Double-stem silicone implant arthroplasty of all metatarsophalangeal joints in patients with rheumatoid arthritis

Double-stem silicone implants have been used to reconstruct destroyed hallux metatarsophalangeal joints (MTPJ) for many years. When smaller implants became available, they were used to reconstruct the lateral four MTPJ. An arthroplasty of all MTPJ was performed using these implants in 44 patients (72 feet) with rheumatoid arthritis (RA). The mean age of patients was 46 years (range, 21 to 66) and 84% were female. Previous surgery had been performed on 28% of the feet. All patients were followed prospectively for an average of 67 months (range, 36 to 111). The patients were evaluated clinically and radiographically; results were recorded on a standardized foot form that allowed computer analysis of the data. The results showed improvement in the hallux valgus angle from 41.6 degrees to 16.1 degrees postoperatively, with no loss of correction over time. Similarly, other forefoot deformities, such as plantar callus and lateral toe abnormalities, all improved both clinically and radiographically. The pain, walking, and function scores all improved, with the greatest improvement being pain relief. Radiographic analysis showed some evidence of fracture in seven hallux (9.7%) and nine lateral toe (3%) implants. Only three toes with implant fracture had some pain at follow-up examination. Three other lateral toe implants were removed for pain. There was no evidence of deep infection or silicone synovitis. Other complications included superficial infection, delayed wound healing, and second surgery for heterotopic bone excision.(ABSTRACT TRUNCATED AT 250 WORDS)     

Can Young People with Autism Refer to Knowledge States? Evidence from Their Understanding of "Know" and "Guess"

A number of studies have reported that most individuals with autism have difficulty in attributing mental states. The primary aim of the present study was to compare the ability of children with autism to refer to knowledge states with that of mainstream school children and children with Down's syndrome. The second aim was to investigate the role of verbal mental age in referring to knowledge states. The third aim was to compare the ease with which the children referred to their own mental state and to that of others. The results suggest that some individuals with autism are able to attribute knowledge to themselves and others but that they need to have higher verbal skills than is necessary in normal individuals. The level of language skill predicted the performance of the individuals with autism, but not that of the children in the other groups. There was no good evidence that referring to one's own mental states was easier than referring to another person's, a finding which supports representational theory rather than the simulationist position.     

Antibody-directed enzyme prodrug therapy: pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial

Antibody-directed enzyme prodrug therapy (ADEPT) was administered to ten patients in a phase I clinical trial. The aim was to measure plasma levels of the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-l-glutamic acid (CMDA) and the bifunctional alkylating drug (CJS11) released from it by the action of tumour-localised carboxypeptidase G2 (CPG2) enzyme. New techniques were developed to extract the prodrug and drug from plasma by solid-phase adsorbtion and elution and to measure CPG2 activity in plasma and tissue. All extracts were analysed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). CPG2 activity was found in metastatic tumour biopsies but not in normal tissue, indicating that localisation had been successful. The clearing agent SB43-gal, given at 46.5 mg/m², achieved the aim of clearing non-tumour-localised enzyme in the circulation, indicating that conversion of prodrug to drug could take place only at the site of localised conjugate. Plasma prodrug did not always remain above its required threshold of 3 μM for the “therapeutic window” of 120 min after dosing, but the presence of residual prodrug after the first administration of each day indicated that this could be achieved during the remaining four doses over the following 8 h. Despite considerable inter-patient prodrug plasma concentration variability, the elimination half-life of the prodrug was remarkably reproducible at 18 ± 8 min. Rapid appearance of the drug in plasma indicated that successful conversion from the prodrug had taken place, but also undesirable leakback from the site of localisation into the bloodstream. However, drug plasma levels fell rapidly by at least 50% at between 10 and 60 min with a half-life of 36 ± 14 min. Analysis of the plasma extracts by LC/MS indicated that this technique might be used to confirm qualitatively the presence of prodrug, drug and their metabolites. Received: 21 July 1996 / Accepted: 20 January 1997     

Infantile hypertrophic pyloric stenosis in a regional centre

Background  

It has been suggested that only specialist paediatric surgeons should manage infantile hypertrophic pyloric stenosis (IMPS).     

Familiar Face and Voice Matching and Recognition in Children with Autism

Relatively able children with autism were compared with age- and language-matched controls on assessments of (1) familiar voice-face identity matching, (2) familiar face recognition, and (3) familiar voice recognition. The faces and voices of individuals at the children's schools were used as stimuli. The experimental group were impaired relative to the controls on all three tasks. Face recognition and voice recognition correlated significantly with voice-face identity matching, but not with each other, suggesting that the recognition impairments jointly cause the matching impairment. Neither chronological age nor verbal mental age were consistently related to the recognition and matching impairments.     

