Modulation of anti-acetylcholine receptor antibody specificities and of experimental autoimmune myasthenia gravis by synthetic peptides.

Synthetic peptides corresponding to selected sequences from the nicotinic acetylcholine receptor (AChR) were employed to identify possible antigenic determinants within the receptor which can modulate the anti-AChR response and experimental autoimmune myasthenia gravis (EAMG). Immunization of rabbits with peptides T alpha 73-89, T alpha 351-368, T delta 354-367 and H alpha 351-368, prior to AChR inoculation, affected the course of EAMG in six out of eight rabbits. These six protected rabbits survived three inoculations of AChR and survived for at least five months after the third injection with AChR, whereas control rabbits died following one or two injections of AChR. The survival of peptide-preimmunized rabbits injected with AChR seemed to correlate with the antibody specificities in immunoblots. Following AChR inoculation there was a shift in reactivity, from a subunit-restricted response, to reactivity with all subunits of the receptor. This shift was delayed in protected rabbits. This may indicate that the reactivity with the entire Torpedo receptor molecule represents a loss of tolerance to AChR which culminates in the autoimmune disease, EAMG.     

Candida sepsis during total parenteral nutrition: An endogenous infection indicating the severity of patients' disease state

Between 1986 and 1989 we encountered 33 episodes of candida sepsis among 1169 patients receiving TPN for a total of 23350 days (2.8% candida infection rate). Total hospital stay averaged 78 (range 10-230) days and patients received TPN for an average of 21.5 (range 3-83) days before developing candida sepsis. Candida sepsis developed in 8 patients (26.6%) hospitalised in an ICU; 6 patients (20%) receiving high doses of glucocorticoids, 5 patients (16.6%) treated by cytotoxic agents; 23 patients (76.6%) received various combinations of broad-spectrum antibiotics. The number of tubes going in or out numbered an average of 3.6/patient (peripheral and/or central I.V.; endotracheal; tracheostomy; urinary catheter; arterial line; abdominal or chest drains). 18 patients underwent 38 (2.1/patient) operative procedures. 20 patients (66%) suffered fron mono- or polymicrobial bacterial sepsis in addition to candida sepsis, 16 of them metachronously. Candida species isolated were C. albicans - 14 patients; C. tropicalis - 6 patients; C. parapsylosis - 6 patients; not specified - 4 patients. In addition to positive blood cultures we found positive candida cultures in urine, peritoneal cavity, chest cavity, wounds, respiratory tract, intravascular catheters, often in more than one site per patient. All patients were treated with Amphotericin at an average dose of 770 mg/patient. Mortality rate in patients with candida sepsis was 33%. TPN associated candida sepsis seems to be an endogenous self-infecting process in a select group of severely injured-infected-depleted-immunosuppressed patients and is thus completely different from the usual exogenous bacterial TPN associated sepsis. The major risk factors for fungaemia and candida sepsis are the combination of severe underlying disease state, multiple surgical interventions and intravascular lines, the use of broad spectrum antibiotics, TPN, injury and malnutrition associated immunosuppression, multiple tubes and catheters, and intra-abdominal or intra-thoracic infection.     

Feeding jejunostomy for post-operative nutritional support

Enteral feeding by tube jejunostomy, inserted during definitive surgery, was used in 19 adult patients operated upon in a 24 month period. Jejunostomy feeding was associated with a low rate of minor complications enabling delivery of adequate caloric and protein input shortly after major abdominal operations and up to 9 months later. We feel that the insertion of a regular size jejunostomy tube during surgery is a simple, brief and safe procedure which offers efficient and inexpensive nutritional support, and thus has an important role in the post-operative management of selected patients. It is also easily used in the home setting if needed.     

Isolation and characterization of rat skeletal muscle and cytoplasmic actin genes.

Southern blots of rat genomic DNA indicate the existence of at least 12 EcoRI DNA fragments containing actin gene sequences. By using specific probes and stringent conditions of hybridization, it was found that only one of these fragments contains sequences of the skeletal muscle alpha-actin gene. Recombinant bacteriophages originating from eight different actin genes were isolated from rat genomic DNA libraries. One of them, Act 15, contains the skeletal muscle actin gene. Another clone, Act I, contains a gene coding for a cytoplasmic actin, identified tentatively as the beta-actin gene. Both genes have a large intron very close to the 5' end of their transcribed region, followed by several small introns. DNA sequence analysis and comparison with the available data on actin genes in other organisms indicated an interesting relationship between the positions of introns and the evolutionary relatedness. Several intron sites are conserved from at least the echinoderms to the vertebrates; others appear to be present in some actin genes and not in others.     

