Asymptomatic Achilles, patellar, and quadriceps tendinopathy: a longitudinal clinical and ultrasonographic study in elite fencers.

Lower limb tendon changes detected at imaging are common among asymptomatic athletes. We aimed to prospectively assess the clinical status, tendon structure, and vascularity of lower limb tendons of elite fencers, and predict the risk of developing symptoms over time. Clinical examination, changes at ultrasonography (US), and Power Doppler (PD) flow of both the Achilles, patellar, and quadriceps tendon were assessed in 37 elite fencers in January 2007 and 3 years after. Two hundred and twenty-two tendons were examined. At the last appointment, patellar tendons diagnosed as abnormal at baseline were more likely to develop symptoms than those normal at baseline (P < 0.05, Fisher's exact test), while US and PD abnormalities on Achilles and quadriceps tendons were no predictive for development of symptoms over years. A very low percentage of tendons diagnosed as normal at baseline (1.45%) showed US abnormalities at 3-year follow-up. In asymptomatic elite fencers, structural changes are relatively common at US and PD assessment of Achilles, quadriceps, and patellar tendons. It seems unlikely that additional PD investigations provide further information or change prognosis in patients with US diagnosis of tendinopathy.

Novel atypical antipsychotic agents: rational design, an efficient palladium-catalyzed route, and pharmacological studies.

Using rational drug design to develop atypical antipsychotic drug candidates, we generated novel and metabolically stable pyrrolobenzazepines with an optimized pK(i) 5-HT(2A)/D(2) ratio. 5a, obtained by a new palladium-catalyzed three-step synthesis, was selected for further pharmacological and biochemical investigations and showed atypical antipsychotic properties in vivo. 5a was active on conditioned avoidance response at 0.56 mg/kg, it had low cataleptic potential and proved to be better than ST1899, clozapine, and olanzapine, representing a new clinical candidate.

Pyrrolo[1,3]benzothiazepine-based serotonin and dopamine receptor antagonists. Molecular modeling, further structure-activity relationship studies, and identification of novel atypical antipsychotic agents.

Recently we reported the pharmacological characterization of the 9,10-dihydropyrrolo[1,3]benzothiazepine derivative (S)-(+)-8 as a novel atypical antipsychotic agent. This compound had an optimum pK(i) 5-HT(2A)/D(2) ratio of 1.21 (pK(i) 5-HT(2A) = 8.83; pK(i) D(2) = 7.79). The lower D(2) receptor affinity of (S)-(+)-8 compared to its enantiomer was explained by the difficulty in reaching the conformation required to optimally fulfill the D(2) pharmacophore. With the aim of finding novel atypical antipsychotics we further investigated the core structure of (S)-(+)-8, synthesizing analogues with specific substituents; the structure-activity relationship (SAR) study was also expanded with the design and synthesis of other analogues characterized by a pyrrolo[2,1-b][1,3]benzothiazepine skeleton, substituted on the benzo-fused ring or on the pyrrole system. On the 9,10-dihydro analogues the substituents introduced on the pyrrole ring were detrimental to affinity for dopamine and for 5-HT(2A) receptors, but the introduction of a double bond at C-9/10 on the structure of (S)-(+)-8 led to a potent D(2)/5-HT(2A) receptor ligand with a typical binding profile (9f, pK(i) 5-HT(2A)/D(2) ratio of 1.01, log Y = 8.43). Then, to reduce D(2) receptor affinity and restore atypicality on unsaturated analogues, we exploited the effect of specific substitutions on the tricyclic system of 9f. Through a molecular modeling approach we generated a novel series of potential atypical antipsychotic agents, with optimized 5HT(2A)/D(2) receptor affinity ratios and that were easier to synthesize and purify than the reference compound (S)-(+)-8. A number of SAR trends were identified, and among the analogues synthesized and tested in binding assays, 9d and 9m were identified as the most interesting, giving atypical log Y scores respectively 4.98 and 3.18 (pK(i) 5-HT(2A)/D(2) ratios of 1.20 and 1.30, respectively). They had a multireceptor affinity profile and could be promising atypical agents. Compound 9d, whose synthesis is easier and whose binding profile is atypical (log Y score similar to that of olanzapine, 3.89), was selected for further biological investigation. Pharmacological and biochemical studies confirmed an atypical antipsychotic profile in vivo. The compound was active on conditioned avoidance response at 1.1 mg/kg, a dose 100-times lower than that required to cause catalepsy (ED(50) >90 mg/kg), it induced a negligible increase of prolactin serum levels after single and multiple doses, and antagonized the cognitive impairment induced by phencyclidine. In conclusion, the pharmacological profile of 9d proved better than clozapine and olanzapine, making this compound a potential clinical candidate.

