Shared Reflection to Maximize Resources and Minimize Costs: The Reflecting Team Applied to a Hospital Environment.

Severe mental illness entails multiple hospital admissions and a large use of public resources. The Reflecting Team (RT), together with other dialogue strategies, place in a single therapeutic space, the patient, his family and a team of professionals to find together a solution to a situation of stagnation. The aim of this study was to evaluate feasibility and cost-effectiveness of a RT intervention in psychiatric inpatients in a public hospital. Six RT were performed, and clinical variables were collected retrospectively for six months pre-RT and post-RT. Both number of hospital admissions and total time spent in the psychiatric acute unit show a significant decrease. All computed cost showed statistically significant reduction. The results suggest RT might be a good strategy to introduce a positive change in the treatment of those psychiatric cases in which the patient and family find themselves caught in a system that seems to offer stale and ineffective help to problems that have become chronic.

Facilitating the design of HL7 domain models through a model-driven solution.

BACKGROUND AND GOAL: Health information systems are increasingly sophisticated and developing them is a challenge for software developers. Software engineers usually make use of UML as a standard model language that allows defining health information system entities and their relations. However, working with health system requires learning HL7 standards, that defines and manages standards related to health information systems. HL7 standards are varied, however this work focusses on v2 and v3 since these are the most used one on the area that this work is being conducted. This works aims to allow modeling HL7 standard by using UML. METHODS: Several techniques based on the MDE (Model-Driven Engineering) paradigm have been used to cope with it. RESULTS: A useful reference framework, reducing final users learning curve and allowing modeling maintainable and easy-going health information systems. CONCLUSIONS: By using this approach, a software engineer without any previous knowledge about HL7 would be able to solve the problem of modeling HL7-based health information systems. Reducing the learning curve when working in projects that need HL7 standards.

Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer.

Despite improvements in surgery and medical treatments, epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy. Aim of this study is to investigate the preclinical immunotherapy activity of cytokine-induced killer lymphocytes (CIK) against epithelial ovarian cancers, focusing on platinum-resistant settings. We generated CIK ex vivo starting from human peripheral blood samples (PBMCs) collected from EOC patients. Their antitumor activity was tested in vitro and in vivo against platinum-resistant patient-derived ovarian cancer cells (pdOVCs) and a Patient Derived Xenograft (PDX), respectively. CIK were efficiently generated (48 fold median ex vivo expansion) from EOC patients; pdOVCs lines (n = 9) were successfully generated from metastatic ascites; the expression of CIK target molecules by pdOVC confirmed pre and post treatment in vitro with carboplatin. The results indicate that patient-derived CIK effectively killed autologous pdOVCs in vitro. Such intense activity was maintained against a subset of pdOVC that survived in vitro treatment with carboplatin. Moreover, CIK antitumor activity and tumor homing was confirmed in vivo within an EOC PDX model. Our preliminary data suggest that CIK are active in platinum resistant ovarian cancer models and should be therefore further investigated as a new therapeutic option in this extremely challenging setting.

The blind men and the elephant: Systematic review of systematic reviews of cannabis use related health harms.

Cannabis is the third most used psychoactive substance worldwide. The legal status of cannabis is changing in many Western countries, while we have very limited knowledge of the public health impact of cannabis-related harms. There is a need for a summary of the evidence of harms and risks attributed to cannabis use, in order to inform the definition of cannabis risky use. We have conducted a systematic review of systematic reviews, aiming to define cannabis-related harms. We included systematic reviews published until July 2018 from six different databases and following the PRISMA guidelines. To assess study quality we applied the AMSTAR 2 tool. A total of 44 systematic reviews, including 1,053 different studies, were eligible for inclusion. Harm was categorized in three dimensions: mental health, somatic harm and physical injury (including mortality). Evidence shows a clear association between cannabis use and psychosis, affective disorders, anxiety, sleep disorders, cognitive failures, respiratory adverse events, cancer, cardiovascular outcomes, and gastrointestinal disorders. Moreover, cannabis use is a risk factor for motor vehicle collision, suicidal behavior and partner and child violence. Cannabis use is a risk factor for several medical conditions and negative social consequences. There is still little data on the dose-dependency of these effects; evidence that is essential in order to define, from a public health perspective, what can be considered risky use of cannabis. This definition should be based on quantitative and qualitative criteria that informs and permits the evaluation of current approaches to a regulated cannabis market.

