Thalidomide for improving cutaneous and pulmonary sarcoidosis in patients resistant or with contraindications to corticosteroids.

BACKGROUND: Limited data report thalidomide improves cutaneous sarcoidosis; no benefit has been reported for pulmonary localization. OBJECTIVES: To evaluate feasibility and efficacy of prolonged treatment with thalidomide for cutaneous sarcoidosis associated to pulmonary involvement in patients with resistance or contraindications to steroids. METHODS: Nineteen patients were treated with thalidomide for 24 months starting with 200 mg/d for first 2 weeks, followed by 100 mg/d for 11 weeks and a maintenance dose of 100mg on alternate days for 35 weeks, and a gradual scaling down until therapy interruption. Criteria of efficacy were: skin score, serum ACE levels (s-ACE), chest X-ray (CXR), lung function tests (LFTs), and diffusing lung capacity for CO (DLCO). The skin score was computed as arithmetic sum of seven score parameters (min: 0, max: 28). RESULTS: Skin score significantly decreased (P<0.001). Lower skin scores occurred after 3 and 6 months (P<0.05). s-ACE levels decreased over time at the third month (P<0.001). CXR assessed by radiological stage significantly improved during the first 6 months (P<0.001). DLCO showed a continuous trend of improvement. Minor side effects that have forced the suspension of the drug were drowsiness/sedation (74%), constipation (68%), and weight gain (53%). Deep vein thrombosis of the lower limbs occurred in one patient (who did not drop out the study). Eight patients (42%) abandoned thalidomide for axonal sensitive peripheral neuropathy (PN) between the ninth and the 24th month of treatment. CONCLUSIONS: Thalidomide, long-term at mid-low doses, can be considered as an effective therapeutic alternative in chronic sarcoidosis with resistance or contraindications to steroids.

Betamethasone, progesterone and RU-486 (mifepristone) exert similar effects on connexin expression in trophoblast-derived HTR-8/SVneo cells.

Connexins (Cx) are membrane proteins able to influence cell trophoblast responses, such as proliferation, differentiation, migration and invasiveness. Likewise, glucocorticoids are also known to modulate many factors involved in implantation, including trophoblast gap-junction intercellular communication, although their influence on pregnancy is controversial. In order to investigate the effects of betamethasone, a synthetic glucocorticoid, on Cx and glucocorticoid receptor (GR) expression and localisation, as well as on cell proliferation, the extravillous trophoblast-derived HTR-8/SVneo cell line was used as a model. The results, confirmed by means of immunofluorescence, demonstrate that betamethasone selectively modifies GR and Cx expression, enhancing the GRα isoform without affecting GRß, and inhibiting Cx40 expression whilst increasing that of Cx43 and Cx45. Furthermore, betamethasone was shown to exert an inhibitory action on cell proliferation. In this model the abortion drug RU-486 (mifepristone), reported to be a GR antagonist, did not counteract this effect of betamethasone. On the contrary, it induced responses similar to those of the hormone. Knowing that RU-486 is also a potent progesterone-receptor antagonist, the effect of progesterone alone and in combination with the drug on Cx expression and cell proliferation was then tested. Progesterone showed the same effect as betamethasone on Cx expression, but it did not affect proliferation. Based on these results, neither the abortion effects of RU-486 nor the protective action of betamethasone and progesterone are exerted by modulation of Cx. RU-486 did not antagonise the progesterone effect, suggesting that its abortive action does not involve alteration of trophoblast Cx expression.

Psoriasis induced by infliximab in a patient suffering from Crohn's disease.

