Parietal interhemispheric transfalcine transtentorial approach for posterior incisural space lesions: from the lab to the operative room.

The operative approach to the posterior incisural space is challenging because of its deep location, the surrounding eloquent areas, and the intimate relationship with the deep veins. Several approaches have been proposed to manage the lesions in this region: supratentorial, infratentorial and a combination of them. Brain retraction, injury to the occipital lobe and corpus callosum, and venous bleeding are the principle drawbacks of these routes. We performed anatomical dissection study using 10 embalmed human cadaver specimens injected with colored latex exploring a different route, parietal interhemispheric transfalcine transtentorial (PITT). Then we used a PITT approach on two patients with posterior incisural space (PIS) lesions. The PITT approach led to successful and safe complete removal of PIS lesions in our cases. No complications were reported. The present approach could be a valuable option in case of PIS lesions, especially those associated with downward displacement of the deep venous complex; thanks to the gravity it reduce the complications related to the occipital lobe retraction and manipulation. Moreover, cutting the superior-anterior edge of the tentorium, the sub-tentorial space could be reached.

Neurological outcomes after surgery for spinal metastases in symptomatic patients: Does the type of decompression play a role? A comparison between different strategies in a 10-year experience.

INTRODUCTION: The impact of neurological deficits plays a role of inestimable importance in patients with a neoplastic disease. The role of surgery for the management of symptomatic spinal cord compression (SSCC) cannot be overemphasized, as surgery represents often the first and paramount step in patients presenting with motor deficits. The traditional paradigm of simple bilateral laminectomy for the treatment of spinal cord compression has been reviewed. The need to achieve a proper circumferential decompression of the spinal sac has been progressively highlighted in combination with the development of the more comprehensive and multidisciplinary concept of separation surgery. OBJECTIVE: The aim of this paper is to analyze different strategies of decompression, while evaluating whether circumferential/anterior decompression is able to guarantee a better control and restoration of neurological functions in patients with motor impairment, if compared to traditional posterior decompression. MATERIALS AND METHODS: This is a retrospective observational study investigating symptomatic patients that underwent surgical treatment for spinal metastases at author's Institutions from January 2010 to June 2019. Data recorded concerned patient demographics, tumor histology, peri-operative and follow-up neurological status (ASIA), ambulation ability, stability (SINS), grade (ESCC) and source of epidural compression and type of decompression (anterior/anterior-lateral (AD); posterior/posterior-lateral (PD/PDL); circumferential (CD)). RESULTS: A total number of 84 patients was included. AD/CD patients showed higher chance of neurological improvement and reduced rates of worsening compared to PD/PLD group (94.1%/100% vs 60.4%; 11.8% vs 45.8% respectively). Univariate logistic regression identified immediate post-operative improvement to be a significative protective factor for worsening at last follow-up. Stratifying patients for site of compression and considering anterior and circumferential groups, immediate post-operative neurological improvement, was mostly associated with AD and CD (p 0.011 and 0.025 respectively). Walking at last follow up was influenced by post-operative maintenance of ambulation (p 0.001). CONCLUSION: The necessity to remove the epidural metastatic compression from its source should be considered of paramount importance. Since the majority of spinal cord compression involves firstly the ventral part of the sac, CD/AD are associated with better neurological outcomes and should be achieved in case of circumferential or anterior/anterolateral compression.

Trans-sulcal versus trans-parenchymal approach in supratentorial cavernomas. A multicentric experience.

OBJECTIVES: Cavernous malformations (CM) are low-flow vascular lesions that can cause significant symptoms and neurological deficits. Different intraoperative surgical approaches have been developed. Aim of the present investigation is the comparison between the trans-sulcal approach (TS) and the trans-parenchymal neuronavigation-assisted approach (TPN) in a surgical series from two neurosurgical centers. The technique and clinical outcomes are discussed, with a specific focus on seizure outcome. PATIENTS AND METHODS: Clinical and radiological data from two neurosurgical centers ("A. Gemelli" Hospital in Rome and A.O.U. Città della Salute e della Scienza in Turin) were retrospectively reviewed in order to evaluate the different outcome of TS and TPN approach for cavernous malformation treatment. RESULTS: A total of 177 patients underwent surgical intervention for supratentorial CM, 130 patients with TPN approach and 47 with TS approach. TS approach was associated with higher rate of seizure in early post-operative period both in epileptic patients (p < 0,001) and in patients without history of seizures before surgery (p = 0,002). Moreover, length of incision (p < 0,001), area of craniotomy (p < 0,001) and corticectomy (p < 0,001) were bigger in TS than in TPN approach. Brain contusion (p < 0,001) and fluid collection (p < 0,001) were more likely to be discovered after TS approach. CONCLUSIONS: TPN is a valuable approach for resection of CM. Minor complications are significantly lower in TPN approach when compared with TS approach. In addition, it is associated with lower rate of early post-operative seizure and shorter length of stay.

