Mapping of MRX81 in Xp11.2-Xq12 suggests the presence of a new gene involved in nonspecific X-linked mental retardation

X-linked nonspecific mental retardation (MRX) accounts for approximately 25% of mental retardation in males. A number of MRX loci have been mapped on the X chromosome, reflecting the complexity of gene action in central nervous system (CNS) specification and function. Eleven MRX genes have been identified, but many other causative loci remain to be refined to the single gene level. In 21 MRX families, the causative gene is located in the pericentromeric region; and we report here the identification by linkage analysis of a further such locus, MRX81. The new MRX locus was identified by two- and multi-point parametric analysis carried out on a large Italian family. Tight linkage of MRX81 to DNA markers ALAS2, DXS991, and DXS7132 was observed with a maximum LOD score of 3.43. Haplotype construction delineates an MRX81 critical region of 8 cM, the smallest MRX pericentromeric interval so far described, between DXS1039 and DXS1216, and placing it in Xp11.2-Xq12. So far, automated sequencing of two candidates in the region, the MRX gene oligophrenin (OPHN1) and the brain-specific ephrinB1 (EFNB1) gene, in DNA from affected males excluded their candidacy for MRX81, suggesting a novel disease gene.     

Kinetic Studies of the Copolymerization of Ethylene with Norbornene by ansa‐Zirconocene/Methylaluminoxane Catalysts: Evidence of a Long‐Lasting “Quasi‐Living” Initial Period

Copolymers of ethylene (E) with norbornene (N) were synthesized using the catalysts rac‐Et(Ind)₂ZrCl₂/MAO ( 1 ), 90%rac/10%meso‐Et(4,7‐Me₂Ind)₂ZrCl₂/MAO ( 2 ), and rac‐H₂C(3‐t‐BuInd)₂ZrCl₂/MAO ( 3 ). Catalyst activity, molar mass (MM), and copolymer composition were studied as a function of time. The polymers showed an unusually narrow molar mass distribution (MMD) and a significant increase of their MM with time for up to one hour, suggesting a “quasi‐living” polymerization at 30 °C. The experimental data were fitted to kinetic equations and the propagation and transfer reactions were described in quantitative terms. Norbornene greatly depressed the propagation rate, along with the chain transfer rate. The more sterically hindered catalysts of the series showed lower propagation and chain transfer turnover frequency than 1 and yielded polymers with a low ( 2 ) to very low ( 3 ) norbornene content. The presence of norbornene in solution seemed to be one of the main factors responsible for the observed “quasi‐living” character of the copolymerization, probably due to coordination of norbornene to the active site. Time‐resolved kinetic studies also allowed for the calculation of the fraction of active metal centers, ranging from 56% ( 3 ) and 66–68% ( 1 ) to 94% ( 2 ) of the total zirconium present, depending on catalyst structure.

Left: molar mass (top) and polydispersity (bottom) as a function of the normalized polymer yield. The dashed line is the theoretical curve for ideal living polymerization. Catalysts 1 (□), 2 (?), and 3 (○) at N/E ratio 12.5 and catalyst 1 (?) at N/E ratio 28.4. Right: enlargement of the low yield section.     

Characterization of 27-hydroxy-13-desmethyl spirolide C and 27-oxo-13,19-didesmethyl spirolide C. Further insights into the complex Adriatic Alexandrium ostenfeldii toxin profile

Alexandrium ostenfeldii is a widespread toxic dinoflagellate that has recently bloomed across the Adriatic Sea, seriously threatening both shellfish consumers and aquacultures. In 2007 we reported on preliminary studies carried out on field samples and cultures of A. ostenfeldii. At the time, along with three major spirolides – among which 27-hydroxy-13,19-didesmethyl spirolide C (3) proved to be a novel compound – a number of new minor spirolides were detected. Unfortunately, for all of them only Mass Spectrometry-based structural hypotheses could be ventured due to their very small amount. In the present paper we report on isolation and High Resolution Mass Spectrometry- and NMR-based structural elucidation of two of those minor spirolides detected in our previous study.     

