Pancreaticoduodenectomy with Anatomical Vascular Variant in Groove Pancreatitis-A Case Report.

Groove pancreatitis represents a chronic focal form of pancreatitis affecting the zone between the pancreatic head and the duodenal "C" loop, known as the groove area. This is a rare condition that affects the pancreatic periampullary part, including the duodenum and the common bile duct, which is usually associated with long-term alcohol and tobacco misuse, and is more frequent in men than in women. The most common clinical symptoms of groove pancreatitis include weight loss, acute abdominal pain, nausea, and jaundice. This report is about a 66-year-old woman with a history of heavy smoking, presenting with weight loss, nausea, and upper abdominal pain. Contrast-enhanced computed tomography revealed the existence of chronic pancreatitis as well as the dilatation of the main pancreatic duct, a cyst of the pancreatic head, and enlargement of the biliary tract. Conservatory treatment was initiated but with no improvement of symptoms. Since endoscopic retrograde cholangiopancreatography was not possible due to the local changes, we decided to perform pancreatoduodenectomy, as surgery appears to be the single effective treatment.

Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism in mice.

Initiating drug use during adolescence increases the risk of developing addiction or other psychopathologies later in life, with long-term outcomes varying according to sex and exact timing of use. The cellular and molecular underpinnings explaining this differential sensitivity to detrimental drug effects remain unexplained. The Netrin-1/DCC guidance cue system segregates cortical and limbic dopamine pathways in adolescence. Here we show that amphetamine, by dysregulating Netrin-1/DCC signaling, triggers ectopic growth of mesolimbic dopamine axons to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to enduring cognitive deficits. In adolescent females, compensatory changes in Netrin-1 protect against the deleterious consequences of amphetamine on dopamine connectivity and cognitive outcomes. Netrin-1/DCC signaling functions as a molecular switch which can be differentially regulated by the same drug experience as function of an individual's sex and adolescent age, and lead to divergent long-term outcomes associated with vulnerable or resilient phenotypes.

Structured LDH/Bentonite Composites for Chromium Removal and Recovery from Aqueous Solutions.

This study focuses on chromium removal through adsorption and ion exchange using structured calcined layered double hydroxide (LDH) (MgAl)-bentonite composites. Firstly, the powders were structured into granulates to study the effect on Cr sorption kinetics to circumvent the limitations of working with powders in real-life applications. Secondly, the regeneration of the structured composites was optimized to enable multi-cycling operation, which is the key for their applicability beyond laboratory scale. Firstly, the LDH/bentonite ratio was optimized to obtain the best performance for the removal of Cr3+ and Cr6+ species. In powder form, the calcined adsorbent containing 80 wt% LDH and 20 wt% bentonite performed best with an adsorption capacity of 48 and 40 mg/g for Cr3+ and Cr6+, respectively. The desorption was optimized by studying the effect of the NaCl concentration and pH, with a 2 M NaCl solution without pH modification being optimal. The kinetic data of the adsorption and desorption steps were modelled, revealing a pseudo-second order model for both. This was also demonstrated using XRD and Raman measurements after the Cr3+ and Cr6+ adsorption tests, indicating successful uptake and revealing the adsorption mechanism. Finally, five consecutive adsorption-desorption cycles were performed, each showing nearly 100% adsorption and desorption.

Omics biomarkers and an approach for their practical implementation to delineate health status for personalized nutrition strategies.

Personalized nutrition (PN) has gained much attention as a tool for empowerment of consumers to promote changes in dietary behavior, optimizing health status and preventing diet related diseases. Generalized implementation of PN faces different obstacles, one of the most relevant being metabolic characterization of the individual. Although omics technologies allow for assessment the dynamics of metabolism with unprecedented detail, its translatability as affordable and simple PN protocols is still difficult due to the complexity of metabolic regulation and to different technical and economical constrains. In this work, we propose a conceptual framework that considers the dysregulation of a few overarching processes, namely Carbohydrate metabolism, lipid metabolism, inflammation, oxidative stress and microbiota-derived metabolites, as the basis of the onset of several non-communicable diseases. These processes can be assessed and characterized by specific sets of proteomic, metabolomic and genetic markers that minimize operational constrains and maximize the information obtained at the individual level. Current machine learning and data analysis methodologies allow the development of algorithms to integrate omics and genetic markers. Reduction of dimensionality of variables facilitates the implementation of omics and genetic information in digital tools. This framework is exemplified by presenting the EU-Funded project PREVENTOMICS as a use case.

