Correlation among olfactory function, motors' symptoms, cognitive impairment, apathy, and fatigue in patients with Parkinson's disease.

Although Parkinson's disease (PD) is usually considered as a movement disorder, it is strongly associated with non-motor symptoms (NMS), including smell and taste dysfunctions, cognitive impairment, apathy, fatigue, and autonomic dysregulation. Olfactory deficit is considered the most common NMS in PD preceding the motor symptoms for years. The aim of this study was to investigate olfactory function, cognitive impairment, apathy, and fatigue in patients with PD in comparison with healthy controls, and subsequently to analyse the correlations between these NMS and motor symptoms severity in subjects with PD. One hundred and forty-seven participants were enrolled (96 PD patients, mean age in years 67.5, SD 7.2; 51 healthy controls; mean age 65.1, SD 11.8). Olfactory function was evaluated using the Sniffin' Sticks test (odor detection threshold, discrimination and identification). The Montreal Cognitive Assessment (MoCA) was used to assess cognitive impairment. Apathy was examined by the self-report version of Starkstein Apathy Scale and fatigue was evaluated with the Parkinson's Disease Fatigue Scale. PD patients showed severe impairment in odor detection threshold, discrimination, and identification compared to healthy controls. Moreover, in PD patients, apathy and fatigue scores were significantly increased, while MoCA scores were decreased in comparison with controls. Multivariate linear regression analyses showed that both apathy and Unified PD Rating Scale (UPDRS) were associated with odor identification, discrimination and Threshold-Discrimination-Identification (TDI) score. In conclusion, our results reported changes in apathy and motor disability as significant predictors in alterations of odor identification, discrimination and TDI score. Furthermore, these data suggest that olfactory dysfunction might progress in tight relation with motor impairment UPDRS but also with non-motor symptoms such as apathy.

Perception of the Ebbinghaus illusion in four-day-old domestic chicks (Gallus gallus).

In the Ebbinghaus size illusion, a central circle surrounded by small circles (inducers) appears bigger than an identical one surrounded by large inducers. Previous studies have failed to demonstrate sensitivity to this illusion in pigeons and baboons, leading to the conclusion that avian species (possibly also nonhuman primates) might lack the neural substrate necessary to perceive the Ebbinghaus illusion in a human-like fashion. Such a substrate may have been only recently evolved in the primate lineage. Here, we show that this illusion is perceived by 4-day-old domestic chicks. During rearing, chicks learnt, according to an observational-learning paradigm, to find food in proximity either of a big or of a small circle. Subjects were then tested with Ebbinghaus stimuli: two identical circles, one surrounded by larger and the other by smaller inducers. The percentage of approaches to the perceptually bigger target in animals reinforced on the bigger circle (and vice versa for the other group) was computed. Over four experiments, we demonstrated that chicks are reliably affected by the illusory display. Subjects reinforced on the small target choose the configuration with big inducers, in which the central target appears perceptually smaller; the opposite is true for subjects reinforced on the big target. This result has important implications for the evolutionary history of the neural substrate involved in the perception of the Ebbinghaus illusion.

Xenon exposure in the neonatal rat brain: effects on genes that regulate apoptosis.

BACKGROUND: In the developing rodent brain, exposure to volatile anesthetics causes widespread neuronal apoptosis in several regions of the brain. Increasing evidence points to a possible neuroprotective role for the anesthetic gas xenon, following neuronal injury. To address this gap in understanding, we explored the transcriptional consequences of xenon in the brains of postnatal day 7 (P7) rats exposed to xenon compared to those of air-breathing animals, with particular emphasis on the mRNA transcript levels of Akt and c-Jun N-terminal kinase kinase 1 (JNKK1), which are important for cell survival and the activation of extrinsic neuroapoptotic pathways, respectively. METHODS: P7 Sprague/Dawley rats were exposed to air (75% nitrogen, 25% oxygen) or xenon (75% xenon, 25% oxygen) for 120 min (N=6/group). Forebrains were harvested for reverse transcription polymerase chain reaction, which enabled quantification of Akt and JNKK1 mRNA transcripts. Suppression subtractive hybridization was used to explore the "genetic signature" of xenon exposure. RESULTS: Compared to control air-breathing animals, xenon-breathing rats exhibited a 0.7-fold decrease in Akt mRNA expression (P<0.01) and a 1.6-fold increase in JNKK1 mRNA levels (P<0.05). CONCLUSION: The concomitant decrease in the Akt mRNA expression level and increase in the JNKK1 mRNA transcript level provide evidence that xenon has a neuroapoptotic effect in the developing rodent forebrain. Given these results, further study into the paradoxical neuroprotective and neuroapoptotic effects of xenon is warranted.

