VE1 immunohistochemistry is an adjunct tool for detection of BRAF V600E mutation: Validation in thyroid cancer patients

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy among other endocrine tumors, and BRAF ^V600E is a frequent genetic mutation occurring in the disease. Although different molecular techniques, most importantly sequencing has been widely recognized as a gold standard but molecular diagnosis remains an expensive, laborious, and time‐intensive process. Recently, immunohistochemistry (IHC) with anti‐BRAF V600E (VE1) antibody has increased practical utility and implemented clinically for the detection of BRAF ^V600E mutation. Therefore, the study aimed to evaluate diagnostic accuracy of VE1 IHC for detecting the BRAF ^V600E mutation frequency and clinical implementation in diagnostic laboratories. In this study, 72 formalin fixed paraffin‐embedded tissues (FFPE) were used to determine the BRAF ^V600E mutation status using IHC and Sanger sequencing. The mutation was found in 29% and 28% cases using IHC and Sanger sequencing, respectively. Furthermore, the results showed 100% sensitivity, 98.07% specificity, 95.2% positive predictive value, and 100% negative predictive value. Notably, significant associations were found between BRAF ^V600E status and tumor stage, tumor focality, and extrathyroidal extensions, respectively. VE1 IHC was found to be a highly sensitive, specific, and diagnostically accurate method in this cohort. Therefore, BRAF ^V600E detection through IHC has been considered as the best tailored technique for routine pathology laboratories.     

The Effect of Standard Versus Longer Intestinal Bypass on GLP-1 Regulation and Glucose Metabolism in Patients With Type 2 Diabetes Undergoing Roux-en-Y Gastric Bypass: The Long-Limb Study

OBJECTIVERoux-en-Y gastric bypass (RYGB) characteristically enhances postprandial levels of glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesized that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the postprandial peak in GLP-1, translating into higher insulin secretion and, thus, additional improvements in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass.RESEARCH DESIGN AND METHODSA total of 53 patients with type 2 diabetes (T2D) and obesity were randomized to either standard limb RYGB (50-cm biliopancreatic limb) or long limb RYGB (150-cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycemic hyperinsulinemic clamps at baseline and 2 weeks and at 20% weight loss after surgery.RESULTSBoth groups exhibited enhancement in postprandial GLP-1 secretion and improvements in glycemia compared with baseline. There were no significant differences in postprandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity.CONCLUSIONSThe findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion. Thus, the characteristic enhancement of GLP-1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments.     

In vivo Heparan Sulfate Treatment Alters the Immune Response of Normal and LLC-Bearing Mice

Despite the large amount of research dedicated to the understanding and treatment of tumor growth, the majority of cancers continue to lack effective therapeutic options. As in the case of most solid tumors, growth requires evasion of the host immune system. Our previous work using the Lewis Lung Carcinoma (LLC) model of tumor bearing (TB)-mice has shown several tumor-induced immune suppressing effects to be present. These effects include a decreased T-cell proliferative response to Con A and altered cytokine secretion patterns that favor neither a Th1 nor a Th2 response. To address these immune alterations, immune modulating approaches have been a central area of study. Of the many potential immune modulating compounds, we believe promising therapeutic potential lies in the heparin family. Heparan sulfate (HS), in particular, has been shown to increase T-cell proliferative response in non TB-mouse splenocytes as well as promotion of a beneficial Th1 response. In this paper, we studied the potential of HS to decrease tumor burden via in vivo treatment of TB-mice. Results showed both normal and TB-mice splenocytes had a dose response change in proliferation as a result of HS treatment. Furthermore, splenocytes from HS treated TB-mice showed a potentially beneficial decrease in basal level proliferation. On gross examination, HS treatment produced a decrease in tumor surface necrosis with a visible (2 ± 1.8%) surface necrotic area in treated mice as opposed to a (43 ± 16%) surface necrotic area in untreated mice. HS treatment decreased TB-mice splenomegaly when comparing mice spleen weights in treated (0.3 ± 0.05 g) vs. untreated (0.14 ± 0.02 g) groups. These results show a potential role of HS as an immune modulating agent with antitumor properties.     

