Elucidation of the mTOR Pathway and Therapeutic Applications in Dermatology. / Bases moleculares y aplicaciones farmacológicas de la vía de mTOR en dermatología.

The member of the phosphatidylinositol 3-kinase family, mammalian target of rapamycin, is involved in modulating inflammatory response and regulating cellular processes associated with growth, differentiation, and angiogenesis. Recent years have seen major advances in our understanding of the mammalian target of rapamycin signaling pathway and the implication of this pathway in multiple genetic and inflammatory diseases and tumors. The development of the mammalian target of rapamycin inhibitors has given rise to new treatment approaches that have led to substantially improved outcomes in many diseases. In this article, we review the role of the mammalian target of rapamycin signaling pathway in the different skin diseases with which it has been associated, examine the therapeutic applications of drugs targeting this pathway, and provide an overview of current trends and future directions in research.

Facial Angiofibroma Severity Index (FASI): reliability assessment of a new tool developed to measure severity and responsiveness to therapy in tuberous sclerosis-associated facial angiofibroma.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by the development of multisystem hamartomatous tumours. Topical sirolimus has recently been suggested as a potential treatment for TSC-associated facial angiofibroma (FA). AIM: To validate a reproducible scale created for the assessment of clinical severity and treatment response in these patients. METHODS: We developed a new tool, the Facial Angiofibroma Severity Index (FASI) to evaluate the grade of erythema and the size and extent of FAs. In total, 30 different photographs of patients with TSC were shown to 56 dermatologists at each evaluation. Three evaluations using the same photographs but in a different random order were performed 1 week apart. Test and retest reliability and interobserver reproducibility were determined. RESULTS: There was good agreement between the investigators. Inter-rater reliability showed strong correlations (> 0.98; range 0.97-0.99) with inter-rater correlation coefficients (ICCs) for the FASI. The global estimated kappa coefficient for the degree of intra-rater agreement (test-retest) was 0.94 (range 0.91-0.97). CONCLUSIONS: The FASI is a valid and reliable tool for measuring the clinical severity of TSC-associated FAs, which can be applied in clinical practice to evaluate the response to treatment in these patients.

Current options for the treatment of facial angiofibromas.

Facial angiofibromas are hamartomatous growths that are closely associated with tuberous sclerosis complex and, in fact, they constitute one of the main diagnostic criteria for that disease. These lesions composed of blood vessels and fibrous tissue appear on the face at an early age. Since they have important physical and psychological repercussions for patients, several treatment options have been used to remove them or improve their appearance. However, the lack of treatment guidelines prevents us from developing a common protocol for patients with this condition. The present article aims to review the treatments for facial angiofibromas used to date and to propose a new evidence-based treatment protocol.

Atopic dermatitis: update and proposed management algorithm.

Atopic dermatitis is a chronic inflammatory disease that affects 20% of children and almost 3% of adults and is associated with considerable impairment of quality of life for both patients and their families. While the condition resolves spontaneously after puberty in over 75% of cases, it can persist into adulthood. Furthermore, in young children severe forms can have serious health consequences and affect social development. There are no appropriate guidelines on how to handle cases that do not respond to routine treatment. In this article, we review the current treatments for moderate to severe atopic dermatitis, describe our experience with this disease, and propose a management algorithm.

Cellulose microfluidic pH boosting on copper oxide non-enzymatic glucose sensor strip for neutral pH samples.

A cellulose microfluidic pH boosting layer adapts a non-enzymatic copper oxide glucose sensor strip for neutral pH samples. This adaptation allows the non-enzymatic technology to realize in-situ glucose measurements. A three-electrode system is constructed to test samples in a classical electrochemical cell, and in a sensing strip to test the microfluidic system. The system consists of copper oxide as working electrode, and silver and carbon paints as reference, and counter electrodes, respectively. The fabrication of the pH-boosting layer is made with natural cellulose. Within this layer are NaOH crystals, grown by a drying processes after immersion of cellulose in a concentrated solution of NaOH. The microfluidic layer is placed on top of the sensing electrodes, and while it transports the fluid sample to the sensing electrodes, the fluid dissolves the NaOH crystals, increasing the pH of the sample. This change allows the non-enzymatic mechanism to sense the glucose concentration in the fluid. Our system shows the capability to measure glucose in samples with neutral pH and human blood with a sensitivity of 70 µA/mM cm2, enough to distinguish between hypoglycemia and hyperglycemia.

Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous sclerosis - associated facial angiofibroma.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by the development of multisystem hamartomatous tumours. Facial angiofibroma appears in up to 80% of patients and has a considerable psychological impact. Various invasive procedures have been used, although they show limited effectiveness and potential adverse effects. OBJECTIVES: To evaluate the sustained clinical benefits and safety profile of topical sirolimus applied to treat facial angiofibromas. METHODS: This study was a non-blinded, uncontrolled case-series comprising 10 patients with TSC-associated facial angiofibroma that was treated with 0.4% sirolimus ointment 3 times a week for 9 months. Patients were clinically evaluated at baseline and at 6, 12, 24 and 36 weeks. Plasma levels of sirolimus were determined. RESULTS: A sustained improvement was observed in erythema and in the size and extension of the lesions as early as the first weeks of treatment. Sirolimus plasma levels remained below detection limits (0.3 ng/mL) in all cases. The formula was well-tolerated with no local or systemic adverse effects. CONCLUSIONS: Topical sirolimus seems to be an effective and safe medical alternative to surgery or laser-based treatments in patients with TSC-associated facial angiofibromas.

Lipochoristoma of the internal auditory canal.

PROBLEM: Approximately 90% of tumours of cerebellopontine angle and internal auditory canal are vestibular schwannomas (acoustic neuromas) and meningiomas. Lipochoristomas are rare benign masses that represent only 0.15% of cases. METHODOLOGY: We report the case of a 39-year-old man who consulted us for right-sided hearing loss and tinnitus. RESULTS: Tonal audiometry showed a down-sloping right sensorineural hearing loss in frequencies above 2000 Hz. Magnetic resonance imaging (MRI) revealed a heterogeneous lesion in the right internal auditory canal with areas of hyperintensity on noncontrast T1-weighted MRI and suppression of much of the signal of the lesion with persistence of some areas of enhancement on T1-weighted fat-suppressed images. CONCLUSION: Correct imaging diagnosis through MRI (high signal intensity on noncontrast T1-weighted images together with a missing signal in fat suppression sequences) is essential in order to avoid unnecessary surgery or radiation therapy, which are not recommended in the treatment of these lesions.

Comparison of four prognostic scales for predicting mortality in patients with severe maternal morbidity. / Comparación de 4 escalas pronósticas para predecir mortalidad en pacientes con morbilidad materna severa.

OBJECTIVE: To compare the prognostic validity of the APACHE II-M and O-SOFA scales versus the APACHE II and SOFA to predict mortality in patients with severe maternal morbidity. DESIGN: A retrospective, longitudinal and analytical cohort study was carried out. SETTING: Medical-surgical intensive care unit (ICU) of a tertiary hospital. PATIENTS: Pregnant or puerperal patients of any age admitted to the ICU. INTERVENTIONS: Calculation of prognostic scores upon admission. VARIABLES OF INTEREST: APACHE II, SOFA, APACHE II-M and O-SOFA scores and maternal mortality. RESULTS: A total of 141 patients were included. The majority (70.2%) were puerperal. The most frequent diagnosis was gestational hypertensive disease (50 cases). The discrimination of each prognostic model was estimated with the area under the ROC curve (AUC-ROC). The calibration was estimated using the mortality ratio and the Hosmer-Lemeshow statistic. The four scales discriminated between survivors and non-survivors with areas under the curve >0.85. The APACHE II-M model was the predictive model with the highest discrimination and calibration. In the Hosmer-Lemeshow regression analysis, mortality as predicted by the APACHE II and O-SOFA was significantly different from the observed mortality. CONCLUSIONS: The APACHE II-M exhibited the greatest prognostic validity in predicting maternal mortality. This difference was given by its improvement in calibration.

Amoebae-resisting bacteria in drinking water: risk assessment and management.

