THYROID HORMONES AS A THIRD LINE OF AUGMENTATION MEDICATION IN TREATMENT-RESISTANT DEPRESSION.

INTRODUCTION: Clinical or subclinical hypothyroidism dictates the severity of depressive episodes and more frequently overlaps psychotic phenomenology. There are also major depressive episodes resistant to treatment in patients with euthyroidism, in which supplementation of antidepressant medication with thyroid hormones is beneficial. MATERIAL: Systematization of meta-analyses from perspectives: hypothyroidism and depression, autoimmune and depression pathology, gestational and puerperal pathology in association with hormonal and dispositional changes, presentation of therapeutic schemes. RESULTS: Hypothyroidism is more commonly comorbid with major depression in women. It associates the need for hospitalizations, psychotic phenomenology, resistance to treatment, somatic comorbidities. Autoimmune pathology is associated with depression and requires thorough investigation. A possible genetic candidate for thyroid dysfunction is the DIO1 gene. FT4 may be a predictor, but the combination of FT4 + TBG measured during the prenatal period has a higher prognostic power for a future depressive episode. CONCLUSION: The article presents psychiatric medication schemes that combine antidepressants and antipsychotics of various classes with other enhancers, an important role going back to step three, which includes thyroid hormones, mainly T3. The doses used are smaller than the amount of endogenous production of T3 daily, with a small risk of inducing clinical hyperthyroidism.

THE NEUROENDOCRINOLOGICAL ASPECTS OF PREGNANCY AND POSTPARTUM DEPRESSION.

INTRODUCTION: Ties between the endocrine system and mental health are undeniably a consistent point of interest in modern day medicine. Furthermore, mental disturbances due to hormonal changes following childbirth have been mentioned in medical literature since Hippocrates. Considering the dramatic endocrine, paracrine and autocrine changes that occur during gestation, labour and postnatal phase, hormonal theories are not to be ignored in the treatment of postpartum disorders. RESULTS: Reproductive hormones are known to modulate behavioural, emotional and cognitive response, therefore rapid changes in estradiol and progesterone plasma concentrations during pregnancy and labour create a vulnerable terrain leading towards postpartum disorders. New research shows that women suffering from postpartum disorders have abnormal neural responses, suggesting a neuroendocrine explanation for postpartum syndromes. CONCLUSION: To facilitate further research in this area, we present new information on several hormonal interactions and the psychiatric response involved in pregnancy and labour, offering an interdisciplinary outlook on pregnancy and postpartum disorders. There is enough evidence to suggest that estradiol, progesterone, oxytocin, cortisol and thyroid hormones are some of many hormones involved in postpartum syndromes and tackling their perinatal imbalance with pharmacological substituents or antagonists could be useful as an adjuvant form of treatment in future patients.

NON-INVASIVE ASSESSMENT OF LIVER STEATOSIS AND FIBROSIS USING TRANSIENT ELASTOGRAPHY AND CONTROLLED ATTENUATION PARAMETER IN TYPE 2 DIABETES PATIENTS.

CONTEXT: Nonalcoholic fatty liver disease is common in type 2 diabetes mellitus patients, being difficult to diagnose. OBJECTIVE: To find a correlation between elastographic parameters and lab results, for facilitating the diagnosis of nonalcoholic fatty liver disease. DESIGN: This is a cross sectional study, conducted at the Departments of Diabetes, Nutrition and Metabolic Diseases, and Gastroenterology and Hepatology, of the Clinical Emergency Hospital "Pius Brinzeu" Timisoara. SUBJECTS AND METHODS: We included 190 type 2 diabetes mellitus patients, collected data regarding medical history, clinical and biological features and applied the Alcohol Use Disorders Identification Test. We excluded patients with other causes of liver disease. Liver steatosis and fibrosis were evaluated through transient elastography, yielding two parameters: liver stiffness as an indicator of liver fibrosis stage, expressed in kPa, and liver steatosis stage, assessed by controlled attenuation parameter, expressed in dB/m. Data were analyzed using SPSS 15. RESULTS: The analyzed group comprised 113 patients. Elastographic measurements showed that 93.8% of the patients had steatosis (controlled attenuation parameter ≥232.5 dB/m) and 70.8% severe steatosis (controlled attenuation parameter ≥290 dB/m). Severe steatosis was more common in women (75.7%) than in men (68.1%) (p<0.0001). From the patients with steatosis, 47.2% had liver stiffness values suggestive for fibrosis and 19.8% for cirrhosis. Most patients with steatosis and severe fibrosis were obese (66.7%). Triglycerides/HDLc ratio >4 correlated with hepatic steatosis (p=0.04), being more common in patients with severe fibrosis/cirrhosis (58.3%) than in those with absent or mild fibrosis (36.2%). CONCLUSIONS: Our study found a clear correlation between type 2 diabetes mellitus and the presence of liver steatosis. It correlates with body mass index, waist circumference (in men) and triglycerides/HDLc ratio. Controlled attenuation parameter is a useful noninvasive method for detection and quantification of liver steatosis.

