Childhood-onset Huntignton´s disease. A rare presentation. / Enfermedad de Huntington de inicio en la infancia. Una presentación poco frecuente.

INTRODUCTION: Huntington's disease (HD) is a rare autosomal dominant disease caused by the expansion of CAG triplets in the gene that encodes huntingtin. There are earlier symptoms' onset in offspring due to the phenomenon of anticipation. The clinical features of childhood-onset HD, before age 10 years, differs from adult-onset form. It is characterized by motor impairment, behavioral difficulties and delay or regression in areas of development; while chorea is rarely seen. In this case we describe clinical aspects of a patient with childhood-onset Huntington's disease. CASE REPORT: A 5-year-old girl with a family history of HD and typical development up to 3 years of age. She progressively acquired language impairment with skills that were below her age in expressive and receptive areas, without deficits in pragmatic and social skills. Regarding motor skills, she manifested instability at walking and standing, with rigidity, dystonia and choreic movements. Atrophy of the basal ganglia was evident on MRI, EEG was normal, and molecular confirmation of CAG triplet revealed repeat length of 51 copies. CONCLUSION: Childhood-onset HD differs from adult-form´s clinical manifestations. It should be considered in patients with progressive motor and cognitive impairment. Due to family inheritance, it is important to carefully examine family history and take it into account even without relatives affected, considering the anticipation phenomenon.

TITLE: Enfermedad de Huntington de inicio en la infancia. Una presentación poco frecuente.Introducción. La enfermedad de Huntington (EH) es una enfermedad de herencia autosómica dominante caracterizada por la expansión de tripletes de citosina-adenina-guanina (CAG) en el gen que codifica la huntingtina. Los síntomas en la descendencia suelen ser más tempranos por el fenómeno de anticipación. La clínica de inicio en la infancia, antes de los 10 años, difiere de la observada en la adultez. Se manifiesta por afectación motora, dificultades conductuales y retraso o regresión del desarrollo. La corea es infrecuente. El objetivo del caso es describir aspectos clínicos de una paciente con EH de inicio infantil. Caso clínico. Niña de 5 años con antecedentes familiares de EH y desarrollo típico hasta los 3 años. Presentó progresivamente afectación del lenguaje con habilidades descendidas para su edad en aspectos expresivos y comprensivos, sin afectación en las habilidades pragmáticas y sociales. En cuanto a la motricidad, la marcha y la bipedestación eran inestables, y mostraba rigidez, distonía y movimientos coreicos. Presentó atrofia de los núcleos lenticulares y caudados en la resonancia magnética, y posteriormente se realizó el diagnóstico molecular con la expansión de tripletes CAG (51 copias). Conclusión. La EH de inicio en la infancia presenta manifestaciones clínicas distintas a la forma del adulto. Debe considerarse en pacientes con afectación motora y cognitiva progresiva. Por la herencia familiar, es importante interrogar cuidadosamente sobre los antecedentes familiares y tenerla en cuenta aun sin familiares afectados por el fenómeno de anticipación.

Pharmacologic treatment of the dysfunctional patient.

It is common knowledge that therapeutical approach of temporomandibular disorders (TMD) is multidisciplinary and directed to remove the cause of disorder, to eliminate symptomatology and to make an improvement to patient's life. Most of the subjects observed have pain, often caused by muscular component (90-95%) and rarely by the intercapsule. Generally, it deals with chronic-ache, bound by a layer of stress and by considerable emotionalism. A correct diagnosis is the indispensable requirement for the drugs prescription, not only, but remarkable is: to attach importance to the knowledge of workings action, the side effects and active principals contraindications took into account. This article will be a question of medicines which are the basis of medical therapy for temporal-jaw excess with: analgesic, antinflammatory, short-relaxing and tranquillizer, tricyclical antidepressant and local anesthetic. As regards to TMD, notice that pharmacological therapy must not be over protracted for too much time, especially for use of benzodiazepine and tricyclic antidepressants, dosage demanded are decisively less if we compare, usually main therapeutical indications. The pharmacological therapy can be an agent for competent method for symptomatology treatment of temporal-jaw disorder but, patient must be acquainted about a fact, trouble often could not disappear only with a drug. To conclude, we can assert that the right use of medicines, in addition with physiotherapeutical therapy and an occlusal splint, represent the most efficient means to deal with the majority of temporal-jaw diseases.

