Cross-sectional characteristics of pediatric-onset discoid lupus erythematosus: Results of a multicenter, retrospective cohort study.

BACKGROUND: The incidence of systemic lupus in children with discoid lupus is unknown. OBJECTIVE: This study assessed the baseline characteristics of patients with pediatric discoid lupus erythematosus (pDLE). METHODS: Medical records at 17 sites were reviewed for pediatric dermatology and rheumatology patients with discoid lupus erythematosus. The inclusion criteria were clinical and/or histopathologic diagnosis of discoid lupus erythematosus with an age at onset of <18 years. Baseline data were collected at the first documented visit. Outcomes included diagnosis of systemic lupus erythematosus (SLE) at the baseline visit using the 1997 American College of Rheumatology (primary) and the 2012 Systemic Lupus International Collaborating Clinics (secondary) criteria. RESULTS: Of the >1500 charts reviewed, 438 patients met the inclusion criteria. The cohort was predominantly female (72%) and racially/ethnically diverse. A diagnosis of SLE at the baseline visit (pDLE + SLE) was rendered in 162 (37%) patients using the American College of Rheumatology and in 181 (41%) patients using the Systemic Lupus International Collaborating Clinics criteria. Patients with pDLE + SLE were older at the time of rash onset (median, 12.9 vs 8.9 years; P < .001), with shorter time from discoid lupus erythematosus onset to diagnosis, compared with patients with pDLE-only (median, 2 vs 7 months; P < .001). Patients with pDLE + SLE were more likely to be female (P = .004), with generalized discoid lupus erythematosus and clinically aggressive disease, including end-organ involvement, positive serologies, and higher- titer levels of antinuclear antibodies (P < .001). LIMITATIONS: Retrospective study. CONCLUSION: A diagnosis of discoid lupus erythematosus in adolescence should prompt thorough screening for SLE.

Evaluation of the reliability and validity of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) in paediatric cutaneous lupus among paediatric dermatologists and rheumatologists.

BACKGROUND: The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is a reliable outcome measure for cutaneous lupus erythematosus (CLE) in adults used in clinical trials. However, it has not been validated in children, limiting clinical trials for paediatric CLE. OBJECTIVES: This study aimed to validate the CLASI in paediatrics. METHODS: Eleven paediatric patients with CLE, six dermatologists and six rheumatologists participated. The physicians were trained to use the CLASI and Physician's Global Assessment (PGA), and individually rated all patients using both tools. Each physician reassessed two randomly selected patients. Within each physician group, the intraclass correlation coefficient (ICC) was calculated to assess the reliability of each measure. RESULTS: CLASI activity scores demonstrated excellent inter- and intrarater reliability (ICC > 0·90), while the PGA activity scores had good inter-rater reliability (ICC 0·73-0·77) among both specialties. PGA activity scores showed excellent (ICC 0·89) and good intrarater reliability (ICC 0·76) for dermatologists and rheumatologists, respectively. Limitations of this study include the small sample size of patients and potential recall bias during the physician rerating session. CONCLUSIONS: CLASI activity measurement showed excellent inter- and intrarater reliability in paediatric CLE and superiority over the PGA. These results demonstrate that the CLASI is a reliable and valid outcome instrument for paediatric CLE.

Gender differences in tuberculosis treatment outcomes: a post hoc analysis of the REMoxTB study.

