Smad7 positively regulates keratinocyte proliferation in psoriasis.

BACKGROUND: Transforming growth factor (TGF)-ß1 exerts inhibitory effects on keratinocyte proliferation. OBJECTIVES: To examine whether Smad7, a known inhibitor of TGF-ß1 signalling, is involved in psoriasis-associated keratinocyte hyperproliferation. METHODS: Smad7 was evaluated in skin sections of patients with psoriasis and healthy controls and in mice with Aldara-induced skin pathology by real-time polymerase chain reaction and immunohistochemistry. To assess whether Smad7 positively regulates in vivo keratinocyte growth, mice treated with Aldara received daily cutaneous administration of Smad7 antisense oligonucleotide (AS). Keratin (K)6 and K16, cell-cycle-associated factors, cell-cycle and cell proliferation were evaluated in HaCaT cells either treated with Smad7 AS or transfected with Smad7 plasmid and in mice given Smad7 AS. RESULTS: Smad7 was highly expressed in keratinocytes of patients with psoriasis and of mice treated with Aldara. In HaCaT cells, Smad7 knockdown inhibited cell growth, reduced K6 and K16 expression and promoted accumulation of cells in the S-phase of the cell cycle. Smad7-deficient keratinocytes exhibited reduced levels of CDC25A protein, a phosphatase that facilitates progression of cells through the S-phase, and hyperphosphorylation of eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, Smad7 overexpression in HaCaT cells was followed by induction of K6 and K16 and increased cell proliferation. Topical application of Smad7 AS to Aldara-treated mice reduced epidermal thickness. CONCLUSIONS: Our data show that Smad7 is overexpressed in human and murine psoriasis and suggest a key role of this molecule in the control of keratinocyte proliferation.

Predictive factors of callosotomy in drug-resistant epileptic patients with a long follow-up.

Some possible factors to predict outcome after callosotomy were investigated in a personal series composed of 36 patients. Twenty-seven of them were submitted to anterior callosotomy, 1 to posterior callosotomy and the remaining 8 patients to two stage complete division of corpus callosum. All factors, either positive or negative, do not appear completely reliable; they can be envisaged only in relative terms and do not seem to be relevant to make surgical decision or to discard surgery. In author's series, dealing specifically with drop-attacks, it clearly appeared that abrupt falls to the ground unpreceded by other epileptic features did definitely better. This was the only statistically significant datum.

Modifications in morphology of epileptic seizures after callosotomy.

The callosotomy on drug-resistant epileptic seizures may abolish or reduce their frequency and may modified the morphology of different kind of seizures. Our series is composed of 36 patients. Drop-attacks and complex partial seizures (CP) were present in all patients, generalized tonic-clonic seizures (GTC) in 16 (44.4%) and simple partial seizures (SP) and myoclonic attacks (MY) in 6 patients each. We found two kinds of modifications: a) lateralization of hypotonia which becomes hemisomatic, with lateral bending to the hypotonic side; b) different way of falling, due not only to the lateralization of hypotonia but also to the gradual impairment of muscle tone. Modifications in CP mainly concerned automatisms, which disappeared in 39.1% of patients, while 34.8% of them had a significant reduction in automatisms; this reduction consisted in simplification of automatic movements and in shorter duration of seizures.

EEG Patterns after callosotomy.

In 36 patients with drug-resistant epilepsy submitted to anterior callosotomy (27 cases), to two-stage total callosotomy (8 cases) and to posterior callosotomy (1 case) the EEG variations concerning background activity, focal activity and sharp-waves (SW) bisynchronous activity were evaluated. EEG modifications observed after callosotomy are the following: background rhythm tends to be better organised as spectral analysis demonstrated, this finding usually coincide with reduction of bisynchronous discharges. It appears that improvement in background activity cannot be correlated with outcome, but it seems to be to some extent since at the same time cognitive functions also seem to improve; however, this last aspect need to be checked in much larger series. The number and location of EEG foci do not change, but they appear to be more active; this is likely to depend only on the concomitant reduction of bisynchronous activity. No correlation seems to exist between the number and the location of foci, which are generally multiple. Lateralization of bisynchronous discharges as well as the reduction of their frequency and duration were observed. However, the clinical course is quite different: in some patients we have achieved good clinical responses in others postoperative results were poor. Lateralization of bisynchronous discharges is never absolute, on the grounds that in prolonged recordings bisynchronous discharges are nearly always present. Bisynchronous discharges in some cases are alternatively predominant in both hemispheres even within minutes or seconds. It was observed that after certain time, generally some months, lateralized discharges tend to generalize again, confirming that corpus callosum is replaced in discharge diffusion by other structures (brain-stem, diencephalon).

