Differences In Clinical Severity Research Articles

Are de novo acute heart failure and acutely worsened chronic heart failure two subgroups of the same syndrome?

Acute heart failure (AHF) is one of the most common diseases in emergency medicine, associated with poor prognosis and high in-hospital and long-term mortality. To investigate clinical presentation of patients with de novo AHF and acute worsening of chronic heart failure (CHF) and to identify differences in blood levels of biomarkers and echocardiography findings. This prospective study comprised 64 consecutive patients being grouped according to the onset of the disease into patients with the de novo AHF (45.3%), and patients with acute worsening of CHF (54.7%). Acute congestion (60%) was the most common manifestation of de novo AHF, whereas pulmonary oedema (43.1%) was the most common manifestation of acutely decompensated CHF. Patients with acutely decompensated CHF had significantly higher blood values of creatinine (147.10 vs 113.16 micromol/l; p < 0.05), urea (12.63 vs. 7.82 mmol/l; p < 0.05), BNP (1440.11 vs. 712.24 pg/ml; p < 001) and NTproBNP (9097.00 vs. 2827.70 pg/ml; p < 0.01) on admission, and lower values of M-mode left ventricular ejection fraction (LVEF) during hospitalization (49.44% vs. 42.94%; p < 0.05). The follow-up after one year revealed still significantly higher BNP (365.49 vs. 164.02 pg/ml; p < 0.05) and lower average values of both LVEF in patients with acutely worsened CHF (46.62% vs. 54.41% and 39.52% vs. 47.88%; p < 0.05). Considering differences in clinical severity on admission, echocardiography and natriuretic peptide values during hospitalization and after one year follow-up, de novo AHF and acutely worsened CHF are two different subgroups of the same syndrome.

Efficacy of Besifloxacin in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Keratitis

The purpose of this study was to determine the effectiveness of topically applied besifloxacin (0.6%), gatifloxacin (0.3%), and moxifloxacin (0.5%) for the late treatment of experimental methicillin-resistant Staphylococcus aureus (MRSA) keratitis. One hundred colony-forming units (CFUs) of bacteria were injected intrastromally into rabbit corneas. Sixteen hours after infection, one topical drop of phosphate-buffered saline, besifloxacin, gatifloxacin, or moxifloxacin was applied to each eye every 15 minutes for 5 doses and then every 30 minutes for 14 doses. Eyes were examined before and after treatment by slit lamp biomicroscopy. Corneas were harvested from treated and untreated rabbits for the quantitation of bacteria. Minimal inhibitory concentrations (MICs) were determined in vitro for each fluoroquinolone. None of the treatments had an effect on clinical severity (P > 0.05). Although there were no differences in clinical severity between any groups after treatment, the mean log10 CFU of MRSA recovered from besifloxacin-treated corneas (5.111 +/- 0.251) was significantly lower than the CFU recovered from corneas treated with phosphate-buffered saline (7.006 +/- 0.144), gatifloxacin (7.108 +/- 0.346), and moxifloxacin (7.473 +/- 0.144; P < 0.001). CFU recovered from gatifloxacin- and moxifloxacin-treated corneas were not significantly different from phosphate-buffered saline-treated corneas (P = 1.000). The MICs against the MRSA strain were 8 microg/mL for both gatifloxacin and moxifloxacin, whereas the MIC for besifloxacin was 1 microg/mL. Besifloxacin had an 8-fold lower MIC for MRSA than gatifloxacin and moxifloxacin and was significantly more effective than gatifloxacin and moxifloxacin in reducing the number of MRSA in the rabbit cornea 16 hours after infection.

Investigating the pathology of Emery–Dreifuss muscular dystrophy

EDMD (Emery-Dreifuss muscular dystrophy) is caused by mutations in either the gene encoding for lamin A/C (LMNA) located at 1q21.2-q21.3 or emerin (EMD) located at Xq28. Autosomal dominant EDMD caused by LMNA mutations is more common than the X-linked form and often more severe, with an earlier onset. At the histological and histochemical levels, both X-linked and autosomal dominant EDMD appear similar. However, individuals with the same genetic disorder often show remarkable differences in clinical severity, a finding generally attributed to the genetic background. The clinical and pathological findings in EDMD patients found to have mutations in more than one gene are also discussed. There is now much interest in the phenotype of several animal models for EDMD which should lead to an increased insight into the pathogenesis of this disorder, particularly that relating to the heart phenotype.

