Time Dependence of the Electron and Positron Components of the Cosmic Radiation Measured by the PAMELA Experiment between July 2006 and December 2015.

Cosmic-ray electrons and positrons are a unique probe of the propagation of cosmic rays as well as of the nature and distribution of particle sources in our Galaxy. Recent measurements of these particles are challenging our basic understanding of the mechanisms of production, acceleration, and propagation of cosmic rays. Particularly striking are the differences between the low energy results collected by the space-borne PAMELA and AMS-02 experiments and older measurements pointing to sign-charge dependence of the solar modulation of cosmic-ray spectra. The PAMELA experiment has been measuring the time variation of the positron and electron intensity at Earth from July 2006 to December 2015 covering the period for the minimum of solar cycle 23 (2006-2009) until the middle of the maximum of solar cycle 24, through the polarity reversal of the heliospheric magnetic field which took place between 2013 and 2014. The positron to electron ratio measured in this time period clearly shows a sign-charge dependence of the solar modulation introduced by particle drifts. These results provide the first clear and continuous observation of how drift effects on solar modulation have unfolded with time from solar minimum to solar maximum and their dependence on the particle rigidity and the cyclic polarity of the solar magnetic field.

Perisurgical and intra-rehabilitative salivary steroid hormone profiles in bicompartmental arthroplasty.

Sex hormones play a role in pain perception, a key variable in evaluating the progression and treatment of osteoarthritis. The aim of this study was to determine the relationship between salivary concentrations of four steroid hormones and functional/clinical outcomes after hip and knee arthroplasty. Saliva samples were collected from 24 otherwise healthy patients with osteoarthritis before surgery, on admission to rehabilitation, and at hospital discharge. Salivary concentrations of testosterone, 17ß-estradiol, dehydroepiandrosterone (DHEA), and cortisol were immunoassayed. Changes in hormone levels were compared with clinical outcomes, as assessed by functional independence measure (FIM®), Barthel Index (BI), and visual analog scale for pain (VAS) scores. Changes in testosterone levels were significantly inversely correlated with VAS (r= -0.53, p=0.043) and FIM® and BI scores in all patients (r= -0.30, p= 0.043, and r= -0.35, p=0.031, respectively). The testosterone to cortisol ratio was inversely correlated with BI scores in all patients (r= -0.30, p=0.040), and in the men (r= -0.55, p=0.005) and the women (r= -0.28, p=0.042) when analyzed separately. Changes in salivary testosterone concentrations closely correlated with clinical outcome measurements for total hip and knee arthroplasty. Clinical outcome after arthroplasty was generally better among the men.

Bioactive motifs of agouti signal protein.

The switch between the synthesis of eu- and pheomelanins is modulated by the interaction of two paracrine signaling molecules, alpha-melanocyte stimulating hormone (MSH) and agouti signal protein (ASP), which interact with melanocytes via the MSH receptor (MC1R). Comparison of the primary sequence of ASP with the known MSH pharmacophore provides no suggestion about the putative bioactive domain(s) of ASP. To identify such bioactive motif(s), we synthesized 15-mer peptides that spanned the primary sequence of ASP and determined their effects on the melanogenic activities of murine melanocytes. Northern and Western blotting were used, together with chemical analysis of melanins and enzymatic assays, to identify three distinct bioactive regions of ASP that down-regulate eumelanogenesis. The decrease in eumelanin production was mediated by down-regulation of mRNA levels for tyrosinase and other melanogenic enzymes, as occurs in vivo, and these effects were comparable to those elicited by intact recombinant ASP. Shorter peptides in those motifs were synthesized and their effects on melanogenesis were further investigated. The amino acid arginine, which is present in the MSH peptide pharmacophore (HFRW), is also in the most active domain of ASP (KVARP). Our data suggest that lysines and an arginine (in motifs such as KxxxxKxxR or KxxRxxxxK) are important for the bioactivity of ASP. Identification of the specific ASP epitope that interacts with the MC1R has potential pharmacological applications in treating dysfunctions of skin pigmentation.

Cysteine transport in melanosomes from murine melanocytes.

