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.

Vitamins D2 and D3 in new world primates: influence on calcium absorption.

In Cebus albifrons monkeys it was demonstrated that vitamin D(3) promotes the intestinal absorption of calcium-47 and that vitamin D(2) does not increase absorption above that seen in monkeys deficient in vitamin D. These data support previous observations that vitamin D(2) is not effective in preventing metabolic bone disease in this species.

A new type D retrovirus isolated from macaques with an immunodeficiency syndrome.

Macaque monkeys with the recently described acquired immunodeficiency syndrome show a marked defect in T-lymphocyte function and die with opportunistic infections and lymphoproliferative abnormalities. In the study described here a new type D retrovirus was isolated from two Macaca cyclopis with this syndrome. This virus is related to, but distinct from, Mason-Pfizer monkey virus, a type D retrovirus previously isolated from a mammary tumor of a rhesus monkey (Macaca mulatta).

A region of the Herpesvirus saimiri genome required for oncogenicity.

Herpesvirus saimiri naturally infects squirrel monkeys (Saimiri sciureus) without producing signs of disease; infection of other New World primates, however, results in a rapidly progressing, malignant, T-cell lymphoma. Results described in this report identify a region of the viral genome that is required for oncogenicity in owl monkeys (Aotus trivirgatus); this region is not required for replication of the virus. This is believed to be the first such genomic region identified in a herpesvirus system.

Acute lymphocytic leukemia in owl monkeys inoculated with herpesvirus saimiri.

Our study demonstrates for the first time that Herpesvirus saimiri can induce acute lymphocytic leukemia in owl monkeys (Aotus trivirgatus) and that malignant lymphoma can be induced in this species of nonhuman primates by the inoculation of the virus by various routes (intravenous, sub-cutaneous, and intradermal).

Induction of AIDS-like disease in macaque monkeys with T-cell tropic retrovirus STLV-III.

The T-cell tropic retrovirus of macaque monkeys STLV-III has morphologic, growth, and antigenic properties indicating that it is related to HTLV-III/LAV, the etiologic agent of the acquired immune deficiency syndrome (AIDS) in humans. Four of six rhesus monkeys died within 160 days of STLV-III inoculation with a wasting syndrome, opportunistic infections, a primary retroviral encephalitis, and immunologic abnormalities including a decrease in T4+ peripheral blood lymphocytes. These data show that an immunodeficiency syndrome can be produced experimentally in a nonhuman primate by an agent from the HTLV-III/LAV group of retroviruses. The STLV-III-macaque system will thus provide a useful model for the study of antiviral agents and vaccine development for human AIDS.

Isolation of T-cell tropic HTLV-III-like retrovirus from macaques.

The isolation of a T-cell tropic retrovirus from three immunodeficient macaques and one macaque with lymphoma is described. The morphology, growth characteristics, and antigenic properties of this virus indicate that it is related to the causative agent of acquired immune deficiency syndrome in humans (HTLV-III or LAV). This virus is referred to as simian T-lymphotropic virus type III (STLV-III) of macaques. The existence of a cytopathic, T-cell tropic virus resembling HTLV-III in monkeys may facilitate study of disease induction and vaccine development in an animal model.

Serologic identification and characterization of a macaque T-lymphotropic retrovirus closely related to HTLV-III.

Human T-lymphotropic virus type III (HTLV-III) is thought to play an etiologic role in the development of the acquired immune deficiency syndrome (AIDS). In this study the serologic characterization of a new simian retrovirus that is related to HTLV-III is described. This new virus, here referred to as STLV-III, was isolated from sick macaques at the New England Regional Primate Research Center. Radioimmunoprecipitation analysis revealed STLV-III-specific proteins of 160, 120, 55, and 24 kilodaltons, all similar in size to the major gag and env proteins of HTLV-III. These antigens were recognized by representative macaque serum samples and human reference serum samples positive for HTLV-III antibodies. Monoclonal antibodies directed to p24, the major core protein of HTLV-III, also immunoprecipitated a 24-kilodalton species in lysates of cells infected with the macaque virus. This HTLV-III-related virus, which naturally infects a nonhuman primate species, may provide a useful model for the study of HTLV-III and the pathogenesis of AIDS.

Lymphoma in macaques: association with virus of human T lymphotrophic family.

Human T-cell leukemia virus has been linked with adult T-cell leukemia-lymphoma (ATLL), a tumor of mature T cells that occurs at elevated rates in southwestern Japan and in the Caribbean Basin. Human T-cell leukemia virus (HTLV) or a closely related virus, has also been found in varying proportions of healthy individuals of several species of Old World monkeys. In the present study, conducted with macaques from Taiwan and the New England Regional Primate Research Center, antibodies to membrane antigens of HTLV-infected cells (HTLV-MA) were found in 11 of 13 macaques with malignant lymphoma or lymphoproliferative disease but in only 7 of 95 of healthy macaques. This indicates that antibodies to HTLV are significantly associated with the development of naturally occurring lymphoid neoplasms in at least some species of nonhuman primates.

Clinicopathologic characterization of Herpesvirus saimiri malignant lymphoma in New Zealand white rabbits.