Reported food allergy to peanut, tree nuts and fruit: comparison of clinical manifestations, prescription of medication and impact on daily life

Peanut (PN), tree nuts (TN) and fruits are frequent causes of food allergy (FA). Peanut and TN are believed to cause more severe reactions than fruits. However, there are no studies comparing the severity of PN, TN and fruit allergy within one patient group. Four-hundred and eleven adult patients referred to our tertiary allergy center with suspicion of FA completed a standardized questionnaire. Patients with a typical history of immunoglobulin E (IgE)-mediated allergy, e.g. oropharyngeal symptoms to PN, TN (hazelnut, walnut, cashew nut) or fruit (apple, kiwi, peach, pear and cherry) were recruited (218/411). The objective was to evaluate differences in clinical severity between PN, TN and fruit allergy and how this was reflected by prescription of emergency medication and impact on daily life. Eighty-two percent of the included 218 patients were sensitized to the respective foods. The percentages of severe symptoms (i.e. respiratory or cardiovascular symptoms) in PN, TN and fruit allergic patients were respectively 47%, 39% and 31% (respiratory) and 11%, 5.0% and 3.4% (cardiovascular). Prescription and use of emergency medication (epinephrine, antihistamines and steroids) did not differ among the three groups. The majority of patients with a PN or TN allergy (72%) and fruit allergy (62%) reported that FA influences their daily life considerably. Fruit allergy causes less severe symptoms than TN and especially PN allergy. However, this is not reflected in the prescription or use of emergency medication. This may indicate that physicians are not fully acquainted with the guidelines for prescription of emergency medication. A high impact on daily life was found both in PN, TN and in fruit allergy.

Thrombolysis for Ischemic Stroke in Children

Few pediatric reports of thrombolysis exist. We sought to determine national rates of thrombolysis among pediatric ischemic stroke patients using a national database. Patients between the ages of 1 and 17 years, entered in the Nationwide Inpatient Sample between 2000 and 2003, with International Classification of Diseases codes for ischemic stroke were included in the study. Differences in mean age, gender distribution, ethnicity, secondary diagnoses, medical complications, associated procedure rates, modes of discharge, and hospital costs between pediatric stroke patients receiving and not receiving thrombolysis were estimated. In the United States, between 2000 and 2003 an estimated 2904 children were admitted with ischemic stroke, of which 46 children (1.6%) received thrombolytic therapy. Children who received thrombolysis were on the average older (11 versus 9 years), more likely to be male (100% versus 53.8%), with significantly higher hospital costs ($81,800 versus $38,700). These children were also less likely to be discharged home with higher rates of death and dependency, although differences in clinical severity between the 2 groups was not known. Thrombolysis, though not indicated for patients <18 years of age, is currently being administered to children, with unclear benefit. Larger studies are needed to evaluate the safety and efficacy of this treatment for children.

Toll-Like Receptors 2 and 4 Are Involved in the Induction of Graft-Versus-Host-Disease in Mice.

