Influence of Achalasia on the Spirometry Flow-Volume Curve and Peak Expiratory Flow.

BACKGROUND: Achalasia is an esophageal motor disorder characterized by aperistalsis and the failure of the relaxation of the lower esophageal sphincter. We want to find out whether external compression or recurrent micro-aspiration of undigested food has a functional effect on the airway. METHODS: The aim of this research was to analyze the influence of achalasia on the peak expiratory flow and flow-volume curve. All of the 110 patients performed spirometry. RESULTS: The mean diameter of the esophagus was 5.4 ± 2.1 cm, and nine of the patients had mega-esophagus. Seven patients had a plateau in the inspiratory part of the flow-volume curve, which coincides with the patients who had mega-esophagus. The rest of the patients had a plateau in the expiration part of the curve. The existence of a plateau in the diameter of the esophagus of more than 5 cm was significant (p 0.003). Statistical significance between the existence of a plateau and a lowered PEF (PEF < 80) has been proven (p 0.001). Also, a statistical significance between the subtype and diameter of more than 4 cm has been proved. There was no significant improvement in the PEF values after operation. In total, 20.9% of patients had a spirometry abnormality finding. The frequency of the improvement in the spirometry values after surgery did not differ significantly by achalasia subtype. The improvement in FEV1 was statistically significant compared to the FVC values. CONCLUSIONS: Awareness of the influence of achalasia on the pulmonary parameters is important because low values of PEF with a plateau on the spirometry loop can lead to misdiagnosis. The recognition of various patterns of the spirometry loop may help in identifying airway obstruction caused by another non-pulmonary disease such as achalasia.

Pineal tumor surgery-the choice of the approach related to tumor characteristics and posterior fossa anatomy.

OBJECTIVE: This research aimed to determine whether an adequate surgical approach can be chosen based on clearly defined values of anatomical landmarks (tentorial angle), and tumor size and extension. METHODS: We conducted a retrospective analysis of patients operated on because of pineal tumors. The cohort was divided depending on the surgical approach. On preoperative magnetic resonance imaging, we measured maximal diameters, tumor volume, and tumor propagation. In the group of patients operated with the supracerebellar infratentorial approach, we also tested the correlation of tentorial angle with residual tumor. Differences among groups in resection, complications rate, and outcome were tested by the Chi-square test. Finally, in both groups, the correlation of residual tumor with tumor volume, propagation, and diameters was tested using the receiver operating characteristic curve. RESULTS: In group operated with supracerebellar approach total resection was achieved in 78% of the patients. The critical value of cranio-caudal diameter correlated with tumor residue was 31mm, for lateral-lateral diameter 25mm, for the lateral extension 14mm, and tumor volume 12cm3. Tentorial angle did not influence the extent of the resection. In group operated with occipital transtentorial approach the critical tumor volume related to tumor residue was 9mm3, anterior-posterior diameter 29mm, and cranio-caudal diameter 28mm. The extent of the resection was significantly higher in the supracerebellar group. CONCLUSIONS: In both approaches, tumors larger than 3cm show increased risk of subtotal resection. Except when most tumor volume is localized above the venous system, we advocate a supracerebellar corridor as an effective approach that is not limited by tentorial angle.

Nanodiamond-Enhanced Magnetic Resonance Imaging.

Nanodiamonds (ND) hold great potential for diverse applications due to their biocompatibility, non-toxicity, and versatile functionalization. Direct visualization of ND by means of non-invasive imaging techniques will open new venues for labeling and tracking, offering unprecedented and unambiguous detection of labeled cells or nanodiamond-based drug carrier systems. The structural defects in diamonds, such as vacancies, can have paramagnetic properties and potentially act as contrast agents in magnetic resonance imaging (MRI). The smallest nanoscale diamond particles, detonation ND, are reported to effectively reduce longitudinal relaxation time T1 and provide signal enhancement in MRI. Using in vivo, chicken embryos, direct visualization of ND is demonstrated as a bright signal with high contrast to noise ratio. At 24 h following intravascular application marked signal enhancement is noticed in the liver and the kidneys, suggesting uptake by the phagocytic cells of the reticuloendothelial system (RES), and in vivo labeling of these cells. This is confirmed by visualization of nanodiamond-labeled macrophages as positive (bright) signal, in vitro. Macrophage cell labeling is not associated with significant increase in pro-inflammatory cytokines or marked cytotoxicity. These results indicate nanodiamond as a novel gadolinium-free contrast-enhancing agent with potential for cell labeling and tracking and over periods of time.