Pelvic discontinuity in acetabular revisions: does CT scan overestimate it? A comparative study of diagnostic accuracy of 3D-modeling and traditional 3D CT scan.

PURPOSE: 3D CT scan is actually the gold standard for preoperative diagnosis of pelvic discontinuity (PD) in hip revision surgery. Aim of this study was to compare the accuracy of 3D-modeling with traditional and 3D CT scan. MATERIALS AND METHODS: We retrospectively identified 56 patients who underwent total hip arthroplasty revisions with Paprosky Type-3 periacetabular bone defects. Preoperative X-rays, CT scans and 3D-models were blindly reviewed by two orthopedic surgeons to detect possible pelvic discontinuities. Results were compared with surgical notes. Independent sensitivities, specificities, positive predictive values and negative predictive values were calculated for X-rays, CT scan and 3D models. Analysis of interobserver reliability was performed. RESULTS: Fifty-six patients met inclusion criteria. In nine patients, surgical notes indicated a pelvic discontinuity. On 3D CT scans, PD was identified in 25 cases for observer 1 and in 24 cases for observer 2. Analyzing 3D-models, PD was identified in eleven patients by both observers. The nine patients, with PD reported on the surgical report, were all identified with both the techniques. The specificity of standard 3D CT was 0.66 for observer 1 and 0.68 for observer 2 and increased to 0.96 for both observers with the utilization of 3D-models. The positive predictive value increased from 0.36 (observer 1) and 0.38 (observer 2) with the CT evaluation to 0.82 in the 3D-models evaluation. The analysis of 3D models was characterized by a perfect intraobserver reliability (intraobserver correlation coefficient = 1). The observers showed substantial agreement for PD classification; the kappa values were 0.96 and 0.77, respectively, for CT scan and 3D-model evaluation. CONCLUSIONS: 3D-modeling showed higher specificity than traditional and 3D CT scans in identification of PD in Paprosky Type-3 periacetabular bone defects.

Constituyentes psicoactivos del cannabis y sus implicaciones clínicas: una revisión sistemática / Psychoactive constituents of cannabis and their clinical implications: a systematic review

Objetivo: Esta revisión sistemática pretende resumir la actual evidencia sobre qué cannabinoides naturalmente presentes contribuyen a la psicoactividad final del cannabis, considerando sus concentraciones registradas y su farmacodinamia en humanos. Metodología: Siguiendo las guías PRISMA, se revisaron artículos científicos publicados antes de marzo 2016 en Medline, Scopus-Elsevier, Scopus, ISI-Web of Knowledge y COCHRANE, que cumplieran unos criterios establecidos a-priori. Resultados: En 40 artículos científicos, se identificaron tres cannabinoides naturalmente presentes (Delta-9-Tetrahydrocannabinol, Delta-8-Tetrahydrocannabinol y cannabinol) y un metabolito humano (11-OH-THC) con relevancia clínica. De éstos, el metabolito produce los efectos psicoactivos más potentes. El cannabidiol (CBD) no es psicoactivo, pero sí ejerce un efecto modulador sobre los efectos psicoactivos del cannabis. La concentración 9-THC en derivados cannábicos (hasta 40%) supera en gran medida la de otros cannabinoides (hasta 9%). La farmacodinamia descrita varía, dada la heterogeneidad en aspectos clave de la metodología (dosis, rutas de administración y experiencia previa con cannabis de los participantes). Conclusiones: Los resultados evidencian que el 9-THC es el cannabinoide que más contribuye al efecto psicoactivo del cannabis. Otros cannabinoides psicoactivos contribuirían mínimamente, dada su menor potencia psicoactiva y su baja concentración en los derivados cannábicos. La falta de estándares metodológicos dificulta el avance en los conocimientos sobre los efectos del cannabis en la salud. Establecer una unidad estándar de cannabis basada en 9-THC ayudaría a superar estas limitaciones