The scheduling of adolescence with Netrin-1 and UNC5C.

Dopamine axons are the only axons known to grow during adolescence. Here, using rodent models, we examined how two proteins, Netrin-1 and its receptor, UNC5C, guide dopamine axons towards the prefrontal cortex and shape behaviour. We demonstrate in mice ( Mus musculus ) that dopamine axons reach the cortex through a transient gradient of Netrin-1 expressing cells - disrupting this gradient reroutes axons away from their target. Using a seasonal model (Siberian hamsters; Phodopus sungorus ) we find that mesocortical dopamine development can be regulated by a natural environmental cue (daylength) in a sexually dimorphic manner - delayed in males, but advanced in females. The timings of dopamine axon growth and UNC5C expression are always phase-locked. Adolescence is an ill-defined, transitional period; we pinpoint neurodevelopmental markers underlying this period.

IMPACT OF NUTRITIONAL CORRECTION OF PROTEIN METABOLISM DISORDERS ON THE CLINICAL COURSE OF PULMONARY TUBERCULOSIS.

OBJECTIVE: The aim: To study the impact of nutritional correction of protein metabolism disorders on the clinical course of pulmonary tuberculosis. PATIENTS AND METHODS: Materials and methods: The study involved 67 patients with pulmonary tuberculosis, which were divided into two groups: group I - 35 patients who underwent nutritional correction of protein metabolism disorders against the background of antimycobacterial therapy (AMBT) and group II - 32 patients who received standard AMBT. An assessment of clinical indicators and the condition of protein metabolism (PM) was conducted by determining the concentration of individual non-essential, essential amino acids and their total amount. RESULTS: Results: The proposed correction scheme includes food products containing essential nutrients and biologically active compounds that have a positive impact on the corresponding links of pathogenesis and can be used throughout all phases of treatment. Its application had a positive impact on the indicators of PM (significant (p<0.05) increase in total amount of essential amino acids (TAEAA), total amount of non-essential amino acids (TANEAA) and total amount of amino acids (TAAA) in blood serum and the concentration of individual essential and non-essential amino acids (significantly reached the level of indicators in healthy individuals) and clinical course of tuberculosis (intoxication syndrome disappeared earlier by 10.8 ± 0.97 days, and respiratory one by 8.95 ± 1.68 days), there was an increase in the frequency of healing of decay cavities at the time of completion of treatment by 34.0% and a significant (p<0.05) reduction in the average duration of treatment by 21.1±2.91 days. CONCLUSION: Conclusions: The application of nutritional correction of protein metabolism in the complex treatment of patients with pulmonary tuberculosis made it possible to obtain a pronounced positive impact on the clinical course of the disease and the condition of protein metabolism, which contributed to an increase in the effectiveness of treatment and rehabilitation.

Mutation-specific dual potentiators maximize rescue of CFTR gating mutants.

BACKGROUND: The potentiator ivacaftor (VX-770) has been approved for therapy of 38 cystic fibrosis (CF) mutations (∼10% of the patient population) associated with a gating defect of the CF transmembrane conductance regulator (CFTR). Despite the success of VX-770 treatment of patients carrying at least one allele of the most common gating mutation G551D-CFTR, some lung function decline and P. aeruginosa colonization persist. This study aims at identifying potentiator combinations that can considerably enhance the limited channel activity of a panel of CFTR gating mutants over monotherapy. METHODS: The functional response of 13 CFTR mutants to single potentiators or systematic potentiator combinations was determined in the human bronchial epithelial cell line CFBE41o- and a subset of them was confirmed in primary human nasal epithelia (HNE). RESULTS: In six out of thirteen CFTR missense mutants the fractional plasma membrane (PM) activity, a surrogate measure of CFTR channel gating, reached only ∼10-50% of WT channel activity upon VX-770 treatment, indicating incomplete gating correction. Combinatorial potentiator profiling and cluster analysis of mutant responses to 24 diverse investigational potentiators identified several compound pairs that improved the gating activity of R352Q-, S549R-, S549N-, G551D-, and G1244E-CFTR to ∼70-120% of the WT. Similarly, the potentiator combinations were able to confer WT-like function to G551D-CFTR in patient-derived human nasal epithelia. CONCLUSION: This study suggests that half of CF patients with missense mutations approved for VX-770 administration, could benefit from the development of dual potentiator therapy.

Structure-guided combination therapy to potently improve the function of mutant CFTRs.

