Apoferritin encapsulation of cysteine protease inhibitors for cathepsin L inhibition in cancer cells.

Cysteine proteases play a key role in tumorigenesis causing protein degradation and promoting invasive tumour growth. Cathepsin L is overexpressed in cancer cells and could provide a specific target for delivery of anticancer agents. We encapsulated novel dipeptidyl nitrile based cysteine protease inhibitors (Neq0551, Neq0554 and Neq0568) into biocompatible apoferritin (AFt) protein nanocages to achieve specific delivery to tumours and pH-induced drug release. AFt-encapsulated Neq0554 demonstrated ∼3-fold enhanced in vitro activity (GI50 = 79 µM) compared to naked agent against MiaPaCa-2 pancreatic carcinoma cells. Selectivity for cancer cells was confirmed by comparing their activity to non-tumourigenic human fibroblasts (GI50 > 200 µM). Transferrin receptor (TfR-1) expression, detected only in lysates prepared from carcinoma cells, may contribute to the cancer-selectivity. The G1 cell cycle arrest caused by AFt-Neq0554 resulting in cytostasis was corroborated by clonogenic assays. Superior and more persistent inhibition of cathepsin L up to 80% was achieved with AFt-encapsulated agent in HCT-116 cells following 6 h exposure to 50 µM agent. The selective anticancer activity of AFt-encapsulated cysteine protease inhibitor Neq0554 reported here warrants further preclinical in vivo evaluation.

A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia.

NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the "supernumerary" group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in the X-linked nuclear-encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early-onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11, but all are associated with a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects.

Injection of auxiliary electrons for increasing the plasma density in highly charged and high intensity ion sources.

Different electron guns based on cold- or hot-cathode technologies have been developed since 2009 at INFN for operating within ECR plasma chambers as sources of auxiliary electrons, with the aim of boosting the source performances by means of a higher plasma lifetime and density. Their application to microwave discharge ion sources, where plasma is not confined, has required an improvement of the gun design, in order to "screen" the cathode from the plasma particles. Experimental tests carried out on a plasma reactor show a boost of the plasma density, ranging from 10% to 90% when the electron guns are used, as explained by plasma diffusion models.

A case of Solitary fibrous pleura tumor associated with severe hypoglycemia: the Doege-Potter 's Syndrome.

Solitary fibrous pleura tumor is a rare primary intrathoracic tumor of the pleura. It usually has an indolent clinical course, but sometimes it can have an aggressive behaviour. In 1930 Doege and Potter independently described this neoplasm, presenting with symptoms of hypoglycemia, hence the eponim of Doege-Potter's Syndrome. In this report, we illustrate a case of Doege Potter's Syndrome, treated with complete surgical resection.

Ethnicity-related variations of left ventricular remodeling in adolescent amateur football players.

Adult and adolescent elite black athletes display - as compared with their white counterparts - excessively increased left ventricle (LV) wall thickness (LVWT), mass (LVM), and relative wall thickness (RWT). To investigate such ethnicity-related differences in non-professional adolescent athletes, 138 male, amateur football players [age 14.0 ± 1.7 years, 42 West-African blacks (BA) and 96 Italian whites (WA)] underwent an echocardiographic study of LV diameters, LVWT, maximal wall thickness (MWT), LVM, and RWT as remodeling index. BA vs WA exhibited greater thickness of septum and posterior wall, higher MWT (10.3 ± 1.7 vs 8.8 ± 1.1 mm), and higher LVM (117 ± 27 vs 101 ± 20 g/m(2)) and RWT (0.44 ± 0.07 vs 0.35 ± 0.04). Age, systolic blood pressure, body mass index, and ethnicity predicted MWT and LVM, whereas ethnicity was the sole strong predictor of RWT. The greater MWT, LVWT, and LVM of 14-year-old, amateur-level BA vs WA indicates that ethnicity substantially affects LV structure in adolescent, non-professional athletes. In contrast with MWT and LVM, elevated RWT was predicted by black ethnicity only. We suggest that concentric-type LV remodeling is a peculiar LV phenotype in adolescent African athletes.

[Earthquake in Abruzzo, public health interventions. Preliminary report]. / Interventi sanitari in occasione del sisma in Abruzzo. Rapporto preliminare.