Spontaneous regression of calcified thoracic herniations: Can Hounsfield-units radiodensity have a predictive value?

INTRODUCTION: Spontaneous regressions of calcified thoracic disc herniations (TDH) have been rarely described. Since now, no previous papers hypothesized that radiological factors could be able to predict the evolution of the herniation. This study shows that the radiodensity of the herniated material in herniations with spontaneous resolution might differ from that of operated herniations. METHODS: This is a retrospective study. A cohort of patients that underwent surgical removal of a calcified thoracic disc herniation has been compared to two cases conservatively treated and a case with spontaneous regression. CT scans were evaluated to compute the average radiodensity [in Hounsfield units (HU)] of the calcified components of the herniations. All the slices of the CT scans involving the calcification were evaluated in their axial images and in their coronal and sagittal reformations. Comparison of the slices radiodensity (spontaneously resolved versus surgically treated) was performed with the unpaired Student's t test. RESULTS: The mean density of calcification in the case with spontaneous regression was found to be 454 HU. In the control group of surgical cases observed, and the conservatively treated cases, the mean HU density showed higher values (respectively, 827 and 853 HU) (p < 0.01). CONCLUSION: Qualitative differences between calcified TDH that resolve spontaneously or need surgical treatment might be shown by differences of radiodensity. This comparative study, in spite of the limitations due to small numbers, provides a new insight in the interpretation of the phenomenon of spontaneous resolution of calcified TDH. These slides can be retrieved under Electronic Supplementary Material.

Quality of life in renal transplant patients over 60 years of age.

Kidney transplantation not only drastically improves the life-expectancy of hemodialyzed patients, but it also affords psychological and social advantages with improvements in short- and long-term personal and working lives. Quality of life (QoL) is one of the parameters of psychological well-being. There is an improvement of QoL from pre- to posttransplant, but it is not to the level of healthy samples. The aim of this study was to examine QoL in older renal transplant recipients. All recipients older than age 60 were included, with a minimum follow-up of 12 months. To measure QoL, the nationally standardized ShortForm-36 (SF-36) questionnaire was administered. The SF-36 responses by our patients were compared with national age- and gender-appropriate norms, and also between genders. The enrolled population included 19 women (36.5%) and 33 men (63.5%), with a mean age of 66.8 years (range, 60-73 years). Enrolled women reported significant limitations compared to gender- and age-matched norms in social activities (42.11 vs 70.58), perception of pain (22.11 vs 59.17), and general health perception (39.58 vs 48.69). Enrolled men reported significant limitations compared to gender- and age-matched norms in social activities (46.59 vs 78.35), perception of pain (18.18 vs 73.62), psycho-physical energy (50.15 vs 67.88), and general health perception (37.33 vs 61.66). No significant differences were noted between the genders. This study clearly showed how the psychological state was not as good as the clinico-physical recovery following renal transplantation in older recipients.

Effect of dietary protein restriction on the progression of renal failure: a prospective randomized trial.

