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Objectives/hypothesis: We sought to analyze key factors that influence the management of lateral skull base defects and implement an algorithm to improve outcomes of reconstruction., Study Design: Retrospective chart review., Setting: Single tertiary academic referral center., Methods: Adults who underwent temporal bone resection were included. Variables included tumor characteristics, ablative procedure, reconstructive method, and wound complications., Results: Seventy-one patients were studied. Lateral temporal bone resection was performed in 55 patients (77%), subtotal temporal bone resection in 14 (20%), and total petrosectomy in two (3%). Primary closure was achieved in 46 patients (35%), with rotational muscle flaps in 21 (46%). The pectoralis major myocutaneous flap (PMMF) was used in nine patients (13%) without major complications. Single-stage free tissue transfer was undertaken in 10 patients (14%) with no flap failures. Primary closure was achieved in 16 of 32 of previously untreated cases (50%) compared to nine of 39 cases of previously treated disease (23%) (P = 0.03). Pedicled or free flaps were used in 18 of 39 cases of previously treated disease (46%) compared to three of 32 previously untreated cases (9%) (P < 0.001). Pedicled or free flaps were used in 13 of 22 cases (59%) in which partial or total auriculectomy was performed, whereas primary closure was achieved in 39 of 49 cases (80%) in which the pinna was preserved (P < 0.001)., Conclusion: Advanced tumors that require adjuvant therapy, revision cases for recurrent disease, and cases involving auriculectomy warrant free flap or PMMF reconstruction, with the latter preferred in poor free flap candidates., Level of Evidence: 4. Laryngoscope, 126:1911-1917, 2016., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To analyze disease presentation, treatment, and clinical course of a consecutive series of patients with primary cerebellopontine angle (CPA) epidermoids., Patients: Forty-seven consecutive patients with previously untreated CPA epidermoids., Intervention(s): Observation and microsurgery., Main Outcome Measures: Disease- and treatment-associated morbidity, recurrence., Results: Forty-seven patients (mean age 39 years; 53% women) were analyzed and the average duration of follow-up was 42 months. The most common presenting symptom was headache (27; 57%); 13 (28%) exhibited preoperative asymmetric sensorineural hearing loss, 3 (6%) facial nerve paresis, and 3 (6%) hemifacial spasm. Thirteen patients (28%) were initially observed over a mean interval of 56 months; however, five experienced disease progression requiring operation. Thirty-nine patients (83%) underwent surgical resection; 18 (46%) received gross total, 5 (13%) near total, and 16 (41%) aggressive subtotal resection. Three patients (8%) recurred at a median of 53 months; two after subtotal and one after gross total resection. Ninety-three percent of patients with useful hearing maintained serviceable hearing following treatment and one patient (3%) experienced mild long-term postoperative facial nerve paresis (HB II/VI). All patients with preoperative facial nerve paresis recovered normal function postoperatively. There were no episodes of stroke or death., Conclusions: Surgical intervention is effective in alleviating symptoms of cranial neuropathy and brainstem compression from CPA epidermoids. Gross total resection is preferred; however, aggressive subtotal removal should be considered with adherent or extensive disease as reoperation rates are low, even in the setting of aggressive subtotal resection. Conservative observation with serial imaging is a viable initial strategy in asymptomatic or minimally symptomatic patients.

Objective: Closed-loop (CL) insulin delivery effectively maintains glucose overnight but struggles when challenged with meals. Use of single-day, 30-μg/meal pramlintide lowers meal excursions during CL. We sought to further elucidate the potential benefits of adjunctive agents after 3-4 weeks of outpatient dose titration., Research Design and Methods: Two CL studies were conducted: one evaluating adjunctive pramlintide and the other liraglutide. Ten subjects (age 16-23 years; A1C 7.2 ± 0.6% [55 ± 6.6 mmol/mol]) completed two 24-h sessions: one on CL alone and one on CL plus 60-μg pramlintide (CL + P), after a 3-4-week outpatient dose escalation. Eleven subjects (age 18-27 years; A1C 7.5 ± 0.9% [58 ± 9.8 mmol/mol]) were studied before and after treatment with 1.8 mg liraglutide (CL + L) after a similar 3-4-week dose escalation period. Timing and content of meals during CL were identical within experiments; meals were not announced., Results: Pramlintide delayed the time to peak plasma glucose (PG) excursion (CL 1.6 ± 0.5 h vs. CL + P 2.6 ± 0.9 h, P < 0.001) with concomitant blunting of peak postprandial increments in PG (P < 0.0001) and reductions in postmeal incremental PG area under the curve (AUC) (P = 0.0002). CL + L also led to reductions in PG excursions (P = 0.05) and incremental PG AUC (P = 0.004), with a 28% reduction in prandial insulin delivery. Outpatient liraglutide therapy led to a weight loss of 3.2 ± 1.8 kg, with a 26% reduction in total daily insulin dose., Conclusions: Adjunctive pramlintide and liraglutide treatment mitigated postprandial hyperglycemia during CL control; liraglutide demonstrated the additional benefit of weight loss in an insulin-sparing manner. Further investigations of these and other adjunctive agents in long-term outpatient CL studies are needed., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Over the years the authors have evaluated a number of patients with vestibular schwannomas (VS) who have also been diagnosed with a pituitary adenoma (PA). No associations between these tumors have been established to date. The objective of the current study is to investigate the epidemiological association between VS and PA via a population-based study and to supplement these data with a retrospective case series of 12 patients who were evaluated at the authors' center over the past 15 years. An analysis of the Surveillance, Epidemiology, and End Results database including all patients identified with a diagnosis of VS and/or PA was performed. A comparison between the observed and expected annual incidence was calculated and population differences between those with VS + PA were compared with single tumor populations. 9888 patients with VS and 26,577 patients with PA were identified among 822.9 million person-years. Within these populations, 31 patients were diagnosed with both tumor types. Overall, 1 in every 319 patients with VS was also diagnosed with a PA. The average annual incidence for VS was 1.2 per 100,000 persons per year while the average PA rate was 3.2 per 100,000 persons per year. The observed rate of co-incident VS and PA was greater than what is expected by chance alone assuming independence. The cohort of patients with coexisting VS and PA were older and more commonly male compared to VS-only or PA-only groups. These data strongly suggest that a common environmental or genetic predisposition exists for VS and PA development. Further study of this population may help elucidate the cause of tumorigenesis in a subset of patients with seemingly sporadic tumors.