BACKGROUND: Intestinal Graft-versus-Host disease is a frequent and often lethal complication after allogenic stem cell transplantation. Since NOD2 polymorphisms have been recognized as potential triggers of severe intestinal GvHD in humans, we have developed murine transplantation models to investigate the role of different pattern recognition receptors (PRR) in GvHD and GvL. Here we report our results on the role of TLR2 and TLR4 for the induction of GvHD.METHODS: Severity of GvHD in wildtype (wt) C57B/10 (H-2Db), TLR2−/−, TLR4−/−, and combined TLR2−/−TLR4−/− C57B/10 mice was investigated. Mice received treosulfan 2000 mg/kg from day -3 to -1 and cyclophosphamide 200 mg/kg day -1 prior to injection of 10×10^6 H-2Dd BM cells and 5×10^6 splenocytes (SC). Survival and GvHD score were assessed daily. Engraftment was determined every 2 weeks in pB and at the end of the experiments in bone marrow by flow cytometry. T cell alloreactivity in GvH direction was assessed by MLR using splenocytes as stimulators from PRR-deficient mice or wt as control and CFSE-staining as read-out. The relevance of PRR ligands for the enhancement of GvH alloreactivity was determined by addition of lipid A, lipopetides, or CpG.RESULTS:in vivo data: The transfer of 10×10^6 BMC + 5×10^6 SC induced a severe GvHD in all wt recipients, leading to death of 90% of the animals within 20 days. Recipient mice lacking either TLR2 or TLR4 showed only a slightly and not significantly decreased GvHD lethality. In recipients lacking both PPRs, i.e. TLR2 and TLR4, GvHD was generally milder and the majority (60%) of the animals survived until day 20 (p<0.05). However, the long term survival was not significantly improved. Differences in clinical severity of GvHD were confirmed histologically.In vitro data: Stimulation with cells from TLR2−/− and TLR4−/− mice resulted in a decreased alloreactivity in MLR. A median of 2% of Balb/c CD4+ T cells proliferated in response to C57B/10 stimulators. The addition of the TLR2 and TLR4 ligands lipopeptide, Lipid A and CpG significantly (p<0.05) increased the proliferation of CD4+ T cells in a specific manner more than twofold.CONCLUSION: Our in vivo and in vitro data consistantly show that bacterial components are involved in triggering GvH alloreactivity via different types of PPRs. Binding of bacterial substances to TLR2 and TLR4 leads to activation of the immune system and subsequent induction of GvHD. Our data provide an experimental basis for the development of strategies for modulation of the intestinal gut flora by selective gut decontamination and/or probiotic regimens to prevent GvHD in humans.

Differences in Clinical Severity between Genotype A and Genotype B Human Metapneumovirus Infection in Children

The clinical spectrum of 69 episodes of metapneumovirus pediatric infection (55 episodes caused by genotype A and 14 episodes caused by genotype B) was analyzed. Diagnosis of pneumonia was more common and the illness severity index (determined on the basis of need for hospitalization, oxygen saturation <90%, and intensive care unit stay) was higher for patients with metapneumovirus genotype A infection.

Disease severity in dominant Emery Dreifuss is increased by mutations in both emerin and desmin proteins

Individuals with the same genetic disorder often show remarkable differences in clinical severity, a finding generally attributed to the genetic background. We identified two patients with genetically proven Emery-Dreifuss muscular dystrophy (EDMD) who followed an unusual course and had uncommon clinicopathological findings. We hypothesized digenic inheritance and looked for additional molecular explanations. Mutations in additional separate genes were identified in both patients. The first patient was a member of a family with molecularly proven X-linked EDMD. However, the clinical features were unusually severe for this condition in the propositus: he presented at 2.5 years with severe proximal weakness and markedly elevated serum creatine kinase. Muscle weakness rapidly progressed, leading to loss of independent ambulation by the age of 12. In addition, the patient developed cardiac conduction system disease requiring pacing at the age of 11 and severe dilated cardiomyopathy in the early teens. Despite pacing, he had several syncopal episodes attributed to ventricular dysrhythmias. As these resemble the cardiac features of patients with the autosomal dominant variant of EDMD, we examined the lamin A/C gene, identifying a de-novo mutation in the propositus. The second patient had a cardioskeletal myopathy, similar to his mother who had died more than 20 years previously. Because of the dominant family history, a laminopathy was suspected and a mutation in exon 11 of the LMNA gene was identified. This mutation, however, was not present in his mother, but instead, surprisingly, was identified in his virtually asymptomatic father. Unusual accumulations of desmin found in the cardiac muscle of the propositus prompted us to examine the desmin gene in this patient, and in so doing, we identified a desmin mutation, in addition to the LMNA mutation in the propositus. These cases suggest that separate mutations in related proteins that are believed to interact, or that represent different parts of a presumed functional pathway, may synergistically contribute to disease severity in autosomal dominant EDMD. Furthermore, digenic inheritance may well contribute to the clinical severity of many other neuromuscular disorders.

