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Background Heart Failure with Preserved Ejection Fraction remains to be a global health concern since there is no proven effective therapy as of the moment. Data from 2017 have shown that half of the population with heart failure has preserved ejection fraction (HFpEF) and there is an observed increasing trend in numbers. HFpEF carries significant disease burden and greatly affects Quality of Life. Objective To determine the efficacy of Vericiguat in improving the quality of life among patients with Heart Failure with preserved Ejection Fraction. Methodology A comprehensive literature search was made by the authors for Randomized Controlled Trials comparing the efficacy of Vericiguat with placebo in improving the Quality of Life among patients with HFpEF. Authors were contacted if there were missing data. Two authors independently extracted data and appraised the different studies' characteristics, quality and outcomes. RevMan 5.4 was used for the statistical analysis. Results The authors found two RCTs with 1,218 participants. Pooled analysis of the moderate to high quality studies showed no statistically significant mean difference in the different domains of the Kansas City Cardiomyopathy Questionnaire including the Clinical Summary Score, Physical Limitation Score, Total Symptom Score, and Overall Summary Score (1.61 [−1.44, 4.66] p=0.30; 2.22 [−1.16, 5.60] p=0.20; 0.14 [−3.00, 3.29] p=0.93; and 1.35 [−1.65, 4.35] p=0.38, respectively) between Vericiguat and placebo. For the safety and adverse events, there was no statistically significant difference between Vericiguat and placebo with regards to syncope, hypotension and death, with RR of 1.10 [0.06, 18.61] p=0.95; 1.22 [0.70, 2.14] p=0.48 and 1.79 [0.67, 4.75] p=0.24, respectively. Conclusion Vericiguat compared to placebo did not significantly improve the Quality of Life among adult patients with Heart Failure with Preserved Ejection Fraction. Funding Acknowledgement Type of funding sources: None.

Parkinson’s Disease (PD) is a neurodegenerative disease that causes damage to the cognitive and motor system due to the death of dopaminergic neurons, which are responsible for the synthesis of the neurotransmitter dopamine. The study aimed to compare the monoamine oxidase B (MAO-B) inhibitory activity of natural molecules described in the literature with Selegiline, as potential drugs for the treatment of PD through molecular modeling, molecular docking and prediction of ADME/Tox properties. Thus, it was found the structure of the four natural molecules, Amburoside A, Harman, Harmaline and Harmalol, showed antiparkinsonian biological activity. Maps Electrostatic Potential showed similar regions between the molecules, except for Amburoside A, and Harmaline had a greater similarity in the positive potential with Selegiline. Molecular docking demonstrated that the studied molecules interact with 4–6 amino acids from the active site of the MAO-B enzyme, indicating that it has an inhibitory action on the enzyme, through hydrogen bonding and hydrophobic interactions. For ADME property predictions, most of the molecules showed good human oral absorption, all showed average permeability in Caco-2 cells, most showed average permeability in MDCK cells, showed low binding to plasma proteins, and for permeability in the blood-brain barrier, they were between good and medium. Overall, Harmaline has more properties similar to Selegiline. For toxicological properties, all molecules including Selegiline showed a positive result for the possibility of mutagenicity, whereas for the parameter of carcinogenicity in rats only the molecules Harmaline and Harmalol were positive, but no molecule was positive for carcinogenicity in mice. Therefore, the molecule that presented the best results was Harmaline, opening perspectives for the execution of in vitro studies.

Mosquitoes in the genus Aedes are responsible for the four important human disease viruses, such as, dengue, yellow fever, chikungunya and Zika. Although important advances have emerged in the development of alternative measures for mosquito control, chemical insecticides still remain a vital part of integrated control programs. In this sense, a set of benzylidenemalononitriles were synthetized in very good yields (99-71%), using only water and glycerol at temperature room. A comparative study of the larvicidal activity between benzylidenemalononitriles showed that the 2g (R= 4-Cl) compounds possess much better larvicidal activity (LC50 and LC90 of 9.42 and 15.02, respectively at 24h). Study of molecular docking was applied to identify the mode iteration of compound 2g with binding site at the enzyme acetylcholinesterase, the profile of interaction showed a score 48.9795, with five bonds in three different amino acids.

Cannabis sativa withdrawal syndrome is characterized mainly by psychological symptoms. By using computational tools, the aim of this study was to propose drug candidates for treating withdrawal syndrome based on the natural ligands of the cannabinoid type 1 receptor (CB1). One compound in particular, 2-n-butyl-5-n-pentylbenzene-1,3-diol (ZINC1730183, also known as stemphol), showed positive predictions as a human CB1 ligand and for facile synthetic accessibility. Therefore, ZINC1730183 is a favorable candidate scaffold for further research into pharmacotherapeutic alternatives to treat C. sativa withdrawal syndrome.