Composite bi-layered erodible films for potential ocular drug delivery.

Bi-layered hydroxypropylmethylcellulose and Eudragit based films were formulated as potential ocular drug delivery systems using chloramphenicol as a model antibiotic. Films were plasticized with polyethylene glycol 400 present in the Eudragit layer or both Eudragit and hydroxypropylmethylcellulose layers, and loaded with chloramphenicol (0.5% w/v in solution) in the hydroxypropylmethylcellulose layer. The weight, thickness and folding endurance of the optimized formulations were measured and further characterised for transparency, tensile, mucoadhesive, swelling and in vitro drug dissolution properties. The physical form of chloramphenicol within the films was evaluated using differential scanning calorimetry (DSC), and X-ray diffraction (XRD), complimented with scanning electron microscopy and energy dispersive X-ray spectroscopy. Fourier transform infrared spectroscopy was used to assess the interactions between the drug and the film components and confirm chloramphenicol's presence within the sample. Optimum films showed high transparency (≥80% transmittance), ease of peeling from Petri dish and folding endurance above 250. Average thickness was lower than contact lenses (0.4-1mm), confirming them as thin ocular films. The tensile properties showed a good balance between toughness and flexibility, and mucoadhesivity showed that they could potentially adhere to the ocular surface for prolonged periods. The drug loaded films showed swelling capacity that was greater than 300% of their original weight. The physical form of chloramphenicol within the films was amorphous (DSC and XRD) whilst in vitro drug dissolution showed sustained drug release from the films for four hours, before complete erosion. The chloramphenicol loaded films represent a potential means of treating common eye infections.

Intramolecular Communication in Anionic Oxidized Phosphanes through a Chelated Proton.

Oxidation of the 1,2-(PR2 )2 -1,2-closo-C2 B10 H10 (R=Ph, iPr) platform with hydrogen peroxide in acetone is a two-step procedure in which partial deboronation of the closo cluster and oxidation of the phosphorus atoms occur. Based on NMR spectroscopic and kinetic data, we demonstrate that the phosphorus atoms are oxidized in the first step, followed by cluster deboronation. DFT calculations and natural-bond orbital (NBO) analysis were used to obtain insight into the electronic structures of diphosphane ortho-carborane derivatives.

Contrast-enhanced ultrasound (CEUS) for the evaluation of focal liver lesions - a prospective multicenter study of its usefulness in clinical practice.

