged (val)ganciclovir [(V)GCV] exposure for ≥6 weeks is a known predisposing factor for cytomegalovirus (CMV) drug resistance. However, the selection of this threshold was based on limited data. In this study, we sought to reappraise the risk factors for the development of (V)GCV resistance through a specific focus on kidney transplant recipients (KTRs). Methods: This single-center retrospective study included 313 consecutive KTRs treated for a first CMV episode. Adjusted Cox multivariate regression analysis was used for identifying independent risk factors. Results: Antiviral drug resistance was identified in 20 (6%) KTRs. A cumulative (V)GCV exposure for more than 6 weeks (regardless of the viral load) was not associated with antiviral drug resistance (hazard ratio [HR] = 2.45, 95% confidence interval [CI] = 0.33-18.30, P = .38). In contrast, persistent CMV DNAemia requiring (V)GCV treatment for more than 8 weeks was the main independent risk factor for antiviral drug resistance (HR = 11.68, 95% CI = 2.62-52.01, P = .001). The (V)GCV treatment for more than 8 weeks was given to 9% and 18% of patients who had persistent or recurrent CMV DNAemia, respectively. These scenarios were associated with the occurrence of drug resistance in 39% and 12% of cases, respectively. Conclusions: Cumulative (V)GCV exposure ≥6 weeks regardless of the viral load is not associated with antiviral drug resistance. In contrast, prolonged exposure to (V)GCV during CMV replication (with a cutoff ³8 weeks) seems to be a key factor.

Social marketing approaches to nutrition and physical activity interventions in early care and education centres: a systematic review.

INTRODUCTION: Social marketing is a promising planning approach for influencing voluntary lifestyle behaviours, but its application to nutrition and physical activity interventions in the early care and education setting remains unknown. METHODS: PubMed, ISI Web of Science, PsycInfo and the Cumulative Index of Nursing and Allied Health were systematically searched to identify interventions targeting nutrition and/or physical activity behaviours of children enrolled in early care centres between 1994 and 2016. Content analysis methods were used to capture information reflecting eight social marketing benchmark criteria. RESULTS: The review included 135 articles representing 77 interventions. Two interventions incorporated all eight benchmark criteria, but the majority included fewer than four. Each intervention included behaviour and methods mix criteria, and more than half identified audience segments. Only one-third of interventions incorporated customer orientation, theory, exchange and insight. Only six interventions addressed competing behaviours. We did not find statistical significance for the effectiveness of interventions on child-level diet, physical activity or anthropometric outcomes based on the number of benchmark criteria used. CONCLUSION: This review highlights opportunities to apply social marketing to obesity prevention interventions in early care centres. Social marketing could be an important strategy for early childhood obesity prevention efforts, and future research investigations into its effects are warranted.

Medical and surgical treatment for ocular myasthenia.

BACKGROUND: Approximately 50% of people with myasthenia gravis present initially with purely ocular symptoms, so called ocular myasthenia and between 50 to 60% of these people will progress to develop generalized disease. The vast majority will do so within the first one to two years. There is controversy surrounding the appropriate management of patients with ocular myasthenia. OBJECTIVES: To perform a systematic review of the literature relevant to the treatment of ocular myasthenia and to answer three specific questions. Are there any medical or surgical treatments that have an impact on the risk of progression from ocular to generalized myasthenia gravis? Are there any medical or surgical treatments that improve symptoms of diplopia or ptosis in ocular myasthenia? What is the frequency of side effects associated with treatments used in people with ocular myasthenia? SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (searched December 2004), MEDLINE (1996 to 2004) and EMBASE (1980 to 2004) for randomized controlled trials as well as case-control and cohort studies. The titles and abstracts of all articles were read by both authors and the full text of all articles that were of possible relevance was reviewed in full. The references of all manuscripts included in the review were scanned to identify additional articles of relevance and experts in the field were contacted to identify additional published and unpublished data. Where necessary and possible, we contacted authors for further information. SELECTION CRITERIA: To be included in the review, studies had to meet three criteria: (a) randomized (or quasi-randomized) controlled study design; (b) active treatment compared to placebo, no treatment or some other treatment; and (c) results reported separately for patients with ocular myasthenia (grade 1) as defined by the Myasthenia Gravis Foundation of America. DATA COLLECTION AND ANALYSIS: We collected data regarding the risk of progression to generalized myasthenia gravis, improvement in ocular symptoms, and the frequency of treatment-related side effects. MAIN RESULTS: We identified two randomized controlled trials relevant to the treatment of ocular myasthenia, only one of which reported results in terms of the pre-specified outcome measures used in this review. This study included only three participants and was of limited methodological quality. In the absence of data from randomized controlled trials, we present a review of the available observational data. AUTHORS' CONCLUSIONS: There are no data from randomized controlled trials on the impact of any form of treatment on the risk of progression from ocular to generalized myasthenia gravis. The available randomized controlled literature does not permit any meaningful conclusions about the efficacy of any form of treatment for ocular myasthenia. Data from several reasonably good quality observational studies suggest that corticosteroids and azathioprine may be beneficial in reducing the risk of progression to generalized myasthenia gravis.