[Lethal neurological involvement during incontinentia pigmenti]. / Atteinte neurologique létale au cours d'une incontinentia pigmenti.

INTRODUCTION: We present a case of incontinentia pigmenti associated with lethal neurological involvement. CASE REPORT: A newborn, three day-old female child presented with an erythromatous vesicular eruption and epileptic seizures secondary to extensive necrosis of the brain tissue. She died at 13 days of age following a seizure. The genetic analysis concluded in a sporadic case of incontinentia pigmenti. DISCUSSION: Thirty-eight cases of incontinentia pigmenti, associated with severe brain damage have been reported in the literature. The neurological manifestations appear rapidly after birth in the form of epilepsy. The seizures can lead to severe psychomotor retardation and, in most cases, precede the installation of motor deficiency. The lesions observed on imaging are hypodensity of varying localization and which do not correspond to any vascularization pattern. Autopsy reveals areas of brain tissue destruction. Recent genetic data suggest two physiopathological hypotheses, which both rely on NF-Kb dysfunction. The cutaneous cells expressing muted chromosome x exhibit a reduced rate of free NF-kB and are more sensitive to the apoptotic signals. Like the cutaneous cells, the brain tissue cells expressing muted chromosome x may be eliminated when becoming apoptotic. Furthermore, NF-kB is one of the links of the transduction system of the messages received by the VEGF receptor, the endothelial growth factor. A perturbation of the transmission of this message might alter cerebral microvascularization.

Pyrrolo[1,3]benzothiazepine-based atypical antipsychotic agents. Synthesis, structure-activity relationship, molecular modeling, and biological studies.

The prototypical dopamine and serotonin antagonist (+/-)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine (5) was resolved into its R and S enantiomers via crystallization of the diastereomeric tartaric acid salts. Binding studies confirmed that the (R)-(-)-enantiomer is a more potent D(2) receptor antagonist than the (S)-(+)-enantiomer, with almost identical affinity at the 5-HT(2) receptor ((S)-(+)-5, log Y = 4.7; (R)-(-)-5, log Y = 7.4). These data demonstrated a significant stereoselective interaction of 5 at D(2) receptors. Furthermore, enantiomer (S)-(+)-5 (ST1460) was tested on a panel of receptors; this compound showed an intriguing binding profile characterized by high affinity for H(1) and the alpha(1) receptor, a moderate affinity for alpha(2) and D(3) receptors, and low affinity for muscarinic receptors. Pharmacological and biochemical investigation confirmed an atypical pharmacological profile for (S)-(+)-5. This atypical antipsychotic lead has low propensity to induce catalepsy in rat. It has minimal effect on serum prolactin levels, and it has been selected for further pharmacological studies. (S)-(+)-5 increases the extracellular levels of dopamine in the rat striatum after subcutaneous administration. By use of 5 as the lead compound, a novel series of potential atypical antipsychotics has been developed, some of them being characterized by a stereoselective interaction at D(2) receptors. A number of structure-activity relationships trends have been identified, and a possible explanation is advanced in order to account for the observed stereoselectivity of the enantiomer of (+/-)-5 for D(2) receptors. The molecular structure determination of the enantiomers of 5 by X-ray diffraction and molecular modeling is reported.

