The neuroprotective agent SR 57746A abrogates experimental autoimmune encephalomyelitis and impairs associated blood–brain barrier disruption: Implications for multiple sclerosis treatment

Experimental autoimmune encephalomyelitis (EAE) is a T cell autoimmune disorder that is a widely used animal model for multiple sclerosis (MS) and, as in MS, clinical signs of EAE are associated with blood–brain barrier (BBB) disruption. SR 57746A, a nonpeptide drug without classical immunosuppressive properties, efficiently protected the BBB and impaired intrathecal IgG synthesis (two conventional markers of MS exacerbation) and consequently suppressed EAE clinical signs. This compound inhibited EAE-induced spinal cord mononuclear cell invasion and normalized tumor necrosis factor α and IFN-γ mRNA expression within the spinal cord. These data suggested that pharmacological intervention aimed at inhibiting proinflammatory cytokine expression within the central nervous system provided protection against BBB disruption, the first clinical sign of EAE and probably the key point of acute MS attacks. This finding could lead to the development of a new class of compounds for oral therapy of MS, as a supplement to immunosuppressive agents.

Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17

Pallido-ponto-nigral degeneration (PPND) is one of the most well characterized familial neurodegenerative disorders linked to chromosome 17q21–22. These hereditary disorders are known collectively as frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17). Although the clinical features and associated regional variations in the neuronal loss observed in different FTDP-17 kindreds are diverse, the diagnostic lesions of FTDP-17 brains are tau-rich filaments in the cytoplasm of specific subpopulations of neurons and glial cells. The microtubule associated protein (tau) gene is located on chromosome 17q21–22. For these reasons, we investigated the possibility that PPND and other FTDP-17 syndromes might be caused by mutations in the tau gene. Two missense mutations in exon 10 of the tau gene that segregate with disease, Asn279Lys in the PPND kindred and Pro301Leu in four other FTDP-17 kindreds, were found. A third mutation was found in the intron adjacent to the 3′ splice site of exon 10 in patients from another FTDP-17 family. Transcripts that contain exon 10 encode tau isoforms with four microtubule (MT)-binding repeats (4Rtau) as opposed to tau isoforms with three MT-binding repeats (3Rtau). The insoluble tau aggregates isolated from brains of patients with each mutation were analyzed by immunoblotting using tau-specific antibodies. For each of three mutations, abnormal tau with an apparent Mr of 64 and 69 was observed. The dephosphorylated material comigrated with tau isoforms containing exon 10 having four MT-binding repeats but not with 3Rtau. Thus, the brains of patients with both the missense mutations and the splice junction mutation contain aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration.

Phenotype-genotype studies in kuru: Implications for new variant Creutzfeldt–Jakob disease

The PRNP polymorphic (methionine/valine) codon 129 genotype influences the phenotypic features of transmissible spongiform encephalopathy. All tested cases of new variant Creutzfeldt–Jakob disease (nvCJD) have been homozygous for methionine, and it is conjectural whether different genotypes, if they appear, might have distinctive phenotypes and implications for the future “epidemic curve” of nvCJD. Genotype-phenotype studies of kuru, the only other orally transmitted transmissible spongiform encephalopathy, might be instructive in predicting the answers to these questions. We therefore extracted DNA from blood clots or sera from 92 kuru patients, and analyzed their codon 129 PRNP genotypes with respect to the age at onset and duration of illness and, in nine cases, to detailed clinical and neuropathology data. Homozygosity at codon 129 (particularly for methionine) was associated with an earlier age at onset and a shorter duration of illness than was heterozygosity, but other clinical characteristics were similar for all genotypes. In the nine neuropathologically examined cases, the presence of histologically recognizable plaques was limited to cases carrying at least one methionine allele (three homozygotes and one heterozygote). If nvCJD behaves like kuru, future cases (with longer incubation periods) may begin to occur in older individuals with heterozygous codon 129 genotypes and signal a maturing evolution of the nvCJD “epidemic.” The clinical phenotype of such cases should be similar to that of homozygous cases, but may have less (or at least less readily identified) amyloid plaque formation.

Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma

Neuroblastoma (NB) is a common pediatric tumor that exhibits a wide range of biological and clinical heterogeneity. EPH (erythropoietin-producing hepatoma amplified sequence) family receptor tyrosine kinases and ligand ephrins play pivotal roles in neural and cardiovascular development. High-level expression of transcripts encoding EPHB6 receptors (EPHB6) and its ligands ephrin-B2 and ephrin-B3 (EFNB2, EFNB3) is associated with low-stage NB (stages 1, 2, and 4S) and high TrkA expression. In this study, we showed that EFNB2 and TrkA expressions were associated with both tumor stage and age, whereas EPHB6 and EFNB3 expressions were solely associated with tumor stage, suggesting that these genes were expressed in distinct subsets of NB. Kaplan-Meier and Cox regression analyses revealed that high-level expression of EPHB6, EFNB2, and EFNB3 predicted favorable NB outcome (P < 0.005), and their expression combined with TrkA expression predicted the disease outcome more accurately than each variable alone (P < 0.00005). Interestingly, if any one of the four genes (EPHB6, EFNB2, EFNB3, or TrkA) was expressed at high levels in NB, the patient survival was excellent (>90%). To address whether a good disease outcome of NB was a consequence of high-level expression of a “favorable NB gene,” we examined the effect of EPHB6 on NB cell lines. Transfection of EPHB6 cDNA into IMR5 and SY5Y expressing little endogenous EPHB6 resulted in inhibition of their clonogenicity in culture. Furthermore, transfection of EPHB6 suppressed the tumorigenicity of SY5Y in a mouse xenograft model, demonstrating that high-level expressions of favorable NB genes, such as EPHB6, can in fact suppress malignant phenotype of unfavorable NB.

Hyposecretion of the adrenal androgen dehydroepiandrosterone sulfate and its relation to clinical variables in inflammatory arthritis

Hypothalamic–pituitary–adrenal underactivity has been reported in rheumatoid arthritis (RA). This phenomenon has implications with regard to the pathogenesis and treatment of the disease. The present study was designed to evaluate the secretion of the adrenal androgen dehydroepiandrosterone sulfate (DHEAS) and its relation to clinical variables in RA, spondyloarthropathy (Spa), and undifferentiated inflammatory arthritis (UIA). Eighty-seven patients (38 with RA, 29 with Spa, and 20 with UIA) were studied, of whom 54 were women. Only 12 patients (14%) had taken glucocorticoids previously. Age-matched, healthy women (134) and men (149) served as controls. Fasting blood samples were taken for determination of the erythrocyte sedimentation rate (ESR), serum DHEAS and insulin, and plasma glucose. Insulin resistance was estimated by the homeostasis-model assessment (HOMAIR). DHEAS concentrations were significantly decreased in both women and men with inflammatory arthritis (IA) (P < 0.001). In 24 patients (28%), DHEAS levels were below the lower extreme ranges found for controls. Multiple intergroup comparisons revealed similarly decreased concentrations in each disease subset in both women and men. After the ESR, previous glucocorticoid usage, current treatment with nonsteroidal anti-inflammatory drugs, duration of disease and HOMAIR were controlled for, the differences in DHEAS levels between patients and controls were markedly attenuated in women (P = 0.050) and were no longer present in men (P = 0.133). We concluded that low DHEAS concentrations are commonly encountered in IA and, in women, this may not be fully explainable by disease-related parameters. The role of hypoadrenalism in the pathophysiology of IA deserves further elucidation. DHEA replacement may be indicated in many patients with IA, even in those not taking glucocorticoids.

The Clinical Utility of the Adult Attachment Projective Picture System: A Clinician's Perspective

The Adult Attachment Projective Picture System (AAP) is the first performance- based measure of adult attachment to be developed. The purpose of the measure is to provide a clinical understanding of an adult client's attachment status and associated coping mechanisms. The AAP is a relatively new measure that has yet to be examined from a utility perspective. In the current study, seven psychologists completed a structured survey in order to identify their perspectives of the AAP and its utility as a clinical instrument. A phenomenological qualitative analysis of the data was conducted to derive themes about the AAP and its clinical utility. Analyses aimed to answer the following: What clinical considerations do clinician's focus on when deciding to use this measure? What are common factors among clinician's who do use the measure as well as those who do not? What aspects of the measure are user-friendly and what aspects are difficult? General themes that emerged include (a) the clinical information provided by the AAP is viewed by those who use it as unique and beneficial; (b) time commitment and cost for the clinician are common considerations when clinician's are deciding whether or not to use the AAP or when pursuing training; (c) the AAP provides an increased understanding of one's relational capacities and defenses; and (d) the coding system and transcription process are difficult aspects of the AAP and influence how and/or when it is used. In addition to these themes, multiple respondents discussed potential changes for the AAP that would increase their future use of the instrument. Finally, the implications of these results are discussed.

