Therapeutic Effect of the Mitochondria-Targeted Antioxidant SkQ1 on the Culture Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a heterogeneous autoimmune disease of unknown etiology characterized by inflammation, demyelination, and axonal degeneration that affects both the white and gray matter of CNS. Recent large-scale epidemiological and genomic studies identified several genetic and environmental risk factors for the disease. Among them are environmental factors of infectious origin, possibly causing MS, which include Epstein-Barr virus infection, reactivation of some endogenous retrovirus groups, and infection by pathogenic bacteria (mycobacteria, Chlamydia pneumoniae, and Helicobacter pylori). However, the nature of the events leading to the activation of immune cells in MS is mostly unknown and there is no effective therapy against the disease. Amazingly, whatever the cause of the disease, signs of damage to the nerve tissue with MS lesions were the same as with infectious leprosy, while in the latter case nitrozooxidative stress was suggested as the main cause of the nerve damage. With this in mind and following the hypothesis that excessive production of mitochondrial reactive oxygen species critically contributes to MS pathogenesis, we studied the effect of mitochondria-targeted antioxidant SkQ1 in an in vitro MS model of the primary oligodendrocyte culture of the cerebellum, challenged with lipopolysaccharide (LPS). SkQ1 was found to accumulate in the mitochondria of oligodendrocytes and microglial cells, and it was also found to prevent LPS-induced inhibition of myelin production in oligodendrocytes. The results implicate that mitochondria-targeted antioxidants could be promising candidates as components of a combined therapy for MS and related neurological disorders.

Lessons From Leprosy: Peripheral Neuropathies and Deformities in Chronic Demyelinating Diseases.

In light of the World Health Organization's push to accelerate progress toward a leprosy-free world by 2020, it is fitting to look back on the evolution of progress in treating lepromatous neuropathy and limb deformities. To date, no surgeon has had as great an impact on the understanding and treatment of this disease as Dr Paul Brand. Before Dr Brand's accomplishments, few surgeons participated in the management of the deformed leprous patient. By challenging conventional beliefs, Dr Brand revealed that many of the deformities associated with leprosy were in fact caused by nerve damage and subsequent limb anesthesia. His pioneering work centered on tendon transfers to provide hand and foot mobility to leprous patients, revolutionizing the surgical management of this patient population and restoring functionality to the lives of otherwise stigmatized and functionally handicapped individuals. In the process, he provided us with the surgical principles and techniques that we still apply today. Because of its predilection for the peripheral nervous system, leprosy also provides an excellent opportunity to investigate mechanisms of demyelination and chronic nerve degeneration in nonacute peripheral neuropathies. Processes underlying demyelination of infectious, traumatic, and genetic etiologies overlap and precede the onset of acute neuronal derangement. Glial pathology has been shown to be a common pathological element in leprosy, Charcot-Marie-Tooth type I, multiple sclerosis, and chronic nerve compression injury. The aim of this article is to provide an overview of lepromatous neuropathy with its subsequent deformities as it relates to the pathophysiology, surgical management, and potential therapeutic targets of other modern peripheral neuropathies.

Abordagem domiciliar de situações clínicas comuns em adultos

Curso da atenção domiciliar que apresenta as principais situações clínicas comuns em adultos, descrevendo o manejo dos pacientes na atenção domiciliar e reforçando o papel do cuidador como parte fundamental da equipe de cuidado. São apresentadas as seguintes situações clínicas: asma, doença pulmonar obstrutiva crônica, pneumonia, coronariopatia, doença vascular periférica, insuficiência cardíaca, hanseníase, SIDA, malária, tuberculose, infecção do trato urinário, osteomielite, pós-operatório em ortopedia, transtornos psiquiátricos, abordagem ao usuário de álcool e outras drogas, esclerose múltipla e esclerose lateral amiotrófica. Em cada uma das situações são tratados os aspectos conceituais, o diagnóstico, o manejo na atenção domiciliar, as orientações que devem ser fornecidas ao cuidador, o plano de alta na atenção domiciliar e quando referenciar para outros serviços.

Health-related quality of life for patients with progressive multiple sclerosis: influence of rehabilitation.