We describe the case of a 30-year-old female with no family history of psoriasis and suffering from Crohn's disease successfully treated with infliximab at the dosage of 5 mg/kg. On the 15th week from the start of therapy, the patient developed a palmoplantar pustular psoriasis, which spread to the arms, trunk and scalp with erythematosquamous plaques. Deeming the dermatitis onset due to the anti-TNF-alpha, we decided to discontinue infliximab, while starting with a topical therapy with emollients and corticosteroids and a systemic therapy with cyclosporine. These treatments achieved a clear improvement of psoriasis after 2 months and a complete regression of skin lesions after 4 months. Several cases have been reported of psoriasis induced by anti-TNF-alpha, which have shown to exert an effective therapeutic action on this disease. The pathogenic mechanism of such a paradoxical effect has not yet been explained, though a number of hypotheses were proposed, among which one of the most intriguing is that the rapid and strong blockade of TNF-alpha could result in an enhancement of INF-alpha activity with consequent induction of psoriasis.

Functional recovery after extra-ocular muscle deafferentation in the rabbit.

The present research analysed on chronic animals the functional recovery of eye motility after impairment of the proprioceptive input at the level of the semilunar ganglion. The horizontal vestibulo-ocular reflex (HVOR) was recorded in normal pigmented rabbits before and after a partial electrolytic lesion of the semilunar ganglion. The recordings were repeated daily for 8-10 days to evaluate the recovery. Immediately after the lesion, as previously observed, HVOR slow phases were unaffected, while quick phases (QPs) showed a reduction in peak velocity and a deviation of trajectories from the horizontal plane. QP peak velocity was almost completely restored within 3-5 days, while trajectory deviation was not corrected during the observation period. Furthermore, in some animals, the variability of trajectories showed, starting from days 3-5, a progressive increase that led to a greater spatial disorganization. A process of lesion-induced plasticity takes place. but only the velocity of QPs can be recovered rapidly, while the QP trajectory impairment does not appear to be compensated substantially, which underlines a determinant role in the control of QP spatial orientation exerted by EOM proprioceptive signals.

In the centenary of the birth of Anna Maria Di Giorgio (1897-1961).

Anna Maria Di Giorgio was born on December 22nd,1897 in San Daniele del Friuli. She graduated in Natural Sciences at the University of Florence in 1921. Her career was undertaken in the Institute of Human Physiology of that University under the guide of prof. Gilberto Rossi, one of the most illustrious italian Physiologists, who was her mentor. She was the first woman to win a competition for a Universitary Professorship of Physiology. She was appointed director of the Institutes of Physiology of the Universities of Siena (1938-42) and Turin (1942-61) where she died in 1961. In the centenary of her birth it seemed worthy to commemorate prof. Di Giorgio and her scientific work. She brought fundamental contributions in the field of Neurosciences, in particular on the cerebellum, vestibular apparatus and psychophysiology of vision. She was a pioneer in showing for the first time the plasticity in the spinal cord by the end of the twenties. In addition, she discovered a nystagmogenic center in the cerebral cortex. Her physiological findings have been widely confirmed and are now patrimony of the Neurosciences.

Domenico Cotugno, a pioneer in neurosciences.

Dominico Cotugno was born in Ruvo Pugliese on January 29, 1736. In 1756, he graduated in Medicine from the Medical School in Salerno. In 1761, Cotugno published the "Aquaeductibus auris humanae internae anatomica dissertatio" ("Anatomical dissertation on acqueducts of the human inner ear") in which he provided the first detailed description of aqueducts of the vestibule and cochlea and formulated the theory of resonance subsequently resumed by Helmholtz. Cotugno gave also the first description of the naso-palatine nerve and of its role in sneezing. In 1764, he published "Commentarius de ischiade nervosa" ("Remarks on nervous ischialgia") advancing the hypothesis that some acrid fluid might penetrate the sheaths of the sciatic nerve. In 1766, he was appointed Professor of Anatomy at the University of Naples. In 1769, he published "De sedibus variolarum syntagma" ("Investigation on the localization of variola pustules"). Furthermore, he discovered albuminuria about a half century before Bright and was also one of the first scientists to identify urea in human urine. He died at the age of 86 in 1822.