Background: Despite the widespread implementation of Tall Man lettering, little evidence exists regarding whether this technique has reduced drug errors due to look-alike sound-alike (LA-SA) drug names. This study evaluated rates of potential LA-SA drug errors in the drug management process through to the point of dispensing before and after implementation of Tall Man lettering in 2007., Methods: We used detailed pharmacy data for paediatric inpatients (<21 years old) from 42 children's hospitals in 2004-2012. After prespecifying a set of 8 potential LA-SA drug error patterns we searched within each hospitalisation for the occurrence of one of these patterns for a total of 12 LA-SA drug pairs deemed highly relevant to paediatric inpatients. To assess for potential change of error rates before and after Tall Man lettering implementation, we performed segmented regression analyses for each of 11 LA-SA drug pairs (because 1 pair had no detected potential errors) and for the overall total errors of all 11 LA-SA drug pairs., Results: Among 1 676 700 hospitalisations, no statistically significant change was detected for either the intercept or the slope of LA-SA error rate for each of the 11 drug pairs or for the combined error rate. In a sensitivity analysis of the moving average of the potential error rate over the entire study period, no downward trend in potential LA-SA drug error rates was evident over any time period 2004 onwards., Conclusions: Implementation of Tall Man lettering in 2007 was not associated with a reduction in the potential LA-SA error rate. Whether Tall Man lettering is effective in clinical practice warrants further study., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The thyroglossal duct cyst is one of the more common congenital anterior neck masses. In rare cases, carcinoma has been detected within one of these cysts on histopathologic analysis of resected tissue. Since the incidence of thyroglossal duct cyst carcinoma is low, the appropriate management of the thyroid gland proper is not algorithmic. We present 2 cases of papillary thyroid carcinoma that were discovered in a thyroglossal duct cyst, and we describe the diagnostic and therapeutic measures taken in each case. Particular attention is paid to two points: (1) fine-needle aspiration biopsy may not be sufficient to rule out carcinoma and (2) removal of the thyroid gland may be advisable in selected situations.

Due to the high rates of complications and failure experienced with current glaucoma procedures, there is a continuous search for a safer and more effective glaucoma surgery. A new class of procedures termed minimally invasive glaucoma surgeries (MIGS) aim to fill this void by offering an alternative method of IOP reduction associated with markedly reduced complication rates and shorter recovery times. The iStent, a trabecular microbypass stent, is a MIGS device that has quickly gained popularity. The device allows aqueous humor to directly drain from the anterior chamber into Schlemm's canal by bypassing an obstructed trabecular meshwork. This review examines publications about the iStent, focusing on the device's efficacy, safety, and cost when a single iStent or multiple iStents are implanted in combination with cataract surgery or as a solo procedure. Current data suggest that the iStent is a safe and effective tool in the management of mild-to-moderate glaucoma, notable for its limited complications and absence of serious adverse events following implantation. As valuable experience is gained performing ab interno MIGS, increasing familiarity with angle anatomy and iStent placement, and as newer stent designs are developed, there is promise of continual improvement in the surgical management of glaucoma.

Background: Tissue infiltration by neutrophils during acute inflammatory states causes substantial tissue injury. While the magnitude of tissue neutrophil accumulation in innate immune responses is profoundly greater in males than females, fundamental aspects of the molecular mechanisms underlying these sex differences remain largely unknown., Methods: We investigated sex differences in neutrophil stimulation and recruitment in ischemia/reperfusion (I/R; mesenteric or renal) or carrageenan pleurisy in rats or mice, as well as skin injury in human volunteers. The induction of potent chemoattractive mediators (chemokines) and neutrophil adhesion molecules were measured by real-time PCR, flow cytometry, and protein assays., Results: Mesenteric I/R in age-matched Wistar rats resulted in substantially more neutrophil accumulation and tissue injury at 2 h reperfusion in males than females. Using intravital microscopy, we show that the immediate (<30 min) neutrophil response to I/R is similar in males and females but that prolonged neutrophil recruitment occurs in males at sites local and distal to inflammatory insult partly due to an increase in circulating neutrophil populations with elevated surface expression of adhesion molecules. Sex differences in neutrophil kinetics were correlated with sustained induction of chemokine Cxcl5 in the tissue, circulation, and bone marrow of males but not females. Furthermore, blockade of Cxcl5 in males prior to ischemia resulted in neutrophil responses that were similar in magnitude to those in females. Conversely, administration of Cxcl5 to males in the absence of I/R was sufficient to increase levels of systemic neutrophils. Cxcl5 treatment of bone marrow neutrophils in vitro caused substantial induction of neutrophil-mobilizing cytokine granulocyte colony-stimulating factor (GCSF) and expression of β2 integrin that accounts for sexual dimorphism in circulating neutrophil populations in I/R. Moreover, male Cxcl5-stimulated bone marrow neutrophils had an increased capacity to adhere to β2 integrin ligand ICAM-1, implicating a greater sensitivity of male leukocytes to Cxcl5-mediated activation. Differential induction of Cxcl5 (human CXCL6) between the sexes was also evident in murine renal I/R, rat pleurisy, and human skin blisters and correlated with the magnitude of neutrophil accumulation in tissues., Conclusions: Our study reveals that sex-specific induction of chemokine Cxcl5/CXCL6 contributes to sexual dimorphism in neutrophil recruitment in diverse acute inflammatory responses partly due to increased stimulation and trafficking of bone marrow neutrophils in males.

Objective: To characterize disease presentation and outcomes following surgical treatment of parotid malignancies with occult temporal bone facial nerve (FN) involvement., Study Design: Case series with chart review., Setting: Tertiary academic referral center., Subjects and Methods: Thirty consecutive patients (mean age 58 years; 77% men) who underwent surgery for parotid malignancies with occult perineural involvement of the intratemporal FN were included. Primary outcome measures included margin status and recurrence., Results: The mean duration of clinical follow-up was 49 months, and the most common presenting symptom was FN paresis (n = 23; 77%) followed by pain (n = 15; 50%). To obtain a proximal FN margin, 27 patients (90%) underwent mastoidectomy, and 3 patients (10%) had lateral temporal bone resection. The intratemporal FN margin was cleared in 26 patients (87%), most commonly in the mastoid segment (60%). Adjuvant therapy was given in 25 patients (83%). Ten patients (33%) experienced locoregional (4; 13%) and/or distant (8; 27%) recurrence at a median of 19 months (mean 26, 2-54 months) following surgery. Locoregional failure was significantly more common in cases with a positive intratemporal FN margin (66% vs 8%; P = .045). Overall 1-, 3-, and 5-year disease-specific survival rates were 83%, 79%, and 72%, respectively., Conclusions: Perineural invasion of the intratemporal FN by parotid malignancy is uncommon. Normal preoperative FN function does not preclude histopathologic involvement. Temporal bone FN exploration should be considered when a positive margin is encountered at the stylomastoid foramen, as failure to do so is associated with an increased rate of locoregional recurrence., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Objectives: Even after evolution of computerized tomography and improved surgical measures, treatment of intraarticular calcaneal fractures remains a controversy. Hence this study was carried out to compare functional outcomes of displaced intraarticular calcaneal fractures, treated with operative management with plating and conservative management with cast., Material and Methods: This study was carried out as a prospective, comparative study. Twenty nine (30 fractures) patients with acute, displaced intraarticular fractures of calcaneum aged 18-50 years, were enrolled in the study. Open fractures and fractures older than two weeks were excluded. 30 fractures were divided into two groups (operative and conservative; n = 15 in each). Evaluation in form of post treatment restoration of Bohler's angle, heel varus angle and with Creighton-Nebraska (C-N) score for functional outcome was done at the end of 12 months., Results: When we consider the clinical evaluation under the C-N score, the results of operatively managed calcaneal fractures are slightly better than those of the conservative group. But this did not have any statistical significance. Also, there was significant difference in pre and post treatment Bohler's angle and heel varus angle in operative group. Three cases of plating suffered from post-operative wound dehiscence., Conclusion: A relatively better functional outcome was observed in displaced and comminuted fractures in plating, provided that the Bohler's angle was restored. In conservative group, functional outcome of minimally displaced fractures were better than displaced comminuted fractures. Post treatment Bohlers angle has prognostic importance in functional outcome.

