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PubMed2000

Subgroups, treatment effects, and baseline risks: some lessons from major cardiovascular trials.

BACKGROUND: The objective of this study was to determine how subgroup analyses are performed in large randomized trials of cardiovascular pharmacotherapy. METHODS AND RESULTS: We reviewed 67 randomized, double-blind, controlled trials involving pharmacotherapy in at least 1000 patients with unstable angina, myocardial infarction, left ventricular dysfunction, or heart failure with clinical outcomes as primary end points, published between 1980 and 1997. Nine had no subgroup analyses but 43 reported on 5 or more subgroups and 31 reported subgroups without formal statistical tests for treatment-subgroup interactions. In most trials, a rationale for subgroup selection was missing. All but 6 focused on single-factor subgroups. CONCLUSIONS: Trial subgroups should ideally be defined a priori on 2 bases: single-factor subgroups with a strong rationale for biological response modification and multifactorial prognostic subgroups defined from baseline risks. However, single-factor subgroup analyses are often reported without a supporting rationale or formal statistical tests for interactions. We suggest that clinicians should interpret published subgroup-specific variations in treatment effects skeptically unless there is a prespecified rationale and a significant treatment-subgroup interaction.

Angina, Unstable↗
PubMed1997

An indirect means of assessing potential nutritional effects of dietary olestra in healthy subgroups of the general population.

The potential for olestra to affect the absorption of dietary components was measured in 18- to 44-y-old humans and the weanling pig. Results from the studies were assessed to determine if they were relevant to subgroups of the population not included in the studies. Hypothetrically, two factors that might cause the study results not to be relevant to certain subgroups are dietary pattern and metabolic need. A dietary pattern resulting in olestra-to-nutrient intake ratios greater than those tested in the studies might produce effects greater than those measured. Metabolic needs (i.e., nutrient requirements) among subgroups greater than those of the study population might mean that any effects on nutrient absorption seen in the studies would be larger among subgroups. If olestra-to-nutrient ratios and nutrient requirements of a subgroup were less than those covered in the studies, then the effects of olestra on the nutritional status of the subgroup should be no different than the effects measured in the studies. Subgroups with high olestra-to-nutrient intake ratios were identified by calculating the ratios for those nutrients assessed in the studies [i.e., macronutrients, vitamins A (including beta-carotene), D, E and K, folate, vitamin B12, calcium, iron and zinc]. Subgroups with the greatest olestra-to-nutrient intake ratios for one or more nutrients included children, teenagers and young adults, women from low income families and vegetarians. Subgroups with the greatest metabolic need for one or more nutrients included children, teenagers, and pregnant and lactating women. The olestra-to-nutrient ratios and nutrient requirements of the subgroups having the greatest ratios and requirements were compared with those of the test population. The olestra-to-nutrient intake ratios fed in the studies were greater than those for any subgroup for all nutrients except calcium, which is not affected by olestra. Metabolic needs of the test population were greater than those of all population subgroups for all nutrients. The effects of olestra on nutritional status should not be different or greater than those measured in the controlled clinical tests for subgroups not directly tested.

Adolescent↗
PubMed2000

Phylogenetic analysis of human herpesvirus-8 in South Africa and identification of a novel subgroup.

The incidence of Kaposi's sarcoma in South Africa is increasing in parallel with the human immunodeficiency virus type 1 epidemic. An 804 bp region in the ORF75 gene of 40 human herpesvirus-8 (HHV-8) isolates from South Africa was sequenced and the phylogenetic relationships were compared to published sequences. Nineteen strains clustered with subgroup B and 11 with subgroup A; however, the bootstrap values supporting these subgroups were not significant. Three strains grouped significantly with the C subgroup, while eight sequences did not cluster with any of the previously classified subgroups and were termed novel (N). The N subgroup differed from the A, B and C subgroups by DNA distances of 4.8, 4.2 and 4.5%, respectively, although within the N subgroup there was only 0.4% variation. The inclusion of this subgroup increased the number of previously described subgroup-specific polymorphisms from 17 to 47 over an 804 bp region. There was sufficient inter-subgroup genetic diversity for a single-strand conformational polymorphism assay to be used to identify them rapidly. Thus, based on analysis of the ORF75 gene, a unique HHV-8 subgroup, termed N, is present in South Africa, which accounts for 20% of circulating strains. Further studies are required to determine the degree of genetic divergence, distribution and pathogenic potential of this novel subgroup.

