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In a new, typical case of Schwartz-Jampel syndrome (SJS) the origin of the disorder was found to be purely myogenic. Concentric needle EMG showed abundant and persistent spontaneous activity, maximal at insertion, and uninfluenced by local curarization. Single-fiber EMG showed rather stable, sometimes intermittent, discharge series with occasional amplitude and/or frequency fluctuations. It could be demonstrated that this activity did not consist of complex repetitive discharges, but of independent activity of individual muscle fibers. This contrasts with findings by other investigators that have been published in this journal. Light microscopic studies of quadriceps and intercostal muscles showed no abnormalities, whereas electron-microscopic findings were in accordance with earlier studies in SJS. Endplate analysis revealed no specific changes; the postsynaptic structures gave the impression of an accelerated-maturation.

The HIV-1 isolate CBL-4 (RUT), originating from Tanzania, was characterized using a comprehensive virus-typing system. This system included sequence analysis of the region coding for the neutralization domain in the third variable region (V3) of the external envelope and of the tat responsive (TAR) region after polymerase chain reaction (PCR) amplification of these sequences from cellular DNA in the CBL-4 (RUT) producer line. Based on independent cluster analysis of TAR and V3 sequences the CBL-4 (RUT) virus was positioned closest to the Z6 (and ELI) African virus family. The V3 amino acid sequence on the surface of the virus particle was confirmed by the inhibition of neutralization of CBL-4 (RUT) by a synthetic peptide derived from the nucleic acid sequence. Using antisense phosphate-methylated DNA covering the TAR loop region of LAV-1/HTLV-IIIB, inhibition of HTLV-IIIB and HTLV-IIIRF infection was seen, whereas no inhibition was observed for CBL-4 (RUT), indicating two or more mismatches in the TAR loop region, a characteristic shared with Z6 virus, but not with ELI. We propose a virus-typing system based on sequence analysis confirmed by virus neutralization with a peptide binding antibody and inhibition by antisense phosphate-methylated DNA to group viruses for laboratory use and vaccine design.

Phosphate-methylated DNA hybridizes strongly and specifically to natural DNA and RNA. Hybridization to single-stranded and double-stranded DNA leads to site-selective blocking of replication and transcription. Phosphate-methylated DNA was used to interrupt the life cycle of the human immunodeficiency virus type-1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS). Both antisense and sense phosphate-methylated DNA 20-nucleotide oligomers, targeted at the transactivator responsive region and the primer binding site, caused complete inhibition of viral infectivity at a low concentration. Hybridization of phosphate-methylated DNA with folded and unfolded RNA was studied by ultraviolet and proton nuclear magnetic resonance spectroscopy. The combined results of hybridization studies and biological experiments suggest that the design of effective antisense phosphate-methylated DNA should focus on hairpin loop structures in the viral RNA. For sense systems, the 5' end of the integrated viral genome is considered to be the important target site.

We carried out a light and electron microscopic study on end plates and related structures in external intercostal muscles from subjects aged between 4 and 77 years. Light microscopically end plates maintained the same size, did not increase in number and showed no sprouting of terminal axons, all indicating that major compensatory histological changes to maintain adequate neuromuscular transmission with age were not required. At the ultrastructural level end plates became more complex mainly at the postsynaptic side. The latter included increased length and branching of the postsynaptic membrane with enlargement of the postsynaptic area, and degeneration of junctional folds. However, some neuromuscular junctions (NMJs) showed little branching of the postsynaptic membrane, even in old age. At the presynaptic side nerve terminals with an irregular shape were noted in the aged. Schwann cell processes were seen to intrude into the primary synaptic cleft. From these data we suggest that degeneration of the postsynaptic membrane with consequent focal denervation of NMJs is a primary event in the age-related changes of end plates. The muscle fibres showed a minor degree of type grouping in old age doubtless due to loss of motor neurons with age.