Recent studies have found that vasogenic brain edema is present during hepatic encephalopathy following acute liver failure and is dependent on increased matrix metalloproteinase 9 (MMP9) activity and downregulation of tight junction proteins. Furthermore, circulating transforming growth factor β1 (TGFβ1) is increased following liver damage and may promote endothelial cell permeability. This study aimed to assess whether increased circulating TGFβ1 drives changes in tight junction protein expression and MMP9 activity following acute liver failure. Blood-brain barrier permeability was assessed in azoxymethane (AOM)-treated mice at 6, 12, and 18 h post-injection via Evan's blue extravasation. Monolayers of immortalized mouse brain endothelial cells (bEnd.3) were treated with recombinant TGFβ1 (rTGFβ1) and permeability to fluorescein isothiocyanate-dextran (FITC-dextran), MMP9 and claudin-5 expression was assessed. Antagonism of TGFβ1 signaling was performed in vivo to determine its role in blood-brain barrier permeability. Blood-brain barrier permeability was increased in mice at 18 h following AOM injection. Treatment of bEnd.3 cells with rTGFβ1 led to a dose-dependent increase of MMP9 expression as well as a suppression of claudin-5 expression. These effects of rTGFβ1 on MMP9 and claudin-5 expression could be reversed following treatment with a SMAD3 inhibitor. AOM-treated mice injected with neutralizing antibodies against TGFβ demonstrated significantly reduced blood-brain barrier permeability. Blood-brain barrier permeability is induced in AOM mice via a mechanism involving the TGFβ1-driven SMAD3-dependent upregulation of MMP9 expression and decrease of claudin-5 expression. Therefore, treatment modalities aimed at reducing TGFβ1 levels or SMAD3 activity may be beneficial in promoting blood-brain barrier integrity following liver failure.

Endovascular treatment of broad-necked bifurcation aneurysms remains challenging. Stent-assisted coiling has been successful but requires catheterization of the branches off the parent vessel. We present the case of a patient who failed primary and stent-assisted coiling of a large basilar tip aneurysm because the morphology of the aneurysm precluded successful distal catheterization of the posterior cerebral artery (PCA) branches. Using the PulseRider device, which does not require catheterization of bifurcation branches, we were able to treat the aneurysm successfully., (2015 BMJ Publishing Group Ltd.)

Importantly, NMSCs are increasing in prevalence, and full recognition of these diseases as life-threatening entities is paramount. Overall, data supporting adjuvant or systemic therapy in NMSCs are limited, but there are enough reports in the literature to suggest some benefit with systemic agents. Where available, we recommend patients investigate clinical trial options, including phase I studies. Newer targeted therapies and activation of the immune system may provide for a dramatic step forward in the management of these diseases; however, formal clinical trials are necessary to establish these new treatments as a standard of care.

Nuclear factor-kappa B (NF-κB) activation is widely implicated in multiple organ failure (MOF); however, a direct inhibitor of IκB kinase (IKK), which plays a pivotal role in the activation of NF-κB, has not been investigated in shock. Thus, the aim of the present work was to investigate the effects of an IKK inhibitor on the MOF associated with hemorrhagic shock (HS). Therefore, rats were subjected to HS and were resuscitated with the shed blood. Rats were treated with the inhibitor of IKK or vehicle at resuscitation. Four hours later, blood and organs were assessed for organ injury and signaling events involved in the activation of NF-κB. Additionally, survival following serum deprivation was assessed in HK-2 cells treated with the inhibitor of IKK. HS resulted in renal dysfunction, lung, liver and muscular injury, and increases in serum inflammatory cytokines. Kidney and liver tissue from HS rats revealed increases in phosphorylation of IKKαβ and IκBα, nuclear translocation of NF-κB and expression of inducible isoform of nitric oxide synthase (iNOS). IKK16 treatment upon resuscitation attenuated NF-κB activation and activated the Akt survival pathway, leading to a significant attenuation of all of the above parameters. Furthermore, IKK16 exhibited cytoprotective effects in human kidney cells. In conclusion, the inhibitor of IKK complex attenuated the MOF associated with HS. This effect may be due to the inhibition of the NF-κB pathway and activation of the survival kinase Akt. Thus, the inhibition of the IKK complex might be an effective strategy for the prevention of MOF associated with HS.

Methods: Male rats were 'pretreated' with phosphate-buffered saline (PBS; i.p.) or LPS (1 mg/kg; i.p.) 24 h prior to HS. Mean arterial pressure (MAP) was maintained at 30 ± 2 mmHg for 90 min or until 25% of the shed blood had to be re-injected to sustain MAP. This was followed by resuscitation with the remaining shed blood. Four hours after resuscitation, parameters of organ dysfunction and systemic inflammation were assessed., Results: HS resulted in renal dysfunction, and liver and muscular injury. At a first glance, LPS preconditioning attenuated organ dysfunction. However, we discovered that HS-rats that had been preconditioned with LPS (a) were not able to sustain a MAP at 30 mmHg for more than 50 min and (b) the volume of blood withdrawn in these animals was significantly less than in the PBS-control group. This effect was associated with an enhanced formation of the nitric oxide (NO) derived from inducible NO synthase (iNOS). Thus, a further control group in which all animals were resuscitated after 50 min of hemorrhage was performed. Then, LPS preconditioning aggravated both circulatory failure and organ dysfunction. Most notably, HS-rats pretreated with LPS exhibited a dramatic increase in NF-κB activation and pro-inflammatory cytokines., Conclusion: In conclusion, LPS preconditioning predisposed animals to an earlier vascular decompensation, which may be mediated by an excess of NO production secondary to induction of iNOS and activation of NF-κB. Moreover, LPS preconditioning increased the formation of pro-inflammatory cytokines, which is likely to have contributed to the observed aggravation of organ injury/dysfunction caused by HS.

Background & Aims: Little is known about how weight loss affects magnetic resonance imaging (MRI) of liver fat and volume or liver histology in patients with nonalcoholic steatohepatitis (NASH). We measured changes in liver fat and liver volume associated with weight loss by using an advanced MRI method., Methods: We analyzed data collected from a previous randomized controlled trial in which 43 adult patients with biopsy-proven NASH underwent clinical evaluation, biochemical tests, and MRI and liver biopsy analyses at the start of the study and after 24 weeks. We compared data between patients who did and did not have at least 5% decrease in body mass index (BMI) during the study period., Results: Ten of 43 patients had at least a 5% decrease in BMI during the study period. These patients had a significant decrease in liver fat, which was based on MRI proton density fat fraction estimates (18.3% ± 7.6% to 13.6% ± 13.6%, P = .03), a relative 25.5% reduction. They also had a significant decrease in liver volume (5.3%). However, no significant changes in levels of alanine aminotransferase or aspartate aminotransferase were observed with weight loss. Thirty-three patients without at least 5% decrease in BMI had insignificant increases in estimated liver fat fraction and liver volume., Conclusions: A reduction in BMI of at least 5% is associated with significant decrease in liver fat and volume in patients with biopsy-proven NASH. These data should be considered in assessing effect size in studies of patients with nonalcoholic fatty liver disease or obesity that use MRI-estimated liver fat and volume as end points., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