Adult↗
PubMed1987

Subgroup characteristics of respiratory syncytial virus strains recovered from children with two consecutive infections.

Respiratory syncytial virus strains from 13 children who had repeat infections at least 1 year apart were identified as either subgroup A or subgroup B according to reaction patterns with several monoclonal antibodies directed against the large surface glycoprotein (G), fusion protein (F), nucleoprotein (NP), and matrix protein (M). The virus strains were characterized by enzyme immunoassay, polyacrylamide gel electrophoresis, and immunofluorescence procedures. During the first infection, 10 children had subgroup A strains and 3 had subgroup B strains. Of the 10 children with subgroup A strains during their first infection, 6 had subgroup B and 4 had subgroup A strains during the second infection. Of the three children with subgroup B strains during their first infection, one had subgroup A and two had subgroup B strains during their second infection. No child experienced unusually severe respiratory tract illnesses during second infections with respiratory syncytial virus. Fourfold or greater rises in serum antibody as determined by enzyme immunoassay were as common after the first infection as after the second infection among the seven children tested. Thus, second infections with strains of either subgroup of respiratory syncytial virus did not potentiate respiratory illness, and infection with subgroup A strains of respiratory syncytial virus provided some protection from a second infection with the homologous, but not the heterologous, subgroup of the virus.

Acute Disease↗
PubMed1988

Occurrence of respiratory syncytial virus subgroup A and B strains in Japan, 1980 to 1987.

The subgroup characteristics of 71 strains of respiratory syncytial virus (RSV) isolated in Sapporo, Japan, during 5 epidemic years from 1980 to 1987 were determined by the use of 17 monoclonal antibodies (MAbs) raised against the RSV Long strain, which is now recognized as the prototype subgroup A strain. Nine of these MAbs immunoprecipitated the fusion protein (F), five immunoprecipitated the large glycoprotein (G), two immunoprecipitated the nucleoprotein (NP), and one immunoprecipitated the phosphoprotein (P). Based on the pattern of reaction of these MAbs to RSV isolates in an indirect immunofluorescence assay, we were able to distinguish two different subgroups. Subgroup A strains reacted to all 17 MAbs. Subgroup B strains reacted to none of the anti-G MAbs, eight of the nine anti-F MAbs, and all anti-NP and anti-P MAbs. Subgroup A included 38 (53.5%) isolates from every epidemic year. Subgroup B included 32 (45.1%) strains isolated in the last 4 epidemic years. One virus strain with an intermediate character of reactivity was isolated in 1983. From the first epidemic year, six subgroup A strains and no B strains were isolated. During the next three annual epidemics, subgroup B strains were predominantly isolated, i.e., 8 of 13, 10 of 13, and 13 of 17 strains. However, in the last epidemic year only one strain of 22 isolates belonged to subgroup B, and the remainder belonged to subgroup A. This variability of dominance in the occurrence of different RSV subgroup strains may suggest a possible role of the subgroup-specific immune response in RSV epidemics.

Antibodies, Monoclonal↗
PubMed1990

A subgroup-specific antigenic site in the G protein of respiratory syncytial virus forms a disulfide-bonded loop.