PURPOSE: To assess the value of contrast-enhanced ultrasound (CEUS) for differentiating malignant from benign focal liver lesions (FLLs) and for diagnosing different FLL types. MATERIAL AND METHODS: CEUS performed in 14 Romanian centers was prospectively collected between February 2011 and June 2012. The inclusion criteria were: age > 18 years; patients diagnosed with 1 - 3 de novo FLLs on B-mode ultrasound; reference method (computed tomography (CT), magnetic resonance imaging (MRI) or biopsy) available; patient's informed consent. FLL lesions were characterized during CEUS according to the European Federation of Societies for Ultrasound in Medicine and Biology guidelines. For statistical analysis, indeterminate FLLs at CEUS were rated as false classifications. RESULTS: A total number of 536 cases were included in the final analysis, 344 malignant lesions (64.2 %) and 192 benign lesions (35.8 %). The reference method was: CT/MRI - 379 cases (70.7 %), pathological exam - 150 cases (27.9 %) and aspiration of liver abscesses - 7 cases (1.4 %). CEUS was conclusive in 89.3 % and inconclusive in 10.7 % of cases. To differentiate between malignant and benign FLLs, CEUS had 85.7 % sensitivity, 85.9 % specificity, 91.6 % positive predictive value, 77.1 % negative predictive value and 85.8 % accuracy. The CEUS accuracy for differentiation between malignant and benign liver lesions was similar in tumors with diameter ≤ 2 cm and those with diameter > 2 cm. CONCLUSION: CEUS represents a useful method in clinical practice for differentiating between malignant and benign FLLs detected on standard ultrasonography, and the results of this study are in concordance with previous multicenter studies: DEGUM (Germany) and STIC (France).

Multi-layer haemocompatible diamond-like carbon coatings obtained by combined radio frequency plasma enhanced chemical vapor deposition and magnetron sputtering.

Radio-frequency Plasma Enhanced Chemical Vapour Deposition (in different methane dilutions) was used to synthesize adherent and haemocompatible diamond-like carbon (DLC) films on medical grade titanium substrates. The improvement of the adherence has been achieved by interposing a functional buffer layer with graded composition TixTiC1-x (x = 0-1) synthesized by magnetron co-sputtering. Bonding strength values of up to ~67 MPa have been measured by pull-out tests. Films with different sp(3)/sp(2) ratio have been obtained by changing the methane concentration in the deposition chamber. Raman spectroscopy, X-ray photoelectron spectroscopy and X-ray diffraction were employed for the physical-chemical characterization of the samples. The highest concentration of sp(3)-C (~87 %), corresponding to a lower DLC surface energy (28.7 mJ/m(2) ), was deposited in a pure methane atmosphere. The biological response of the DLC films was assayed by a state-of-the-art biological analysis method (surface enhanced laser desorption/ionization-time of flight mass spectroscopy), in conjunction with other dedicated testing techniques: Western blot and partial thromboplastin time. The data support a cause-effect relationship between sp(3)-C content, surface energy and coagulation time, as well as between platelet-surface adherence properties and protein adsorption profiles.

Technical performance of colonoscopy -- multicenter study in university and non-university centers of Romania.

UNLABELLED: The aim of the paper was to evaluate the national availability of colonoscopy and the quality parameters of this procedure in our country. MATERIAL AND METHOD: During a 6 months period (01.07- 31.12.2009), we performed a prospective multicenter study in which 76 centers were invited to respond to a questionnaire regarding colonoscopy, 39 centers agreeing to participate. We assessed: the number of colonoscopies, the number of total colonoscopies and the causes of incomplete colonoscopies. RESULTS: During the study period, 16,083 colonoscopies were performed, 12,294 (76.4%) of them total colonoscopies. In 1,191 cases, stenosis was the cause of incomplete colonoscopy. If we consider this an objective reason for an incomplete colonoscopy, there were 12,294 total colonoscopies (82.4%). Comparing university centers with non-university ones, the proportion of total colonoscopies was 10,400/12,475 (83.4%) vs. 1,894/2,417 (78.4%) (p less then 0.0001). However, comparing the present study with previous ones, performed in 2003 and 2007, the proportion of total colonoscopies increased from 70.5% to 76.9% and 82.4% respectively (2003 vs. 2007 p less then 0.0001; 2007 vs. 2009 p less then 0.0001), while the quality difference between university and non-university hospitals persisted. CONCLUSIONS: the quality of colonoscopy in Romania increased in the last 5 years, while the quality difference between university and non-university hospitals persisted.

Clinical aggression of prolactinomas: correlations with invasion and recurrence.

