SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis.

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.

[The evaluation of the time of gastric radio-isotopic emptying in subjects with non-insulin dependent diabetes mellitus]. / Valutazione dei tempi di svuotamento gastrico radio-isotopico in soggetti con NIDDM in terapia con cisapride.

Abnormal gastro-intestinal motility is a well-recognized complication of autonomic neuropathy in diabetics; delayed gastric emptying is frequently documented. Various pharmacologic agents have been used to treat this complication such as cisapride. We have evaluated the effects of cisapride on gastric emptying in nine diabetic patients with autonomic neuropathy through radio-scintigraphic method. Gastric emptying diabetic patients was significantly prolonged compared control subjects (p < 0.01). In our study cisapride increased gastric emptying, but this did not reach statistical significance. We concluded that cisapride may be considered as a good alternative in cases where limited efficacy or side effects preclude the use of metoclopramide.

[Effects of fenoverine on biliary kinetics evaluated by hepatobiliary scintigraphy with 99mTc-Br-IDA]. / Effetti della fenoverina sulla cinetica biliare valutata con scintigrafia epatobiliare con 99mTc-Br-IDA.

Hepatobiliary scintigraphy was used to evaluate the action of fenoverine in 16 patients suffering from dyskinesia of the biliary tract; the drug was administered in doses of 300 mg per day per os for 20 days, the patients being subjected to hepatobiliary scintigraphy before and after treatment. The following parameters--accurate indicators of the motor coordination of the biliary tract--were evaluated: tracer appearance time in the gallbladder (Tc) and in the intestine (Ti). After treatment there was a normalization of these two parameters which initially were extended. Statistical analysis showed a highly significant reduction in these times. Stress is laid on the importance of hepatobiliary scintigraphy in the diagnosis of biliary dyskinesia and on the effectiveness of fenoverine in the treatment of this conditions.

[Study of the thyroid function in a representative sample of the population of 3 islands of the Eolian archipelago: Filicudi, Alicudi and Panarea]. / Studio della funzione tiroidea in un campione rappresentativo della popolazione di tre isole dell'arcipelago eoliano: Filicudi, Alicudi e Panarea.

The thyroid function has been subject of study on a casual and significant sample consisting of 189 individuals living in Filicudi, Alicudi and Panarea, the smallest of the inhabited islands in the Eolian archipelago. The prevalence of palpable thyroid (group 1) has resulted to be of 26.45% while the one of the visible goitre (group 2) has resulted of 5.29%. The T3 has resulted significantly lower, in the subjects with thyroid of group 2, than in the ones with thyroid of the group 0 or 1 (p less than 0.02). In the subject who are over sixty years old the circulating fT3 has resulted significantly lower and the T3 significantly more elevated than in the people who are in their twenties. Seven cases of thyrotoxicosis have been ascertained. These data show an unexpected frequency of hypertrofic thyroid in a population among which the jodic deficiency hasn't reason to be; the presence of thyrotoxicosis could be connected with the prevalence of the goitre.

Effects of L-carnitine on adriamycin-induced cardiomyopathy in rabbit.

The authors conducted an investigation in order to ascertain whether or not L-carnitine, by promoting the utilization of FFA for energy and neutralizing FFA toxicity occurring after ischaemia, could prevent or confine adriamycin-induced cardiotoxicity in rabbits. The results show that L-carnitine determines a higher survival rate and reduced onset of cardiomyopathy. Histopathological examination of myocardial tissue under light and electron microscopy revealed a marked decrease in mitochondrial lesions.

[Behavior of the somatotroph in prepubertal subjects with underdeveloped gonads]. / Comportamento del somatotropo in soggetti in fase prepubere con ipoevolutismo gonadale.

After a rapid review of the reciprocal effects of hGH and testosterone in somatic development during puberty, the behaviour of the growth hormone after appropriate stimulation was examined in prepuberal subjects with underdeveloped gonads. These subjects revealed defective secretion of the hormone which may be explained by a reduction in the efficiency of the diencephalohypophyseal factors controlling puberty and sexual function.

Quinidine-digoxin interaction: time course and pharmacokinetics.

