Osteophyte growth in early thumb carpometacarpal osteoarthritis.

OBJECTIVE: Osteophyte formation is a critical part of the degeneration of a joint with osteoarthritis (OA). While often qualitatively described, few studies have succeeded in quantifying osteophyte growth over time. Using computed tomography (CT) image data from a longitudinal, observational study of thumb carpometacarpal (CMC) OA, our aim was to quantify osteophyte growth volume and location over a three-year period in men and women. METHOD: Ninety patients with early thumb OA were recruited and assessed at baseline, 1.5 years, and 3 years with CT imaging. Osteophyte volume and location on the trapezium and first metacarpal were determined using a library of 46 healthy subjects as a nonarthritic reference database. RESULTS: There was a significant increase in osteophyte volume for women and men over the three-year follow-up in the trapezium (86.8 mm3-120.5 mm3 and 165.1 mm3-235.3 mm3, means respectively) and in the proximal metacarpal (63 mm3-80.4 mm3, and 115.8 mm3-161.7 mm3, respectively). The location of osteophyte initiation and growth was consistent across subjects and was located in non-opposing regions on the trapezium and first metacarpal. Osteophyte growth occurred about the radial and ulnar margins of the trapezial facet, while on the proximal metacarpal, growth occurred principally about the volar and dorsal margins of the facet. CONCLUSION: Osteophyte growth occurred in early thumb osteoarthritis over three years. Growth was localized in specific, non-opposing regions on the trapezium and metacarpal, raising intriguing questions about the triggers for their formation, whether the mechanisms are mechanical, biological or a combination of both.

Experimental effects of acute exercise on forgetting.

OBJECTIVE: Prior research has evaluated the effects of acute exercise on episodic memory function. These studies have, on occasion, demonstrated that acute exercise may enhance both short- and long-term memory. It is uncertain as to whether the acute exercise improvements in long-term memory are a result of acute exercise attenuating declines in long-term memory, or rather, are driven by the enhancement effects of acute exercise on short-term memory. The present empirical study evaluates whether the decline from short- to long-term is influenced by acute exercise. This relationship is plausible as exercise has been shown to activate neurophysiological pathways (e.g., RAC1) that are involved in the mechanisms of forgetting. METHODS: To evaluate the effects of acute exercise on forgetting, we used data from 12 of our laboratory's prior experiments (N = 538). Across these 12 experiments, acute exercise ranged from 10 to 15 mins in duration (moderate-to-vigorous intensity). Episodic memory was assessed from word-list or paragraph-based assessments. Short-term memory was assessed immediately after encoding, with long-term memory assessed approximately 20-min later. Forgetting was calculated as the difference in short- and long-term memory performance. RESULTS: Acute exercise (vs. seated control) was not associated with an attenuated forgetting effect (d = 0.10; 95% CI: -0.04, 0.25, P = 0.17). We observed no evidence of a significant moderation effect (Q = 6.16, df = 17, P = 0.17, I2 = 0.00) for any of the evaluated parameters, including study design, exercise intensity and delay period. CONCLUSION: Across our 12 experimental studies, acute exercise was not associated with an attenuated forgetting effect. We discuss these implications for future research that evaluates the effects of acute exercise on long-term memory function.

Sunlight--can it prevent as well as cause cancer?

