Inherited disorders of the extracellular matrix

Primary and secondary defects in extracellular matrix proteins emphasize the role of these proteins in neuromuscular disorders; mutations have been found in the genes for the laminin-alpha 2 chain, for all three alpha chains of collagen VI and for integrin alpha 2. Secondary alterations in protein expression occur in association with these primary defects, and in other disorders they implicate the extracellular matrix. Animal models are helping to elucidate the function of some of these proteins, to develop therapeutic strategies and to suggest candidate proteins for other neuromuscular disorders.     

Mesenteric cystic neoformations: Report of two cases

(Received for publication on Apr. 28, 1997; accepted on May 15, 1998)     

Lasting reduction in mesolimbic dopamine neuronal activity after morphine withdrawal

The activity of mesolimbic dopaminergic neurons was investigated in rats at various times after a chronic regimen of morphine, which produced, upon suspension, a marked somatic withdrawal syndrome. Single-cell extracellular recording techniques, coupled with antidromic identification from the nucleus accumbens, were used to monitor neuronal activity while behavioural observations allowed quantification of the somatic signs of morphine withdrawal. Temporal correlation of electrophysiological indices, such as firing rate and burst firing, with scores obtained through behavioural assessments proved negative, in that somatic signs were pronounced at 24 h after suspension of treatment and then subsided to control values at 72 h after the last morphine injection. In contrast, the firing rate and burst firing of mesolimbic dopaminergic neurons were found to be reduced at 1, 3 and 7 days after morphine withdrawal. After 14 drug-free days, electrophysiological analysis revealed an apparent normalization of various parameters. However, at this time, intravenous administration of morphine produced an increment of electrical activity which was significantly higher than that obtained in control (saline treated) rats. Further, administration of the opiate antagonist naltrexone, administered without prior morphine, at 3, 7 and 14 days after the last morphine administration, failed to alter dopaminergic neuronal activity. The results indicate: (i) that the activity of mesolimbic dopaminergic neurons remains reduced well after somatic signs of withdrawal have disappeared; (ii) after 14 days of withdrawal, the augmented magnitude of the electrophysiological response to exogenous morphine suggests an increased sensitivity of opiate receptors; and (iii) the lack of relationship between dopaminergic activity and somatic signs of withdrawal corroborates the notion that dopaminergic activity in the mesolimbic system does not participate in the neurobiological mechanisms responsible for somatic withdrawal. The present results may be relevant to the phenomenon of drug addiction in humans and consequent relapse after drug-free periods.     

Clinical spectrum and diagnostic difficulties of infantile ponto-cerebellar hypoplasia type 1

We present the clinical and histopathological features and the diagnostic difficulties encountered in five children affected by a motor neuron disorder other than spinal muscular atrophy. Investigations performed suggested the diagnosis of ponto-cerebellar hypoplasia type 1 (PCH-1). Severe respiratory difficulty was present at birth in two of these children; hypotonia, arthrogryposis, microcephaly and nystagmus were present in all. Early and progressive bulbar involvement with swallowing difficulties and stridor was also a common feature in these infants. Severe cognitive delay was invariably present. Brain magnetic resonance imaging showed ponto-cerebellar hypoplasia in four children while striking atrophy of the cerebellar vermis and cerebellar hemispheres were present in the fifth child. Electrophysiological and pathological investigations of proximal muscles performed at presentation in all these children were not conclusive, while the post-mortem studies, or the study of distal muscles during life, showed a clear neurogenic picture. Genetic studies excluded involvement of the SMN gene, or of other genes located on chromosome 5q, confirming that ponto-cerebellar hypoplasia type 1 is a different entity from typical proximal spinal muscular atrophy.     

Aesthetic considerations in facial reconstructive surgery: The V-Y flap revisited

The subcutaneous pedicled V-Y advancement flap (also known as the kite flap of Dufourmentel) has been described by many authors. Its versatility in reconstructive surgery is well known, both in facial reconstructive surgery as well as surgery of the trunk and extremities. Its advantages in achieving aesthetic reconstruction in specific facial regions have been less well emphasized in the literature. The flap can be designed within natural facial creases and heals inconspicuously because of its widely based subcutaneous or muscle pedicle which incorporates venous and lymphatic drainage over most of its length. The undesirable biscuiting or flap edema frequently observed with other conventional transposition flaps is avoided. We have found the V-Y flap particularly useful in reconstructing the lower eyelid/medial canthus, supra-alar, and nasolabial regions. Our experience with over 40 such flaps is described, and technical considerations in designing and elevating the flap are discussed.     

Chemotherapy as first treatment for primary malignant non-Hodgkin's lymphoma of the central nervous system preliminary data

Non-Hodgkin's lymphoma of the central nervous system (NHL-CNS) is thought to account for about 1 % of primary brain tumours. Radiation therapy has mainly been applied to treat cerebral lymphoma, but the low cure rate and the lack of enduring response have stimulated the search for alternatives. With the aim of postponing radiotherapy as long as possible, we tested the efficacy of a M-BACOD schedule administered immediately after histological diagnosis in 14 patients. After two M-BACOD courses 10 (71%) patients displayed an objective response (i.e. were apparently tumour-free when examined by CT). In 6 (60%) M-BACOD-responsive patients, radiotherapy was delayed for 5 months (without recurrences after a follow-up ranging from 9 to 18 months). Moreover, in 3 M-BACOD-responsive patients, no recurrence took place (even without radiotherapy) after a follow-up of 6–12 months. We conclude that radiation can be postponed after chemotherapy or delayed until tumor recurrence.This paper was presented at the 3rd Meeting of the European Neurological Society, Lausanne, 27 June–1 July, 1992     

Noradrenaline transport by rat heart sympathetic nerves: A re-examination of the role of sodium ions