Emergence in two chimpanzees of HIV-1 HTLV-IIIB variants resistant to neutralization by the pre-existing antibody is described. Viruses isolated from the HTLV-IIIB gp120 vaccinated and challenged animal were more resistant to neutralization, had more heterogenic genomes and showed more pronounced antigenic drift as determined by serotypic neutralization analysis than viruses isolated from the naive infected animal, indicating immune pressure as the selective mechanism. The earliest selecting antibody population detected in the chimpanzees appeared to be conformationally dependent. This was demonstrated by its ability to neutralize only the most replication-competent sub-populations of the HTLV-IIIB inoculum strain, yet was found to bind a HTLV-IIIB common nonapeptide (IQRGPGRAF) derived from the gp120 isolate-specific 3rd variable domain (V3) also known to induce isolate-specific neutralization in multiple species. Each of the recovered isolates had become resistant to neutralization by both a monoclonal (0.5 beta) and polyclonal HTLV-IIIB gp120 V3-specific antibody by as much as 16 to 256-fold. Amplification of the V3 coding sequence by polymerase chain reaction and subsequent sequence analysis of the neutralization-resistant variants obtained from in vivo infected animals indicated that resistance to neutralization was conferred by changes outside the direct binding site for the selective neutralizing antibody. Further studies indicated that apparent neutralization-resistant variants, yielded after in vitro passage through chimpanzee and human peripheral blood mononuclear cell cultures void of HIV-specific antibody, result from the homogenic amplification of the more replication competent sub-population pre-existing in the original viral stock. These faster replicating sub-populations appear to dominate initially and therefore are the initial prime targets recognized by the chimpanzee humoral immune system upon infection in vivo and thus eliminated. The described finding of virus escape due to a conformationally-induced flexibility of the major neutralization epitope termed "conformational-V3 hypervariability", coupled to the known primary amino acid hypervariability of this epitope (V3) termed "linear-V3 hypervariability", may be all that is required by the virus to survive in an otherwise effective humoral immune system.

Two congenital anterior horn cell diseases may be responsible for neonatal muscular atrophy. The acute Werdnig-Hoffmann disease (SMA-I) has a progressive course, the anterior horn cell degeneration (AHCD) is non progressive in the postnatal period. In case of Werdnig-Hoffmann disease symptoms of hypotonia and muscle weakness may be present at birth, but become progressive during the first months of live. The full clinical picture of AHCD is present at birth. In the latter clinical symptoms of fetal hypokinesia may be noticed during intrauterine life. Histopathological muscle investigation reveals a more or less characteristic neurogenic pattern in Werdnig-Hoffmann disease, in AHCD neurogenic and myopathic changes are variable. Two examples of these diseases will be discussed.

A national multicentre study was performed to investigate the effects of donorselection and the use of heat-treated plasma products on seroconversion to HIV in 157 Dutch haemophiliacs. All patients included in the study were seronegative for HIV antibodies in 1983. Thirteen percent (20/157) seroconverted between 1983 and 1986. Nineteen of 20 seroconversions could be related to the use of non heat-treated products in the year preceding HIV antibody seroconversion. One seroconversion occurred in a person using heat-treated non donor screened product. Seroconversion rate decreased as a result of the policy to discourage high risk blood donors and no seroconversions were observed following the introduction of donor screening in 1985.

A newborn is described in whom trisomy 12 mosaicism was detected prenatally at third trimester amniocentesis during the fourth pregnancy of a 34-year-old woman. After birth, trisomy 12 cells were found in placental tissue and in cultured urine sediment cells. A sample of cord blood and a skin biopsy revealed only normal (46,XX) cells. Both parents had a normal karyotype. After a difficult start with unexplained hypoglycaemias and convulsion equivalents, the girl is doing well at the age of 9 months: there are no signs of central motor disturbance. The importance of the use of cultured urine sediment cells in confirming chromosomal mosaicism is stressed.

A case of congenital multiple angiomatosis with cerebral involvement is presented. Postmortem investigation showed identical angiomas on skin and brain. The cerebral vascular tumor has caused altered vascularization of the hemisphere, resulting in a development arrest of the corpus callosum and a fetal appearance of the parietal and temporal vessels.

Different stages of HIV infection are marked by expression of HIV genes, production of HIV antibodies, formation of antigen/antibody complexes and clearance of such complexes. Transient HIV antigenemia appearing generally 6-8 weeks prior to HIV antibody (HIV-Ab) seroconversion and lasting 3-4 months is generally seen in acute infection. If IgG antibodies to both envelope and core protein persist in the absence of HIV-Ag the short-term prognosis is relatively good. However, HIV-Ag seroconversion may appear at any time after HIV-Ab seroconversion. Progression to AIDS is strongly associated with declining or absent levels of IgG antibodies to p24. Titers of antibodies to HIV p24 below 64 are strongly associated with the presence of HIV antigen and a poor clinical outcome. HIV antigen may be less efficiently detected with the present assays in sera from regions where the prototype strains of HIV (HTLV-III and LAV) are less prevalent, like Central Africa. Levels of HIV-Ag in serum, and possibly in CSF, can be decreased by nucleoside analogues, like AZT. This indicates HIV-Ag and possibly antibody to HIV core protein p24 as suitable markers for selecting individuals for antiviral therapy as well as monitoring the efficacy of such therapy.