A stability-indicating reverse phase high performance liquid chromatography method was developed and validated for cefixime and linezolid. The wavelength selected for quantitation was 276 nm. The method has been validated for linearity, accuracy, precision, robustness, limit of detection and limit of quantitation. Linearity was observed in the concentration range of 2-12 μg/ml for cefixime and 6-36 μg/ml for linezolid. For RP-HPLC, the separation was achieved by Phenomenex Luna C18 (250×4.6 mm) 5 μm column using phosphate buffer (pH 7):methanol (60:40 v/v) as mobile phase with flow rate 1 ml/min. The retention time of cefixime and linezolid were found to be 3.127 min and 11.986 min, respectively. During force degradation, drug product was exposed to hydrolysis (acid and base hydrolysis), H2O2, thermal degradation and photo degradation. The % degradation was found to be 10 to 20% for both cefixime and linezolid in the given condition. The method specifically estimates both the drugs in presence of all the degradants generated during forced degradation study. The developed methods were simple, specific and economic, which can be used for simultaneous estimation of cefixime and linezolid in tablet dosage form.

We used a mathematical model describing traveling-wave electroosmotic micropumps to explain their rather poor ability to work against pressure loads. The mathematical model is based upon the Poisson-Nernst-Planck-Navier-Stokes approach, that is, a direct numerical simulation, which allows a detail study of the energy transformations and the charging dynamics of the electric double layers. Using Matlab and COMSOL Multiphysics, we performed a set of extensive parametric studies to determine the dependence of generated electroosmotic flow on the geometric arrangement of the pump. The results suggest that the performance of AC electroosmotic pumps should improve with miniaturization. The AC electroosmosis is likely to be suitable only at submicrometer scale, as the pump's ability to work against pressure load diminishes rapidly when increasing the channel diameter., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Development of cardiac dysfunction is associated with increased morbidity and mortality in patients with sepsis. Increasing evidence shows that gender determines the degree of inflammatory response of the host and that females tolerate sepsis better than males. It is unknown whether gender affects the cardiac dysfunction in animals or patients with sepsis. To investigate this, male or female C57BL/6 mice were subjected to either lipopolysaccharide (LPS)/peptidoglycan (PepG) co-administration or cecal ligation and puncture (CLP). At 18 hours after LPS/PepG injection or 24 hours after CLP, cardiac function was evaluated by echocardiography. The septic insult caused a significant cardiac dysfunction in both genders. However, the cardiac dysfunction was significantly less pronounced in females in comparison with males subjected to LPS (3 mg/kg)/PepG (0.1 mg/kg) or CLP. Compared with males injected with LPS (3 mg/kg)/PepG (0.1 mg/kg), western blotting analysis of the myocardium from females injected with LPS/PepG revealed i) profound increases in phosphorylation of Akt and eNOS; ii) significant decreases in phosphorylation of IκBα, nuclear translocation of the NF-κB subunit p65, decreased expression of iNOS and decreased synthesis of TNF-α and IL-6 in the heart. However, the gender dimorphism of the cardiac dysfunction secondary to LPS/PepG was not observed when higher doses of LPS (9 mg/kg)/PepG (1 mg/kg) were used. In conclusion, the cardiac dysfunction caused by sepsis was less pronounced in female than in male mice. The protection of female hearts against the dysfunction associated with sepsis is (at least in part) attributable to cardiac activation of the Akt/eNOS survival pathway, decreased activation of NF-κB, and decreased expression of iNOS, TNF-α and IL-6. It should be noted that the observed gender dimorphism of the cardiac dysfunction in sepsis was not seen when a very severe stimulus (high dose of LPS/PepG co-administration) was used to cause cardiac dysfunction.

Two methods, absorption correction and multivariate spectrophotometric methods were developed for simultaneous estimation of Celecoxib (CEL) and Diacerein (DIA) in combined dosage form. Absorption correction method involves direct estimation of DIA at wavelength 341 nm in which CEL has zero absorbance and shows no interference. For estimation of CEL, corrected absorbance was calculated at 253 nm due to the interference of DIA at this wavelength. Linearity was observed in the range of 6-22 μg mL(-1) for CEL and 3-11 μg mL(-1) for DIA. The method was validated as per ICH guidelines. Chemometric methods including classical least square (CLS), inverse least square (ILS), principal component regression (PCR) and partial least square (PLS) were studied for simultaneous determination of CEL and DIA in capsule using spectrophotometry. A set of 25 standard mixtures containing both drugs were prepared in range of 5-25 μg mL(-1) for CEL and 3-15 μg mL(-1) for DIA. Analytical figure of merit (FOM), such as sensitivity, selectivity, analytical sensitivity, limit of detection and limit of quantitation were determined for chemometric methods. The proposed methods were applied for determination of two components from combined dosage form., (Copyright © 2014 Elsevier B.V. All rights reserved.)

UV spectrophotometric and high performance liquid chromatography (HPLC) methods were developed for simultaneous determination of meropenem (MERM) and sulbactam sodium (SB) in injection. UV spectrophotometric methods were developed using 0.1N sodium hydroxide as solvent. The Beer's plot for dual wavelength method was linear in the range of 4-24 μg mL(-1) and 2-12 μg mL(-1) for MERM and SB, respectively. The percent recoveries were found to be 98.52±1.23% for MERM and 101.45±1.1% for SB. Chemometrics assisted UV spectrophotometry was performed using Partial Least Square (PLS) analysis model and Principal Component Regression (PCR) analysis model. The % recoveries of the MERM were found to be 100.61±0.06% and 101.31±0.12% using PLS and PCR, respectively. The % recoveries of the SB were found to be 98.29±0.09% and 97.61±0.13% using PLS and PCR, respectively. Chromatography was performed on Hypersil BDS C18 column using methanol:acetonitrile:water (10:20:70 v/v/v) as mobile phase. The retention times of MERM and SB were found to be 2.9 min and 2.25 min, respectively. Developed HPLC method was found to be linear in the range of 50-250 μg mL(-1) and 25-125 μg mL(-1) for MERM and SB, respectively. The % recoveries were found to be 98.85±0.25% and 98.63±0.34% for MERM and SB, respectively. The developed analytical methods did not show any interference of the excipients when applied to pharmaceutical dosage form., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Computed tomography (CT) and magnetic resonance (MR) enterography are now widely used to diagnose and monitor Crohn's disease., Aim: We sought to assess the use of enterography for management of inflammatory bowel disease (IBD) in our medical center., Methods: We performed a retrospective review of all patients diagnosed with IBD who underwent MR or CT enterography from November 1, 2010 to October 25, 2012 at our institution. We assessed disease complications identified by enterography, agreement between disease activity determined by endoscopy and enterography, association between inflammatory markers and enterography-determined disease activity and recommended changes in medical and surgical management following enterography., Results: A total of 311 enterography studies (291 MR and 20 CT enterographies) were performed on 270 patients, including 258 (83.0 %) on patients with presumed Crohn's disease and 53 (17.0 %) with presumed ulcerative colitis. Active small bowel (SB) disease was noted in 73/311 (23.5 %) studies. Complications including strictures, perianal fistulas, abscesses and SB fistulas were noted in 108/311 (34.7 %) studies. Endoscopic and enterography defined active disease had an agreement of κ = 0.36 in the ileum (n = 179). A total of 142/311 (45.7 %) enterographies were associated with recommended medication changes within 90 days while surgery or endoscopic dilation of stricture was recommended following 41/311 (13.2 %) enterographies. Enterography resulted in a change in diagnosis from ulcerative colitis to Crohn's in 5/311 (1.6 %) studies., Conclusion: Enterography reveals active disease and complications not evident on endoscopy and should be considered in the initial diagnosis, assessment of disease activity, and monitoring of therapy in patients with IBD.