Parkinson's Disease (PD) is the second most common neurodegenerative disease in the elderly population, with a higher prevalence in men, independent of race and social class; it affects approximately 1.5 to 2.0% of the elderly population over 60 years and 4% for those over 80 years of age. PD is caused by the necrosis of dopaminergic neurons in the substantia nigra, which is the brain region responsible for the synthesis of the neurotransmitter dopamine (DA), resulting in its decrease in the synaptic cleft. The monoamine oxidase B (MAO-B) degrades dopamine, promoting the glutamate accumulation and oxidative stress with the release of free radicals, causing excitotoxicity. The PD symptoms are progressive physical limitations such as rigidity, bradykinesia, tremor, postural instability and disability in functional performance. Considering that there are no laboratory tests, biomarkers or imaging studies to confirm the disease, the diagnosis of PD is made by analyzing the motor features. There is no cure for PD, and the pharmacological treatment consists of a dopaminergic supplement with levodopa, COMT inhibitors, anticholinergics agents, dopaminergic agonists, and inhibitors of MAO-B, which basically aims to control the symptoms, enabling better functional mobility and increasing life expectancy of the treated PD patients. Due to the importance and increasing prevalence of PD in the world, this study reviews information on the pathophysiology, symptomatology as well as the most current and relevant treatments of PD patients.

Made available in DSpace on 2018-12-11T17:29:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-01-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Tuberculosis (TB) remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide (NO) donors, have been described to exhibit antitubercular activity. Herein, a novel series of hybrid furoxan derivatives (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-c, 8a-c and 14a-c) were designed, synthesized and evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC90values ranging from 1.03 to 62 μM (H37Rv) and 7.0–50.0 μM (MDR-TB). For the most active compounds (8c, 14a, 14b and 14c) the selectivity index ranged from 3.78 to 52.74 (MRC-5 cells) and 1.25–34.78 (J774A.1 cells). In addition, it was characterized for those compounds logPo/wvalues between 2.1 and 2.9. All compounds were able to release NO at levels ranging from 0.16 to 44.23%. Among the series, the phenylsulfonyl furoxan derivatives (compounds 14a-c) were the best NO-donor with the lowest MIC90values. The most active compound (14c) was also stable at different pHs (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat tuberculosis. School of Pharmaceutical Sciences UNESP – Univ Estadual Paulista Dipartimento di Scienza e Tecnologia del Farmaco Università degli Studi di Torino School of Pharmaceutical Sciences UNESP – Univ Estadual Paulista FAPESP: 2013/14957-5 FAPESP: 2014/02240-1 FAPESP: 2014/11586-9 FAPESP: 2014/24811-0

Three series of biarylpyrazole imidazole and triazoles are described, which vary in the linker between the biaryl pyrazole and imidazole/triazole group. The imidazole and triazole series with the short −CH2– linker displayed promising antimycobacterial activity, with the imidazole–CH2– series (7) showing low MIC values (6.25–25 μg/mL), which was also influenced by lipophilicity. Extending the linker to −C(O)NH(CH2)2– resulted in a loss of antimycobacterial activity. The binding affinity of the compounds with CYP121A1 was determined by UV–visible optical titrations with KD values of 2.63, 35.6, and 290 μM, respectively, for the tightest binding compounds 7e, 8b, and 13d from their respective series. Both binding affinity assays and docking studies of the CYP121A1 inhibitors suggest type II indirect binding through interstitial water molecules, with key binding residues Thr77, Val78, Val82, Val83, Met86, Ser237, Gln385, and Arg386, comparable with the binding interactions observed with fluconazole and the natural substrate dicyclotyrosine.

Tuberculosis, caused by the Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide- containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 μM against active and non- replicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective leading to the reduction of the number of Mtb to undetected levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks the process of translation. Altogether, these results indicated benzofuroxan derivative 8 to be a promising lead compound for the development of a novel chemical class of antitubercular drugs.

In the search for new therapeutic tools against tuberculosis and to further address the therapeutic potential of pyridine-2-thiol 1-oxide (Hmpo) metal complexes, two new octahedral [M(III)(mpo)3] complexes, with M = Ga or Bi, were synthesized and characterized in the solid state and in solution. Attempts to crystallize [Ga(III)(mpo)3] in CH2Cl2 led to single crystals of the reaction product [GaCl(mpo)2], where the gallium(III) ion is in a square basis pyramidal environment, trans-coordinated at the basis to two pyridine-2-thiolato 1-oxide anions acting as bidentate ligands through their oxygen and sulfur atoms. The biological activity of the new [M(III)(mpo)3] complexes together with that of the previously reported Fe(III) analogous compound and the pyridine-2-thiol 1-oxide sodium salt (Na mpo) was evaluated on Mycobacterium tuberculosis. The compounds showed excellent activity, both in the standard strain H37Rv ATCC 27294 (pan-susceptible) and in five clinical isolates that are resistant to the standard first-line anti-tuberculosis drugs isoniazid and rifampicin. These pyridine-2-thiol 1-oxide derivatives are promising compounds for the treatment of resistant tuberculosis., Instituto de Física La Plata