An antigenic site (represented by 15 amino acids, residues 174 to 188, designated peptide 12) of the large glycoprotein G of respiratory syncytial virus was demonstrated to be subgroup specific in peptide enzyme-linked immunosorbent assay tests with murine monoclonal antibodies and human postinfection sera. The role of individual amino acids in this subgroup-specific site was determined by use of single-amino-acid-deletion sets of peptides. When monoclonal antibodies were reacted with the deletion sets, a broad amino acid dependence of 11 or 12 residues, Cys-176 (Ile-175 in subgroup B) to Cys-186, was found. Human postinfection sera exhibited a narrower reaction profile (for subgroup A, Cys-182 to Trp-183; for subgroup B, Cys-176 to Lys-183). Reduction of peptides on microtiter plates by treatment with dithiothreitol completely destroyed their antigenic activity in tests with monoclonal antibodies and human postinfection sera of subgroup B. A variant of peptide 12 containing all four cysteines of the G protein (represented by 16 amino acids, residues 172 to 187, designated peptide 12var) also was subgroup specific. We concluded that the activity of the antigenic site in tests with monoclonal antibodies for subgroups A and B appears to depend on intrapeptide disulfide bonds. Reactions with postinfection sera of subgroup B also may depend on a disulfide bond. In contrast, postinfection sera of subgroup A appeared to have the capacity to identify a subgroup-specific site in a linear form of the selected 15-amino-acid-long peptide. Treatment of peptides with dithiothreitol had no effect on their antigenic activity in tests with human postinfection sera of subgroup A. These findings have relevance for molecular engineering of peptide antigens for use in respiratory syncytial virus subgroup-specific site-directed serology.

Amino Acid Sequence↗
PubMed1998

The unique envelope gene of the subgroup J avian leukosis virus derives from ev/J proviruses, a novel family of avian endogenous viruses.

A new subgroup of avian leukosis virus (ALV), designated subgroup J, was identified recently. Viruses of this subgroup do not cross-interfere with viruses of the avian A, B, C, D, and E subgroups, are not neutralized by antisera raised against the other virus subgroups, and have a broader host range than the A to E subgroups. Sequence comparisons reveal that while the subgroup J envelope gene includes some regions that are related to those found in env genes of the A to E subgroups, the majority of the subgroup J gene is composed of sequences either that are more similar to those of a member (E51) of the ancient endogenous avian virus (EAV) family of proviruses or that appear unique to subgroup J viruses. These data led to the suggestion that the ALV-J env gene might have arisen by multiple recombination events between one or more endogenous and exogenous viruses. We initiated studies to investigate the origin of the subgroup J envelope gene and in particular to determine the identity of endogenous sequences that may have contributed to its generation. Here we report the identification of a novel family of avian endogenous viruses that include env coding sequences that are over 95% identical to both the gp85 and gp37 coding regions of subgroup J viruses. We call these viruses the ev/J family. We also report the isolation of ev/J-encoded cDNAs, indicating that at least some members of this family are expressed. These data support the hypothesis that the subgroup J envelope gene was acquired by recombination with expressed endogenous sequences and are consistent with acquisition of this gene by only one recombination event.

Amino Acid Sequence↗
PubMed1992

Subgroups of Tcr alpha chains and correlation with T-cell function.

T-cell receptor (Tcr) alpha chains are classified into four subgroups (I, II, III, and miscellaneous) based on the amino acid residues at positions 61 and 62. Subgroup I has Gly Phe at these positions, subgroup II has Arg Phe, subgroup III has Arg Leu, and subgroup miscellaneous has several other combinations. Variability plots for subgroups I, II, and III sequences show higher values around positions 93-103, 105, 108, 111, 113, and 115, suggesting that these positions may interact with the processed antigen molecules. Smaller peaks are present at various other regions which may bind the major histocompatibility complex class I or II molecules. The patterns of variability within one subgroup are similar for all species, for human alone, and for mouse alone. These subgroup patterns appear much less complicated than patterns for sequences in all subgroups taken together, implying that subgroups may be related to Tcr functions. Among 83 mouse chains, 15 are from cytotoxic cells and 40 from helper cells. Of the 15 from cytotoxic cells, 11, 2, 0, and 2 are in subgroups I, II, III, and miscellaneous; and of the 40 from helper cells, 9, 16, 12, and 3 are in subgroups I, II, III, and miscellaneous, respectively. Thus, a correlation between sequence and function of Tcr alpha chains seems possible.