Objective: This systematic review aims to summarize current evidence on which naturally present cannabinoids contribute to cannabis psychoactivity, considering their reported concentrations and pharmacodynamics in humans. Design: Following PRISMA guidelines, papers published before March 2016 in Medline, Scopus-Elsevier, Scopus, ISI-Web of Knowledge and COCHRANE, and fulfilling established a-priori selection criteria have been included. Results: In 40 original papers, three naturally present cannabinoids (Delta-9- Tetrahydrocannabinol, Delta-8-Tetrahydrocannabinol and Cannabinol) and one human metabolite (11-OH-THC) had clinical relevance. Of these, the metabolite produces the greatest psychoactive effects. Cannabidiol (CBD) is not psychoactive but plays a modulating role on cannabis psychoactive effects. The proportion of 9-THC in plant material is higher (up to 40%) than in other cannabinoids (up to 9%). Pharmacodynamic reports vary due to differences in methodological aspects (doses, administration route and volunteers' previous experience with cannabis). Conclusions: Findings reveal that 9-THC contributes the most to cannabis psychoactivity. Due to lower psychoactive potency and smaller proportions in plant material, other psychoactive cannabinoids have a weak influence on cannabis final effects. Current lack of standard methodology hinders homogenized research on cannabis health effects. Working on a standard cannabis unit considering 9-THC is recommended

TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin: TOP2A as marker of response to PLD in ovarian cancer.

OBJECTIVE: The treatment of platinum resistant/refractory epithelial ovarian cancer (EOC) is a challenge for oncologists. One of the most utilized drugs in these patients is pegylated liposomal doxorubicin (PLD). As PLD is active only in a small subset of patients and causes side effects, selection of responsive patients is an unmet need and might be guided by the status of the DNA topoisomerase II alpha (TOP2A) that is poisoned by the drug. METHODS: From 176 ovarian cancers treated in three institutions, we selected 38 patients treated with PLD monotherapy as second/third line of treatment. TOP2A gene copies were measured using Fluorescent In Situ Hybridization (FISH) and expression evaluated using immunohistochemistry. Patients' derived xenografts (PDXs) of ovarian cancers were used to assess the correlation between TOP2A protein expression and response to PLD. RESULTS: Clinical data showed that TOP2A gene gain that is paralleled by increased expression of the protein, was associated with a higher probability of clinical benefit from PLD. Treatment of PDXs demonstrated that only xenografts showing a high percentage of TOP2A expressing cells underwent tumor shrinkage when treated with PLD. CONCLUSIONS: These data show that TOP2A gene gain and protein over-expression might predict activity of PLD in platinum resistant/refractory EOC.

17beta-oestradiol-induced gene expression in cattle prostate: biomarkers to detect illegal use of growth promoters.

The effects of 17beta-oestradiol (E2) on gene expression in cultures of bovine primary prostate stromal cells (BPSCs) and prostate gland tissue were studied. In the first part of the study, BPSCs were grown in the presence of E2 from the first passage to the end of the experiment; a second group was treated in the same way but the treatment was suspended for 48 hours before the end of the experiment; a third group of BPSCs served as a control. In the second part of the study, five male veal calves, aged 130 days, were treated four times intramuscularly with 10 mg of E2 at intervals of two weeks and then euthanased two weeks after the last treatment. Quantitative PCR and immunohistochemistry were used to evaluate the expression of fibroblast growth factor (FGF) receptors (FGFRs), FGFs, progesterone receptor, androgen receptor and oestrogen receptor in BPSCs and prostate tissue. E2 induced a significant over-expression of progesterone receptor in both BPSCs and prostate tissue. There was also a marked up-regulation of FGFR types 1, 2 and 3 genes observed in the BPSCs.

MET receptor is overexpressed but not mutated in oral squamous cell carcinomas.