Some hypophyseal adenomas are discrete, well-marked lesions, which can be curatively removed by surgical resection, while others seem aggressive, invasive, recidive-prone, most often progressing in spite of any pharmacological, surgical or radiotherapeutical interventions. There is also a great variability within the incidence of aggression and invasion among the various types of hypophyseal immunotypes. Despite their well-differentiated nature and their "benign" constitution, an important number of hypophyseal tumors will be surely invasive within the sclerous, osseous and neural structures. Because the aggressive behavior of invasive adenomas is generally resolved by surgical treatment, this aspect of their biology does not perfectly reflect within their histopathological aspect. In fact, the invasive tumors with local extreme aggression are most often deceiving due to their relatively harmless histopathological aspect. The usual morphological signs of tumor aggression, namely pleomorphism, nuclear atypia, hemorrhage, high cellular and mitotic activity, poorly correlate with the invasive potential of pituitary tumors, with their proliferation capacity, their tendency of post-surgical recurrence or with their global biological behavior.

The role of capsule endoscopy in the detection of small bowel disease.

Videocapsule endoscopy (VCE) can identify lesions in the small bowel which would otherwise be hard to detect. We have selected 53 patients with digestive symptoms in which upper and lower endoscopy had provided no findings. Patients were classified into three groups, based on their main indication for VCE exploration: group one--obscure gastrointestinal bleeding (OGIB); group two--unspecific abdominal symptoms; group 3--monitoring of a prior known pathology. We found that VCE has high predictive values, sensibility and specificity in the diagnosis of OGIB. VCE was also useful in the detection and extent evaluation of lesions in Crohn's and celiac disease. VCE is also able to detect tumors of the small bowel with sufficient accuracy, and can be used to monitor patients with hereditary pre-malignant diseases such as FAP. There were few light adverse effects and no major complications. We conclude that VCE is a safe and effective procedure for the detection of small bowel lesions.

Utility of endoscopic ultrasound multimodal examination with fine needle aspiration for the diagnosis of pancreatic insulinoma - a case report.

Insulinomas are benign insulin-secreting neuroendocrine tumors originating in the pancreatic beta cells. Symptoms are caused by hypoglycemia and clinical diagnosis is based on establishing their relationship to fasting, usually via a fasting test. The most conclusive imaging tests are endoscopic ultrasound (EUS) and CT. Surgery is the treatment of choice. A 33 year old male presented with a 2-year history of hunger which had intensified in the previous 6 months with added accompanying symptoms, culminating with an acute episode - loss of consciousness and seizures - which resolved after administering i.v. glucose. A fasting test was performed, with results suggestive for an insulinoma. Dual-phase CT showed a mass in the tail of the pancreas but no contrast enhancement. EUS was used for further assessment: B-mode showed a hypoechoic focal mass with a cystic component, on contrast enhancement the pattern was hypovascular, and elastography showed soft tissue. EUS fine needle aspiration (FNA) was performed and the immunohistochemistry (IHC) assay was conclusive for a neuroendocrine tumor of the pancreas. Treatment consisted of caudal pancreatectomy, with no recurrence after 1-year follow-up. Although this case started with a classic clinical presentation of an insulinoma, imaging studies related to tumor vascularization raised doubts about the actual diagnosis. Nevertheless, multimodal EUS assessment with FNA was considered to be the most appropriate diagnostic technique for detection, characterization and staging of the mass. EUS findings together with the IHC assay were able to offer the definite diagnosis of a benign neuroendocrine tumor and allowed us to refer the patient for appropriate treatment.

Thyroid stiffness assessment by acoustic radiation force impulse elastography (ARFI).

PURPOSE: To evaluate and compare the values of thyroid tissue elasticity in subjects without known thyroid pathology, in patients with Graves' disease and with chronic autoimmune thyroiditis (CAT). PATIENTS AND METHODS: We performed a prospective study that included 74 subjects, 23 without thyroid pathology, 29 with Graves' disease and 22 with CAT (diagnosed by specific tests). In all patients, 10 elastographic measurements were performed in the right thyroid lobe (RTL) and 10 in the left thyroid lobe (LTL) using a 2-6 MHz convex probe. Median values were calculated for each thyroid lobe, measured in meters/second (m/sec). We calculated a mean ARFI value from measurements made in the RTL and LTL. RESULTS: Thyroid stiffness was statistically significant lower in normal subjects vs. those with Graves' disease (2.07±0.44 m/sec vs. 2.82±0.47 m/sec, p<0.001) and with CAT (2.07±0.44 m/sec vs. 2.49±0.48 m/sec, p=0.004). We also found a statistically significant difference between subjects without thyroid pathology and those with autoimmune thyroid pathology (Graves' disease and CAT) (2.07±0.44 m/sec vs. 2.68±0.50 m/sec, p<0.001). CONCLUSION: ARFI seems to be a useful method for the evaluation of diffuse thyroid gland pathology and is able to predict with sufficient accuracy the presence of thyroid diffuse diseases (AUROC=0.80).