Long-term therapeutic efficacy and toxicity of recombinant interferon-alpha 2a in polycythaemia vera.

We report on long-term therapeutic efficacy and toxicity of recombinant interferon-alpha 2a (rIFN-alpha) in a series of 38 patients with polycythaemia vera (PV). In all patients haematocrit was first brought into the normal range by venesection; rIFN-alpha was then begun at a starting weekly dose of 9,000,000 IU. Complete response (CR) was defined as persistence of normal haematocrit without venesection and partial response (PR) as >50% reduction of phlebotomy requirement. Eleven patients (28.9%) achieved CR and 8 (21.0%) PR. Median duration of treatment for all responsive patients was 40 months; 12 patients are still responsive and under treatment after 13, 15, 25, 35, 40, 41, 43, 49, 50, 51, 52 and 52 months of therapy with rIFN-alpha. In responsive patients, rIFN-alpha also normalized leucocyte counts, platelet counts and spleen enlargement; rIFN-alpha also relieved generalized pruritus in all 10 patients displaying this symptom. Early toxicity (flu-like syndrome) was observed in 23.6% and late toxicity (severe weakness) in 13.1% of patients, requiring rIFN-alpha treatment suspension in all cases. Progression to leukaemia was observed in none of the 10 patients treated only with rIFN-alpha and in one of the 12 who received alkylating agents before enrolment in this study. According to these data, rIFN-alpha seems to be an effective and safe treatment option for PV.

Cytokine effect on ex vivo expansion of haemopoietic stem cells from different human sources.

Human pluripotential stem cells (PSC) are currently the target for transplantation attempts and genetic manipulation. We have therefore investigated the frequency and the expansion potential of PSC's in different types of blood samples. CD 34+ cells were thus obtained from human bone marrow (BM), as well as from peripheral blood (PB) and cord blood (CB) samples. After immuno-magnetic separation the highest yields of CD 34+ cells were from BM (1.08-2.25%) and CB (0.42-1.32%) while PB samples gave much lower values. Suspension cultures of PSC's from the three sources were then set up, in the presence of combinations of haemopoietic growth factors. A remarkable amplification of the nucleated cell pool was observed reaching a maximum between 10 and 15 days of culture; earliest and maximum expansion (up to 220-fold) was achieved when Erythropoietin (Epo) was added to the culture medium, but this resulted in reduction of colony-forming cells and differentiation into erythroid progenitors. Clonogenic tests for BFU-E's derived colonies showed a peak value at 5 days of liquid culture. Further studies are advisable to establish the best cytokine combination for a valuable ex vivo expansion, coupled with preservation of stem cell properties.

Hemodilution reduces clinic and ambulatory blood pressure in polycythemic patients.

Limited information is available for humans on whether blood viscosity affects total peripheral resistance and, hence, blood pressure. Our study was aimed at assessing the effects of acute changes in blood viscosity on both clinic and 24-hour ambulatory blood pressure (BP) values. In 22 normotensive and hypertensive patients with polycythemia, clinic and 24-hour ambulatory BPs were measured before and 7 to 10 days after isovolumic hemodilution; this was performed through the withdrawal of 400 to 700 mL of blood, with concomitant infusion of an equivalent volume of saline-albumin solution. Hematocrit, plasma renin activity, plasma endothelin-1, right atrial diameter (echocardiography), and blood viscosity were measured under both conditions. Plasma renin activity and right atrial diameter were used as indirect markers of blood volume changes. Plasma endothelin-1 was used to obtain information on a vasomotor substance possibly stimulated by our intervention, which could counteract vasomotor effects. Isovolumic hemodilution reduced hematocrit from 0.53+/-0.05 to 0.49+/-0.05 (P<.01). Plasma renin activity, plasma endothelin-1 and right atrial diameter were unchanged. Clinic blood pressure was reduced by hemodilution (systolic, 144.3+/-5.4 to 136.0+/-3.9 mm Hg[mean+/-SEM]; diastolic, 87.0+/-2.8 to 82.1+/-2.6 mm Hg, P<.05 for both) and a reduction was observed also for 24-hour average ABP (systolic, 133.6+/-2.9 to 129.5+/-2.7 mm Hg; diastolic, 80.0+/-2.0 to 77.3+/-1.7 mm Hg, P<.05 for both). The reduction was consistent in hypertensive patients (n = 12), whereas in normotensive patients (n = 10) it was small and not significant. Both clinic and 24-hour average heart rates were unaffected by the hemodilution. Thus, in polycythemia, reduction in blood viscosity without changing blood volume causes a significant fall in both clinic and 24-hour ambulatory BPs; this is particularly true when, as can often happen, blood pressure is elevated. This emphasizes the importance this variable may have in the determination of blood pressure and the potential therapeutic value of its correction when altered.