Clinical Impact of Patient-Prosthesis Mismatch After Aortic Valve Replacement With a Mechanical or Biological Prosthesis.

BACKGROUND: Patient-prosthesis mismatch (PPM) may impair functional capacity and survival after aortic valve replacement. This study aimed to investigate the impact of PPM on long-term survival and quality of life after mechanical and biological aortic valve replacement. METHODS: This study included 595 consecutive patients who had undergone isolated aortic valve replacement. Patients were divided into 2 groups according to prosthesis type. The baseline and operative characteristics, survival rates, complications, and quality of life of the groups with and without PPM were compared for up to 6 years. The PPM calculation was performed using the effective orifice area value provided by the manufacturer divided by the patient's body surface area. RESULTS: The moderate to severe PPM rates were 69.8% and 3.7% after biological and mechanical prosthesis implantation, respectively. Mean survival for patients in the biological group who had PPM was statistically significantly shorter (50.2 months [95% CI, 45.2-55.3]) than for patients in the biological group without PPM (60.1 months [95% CI, 55.7-64.4]; P = .04). In the mechanical prosthesis group, there was no difference in mean survival between the subgroup with PPM (66.6 months [95% CI, 58.3-74.9]) and the subgroup without PPM (64.9 months [95% CI, 62.6-67.2]; P = .50). A quality-of-life questionnaire's scores did not differ between the groups. CONCLUSION: Mismatch is common after biological valve implantation and statistically significantly affects long-term survival and quality of life. If the risk of PPM after implantation of a biological prosthesis is suspected, adopting strategies to avoid PPM at the time of surgery is warranted.

King's Sarcoidosis Questionnaire (KSQ) - Validation study in Serbian speaking population of sarcoidosis patients.

INTRODUCTION: Sarcoidosis is a multiorgan, multisystem chronic disease of unknown etiology and unpredictable course. Health status is reduced in sarcoidosis and assessing it is a difficult multitask effort due to many faces this disease might have. Recently, a new questionnaire for assessing health status in sarcoidosis was developed by a group of authors from England-King's Sarcoidosis Questionnaire (KSQ). The benefit of KSQ is the ability to develop the best care plan for the patient, as well as to differentiate the efficacy of the administered treatment. OBJECTIVE: The aim of this study was to validate the KSQ in Serbian speaking population of sarcoidosis patients. The test itself is a modular, multi-organ health status measure for patients with sarcoidosis for use in clinic and the evaluation of therapies. The correlation of KSQ with different clinical course of sarcoidosis (acute vs chronic disease) and with the clinical outcome status (COS) in sarcoidosis was also investigated. METHODS: A total of 159 biopsy positive sarcoidosis patients participated in this study. The average age of the participants was 49.67, majority was female (67.3%) and majority had only pulmonary form of sarcoidosis (71.7%). KSQ - new disease-specific health status instrument, was compared with 5 other already existing instruments already used and validated in sarcoidosis (Saint George Respiratory Questionnaire- SGRQ, Daily Activity List -DAL, Fatigue Assessment Scale- FAS, Medical Research Council dyspnea scale-MRC, Borg Dyspnea Scale and 15D as general questionnaire. RESULTS: KSQ has significant correlation with other quality of life questionnaires already used in sarcoidosis. Translated version of KSQ shows significant internal reliability, similar to the original KSQ. Serbian version of KSQ has significant correlation with different clinical course of sarcoidosis and with COS as well. The translated version of KSQ is reliable sarcoidosis specific instrument for assessing health status in these patients.

