Correlation of serum protein biomarkers with disease activity in psoriatic arthritis.

Objective: To assess the correlation of serum protein biomarkers with disease activity across different domains of psoriatic arthritis (PsA).Material and methods: A cross-sectional cohort of 45 adult patients with PsA fulfilling the classification for psoriatic arthritis (CASPAR) criteria was recruited from University of California San Diego (UCSD) Arthritis Clinics. Clinical data and serum samples were collected and serum was analyzed for protein biomarkers hypothesized to be relevant to disease activity in PsA. Correlations were evaluated for clinical disease activity measures across disease domains.Results: Biomarkers with the highest correlation to the composite indices and disease domains were SAA, IL-6, YKL-40, and ICAM-1. In addition, several biomarkers were moderately correlated with individual composite indices and/or disease domains. Low or no correlation was observed with some biomarkers, e.g. MMP-3, MMP-1, EGF, VEGF, and IL-6R. In contrast, the correlation of all biomarkers with certain disease domains was low; specifically, pain, percent body surface area of psoriasis, and patient global assessment. The multi-biomarker disease activity score (MBDA) developed for rheumatoid arthritis (RA) showed high correlations with most composite indices and some disease domains in PsA.Conclusions: These data suggest biomarker analysis can reflect disease activity across disease domains in PsA. Certain domains would likely benefit from the evaluation of additional biomarkers.

Persistence of low disease activity after tumour necrosis factor inhibitor (TNFi) discontinuation in patients with psoriatic arthritis.

OBJECTIVE: To determine the duration of clinical benefit among patients with psoriatic arthritis (PsA) discontinuing tumour necrosis factor inhibitor (TNFi) therapy while in low disease activity (LDA), and to identify patient characteristics associated with prolonged clinical benefit. METHODS: We performed an observational cohort study assessing patients with PsA from the Consortium of Rheumatology Researchers of North America (CORRONA) registry who had discontinued TNFi after achieving LDA, defined as clinical disease activity index (CDAI) score ≤10 and physician's global assessment (PGA) of skin psoriasis ≤20/100. Kaplan-Meier method was used to estimate the duration of clinical benefit. RESULTS: Of the 5945 patients with PsA in CORRONA, 302 patients had discontinued TNFi (n=325) while in LDA and had follow-up data available. At time of discontinuation, mean PsA duration was 9.8 years, mean CDAI was 3.9, and mean duration of TNFi use was 1.5 years; 52.6% of patients had discontinued their first TNFi. Median time to loss of benefit was 29.2 months. 179 (55.1%) patients had persistent benefit at their previous clinic visit. An increased risk of losing clinical benefit was seen among patients with higher disease activity at discontinuation (CDAI≥3.2 vs <3.2; HR 1.43 (p=0.32)) and among smokers (HR 1.78 (p=0.027)). CONCLUSIONS: Patients with PsA who achieve LDA may maintain clinical benefit after discontinuation of TNFi therapy.

Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke.

Neuronal injury in ischemic stroke is partly mediated by cytotoxic reactive oxygen species. Although the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier (BBB), its oxidized form, dehydroascorbic acid (DHA), enters the brain by means of facilitative transport. We hypothesized that i.v. DHA would improve outcome after stroke because of its ability to cross the BBB and augment brain antioxidant levels. Reversible or permanent focal cerebral ischemia was created by intraluminal middle cerebral artery occlusion in mice treated with vehicle, AA, or DHA (40, 250, or 500 mg/kg), either before or after ischemia. Given before ischemia, DHA caused dose-dependent increases in postreperfusion cerebral blood flow, with reductions in neurological deficit and mortality. In reperfused cerebral ischemia, mean infarct volume was reduced from 53% and 59% in vehicle- and AA-treated animals, respectively, to 15% in 250 mg/kg DHA-treated animals (P < 0.05). Similar significant reductions occurred in nonreperfused cerebral ischemia. Delayed postischemic DHA administration after 15 min or 3 h also mediated improved outcomes. DHA (250 mg/kg or 500 mg/kg) administered at 3 h postischemia reduced infarct volume by 6- to 9-fold, to only 5% with the highest DHA dose (P < 0.05). In contrast, AA had no effect on infarct volumes, mortality, or neurological deficits. No differences in the incidence of intracerebral hemorrhage occurred. Unlike exogenous AA, DHA confers in vivo, dose-dependent neuroprotection in reperfused and nonreperfused cerebral ischemia at clinically relevant times. As a naturally occurring interconvertible form of AA with BBB permeability, DHA represents a promising pharmacological therapy for stroke based on its effects in this model of cerebral ischemia.