Submitted by Guilherme Lemeszenski (guilherme@nead.unesp.br) on 2013-08-22T18:41:35Z No. of bitstreams: 1 S1517-83822013000100041.pdf: 618977 bytes, checksum: f53802b49d94a03483d316114de310f3 (MD5) Made available in DSpace on 2013-08-22T18:41:35Z (GMT). No. of bitstreams: 1 S1517-83822013000100041.pdf: 618977 bytes, checksum: f53802b49d94a03483d316114de310f3 (MD5) Previous issue date: 2013-01-01 Made available in DSpace on 2013-09-30T18:07:00Z (GMT). No. of bitstreams: 2 S1517-83822013000100041.pdf: 618977 bytes, checksum: f53802b49d94a03483d316114de310f3 (MD5) S1517-83822013000100041.pdf.txt: 19426 bytes, checksum: 0191b0cc8230f836e26db37792db58c6 (MD5) Previous issue date: 2013-01-01 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T13:25:05Z No. of bitstreams: 2 S1517-83822013000100041.pdf: 618977 bytes, checksum: f53802b49d94a03483d316114de310f3 (MD5) S1517-83822013000100041.pdf.txt: 19426 bytes, checksum: 0191b0cc8230f836e26db37792db58c6 (MD5) Made available in DSpace on 2014-05-20T13:25:05Z (GMT). No. of bitstreams: 2 S1517-83822013000100041.pdf: 618977 bytes, checksum: f53802b49d94a03483d316114de310f3 (MD5) S1517-83822013000100041.pdf.txt: 19426 bytes, checksum: 0191b0cc8230f836e26db37792db58c6 (MD5) Previous issue date: 2013-01-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) We assessed the performance of REMA in comparison with BACTEC MGIT 960 in the susceptibility testing of 80 Mycobacterium tuberculosis clinical isolates from Clemente Ferreira Institute against four drugs. REMA proved to be a rapid and accurate method, providing excellent correlation with BACTEC MGIT 960, with the exception of results for the ethambutol drug. Universidade Estadual Paulista Faculdade de Ciências Farmacêuticas Universidade de São Paulo Faculdade de Ciências Farmacêuticas Universidade Estadual de Maringá (UEM) Departamento de Análises Clínicas e Biomedicina Instituto Clemente Ferreira Universidade Estadual Paulista Faculdade de Ciências Farmacêuticas

Non-compaction of the left ventricle (NCLV) is a cardiomyopathy characterized by prominent left ventricular trabeculae and deep intertrabecular recesses. Associated extracardiac anomalies occur in 14–66% of patients of different series, while chromosomal anomalies were reported in sporadic cases. We investigated the prevalence of chromosomal imbalances in 25 syndromic patients with NCLV, using standard cytogenetic, subtelomeric fluorescent in situ hybridization, and array-comparative genomic hybridization (CGH) analyses. Standard chromosome analysis disclosed an abnormality in three (12%) patients, including a 45,X/46,XX mosaic, a 45,X/46,X,i(Y)(p11) mosaic, and a de novo Robertsonian 13;14 translocation in a child affected by hypomelanosis of Ito. Cryptic chromosome anomalies were found in six (24%) cases, including 1p36 deletion in two patients, 7p14.3p14.1 deletion, 18p subtelomeric deletion, 22q11.2 deletion associated with velo-cardio-facial syndrome, and distal 22q11.2 deletion, each in one case. These results recommend accurate clinical evaluation of patients with NCLV, and suggest that chromosome anomalies occur in about one third of syndromic NCLV individuals, without metabolic/neuromuscular disorder. Array-CGH analysis should be included in the diagnostic protocol of these patients, because different submicroscopic imbalances are causally associated with this disorder and can pinpoint candidate genes for this cardiomyopathy.