Amino Acid Sequence↗
PubMed1991

EEG power variation in schizophrenic subgroups: effects of emotionally salient stimuli.

Eighteen unmedicated chronic schizophrenic patients and 13 normal controls were tested in a paradigm designed to examine functional changes in electroencephalographic (EEG) activity following presentation of emotionally salient auditory stimuli and control tones. Five standard bands of EEG spectral power were examined at bilateral frontal and temporal surface recording sites. The schizophrenic subjects were assigned to diagnostic subgroups on the basis of DSM-III-R criteria following independent clinical examination by two staff psychiatrists. Those subjects who met DSM-III-R criteria for paranoid schizophrenia were assigned to one subgroup (PS subgroup), while those who met DSM-III-R criteria for either residual or undifferentiated schizophrenia were assigned to a second subgroup (R/US subgroup). Analysis of Variance of EEG activity recorded at bilateral frontal (F1 and F2) and temporal (T3 and T4) scalp leads revealed significant diagnosis-related differences in alpha and beta-2 activity at temporal recording sites, and in beta-1 and beta-2 activity at frontal recording sites. Post-hoc tests revealed that significant differences in all four measures occurred in the R/US subgroup, which showed a decrease in temporal alpha and an increase in temporal beta-2 power as compared to controls. These variations in EEG activity appeared to demonstrate a degree of subgroup specificity, as the R/US subgroup also differed significantly from the PS subgroup on most of these measures. Significant subgroup-specific lateralization effects were also observed for temporal lobe delta activity and for frontal lobe beta-1 activity. These findings are interpreted in terms of subgroup-specific alterations in the processing of sensory information in schizophrenia, particularly when such information is emotionally salient. They suggest that subgroup differences in emotional and clinical state may be reflected in differential changes in EEG spectra within the schizophrenic population.

Acoustic Stimulation↗
PubMed2006

Identifying sedentary subgroups: the National Cancer Institute's Health Information National Trends Survey.

BACKGROUND: Developing effective interventions for the 24% to 28% of U.S. adults who are sedentary requires a better understanding of the factors related to sedentary lifestyles as well as the communication channels to reach various subgroups. This study identified key sociodemographic and health communication characteristics of various subgroups with high rates of inactivity using signal detection methodology. METHODS: The sample from the nationally representative Health Information National Trends Survey 2003 (n=6369) was randomly split into two samples. Exploratory analyses (conducted 2004 and 2005) were employed on the first sample to identify various subgroups, and the stability of inactivity rates in those subgroups was examined in the second sample. RESULTS: Eight subgroups with varying levels of inactivity were identified. Three subgroups had inactivity levels of 40% or higher, while the lowest subgroup had a level of less than 15%. The highest inactivity subgroup consisted of individuals with at least some college education who were in fair/poor health and who watched 4 or more hours of television per day. The second-highest inactivity subgroup was composed of those without a college education who tended not to use or attend to many communication channels. The third highest inactive subgroup consisted of those without a college education who read the newspaper and were obese. Levels of inactivity in the second independent sample subgroups were not significantly different from those found in the exploratory sample. CONCLUSIONS: This study identified empirically based, physically inactive subgroups that differed on sociodemographic and health communication characteristics. This information should be useful in creating future evidence-based, targeted, and tailored intervention strategies.

Adult↗
PubMed1997

Five subgroups of Blastocystis hominis from symptomatic and asymptomatic patients revealed by restriction site analysis of PCR-amplified 16S-like rDNA.