Congenital myasthenia (CM) constitutes a heterogeneous group of disorders with different underlying defects. The authors investigated a case of CM, presenting with congenital contractures. Endplate studies in the first year of life showed a developmental disorder of postsynaptic membranes. Clinical follow-up demonstrated a beneficial effect of pyridostigmine, resulting in normal motor development. Results of a second biopsy at age 4 are reported in this paper. Microelectrode study showed small Mepp amplitudes, which returned to nearly normal in the presence of neostigmine. In the electronmicroscope the postsynaptic membranes showed a paucity of infoldings, as in the first biopsy. These membranes showed only scanty, patchy enhancement with two different methods for localization of AChR. The extrajunctional membranes showed evidence of local presence of AChR. Our results show a developmental disorder of postsynaptic membranes with a deficiency and altered distribution of AChRs.

A 9-year-old girl suffering from progressive fluctuating dystonia is reported. Some problems of diagnosis are discussed. The differential diagnosis is described and a comparison is made with cases from the literature.

Chronic benign neutropenia of infancy is a disease which develops a few months after birth and which is characterized by a severe selective neutropenia, accompanied by benign but persisting infections. The cause of the disease is still unknown. The sera from 5 such patients were tested for the presence of granulocyte antibodies as a possible cause of the disease. For the detection of these antibodies immunofluorescence, agglutination and granulocytotoxicity were used. All sera contained antibodies which reacted both with the neutrophils of one or both parents of the patient and a part of a panel of unrelated donors. From the reaction patterns against the panel we could identify the specificity of three sera. Two sera were directed to the neutrophil-specific antigen NA2, and the third one reacted with a hitherto not yet recognized neutrophil-specific alloantigen which we called NE1. In 4 patients we could confirm the autoimmune character of the disease by demonstrating the antibody on the patients' own granulocytes. These results suggest that autoimmunity may be the cause of many cases of benign infantile neutropenia.

PEPSCAN analysis, performed using 536 overlapping nonapeptides derived from the HTLV-III B nucleotide sequence of the region encoding the external envelope protein of 120 kDa (gp120), identified in the V3 region of gp120 a major binding site for antibodies of HIV-1-infected humans. The minimal amino acid sequence of this antibody binding site was demonstrated by multiple length scanning to be five to eight amino acids in length: (G)PGRAF(VT), i.e. amino acids 312-319. A peptide (Neu 21) containing this binding site for human antibodies (KSIRIQRGPGRAFVTIG) was synthesized and shown to induce HTLV-III B cell fusion-inhibiting antibodies in rabbits and mice. Antibodies binding to this HTLV-III B/LAV-1-specific peptide were shown to be primarily of the IgG 1 subclass, appeared within 6 months after HIV-1 antibody seroconversion in six out of 14 men studied, and persisted throughout the follow-up period of 10-24 months. The other eight seroconverting men did not develop antibodies to Neu 21 during the observation period. The appearance of antibodies to Neu 21 paralleled the capacity of the serum to inhibit HTLV-III B in cell fusion. HIV-1-infected men with Kaposi's sarcoma exhibited a similar frequency of antibodies to the synthetic peptide Neu 21 (14 out of 39, 36%) as asymptomatic HIV-1-infected men (112 out of 319, 35%). Adults with Pneumocystis carinii pneumonia had a significantly lower frequency (11 out of 78, 14%) of antibodies to Neu 21. Similarly, a low prevalence of antibodies to Neu 21 (8 out of 43, 19%) was observed among symptomatic HIV-1-infected children.