One hundred twenty-eight patients with different renal diseases and chronic renal failure, stratified according to the underlying disease, were enrolled in a randomized controlled trial to investigate the effects on the rate of decline of renal function of two diets, a controlled protein diet (CPD) of 1 g protein/kg ideal body-weight (i.b.w.)/day, and a low-protein diet (LPD) of 0.6 g protein/kg i.b.w./day, given for 27.1 +/- 21.8 months. Dietary compliance was assessed by a dietary questionnaire, dietary interviews and measurement of 24-h urinary urea excretion. At the end of 6 months, actual mean protein intake was higher than expected (1.06 +/- 0.25 g/kg i.b.w./day) in CPD patients, and (0.80 +/- 0.21 g/kg i.b.w./day) in LPD patients: values were similar at 12 and 18 months after the time of enrollment. The end-point, defined as halving of creatinine clearance, was reached in 40% of patients on CPD, and in 28.6% of those on LPD (P = 0.038 by comparative life-table analysis). Multivariate regression analysis confirmed that CPD was associated with a higher risk of progression than LPD, and that two additional parameters (creatinine clearance at the time of randomization and average proteinuria during the follow-up) were significant independent risk factors, even more important than protein intake.

Treatment of proteinuric patients with a vegetarian soy diet and fish oil.

Our aim was to determine whether a longer period of treatment with a vegetarian soy diet with addition of fish oil supplements would accentuate the beneficial effects on hyperlipidemia and proteinuria of nephrotic patients we found in a previous study. After an 8-week baseline period on free diet, patients were randomly allocated either on soy diet alone (SD) or to SD plus 5 g/day of fish oil (SD + FO) orally for two months. Then they crossed over to the other treatment for two additional months. They finally resumed eating the free diet for 3 months. We selected 20 outpatients with chronic glomerulonephritis, proteinuria in the nephrotic range, fasting serum cholesterol > 250 mg/dl, mean serum creatinine concentrations 1.75 +/- 0.23 mg/dl. Serum lipid profile, urinary protein loss and nutritional parameters were monitored. With the soy diet, we obtained a significant decrease both of hyperlipidemia and of proteinuria. The effect of the soy diet on proteinuria increased over the 4 months. The addition of a moderate amount (5 g/day) of fish oil in a randomized cross-over design had no further beneficial effect. Stability of serum albumin, transferrin and the body mass index documented good nutritional status. In conclusion, the dietary manipulation with our vegetarian soy diet confirmed the beneficial effects on hyperlipidemia and proteinuria of nephrotic patients. Such effects persisted and even ameliorated after 4 months of diet. The addition of moderate oral supplements of fish oil did not potentiate the beneficial effect.

Effect of vegetarian soy diet on hyperlipidaemia in nephrotic syndrome.

Nephrotic patients with persistent proteinuria also have various lipid abnormalities that may promote atherosclerosis and more rapid progression of renal disease. We aimed to find out whether dietary manipulation can correct the hyperlipidaemia found in these patients. After a baseline control period of 8 weeks on their usual diets, 20 untreated patients with chronic glomerular diseases, stable long-lasting severe proteinuria (5.9 [SD 3.4] g/24 h) and hyperlipidaemia (mean serum cholesterol 8.69 [3.34] mmol/l) ate a vegetarian soy diet for 8 weeks. The diet was low in fat (28% of total calories) and protein (0.71 [0.36] g/kg ideal body weight daily), cholesterol free, and rich in monounsaturated and polyunsaturated fatty acids (polyunsaturated/saturated ratio 2.5) and in fibre (40 g/day). After the diet period the patients resumed their usual diets for 8 weeks (washout period). During the soy-diet period there were significant falls in serum cholesterol (total, low-density lipoprotein, and high-density lipoprotein) and apolipoproteins A and B, but serum triglyceride concentrations did not change. Urinary protein excretion fell significantly. The concentrations of all lipid fractions and the amount of proteinuria tended to return towards baseline values during the washout period. We do not know whether the favourable effect of this dietary manipulation on proteinuria was due to the qualitative or quantitative modifications of dietary protein intake or was a direct consequence of the manipulation of dietary lipid intake.

The murine IFN-gamma receptor does not transduce the activation signal to a murine promoter in human cells.

MuIFN-gamma receptor cDNA has been stably transfected in the human WISH cell line. A stable transfectant, denominated WISH-C2, expressed 46;000 receptors/cell whose affinity was similar to that observed on murine cells (Kd = 2.6 x 10(-9) M). When WISH-C2 cells were treated with Hu- or MuIFN-gamma, antiviral and antiproliferative activities were observed with HuIFN-gamma only. These findings suggest that other species-specific components associated to the binding site are required for the signal transduction. To overcome the complexity of measuring biological functions that very likely involve more than one regulatory and structural gene, we set up for the first time a system where a reporter gene driven by a murine promoter was used to directly evaluate the interaction of MuIFN-gamma receptor with an inducible promoter through the missing transducer factor.

