Quantitative trait loci for cellular defects in glucose and fatty acid metabolism in hypertensive rats.

Coronary heart disease, hypertension, non-insulin-dependent diabetes and obesity are major causes of ill health in industrial societies. Disturbances of carbohydrate and lipid metabolism are a common feature of these disorders. The bases for these disturbances and their roles in disease pathogenesis are poorly understood. The spontaneously hypertensive rat (SHR), a widely used animal model of essential hypertension, has a global defect in insulin action on glucose metabolism and shows reduced catecholamine action on lipolysis in fat cells. In our study we used cellular defects in carbohydrate and lipid metabolism to dissect the genetics of defective insulin and catecholamine action in the SHR strain. In a genome screen for loci linked to insulin and catecholamine action, we identified two quantitative trait loci (QTLs) for defective insulin action, on chromosome 4 and 12. We found that the major (and perhaps only) genetic determinant of defective control of lipolysis in SHR maps to the same region of chromosome 4. These linkage results were ascertained in at least two independent crosses. As the SHR strain manifests many of the defining features of human metabolic Syndrome X, in which hypertension associates with insulin resistance, dyslipidaemia and abdominal obesity, the identification of genes for defective insulin and catecholamine action in SHR may facilitate gene identification in this syndrome and in related human conditions, such as type-2 diabetes and familial combined hyperlipidaemia.

Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats.

The human insulin-resistance syndromes, type 2 diabetes, obesity, combined hyperlipidaemia and essential hypertension, are complex disorders whose genetic basis is unknown. The spontaneously hypertensive rat (SHR) is insulin resistant and a model of these human syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridaemia and hypertension map to a single locus on rat chromosome 4. Here we combine use of cDNA microarrays, congenic mapping and radiation hybrid (RH) mapping to identify a defective SHR gene, Cd36 (also known as Fat, as it encodes fatty acid translocase), at the peak of linkage to these QTLs. SHR Cd36 cDNA contains multiple sequence variants, caused by unequal genomic recombination of a duplicated ancestral gene. The encoded protein product is undetectable in SHR adipocyte plasma membrane. Transgenic mice overexpressing Cd36 have reduced blood lipids. We conclude that Cd36 deficiency underlies insulin resistance, defective fatty acid metabolism and hypertriglyceridaemia in SHR and may be important in the pathogenesis of human insulin-resistance syndromes.

Macrophage activation syndrome and other systemic inflammatory conditions after BMT.

Autologous hematopoietic cell transplantation (HCT) is being used to treat autoimmune diseases refractory to conventional therapy, including rheumatoid arthritis. Macrophage activation syndrome (MAS) is a descriptive term for a systemic inflammatory disorder that has been described in patients with juvenile rheumatoid arthritis (JRA). This case report describes a young adult with systemic JRA (sJRA) who developed MAS on day # 12 post-autologous transplantation. The patient developed high fever, laboratory evidence of disseminated intravascular coagulation (DIC), hepatocellular injury, pancytopenia and hyper-ferritinemia. All viral, bacterial and fungal studies were negative and the patient improved with high-dose glucocorticosteroid and cyclosporine therapy. Extreme elevation of serum ferritin was documented and helpful in monitoring response to therapy. A number of systemic inflammatory syndromes have been described in association with HCT. These include DIC, 'engraftment syndrome,' infection-associated hemophagocytic syndrome and familial hemophagocytic lymphohistiocytosis. Macrophage activation syndrome presents with features of DIC and is closely related or identical to infection-associated hemophagocytic syndrome. The diagnosis needs to be established in a timely fashion because early and appropriate treatment may improve outcome.

