The nACHR4 594C/T polymorphism in Alzheimer disease

Alzheimer disease (AD) is the most common form of dementia with complex etiology and multifactorial origin. Although several neurochemical deficits have been described in AD patients, explanation of the nature of the cognitive disturbance is focused on the "cholinergic hypothesis." The neuronal nicotinic acetylcholine receptor (neuronal nAChR) belongs to the superfamily of ionic channel activated by ligand. This paper presents a population-based population association study, testing the hypothesis that variants of the nAChR gene confer genetic susceptibility to AD. The authors analyzed two cohorts constituted by 60 controls and 80 AD patients in which significant increase of 594T polymorphism in patients affected by AD versus controls was found. However, further studies are necessary to confirm this polymorphism trend and to establish the polymorphism functionality and its correlation with behavioral and cognitive deficit.     

Association between the HLA-A2 allele and Alzheimer disease

In the elderly, the most common cause of dementia is Alzheimer disease (AD), which is responsible for the age-related progressive neurodegenerative inflammatory condition mediated by the disease. It has been seen that several genetic and environmental factors are involved in AD onset. Epidemiologic data suggest that some genetic determinants of AD might reside in those polymorphisms that regulate immune inflammatory responses, such as the major histocompatibility complex (MHC). Therefore, several MHC polymorphisms have been in the spotlight of a large number of AD association studies. A possible association of HLA-A2 allele with increased susceptibility to AD has been the subject of debate for more than 20 years, even if the results of these studies, in the various populations, are discordant. Thus, to gain insight in this matter, the authors have studied the HLA-A2 allele for a possible association with sporadic AD in a homogeneous population of Italian patients. For this reason, the distribution of HLA-A2 allele in patients with sporadic AD and controls was analyzed by PCR-SSP assay. The results demonstrated a significant difference in the frequency of HLA-A2 allele between patients with sporadic AD and controls (46% versus 38%). Thus, these data confirm a positive role of HLA-A2 allele in the risk of developing AD. However, some of the observed discrepancies may result from clinical or genetic heterogeneity of the populations under study or methodologic biases. Besides, whenever external agents such as viruses play a role, these might different in the various populations leading to various associations. However, it has to be taken into account that there are many molecular HLA-A2 subtypes with different frequencies in various populations. Therefore, further studies should include molecular typing of HLA-A2 subtypes.     

Architectural (Type IA) focal cortical dysplasia and parvalbumin immunostaining in temporal lobe epilepsy

PURPOSE: We analyzed 26 surgically treated patients operated on for intractable epilepsy associated with type IA (architectural) cortical dysplasia, to investigate neuropathologic and immunocytochemical features, particularly of the gamma-aminobutyric acid (GABA)ergic system, and to compare the findings with those observed in normal cortex. METHODS: Routinely stained slides and serial sections immunostained for neurofilaments (SMI 311), microtubule-associated protein-2 (MAP-2), neuron-specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), parvalbumin (PV), calbindin (CB), and calretinin (CR) were processed. Some sections were processed by using single-immunoperoxidase procedures; others were processed for double immunofluorescence labelling and observed by confocal microscopy. The density of inhibitory PV-immunoreactive interneurons was quantitatively assessed in all patients and control cases by using a two-dimensional cell-counting technique on PV immunostained sections. RESULTS: The density of PV-immunoreactive interneurons was significantly reduced in this group of patients, whereas CB- and CR- positivity appeared similar to those in normal cortex. In five cases, architectural abnormalities, in addition to those that defined type 1A dysplasia, were present and characterized by abnormal clusters of neurons and laminar cellular loss in superficial cortical laminate. CONCLUSIONS: The reduction of PV expression in type IA cortical dysplasia suggests an impairment of the GABAergic system as a possible mechanism for the epileptogenicity; in addition, PV immunoreactivity can be helpful in the neuropathologic characterization of this form of cortical dysplasia.     