Oral squamous cell carcinoma (SCC) is a neoplasm characterized by a high degree of local invasion and an elevated rate of metastasis to cervical lymph nodes. It has been shown that the Hepatocyte Growth Factor/Scatter Factor Receptor Met is constitutively activated in many human tumors of epithelial origin and that it plays a critical role to confer invasive properties to neoplastic cells. Most frequently, Met activation is due to receptor overexpression, but also point mutations in the tyrosine kinase domain can lead to deregulated activation. Here we show that in all the primary tumors examined this receptor is overexpressed. Direct sequencing of Met mRNAs failed to find any activating mutation in its intracellular domain. Moreover, in cell lines derived from squamous cell carcinomas, HGF-induced activation of Met resulted in the acquisition of invasive properties. All together these data suggest that the MET oncogene is involved in progression of squamous cell carcinoma toward an invasive-metastatic behavior.

Complicaciones orgánicas de la cocaína / No disponible

Además de poseer una importante capacidad adictiva, la cocaína tiene una elevada toxicidad orgánica. Se revisa las distintas complicaciones asociadas al consumo de cocaína en cada órgano o sistema e intenta explicar los mecanismos etiopatogénicos conocidos así como los posibles tratamientos. Entre todas las posibles complicaciones de la cocaína destacan, por su frecuencia y gravedad, las alteraciones cardiovasculares que incluyen arritmias, infartos agudos de miocardio e ictus, poniendo de relieve, la importancia del consumo de cocaína en la patología cardiaca de los pacientes jóvenes. Así mismo, resaltar, las alteraciones neurológicas, sobretodo las convulsiones generalizadas con una elevada mortalidad, las cefaleas, por su elevada frecuencia y las complicaciones gastrointestinales como las perforaciones yuxtapilórica que requerirán tratamiento quirúrgico (AU)

Cocaine abuse has been associated to several medical complications besides its addictive potential. We review the distinct medical complications for each system and try to explain the current hypothesis about their etiology and recommended treatment. Among all possible complications of cocaine, the most common are related to the cardiovascular system. The possibility of cocaine effect should be seriously considered in young patients with minimal risk factors for cardiac disease presenting with myocardial infartation, dilated cardiomyopathy, myocarditis or cardiac arrhythmias. They are also of interest, neurological and gastrointestinal complications (AU)

Staging of head and neck squamous cell carcinoma using the MET oncogene product as marker of tumor cells in lymph node metastases.

In head and neck squamous cell carcinomas (HNSCC), metastasis to cervical lymph nodes is a major determinant of patient outcome. To detect metastases, we used the MET oncogene as marker, which encodes the receptor for hepatocyte growth factor/scatter factor, mediating epithelial cell motility and invasiveness. The MET gene is expressed in epithelia and over-expressed in carcinomas of specific histotypes, but not in lymphatic tissue. A total of 151 lymph nodes from 20 squamous cell carcinomas were studied with both in-depth histology and end-point and real-time quantitative RT-PCR. MET-encoded sequences were found in 61 of 151 nodes (40%), of which 24 (16%) were found metastatic by in-depth histopathology. Parallel routine histopathologic analysis of 654 lymph nodes from the same cases identified 36 metastases (5%). Real-time quantitative RT-PCR was used to measure MET gene-specific mRNA in normal tissues, primary tumors and lymphatic metastases and showed a 2-8-fold increased expression in tumor cells which metastasize. RT-PCR for 3 cytokeratins expressed in HNSCC (K4, K10 and K13) proved to be less sensitive in detecting occult lymphatic metastases. Western blot analysis demonstrated the presence of the full-size MET receptor in primary tumors and lymph node metastases; immunohistochemistry showed receptor localization in tumor cells. Altogether, these data demonstrate that the MET gene product is a valuable marker with which to detect occult tumor cells in lymph nodes, thanks to its high expression in metastatic cells. After RT-PCR analysis we were able to attribute a more advanced stage to 10 out of 20 HNSCC cases, including 5 cases classified as tumor-free after routine histopathology.

The expression of Met/hepatocyte growth factor receptor gene in giant cell tumors of bone and other benign musculoskeletal tumors.