On 6th April 2009, at 3.32 AM, there was in L'Aquila and in some neighbouring villages, after an earthquake swarm last some months, an earthquake of M(L) = 5.8 (Richter magnitude scale) on depth of 8.8 km. The event was sensed in a very broad area, till in Rome and Ancon. The operative committee of the Civil Protection Department immediately gathered and a first operating group was despatched in the epicentre; the voluntary association of civil protection were in a pre-alarm situation and then were activated. This work want describe all the activities from 6th April 2009 till 31th August 2009, giving too a synthesis of the normative lines in case of catastrophic events typology C, otherwise all that events impossible to manage without national intervention.

Online convective therapies: results from a hemofiltration trial.

With the introduction of the on-line preparation of dialysis fluids, the hemofiltration technique, which has never had a widespread diffusion in its old version with the infusion bags, has gained a new interest. We planned a prospective, randomized, 3-year-long study comparing survival and morbidity in ultrapure bicarbonate dialysis (BD) with on-line predilution hemofiltration (HF). Since comorbidity is one of the main factors limiting survival, the study was addressed to patients with a severe degree of comorbidity. The paper presents the preliminary results of the trial. Sixty-four patients were enrolled and randomized to either BD (N = 32) or HF (N = 32). Mean age and dialysis vintage were comparable. Twenty patients died during the study, 12 in BD and 8 in HF. The relative risk of death was 11% higher in patients treated with BD compared to those in the HF group (p < 0.005). The number of hospitalisation events per single patient was lower, even though not significantly, in HF compared to BD (1.94 + 1.26 in HF vs 2.48 + 1.98 in BD, p = NS). As concerns biochemistry, apart from beta-2-microglobulin, any other substantial difference was not found during the study, though the small solute concentration was generally a little more elevated in HF than in BD. Dialysis hypotension showed a trend to decrease in both the dialysis modalities up to near half of the trial, then, during the last year, it remained quite stable in HF, while, on the contrary, it increased in the BD group. By the end of the protocol, patients in HF showed a 2.5% incidence of acute dialysis hypotension, while patients in BD had 23%.

Glassy phases in random heteropolymers with correlated sequences.

We develop an analytic approach for the study of lattice heteropolymers and apply it to copolymers with correlated Markovian sequences. According to our analysis, heteropolymers present three different dense phases depending upon the temperature, the nature of the monomer interactions, and the sequence correlations: (i) a liquid phase, (ii) a "soft glass" phase, and (iii) a "frozen glass" phase. The presence of the intermediate "soft glass" phase is predicted, for instance, in the case of polyampholytes with sequences that favor the alternation of monomers. Our approach is based on the cavity method, a refined Bethe-Peierls approximation adapted to frustrated systems. It amounts to a mean-field treatment in which the nearest-neighbor correlations, which are crucial in the dense phases of heteropolymers, are handled exactly. This approach is powerful and versatile; it can be improved systematically and generalized to other polymeric systems.

Phase diagram of random heteropolymers.

We propose a new analytic approach to study the phase diagram of random heteropolymers, based on the cavity method. For copolymers we analyze the nature and phenomenology of the glass transition as a function of sequence correlations. Depending on these correlations, we find that two different scenarios for the glass transition can occur. We show that, beside the much studied possibility of an abrupt freezing transition at low temperature, the system can exhibit, upon cooling, a first transition to a soft glass phase with fully broken replica symmetry and a continuously growing degree of freezing as the temperature is lowered.

[On-line haemodiafiltration with sorbent-regenerated ultrafiltrate as replacement fluid: Beta2-microglobulin removal versus filtration fraction]. / Emodiafiltrazione on-line con reinfusione endogena (HFR): rimozione di Beta2-microglobulina (Beta2-m) vs frazione di filtrazione (FF%).