Environmental Risk Factors and Early-Life Exposures in Juvenile Idiopathic Arthritis: A Case-Control Study.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of disorders characterized by chronic arthritis in children with unknown etiology. Although research evaluating environmental or early-life exposures in JIA is scarce, there are data to suggest that infections, smoking exposure, and lack of breastfeeding play a role. This case-control study investigated the association of selected environmental and early-life risk factors with the development of JIA. METHODS: JIA cases were identified at a major pediatric rheumatology outpatient clinic. Each case was asked to identify up to 3 healthy playmates of similar age and same sex to serve as controls. Parents/caregivers of cases and controls completed a questionnaire on selected environmental and early-life exposures. Conditional logistic regression adjusted for age and socioeconomic status was used to determine the odds ratio (OR) for developing JIA with 95% confidence intervals (95% CIs) for the playmate-matched design. RESULTS: Included in the study were 225 JIA cases and 138 controls. Compared to playmate-matched controls, preterm delivery (OR 1.8 [95% CI 1.2-2.7]) was associated with JIA. There was no association between JIA and household smoking or maternal prenatal smoking, breastfeeding, hospitalization with infection in the first year of life, daycare attendance before 6 years of age, household pets, or residential area prior to the onset of JIA. CONCLUSION: There was no association between the previously reported risk factors of smoking, early-life infection, or breastfeeding and development of JIA in this study. The association of preterm delivery with JIA needs to be further studied.

Psychosomatic musculoskeletal pain in childhood: clinical and psychological analyses of 100 children.

The clinical and psychological findings on 100 children with psychosomatic musculoskeletal pain seen at a major pediatric rheumatology referral center are reported. Most (76%) were female, median age was 13 years, and median duration of symptoms was 1 year. Multiple painful sites were common (66%). The pain was constant (63%) or intermittent (37%); 45% had hyperesthesia, and almost all maintained a cheerful affect when complaining of severe pain. Two predominant abnormal family milieu were seen. One was cohesive, stable, and organized, but intolerant of separation and individuation. The other was chaotic, emotionally unsupportive, with high levels of conflict. Members of the cohesive family type reported significantly less distress than members of chaotic families. Enmeshment between mother and child was common in both family types. Although frequently viewed as bright, most of these children had normal intelligence, and some had unrecognized academic difficulty. These children, compared with those with arthritis, had a significantly lower global well-being score. Clinical depression was unusual (11%). Most (97%) responded favorably to intensive physical and occupational therapy along with individual or family psychotherapy; 78% become symptom free or fully functional. Children with these signs and symptoms should have full psychological evaluations and respond well to treatment directed toward decreasing pain and restoring function.

Expression of the chemokines MIP-1alpha, MCP-1, and RANTES in experimental autoimmune uveitis.

PURPOSE: To determine the location of the CC chemokines macrophage inflammatory protein (MIP)-1alpha, monocyte chemoattractant protein (MCP)-1, and regulated on activation of normal T-cell-expressed and secreted (RANTES) during disease progression in experimental autoimmune uveitis (EAU) and their relationship with the presence of the T helper cell (Th)1-type cytokine IFNgamma. METHODS: EAU was induced by immunization of Lewis rats with retinal extract. Consecutive cryostat sections were prepared from eyes at different stages of EAU, graded for severity of uveitis and stained by using antibodies to MCP-1, MIP-1alpha, and RANTES and to cell surface markers. Supernatants from superficial cervical lymph node cells were examined by ELISA for IFNgamma, IL-4, and IL-10. RESULTS: MIP-1alpha and IFNgamma were present most frequently and most extensively at peak disease but also were detectable in the choroid 8 days after immunization, before clinical disease onset. MCP-1 and RANTES were present at peak disease, but much less frequently. RANTES was occasionally found in the choroid before clinical disease. By days 19 to 21 after immunization, although infiltrating cells were present, there were only residual low levels of chemokine staining. MCP-1 and RANTES were detected on CD3-positive cells and on some ED1-positive cells, whereas MIP-1alpha was also associated with vessels and areas of exudate. Lymph node cells cultured from animals with peak disease had increased levels of IFNgamma and IL-10, but for IFNgamma this occurred only after stimulation in vitro with retinal extract. CONCLUSIONS: Although MCP-1 and RANTES were associated predominantly with cells infiltrating the retina, MIP-1alpha was also associated with resident cells. All three are likely to exacerbate EAU-MIP-1alpha, to the greatest degree.