Overexpression of the hepatocyte growth factor receptor (Met/HGF receptor), a transmembrane tyrosine kinase encoded by the MET proto-oncogene, is involved in transformation and invasive behavior of human carcinomas and sarcomas. We have previously found that bone sarcomas express high levels of Met/HGF receptor while in some cases the ligand HGF is co-expressed with the receptor, activating an autocrine loop. In this study, we analyzed 40 biopsy samples of a collection of giant cell tumors and other rare benign tumors of bone for expression of the MET proto-oncogene. These included nonossifying fibromas, osteoblastomas, desmoplastic fibromas of bone, chondroblastomas, and giant cell tumors of bone. Snap frozen samples were tested for the MET and HGF gene expression by immuno-histochemistry and Western blotting with anti-MET antibodies and RT-PCR. Over 50% of all cases scored positive for MET expression being constantly positive in recurrent or locally aggressive lesions. Sporadic co-expression of the Met/HGF receptor and ligand is also demonstrated. Met/HGF receptor expression in benign bone neoplasms suggests its early involvement in sarcomagenesis.

Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas.

A metastatic cancer develops by accumulation of mutations in genes that control growth, survival and spreading. The latter genes have not yet been identified. In lymph node metastases of head and neck squamous cell carcinomas (HNSCC), we found mutations in the MET oncogene, which encodes the tyrosine kinase receptor for Scatter Factor, a cytokine that stimulates epithelial cell motility and invasiveness during embryogenesis and tissue remodeling. We identified two somatic mutations: the Y1230C, known as a MET germline mutation which predisposes to hereditary renal cell carcinoma, and the Y1235D that is novel and changes a critical tyrosine, known to regulate MET kinase activity. The mutated MET receptors are constitutively active and confer an invasive phenotype to transfected cells. Interestingly, cells carrying the MET mutations are selected during metastatic spread: transcripts of the mutant alleles are highly represented in metastases, but barely detectable in primary tumors. These data indicate that cells expressing mutant MET undergo clonal expansion during HNSCC progression and suggest that MET might be one of the long sought oncogenes controlling progression of primary cancers to metastasis.

Toxicología del cannabis / Cannabis toxicology

Se resume de forma estructurada y comprensible las múltiples informaciones existentes sobre de la detección del cannabis y sus metabolitos en el organismo. Para ello se repasan de forma concisa varios aspectos farmacocinéticos de la marihuana que permiten comprender e interpretar los resultados analíticos. En la detección del THC del organismo se pueden utilizar principalmente tres técnicas de laboratorio que son la cromatografía , el inmunoensayo y la cromatrogafía de gases con o sin espectrometría de masas. Los diversos métodos de laboratorio se diferencian en su sensibilidad, especificidad, complejidad y coste. La elección de un método de laboratorio dependerá de los objetivos de la prueba. Aunque no hayan aparecido en los últimos años nuevas informaciones sobre el perfil metabólico del ∆9 -Tetrahydrocannabinol en humanos, sí podemos decir que el interés por detectar y medir metabolitos del THC en orina u otros fluidos biológicos para determinaciones forenses o médicas ha ido incrementando (AU)

There are different existing ways to monitor cannabis and the major cannabinoid metabolites in human body. These subject included information about phamacokinetics and metabolism of tetrahydrodannabinol and other cannabionoids to allow comprehension and interpretation of analytical results. Detection of marijuana can be done in the laboratory with several methodology like chromatography, immunoassay and Gas chromatography with mass spectrometer in different body fluids. The different methodology for drug test used will differed on sensitivity, specificity, difficulty and cost. The choice for one or another will depend on the different aim of the test. Although no new data have emerged regarding the metabolic profile of ∆9 -Tetrahydrocannabinol in humans in the past few years, interest in the measurement of urinary metabolites for forensic and medical purpose has increased (AU)

Novel mutation in the ATP-binding site of the MET oncogene tyrosine kinase in a HPRCC family.

Germline mutations in the tyrosine-kinase domain of the MET proto-oncogene were found in patients suffering from the hereditary predisposition to develop multiple papillary renal-cell carcinomas (hereditary PRCC, HPRCC). PRCCs are often multiple and bilateral even in patients without a family history. We analyzed the germline of patients carrying multiple or single papillary tumors with and without family history. One patient had a familial cancer and carried a novel (V1110I) germline MET mutation, located in MET gene exon 16. This mis-sense mutation was found in affected members of this patient's family. Interestingly, the V1110I mutation is located in the ATP-binding site of the MET kinase and is homologous to the V157I mutation that triggers the sarcomagenic potential of the v-erbB oncogene. The V1110I mutated MET receptor is an active kinase and transforms NIH-3T3 fibroblasts in the in vitro assays. Patients without familiality did not show germline mutations in the MET kinase domain, showing that multiple and bilateral papillary kidney tumors develop in the absence of these mutations. In conclusion, we describe a new mutation in the MET oncogene kinase domain, associated to HPRCC, affecting an amino-acid residue critical for kinase activation in different oncogenes.

