Y155H amino acid substitution in influenza A(H1N1)pdm09 viruses does not confer a phenotype of reduced susceptibility to neuraminidase inhibitors.

The Y155H amino acid substitution in the neuraminidase gene (NA) has previously been associated with highly reduced inhibition by neuraminidase inhibitors in the seasonal H1N1 influenza A virus which circulated in humans before the 2009 pandemic. During the 2012/13 epidemic season in Spain, two A(H1N1) pdm09 viruses bearing the specific Y155H substitution in the NA were detected and isolated from two patients diagnosed with severe respiratory syndrome and pneumonia requiring admission to the intensive care unit. Contrary to what was observed in the seasonal A(H1N1) viruses, neither of the Y155H A(H1N1) pdm09 viruses described here showed a phenotype of reduced inhibition by NAIs as determined by the neuraminidase enzyme inhibition assay (MUNANA). High-throughput sequencing of the NA of both Y155H viruses showed that they were composed to >99% of H155 variants. We believe that this report can contribute to a better understanding of the biological significance of amino acid substitutions in the neuraminidase protein with regard to susceptibility of influenza viruses to neuraminidase inhibitors. This is of critical importance for optimal management of influenza disease patients.

[Analysis of gastric emptying dynamics in relationship to qualitative composition of intake. Comparison between normal-weight and obese subjects]. / Análisis de la dinámica de vaciamiento gástrico en relación con la composición cualitativa de la ingesta. Comparación entre sujetos con normopeso y obesos.

AIMS: To analyze whether the gastric emptying profile could define obesity and to study the impact of macronutrients diet composition on gastric emptying in obese and non obese people. MATERIAL AND METHODS: 47 subjects were selected (12 non obese and 35 obese). The study was organized in 4 visits. In each visit the subject was given isocaloric breakfast differing in macronutrient composition, (either equilibrated, or lipid, protein or carbohydrate rich) quantitative gastric emptying assay was done realized, every 15 minutes for two hours using a radionuclide technique. The week prior to the visit, the subject followed a standard 1,800 cal/day diet. RESULT: A significant interaction between time and diet composition is shown regardless of the group (obese or non-obese) the subject belongs to. The different macronutrient composition differentially affected gastric emptying only in the obese group. Post hoc analysis of the results showed significant differences after 45 min post breakfast between protein and carbohydrate rich breakfast. CONCLUSIONS: Gastric emptying in obese but not in non obese subjects, was significantly modified depending on the intake qualitative composition. These differences are clear when protein rich (significantly slower emptying) is compared versus hydrocarbon enriched diet (significantly faster emptying). A significant difference in gastric emptying between obese and non-obese subjects cannot be established.

[Nonalcoholic steatohepatitis, the enigma of bad progression]. / Esteatohepatitis no alcohólica, el enigma de una mala evolucion.

Still, very little is known about the precise pathogenetic mechanisms, the triggering events and in particular, the evolution and treatment of nonalcoholic steatohepatitis (NASH). It is part of the broad spectrum of nonalcoholic fatty liver diseases (NAFLDs). Mainly, it has been reported as a benign disease, associated with metabolic disorders commonly occurrence en the general population. Nevertheless, the syndrome can lead to cirrhosis, liver failure or hepatocellular carcinoma, requiring liver transplantation. We present one patient with diagnosis of NASH, who was treated initially for overweight, HTA and hyperlipaemia with incompleted response and who showed a quickly progress to cirrhosis but no cause of liver decompensated disease could be identified. Currently she is at end-stage waiting a liver transplantation. Controlled and multicentric studies with the same definition of NASH and the study end-points are needed, and will provide information about diagnosis features and novel therapies to early management of the disease.

Substance P, nicotinic acetylcholine receptors and antinociception in the rat.