Cell fusion of HTLV-IIIB-infected EBV-transformed B cells and CD4+ T cells was inhibited by sera from eight of nine HIV infected chimpanzees. Syncytia formation was reduced by sixty percent relative to control after only 5 minutes of preincubation of the HIV infected cells with immune primate serum, indicating that these antibodies have high affinity for HIV protein on the surface of infected cells. Serum dilutions that blocked formation of syncytia irreversibly within 24 hrs also blocked expression of HIV antigens by the target CD4+ cells. Three of four animals inoculated with the LAV or HTLV-IIIB strain of HIV developed antibodies inhibiting CD4-dependent cell fusion by HIV glycoprotein (CFI-antibodies) 2-3 months after inoculation coincident with development of HIV specific IgG antibodies. Similar early CFI-antibody responses occurred in two second passage chimpanzees. In contrast, a chimpanzee infected with a third passage of LAV had a delayed CFI-antibody response, indicating that variants of HIV with divergent CFI epitopes did eventually emerge. Delayed development of CFI-antibodies (6-11 months after inoculation) relative to HIV specific IgG ELISA antibody was also seen in a chimpanzee on primary passage and a chimpanzee on second passage of HTLV-IIIB. No CFI-antibodies were detected in a chimpanzee following inoculation with human brain tissue, while antibodies to other structural proteins were recognized by immunoblotting. These results indicate that changes in CFI epitopes occur under immune pressure and that the appearance of CFI-antibodies depends on the time after infection and on the degree to which CFI epitopes of the inoculum strain diverge from those of the test strain.

Sera from chimpanzees inoculated respectively with HTLV-III B, LAV, HTLV-III RF and brain tissue from an AIDS patient were analysed for neutralizing activity by two methods: a cell fusion inhibition test (CFI) using HTLV-III B infected cells as inoculum and CD4+ cells as target and a replication inhibition test (RIT) using cell-free HTLV-III B as well as HTLV-III RF as inoculum and also CD4+ cells as target. All chimpanzees seroconverted for HTLV-III B antibodies within 2 months after inoculation and the ten sera included in the study recognized the HTLV-III B core proteins p17 and p24 and the transmembrane protein gp41 by immunoblotting. The HTLV-III B external envelope gp120 was recognized by eight sera with antibodies active in the CFI (CFI-Ab) or in the RIT (VN-Ab) using HTLV-III B as inoculum, while neither of two sera without such reactivity did. HTLV-III B CFI-Ab and HTLV-III B VN-Ab concurred in nine of ten serum samples. LAV and HTLV-III B infection induced HTLV-III B CFI-Ab and HTLV-III B VN-Ab within 9 months after inoculation in all four chimpanzees tested. However, only the serum of one of the four animals also neutralized HTLV-III RF. HTLV-III RF inoculation evoked only HTLV-III RF VN-Ab within nine months. Between 11 and 18 months neutralizing activity to both HTLV-III B and HTLV-III RF was found in all four sera of chimpanzees inoculated with HTLV-III B, LAV or HTLV-III RF.(ABSTRACT TRUNCATED AT 250 WORDS)

Human antibodies to HIV antigens expressed on the surface of infected cells may inhibit cell fusion with uninfected CD 4-positive cells and mediate killing of the infected cells by effector cells bearing the Fc receptor. Sequential sera from ten HIV-antibody seroconverted men, of which five progressed to ARC or AIDS (CDC stage IV) during the follow-up period of two years, were tested for the ability to inhibit CD 4-dependent cell fusion, (CFI) and to mediate antibody-dependent cellular cytotoxicity (ADCC). Nine patients developed HIV-specific ADCC and seven CFI-antibodies using the HIV strain HTLV-IIIB as target antigen. These antibodies appeared approximately at the same time 2-12 months after primary infection, defined as antibody seroconversion or antigenaemia. ADCC antibodies were detectable at higher titers as compared to CFI-antibodies. All sera of asymptomatic individuals (CDC stage II and III) were CFI antibody positive and had a higher mean ADCC titer as compared to sera from patients progressing to AIDS or ARC. ADCC and CFI antibodies coincided in some cases in the complete absence of core antibodies. Because the relationship between ADCC and CFI was not exclusive it is concluded that distinct domains of the HIV envelope induce natural antibodies mediating ADCC and CFI.