BACKGROUND: In the REMoxTB study of 4-month treatment-shortening regimens containing moxifloxacin compared to the standard 6-month regimen for tuberculosis, the proportion of unfavourable outcomes for women was similar in all study arms, but men had more frequent unfavourable outcomes (bacteriologically or clinically defined failure or relapse within 18 months after randomisation) on the shortened moxifloxacin-containing regimens. The reason for this gender disparity in treatment outcome is poorly understood. METHODS: The gender differences in baseline variables were calculated, as was time to smear and culture conversion and Kaplan-Meier plots were constructed. In post hoc exploratory analyses, multivariable logistic regression modelling and an observed case analysis were used to explore factors associated with both gender and unfavourable treatment outcome. RESULTS: The per-protocol population included 472/1548 (30%) women. Women were younger and had lower rates of cavitation, smoking and weight (all p < 0.05) and higher prevalence of HIV (10% vs 6%, p = 0.001). They received higher doses (mg/kg) than men of rifampicin, isoniazid, pyrazinamide and moxifloxacin (p ≤ 0.005). There was no difference in baseline smear grading or mycobacterial growth indicator tube (MGIT) time to positivity. Women converted to negative cultures more quickly than men on Lowenstein-Jensen (HR 1.14, p = 0.008) and MGIT media (HR 1.19, p < 0.001). In men, the presence of cavitation, positive HIV status, higher age, lower BMI and 'ever smoked' were independently associated with unfavourable treatment outcome. In women, only 'ever smoked' was independently associated with unfavourable treatment outcome. Only for cavitation was there a gender difference in treatment outcomes by regimen; their outcome in the 4-month arms was significantly poorer compared to the 6-month treatment arm (p < 0.001). Women, with or without cavities, and men without cavities had a similar outcome on all treatment arms (p = 0.218, 0.224 and 0.689 respectively). For all other covariate subgroups, there were no differences in treatment effects for men or women. CONCLUSIONS: Gender differences in TB treatment responses for the shorter regimens in the REMoxTB study may be explained by poor outcomes in men with cavitation on the moxifloxacin-containing regimens. We observed that women with cavities, or without, on the 4-month moxifloxacin regimens had similar outcomes to all patients on the standard 6-month treatment. The biological reasons for this difference are poorly understood and require further exploration.

The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder.

This article aims to review research in nonhuman primates demonstrating that norepinephrine can enhance the cognitive functioning of the prefrontal cortex through actions at alpha 2 A-adrenergic receptors postjunctional to noradrenergic terminals. As prefrontal cortex cognitive deficits are prominent in several psychiatric disorders, including attention-deficit hyperactivity disorder, these basic findings may have relevance for the development of novel pharmacotherapies.

Effect of ketorolac on bleeding time and postoperative pain in children: a double-blind, placebo-controlled comparison with meperidine.

STUDY OBJECTIVE: To determine whether ketorolac 0.75 mg/kg would provide a comparable degree of analgesia to that of meperidine 1 mg/kg in terms of postoperative opioid requirements and pain scores in children undergoing surgeries associated with mild to moderate postsurgical discomfort. DESIGN: Randomized, prospective, placebo-controlled, double-blinded study of the initial 6 postsurgical hours. SETTING: University affiliated teaching hospital. PATIENTS: 90 healthy ASA status I and II children scheduled for elective general, orthopedic, or genitourinary procedures associated with mild to moderate postsurgical pain. Extensive surgical procedures associated with a significant risk of bleeding were excluded. INTERVENTIONS: Ketorolac 0.75 mg/kg, meperidine 1 mg/kg, or placebo (normal saline) was administered intramuscularly (IM) at the beginning of surgery. MEASUREMENTS AND MAIN RESULTS: Bleeding times were measured prior to and 180 minutes after study drug administration. Time to first rescue medication, total opioid requirement, pain scores, incidence of vomiting and length of stay were evaluated. Placebo-treated patients were rescued earlier (p < 0.0001) and required twice the rescue dosage (p = 0.013) when compared with either the ketorolac or meperidine groups. The ketorolac and meperidine groups did not differ with regard to time until first rescue, cumulative proportion requiring rescue, or the number of rescue doses required. A single dose of IM ketorolac prolonged bleeding time by 53 +/- 75 seconds (p = 0.006). CONCLUSIONS: Ketorolac provided analgesia comparable to that of meperidine and significantly reduced opioid requirements. Since ketorolac was not associated with a reduction in postoperative vomiting or length of stay, and in view of the uncertain risk of bleeding, it offers no advantage over meperidine in the management of mild to moderate acute postsurgical pain.