Free-living amoebae have been detected in a large number of man-made water systems, including drinking water distribution systems. Some of these amoebae can host amoebae-resisting bacteria, and thus act potentially as reservoirs and vehicles for a number of pathogens. The objectives of this study were to characterize the amoebae and amoebae-resisting bacteria present in different raw waters used for drinking water production, and to assess the efficiency of different treatments applied for drinking water production in removing or inactivating these amoebae. The preliminary results of this study confirm the presence of amoebae and amoebae-resisting bacteria in raw waters used for drinking water production. Due to their capacity to encyst, most of these amoebae are extremely resistant to disinfection processes. In these conditions, preventing the dissemination of these micro-organisms through drinking water will mainly require their physical removal by clarification and filtration processes. The particular hazard that amoebae-resisting bacteria represent in drinking water production should be taken into account in any risk assessment conducted in the framework of a water safety plan, and control strategies based on physical removal rather than disinfection should be adopted where necessary.

Aneuploidy identification in pre-B acute lymphoblastic leukemia patients at diagnosis by Multiplex Ligation-dependent Probe Amplification (MLPA).

Three-quarters of the patients with acute lymphoblastic leukemia (ALL), show numerical or structural chromosomal alterations, which are important factors in leukemogenesis. The use of Multiplex Ligation-dependent Probes Amplification (MLPA) has been mainly limited for searching copy number alterations of genes, suggesting that MLPA could detect numerical alterations in cancer. However, the use of MLPA in pediatrics to analyze subtelomeric sequences for aneuploidy detection has not been considered in previous studies. The aim of this study was to identify aneuploidy for the first time using MLPA and correlate the results with karyotype and DNA-index (DI), from preB ALL patients. Forty-two bone marrow samples were analyzed by cytogenetics and flow cytometry to determine the DI. The chromosomal gains and/or losses were detected by the SALSA MLPA P036 Subtelomere Mix 1 probemix®. The chromosomal number matched in 36 out of 42 samples between MLPA and karyotype (R2=0.7829, p=3.7×10-10), 18/42 between MLPA and DI (R2=0.1556, p=0.023), and 20/42 between karyotype and DI (R2=0.1509, p=0.015). MLPA results correlated with karyotype and DI. The use of MLPA led us to identify a gained marker chromosome. Our results indicate that MLPA could be a useful and fast alternative tool for aneuploidy identification in pediatric leukemia.

Comparación de 4 escalas pronósticas para predecir mortalidad en pacientes con morbilidad materna severa / Comparison of four prognostic scales for predicting mortality in patients with severe maternal morbidity

Objetivo Comparar la validez pronóstica del APACHE II-M y O-SOFA versus el APACHE II y SOFA para predecir mortalidad en pacientes con morbilidad materna severa. Diseño Estudio de cohorte, retrospectivo, longitudinal y analítico. Ámbito Unidad de cuidados intensivos (UCI) médico-quirúrgica de un hospital de tercer nivel. Pacientes Pacientes embarazadas o puérperas de cualquier edad ingresadas en la UCI. Intervenciones Cálculo de scores pronósticos al ingreso. Variables de interés APACHE II, SOFA, APACHE II-M, O-SOFA y mortalidad materna. Resultados Se incluyeron 141 pacientes. Noventa y nueve (70,2%) fueron puérperas. El diagnóstico más frecuente fue la enfermedad hipertensiva del embarazo (50 casos). La discriminación de cada modelo pronóstico se estimó con el área bajo la curva ROC (ABC-ROC). La calibración se estimó utilizando la razón de mortalidad y el estadístico de Hosmer-Lemeshow. Las 4 escalas discriminaron entre supervivientes y no supervivientes con áreas bajo la curva >0,85. El modelo APACHE II-M fue el modelo pronóstico con mayor discriminación y calibración. En la regresión de Hosmer-Lemeshow la predicción de mortalidad de APACHE II y O-SOFA fue significativamente diferente a las muertes observadas. Conclusiones el APACHE II-M tuvo la mayor validez pronóstica para predecir muerte materna. Esta diferencia está dada por su mejoría en la calibración. (AU)