Isolation, amino acid sequence and action of guinea-pig ACTH on aldosterone production by glomerulosa cells.

Though minor sequence differences between-species have been reported for adrenocorticotrophin, ACTH(1-39), the steroidogenic moiety ACTH(1-24) has appeared invariant in mammals. We here report the isolation, purification and amino acid sequencing of guinea-pig (GP) ACTH in which Pro24 is replaced by Ala24, and the demonstration that GP-ACTH stimulates aldosterone production to maximal levels well above those seen with human ACTH(1-39) or Synacthen, ACTH(1-24) amide, the synthetic ACTH fragment widely used for diagnostic and therapeutic purposes.

Stress-Related Changes in beta-Endorphin Processing: The Limitations of Slaughterhouse Material.

Abstract In the sheep, unlike many other species, a significant proportion (>25%) of immunoreactive beta-endorphin in the anterior pituitary is post-translationally modified to opioid-inactive, alpha-N-acetylated forms. In a study to determine the precise molecular nature of alpha-N-acetylated beta-endorphin immunoreactivity, we noted a striking difference in high-performance liquid chromatography profiles of anterior pituitary extracts between sheep killed on the farm, and age-, sex- and strain-matched slaughterhouse animals. These altered patterns of a-N-acetylated beta-endorphin processing were reproduced in farm animals by chronic (

Juvenile rheumatoid arthritis: outcome and treatment for the 1990s.

There has been much discontent with the hazards and the uncertain responses of patients with juvenile rheumatoid arthritis (JRA) to time-honored modalities of management. The treatment of JRA is often thought of as a pyramid with the base formed by nonsteroidal anti-inflammatory drugs, patient and family education, physical therapy, occupational therapy, and family support. Mechanisms of human disease have begun to open the gates to understanding the why and when of connective tissue diseases; they also offer the prospect of direct therapeutic intervention. In this article, the authors scrutinize the paradigms that guide our treatment strategies, review current practices, update data derived from those practices, and propose reassessment of therapy in the 1990s.

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When a patient taking methotrexate should have a liver biopsy to assess for liver damage is a difficult and critical question for rheumatologists. It is not cost effective nor medically necessary to perform biopsies on all patients after a specific dose of methotrexate has been reached, nor after they have been treated for a definite length of time. Clinicians should take into account a patient's possible pre-existing factors (hepatitis, diabetes, obesity, past and present alcohol consumption), concomitant medications, intercurrent illnesses and serial laboratory evaluations when assessing the need for a biopsy in an individual patient being treated with methotrexate.

alpha-N-acetylated beta-endorphin is differentially processed in the normal and hypothalamo-pituitary-disconnected (HPD) ewe.

We have used specific radioimmunoassay and high-performance liquid chromatography (HPLC) to determine content and molecular forms of pituitary alpha-N-acetylated endorphin (NacEP) in the intact and hypothalamo-pituitary-disconnected (HPD) sheep. No significant differences were seen in anterior pituitary (AP) immunoreactive (ir-) NacEP levels (control = 4.34 +/- 0.45 ng/mg; HPD = 4.38 +/- 0.83 ng/mg; n = 4) or in HPLC profiles following pituitary disconnection. In contrast, levels of ir-NacEP in the HPD intermediate lobe (IL) (263 +/- 16.5 ng/mg; n = 4) were double those in the control (110 +/- 14 ng/mg; n = 4), accompanied by a marked change in the molecular profile. In the control IL, the major species were Nac alpha EP (30%), Nac gamma EP (30%) and Nac beta EP1-27 (35%); in HPD IL, Nac beta EP1-27 (65%) is the dominant molecular form, with Nac alpha EP (11%) and Nac gamma EP (9%) relatively minor components.

Short- and long-term outcomes of children with complex regional pain syndrome type I treated with exercise therapy.