Cerebellar language and cognitive functions in childhood: A comparative review of the clinical research

Background: Recent research addressing evidence from functional neuroimaging studies, neurophysiological research, and new advances in neuropsychology together with traditional cerebellar lesion studies have recently implicated the cerebellum in adult language and cognitive functions. However, more limited information is currently available in describing the functional connectivity present in the paediatric population. Aims: It is the purpose of this paper to review recent clinical research pertaining to paediatric populations, outlining the impact of site of lesion and specific associated clinical changes in children with cerebellar disturbances. Main contribution: The specific contribution of the right cerebellar hemisphere to language function is identified to also exist in the paediatric population, highlighting the existence of functional connections between this region of the brain and left frontal cortical areas early in development. Conclusions: Implications for future research in paediatric populations are extensive, as a greater awareness and an understanding of the recently acknowledged involvement of the cerebellum in cognition and nonmotor linguistic function is anticipated to also add new dimension and direction to the analysis of childhood language outcomes associated with the cerebellum.

Principles and clinical application of assessing alterations in renal elimination pathways

Drugs and metabolites are eliminated from the body by metabolism and excretion. The kidney makes the major contribution to excretion of unchanged drug and also to excretion of metabolites. Net renal excretion is a combination of three processes - glomerular filtration, tubular secretion and tubular reabsorption. Renal function has traditionally been determined by measuring plasma creatinine and estimating creatinine clearance. However, estimated creatinine clearance measures only glomerular filtration with a small contribution from active secretion. There is accumulating evidence of poor correlation between estimated creatinine clearance and renal drug clearance in different clinical settings, challenging the 'intact nephron hypothesis' and suggesting that renal drug handling pathways may not decline in parallel. Furthermore, it is evident that renal drug handling is altered to a clinically significant extent in a number of disease states, necessitating dosage adjustment not just based on filtration. These observations suggest that a re-evaluation of markers of renal function is required. Methods that measure all renal handling pathways would allow informed dosage individualisation using an understanding of renal excretion pathways and patient characteristics. Methodologies have been described to determine individually each of the renal elimination pathways. However, their simultaneous assessment has only recently been investigated. A cocktail of markers to measure simultaneously the individual renal handling pathways have now been developed, and evaluated in healthy volunteers. This review outlines the different renal elimination pathways and the possible markers that can be used for their measurement. Diseases and other physiological conditions causing altered renal drug elimination are presented, and the potential application of a cocktail of markers for the simultaneous measurement of drug handling is evaluated. Further investigation of the effects of disease processes on renal drug handling should include people with HIV infection, transplant recipients (renal and liver) and people with rheumatoid arthritis. Furthermore, changes in renal function in the elderly, the effect of sex on renal function, assessment of living kidney donors prior to transplantation and the investigation of renal drug interactions would also be potential applications. Once renal drug handling pathways are characterised in a patient population, the implications for accurate dosage individualisation can be assessed. The simultaneous measurement of renal function elimination pathways of drugs and metabolites has the potential to assist in understanding how renal function changes with different disease states or physiological conditions. In addition, it will further our understanding of fundamental aspects of the renal elimination of drugs.

Diabetic cardiomyopathy: Evidence, mechanisms, and therapeutic implications

The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial. This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications. The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes. The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity). This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease.

Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications

Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor ( CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP.

A proposed new classification system for whiplash associated disorders - implications for assessment and management

The development of chronic symptoms following whiplash injury is common and contributes substantially to costs associated with this condition. The currently used Quebec Task Force classification system of whiplash associated disorders is primarily based on the severity of signs and symptoms following injury and its usefulness has been questioned. Recent evidence is emerging that demonstrates differences in physical and psychological impairments between individuals who recover from the injury and those who develop persistent pain and disability. Motor dysfunction, local cervical mechanical hyperalgesia and psychological distress are present soon after injury in all whiplash injured persons irrespective of recovery. In contrast those individuals who develop persistent moderate/severe pain and disability show a more complex picture, characterized by additional impairments of widespread sensory hypersensitivity indicative of underlying disturbances in central pain processing as well as acute posttraumatic stress reaction, with these changes present from soon after injury. Based on this heterogeneity a new classification system is proposed that takes into account measurable disturbances in motor, sensory and psychological dysfunction. The implications for the management of this condition are discussed. (C) 2004 Elsevier Ltd. All rights reserved.

