Identification of a Novel Deletion Variant (c.2999_3005delTGTGTGT/p.Asn1000SerfsTer4) in NPHP4 Associated With Nephronophthisis-4.

BACKGROUND: Nephronophthisis-4 (NPHP4) is an inherited renal ciliopathy described by renal fibrosis and progressive impairment of kidney function. This study aimed to investigate the genetic basis and clinical manifestations of NPHP4 in two Iranian siblings. METHODS: The proband was a 27-year-old male with features of end-stage renal disease, including anemia, uremia, polyuria, and polydipsia. It is worth mentioning that he has a 22-year-old sister with a similar presentation. Clinical diagnosis procedures, such as renal biopsy, brain imaging, blood and urine tests, cardiac evaluation, ophthalmic inspection, and auditory function assessment, were carried out to evaluate organ involvement and potential comorbidities. Whole-exome sequencing (WES) and segregation analysis were performed to identify and confirm genetic variants associated with the condition. Computational variant analysis was conducted to evaluate the pathogenicity of the candidate variant. Furthermore, the SWISS-MODEL server was utilized for protein modeling. RESULTS: The brain, cardiac, ocular, and auditory functions were normal. Renal biopsy of the proband showed chronic interstitial inflammation and fibrosis. We found a novel homozygous 7-base pair deletion (c.2999_3005delTGTGTGT/ p.Asn1000SerfsTer4) in exon 21 of NPHP4 by WES. Segregation analysis confirmed homozygosity for the NPHP4 variant in affected individuals and heterozygous carrier status in parents, supporting autosomal recessive inheritance. 3D protein modeling indicated significant structural changes due to the variant. CONCLUSION: This study expands the genetic causes and phenotypic spectrum of nephronophthisis-4 and reveals the importance of genetic analysis in diagnosing and managing rare inherited kidney disorders, particularly those involving consanguinity.

Enhancing Intraoperative Tissue Identification: Investigating a Smart Electrosurgical Knife's Functionality During Electrosurgery.

OBJECTIVE: Detecting the cancerous growth margin and achieving a negative margin is one of the challenges that surgeons face during cancer procedures. A smart electrosurgical knife with integrated optical fibers has been designed previously to enable real-time use of diffuse reflectance spectroscopy for intraoperative margin assessment. In this paper, the thermal effect of the electrosurgical knife on tissue sensing is investigated. METHODS: Porcine tissues and phantoms were used to investigate the performance of the smart electrosurgical knife after electrosurgery. The fat-to-water content ratio (F/W-ratio) served as the discriminative parameter for distinguishing tissues and tissue mimicking phantoms with varying fat content. The F/W-ratio of tissues and phantoms was measured with the smart electrosurgical knife before and after 14 minutes of electrosurgery. Additionally, a layered porcine tissue and phantom were sliced and measured from top to bottom with the smart electrosurgical knife. RESULTS: Mapping the thermal activity of the electrosurgical knife's electrode during animal tissue electrosurgery revealed temperatures exceeding 400 °C. Electrosurgery for 14 minutes had no impact on the device's accurate detection of the F/W-ratio. The smart electrosurgical knife enables real-time tissue detection and predicts the fat content of the next layer from 4 mm ahead. CONCLUSION: The design of the smart electrosurgical knife outlined in this paper demonstrates its potential utility for tissue detection during electrosurgery. SIGNIFICANCE: In the future, the smart electrosurgical knife could be a valuable intraoperative margin assessment tool, aiding surgeons in detecting tumor borders and achieving negative margins.

Ag2O@UiO-66 new thin film as p-n heterojunction: permanent photoreduction of hexavalent Cr.