An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder.

OBJECTIVE: Medications such as clonidine have been shown to facilitate calming, to enhance frustration tolerance, and to reduce aggression in hyperactive children. The use of guanfacine (Tenex), an alpha 2 noradrenergic agonist similar to clonidine, was studied as an alternative because of its longer excretion half-life, decreased sedative side effects, and more selective binding profile. METHOD: Thirteen psychiatric outpatients diagnosed with ADHD were rated at baseline and while taking guanfacine to determine its efficacy as a treatment for ADHD. Comparisons of Conners parent ratings within subject were used to measure behavioral changes in the subjects. RESULTS: During guanfacine treatment, patients' mean scores improved significantly overall (1.27 off, 0.85 on, t = 2.55, p < .015) and in Conners Hyperactivity (1.63 off, 0.94 on, t = 3.69, p < .01), Inattention (1.92 off, 1.21 on, t = 3.32, p < .01), and Immaturity (1.81 off, 0.92 on, t = 3.77, p < .01) factors. CONCLUSIONS: This preliminary study indicates that guanfacine is a beneficial and useful treatment of ADHD, reducing hyperactive behaviors and enabling greater attentional ability with minimal side effects. We are currently collecting data in a double-blind study measuring guanfacine's efficacy with and in comparison to methylphenidate.

An immunohistologic study of granulomatous inflammation in SIV-infected rhesus monkeys.

We studied granulomatous inflammation in simian AIDS using histologic, immunohistologic, and in situ hybridization techniques. Complete Freund's adjuvant was used to induce granulomas in two control animals and two macaques infected with simian immunodeficiency virus (SIV) and having low peripheral CD4+ T cell counts. Control animals developed large (> 2 cm diameter) epithelioid granulomas containing CD68+ macrophages (m phi s), epithelioid m phi s and multinucleated giant cells (MNGCs), CD4+ and CD8+ T cells, and small perivascular collections of CD20+ B cells. Lymphocytes rarely expressed proliferating cell nuclear antigen (Ki-67), and only rare endothelial cells expressed vascular cell adhesion molecule 1 (VCAM-1). In contrast, SIV+ animals had smaller (< 0.5 cm diameter) epithelioid granulomas characterized by numerous large, dense CD8+, CD20+ lymphocyte aggregates with prominent local division (Ki-67+). Despite low blood CD4+ T cell numbers, there was a substantial CD4+ T cell infiltrate, accompanied by enhanced endothelial VCAM-1 expression. These granulomas contained no detectable SIV antigen or RNA. Thus, in simian AIDS, experimentally induced granulomatous responses are grossly attenuated, yet associated with increased local endothelial-leukocyte signaling and lymphocyte division.

Plasma adenosine changes during cardiac surgery.

Changes in plasma adenosine and inosine were measured during high-dose narcotic anesthesia and surgery for coronary artery bypass grafting (CABG), and mitral or aortic valve replacement (V). Arterial and mixed venous blood samples were obtained for measurement of adenosine and inosine at eight sampling intervals ranging from preanesthesia induction to discontinuation of cardiopulmonary bypass (CPB). Arterial but not mixed venous adenosine was markedly elevated in blood samples 10 minutes after intubation, but the fourfold elevation was significant only in the CABG patient group. Mixed venous inosine and adenosine were most consistently elevated in post-CPB samples. In a separate study of arterial adenosine changes during induction, a uniform drug administration protocol was used, and again adenosine was significantly increased immediately after intubation. It is possible that adenosine and perhaps inosine may contribute to cardiovascular responses following induction-intubation and also after discontinuing CPB.

Opposite alterations in cerebrospinal fluid uridine after severe cerebral ischemia or intrathecal blood injection.

