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We present a simple explicit construction of hyper-Kähler and hyper-symplectic (also known as neutral hyper-Kähler or hyper-para-Kähler) metrics in 4D using theBianchi type groups of classA. The construction underlies a correspondence between hyper-Kähler and hyper-symplectic structures of dimension 4. [ABSTRACT FROM AUTHOR]

Abstract Background Adverse drug reactions (ADR) are a substantial cause of hospital admissions. We conducted a nationwide study to estimate the burden of hospital admissions for ADRs in Spain during a six-year period (2001-2006) along with the associated total health cost. Methods Data were obtained from the national surveillance system for hospital data (Minimum Basic Data Set) maintained by the Ministry of Health and Consumer Affairs, and covering more than 95% of Spanish hospitals. From these admissions we selected all hospitalization that were code as drug-related (ICD-9-CM codes E), but intended forms of overdoses, errors in administration and therapeutics failure were excluded. The average number of hospitalizations per year, annual incidence of hospital admissions, average length of stay in the hospital, and case-fatality rate, were calculated. Results During the 2001-2006 periods, the total number of hospitalized patients with ADR diagnosis was 350,835 subjects, 1.69% of all acute hospital admissions in Spain. The estimated incidence of admissions due to ADR decreased during the period 2001-2006 (p < 0.05). More than five percent of patients (n = 19,734) died during an ADR-related hospitalization. The drugs most commonly associated with ADR-related hospitalization were antineoplastic and immunosuppressive drugs (n = 75,760), adrenal cortical steroids (n = 47,539), anticoagulants (n = 26,546) and antibiotics (n = 22,144). The costs generated by patients in our study increased by 19.05% between 2001 and 2006. Conclusions Approximately 1.69% of all acute hospital admissions were associated with ADRs. The rates were much higher for elderly patients. The total cost of ADR-related hospitalization to the Spanish health system is high and has increased between 2001 and 2006. ADRs are an important cause of admission, resulting in considerable use of national health system beds and a significant number of deaths.

In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (σ 1 R) and inhibition of key enzymes in Alzheimer's disease (AD), such as acetylcholinesterase (AChE), 5-lipoxygenase (5-LOX), and monoamine oxidases (MAOs). In general, new compounds scavenge free radical species, are predicted to be brain-permeable, and protect neuronal cells against mitochondrial oxidative stress. N-(2-(1-Benzylpiperidin-4-yl)ethyl)-6,7-dimethoxy-4-oxo-4H-chromene-2-carboxamide (18) is highlighted due to its interesting biological profile in σ 1 R, AChE, 5-LOX, MAO-A and MAO-B. In phenotypic assays, it protects a neuronal cell line against mitochondrial oxidative stress and promotes maturation of neural stem cells into a neuronal phenotype, which could contribute to the reparation of neuronal tissues. Molecular modelling studies of 18 in AChE, 5-LOX and σ 1 R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-{8[(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]octyl}-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 =68.2 nM), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β-amyloid (Aβ) anti-aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μM), affording good neuroprotection against toxic insults such as Aβ1-40 , Aβ1-42 , H2 O2 , and oligomycin A/rotenone on SH-SY5Y cells, at 1 μM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

On the basis of N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (II, ASS234) and QSAR predictions, in this work we have designed, synthesized, and evaluated a number of new indole derivatives from which we have identified N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine (2, MBA236) as a new cholinesterase and monoamine oxidase dual inhibitor.

One of the complications of the treatment of head and neck carcinoma patients is hypothyroidism. The objective of our study was to quantify the prevalence of hypothyroidism in patients with laryngeal or hypopharyngeal cancer treated with a total laryngectomy and to evaluate the importance of different variables in the appearance of hypothyroidism in this group of patients. A transversal study in 182 patients treated with total laryngectomy between 1986 and 1998 was carried out. TSH and FT4 were determined in all patients. Hypothyroidism was classified as subclinical (increased TSH and normal T4 levels) and clinical (increased TSH and decreased T4 levels). Univariate and multivariate analysis was carried out to examine the relationship between hypothyroidism and different variables. Our results showed that the prevalence of hypothyroidism in our group of patients was 52% (27% subclinical and 25% clinical). Sex, initial extension of the tumour, hemithyroidectomy, use of chemotherapy and radiotherapy were variables associated with the appearance of hypothyroidism in the univariate analysis (P < 0.05). When all these variables were included in a multivariate study, only hemithyroidectomy (RR 3,6; CI 95% 1,7-7,2) and combined treatment with radiotherapy (RR 3,4; CI 95% 1,2-9,6) appeared as prognostic factors. In conclusion, hypothyroidism is a frequent complication in patients treated with a total laryngectomy (52%), especially when this treatment includes hemithyroidectomy and/or radiotherapy. We consider that it is important to check the thyroid function periodically in these patients to obtain early diagnosis and appropriate treatment.

