Structural rearrangements as a recurrent pathogenic mechanism for SETBP1 haploinsufficiency.

Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the precise breakpoint is crucial from a diagnostic point of view, highlighting possible gene disruption and addressing to appropriate genotype-phenotype association. Structural rearrangements can either occur randomly within the genome or present with a recurrence, mainly due to peculiar genomic features of the surrounding regions. We report about three non-related individuals, harboring chromosomal structural rearrangements interrupting SETBP1, leading to gene haploinsufficiency. Two out of them resulted negative to Chromosomal Microarray Analysis (CMA), being the rearrangement balanced at a microarray resolution. The third one, presenting with a complex three-chromosome rearrangement, had been previously diagnosed with SETBP1 haploinsufficiency due to a partial gene deletion at one of the chromosomal breakpoints. We thoroughly characterized the rearrangements by means of Optical Genome Mapping (OGM) and Whole Genome Sequencing (WGS), providing details about the involved sequences and the underlying mechanisms. We propose structural variants as a recurrent event in SETBP1 haploinsufficiency, which may be overlooked by laboratory routine genomic analyses (CMA and Whole Exome Sequencing) or only partially determined when associated with genomic losses at breakpoints. We finally introduce a possible role of SETBP1 in a Noonan-like phenotype.

Microgravity heat pump for space station thermal management.

A highly efficient recuperative vapor compression heat pump was developed and tested for its ability to operate independent of orientation with respect to gravity while maximizing temperature lift. The objective of such a heat pump is to increase the temperature of, and thus reduce the size of, the radiative heat rejection panels on spacecrafts such as the International Space Station. Heat pump operation under microgravity was approximated by gravitational-independent experiments. Test evaluations include functionality, efficiency, and temperature lift. Commercially available components were used to minimize costs of new hardware development. Testing was completed on two heat pump design iterations--LBU-I and LBU--II, for a variety of operating conditions under the variation of several system parameters, including: orientation, evaporator water inlet temperature (EWIT), condenser water inlet temperature (CWIT), and compressor speed. The LBU-I system employed an ac motor, belt-driven scroll compressor, and tube-in-tube heat exchangers. The LBU-II system used a direct-drive AC motor compressor assembly and plate heat exchangers. The LBU-II system in general outperformed the LBU-I system on all accounts. Results are presented for all systems, showing particular attention to those states that perform with a COP of 4.5 +/- 10% and can maintain a temperature lift of 55 degrees F (30.6 degrees C) +/- 10%. A calculation of potential radiator area reduction shows that points with maximum temperature lift give the greatest potential for reduction, and that area reduction is a function of heat pump efficiency and a stronger function of temperature lift.

[Follow-up of residual renal function in patients with serious forms of posterior urethral valves]. / Valutazione a distanza della funzione renale residua (FRR) in portatori di forme gravi di valvole dell'uretra posteriore (VUP).

We report the results of the trend of the residual renal function (RRF) of 15 patients with serious forms of hind urethral valves (HUV) which agreed to be long term regularly controlled after surgical correction at the Children's Surgical Hospital of Bologna University. The nephrological follow-up started in 1985 is based on a periodical control at least once a year, of some indicatives parameters of the glomerulars activity (creatinine clearance according Schwartz and creatinine reciprocal), of the tubular activity (urinary flux ml/kg/h, per cent fraction of Na excretion) and the dynamical test of the RRF started in 1991. The results although the low cases studies, are not statistically significant, the Authors underline the validity of the adopted method. Although of the simplified and/or indirect type, this is able to give clinically reliable informations of the renal functionality evolution avoiding particularly complex or invasive analysis.

[Effects of various dosage of ketoprofen salt suppositories in acute inflammatory disease in infants (3-36 month old) and children (3-13 year old)]. / Effetti di diversi dosaggi di ketoprofene sale di lisina in supposte nelle affezioni flogistiche nel lattante di 6-36 mesi e nel bambino di 3-13 anni.