Effectiveness, safety, and tolerability of risperidone in adolescents with schizophrenia: an open-label study

Data on risperidone's efficacy and tolerability in adolescents with schizophrenia are scarce. We found only one prospective, open-label study in this population. The aim of this open-label, prospective study was to estimate the effectiveness, safety, and tolerability of risperidone treatment in adolescents with first-episode schizophrenia. Subjects were adolescent inpatients diagnosed with Diagnostic and Statistical Manual of Mental Disorders (fourth edition) first-episode schizophrenia by the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Episode version. Most of the patients (10/11) were drug na?ve. Improvement was assessed during the first 6 weeks of treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Impression (CGI) scale. Side effects were monitored using the Abnormal Involuntary Movement Scale, the Simpson-Angus Scale, the Barnes Akathisia Rating Scale, and the Udvalg for Kliniske Undersogelser Side Effect Rating Scale. Eleven adolescents between 15.5 and 20 years of age (mean = 17.27, SD = 1.27 years) were included in this study. Risperidone in an average dose of 3.14 mg/day (SD = 1.60 mg/day) produced a significant improvement on the total PANSS score (28%, p < 0.01), BPRS score (30.11%, p < 0.01), and CGI-Severity score (31.36%, p < 0.01). Risperidone was ineffective in the treatment of negative signs as assessed by the PANSS. The major side effects were extrapyramidal side effects, somnolence, depression, and weight gain. In conclusion risperidone appears to be a safe, acceptably tolerated, and effective antipsychotic medication for the treatment of adolescent-onset schizophrenia.     

Signal peptides and trans-membrane regions are broadly immunogenic and have high CD8+ T cell epitope densities: Implications for vaccine development

Cell mediated immune response has a major role in controlling the elimination of infectious agents. The rational design of sub-unit peptide vaccines against intracellular pathogens or cancer requires the use of antigenic sequence/s that can induce highly potent, long lasting and antigen-specific responses in the majority of the population. A promising peptide selection strategy is the detection of multi-epitope peptide sequences with an ability to bind multiple MHC alleles. While past research sought the best epitopes based on their specific antigenicity, we ask whether specific defined domains have high epitope densities. Signal peptides and trans-membrane domains were found to have exceptionally high epitope densities. The improved MHC binding of these domains relies on their hydrophobic nature and, in signal peptides, also on their specific sequence. The high epitope density of SP was computed using in-silico methods and corroborated by the high percentage of identified SP epitope in the IEDB (immune epitope database). The enhanced immunogenicity of SP was then experimentally confirmed using a panel of nine peptides derived from Mycobacterium tuberculosis (MTb) proteins used in human PBMC proliferation assays and T cell lines functional assays. Our results show the exceptionally high antigen specific response rates and population coverage to SP sequences compared with non-SP peptide antigens derived from the same proteins. The results suggest a novel scheme for the rational design of T cell vaccines using a domain based rather than an epitope based approach.     

'1-8 interferon inducible gene family': putative colon carcinoma-associated antigens

D(b-/-)xbeta2 microglobulin (beta2m) null mice transgenic for a chimeric HLA-A2.1/D(b)-beta2m single chain (HHD mice) are an effective biological tool to evaluate the antitumour cytotoxic T-lymphocyte response of known major histocompatibility-restricted peptide tumour-associated antigens, and to screen for putative unknown novel peptides. We utilised HHD lymphocytes to identify immunodominant epitopes of colon carcinoma overexpressed genes. We screened with HHD-derived lymphocytes over 500 HLA-A2.1-restricted peptides derived from colon carcinoma overexpressed genes. This procedure culminated in the identification of seven immunogenic peptides, three of these were derived from the 'human 1-8D gene from interferon inducible gene' (1-8D). The 1-8D gene was shown to be overexpressed in fresh tumour samples. The three 1-8D peptides were both antigenic and immunogenic in the HHD mice. The peptides induce cytotoxic T lymphocytes that were able to kill a colon carcinoma cell line HCT/HHD, in vitro and retard its growth in vivo. One of the peptides shared by all the 1-8 gene family primed efficiently normal human cytotoxic T lymphocyte precursors. These results highlight the 1-8D gene and its homologues as putative immunodominant tumour-associated antigens of colon carcinoma.     

Hand preference in sequential and spatial discrimination tasks.

Hand preference in sensorimotor discrimination tasks was tested on 80 right handed subjects in four experiments. One set of experiments compared the abilities of the two hands to perform sequential tasks. The other set compared spatial abilities of the two hands. Within each set one experiment involved unimanual performance, and the other bimanual performance. The results showed that subjects performed better with their right hand on the bimanual sequential task, and better with their left hand on the bimanual spatial task. No hand preference was found in the unimanual tasks. The results are interpreted as reflecting the differential sensorimotor dominance of the left and right hemispheres for sequential and spatial tasks respectively.