A controlled study on the effects of hyperthermia at 434 MHz and conventional ultrasound upon muscle injuries in sport.

BACKGROUND: Hyperthermia equipment using a 434 MHz applicator with water bolus elevate to therapeutic temperatures (from 41 to 45 degrees C) delineated volumes of tissue target, down to a depth of 3 to 5 cm. The aim of our study was to evaluate the efficacy of hyperthermia in the treatment of muscle injuries, in comparison with a conventional modality like ultrasound. METHODS: A prospective randomised controlled design was used. Forty patients, 29 males and 11 females, with mean age of 26.2+/-3 ranging between 18 and 35 years affected by acute muscular injuries of different sites and severity participated this study. Twenty-one patients received hyperthermia (group A) and the remaining 19 (group B) ultrasound. Both groups received nine applications, three times per week with a duration of 30' for the group (A), and 15' for the group (B). All the patients underwent a clinical examination including a pain measurement and a ultrasound scanning before, at the end and after one month follow-up. An additional ultrasonography was made after the fourth session to compare the effect of each treatment on the initial course of haematoma resolution. RESULTS: Both groups had a significant decrease of the pain (p< 0.001). The hyperthermia group showed a significantly higher effect on VAS score and on haematoma resolution after two weeks of treatment. CONCLUSIONS: Even with a limited number of cases our results show that the hyperthermia is a highly innovative, safe and reliable modality for the treatment of acute sport muscle injuries.

[Pseudoainhum in lamellar ichthyosis]. / Pseudoaïnhum au cours d'une ichtyose lamellaire.

INTRODUCTION: Pseudoainhum is an affection characterized by the appearance of a constricting band around a digit or limb which may lead to spontaneous amputation. There are various etiologies which can be either congenital or resulting from a concomitant disease. We report herein an original case which occurred during lamellar ichthyosis. CASE-REPORT: We present the case of a thirty-year-old woman affected by a severe form of lamellar ichthyosis who, in a few months, developed a pseudoainhum of the third left finger. Biological results were normal. X-rays of this finger showed distal resorption of the bone. The painful evolution and the absence of any conservative treatment compelled us to propose amputation of the third phalanx. DISCUSSION: Other cases of pseudoainhum have been observed in many disease responsible for vascular or neurological abnormalities. They can also result in physical traumatisms or be associated with many dermatoses, such as hereditary palmar and plantar keratodermas. As far as we know, this lesion has never been described during lamellar ichthyosis but could result in the keratinization disorders observed in this congenital ichthyosis.

The significance of the 'dust-like particles' pattern of immunofluorescence. A study of 66 cases.

Subacute cutaneous lupus erythematosus (SCLE) is a marker of a unique subset of lupus erythematosus patients. A 'dust-like particles' direct immunofluorescence (DIF) staining pattern, which consists of fine granular particles of immunoglobulin(s) scattered through the epidermis and the cellular infiltrates of the dermis, was reported to be specific for SCLE. In this study, we assessed the real specificity of this staining pattern, which had not yet been evaluated. We systematically searched for the dust-like particles staining pattern among the 4374 skin biopsy specimens submitted for direct cutaneous immunofluorescence during a 7-year period (1989-96). The corresponding patient records were reviewed. Dust-like particles were observed in 66 samples originating from 60 patients. Only 53% of the patients had SCLE. The remaining patients had systemic lupus erythematosus with visceral involvement (17%), discoid lupus erythematosus (3%), mixed connective tissue disease (2%). Sjögren syndrome (2%) and other diseases. Eighty-five per cent of the patients had connective tissue disease. Seventy-seven per cent of the patients were positive for antinuclear antibodies, but only 36% were positive for anti-Ro (SSA) antibodies. This study shows that the dust-like particles staining pattern is not specific for SCLE, but is highly suggestive of connective tissue disease. The nature of the antigen responsible for the immunoglobulin deposition and the prognostic significance of this DIF pattern remain to be established.