Anti-inflammatory effects of combined treatment with acetyl salicylic acid and atorvastatin in haemodialysis patients affected by Normal Weight Obese syndrome.

Low-grade inflammation is a common feature of chronic kidney disease (CKD) and persistent systemic inflammation is thought to be a strong predictor of cardiovascular events. Inflammation plays a role in determining the serum albumin levels in haemodialysis patients (HD) independently of the nutritional status. Increased cardiovascular mortality in CKD has been associated with the increased incidence of obesity in uremic patients. Ingenbleek suggested a prognostic inflammation and nutritional index (PINI), based on serum albumin, pre-albumin, C-reactive protein, and alpha1 acid glycoprotein, to identify and to follow up acutely ill patients at risk of major complications. The aims of the present study were: to verify the incidence of Normal Weight Obese (NWO) syndrome; to evaluate by PINI the effect of 8 weeks acetyl salicylic (100 mg/die) and atorvastatin (10 mg/die) combined treatment on chronic inflammation in 52 selected HD patients. Laboratory evaluation, anthropometric and body composition measurements were detected. At baseline the 56.25% of non-obese, the 84.21% of pre-obese-obese, and the 41.17% of NWO women showed PINI values >1 (normal status PINI<1). After the pharmacological treatment, high significant (P<0.001) reduction in lipid profile, an elevated increase of HDL levels, and a significant reduction of inflammatory markers were obtained. Firstly, our results showed that ASA and atorvastatin combined treatment was effective in reducing inflammatory status in HD patients independently of body composition: at the end of the study only 7.49% of the patients exhibited PINI>1. Further studies will be necessary to understand the causes of inflammation in non-responder patients.     

Surveillance of suspected adverse reactions to natural health products: the case of propolis.

Natural health products are promoted to the public as equally or more effective and less toxic than conventional drugs. However, some 'natural' medicines are known to have adverse effects. From April 2002 to August 2007, 18 suspected adverse reactions associated with propolis-containing products were reported to the national surveillance system of natural health products, coordinated by the Italian National Health Institute. Sixteen reports concerned allergic reactions (with dermatological or respiratory symptoms), while two concerned the digestive tract. Some of the reactions were serious: six patients were admitted to hospital or visited an emergency department and in two of these a life-threatening event was reported. In seven patients (four of whom were children), an allergic predisposition was indicated. Propolis, a resinous substance collected by honeybees from the buds of living plants, has been used for several purposes (dermatitis, laryngitis, oral ulcers) because of its wide range of suggested activities (antibacterial, antiviral, antifungal, anti-inflammatory, antioxidant and chemopreventive actions). However, propolis is also a potent sensitizer and should not be used in patients with an allergic predisposition, in particular an allergy to pollen. In Italy, products containing bee derivatives (bee pollen, royal jelly or propolis) are available to the public as food supplements. No label warning of possible adverse reactions is found on the packaging, although it is well known that atopic and asthmatic individuals may be at an increased risk of allergic reactions after using these products. The public and healthcare practitioners should be aware of the risk of allergic reactions to products derived from bees and a warning should be added to the packaging of these products.     

Total thyroidectomy for management of benign thyroid disease: review of 526 cases