Holtzman and Harlan Sprague-Dawley rats: differences in DRL 72-sec performance and 8-hydroxy-di-propylamino tetralin-induced hypothermia.

Several compounds were tested on the differential-reinforcement-of-low-rate 72-sec (DRL 72-sec) schedule, a behavioral screen to determine putative antidepressants; these compounds were evaluated in two outbred stocks of rats, Harlan and Holtzman Sprague-Dawley rats. A dose-response determination for the tricyclic antidepressants, imipramine and desipramine, the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, fluoxetine, the 5-HT2 receptor antagonist, ketanserin, the 5-HT1A receptor agonist, (+/-)8-hydroxy-di-propylamino tetralin (8-OH-DPAT) and the dopamine releasing compound, amphetamine, were assessed in both rat stocks. The two stocks of rats differed in their baseline performance on the DRL 72-sec schedule. The Harlan rats had a higher reinforcement rate and a lower response rate than the Holtzman rats. In Holtzman, but not in Harlan rats, imipramine, ketanserin, fluoxetine and 8-OH-DPAT increased reinforcement rate and decreased response rate on the DRL 72-sec schedule, confirming previous studies. However, desipramine was the only drug to increase reinforcement rate and decrease response rate in both Holtzman and Harlan rats; in Harlan rats, drugs that primarily act upon the 5-HT system, imipramine, ketanserin, fluoxetine and 8-OH-DPAT, disrupted the DRL 72-sec performance and did not increase the number of reinforcements over baseline as was seen in Holtzman rats. Amphetamine disrupted DRL 72-sec performance in both Holtzman and Harlan rats in a similar manner. The hypothermic response to 8-OH-DPAT was also assessed in the two stocks of rats; Holtzman rats had a smaller decrease in core body temperature than Harlan rats. The observed behavioral and pharmacological differences between Holtzman and Harlan rat stocks may be genetically and/or environmentally mediated.

Sensitization to amphetamine on the differential-reinforcement-of-low-rate 72-s schedule.

The purpose of the present study is to determine whether the effect of specific intermittent injections of amphetamine (AMPH) on a differential reinforcement schedule of low rate (DRL) would result in a sensitized response to subsequent AMPH injections. Two groups of rats were trained on a DRL 72-s schedule until they reached stable baseline performance. One group (SENS, n = 8) was treated intermittently (no more than twice a week) with 1.5 mg/kg amphetamine for 3.5 weeks. The other group (CONT, n = 8) received intermittent saline (SAL) 1 ml/kg for 3.5 weeks. Acute injections of 1.5 mg/kg AMPH in the SENS group, engendered an increase in response rate, a decrease in reinforcement rate and disruption of the inter-response time (IRT) distribution profile. Acute SAL injections in the CONT group had no effect. Rats pretreated with intermittent 1.5 mg/kg AMPH, when treated with a lower dose of AMPH (0.5 mg/kg), showed an increase in response rate, a decrease in reinforcement rate and disruption of the IRT distribution profile by decreasing peak area and shifting the peak location towards a shorter IRT duration. Therefore, in rats pretreated intermittently with 1.5 mg/kg AMPH (SENS group), the dose of 0.5 mg/kg AMPH elicited a similar change in DRL 72-s response pattern, as did the acute injection of 1.5 mg/kg AMPH. In contrast, in rats pretreated with SAL (CONT group), the low dose of AMPH had either no or small effects. Thus, pretreatment with 1.5 mg/kg AMPH increases the magnitude of the response to 0.5 mg/kg AMPH. These results indicate that rats performing on the DRL 72-s schedule exhibit sensitization to AMPH, after AMPH is given intermittently over a 3-week period.