Multiple cytokine interactions regulate Ly-6E antigen expression: cooperative Ly-6E induction by IFNs, TNF, and IL-1 in a T cell lymphoma and in its induction-deficient variants.

The cell surface Ly-6E antigen, known to play a role in T cell activation, is up-regulated by IFNs. In the present study, we investigated the possible interactions between IFNs and other cytokines in this regulation. As a model system, we used the YAC T cell lymphoma, in which Ly-6E is normally absent but can be highly induced both at the mRNA and surface protein levels by IFN-gamma or IFN-alpha/beta. The combination of the two IFNs was found to result in markedly synergistic Ly-6E induction in this cell line. Moreover, mutants of YAC cells were isolated that did not respond to the Ly-6E-inducing action of IFN-gamma or IFN-alpha/beta alone but did respond to their combination. Such a synergistic interaction is consistent with the notion that the two IFN types utilize different intracellular mechanisms to induce Ly-6E expression. Ly-6E induction mediated by IFN-gamma or IFN-alpha/beta was also enhanced by cotreatment with TNF-alpha or IL-1 alpha, which by themselves had no detectable Ly-6E-inducing effect. These two cytokines similarly synergized with IFNs to trigger a response in several Ly-6E-induction-deficient mutants. However, their action could be dissociated in one mutant (B54) where the response to IFN-alpha/beta was enhanced by TNF-alpha, but not by IL-1 alpha. Altogether, these data indicate that Ly-6E antigen expression is regulated by the interaction of several inflammatory cytokines, which may provide a mechanism for the local modulation of T cell activation. The YAC cell mutants described here should facilitate further analysis of the molecular bases of Ly-6E regulation.

The role of interferons in the resistance to murine cytomegalovirus.

The protective effect of IFN alpha/beta or IFN-gamma against MCMV infection in mouse embryo fibroblasts (MEF) of genetically resistant and susceptible strains have been examined. For this purpose, MEF derived from Balb/c, C3H, DBA2, C57BL6 mouse strains were used. Cells were pretreated for 24 hrs with either IFN alpha/beta or IFN-gamma and subsequently infected with MCMV at different M.O.I. No difference in susceptibility to MCMV was observed between untreated Balb/c, C3H, C57 and DBA2-MEF when infected at a M.O.I. of 5 whereas at a M.O.I. of 1 or 0.5 untreated DBA2-MEF displayed the highest susceptibility to viral infection. Pretreatment of MEF with IFN alpha/beta showed that the degree of protection to MCMV was dependent on the M.O.I. used. At a M.O.I. of 5, IFN alpha/beta did not inhibit viral replication in any MEF tested, whereas at a M.O.I. of 1 or 0.5 was protective in C3H-MEF and to a lesser extent in Balb/c-MEF. No protection was observed in DBA2 and C57-MEF. Different results were observed when MEF were pretreated with IFN-gamma. C57-MEF were protected when infected at a M.O.I. of 5 or 1; no protection was observed at a M.O.I. of 0.5. Balb/c-MEF were protected only at a M.O.I. of 1. No protection was observed in C3H and DBA2-MEF.

Affinity purification, peptide analysis, and cDNA sequence of the mouse interferon gamma receptor.