The new nanosphere Ag2O@UiO-66 thin-film was synthesized on a stainless steel mesh surface via an electrophoretic deposition method, and is used as an effective and low-cost photocatalyst using visible light. The synthesized nanocomposite was used to perform photo-reduction of Cr(vi) ions under white light irradiation. The best removal rate (72% after 15 minutes) was obtained by the film with 0.034 grams of deposited composite having relative percentages of Ag2O : UiO-66 of 70 : 30. The interesting obtained results confirm that the p-n heterojunction of the composite is the main cause of the desired charge separation and the photoreduction speed increase. In the following, the resulting compounds were characterized by X-ray diffraction (XRD), Fourier transform infrared (FT-IR), transmittance electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM), energy diffraction X-ray spectroscopy (EDAX) and the Brunauer, Emmett, and Teller (BET) method. Scavenging studies performed in the presence of familiar scavengers confirmed that superoxide radicals (˙O2-) and dissolved oxygen gas have a significant role in the photocatalytic reduction process.

Tissue-mimicking phantom materials with tunable optical properties suitable for assessment of diffuse reflectance spectroscopy during electrosurgery.

Emerging intraoperative tumor margin assessment techniques require the development of more complex and reliable organ phantoms to assess the performance of the technique before its translation into the clinic. In this work, electrically conductive tissue-mimicking materials (TMMs) based on fat, water and agar/gelatin were produced with tunable optical properties. The composition of the phantoms allowed for the assessment of tumor margins using diffuse reflectance spectroscopy, as the fat/water ratio served as a discriminating factor between the healthy and malignant tissue. Moreover, the possibility of using polyvinyl alcohol (PVA) or transglutaminase in combination with fat, water and gelatin for developing TMMs was studied. The diffuse spectral response of the developed phantom materials had a good match with the spectral response of porcine muscle and adipose tissue, as well as in vitro human breast tissue. Using the developed recipe, anatomically relevant heterogeneous breast phantoms representing the optical properties of different layers of the human breast were fabricated using 3D-printed molds. These TMMs can be used for further development of phantoms applicable for simulating the realistic breast conserving surgery workflow in order to evaluate the intraoperative optical-based tumor margin assessment techniques during electrosurgery.

Prevalence of Renal Osteodystrophy and its Related Factors among End-stage Renal Disease Patients Undergoing Hemodialysis: Report from Imam Reza Referral Hospital of Medical University of Kermanshah, Iran.

OBJECTIVES: We sought to determine the prevalence of renal osteodystrophy (ROD) and its related factors in a group consisting of end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis. METHODS: A total of 128 ESRD patients (52 men and 76 women) with a mean age of 59.3 years undergoing maintenance hemodialysis at Imam Reza Referral Hospital, Iran were included in this cross-sectional study. We measured serum parathyroid hormone (PTH) levels and determined 150 to 300 pg/mL as the desirable range for the values. Values lower or higher than this range were used to determine ROD. Furthermore, this study investigated the association of ROD with clinical and laboratory variables (age at the onset of renal failure, hemodialysis sessions per week, clinical symptoms associated with ROD, and serum calcium and phosphate levels). RESULTS: ROD was diagnosed in 93 (72.7%) out of 128 patients studied. Of them, 53 (41.4%) patients had PTH levels above 300 pg/mL (high bone turnover, HTO group) and 40 patients (31.3%) had PTH levels below 150 pg/mL (low bone turnover, LTO group). No statistically significant difference was detected in terms of ROD-related clinical findings (p = 0.110), age at the time of ESRD diagnosis (p = 0.200), and the number of hemodialysis sessions per week (p = 0.200). Hyperphosphatemia was more prevalent in the ROD group (n = 52, 57.1%) compared with 11 patients (31.4%) included in the group without ROD (p = 0.004). CONCLUSIONS: The prevalence rate of ROD in this study was significant, and it was largely consistent with the rate reported in some Asian countries. Hyperphosphatemia were laboratory variables closely related to ROD.

Intraoperative tumor margin assessment using diffuse reflectance spectroscopy: the effect of electrosurgery on tissue discrimination using ex vivo animal tissue models.