Objective To compare the prognostic validity of the APACHE II-M and O-SOFA scales versus the APACHE II and SOFA to predict mortality in patients with severe maternal morbidity. Design A retrospective, longitudinal and analytical cohort study was carried out. Setting Medical-surgical intensive care unit (ICU) of a tertiary hospital. Patients Pregnant or puerperal patients of any age admitted to the ICU. Interventions Calculation of prognostic scores upon admission. Variables of interest APACHE II, SOFA, APACHE II-M and O-SOFA scores and maternal mortality. Results A total of 141 patients were included. The majority (70.2%) were puerperal. The most frequent diagnosis was gestational hypertensive disease (50 cases). The discrimination of each prognostic model was estimated with the area under the ROC curve (AUC-ROC). The calibration was estimated using the mortality ratio and the Hosmer-Lemeshow statistic. The four scales discriminated between survivors and non-survivors with areas under the curve >0.85. The APACHE II-M model was the predictive model with the highest discrimination and calibration. In the Hosmer-Lemeshow regression analysis, mortality as predicted by the APACHE II and O-SOFA was significantly different from the observed mortality. Conclusions The APACHE II-M exhibited the greatest prognostic validity in predicting maternal mortality. This difference was given by its improvement in calibration. (AU)

Symptomatic diverticulum of the 4th ventricle.

A case of symptomatic diverticulum of the 4th ventricle in a 57-year-old man is presented. This clinicopathological observation supports a relationship between ventricular diverticula and ependyma-lined paraventricular cysts.

Treatment of invasive growth hormone pituitary adenomas with long-acting somatostatin analog SMS 201-995 before transsphenoidal surgery.

The purpose of this study was to determine whether the long-acting somatostatin analog SMS 201-995 (octreotide) shrinks growth hormone (GH)-secreting adenomas and improves the results of subsequent transsphenoidal surgery. Ten previously untreated active acromegalic patients (nine women and one man) with invasive tumors were treated with SMS 201-995 (100 micrograms subcutaneously every 8 hours) for 6 weeks prior to transsphenoidal surgery. The clinical activity, mean GH secretion, insulin-like growth factor (IGF)-I concentration, and tumor volume were measured under basal conditions and on Days 14, 28, and 42 of treatment. The SMS 201-995 improved the symptoms of acromegaly in all patients. Mean levels of both GH and IGF-I (+/- standard deviation) were significantly decreased by Day 14 (from 92.9 +/- 30.5 to 44.9 +/- 20.3 micrograms/liter and from 10.6 +/- 7.4 to 5.9 +/- 2.6 U/ml, respectively), after which there were only slight further decreases. Six (60%) of the 10 patients experienced tumor shrinkage ranging from 9% to 78% (mean 30%). When it occurred, tumor shrinkage was significant by Day 14 (7.9 +/- 6.3 to 6.5 +/- 5.1 cu cm) and no further shrinkage was achieved by longer administration. Transsphenoidal surgery reduced postoperative GH levels to less than 2 micrograms/liter and IGF-I to less than 1.5 U/ml in six patients (60%). This percentage of cure is higher than expected from the literature and the authors' previous experience. However, an investigation of the influence of this drug on several parameters, such as reduction of tumor size or GH and IGF-I concentrations, has failed to prove any relationship. Only pretreatment size of the tumor was of predictive value with respect to the surgical outcome.

[Spontaneous intracranial hypotension. Radiological findings]. / Hipotensión intracraneal espontánea. Hallazgos radiológicos.

INTRODUCTION: Spontaneous intracranial hypotension (SIH) is an uncommon condition. The main symptom is headache which appears on standing and is relieved by lying down. Diagnosis is confirmed if a CSF pressure of less than 6 cm of water is found in the absence of other causes of intracranial hypotension. OBJECTIVE: To describe the cranial MR and CT findings of 7 cases with SIH. MATERIAL AND METHODS: We studied 7 patients in whom the diagnosis had been confirmed by lumbar puncture. The findings of 5 cranial CT studies (not using contrast), 5 MR without gadolinium and 4 MR with gadolinium were studied. The CT were carried out during the first week after clinical signs appeared, and the MR at between 1 week and 4 months after onset. We reviewed previous findings in the literature. RESULTS: 1. Cranial CT: in one case there was an enlarged subarachnoid space; 2. MR without gadolinium: there was descent of the cerebellar tonsils in 4 patients, meningeal thickening in 5 cases and subdural collections in two patients. In no case was descent of the iter seen; 3. MR with gadolinium: aural contrast was taken up in all cases. CONCLUSIONS: The CT without contrast done at the onset of the condition did not usually give data which was useful for diagnosis. The principal MR findings in our series (meningeal thickening, descent of the cerebellar tonsils, subdural collections and gadolinium uptake) in an appropriate clinical context may be sufficient for diagnosis of this condition before lumbar puncture.