Total thyroidectomy is not frequently performed in cases of benign disease because of the associated risk of postoperative hypoparathyroidism and recurrent laryngeal nerve (RLN) damage. We chose a series of patients who had undergone total thyroidectomy (TT) for benign thyroid tumors to evaluate the safety of this approach and its role in the treatment of nonmalignant lesions of the thyroid. We considered only patients with a minimum follow-up of 24 months. Records of 526 patients who underwent TT were carefully reviewed, assessing for perioperative complications and late sequelae. The mean age was 44 +/- 15.7 years; 109 patients (20.7%) were male and 417 (79.3%) were female. Altogether, 65 patients (12.3%) were operated on for toxic goiter, 429 (81.6%) for bilateral nodular goiter, and 32 (6.1%) for thyroiditis. Postoperative hemorrhage requiring reoperation occurred in 8 cases (1.5%). The incidences of permanent RLN palsy (considered as a percentage of the nerves at risk) and permanent hypocalcemia were 0.4% and 3.4%, respectively. A trend toward a decrease in the complication rate was observed during the last 5 years. There were no disease recurrences during a mean follow-up of 44 months. The results of our series show that TT can be performed safely in patients, with a low incidence of lifetime disabilities. TT has the advantage of reducing/avoiding the risk of disease recurrence and reoperation and should therefore be considered a valuable option for treating benign thyroid diseases.     

Dual effect mediated by protease-activated receptors on the mechanical activity of rat colon

1. The present study examined the mechanical effects of agonist enzymes and receptor-activating peptides for protease-activated receptor (PAR)-1 and PAR-2 on longitudinal and circular muscle of rat isolated colonic segments in the attempt to clarify the PAR functional role in intestinal motility. 2. The responses to PAR-1 and PAR-2 activation were examined in vitro by recording simultaneously the changes of endoluminal pressure (index of circular muscle activity) and of isometric tension (index of longitudinal muscle activity). 3. Both PAR-1 agonists, thrombin (0.1 nM - 3 microM) and SFLLRN-NH2 (1 nM - 3 microM), and PAR-2 agonists, trypsin (0.1 nM - 10 microM) and SLIGRL-NH2 (1 nM - 10 microM), induced different effects in the two muscular layers: a reduction of the spontaneous contractions in the circular muscle and a contractile effect or biphasic, relaxation followed by contraction, depending on the concentration, in the longitudinal muscle. 4. The inhibitory effects were greatly reduced or abolished by apamin (0.1 microM) indicating that they mainly occur via activation of Ca2+-dependent small conductance, K+-channels. 5. The responses to PAR-1 and PAR-2 were unaffected by tetrodotoxin (1 microM) or indomethacin (1 microM) suggesting that are independent by products of cyclooxygenase or by neural action potentials. 6. These findings indicate that both PAR-1 and PAR-2 are functionally expressed in rat colon. PARs mediate changes of the mechanical activity of longitudinal and circular muscle which might explain the alterations of colonic motility observed during inflammatory conditions.     

Teratogenic potential of the newer antiepileptic drugs: what is known and how should this influence prescribing?

The treatment of women of childbearing age who have epilepsy raises many questions because of the interactions between epilepsy, antiepileptic therapy and different aspects of reproductive life. Menstrual cycle disorders and reduced fertility have been partially ascribed to antiepileptic drugs (AEDs). Furthermore, most AEDs induce the cytochrome P450 (CYP) enzymatic system, altering the metabolism of sex hormones and contributing to the failure of oral contraceptives. Pregnancy represents, in this context, the most critical period because of the well known teratogenic potential of all established AEDs. For most of these drugs no specific patterns of malformations have been identified, although during the past few decades basic knowledge has been acquired, particularly concerning the mechanisms of AED-induced teratogenesis and related risk factors. These issues form the basis of the current guidelines for the management of epilepsy in pregnant women. In the past decade, several new AEDs have been introduced into clinical practice. For a number of reasons, these drugs appear to be more favourable than the older ones as treatments for epilepsy in women of childbearing age. They possess a good pharmacokinetic profile that makes them more stable during pregnancy, and they have a low potential for interaction with other drugs. They are also less likely than the older AEDs to be metabolised to compounds that are teratogenic. Furthermore, most of them do not possess antifolate properties. With the exception of topiramate and vigabatrin, the newer AEDs do not appear to be teratogenic in animals when administered in subtoxic doses. However, animal teratology may not be a reliable predictor of human teratogenicity, and there is a significant lack of information regarding the teratogenic profile of these newer agents in humans. Because clinical experience with these agents is limited, it is advisable to avoid exposure of the embryo to these drugs when pregnancy is planned. The establishment of pregnancy registries could allow for the rapid collection of data related to the administration of new AEDs in pregnancy and the outcomes of such exposure.     