Current literature has suggested that sentinel lymph node biopsy may replace axillary dissection as the nodal staging procedure of choice in early breast cancer. The aim of this study is to evaluate the effectiveness and accuracy of sentinel lymph node biopsy using methylene blue dye in predicting axillary nodal status in early breast cancer with clinically impalpable axillary lymph nodes. In the period between June 2005 and May 2009, 50 patients with early breast cancer and clinically impalpable axillary lymph nodes, underwent sentinel lymph node biopsy using methylene blue dye followed by completion of axillary dissection in the same setting after taking a written consent from the patients. Of the included 50 patients, sentinel lymph node biopsy was successful in 48 patients (96.0%). Accuracy of sentinel lymph node biopsy was 95.8%, sensitivity was 90.0%, false negative rate was 6.7%, negative predictive value was 93.3%.

Mammography is an essential tool for early detection of breast cancer. Breast imaging based on three-dimensional digital breast tomosynthesis (DBT) is a new method for breast cancer screening and diagnosis that uses three-dimensional digital images to allow separation of overlapping breast structures, which may allow for improved visualization of potentially significant findings. This article will highlight the utility of DBT as a tool for the detection of breast pathology; it will demonstrate normal findings as well as breast pathology on DBT and two-dimensional conventional mammography. DBT is a very promising modality, which may decrease the false-positive rate of mammography and find additional abnormalities not seen on two-dimensional mammography., (© 2014.)

The β-common receptor (βcR) plays a pivotal role in the nonhematopoietic tissue-protective effects of erythropoietin (EPO). Here we determined whether EPO reduces the acute kidney injury (AKI) caused by sepsis and whether this effect is mediated by the βcR. In young (2 months old) C57BL/6 wild-type and βcR knockout mice, lipopolysaccharide caused a significant increase in serum urea and creatinine, hence AKI. This AKI was not associated with any overt morphological alterations in the kidney and was attenuated by EPO given 1 h after lipopolysaccharide in wild-type but not in βcR knockout mice. In the kidneys of endotoxemic wild-type mice, EPO enhanced the phosphorylation of Akt, glycogen synthase kinase-3β, and endothelial nitric oxide synthase, and inhibited the activation of nuclear factor-κB. All these effects of EPO were lost in βcR knockout mice. Since sepsis is more severe in older animals or patients, we tested whether EPO was renoprotective in 8-month-old wild-type and βcR knockout mice that underwent cecal ligation and puncture. These older mice developed AKI at 24 h, which was attenuated by EPO treatment 1 h post cecal ligation and puncture in wild-type mice but not in βcR knockout mice. Thus, activation of the βcR by EPO is essential for the observed reduction in AKI in either endotoxemic young mice or older mice with polymicrobial sepsis, and for the activation of well-known signaling pathways by EPO.

Nuclear factor κB (NF-κB) plays a pivotal role in sepsis. Activation of NF-κB is initiated by the signal-induced ubiquitylation and subsequent degradation of inhibitors of kappa B (IκBs) primarily via activation of the IκB kinase (IKK). This study was designed to investigate the effects of IKK inhibition on sepsis-associated multiple organ dysfunction and/or injury (MOD) and to elucidate underlying signaling mechanisms in two different in vivo models: male C57BL/6 mice were subjected to either bacterial cell wall components [lipopolysaccharide and peptidoglycan (LPS/PepG)] or underwent cecal ligation and puncture (CLP) to induce sepsis-associated MOD. At 1 hour after LPS/PepG or CLP, mice were treated with the IKK inhibitor IKK 16 (1 mg/kg body weight). At 24 hours, parameters of organ dysfunction and/or injury were assessed in both models. Mice developed a significant impairment in systolic contractility (echocardiography), and significant increases in serum creatinine, serum alanine aminotransferase and lung myeloperoxidase activity, thus indicating cardiac dysfunction, renal dysfunction, hepatocellular injury and lung inflammation, respectively. Treatment with IKK 16 attenuated the impairment in systolic contractility, renal dysfunction, hepatocellular injury and lung inflammation in LPS/PepG-induced MOD and in polymicrobial sepsis. Compared with mice that were injected with LPS/PepG or underwent CLP, immunoblot analyses of heart and liver tissues from mice that were injected with LPS/PepG or underwent CLP and were also treated with IKK 16 revealed: (1) significant attenuation of the increased phosphorylation of IκBα; (2) significant attenuation of the increased nuclear translocation of the NF-κB subunit p65; (3) significant attenuation of the increase in inducible nitric oxide synthase (iNOS) expression; and (4) a significant increase in the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). Here, we report for the first time that delayed IKK inhibition reduces MOD in experimental sepsis. We suggest that this protective effect is (at least in part) attributable to inhibition of inflammation through NF-κB, the subsequent decrease in iNOS expression and the activation of the Akt-eNOS survival pathway.

A 39-year-old female previously treated with shock wave lithotripsy developed extensive ureteral stricture disease. After 2 unsuccessful attempts at retrograde balloon dilatation, she was evaluated at our center for further management. Successful reconstruction was performed with laparoscopic-assisted vesicocalicostomy.

There is limited evidence that the tissue-protective effects of erythropoietin are mediated by a heterocomplex of the erythropoietin receptor and the β-common receptor ('tissue-protective receptor'), which is pharmacologically distinct from the 'classical' erythropoietin receptor homodimer that is responsible for erythropoiesis. However, the role of the β-common receptor and/or erythropoietin in sepsis-induced cardiac dysfunction (a well known, serious complication of sepsis) is unknown. Here we report for the first time that the β-common receptor is essential for the improvements in the impaired systolic contractility afforded by erythropoietin in experimental sepsis. Cardiac function was assessed in vivo (echocardiography) and ex vivo (Langendorff-perfused heart) in wild-type and β-common receptor knockout mice, that were subjected to lipopolysaccharide (9 mg/kg body weight; young mice) for 16-18 hours or cecal ligation and puncture (aged mice) for 24 hours. Mice received erythropoietin (1000 IU/kg body weight) 1 hour after lipopolysaccharide or cecal ligation and puncture. Erythropoietin reduced the impaired systolic contractility (in vivo and ex vivo) caused by endotoxemia or sepsis in young as well as old wild-type mice in a β-common-receptor-dependent fashion. Activation by erythropoietin of the β-common receptor also resulted in the activation of well-known survival pathways (Akt and endothelial nitric oxide synthase) and inhibition of pro-inflammatory pathways (glycogen synthase kinase-3β, nuclear factor-κB and interleukin-1β). All the above pleiotropic effects of erythropoietin were lost in β-common receptor knockout mice. Erythropoietin attenuates the impaired systolic contractility associated with sepsis by activation of the β-common receptor, which, in turn, results in activation of survival pathways and inhibition of inflammation.