Reduced parenchymal cerebral blood flow is associated with greater progression of brain atrophy: The SMART-MR study

Global cerebral hypoperfusion may be involved in the aetiology of brain atrophy; however, long-term longitudinal studies on this relationship are lacking. We examined whether reduced cerebral blood flow was associated with greater progression of brain atrophy. Data of 1165 patients (61 ± 10 years) from the SMART-MR study, a prospective cohort study of patients with arterial disease, were used of whom 689 participated after 4 years and 297 again after 12 years. Attrition was substantial. Total brain volume and total cerebral blood flow were obtained from magnetic resonance imaging scans and expressed as brain parenchymal fraction (BPF) and parenchymal cerebral blood flow (pCBF). Mean decrease in BPF per year was 0.22% total intracranial volume (95% CI: –0.23 to –0.21). Mean decrease in pCBF per year was 0.24 ml/min per 100 ml brain volume (95% CI: –0.29 to –0.20). Using linear mixed models, lower pCBF at baseline was associated with a greater decrease in BPF over time (p = 0.01). Lower baseline BPF, however, was not associated with a greater decrease in pCBF (p = 0.43). These findings indicate that reduced cerebral blood flow is associated with greater progression of brain atrophy and provide further support for a role of cerebral blood flow in the process of neurodegeneration.     

The clinical effectiveness of reconstructing 18F-sodium fluoride PET/CT bone using Bayesian penalized likelihood algorithm for evaluation of metastatic bone disease in obese patients

Objective:A new Bayesian penalized likelihood reconstruction algorithm for positron emission tomography (PET) (Q.Clear) is now in clinical use for fludeoxyglucose (FDG) PET/CT. However, experience with non-FDG tracers and in special patient populations is limited. This pilot study aims to compare Q.Clear to standard PET reconstructions for ¹⁸F sodium fluoride (¹⁸F-NaF) PET in obese patients.Methods:30 whole body ¹⁸F-NaF PET/CT scans (10 patients with BMI 30–40 Kg/m² and 20 patients with BMI >40 Kg/m²) and a NEMA image quality phantom scans were analyzed using ordered subset expectation maximization (OSEM) and Q.Clear reconstructions methods with B400, 600, 800 and 1000. The images were assessed for overall image quality (IQ), noise level, background soft tissue, and lesion detectability, contrast recovery (CR), background variability (BV) and contrast-to-noise ratio (CNR) for both algorithms.Results:CNR for clinical cases was higher for Q.Clear than OSEM (p < 0.05). Mean CNR for OSEM was (21.62 ± 8.9), and for Q.Clear B400 (31.82 ± 14.6), B600 (35.54 ± 14.9), B800 (39.81 ± 16.1), and B1000 (40.9 ± 17.8). As the β value increased the CNR increased in all clinical cases. B600 was the preferred β value for reconstruction in obese patients. The phantom study showed Q.Clear reconstructions gave lower CR and lower BV than OSEM. The CNR for all spheres was significantly higher for Q.Clear (independent of β) than OSEM (p < 0.05), suggesting superiority of Q.Clear.Conclusion:This pilot clinical study shows that Q.Clear reconstruction algorithm improves overall IQ of ¹⁸F-NaF PET in obese patients. Our clinical and phantom measurement results demonstrate improved CNR and reduced BV when using Q.Clear. A β value of 600 is preferred for reconstructing ¹⁸F-NaF PET/CT with Q.Clear in obese patients.Advances in knowledge:¹⁸F-NaF PET/CT is less susceptible to artifacts induced by body habitus. Bayesian penalized likelihood reconstruction with¹⁸F-NaF PET improves overall IQ in obese patients.     

Abdominal Dermis-Fat Graft Versus Conventional Temporalis Myofascial Flap Interposition in Temporomandibular Joint Ankylosis: A Prospective Clinical Comparative Study

IntroductionTemporomandibular joint (TMJ) ankylosis is an extremely disabling condition with almost complete inability to open the jaws causing difficulty in chewing, speech, poor oral hygiene and cosmetic disfigurement. Temporalis myofascial flap still remains the most common interpositional material used; however, patients usually complain of pain during movement, unesthetic bulging in the temporal region and trismus due to scar contracture. The main aim of the study was to evaluate the efficacy of abdominal dermis-fat graft and compare it with temporalis myofascial flap as to see which of the two grafts offers more advantages and provides better postoperative results following TMJ ankylosis surgery. Materials and MethodsA total of 30 diagnosed cases of TMJ ankylosis were randomly divided into two groups of 15 patients each. All the patients underwent TMJ ankylosis release under general anesthesia followed by abdominal dermis-fat interposition in Group A and temporalis muscle in Group B. The patients were assessed for pre-operative and postoperative mouth opening (immediate and 6 month postoperative), pain during physiotherapy, donor and surgical site complications and recurrence of ankylosis.ResultsThe mean maximum inter-incisal opening in dermis-fat group was significantly higher than temporalis group both at immediate and 6 month postoperative periods (p = 0.041, 0.001). Physiotherapy was less painful in dermis-fat group than in temporalis group, and the differences in VAS scores among the 2 groups showed high statistical significance (p < 0.001). Hypertrophic scar developed at the donor site in 2 patients in dermis-fat group; however, it was located below the beltline and hardly noticeable. A total of 9 patients (4 in Group A and 5 in Group B) developed temporary facial nerve weakness, and no case of re-ankylosis was noted in either group.ConclusionDermis-fat graft in temporomandibular joint ankylosis showed better results than conventional temporalis myofascial flap in terms of postoperative mouth opening, physiotherapy and jaw function with esthetically acceptable results.     