Acoustic radiation force impulse elastography as compared to transient elastography and liver biopsy in patients with chronic hepatopathies.

PURPOSE: To compare two methods of noninvasive assessment: transient elastography (TE) and acoustic radiation force impulse elastography (ARFI). PATIENTS AND METHODS: Our study included 114 subjects: 38 healthy volunteers, (considered to have no fibrosis - F 0) and 76 patients with chronic liver disease: 53 who had undergone liver biopsy (LB) (7 with F 1, 24 with F 2, 22 with F 3 Metavir) and 23 previously diagnosed with cirrhosis (F4 Metavir). In each patient we performed a liver stiffness measurement by means of TE and ARFI. ARFI (shear wave velocity quantification) was performed at 3 points: at 0 - 1 cm, at 1 - 2 cm and at 2 - 3 cm under the capsule. For each depth, 5 valid measurements were made, and a median value was calculated, measured in m/sec. RESULTS: A direct, strong, linear correlation (Spearman rho = 0.848) was found between TE and the stage of fibrosis (p < 0.001). A significant, direct correlation was found between ARFI measurements made 1 - 2 cm and 2 - 3 cm below the liver capsule and the severity of fibrosis (rho = 0.675 and 0.714 respectively). The subcapsularly measured ARFI values showed a poor correlation with fibrosis (rho = 0.469). The best test for predicting significant fibrosis (F ≥ 2) was TE, with the area under receiver-operating characteristic curve (AUROC) 0.908, significantly larger than the AUROCs for ARFI. If only ARFI is considered, measurements made 1 - 2 and 2 - 3 cm below the capsule have the best predictive value, with AUROCs not significantly different from each other (0.767 and 0.731, respectively). For predicting fibrosis (F > 0), TE had the best predictive value: optimized cut-off 5.65 kPa (AUROC -0.898). For ARFI, the cut-offs were: 1.4 m/sec, AUROC -0.747 (1 - 2 cm), and 1.26 m/sec AUROC -0.721 (2 - 3 cm). For predicting cirrhosis (F = 4 Metavir), the optimized cut-offs were: TE -12.9 kPa (AUROC -0.994); ARFI - 1.78 m/sec for measurements made 2 - 3 cm below the capsule, AUROC - 0.951. CONCLUSION: At present, liver elasticity evaluation by means of ARFI is not superior to TE for the assessment of liver fibrosis. For ARFI, the most reliable results are obtained if measurements are made 1 - 2 and 2 - 3 cm below the liver capsule. ARFI is an accurate test for the diagnosis of cirrhosis.

What did we learn from the first 3,459 cases of liver stiffness measurement by transient elastography (FibroScan®)?

PURPOSE: Chronic viral hepatopathies can be evaluated through invasive or noninvasive methods. The aim of this paper was to assess the indications and results of transient elastographic (TE) evaluation of the liver in patients with chronic viral hepatitis and cirrhosis. MATERIALS AND METHODS: We retrospectively assessed all the liver stiffness measurements (LSM) (FibroScan®) performed over a two-year period (2007 - 2009). RESULTS: 3,459 TE evaluations were made mainly for the assessment of: HCV hepatitis, HBV infection (chronic hepatitis and inactive HBV carriers), biviral hepatitis (B + C or B + D), cirrhosis and in 176 normal subjects (to establish the normal values of LSM). From the 3,459 FS evaluations, we could not obtain valid LSM in 183 cases (5.3 %). 93.9 % of the patients in the failure group were overweight (BMI > 25 kg/m²). In 527 cases (16 %) the SR (success rate = number of valid measurements/total number of measurements) was < 60 %. TE reproducibility was analyzed in 287 cases. The ICCs for the three operators were 0.985, 0.949, and 0.874 respectively, and the overall ICC was 0.982. 596 cases of cirrhosis were evaluated. A cut-off value of 23.3kPa was found to predict the presence of at least grade 2 esophageal varices. CONCLUSION: LSM by means of TE is a promising noninvasive evaluation method, which can be used in numerous clinical situations, some in which its value is well established (suspicion of LC, predicting significant fibrosis) and some in which its value is less known (HBV chronic hepatitis, inactive HBV carriers or severity of portal hypertension).