Excessive exposure to sunlight is known to damage the skin. However, the emphasis of most studies has been on the consequences of sunlight exposure to fair-skinned individuals, and the situation of people with heavy skin pigmentation residing in, or migrating to, geographic locations with limited sunlight incidence has been largely neglected. Recent epidemiological studies suggested the hypothesis that sunlight deprivation, and the associated reduction in the circulating levels of vitamin D3 (vit D3) derivatives may lead to the increased incidence of the carcinomas of the breast, colon, and prostate. Two endocrine pathways may mediate these effects. The pineal function can potentially be involved, but the formation of vit D3 derivatives is gaining credibility as a mechanism for the retardation of cancer progression. Evidence is accumulating that such compounds, e.g., 1,25-dihydroxyvitamin D3 (1,25D3) induce differentiation of several neoplastic cell types, arrest or retard their proliferation, and act as chemopreventive agents in animal carcinogenesis. We also propose that the antineoplastic effects of vit D3 derivatives are exerted at several steps in tumor progression and that immunomodulating effects of 1,25D3 may contribute to these effects of sunlight. The recent findings that common cancers, e.g., carcinoma of the prostate and the breast, behave more aggressively in black Americans than in white Americans may be explained on this basis. Although more data are needed on the effects of sunlight on the circulating levels of 1,25D3, a corollary of this hypothesis is that there should be no broad condemnation of moderate sunlight exposure, as it may be available in insufficient amounts to some Americans.

Comparison of micro-CT post-processing methods for evaluating the trabecular bone volume fraction in a rat ACL-transection model.

Trabecular bone volume fraction assessments are likely sensitive to the analysis method and selection of the region of interest. Currently, there are several methods for selecting the region of interest to analyze trabecular bone in animal models of post-traumatic osteoarthritis. The objective of this study was to compare three published methods for determining the trabecular bone volume fraction of the medial tibial epiphyses in ACL transected and contralateral ACL intact knees. Micro-computed tomography images of both knees were obtained five weeks post-operatively and evaluated using three methods: (1) the Whole Compartment Method that captured the entire medial compartment, (2) the centrally located Single Core Method, and (3) the Triplet Core Method that averaged focal locations in the anterior, central, and posterior regions. The Whole Compartment Method detected significant bone loss in the ACL transected knee compared to the ACL intact knee (p<0.001), with a loss of 15.2±3.9%. The Single Core and the Triplet Core Methods detected losses of 7.5±10.5% (p=0.061) and 14.1±13.7%(p=0.01), respectively. Details regarding segmentation methods are important for facilitating comparisons between studies, and for selecting methods to document trabecular bone changes and treatment outcomes. Based on these findings, the Whole Compartment Method is recommended, as it was least variable and more sensitive for detecting differences in the bone volume fraction in the medial compartment.

Tardive dyskinesia. A discontinuation study.

Twenty-one nonschizophrenic and 12 schizophrenic outpatients with tardive dyskinesia (TD) were followed up for a mean of 12.0 and 8.6 months, respectively, following discontinuation of neuroleptic therapy. Of the 33 patients, only one demonstrated complete reversal of TD. Cumulative survival curves of the length of time to first improvement (reduction in movement ratings by 50% of baseline) did not differ between the two groups. The median time to first improvement was seven months. If a patient can be kept off of a neuroleptic regimen for 18 months, the estimated probability of showing a 50% reduction in movement is 87.2%. In the nonschizophrenic group, depressed mood was negatively correlated with severity of abnormal movements.

Lowering of p27Kip1 levels by its antisense or by development of resistance to 1,25-dihydroxyvitamin D3 reverses the G1 block but not differentiation of HL60 cells.

Cyclin-dependent kinase inhibitors are proteins with functions which appear to involve regulation of cell cycle traverse, and have been suggested to have a role in cell differentiation. However, there is as yet no rigorous proof that this is the case. We have addressed the participation of one of these inhibitors, p27Kip1, in the induction of differentiation and the subsequent G1 block induced in HL60 cells by 1,25-dihydroxyvitamin D3 (1,25D3). First, it was noted that sublines of HL60 cells able to grow rapidly in the presence of 1,25D3 have protein levels of p27Kip1 lower than the levels in cells subjected to 1,25D3-induced growth inhibition, but higher than in untreated parental cells. In contrast, there was no discernible relationship between the levels of p27Kip1 and the expression of differentiation markers. Further, HL60 cells treated with 1,25D3 and an oligonucleotide antisense, but not mismatched, to p27Kip1 showed an almost complete elimination of the 1,25D3-induced G1 block, but no decrease in the expression of differentiation markers. Similar results were obtained following transient transfection with an expression vector bearing the entire p27Kip1 coding sequence in the anti-sense orientation. This is the first direct demonstration that p27Kip1 plays a role in the 1,25D3-induced G1 arrest, and that partial reduction in its levels has no effect on the induction of differentiation in HL60 cells.

