HLA and amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with loss of upper and lower motor neurones. It leads to death by respiratory failure and has a typical prognosis of 2-3 years. The immune system has been shown to play a role in the pathophysiology of ALS. Some of the most important immune genes are within the human leukocyte antigen (HLA) region, and a recent genome-wide association study (GWAS) has identified a risk allele for ALS within the HLA region. Older studies have also suggested an HLA association with ALS, with certain HLA alleles showing differing expression between patients and controls. This systematic review and meta-analysis examines the previous studies performed in this field.Methods: We used established publication search engines. Findings were excluded if they did not meet the selection criteria. We then undertook statistical meta-analysis on the eligible papers, using a fixed effects model.Results: There were eight eligible papers. There were three statistically significant meta-analysis findings, although these would not be significant after correction for multiple comparisons. The frequencies of HLA-A9 and HLA-DR4 genotypes were lower in ALS subjects than controls, and HLA-B35 was higher in ALS subjects.Discussion: This systematic review and meta-analysis do not confirm all the previously reported associations of HLA with ALS, but shows three alleles of interest. However, there are limitations to the studies, which include the use of older serotyping methodology and the small numbers of subjects. Given the recent GWAS association with HLA, further modern HLA studies are warranted.

Perceptions of autism spectrum disorder among the Swahili community on the Kenyan coast.

BACKGROUND: In high-income and Western societies there is great understanding and awareness of autism spectrum disorder (ASD); however, for many low-middle income countries, research and knowledge is notably lacking. In Africa, there is a growing prevalence of ASD due to increased diagnosis, yet it is still a poorly understood condition. AIMS: Emerging literature has emphasised how cultural and societal beliefs underpin the level of understanding of ASD, and which typically results in lack of awareness and acceptance. As such it is important to investigate the cultural perceptions towards ASD within low-middle income communities of African culture, to further understand the challenges and barriers individuals with ASD face. The aim of the current study was to probe participants from the Swahili community, on the coast of Kenya, of their cultural views towards ASD. METHOD: Semi-structured interviews were conducted with seven participants, and the data analysed using thematic analysis. RESULTS: Three key themes developed from the data; stigma, lack of awareness, and Government responsibility. CONCLUSION: Cultural perceptions negatively impacted awareness and are exacerbated by lack of directive from the Government in providing appropriate diagnostic and educational support.

Autopathogenic T helper cell type 1 (Th1) and protective Th2 clones differ in their recognition of the autoantigenic peptide of myelin proteolipid protein.

We previously generated a panel of T helper cell 1 (Th1) clones specific for an encephalitogenic peptide of myelin proteolipid protein (PLP) peptide 139-151 (HSLGKWLGHPDKF) that induces experimental autoimmune encephalomyelitis (EAE) upon adoptive transfer. In spite of the differences in their T cell receptor (TCR) gene usage, all these Th1 clones required W144 as the primary and most critical TCR contact residue for the activation. In this study, we determined the TCR contact residues of a panel of Th2/Th0 clones specific for the PLP peptide 139-151 generated either by immunization with the PLP 139-151 peptide with anti- B7-1 antibody or by immunization with an altered peptide Q144. Using alanine-substituted peptide analogues of the native PLP peptide, we show that the Th2 clones have shifted their primary contact residue to the NH2-terminal end of the peptide. These Th2 cells do not show any dependence on the W144, but show a critical requirement for L141/G142 as their major TCR contact residue. Thus, in contrast with the Th1 clones that did not proliferate to A144-substituted peptide, the Th2 clones tolerated a substitution at position 144 and proliferated to A144 peptide. This alternative A144 reactive repertoire appears to have a critical role in the regulation of autoimmune response to PLP 139-151 because preimmunization with A144 to expand the L141/G142-reactive repertoire protects mice from developing EAE induced with the native PLP 139-151 peptide. These data suggest that a balance between two different T cell repertoires specific for same autoantigenic epitope can determine disease phenotype, i.e., resistance or susceptibility to an autoimmune disease.

Evaluation of RIDA®GENE norovirus GI/GII real time RT-PCR using stool specimens collected from children and adults with acute gastroenteritis.