Lateral deviation of the eyes on forced lid closure in patients with cerebral lesions.

We examined 35 patients with unilateral cerebral lesions to determine the incidence of lateral deviation of the eyes under forcefully closed lids and the reliability of this sign in predicting the side of the lesion. Only patients with radiologically confirmed unilateral lesions were studied. Over 70% of patients had contralateral ocular deviation (Cogan's "spasticity of conjugate gaze"), 20% had ipsilateral deviation, and less than 9% of the patients had no deviation. Lateral ocular deviation was as sensitive, but not as specific, as a unilateral Babinski plantar response in determining the side with the lesion. Contralateral deviation was more common with parietotemporal localization, suggesting that the phenomenon reflects an underlying disturbance of attentional mechanisms.

Autoantibodies in thymoma-associated myasthenia gravis with myositis or neuromyotonia.

BACKGROUND: About 50% of patients with thymoma have paraneoplastic myasthenia gravis (MG). Myositis and myocarditis or neuromyotonia (NMT) will also develop in some. Patients with thymoma-associated MG produce autoantibodies to a variety of neuromuscular antigens, particularly acetylcholine receptor (AChR), titin, skeletal muscle calcium release channel (ryanodine receptor [RyR]), and voltage-gated potassium channels (VGKC). OBJECTIVE: To examine whether neuromuscular autoantibodies in patients with thymoma correlate with specific clinical syndromes. METHODS: Serum and plasma samples from 19 patients with thymoma-associated MG, of whom 5 had myositis and 6 had NMT, underwent testing for antibodies to AChR, titin, RyR, and VGKC. RESULTS: Antibodies to AChR and titin were found in 19 and 17 patients, respectively. Antibodies to RyR correlated with the presence of myositis (P = .03); they were found in all 5 patients with myositis and in only 1 patient with NMT, but also in 4 of 8 patients with neither disease. Antibodies to VGKC were found in 4 patients with NMT, 1 of 3 patients undergoing testing for myositis, and 2 of 7 patients undergoing testing with neither comorbidity. Presence of RyR antibodies correlated with high levels of titin antibodies. CONCLUSIONS: The results appear to distinguish partially between 3 groups of patients with thymoma-associated MG: the first with RyR antibodies and myositis or myocarditis, the second with NMT without RyR antibodies, and the third without RyR antibodies, myositis, or NMT. Differences in the thymoma may underlie these pathologic associations.

Cardiomyopathy associated with the acquired immune deficiency syndrome.

Three cases of congestive cardiomyopathy complicating the acquired immune deficiency syndrome (AIDS) are reported. In one case, acute cardiac decompensation resulted in prolonged but ultimately reversible cardiogenic shock. In the second case, clinical signs of cardiac disease were precipitated by acute renal failure and fluid overload. In the third, congestive heart failure developed spontaneously and responded promptly to administration of diuretics but the patient died suddenly, apparently due to an arrhythmia. The etiology of cardiomyopathy in AIDS is unclear and the manifestations of cardiomyopathy in this setting range from subclinical to life threatening.