[Clinical value of antibodies to lysobisphosphatidic acid in patients with primary antiphospholipid syndrome]. / Significato clinico degli anticorpi anti acido lisobisfosfatidico nei pazienti con sindrome da antifosfolipidi primaria.

To assess the clinical value of anti-lysobisphosphatidic acid (anti-LBPA) antibodies in patients with primary antiphospholipid syndrome (APS), the sera of 140 primary APS patients were tested and compared with those of 70 control subjects affected with rheumatic systemic diseases (n. 24) or autoimmune thyroiditis (n. 46). Anti-LBPA anticardiolipin (aCL) and anti-beta2 Glycoprotein I (anti-beta2GPI) antibodies were determined using a "home made" ELISA method. Lupus anticoagulant (LA) was assessed using a series of clotting tests in accordance with the literature. IgG anti-LBPA was significantly prevalent in primary APS (p=0.000) with a sensitivity of 58.6% and a specificity of 92.9%. IgM anti-LBPA showed a significant frequency in primary APS (p=0.000) with a sensitivity of 28.6% and a specificity of 97.1%. Anti-LBPA's sensitivity and specificity for APS were lower or equal to those of aCL and anti-beta2GPI. The prevalence of anti-LBPA in the different clinical and laboratory subsets of APS was lower than those of aCL and anti-beta2GPI. It is interesting to observe that both IgG and IgM anti-LBPA were never found alone. The comparison between anti-LBPA and LA showed that the former had a higher sensitivity but a lower specificity. In conclusion, in view of our results anti-LBPA cannot at present be considered a further tool to be utilized to diagnose APS and to differentiate the different clinical and laboratory subsets of this disease.

Laboratory classification categories and pregnancy outcome in patients with primary antiphospholipid syndrome prescribed antithrombotic therapy.

BACKGROUND: A relationship between antibody profile and pregnancy outcome in patients with a previous diagnosis of primary antiphospholipid syndrome (APS) has not been clearly documented. METHODS: Women attending our Center with primary APS characterized by the presence in the blood of one or more of the following: Lupus Anticoagulant (LA), IgG/IgM anticardiolipin (aCL), IgG/IgM anti-human beta2-Glycoprotein I (abeta2GPI) antibodies (confirmed after a minimum of 3 months) were considered eligible for this study. Women who became pregnant during the study period with the exception of those with congenital thrombophilia or other congenital abnormalities were included in our analysis. Primary outcome events, defined as early abortion or fetal death, were evaluated in relation to the laboratory classification category assigned to each patient at the time they were diagnosed with APS. RESULTS: A total of 97 pregnancies occurring in 79 primary APS patients during the study period were analyzed. Twelve out of 97 pregnancies were unsuccessful, 11 out of 65 (16.9%) in category I patients (more than one positive laboratory test) and 1 out of 32 (3.1%) in category II patients (single positive test; adjusted hazard ratio 1.9; 95% CI, 0.2 to 18.9, p=0.6). Pregnancy loss took place in 10 out of 19 pregnancies (52.6%) in women belonging to category I with triple positivity and in 1 out of 46 pregnancies (2.2%) in patients with double positivity. The rate of pregnancy loss was more frequent in the 19 pregnancies of patients with triple positivity than in the 46 pregnancies of double positive patients (adjusted hazard ratio 23, 95% CI, 1.3 to 408, p=0.03). CONCLUSION: Poor pregnancy outcomes occur more frequently in category I than in category II primary APS patients. However, it has been seen that a greater predictability is achieved when category I patients are grouped into triple and double positivity states.