In two multicentric randomized, double-blind, parallel design trials the more appropriate dose of ketoprofen lysine salt suppositories, by considering benefit-risk ratio, was determined in children affected by acute inflammatory disease of respiratory or urinary tract with fever and pain. Fifty-three children ranging 6-36 months (infants) randomly assigned to 20, 30, 40 mg dose levels, and 54 children ranging 3-13 years (children) randomly assigned to 40, 60, 80 mg dose levels were included in the studies. Efficacy variables considered were hyperthermia and pain; body temperature was measured rectally, at fixed intervals and pain was evaluated by Maunuskela scale at the same interval times. Standard laboratory test were obtained at the beginning and end of treatment, and blood arterial pressure and heart rate were recorded regularly. Systemic and local tolerability were also determined. In infants all doses were associated with analgesia and temperature reduction; antipyretic effect was statistically significant starting from the first hour (p = 0.007). The dose of 30 mg resulted different from 20 mg dose from third hour (p < 0.05). The appropriate dose that better relate antipyretic and analgesic efficacy with a good tolerability was 30 mg. In children the analgesic and antipyretic efficacy was well established at all doses tested, however the effects were more marked and prolonged at 60 and 80 mg doses, with a better tolerability for 60 mg dose. The tolerability of all doses studied was good. Doses of 30 mg in infants and 60 mg in children correspond to a range of 2.0-3.5 mg of ketoprofen lysine salt for kg body weight, for each administration.

Efficacy and safety of pidotimod in the treatment of recurrent respiratory infections in children.

The activity of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) was evaluated in a double-blind, placebo-controlled, randomized, multicentre trial, on 120 pediatric patients affected by recurrent respiratory infections. The clinical course of acute infections was favourable both in placebo and in treatment group, but recovery was quicker with pidotimod than with placebo. Antibiotic therapy and time of hospitalization were shorter in the patients taking pidotimod, and main symptomatic parameters (pharyngalgia, dysphagia, mucous membrane inflammation, adenopathy, anorexia) receded quickly. In patients receiving the drug as well as in placebo group changes in laboratory parameters, indicating recovery from the acute infectious events, were observed. A significant trend to normalization of the immune response, evidenced by chemotaxis and leukocyte phagocytosis index, was found only in patients treated with pidotimod. A significant decrease in the risk of relapses was observed in patients treated with pidotimod (35%), as well as a reduction of hospitalization (86%) and a decreased antibiotic therapy (47%). If a relapse occurred, the response of treated patients was quicker (fever, antibiotic therapy, hospitalization). These findings allow to correlate the individual immune response activation to the resistance to recurrent infections and also to a better response to therapy in case of clinically relevant disease. No side effects were observed. Only in 12 patients (5 pidotimod, 7 placebo) mild reactions were observed, but they were attributed to concomitant antibiotic treatment or other factors. No alterations in main laboratory parameters were seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Pidotimod in the treatment of recurrent respiratory infections in paediatric patients.

50 young patients suffering from recurrent respiratory infections (RRI) were treated with pidotimod ((R)-3-[(S)-(5-oxo-2- pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) (one 400 mg ampoule twice a day) or placebo, according to a double-blind experimental design. The treatment period was 20 days and there was then a 60-day follow-up period. Evaluation was both clinical (number and severity of the respiratory infectious episodes) and immunological, investigating the OKT 4 and OKT 8 lymphocyte sub-populations and OKT 4/OKT 8 ratio. The group of children treated with pidotimod showed a decrease in the number of infections. Patients free from RRI episodes, after 20 days of therapy, were 68% of the group treated with pidotimod compared with 8% of the placebo group. In addition, the mean duration of the episodes was lower in treated patients than in patients of the control group. Such differences were statistically significant. It was also observed that administration of the drug potentiated the immune response such that the clinical picture remained improved for a further 60 days after treatment cessation. Furthermore, only in the pidotimod group there were improving changes of OKT 4 and OKT 8 percentages which affected the OKT 4/OKT 8 ratio.