Background: The authors reviewed the incidence of stomal recurrence (SR) in a population of laryngectomized patients to study associated risk factors and determine the usefulness of certain preventive procedures., Methods: A retrospective study was performed in 296 patients with larynx and hypopharynx carcinoma treated by total laryngectomy., Results: Of the 296 patients, 6 (2%) were initially seen with SR. In all cases, a risk factor was found to be involved: subglottic extension (5 cases), tracheotomy prior to laryngectomy (1 case). Since 1989, when preventive measures were systematically introduced in patients presenting risk factors, there have been no further cases of SR. The surgical measures in tumors with subglottic extension consisted of hemithyroidectomies, paratracheal lymph node dissection, and extensive tracheal resection; in the case of a tracheotomy prior to the laryngectomy, extensive resections of the tracheal stoma were carried out., Conclusions: The systematic use of preventive surgical measures together with postoperative radiotherapy to the stoma and superior mediastinum have led to a decrease in the appearance of SR.

Until recently, standard treatment for stage III laryngeal carcinoma (LC) was total laryngectomy and radiotherapy. Recent data suggest that induction chemotherapy (ICH) plays a role in preserving function in advanced head and neck cancer. No reports to date prospectively evaluate ICH exclusively in stage III LC. The authors designed a sequential phase II trial to assess if ICH allowed a conservative treatment in this disease. The objective of the first part of the study was to rule out a complete response rate with ICH below 30% with P < .05. ICH protocol consisted of three courses of cisplatin 100 mg/M2 on day 1 and 5-fluorouracil 5000 mg/M2 continuous infusion over 120 hours. Radiotherapy was administered to patients who attained a complete response (CR). Functional surgery (FS) was planned for patients with partial response. A total laryngectomy followed by radiotherapy was performed when FS was not feasible. Fifty-two previously untreated patients (all males) with squamous stage III LC were diagnosed in our institution, and 46 were entered in the ICH trial. After 9 patients were included, data showed 7 (78%) CR, ruling out a CR rate of less than 30%. After ICH, a CR was achieved in 29 (63%) of 46 patients. At the end of treatment, 35 patients (76%) had a functioning larynx. With a median follow-up of 3 years, larynx function was preserved in 26 (57%) of 46 patients and in 64% of survivors. Four-year actuarial larynx function preservation, overall survival, and disease-free survival were 55%, 77%, and 67%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The esthesioneuroblastoma is an uncommon but curable disease in a high proportion of cases. The treatment is controversial. Radiotherapy, alone or combined with surgery, has demonstrated to be an effective treatment in early stages. Chemotherapy, associated to radiotherapy, can improve the outcome in advanced stages and reduce the morbidity related to surgery. Three cases treated with radiotherapy, and one case treated with chemotherapy followed by radiotherapy are reported. Diagnosis and treatment management are discussed.

To assess myocardial cell damage due to doxorubicin cardiotoxicity, we prospectively studied 30 patients with sarcomas who were receiving chemotherapy, including doxorubicin. Sixteen patients were treated by continuous infusion over 72 hr and 14 patients were treated by bolus injection. Antimyosin studies and left ventricular ejection fraction (LVEF) measurements were performed before chemotherapy and at intermediate and maximal cumulative doses. Myocardial antimyosin uptake was quantified by a heart-to-lung ratio (HLR). Myocardial antimyosin uptake was observed in all patients at 240-300 mg/m2 when ejection fraction was still maintained. Seven patients presented with a decrease of > or = 10% in absolute ejection fraction units at 420-600 mg/m2. Five of these patients had mild congestive heart failure. All patients who presented with a decrease in LVEF > or = 10% at 420-600 mg/m2 had increased antimyosin uptake with HLR > or = 1.90 at a cumulative dose of 240-300 mg/m2. Patients who were treated with continuous infusion had less antimyosin uptake than those who were treated with bolus administration (mean HLR of 1.70 +/- 0.09 versus HLR of 2.01 +/- 0.16 at a cumulative dose of 240-300 mg/m2, p < 0.01; HLR of 1.86 +/- 0.12 versus HLR of 2.32 +/- 0.34 at a cumulative dose of 420-600 mg/m2, p < 0.01). Two of 16 patients treated by continuous infusion and 5 of 14 patients treated by bolus injection presented with a decrease in ejection fraction > or = 10%. LVEF after chemotherapy in the infusion group was 56% +/- 5% and 48% +/- 8% (p < 0.05) in the bolus group. Antimyosin studies are helpful in the assessment of doxorubicin cardiotoxicity. Intense antimyosin uptake at intermediate cumulative doses identifies patients at risk of cardiotoxicity before ejection fraction deteriorates. Patients with sarcomas treated by continuous infusion present with less antimyosin uptake than those treated with bolus injection, indicating less severe cardiotoxicity.