The synthesis of pheomelanin requires the incorporation of thiol-containing compound(s) during the process of mammalian melanogenesis. Since melanins are produced only in specialized, membrane-bound organelles, known as melanosomes, such thiol donor(s) must cross the membrane barrier from the cytosol to the melanosome interior. Cysteine and/or glutathione (GSH) were proposed as suitable thiol donors, although uptake of these compounds into melanosomes was not previously characterized. In this study, we show that cysteine is transported, in a temperature- and concentration-dependent manner, across membranes of melanosomes derived from murine melanocytes. Additional proof that cysteine uptake results from a carrier-mediated process and is not due to simple diffusion or to a membrane channel, was obtained in countertransport experiments, in which melanosomes preloaded with cysteine methyl ester took up significantly more [35S]cysteine than did unloaded controls. In contrast, we were unable to detect any significant uptake of [35S]GSH over a wide concentration range, in the presence or in the absence of reducing agent. This study is the first demonstration of melanosomal membrane transport of cysteine, and it strongly suggests that free cysteine is the thiol source utilized for pheomelanin synthesis in mammalian melanocytes.

Penile metastasis from carcinoma of the prostate in a patient with high serum prostate specific antigen levels.

Prostatic carcinoma metastasizing to the penis is rare. Prognosis is poor with survival ranging from 1 to 24 months. A patient with prostate cancer and a serum Prostate Specific Antigen (PSA) level over 200 ng/ml, submitted to radical retropubic prostatectomy (RRP) and after 2 months presenting with two painful nodules in the penis, is described.

[Response of interleukin-6 in patients undergoing a laparoscopic or laparotomic cholecystectomy]. / Risposta della interleukina-6 in pazienti sottoposti a colecistectomia laparoscopica o laparotomica.

BACKGROUND: It is well known that surgery induces an acute inflammatory response associated with significant increase of interleukin-6 (IL-6) and C reactive protein (CRP). Laparoscopic cholecystectomy (LC) is a so called "mini-invasive" surgical intervention and on the basis of this consideration it has been investigated if and how serological markers of inflammation are modified in patients after laparoscopic cholecystectomy compared to patients undergoing open cholecystectomy. METHODS: The acute phase of inflammation (IL-6, CRP and body temperature) was evaluated in 53 patients one day before surgery and p.o. after 1, 3 and 6 days; 26 patients underwent "open" cholecystectomy and 27 LC. RESULTS: One day after surgery patients with open cholecystectomy showed significant increase (p < 0.05) of IL-6, CRP and body temperature, while these parameters were almost unchanged in patients with LC. In patients with "open" cholecystectomy, 2 p.o. complications (pneumonia) were observed. CONCLUSIONS: In conclusion, LC, although it requires longer operative time, strongly reduces p.o. pain, hospitalization, promotes earlier recovery and return to normal activity, avoiding the acute phase of p.o. inflammation with better p.o. morbidity compared to open surgery.

[Risk of surgery in geriatric age: prospective evaluation of risk factors]. / Rischio chirurgico in età geriatrica: valutazione prospettica d'indici di rischio.

The use of Risk Index in surgery is aimed to plan surgical strategy in order to achieve a better post-operative prognosis. This is especially true in geriatric surgery where ASA Index and, more recently, Reiss Index are widely employed. Since the mentionated Risk Indices are calculated on the basis of different factors, in this prospective study we compared the two Risk Indices with the aim of verify which index offers better prognostic indications. 125 consecutive patients, aged older 70 years, undergoing surgical treatment, were investigated. The patients were grouped according to ASA Index and Reiss Index and postoperative morbidity and mortality rate was calculated. Both Indices resulted good predictive for the postoperative prognosis (ASA: G Statistic = 31.531, p < 0.001; Reiss: G Statistic = 18.416, p < 0.001), but ASA Index sensitivity was better (Specificity = 100%, sensitivity = 28%, false negative rate = 72%) than Reiss Index (Specificity = 100%, sensitivity = 0, false negative rate = 100%). Therefore ASA Index has clinical valid role in valuing surgical risk in elderly.

[Risk indices in geriatric surgery: ASA index versus Reiss index]. / Indici di rischio in chirurgia geriatrica: indice ASA versus Indice Reiss.