PURPOSE: In order to encourage the removal of middle molecules in hemodiafiltration (HDF) techniques an attempt is made to maximize convective clearance by increasing the ultrafiltration rate. However, convective clearance is limited by the maximum filtration fraction (FF%) obtainable, by the pre- or post reinfusion method and by the convective surface and the capacity of the filter used. This study aimed to evaluate the effect of the FF% in the removal of Beta2-microglobulin (Beta2-m) during hemodiafiltration reinfusion (HFR) to identify the best ultrafiltration strategies; and therefore, a better removal of medium molecular weight solutes in this hemodiafiltrative technique recently introduced in clinical practice. METHODS: Ten chronic uremic patients (eight males, two females; age 66 +/- 18 yrs) already on renal dialysis therapy (RDT) for 80 +/- 36 months, were subjected to four HFR sessions, with Td=240 +/- 10 min, Qb=312 +/- 18 and Qd=500 mL/min; the reinfusion rates (Qr) used were 43.6 +/- 7.2 mL/min (25-58) with FF% rates varying from 20-34 (24.2 +/- 3.8) for hematocritic levels of 34.6 +/- 4.2% at the start of the dialysis session. For each session the intradialytic reduction rates (RR%) of urea, creatinine (Cr), phosphate, uric acid and Beta2-m and its average clearance (KBeta2-m mL/min) were evaluated. RESULTS: The results obtained gave a RR% for urea of 69.4 +/- 5 (Kt/Veq=1.23 +/- 0.2) and for Cr, phosphate and uric acid values of, respectively, 61.2 +/- 5.4, 47.5 +/- 10 and 75.8 +/- 6.7. The intradialytic reductions in Beta2-m were 49.3 +/- 10.3% with a variability range from 29-69% and with average KBeta2-m values of 63.8 +/- 13.5 mL/min. The RR% of ss2-m and KBeta2-m were inversely correlated (p<0.01) to the FF% rate applied during the treatment; 75% of the HRF sessions in which we observed a reduction in Beta2-m levels >40% were those where a FF% between 20 and 26% was applied. CONCLUSIONS. From our study, it appears that in HFR the best ultrafiltration strategy from the convective sector in removing Beta2-m has FF% values in the range 20-26%. The occurrence of lower intradialytic reductions of Beta2-m with increasing FF% can be interpreted as a consequence of phenomena related to high intradialytic hemoconcentrations, to the excessive increase in the TMP and/or the increase in the protein cake with a consequent reduction in permeability and mass transfer. Although using a limited convective surface with a limited possibility of increasing the FF%, nevertheless, HFR seems capable of ensuring a satisfactory uremic toxin removal of low and medium molecular weight, which combined with the high biocompatibility deriving from the use of reinfused endogen, can be considered an effective dialytic strategy for preventing or retarding the complications in dialytic patients.

Alcohol addiction: evaluation of alcohol abstinence after a year of psycho-medical-social treatment.

The aim of this study was to evaluate alcohol abstinence in alcoholics and their family relationships after a year of treatment. The 100 alcoholics recruited were divided into two groups: ALC, where treatment consisted of clinical control and meetings of with the family consulting together with their relatives at the Centre for Study and Treatment of Alcoholism and CAT, where treatment consisted of clinical control and weekly attendance together with their relatives at Alcoholics-in-Treatment-Clubs (CAT). The clinical condition of the sample was assessed by laboratory data. The subjects were given an MQ-Quant questionnaire, based on an artificial neural network (ANN) model, which analyses the communicative fatigue of their interactions. The same examination was applied after 1 year excluding patients relapsed and their relatives. Psycho-medical-social treatment by the attendance of alcoholics and their families into a Multifamily Community induces alcohol abstinence of about 79%. This percentage is greater than psycho-medical treatment carried out in the Centre of Alcoholism for ALC group (50%). We observed a significant difference between the communicative fatigue of the ALC group compared to the CAT group.

Primary cutaneous CD30+ large T-cell lymphoma in a patient with psoriasis treated with cyclosporine.

We report the case of a 61-year-old woman who developed an anaplastic CD30+ cutaneous T-cell lymphoma during oral cyclosporine (CsA) therapy for recalcitrant psoriasis. Two months after CsA discontinuation, clinical and histological resolution of the lymphoma was observed. However, 3 years later extracutaneous involvement of the lymphoma could be detected. The association between CsA administration and the occurrence of the lymphoma may be casual, but a relationship with immunosuppression may also be hypothesized. We have reviewed all relevant data in the literature. To our knowledge, this is the first case of primary cutaneous CD30+ anaplastic large T-cell lymphoma in a patient treated with CsA for psoriasis.

Microscopic description of aging dynamics: fluctuation-dissipation relations, effective temperature, and heterogeneities.

We consider the dynamics of a diluted mean-field spin glass model in the aging regime. The model presents a particularly rich heterogeneous behavior. In order to catch this behavior, we perform a spin-by-spin analysis for a given disorder realization. We confirm the connection between statics and dynamics at the level of single degrees of freedom. Moreover, working with single-site quantities, we can introduce a new response-vs-correlation plot, which clearly shows how heterogeneous degrees of freedom undergo coherent structural rearrangements. We discuss the general scenario which emerges from our work and (possibly) applies to more realistic glassy models. Interestingly enough, some features of this scenario can be understood recurring to thermometric considerations.