Biochemical Approach to the Investigation of Pediatric Mitochondrial Disease

The respiratory chain consists of 5 enzymatic components (complexes I to V), each of which contains multiple subunits that are intricately arranged in the inner mitochondrial membrane. All but 1 complex (complex II) have nuclearly and mitochondrially encoded protein subunits. The mitochondrial DNA (mtDNA) encodes 13 subunits and all the tRNAs required for protein translation. However, the mtDNA encodes only a fraction of the proteins required for normal respiratory chain function. In addition to the nuclearly encoded respiratory chain subunits, many more nuclear genes encode assembly and regulatory proteins essential for the normal structure and function of the respiratory chain. Thus, defects in mtDNA or nuclear genes can cause respiratory chain (mitochondrial) disease. Mitochondrial disorders are clinically heterogeneous, often multisystem disorders that can present from birth to old age. Almost any organ or tissue can be involved [1]. Often the severe involvement of 1 organ such as the heart or liver may overshadow more subtle involvement of other systems. On closer examination, dysfunction of the central nervous system, myopathy, renal tubulopathy, optic atrophy, or retinopathy may be found. In contrast to nuclear genetic defects, mtDNA defects may result in marked differences in clinical severity within families, from the asymptomatic individual to early-onset lethal disease. The investigation of mitochondriopathy is a multidisciplinary endeavor involving clinicians, pathologists, biochemical and molecular geneticists, and radiologists. This is illustrated in the following two case reports that describe the investigation of several ‘‘classic’’ presentations of childhood-onset mitochondrial disease: cardiomyopathy [2] and hepatoencephalopathy [3]. For those interested in a more general review of mitochondrial disease, including adult-onset presentations, see Scriver et al. [4].

Mutational analysis of the ATP2A2 gene in two Darier disease families with intrafamilial variability.

Darier disease (DD), an autosomal dominant genodermatosis characterized by warty papules and plaques over seborrhoeic areas, is caused by mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca(2+) ATPase type 2 isoform (SERCA2). While markedly different clinical severity within DD-affected family members is known, the pathomechanism has not been elucidated. Based on the hypothesis that multiple ATP2A2 mutations might contribute to the pathomechanism, we have analysed two DD families in which the clinical severity differs markedly within a single pedigree, and, as controls, eight DD families without differing clinical severity. All the exons and intron-exon borders of ATP2A2 were directly sequenced from the genomic DNA extracted from all the subjects. We identified the heterozygous mutations, G233R in pedigree 1 and C318R in pedigree 2, respectively, whereas no other ATP2A2 mutations in any of severely affected individuals were found. In eight DD pedigrees as control, we have found M1V, N39D, L180R, A838P and 2170 insertion G in each of five pedigrees, but no mutation was found in three DD pedigrees. Our results together with previous data indicate that the distribution of mutations is scattered over the entire ATP2A2 without any, as yet, discernible 'hotspots'. The mutations in pedigrees 1 and 2 with intrafamiliar clinical differences occurred around the Ca(2+)-binding sites on SERCA2, which might be associated with differences in clinical severity. These variations in ATP2A2 mutations alone cannot account for the clinical heterogeneity within DD pedigrees.

Accuracy of clinical criteria for AD in the Honolulu–Asia Aging Study, a population-based study

To determine diagnostic accuracy for AD in a population-based study of Japanese-American men. AD is neuropathologically confirmed for more than 80% of cases at major referral centers (primarily Caucasians); however, information on diagnostic accuracy in population-based studies and studies of different ethnic groups is limited. There were 3,734 men who participated in the Honolulu-Asia Aging Study 1991 through 1993 dementia examination and 2,603 in the 1994 through 1996 examination. Diagnoses were based on published criteria. Neuropathologists blinded to clinical data quantified neurofibrillary tangles (NFT) and neuritic plaques (NP). Of 220 autopsied subjects, clinical evaluation revealed 68 with normal cognition, 73 intermediate, and 79 with dementia: 20 AD, 27 vascular dementia, 19 AD + other, and 13 other dementia. Among 20 cases with pure AD, the median value for maximum neocortical NFT density was 6.9/mm(2) and for neocortical NP density was 8.0/mm2. Corresponding densities for other groups were <3.0/mm2. Using established neuropathologic criteria, 25% (5/20) of clinical AD cases had enough NP to meet definite AD criteria, whereas 65% (13/20) had sufficient NP to meet neuropathologic definite or probable AD criteria. Among nine AD cases with moderately severe dementia, only two (22%) had NP densities great enough to meet definite neuropathologic criteria, whereas seven (78%) met neuropathologic criteria for probable AD. Neuropathologic confirmation and NP density among decedents with clinical AD in this population-based study were lower than reported by referral centers and similar to reports from two other community studies. Ethnic differences in propensity for amyloid deposition as well as differences in clinical severity and representativeness of cases might contribute to these findings.