Intracerebroventricular injections of both nicotine and substance P (SP) induced antinociception in the tail-flick test in rats. The antinociceptive effect was blocked in both cases by mecamylamine and by naloxone, suggesting that central nicotinic acetylcholine receptors and endogenous opioids are implicated in the action of these drugs. A link between substance P neurones and central cholinergic systems, involving nicotinic receptors, was also suggested by the quickly developed cross-tolerance between the antinociceptive effect of substance P and nicotine. A smaller, subeffective dose of substance P was able to block, on acute administration, the antinociceptive action of nicotine, an effect not shared by the two other mammalian tachykinins, neurokinin A or neurokinin B. The results obtained in the present study appear to indicate a dual action of substance P on central nicotinic cholinoceptors.

Involvement of spinal monoaminergic pathways in antinociception produced by substance P and neurotensin in rodents.

The antinociceptive effects of substance P and of neurotensin have been determined in rodents after depletion of serotonin (5-HT) or noradrenaline (NA) in the spinal cord. The antinociceptive effect of substance P, given intraventricularly, in rats and mice was blocked after depletion of 5-HT in the spinal cord with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or with the inhibitor of the synthesis of 5-HT, p-chlorophenylalanine (PCPA), but not after depletion of NA in the spinal cord with the neurotoxin 6-hydroxydopamine (6-OHDA). Conversely, the antinociceptive effect of neurotensin in mice was blocked after lesion of spinal NA pathways with 6-OHDA. When 5-HT spinal pathways of mice were lesioned with 5,7-DHT, neurotensin-induced antinociception was blocked 7 but not 15 days after the lesion. p-Chlorophenylalanine failed to prevent this effect of neurotensin. The results suggest that the antinociceptive effect of substance P depends on the integrity of spinal 5-HT neurones, whereas that of neurotensin depends on spinal NA neurones and, only to a limited extent, on 5-HT neurones. It seems that different descending systems are involved in the antinociception elicited by these two neuropeptides.

Analgesic dipeptide derivatives. 3. Synthesis and structure-activity relationships of o-nitrophenyl-modified analogues of the analgesic compound H-Lys-Trp(NPS)-OMe.

A series of analogues of the analgesic dipeptide derivative H-Lys-Trp(NPS)-OMe has been designed to determine the influence of the (2-nitrophenyl)sulfenyl (NPS) moiety on the activity. The syntheses and antinociceptive effects of these analogues of general formula H-Lys-Trp(R)-OMe [R = phenylsulfenyl (PS) (9); R = (2-carbomethyoxyphenyl)sulfenyl (CmPS) (10); R = (4-nitrophenyl)sulfenyl (pNPS) (11); R = (2,4-dinitrophenyl)sulfenyl (DNPS) (12); R = [2-(acetylamino)-2-carbomethoxyethyl]sulfenyl (AacCmES) (13); R = [2-(acetylamino)phenyl]sulfenyl (AacPS) (17); R = tert-butylsulfenyl (t-BuS) (23); R = (2-carbomethoxyethyl)sulfenyl (CmES) (24)] are described. Reaction of Z-Lys(Z)-Trp-OMe (3) with PS-, CmPS-, pNPS-, DNPS-, and AacCmES-Cl afforded the corresponding 2-(sulfenyl)tryptophan derivatives, which on treatment with boron-tris(trifluoroacetate)/trifluoroacetic acid or trimethylsilyl iodide in acetonitrile (Me3SiI/CH3CN) provided 9-13, respectively. Sulfenylation of 3 with NPS-Cl gave Z-Lys(Z)-Trp(NPS)-OMe, which, on catalytic hydrogenation of the nitro group using 10% Pd/C followed by acetylation of the resulting amino function and removal of the protecting Z groups, gave 17. Condensation of 2-(tert-butylsulfenyl)- and 2-[(2-carbomethoxyethyl)sulfenyl]tryptophan methyl ester, obtained by reaction of methyl 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxyla te with the corresponding thiol, with Z-Lys(Z)-OSu afforded Z-Lys(Z)-Trp(t-BuS)-OMe and Z-Lys(Z)-Trp(CmES)-OMe, which on treatment with Me3SiI/CH3CN provided 23 and 24, respectively. Intracerebroventricular administration of 10 elicited a naloxone-reversible antinociceptive effect in mice similar to that of H-Lys-Trp(NPS)-OMe. No analgesia was however found with the phenylsulfenyl or acyclic sulfenyl substituted dipeptides 9, 11, and 17 or 13, 23, and 24. The Trp(DNPS)-containing analogue was neurotoxic. Structure-activity studies indicate that the role of the NPS and CmPS moieties could be related to the adoption of a preferential active conformation.