Available corrector drugs are unable to effectively rescue the folding defects of CFTR-ΔF508 (or CFTR-F508del), the most common disease-causing mutation of the cystic fibrosis transmembrane conductance regulator, a plasma membrane (PM) anion channel, and thus to substantially ameliorate clinical phenotypes of cystic fibrosis (CF). To overcome the corrector efficacy ceiling, here we show that compounds targeting distinct structural defects of CFTR can synergistically rescue mutant expression and function at the PM. High-throughput cell-based screens and mechanistic analysis identified three small-molecule series that target defects at nucleotide-binding domain (NBD1), NBD2 and their membrane-spanning domain (MSD) interfaces. Although individually these compounds marginally improve ΔF508-CFTR folding efficiency, function and stability, their combinations lead to ~50-100% of wild-type-level correction in immortalized and primary human airway epithelia and in mouse nasal epithelia. Likewise, corrector combinations were effective against rare missense mutations in various CFTR domains, probably acting via structural allostery, suggesting a mechanistic framework for their broad application.

Hormonal vitamin D up-regulates tissue-specific PD-L1 and PD-L2 surface glycoprotein expression in humans but not mice.

PD-L1 (programmed death ligand 1) and PD-L2 are cell-surface glycoproteins that interact with programmed death 1 (PD-1) on T cells to attenuate inflammation. PD-1 signaling has attracted intense interest for its role in a pathophysiological context: suppression of anti-tumor immunity. Similarly, vitamin D signaling has been increasingly investigated for its non-classical actions in stimulation of innate immunity and suppression of inflammatory responses. Here, we show that hormonal 1,25-dihydroxyvitamin D (1,25D) is a direct transcriptional inducer of the human genes encoding PD-L1 and PD-L2 through the vitamin D receptor, a ligand-regulated transcription factor. 1,25D stimulated transcription of the gene encoding PD-L1 in epithelial and myeloid cells, whereas the gene encoding the more tissue-restricted PD-L2 was regulated only in myeloid cells. We identified and characterized vitamin D response elements (VDREs) located in both genes and showed that 1,25D treatment induces cell-surface expression of PD-L1 in epithelial and myeloid cells. In co-culture experiments with primary human T cells, epithelial cells pretreated with 1,25D suppressed activation of CD4+ and CD8+ cells and inhibited inflammatory cytokine production in a manner that was abrogated by anti-PD-L1 blocking antibody. Consistent with previous observations of species-specific regulation of immunity by vitamin D, the VDREs are present in primate genes, but neither the VDREs nor the regulation by 1,25D is present in mice. These findings reinforce the physiological role of 1,25D in controlling inflammatory immune responses but may represent a double-edged sword, as they suggest that elevated vitamin D signaling in humans could suppress anti-tumor immunity.

Carbohydrate-last meal pattern lowers postprandial glucose and insulin excursions in type 2 diabetes.

BACKGROUND: There are limited data regarding the timing of carbohydrate ingestion during a meal and postprandial glucose regulation. METHODS: Sixteen subjects with type 2 diabetes mellitus (T2DM) consumed the same meal on 3 days in random order: carbohydrate first, followed 10 min later by protein and vegetables; protein and vegetables first, followed 10 min later by carbohydrate; or all components together. Blood was sampled for glucose, insulin, glucagon-like peptide-1 (GLP-1), and glucagon measurements at baseline (just before meal ingestion) and subsequently at 30 min intervals up to 180 min. RESULTS: The incremental areas under the curve for glucose (iAUC0-180) and incremental glucose peaks were 53% and 54% lower, respectively, when carbohydrate was consumed last compared with carbohydrate consumed first (3124.7±501.2 vs 6703.5±904.6 mg/dL×180min, p<0.001; 34.7±4.1 vs 75.0±6.5 mg/dL, p<0.001) and 44% and 40% lower, respectively, compared with the all components together condition (3124.7±501.2 vs 5587.1±828.7 mg/dL×180min, p=0.003; 34.7±4.1 vs 58.2±5.9 mg/dL, p<0.001). Postprandial insulin excursions were lower (iAUC0-180: 7354.1±897.3 vs 9769.7±1002.1 µU/mL×min, p=0.003) and GLP-1 excursions higher (iAUC0-180: 3487.56±327.7 vs 2519.11±494.8 pg/mL×min, p=0.019) following the carbohydrate-last meal order compared with carbohydrate first. CONCLUSION: The carbohydrate-last meal pattern may be an effective behavioral strategy to improve postprandial glycemia.