Human immunodeficiency virus (HIV) is lymphotropic and neurotropic. In vivo clinical and immunological abnormalities develop in a large proportion of long-term HIV antibody seropositive persons. Different stages of HIV infection are marked by expression of HIV genes, production of HIV antibodies, formation of antigen/antibody complexes and clearance of such complexes. Transient HIV antigenemia appearing generally 6-8 wk prior to HIV antibody (HIV-Ab) seroconversion and lasting 3-4 mth is generally seen in acute infection. IgM antibodies predominantly to core proteins may occasionally be detectable when, or just before, IgG antibodies appear. If IgG antibodies to both envelope and core proteins persist in the absence of HIV-Ag the short-term prognosis is relatively good. However, HIV-Ag seroconversion may appear at any time after HIV-Ab seroconversion. Progression to AIDS is strongly associated with declining or absent levels of IgG antibodies to p24. IgG2 and IgG4 antibodies to HIV, which are mainly directed to p24, disappear most dramatically. Titers of antibodies to HIV p24 below 64 are strongly associated with the presence of HIV antigen and a poor clinical outcome. HIV antigen was detected frequently in sera from children in all stages of infection in contrast to adults whose sera were generally HIV-Ag negative when asymptomatic and positive when AIDS was apparent. HIV antigen may be less efficiently detected with the present assays in sera from regions where the prototype strains of HIV (HTLV-III and LAV) are less prevalent, like Central Africa. Persistence of HIV-Ag in cerebrospinal fluid (CSF) appears to be pathognomonic for progressive encephalopathy, particularly in children. Levels of HIV-Ag in serum, and possibly in CSF, can be decreased by nucleoside analogues, such as AZT. This indicates HIV-Ag and possibly antibody to HIV core protein p24 as suitable markers for selecting individuals for antiviral therapy as well as monitoring the efficacy of such therapy.

Two boys, aged 12 and 13 years, showed relapsing periods of somnolence and excessive eating, starting after a viral illness. One of them also showed periodic disturbance of sexual impulse control. The symptomatic periods were followed by symptom-free intervals in a highly characteristic pattern. This gave the clue to the diagnosis Kleine-Levin syndrome. The cause of this syndrome is unknown, in some cases a relationship between infectious disease or traumatic brain damage has been postulated. A dysfunction of the hypothalamus and associated structures is suspected. The syndrome has a rather favourable prognosis. The symptoms can be relieved by amphetamines, methylphenidate and probably also by lithium carbonate.

Sera from three chimpanzees infected with a primary lymphadenopathy-associated virus (LAV-1) or human T-lymphotropic virus type III (HTLV-IIIB) passage, from two chimpanzees infected with blood from the primary infected chimpanzees, and from one chimpanzee infected with blood from a secondary passage animal all bound the peptides 3B and 3B/RF, sharing the sequence IQRGPGR, with equally high titers. Pepscan analysis confirmed the amino acids Q, R, G, P, and G as irreplaceable in order to retain antigenicity.

Research into anxiety and related disorders requires the systematic collection of much new data. The areas of research most likely to produce clinically useful information are considered. The richest area of research will probably be biopharmacological. Biological and pharmacological research may be usefully coupled to behavioural recording in order to increase our knowledge of the behavioural/physiological relationships. More data are, however, needed on the social/environmental areas of anxiety and on the natural history of these conditions. Cognitive/behavioural approaches are more likely to be useful than depth psychological approaches.

Sequential sera of 697 homosexual men, participating in a prospective study (1984-1986) of the risk to acquire human immunodeficiency virus (HIV) or AIDS, were tested for antibodies to human T-cell leukaemia virus (HTLV-I) by particle agglutination and immunoblotting. No intravenous drug users were included in this trial. Three men (0.4%) were HTLV-I antibody positive at intake and an additional 2 at the end of the observation period, resulting in an attack rate of approximately 0.3%. One of the 3 men with HTLV-I antibodies at intake was a Brazilian. One man had an acute HTLV-I infection after sexual intercourse with a Brazilian during holiday in Brazil. No serological cross-reactivity with HIV was observed nor a relationship with other sexually transmissible viral or bacterial infections. In contrast to HIV no relationship with anogenital intercourse was noted; both primary HTLV-I infected men practiced only orogenital intercourse. This suggests that HTLV-I was imported in the Dutch homosexual community after HIV was introduced in the Netherlands. HTLV-I appears to spread slower within the homosexual community than HIV and possibly by other routes.

We report the pedigree of a family in which a mother and her two children, a boy and a girl, all suffer from a similar, though variably expressed cerebral disorder, seen on CT as uni- or bilateral cavities within the supratentorial white matter in communication with the ventricular system. Additional white matter hypodensity around the lateral ventricles without ventricular widening provides preliminary evidence of a primary disease of myelination, in the absence of histopathological confirmation. This is probably the first report of "porencephaly" which shows a pattern of autosomal dominant inheritance.