Is everybody always my friend? Perception of approachability in Williams syndrome

Individuals with Williams syndrome (WS) are well known for their friendly behaviour and tendency to approach strangers indiscriminately as if everybody were their friend. This tendency to approach strangers is mirrored in their ratings of unfamiliar face stimuli. Here we examined their perception of unfamiliar expressive faces and found that individuals with WS do not always see faces as being highly approachable. Happy faces were rated as more approachable by individuals with WS than by controls. In contrast, the other less approachable face stimuli were rated lower on approachability by individuals with WS than by controls. Thus, it appears that although individuals with WS will discriminate people in terms of approachability, they have difficulty inhibiting their strong compulsion towards social interaction. The form of this strong pro-social compulsion is discussed both in terms of friendliness and in terms of the heightened salience of social stimuli (social stimulus attraction).     

Dornase alfa as postoperative therapy in cystic fibrosis sinonasal disease

OBJECTIVE: To determine the benefit of nasally inhaled dornase alfa in patients with cystic fibrosis and nasal symptoms. DESIGN: Double-blind placebo-controlled trial. SETTING: Cystic Fibrosis Regional Center of Campania at the University of Naples "Federico II." PATIENTS: A total of 24 patients with cystic fibrosis and chronic sinusitis. INTERVENTIONS: Patients underwent sinonasal surgery during a 3-year period and received once-daily doses of either dornase alfa (2.5 mg) or hypotonic saline solution (5 mL) beginning 1 month after surgery and for a 12-month period. MAIN OUTCOME MEASURES: Primary outcomes were nasal-related symptoms and nasal endoscopic appearance; secondary outcomes were forced expiratory volume in 1 second, nasal computed tomography findings, and saccharine clearance test results. Patients were evaluated before and after treatment. RESULTS: After surgery, all outcomes were significantly improved for each treatment at 1 month (P<.05); primary outcomes were improved at 24 and 48 weeks in the group receiving dornase alfa (P<.05), and at 12 weeks in the group receiving placebo. Secondary outcomes were better in the dornase alfa group (P<.01) than in the placebo group at 12 months except for the saccharine clearance test results. In particular, median relative difference in forced expiratory volume in 1 second between dornase alfa and placebo was significantly improved in the dornase alfa group (P<.01). CONCLUSIONS: Nasally inhaled dornase alfa can be effective in patients with cystic fibrosis and sinonasal disease who do not respond to conventional therapy after surgical treatment. Further studies should be carried out to determine the long-term effect on sinus disease, recurrence of polyps, and quality of life.     

Confirmatory tests in the diagnosis of brain death: comparison between SPECT and contrast angiography

OBJECTIVE: Cerebral blood flow tests have increasingly been advocated for the confirmation of brain death (BD). Four-vessel angiography has been considered the most reliable investigation in the diagnosis of BD for >30 yrs, but it is invasive. (99m)Tc-HMPAO SPECT provides noninvasive, multiplanar imaging of brain tissue perfusion. The aim of this study was to check the reliability of SPECT compared with contrast angiography. DESIGN: Prospective, blind study. SETTING: Neurointensive care unit of a university hospital. PATIENTS: Consecutive clinically brain dead patients with flat electroencephalogram. INTERVENTIONS: BD was diagnosed according to Italian law. (99m)Tc-HMPAO SPECT and four-vessel angiography were performed in the same session; the rater of each investigation ignored the results of the other. Blood pressure, Sp(O2), and P(ECO2) were monitored throughout the study: any episode of hypoxia or hypotension caused exclusion of the patient from the study. MEASUREMENTS AND MAIN RESULTS: Twenty brain dead patients were enrolled. The cause of BD was head injury in seven cases (35%), subarachnoid hemorrhage in seven (30%), spontaneous hemorrhage in one (10%), brain tumors in two (10%), stroke in two (10%), and thrombosis of the sagittal sinus in one (5%). Both angiography and SPECT confirmed BD in 19 of 20 patients: angiography showed the absence of filling of intracranial arteries, while SPECT showed a picture of "empty skull." For the remaining patient, angiography showed slight and late filling of left vertebral, basilar, and posterior cerebral arteries, while SPECT showed faint traces of uptake in the posterior fossa on the right side and on the midline. For this patient, the tests were repeated 48 hrs later, and both showed the arrest of intracranial circulation, thus confirming BD. CONCLUSIONS: Our results confirm the reliability of SPECT in the diagnosis of BD; because SPECT is noninvasive, it is a good candidate for the "gold standard" of diagnosis.     