Purpose We undertook this study to determine the activity and tolerability of sorafenib administered with interferon alfa-2b (IFN-α-2b) as first- or second-line therapy in metastatic renal cell cancer (RCC). Patients and Methods Between November 2004 and October 2006, 40 patients at two sites were enrolled onto a phase II trial of sorafenib plus IFN-α-2b. Treatment consisted of 8-week cycles of sorafenib 400 mg orally bid plus IFN-α-2b 10 million U subcutaneously three times a week followed by a 2-week break. Patients were eligible to receive additional cycles of therapy until disease progression. Dose reduction of both drugs by 50% was permitted once for toxicity. Results The response rate was 33% (95% CI, 19% to 49%; 13 of 40 patients), including 28% partial responses (n = 11) and 5% complete responses (n = 2). Responses were seen in treatment-naïve and interleukin-2 (IL-2) –treated patients within the first two cycles. The median duration of response was 12 months. With a median follow-up time of 14 months, median progression-free survival time was 10 months (95% CI, 8 to 18 months), and median overall survival time has not yet been reached. Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss were the most common toxicities. Grade 3 toxicities were uncommon but included hypophosphatemia, neutropenia, rash, fatigue, and anemia. Dose reductions were required in 65% of patients. Conclusion The combination of sorafenib and IFN-α-2b has substantial activity in treatment-naïve and IL-2–treated patients with RCC. The toxicity exceeded that of either drug alone, but dose reductions and breaks between cycles allowed for chronic therapy. A larger, randomized trial would determine whether there is any advantage to this regimen compared with sorafenib alone.

Despite the resistance developed by the Mycobacterium tuberculosis (MTb) strains, isoniazid (INH) has been recognized as one of the best drug for treatment of Tuberculosis (Tb). The coordination of INH to ruthenium metal centers was investigated as a strategy to enhance the activity of this drug against the sensitive and resistant strains of MTb. The complexes trans -[Ru(NH 3 ) 4 (L)(INH)] 2+ (L = SO 2 or NH 3 ) were isolated and their chemical and antituberculosis properties studied. The minimal inhibitory concentration (MIC) data show that [Ru(NH 3 ) 5 (INH)] 2+ was active in both resistant and sensitive strains, whereas free INH (non-coordinated) showed to be active only against the sensitive strain. The coordination of INH to the metal center in both [Ru(NH 3 ) 5 (INH)] 2+ and trans -[Ru(NH 3 ) 4 (SO 2 )(INH)] 2+ complexes led to a shift in the INH oxidation potential to less positive values compared to free INH. Despite, the ease of oxidation of INH did not lead to an increase in the in vitro INH activity against MTb, it might have provided sensitivity toward resistant strains. Furthermore, ruthenium complexes with chemical structures analogous to those described above were synthesized using the oxidation products of INH as ligands (namely, isonicotinic acid and isonicotinamide). These last compounds were not active against any strains of MTb. Moreover, according to DFT calculations the formation of the acyl radical, a proposed intermediate in the INH oxidation, is favored in the [Ru(NH 3 ) 5 (INH)] 2+ complex by 50.7 kcal mol −1 with respect to the free INH. This result suggests that the stabilization of the acyl radical promoted by the metal center would be a more important feature than the oxidation potential of the INH for the antituberculosis activity against resistant strains.

Made available in DSpace on 2018-12-11T16:57:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-08-04 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Abstract Complexes of the type trans-[PdCl2(HL)(PPh3)], where HL = pyrazole (1); 3,5-dimethylpyrazole (2); 4-nitropyrazole (3); 4-iodopyrazole (4) and PPh3 = triphenylphosphine, were synthesized and characterized by elemental analyses, infrared and 1H NMR spectroscopies. Single-crystal X-ray diffraction determination on 3·0.9 CHCl3 and 4 showed that the coordination geometry around Pd(II) is nearly square-planar, with the chloro ligands in a trans configuration. In vitro antimycobacterial evaluation demonstrated that compound 4 displayed a minimum inhibitory concentration (MIC) of 7.61 ± 2.18 μM, being superior to the values observed for some commonly used antituberculosis drugs and other metal-based complexes. Departamento de Química Geral e Inorgânica, Instituto de Química de Araraquara, UNESP - Univ Estadual Paulista, P.O. Box 355 Department of Chemistry, Campus Universitário de Santiago, University of Aveiro Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas de Araraquara, UNESP - Univ Estadual Paulista, P.O. Box 502 Departamento de Química Geral e Inorgânica, Instituto de Química de Araraquara, UNESP - Univ Estadual Paulista, P.O. Box 355 Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas de Araraquara, UNESP - Univ Estadual Paulista, P.O. Box 502 FAPESP: 2012/15486-3 FAPESP: PT2020 FAPESP: SFRH/BPD/63736/2009

The coexistence of gastrointestinal stromal tumors (GISTs) and pregnancy is very rare. We are the first to add to the literature a case report of GIST occurring during pregnancy with immunohistochemical staining for epidermal growth factor receptor (EGFR) and progesterone receptor (PgR). A role of PgR and EGFR in tumor growth should not be excluded, and these findings indicate that the expression of these receptors could provide pertinent biological information required to determine adequate therapeutic regimens. In conclusion, considering that GIST occurring during pregnancy is a rare event, with frequent delay in diagnosis, it is important to consider this diagnosis for early recognition, correct diagnosis, and a better outcome.