Mutism in 36 patients who underwent callosotomy for drug-resistant epilepsy.

Thirty-six drug-resistant epileptic patients submitted to callosotomy were studied. Anterior callosotomy was performed in 27 patients, total two-stage callosotomy was performed in 8 patients and 1 patient had only posterior callosotomy. We found mutism in 10 patients (2 after complete callosotomy and 8 after anterior section). The patients did not speak, but the comprehension was present: they were able to carry out orders and to write. Their attitude to the environment was characterized by complete indifference. The mutism was always transient, lasting from 4 to 25 days (mean 7 days). Regression of mutism was always complete. We think that this complication should be chiefly attributed mainly to surgical manipulation, even if it is impossible to completely exclude a multi-factorial etiology.

Evolution of neuropsychological changes after partial callosotomy in intractable epilepsy.

Early neuropsychological changes following partial anterior callosotomy were evaluated in 15 patients with epilepsy (10 secondary generalized and 5 Lennox-Gastaut syndromes) by comparing their performances 1 month before surgery and then 15-20 and 90-100 days postoperatively without modifying the anticonvulsant treatment. The following neuropsychological and motor functions were tested: memory, attention, visuo-motor ability, posture, motor dexterity, language, praxis and gnosis. Social behaviour was also investigated. The main results are as follows: (i) most cognitive functions showed no significant variation; (ii) motor organization was still slightly impaired at the second check-up after the surgery; (iii) improvements in social behaviour and posture were frequently observed at the final evaluation. The analysis of individual cases highlights the influence of the extent of commissurotomy, lesions related to the surgical procedure and preoperative brain damage in determining the post-surgical profile. On this basis, the short-term neuropsychological cost of partial callosotomy appears to be low and seems to depend mostly on surgical parameters and brain conditions before the operation.

Callosotomy for the management of intractable non-focal epilepsy: a preliminary personal assessment.

After reviewing the data of the literature, the authors report their personal series composed of twelve cases. In evaluating the results of surgical treatment only the first ten patients are taken into account. As previously stressed in the literature, callosotomy (total in two cases and anterior in the remainder) has proved effective in abolishing or significantly reducing atonic seizures. Tonico-clonic seizures have also benefitted in some cases, while in complex partial and partial seizures the effects of callosotomy have been so far unpredictable, albeit in some patients all kinds of seizures have been abolished or definitely reduced. The most impressive EEG and neuropsychological features after callosotomy are briefly summarized. Anterior callosotomy seems to be a relatively safe procedure, its results appear to be, on the whole, gratifying even though in patients with severe mental retardation and Lennox-Gastaut syndromes remain controversial.

[Remarks on callosotomy in the treatment of drug-resistant epilepsy]. / Remarques sur la callosotomie dans le traitement de l'épilepsie pharmaco-résistante.

In this report 17 patients with long-standing non-focal epilepsy underwent callosotomy (this was total in two patients and performed in two stages, and anterior-subtotal in the remaining patients). In all patients the atonic-hypertonic seizures with sudden falls were the most disabling epileptic fits. Callosotomy proved efficient in controlling atonic fits in 10 out of 15 patients in whom surgical results are evaluated. In 3 additional patients the frequency of atonic fits was reduced by more than 50%. In the remaining two patients, no therapeutic effect was observed. Callosotomy was less effective on seizures which were not atonic. Therefore, this procedure appears to be indicated in patients in whom atonic fits are predominant. The main effect of callosotomy is to transform drug-resistant seizures into drug-sensitive ones. Neuropsychological sequels are insignificant unless the splenium is severed. However, considerable psychic and behavioral improvement was nearly always observed after surgery. Despite the fact that on a therapeutic level results were often satisfactory, a number of practical problems still remain. These concern the full spectrum of indications for callosotomy, the extent of corpus callosum section, choice of methods in severely mentally retarded patients and, finally, the age at which the operation should be carried out.

Ichthyosis accompanied by neurological symptoms with special reference to epilepsy.