Objectives: The present study was undertaken to evaluate the radioprotective and cytoprotective potential of cordifolioside-A, a primary active constituent of n-butanol fraction of Tinospora Cordifolia (NBTC) against 4 Gy-γ radiation in mice and cyclophosphamide induced genotoxicity., Materials and Methods: Presence of cordifolioside-A in NBTC stem ethanolic extract was confirmed by high performance thin layer chromatography (HPTLC) analysis. Radioprotective activity was evaluated at 80 and 120 mg/kg, intraperitoneal (i.p.) dose of NBTC administered 15 days prior to whole body radiation exposure by observing survival rate, change in body weight, hematology, spleen colony forming unit (CFU), and micronucleus (MN) expression. Cytoprotective activity of NBTC was evaluated at 5, 10, and 15 mg/ml concentrations on Allium cepa root meristem growth against cyclophosphamide., Results: HPTLC analysis of standard cordifolioside A, and NBTC confirmed the presence of cordifolioside-A in NBTC with the retention factor value of 0.86. Administration of NBTC (120 mg/kg, i.p.) produced significant protection against radiation in terms of increased survival rate, body weight retention, hematological parameters, spleen CFU assay (P < 0.01), and decreased MN expression (P < 0.01). Cytoprotectivity was observed maximally at 10 mg/ml NBTC concentration with significant increase in root growth (P < 0.01), non-toxic mitotic index (MI) (65.9%) and lesser chromosomal aberrations (15.4%). NBTC at 10 mg/ml concentration showed very few C-anaphase compared to aberrations like fragmentation, C-anaphase, multipolarity and sticky chromosome in cyclophosphamide alone., Conclusion: The results suggest that enriched NBTC containing cordifolioside-A has a potential in vivo radioprotective effect as well as in vitro cytoprotective activity.

Pre-treatment with erythropoietin (EPO) has been demonstrated to exert tissue-protective effects against 'ischemia-reperfusion'-type injuries. This protection might be mediated by mobilization of bone marrow endothelial progenitor cells (EPCs), which are thought to secrete paracrine factors. These effects could be exploited to protect against tissue injury induced in cases where hemorrhage is foreseeable, for example, prior to major surgery. Here, we investigate the effects of EPO pre-treatment on the organ injury and dysfunction induced by hemorrhagic shock (HS). Recombinant human EPO (1000 IU/kg/day i.p.) was administered to rats for 3 days. Rats were subjected to HS on day 4 (pre-treatment protocol). Mean arterial pressure was reduced to 35 ± 5 mmHg for 90 minutes, followed by resuscitation with 20 ml/kg Ringer's lactate for 10 minutes and 50% of the shed blood for 50 minutes. Rats were sacrificed 4 hours after the onset of resuscitation. EPC (CD34(+)/flk-1(+) cell) mobilization was measured following the 3-day pre-treatment with EPO and was significantly increased compared with rats pre-treated with phosphate-buffered saline. EPO pre-treatment significantly attenuated organ injury and dysfunction (renal, hepatic and neuromuscular) caused by HS. In livers from rats subjected to HS, EPO enhanced the phosphorylation of Akt (activation), glycogen synthase kinase-3β (GSK-3β; inhibition) and endothelial nitric oxide synthase (eNOS; activation). In the liver, HS also caused an increase in nuclear translocation of p65 (activation of NF-κB), which was attenuated by EPO. This data suggests that repetitive dosing with EPO prior to injury might protect against the organ injury and dysfunction induced by HS, by a mechanism that might involve mobilization of CD34(+)/flk-1(+) cells, resulting in the activation of the Akt-eNOS survival pathway and inhibition of activation of GSK-3β and NF-κB.

Objective: To compare the sealing ability of ProRoot mineral trioxide aggregate (MTA) to the sealing ability of EndoSequence Bioceramic Root Repair Material (ES-BCRR) putty using a bacterial leakage model., Method and Materials: Root canals of 60 single-rooted extracted teeth were enlarged to an apical diameter of 0.5 mm using EndoSequence files. The apical 3 mm of each root was sectioned at 90 degrees to the long axis of the root. An ultrasonic surgical tip was used to prepare a 3-mm deep root-end preparation in all teeth. Teeth were equally divided into four groups: Group 1, MTA; Group 2, ES-BCRR putty; Group 3, positive control, gutta-percha without sealer; Group 4, negative control, sealed with wax and nail varnish. Prepared teeth were kept moist for 48 hours to allow for initial setting of the materials. After ethylene oxide sterilization, the teeth were suspended in sterilized vials containing 3% phenol lactose broth and inoculated with Enterococcus faecalis through the occlusal access openings. The samples were observed daily for leakage to a maximum of 28 days. Chi-square and Fisher exact tests were used to compare the experimental groups and an alpha level of significance was set at P = .05., Results: In the ES-BCRR group 93% of samples leaked, compared to only 20% of samples in the MTA group. There was a significant difference in leakage between the experimental groups (P < .0001). Also there were no significant differences between the negative control group and MTA group and between the positive control group and ES-BCRR group (P = 1.00)., Conclusion: Samples in the ES-BCRR group leaked significantly more than samples in the MTA group.

Introduction: The effects of dopexamine, a β2-agonist, on perioperative and sepsis-related hemodynamic, microvascular, immune, and organ dysfunction are controversial and poorly understood. We investigated these effects in a rodent model of laparotomy and endotoxemia., Methods: In two experiments, 80 male Wistar rats underwent laparotomy. In 64 rats, this was followed by administration of endotoxin; the remainder (16) underwent sham endotoxemia. Endotoxemic animals received either dopexamine at 0.5, 1, or 2 μg/kg/min or 0.9% saline vehicle (controls) as resuscitation fluid. The effects of dopexamine on global hemodynamics, mesenteric regional microvascular flow, renal and hepatic function and immune activation were evaluated., Results: Endotoxin administration was associated with a systemic inflammatory response (increased plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10, as well as cell-adhesion molecules CD11a and CD11b), and increased pulmonary myeloperoxidase (MPO) activity (indicating pulmonary leukocyte infiltration), whereas biochemical changes demonstrated lactic acidosis with significant renal and hepatic injury. Dopexamine administration was associated with less-severe lactic acidosis (pooled dopexamine versus controls, (lactate, 2.2 mM±0.2 mM versus 4.0 mM±0.5 mM; P<0.001) and reductions in the systemic inflammatory response (pooled dopexamine versus control, 4 hour (TNF-α): 324 pg/ml±93 pg/ml versus 97 pg/ml±14 pg/ml, p<0.01), pulmonary myeloperoxidase (MPO) activity, and hepatic and renal injury (pooled dopexamine versus control (ALT): 81 IU/L±4 IU/L versus 138 IU/L±25 IU/L; P<0.05; (creatinine): 49.4 μM±3.9 μM versus 76.2 μM±9.8 μM; P<0.005). However, in this study, clinically relevant doses of dopexamine were not associated with clinically significant changes in MAP, CI, or gut regional microvascular flow., Conclusions: In this model, dopexamine can attenuate the systemic inflammatory response, reduce tissue leukocyte infiltration, and protect against organ injury at doses that do not alter global hemodynamics or regional microvascular flow. These findings suggest that immunomodulatory effects of catecholamines may be clinically significant when used in critically ill surgical patients and are independent of their hemodynamic actions.