[Sensibility and specificity for pregnancy morbidity of anti-ß2-glycoprotein I antibodies in antiphospholipid syndrome]. / Sensibilità e specificità degli anticorpi anti-β2-glicoproteina I per l'impegno ostetrico della sindrome da anticorpi antifosfolipidi.

OBJECTIVE: This study aimed to evaluate the sensitivity and specificity of the anti-β2-glycoprotein I (GPI) antibodies for pregnancy morbidity in the antiphosoplipid syndrome (APS). METHODS: 335 women were recruited and on the basis of their clinical features were subdivided into 2 groups homogenous for number and age. The first (study) group contained the women whose pregnancy complications satisfied the classification criteria for APS. The second (control) group was made up of women with pregnancy complications not included in the classification criteria for APS. Anti-β2-GPI, anticardiolipin antibodies (aCL) and lupus anticoagulants (LA) were determined in all of these women. RESULTS: The only antiphospholipid antibodies occurring with a significant frequency (p=0,00) in the women with pregnancy criteria for APS were the IgG anti-β2-GPI and the IgG aCL present respectively in 23,92% and in 27,60% of the women. Its association was found to be significant (p=0,000). The distribution of the different levels of positivity of the IgG and IgM anti-β2-GPI in the patients of the study and control groups was not significantly different. The highest sensitivity for pregnancy complications was that of the IgG aCL and of the IgG anti-β2-GPI whose difference was not statistically significant. The comparison of the specificity of the IgG and IgM anti-β2-GPI with that of the IgG and IGM aCL was not statistically significant. CONCLUSIONS: The importance of determining the IgG anti-β2-GPI as part of routine laboratory testing of women with pregnancy complications typical of APS was confirmed. Together with IgG aCL these antibodies have proved to be the most sensitive and specific markers of pregnancy complications in APS.

[Assessment of the presence of mutations of the epidermal growth factor receptors in tumors of various histologies]. / Valutazione della presenza di mutazioni del recettore dell'epidermal growth factor in tumori di varia istologia.

Recent reports from US and Japan have established that mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (Egfr) occur in a subset of patients with lung cancer that respond to therapy with gefitinib, a TK inhibitor. To gain further insights into the role of Egfr in carcinogenesis of lung and tumors of diverse histology, that are currently under investigation with drugs of the same class, we have taken in examination a panel of tumors consisting in 110 pulmonary adenocarcinomas, 40 pulmonary squamous carcinomas, 40 gastric adenocarcinomas and 40 colorectal adenocarcinomas. The sequence analysis of exon 19 and 21 of the Egfr has allowed the identification of 10 cases exhibiting specific deletions in exon 19 and 1 case with point mutation in a conserved residue in exon 21. All Egfr mutations occur specifically in lung adenocarcinomas while tumors of different histology result unaffected. The rate of mutation affecting these other tumors is either very rare, involves different domains of the receptor or other tyrosine kinases. The molecular analysis of the Egfr gene can help identify patients that will benefit from gefitinib therapy.

Neurotrophins and neurotrophin receptors in human lung cancer.

The expression of neurotrophins (NTs) and related high- and low-affinity receptors was studied in surgical samples of histologically diagnosed human tumors of the lower respiratory tract. The experiment was conducted with 30 non-small cell lung cancer specimens and in eight small cell lung cancer specimens by Western blot analysis and immunohistochemistry to assess expression and distribution of NT and NT receptor proteins in tissues examined. Immunoblots of homogenates from human tumors displayed binding of anti-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and NT-3 antibodies as well as of anti-tyrosine-specific protein kinase (Trk) A, TrkB, and TrkC receptor antibodies, with similar migration characteristics than those displayed by human beta-NGF and proteins from rat brain. A specific immunoreactivity for NTs and NT receptors was demonstrated in vessel walls, stromal fibroblasts, immune cells, and sometimes within neoplastic cell bodies. Approximately 33% of bronchioloalveolar carcinomas exhibited a strong membrane NGF and TrkA immunoreactivity, whereas 46% adenocarcinomas expressed an intense TrkA immunoreactivity but a weak immunostaining for NGF within tumor cells. Moreover, squamous cell carcinomas developed an intense TrkA immunoreactivity only within stroma surrounding neoplastic cells. A faint BDNF and TrkB immunoreactivity was documented in adenocarcinomas, squamous cell carcinomas, and small cell lung cancers. NT-3 and its corresponding TrkC receptor were found in a small number of squamous cell carcinomas within large-size tumor cells. No expression of low-affinity p75 receptor protein was found in tumor cells. The detection of NTs and NT receptor proteins in tumors of the lower respiratory tract suggests that NTs may be involved in controlling growth and differentiation of human lung cancer and/or influencing tumor behavior.