Purpose: Alogliptin is the newest dipeptidyl peptidase 4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes either alone or in combination with other antidiabetic agents. The purpose of this review is to highlight the clinical studies that led to Food and Drug Administration approval of alogliptin and to provide insight into the place in therapy for the management of type 2 diabetes mellitus. Summary: As a DPP-4 inhibitor, alogliptin raises postprandial levels of glucagon-like peptide 1, leading to insulin secretion and glucose homeostasis. When given as monotherapy, alogliptin has the ability to reduce glycoslate hemoglobin A1c (HbA1c) by 0.4% to 1.0%. Combination therapy yielded similar reductions with some variability depending on the agent with which alogliptin was combined. The mean HbA1c reduction seen with alogliptin is relative to the degree of HbA1c elevation at baseline. Alogliptin appears to be weight neutral and is relatively well tolerated with few adverse effects. Furthermore, alogliptin has proven to result in comparable efficacy and tolerability in the elderly as in the younger population. Conclusion: Alogliptin alone or in combination with other antidiabetic agents has shown a significant reduction in HbA1c while remaining safe and tolerable. The efficacy profile of alogliptin is comparable to other DPP-4 inhibitors. Additional long-term research is necessary with regard to long-standing efficacy and effects on beta-cell function.

Purpose Alternative dosing strategies for liraglutide in patients with type 2 diabetes mellitus are described. Summary Nausea is the most common adverse effect of liraglutide, affecting upward of 40% of patients depending on the dose of liraglutide and concomitant medications. The frequency of nausea is dose dependent, with a lower rate of nausea reported with 0.6 mg (5.2–10.7%) compared with 1.2 mg (10.5–29.2%) or 1.8 mg (6.8–40%). Due to dose-related adverse effects, it is reasonable to assume that smaller or slower dosage adjustments may improve tolerability and increase the likelihood that the patient will be able to continue therapy long term. Depending on the degree of nausea and the necessary reduction in blood glucose levels, it is reasonable to consider a smaller or slower increase in liraglutide dosage than what is currently recommended by the manufacturer. For instance, increasing the dose of liraglutide by 0.3 mg weekly instead of 0.6 mg weekly may help prevent or decrease the severity of nausea. Alternative dosing strategies may also include increasing the dosage every two weeks or even monthly rather than weekly. Depending on the degree of nausea and glycemic control, providers may recommend patients stop increasing the dosage. It is important to proactively assess each patient’s ability to comply with special instructions to ensure safe use of the product. Conclusion Alternative dosing strategies that allow for slower dosage adjustments or smaller dosages may offer improved tolerability and increase the likelihood that patients will be able to continue long-term therapy with liraglutide.

Binuclear compounds of the type [Pd(μ-L)(N3)(PPh3)]2 {L = pyrazolate (1); 3,5-dimethylpyrazolate (2); 4-iodopyrazolate (3); PPh3 = triphenylphosphine} were synthesized and characterized by elemental analyses, infrared and 1H and 31P{1H} NMR spectroscopies. The crystal and molecular structures of the complex [Pd(μ-dmPz)(N3)(PPh3)]2 (2) were determined by single-crystal X-ray diffraction techniques. In vitro antimycobacterial evaluation demonstrated that compound [Pd(μ-Pz)(N3)(PPh3)]2 (1) displayed a MIC of 8.16 μM, being more active than some commonly used anti-TB drugs and other Pd(II) complexes.

Microdeletion 22q11 (del22q11) is one of the most frequent causes of genetic syndromes. The majority of cases of di George and velocardiofacial syndromes are due to del22q11. These conditions are considered to be developmentally related to neural crest anomalies influencing the differentiation of the branchial arches, including the percursor tissue of the ear. In addition, the UFDIL gene, an ubiquination gene being expressed during embryogenesis in the inner ear primordia, has been identified in the 22q11 critical region. The aim of this study was to evaluate the prevalence of hearing impairment in del22q11 syndrome. Admittance audiometry, behavioural pure tone audiometry and auditory brainstem response (ABR) were performed in 27 children studied at our hospital between 1997 and 1998. Results were related to clinical history, frequency otitis media and immune status. Sensorineural hearing loss was found in 4/27 (15%) patients (severe in three cases, mild in one), conductive hearing impairment in 12/27 (45%) (moderate in four cases, mild in eight) and normal hearing in 11/27 (40%). Interestingly, three of the patients with sensorineural hearing loss had cerebral lesions due to neonatal distress, to hydrocephalus and to post-surgical ischaemia each in one. The prevalence of speech delay, otitis media and low CD3 values was higher among patients with conductive hearing impairment in comparison with those with normal hearing. In conclusion, hearing impairment was documented in 60% of the patients and must be included among the clinical features of del22q11 syndrome. Audiological evaluation is recommended in patients with del22q11 in order to reduce the risk of speech deficit.