Using an intraoperative margin assessment technique during breast-conserving surgery (BCS) helps surgeons to decrease the risk of positive margin occurrence. Diffuse reflectance spectroscopy (DRS) has the potential to discriminate healthy breast tissue from cancerous tissue. We investigated the performance of an electrosurgical knife integrated with a DRS on porcine muscle and adipose tissue. Characterization of the formed debris on the optical fibers after electrosurgery revealed that the contamination is mostly burned tissue. Even with contaminated optical fibers, both tissues could still be discriminated with DRS based on fat/water ratio. Therefore, an electrosurgical knife integrated with DRS may be a promising technology to provide the surgeon with real-time guidance during BCS.

The Implication of Androgens in the Presence of Protein Kinase C to Repair Alzheimer's Disease-Induced Cognitive Dysfunction

Aging, as a major risk factor of memory deficiency, affects neural signaling pathways in hippocampus. In particular, age-dependent androgens deficiency causes cognitive impairments. Several enzymes like protein kinase C (PKC) are involved in memory deficiency. Indeed, PKC regulatory process mediates α-secretase activation to cleave APP in ß-amyloid cascade and tau proteins phosphorylation mechanism. Androgens and cortisol regulate PKC signaling pathways, affecting the modulation of receptor for activated C kinase 1. Mitogen-activated protein kinase/ERK signaling pathway depends on CREB activity in hippocampal neurons and is involved in regulatory processes via PKC and androgens. Therefore, testosterone and PKC contribute in the neuronal apoptosis. The present review summarizes the current status of androgens, PKC, and their influence on cognitive learning. Inconsistencies in experimental investigations related to this fundamental correlation are also discussed, with emphasis on the mentioned contributors as the probable potent candidates for learning and memory improvement.

Protein Kinase Cɛ in the Platelet and Hippocampal Tissue as a Diagnostic Biological Marker in Alzheimer Disease.

INTRODUCTION: Alzheimer Disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory and other cognitive functions. Protein Kinase Cɛ (PKCɛ) is an isoform that most effectively suppresses Amyloid Beta (Aß) production and synaptic loss. METHODS: In this study, spatial learning and memory for treated rats were evaluated by the Morris water maze test. The activity (total PKC), mRNA expression, and protein level of PKCɛ in the platelet and hippocampal tissue were evaluated using immunosorbent assay, real-time qPCR, and western blotting analysis, respectively. RESULTS: The traveled distance was significantly prolonged, and escape latency significantly increased in Aß-treated groups. PKC activity assay showed that there was a remarkable difference between the Aß-treated and sham-operated groups on days 10 and 30 in the hippocampus and also day 30 in platelet after the injection of Aß. A significant effect in PKC activity was observed between days 0 and 10, days 0 and 30, as well as days 5 and 30. Aß significantly downregulated the PKCɛ mRNA expression in the hippocampus of rats on day 30; however, no significant difference was observed in platelet. Western blot analysis demonstrated that Aß significantly reduced PKCɛ protein expression in the hippocampus of treated groups on day 30. CONCLUSION: The expression level of PKCɛ was downregulated following the injection of Aß in the hippocampus, but no significant difference was observed between the AD and sham groups in platelet that may be due to the low concentration of PKCɛ or duration of Aß exposure in the rat brain.

Spectroscopic and computational studies on the interaction of DNA with pregabalin drug.

The interaction of the drug pregabalin (S-3-(aminomethyl)-5-methylhexanoic acid) with CT-DNA was studied by using fluorescence spectroscopy, UV-Vis, CD, molecular docking study and viscometery. The fluorescence and UV absorption spectroscopy indicated that the drug interacted with CT-DNA in a groove binding mode. The binding constant and the number of binding sites were 5.6×10(4)Lmol(-1) and 0.96, respectively. The fluorimetric studies showed that the reaction between the drug and CT-DNA is exothermic (ΔH=33.11kJmol(-1); ΔS=48.84Jmol(-1)K(-1)). Furthermore, the drug does not induce any changes in DNA viscosity. Circular dichroism spectroscopy (CD) was employed to measure the conformational changes of CT-DNA in the presence of the drug, which verified the groove binding mode. The molecular modeling results illustrated that the drug binds to groove of DNA by relative binding energy of docked structure -21.9kJmol(-1).

