Adverse events in MS patients fulfilling or not inclusion criteria of the respective clinical trial - The problem of generalizability.

BACKGROUND: The aim of this study was to evaluate how many MS patients treated with an approved DMD in routine care would have fulfilled the inclusion and exclusion criteria of phase III clinical trial and would therefore be eligible for the respective drug trial. Further, adverse events and disease progression for these patients were compared. METHODS: A comparison of patients fulfilling phase III clinical trial inclusion and exclusion criteria and those who do not with regard to sociodemographic and clinical characteristics, adverse events and disease progression. Database was the REGIMS register, a national, prospective, observational, clinical multicentre registry. 1248 MS Patients were included. RESULTS: 27.2% patients would have been eligible for inclusion into a phase III clinical trial of their indication. Patients who did not meet the criterion age are more likely to have a serious adverse event (SAE), whereas patients who did not fulfil the criterion relapse had a significant lower occurrence of an adverse event (AE). Non-fulfilment of other inclusion criteria (EDSS Score; medication history and MS type) did not show any significant differences in drug safety variables, AE and SAE. CONCLUSION: Our results suggest that a low transferability of phase III clinical trial criteria, to patients in routine care with the exception of age, does not imply a higher risk with regard to adverse and serious adverse events.

Data harmonization for collaborative research among MS registries: A case study in employment.

OBJECTIVE: To assess the feasibility of collaboration and retrospective data harmonization among three multiple sclerosis (MS) registries by investigating employment status. METHODS: We used the Maelstrom guidelines to facilitate retrospective harmonization of data from three MS registries, including the NARCOMS (North American Research Committee on MS) Registry, German MS Register (GMSR), and United Kingdom MS (UK-MS) Register. A protocol was developed based on the guidelines, and summary-level data were used to combine results. Employment status and a limited set of factors associated with employment (age, sex, education, and disability level) were harmonized. A meta-analytic approach was used to pool estimates using a weighted average of logistic regression estimates and their variances in a random effects model. RESULTS: Employment status, age, sex, education, and disability were mapped. The overall employment rate was 57% (11,143 employed out of 19,562 persons with MS) with the GMSR having the highest proportion of participants employed (66.2%), followed by the UK-MS (55.2%) and NARCOMS (43.0%) registries. As disability level increased, the odds of not being employed increased. CONCLUSION: Harmonization across registries was feasible. The Maelstrom guidelines provide a valuable roadmap for conducting high-quality harmonization projects. The pooling of data sources has the potential to be an important mechanism for conducting research in MS.

Displacement of oropharyngeal structures during suction-swallowing cycles.

Suction ability plays an important role in supporting oral nutrition and needs special care following neurological disorders and tumor-associated defects. However, the details of suction are still poorly understood. The present study evaluates displacement of orofacial structures during suction and deglutition based on manometric controlled MRI. Nine healthy subjects were scanned wearing an intraoral mouthpiece for water intake by suction and subsequent swallowing. Suction-swallowing cycles were identified by intraoral negative pressure. Midsagittal MRI slices (3 T; temporal resolution 0.53 s) were analyzed at rest, suction and pharyngeal swallowing. The mandibular displacement was measured as the distance between the anterior nasal spine and the inferior point of the mandible. Following areas were defined: subpalatal compartment (SCA), retrolingual (RLA), epipharyngeal (EPA) and mouth floor area (MFA). During rest, an average distance of 7 cm was observed between the mandibular measurement points. The measured SCA was 3.67 cm(2), the RLA 6.98 cm(2), the EPA 9.00 cm(2) and the MFA 15.21 cm(2) (average values). At the end of suction, the mandibular distance reduces (to 6.88 cm), the SCA increases significantly (to 5.96 cm(2); p = 0.0002), the RLA decreases (to 6.45 cm(2)), the EPA increases (to 10.59 cm(2)) and the MFA decreases (to 15.02 cm(2)). During deglutition, the mandible lifted significantly (to 6.81 cm; p = 0.0276), the SCA reduced to zero, the RLA was not measurable, the EPA reduces significantly (to 3.01 cm(2); p < 0.0001) and the MFA increases (to 16.36 cm(2)). According to these observations, a combined displacement of the tongue in an anteroposterior direction with active tongue dorsum-velum contact appears to be the predominant activity during suction and responsible for the expansion of the subpalatal area.