Analgesic dipeptide derivatives. 4. Linear and cyclic analogues of the analgesic compounds arginyl-2-[(o-nitrophenyl)sulfenyl]tryptophan and lysyl-2-[(o-nitrophenyl)sulfenyl]tryptophan.

The syntheses of Trp(Nps)-Arg-OMe.HCl (15) [Trp(Nps) = 2-[(o-nitrophenyl)sulfenyl]tryptophan], its three stereoisomers, and their corresponding cyclic analogues are reported. The preparation of Trp(Nps)-Lys-OMe (19) and its cyclic analogue is also described. All these compounds have been designed as analogues of the analgesic dipeptide derivatives X-Trp(Nps)-OMe (1b, X = Arg; 2b, X = Lys). In the case of dipeptides containing Arg or D-Arg, the coupling reactions were achieved via the isobutyl chloroformate and N-methylmorpholine mediated mixed anhydride procedure, while in the case of the Lys analogue, the N,N-dicyclohexylcarbodiimide method was employed. Sulfenylation reactions were carried out with Nps-Cl in acidic media. Cyclization to the diketopiperazines was achieved by using acetic acid as catalyst. The antinociceptive effects of all these new Trp(Nps)-containing dipeptides were evaluated after icv administration in mice, and the effects were compared with those of 1b, 2b, Tyr-Arg (Kyotorphin), and Tyr-D-Arg. The most active compounds, 15 and 19, were found to exhibit a naloxone-reversible antinociceptive effect similar to those of 1b and 2b and approximately 50 and 12.5 times higher than those of Kyotorphin and its D isomer, respectively. Trp(Nps)-D-Arg-OMe.HC1, D-Trp(Nps)-Arg-OMe.HC1, and cyclo[Trp(Nps)-Arg].HC1 were also more effective than Kyotorphin (5, 10, and 10 times, respectively). In view of the structure-activity relationships obtained, several similarities between this series of Trp(Nps)-containing dipeptides and that of Kyotorphin analogues have emerged.

Long-lasting neurochemical and functional changes in rats induced by neonatal administration of substance P antiserum.

Substance P (SP) antiserum was administered to rats on the second day of life. Three months later, the content of SP was significantly decreased in the dorsal part of the spinal cord and in the periaqueductal gray matter of these animals, as compared to control rats receiving a neonatal treatment of non-specific immunoglobulins. Further, the levels of Met-enkephalin and 5-hydroxyindole acetic acid (5-HIAA) were concomitantly increased in the same regions. SP receptor binding sites and opioid receptors, which appear earlier in development, were not modified in the two regions studied. On the other hand, the antinociceptive response to intracerebroventricular (i.c.v.) injection of SP or of the synthetic enkephalin analog D-Ala2,D-Leu5-enkephalin, as well as the hypertensive response to i.c.v. SP were blocked. The results suggest that, after administration to newborn rats, the antiserum is able to penetrate into SP neurons, producing a long-lasting SP suppression and a subsensitivity to the pharmacological effects of the neuropeptide. The modifications in the content of Met-enkephalin and 5-HIAA are possibly compensatory changes which subserve the functionality of central cardiovascular and pain regulatory systems after the immunolesion.