Hormonal changes during puberty: V. Transient pubertal gynecomastia: abnormal androgen-estrogen ratios.

The plasma profiles of 8 hormones were followed over the course of prepuberty and puberty in 30 adolescent males who developed gynecomastia and 24 who did not. Throughout puberty, ratios of delta 4-androstenedione to estrone (E1) and estradiol (E2) were significantly lower in the gynecomastia group than in the control group. Similarly, ratios of dehydroepiandrosterone-sulfate to E1 and E2 were significantly lower in the gynecomastia group. In contrast, ratios of plasma testosterone to E1 and E2 as well as plasma progesterone and PRL concentrations, were similar in both groups. Because of the adrenal origin of dehydroepiandrosterone and its sulfate, and of peripheral conversion of adrenal androgens to E1 and to E2, it appears that either decreased adrenal production of androgens and/or increased conversion of dehydroepiandrosterone-sulfate and delta 4-androstenedione to estrogens cause transient gynecomastia in adolescent boys.

Tardive dyskinesia and plasma homovanillic acid.

Using 61 patients with tardive dyskinesia (TD) and 25 normal controls, we explored the possibility that plasma HVA may reflect alterations in central dopamine activity or clinical aspects of TD. There were no significant differences between the two groups in plasma HVA level. Analyses of variance with age and sex as independent variables revealed that the major variance in plasma HVA was accounted for by age in both TD patients (p less than 0.001) and normals (p less than 0.049). Examining the TD patients alone, using multiple regression analysis, revealed that age, neuroleptic dose, and severity of TD accounted for 40% of the variance in plasma HVA in males, with age alone accounting for 28%. By comparison, females showed no association to neuroleptic dose or severity, and age only accounted for 8.9%. When severity of TD was the criterion variable, neuroleptic dose, plasma HVA, and age accounted for 20% of the variance in severity in female TD patients and showed no relationship in males. Possible implications of these differing findings in male and female TD patients are discussed.

Identification of a subgroup of tardive dyskinesia patients by pharmacologic probes.

Some patients with tardive dyskinesia fit the cholinergic-dopaminergic imbalance theory, but some do not. In an attempt to study his heterogeneity further, the authors measured the responses of 10 patients with tardive dyskinesia to intravenous challenge doses of drugs that facilitate or inhibit acetylcholine transmission (physostigmine or benztropine, respectively). They then measured the response of these patients to an open outpatient deanol trial. They found that the responses of half of the patients followed the classic theory, 2 responded paradoxically, and 3 responsed inconsistently. They suggest that there is a subgroup of tardive dyskinesia patients who fit the theory but that more research is needed to identify the subgroups who do not.

Serum prolactin and tardive dyskinesia.

The authors correlated the serum prolactin levels of 19 men with tardive dyskinesia, 29 postmenopausal women with tardive dyskinesia, and 21 men without tardive dyskinesia with the variables age, sex, antipsychotic dosage, and severity of illness. All subjects were taking antipsychotic medication. The prolactin levels of the 14 women with severe tardive dyskinesia were significantly higher than those of the 15 women with mild symptoms. The prolactin levels of the 8 men with severe tardive dyskinesia did not differ from those of the 11 men with mild symptoms. The authors discuss the sex-related association between prolactin and severity of tardive dyskinesia in the context of recent animal studies that have examined the effect of prolactin and estrogens on the striatum.

Sequence conservation in the 3'-untranslated regions of neurone-specific enolase, lymphokine and protooncogene mRNAs.