The Clinical Phenotype and Outcome of Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (β-Ketothiolase or T2 Deficiency) in 26 Enzymatically Proved and Mutation-Defined Patients

Mitochondrial acetoacetyl-CoA thiolase (T2 enzyme) deficiency (MIM 203750) is an autosomal recessive disorder of isoleucine and ketone-body metabolism. We determined the molecular basis of T2 enzyme deficiency in 26 patients at the levels of skin fibroblast enzyme activity, protein integrity, and DNA nucleotide sequence. Thirty different disease-associated alleles were identified. From these data we predicted that T2 in 6 of the 26 patients would have a mild effect on the enzyme protein and 20 would have a severe effect from their mutant genotypes. The corresponding clinical data were collected (by interviews and questionnaires) for the patients in the two groups. We found that genotype does not predict clinical severity and mutant sibs can have different clinical phenotypes; there were no consistent differences in clinical severity between patients with null-conferring or residual-conferring genotypes for T2 activity; only the absence of or a low urinary excretion of tiglyglycine during ketoacidosis correlated with a mild genotype. In general, T2 deficiency has a favorable outcome and 23 of 26 patients developed normally; one died during the first ketoacidotic episode and two have developmental delay. The median age at onset for the first ketoacidotic episode is 15 months (range 3 days to 48 months). The frequency of attacks falls with age, the last in our series occurring at 10 years of age; 11 patients had only one episode and 3 patients had none. We conclude that clinical consequences of T2 deficiency are avoidable with early diagnosis, appropriate management of ketoacidosis, and modest protein restriction.

Novel mutation in RP2 gene in two brothers with X-linked retinitis pigmentosa and mtDNA mutation of Leber hereditary optic neuropathy who showed marked differences in clinical severity

PURPOSE: To report the identification of a novel mutation of the RP2 gene in two Japanese brothers with X-linked retinitis pigmentosa of a differing clinical severity. The mother was a carrier of both retinitis pigmentosa and optic atrophy. METHODS: The older brother had a severe form of retinitis pigmentosa associated with macular degeneration and total optic atrophy, whereas the younger brother presented typical X-linked retinitis pigmentosa. RESULTS: Each patient exhibited a novel 2-bp insertion at codon 278 in exon 3 of the RP2 gene as well as a 11778 mutation in mitochondrial DNA. This suggests that the older brother may have developed Leber hereditary optic neuropathy as well as retinitis pigmentosa. CONCLUSION: Molecular testing confirmed the clinical diagnosis in each case. However, such testing did not explain the differences in the severity of the ophthalmoscopic findings between the two brothers.

Antiphospholipid antibodies, proteins C and S, and coagulation changes in sickle cell disease

The significance, interactions, and sources of coagulation abnormalities and their relationship to clinical severity and painful episodes in sickle cell disease are not clear. To evaluate this, we have examined various measures of coagulation in 37 patients with sickle cell disease (20 patients with HbSS disease and 17 patients with HbSC disease). Measurements have included isotypes of antiphospholipid antibodies (IgG, IgM, IgA) to specific phospholipids; proteins C (activity, total antigen) and S (activity, total and free antigen); measures of coagulation activation (prothrombin fragment 1.2, thrombin-antithrombin, fibrinopeptide A, d-dimers); indicators of clinical severity; and studies obtained during steady states and painful episodes. Results in HbSS disease showed that antiphospholipid antibodies were increased, with IgG phosphatidylserine showing the highest and most frequently increased levels (37% of patients). Protein C (activity) and protein S (activity, total, free antigen) were decreased (P < .01), and all measures of coagulation activation were increased (P < .001). In HbSC disease, antiphospholipid antibodies were normal, protein C (activity) and protein S (free antigen) were decreased (P < .001), and all measures of coagulation activation were increased (P < .02). A strong correlation was observed in HbSS disease between IgG-PS and d-dimers. Moderate correlations occurred between protein C activity and thrombin-antithrombin and fibrinopeptide A, between protein S activity and prothrombin fragment 1.2 and d-dimers, and between protein C and protein S activity. In HbSC disease, moderate and fewer correlations occurred. Significant differences between HbSS disease and HbSC disease were observed in aPLs, proteins C and S, and measures of coagulation activation. Measurements during steady states and during painful episodes were not significantly different. We conclude that the antiphospholipid antibody IgG-PS may contribute to coagulation activation in HbSS disease and that IgG-PS, protein C, and protein S relate to each other and jointly to measures of coagulation activation. The increase level of IgG-PS in HbSS disease most likely reflects exposure of the procoagulant phosphatidylserine on the surfaces of red cell-shed vesicles and sickle red cells, which would further affect coagulation activation. The significant differences in coagulation measures between HbSS disease and HbSC disease are consistent with differences in clinical severity between the diseases. The development of painful episodes does not appear to be related to the coagulation changes.