No mutations of FecB and FecG(H) in Iranian Lory sheep.

The Booroola fecundity gene (FecB) and growth differentiation factor 9 (GDF9) gene belong to the transforming growth factor ß (TGF-ß) superfamily. The mutations of these genes have additive effects on the prolificacy in sheep. The aim of the present study was to determine the possible mutations of FecB and FecG(H) genes in Lory sheep breed of the Lorestan province, Iran. Sixty blood samples were collected and DNA was extracted from whole fresh blood. For detection of FecB and FecG(H) mutations, the PCR products were incubated with AvaII and DdeI restricted enzymes. Based on the results we did not find the FecB and FecG(H) mutations in this sheep breed population, so these mutations cannot the cause of the high prolificacy of Lory sheep breed and more study are needed to determine the genetic or environmental causes of high prolificacy of this sheep breed.

Age at menarche and related factors in girlsof urban areas of Markazi (Central) province of Iran / Edad de la menarquia y factores relacionados en las niñas de zonas urbanas de la provincia Markazi (Central) de Irán

The age at menarche is an indicator of racial, geographical and nutritional patterns of different societies. This cross-sectional study conducted on 1223 girls aged 14-20 in the Markazi (Central) Province, Iran in 2010. In this research, the age at menarche, as the main variable, was determined for each city and compared between different cities. The statistical analyses included c2 test for determining statistically significant differences, variance analysis for determining the difference between groups, and Pearson correlation coefficient for determining the relationship between variables. The average age of first menstruation was 13.21+/-1.33 years in the Markazi Province, with no significant difference among the cities of the province. This age is inversely related to body mass index (BMI), nutritional status and weight. The pattern of distribution of BMI is similar for all the cities in the province. Although, the average age at menarche in the Markazi (central) Province, a cold area, is higher compared to warmer regions in Iran, it may be more influenced by race than by the climate. Considering the lower age at menarche in Markazi Province compared to previous similar studies, it may be stated that social well-being and nutritional standards have improved in the province.

La edad de la menarquia es un indicador de patrones raciales, geográficos y nutricionales de distintas sociedades. Este estudio transversal fue realizado el 2010 en 1223 niñas entre 14 y 20 años en la Provincia Markazi (Central), Irán. En esta investigación, la edad de la menarquia, como la variable principal, se determinaron para cada ciudad y en comparación entre las diferentes ciudades. Los análisis estadísticos incluyeron la prueba c2 para determinar diferencias estadísticamente significativas, el análisis de varianza para determinar la diferencia entre los grupos, y el coeficiente de correlación de Pearson para determinar la relación entre las variables. El promedio de edad de la primera menstruación fue 13,21+/-1,33 años en la provincia de Markazi, sin diferencias significativas entre las ciudades de la provincia. Esta edad es inversamente proporcional al índice de masa corporal (IMC), el estado nutricional y el peso. El patrón de distribución del IMC es similar para todas las ciudades de la provincia. Aunque la edad media de la menarquia en la Provincia Markazi (central), una zona de clima frío, es mayor en comparación con las regiones más cálidas en Irán, puede estar más influenciadas por la raza que por el clima. Teniendo en cuenta la baja edad de menarquia en la Provincia Markazi en comparación con estudios similares anteriores, se puede afirmar que el bienestar social y los niveles de nutrición han mejorado en la provincia.