Cytokine effect on ex vivo expansion of haemopoietic stem cells from different human sources.

Human pluripotential stem cells (PSC) are currently the target for transplantation attempts and genetic manipulation. We have therefore investigated the frequency and the expansion potential of PSC's in different types of blood samples. CD 34+ cells were thus obtained from human bone marrow (BM), as well as from peripheral blood (PB) and cord blood (CB) samples. After immuno-magnetic separation the highest yields of CD 34+ cells were from BM (1.08-2.25%) and CB (0.42-1.32%) while PB samples gave much lower values. Suspension cultures of PSC's from the three sources were then set up, in the presence of combinations of haemopoietic growth factors. A remarkable amplification of the nucleated cell pool was observed reaching a maximum between 10 and 15 days of culture; earliest and maximum expansion (up to 220-fold) was achieved when Erythropoietin (Epo) was added to the culture medium, but this resulted in reduction of colony-forming cells and differentiation into erythroid progenitors. Clonogenic tests for BFU-E's derived colonies showed a peak value at 5 days of liquid culture. Further studies are advisable to establish the best cytokine combination for a valuable ex vivo expansion, coupled with preservation of stem cell properties.

Polycythemia vera treated with recombinant interferon-alpha 2a: evidence of a selective effect on the malignant clone.

We periodically analyzed bone-marrow cytogenetic features in 8 patients belonging to a series of 38 subjects with polycythemia vera (PV), all treated with recombinant interferon-alpha 2a (rIFN-alpha) at a weekly dose of 9,000,000 IU. Six out of these 8 patients never showed any chromosome alterations, while 2 displayed at diagnosis the presence of trisomy 8 in all bone-marrow metaphases. Interestingly enough, in these 2 patients rIFN-alpha treatment was able to induce not only complete hematological response but also the disappearance of trisomy 8, as shown by conventional cytogenetic investigation and fluorescence in situ hybridization performed on bone-marrow cells after 1 year of treatment. This finding indicates that, as previously shown in chronic myeloid leukemia, in PV rIFN-alpha can also eradicate the malignant clone by means of a selective effect on bone-marrow transformed cells.

Role of interferon alpha-2a in the treatment of polycythemia vera.

We studied the effects of recombinant interferon alpha-2a (IFN-alpha) in 36 patients with polycythemia vera (PV) previously treated with phlebotomy and/or conventional cytostatic agents. In each patient, after at least 2 months of discontinuation of any cytotoxic therapy, the hematocrit (Hmt) was first brought to normal value by phlebotomy; IFN-alpha treatment was then begun at a starting dose of 3,000,000 IU s.c. three times a week. Response to treatment, which was assessed monthly, was defined as persistent normalization of Hmt without concomitant phlebotomy; in non-responsive patients the initial IFN-alpha weekly dosage was progressively increased. Twenty patients were responsive with a median duration of response of 7 months (range 2-25+ months); out of these, 7 patients are still under treatment and responsive at 13+, 17+, 20+, 22+, 23+, 25+, 25+ months. These findings indicate that a cohort, although small, of patients with PV (19.4%) are persistently sensitive to IFN-alpha; in this subset of patients, this cytokine can therefore provide a useful treatment option, since, contrary to conventional therapeutic approaches such as radioactive phosphorus, cytostatic agents, or phlebotomy, IFN-alpha is devoid of harmful side effects.