Therapeutic efficacy and safety of pidotimod in the treatment of urinary tract infections in children.

The activity of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) was studied vs. placebo in a double-blind, randomized, multicentre trial, involving 60 pediatric patients with recurrent urinary tract infections. Recovery from acute events was quicker with pidotimod than with placebo (9.6 vs. 12.3 days). In treated patients antibiotic therapy was shorter (6.9 vs. 8.3 days) and main symptomatic parameters (body temperature, vesical tenesmus, stranguria, pollakiuria, total number of symptoms, total symptomatic intensity, rate of asymptomatic patients, haematuria, leukocyturia, positive urinary culture) receded quickly. In patients receiving the drug as well as in patients treated with placebo changes in laboratory parameters were observed, indicating recovery from the acute infectious disease. A significant trend to normalization of the immune response, expressed by chemotaxis and index of leukocyte phagocytosis, was found only in patients treated with pidotimod. After the acute episode a significant decrease of risk of relapses (69%) was observed in these patients. If a relapse occurs, the response of treated patients is quicker (duration of fever, total time of relapses) than for control patients. These findings allow to correlate the individual immune response activation to the resistance to recurrent infections and also to a better response to therapy if the disease occurs and becomes clinically relevant. No side effects were observed. Mild reactions (4 nausea/vomiting, 1 erythema) occurred only in 5 patients (2 pidotimod, 3 placebo) but were attributed to concomitant antibiotic therapy. No alterations of main laboratory parameters were found. These findings confirm the tolerability of the drug also in long-term treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Salivary IgA levels in normal children.

Salivary IgA (SlgA) levels were determined in 1,539 normal children, aged between 8 months and 6 years. In four children (0.26%), an absence and in 25 children (1.62%) a relative defect, (less than 1 mg/dl) were found. These values are similar to those encountered in an adult male population. Conversely, the mean SlgA in all age groups we examined was much lower in comparison to the adult mean. This difference is particularly great for SlgA and much smaller for total salivary proteins. There was no difference between males and females, and no relation with personal or familial history of allergic and/or infectious episodes. The conclusions of this study are as follows: Absolute and relative SlgA defects, when found, are present from birth, The complete maturation of SlgA occurs after 6 years of age, The role of SlgA in the protection against allergic or infectious episodes perhaps ought to be revised.

[Electrocardiogram changes in the rat by coenzyme A action]. / Modificazioni dell'elettrocardiogramma del ratto per azione del coenzima A.

The authors, having in a previous series of experiments observed that coenzyme A, administered intravenously in doses from 200 to 500 U.L., causes an immediate and transient decrease of the sinus rate, wanted to study to which part of the complex molecule of coenzyme A such effect is due. That's why they studied the action, intravenously, of pantothenic acid (200-400 mg/Kg), of cysteine (40-80 mg/Kg), of pantethein (40-100 mg/Kg) and of adenosine (4-10 mg/Kg). The results of the experiments demonstrate that the former bradycardia is due to adenosine, whereas the other substances have not this effect.

[Electrocardiographic changes in the rat induced by digitalis glucosides]. / Modificazioni dell'elettrocardiogramma del ratto per azione di glucosidi digitalici.

Electrocardiographic changes induced by desacetil-lanatoside C and digitoxin, administered intravenously, have been studied in 25 anesthetized rats. No differences were observed between the actions of the two glucosides. Their negative chronotropic action can be effected with two mechanisms: one indirect, through vagal reflex, therefore immediate and, in general, brief; one direct, for direct action on the heart, which is gradual and long lasting. Their action on the a-v conduction is recorded by a rise in the duration of the P-Q tract, or, for higher doses, by blocking fenomena, which are brief and completely reversible. Signs of subendocardial damage are often observed, these too brief. The appearance of extrasystoles is rare.