Clinical presentation of pediatric multiple sclerosis before puberty.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) onset before puberty is extremely rare and establishment of diagnosis is often difficult due to atypical presentation. The study aims to identify the typical presentation of MS in this age group. METHODS: Pediatric MS patients were identified from the database of the Center for Multiple Sclerosis in Childhood and Adolescence at the University Medical Center Göttingen, Germany. Inclusion criteria were a relapsing-remitting initial disease course and minimum disease duration of 4 years. RESULTS: Forty-seven pre-pubertal (<11 years) and 41 post-pubertal (14-16 years) MS patients were compared. Before puberty an even gender ratio was found. The pre-pubertal patients were more likely to have a polysymptomatic severe first attack with motor and brainstem involvement, sphincter dysfunction, cognitive disturbances and milder residual neurological sequelae after the first episode whilst the post-pubertal patients predominantly presented with optic neuritis and sensory symptoms. The initial symptom pattern prevailed over the first 2 years of disease. Presentation of pre-pubertal boys and girls did not differ significantly. CONCLUSIONS: To facilitate early diagnosis it is important to recognize that pre-pubertal MS presents with a specific pattern of symptoms that is maintained over the first two disease years.

Assess, compare and enhance the status of Persons with Multiple Sclerosis (MS) in Europe: a European Register for MS.

OBJECTIVES: Persons with multiple sclerosis (PwMS) experience health-related quality of life (HRQoL) problems greatly differing across Europe, and the European Union (EU) faces deep inequalities in MS management from country to country. Through the establishment of a European MS Register (EUReMS), an effective action is proposed to improve the overall knowledge on MS and support effective intervention programmes at EU and national political level. EUReMS aims to achieve consensus on its mission and vision, to define existing data providers, to develop models driving future MS health policies and research, to develop an information technology (IT) infrastructure for a data set, to develop a European shared governance and to secure providers' data provision into EUReMS. MATERIALS AND METHODS: EUReMS is meant to build on a minimum set of core data from existing national and regional population-based MS registries and from PwMS' perspectives. EUReMS' main partner is the European MS Platform (EMSP) acting in collaboration with associated and collaborating European partners. RESULTS: EUReMS was launched in July 2011. A Consensus Statement on purposes, vision, mission and strategies was produced in December 2011, and a comprehensive survey on existing MS data collections in Europe has been performed, and the EUReMS data mask is currently being discussed. CONCLUSIONS: EUReMS will represent a tool to provide up to date, comparable and sustainable MS data through an effective and credible register, which will encourage extensive knowledge building of MS, more equitable policies and higher standards in MS treatment and services.

Distribution of HIV-1 subtypes among HIV-seropositive patients in the interior of Côte d'Ivoire.

Limited data exist on the distribution of HIV-1 subtypes in Côte d'Ivoire. The aim of this study is to describe the distribution of genetic subtypes of HIV-1 strains in six regions of Côte d'Ivoire. In 1997, we consecutively collected blood from 172 HIV-1-infected patients from six regional tuberculosis treatment centers. Peripheral blood mononuclear cells (PBMCs) from these people were analyzed by a restriction fragment-length polymorphism (RFLP) assay that involves a sequential endonuclease digestion of a 297-base pair polymerase chain reaction (PCR) fragment; plasma samples were tested by a V3-loop peptide enzyme immunoassay (PEIA). DNA sequencing of the protease or env genes was performed on all samples discordant in the two assays as well as a random sample of the concordant subtyped samples. Of 172 specimens, 3 were PCR-negative, and 169 were putatively classified as subtype A by RFLP. The 3 PCR-negative samples were unequivocally subtyped A by PEIA. Of the 169 RFLP subtype A samples, 159 (94%) were subtyped A by PEIA. Of the 10 discordant samples, PEIA testing classified 3 as subtype C, 2 as D, and 5 as F. Sequencing of the env gene classified these samples as 1 subtype A, 4 Ds, and 5 Gs. Thus, 163 (95%) of the specimens were subtype A, 3 subtype D, 4 subtype G, 1 A/D, and 1 A/G (IbNG) circulating recombinant forms (CRF). In conclusion, most HIV-1-infected tuberculosis patients throughout the interior of Côte d'Ivoire are infected with HIV-1 subtype A, which are very likely the A/G (IbNG) CRF. The uniform distribution of this subtype makes Côte d'Ivoire a potential site for vaccine trials.