OBJECTIVE: To report the initial and long-term outcome after an intensive exercise therapy program for childhood complex regional pain syndrome, type I (CRPS). DESIGN: Prospective follow-up. SETTING: A children's hospital. SUBJECTS: We followed 103 children (87 girls; mean age = 13.0 years) with CRPS. Forty-nine subjects were followed for more than 2 years (mean = 5 years 3 months). INTERVENTIONS: An intensive exercise program (most received a daily program of 4 hours of aerobic, functionally directed exercises, 1-2 hours of hydrotherapy, and desensitization). No medications or modalities were used. All had a screening psychological evaluation, and 79 (77%) were referred for psychological counseling. MAIN OUTCOME MEASURES: Outcomes included pain, presence of physical dysfunction, or recurrent episodes of CRPS or other disproportional musculoskeletal pain. RESULTS: The mean duration of exercise therapy was 14 days, but over the past 2 years has decreased to 6 days. Ninety-five children (92%) initially became symptom free. Of those followed for more than 2 years, 43 (88%) were symptom free (15, or 31 %, of these patients had had a reoccurrence), 5 (10%) were fully functional but had some continued pain, and 1 (2%) had functional limitations. The median time to recurrence was 2 months; 79% of the recurrences were during the first 6 months after treatment. CONCLUSION: Intense exercise therapy is effective in initially treating childhood CRPS and is associated with low rate of long-term symptoms or dysfunction.

Reverse, innervated latissimus dorsi flap reconstruction of congenital diaphragmatic absence.

Children with congenital diaphragmatic absence have experienced a high mortality rate regardless of early intervention due to regression to fetal circulation patterns. Advances in neonatal care, particularly extracorporeal membrane oxygenation, have led to the survival of children who previously would not have lived. With growth, the Gore-Tex patch used for emergency repair in severe cases pulls away from the rib periosteum as a result of the expansile growth of the chest wall and the indistensibility of the patch. Recurrent herniation of abdominal contents ensues, slowly restricting pulmonary function and development. When pulmonary function is significantly impaired, we perform a reverse latissimus dorsi flap reconstruction with anastomosis of the thoracodorsal nerve to the phrenic nerve. Our series includes five children aged 5 to 11 months. Follow-up ranges from 22 to 50 months. Three children have proven physiologic neodiaphragmatic motion. The other two are doing well with stable absence of paradoxical motion. There have been no complications. Long-term follow-up will be required to determine their eventual fate. The prognosis is encouraging.

Recovery from spinal cord injury.

There are many classifications of spinal cord injury. The anatomic definitions help in understanding the pathophysiology but are less useful in calculating recovery. Basic classifications, such as those by Guttman and Frankel, are useful for epidemiological studies, especially if one wishes to compare patients internationally or to compare data bases but this information, except in complete lesions, is too limited to allow more refined calculations as to the effectiveness of treatment modalities, especially in partial lesions. An accurate motor index, such as we have described, or such as the Yale index (2), is needed for more specific calculations of recovery if any prediction about the efficacy of various treatments are to be made. We have described our data from the mid-1970s in detail to explain our current treatment protocols. While nothing can be done for the completely paralyzed patient, our treatment of the acute (transiently concussed) near complete lesion and partial lesion must be tailored to maximize recovery. The fact that patients with initially complete motor lesion show some motor recovery in 15% indicates that some lesions are reversible and that we should try to learn to identify these patients and treat them to maximize their recovery. Certain severe partial lesions show poor recovery; we must improve therapy for these patients. Patients with partial lesions and 25-30% motor power below the injury have an 80% (+/- 20%) recovery; we should strive to attain and improve on these good results by appropriate medical and surgical management. In sharing with you our methods and data, we have provided these preliminary conclusions which influence our behavior as neurosurgeons, but it is equally clear that much work still needs to be done. This chapter should represent a reference source with which we can continue to work.

Dismantling the pyramid.

The suggestion is heard, with increasing frequency, that the therapeutic pyramid be dismantled and that medical management be reordered to treat juvenile rheumatoid arthritis as early and as decisively as possible to induce prompt remission of disease, thereby preserving function and the quality of life. We scrutinize paradigms that guide our treatment strategies, review current practices, update data derived from those practices, and propose reassessment for treatment in the 1990s.