[Electrocardiographic changes in the rat induced by high doses of the coenzymatic forms of several vitamins of the B group]. / Modificazioni dell'elettrocardiogramma del ratto per azione di alte dosi delle forme coenzimatiche di alcune vitamine del gruppo B.

No modification, neither immediate nor late, was observed after the intravenous injection of high doses of the coenzymatic forms of thiamine and pyridoxine. On the contrary, after the injection of high doses of the coenzyme A, a sudden, conspicuous and brief (20-25") diminution of heart rate was observed. Such a phenomenon was much more marked and longer if, before the coenzyme A, a digitalic compound (desacetil-lanatoside C or digitoxin) was administered.

[Effects of nicotine on the electrocardiogram of the rat]. / Effetti della nicotina sull'elettrocardiogramma del ratto.

In these experiments in the rat was studied the action of nicotine, administered intravenously in doses from 20 to 900 gamma/Kg. It was seen that, after the injection of lower doses, in the first phase there is always a more or less conspicuous diminution of the heart rate and a light and fleeting rise of the time of a-v conduction; there follows, after 25-30', a phase in which there is, as already noted, a rise of the heart rate. After higher doses was observed always an increase of the heart rate. Extrasystoles due to the action of nicotine was not observed. Sometime were observed signs of subendocardial damage or of fleeting right bundle-branch block. After a dose of 300 gamma (900 gamma/Kg) was observed a conspicuous and brief inhibition of sinus node activity and of the a-v conduction.

[Experimental electrocardiography research. A study in the rat of the cardiovascular effects of verapamil]. / Ricerche di elettrocardiografia sperimentale. Studio nel ratto degli effetti cardiovascolari del verapamil.

Electrocardiographic changes induced by Verapamil, drug inducing inhibition of transmembrane movement of calcium into cardiac cells and mobilization of intracellular Ca++, have been studied in 10 anesthetized rats. Authors observed that Verapamil has: 1) negative chronotropic action on SA node; sometimes appears a superior nodal rhythm; 2) inconstantly, negative dromotropic action with prolonged atrioventricular conduction and "period of Luciani-Wenckebach'; 3) effective antiarrhythmic action; 4) no protective action towards peripheric vascular epinephrine effects; 5) remarkable negative inotropic action, whose Authors consider indirect signs the electrocardiographic changes, which indicate severe coronary failure, and the death of 6 rats by acute pulmonary edema.

[Experimental electrocardiographic research. Study in the rat of the cardiovascular effects of labetalol]. / Ricerche di elettrocardiografia sperimentale. Studio nel ratto degli effetti cardiovascolari del labetalolo.

Electrocardiographic changes induced by Labetalol, a drug blocking alpha- and beta-adrenergic receptors, have been studied in 10 anesthetized rats. Authors observed that Labetalol has: 1) slightly negative chronotropic action; 2)slightly negative dromotropic action on both atrio-ventricular and intraventricular conduction; 3) effective antiarrhythmic and alpha-blocking action and, inconstantly, 4) the so-called "intrinsic sympathicomimetic action" (I.S.A.), typical of several beta-blocking drugs.

[Research in experimental electrocardiography. I: action of DCA-ajmaline on the electrocardiogram of the rat]. / Ricerche di elettrocardiografia sperimentale. Nota I: azione della DCA-ajmalina sull'elettrocardiogramma del ratto.

In the course of their experiments, the Authors did not observe any modifications in the rat electrocardiogram, induced by a 2,5 mg DCA-ajmaline intravenous injection, nor, in particular, any negative bathmotropic action due to it.

[Research in experimental electrocardiography. II: effect of a beta-blockader (pindolol) on the electrocardiogram of the rat]. / Ricerche di elettrocardiografia sperimentale. Nota II: Effetti di un beta-bloccante (il pindololo) sull'elettrocardiogramma del ratto.

From the Authors' observations during this research, there emerges the fact that pindololo does not seem deprived of that cardiodepressive action, which is typical of all beta-blocking drugs.