A baby is described with 45,X/46,XX,i(21q) mosaicism. DNA analysis indicated that the abnormality arose from two independent postzygotic mutations in a 46,XX zygote, involving the paternal chromosomes 21 and X. In agreement with previous reports, most of the clinical dysmorphisms observed were consistent with Down syndrome. Moreover, congenital heart disease consisted of an atrioventricular canal associated with slight hypoplasia of the left ventricle and a mitral anulus, a complex defect including features found in both Down and Turner syndromes.

We have characterized the extent and the phenotype of total and proliferating cell population of aortic plaques in aged rabbits receiving a long-term low-dose cholesterol hyperlipemic diet, which represents an experimental model of atherosclerosis. For nine months, rabbits received the hypercholesterolemic diet alone or in addition to a treatment with propionyl-L-carnitine (PLC), a derivative of carnitine, an intramitochondrial carrier of fatty acids present in most cell types. We observed that, in both PLC-treated and control hyperlipemic rabbits, the ratio between proliferating macrophage-derived and smooth muscle cells was 2:1. PLC in addition to the hypercholesterolemic diet induced a marked lowering of plasma triglycerides, very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) triglycerides, while plasma cholesterol was slightly and transiently reduced. Moreover, PLC-treated hyperlipemic rabbits exhibited a reduction of plaque thickness and extent, a slight but significant reduction of the percentage of macrophage-derived cells as compared to control hyperlipemic animals and a reduction of the number of both proliferating macrophage- and smooth muscle cell-derived foam cells. Finally, both proliferating and non-proliferating plaque cells expressed large amounts of macrophage colony-stimulating factor protein, in particular macrophage-derived foam cells. These results indicate that a modification of plasma lipemic pattern obtained by a long-term oral administration of PLC was associated with a decrease of plaque cell proliferation and severity of aortic atherosclerotic lesions.

We determined the susceptibility profile of 80 Mycobacterium tuberculosis (MTB) clinical isolates from Brazil against isoniazid (INH) and rifampicin (RIF) drugs by two phenotypic methods (Resazurin Microtiter Assay - REMA and BACTEC™ MGIT™ Mycobacterial Detection System). DNA polymorphisms were also determined by PCR-SSCP in isolates resistant to INH and RIF. BACTEC™ MGIT™ 960 detected 22 susceptible isolates to INH and RIF, 48 MDR isolates (resistant at least to INH and RIF) and nine mono-resistant isolates (eight to INH and one to RIF). REMA performance was determined by Receiver Operating Characteristic curve, whose assay was validated utilizing as reference the BACTEC™ MGIT™ 960 system. ROC curve showed cut-off values of 0.0625μg/mL and 0.125μg/mL, for INH and RIF, respectively. REMA-INH demonstrated sensitivity and specificity of 100% while REMA-RIF showed sensitivity of 97.2% and specificity of 100%. PCR-SSCP detected DNA polymorphisms in 87.5% and 75.5% of isolates classified as INH-resistant and RIF-resistant, respectively. One discordant sample found to RIF (resistant by BACTEC™ MGIT™ 960 and susceptible by REMA) showed no mutation by PCR-SSCP. In conclusion, our studies demonstrated that the combination of phenotypic method REMA, which allowed rapid detection of MDR-MTB with higher levels of sensitivity and specificity, with the genotypic method PCR-SSCP, which demonstrated high accuracy in the search of polymorphisms in the resistance genes, proved to be a useful strategy to study MDR-MTB clinical isolates from national reference center located in Sao Paulo city.

Background The results of a pilot colorectal cancer screening programme by biennial immunochemical faecal occult blood test (FOBT) are reported. Methods All residents aged between 50 and 69 years in the Italian province of Lecco were invited to have a FOBT. Those with a positive result were offered colonoscopy. FOBT uptake and compliance with colonoscopy were assessed. Detection rate and positive predictive value (PPV) for cancer and adenoma were calculated. Tumour stages were compared between screen-detected cancers and other colorectal cancers diagnosed within the target age group. Results Some 38 693 (49·6 per cent) of 78 083 individuals had a FOBT and 2392 (6·2 per cent) had a positive result. Colorectal cancer was diagnosed in 4·6 per cent and advanced adenoma in 32·7 per cent. PPVs were 4·0 per cent for cancer, 28·1 per cent for advanced adenoma and 36·6 per cent for any adenoma. There was a significant difference in incidence of stage III/IV disease between screened and non-screened cohorts. Compliance for colonoscopy was 92·0 per cent. Major determinants of compliance were age less than 59 years, female sex, high education level and non-manual work. Conclusion These results justify extension of colorectal cancer screening to other regions of Italy.