The C-terminal protein-coding and the entire 3'-untranslated regions of a cDNA corresponding to human neurone-specific enolase mRNA have been sequenced. The 3'-untranslated region is 892 bases long and shows a high degree of homology with the 3'-untranslated region of rat neurone-specific enolase mRNA. This sequence conservation is not seen in non-neuronal enolase mRNAs. Features of the conserved sequence include an A-rich region approx. 250 bases from the stop codon at a point corresponding to the polyadenylation signal site in non-neuronal enolase mRNA, and a repeating ATTT sequence. This unusual motif in eukaryotic mRNAs has previously been reported in the 3'-untranslated regions of lymphokine and protooncogene mRNAs.

Plasma prolactin and cortisol concentrations in epileptic patients during the night.

Plasma cortisol and prolactin concentrations were determined every four hours, from 8 PM to 8 AM, in 19 epileptic patients during EEG recording of sleep. Data were compared with those obtained from 12 healthy young male volunteers studied under similar conditions. Patients had normal cortisol rhythm, with peak levels at 4 AM or 8 AM and trough at midnight. A sleep-related increase in prolactin concentration was observed in all patients. The range of prolactin concentrations in the patients was also normal. Treatment with valproic acid (ten patients) and frequent abnormal EEG discharges (five patients) did not affect cortisol and prolactin secretion.

Studies of anabolic steroids: v. effect of prolonged oxandrolone administration on growth in children and adolescents with uncomplicated short stature.

A total of 130 patients with uncomplicated short stature (4 to 17 years of age) were treated with oxandrolone, 0.25 mg/kg/day, for up to four years. Oxandrolone therapy resulted in a two-fold increase in mean growth velocity in the first six months of therapy and was an effective growth stimulant for the full four-year period. There was no overall adverse effect of oxandrolone on post-treatment mean growth velocity or on skeletal maturation relative to height gain. There were 37 patients with greater increase in height age than bone age and 22 patients with greater increase in bone age than height age. Assessment of the contribution of oxandrolone therapy to the latter group is difficult because of inadequate methodology and the wide variation in individual growth patterns. Taken in their entirety, the data suggest that oxandrolone is useful in the prolonged treatment of uncomplicated short stature and is not associated with undesirable acceleration of skeletal maturation.

Prenatal sonographic diagnosis of Pena-Shokeir syndrome type I, or fetal akinesia deformation sequence.

We report on a familial case of Pena-Shokeir syndrome type I (fetal akinesia deformation sequence) born to healthy parents. The antenatal ultrasound diagnosis was based on hydramnios, restricted limb movements, decreased fetal chest movements, small chest, arthrogryposis, clubfoot, fixed extension of knees, fixed flexion of elbows, camptodactyly, kyphosis of thoracic spine, cryptorchidism, and small muscle bulk. Thymic hyperplasia was noted at autopsy.

Hypothalamic hamartoma in oral-facial-digital syndrome type VI (Váradi syndrome).

Oral-facial-digital syndrome (OFDS) type VI (Váradi syndrome) is an autosomal recessive trait of orofacial anomalies, cerebellar dysgenesis, and polysyndactyly. Developmental anomalies of the posterior fossa, including cerebellar hypoplasia and variants of the Dandy-Walker complex, are the most common central nervous system malformations reported in patients with this syndrome. We report hypothalamic hamartoma, supernumerary maxillary incisor, and precocious puberty in a boy with OFDS type VI. We propose that hypothalamic hamartoma is an occasional manifestation of OFDS type VI.

The relationship of circulating estradiol to tardive dyskinesia in men and postmenopausal women.

In order to assess the relationship between tardive dyskinesia (TD) and baseline circulating concentrations of estradiol, prolactin and homovanillic acid, we studied 43 outpatient men and postmenopausal women on chronic antipsychotic medication. Serum estradiol did not correlate with severity of TD, antipsychotic medication dose, serum prolactin or plasma HVA. Multiple regression analysis indicated a significant relationship between plasma HVA and severity of TD in postmenopausal women. These findings support the hypothesis that estrogen might serve a protective role against neuroleptic-induced striatal dopamine pathology.