Mutation-specific downregulation of CFTR2 variants by gating potentiators.

Approximately 50% of cystic fibrosis (CF) patients are heterozygous with a rare mutation on at least one allele. Several mutants exhibit functional defects, correctable by gating potentiators. Long-term exposure (≥24 h) to the only available potentiator drug, VX-770, leads to the biochemical and functional downregulation of F508del-CFTR both in immortalized and primary human airway cells, and possibly other CF mutants, attenuating its beneficial effect. Based on these considerations, we wanted to determine the effect of chronic VX-770 exposure on the functional and biochemical expression of rare CF processing/gating mutants in human airway epithelia. Expression of CFTR2 mutants was monitored in the human bronchial epithelial cell line (CFBE41o-) and in patient-derived conditionally reprogrammed bronchial and nasal epithelia by short-circuit current measurements, cell surface ELISA and immunoblotting in the absence or presence of CFTR modulators. The VX-770 half-maximal effective (EC50) concentration for G551D-CFTR activation was ∼0.63 µM in human nasal epithelia, implying that comparable concentration is required in the lung to attain clinical benefit. Five of the twelve rare CFTR2 mutants were susceptible to ∼20-70% downregulation by chronic VX-770 exposure with an IC50 of ∼1-20 nM and to destabilization by other investigational potentiators, thereby diminishing the primary functional gain of CFTR modulators. Thus, chronic exposure to VX-770 and preclinical potentiators can destabilize CFTR2 mutants in human airway epithelial models in a mutation and compound specific manner. This highlights the importance of selecting potentiator drugs with minimal destabilizing effects on CF mutants, advocating a precision medicine approach.

Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell.

Molecular chaperones are pivotal in folding and degradation of the cellular proteome but their impact on the conformational dynamics of near-native membrane proteins with disease relevance remains unknown. Here we report the effect of chaperone activity on the functional conformation of the temperature-sensitive mutant cystic fibrosis channel (∆F508-CFTR) at the plasma membrane and after reconstitution into phospholipid bilayer. Thermally induced unfolding at 37 °C and concomitant functional inactivation of ∆F508-CFTR are partially suppressed by constitutive activity of Hsc70 and Hsp90 chaperone/co-chaperone at the plasma membrane and post-endoplasmic reticulum compartments in vivo, and at single-molecule level in vitro, indicated by kinetic and thermodynamic remodeling of the mutant gating energetics toward its wild-type counterpart. Thus, molecular chaperones can contribute to functional maintenance of ∆F508-CFTR by reshaping the conformational energetics of its final fold, a mechanism with implication in the regulation of metastable ABC transporters and other plasma membrane proteins activity in health and diseases.The F508 deletion (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common CF causing mutation. Here the authors show that cytosolic chaperones shift the F508del channel conformation to the native fold by kinetic and thermodynamic remodelling of the gating energetics towards that of wild-type CTFR.

The adaptation of health care marketing to the digital era.

The purpose of health care marketing is to learn and understand the needs and desires of prospective patients in order to be able to meet those necessities at the highest standards. A big advantage is the targeting capability of the electronic media that has led to its being used by managers of marketing in medical institutions as means of advertisement when they develop the marketing strategies. Regarding social media, it is safe to say that there are communication platforms that can promote certain behaviours thus influencing decision-making. Through social media, people stay in touch with other people and they can provide a mean for medical institutions to permanently communicate with the existing patients or with the potential ones. In addition, social media can be used in advertising and promoting strategies, by posting information about discounts, offers and advantages of accessing the products provided by a certain institution. A study was conducted on 126 patients of a dental clinic in Bucharest. 126 new patients were selected on a period of 22 months from January 2015 until October 2016. The patients never had any treatment in this clinic and were influenced by the Internet to seek for dental care services. The purpose of this study was to evaluate the digital methods of promoting medical services, bringing new patients to a clinic. The results of the study demonstrated the need for digital methods of promoting medical care services in order to expand a business. A strategic way of thinking in this case implied attracting new patients and offering them quality health care services, which ensured their satisfaction and the probability of their recommending the health facility further. This study revealed an important role of social networking sites in promoting. This high response was probably responsible due to targeted promoting services. Almost all the new patients who completed the form will remain patients of this clinic in future.

Correctors and Potentiators Rescue Function of the Truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) Translation Product.