A modular numerical model is used to study the interaction, in terms of energetic relationships, between the cardiovascular system and a pneumatic left ventricle assist device (LVAD). The experiments are performed in two steps: in the first the left ventricle is characterized, with an open loop model of the circulatory system, computing external work (EW), pressure volume area (PVA) and cardiac mechanical efficiency (CME) as a function of atrial pressure and peripheral resistance. PVA is compared to EW and CME surfaces respectively. In the second step the same variables are evaluated, with a closed loop model, assisting synchronously the left ventricle with the LVAD and changing two of its control parameters: driving pressure (DP) and systole-diastole (SD) ratio. The path of the working point is related to the value of the arterial elastance, modified by the LVAD, and only in few points the target to minimize PVA and EW and maximize CME is reached. >

SUMMARYDiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS) are associated with chromosome 22q11.2 deletion. Limited information is available on the T cell receptor (TCR) Vβ repertoire. We therefore investigated TCR Vβ families in lymphocytes isolated from blood and thymic samples of seven patients with DGS and seven patients with VCFS, all with 22q11.2 deletion. We also studied activities related to TCR signalling including in vitro proliferation, anti-CD3-induced protein tyrosine phosphorylation, and susceptibility to apoptosis. Reduced CD3+ T cells were observed in most patients. Spontaneous improvement of T cell numbers was detected in patients, 3 years after the first study. Analysis of CD4+ and CD8+ TCR Vβ repertoire in peripheral and thymic cells showed a normal distribution of populations even if occasional deletions were observed. Lymphoproliferative responses to mitogens were comparable to controls as well as anti-CD3-induced protein tyrosine phosphorylation. Increased anti-CD3-mediated apoptosis was observed in thymic cells. Our data support the idea that in patients surviving the correction of cardiac anomalies, the immune defect appears milder than originally thought, suggesting development of a normal repertoire of mature T cells.

Objective Two-dimensional, Doppler and color-flow echocardiography is accepted as a safe diagnostic tool to guide the surgical treatment of certain congenital heart defects. Its role for surgical indication in patients with complete atrioventricular canal (cAVC) is described in this paper. Methods Between July 1989 and January 1995, 80 patients with cAVC underwent primary repair in our Institution. In 73 surgery was guided only by echocardiography (Group I), while in the remaining 7 patients (Group II) cardiac catheterization was performed because of unclear diagnosis and/or suspected associated malformations. Results Echocardiography showed an overall sensitivity of 100% and specificity of 93% in detecting associated malformations. Discussion Based on these data and on the knowledge of the natural history of pulmonary vascular changes in patients with cAVC we think that echocardiography might be adequate for selection of infants with uncomplicated forms of cAVC for primary repair.

Among 41 consecutive children with classic Noonan syndrome, 27 patients (66%) presented cardiac anomalies. Eight patients (19.5%) had a congenital anomaly of the mitral valve consisting of 5 with partial atrioventricular canal defect and 3 with anomalous insertion of the mitral valve on the ventricular septum. Five patients (12%) presented with a significant left ventricular outflow tract obstruction caused by the anterior leaflet of the mitral valve: two cases with atrioventricular canal and three cases with isolated anomalous insertion of the mitral valve. Echocardiography is the best tool for the diagnosis. Cardiac defects of patients with Noonan syndrome may be explained on the basis of anomalies of the extracellular matrix involving cardiac valves including the mitral valve. In children with Noonan syndrome and left ventricular hypertrophy a careful echocardiographic assessment of the mitral valve should reveal those in whom the left ventricular outflow tract obstruction is anatomical in nature.

Intramuscular myxoma is a rare benign mesenchymal lesion. Only very rare cases of cutaneous localization of this tumor have been described, in particular related to the somatic soft tissues of the face. This unusual localization may clinically mimic nodular or cystic facial lesions having different origins.The aim of our work was to well characterize the phenotype of the spindle cells characteristic of intramuscular mixoma.Tissue samples were processed for morphological and ultrastructural studies. Moreover, immunohistochemical stainings were performed to characterize the expression of different nonmuscular and muscular cytoskeletal proteins.The tumor was composed of sparse spindle cells embedded in a prominent mucoid matrix. Besides the predominance of a fibroblast-like appearance, some neoplastic cells displayed immunohistochemical and ultrastructural features resembling either myofibroblasts or primitive mesenchymal cells, with a modulation of cell actin expression.The presence of multiple phenotypes of nonmuscular, mesenchymal pathway of differentiation can be considered a peculiar feature of intramuscular myxoma.