Background: Abnormal gastrointestinal permeability has been linked to irritable bowel syndrome (IBS). The lactulose-to-mannitol ratio is traditionally used to assess small intestine permeability while sucralose and sucrose are used to assess colonic and gastric permeability respectively. We used a single 4-probe test solution to assess permeability throughout the gastrointestinal tract in IBS patients and healthy controls by measuring the recovery of the probes in urine after ingestion using a modified liquid chromatography mass spectrometry protocol., Methods: Fasting participants (N=59) drank a permeability test solution (100ml: sucralose, sucrose, mannitol, and lactulose). Urine was collected over a 5-h period and kept frozen until analysis. Urinary sugar concentrations were measured using a liquid chromatography/triple quadruple mass spectrometer., Results: Colonic permeability was significantly lower in IBS patients when compared to healthy controls (p=0.011). Gastric and small intestinal permeability did not significantly differ between the groups., Conclusions: The study demonstrates the clinical potential of this non-invasive method for assessing alterations in gastrointestinal permeability in patients with IBS., (Published by Elsevier B.V.)

Background: Ectopic fat deposition in the pancreas and its association with hepatic steatosis have not previously been examined in patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD)., Aim: To quantify pancreatic fat using a novel magnetic resonance imaging (MRI) technique and determine whether it is associated with hepatic steatosis and/or fibrosis in patients with NAFLD., Methods: This is a cross-sectional study including 43 adult patients with biopsy-proven NAFLD who underwent clinical evaluation, biochemical testing and MRI. The liver biopsy assessment was performed using the NASH-CRN histological scoring system, and liver and pancreas fat quantification was performed using a novel, validated MRI biomarker; the proton density fat fraction., Results: The average MRI-determined pancreatic fat in patients with NAFLD was 8.5% and did not vary significantly between head, body, and tail of the pancreas. MRI-determined pancreatic fat content increased significantly with increasing histology-determined hepatic steatosis grade; 4.6% in grade 1; 7.7% in grade 2; 13.0% in grade 3 (P = 0.004) respectively. Pancreatic fat content was lower in patients with histology-determined liver fibrosis than in those without fibrosis (11.2% in stage 0 fibrosis vs. 5.8% in stage 1-2 fibrosis, and 6.9% in stage 3-4 fibrosis, P = 0.013). Pancreatic fat did not correlate with age, body mass index or diabetes status., Conclusions: In patients with NAFLD, increased pancreatic fat is associated with hepatic steatosis. However, liver fibrosis is inversely associated with pancreatic fat content. Further studies are needed to determine underlying mechanisms to understand if pancreatic steatosis affects progression of NAFLD., (© 2013 Blackwell Publishing Ltd.)

Pemphigus vulgaris (PV) is a life-threatening autoimmune bullous disorder. Although systemic corticosteroids are the standard treatment for PV, efficient transition to a steroid-sparing immunosuppressant is critical. There is significant debate in the literature as to what the optimal, first-line steroid-sparing agent should be in patients with PV. Mycophenolate mofetil (MMF), in particular, is a promising agent that should be strongly considered as a first-line steroid-sparing agent. The authors review treatment options for PV and describe a severe case treated successfully with prednisone and MMF as a first-line steroid-sparing agent. The patient's clinical improvement was rapid, and all PV lesions completely resolved. The dosage of prednisone was safely tapered using MMF, and the patient did not experience any flares or significant side effects during the course of treatment. Therapy for PV with systemic corticosteroids and MMF therapy was effective and well tolerated.

Fibroblast growth factor-2 (FGF2) is an angiogenic growth factor that binds to cell surface receptors (FGFR) and heparan sulfate proteoglycans (HSPG), as well as HSPG in the basement membrane. FGF2 plays a critical role in angiogenesis, yet clinical FGF2 trials demonstrated limited success perhaps due to inadequate understanding of FGF2 binding in physiological conditions. We developed a computational model of FGF2 binding to isolated (HSPG or FGFR) or combined (HSPG and FGFR) binding sites under physiological fluid flow and predicted the effects of FGF2 concentration, binding site density, fluid flow rate, and delivery mode (continuous vs. bolus) on FGF2 complex formation. The isolated binding site models showed increased binding with FGF2 and binding site density. However, in the triad model, increasing FGF2 concentration decreased triads (FGF2-HSPG-FGFR) and increased FGF2-HSPG complexes. Fluid flow decreased time to equilibrium and dissociation in isolated binding site models, yet flow effect in the triad model depended on binding site density. Similarly, FGF2 capture and complex stability in bolus delivery depended on bolus size, flow rate, association and dissociation rate constants, as well as binding site density. This model shows the integrated effects of FGF2 binding stoichiometry, fluid flow, and delivery mode, and enhances our understanding of FGF2 complex formation under physiological conditions.

Acquired C1 inhibitor (C1-INH) deficiency exposes patients to angioedema recurrences (acquired angioedema [AAE]) mediated by bradykinin pathway activation. C1-INH replacement and specific inhibition of plasma kallikrein with ecallantide have been successful in the treatment of hereditary angioedema (HAE), a more common related disorder. C1-INH replacement has also been used in the treatment of AAE, but because of the underlying mechanism of rapid catabolism, some patients may not respond. As part of preclinical investigation of ecallantide, a potent bradykinin pathway inhibitor, we evaluated three AAE patients treated successfully with that agent. This study was designed to assess ecallantide for treatment of attacks in AAE. Three patients with AAE were treated a total of 12 times with various dosing regimens of ecallantide based on the protocols established for the studies using ecallantide in HAE (Evaluation of DX-88's Effects in Mitigating Angioedema trials). Response to therapy was also based on outcome measures determined by these protocols. Ecallantide effectively relieved symptoms in three patients with various manifestations of AAE over 12 acute episodes. Kallikrein inhibition with ecallantide appears effective in the treatment of AAE and may be an alternative for patients with resistance to C1-INH replacement therapy.

Background. Ectopic fat deposition in the pancreas and its relationship with hepatic steatosis and insulin resistance have not been compared between patients with nonalcoholic fatty liver disease (NAFLD) and healthy controls. Aim. Using a novel magnetic resonance imaging (MRI) based biomarker, the proton-density-fat-fraction (MRI-PDFF), we compared pancreatic fat content in patients with biopsy-proven NAFLD to healthy controls and determined whether it is associated with insulin resistance and liver fat content. Methods. This nested case-control study was derived from two prospective studies including 43 patients with biopsy-proven NAFLD and 49 healthy controls who underwent biochemical testing and MRI. Results. Compared to healthy controls, patients with NAFLD had significantly higher pancreatic MRI-PDFF (3.6% versus 8.5%, P value <0.001), and these results remained consistent in multivariable-adjusted models including age, sex, body mass index, and diabetes (P value =0.03). We found a strong correlation between hepatic and pancreatic MRI-PDFF (Spearman correlation, P = 0.57, P value <0.001). Participants with increased insulin resistance determined by homeostatic-model-of-insulin-resistance (HOMA-IR) greater than 2.5 had higher pancreatic (7.3% versus 4.5%, P value =0.015) and liver (13.5% versus 4.0%, P value <0.001) MRI-PDFF. Conclusion. Patients with NAFLD have greater pancreatic fat than normal controls. Insulin resistance is associated with liver and pancreatic fat accumulation.