Human immunodeficiency virus (HIV) subtype surveillance of African-born persons at risk for group O and group N HIV infections in the United States.

A population-based surveillance registry was used to identify human immunodeficiency virus (HIV)-infected persons in the United States at increased risk for group O and group N infections (those born in or near African countries where group O infection has been reported). Of 155 eligible subjects, 37 gave samples. By phylogenetic and serologic analysis, 32 were infected with group M (16 with subtype A, 5 with B, 7 with C, and 1 each with subtypes D, F2, G, and recombinant A/J) and 2 with group O but none with group N virus. For 3, samples could not be typed by serology or amplified by polymerase chain reaction using group M-, O-, or N-specific primers. In the United States, group O HIV infection is uncommon; no case of group N infection was found. African-born persons may have HIV strains typical of their birth country. Ongoing subtype surveillance may allow early identification of novel or emerging HIV strains.

Viral and immunologic examination of human immunodeficiency virus type 1-infected, persistently seronegative persons.

Persons who were human immunodeficiency virus type 1 (HIV-1)-infected but who remained persistently seronegative (HIPS) on HIV-1 antibody tests were examined through AIDS case surveillance. Six such individuals (HIPS-1 to -4, -7, and -9) were examined to determine whether their persistent seronegativity was attributable to immune dysfunction or infection with atypical HIV. Of the 6, 4 had antibody titers to at least 1 other common pathogen. In vitro stimulation of peripheral blood mononuclear cells from HIPS-4 and HIPS-7 with pokeweed mitogen or phosphorothioate oligodeoxynucleotide (direct B cell mitogen) did not produce HIV-1-specific antibody. Reconstitution experiments with recombinant interleukin (rIL)-4 and rIL-12 also had no impact on antibody production. Virus isolates from HIPS-4 and -9 were R5X4-tropic, whereas HIPS-7 was CCR5-tropic only. Sequence analysis of long terminal repeat, p24, and env gp41 did not reveal any specific mutation, and phylogenetic analysis confirmed that all 6 virus specimens were HIV-1 subtype B. These data suggest that the lack of a detectable antibody response in these patients may be the result of immune dysfunction.

Identification of a window period for susceptibility to dual infection with two distinct human immunodeficiency virus type 2 isolates in a Macaca nemestrina (pig-tailed macaque) model.

The potential to establish dual retroviral infections was investigated in this study. Groups of macaques infected with human immunodeficiency virus type 2 (HIV-2) isolate (either GB122 or CDC77618) were exposed to the other virus at 2, 4, 8, 12, 14, or 72 weeks after primary inoculation. Dual infections were established in macaques simultaneously exposed to both viruses. In other groups, secondary infections were observed only if challenge occurred at early intervals after primary infection but before a full seroconversion. Polymerase chain reaction and virus-isolation data demonstrated that challenges at 8, 12, 14, or 72 weeks after infection with the initial isolate failed to result in a dual infection. Anti-HIV-2 serologic titers, CD4 levels, virus burden, and the ability to superinfect peripheral blood mononuclear cells in vitro were not correlated with susceptibility to or protection from secondary challenges in this investigation. These findings demonstrate a window period for susceptibility to dual infection and indicate that protection from retroviral infection may be achievable.

Predominance of human immunodeficiency virus type 2 subtype B in Abidjan, Ivory Coast.

We analyzed the genetic variability and phylogenetic relationships among 28 HIV-2 strains collected from patients enrolled in an HIV epidemiologic study in Abidjan, Ivory Coast, during 1995-1996. Although both subtype A (n = 8; 29%) and subtype B (n = 20; 71%) were present in this sampling, the majority of infections were caused by subtype B viruses. These findings contrasted with the reported predominance of HIV-2 subtype A in other African countries. The broad genetic diversity identified among protease gene sequences for HIV-2 subtype A (6%; range 3-15%) and subtype B (7%; range, 2-12%), and their presence in Abidjan during the 1980s, document a long coexistence of two viral subtypes in Ivory Coast. Our data indicate that viruses of subtypes A and B have contributed to the HIV-2 epidemic in Ivory Coast.