Nitric oxide myotoxicity is age related.

Nitric oxide (NO) is generated under normal conditions in skeletal muscle and acts as a messenger that influences contractility, blood flow, and glucose metabolism. Excess NO generation may occur in pathological states, in particular inflammatory conditions. We demonstrate that incubation of rat extensor digitorum longus muscle with the NO donor, S-nitrosocysteine, leads to release of creatine kinase, a marker of muscle injury after a delay of 90 min. Muscle of old animals was more sensitive to the NO donor. Light microscopic analysis does not show abnormalities, with the exception of an increase in interfiber distance. Histological staining identified no pathological elevations of calcium. The study demonstrates the direct toxicity of NO to skeletal muscle, and that muscle of older animals is differentially susceptible to NO toxicity.

Nitric oxide synthase in aging rat skeletal muscle.

The neuronal isoform of nitric oxide synthase (NOS) is expressed at high concentrations in skeletal muscle, and NO influences muscle contractility, glucose utilization, and free radical damage or protection. NOS activity and expression was evaluated in extensor digitorum longus (EDL), soleus, and diaphragm of 8 and 24 month old Fisher 344 rats. In 8-month-old animals, NOS activity was highest in EDL, which contained the highest percentage of NOS containing fibers, and was lowest in soleus. NOS activity and percentage of NOS containing fibers was significantly reduced in all muscle groups with age. To determine if NOS reduction correlated with free radical injury the level of lipid peroxidation, as measured by malonaldehyde equivalents, was determined. With age lipid peroxidation increased in EDL, was reduced in diaphragm, and showed a non-significant change in soleus. Therefore, a straightforward reduction of NOS activity does not correlate with lipid peroxidation. The reduction of NOS with age in skeletal muscle may be most significant for muscle metabolism and force production and be of limited significance for free radical metabolism.

Second occurrence of spinal epidural metastases.

We reviewed records of 79 men with spinal epidural metastases diagnosed from July 1984 to July 1989, imaged by myelography or MRI, and treated with radiation therapy. Thirteen men (16%) had second epidural metastases. The mean time between lesions that developed within two vertebral bodies of a prior lesion was 2.8 months, compared with 15.2 months for lesions that were three or more vertebral bodies from a prior lesion. Some secondary spinal metastases occurring soon after the initial metastasis may represent regrowth of tumor at the border of the radiation port, suggesting that larger radiation ports be constructed for patients with lengthy expected survival times.

The gamma-subunit of the acetylcholine receptor is not expressed in the levator palpebrae superioris.

In extraocular muscle (EOM), expression of the gamma-subunit, which is associated with the fetal-type acetylcholine receptor (AChR), may offer a differential target for immune-mediated damage and could explain the preponderance of ocular manifestations caused by myasthenia gravis (MG). Using Poly(A)+ RNA hybridization, we investigated expression of the gamma-subunit in bovine levator palpebrae superioris (LP), a muscle also differentially involved by MG. There were no transcripts of the gamma-subunit of the AChR, but the epsilon-subunit, associated with the adult-type AChR, was present. The results indicate that the susceptibility of LP to MG is not mediated by gamma-subunit expression and suggest that multiterminal fibers in EOM may be the site of gamma-subunit expression.

Disorders of neuromuscular junction ion channels.

Ion channel defects produce a clinically diverse set of disorders that range from cystic fibrosis and some forms of migraine to renal tubular defects and episodic ataxias. This review discusses diseases related to impaired function of the skeletal muscle acetylcholine receptor and calcium channels of the motor nerve terminal. Myasthenia gravis is an autoimmune disease caused by antibodies directed toward the skeletal muscle acetylcholine receptor that compromise neuromuscular transmission. Congenital myasthenias are genetic disorders, a subset of which are caused by mutations of the acetylcholine receptor. Lambert-Eaton myasthenic syndrome is an immune disorder characterized by impaired synaptic vesicle release likely related to a defect of calcium influx. The disorders will illustrate new insights into synaptic transmission and ion channel structure that are relevant for all ion channel disorders.