5 patients with ichthyosis had a neurological accompaniment: epilepsy in 4, congenital palpebral ptosis, facial pain and neurosis in 1. In one patient epilepsy was combined with multiple malformations (normal dwarfism, prematurely old face, skeletal abnormalities) and oligophrenia. There was considerable variability genetically: 2 sporadic cases, 1 with X-linked transmission, 1 with autosomal dominant and 1 with apparent autosomal recessive heredity. In one case the co-existence of glucose-6-phosphate dehydrogenase deficiency provided proof of X-linked transmission. Further study of larger case-series is needed for a better definition of the nosographic and genetic aspects of non blastomatous neuroectodermatoses in which ichthyosis figures.

[Neurological complications in drug dependence with special reference to the development of epileptic syndromes]. / Complicanze neurologiche nelle tossicodipendenze, con particolare riguardo all'insorgenza di sindromi epilettiche.

33 drug abusers were examined and all of them were addicts to several drugs and always to heroin. Neurological complications occurred rather frequently. One patient had subarachnoid hemorrhage and angiography showed no arteriovenous malformations nor other pathology. Polyneuropathy has been found in one case. 7 patients (21,2%) developed psychotic episodes. Epileptic attacks were found in 5 cases (15,1%). Latency between the onset of drug-abusing and occurrence of the attacks was found to be at least 1 year in two cases and 3 years in the other three. 4 cases suffered from partial complex seizures with secondary generalization and one patient had generalized tonic-clonic attacks. Fits occurred rarely in all cases; one patient had two episodes of partial status. Further research is required because there are few clinical reports in comparison with the experimental ones.

[Clinical and CT aspects of muscular dystonias]. / Aspetti clinici e TC nelle distonie muscolari. Clinical and CT aspects of torsion dystonias.

Clinical, EMG, genetic and CT investigations were performed on 16 subjects suffering from Torsion Dystonia. We obtained the following results: i) genetically most cases were sporadic, only two could be considered autosomic dominant; ii) one of the pedigrees, with many patients, confirmed that spasmodic torticollis is not a distinct form from that of Dystonia Muscolorum Deformans; the two forms must be included in one disease called "Torsion Dystonia", as maintained by some Authors; iii) we found that the various drugs employed, rarely produced improvement, although benzodiaze4pines have given some benefit; iv) CT findings were not specific, though useful for differential diagnosis.

CT and EEG investigations in 100 patients with multiple sclerosis (MS).

100 MS patients were followed up for an average of 5 years. We considered age at onset, duration of the disease, number of attacks, neurological and psychic status, CT and EEG findings and tried correlating the last two with all the previous factors. In remission the most frequent CT abnormality was diffuse atrophy. In acute exacerbations there were 3 possibilities: normality, hypodensity and, much more rarely, hyperdensity with pseudotumoral patterns. A normal CT and short duration of disease were positively correlated with a small number of attacks. There were no positive correlations between CT findings, age at onset and neurological and psychic status. EEG, like CT, may show no changes in a high percentage of cases but there is scant correlation between the two.

[Genetic, polyphysiographic, CT and therapeutic aspects (author's transl)]. / Aspetti genetici, polifisiografici, TC e terapeutici in un caso di encefalopatia mioclonica familiare con particolari caratteristiche cliniche.

Genetic, clinical, polyphysiographic and therapeutical aspects were investigated in a 37 year old patient suffering from: sporadic and localized segmentary myoclonia (present during rest and increasing slightly during movement), cerebellar syndrome, marked hypoacusia, hyper-reflexia of the lower limbs, spike and polyspike EEG discharges and massive myoclonia during photostimulation. A dominant autosomic inheritance of this syndrome was suggested by the occurrence of a more serious and rapid, yet similar, illness in the mother and by EEG alterations in an 8 year old son. The Authors suggest that, from the clinical point of view, they are dealing with an atypical Ramsay-Hunt syndrome (MCD) with signs of Pierre-Marie Heredoataxia. This supports the possibility, however rare, of intermediate forms between MCD and Heredoataxia. The patient underwent polyphysiographic investigations under the following conditions: i) without therapy; ii) with diphenylhydantoin; iii) with phenobarbital; iv) with sodium dipropyl-acetate; v) with clonazepam. The above investigations confirmed the previously described alterations, during wakefulness or sleep, observed in cases of Unverricht-Lundborg syndrome (PME) and Ramsay-Hunt syndrome (MCD). Clonazepam was found to be the most effective drug in attenuating myoclonia, in reducing the EEG spike activity and in reorganizing the phases and cycles of sleep.