Correlation of skull size and brain volume, with age, weight, height and body mass index of Arak Medical Sciences students / Correlación del tamaño craneal y volumen del cerebro, con edad, peso, talla e índice de masa corporal de los estudiantes de Ciencias Médicas de Arak

Anthropometric indices that are indicators of nutrition status in children and adults can be affected by racial and geographic factors. The aim of present study was to investigate the relation of skull size and brain volume of Arak University of Medical Sciences students with their age, weight, height and body mass index. The present study was a cross-sectional study on 18-26 years old students of Arak University of Medical Sciences (150 female and 136 male) in 2009-2010 educational year. Sampling methods were probability and multi-stage methods which were performed using students' educational file and interviewing the subjects. Questions regarding anthropometric data (height, weight, age, body mass index and skull index) were included in the personal questionnaires. Data was analyzed and evaluated statistically using SPSS statistical software. Mean height was 177.27+/-6.41 cm in males and was 166.61+/-5.35 cm in females. Mean weight of males was 73.33+/-9.11 kg and mean weight of females was 55.55+/-7.28. Mean BMI was 23.20+/-2.43 and 21.27+/-2.69 in males and females, respectively. Mean skull index was 1.99+/-0.26 in males and 2.20+/-0.3 in females. Mentioned data were significantly different between males and females. Also mean age of females was less than males. Positive relations were found between skull volume and height, weight, age and BMI in both sexes and this relation is stronger regarding BMI. The present study, supporting the other studies in this field, confirms the relation between skull index and body mass index and indicates the effect of race. Considering the studied population which are students of Arak University of Medical Sciences and are from different regions of the country, similarities between results of this study and studies from Iran and studies conducted in a special region reveals that factor of race is affected by geographical factors.

Los índices antropométricos que son indicadores del estado nutricional en niños y adultos pueden ser afectados por factores raciales y geográficos. El objetivo del presente estudio fue investigar la relación entre el tamaño del cráneo y el volumen del cerebro con la edad, peso, talla e índice de masa corporal en los estudiantes de la Universidad de Ciencias Médicas de Arak. Se realizó un estudio transversal en estudiantes de 18-26 años de edad en la Universidad de Ciencias Médicas de Arak (150 mujeres y 136 hombres) en el año educativo 2009-2010. Los métodos de muestreo fueron probabilidad y métodos de etapas múltiples que se llevaron a cabo utilizando el archivo escolar de los estudiantes y entrevista a los sujetos. Preguntas sobre los datos antropométricos (talla, peso, edad, índice de masa corporal y el índice del cráneo) se incluyeron en los cuestionarios personales. Los datos fueron analizados y evaluados estadísticamente mediante paquete estadístico SPSS. La altura promedio fue 177,27 +/- 6,41 cm en hombres y 166,61 +/- 5,35 cm en las mujeres. La media de peso de los hombres fue 73,33 +/- 9,11 kg y 55,55 +/- 7,28 de las mujeres. El IMC promedio fue 23,20 +/- 2,43 y 21,27 +/- 2,69 en hombres y mujeres, respectivamente. La media del índice craneal fue de 1,99 +/- 0,26 en hombres y 2,20 +/- 0,3 en las mujeres. Los datos mencionados fueron significativamente diferentes entre hombres y mujeres. Además la media de edad de las mujeres fue menor que en los hombres. Las relaciones positivas se encontraron entre el volumen craneal y la altura, peso, edad y el IMC en ambos sexos y esta relación es más fuerte en relación con el IMC. El presente estudio, da apoyo a los otros estudios en este campo, confirma la relación entre el índice craneal y el IMC, y se indica el efecto de la raza. Teniendo en cuenta la población estudiada que son los estudiantes de la Universidad de Ciencias Médicas de Arak en diferentes regiones del país, las similitudes entre los resultados...

Effects of prenatal exposure to extremely low electro-magnetic field on in vivo derived blastocysts of mice.