Postchemotherapy late recurrence of non metastatic gestational trophoblastic disease following a partiale mole. A case report.

The authors describe a case of a 35-year-old woman who showed elevation of betahCG 13 months after the complete regression of betahCG values following chemotherapy for an incomplete mole. This case outlines the necessity for careful monitoring of betahCG levels in low risk gestational trophoblastic diseases for a period of time longer than one year after achieving the first clinical remission.

Localized (solitary) fibrous tumors of the pleura: an analysis of 55 patients.

BACKGROUND: Localized (solitary) fibrous tumors (LFTPs) of the pleura are rare, slow-growing neoplasms thought to originate from submesothelial connective tissue. The aim of this article is to present 55 new cases of LFTP, and to discuss the treatment of choice and the clinical behavior of such neoplasms. METHODS: From July 1990 to November 1999, 55 patients (32 male, 23 female) with an LFTP were surgically treated at our Institution. Neoplasms were considered to be malignant if one or more of the following histologic features were present: high cellularity with crowding and overlapping of nuclei; high mitotic activity; or mild, moderate, or marked pleomorphism. RESULTS: No operative mortality was reported. Forty-eight of the cases arose from the visceral pleura and seven arose from the parietal pleura. A local removal of the neoplasm with free surgical margins was accomplished by video-assisted thoracic surgery in 39 patients and by standard thoracotomy in 10 patients. Four patients underwent formal lung resections, 1 had thymectomy, and 1 had en bloc chest wall resection. Four malignant variants were identified. One patient developed local recurrence and underwent redo surgery with chest wall resection. One patient died of unrelated disease. The remaining patients are alive and disease free at a median follow-up of 53.2 months. CONCLUSIONS: LFTPs show a benign outcome in most of the cases. Video-assisted thoracic surgery, with intraoperative assessment of the surgical margins, represents the treatment of choice.

Stage-independent expression and genetic analysis of tp73 in neuroblastoma.

The tp73 gene, a tp53 homologue, has been sub-regionally mapped at 1p36.3, a chromosomal region frequently deleted in neuroblastoma. Due to its chromosomal localization and to the mono-allelic expression observed in some neuroblastoma cell lines, it was proposed that tp73 might be involved in the pathogenesis of neuroblastoma. Functional assays have demonstrated that tp73 can inhibit cell proliferation and induce apoptosis. The role of this gene in tumorigenesis, however, is still unclear. We analyzed tp73 expression in 95 sporadic neuroblastoma samples by RT-PCR and we detected the tp73 transcript in 46 cases (48.4%), without significant correlation with age, clinical stage or 3-year overall survival. A genetic polymorphism in the 2nd exon of tp73 was utilized to identify the transcribed allele in tumor-cell samples. Expression from only one of the tp73 alleles was found in 13 out of 16 heterozygous tumors, while in 3 samples both alleles were present. Genotype analysis of 73 patients and 150 controls showed a significant deviation (p = 0.0308) from the Hardy-Weinberg equilibrium for a tp73 allele only among neuroblastoma patients. The absence of correlation between tp73 expression and clinical stage, age and survival suggests that this gene does not play an essential function in the clinical course of the disease. However, the distribution of genomic tp73 alleles in patients indicates that a role of this gene in the development of neuroblastoma cannot be completely ruled out. Int. J. Cancer (Pred. Oncol.) 84:365-369, 1999.

Neuroblastoma in two siblings supports the role of 1p36 deletion in tumor development.