BACKGROUND AND PURPOSE: The health-related quality of life of patients with multiple sclerosis (MS) is an important aspect of care outcome. The purpose of this study was to compare health-related quality of life between patients who received weekly comprehensive outpatient rehabilitation for 1 year and a group that did not receive rehabilitation. SUBJECTS: Twelve patients receiving outpatient care for chronic progressive MS (mean age = 44.5 years, SD = 11.6) were compared with 19 similar patients (mean age = 49.2 years, SD = 9.2) on a waiting list who were not receiving outpatient care. METHODS: A pretest-posttest longitudinal design was used to descriptively compare outcome measures. Multivariate regression analyses were used to determine which variables, controlled for baseline health status and other relevant patient characteristics, were related to the best outcomes at the time of the 1-year follow-up. RESULTS: The treatment group showed improvements in six health status measures on the Rand 36-Item Health Survey 1.0 (SF-36) that were not improved in the wait-listed group. Outpatient treatment was the sole predictor of positive outcome for energy/fatigue (partial R2 = .43) and change in general health (partial R2 = .19). In addition, the treatment group was associated with a positive outcome (together with other independent variables) in the domains of social function and social support. CONCLUSION AND DISCUSSION: Patients with chronic progressive forms of MS appear to derive benefits from an ongoing comprehensive outpatient rehabilitation program. [Di Fabio RP, Choi T, Soderberg J, Hansen CR. Health-related quality of life for patients with progressive multiple sclerosis: influence of rehabilitation.

The immune response to mycobacterial 70-kDa heat shock proteins frequently involves autoreactive T cells and is quantitatively disregulated in multiple sclerosis.

Heat shock proteins (HSP) are the most conserved molecules known to date that may also function as immune targets during infection. Hence, theoretically there is a high chance of cross-reactive responses to epitopes shared by host and microbe HSP. If not properly regulated, these responses may contribute to the pathogenesis of autoimmune disease. To determine if immune responses to HSP could contribute to the pathogenesis of multiple sclerosis, we raised T lymphocyte lines specific for the purified protein derivative of Mycobacterium tuberculosis (PPD) from patients with multiple sclerosis, patients with tuberculosis and from healthy individuals. These lines were then screened for their proliferative response to a M. tuberculosis 70-kDa heat shock protein (M.tb.HSP70). The relative frequency of the recognition of highly conserved sequences of M.tb.HSP70 compared to variable ones was also assessed by mapping experiments on those PPD specific T lymphocyte lines which also recognized the mycobacterial 70-kDa heat shock protein. In patients with multiple sclerosis, we observed a significantly higher estimated frequency of PPD-specific T lines responding to M.tb.HSP70 compared to healthy individuals and patients with tuberculosis. Furthermore, mapping experiments using recombinant proteins representing mycobacterial and human HSP70 sequences and a panel of synthetic peptides encompassing the whole sequence of Mycobacterium leprae HSP70, showed that the response to conserved epitopes of HSP70 is a frequent event in each of the three conditions studied, often leading to the cross-recognition of microbial and human sequences. These findings implicate the 70-kDa heat shock proteins as potential autoantigens in multiple sclerosis.

Spinal fluid lymphocytes from a subgroup of multiple sclerosis patients respond to mycobacterial antigens.

Immune responses to heat shock or stress proteins are observed in several chronic autoimmune diseases. Such proteins are major antigens of many bacteria, especially mycobacteria. To determine whether immune responses to stress proteins occur in chronic inflammatory diseases of the central nervous system such as multiple sclerosis (MS) we measured proliferative responses of lymphocytes from spinal fluids and bloods of patients with MS and other neurological diseases to a sonicate of M. tuberculosis, an acetone extract of M. tuberculosis, a recombinant 65-kd heat shock protein of M. leprae, and tetanus toxoid as a control recall antigen. Significantly increased spinal fluid lymphocyte responses to mycobacterial sonicate, relative to responses from paired peripheral blood lymphocytes, were present in 14 of 20 specimens from patients with MS (p < 0.025) and 2 of 9 specimens from patients with other neurological diseases. Spinal fluid lymphocytes also responded to tetanus toxoid, but differences between blood and spinal fluid were not statistically significant. Lymphocytes from 1 patient with MS responded only to M. leprae. There were no proliferative responses to the M. tuberculosis acetone extract. When patients with MS were classified according to duration of disease (< 2- or > 2-yr duration) 9 of 10 patients with recent onset had cerebrospinal fluid cells that responded to M. tuberculosis compared with 5 of 10 with longer duration symptoms (p < 0.012). Our data suggest a selective recruitment and/or expansion of mycobacterial reactive cells to the central nervous system of a subpopulation of patients with MS.(ABSTRACT TRUNCATED AT 250 WORDS)