Prenatal disruption of neocortical development alters prefrontal cortical neuron responses to dopamine in adult rats.

A growing body of evidence suggests that structural changes in the cortex may disrupt dopaminergic transmission in circuits involving the prefrontal cortex (PFC) and may contribute to the etiology of schizophrenia. In this study, we utilize a rodent model of neonatal disruption of cortical development using prenatal administration of the mitotoxin methylazoxymethanol acetate (MAM). Using intracellular recordings in vivo, we compare the physiology of prefrontal cortical neurons and their responses to topical administration of dopamine (DA) in intact animals and adult rats treated prenatally with MAM. Topical administration of DA hyperpolarized the membrane potential (MP) and decreased the firing rate of neurons recorded in deep layers of the PFC in intact animals. Furthermore, electrical stimulation of the VTA evoked fast onset epsps or long-lasting depolarizations in PFC neurons. In comparison, PFC neurons recorded in MAM-treated animals had significantly faster baseline firing rates. Moreover, topical administration of DA did not affect the MP or firing rate of the neurons in MAM-treated animals. However, MAM-treated animals exhibited an increase in the percentage of neurons responding with long-lasting depolarizations to stimulation of the VTA. The results of this study indicate that PFC neurons in the MAM-treated rats are not responsive to DA administered superficially, while at the same time exhibit greater responsiveness to VTA stimulation. These results are consistent with a rewiring of the corticolimbic system in response to neurodevelopmental insults.     

The role of Clock in the developmental expression of neuropeptides in the suprachiasmatic nucleus

The suprachiasmatic nucleus (SCN) is the dominant circadian pacemaker in mammals. To understand better the ontogeny of mouse SCN and the role of the pacemaker in peptide expression, the authors examined the distribution of cells that were immunoreactive for vasopressin (AVP) or vasoactive intestinal polypeptide (VIP) in wild type and Clock mutant mice at two developmental stages. Clock homozygous mice failed to show the dramatic increase in the number of VIP-immunoreactive (VIP-ir) neurons from postnatal day 6 (P6) to P30 that was found in the SCN of wild type mice. The number of AVP-ir neurons was relatively constant in the postnatal SCN but was significantly reduced in Clock/Clock mice. The effects of the Clock mutation varied with position in the SCN for both peptides. Densitometry of immunolabeled brains indicated that the Clock mutation reduced AVP expression specifically in the SCN and not in other brain areas. The SCN did not significantly change shape or size with age or Clock genotype. Taken together, these results indicate that the neonatal mouse SCN has its full complement of cells, some of which are not yet mature in their neuropeptide content. Furthermore, the observation that the Clock mutation appears to act on a subset of AVP and VIP cells suggests heterogeneity within these cell classes in the SCN.     

The effect of [Phe(1)psi(CH(2)-NH)Gly(2)]-nociceptin(1-13)NH(2) on feeding and c-Fos immunoreactivity in selected brain sites

Nociceptin/orphanin FQ (N/OFQ) is an endogenous ligand of the ORL1 receptor. N/OFQ, when administered centrally, stimulates feeding in a fashion similar to other opioids. Intracerebroventricular administration of N/OFQ induces changes in c-Fos immunoreactivity in several feeding-related brain sites. A synthetic pseudopeptide, [Phe(1)iota(CH(2)-NH)Gly(2)]-nociceptin(1-13)-NH(2) (hereafter: [FG]N/OFQ(1-13)NH(2)), has been labeled both as an ORL1 agonist and antagonist. The present study was designed to examine the influence of [FG]N/OFQ(1-13)NH(2) on food intake in rats. We also evaluated c-Fos immunoreactivity in those areas of the brain which have been shown to exhibit altered c-Fos expression upon N/OFQ administration. We found that [FG]N/OFQ(1-13)NH(2) increases food consumption in satiated rats. This effect is short-lasting and can be reversed by the opioid antagonist naloxone. Co-administration of [FG]N/OFQ(1-13)NH(2) does not affect orexigenic response to N/OFQ. Intracerebroventricularly-injected [FG]N/OFQ(1-13)NH(2) induces c-Fos expression in the nucleus of the solitary tract, hypothalamic paraventricular and supraoptic nuclei, central nucleus of amygdala, lateral septal and lateral habenular nuclei-brain areas that have been shown to be activated by N/OFQ. These results support the hypothesis that [FG]N/OFQ(1-13)NH(2) acts as an agonist of ORL1 receptor in vivo.