Transient neurologic deficit caused by chronic subdural hematoma.

Transient neurologic deficits are an unusual presentation of chronic subdural hematoma. Presented herein are three patients with transient aphasia and right-sided sensory-motor abnormalities caused by subdural hematoma. Review of the literature revealed 32 cases similar to ours. Presenting complaints were aphasia (77%), sensory symptoms (57%), headache (48%), hemiparesis (50%), and visual disturbance (3%). Fifteen patients underwent cerebral angiography; only three showed significant carotid atherosclerosis. Electroencephalograms were performed in seven patients; five revealed lateralized slowing, but none showed epileptiform activity. Drainage of the hematoma was uniformly curative, although six patients had transient postoperative symptoms. Patients presenting with transient deficits require imaging to rule out the presence of a chronic subdural hematoma.

Nitric oxide: biologic effects on muscle and role in muscle diseases.

Nitric oxide is a ubiquitous cell-signaling molecule involved in regulation of numerous homeostatic mechanisms and in mediation of tissue injury. Nitric oxide influences contraction, blood flow, and metabolism, as well as myogenesis. Nitric oxide exerts its influence by activation of guanylate cyclase and nitrosylation of proteins, which include glyceraldehyde-3-phosphate dehydrogenase, the ryanodine receptor and actomyosin ATPase. Skeletal muscle expresses all three isoforms of the nitric oxide synthase, including a muscle-specific splice variant; expression of the isoforms is fiber-type specific and influenced by age and disease. Nitric oxide produced with certain systemic conditions and local inflammation is likely toxic to skeletal muscle, either directly or in reactions with oxygen-derived radicals. Although nitric oxide impacts on many functions in muscle, its effects are subtle, and much work remains to be done to determine its importance in the pathogenesis of muscle diseases.

T cell recognition of muscle acetylcholine receptor in ocular myasthenia gravis.

We examined the proliferative response of blood CD4(+) cells to muscle acetylcholine receptor (AChR) subunits and the epitope repertoire of the epsilon and gamma subunits, in ocular myasthenia gravis (oMG) patients and healthy subjects. oMG patients seldom recognized all subunits. The frequency and intensity of recognition was the same for all subunits, irrespective of the disease duration. The responses in oMG were lower than in generalized myasthenia gravis. Healthy subjects had frequent, low responses to one or more subunits. oMG patients recognized several epitopes on the gamma and epsilon subunits, that partially overlapped those recognized in gMG. The subunits and epitopes recognized by individual oMG patients changed over time. Thus, oMG patients have minimal and unstable sensitization of anti-AChR CD4(+) cells, in agreement with their low and inconsistent synthesis of anti-AChR antibody.

Expression of acetylcholine receptor isoforms at extraocular muscle endplates.

PURPOSE: To determine the expression of fetal and adult acetylcholine receptor (AChR) isoforms among extraocular muscle (EOM) en plaque and en grappe endplates. METHODS: Antibodies against peptide fragments of the gamma- and epsilon-subunits of the fetal and adult AChRs and alpha-bungarotoxin were used in immunofluorescence experiments to stain rat neonatal leg, adult diaphragm, and extraocular rectus muscle endplates. RESULTS: Anti-epsilon antibodies intensely stained diaphragm endplates weakly stained rare neonatal endplates. Anti-gamma antibodies stained neonatal, but not diaphragm, endplates. Anti-epsilon antibodies bound to all en plaque and en grappe endplates of extraocular muscle. Anti-gamma antibodies bound to global and orbital en grappe endplates. All en plaque endplates of the orbital region and a subset of endplates in the global region stained with anti-gamma antibodies. CONCLUSIONS: All en grappe endplates and certain en plaque endplates of EOM are the only mature endplates that coexpress the adult and fetal AChR isoforms. The expression of both isoforms may be important to determine contractile properties, protein expression regulation, and EOM susceptibility to myasthenia gravis.