The paper deals with the retrospective review done by the AA. about the treatments used for squamous carcinomata of the pyriform sinus at Santa Creu i Sant Pau Hospital, Barcelona, between the years 1984-1990. In this term 76 sinus pyriform carcinomata were diagnosed, 12 of which (16%) were managed palliatively. In the other 64 cases radical treatment was advised and followed: 5 cases underwent radical cobalt-therapy; polychemotherapy followed by radiotherapy in 27; surgery plus radiotherapy in 7; and polychemotherapy completed with surgery and radiotherapy in the remaining 25 cases. Considerations on the realized pharyngectomies and their reconstructive steps and complications are commented. Inventory and end results in each group are reported. The beneficial local influence was evident when surgery was employed (100% with surgery plus radiotherapy and 92% with polychemotherapy, surgery and radiotherapy). Local control was inferior if surgery was discarded (20% in radiotherapy and 37% by polychemotherapy followed by radiotherapy). Actuarial survival for the lump sum amounted for the 40 percent after 5 years follow-up. It must be emphasized that these groups are not comparable because the choice treatment in each case was indicated in view of the initial stage.

To assess chemotherapeutically induced myocardial damage, myosin-specific antibody scans and ejection fraction measurements were performed in 32 patients with breast cancer and in 9 patients with other tumours. All patients had received chemotherapy including anthracyclines. The ejection fraction decreased by less than or equal to 10% in 14 of 41 (34%) patients after chemotherapy. Antimyosin uptake in the myocardium was observed in 38 of 41 (92%) patients after chemotherapy. Antimyosin uptake was quantified by means of a heart-to-lung ratio, revealing a correlation between the degree of antimyosin uptake in the myocardium and the cumulative dose of anthracycline. Patients with a decreased ejection fraction showed more intense antimyosin uptake, indicating more severe myocardial damage. A higher degree of antimyosin uptake was found in 17 breast cancer patients treated with doxorubicin compared with 15 patients treated with mitoxantrone. We conclude that antimyosin studies provide a sensitive, non-invasive method to monitor myocardial damage in patients treated with anthracyclines. Antimyosin uptake in the myocardium precedes ejection fraction deterioration. This technique may be helpful in the early identification of patients at risk of congestive heart failure during chemotherapy including anthracyclines.

We present the case of a 70 year old man with cricoid chondrosarcoma treated with total laryngectomy. This report reviews the occidental literature, with nine cases reported by national authors in the las 25 years. We have recollected 104 laryngeal chondrosarcoma, in all. Clinical and diagnostical data, location, and treatment were analysed and compared with our case.

A retrospective analysis was made of 78 patients presenting breast neoplasm with hepatic metastases confirmed by ultrasound. Clinical hepatomegaly was present in 61%. The serum glutamic-oxaloacetic transaminase (SGOT) was elevated in 72%, the serum glutamic-pyruvic transaminase (SGPT) in 56%, the serum alkaline phosphatase (Aph) in 86%, and the gamma-glutamil transpeptidase (GGT) in 76%. A hypoechogenic multiple nodular pattern (HMN) was observed in 69%, a diffuse hypoechogenic pattern (DH) in 15%, and a mixed multiple nodular pattern (MMN) in 11%. No single nodular pattern was presented in any patient. The univariate analysis showed a better survival rate in patients with a mixed pattern (mean 11 months, range 1-29 months) (p = 0.027). No significant differences were observed regarding the remaining patterns, age, presence or not of hepatomegaly, or altered enzymatic values.