Aminoguanidine prolongs survival in azotemic-induced diabetic rats.

Toxic effects of hyperglycemia-induced advanced glycosylated end products (AGEs) may explain some vasculopathic complications of diabetes. Aminoguanidine, a known inhibitor of AGE formation, was administered by gavage to Sprague-Dawley streptozotocin-induced diabetic rats made azotemic by surgical reduction of renal mass. All rats became hyperglycemic. Renal ablation caused renal insufficiency, as evidenced by markedly reduced endogenous creatinine clearances at days 7 and 14. Aminoguanidine-treated rats had significantly (P < 0.04) superior survival to that of untreated azotemic diabetic rats. We infer from the extended life in a rat model of uremia in diabetic nephropathy that aminoguanidine may prove beneficial in human diabetes.

Neonatal diagnosis of fetal alcohol syndrome: not necessarily a hopeless prognosis.

A neonatal examination for fetal alcohol syndrome (FAS) should promote the guidance of parents, the planning of remediation for affected children, and the collection of prevalence data. A blinded examination of FAS characteristics conducted as part of a large prospective study of disadvantaged alcohol-exposed infants identified eight neonates who met the published criteria for FAS. These children were followed through the preschool years with a blinded assessment protocol. Seven of these children were found to have no impairment in cognitive and language development, when compared with their peers, and to be of average size. The one child who was mentally and growth retarded at follow-up who had been diagnosed as FAS might not have been diagnosed FAS using clinical criteria (as opposed to blinded research criteria), because his mother provided in-pregnancy reports of only low alcohol intake; she later acknowledged drinking an average of over 21 drinks/week during the pregnancy. The findings are positive in that they provide hope for children who present FAS at birth, although concern with adverse outcomes is certainly not dispelled. In particular, the possibility of later-emerging impairment in more complex tasks is not ruled out.

WISC-R IQ estimates from the Luria-Nebraska Neuropsychological Battery.

Multiple regression equations predicting WISC-R IQs from Luria-Nebraska T scores and subjects' chronological age were developed and cross-validated on a total sample of 152 adolescent psychiatric patients. Data from a randomly drawn subsample of 100 subjects were entered into three stepwise multiple-regression analyses to derive equations predicting WISC-R IQs. These equations were applied to the remaining subsample (n = 52) as were the equations developed by McKay, et al. (1981) for estimating adult WAIS IQs. Mean differences, correlations, and classification hit rates between the two sets of predicted IQs and the actual WISC-R IQs were examined. Findings were similar to those of previous studies examining the predictive relationship between the Luria-Nebraska and adult intelligence. As expected, chronological age entered significantly into all three stepwise multiple-regression analyses. The newly derived equations had significantly higher correlations with the WISC-R for Verbal and Full Scale IQs and significantly better predictive accuracy for Full Scale IQ. Rates of IQ misclassification warrant caution in the use of these methods, but it is concluded that the equations derived here predict about as well as do short forms of the WISC-R.

Definitional issues and neurobiological foundations of selected severe neurodevelopmental disorders.

This article reviews current definitional issues, selected neuropsychological findings, and presumed neurobiological underpinnings of two of the more commonly identified severe neurodevelopmental disorders: mental retardation and autistic disorder. Although these disorders represent two of the more common severe neurodevelopmental disorders encountered by child neuropsychologists practicing in clinical and research settings, they have not received the amount of attention from the field of neuropsychology as other kinds of neurodevelopmental disorders. Although there are few definitional controversies surrounding these disorders, findings accrued to date reveal solid evidence for neurological processes underlying each of these disorders. In addition, each of these diagnoses likely represents a heterogeneous group of disorders, suggesting that a syndrome analysis approach would prove beneficial for increasing our understanding of each disorder. Conclusions are drawn for the clinician and researcher, particularly with respect to using a neuropsychological perspective and assessment strategies with children with more severe disorders.