Tremor and tardive dyskinesia.

A retrospective review of charts for the prevalence of tremor in patients with tardive dyskinesia revealed that 10% of 232 patients with a diagnosis of tardive dyskinesia also had parkinson-like tremor. No demographic or clinical risk factors for this tremor could be identified. The body areas affected by tremor are described, and it is suggested that tremor occurring in areas other than the wrist may pose a problem in differential diagnosis of patients with tardive dyskinesia. Changes in tremor and tardive dyskinesia after alterations in medication dose are reported, and recommendations for management are given.

Serum cortisol responses in febrile children.

Adrenocortical stress response in children with a variety of febrile illnesses was prospectively evaluated in 76 patients presenting to a general pediatric clinic with temperature greater than 101 degrees F (38.3 degrees C). Serum cortisol concentrations at presentation and again after recovery from infection were determined. Overall mean magnitude change in cortisol concentrations was 3.6-fold. Cortisol response was unrelated to the height of temperature but significant differences depending on clinical diagnosis were identified. The largest response (5-fold) was observed in patients with pneumonia, bacterial meningitis and fever of undetermined etiology. Current recommendations to double or triple replacement hydrocortisone dosage during times of increased stress in children with adrenal insufficiency are adequate only for simple febrile illnesses such as upper respiratory infection and streptococcal pharyngitis but could be subtherapeutic for infections such as pneumonia, meningitis and fever of undetermined origin, which imply a greater systemic involvement. It is possible, but untested, that a 4- to 5-fold increase in dosage would be more appropriate in those conditions.

The treatment of tardive dyskinesia with baclofen.

Thirty-one psychiatric outpatients with tardive dyskinesia (TD) on neuroleptic medication were followed in a double-blind, randomized trial comparing baclofen (30-90 mg per day) to placebo. A repeated measures analysis of variance revealed no statistical difference between the baclofen-treated group and the placebo group for the total Abnormal Involuntary Movement Scale (AIMS) scores. There was a trend (P = 0.09) for an initial improvement, then a worsening of frequency counts across four visits. The authors attempt to explain this finding on the basis of information obtained from animal research.

Natural course of 'subclinical' hypothyroidism in childhood and adolescence.

OBJECTIVES: To describe the natural course of "subclinical" hypothyroidism due to autoimmune thyroiditis in children and adolescents, and to determine whether, like euthyroid childhood autoimmune thyroiditis, it would also run a more benign course in this age group than in adults. DESIGN: Case series. SETTING: Pediatric endocrine clinic in a tertiary medical center. PATIENTS: Eighteen patients (age range, 5 to 19 years) with juvenile autoimmune thyroiditis and an initially elevated serum thyrotropin (thyroid-stimulating hormone) concentration were followed up from documentation of the elevated serum thyrotropin concentration for a mean of 5.8 years. Eleven patients never received treatment, and seven were followed up after discontinuation of therapy. MAIN OUTCOME MEASURES: Changes in the serum thyrotropin and thyroxine concentrations and thyroid gland size, as well as signs and symptoms of hypothyroidism, were monitored throughout the observation period. RESULTS: The mean duration of observation during which the patients did not receive any therapy was 47.3 months. At the end of the observation period, seven patients were euthyroid, 10 continued to have an elevated serum thyrotropin concentration with a normal serum thyroxine concentration, and one became hypothyroid. CONCLUSIONS: "Subclinical" juvenile hypothyroidism may be a benign and remitting process in many older children and adolescents. In view of the undefined risks of levothyroxine sodium therapy, it may be possible to follow up expectantly selected younger patients with a minimally elevated serum thyrotropin concentration, rather than to treat them empirically.