1. Rats which survived hypoglycemia by insulin, hypoxia by 10% O2, or ischemia by carotid ligation and hypotension to 40 mm Hg, evidenced no changes in cerebrospinal fluid (CSF) uridine. Animals which died soon after the above interventions or as a result of KCl-induced cardiac arrest had elevated CSF uridine concentrations. 2. Injection of whole blood or the soluble contents of lysed blood cells into the lateral ventricle of rats reduced CSF uridine to less than one-half normal at 24 hrs but values returned to normal 3 days later. Changes in hypoxanthine resembled those of uridine, but were less dramatic, whereas xanthine concentrations were largely unaltered. Intraventricular injection of plasma or saline did not alter CSF uridine. 3. It seems most likely that low CSF uridine concentrations previously reported in head injury patients may be secondary to the effects of blood cell contents in the cerebrospinal fluid, rather than responses to altered metabolism in neurons or glia cells.

Comparative biology of natural and experimental SIVmac infection in macaque monkeys: a review.

Epidemiologic and clinicopathologic data from 11 macaques with naturally acquired SIV infection--10 of which have died--were compared with those from 34 rhesus monkeys that have died of experimental SIVmac infection. Several differences, including gender affected, age at time of death, and the occurrence of certain opportunistic infections, could be explained by the experimental design; others remained unexplained. The most striking difference was the 41% incidence of meningoencephalomyelitis in the experimental group and its absence in naturally SIV-infected animals.

Infrared spectroscopic investigations of pulmonary surfactant. Surface film transitions at the air-water interface and bulk phase thermotropism.

The molecular structure of the phospholipid component of intact pulmonary surfactant isolated from bovine lung lavage has been examined by Fourier transform infrared spectroscopy. Two different physical states of the surfactant were examined by means of different infrared spectroscopic sampling techniques. Transmission infrared experiments were used to study the surfactant in the bulk phase. In these experiments, the thermotropic behavior of the bulk surfactant was monitored by temperature-induced variations in the phospholipid acyl chain CH2 stretching frequencies. A broad phase transition (confirmed by differential scanning calorimetry) was noted with an onset temperature near 15 degrees C and a completion temperature near 42 degrees C. In addition to the bulk transmission experiments, external reflection infrared spectroscopy was used to examine surfactant films in situ at the air-water interface. As surface pressure was increased from 0 to 43 dyn/cm, a gradual and continuous decrease in the CH2 stretching frequency was noted for the surfactant. Thus, under surface pressures which correspond to large lung volumes in vivo, the surfactant acyl chains exist mostly in the ordered (trans) configuration. The frequency shift in the CH2 stretching mode is consistent with a continuous ordering of the acyl chains upon compression over the pressure range 0-43 dyn/cm, and implies that a weakly cooperative phase transition occurs in the hydrocarbon region of the surface film. The surface film transition is especially noted in the pressure-area curve of the surfactant and approximates in two dimensions the broad thermotropic phase transition of the bulk phase surfactant. Substantial differences were observed between the response to surface pressure changes of intact surfactant compared with the main surfactant phospholipid, 1,2-dipalmitoyl-sn--glycero-3-phosphocholine. The changes in response are attributed to the presence of additional surfactant components. The current work demonstrates the ability of infrared spectroscopy to obtain structural information on the surfactant in physical states that directly relate to those in vivo.

Immunophenotypic characterization of mononuclear phagocytes and dendritic cells in lymphoid organs of the rhesus monkey.

Mononuclear phagocytes and dendritic cells are potent antigen-presenting cells that localize to distinct microenvironmental compartments in many different organs. These cells are particularly plentiful in spleen and lymph node. Recently, these cells have been identified and immunophenotypically characterized in human tissue sections using monoclonal antibodies. However, similar studies in animal species, particularly those representing models of human diseases, have yet to be completely performed. We have evaluated 18 monoclonal reagents raised against human determinants for their reactivity with macrophages and dendritic cells in lymphoid organs of rhesus monkeys. Six of the 18 (EBM11, 25F9, Mol, R4/23, To5, and SK9) produced labeling patterns in rhesus monkey lymphoid tissue that paralleled the staining patterns described for human tissues. Seven others (KB90, FMC17, Mo3, PHM3, PHM2, G16/1, and 27E10) stained varying subsets of specific cells types in these simian tissues. These reagents are requisite for the future study in an experimental animal of the afferent immune response in both normal and disease states.