[The treatment of upper digestive hemorrhage of peptic origin: intravenous ranitidine versus intravenous omeprazole]. / Tratamiento de la hemorragia digestiva alta de origen péptico: Ranitidina intravenosa versus Omeprazol intravenoso.

OBJECT: To evaluate the effectiveness of Ranitidine i.v. versus Omeprazole i.v. for gastrointestinal bleeding of peptic origin. MATERIAL AND METHODS: Prospective, comparative, randomized and open study of 81 in-patients, hospitalized consecutively during 13 months, with gastrointestinal bleeding of peptic origin and signs of recent hemostasis (S.R.H.), belonging to the groups Forrest Ib and II. Treatment groups: group A: Ranitidine: initial injection of 50 mg. i.v., followed by 100 mg/6 hours i.v., during the first 72 hours and afterwards by 150 mg/12 hours, orally; group B: Omeprazole: initial injection of 80 mg. i.v., followed by 40 mg/8 hours i.v. during the first 72 hours and afterwards by 20 mg/24 hours, orally. Evaluation criteria: persistent haematemesis and melena; need for transfusions: treatment failure average period of hospitalization and disappearance of S.R.H. after 72 hours. RESULTS: 43 patients received Ranitidine and 38 Omeprazole. Both groups were homogeneous in regard to variables ar hospitalization. No significant differences were found between these two groups: persistent melena (26% group A vs. 8% group B); patients who needed transfusion (39% vs. 31%); treatment failure (19% vs. 5%); average period of hospitalization; and disappearance of S.R.H. (81% vs. 95%). None of the patients died. CONCLUSIONS: The effectiveness of Ranitidine i.v. and Omeprazole i.v., in the dosage used and in a selected group of patients with gastrointestinal bleeding, is similar. However, there is a trend to register less treatment failures and a higher percentage of S.R.H. disappearance with the patients treated with Omeprazole. Further studies with more patients are necessary to confirm this tendency.

Economic evaluation of colorectal cancer screening with fecal occult blood detection.

OBJECTIVE: To analyze the cost/benefit (CBA), cost/effectiveness (CEA) and cost/utility (CUA) of colorectal cancer (CC) screening through the detection of fecal occult blood (FOB). METHODS: A retrospective 10-year study was carried out in primary care hospitals to observe the evolution of CC in the study zone; subsequently, CC screening with FOB detection was done, and the entire population aged 50 to 75 years living in the Casas Ibáñez Health Zone was invited to take part. When the results had been evaluated, the screening program was evaluated in economic terms to determine CBA and to compare screening costs (option A) with the cost of allowing CC to develop without intervention (doing nothing), according to the previous retrospective study. The CEA calculated the cost of each cancer found in an asymptomatic stage, and the CUA calculated the cost of each year adjusted to quality of life (QUALY) for both options. RESULTS: The CBA showed that screening for CC with FOB detection (option A) produced a savings of 2,001,067 Spanish pesetas (USD15,310) in comparison with option B (doing nothing). The CEA showed that each cancer detected by screening at an asymptomatic stage cost 806,025 pesetas (USD6,167). The CUA showed that each QUALY for men in option A cost 1,051,185 pesetas (USD8,043), whereas for option B each QUALY would cost 4,220,315 pesetas (USD32,290). For women, each QUALY cost 564,795 pesetas (USD4,321.31) in option A and 2,413,834 pesetas (USD18,469) in option B. CONCLUSIONS: Our economic evaluation demonstrates that the cost/benefit, cost/effectiveness and cost/utility ratios for CC screening through FOB detection with the Hemoccult test are better than for the alternative of doing nothing.

Colorectal cancer screening through detection of fecal occult blood in a controlled health zone.