BACKGROUND: Indisputable population exposure to widespread electromagnetic fields, has grown concerns over the probable health effects of these fields. OBJECTIVE: The present study was aimed to examine the possible effects of 50 Hz extremely low frequency electromagnetic field (ELF-EMF) exposure on the number and quality of mice blastocysts. MATERIALS AND METHODS: In present study, 66 NMRI pregnant females divided into two treated and non-treated groups. The treated group exposed to ELF-EMF (50 Hz and 6×10(-3) T). Subsequently, embryos were collected by flushing the uterine horn and Fallopian tubes on the day 3 of gestation. Number of trophoectoderm (TE) and Inner Cell Mass (ICM) cells in blastocysts were determined after differential nuclei staining using a modified method. Furthermore, number of all flushed blastocysts calculated in each group. RESULTS: There was no significant difference in mean number of blastocysts in treated (6.64±1.34) and none treated (8.22±1.59) groups. In treated group, there were significant decreased in total cell number of blastocysts (p=0.000), number of ICM cells (p=0.000), and number of TE cells (p=0.001) whereas the ratio of ICM/TE cells increased (p=0.002). CONCLUSION: The data indicate that ELF-EMF is able to affect cellular composition of blastocysts, but it can't omit total volume of blastocysts.

Prenatal Water Deprivation Induces Apoptosis in Sexual Dimorphic Nucleus of the Brain of Male New Born Sprague-Dawley Rats / Deprivación Prenatal de Agua Induce Apoptosis en Núcleos Dimórficos Sexuales del Ccrebro de Ratas Sprague-Dawley Macho Recién Nacidas

Considering the size of some nuclei and area, sex hormones control the sexual development of the brain. The sexual development of the brain can also be influenced by environmental stress. This study aimed to clear the effect of prenatal water deprivation on the development of sexual dimorphic nucleus (SDN) of the brain. In this research, pregnant rats were divided into two groups (control and treated). For the treated animals, water was removed from the ewes for 48 h at the end of third trimester of gestation (19-21 days). TUNEL staining was used for detection of apoptosis in paraffin embedded diencephalon selected sections. The ratio of apoptotic cells to non- apoptotic ones was calculated as apoptotic index. Differences of apoptotic index and serum testosterone were examined for statistical significance using Paired T- test (p<0.05). The apoptotic index was 0.0160±.01174 percent for control and 0.1870±.02541 percent for treated groups. The concentration of serum testosterone was 22.4±1.3 for control and 13.37±3.3 for treated groups. Prenatal water deprivation induces apoptosis in developing SDN nucleus of male rats that is derived by reducing the concentration of serum testosterone. The study shows the importance of low concentration acting testosterone for development of SDN nucleus that can be affected by environmental stress.

Considerando el tamaño de algunos núcleos y áreas, las hormonas sexuales controlan el desarrollo sexual del cerebro. El desarrollo sexual del cerebro también puede verse influido por el estrés ambiental. Este estudio tuvo como objetivo establecer el efecto de la privación prenatal de agua en el desarrollo del núcleo dimórfico sexual (NDS) del cerebro. Las ratas preñadas fueron divididas en dos grupos (control y tratados). Para los animales tratados, el agua se retiró de los bebederos durante 48h al final del tercer trimestre de gestación (días 19-21). La técnica TUNEL se utilizó para detectar apoptosis en secciones del diencéfalo incluidas en parafina. La proporción de células apoptóticas y no-apoptóticas fue calculada como índice de apoptosis. Las diferencias del índice de apoptosis y testosterona sérica fueron examinadas para observar significación estadística mediante t de Student pareado (p <0,05). El índice de apoptosis fue 0,0160±0,01174 por ciento para el control y 0,1870±0,02541 por ciento para los grupos tratados. La concentración de testosterona en suero fue de 22,4±1,3 para el grupo control y 13,37±3,3 para los grupos tratados. La privación de agua prenatal indujo la apoptosis en el desarrollo del NDS de las ratas macho derivadas por la reducción de concentración de testosterona sérica. El estudio muestra la importancia de una baja concentración de testosterona para el desarrollo de los NDS, que pueden verse afectados por el estrés ambiental.

p75NTR suppression in rat bone marrow stromal stem cells significantly reduced their rate of apoptosis during neural differentiation.