Thalamic amnesia: Korsakoff syndrome due to left thalamic infarction.

In order to support the concept that a lesion of the thalamus is sufficient to cause a Korsakoff syndrome, we are presenting 5 patients, all of whom developed the syndrome after sustaining a left (dominant) thalamic infarction. Two patients had pure thalamic strokes followed by a permanent Korsakoff syndrome. One of these patients was studied with neuropsychometric testing, as well as with a modern MRI scan. In 2 other patients, clinical and imaging data indicate that infarction was not limited to the thalamus. Another patient had bilateral thalamic infarcts but only a temporary Korsakoff syndrome. Neuropathological data are needed to elucidate the exact anatomical substrate of dominant thalamic Korsakoff syndrome.

Contributions of risk factors to elevated blood and dentine lead levels in preschool children.

The relationship between blood lead level (PbB) and an array of socio-demographic, behavioral, caregiving and environmental risk factors was investigated in a cohort of socioeconomically disadvantaged urban children at ages 2, 3 and 4 years and 10 months. The risk factors were also related to dentine lead level (PbD) from shed deciduous teeth. Strong persistent pairwise relationships with PbB and PbD were observed for maternal IQ, parental education, examiner ratings of the condition and cleanliness of the physical environment, and the HOME scale, which assesses the quality of the caretaking environment. The association between dirt pica and PbB was strong at 2 years (r = 0.30), but was less pronounced in subsequent assessments as the prevalence of pica decreased. Insignificant or weak relationships were found for maternal assessments of paint-and-plaster peeling in the home and non-dirt pica. The HOME scale and the ratings of the condition of the physical environment were significantly related to PbB and PbD even after adjustment for socio-demographic factors. These two measures were also strongly related to an array of developmental outcomes. The results indicate that statistical adjustment specifically for the quality of the caretaking environment can lead to substantial reductions in estimates of adverse lead effects.

Prenatal alcohol exposure and preschool physical growth: a longitudinal analysis.

This report examines the effects of fetal alcohol exposure on size and growth in an urban cohort followed prospectively through early childhood. Indices of prenatal drinking were related to measurements of weight, stature (length), and head circumference obtained at birth and during five subsequent in-home assessments. Small but statistically significant relationships were detected between short-term recall estimates of drinking during pregnancy and weight and length at birth. The strength of these relationships diminished during the preschool assessments. However, estimates of catch-up growth associated with alcohol exposure were not statistically significant. With the exception of a single case with a profile of signs characteristic of fetal alcohol syndrome, an adverse effect of prenatal alcohol exposure on head circumference was not indicated.

Prenatal alcohol exposure and sustained attention in the preschool years.

The effects of fetal alcohol exposure on sustained attention in the preschool years were investigated in a sample of socioeconomically disadvantaged urban children. The 245 children examined were the 4-year 10-month-old follow-up cohort of a prospective study begun while their mothers were pregnant. Sustained attention was assessed by an automated, computer-administered vigilance task. Indices of fetal alcohol exposure included three measures of maternal drinking and two early indicators of fetal alcohol damage. The data were analyzed using univariate and multivariate regression techniques, both with and without adjustment for covariates. None of the analyses supported the hypothesis that fetal alcohol exposure adversely affects sustained attention performance in preschool children. We infer that, if there is an effect of prenatal alcohol exposure on vigilance task performance, that effect is small.

Psychometric validity of proration and Digit Span substitution for estimating WISC--R verbal and Full Scale IQs.

This study investigated the merits of substituting the Digit Span subtest for an invalid Verbal Scale subtest versus a proration method in calculating WISC--R Verbal and Full Scale IQ. Subjects were 93 child and adolescent psychiatric patients (67 boys and 26 girls) who ranged in age from 8 to 16 yr. Analysis indicated that the use of Digit Span as a substitute for the regularly administered Verbal subtests was inferior to the use of the comparable proration method. Although relatively few cases of misclassification occurred for either method in relation to Full Scale IQ, the rate of Verbal IQ misclassification by the Digit Span substitution method was significantly greater than with use of its proration. When faced with a choice, clinicians should attach greater validity to prorated estimates of a child's WISC--R Verbal IQ.