Otolithic and extraocular muscle proprioceptive influences on the spatial organization of the vestibulo- and cervico-ocular quick phases.

The cervico-ocular reflex (COR) was studied alone or in combination with the vestibulo-ocular reflex (VOR) in the rabbit. Step stimulations of the body with respect to the fixed head induced small slow compensatory responses followed by large compensatory quick phases (QP). These responses remained aligned with the horizon at different head pitch angles. The QP reorientation in space was due to the gravity influence on the otolithic receptors. The vestibular induced QPs exhibit a similar pattern. Because of this reorientation, the reduction of the amplitude of the vestibular induced QPs, due to the addition of the COR, was maintained even at different static head positions. The electrolytic lesion of the ophthalmic branch of the trigeminal nerve deeply affected the space orientation of the COR. In particular, the cervically induced compensatory QPs of the eye ipsilateral to the lesion showed a remarkable variability of their trajectories and they lost space reorientation. These findings suggest that the coordinate system controlling the QPs is influenced by signals originating from both head position in space and eye position in the orbit.

Luciani's work on the cerebellum a century later.

In 1891, Luigi Luciani published his famous monograph on the cerebellum and formulated his triad of the cerebellar symptoms: atonia, asthenia and astasia, which explained all troubles provoked by cerebellar lesions; later he added a fourth sign, dysmetria. In spite of the fact that it was advanced in a pre-electrophysiological period, Luciani's interpretation of the cerebellar role in many motor functions survives more than a century later and his terminology has entered the routine of the neurological examination. With the modern knowledge of cerebellar circuitries, we can state that Luciani rightly pointed out the role of the cerebellum in regulating postural tone and muscular force, and that conversely he was wrong in denying cerebellar influence in co-ordination of multi-joint movements and the somatotopic localizations in the cerebellar cortex and nuclei. In spite of this, Luciani's work represents a milestone in cerebellar physiology.

Influence of the extraocular muscle proprioceptors on the orientation of the vestibulo-ocular reflex.

In the intact brain lamb, unilateral electrolytic lesion of the medial dorso-lateral portion of the semilunar ganglion containing the first order neurons of the eye muscle proprioception induced modifications of the horizontal and vertical vestibulo-ocular reflex (HVOR and VVOR) which consisted in marked alterations of the trajectories of the quick phases, while the slow phases were scarcely affected. Similar results were observed after section of the branches described by Winckler in the retrobulbar region along the extraocular muscle proprioceptive information travels. These findings extend those of previous investigations carried out in decorticate animals.

Positive action of propionyl-L-carnitine on mechanical performance of papillary muscle from Syrian hamsters with hereditary dilated cardiomyopathy.

Propionyl-L-carnitine has been shown to exert a beneficial effect on cardiac function in different experimental models of cardiomyopathy in the rat, most likely by improving cardiac metabolism and energy production. We have previously shown that, in a strain of hamsters with hereditary dilated cardiomyopathy (BIO TO.2), the mechanical activity of papillary muscle (length-tension, velocity of shortening, shortening, work and power relationship) is significantly depressed when compared to the same parameter in normal hamsters (BIO F1.B). The repeated oral treatment with propionyl-L-carnitine (60 mg/kg per os for 7 weeks) to BIO TO.2 hamsters had a significant positive inotropic effect, as indicated by an increase in developed tension up to the levels observed in papillary muscles from normal hamsters. This action is most likely associated with metabolic effects similar to those observed in rats.

Extraocular muscle proprioception and eye position.

In the lamb, acute unilateral section of the ophthalmic branch induced in the ipsilateral eye occasional oscillations of the resting position and misalignment of the horizontal vestibulo-ocular reflex (HVOR) with respect to the stimulus. Additional electrolytic lesion of the cells innervating the proprioceptors of the medial rectus muscle, or of the lateral rectus muscle in the contralateral semilunar ganglion, provoked a 4 degrees-7 degrees consensual eye deviation towards and away from the lesioned side, respectively. The optokinetic beating field was similarly deviated. Under these experimental conditions, HVOR showed enhanced gain and marked misalignment in both eyes. Therefore, the selective suppression of muscular proprioceptive input deviated both eyes towards the direction opposite to the muscle whose gangliar proprioceptive representation has been destroyed.