Patient and graft survival after liver transplantation for hereditary hemochromatosis: Implications for pathogenesis

The clinical outcome of patients who have undergone liver transplantation for hereditary hemochromatosis (HH) or who have received iron-loaded donor grafts is unclear. We reviewed 3,600 adult primary orthotopic liver transplants and assessed the outcomes in 22 patients with HH. We also evaluated graft function and iron mobilization in 12 recipients of iron-loaded donor grafts. All 22 subjects who received liver transplants for HH were male; 13 had other risk factors for liver disease. HH patients had comparatively poor outcomes following transplantation: survival at 1, 3, and 5 years posttransplantation were 72%, 62%, and 55%, respectively. Recurrent hepatocellular cancer was the most common cause of death. There was no convincing evidence of reaccumulation of iron in the grafted liver in HH; however, 1 subject demonstrated increased serum ferritin concentration and grade 2 hepatic siderosis. Liver iron stores were slow to mobilize in 7 of the 12 recipients of iron-loaded grafts. These recipients had appropriate early graft function, but 2 patients with heavy iron loading and increased hepatic iron developed hepatic fibrosis. In conclusion. (1) HH is an uncommon indication for liver transplantation, and the majority of patients requiring transplantation had other risk factors for chronic liver disease; (2) reaccumulation of liver iron in HH patients is very unusual, but increased iron stores may be slow to mobilize in normal recipients of iron-loaded grafts, potentially compromising late graft function; (3) post-liver transplant survival is reduced in HH, and affected patients require careful clinical evaluation of perioperative and postoperative risk factors. Our data suggest that iron excess in HH does not wholly depend on intestinal iron absorption but is also influenced by liver factors that moderate iron metabolism.

Beating the urge: Implications of research into substance-related desires

Despite the advent of improved pharmacological treatments to alleviate substance-related desires, psychological approaches will continue to be required. However, the current psychological treatment that most specifically focuses on desires and their management-cue exposure (CE)-has not lived up to its original promise. This paper argues that current psychological approaches to desire do not adequately incorporate our knowledge about the factors that trigger, maintain, and terminate episodes of desire. It asserts that the instigation and maintenance of desires involve both associative and elaborative processes. Understanding the processes triggering the initiation of intrusive thoughts may assist in preventing some episodes, but occasional intrusions will be inevitable. A demonstration of the ineffectiveness of thought suppression may discourage its use as a coping strategy for desire-related intrusions, and mindfulness meditation plus cognitive therapy may help in accepting their occurrence and letting them go. Competing tasks may be used to reduce elaboration of desires, and competing sensory images may have particular utility. The application of these procedures during episodes that are elicited in the clinic may allow the acquisition of more effective strategies to address desires in the natural environment. (C) 2004 Elsevier Ltd. All rights reserved.

Antibiotic therapy for Klebsiella pneumoniae bacteremia: Implications of production of extended-spectrum beta-lactamases

The prevalence of extended-spectrum beta-lactamase (ESBL) production by Klebsiella pneumonia approaches 50% in some countries, with particularly high rates in eastern Europe and Latin America. No randomized trials have ever been performed on treatment of bacteremia due to ESBL-producing organisms; existing data comes only from retrospective, single-institution studies. In a prospective study of 455 consecutive episodes of Klebsiella pneumoniae bacteremia in 12 hospitals in 7 countries, 85 episodes were due to an ESBL-producing organism. Failure to use an antibiotic active against ESBL-producing K. pneumoniae was associated with extremely high mortality. Use of a carbapenem ( primarily imipenem) was associated with a significantly lower 14-day mortality than was use of other antibiotics active in vitro. Multivariate analysis including other predictors of mortality showed that use of a carbapenem during the 5-day period after onset of bacteremia due to an ESBL-producing organism was independently associated with lower mortality. Antibiotic choice is particularly important in seriously ill patients with infections due to ESBL-producing K. pneumoniae.