Differences in cervical cancer mortality among black and white women

Objective: To determine whether stage of disease and treatment patterns account for mortality differences between black and white women with cervical cancer. Methods: Using data obtained from the Surveillance, Epidemiology, and End Results (SEER) Program for 1988–1994, we determined the associations between race and stage, and race and treatment. Racial differences in survival for up to 7 years of follow-up were adjusted for age, marital status, SEER location, International Federation of Gynecology and Obstetrics (FIGO) stage of disease, lymph node status, grade, histology, and treatment. Results: Cumulative mortality was 36% (366 deaths in 1029 women) for black women and 24% (1215 deaths in 5021 women) for white women; unadjusted hazard ratio was 1.60 (95% confidence interval [CI] 1.43, 1.80). Black women were more likely to present with advanced disease than white women (43.8% compared with 34.8%). In a model adjusting for demographics and FIGO stage, the hazard ratio for black women compared with white women decreased to 1.35 (95% CI 1.19, 1.54). Treatment varied by race, with black women receiving surgery less often (33.5% compared with 48.2%, respectively) and radiation therapy more often (35.3% and 25.2%, respectively) than white women. In a comprehensive model including demographic factors, FIGO stage, other tumor characteristics, and treatment, the adjusted hazard ratio for mortality remained high for black women at 1.30 (95% CI 1.14, 1.48). Conclusion: Race remains an independent predictor of cervical cancer survival after accounting for age, stage of disease, treatment patterns, and other factors. Future studies should assess racial differences in clinical severity of disease, comorbidity, and socioeconomic status.

Familial phenotype differences in PKD1

Familial phenotype differences in PKD1. Mutations within the PKD1 gene are responsible for the most common and most severe form of autosomal dominant polycystic kidney disease (ADPKD). Although it is known that there is a wide range of disease severity within PKD1 families, it is uncertain whether differences in clinical severity also occur among PKD1 families. Ten large South Wales ADPKD families with at least 12 affected members were included in the study. From affected members, clinical information was obtained, including survival data and the presence of ADPKD-associated complications. Family members who were at risk of having inherited ADPKD but were proven to be non-affected were included as controls. Linkage and haplotype analysis were performed with highly polymorphic microsatellite markers closely linked to the PKD1 gene. Survival data were analyzed by the Kaplan-Meier method and the log rank test. Logistic regression analysis was used to test for differences in complication rates between families. Haplotype analysis revealed that each family had PKD1-linked disease with a unique disease-associated haplotype. Interfamily differences were observed in overall survival (P = 0.0004), renal survival (P = 0.0001), hypertension prevalence (P = 0.013), and hernia (P = 0.048). Individuals with hypertension had significantly worse overall (P = 0.0085) and renal (P = 0.03) survival compared with those without hypertension. No statistically significant differences in the prevalence of hypertension and hernia were observed among controls. We conclude that phenotype differences exist between PKD1 families, which, on the basis of having unique disease-associated haplotypes, are likely to be associated with a heterogeneous range of underlying PKD1 mutations.