Mutant HFE genotype leads to significant iron overload in patients with liver diseases from western Romania.

The present study aimed at assessing the frequency of HFE mutations (C282Y, H63D and S65C) in western Romanian patients with liver disease of diverse aetiologies suspected of iron overload. A total of 21 patients, all Romanian residents hospitalized with clinical suspicion of iron overload and liver disease, were assayed for C282Y, H63D and S65C mutations, serum ferritin and viral hepatitis markers. Overall, 9 out of the 21 patients (42.86%) were found to harbour mutations in the HFE gene: 4 homozygotes C282Y (19.0%), 1 compound heterozygote C282Y/H63D (4.8%), 1 single heterozygote C282Y (4.8%), 2 single heterozygotes H63D (9.5%), 1 single heterozygote S65C (4.8%), and 12 wild-type cases (57.1%). Among the subgroup of 10 patients with the most prominent signs of iron overload (hyperferritinaemia and/or hepatocyte iron score > or = 1), without hepatocellular carcinoma, the HFE genotypes were conclusive in 5 cases (50%). They had significantly increased ferritin levels compared to wild-type cases (P = 0.029). The inclusion of iron studies during routine clinical visits, coupled with the availability of HFE genotyping for family and population studies, should facilitate the early detection of hereditary haemochromatosis in Romania.

Quantification of the activity of biomolecules in microarrays obtained by direct laser transfer.

The direct-writing technique laser-induced forward transfer has been employed for the micro-array printing of liquid solutions of the enzyme horseradish peroxidase and the protein Titin on nitrocellulose solid surfaces. The effect of two UV laser pulse lengths, femtosecond and nanosecond has been studied in relation with maintaining the activity of the transferred biomolecules. The quantification of the active biomolecules after transfer has been carried out using Bradford assay, quantitative colorimetric enzymatic assay and fluorescence techniques. Spectrophotometric measurements of the HRP and the Titin activity as well as chromatogenic and fluorescence assay studies have revealed a connection between the properties of the deposited, biologically active biomolecules, the experimental conditions and the target composition. The bioassays have shown that up to 78% of the biomolecules remained active after femtosecond laser transfer, while this value reduced to 54% after nanosecond laser transfer. The addition of glycerol in a percentage up to 70% in the solution to be transferred has contributed to the stabilization of the micro-array patterns and the increase of their resolution.

Changes in prescribed doses for the Seattle neutron therapy system.

From the beginning of the neutron therapy program at the University of Washington Medical Center, the neutron dose distribution in tissue has been calculated using an in-house treatment planning system called PRISM. In order to increase the accuracy of the absorbed dose calculations, two main improvements were made to the PRISM treatment planning system: (a) the algorithm was changed by the addition of an analytical expression of the central axis wedge factor dependence with field size and depth developed at UWMC. Older versions of the treatment-planning algorithm used a constant central axis wedge factor; (b) a complete newly commissioned set of measured data was introduced in the latest version of PRISM. The new version of the PRISM algorithm allowed for the use of the wedge profiles measured at different depths instead of one wedge profile measured at one depth. The comparison of the absorbed dose calculations using the old and the improved algorithm showed discrepancies mainly due to the missing central axis wedge factor dependence with field size and depth and due to the absence of the wedge profiles at depths different from 10 cm. This study concludes that the previously reported prescribed doses for neutron therapy should be changed.