Histological and biological developmental characterization of the human cerebellar cortex

The aim of this study was to investigate the histological and biological features of the human cerebellar cortex development and differentiation. We analyzed 52 brains of fetal and infant death victims, aged from 17 gestational weeks to 12th postnatal month. In particular, in the cerebellar cortex at different ages we evaluated, besides the structural aspects, the expression of several biomarkers implicated in proliferative processes (c-fos, PCNA and apoptosis). We observed morphological patterns progressively evolving every month, from the indefinite structure of the second gestational trimester to the four-layered structure (external granular layer, molecular layer, Purkinje cell layer, internal granular layer) of the late fetal cortex and subsequently to the three-layered postnatal definitive morphology, due to involution of the external granular layer. The evaluation of the biological features of the cerebellar cortex showed high proliferative activity mainly confined to the transient external granular layer in prenatal life, and high apoptotic index after birth. Thus, the histological examination, better with the support of biomarker investigations, allows with accuracy to describe the dynamic sequence of steps that occur in human cerebellar cortex development and to establish in each case the age, namely the pre- or postnatal month of life. Consequently, we can diagnose delayed or altered processes of differentiation during the development of the human cerebellar cortex.     

Endoscopic treatment of benign tumors of the nose and paranasal sinuses.

OBJECTIVE: The endoscopic approach can be successfully employed for the treatment of benign tumors such as fibroosseus and vascular lesions, pleomorphic adenomas, gliomas, and schwannomas. STUDY DESIGN AND SETTING: Nineteen patients diagnosed with benign tumors of the nasal cavity and paranasal sinuses and treated using an endoscopic approach were retrospectively reviewed. The endoscopic approach was used exclusively in 15 cases and was associated with an external approach in 4 cases (due to an intracranial extension of the tumor in 3 patients and its location at the level of the anterior wall of the frontal sinus in the last case). RESULTS: The resection of the lesions was radical in 18 patients and subtotal in 1 case. The mean follow-up was 27 months and only 1 recurrence (5%) was observed in the juvenile angiofibroma group 20 months postoperatively. CONCLUSION: and significance In selected cases, endoscopic surgery can be considered an effective treatment for the resection of benign tumors involving the sinonasal tract.     

The risk of pneumonectomy over the age of 70. A case-control study.

OBJECTIVE: A higher mortality has been reported after pneumonectomy over the age of 70. The aim of the study was to quantify the additional risk due to age after standard pneumonectomy for lung cancer by a case-control study. METHODS: Our clinical database was reviewed to search for patients aged 70 years or more who underwent standard pneumonectomy for lung cancer between 1998 and 2005. A control group of patients younger than 70 (one case/two controls) was matched for sex, cardiovascular disease, American Association of Anaesthetists score, respiratory function, side of pneumonectomy, induction chemotherapy and stage. Overall mortality and morbidity were compared. Long-term survival data were also analysed. RESULTS: During the considered period, 35 patients aged 70 years or more underwent pneumonectomy (30 males, median age 73 years, 15 right-sided procedures). The control group was composed of 70 patients. The two groups were homogeneous in the variables used for matching. Overall mortality and morbidity were 11.4 and 54.2% in the elderly group as compared to 4.3 and 41.6% in controls (p-value not significant). Elderly patients experienced a higher rate of respiratory complications (25.7%) as compared to controls (8.3%, p=0.01). At univariate analysis, the only risk factor for death was the occurrence of respiratory complications (OR 6.5, CI 1.8-18.2). At multivariate analysis, age >or=70 years (OR 5.36, CI 1.48-19.3) and preoperative chemotherapy (OR 7.65, CI 2.04-28.6) were confirmed as predictors of respiratory complications. Five-year survival was 17.5% in the elderly group and 53.6% in the control group (p=0.003). Elderly patients with a better respiratory function (FEV1>70%) had a 5-year survival of 45.4%. CONCLUSIONS: In the elderly patients, the risk of respiratory complications after pneumonectomy is increased as compared to younger patients with equivalent respiratory function. Age and preoperative chemotherapy are independent risk factors for respiratory complications. A lower mortality and a better long-term survival are obtained in elderly patients with a better respiratory function (FEV1>or=70%).     

A new priority policy for patients with hepatocellular carcinoma awaiting liver transplantation within the model for end-stage liver disease system.