Implications of progressive multifocal leukoencephalopathy and JC virus for the etiology of MS.

JCV infects oligodendrocytes and, to a lesser extent, astrocytes in the brain and spinal cord and causes the demyelinating disease known as progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals. The possibility exists that this opportunistic infection reactivates from a latent state in the brain. It is proposed that the pathogenetic immune response in a multiple sclerosis (MS) brain may be directed predominantly toward antigens of a DNA virus, such as JCV, which is latent in glial cells. The target antigens could be synthesized only during transient viral reactivation or could persist, thus explaining the two basic patterns of neurological symptoms in MS. It is further proposed that the viral genome as a minichromosome becomes focally distributed in glial cells following vertical passage in dividing progenitor cells after infection early in life. The concept that the host response to a single agent can evoke two distinct pathologies (PML and MS) derives from a chronic mycobacterial infection of peripheral nerves-leprosy.

Assessing the role of HLA-linked and unlinked determinants of disease.

The relationship between increased risk in relatives over population prevalence (lambda R = KR/K) and probability of sharing zero marker alleles identical by descent (ibd) at a linked locus (such as HLA) by an affected relative pair is examined. For a model assuming a single disease-susceptibility locus or group of loci tightly linked to a marker locus, the relationship is remarkably simple and general. Namely, if phi R is the prior probability for the relative pair to share zero marker alleles identical by descent, then P (sharing 0 markers/both relatives are affected) is just phi R/lambda R. Alternatively, lambda AR, the increased risk over population prevalence to a relative R due to a disease locus tightly linked to marker locus A, equals the prior probability that the relative pair share zero A alleles ibd divided by the posterior probability that they share zero alleles ibd, given that they are both affected. For example, for affected sib pairs, P (sharing 0 markers/both sibs are affected) = .25/lambda S. This formula holds true for any number of alleles at the disease locus and for their frequencies, penetrances, and population prevalence. Similar formulas are derived for sharing one and two markers. Application of these formulas to several well-studied HLA-associated diseases yields the following results: For multiple sclerosis, insulin-dependent diabetes mellitus, and coeliac disease, a single-locus model of disease susceptibility is rejected, implying the existence of additional unlinked familial determinants. For all three diseases, the effect of the HLA-linked locus on familiality is minor: for multiple sclerosis, it accounts for only a 2.5-fold increased risk to sibs over the population prevalence, compared to an observed value of 20; for coeliac disease, it accounts for approximately a 5.25-fold increased risk to sibs, while the observed value is on the order of 60; for insulin-dependent diabetes mellitus, it accounts for a 3.42-fold increased risk in sibs, while the observed value is 15. In all cases, the secondary determinants must be outside the HLA region. For tuberculoid leprosy, an unlinked familial determinant is also implicated (increased risk to sibs due to HLA = 1.49; observed value = 2.38). For hemochromatosis and Hodgkin's disease, there is little evidence for HLA-unlinked familial determinants. With this formula, it is also possible to examine the hypothesis of pleiotropy versus linkage dis-equilibrium by comparing lambda AS with the increased risk to sibs due to the associated allele(s).(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies to Newcastle disease virus in various human diseases.