In vitro sensitivity of human erythroid progenitors to hemopoietic growth factors: studies on primary and secondary polycythemia.

BACKGROUND: Primary proliferative polycythemia is a clonal disease characterized by excessive hemopoiesis and associated with a lower than normal erythropoietin plasma level; in vitro colony studies may reveal increased sensitivity of the abnormal clone to hemopoietic growth factors. MATERIALS AND METHODS: We studied the in vitro formation of erythroid colonies (BFU-E derived clone) in cultures set up with a serum-free medium and containing Epo, interleukin 3 (IL-3) and stem cell factor (SCF), in various combinations. The clonogenic test was performed by plating non adherent mononuclear cells from the peripheral blood of normal subjects and from patients with PPP and secondary polycythemia (SP). RESULTS: SCF is a major amplifier of erythroid colony growth, in the presence of Epo; in cultures from PPP patients, however, the presence of SCF, in addition to Epo, enhances colony formation at about the same rate as in cultures from normal subjects. When SCF is omitted, the presence of even modest amounts of Epo and IL-3 is sufficient to obtain a statistically significant difference between colony formation from PPP patients on the one side, and SP patients and normal subjects on the other. CONCLUSIONS: Our results show that in vitro culture studies may contribute an additional diagnostic criterion for distinguishing between PPP and SP in uncertain cases. It is also possible that hypersensitivity to erythropoietic factors may play a role in the pathogenetic mechanism of primary proliferative polycythemia.

Evaluation of hypothalamic-pituitary function in patients with thalassemia major.

The increased survival of patients with thalassemia major, made possible by more adequate therapeutic regimens, has emphasized the importance of the endocrine abnormalities often associated with this disease. In twelve thalassemic patients, we evaluated the hypothalamic-pituitary function by measuring plasma levels of anterior pituitary hormones under basal conditions and in the course of provocative tests. An impairment of growth hormone (GH) secretion was demonstrated in a considerable proportion (7/12) of these patients. In some of them failure of GH response to insulin-hypoglycemia and normal hormone rise after growth hormone-releasing hormone indicate a hypothalamic defect. A defective prolactin secretion was observed in the female hypogonadic but not in the male thalassemic patients. This abnormality appears to be dependent on estrogen deficiency rather than on a hypothalamic-pituitary dysfunction. In our series a high prevalence (8/12) of hypogonadism was also noticed. In these cases, the low gonadotropin levels and their unresponsiveness to gonadotropin-releasing hormone are compatible with a hypothalamic and/or pituitary damage. Lastly, the enhanced ACTH responses to the stimuli associated to a reduced cortisol release suggest the existence, in these patients, of a diminished adrenocortical reserve. On the whole, this study has shown several derangements of the hypothalamic-pituitary function in thalassemia. This emphasizes the need for careful endocrine surveillance in this disease.

Relevance of red cell distribution width (RDW) in the differential diagnosis of microcytic anaemias.

The authors studied the red cell distribution width (RDW) index (obtained by Coulter Counter S Plus IV) in normal subjects and in patients with beta-thalassaemia trait and iron deficiency anaemia. Statistics and reference limits for the above three conditions are given. In order to make a differential diagnosis between beta-thalassaemia trait and iron deficiency anaemia, linear discriminant analysis was carried out. Global correct classification was 91.5% on our first sample of patients and 88.8% on a subsequent validation sample of microcytic patients. The percent of correct beta-thalassaemia trait diagnoses was 94.4% and 86.7% for the first and validation samples respectively. For iron deficiency anaemia correct diagnoses of 86.2% and 90.9% were achieved.

[Early postoperative enteral nutrition and total parenteral nutrition. Technics compared in patients undergoing radical surgery for carcinoma of the large intestine. Preliminary report]. / Nutrizione enterale precoce postoperatoria (NEPPO) e nutrizione parenterale totale (NPT). Tecniche a confronto in pazienti sottoposti a chirurgia demolitiva per carcinoma del grosso intestino. Nota preliminare.