AIM: to determine the viability and utility of fecal occult blood (FOB) screening (Hemoccult II) as a method for the early diagnosis of colorectal cancer in a well-controlled health area. METHODS: between February 1994 and September 1996, personal letters were sent to all persons in the Casas Ibáñez health area (Albacete) aged between 50 and 75 years (4986 persons). All the tests were read by the same team member. A clinical history was taken of persons with positive test results, and they were offered colonoscopy. If a growth was found which was suitable for endoscopic resection, this was done. If the growth was totally resected an annual check-up was advised. Malignant and partially resected premalignant growths were referred for surgical treatment. We analyzed percent participation, attendance for testing, negative and positive tests, growths diagnosed, false-positive tests and positive predictive value. RESULTS: the a participation rate was 56.25%. In the 157 colonoscopies performed, 39 neoplasic polyps and 9 cancers were found (7 of which were Dukes stage A and 2 of which were Dukes stage C-D). Sensitivity was 97% and specificity was 96%. The positive predictive value was 30.37%. The positivity rate was 6.08%, while the predictive value for cancer was 5.38% and the predictive value for adenoma was 23.35%. CONCLUSIONS: FOB screening, in our setting, proved to have a high recruitment capacity with a positive predictive value for colorectal carcinoma which was slightly higher than the value obtained in other countries of similar socioeconomic status. Furthermore, we found a significant improvement in the diagnostic stage of colorectal carcinoma at the time of resection.

[Meningococcal C disease epidemic in Galicia 1996: the decision making process]. / El procedimiento de toma de decisión para controlar la epidemia de meningitis C en Galicia en 1996.

In this article we describe the decision making process used to choose the best alternative for bringing under control an epidemic of meningococcal C disease, which occurred in Galicia in 1996. In the decision making process, we used a methodology which consisted on the identification and definition of a problem, in order to identify alternative solutions and to select one, and finally implement and evaluate it. The health problem was detected studying the data obtained from a survey conducted following an outbreak of meningococcal C disease in february 1995 and from the active epidemiological surveillance system created thereafter. Because this was a new, complex and severe problem, with far-reaching social consequences, critical for our organization, and with long-term implications, and because it was considered important to take the decision as objectively as possible and to clearly explain it, the methodology chosen to solve the problem was a non-programmed, multicriteria making decision process, carried out by a working group using a criterion weighting approach. This working group was created within the General Directorate of Public Health, composed of specialist and of people responsible for the different areas involved. The working group put into practice the different steps of the methodology. The assessment criteria and their respective weights were: effect (efficacy measured by the number of cases we could have prevented if the alternatives were applied in the previous season) 40%; cost (in millions of pesetas) 15%; acceptability (acceptance of and response to each strategy from different groups: general population, health care professionals, other Administrations with competency in Public Health) 30%; and coherence (adherence to the currently accepted strategies for disease control in other countries)15%. When these criteria were applied to the ten alternatives considered, a score was obtained for each one of them. The highest scoring alternative corresponded to the massive vaccination of the total population of Galicia between 18 months and 19 years of age.

[The treatment of children with difficult to control epilepsy]. / Tratamiento de los niños con epilepsia de difícil control.

A survey is conducted of the way difficult-to-control epileptic seizures are currently managed in paediatric practice. We also highlight the alternative means of therapy available, such as epilepsy surgery, a ketogenic diet, the use of hormones, steroids, gamma globulin and the stimulation of the vagal nerve, together with their indications, their efficiency in the different types of epilepsy and their contraindications. Mention is also made of the new antiepileptic drugs that have appeared since the nineties, as well as the reappearance of others that had fallen into disuse.

[Clinical findings in active cerebral neurocysticercosis in pediatrics]. / Manifestaciones clínicas de la neurocisticercosis cerebral activa en pediatría.