Persistently negative HIV-1 antibody enzyme immunoassay screening results for patients with HIV-1 infection and AIDS: serologic, clinical, and virologic results. Seronegative AIDS Clinical Study Group.

OBJECTIVE: To describe persons with HIV infection and AIDS but with persistently negative HIV antibody enzyme immunoassay (EIA) results. DESIGN: Surveillance for persons meeting a case definition for HIV-1-seronegative AIDS. SETTING: United States and Canada. PATIENTS: A total of eight patients with seronegative AIDS identified from July 1995 through September 1997. MAIN OUTCOME MEASURES: Clinical history of HIV disease, history of HIV test results, and CD4 cell counts from medical record review; results of testing with a panel of EIA for antibodies to HIV-1, and HIV-1 p24 antigen; and viral subtype. RESULTS: Negative HIV EIA results occurred at CD4 cell counts of 0-230 x 10(6)/l, and at HIV RNA concentrations of 105,000-7,943,000 copies/ml. Using a panel of HIV EIA on sera from three patients, none of the HIV EIA detected infection with HIV-1, and signal-to-cut-off ratios were < or = 0.8 or all test kits evaluated. Sera from five patients showed weak reactivity in some HIV EIA, but were non-reactive in other HIV EIA. All patients were infected with HIV-1 subtype B. CONCLUSIONS: Rarely, results of EIA tests for antibodies to HIV-1 may be persistently negative in some HIV-1 subtype B-infected persons with AIDS. Physicians treating patients with illnesses or CD4 cell counts suggestive of HIV infection, but for whom results of HIV EIA are negative, should consider p24 antigen, nucleic acid amplification, or viral culture testing to document the presence of HIV.

Genetic analysis of human immunodeficiency virus in Abidjan, Ivory Coast reveals predominance of HIV type 1 subtype A and introduction of subtype G.

To better understand the molecular epidemiology of HIV genetic diversity in Abidjan, Ivory Coast, we performed a genetic analysis of 170 HIV-1-seropositive specimens representing newly diagnosed tuberculosis patients (n = 143) and women monitored in a mother-to-child transmission cohort study (n = 27). Preliminary screening with RFLP presumptively classified 162 (95.3%) of these as subtype A. The envelope region of 108 specimens was subtyped by sequence analysis: 102 (94.4%) were subtype A, 2 (1.9%) were subtype D, and 4 (3.7%) were subtype G. Subtyping gag and env regions of the genome suggested that five of the six nonsubtype A isolates exhibited a potentially mosaic structure. A comparative phylogenetic analysis of HIV-1 subtype A C2V3 from 27 Ivory Coast and 21 Ugandan sequences revealed a striking clustering among Ivory Coast variants, and an independent segregation from Ugandan subtype A. Despite independent clustering with other subtype A specimens, limited variability of the V3 loop apex was observed; the globally predominant V3 motif, GPGQ, represented 90.1% of the HIV-1 strains. This study demonstrates that clade A is the predominant HIV-1 subtype in HIV-seropositive individuals in Abidjan, Ivory Coast and that these strains are phylogenetically distinct from other subtype A strains observed in East Africa.

Genetically divergent strains of human immunodeficiency virus type 2 use multiple coreceptors for viral entry.