Summary The effect of sodium ion on ³H-(–)-noradrenaline (0.0875 to 0.5 M) transport by rat heart atrial hemi-appendages incubated in vitro has been studied, and the following observations made: a) When sodium was omitted (choline and lithium substitution) there was no evidence for active noradrenaline transport, and only a component that did not show saturation kinetics up to 1 M noradrenaline, remained. b) Omission of sodium or addition of 4×10^–5 M desipramine inhibited noradrenaline transport to exactly the same extent, and their effects were not additive. Alprenolol did not reduce this sodium-independent transport, but tropolone lowered it somewhat. c) No evidence for corticosterone-sensitive noradrenaline transport (uptake-2) was found in this preparation at the low amine concentrations used. d) In control medium, the kinetic parameters of transport were: K _m: 0.59 ± 0.063 M and V _max: 2.44 ± 0.43 (pmoles/mg protein/min). With 26 mM sodium and the rest substituted by choline, K _m:2.26 ± 0.70 M (P0.001) and V _max: 2.74 ± 0.43 (pmoles/mg protein/min) (not significant). Also with 26 mM sodium, but with sucrose substitution, K _m: 0.76 ± 0.13 M (N.S.) and V _max: 1.06 ± 0.13 (pmol/mg/min) (P<0.05). Such results indicate that sodium only modifies the affinity of the transport system for noradrenaline, without changing V _max, and that changes in the latter are only a consequence of a reduction of the ionic strength. e) When noradrenaline transport was studied at different concentrations of external sodium, at constant ionic strength and with precautions to minimize the noradrenaline-releasing effect of low sodium, it was found that the data could be best represented by two hyperbolas placed in series. This suggests that the noradrenaline carrier has two sites for sodium, that do not interact with each other. When the same experiments were repeated in the absence of chloride, it was found that the noradrenaline transport system had lost virtually all its affinity for sodium. f) The effect of prolonged tissue incubation in the absence of sodium was found to produce a relatively small inactivation of noradrenaline transport. Such phenomenon was enhanced by raising the calcium concentration to 2 mM.     

Non-occupational risk factors for adult soft-tissue sarcoma in northern Italy

The role of socioeconomic and anthropometric indicators, tobacco, alcohol consumption, dietary habits, and medical history in the etiology of soft-tissue sarcoma (STS) was examined in a hospital-based case-control study, conducted in the Friuli-Venezia Giulia region of northeast Italy, between 1985 and 1990. A total of 88 STS cases (53 males and 35 females; median age: 52 years) and of 610 controls (306 males and 304 females; median age: 54 years) were interviewed. There were significant excess risks associated with a history of herpes zoster infection (odds ratio [OR]=2.4,95 percent confidence interval [CI]=1.1–5.3), chicken pox (OR=2.2, CI=1.2–4.3) and mumps in childhood (OR=2.0, CI=1.1–3.9). History of diabetes was also linked to a nonsignificant increase in STS risk (OR=1.8, CI=0.6–5.4), whereas exposure to radiation for diagnostic or therapeutic purposes was not related to the probability of developing STS. None of the investigated socioeconomic and anthropometric indicators seemed to affect STS risk; neither did tobacco smoking, nor consumption of alcohol, coffee, and tea beverages. Conversely, among the dietary habits investigated, a significant positive association emerged with an increasing frequency of consumption of dairy products (% MathType!MTEF!2!1!+-% feaafeart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXafv3ySLgzGmvETj2BSbqefm0B1jxALjhiov2D% aebbfv3ySLgzGueE0jxyaibaiiYdd9qrFfea0dXdf9vqai-hEir8Ve% ea0de9qq-hbrpepeea0db9q8as0-LqLs-Jirpepeea0-as0Fb9pgea% 0lrP0xe9Fve9Fve9qapdbaqaaeGacaGaaiaabeqaamaabaabcaGcba% Gaae4XdmaaCaaaleqabaGaaGOmaaaaaaa!3DA2!\[{\rm{\chi }}^2\]for trend=6.8, P<0.01) and oil (% MathType!MTEF!2!1!+-% feaafeart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXafv3ySLgzGmvETj2BSbqefm0B1jxALjhiov2D% aebbfv3ySLgzGueE0jxyaibaiiYdd9qrFfea0dXdf9vqai-hEir8Ve% ea0de9qq-hbrpepeea0db9q8as0-LqLs-Jirpepeea0-as0Fb9pgea% 0lrP0xe9Fve9Fve9qapdbaqaaeGacaGaaiaabeqaamaabaabcaGcba% Gaae4XdmaaCaaaleqabaGaaGOmaaaaaaa!3DA2!\[{\rm{\chi }}^2\]for trend=4.3, P<0.05), while a negative association was seen for intake of whole grain bread and pasta (OR for highest cf lowest tertile=0.4, CI=0.2–0.9).Support for this project was contributed by the Italian Association for Cancer Research, Milan, and the Italian National Research Council (CNR Applied Project Oncology, Contract 87.01544.44).     

Skeletal muscle involvement in infantile systemic hyalinosis

Infantile Systemic Hyalinosis is a rare autosomal recessive entity, characterised by deposition of hyaline material in skin and bone, often complicated by visceral involvement. The characteristic features are marked delay in motor milestones attributed to severe progressive flexion contractures of proximal and distal joints, and skin and mucosal hypertrophy and thickening, followed by failure to thrive. Pain secondary to osteolytic lesions is also a predominant feature. We report a patient with Infantile Systemic Hyalinosis, confirmed by the clinical findings, who also displayed clear evidence of proximal muscle weakness. Muscle biopsy revealed myopathic changes, which have not been reported previously. We suggest that skeletal muscle is involved in Infantile Systemic Hyalinosis and contributes to the characteristic poor outcome of these patients.