The best prioritization of patients with hepatocellular carcinoma (HCC) waiting for liver transplantation under the model for end-stage liver disease (MELD) allocation system is still being debated. We analyzed the impact of a MELD adjustment for HCC, which consisted of the addition of an extra score (based on the HCC stage and waiting time) to the native MELD score. The outcome was analyzed for 301 patients with chronic liver disease listed for liver transplantation between March 1, 2001 and February 28, 2003 [United Network for Organ Sharing (UNOS)-Child-Turcotte-Pugh (CTP) era, 163 patients, 28.8% with HCC] and between March 1, 2003 and February 28, 2004 (HCC-MELD era, 138 patients, 29.7% with HCC). In the HCC-MELD era, the cumulative dropout risk at 6 months was 17.6% for patients with HCC versus 22.3% for those patients without HCC (P = NS), similar to that in the UNOS-CTP era. The cumulative probability of transplantation at 6 months was 70.3% versus 39.0% (P = 0.005), being higher than that in the UNOS-CTP era for patients with HCC (P = 0.02). At the end of the HCC-MELD era, 12 patients with HCC (29.3%) versus 57 without HCC (58.8%) were still on the list (P = 0.001). Both native and adjusted MELD scores were higher (P < 0.05) and progressed more in patients with HCC who dropped out than in those who underwent transplantation or remained on the list (the initial-final native MELD scores were 17.3-23.1, 15.5-15.6, and 12.8-14.1, respectively). The patients without HCC remaining on the list showed stable MELD scores (initial-final: 15.1-15.4). In conclusion, the present data support the strategy of including the native MELD scores in the allocation system for HCC. This model allows the timely transplantation of patients with HCC without severely affecting the outcome of patients without HCC.     

Hepatitis B and Delta virus infection among heterosexuals,homosexuals and bisexual men

The hepatitis B virus (HBV) and hepatitis Delta virus (HDV) infection rates were estimated in patients attending a venereal disease outpatient clinic: 759 heterosexuals and 154 homosexual-bisexual men. The anti-HBC prevalence was higher in homo-bisexual men (68.8 per 100) than in heterosexuals (41.8 per 100), whereas HBsAg was roughly the same in the two groups (about 6 per 100). The anti-HBc prevalence rate among heterosexuals was higher than that estimated in hospital personnel from the same geographical area. A positive association between anti-HBc prevalence and present or past sexually transmitted diseases (STD) was found among homo-bisexual men. Anti-HBc was also positively associated with herpes simplex type 2 antibodies in both heterosexuals and homo-bisexual men. These data are consistent with the hypothesis that sexual behavior also plays a role in the spread of infection among heterosexuals. Ten of the 46 HBsAg-positive subjects were anti-HDV positive: 6 of the 36 heterosexuals and 4 of the 10 homosexuals. All HDV-positive subjects had present or past STDs. These findings suggest sexual transmission of HDV infection.     

An outbreak of cholera in a refugee camp in Africa

A total of 541 cases of cholera were observed between May 7 and July 19, 1985 among the 9,929 displaced persons present in a refugee camp in Africa.In spite of malnutrition and other diseases affecting this population, only 12 deaths occurred.Antiepidemic measures consisted of preparation of isolation-wards, treatment of contaminated materials, training of refugees and patient care. Mass prophylaxis, initially considered, was dropped before the end of the epidemic.Corresponding author.     

A subset of high-grade pulmonary neuroendocrine carcinomas shows up-regulation of matrix metalloproteinase-7 associated with nuclear β-catenin immunoreactivity,independent of EGFR and HER-2 gene amplification or expression

Nuclear translocation of β-catenin has been correlated with epidermal growth factor receptor (EGFR) overexpression/activation in nonsmall cell lung cancer. Less is known on β-catenin transactivation in high-grade pulmonary neuroendocrine tumors and on the status of β-catenin activating EGFR and human epidermal growth factor receptor 2 (HER-2) or β-catenin target genes cyclin D1 and matrix metalloproteinase-7 (MMP-7). β-catenin immunoreactivity was evaluated in 51 large-cell neuroendocrine carcinomas (LCNEC) and 45 small-cell lung carcinomas (SCLC). Nineteen cases were assessed for β-catenin gene exon 3 mutations, expression of MMP-7, and expression/gene amplification of EGFR, HER-2, and cyclin D1. β-catenin was expressed in all 96 high-grade neuroendocrine tumors, the vast majority (94%) showing >50% immunopositive cells. A disarrayed immunoreactivity, however, was commonly encountered consisting in variably altered membrane-associated patterns of staining along with progressive accumulation of cytoplasmic immunoreactivity. In LCNEC, but not in SCLC, the disarrayed patterns correlated with EGFR and HER-2 protein expression. β-catenin nuclear accumulation was found in nine tumors, including seven LCNEC and two SCLC, and was always associated with disarrayed immunoreactivity and increased MMP-7, but not cyclin D1 expression. These cases, however, did not show β-catenin gene mutations or EGFR and HER-2 gene amplification or expression. No association was found between nuclear β-catenin and any clinicopathological variable including patients' survival. The subcellular compartmentalization of β-catenin is profoundly altered in high-grade pulmonary neuroendocrine tumors. A minor subset of these tumors shows β-catenin nuclear accumulation in association with increased expression of MMP-7, but not of cyclin D1, independent of EGFR and HER-2 gene amplification or expression. The authors have no significant financial or other relationship with the manufacturers of any commercial products or commercial services presented in this paper     

Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies

Marfan Syndrome (MFS) is an autosomal dominant disorder of the connective tissue due to mutations of Fibrillin-1 gene (FBN1) in more than 90% of cases and Transforming Growth Factor-Beta-Receptor2 gene (TGFB2R) in a minority of cases. Genotyping is relevant for diagnosis and genotype-phenotype correlations. We describe the FBN1 genotypes and related phenotypes of 81 patients who were referred to our attention for MFS or Marfan-like phenotypes. Patients underwent multidisciplinary pertinent evaluation in the adult or paediatric setting, according to their age. The diagnosis relied on Ghent criteria. To optimise DHPLC analysis of the FBN1 gene, all coding regions of the gene were directly sequenced in 19 cases and 10 controls: heterozygous amplicons were used as true positives. DHPLC sensitivity was 100%. Then, DHPLC was used to screen 62 other cases. We identified 74 FBN1 mutations in 81 patients: 64 were novel and 17 known. Of the 81 mutations, 41 were missense (50.6%), 27, either nonsense or frameshift mutations and predicted a premature termination codon (PTC) (33%), 11 affected splice sites (13.6%), and two predicted in-frame deletions (2.5%). Most mutations (67.9%) occurred in cbEGF-like modules. Genotype was clinically relevant for early diagnosis and conclusion of the diagnostic work-up in patients with incomplete or atypical phenotypes.     

Co-expression of B7-1 and ICAM-1 on tumors is required for rejection and the establishment of a memory response

Although the transfection of B7-1 cDNA into a few mouse tumor cell lines can induce anti-tumor T cell immunity, its expression alone is ineffective in many other tumor cell lines tested. We were interested to study what factors limit B7-1 co-stimulatory activity, and decided to investigate whether B7-1 requires the cooperation of ICAM-1 to provide the minimal co-stimulatory signal for establishing an efficient anti-tumor immunity. We show that the transfection of B7-1 cDNA into three ICAM-1⁺ (plasmocytoma J558L, T lymphomas EL-4 and RMA), but not into two ICAM-1^? tumor cell lines (adenocarcinoma TS/A and melanoma B16.F1), is sufficient to induce their complete rejection in syngeneic mice. The expression of ICAM-1 is necessary for the rejection of the B7 expressing tumors, since the primary response elicited by B7-1⁺ EL-4 and RMA clones expressing reduced levels of ICAM-1 is severely reduced. Furthermore, super-transfection of ICAM-1 cDNA into B7-1⁺ adenocarcinoma and melanoma clones optimizes their primary rejection. Histologic examination of transfected tumors reveals that B7-1 and ICAM-1 exert a potent pro-inflammatory activity. The intra-tumor infiltration is composed of both eosinophils and lymphomono-cytes, and is already massive 5 days after the tumor challenge. The primary rejection of the B7-1⁺ ICAM-1⁺ tumors depends critically on CD8⁺ T cells, natural killer cells and granulocytes, but is independent of CD4⁺ T cells. Remarkably, in addition to its effects on the early phases of the immune response, the co-expression of ICAM-1 and B7-1 on tumors is also necessary for the efficient induction of a memory response. In fact, only the primary challenge with B7-1⁺, ICAM-1⁺ tumor cells protects the majority of the mice from a second injection of parental tumor cells. Collectively, our findings indicate that B7-1 and ICAM-1 are fundamental components for triggering the primary rejection of tumors and establishing a protective memory response. These findings may help to define new strategies for the rational application of co-stimulation in tumor immunotherapy.