Several members of the seven-transmembrane chemokine receptor family have been shown to serve, with CD4, as coreceptors for entry by human immunodeficiency virus type 1 (HIV-1). While coreceptor usage by HIV-1 primary isolates has been studied by several groups, there is only limited information available concerning coreceptor usage by primary HIV-2 isolates. In this study, we have analyzed coreceptor usage of 15 primary HIV-2 isolates, using lymphocytes from a donor with nonfunctional CCR5 (CCR5 -/-; homozygous 32-bp deletion). Based on the infections of PBMCs, seven of these primary isolates had an absolute requirement for CCR5 expression, whereas the remaining eight exhibited a broader coreceptor usage. All CCR5-requiring isolates were non-syncytium inducing, whereas isolates utilizing multiple coreceptors were syncytium inducing. Blocking experiments using known ligands for chemokine receptors provided indirect evidence for additional coreceptor utilization by primary HIV-2 isolates. Analysis of GHOST4 cell lines expressing various chemokine receptors (CCR1, CCR2b, CCR3, CCR4, CCR5, CXCR4, BONZO, and BOB) further defined specific coreceptor usage of primary HIV-2 isolates. The receptors used included CXCR4, CCR1-5, and the recently described receptors BONZO and BOB. However, the efficiency at which the coreceptors were utilized varied greatly among the various isolates. Analysis of V3 envelope sequences revealed no specific motif that correlated with coreceptor usage. Our data demonstrate that primary HIV-2 isolates are capable of using a broad range of coreceptors for productive infection in vitro. Additionally, our data suggest that expanded coreceptor usage by HIV-2 may correlate with disease progression.

Detection of genetically diverse human immunodeficiency virus type 1 group M and O isolates by PCR.

A panel of 136 genetically diverse group M and 5 group O adult isolates from outside the United States and Europe were evaluated by PCR with the Roche AMPLICOR HIV-1 test, a modified version of the AMPLICOR HIV-1 test, and a new primer pair/probe system. Detection of some of these isolates was less efficient with the AMPLICOR HIV-1 test; however, the assay was significantly improved by reducing the sample input and lowering the annealing temperature. The new primer pair/probe set detected 140 of 141 isolates, including the 5 group O isolates that were not detected with either of the AMPLICOR HIV-1 test formats.

A hospital-based, hazardous materials decontamination and treatment unit: utilization patterns over a nine-month period.

Federal [U.S.] law and the Joint Commission on the Accreditation of Healthcare Organizations mandate plans and mechanisms for response by hospitals to hazardous material incidents/accidents be developed and implemented. This paper describes the response of the University Hospitals of Cleveland to these regulations and to the anticipated needs of the community and local industry. The physical plant constructed and its relationship to the emergency department personnel for staffing this unit are described. Utilization patterns since implementation of this program are presented.

Immunologic characterization of jird lymphocyte responsiveness to Brugia pahangi ribosomal protein S13.

Ribosomal protein S13 of the nematode Brugia pahangi is recognized by B and T cells from parasite-infected animals. To identify helper T cell sites on the protein, 15 overlapping synthetic peptides spanning the entire molecule (Bp17.4) were tested for their ability to stimulate lymph node and spleen cells of peptide-immunized and recombinant antigen-immunized jirds. Lymph node cells from animals immunized with peptides 6, 8, 9, 13, and 14, corresponding to Bp17.4 amino acids (AA) 50-70, 70-90, 80-100, 120-140, and 130-150, respectively, showed strong and specific responses to the homologous peptide, while only those lymph node cells from jirds immunized with peptides 8, 9, 13, and 14 proliferated in response to Bp17.4. These results suggest the existence of at least two T cell epitopes. Lymph node cells from infected jirds also responded to these peptides and to Bp17.4 (80,000 cpm). In contrast to the lymph node cells, spleen cells from microfilaria-positive animals failed to mount significant responses to any of the peptides or to Bp17.4. Splenic T cell responsiveness was restored upon removal of nylon wool adherent cells, suggesting active regulation of Bp17.4 reactivity. In liquid-phase competitive inhibition immunoassays, peptides 1 (AA 1-30) and 6 (50-70) blocked antibody binding and, therefore, these regions contain conformational antibody-binding sites. This model system should prove useful for analyzing regulation of epitope-specific responses in experimental filariasis.

Differentiation of an immature T cell line: a model of thymic positive selection.

Thymocyte differentiation is dependent upon recognition of major histocompatibility complex (MHC) molecules on thymic stroma, a process called positive selection. Here we describe an immature CD4+8+ T cell line derived from a TCR transgenic mouse that differentiates into CD4+8- cells in response to antigen and nonthymic antigen-presenting cells. When injected intrathymically, these cells differentiate in the absence of antigen. The ability of immature T cells to recognize MHC molecules in the absence of foreign antigen in the thymus can thus be attributed to a unique property of thymic antigen-presenting cells. These studies also demonstrate the phenotypic and functional changes associated with TCR-mediated T cell maturation and establish an in vitro model system of positive selection.