W1282X is the fifth most common cystic fibrosis transmembrane regulator (CFTR) mutation that causes cystic fibrosis. Here, we investigated the utility of a small molecule corrector/potentiator strategy, as used for ΔF508-CFTR, to produce functional rescue of the truncated translation product of the W1282X mutation, CFTR1281, without the need for read-through. In transfected cell systems, certain potentiators and correctors, including VX-809 and VX-770, increased CFTR1281 activity. To identify novel correctors and potentiators with potentially greater efficacy on CFTR1281, functional screens were done of ∼30,000 synthetic small molecules and drugs/nutraceuticals in CFTR1281-transfected cells. Corrector scaffolds of 1-arylpyrazole-4-arylsulfonyl-piperazine and spiro-piperidine-quinazolinone classes were identified with up to ∼5-fold greater efficacy than VX-809, some of which were selective for CFTR1281, whereas others also corrected ΔF508-CFTR. Several novel potentiator scaffolds were identified with efficacy comparable with VX-770; remarkably, a phenylsulfonamide-pyrrolopyridine acted synergistically with VX-770 to increase CFTR1281 function ∼8-fold over that of VX-770 alone, normalizing CFTR1281 channel activity to that of wild type CFTR. Corrector and potentiator combinations were tested in primary cultures and conditionally reprogrammed cells generated from nasal brushings from one W1282X homozygous subject. Although robust chloride conductance was seen with correctors and potentiators in homozygous ΔF508 cells, increased chloride conductance was not found in W1282X cells despite the presence of adequate transcript levels. Notwithstanding the negative data in W1282X cells from one human subject, we speculate that corrector and potentiator combinations may have therapeutic efficacy in cystic fibrosis caused by the W1282X mutation, although additional studies are needed on human cells from W1282X subjects.

From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.

More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients.

Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ΔF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ΔF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ΔF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ΔF508-CFTR density and function. VX-770-induced destabilization of ΔF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of ΔF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF.

Prospective European survey on atrial fibrillation ablation: clinical characteristics of patients and ablation strategies used in different countries.

BACKGROUND: Atrial fibrillation (AF) ablation is widely adopted. Our aim was to conduct a prospective multicenter survey to verify patients' characteristics, approaches, and technologies adopted across Europe. METHODS AND RESULTS: A total of 35 centers in 12 countries actively participated in the study and 940 patients (median age 60 years) were enrolled. AF was paroxysmal, persistent, and long-lasting persistent in 52.4%, 36%, and 11.6% of patients, respectively; 95.5% of patients were symptomatic and 91.4% were refractory to antiarrhythmic therapy. Redo procedures were performed in 20.9%. Pulmonary vein isolation (PVI) emerged as the cornerstone of ablative therapy and has been performed in 98.7% of procedures, with confirmation of PVI in 92.9% of cases. The ablation of nonparoxysmal AF was not generally limited to isolating the PVs and several adjunctive approaches are adopted, particularly in the case of long-lasting persistent AF. Linear lesions or elimination of complex fractionated atrial electrograms were more frequently added. Circular mapping catheters and imaging techniques were seen to be used in about two-thirds of cases. Radiofrequency energy was delivered through open irrigated catheters in 68% of cases. CONCLUSIONS: European centers are largely following the recommendations of the guidelines and the expert consensus documents for AF ablation. AF ablation is mainly performed in relatively young patients with symptomatic drug refractory AF and no or minimal heart disease. Patients with paroxysmal AF are the most frequently treated with a quite uniform ablative approach across Europe. A less standardized approach was observed in nonparoxysmal AF patients.

New type of chitosan/2-hydroxypropyl-ß-cyclodextrin composite membrane for gallic acid encapsulation and controlled release.

A new type of chitosan/2-hydroxypropyl-ß-cyclodextrin composite membrane have been developed for the encapsulation and controlled release of gallic acid. The morphology of the composite membrane was investigated by infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM), whereas swelling gallic acid and release properties were investigated by UV-visible spectroscopy. The release behavior with pH changes was also explored. The composite membrane based on chitosan/2-hydroxypropyl-ß-cyclodextrin with gallic acid included showed improved antioxidant capacities compared to plain chitosan membrane. The information obtained in this study will facilitate the design and preparation of composite membrane based on chitosan and could open a wide range of applications, particularly its use as an antioxidant in food, food packaging, biomedical (biodegradable soft porous scaffolds for enhance the surrounding tissue regeneration), pharmaceutical and cosmetics industries.