Sera of patients with infectious mononucleosis (IM) and various other diseases were studied for agglutinins against Newcastle disease virus (NDV)-modified human group O red blood cells (NDVO) and antibodies to the NDV preparations. In agreement with previous studies, the NDVO antibodies are found in a wide variety of diseases in addition to IM, including Japanese IM-like syndrome (22%), syphilis (24%), lepromatous leprosy (30%), systemic lupus erythematosus (29%), multiple sclerosis (18%) and cancer (17%); these antibodies were also found in patients with renal allografts (29%). It was also noted that the Victoria (VIC), Roakin and Herts strains, but not B1 strain of NDV are active in the NDVO agglutination, and VIC and Roakin strains, but not B1 strain in the immunodiffusion. Immunodiffusion and enzyme immunoassay with various preparations of the VIC strain revealed that the major antigen(s) of the virus under study is carried by the hemagglutinin-neuraminidase (H-N) glycoproteins. The H-N molecule was also shown to be able to modify human erythrocytes for the agglutination by the pathologic sera.

Specificity of antibodies to Newcastle disease virus.

Specificity of antibodies to Victoria strain of Newcastle disease virus (NDV) found in infectious mononucleosis (IM) and other pathologic sera was investigated by agglutination of NDV-modified human O red blood cells, as well as by immunodiffusion and enzyme immunoassay with various preparations of the virus. These studies clearly demonstrated that the NDV antibodies are distinct from P-B or H-D antibodies. The unexpected observation that guinea pig kidney (GPK) tissues absorbed NDV antibodies allowed their classification into a group of 'GPK-positive' heterophile antibodies. The simultaneous occurrence of the NDV antibodies and H-D antibodies in IM and other diseases suggests the possibility that multiple new antigenic determinants, especially those of carbohydrate nature, may appear due to the alteration of self-antigens as a result of various pathologic processes.

On the significance of C2, C4, and factor B polymorphisms in disease.

In this review article, recent evidence is presented that some diseases like insulin-dependent diabetes mellitus, multiple sclerosis, and idiopathic membranous nephropathy, which are primarily associated with HLA-D,DR, are also related to the rare C2, C4, and Factor B alleles. Circumstantial evidence is available that at least some of these rare variants may be functionally deficient. Based on the concept of functionally interacting gene clusters, mutant complement genes may lead to impaired effector mechanisms in virus neutralization or lysis of virus-infected cells. Other mechanisms such as alteration of vascular permeability may be involved in the development of proliferative retinopathy and familial hypertension. In lepromatous lepra, an impaired cell-mediated lysis of M. leprae may be related to the hemolytically inactive C4F1 allelic product.

Imbalance in T cell subsets in human diseases.

T cell subsets have been evaluated in 232 patients with various immunological diseases and 41 normal individuals used as a control group. An increase in the helper/suppressor ratio (OKT4:OKT8) was often noted in multiple sclerosis (acute attacks and progressive forms), autoimmune hemolytic anemia (without steroids), membranous and IgA-deposit glomerulonephritis, HBs-negative chronic active hepatitis, lepromatous patients with erythema nodosum, and myasthenia gravis. Ratios were usually normal in membranoproliferative nephritis, in lupus erythematosus (at least in steroid treated cases) and in nephrotic syndrome. High values of helper cells have been found in Sezary's syndrome (with low or no suppressor cells) and in mycosis fungoides. Variable data have been obtained in immunodeficiency syndromes. These data have been correlated with age, sex and clinical parameters, as well as with other immunological tests (E rosettes, mitogen responses, mixed lymphocyte reaction, Concanavalin A-induced suppression). From our investigations we have concluded that the study of OKT antibody-defined T cell subsets offers a valuable technique for the further investigation of human immunological diseases.

[Transfer factor. Properties and possible therapeutic applications (author's transl)]. / Transferfaktor. Eigenschaften und therapeutische Anwendungsmöglichkeiten

Transfer factor (TF) is a dialysable and ultrafilterable extract from human leukocytes. It contains only substances with a molecular weight of less than 10 000. Several biological activities of TF are so far known. These refer to the transfer of specific cellular immunity from one individual to another and a stimulating effect, probably of an unspecific nature, on the cellular immune system. So far, favorable therapeutic results have been obtained in chronic candidiasis and a few other chronic infectious diseases, in the Wiskott-Aldrich syndrome and possibly also in some special malignant tumors. The small number of treatments does not permit any firm conclusions to be drawn.