OBJECTIVE: We describe our experience in the study of active cerebral cysticercosis in paediatrics over a period of 6 years, involving a total of 85 cases, which were studied from the clinical, immunological and radiological points of view. The aim of this communication is to present the clinical characteristics of the disorder and its course when symptomatic treatment is given. DEVELOPMENT: The commonest age of presentation was school age. However, we had a large number of children under 4 years old. This shows that there is considerable endemicity in a group in which the disorder is considered to be less frequent. There were slightly more females than males, which is in accordance with another Mexican series. The predominant socio-economic level was poor (59%). The patients come from urban areas more and more frequently. The commonest signs were: convulsive crises, intracranial hypertension and headache without intracranial hypertension. The commonest type of crisis was partial, in its different forms. CONCLUSIONS: The course was mild and satisfactory in 90% of the patients. The good clinical progress was independent of the use of antiparasitic treatment.

[Is there a place for otorhinolaryngology in primary care? Analysis of different areas]. / Qué papel tiene la otorrinolaringología en la asistencia primaria? Un análisis de variación en áreas concretas.

Otolaryngological disorders do have a high incidence, and prevalence and require specific physical examinations amongst general population. As a result, it is believed that it would be efficient to have otorhinolaryngologists within the primary care system. The main aim of this study was to assess the differences in hospital referrals comparing primary care units with and without ENT specialists. The study was carried out in Osona County (Catalonia, Spain). We studied the referrals to the hospital from two different primary care units, one with otorhinolaryngology services and the other without them. We analysed the morbidity, follow up and demographic variables of first visits in the hospital ENT department referred by these two primary care units. The primary care organisation without ENT specialist tends to refer more patients (3.96 first visits more per 1000 inhabitants a year, CI 95% 2.84-5.09) with ENT problems than the primary care one with ENT specialist. The difference is mainly due to an higher number of referrals that do not require hospital treatment (i.e. acute otitis, patients without an ENT clear diagnosis). In the area with ENT specialist, GP's also tend to refer patients directly to the hospital, hampering the organisation efficiency. The referrral pattern of GPs from the two organisations is quite similar, and they refer a high percentage of patients that do not need ENT hospital care. The study shows that ENT specialists in primary care units refer less patients with ENT disorders that can be successfully diagnosed and treated outside the hospital.

[Carotid paraganglioma: a case report]. / Paraganglioma carotídeo. Caso clínico.

Carotid paraganglioma are tumors arising from chemoreceptor paraganglioma cells. These cells have proved to have an embryologic origin from the neural crests. Due to their low incidence these tumors are not an habitually found in daily practices. We present a case of carotid body paraganglioma diagnosed by clinical exploration, CT scan, magnetic resonance imaging and magnetic resonance angiography which was successfully treated by surgery. The diagnostic and therapeutic difficulties present in these tumors are discussed.

[Madelung's disease]. / Enfermedad de Madelung.

Madelung's disease or Benign Symmetric Lipomatosis is a rare disease characterised by masses of adipose tissue spread symmetrically along the neck, trunk, shoulders and upper arms. It affects men from 30 to 60 years old with a previous history of alcoholism. Surgery is the only effective treatment.

The burden of infections by parainfluenza virus in hospitalized children in Spain.

We designed a prospective study to describe the clinical impact of the parainfluenza viruse (PIV) types detected in hospitalized children with respiratory tract infections from September 2008 to August 2010 in Spain. PIV infections were a significant proportion of viral respiratory detections (11.8% of cases). PIV types 3 and 4 were most commonly detected. There were clinical differences between PIV and respiratory syncytial virus infections.

[Primary renal carcinoid tumor]. / Tumor carcinoide renal primario.

Primary renal carcinoid tumors are very rare, so their characteristic imaging findings have not been well defined. We describe the case of a man with a large right renal mass associated to a retroperitoneal lymph-node conglomerate. Increased urine concentrations of 5-hydroxy-indole-acetic acid and the histologic findings led to the diagnosis of primary renal carcinoid tumor. We review the epidemiology, clinical presentation, and findings at ultrasonography, computed tomography, and magnetic resonance image for primary renal carcinoid tumors.