BACKGROUND: Norovirus is the leading cause of epidemic and sporadic acute gastroenteritis (AGE) in the United States. Widespread prevalence necessitates implementation of accurate norovirus detection assays in clinical diagnostic laboratories. OBJECTIVE: To evaluate RIDA®GENE norovirus GI/GII real-time RT-PCR assay (RGN RT-PCR) using stool samples from patients with sporadic AGE. STUDY DESIGN: Patients between 14 days to 101 years of age with symptoms of AGE were enrolled prospectively at four sites across the United States during 2014-2015. Stool specimens were screened for the presence of norovirus RNA by the RGN RT-PCR assay. Results were compared with a reference method that included conventional RT-PCR and sequencing of a partial region of the 5'end of the norovirus ORF2 gene. RESULTS: A total of 259 (36.0%) of 719 specimens tested positive for norovirus by the reference method. The RGN RT-PCR assay detected norovirus in 244 (94%) of these 259 norovirus positive specimens. The sensitivity and specificity (95% confidence interval) of the RGN RT-PCR assay for detecting norovirus genogroup (G) I was 82.8% (63.5-93.5) and 99.1% (98.0-99.6) and for GII was 94.8% (90.8-97.2) and 98.6% (96.9-99.4), respectively. Seven specimens tested positive by the RGN-RT PCR that were negative by the reference method. The fifteen false negative samples were typed as GII.4 Sydney, GII.13, GI.3, GI.5, GI.2, GII.1, and GII.3 in the reference method. CONCLUSIONS: The RGN RT-PCR assay had a high sensitivity and specificity for the detection of norovirus in stool specimens from patients with sporadic AGE.

Incomplete lupus erythematosus.

Thirty-eight patients with incomplete lupus erythematosus (ILE) (defined as the presence of fewer than four of the criteria of the American College of Rheumatology for systemic lupus erythematosus [SLE]) were identified and compared with 42 patients with SLE. Both groups were comparable with respect to age, sex, and race. Patients with ILE had symptoms for an average of 38 months before seeking rheumatologic care and were followed up for a mean of 19 months; patients with SLE averaged 9 months with symptoms before their diagnosis was made and were followed for a mean of 30 months. Characteristic clinical features of patients with ILE included positive antinuclear antibody titers (83%), polyarticular nonerosive arthritis (47%), and cutaneous findings (61%). These were comparable with findings in the the SLE group. However, patients with ILE had significantly fewer systemic manifestations than did those with SLE. Patients with ILE were treated with nonsteroidal anti-inflammatory drugs more frequently (47%) than were patients with SLE, while the latter group received more topical and oral corticosteroids and immunosuppressives. Only two of the patients with ILE went on to have typical SLE. Thus, ILE may be frequent, mild, and relatively stable or benign, apparently evolving slowly if at all into SLE or other rheumatic disease.

Loricrin expression is coordinated with other epidermal proteins and the appearance of lipid lamellar granules in development.

In mouse, epidermal development proceeds from a single basal cell layer covered by a specialized single cell layer called the periderm at E14 to a fully differentiated stratified squamous epithelium at E18. To determine when loricrin, a major cell envelope component, is expressed during development, we examined fetal skin from mice of gestational ages E13 through E19 and compared the temporal pattern of loricrin expression with that of other differentiation markers. We found that loricrin mRNA and protein were expressed by E16, following the expression of keratins K1 and K10 and preceding the expression of profilaggrin. Interestingly, both loricrin and profilaggrin were initially expressed focally in areas corresponding to more advanced morphologic stages of maturation. Because the cornified envelope is a composite structure consisting of both protein and lipid components, we also monitored the appearance of lipid lamellar granules during epidermal development. These granules were first evident at E16 and the extrusion of lipids from the granules into the intercellular space occurred at E17, prior to the cross linking of loricrin into the cell envelope. Our results document that loricrin is expressed and accumulates at the cell periphery subsequent to the extrusion of lipids, but prior to processing of profilaggrin. We suggest that the sequential regulation of these events is critical for formation of epidermal barrier function during development.

Vasculitis associated with malignancy. Experience with 13 patients and literature review.