DNA polymorphism of Blastocystis hominis isolates was examined by the amplification of a gene fragment coding for the 16S-like rDNA. Using identical primers, fragments of approximately 850 bp were amplified from 110 B. hominis isolates and fragments of 1.1 kbp were amplified from 48 isolates. Digestion of the amplification products with the restriction enzymes HinfI, RsaI, and AluI revealed different profiles for each fragment length. Subgroup I and II, resulting from digestion of the smaller 850 bp fragment, have identical HinfI and AluI restriction bands, subgroup III and IV have identical RsaI fragments after digestion of the 1.1 kbp DNA. Subgroup V resembles subgroup III in a few bands after the RsaI and AluI restriction, respectively. Ninety (54%) of the isolates studied were assigned to subgroup I, 20 (12%) to subgroup II, 35 (21%) to subgroup III, 12 (7%) to subgroup IV, and 1 (1%) to subgroup V. Five (3%) of the examined people were coinfected with B. hominis of the subgroup III, 3 (2%) carried B. hominis of the subgroup I and II. These results show that there are 5 B. hominis subgroups none of which was found to be significantly correlated with the reported disease.

Animals↗
PubMed1979

Production of avian oncoviral subgroups after multiple infection.

The number of different oncoviral env genes that can be expressed by a single chicken embryo fibroblast was investigated. Fibroblasts were infected with one to three subgroups of Rous-associated virus, which is a nontransforming avian oncovirus, then superinfected with a transforming virus, Rous sarcoma virus, of a different subgroup. The subgroups of viruses released by the resulting clones were analyzed. When two viral subgroups were used for preinfection, all the resulting clones produced transforming virus particles having the subgroup of the superinfecting virus, and most clones produced transforming virus particles of all the infecting viral subgroups. However, when cells were preinfected with three viral subgroups, many of the resulting clones did not produce transforming virus particles having the subgroup of the superinfecting virus, and only 1 of 23 clones produced transforming particles of all the infecting viral subgroups. DNA annealing experiments showed that cells infected with three or four viral subgroups had an additional 8 to 20 copies of proviral DNA per cell. Finally, most clones resulting from cells simultaneously infected with three or four viral subgroups were able to produce virus of all infecting subgroups. It appears that the number of exogenous oncoviral env genes that can be expressed by a single cell is limited, and in the range of 4 to 8-20 per cell.

Animals↗
PubMed2005

Subgroup analysis and covariate adjustment in randomized clinical trials of traumatic brain injury: a systematic review.

OBJECTIVE: Few randomized clinical trials (RCTs) in the field of traumatic brain injury (TBI) have shown a significant treatment benefit. We critically reviewed the use of two types of secondary analyses, covariate adjustment and subgroup analysis, which are common in TBI trials. METHODS: We performed a systematic review of therapeutic phase III RCTs, including adult patients with acute, moderate-to-severe TBI. Glasgow Outcome Scale (GOS) at > or =3 months as outcome, and > or =50 patients per arm were required. We compared the actual reporting of covariate adjustment and subgroup analyses with the Consolidated Standards of Reporting Trials (CONSORT) recommendations. Likewise, we reviewed six protocols of large multicenter RCTs and compared planned and reported subgroups. RESULTS: We identified 18 RCTs (n = 6439). Sixteen trials used GOS at 6 months as outcome. Five RCTs reported covariate adjustment. The number of covariates was limited (< or =5), most frequently including age. Many covariates were outcome predictors. Four RCTs reported only adjusted treatment effects as the main efficacy parameter. Eleven RCTs reported subgroup analyses. Several subgroup factors (< or =7, mainly outcome predictors) and outcomes (< or =4) were included. The highest total number of subgroups was 15, and only three RCTs completely pre-specified subgroups. Notably, 10 of 11 RCTs performed inappropriate separate subgroup analyses. Of 11 RCTs, 5 gave subgroups the same emphasis as the overall effect. Reported subgroup analyses were insufficiently described and clearly differed from those planned in the protocol. CONCLUSION: The reported covariate adjustment and subgroup analyses from TBI trials had several methodological shortcomings. Appropriate performance and reporting of covariate adjustment and subgroup analysis should be considerably improved in future TBI trials because interpretation of treatment benefits may be misleading otherwise.

Brain Injuries↗
PubMed1995

Evaluation of subgroup-specific peptides of the G protein of respiratory syncytial virus for characterization of the immune response.

