Central effects of systemic lidocaine mediated by glycine spinal receptors: an iontophoretic study in the rat spinal cord

The objective of this investigation was to demonstrate the possible interactions of systemic lidocaine (lido) with inhibitory receptors in the spinal cord. In the lumbar dorsal horn of anesthetized and curarized rats, 60 physiologically identified, wide dynamic range (WDR) neurons, were recorded extracellularly. Glutamate, glycine and its selective antagonist, strychnine, were iontophoretically applied onto the neurons either singularly or concurrently. The effects of systemic lido on the drug-induced frequency changes and the interaction with the glycine receptors, using strychnine as a probe, were studied. It was consistently found that (i) lido (3–4 mg/kg) inhibited the excitatory responses to iontophoretic glutamate, (ii) this inhibition was significantly antagonized by concurrent iontophoretic strychnine, (iii) iontophoretic glycine induced comparable glutamate inhibition that was reversed by strychnine. In contrast, no effect on glutamate-induced excitations was observed when lido was applied by micropressure or a different local anesthetic was systemically administered. The results suggest that central inhibitory effects of lido could by mediated by spinal strychnine-sensitive glycine receptors, activated by lido itself or possibly by its glycine residue-bearing metabolites.     

Use of ultrasound to assess healing of a mandibular distraction wound.

PURPOSE: A standardized, noninvasive technique to assess healing of the mandibular distraction wound is not available. Current methods include clinical examination, plain radiography, and computed tomography. These imaging techniques are expensive and obligate the patient to serial radiation exposure. In addition, anatomic overlap and metal artifacts may obscure the distraction gap. In contrast, ultrasound has been shown to be a noninvasive, efficient, and inexpensive way to evaluate bone healing. The purpose of this study was to test the feasibility of ultrasound to evaluate an experimental mandibular distraction osteogenesis wound. MATERIALS AND METHODS: Distraction devices were placed via a submandibular incision into 24 minipigs. The protocol consisted of 0-day latency and distraction rates of 1, 2, or 4 mm/d for a 12-mm gap. The wounds were assessed in vivo after 0, 8, 16, and 24 days of neutral fixation. Ex vivo radiographs were used to estimate bone fill using a semiquantitative score. A semiquantitative ultrasound score was assigned, and the beam penetration depth was measured in millimeters. RESULTS: In all groups, clinical stability of the distraction wound increased with the duration of fixation. Plain radiographs, taken during neutral fixation, showed that the desired distraction gap was achieved and maintained. The ultrasound score increased with fixation time, whereas beam penetration depth decreased as expected. Ex vivo radiographs showed increasing bone fill score with time and paralleled the ultrasound score. CONCLUSIONS: The results of this feasibility study indicate that ultrasound is potentially useful for the assessment of bone formation in distraction osteogenesis wounds.     

Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an Italian series of patients affected by Paget's disease of bone (PDB).

PDB is genetically heterogeneous. Mutations of the sequestosome1 gene have been reported in sporadic and familial forms of Paget's in patients of French Canadian and British descent. Mutational analyses in different ethnic groups are needed to accurately investigate hereditary diseases. We describe two novel mutations of sequestosome1 in 62 Italian sporadic patients, confirming the role of the encoded protein in this disorder. INTRODUCTION: Paget's disease of bone (PDB) is a relatively common disease of bone metabolism reported to affect up to 3% of whites over 55 years of age. The disorder is genetically heterogeneous, and at present, there is scientific evidence that at least eight different human chromosomal loci are correlated with its pathogenesis. Mutations of the sequestosome1 (SQSTM1) gene were identified as responsible for most of the sporadic and familial forms of Paget in patients of French Canadian and British descent. Such mutations were located at exon 7 and 8 levels, encoding for the ubiquitin protein-binding domain (UBA) and representing a mutational hot spot area. MATERIALS AND METHODS: To verify the involvement of this gene in Italian subjects affected by PDB, we performed mutational analysis in 62 sporadic PDB cases. RESULTS: We described three different mutations at exon 8 level: P392L, already described in the French Canadian population and families predominantly of British descendent, and two novel mutations consisting of the amino acid substitutions M404V and G425R. No significant differences in the clinical history of PDB have been observed in patients with SQSTM1 mutations in respect to those without. CONCLUSIONS: Even though our findings suggest a minor involvement of the SQSTM1 gene in the pathogenesis of sporadic Italian Paget's cases, the identification of different significant mutations within the SQSTM1 gene in unrelated, but clinically similar individuals, offers extremely convincing evidence for a causal relationship between this gene and PDB. Longitudinal studies are needed to assess the penetrance of genotype/phenotype correlations. Our findings confirm the evidence of a clustered mutation area at this level in this disorder.     

Carvedilol protects ischemic cardiac mitochondria by preventing oxidative stress.