Vasculitis is a syndrome which may complicate certain infectious, rheumatic, and allergic diseases. We identified 13 patients, over the past 17 years, who had both vasculitis and lympho- or myeloproliferative disorders and relate their clinical, laboratory, histologic, and immunologic features, course, therapy, and outcome. Nine patients were male, 4 female; ages ranged from 28 to 82 years. Ten of 13 patients presented with cutaneous vasculitis antedating malignancy by an average of 10 months. Three of 13 developed cutaneous vasculitis after malignancy. A statistically significant association between cutaneous vasculitis and lympho- or myeloproliferative malignancies was noted when compared with all other tumors. Dermatologic manifestations included palpable purpura (5 patients), maculopapular eruptions (4), urticarial and petechial lesions (3), and ulcers (1). Hepatitis B surface antigen, Coombs antibodies, rheumatoid factor and antinuclear antibodies were not found. Serum cryoglobulins were detected in 3 patients; serum C3 and C4 were normal in 8 of 9 patients evaluated. Histologic examinations revealed necrotizing leukocytoclastic vasculitis with disruption of endothelial integrity, destruction of endothelium, and neutrophil infiltration. Occasional perivascular mononuclear cell invasion was also noted in 4 patients. Immunofluorescent staining for IgG, IgA, IgM, C3, and C4 was negative in all patients studied. Symptoms were, in general, poorly responsive to therapy, which included nonsteroidal antiinflammatory drugs, antihistamines, antiserotonin agents, and corticosteroids. Chemotherapy directed at the underlying malignancy was also generally ineffective, although the vasculitis appeared to lessen in severity. Vasculitis appeared to lessen in severity as bone marrow function deteriorated. Ten patients died, all as a direct result of their malignancy. We have described a unique clinical syndrome of lympho- and myeloproliferative disease presenting with small-vessel vasculitis. Recognition that rheumatic symptoms may reflect or antedate malignancy may permit early diagnosis, aggressive treatment, and elucidation of pathogenesis.

Sequence heterogeneity and polymorphic gene arrangements of the Leishmania guyanensis gp63 genes.

The Leishmania GP63 major surface protein gene family encodes multiple isoforms which differ predominantly in the carboxyterminal region. We have isolated 4 full-length gp63 cDNA clones derived from stationary-phase promastigote RNA of a cloned isolate of Leishmania guyanensis, a member of the braziliensis complex. These genes, along with the previously published L. guyanensis gp63 gene sequence [15], appeared to be mosaics of different combinations of 5' and 3' untranslated regions and sequences encoding the propeptide, internal, and C-terminal regions of GP63. The predicted L. guyanensis GP63 isoforms shared as little as 55% sequence identity, comparable to the inter-species diversity of GP63. The genomic organization of gp63 genes in L. guyanensis is highly complex: there are at least 4 distinct polymorphic forms of tandemly linked gene clusters, with intra-gene cluster variation in gene sequence and in the number of gene repeats. Southern blot analysis suggested that the arrangement of gp63 genes in this L. guyanensis isolate did not differ from that in the parental lines.

Expression of myelin proteolipid protein in oligodendrocytes and transfected cells.

The data presented in this paper show that the appropriate tools are now available to study the behavior of PLP and DM20 transcripts engineered with either point mutations or deletion of specific domains. Such studies should begin to provide new insights into the functions of PLP and DM20 and their role in relation to the optimal functioning of the nervous system.

What is lupus? What is not lupus?

Present understanding suggests that lupus reflects a spectrum of syndromes that share many clinical, inflammatory, and immunologic features. Those patients not fulfilling criteria for systemic lupus erythematosus (SLE) do not seem to evolve frequently to classic SLE, tend to have a good prognosis, and may be managed conservatively. This is important for clinical management. Whether this pertains to etiopathogenesis is speculative and will await information not yet available.

Early pregnancy factor suppresses experimental autoimmune encephalomyelitis induced in Lewis rats with myelin basic protein and in SJL/J mice with myelin proteolipid protein peptide 139-151.