The time course of the rise in serum digoxin concentration was followed in 18 patients treated with digoxin as quinidine treatment was started with a loading dose. The mean serum digoxin levels rose significantly during the first 24 hours after administration of quinidine was begun, and reached a new steady state concentration after about 48 hours. Digoxin kinetics were studied in two groups of normal volunteers: Group 1 (n = 7) received a small dose of quinidine, 800 mg/day, and group II (n = 8) received 1,600 mg/day. There was no significant mean change in the apparent volume of distribution of digoxin in either group. In group I (small dose), quinidine reduced the digoxin clearance values: total clearance by 30 percent, renal clearance by 32 percent and nonrenal clearance by 29 percent. In group II (large dose), quinidine reduced digoxin total clearance by 36 percent, renal clearance by 54 percent and nonrenal clearance by 22 percent. The reduction in digoxin volume of distribution and renal clearance during quinidine treatment were a function of the serum quinidine concentration. The change in nonrenal clearance of digoxin was independent of serum quinidine concentration.

[Characteristics of the rash in Mediterranean boutonneuse fever]. / Rilievi e considerazioni sul rash della fabbre bottonosa mediterranea.

The typical papulomacular picture of boutonneuse fever is described. A series of atypical exanthemas is presented: simply erythemato-macular and typhus-like, nodular, vesicular. Skin biopsies showing the endothelial, thrombotic and parietal aspects of periadventitial infiltration (this being sometimes moderately and extensively pericapillary) are also presented. The reason for the absence of extensive thrombisation in extensive, marked rickettsiotic endothelitis are discussed, and stress is laid to the hitherto little-discussed, but significant involvement of dermal collagen.

[Complications of boutonneuse fever]. / Le complicanze della febre bottonosa.

Complications are rare in boutonneuse fever. This is clear from the brief review offered of the relevant literature. Reference is made to the clinical records of a personal series collected in Sicily during the current endemo-epidemic expansion of the disease through some regions of Italy. Primary complications appear in the form of cutaneous vesicles, a pyramidally located psychosensorial syndrome, transient atrial fibrillation and myocardial ischaemia, anuria with hyperazotaemia and another severe renal impairment. Careful clinical investigation of cases with unusual symptoms is recommended, coupled with systematic pathogenetic examination along modern lines.

[Boutonneuse fever in clinical practice]. / La febbre bottonosa nella pratica clinica.

Boutonneuse fever has become endemic in some parts of Sicily and the Italian mainland over the last five years. An account is given of the features assisting its clinical recognition and serological verification. The main nosographical aspects of the disease are described. The conditions required for certain, probable and presumed diagnosis are stated, stress being laid on the prime importance of timely clinical assessment, and the possibility of serological ascertainment when the disease is waning, or even later. Serum diagnosis via complement fixation or microagglutination will be positive in the second half of the second seven-day period of fever. It is specific with Rickettsia conorii antigens, though these have not been easy to find so far. The Weil-Felix reaction with Proteus OX19 and OX2 is significantly positive in advanced coalescence. While this is always a practical possibility, it is of indicative, and usually retrospective, value only.

[Characteristics of the "tache noire" of boutonneuse fever]. / Rilievi e considerazioni sulla "tache noire" della "febbre bottonosa".

Humans show little sensitivity to the bites of healthy Rhipicephalus sanguineus and the skin lesion is extremely slight. The "tache noire" - innoculation eschar - corresponding to the infecting bite of the tick with R. conori is discussed and histopathological findings reported. The patient is frequently unaware of the eschar on his body and elements relating to the duration of the infecting bite are deduced. Apart from its typical features, the tache noire may be very small, with surrounding hyper-ergic reaction, or it may even not be present, depending on different conditions of tissue reactivity. The pathogenesis is mentioned and the need for careful research for diagnostic purposes stressed.

[Cardiovascular involvement and complications in Mediterranean boutonneuse fever]. / Compromissione e complicanze cardiovascolari nella febbre bottonosa mediterranea.

After a review of the literature on heart damage in rickettsiosis, the data from a clinical and ecgraphic investigation of 17 patients suffering from boutonneuse fever are reported. There was little cardiovascular involvement and inconstant hypotension but two heart complications are described, one myocardial ischaemia which cleared up a few days after the end of the diseases, and an atrial fibrillation that lasted two days. Stress is laid on the need for constant ecgraphic monitoring, even in this minor rickettsiosis.

[Pseudo-tumoral calcinosis universalis]. / Calcinosis universalis pseudo-tumorale.

Marked deposits of calcium salts were noted in the triceps and gluteal and peritrochanteric areas in a 16-yr-old girl. Blood calcium values basal and after stimulation were normal. The classification of the case as a form of pseudotumoral calcinosis universalis is discussed.