Twenty-two of 39 rabbits inoculated with Herpesvirus saimiri developed malignant lymphoma and either died or were killed between 17 and 165 days after inoculation. No clinical signs were present in animals developing the disease before 46 days, but all other rabbits had a severe conjunctivitis, nasal discharge, and dyspnea resulting from a lymphocytic invasion of the ocular and nasal tissues. Four rabbits developed terminal leukemia. Pathologically, the disease resembled H. saimiri malignant lymphoma in nonhuman primates; there was extensive diffuse infiltration of most organs and tissues with either a lymphocytic or lymphoblastic infiltrate. Tumor nodules or masses seen in some forms of malignant lymphoma were not present. In contrast to nonhuman primates, all affected rabbits showed invasion of the skin of the nose and eyelids, conjunctiva, iris, ciliary body, and choroid. In 3 rabbits there was slight infiltration into the brain, not noted in nonhuman primates. The susceptibility of rabbits extended the host range of H. saimiri beyond the order Primates.

Huntington's dementia. Clinical and neuropsychological features.

The neuropsychiatric syndrome of Huntington's disease is outlined in this report with an emphasis on the cognitive deficits that lend themselves to future neurobehavioral research. Eighteen patients without disabling cognitive or psychiatric symptoms were evaluated for a period of 3 to 15 weeks, with assessment of their cognitive disorder, psychiatric, and neurological symptoms. Neuropsychological examination included repeated mental status examination, the Wechsler Adult Intelligence Scale (WAIS), and, for some, parietal lobe testing. In addition to suffering from a loss of finely detailed memories, patients demonstrated impaired organizing, sequencing, planning, and recalling of information on request. On the WAIS, mean verbal and performance scores were not significantly different. Neuropsychological findings suggested that the Huntington's disease pattern of cognitive impairment is not initially diffuse and homogeneous, but characterized by a relative sparing of several higher cortical functions. Many patients had increased irritability and labile affect. The similarity of Huntington's disease to frontal lobe syndromes is also discussed.

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.

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.

Bromocriptine in Huntington chorea.

Following a recent report that apomorphine hydrochloride alleviates the involuntary movements of Huntington chorea, we have investigated another dopamine receptor agonist, bromocriptine, in this disease. A double-blind crossover study in six patients showed that rather than improving chorea, bromocriptine induced an exacerbation. This finding supports the view that choreatic movements correlate with overactivity in dopaminergic systems.

Failure of Herpesvirus saimiri to enhance atherogenesis in owl monkeys (Aotus trivirgatus).

A retrospective study was performed to evaluate the potential of a mammalian oncogenic virus, Herpesvirus saimiri, to cause atherosclerosis in owl monkeys (Aotus trivirgatus). This was undertaken since an avian oncogenic herpesvirus, Marek's disease virus, does so in chickens. Data from earlier studies were reviewed and 3 groups of animals were selected. These included 23 animals infected with herpesvirus that died an average of 156 days later with malignant lymphoma; 11 infected an average of 207 days before being killed without lymphoma; and 21 uninfected control animals that died from a variety of diseases. Aortas and hearts from all animals were recovered from storage in formalin and examined for histopathological evidence of atherosclerosis in aortas and coronary arteries. Mild to moderate atherosclerosis characterized by intimal proliferation and the presence of fat droplets was present in 60% of the monkeys and did not differ in occurrence between the groups. Mean intimal thickness did not vary significantly between groups either. A case of naturally-occurring severe atherosclerosis is also reported here. Thus, although this species is susceptible to atherosclerosis, neither the occurrence nor severity of that disease is affected by infection with an oncogenic virus within the time periods studied here.

The role of calcium and fluoride in osteoporosis in rhesus monkeys.

Twenty-two female Rhesus monkeys were fed purified diets varying in calcium and fluoride content for five years and studied, using radiographic, photon absorptiometric and histologic techniques. The results suggested that: 1) the addition of fluoride (50 ppm) to a diet containing 1 per cent calcium resulted in a reduction in bone growth rate and resorption, without affecting bone size or density nor resulting in fluorosis; 2) a diet containing 0.15 per cent calcium resulted in osteoporosis due to an increase in bone resorption; and 3) fluoride added to a similar low calcium diet prevented osteroporosis by reducing bone growth rate and resorption resulting in bones with normal density, but at the same time fluoride interfered with mineralization of osteoid leading to osteomalacia.

Plasma levels of d-amphetamine in hyperactive children. Serial behavior and motor responses.

Amphetamine has been clearly documented to be an efficacious treatment for hyperactive children. The pharmacokinetics of amphetamine have been studied in adults, but not in children. Sixteen male children who scored greater than 2SD from norms on Factors I and IV of Conner's Teacher Rating Scale and who were not excluded for reasons to do with medical or psychiatric conditions, intelligence, or age, had a plasma d-amphetamine apparent elimination half-life of 6.8 +/- 0.5h. Peak plasma level occurred between 3 and 4h (62.7 +/- 3.8 and 65.9 +/- 3.6 ng/ml, respectively). Six of these children had a repeat study and there were no significant differences within subject in apparent elimination half-lives and attained peak blood levels. The variation in plasma levels was greater during absorption than during elimination. Both behavioral and motor activity responses as analyzed by differences between amphetamine and placebo days (by paired t-tests) indicate significant responses between hours 1--4; however, these responses do not correlate with plasma amphetamine levels; they occur during the absorption phase. The decreased response to later similar plasma levels of d-amphetamine may be related to depletion of catecholamine stores, to replacement by a 'false neurotransmitter' metabolite of amphetamine, or to alteration in receptor sensitivity.

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.