Early pregnancy factor (EPF) is a secreted protein with immunosuppressive and growth factor properties. During pregnancy, it appears in maternal serum within 6-24 h of fertilization, is present for at least the first two-thirds of pregnancy in all species studied and is essential for embryonic survival. It is a homologue of chaperonin 10, a heat shock protein, but, unlike other members of this family, EPF has an extracellular role. As it has the ability to modulate CD4+ T cell-dependent immune responses, its role in treatment of experimental autoimmune encephalomyelitis (EAE) was investigated. EAE is a CD4+ T cell-mediated disease, the best available animal model of multiple sclerosis (MS). Two models of EAE were investigated, acute EAE induced in Lewis rats by inoculation with myelin basic protein (MBP-EAE) and chronic relapsing EAE induced in SJL/J mice by inoculation with myelin proteolipid protein peptide (residues 139-151) (PLP-EAE). EPF, delivered intraperitoneally or orally to rats or intraperitoneally to mice, suppressed clinical signs of disease. Mice with PLP-EAE were also treated with interferon-beta, with and without EPF. Both EPF and IFN-beta suppressed clinical signs of EAE and, when administered together, gave greater suppression than when given separately. These findings suggest that EPF may be a potential candidate for use in treatment of MS and may be of use in combined therapy with IFN-beta.

Magnetic resonance imaging in patients with inflammatory arthritis of the knee.

Magnetic resonance imaging (MRI) permits visualization of anatomic structures not appreciated by conventional radiographic imaging and may quantify inflammatory disease and its progression with greater sensitivity than available techniques. We therefore compared MRI with clinical evaluation and with radiographic examination of 17 patients with inflammatory arthritis of the knee. We sought to determine anatomic integrity of bone, cartilage, menisci, and ligaments, and to quantify joint effusion and synovial proliferation. Patients studied had rheumatoid arthritis (10 patients), juvenile rheumatoid arthritis (4 patients), ankylosing spondylitis (1 patient), and monoarticular arthritis (2 patients). In all patients MRI revealed clinically important abnormalities not detected by physical or conventional radiographic exams. These included proliferative synovitis (13 patients), cartilage thinning (2 patients), cartilage erosion (8 patients), bone infarction (1 patient), meniscal injury (1 patient), and synovial invagination into bone (1 patient). Also MRI indicated inflammatory disease to be quantitatively greater than had been appreciated on clinical examination or routine X-ray studies--proliferative synovitis (12 patients), erosion (7 patients), effusion (8 patients), cartilage thinning (11 patients), and ligamentous/meniscal damage (1 patient). These findings led to reassessment of anatomic staging and influenced therapeutic decision for these patients. Thus MRI provides clinically important information about joint integrity and inflammatory disease, with a sensitivity and resolution considerably beyond conventional techniques.

Sweet's syndrome with an exogenous cause.

A sixty-six-year-old white man presented with a five-day history of painful erythematous papules, plaques, pustules, and hemorrhagic bullae on both hands. His history was remarkable for having prepared and pickled fifteen quarts of home-grown jalapeño peppers several days before the eruption occurred. The light microscopic examination of sections of lesional skin stained with hematoxylin and eosin revealed pathologic findings characteristic of Sweet's syndrome. We report this case because of its unusual presentation and apparent exogenous cause.

Clinical laboratory evaluation of a PCR assay for the detection of HCMV.

OBJECTIVE: In limited laboratory space and consonant with limited opportunities for contamination, to implement and incorporate into our diagnostic virology laboratory, a polymerase chain reaction assay for human cytomegalovirus detection with maximum sensitivity. DESIGN: Polymerase chain reaction, adapted for use with the enzyme uracil-n-glycosylase to avoid the potential for false positive reactions due to amplicon carryover was developed, optimized using two primer pairs, and performed on 361 specimens, i.e., body fluids and tissues submitted to the viral laboratory for detection of human cytomegalovirus. Polymerase chain reaction results were compared to shell vial assay. SETTING: Louisiana State University Health Sciences Center, Shreveport LA. MAIN OUTCOME MEASUREMENTS: Using the shell vial assay as the reference, analytical sensitivity (lower limit of detection) as well as laboratory sensitivity and specificity of both primer pairs. RESULTS: The lower limit of detection of our polymerase chain reaction assay was determined to be one focus-forming unit. Using the shell vial assay as the reference test, the sensitivity and specificity of both primer pairs were 96.5% and 94.3%, respectively. Polymerase chain reaction detected human cytomegalovirus in 6% of our culture-negative specimens. CONCLUSION: Based upon this study, our recommendations include the following: 1) a housekeeping gene amplification control is required for diagnostic polymerase chain reaction; 2) a single primer pair can be utilized for clinical work without sacrificing too much sensitivity; and 3) the laboratory should maintain close contact with clinicians to discuss polymerase chain reaction interpretation.