A new rapid bedside assay for quantitative testing of D-Dimer (Cardiac D-Dimer) in the diagnostic work-up for deep vein thrombosis

The accuracy of a new bedside, rapid and quantitative D-Dimer assay (Cardiac D-Dimer) was evaluated in outpatients with clinically suspected deep vein thrombosis (DVT); VIDAS test was used as reference method. Eighty consecutive outpatients with suspected DVT of a lower limb were included in the study. Patients were classified as DVT positive or negative according to results of objective test (serial CUS), pretest clinical probability and 3-month follow-up. DVT was diagnosed in 32/80 patients (40%). The performance of the two D-Dimer assays was comparable, as indicated by the areas under the ROC curves (0.89 and 0.88, for Cardiac D-Dimer and VIDAS, respectively) and the coefficient of correlation (r=0.91). The reproducibility of the test was acceptable (from 6.2% to 12.0%). The sensitivity and negative predictive values were 100% for both tests. The specificity (SP) and positive predictive values (PPV) were similar (SP: 50.0% and 52.0%, PPV: 57.1% and 58.2%, for Cardiac D-Dimer and VIDAS, respectively). The Cardiac D-Dimer test proved to be very accurate and produced results fully comparable to those obtained with the VIDAS test. Since the test can be directly performed in the emergency room within a few minutes, it seems to have great clinical potential. The place of this assay in the diagnostic strategy of DVT remains to be determined in prospective management studies.     

Intravascular hemolysis in patients with new-generation prosthetic heart valves: a prospective study

OBJECTIVE: A prospective clinical study was designed to assess the frequency and severity of intravascular hemolysis in patients with new-generation, normally functioning prosthetic heart valves. METHODS: Hemolysis was evaluated in 172 patients with a mechanical prosthesis (53 CarboMedics and 119 Sorin Bicarbon) and in 106 patients with a bioprosthesis (15 St Jude Medical Toronto, 19 Baxter Perimount, and 72 Medtronic Mosaic) in the aortic position, mitral position, or both. Aortic valve replacement was performed in 206 patients, mitral valve replacement in 59 patients, and double valve replacement in 13 patients. The presence of hemolysis was assessed on the basis of the level of serum lactic dehydrogenase and serum haptoglobin and the presence and amount of reticulocytes and schistocytes in the peripheral blood. Severity of intravascular hemolysis was estimated on the basis of serum lactic dehydrogenase. Clinical, echocardiographic, and hematologic evaluations were performed 1, 6, and 12 months after discharge. RESULTS: None of the 278 patients experienced decompensated anemia, whereas at 12 months, mild subclinical hemolysis was identified in 49 patients, 44 (26%) with a mechanical prosthesis and 5 (5%) with a bioprosthesis (P <.001). At multivariate analysis, independent predictors of the presence of subclinical hemolysis were mitral valve replacement (P <.001), use of a mechanical prosthesis (P =.002), and double valve replacement (P =.02). Frequency of hemolysis in patients with stented aortic bioprostheses was 3%, whereas it was absent in those with stentless valves. Among mechanical valve recipients, double versus single valve replacement (P =.04) and mitral versus aortic valve replacement (P =.05) were correlated with the presence of hemolysis; double valve recipients also showed a more severe degree of hemolysis (P =.03). In patients with a Sorin Bicarbon prosthesis, hemolysis was less frequent (22% vs 34%, P =.09) and severe (P <.001) than in those with a CarboMedics prosthesis. CONCLUSIONS: In normally functioning prosthetic heart valves, subclinical hemolysis is a frequent finding. A low incidence of hemolysis is found in stented biologic prostheses, and it is absent in stentless aortic valves. Modifications of valve design may contribute to minimize the occurrence of hemolysis in mechanical prostheses.