The use of the Risk Index in surgery is aimed to plan surgical strategy in order to achieve a better postoperative prognosis. This is especially true in geriatric surgery where the ASA Index and, more recently, the Reiss Index are widely employed. Since the mentioned Risk Indices are calculated on the basis of different factors, in this study we compared the two Risk Indices with the aim of verifying which index offers better prognostic indications. 210 patients, aged over 70 years, undergoing surgical treatment, were investigated. The patients were grouped according to the ASA and Reiss Indices. The ASA Index showed good correlation only with postoperative mortality. The three classes of Reiss Index showed a significant correlation with the incidence of post-operative morbidity and mortality (p.o. morbidity: 7.1%, 21.5%, 30.3%; p.o. mortality; 1.7%, 9.2%, 24.2% -Chi 2 = 20.7; p < 0.001). Our results support the hypothesis that Reiss index offers better prognostic evaluation of postoperative outcome, suggesting its use in assessing postoperative prognosis in geriatric patients. In addition, our observation confirms the criticism reported of the ASA Index, merely considered as an indicator of health status regardless of surgical treatment. In conclusion, routine preoperative evaluation of the Reiss Index should be advised in geriatric patients with the aim to forecasting surgical risk in the first place, and them modifying operative strategy in order to improve postoperative results.

Plasma thrombin-antithrombin complexes, latent coagulation disorders and metastatic spread in lung cancer: a longitudinal study.

In patients affected with different tumours, disorders concerning clotting are frequently observed. The biological processes leading to coagulation are probably involved in the mechanisms of metastasis. We studied plasma levels of thrombin-antithrombin III complexes (TAT) in 90 patients affected with lung tumours subgrouped in small cell and non-small cell (NSC) lung cancer: 17 patients had no evidence of disease after surgery (NE); the remaining 73 patients were divided according to the absence (LOC) or the presence (META) of metastases. All the patients were followed up for several months. In all the lung cancer patient groups, at the beginning of the study we detected TAT levels that were higher than in controls. During the follow-up period, the NSC-NE patients with no recurrence of the disease as well as the NSC-LOC patients responding to the treatment had a decrease in TAT levels (p < 0.01 and p < 0.05, respectively). The NSC-META patients with progression of their disease had, in contrast, an increase in TAT levels (p < 0.01). Our data reveal the presence of 'latent coagulation disorders' as assessed by the presence of high TAT levels in the majority of lung cancer patients. The follow-up study indicates that in the NSC group, a relation exists between coagulation activation and rate of tumour progression and/or response to treatment. In cancer patients the early detection of coagulation disorders could also allow, therefore, the prevention of thromboembolism and/or haemorrhage by administration of appropriate treatment.

Distinctive features of the alpha 1-domain alpha helix of HLA-C heavy chains free of beta 2-microglobulin.

Only a few monoclonal antibodies are available with a restricted specificity to HLA-C products. In the present report, we demonstrate that antibody L31, previously shown to react with beta 2m-less (free) class I MHC heavy chains, binds to an epitope (residues 66-68 of the alpha 1 domain alpha helix) present on all the HLA-C alleles corresponding to the accepted (CW1 through CW8) serologic specificities, and on a few HLA-B heavy chains sharing with HLA-C an aromatic residue at position 67. Extensive IEF blot testing of HLA homozygous, EBV-transformed B-lymphoid cells indicates that HLA-C molecules are present at significantly lower levels than HLA-B polypeptides not only at cell surface, as previously demonstrated, but also in total cellular extracts. Testing of metabolically labeled HLA-CW1, -CW5, and -CW6 transfectants and HLA homozygous lymphoid cells, particularly HLA-CW1-expressing cells, demonstrates that the L31 epitope is present on a subpopulation of naturally occurring HLA-C molecules distinct from that identified by antibody W6/32 to beta 2m-associated heavy chains. Pulse-chase experiments demonstrate that this epitope is transiently made available to antibody binding at early biosynthetic stages, but becomes hidden upon assembly with beta 2m. Thus, free HLA-C and other Y/F67+ heavy chains are characterized by distinctive antibody binding features in a region (residues 66-68) included in a previously identified HLA-C restricted motif, which has been suggested to be the primary cause of distinctive features of the antigen-binding groove, low affinity for endogenous peptide antigens and beta 2m, and preferential uptake of exogenous peptides, possibly of viral origin. We also show that HLA-CW1 heavy chains, both free and beta 2m associated, acquire sialilation. Free HLA-CW1 heavy chains are expressed at the cell surface even when unsialilated, albeit at low levels.