Alterations in cerebrospinal fluid uridine, hypoxanthine, and xanthine in head-injured patients.

1. Examination of the cerebrospinal fluid (CSF) of head-injured patients reveals that the concentration of intraventricular xanthine is elevated and that of uridine is decreased relative to those of adult lumbar CSF. 2. No correlations were observed between CSF lactate and CSF hypoxanthine, xanthine, or uridine, suggesting that changes in purine metabolites and the pyrimidine nucleoside do not index similar cellular events as does lactic acid production. 3. Ventricular CSF from hydrocephalic infants had uridine and hypoxanthine concentrations not significantly different from those of normal adult lumbar CSF, but xanthine was significantly elevated. 4. Since uridine has anticonvulsant properties and is a crucial substrate for cerebral metabolism, it may be useful to evaluate this pyrimidine for use in the management of patients with head injury.

Prevalence of antibodies to 3 retroviruses in a captive colony of macaque monkeys.

The prevalence of antibodies to 3 retroviruses in the macaque colony of the New England Regional Primate Research Center (NERPRC) was determined using enzyme-linked immunosorbent assay procedures as well as radioimmunoprecipitation-SDS polyacrylamide gel electrophoresis and indirect immunofluorescence tests. Out of 848 macaques, 3 (0.35%) had antibodies to simian immunodeficiency virus (SIV), 27 (3.2%) had antibodies to simian T-lymphotropic virus type I (STLV-1) and approximately 285 (34%) had antibodies to type D retrovirus. Of 3 macaques infected with SIV, 2 were rhesus monkeys (Macaca mulatta) and I was a cynomolgus monkey (Macaca fascicularis). STLV-1 and D retrovirus infection occurred in all 4 macaque species examined. SIV, STLV-1 and D retroviruses were isolated from sero-positive macaques. The low prevalence of SIV infection suggests that SIV is not being readily transmitted among macaques at NERPRC; this contrasts markedly with the high SIV prevalence in some captive mangabey colonies. In contrast to African green monkeys from eastern Africa, 160 Caribbean green monkeys examined showed no sign of SIV infection. These results provide a framework for monitoring spontaneous disease associated with infection by these 3 retroviruses and will help in further definition of STLV-1 and SIV infection of non-human primates as animal models for human disease.

Simian immunodeficiency virus-induced meningoencephalitis: natural history and retrospective study.

Simian immunodeficiency virus (SIV) is a lentivirus with morphological and antigenic similarities to human immunodeficiency virus, the causative agent of acquired immunodeficiency syndrome (AIDS) of humans. Macaque monkeys infected with SIV show profound immunological impairment, clinically characterized by multiple opportunistic infections and neoplasms. Retrospective examination of autopsy tissue from 27 SIV-infected animals demonstrated that approximately 60% of the experimentally inoculated animals had a meningoencephalitis characterized by perivascular infiltrates of macrophages and multinucleate giant cells in the white and gray matter and leptomeninges. Ultrastructurally, these macrophages contained typical lentiviral particles within membrane-bound intracytoplasmic vacuoles. Other findings in the central nervous system included discrete randomly located neuroglial nodules, endothelial hypertrophy, and leptomeningeal thickening. The results indicate tha the meningoencephalitis induced by SIV in monkeys is similar to the lesions of the central nervous system in patients with AIDS and that SIV infection in the macaque is a useful animal model to study the pathogenesis of human immunodeficiency virus--related subacute encephalitis or AIDS encephalopathy.