Validation of the Roche COBAS Amplicor system for Chlamydia trachomatis.

OBJECTIVE: Validation of the Roche Amplicor polymerase chain reaction (PCR) using the Comprehensive Bio-Analytical System (COBAS) automated PCR analyzer in our laboratory. DESIGN: Endocervical swab specimens for both EIA and PCR were collected from a total of 193 women. EIA for chlamydia was performed using the MicroTrak Chlamydia Kit (Wampole Labs, Cranbury, NJ). PCR was performed using Roche Amplicor reagents on the COBAS instrument. SETTING: Louisiana State University Health Sciences Center at Shreveport, Shreveport LA. PATIENTS: All cervical swab specimens, (n = 193), collected from patients presenting either to the Women's Health or Primary Care Clinic (Obstetrics and Gynecology and Family Practice) were included in this study. RESULTS: Most of the specimens, 138/193 or 71.5%, tested negative by both techniques. Three of the 193 specimens, 1.5%, were inhibitory for PCR since the internal control was negative. Fifty-one specimens, 26.4%, tested positive by both techniques or by PCR alone. No specimens were positive by EIA only. Twenty-eight of the 51 were positive by both methods, (14.5% of the total tested; 54.9% agreement among the specimens testing positive). An additional 23 were positive by PCR alone, i.e., 11.9% total discrepant positive specimens; 45% discordant results among the specimens testing positive). Seventeen PCR-positive specimens divided among four separate runs were retested by PCR. Of these, 15 were repeat positive, giving the test a reproducibility of 88.2%. CONCLUSIONS: Our results concur with previously published comparison data for EIA and PCR testing. We conclude that the PCR should detect a significantly increased number of chlamydia infections among our LSUHSC-S population, but there are drawbacks to using this technique. Specimen preparation time for PCR is almost twice as long as EIA, and the Roche PCR assay is not licensed for ocular specimens as is our EIA procedure. In addition, since neither technique is accepted for testing for medicolegal purposes, we must continue the use of culture for cases of suspected sexual abuse.

The relationship between the sexual attitudes of parents and their college daughters' or sons' sexual attitudes and sexual behavior.

This study determined if three selected sexual attitudes of parents were related to similar sexual attitudes of their college daughters or sons and to five sexual behaviors. Only never married, college freshmen (N = 83) with both parents participating were utilized. A self-report questionnaire was administered to students at a large midwestern university and distributed to and returned from parents by mail. The Pearson product-moment correlation and the stepwise and multiple regressions were used to test four hypotheses. Mothers' sexual attitudes had a stronger relationship than fathers' attitudes with offspring sexual attitudes and behaviors, particularly for daughters. Generally, mothers with the most positive attitudes toward sexual-self had daughters who were more responsive relative to personal sexual expression (masturbation frequency and orgasmic experience), but who were not any more involved heterosexually (frequency of coitus and number of coital partners). Fathers' sexual attitudes had little relationship to offspring sexual attitudes and behavior. None of the male students' sexual behaviors were related strongly to parent sexual attitudes. Implications for school and parent sexuality education programs are briefly discussed.

Levels of phosphorylated axonal neurofilament subunit H (pNfH) are increased in acute ischemic stroke.