Human immunodeficiency virus type 1 (HIV-1)-seronegative injection drug users at risk for HIV exposure have antibodies to HLA class I antigens and T cells specific for HIV envelope.

The question of whether persistently seronegative persons at high risk for human immunodeficiency virus type 1 (HIV-1) infection exhibit HIV-1-specific T cell responses and antibodies to HIV-1 envelope epitopes shared with selected HLAs was assessed. These antibodies are not detectable by conventional serologic methods. Envelope-specific helper T (Env-Th) cell responses and antibodies specific for the HIV/HLA epitopes were studied in 21 HIV-1-negative injection drug users (IDUs). HIV/HLA antibodies were detected in 7 (33.3%) of 21 IDUs and 4 (4.3%) of 94 low-risk controls. Env-Th cell responses were detected in 16 (76.2%) of 21 IDUs and in 2 (3.1%) of 65 low-risk controls. All HIV/HLA antibody-positive IDUs also had Env-Th cell responses. These findings confirm the presence of HIV-1-specific immunity in conventionally seronegative individuals. Further characterization of these responses could provide the basis for new preventive strategies.

[Acute cholecystitis: video-laparoscopic or laparotomic treatment? Role of the immune system]. / Colecistite acuta: trattamento videolaparoscopico o laparotomico? Ruolo del sistema immunitario.

Recent clinical studies suggest that laparoscopic cholecystectomy (LC) causes less depression of cell-mediated immunity than open cholecystectomy. LC is a so called "mini invasive" surgical presidia, and on the basis of this consideration we have investigated if and how the immune response is modified in patients with acute cholecystitis after laparoscopic cholecystectomy compare to patients undergone open cholecystectomy. Immune-activity (neutrophils, total lymphocytes count, lymphocytes subpopulations, HLA-DR, 6-Interleukin, skin multitests) was evaluated in 28 patients 24-36 hours before surgery and p.o. after 1, 3 and 6 days: 16 patients underwent "open" cholecystectomy and 12 LC. One day after surgery patients with open cholecystectomy showed significant increase (p < or = 0.05) of plasma neutrophils and 6-Interleukin, while these parameters were almost unchanged in patients with LC. Moreover, skin tests showed ipo or anergic response in the majority (81.8%) of patients with "open" surgery compare to patients with LC (10.5%): (p < or = 0.05). Finally monocyte antigen HLA-DR was also reduced in patients with "open" cholecystectomy: in this group we also recorded 2 cases (12.5%) of respiratory tract infection. In conclusion, LC for acute cholecystitis, avoids p.o. immunosuppression with better p.o. morbidity compare to open surgery.

[Chronic abdominal pain: role of video-laparoscopic adhesiolysis]. / Il dolore addominale cronico: ruolo della adesiolisi videolaparoscopica.

Adhesions have been suggested as a possible cause of chronic abdominal pain, but the reports of their etiological role conflict. Lysis of adhesions has been proposed as the therapeutic modality of choice, although the reports of success are controversial. The aim our prospective study was to determine whether laparoscopic adhesiolysis ameliorates chronic abdominal pain in patients with abdominal adhesions. Forty-one patients with chronic abdominal pain lasting for more than 6 months, but with no abnormal findings other than adhesions found at laparoscopy, underwent laparoscopic adhesiolysis. 37 patients (90.2%) were available for follow-up after a median time interval of 18 months (range: 12-41 months). Twenty-two patients (59.4%) were free from abdominal pain and 9 (24.3%) patients reported significant amelioration of their pain. Six (16.2%) patients had no amelioration. In conclusion the laparoscopy is an effective tool for the evaluation of patients with chronic abdominal pain, and laparoscopic adhesiolysis cures of ameliorates chronic abdominal pain in more than 80% of patients.