Tropisetron: optimal dosage for children in prevention of chemotherapy-induced vomiting

The antiemetic efficacy and tolerability of Tropisetron (Navoban, Novartis Pharma Switzerland AG, Bern), a selective 5-hydroxytriptamine receptor antagonist, has been assessed in the prevention of acute vomiting in children receiving chemotherapy for solid tumors. Tropisetron iv was given 30 min before administration of chemotherapy at a dose of 5 mg in children <20 kg body weight and at a dose of 10 mg in those >20 kg. A total of 50 children were studied in 189 courses of chemotherapy. Control of emesis was defined as total in absence of acute vomiting, as major if 1 or 2 events of acute vomiting occurred, and as not controlled if >2 events of acute vomiting occurred. Response was studied, taking into account Tropisetron dosage, degree of emetogenicity of the chemotherapeutic agents in pretreated and non-pretreated patients, and according to age groups. Tropisetron, administered in a single daily dose of 8-12 mg/m(2), was found to be very effective in completely controlling acute emesis in 92% of the courses of moderately and highly emetogenic chemotherapy administered to pediatric patients with solid tumors. Moreover, Tropisetron, at this dosage, did not lead to any adverse effects.     

The role of levamisole in the adjuvant treatment of stage III colon cancer patients: a randomized trial of 5-fluorouracil and levamisole versus 5-fluorouracil alone

Adjuvant 5-fluorouracil (5FU) and levamisole (Lev) have been considered standard treatment for stage III colon cancer patients. However, the uncertain contribution of Lev to the efficacy of treatment has led many oncologists to prefer the 5FU/leucovorin combination. To establish the role of Lev, we conducted a randomized trial comparing the 5FU/Lev combination with 5FU alone in patients with Dukes' C colon cancer. Patients with stage III colon cancer were randomized to receive 5FU alone (450 mg/m² IV bolus daily for 5 days and then, beginning at day 28, weekly for 48 weeks) or the same plus Lev (50 mg orally three times/day for 3 days, repeated every 2 weeks for 1 year). From December 1994 to March 1998, 92 patients were assigned to receive 5FU/Lev, and 93 were assigned to receive 5FU alone. Leukopenia and hepatic toxicity were more frequent in patients receiving 5FU/Lev as compared with those receiving 5FU (respectively, p=0.003 and p=0.039), whereas other toxicities were equivalent and mild in both arms. After a median follow-up time of 48 months, 80 patients have had recurrences (40 in each arm) and no advantages in terms of disease-free survival and overall survival could be demonstrated for the combination arm. The addition of Lev to 5FU does not seem to be relevant for the clinical activity of this adjuvant regimen, whereas toxicity related to Lev should be considered when an adjuvant treatment for stage III colon cancer patients is proposed.     

Stable expression of antisense urokinase mRNA inhibits the proliferation and invasion of human hepatocellular carcinoma cells

Urokinase-type plasminogen activator (u-PA) plays a key role in malignant tumor behavior. We have previously shown that the expression of high levels of u-PA mRNA in human hepatocellular carcinoma (HCC) biopsies was inversely correlated with the survival of the patients. In order to evaluate the involvement of u-PA in the invasive and infiltrating properties of HCC cells, the SKHep1C3 cell line was stably transfected with an expression vector containing the 5' portion (257 bp) of u-PA cDNA in the antisense orientation. u-PA mRNA expression and its protein level and enzymatic activity were specifically inhibited in the antisense transfectants. A comparable inhibition of the u-PA receptor (u-PAR) mRNA and protein was also evidenced in the antisense transfected cells compared with the control ones. At the functional level, the SKHep1C3-AS cells showed a significant reduction in proliferation, Matrigel invasion, and motility assays compared to parental and vector-alone cells. These results indicate that u-PA is an essential factor in the growth and invasiveness of human hepatocarcinoma cells. Antisense u-PA strategy might be a potential approach to reduce tumor growth as well as the invasive capacity of the malignant cells in HCC.