Familial neuroblastoma occurs rarely. We studied a family with three children; one of them has a disseminated (stage 4) and another has a localized (stage 2) neuroblastoma. We observed subtelomeric locus D1Z2 (1p36) deletion in both tumors by using double-color fluorescence in situ hybridization. The MYNC gene was found in single copy in both tumors. Loss of heterozygosity (LOH) and restriction fragment length polymorphism analyses were performed by using DNA from frozen tumor cells and from microdissected tumor areas excised from paraffin-embedded sections. We detected somatic LOH at locus D1S468 (1p36) in a tumor-cell population with a trisomy 1 of the stage-2 patient. Neuroblastoma cells of the stage-4 patient were diploid and showed allelic loss at the following loci: D1S172, D1S80, D1S94, D1S243, D1S468, D1S214, D1S241, and D1S164. Haplotype study showed that the siblings inherited the same paternal 1p36-->pter chromosome region by homologous recombination and that, in the two tumors, arm 1p of different chromosomes of maternal origin was damaged. Our results suggest that the siblings inherited the predisposition to neuroblastoma associated with paternal 1p36 region and that tumors developed as a consequence of somatic loss of the maternal 1p36 allele.

Paraganglioma of the cauda equina. Case report with 33-month recurrence free follow-up and review of the literature.

Paraganglioma of the cauda equina is an unusual tumor and do not have the secretory properties of the same tumors arising outside the nervous system. In none of the few cases reported in literature a preoperative diagnosis was possible, and the surgical findings raised questions in the differential diagnosis with ependymomas. A rare case of paraganglioma of the cauda equina studied both pre- and postoperatively by MRI, and treated with subtotal excision combined with radiotherapy is described. Results and recurrence rates of the cases reported in literature are reviewed. Though MRI imaging has proven to be more sensitive than other radiological procedures, we stress the difficulties of preoperative diagnosis of paragangliomas in this site. The correct diagnosis of the paraganglioma of the cauda equina still relies on immunochemistry and electron microscopy. Total excision is often very difficult owing the tendency of these neoplasms to infiltrate cauda's roots. A 33-month recurrence free follow-up of our patient confirms that successful treatment is achieved by subtotal resection combined with radiotherapy.

Effects of all-trans retinoic acid and interferon alpha in peripheral neuroectodermal tumor cell cultures and xenografts.

Peripheral neuroectodermal tumors (PNET) have an unsatisfactory outcome when treated with standard approaches. Among novel treatments, the use of biological response modifiers has rarely been reported in this group of malignancies. We have previously demonstrated that both all-trans retinoic acid (ATRA) and interferon á (IFNá) can inhibit proliferation of human PNET cells and that ATRA can up-regulate IFNá receptor expression in vitro. In this study we evaluated the anti-tumor effects of ATRA and IFNá in PNET cells in vitro and in a human PNET xenograft model, using CHP100 cells. A synergistic inhibitory effect of ATRA and IFNá was observed on CHP100 cells in vitro. On the contrary, a significant inhibition of tumor growth was observed in mice treated with ATRA alone, whereas neither IFNá nor the combination of ATRA and IFNá, reached a statistically significant anti-tumor effect. Histologic examination of tumors revealed the presence of necrosis upon treatment with IFNá, whereas almost no necrosis, but a more differentiated morphology, confirmed by electron microscopy analysis, was associated with the ATRA containing treatments. Taken together these data show an in vitro and in vivo anti-tumor activity of ATRA in human PNET cells, although no synergism of ATRA and IFNá was observed in our xenograft model.

Genetic changes associated with primary Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a malignant tumor of the skin with a well-established neuroendocrine phenotype but an unknown histogenetic origin. Cytogenetic and molecular studies have shown evidence for genetic changes on the distal portion of chromosome 1p in different tumors with well-established neuroendocrine origins, specifically neuroblastomas, malignant melanomas, and pheochromocytomas. Involvement of chromosome 1 in MCC recently has been demonstrated by cytogenetic analysis and analysis of loss of heterozygosity (LOH) in metastatic tumor tissue. We performed analysis of LOH of the distal portion of chromosome 1p in paraffin material of 10 primary MCCs after tissue microdissection, using the polymorphic markers D1S160, D1S243, D1S468, D1S1646, and D1S1598. Seven of 10 analyzed MCCs shared a distal deletion involving 1p35-36. None of the cases showed 1p involvement proximal to 1p35. The findings are similar to those described for malignant melanoma, pheochromocytoma, and neuroblastoma, tumors known to originate from neural crest cells. In conjunction with previous cytogenetic data, we conclude that Merkel cell carcinogenesis shares pathogenetic mechanisms with other neoplasms of neural crest derivation.