Expression of distinct conformations of free HLA-Cw4 heavy chains in transfected neuroblastoma cells.

Epitope mapping of HLA-Cw4 indicates that the two monoclonal antibodies (mAbs) L31 and M38, specific for beta 2-microglobulin (beta2m)-free HLA-C heavy chains, react preferentially with the KYK motif, located in the binding groove (alpha1 domain). Transfection of HLA-Cw4 cDNA into a neuroblastoma cell line, which normally expresses negligible HLA class I, resulted in the constitutive surface expression of molecules displaying different reactivities with the two mAbs. This cellular system was used to determine whether L31 and M38 recognize distinct conformations of beta2m-free HLA-C proteins, and to investigate their mechanism of expression. Interferon-gamma greatly enhanced the expression of L31-reactive free chains, while abolishing that of M38-reactive molecules. The cytokine-induced expression of L31-reactive molecules was inhibited by anti-sense oligonucleotides specific for beta2m mRNA, while constitutive expression of L31-reactive molecules was only partially affected. Exogenous beta2m resulted in a reduction of constitutive L31 reactivity, and in a concomitant increase of M38 reactivity. These results indicate that: 1) at the cell surface, L31 and M38 react with two distinct conformations of HLA-Cw4 beta2m-free heavy chains, of which the L31-reactive conformation is the least folded; 2) the expression of both conformers can be modulated by endogenous or exogenous beta2m; and (3) L31-reactive molecules exposed at the cell surface are likely to derive from the dissociation of empty HLA-Cw4/beta2m complexes.

[Cholelithiasis in the patient with cirrhosis of the liver: surgical aspects]. / La calcolosi della colecisti nel paziente con cirrosi epatica: aspetti di interesse chirurgico.

Open cholecystectomy in cyrrotic patients with good liver functions has operative mortality similar to normal subject (0.5-1%), while in patients with severe hepatic cyrrosis mortality varies between 7 and 83%. In this study we have evaluated the post operative results in cyrrotic patients undergone to open cholecistectomy in order to evaluate indications, controindications and risk factors related to surgery. In the last 7 years 34 patients with liver cyrrosis have been operated for biliary calculi, one of them had laparoscopic cholecystectomy. Morbidity was 29.4% (10 cases) mortality 8.8% (3 cases). Jaundice was the main indication for emergency (66.6%) in the two cases it was related to uncompensated liver functions. Endoscopic Retrograde Cholangio-Pancreatography (ERCP) can demonstrate today the causes of jaundice avoiding unecessary operations. Post operative evaluations of our series confirm that operative risk is strictly related to epatic disease and to an appropriate surgical option. Moreover patients with compensated liver cyrrosis, (Child A), do not represent anymore a controindication to laparoscopic cholecystectomy that has less septic post operative complications when compared to open surgery.

Expression of beta 2m-free HLA class I heavy chains in neuroblastoma cell lines.

Flow cytometry with the specific monoclonal antibody (MoAb) L31 was used to analyse the expression of HLA class I heavy chains not bound with beta 2-microglobulin (beta 2m) by neuroblastoma (NB) cell lines IMR-32 and LA-N-1. The cells, which express barely detectable amounts of beta 2m-free (L31-positive molecules) and beta 2m-complexed HLA class I antigens (W6.32- and BBM.1-reactive molecules), expressed MHC class I molecules not bound to light chains upon differentiation with either retinoic acid or serum starvation. The expression was not accompanied by an increase of surface heterodimers. Conversely, recombinant interferon-gamma (rIFN-gamma) treatment led IMR-32 and LA-N-1 cells to almost exclusively express beta 2m-complexes HLA class I heavy chains. Surface beta 2m-free MHC class I molecules displayed a molecular mass of approximately 45 kDa and did not bind exogenously added beta 2m. No changes in the synthesis of either HLA class I and beta 2m mRNAs or of L31 proteins were observed in differentiated NB cells, thus suggesting that the surface exposure of unusual HLA class I antigens is regulated post-translationally. These findings indicate that, in addition to activated lymphocytes, the surface expression of beta 2m-free class I heavy chains is a feature of other cell types, such as NB cells.