Two synthetic peptides, designated peptides 12G(A) and 12G(B), representing amino acids 174-188 of the G glycoprotein of respiratory syncytial virus (RSV) subgroup A (strain A2) and subgroup B (strain CH18537) were evaluated for their properties as subgroup-specific antigens for enzyme immunoassay (ELISA). These peptides were used to characterize the immune response of children with naturally occurring RSV infection during six annual epidemics in the Huntington area, West Virginia, USA; viz. 1978-1979, 1979-1980, 1980-1981, 1983-1984, 1989-1990, and 1990-1991. The study group comprised 43 paired sera from 42 infants and children, who ranged in age between 1 month and 5.5 years of age (median age 16 months). The inclusion criteria were subgroup identification of RSV, respiratory tract illness requiring admission to hospital, and the availability of paired sera. Five of 30 children with subgroup A and 3 of 13 children with subgroup B infections developed homologous or dual fourfold or greater antibody responses to peptides 12G(A) and 12G(B) during convalescence; six of these eight children also developed antibody rises to whole virus antigens. Twenty children (14 subgroup A and 6 subgroup B) developed such responses in antibody only to whole virus (not to the peptides), and 15 children (11 subgroup A and 4 subgroup B) failed to develop a rise in antibody. Children who developed rises in antibody to the peptides were usually less than 9 months of age, suggesting that a response to peptides was more likely to occur during primary infection. Peptides 12G(A) and 12G(B) of RSV G protein lacked sufficient sensitivity and specificity to serve as antigens for ELISA for characterizing the subgroup-specific immune responses to RSV infection in infants and children.

Aging↗
PubMed2006

Safety and efficacy of oral terbinafine in the treatment of onychomycosis: analysis of the elderly subgroup in Improving Results in ONychomycosis-Concomitant Lamisil and Debridement (IRON-CLAD), an open-label, randomized trial.

OBJECTIVES: The primary objective of this subanalysis was to examine the safety, tolerability, and efficacy of terbinafine in the treatment of toenail onychomycosis in the patients aged > or = 65 years in the Improving Results in Onychomycosis Concomitant Lamisil And Debridement (IRON-CLAD) trial. (Lamisil and IRON-CLAD are trademarks of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.) The secondary objective was to determine if toenail debridement would provide additional efficacy benefits in this subgroup. METHODS: The IRON-CLAD trial was an open-label, randomized, multicenter study of adults who underwent 4 weeks of screening and received terbinafine 250 mg/d for 12 weeks with or without aggressive toenail debridement (at baseline and weeks 6, 12, and 24). Clinic visits occurred at weeks 6, 12, 24, and 48. Safety and tolerability were assessed by adverse event (AE) rates based on changes in laboratory values, patient-volunteered information, answers to investigator questions, and physical examinations. Efficacy was evaluated by mycologic cure (negative microscopy of potassium hydroxide samples and negative culture), clinical cure (> or = 87.5% nail clearing), and complete cure (mycologic cure and complete toenail clearing) at week 48. The present subanalysis of IRON-CLAD results assessed participants aged > or = 65 years (older subgroup). RESULTS: A total of 504 patients were randomized, of whom 75 were aged > or = 65 years. In the older subgroup, the mean (SD) age was 68.9 (3.04), 86.7% (65/75) were white, and 66.7% (50/75) were male. Incidence of AEs reported during the treatment period or within 30 days after treatment discontinuation (treatment-emergent AEs [TEAEs]) was 28.0% in the older subgroup and 23.0% in the overall study population. Most TEAEs were mild (73.7%) to moderate (23.7%) in severity, and most (86.8%) were not suspected by the investigators to be related to study treatment. The most frequently occurring TEAEs in the older subgroup were nausea (4.0%), sinusitis (4.0%) arthralgia (2.7%), and hypercholesterolemia (2.7%). The proportion of participants who withdrew from the trial due to TEAEs was 4.0% (3/75) in the older group and 2.8% (14/504) in the overall population. Only 3 of 11 discontinuations in the older subgroup were due to a TEAE suspected by the investigator to be related to study treatment. Sixty-four percent of the older subgroup took antihypertensive medications, 25% took antidiabetics, and 47% took antilipemic medications. There were no clinical signs of drug interactions in the older subgroup. Clinical efficacy outcomes in the older subgroup were generally good and appeared to be comparable with those in the younger subgroup. At week 48, mycologic cure had occurred in 64.0% (95% CI, 53.1%-74.9%) of the older subgroup, clinical cure in 41.3% (95% CI, 30.2%-52.5%), and complete cure in 28.0% (95% CI, 17.8%-38.2%). Debridement did not appear to affect mycologic outcomes or clinical effectiveness, but rates of clinical and complete cure appeared to be higher among older patients who underwent adjuvant debridement. CONCLUSIONS: The results of this subanalysis suggest that terbinafine was well tolerated and efficacious in these patients aged > or = 65 years with moderate to severe toenail onychomycosis, many of whom were taking antihypertensives, antidiabetics, or lipid-lowering agents concomitantly. There were no reported clinical signs of drug interactions.