Aging seems to be related to various vascular diseases, such as dissecting aneurysm and atherosclerosis. The nature of the relationship between aging and these vascular diseases has not been completely clarified. The goal of this study was to investigate, using morphological and morphometrical methods, the age related modifications of the arterial wall in rabbits of three different ages, evaluating separately two different vascular districts and the various aortic segments. Our results confirm that the most relevant age-related structural aortic changes were the increase of thickness, length, volume and diameter of the vessels, together with the development of an intimal thickening. The latter was diffuse in the aorta and focal in coronary vessels and it appears earlier in the aorta than in the coronaries, being absent in the coronaries of young rabbits. In addition, morphological and ultrastructural studies revealed the presence in aged rabbits of some marked intimal storage of a ground substance into intimal thickening of proximal aortic segments. Morphometric studies demonstrated an age-related decrease of aortic cellularity of tunica media and a parallel increase of the content of collagen and glycosaminoglycans, whereas elastin did not vary. The different relationships between cells and interstitial tissue occurring with aging are most probably a phenomenon of adaptation to the changing forces acting on the arterial wall and they might constitute the structural background of the increased arterial susceptibility to various noxae. Finally, the intimal storage of the ground substance, probably related to a functional disturbance of endothelium and or smooth muscle cells, may play an initiating role in atherogenesis.

The frequency of congenital heart disease in children with Down's Syndrome is high and ranges between 40 and 50% of cases. It was evident for many years that patients with trisomy 21 present certain congenital heart defects (atrioventricular canal, ventricular septal defect, tetralogy of Fallot) and seem to be "protected" from others (situs inversus and situs ambiguus, ventricular inversion, transposition of the great arteries). Recent observations also suggest that left-sided obstructive lesions and the muscular ventricular septal defect are very rare. The role of a suspected "increased adhesivanes of trisomy 21 cells" and of the anomalies of neutral crest needs to be investigated. The interaction between studies of clinicians and basic research will improve the knowledge of these genetically determined heart defects.

The expression of renin and angiotensinogen genes and their proteins were studied during the progression of diabetes using adult BioBreeding spontaneously diabetic rats at 1 day and 2-12 months of diabetes. The number of renin-stained cells per juxtaglomerular apparatus was determined by immunocytochemistry. Initially, at 2 months of diabetes the number of renin-stained cells per juxtaglomerular apparatus increased significantly (p less than 0.0001, 2 months versus resistant groups) and was followed by a decrease in the number and intensity of renin-stained cells after 12 months of diabetes (p = 0.007, 2 months versus 12 months). A significant negative correlation was observed between the number of renin-containing cells and the duration of diabetes (r = 0.99, p = 0.014). Immunoreactive angiotensinogen was restricted to the proximal tubule and appeared increased after 4 and 8 months of diabetes as compared with the 2- and 12-month diabetic groups. Renin messenger RNA (mRNA) levels increased with the onset of diabetes and decreased markedly during chronic diabetes. At 1 day of diabetes, renin mRNA levels were 700% higher than at 12 months of diabetes. Angiotensinogen mRNA levels were unchanged. We conclude that diabetes results in an initial increase in renin gene expression, and as the duration of diabetes lengthens, there is a progressive decrease in renin gene expression and in the number of cells containing renin. These findings suggest that as the duration of diabetes and the age of the animal lengthens, there is a decrease in the number of cells expressing the renin gene.

The pulmonary circulation is dependent on the ductus arteriosus in all patients with pulmonary atresia and intact ventricular septum and in some with pulmonary atresia and ventricular septal defect (tetralogy of Fallot type). To assess the time of ductal closure in these two patient categories, we compared the ages at first operation in 58 patients with pulmonary atresia and intact ventricular septum and 32 with pulmonary atresia and septal defect. The age distribution differed significantly between the groups. Whereas 90% of the children with intact ventricular septum required surgery in the first week of life, 50% of those with ventricular septal defect underwent surgery after the first month and 25% after the third month. The previously described and now confirmed anatomic differences of ductus arteriosus or different levels of endogenous prostaglandins may explain persistent patency of the ductus in pulmonary atresia with ventricular septal defect. The phenomenon may have important clinical implications regarding the timing and choice of surgical procedure.

To the Editor. We read the interesting paper by Chang et al.1 Among 177 patients with atrioventricular canal (AVC), the authors report on a significantly younger mean age at surgery for children with Down syndrome compared with patients without trisomy 21. In the “Discussion” section the authors explain their data on the basis of the effort to prevent the early occurrence of permanent pulmonary vascular changes in children with Down syndrome.2Unfortunately, the authors do not report how many of their patients presented the complete or the partial forms of AVC. This data could be useful in understanding the reason for early surgery in children with Down syndrome because it is well-known that complete AVC is prevalent …