The combination of obesity and type 2 diabetes is a serious health problem, which is projected to afflict 300 million people worldwide by 2020. Both clinical and translational laboratory studies have demonstrated that chronic inflammation is associated with obesity and obesity-related conditions such as insulin resistance. However, the precise etiopathogenetic mechanisms linking obesity to diabetes remain to be elucidated, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the "inflammasome," a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin- (IL-) 1 β and IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in metabolic disease pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation.

Changes in higher order chromatin organisation have been linked to transcriptional regulation; however, little is known about how such organisation alters during embryonic development or how it is regulated by extrinsic signals. Here we analyse changes in chromatin organisation as neural differentiation progresses, exploiting the clear spatial separation of the temporal events of differentiation along the elongating body axis of the mouse embryo. Combining fluorescence in situ hybridisation with super-resolution structured illumination microscopy, we show that chromatin around key differentiation gene loci Pax6 and Irx3 undergoes both decompaction and displacement towards the nuclear centre coincident with transcriptional onset. Conversely, down-regulation of Fgf8 as neural differentiation commences correlates with a more peripheral nuclear position of this locus. During normal neural differentiation, fibroblast growth factor (FGF) signalling is repressed by retinoic acid, and this vitamin A derivative is further required for transcription of neural genes. We show here that exposure to retinoic acid or inhibition of FGF signalling promotes precocious decompaction and central nuclear positioning of differentiation gene loci. Using the Raldh2 mutant as a model for retinoid deficiency, we further find that such changes in higher order chromatin organisation are dependent on retinoid signalling. In this retinoid deficient condition, FGF signalling persists ectopically in the elongating body, and importantly, we find that inhibiting FGF receptor (FGFR) signalling in Raldh2-/- embryos does not rescue differentiation gene transcription, but does elicit both chromatin decompaction and nuclear position change. These findings demonstrate that regulation of higher order chromatin organisation during differentiation in the embryo can be uncoupled from the machinery that promotes transcription and, for the first time, identify FGF as an extrinsic signal that can direct chromatin compaction and nuclear organisation of gene loci., Competing Interests: The authors have declared that no competing interests exist.

Drug-eluting stents (DESs) prevail in the treatment of carotid artery diseases in the interventional cardiology world owing to their efficacy for significant reduction of restenosis. A current successful DES requires a polymer coating for drug delivery. Clinical trials examining several pharmaceutical agents have demonstrated marked reduction in restenosis following stenting. The development of DES is one of the major revolutions in the field of interventional cardiology. The ideal drug to prevent restenosis must have an anti-proliferative and anti-migratory effect on smooth muscle cells but, on the other hand, it must also enhance re-endothelialization in order to prevent late thrombosis. Additionally, it should effectively inhibit the anti-inflammatory response after balloon induced arterial injury. Although DES have significantly reduced the angiographic restenosis rate and have improved clinical outcomes, late thrombosis and restenosis remain an important subject of ongoing research.

Background: Research examining the role of stress in gastrointestinal (GI) symptoms such as chronic abdominal pain (CAP) is controversial. The purpose of this study was to examine the expression of genes involved in metabolic stress and toxicity in men and women with high and low levels of perceived stress with and without CAP., Methods: Data and samples were collected and the expression of genes involved in metabolic stress and toxicity was analyzed in 26 individuals who had consented to participate in a natural history protocol. Subjects completed the 10-item Perceived Stress scale (PSS). Fasting participants' peripheral whole blood was collected for proteomic and genomic studies. Polymerase chain reaction (PCR) array was used to analyze the expression of 84 key genes involved in human stress and toxicity plus 5 housekeeping genes. Plasma interleukin-1 alpha (IL-1α) protein was quantified via enzyme-linked immunosorbent assay (ELISA)., Results: Interleukin-1 alpha gene (IL1A) was upregulated in females with high stress versus females with low stress by 2.58-fold (95% CI [0.88, 4.28]). IL1A was upregulated in participants with high stress and CAP versus those with low stress and CAP by 3.47-fold (95% CI [1.14, 5.80])., Conclusions: An upregulation of the gene coding the pro-inflammatory cytokine IL-1α suggests that the mechanism behind stress-related changes in GI symptoms is pro-inflammatory in nature. The results of this study contribute to the knowledge of the mechanism behind stress-related CAP symptoms and gender differences associated with these disorders.

Many therapies exist in the arsenal of drugs available to dermatologists for the treatment of acne vulgaris. Among them, hormonal therapy stands out as a unique and highly efficacious treatment modality. Although some dermatologists may be hesitant to prescribe hormonal therapies, they can be safely and appropriately used in eligible female patients to treat acne vulgaris. Herein, current issues regarding the hormonal treatment of acne in the form of combined oral contraceptives (COCs) are presented, and a practical method for implementing this therapy is proposed. Specifically, drug selection, associated risks, benefits, monitoring, and counseling are discussed, with emphasis on the practicality of use in the clinical setting.

Erythropoietin (EPO) is known to have numerous biological functions. Its primary function in the body is to increase red blood cell numbers by way of preventing the apoptosis of erythroid progenitor cells via the homodimeric EPO receptor. The discovery that the local production of EPO within the brain in response to hypoxia or ischemia protects neurons against injury via an anti-apoptotic effect formed the basis of the hypothesis that the local generation of EPO limits the extent of injury. Although the hypothesis proved to be true in pre-clinical models of ischemia/reperfusion injury and inflammation, the randomized, controlled clinical trials that followed demonstrated serious adverse events of EPO due to activation of the hematopoietic system. Consequently, derivatives of EPO that lacked erythropoietic activity were discovered to reduce injury in many pre-clinical models associated with ischemia and inflammation. Unfortunately, there are no published clinical trials to determine the efficacy of non-erythropoietic derivatives of EPO in humans.

We sought to determine the angiographic severity of coronary lesions leading to ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) with a focus on determining the impact of interval from initial angiogram to subsequent clinical event. In the late 1980s angiographic data on lesion characteristics that culminated in STEMI and NSTEMI were obtained from angiograms obtained several months before MI. It is not clear whether the conclusions on lesion severity would be different if elapsed interval from baseline angiogram to clinical event was factored in the analysis. From 2003 through 2010, we identified 84 patients with NSTEMI and 41 patients with STEMI in vessels without previous intervention. These patients had ≥1 previous angiographic study at our center. Angiograms were reanalyzed with quantitative coronary angiography, and relevant clinical data were obtained from medical records. Similar to previous studies, 71% of patients with STEMI and 63% of patients with NSTEMI had <50% baseline stenosis at the culprit site when the interval from initial angiogram to MI was >3 months. Interestingly, lesions that led to STEMI ≤3 months after evaluation were more severe than those leading to STEMI in >3 months (59 ± 31% vs 36 ± 21%, p = 0.02) with 57% of lesions having >50% stenosis. Although most MIs occurred at sites that did not have significant obstruction when examined >3 months before MI, most baseline lesions showed significant luminal narrowing when examined ≤3 months before STEMI. In conclusion, high-grade coronary stenosis may be an important predictor of STEMI in subsequent months., (Copyright © 2012 Elsevier Inc. All rights reserved.)