For the study of stroke outcomes, there is the need for measurements of severity of stroke damage. Phosphorylated neurofilament heavy protein (pNfH) levels are elevated in axonal injury. We have measured levels of pNfH in stroke and correlated these levels with measures of stroke severity. Blood samples were collected from 54 ischaemic stroke patients at day 1, week 1 (days 7-10) and weeks 3-6, and an ELISA was used to measure pNfH levels in each patient at each time-point. Serum pNfH levels were significantly elevated in stroke patients compared to healthy controls. The levels were low at day 1, higher at day 7 and reached a peak at week 3, the latest day that we assessed. Significant associations were found between the pNfH levels at week 3 and early and stroke severity, size and outcome. Blood pNfH levels that reflect the severity of ischaemic stroke, are correlated with outcome and rise during the weeks after stroke. This may be a useful measure of tissue damage in stroke.

Prominent brainstem and cerebellar involvement in multiple sclerosis with psoriasis.

INTRODUCTION: We identified a subgroup of 20 patients with multiple sclerosis (MS) and psoriasis within a total group of 692 patients with MS. RESULTS: There was a high (80%) incidence of brainstem and/or cerebellar involvement and a high mean (+/-SD) Multiple Sclerosis Severity Score (6.06 +/- 2.88) in this subgroup. Of the patients who were human leukocyte antigen typed, 53% carried the MS-associated allele, DRB1*1501, and 27% carried the psoriasis-associated DRB1*07 allele. CONCLUSION: The high incidence of brainstem and cerebellar involvement might be explained by the greater severity of MS and the high frequency (60%) of carriage of DRB1*04, DRB1*07, and/or DRB1*13 alleles, which are associated with brainstem and cerebellar involvement in MS.

Sexual dimorphism in autoimmune disease.

We briefly survey the concept of autoimmunity and nominate the range of autoimmune diseases that include multisystemic and organ-specific disorders, and cite prevalences of autoimmune diseases in males and females, in humans and in experimental animals. Most human autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and autoimmune thyroid disease, have an increased incidence and prevalence in females, but a few others such as autoimmune diabetes, the Guillain Barré syndrome (GBS) and psoriasis are increased in males. Animal models of autoimmunity show an equivalent sexual dimorphism. The possible reasons for the differing incidence and prevalence of autoimmune diseases in females and males engage our attention. Environmental exposures may differ for females and males. There are innate differences in the function of the female and male immune systems, and there is some evidence for differences between females and males in the ability of a target organ for autoimmunity to withstand damage. In seeking reasons for these differences, we review the role of sex hormones in immunity and include results of trials of hormone therapy in autoimmune diseases. The association of autoimmunity and pregnancy, a female-specific condition, is discussed, and the claimed effects of lymphoid cell microchimerism on provocation of autoimmunity are reviewed. Genetic predisposition is an important factor in autoimmune disease and we particularly focus on genes on the X and Y chromosomes, the role of X chromosome inactivation, and the interaction of the sex of the patient with other genetic factors. The possible role of epigenetic mechanisms, including environmental influences, is then surveyed. We assert that sex is a vital variable that must be considered in all immunological studies, as it should be at all levels of biological research.

NF-kappa B, a potential therapeutic target for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) that afflicts over 2 million people worldwide. On the basis of the temporal course of disease, MS can be subdivided into three clinical groups: relapsing remitting MS (RR-MS), secondary progressive MS and primary progressive MS. There is a high degree of clinical diversity within these subgroups. The pathogenesis of MS in most patients is likely to result from autoreactive, activated CD4(+) T cells moving from the periphery across the blood brain barrier into the CNS. Most therapeutic agents used in MS (e.g. immunosuppressive and immunomodulatory drugs and cell cycle interruption drugs) are only used for RR-MS. These treatments show some efficiency in lessening the relapse rate in RR-MS and time to progression, but cannot cure MS. Thus, there is a need for new efficient treatments for all types of MS. An increasing number of studies indicate that nuclear factor-kappaB plays an important role in controlling expression of genes relevant to the pathogenesis of autoimmunity. Genetic factors related to NF-kappaB may also be determinants of MS susceptibility, as polymorphisms in the molecules involved in regulation of the NF-kappaB signal transduction pathway differ between RR-MS and progressive MS. Herein, the role of NF-kappaB in MS will be reviewed and its potential as a new therapeutic target in MS will be considered and compared with existing treatments.