A preliminary study has been carried out on 10 patients suffering from cancer of the colon and rectum, all subjected to radical surgery. The clinical effectiveness of two alternative techniques of postoperative artificial nutrition, EPEN and TPN, are compared. The results confirm that enteral nutrition is technically applicable and well tolerated in the immediate post-operative period in these patients; it also presents a lower cost, it is more manageable and present a lower incidence of complications compared to TPN while offering similar metabolic and nutritional results.

Causes of death in essential mixed cryoglobulinemia.

Ninety-three patients with essential mixed cryoglobulinemia have been followed for more than 5 years in 75% of cases; 21 patients died during this period and the mean age at death was 54 years. The most common cause of death was renal failure. The percentages of patients who survived after 5 and 10 years from the diagnosis were 87 and 74%, respectively. The cryoglobulin type seems to be an important prognostic factor: in our population the type II/III ratio is 6/7 at diagnosis, while it becomes 2/1 when the patients who died are considered.

Plasma cyclic nucleotide levels in patients with homozygous beta-thalassaemia.

To investigate the possibility that a proliferative non-neoplastic process influences extracellular cyclic nucleotide concentrations, we measured plasma cyclic AMP and cyclic GMP levels in 38 patients with homozygous beta-thalassaemia. This group consisted of 20 patients with thalassaemia major transfused regularly (mean pre transfusion Hb levels, 11 g/dl), and 18 patients with thalassaemia intermedia who did not require regular blood transfusion (mean Hb levels, 8.7 g/dl). In the patient group, plasma cyclic AMP levels were similar to those of 37 normal subjects matched for age and sex, whereas plasma cyclic GMP levels were markedly higher. Moreover, in the thalassaemic patients there was a significant negative correlation between plasma cyclic GMP levels and haemoglobin concentrations, suggesting that their marked erythroid hyperplasia may play a role in determining alterations in extracellular cyclic GMP levels.

Treatment with sulfinpyrazone of essential mixed cryoglobulinemia.

Platelet production time (PPT), circulating platelet aggregates (CPA ratio) and plasma beta-thromboglobulin (beta TG) were determined in patients with essential mixed cryoglobulinemia (EMC) before and after two months' treatment with sulfinpyrazone. Sulfinpyrazone determined a clinical improvement in 8 of the 16 patients. Basal PPT and CPA ratio were reduced compared with normal values but not significantly; after sulfinpyrazone treatment both PPT and CPA ratio increased to normal levels. High plasma beta TG levels were found before and after treatment. These data suggest that in some cases of EMC there is a picture of in vivo platelet activation, but with the small number of patients it was not possible to evaluate a possible correlation between platelet hyperactivity and the clinical picture.

Unusual bone marrow hyperplasia in a case of thalassemia intermedia.

A case of beta thalassemia intermedia is described. Beside the typical hematologic picture and extramedullary erythropoiesis in the liver always present in such a clinical form, atypical masses due to foci of erythropoiesis were found at paravertebral, parasternal and subcostal sites. The size of these masses caused problems in differential diagnosis; they have been solved by computerized axial tomography.

The importance of the genetic picture and globin synthesis in determining the clinical and haematological features of thalassaemia intermedia.

Twelve carriers of thalassaemia intermedia were studied. Their clinical and haematological picture was distinctly different from that in both heterozygotes and homozygotes for beta thalassaemia. Several genetic patterns were found responsible for thalassaemia intermedia: beta/delta beta thalassaemia, alpha 2 beta/beta thalassaemia-heterocellular HPFH. In a few subjects the genetic picture indicated that the patients were homozygous for beta thalassaemia, in spite of the mildness of the clinical situation. The lack of genetic uniformity was refelcted in very wide Hb A2 (2.5--8.7%) and Hb F (7.5--96.9%) ranges, as opposed to the noticeable degree of biochemical uniformity indicated by the very similar imbalance of globin chain synthesis: 0.33-0.54 for the non-alpha/alpha chain ratio in the peripheral blood. The mean for this parameter (0.43 +/- 0.05) was significantly different (P less than 0.001) from that observed in heterozygous carriers (0.60 +/- 0.10) and homozygous carriers (0.11 +/- 0.05) for beta thalassaemia. The marrow blood displayed a comparable pattern. It is therefore suggested that the severity of thalassaemia is attributable to the degree of chain synthesis imbalance.