Expression and parental imprinting of the H19 gene in human rhabdomyosarcoma.

The expression of Insulin-like Growth Factor 2 (IGF-2) and H19, two genes located on human chromosome 11p15 and provided with cell growth modulating activity, is regulated by parental imprinting, in that the activity of their alleles is dependent on the parental origin. Parental bias in the genetic alterations of chromosome 11p15 observed in several pediatric cancers suggests the involvement of imprinted genes in tumor development. We have previously reported that the number of functional IGF-2 alleles is frequently increased in rhabdomyosarcoma (RMS), as a consequence of either relaxation of imprinting (LOI) or gene duplication. Here we show that the expression of the H19 gene is significantly suppressed with respect to normal muscle tissue in 13 out of 15 rhabdomyosarcomas with embryonal histology (ERMS) and in three out of 11 rhabdomyosarcomas classified as alveolar subtype (ARMS). Since a growth-inhibitory activity has been found associated with the H19 gene, the extinction of its expression can contribute to RMS development. Parental imprinting of the H19 gene was found conserved in all informative RMSs, including those whose ICF-2 imprinting was relaxed, indicating that LOI is a gene-specific event. Seven ERMSs and one ARMS displaying low H19 RNA levels showed an underrepresentation of the expressed allele in their genotype. This result is consistent with the paternal imprinting of the H19 gene and with the preferential loss of the maternal 11p15 alleles in these neoplasms. Low H19 expression was also found in four out of eight RMSs retaining the heterozygosity at 11p15, but showing IGF-2 LOI. These findings suggest that the genetic and epigenetic alterations affecting chromosome 11p15 in a high number of RMSs cause deregulation of more than one imprinted gene, possibly affecting tumor growth, including the extinction of H19 expression and an increase in the number of active IGF-2 alleles.

Sarcomatoid transitional cell carcinoma of the renal pelvis. A report of five cases with clinical, pathological, immunohistochemical and DNA ploidy analysis.

Sarcomatoid transitional cell carcinoma of the renal pelvis is a rare neoplasm with only 7 well illustrated examples reported. These tumours can assume a partial or complete spindle cell pattern of growth, leading to the erroneous classification as sarcomas. We describe the clinic-pathologic features of five additional examples of sarcomatoid carcinoma of the renal pelvis observed in three males and two females. The age ranged from 65-to-82 years-old (mean 71.6). All these patients were treated by nephrectomy and died of disease between 6 and 20 months (mean 11.2) after the onset of symptoms. An immunohistochemical study demonstrated coexpression of keratins, epithelial membrane antigen and vimentin. The image DNA ploidy of all the tumours showed an aneuploid pattern.

Intraoperative radioimmunolocalization of an anti-CEA MAb F(Ab')2 (FO23C5) in CEA serum-negative colorectal cancer patients.

Serum positivity to an antigen recognized by the monoclonal antibody (MAb) which will be administered is frequently being used as a predictive criterion for positive MAb tumor localization. In the present study, which is based on our previous data that clearly showed no correlation between quantitative levels of CEA in sera and in carcinoma tissues, we selected a population of 12 primary colorectal carcinoma patients which were serum CEA-negative. The main purpose was to assess the potential diagnostic use of Radioimmunoguided Surgery (RIGS) with an anti-CEA FO23C5 F(Ab')2 MAb and its clinical value in this series of patients. In all RIGS patients, the MAb localized to histologically confirmed tumor; this included 96% of primary tumor tissues, 29% of lymph nodes and one occult liver metastasis. Thus, serum CEA positivity should not be a criterion for the use of anti-CEA MAbs for the diagnosis of colon cancer, since the serum CEA level is not indicative of CEA expression in tumors.