Most of the transplanted cells within central nervous system (CNS) undergo extensive cell death. Preventing the death of stem cell-derived neuron-like cells within adult CNS would enhance the efficiency of transplantation in clinics. We have employed an interfering RNA (RNAi) approach to elevate the survival rate of neurally differentiated bone marrow stromal stem cells (BMSCs), by means of suppressing p75NTR expression. Our data revealed that stably overexpressing a specific shRNA against p75NTR transcript could effectively reduce the expression of endogenous p75NTR in neurally differentiated BMSCs. As p75NTR can induce neuronal death in target cells, its suppression is followed by a significant reduction of apoptosis in neural-like cells derived from BMSCs. Thus, our data provides a method to increase the survival of stem cells being employed in transplantation within CNS and hence increase the success rate of cell-based therapies in damaged area of brain and spinal cord.

Preparation and Determination of Drug-Polymer Interaction and In-vitro Release of Mefenamic Acid Microspheres Made of CelluloseAcetate Phthalate and/or Ethylcellulose Polymers.

The objective of this study was to formulate and evaluate the drug-polymer interaction of mefenamic acid (MA) using two polymers with different characteristics as ethylcellulose (EC) and/or cellulose acetate phthalate (CAP). Microspheres were prepared by the modified emulsion solvent evaporation (MESE). The effect of drug-polymer interaction was studied for each of microspheres. Important parameters in the evaluation of a microencapsulation technique are encapsulation efficiency, yield production, particle size, surface characteristics of microspheres, scanning electronic microscopy (SEM), powder X-ray diffraction analysis (XRD), and differential scanning calorimetry (DSC). The in-vitro release studies are performed in Tris buffer (pH 9) with Sodium lauryl sulfate (SLS). Microspheres containing CAP and EC showed 68-97% and 63-76% of entrapment efficiency, respectively. The thermogram X-ray and DSC showed stable character of MA in the microspheres and revealed an absence of drug polymer interaction. The prepared microspheres were spherical in shape and had a size range of 235-436 µm for CAP-microspheres and 358-442 µm for EC-microspheres. The results suggest that MA was successfully and efficiently encapsulated; the release rates of matrix microspheres are related to the type of polymer, only when polymers (EC and CAP combine with 1 : 1 ratio) were used to get prolonged drug release with reducing the polymers content in the microspheres. Data obtained from in-vitro release for microspheres and commercial capsule were fitted to various kinetic models and the high correlation was obtained in the peppas model. Mefenamic acid, Ethylcellulose, Cellulose acetate phthalate, Microparticles, Modified emulsion-solvent evaporation.

A phase II trial of sorafenib in metastatic melanoma with tissue correlates.

BACKGROUND: Sorafenib monotherapy in patients with metastatic melanoma was explored in this multi-institutional phase II study. In correlative studies the impact of sorafenib on cyclin D1 and Ki67 was assessed. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-six patients treatment-naïve advanced melanoma patients received sorafenib 400 mg p.o. twice daily continuously. Tumor BRAF(V600E) mutational status was determined by routine DNA sequencing and mutation-specific PCR (MSPCR). Immunohistochemistry (IHC) staining for cyclin D1 and Ki67 was performed on available pre- and post treatment tumor samples. The main toxicities included diarrhea, alopecia, rash, mucositis, nausea, hand-foot syndrome, and intestinal perforation. One patient had a RECIST partial response (PR) lasting 175 days. Three patients experienced stable disease (SD) with a mean duration of 37 weeks. Routine BRAF(V600E) sequencing yielded 27 wild-type (wt) and 6 mutant tumors, whereas MSPCR identified 12 wt and 18 mutant tumors. No correlation was seen between BRAF(V600E) mutational status and clinical activity. No significant changes in expression of cyclin D1 or Ki67 with sorafenib treatment were demonstrable in the 15 patients with pre-and post-treatment tumor samples. CONCLUSIONS/SIGNIFICANCE: Sorafenib monotherapy has limited activity in advanced melanoma patients. BRAF(V600E) mutational status of the tumor was not associated with clinical activity and no significant effect of sorafenib on cyclin D1 or Ki67 was seen, suggesting that sorafenib is not an effective BRAF inhibitor or that additional signaling pathways are equally important in the patients who benefit from sorafenib. TRIAL REGISTRATION: Clinical Trials.gov NCT00119249.