Adolescent↗
PubMed2005

Behavioral differences between subgroups of rats with high and low threshold to clonic convulsions induced by DMCM, a benzodiazepine inverse agonist.

In epileptic patients, there is a high incidence of psychiatric comorbidities, such as anxiety. Gamma-aminobutyric acid (GABA) ionotropic receptor GABA(A)/benzodiazepine allosteric site is involved in both epilepsy and anxiety. This involvement is based on the fact that benzodiazepine allosteric site agonists are anticonvulsant and anxiolytic drugs; on the other hand, benzodiazepine inverse agonists are potent convulsant and anxiogenic drugs. The aim of this work was to determine if subgroups of rats selected according to their susceptibility to clonic convulsions induced by a convulsant dose 50% (CD50) of DMCM, a benzodiazepine inverse agonist, would differ in behavioral tests commonly used to measure anxiety (elevated plus-maze, open field) and depression (forced swimming test). In the first experiment, subgroups of adult male Wistar rats were selected after a single dose of DMCM and in the second experiment they were selected after two injections of DMCM given after an interval of 1 week. Those rats presenting full clonic convulsions were termed Low Threshold rats to DMCM-induced clonic convulsions (LTR) and those not having clonic convulsions High Threshold rats to DMCM-induced clonic convulsions (HTR). In both experiments, only those rats presenting full clonic convulsions induced by DMCM and those not showing any signs of motor disturbances were used in the behavioral tests. The results showed that the LTR subgroup selected after two injections of a CD50 of DMCM spent a significantly lower time in the open arms of the elevated plus-maze and in the off the walls area of the open field; moreover, this group also presented a higher number of rearings in the open field. There were no significant differences between HTR and LTR subgroups in the forced swimming test. LTR and HTR subgroups selected after only one injection of DMCM did not differ in the three behavioral tests. To verify if the behavioral differences between HTR and LTR subgroups of rats selected after two injections of DMCM were due to the clonic convulsion, another experiment was carried out in which subgroups of rats susceptible and nonsusceptible to clonic convulsions induced by a CD50 of picrotoxin, a GABA(A) receptor channel blocker, were selected and submitted to the elevated plus-maze and open field tests. The results obtained did not show any significant differences between these two subgroups in the elevated plus-maze and open field tests. In another approach to determine the relation between fear/anxiety and susceptibility to clonic convulsions, subgroups of rats were selected in the elevated plus-maze as more or less fearful/anxious. The CD50 for clonic convulsions induced by DMCM was determined for each of these two subgroups. The results showed a significantly lower CD50 for the more fearful/anxious subgroup, which means a higher susceptibility to clonic convulsions induced by DMCM. The present findings show a relation between susceptibility to clonic convulsions and fear/anxiety and vice versa which may be due to differences in the assembly of GABA(A)/allosteric benzodiazepine site receptors in regions of the brain.