The receptor for mouse interferon gamma (IFN-gamma) was purified from detergent-solubilized plasma membranes of EL-4, a thymoma cell line which expresses a high number of receptors on its cell surface. The purification was carried out by immunoaffinity chromatography using an anti-receptor monoclonal antibody. The purified receptor was subjected to NH2-terminal sequence analysis as well as sequencing of endopeptidase-generated peptides. One of the peptides was found to be identical to a portion of the published amino acid sequence of the human IFN-gamma receptor deduced from cDNA. This information was utilized to construct a mixed-sequence oligodeoxynucleotide probe which permitted the isolation of a full-length cDNA clone coding for the mouse IFN-gamma receptor. The mouse IFN-gamma receptor cDNA is comprised of 105 base pairs of the 5'-untranslated region, an open reading frame coding for a 477-amino acid serine-rich protein having calculated Mr 52,276, and a 3'-untranslated region of 539 base pairs. The receptor is first synthesized as a pre-protein from which a 25-amino acid signal peptide is cleaved. The receptor contains a hydrophobic transmembrane portion near the center of the molecule. Northern blot analysis of various cell lines showed that each contained a single 2.0-kilobase mRNA. A direct correlation between the amount of IFN-gamma receptor mRNA and the level of receptor expressed on the cell surface was observed. The mouse and human IFN-gamma receptors are structurally similar, showing 51% over-all homology in amino acid sequence. Mouse IFN-gamma receptor cDNA when inserted in a mammalian shuttle vector and transfected into COS-7 monkey cells was able to direct the expression of specific binding activity for mouse IFN-gamma.

Analysis of murine interferon-gamma binding to its receptor on intact cells and solubilized membranes. Identification of an 80 kDa receptor.

The receptor for murine-interferon-gamma (Mu-IFN-gamma) has been characterized for its molecular size and equilibrium binding constant on a thymoma cell line, EL-4. Binding of 125I-IFN-gamma to intact cells and their solubilized membranes has shown a single class of receptor with Kd values of 1.9 x 10(-9) M and 1.3 x 10(-8) M, respectively. It was shown that solubilization of the Mu-IFN-gamma receptor with a Zwitterionic detergent (Chaps) preserves its binding activity. A direct comparison of the molecular mass of the Mu-IFN-gamma receptor on intact cells versus detergent-solubilized membranes was performed using a radiolabeled photoactivated crosslinking reagent and direct hybridization with 125I-labeled IFN-gamma on Western blots of solubilized receptor. The results indicate that both types of receptors have an identical molecular mass of approximately 80 kDa.

Functional characterization of murine cell lines expressing high, intermediate, or negative levels of surface receptors for interferon-gamma.

Using radioiodinated murine interferon-gamma (IFN-gamma), various cell lines were analyzed for their capacity to bind IFN-gamma and to respond to its biological activity as measured by activation of the 2',5'-oligoadenylate (2-5A) synthetase, induction of the antiviral activity, and inhibition of [3H]thymidine uptake. A T-cell lymphoma, EL-4, was found to express relatively high number of specific membrane receptors for IFN-gamma (60,000/cell) with a dissociation constant of around 9 X 10(-10) M. By contrast, a fibroblast cell line, K-BALB, transformed by the Kirstein murine sarcoma virus, was found negative for binding of radioiodinated IFN-gamma, even in the presence of high ligand concentrations. Other cell lines displayed numbers of receptors varying between 650 to 20,000 binding sites/cell with KD ranging between 5 X 10(-9) to 9 X 10(-10) M. When incubated with EL-4 expressing high levels of specific receptors, IFN-gamma caused stimulation of cell growth, but not resistance to viral (vesicular stomatitis virus) infection and expression of 2-5A synthetase. By contrast, when L1210 and TS/A cells, expressing intermediate levels of specific receptors, were incubated with IFN-gamma, inhibition of cell growth, induction of antiviral resistance and activation of 2-5A synthetase was observed. Finally, K-BALB cells, lacking specific receptors for IFN-gamma, were completely unsensitive to its biological activity. The present system could represent a useful model for the characterization of the interaction of IFN-gamma with target cells at molecular levels.

Interferons-alpha/beta- and -gamma-resistant Friend cell variants exhibiting receptor sites for interferons but no induction of 2-5A synthetase and 67K protein kinase.