Serum levels of GM-CSF 20 years after sulfur mustard exposure: Sardasht-Iran Cohort Study.

Sulfur mustard (SM) is highly toxic for various organs. The eyes, skin, respiratory tract, as well hematopoietic and immune systems are the main organs affected by SM. Granulocyte-macrophage colony stimulating factor (GM-CSF) is a potent cytokine that plays an important role in the hematopoietic and immune system. The aim of this study was to determine the serum levels of GM-CSF and its relation to blood cell count and other inflammatory cytokines 20 years after SM exposure. The association of GM-CSF with the clinical severity of pulmonary, ophthalmic and dermatologic complications has also been studied. In this historical cohort study named as Sardasht-Iran Cohort Study (SICS), 369 SM exposed male participants and 125 unexposed volunteers were studied. The serum concentrations of cytokines were measured by ELISA technique. The severity of clinical complications was graded according to the criteria verified by the Medical Committee of the Foundation of Martyr and Veterans Affairs. The serum levels of GM-CSF in the SM exposed group did not display any significant differences with the control group. Median of GM-CSF was 7.33 and 9.39 pg/ml in the SM exposed group and the controls respectively. There was a positive correlation between the serum levels of GM-CSF and the percent of eosinophils only in the exposed group. Moreover, positive correlations were found between circulating levels of GM-CSF with IL-1alpha, IL-1beta, TNF-alpha and IL-6. This correlation was not observed between GM-CSF and IL-8 in both study groups. The serum levels of GM-CSF did not show any significant association with clinical complications.

Serum soluble Fas ligand and nitric oxide in long-term pulmonary complications induced by sulfur mustard: Sardasht-Iran Cohort Study.

Sulfur mustard (SM) has short- and long-term toxicity against various organs including the respiratory system. However, the basic and molecular mechanisms of SM long-term toxicity have not clearly been defined. Thus, the aim of this study was to evaluate the association of soluble Fas ligand (sFasL) as well as nitric oxide (NO) serum levels with long-term pulmonary complications in a SM exposed population 20 years after SM exposure. In this historical cohort study 372 male SM exposed subjects and 128 age-matched unexposed controls were studied. Clinical evaluation and pulmonary function tests were carried out for all participants and serum concentrations of sFasL and NO measured. According to our results, the serum levels of sFasL and NO were not significantly different between the exposed and control groups. However, the serum levels of sFasL in the exposed group with pulmonary problems were significantly higher than their corresponding in the control group (116.711+/-81.166 vs 86.027+/-30.199 and p=0.028). Furthermore a significant elevation in sFasL levels was found in the exposed subjects with pulmonary problems compared to those exposed participants without pulmonary problems (116.711+/-81.166 vs 90.692+/-57.853 and p=0.004). Based on Global Initiative for chronic Obstructive Lung Disease (GOLD) classification analysis a positive correlation was observed between sFasL levels and pulmonary problems. There was also a significant negative correlation between sFasL and the white blood cell (WBC) count in the SM exposed cohort, but not in the control group. No significant association was shown between NO and pulmonary impairment in the SM exposed subjects. Thus, our results indicate that elevated serum levels of sFasL may be associated with progression of pulmonary diseases in the SM exposed subjects.