Ischemia negatively affects mitochondrial function by inducing the mitochondrial permeability transition (MPT). The MPT is triggered by oxidative stress, which occurs in mitochondria during ischemia as a result of diminished antioxidant defenses and increased reactive oxygen species production. It causes mitochondrial dysfunction and can ultimately lead to cell death. Therefore, drugs able to minimize mitochondrial damage induced by ischemia may prove to be clinically effective. We analyzed the effect of carvedilol, a beta-blocker with antioxidant properties, on mitochondrial dysfunction. Carvedilol decreased levels of TBARS (thiobarbituric acid reactive substances), an indicator of oxidative stress, which is consistent with its antioxidant properties. Regarding cell death by apoptosis, although ischemia did increase caspase-8-like activity, there were no changes in caspase-3-like activity, which is activated downstream of caspase-8; this may indicate that the apoptotic cascade is not activated by 60 minutes of ischemia. We conclude that carvedilol protects ischemic mitochondria by preventing oxidative mitochondrial damage, and, by so doing, it may also inhibit the formation of the MPT pore.     

An unusual association with Raynaud's phenomenon

A 36-yr-old lady with a year of typical Raynaud's and polyarthralgiahad a normal examination other than cold peripheries and bloodpressure of     

Age-related changes in the turnover rates of D1-dopamine receptors in the retina and in distinct areas of the rat brain

The steady-state density and the turnover rates of D₁-dopamine receptors were investigated in the striatum, nucleus accumbens, substantia nigra, and retina of adult (3-month-old) and aged (23-month-old) rats. The turnover rates were measured by monitoring the repopulation kinetics of D₁-dopamine receptors labeled with [³H]-SCH 23390 after the irreversible inactivation induced by a single dose of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 10 mg/kg, s.c.). In all the neural tissues examined, the repopulation of D₁ dopamine receptors could be adequately described by a theoretical model that assumes a constant rate of receptor production (i.e. zero order) and a rate of degradation that is dependent on the receptor density at any time (i.e. first order). The results obtained indicate that the reduction in the density of D₁-dopamine receptors in the striatum, nucleus accumbens and substantia nigra of aged rats is the result of a larger decrease in the receptor production rate (−44 to −60%) than in the receptor degradation rate (−21 to −46%). By contrast, the production rate of D₁-dopamine receptors in the retina of aged rats remains unchanged, whilst the degradation rate is reduced by 25%. This results in an age-related increase in the density of D₁-dopamine receptors in the rat retina.     

Power calculation for cohort studies with improved estimation of expected numbers of deaths

Summary This paper focuses on improving the accuracy of sample size calculations for cohort studies by careful calculation of the expected number of deaths in the population, taking into account either prior information or realistic assumptions about variables which may affect the mortality or incidence. Sometimes small changes in the assumptions can dramatically alter the expected numbers and may necessitate modifications in the design of the study. Possible modification include extension of the follow-up time, and recognition that the real strength of the study may lie in the potential for pooling several similar studies. The problem will be discussed with reference to two examples of occupational cohort studies where differing prior information was available.

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Zusammenfassung Diese Arbeit beschäftigt sich mit der Genauigkeit der Berechnung des Stichprobenumfangs in Kohortenstudien, wenn detaillierte Berechnungen für die erwartete Zahl der Verstorbenen berücksichtigt werden. Dies kann entweder durch die Ausnutzung vorhandener Informationen oder durch realistische Annahmen über die Faktoren, die Mortalität oder Inzidenz beeinflussen, geschehen. Schon kleine Unterschiede in diesen Annahmen kann die erwartete Zahl der Verstorbenen erheblich verändern und es notwendig machen, das Design einer Studie zu verändern. Solche Modifikationen bestehen z.B. in der Verlängerung der Follow-up Zeit der Studie oder in der Einsicht, dass es nötig ist, Daten aus mehreren Studien zusammenzufassen. Die Probleme werden anhand von zwei Beispielen aus dem Bereich der Berufsepidemiologie diskutiert.

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Résumé Cet article concerne la précision des estimations de taille d'échantillons pour les études de cohortes. Le calcul précis du nombre de décès attendus dans la population prend en compte les variables susceptibles d'affecter la mortalité ou l'incidence, provenant soit d'une connaissance préalable, soit d'hypothèses réalistes. De modestes changements d'hypothèses peuvent parfois altérer de façon substantielle les nombres attendus et nécessiter des modifications dans le protocole de l'étude. Parmi les modifications possibles, il faut citer la prolongation du temps de suivi de l'étude ainsi que le constat que la valeur réelle de l'étude pourrait reposer sur la possibilité de mise en commun de plusieurs études similaires. Le problème est discuté à l'aide de deux exemples d'études de cohortes professionnelles pour lesquelles différentes informations préalables sont disponibles.