A number of Friend leukemia cell variants with a interferon-gamma (IFN-gamma)-resistant phenotype have been isolated. They appear resistant to the antiproliferative action of IFN-gamma and to the induction of the antiviral state assessed by Friend leukemia virus release and vesicular stomatitis virus yield. Selection was performed via a prolonged exposure to increasing amounts of highly purified recombinant IFN-gamma of wild-type Friend cells or of variant clones thereof already resistant to IFN-alpha/beta (Affabris et al., 1982, Virology 120, 441-452). Only the clones derived from IFN-alpha/beta-resistant variants showed a phenotype fully resistant to IFN-gamma treatment while keeping their previously acquired resistance to IFN-alpha/beta. These cells are not deficient in high-affinity receptors for IFN-gamma so that their resistant phenotype appears to be mediated by events distal to binding of IFN-gamma to its receptors. Furthermore, analysis of IFN-induced dsRNA-dependent 2-5A synthetase and 67K protein kinase enzymatic activities, biochemical markers for cellular responses to IFN, showed that both these activities were not induced in IFN-alpha/beta and IFN-gamma-resistant clones when treated with either type of IFN. Accordingly, no increased expression of 2-5A synthetase mRNA(s) could be detected by probing poly(A)+-enriched RNA from cells exposed to IFN-alpha/beta or IFN-gamma treatment with murine or human specific cDNAs. On the other hand, no major changes in restriction patterns of 2-5A synthetase gene(s) were observed in these variant cells by restriction endonuclease digestion and Southern blotting. In addition, analysis of 2-5A synthetase mRNA induction, performed on wild-type cells, showed that the kinetic of induction due to IFN-gamma treatment is slower than that obtained with IFN-alpha/beta.

Activation of protein kinase C down-regulates IFN-gamma receptors.

Treatment of mouse EL-4 cells with intracellular activators of protein kinase C, namely 4-phorbol 12-myristate 13-acetate (PMA) and diacylglycerol, resulted in 90% reduction in cell surface interferon-gamma (IFN-gamma) receptors as judged by iodinated-IFN-gamma binding. This did not seem to be due to a decreased in the receptor affinity, since that of the remaining surface receptors appeared to be significantly increased as shown in Scatchard plot analysis. Kinetics experiments revealed that a PMA treatment as short as 15 min was sufficient to induce a decrease of 30% of IFN-gamma receptors, whereas the highest levels of down-regulation were observed after 60-90 min. Treatment of EL-4 cells with calcium ionophore, A23187, although ineffective by itself, dramatically increased the ability of suboptimal PMA concentrations to mediate IFN-gamma receptor down-regulation. Finally, specificity studies revealed that PMA is particularly effective in decreasing the binding of IFN-gamma to T-lymphocytes. Altogether these results suggest a possible involvement of protein kinase C in the regulation of IFN-gamma receptor expression.

Binding of murine 125I-labelled natural interferon-gamma to murine cell receptors.

Natural murine interferon-gamma (naMuIFN-gamma) produced by T-lymphoma cells (L12-R4) stimulated with phorbol myristic acetate was purified by use of an anti-MuIFN-gamma immunoadsorbent and was labelled with 125I to study its binding to murine cell receptors. All the cell lines examined bound naMuIFN-gamma, although the binding affinity varied considerably. By adding increasing concentrations of unlabelled naMuIFN-gamma in competition binding assays we determined dissociation constants (KD) of 8.2 X 10(-10) and 7.4 X 10(-10) M for L1210 and TS/A cells, respectively, and of 6.5 X 10(-9)M for L-929 cells. The numbers of receptors present per cell of these lines were 3000, 1000 2000 respectively. Highly purified naMuIFN-gamma as well as recombinant MuIFN-gamma competed for binding sites with 125I-labelled IFN-gamma on L1210 cells, although the latter displayed a KD greater than the former (5.8 X 10(-9) M compared to 8.2 X 10(-10) M). Moreover, protease, but not endoglycosidase, treatment of target cells prevented the subsequent binding of 125I-labelled IFN-gamma, suggesting that a protein moiety is involved in the binding of the ligand. These studies demonstrate that naMuIFN-gamma binds in a specific manner and with high affinity to murine cell receptors.

A method for the rapid detection of streptococcal group A antigen by specific monoclonal antibody.

In this study we evaluate the efficacy of a method for the rapid detection of group A streptococci employing a hybridoma mouse antibody specific against group A streptococcal carbohydrate. Using coagglutination technique we demonstrated an absolute specificity. The sensitivity was absolute if the preparation contained greater than or equal to 5 X 10(4) cocci. This test seems therefore a valid criterion for symptomatic patients with a larger number of group A streptococci in throat specimens, more sensitive than other methods, but not sensitive enough for carriers of few bacteria.