Impact of Perioperatively Administered Amino Acids, Lidocaine, and Magnesium on Inflammatory Response and Pain Associated with Abdominal Surgery: A Prospective Clinical Study.

BACKGROUND Abdominal surgery is associated with a systemic inflammatory response which facilitates postoperative complications through immune imbalance and hypercatabolism. The aim of the study was to evaluate the effect of the combined perioperative lidocaine, magnesium, and amino acids on postoperative inflammation and pain. MATERIAL AND METHODS This prospective, randomized, double-blind study included 2 groups of patients undergoing abdominal surgery: Group 1 - receiving the aforementioned substances; and Group 2 - control (undergoing conventional general anesthesia). The following parameters were evaluated intraoperatively: arterial blood pressure, end-tidal CO2 level, urine output, bispectral index, base excess, oxygen saturation, operating room temperature and body temperature (BT), opioid use, and surgery duration; and postoperatively: total leukocyte (WBC), neutrophil, lymphocyte and platelet count; fibrinogen, C-reactive protein (CRP), procalcitonin (PCT) and interleukin (IL)-6 levels; numeric rating scale (NRS) pain level, first flatus and bowel movement, and postoperative complications. The postoperative parameters were evaluated 2 h and 6 h postoperatively, as well as on postoperative days (POD) 1, 2, 3, and 5. RESULTS Group 1 showed lower counts of WBC, neutrophils, and lymphocytes and lower fibrinogen, CRP, PCT, IL-6, and BT in the first 5 POD, as well as NRS scores and time to first flatus/bowel movement. The groups did not differ significantly regarding postoperative complications. CONCLUSIONS The isolated effects of lidocaine, magnesium, and amino acids in surgery have been described previously. To the best of our knowledge, this is the first study to show the anti-inflammatory and analgesic effects of simultaneous use of these substances in abdominal surgery.

The Clinical Impact of the Extension of Acute Type A Aortic Surgery on Long-Term Outcomes: Should We Tend to Be Conservative?

Background and Objectives: Despite advances in surgical techniques, industry adjuncts, and cerebral perfusion techniques, the in-hospital mortality rate of type A acute dissection (TAAD) remains at 15-30%. This study aimed to investigate the influence of different extents of aortic resection on survival and quality of life (QoL) after long-term follow-up. Materials and Methods: A retrospective observational trial was performed, including 165 patients operated upon for TAAD. Patients were divided into two groups according to the extent of their aortic repair: the first group comprised patients who had ascending aorta replacement and the second included patients who had hemiarch or total arch replacement. The groups were compared with regard to their baseline characteristics, operative characteristics, survival, complications, and QoL during nine years of follow-up. Results: The mean follow-up time was 75.6 months (1-108 months). The mean survival in the ascending aorta repair group was 89.651 (81.242-98.061) months and was 54.801 (40.053-69.548) months in the hemiarch and arch group; the difference between the groups was significant (log-rank p < 0.001). The rate of new postoperative neurological deficits was statistically higher in the hemiarch and arch group (17.5% vs. 8.4%, p = 0.045), the most common being stroke, and was also more frequent in the hemiarch and arch group than in the ascending aorta group (with statistical significance (15.7% vs. 6.5%)). The mean SF-12 physical score from the QoL questionnaire was higher in the ascending aorta replacement group than in the hemiarch and arch group (50.1 ± 7.3 vs. 44.0 ± 11.9, p = 0.017). Additionally, the mean SF-12 mental score was higher in the ascending aorta replacement group (52.3 ± 7.3 vs. 47.1 ± 12.8, p = 0.032). Conclusions: A more aggressive approach involving aortic arch repair means a lower survival rate and lesser quality of life after long-term follow-up in comparison with the replacement of the ascending aorta. If clinically applicable, a more defensive strategy may be considered.

Outcomes of Open Surgery for Retroperitoneal Hematoma in Covid-19 Patients: Experience from a Single Centre.