Animals↗
PubMed1999

Division of the irritable bowel syndrome into subgroups on the basis of daily recorded symptoms in two outpatients samples.

BACKGROUND: If subgroups exist in a sample of patients with irritable bowel syndrome (IBS), they may represent different etiologic and pathophysiologic entities. Our aim was to identify subgroups on the basis of symptoms in IBS. METHODS: Two independent groups of 56 (sample I) and 52 (sample II) outpatients recorded their abdominal symptoms daily for 6 weeks and 1 week, respectively. The daily records were assessed by using cluster analysis. RESULTS: Similar subgroups appeared in both samples. Three bowel habit subgroups were identified. The first was distinguished by hard stools, varying stool consistency, and highly disturbed stool passage, the second by loose stools and urgency, and the third by normal stools and the least disturbed stool passage. Two pain/bloating subgroups were identified, one distinguished by little and the other by considerable pain and bloating. No relation was found between pain/bloating and bowel habit subgroup membership. Most patients had stool frequency within the normal range regardless of subgroup. In sample I the subgroups had stable symptoms during the study, and subgroup placement was not related to the presence of dyspepsia, smoking habits, or use of bulk agent and/or sporadic intake of loperamide. The degree of pain and bloating was inversely related to illness duration. CONCLUSIONS: Subgroups exist in IBS. Division of IBS into bowel habit subgroups should be based on stool consistency, not frequency. Mechanisms mediating pain and bloating may be different from those mediating symptoms at defecation.

Abdominal Pain↗
PubMed1987

Preparation and characterization of monoclonal antibodies directed against five structural components of human respiratory syncytial virus subgroup B.

Mouse hybridomas producing antibodies against the structural proteins of strain WV4843, a subgroup B strain of respiratory syncytial (RS) virus, were produced by fusion of Sp2/0 myeloma cells with spleen cells from BALB/c mice immunized with purified preparations of the virus. After immunoprecipitation test with [35S]methionine-labelled extracellular virions, 35 clones found to produce antibodies against the fusion (F) protein, six against the member (M) protein, 21 against the nucleocapsid (NP) and eight against the phospho- (P) protein were further characterized. Immunoprecipitation with [3H]glucosamine-labelled intracellular virus polypeptides detected nine hybridoma cell lines producing antibodies against the large glyco- (G) protein of the virus. By competitive binding ELISA tests with monoclonal antibodies against each of the structural components, a minimum of two, 24, four, 15 and three epitopes were detected on the G, F, M, NP and P proteins, respectively. Eleven monoclonal antibodies directed against nine epitopes of the F protein could neutralize the infectivity of the virus. In contrast, none of the nine monoclonal antibodies against G could neutralize the infectivity of the virus. In order to find out more about the antigenic relationship between human and bovine RS virus strains all monoclonal antibodies were reacted with subgroup A RS virus and also with three different strains of bovine RS virus and one strain of caprine RS virus in immunofluorescence, ELISA and immunoprecipitation tests. In addition, 31 previously developed monoclonal antibodies against subgroup A virus were reacted with the bovine and caprine strains. The numbers of monoclonal antibodies of subgroup B specific for the B type of the two human subgroups were 9/9, 3/35, 0/6, 0/21, 0/8, for the G, F, M, NP and P proteins, respectively. No antigenic variations were found between the three bovine strains and the caprine strain. They did not react with the nine monoclonal antibodies against the G protein of subgroup B, nor did they react with nine monoclonal antibodies against subgroup A. Most but not all of the monoclonal antibodies against the other structural proteins of the two human RS virus subgroups reacted with the four strains. All 11 monoclonal antibodies against the F protein of subgroup B that could neutralize the infectivity of subgroup B also reacted with the bovine strains and neutralized their infectivity. It is concluded that although the bovine strains share many epitopes with the two human subgroups, they are antigenically distinct from the human viruses.

Antibodies, Monoclonal↗