Immunological mechanisms giving rise to latency of herpes simplex virus in the spinal ganglia of the mouse

In the model of genital herpes simplex virus (HSV)-infection of mice, early latency could be induced by passive immunization with HSV-specific antibodies and, to a lesser degree, by adoptive transfer of immune lymphocytes prepared from spleen and draining lymph nodes of genitally infected syngeneic mice. Conversely, spontaneously occurring latency was inhibited by treatment of the animals with cyclophosphamide (Cph) and, to a lesser degree, with cyclosporin A (CyA). Whereas the effect of CyA could be compensated by passively administered HSV-specific antibodies, that of Cph could not. Apparently specific antibodies cooperate with a non-specific proliferating cell type, probably macrophages and/or NK-cells, as could be demonstrated by significantly reduced antibody effect in silica-treated mice. Moreover, F(ab)₂ fragments, in contrast to complete antibody molecules, were inactive. HSV-specific antibodies and also immune lymphocytes had little effect on virus production in the mucous membranes, immune lymphocytes being at least as active as antibodies. It is therefore not probable that latency is induced by attenuation of the peripheral disease. It can rather be concluded that the neuron itself is the target for the action of specific antibodies, cooperating in turn with macrophages and/or NK cells.With support of the Deutsche Forschungsgemeinschaft, Schn 174/6-3     

Life expectancy in patients attending multiple sclerosis clinics.

One multiple sclerosis (MS) is diagnosed, important considerations often include life expectancy and the availability of life insurance. We designed a study specifically to examine life expectancy among MS clinic patients and analyzed the data using standard actuarial methods, both including and excluding suicides. The data show that severe MS disability, as measured by an Expanded Disability Status Score (EDSS) of greater than or equal to 7.5, is a major risk factor for death with case fatality ratios for this group of patients approaching 4 times the rate for controls. Conversely, excluding deaths by suicide, case fatality ratios for those with mild and moderate disability (EDSS less than or equal to 7.0) approach 1.4 times and 1.6 times for age- and sex-matched comparison groups. Life tables indicate that the overall life expectancy for MS is only about 6 to 7 years less than that for the "insured" population without MS.     

Oligoclonal immunoglobulins in subacute sclerosing panencephalitis and multiple sclerosis: a study of idiotypic determinants.

Studies have been made of the idiotypic determinants of subacute sclerosing panencephalitis (SSPE) antibodies using rabbit antisera to serum and spinal fluid fractions.Evidence is presented indicating that serum and cerebrospinal fluid (CSF) anti-measles antibodies, as judged by their idiotypes, differ in their relative concentrations in the two compartments. The results indicate that some of these antibody subpopulations originate within the CNS, while others are made largely or entirely outside. In addition to strong idiotypic specificity, a limited cross-idiotypic specificity relating antibodies from three out of fourteen SSPE patients has been identified. In the course of these studies, measles virus was found to agglutinate red cells coated with antibody fraction to high titres. This system has proved useful in demonstrating the competition between anti-idiotypic antibody and antigen for the combining sites of the measles antibody. Two anti-idiotypic antisera have also been obtained against the spinal fluid IgG of multiple sclerosis (MS) patients. The possible use of these marker reagnets as well as related methodologies in the search for the antigens involved in MS bands is discussed.     

A dinucleotide mutation in the endothelin-B receptor gene is associated with lethal white foal syndrome (LWFS); a horse variant of Hirschsprung disease

Lethal white foal syndrome (LWFS) is a congenital anomaly of horses characterized by a white coat colour and aganglionosis of the bowel, which is similar to Hirschsprung disease (HSCR). We decided to investigate possible mutations of the endothelin-B receptor gene ( EDNRB ) in LWFS as recent studies in mutant rodents and some patients have demonstrated EDNRB defects. First, we identified a full-length cDNA for horse EDNRB . This cDNA fragment contained a 1329 bp open reading frame which encoded 443 amino acid residues. The predicted amino acid sequence was 89, 91 and 85% identical to human, bovine and mouse as well as rat EDNRB respectively, but only 55% identical to the human, bovine and rat endothelin A receptor (EDNRA). Secondly, sequence analysis, together with allele-specific PCR and the amplification- created restriction site (ACRS) technique, revealed a dinucleotide TC-- >AG mutation, which changed isoleucine to lysine in the predicted first transmembrane domain of the EDNRB protein. This was associated with LWFS when homozygous and with the overo phenotype when heterozygous.      

Hyperbaric oxygen therapy in chronic stable multiple sclerosis: double-blind study

We carried out a randomized, double-blind, placebo-controlled trial of hyperbaric oxygen therapy (HBO) in patients with chronic stable MS. Eighty-two patients were treated in a multiplace hyperbaric chamber with gas supplied by mask. Forty-one patients received 20 consecutive daily treatments of 100% O2 followed by 7 "booster" treatments in the next 6 months; 41 control patients received "air" (12.5% O2 at 1.75 atmospheres absolute). There was no significant difference in treatment and control groups in the Extended Kurtzke Disability scores, Kurtzke Functional scores, magnetic resonance imaging, or evoked potentials after the initial 20 treatments or after the boosters. HBO is not effective in treating chronic stable MS.     