Pulmonary artery leiomyosarcoma with thyroid metastases.

Primary pulmonary artery sarcomas are uncommon and usually fatal tumours. The diagnosis of these tumours is delayed in most cases as they are mistaken for pulmonary thromboembolism. We present a fatal case of a woman referred to us five months after a primary diagnosis of pulmonary thromboembolism, due to an increase in dyspnea and presence of hemoptysis despite having undergone anticoagulant treatment. On the basis of the findings obtained by computed tomography, echocardiogram and MRI, a mass arising from the pulmonary trunk was evidenced, that suggested other diagnostic hypotheses. The worsening of patient's conditions did not allow an endovascular catheter biopsy and diagnosis was made at autopsy. The mass was a leiomyosarcoma of the pulmonary artery with thyroid metastases, which is an uncommon findings.

Ascent of dinosaurs linked to an iridium anomaly at the Triassic-Jurassic boundary.

Analysis of tetrapod footprints and skeletal material from more than 70 localities in eastern North America shows that large theropod dinosaurs appeared less than 10,000 years after the Triassic-Jurassic boundary and less than 30,000 years after the last Triassic taxa, synchronous with a terrestrial mass extinction. This extraordinary turnover is associated with an iridium anomaly (up to 285 parts per trillion, with an average maximum of 141 parts per trillion) and a fern spore spike, suggesting that a bolide impact was the cause. Eastern North American dinosaurian diversity reached a stable maximum less than 100,000 years after the boundary, marking the establishment of dinosaur-dominated communities that prevailed for the next 135 million years.

Hairpin formation and elongation of biomolecules.

We introduce a model of thermalized conformations in space of RNA-or single stranded DNA-molecules, which includes the possibility of hairpin formation. This model contains the usual secondary structure information, but extends it to the study of one element of the ternary structure, namely the end-to-end distance. The computed force-elongation characteristics are in good agreement with some recent measurements on single stranded DNA molecules.

A short duration of the Cretaceous-Tertiary boundary event: evidence from extraterrestrial helium-3.

Analyses of marine carbonates through the interval 63.9 to 65.4 million years ago indicate a near-constant flux of extraterrestrial helium-3, a tracer of the accretion rate of interplanetary dust to Earth. This observation indicates that the bolide associated with the Cretaceous-Tertiary (K-T) extinction event was not accompanied by enhanced solar system dustiness and so could not have been a member of a comet shower. The use of helium-3 as a constant-flux proxy of sedimentation rate implies deposition of the K-T boundary clay in (10 +/- 2) x 10(3) years, precluding the possibility of a long hiatus at the boundary and requiring extremely rapid faunal turnover.

Sodium sensitivity of blood pressure in long-term detoxified alcoholics.

To investigate whether sodium sensitivity of blood pressure participates in the relationship of arterial hypertension to chronic alcohol consumption, 30 alcoholics detoxified from 6 to 12 months and 30 teetotaler controls underwent a dietary sodium manipulation study. They received a daily 55 mmol sodium diet for 7 days, followed by a 260 mmol sodium diet for 7 days. Changes in 24-hour urinary sodium excretion between the end of each period were similar in alcoholics and controls (202+/-16 SEM mmol and 227+/-11, respectively). Plasma renin activity in alcoholics was lower than in controls at both low (2.4+/-0.4 ng angiotensin I/mLxh(-1) versus 3. 7+/-0.2, P<0.003) and high sodium intake (0.47+/-0.10 versus 0. 82+/-0.10, P<0.05), with smaller variations in alcoholics (-1.9+/-0. 3 versus -2.9+/-0.2, P<0.009). In alcoholics, alteration in sodium intake was followed by greater changes in both systolic and mean blood pressure (ambulatory blood pressure monitoring), which rose by 10.6+/-2.2 mm Hg and 7.3+/-1.5 versus 4.7+/-1.4 and 3.9+/-1.0 in controls, respectively (P<0.03 for systolic and P<0.05 for mean blood pressure). The ratio of changes in mean blood pressure to those in 24-hour urinary sodium excretion was higher in alcoholics (0.044+/- 0.011 mm Hgxmmol(-1) versus 0.018+/-0.0041, P<0.005). Our data show that in detoxified alcoholics, there is an abnormal response of both blood pressure and plasma renin activity to variations in salt intake similar to that in sodium-sensitive arterial hypertension. The precise relationship between the sodium sensitivity of blood pressure in detoxified alcoholics and the long-term influence of alcohol on blood pressure remains to be elucidated.