[The choice of substrates in total parenteral nutrition]. / La scelta dei substrati in nutrizione parenterale totale.

This review contains a full outline on the choice of substrates in total parenteral nutrition (NPT). The basic properties of "conventional" substrates (glucose, long chain triglyceride-containing fat, common amino acid mixtures) are used to outline the general principles for NPT support in normal conditions and in stress (surgical and nonsurgical trauma, sepsis). Without taking into account factors which are not strictly metabolic (vascular access, local availability of products, costs), particular attention is then paid to "non-conventional" substrates and substrate mixtures, including some under study, with specific reference to properties and features which may motivate their choice.

Botulinum A toxin effects on rat jaw muscle spindles.

Botulinum A toxin (Botox) is used for the treatment of many muscular dystonias. However, the relief of the sustained and abnormal postures induced by Botox administration is not fully explained. In this work the possibility was considered that Botox can produce a block not only at the alpha motor endings, but also at the gamma motor endings, consequently reducing the spindle inflow to the alpha motoneurons, which have a great role in maintaining the tonic myotatic reflex. Jaw muscle spindle discharge was recorded before and after Botox injection in the deep masseter muscle. The drug consistently reduced the spindle afferent discharge. Such an effect is suggested to be direct on gamma endings as: i) muscle tension was not modified by Botox during the recording time; ii) saline administration never changed the spindle discharge. The Botox effect on muscle spindles suggests that the relief from dystonias could be due not only to a partial motor paralysis, but also to a decrease of the reflex muscular tone.

[The definition of a reference protocol for the clinical study of vertigo drugs]. / Definizione di un protocollo quadro per lo studio clinico di farmaci antivertiginosi.

The aim of this paper is to define the problems that arise in the clinical evaluation of drugs for the treatment of vertigo. Among these are the objective criteria used in defining vertigo and those used in evaluating efficacy of the drugs. The resulting protocol for a clinical study of vestibular drugs is a document that clarifies the debated points in the field, and above all furnishes guidelines for establishing uniformity in clinical studies. This, therefore, may become the reference protocol in Italy for clinical evaluations of drugs for the treatment of vertigo.

Peripheral territory and neuropeptides of the trigeminal ganglion neurons centrally projecting through the oculomotor nerve demonstrated by fluorescent retrograde double-labeling combined with immunocytochemistry.

The peripheral territories of sheep trigeminal neurons which send their central process to the brainstem through the oculomotor nerve were investigated by the use of fluorescent tracers in double-labeling experiments. For this purpose Diamidino yellow (DY) injection into the oculomotor nerve was combined with Fast blue (FB) injection either into the extraocular muscles (EOMs), or the cornea, or the superior eyelid. Double-labeled DY + FB cells were found in the ophthalmic region of the trigeminal ganglion in addition to single-labeled DY or FB cells. The DY and DY + FB-labeled trigeminal cells were analysed immunocytochemically for their content of substance P (SP)-, calcitonin gene-related peptide (CGRP)-, and cholecystokinin-8 (CCK-8)-like. All single-labeled DY cells showed SP-, CGRP- or CCK-8-like immunoreactivity. Double-labeled DY + FB neurons innervating the EOMs were immunoreactive for each of the three peptides, whereas double-labeled neurons supplying the cornea were only CGRP-like positive. The findings suggest that, in the sheep, trigeminal neurons which send their process centrally through the oculomotor nerve supply the EOMs, the cornea, and the superior eyelid and contain neuropeptides which are usually associated with pain sensation.