Multifocal CT enhancement in MS

Review of 146 CTs in 125 MS patients showed that 53.4% (39/73) of those done during acute relapse showed enhancing lesions. Of scans done during the "active" stage of disease, 40.8% (20/49) showed enhancement, whereas only 12.5% (3/24) showed enhancement during clinically inactive periods. Autopsy confirmation that enhancing lesions represent demyelinating plaques was obtained in one patient. This study shows that enhancing lesions in MS reflect biologic activity and are most likely to be seen during acute clinically apparent relapses. More than one-half of the patients hospitalized with acute attacks appeared to be having multifocal relapses. These findings show that acute relapses are commonly multifocal and suggest that they are mediated by blood-borne factors.     

Relationship between HLA-DRB1 and DQ alleles and the genetic susceptibility to type 1 diabetes

Objective　To study the relationship between human leukocyte antigen (HLA)-DRB1 and DQ alleles and the genetic susceptibility of type 1 diabetes in North Chinese children. Methods　Polymerase chain reaction (PCR) techniques were used to amplify the second exon of DRB1 and DQ alleles, after which sequence specific olignucleotide probe (SSOP) dot blot hybridization techniques were used to analyze the amplified products. Results　DRB1*0301, DQA1*0301, DQB1*0201 alleles and DRB1*0301-DQA1*0501-DQB1*0201 haplotype were significantly increased in patients, while DQA1*0103 and DQB1*0601 alleles were significantly increased in controls. The distribution of DR4 and DR9 haplotypes in patients and controls were not significantly different, but DR3/DR4 and DR4/DR9 heterozygotes were significantly increased in patients. Conclusions　DRB1*0301, DQA1*0301 and DQB1*0201 confer susceptibility while DQA1*0103 and DQB1*0601 confer protection to type 1 diabetes. DRB1*0301-DQA1*0501-DQB1*0201 haplotype offers a predisposition to type 1 diabetes in North Chinese. Although the distribution of DR4 and DR9 in patients and controls had no significant difference, DR3/DR4 and DR3/DR9 heterozygotes were significantly increased in patients, showing that the susceptive effects of DR3 and DR4 or DR4 and DR9 haplotypes could be added up.     

A novel sodium channel mutation in a family with hypokalemic periodic paralysis

OBJECTIVE: To identify the cause of hypokalemic periodic paralysis (HOKPP) in a family whose disease is not caused by a mutation in the dihydropyridine-sensitive (DHP) receptor alpha1-subunit gene (CACNA1S). BACKGROUND: Hypokalemic periodic paralysis is primarily caused by mutations within CACNA1S. Genetic heterogeneity for HOKPP has been reported, but no other locus has been identified. METHODS: Single-stranded conformational polymorphism (SSCP) analysis and PCR direct sequencing were used to screen the skeletal muscle alpha1-sodium channel gene (SCN4A) for a mutation in our family. RESULTS: SSCP analysis showed an abnormally migrating conformer in exon 12. Direct sequencing of the conformer showed a guanine to adenine transition at position 2006 in the cDNA sequence; this results in an amino acid substitution of a highly conserved arginine (Arg) to histidine (His) at position 669. This sequence alteration segregated only with the affected members of the kindred and was not found in a panel of 100 DNA samples from healthy controls. The amino acid substitution alters the outermost positive charge in the membrane spanning segment DII/S4, which is involved in voltage sensing. CONCLUSIONS: The first arginine in DII/S4 and in DIV/S4 within the skeletal muscle sodium channel and the L-type calcium channel genie CACNA1S appear to be critical for normal function. In all four cases, Arg to His mutations result in a disease phenotype. The identification of a mutation within the skeletal muscle sodium channel resulting in hypokalemic periodic paralysis represents a novel finding.     

Efficacy of "high-intensity" blue-light and "standard" daylight phototherapy for non-haemolytic hyperbilirubinaemia

We report our clinical experience with phototherapy in 3802 infants; 3629 were exposed to "standard" daylight phototherapy and 173 to "high-intensity" blue-light phototherapy. High-intensity blue-light phototherapy was twice as effective as standard daylight phototherapy in decreasing bilirubin concentrations. No failures occurred with high-intensity phototherapy compared with an overall failure rate of 1.84/1000 with daylight lamps; these cases were transferred to high-intensity phototherapy with prompt response. Rebound after cessation of phototherapy was greater in those exposed to high-intensity blue light with a significantly greater number requiring a second exposure. However, the incidence was still low. No third exposure was required in any infant. Nursing of infants under high-intensity blue light was more difficult and inconvenient as was clinical monitoring. The light also caused more stress on the nursing and medical personnel. However, the infants tolerated both types of phototherapy equally well. High-intensity blue-light phototherapy would seem to be the treatment of choice for infants with rapidly increasing or very high bilirubin levels, as well as in those not responding adequately to daylight phototherapy.