Cross-validation of a psychometric system for screening neuropsychological abnormality in older children.

The Discriminant Equation (DE) represents a recently developed system for screening neuropsychological abnormality in older children. The DE was subjected to cross-validation on a sample of 82 child and adolescent psychiatric patients referred for a comprehensive neuropsychological assessment. An overall hit rate of 79.3% correct classification was found which supported the validity of the DE in predicting neuropsychological impairment. The findings are discussed in relation to population characteristics and the nature of the criterion to be predicted as they may affect the application of neuropsychological screening procedures.

Autosomal dominant iridogoniodysgenesis: glaucoma management.

In a family of 55 people in seven generations 28 were known to be affected with autosomal dominant iridogoniodysgenesis. Their glaucoma was characterized by early onset of high intraocular pressures, lability of the pressure both with and without medical treatment, poor response to such treatment and resistance of the optic nerve head to damage even into early middle age. Among the surgical procedures undertaken, goniotomy was not successful but, oddly, iridencleisis was. All indications were that surgery could be delayed into adult life.

Autosomal dominant iridogoniodysgenesis: genetic features.

Twenty-two members of two families have been identified as being affected with iridogoniodysgenesis. The major clinical features of this disorder are mesodermal remnants in the iridociliary angle associated with abnormal angle vasculature, marked hypoplasia of the iris stroma and increased intraocular pressure leading to glaucoma. The involvement of the two eyes is remarkably symmetric. Pedigree analysis of the larger family provided firm evidence for regular autosomal dominant inheritance as the mechanism of genetic transmission.

Ocular melanoma: a population-based study.

During the 10-year period ending December 1976 ocular malignant melanoma developed in 99 patients in Alberta. To investigate the natural history of this disease we reviewed certain clinical and epidemiologic features of these cases. Of all the melanomas during that time 16% occurred in the eye, and of all the ocular malignant diseases 70% were malignant melanomas. The more malignant mixed cell tumours were much more frequent in the women than in the men, while the converse was true of the less malignant spindle cell melanomas. Within each cell type the women survived longer than the men. The actuarial 5-year survival rate of the entire group was 62%. Metastases occurred in 29 of the 99 patients; the liver was the only or initial site in 22 (76%). Our study shows that there has been no improvement in the survival rate of patients with ocular melanoma over the past 10 years. Our therapeutic methods must be improved.

The water provocative test in preglaucomatous chickens.

Our ability to induce glaucoma in birds provides an experimental system for exploring the mechanisms involved in the provocative water test. Waters loads of a level comparable to those used clinically produced larger intraocular pressure (IOP) changes in preglaucomatous and glaucomatous birds than in control birds. The magnitude of the response corresponded to the level of IOP before testing, that is, to the severity of the glaucoma. Changes in systemic blood pressure were not involved in the response. While hyotonicity of plasma may be the systemic determinant, the normal range of variation in this factor does not allow us at present to consider this a causal relationship.

Kidney metabolite levels and ammonia production in acute acid-base alterations in the rat.

Acute acid-base disturbances cause rapid changes in renal ammonia production in the rat. To investigate the regulation of ammonia production in acute acid-base stresses, we examined the effects of such conditions on tissue levels of metabolites such as alpha-ketoglutarate (KG), which inhibits kidney mitochondrial glutamine uptake and deamidation at physiological concentrations. In rats given low (5 mmol/kg) or high (20 mmol/kg) doses of NH4Cl by stomach tube or placed in a 10% CO2 atmosphere, kidney KG levels fell after 1-h by 44, 69, or 73%, respectively. NaHCO3 administration produced no change in KG levels. Renal glutamate and glutamine levels changed little, if at all, in any group, and renal phosphoenolpyruvate levels were not altered except for a decrease in the NH4HCO3 group. In livers of the same rats, treatments produced different patterns of metabolite changes; KG fell only in the NaHCO3 and NH4HCO3 groups. These results support the concept that KG is a specific regulator of renal ammonia production in acute acid-base stresses.