Fundamentals and recent progress relating to the fabrication,functionalization and characterization of mesostructured materials using diverse synthetic methodologies

Since 1990 and the invention of the very first generation of ordered mesoporous silica materials, several innovative methodologies have been applied to synthesize, characterize, and modify silica/non-silica mesoporous materials. The growth of the mesoporous materials field has generated significant environmental and economic advantages compared to various other industrial developments. According to the literature, there are several key synthesis approaches and parameters that can affect the structural, textural and morphological characteristics of mesoporous materials. To date, huge attempts have been made to maximize the activities and selectivities of these materials through either the in situ or post-synthesis functionalization of the large interior surface areas and internal mesostructured frameworks in the presence of specific organic/inorganic components. However, the main challenge is to provide good control over the incorporation and distribution of multiple guest components within the mesostructured hosts. Mesostructured materials have received great attention for various applications, such as being used in electronics, medicine, photocatalysis, catalyst supports, catalysis, absorbers, sensors, gas separation, etc. In the current paper, several recent developments have been highlighted and reviewed regarding the fabrication and characterization of siliceous/non-siliceous mesoporous materials via various synthetic approaches. Furthermore, the availability of diverse functionalization methods has been reviewed to provide comprehensive approaches for synthesizing new generations of suitably modified mesoporous materials with superior structural, physicochemical, and textural characteristics.

Since 1990 and the invention of the very first generation of ordered mesoporous silica materials, several innovative methodologies have been applied to synthesize, characterize, and modify silica/non-silica mesoporous materials.     

The renin-angiotensin-aldosterone system and hypertension in primary hyperparathyroidism

To evaluate the role of the renin-angiotensin-aldosterone system in the hypertension associated with primary hyperparathyroidism, we measured plasma renin activity and aldosterone concentration before and after maneuvers to suppress and stimulate this system in 11 hypertensive patients with primary hyperparathyroidism. We also measured plasma or urinary norepinephrine concentration to examine the role of catecholamines in the hypertension. The results were compared with an age- and race-matched control population. While the mean plasma aldosterone concentrations were normal, the mean plasma renin activity in response to furosemide stimulation was subnormal in subjects with hyperparathyroidism. Plasma or urinary norepinephrine concentrations were within the normal range. Thus a specific abnormality of the renin-angiotensin-aldosterone system or catecholamines could not be identified in these hypertensives with primary hyperparathyroidism.     

Impact of Ciprofloxacin and Clindamycin Administration on Gram-Negative Bacteria Isolated from Healthy Volunteers and Characterization of the Resistance Genes They Harbor

The aim of this study was to assess the impact of ciprofloxacin, clindamycin, and placebo administration on culturable Gram-negative isolates and the antibiotic resistance genes they harbor. Saliva and fecal samples were collected from healthy human volunteers before and at intervals, up to 1 year after antibiotic administration. Samples were plated on selective and nonselective media to monitor changes in different colony types or bacterial species. Following ciprofloxacin administration, there was a decrease of Escherichia coli in feces and after clindamycin administration a decrease of Bacteroides in feces and Leptotrichia in saliva, which all returned to pretreatment levels within 1 to 4 months. Ciprofloxacin administration also resulted in an increase in ciprofloxacin-resistant Veillonella in saliva, which persisted for 12 months. Additionally, 949 aerobic and anaerobic isolates purified from ciprofloxacin- and clindamycin-containing plates were screened for the presence of resistance genes. Resistance gene carriage was widespread in isolates from all three treatment groups, and no association was observed between genes and antibiotic administration. Although the anaerobic component of the microbiota was not a major reservoir of aerobe-associated antimicrobial resistance (AMR) genes, we detected the sulfonamide resistance gene sul2 in anaerobic isolates. The longitudinal nature of the study allowed identification of distinct Escherichia coli clones harboring multiple resistance genes, including one carrying an extended-spectrum β-lactamase bla_CTX-M group 9 gene, which persisted in the gut for up to 4 months. This study provided insight into the effects of antibiotic administration on healthy microbiota and the diversity of resistance genes harbored therein.