3rd workshop of the European CMT consortium: 54th ENMC International Workshop on genotype/phenotype correlations in Charcot-Marie-Tooth type 1 and hereditary neuropathy with liability to pressure palsies 28-30 November 1997, Naarden, The Netherlands.

3rd workshop of the European CMT consortium: 54th ENMC International Workshop on genotype/phenotype correlations in Charcot-Marie-Tooth type 1 and hereditary neuropathy with liability to pressure palsies 28-30 November 1997, Naarden, The Netherlands.

Crucial role for 5-HT in cholera toxin but not Escherichia coli heat-labile enterotoxin-intestinal secretion in rats

Background & Aims: Many consider cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) to be functionally identical. Both increase intracellular adenosine 3',5'-cyclic monophosphate concentration; however, differences between the two and the severity of the diseases they cause have been reported. The secretagogue 5-hydroxytryptamine (5-HT) is implicated in CT-induced secretion, but its role in LT-induced secretion is unclear. We tested the hypothesis that LT fails to recruit 5-HT in its secretory processes. Methods: In vivo small intestinal perfusions were undertaken in adult male Wistar rats after incubation with equipotent doses of CT or LT, or saline. Small intestinal 5-HT release and the effect on net small intestinal water and electrolyte transport of (1) pharmacological depletion of 5-HT; (2) blockade of 5-HT type 2, 3, and 4 receptors; and (3) pretreatment with lidocaine, hexamethonium, and atropine were determined. Results: CT- but not LT-induced secretion was accompanied by 5-HT release, reduced by 5-HT depletion, and inhibited by each 5-HT antagonist. By contrast, lidocaine and hexamethonium inhibited secretion induced by both toxins. Conclusions: LT induces secretion without recruiting a 5-HT–dependent cascade. This may account for differences in clinical severity of the diseases CT and LT cause and has implications for the development of antisecretory therapies. GASTROENTEROLOGY 1998;115:883-890

Association between regional brain volumes and clozapine response in schizophrenia

Background: Clozapine has shown considerable therapeutic promise in the treatment of schizophrenia; however, the clinical risks and initial high treatment costs associated with its administration motivate the search to identify patients who will best respond. Neuroimaging studies have suggested that prefrontal sulcal prominence may be a predictor of nonresponsiveness. Methods: We used magnetic resonance imaging (MRI) to test whether volumes in any cortical regions of the brain were associated with symptom improvement with clozapine treatment. The 21 schizophrenic men studied were clinically evaluated during treatment with typical neuroleptics (baseline) and after a mean of 6.2 months treatment with clozapine (final dose 300–900, median = 562 mg/day). At least a 20% improvement on total Brief Psychiatric Rating Scale (BPRS) was seen in 47.6% of the schizophrenics. Clinical improvement was regressed on baseline differences in clinical severity, and the residual scores were related to MRI values. Results: Patients with larger anterior superior temporal lobe cerebrospinal fluid volumes (primarily sylvian fissure) showed greater improvement on total BPRS and withdrawal/retardation symptoms. Conclusions: Even schizophrenics with significant brain dysmorphology can have a positive clinical response to clozapine.

Epidermal Apoptotic Cell Death in Erythema Multiforme and Stevens-Johnson Syndrome

To clarify the mechanism of epidermal cell death in erythema multiforme. Retrospective study. Academic referral center. Nine patients with Stevens-Johnson syndrome (SJS), 9 patients with Hebra disease (EMH), and 5 healthy volunteers. Biopsy specimens were obtained from the border of the fresh lesions before treatment. Control specimens were obtained from normal skin. Histopathological epidermal apoptosis detected with nuclear DNA fragmentation and counts of dermal immunoreactive perforin-positive infiltrates were compared between SJS and EMH. Eight patients (89%) with SJS showed clear apoptosis with keratinocyte DNA fragmentation. All SJS samples had intensive perforin-positive dermal infiltrates. Only 3 patients (33%) with EMH showed apoptotic change, and it was to a far less extent with far less dermal perforin-positive infiltrates. Control specimens showed no apoptotic cells in the epidermis or expression of perforin in the dermis. Perforin mediates apoptosis in the pathogenesis of the epidermal cell changes in SJS but not in EMH. In addition to the differences in clinical severity and histopathological conditions, our findings indicate a pathogenic difference between SJS and EMH.