Background: Spontaneous retroperitoneal hematoma is a severe and potentially fatal complication that appears in the course of anticoagulation therapy. Therapeutic doses of low molecular weight heparin (LMWH) are used for the prevention of thrombosis in patients seriously ill with Covid-19. Methods: We describe 27 (0.14%) patients with retroperitoneal hematomas who required emergency surgery out of 19108 patients with Covid-19 who were hospitalized in Batajnica COVID Hospital between March 2021 and March 2022. All the patients were on therapeutic doses of LMWH. The existence of retroperitoneal hematoma was confirmed by abdominal ultrasound and computed tomography scans. Results: Open surgery was performed on 27 patients with spontaneous retroperitoneal hematomas (12 female and 15 male). The mean age of the study population was 71.6+-11.9 years. D-dimer was significantly elevated two days before the surgery in comparison with the values on the day of surgery (p=0.011). Six patients (22.23%) survived, while 21 (77.77%) patients died. Conclusion: Bleeding in Covid-19 patients treated by LMWH is associated with an increased risk of developing retroperitoneal hematoma. Open surgery for retroperitoneal hematoma in Covid-19 patients on anticoagulation therapy is a procedure associated with a high rate of mortality.

Reduction of transverse rectal diameter and its effect on bladder dynamics in children with spinal dysraphism.

INTRODUCTION: To examine the reduction of transverse rectal diameter and its effect on bladder dynamics in children with spinal dysraphism. METHODS: We prospectively evaluated 61 consecutive children with spinal dysraphism, 25 (41%) boys and 36 (59%) girls, aged 4 to 16 years; mean age 9.3 ± 3.8 years, who received bowel management. All children underwent echosonographic measurement of transverse rectal diameter before and after starting bowel management. Also, all the patients had undergone urodynamic studies before and after starting bowel management, with no changes in their urological treatment. RESULTS: Bowel management caused an decrease in transverse rectal diameter by 56 ± 7.2% (p < 0.001). In addition, a decrease was observed for maximal detrusor pressure by 27.8 ± 7.8% (p < 0.001), leak point pressure by 37.2 ± 4.4% (p < 0.001), and PVR by 36.7 ± 8.0 (p < 0.001). Maximum bladder capacity was significantly increased after bowel management in both non-adjusted (36.4 ± 14.8%; p < 0.001) and adjusted analysis for age (39.4 ± 14.3%, p < 0.001). Detrusor compliance was also increased by 89.2 ± 24.8% (p < 0.001). Female gender and % change of maximal detrusor pressure were significant predictors of transversal rectal diameter change in univariate as well as in multivariate analysis (OR = 10.548, 95% CI 2.309-48.180; p = 0.002 and OR = 1.121, 95% CI 1.009-1.245; p = 0.034). CONCLUSIONS: Decrease in transverse rectal diameter may be useful for bladder function and urodynamic findings in children with spinal dysraphism. Therefore, decrease in transverse rectal diameter should be a supplement to standard urotherapy.

Gastrointestinal Biopsy Obtained During Cancer Screening, a Biological Marker for α-Synucleinopathy?

The hallmark alteration in α-synucleinopathies, α-synuclein, is observed not only in the brain but also in the peripheral tissues, particularly in the intestine. This suggests that endoscopic biopsies performed for colon cancer screening could facilitate the assessment of α-synuclein in the gastrointestinal (GI) tract. Using immunohistochemistry for α-synuclein, we assessed whether GI biopsies could be used to confirm an ongoing α-synucleinopathy. Seventy-four subjects with cerebral α-synucleinopathy in various Braak stages with concomitant GI biopsies were available for study. In 81% of the subjects, α-synuclein was seen in the mucosal/submucosal GI biopsies. Two subjects with severe cerebral α-synucleinopathy and a long delay between biopsy and death displayed no α-synuclein pathology in the gut, and 11 subjects with sparse cerebral α-synucleinopathy displayed GI α-synuclein up to 36 years prior to death. The finding that there was no GI α-synuclein in 19% of the subjects with cerebral α-synucleinopathy, and α-synuclein was observed in the gut of 11 subjects (15%) with sparse cerebral α-synucleinopathy even many years prior to death is unexpected and jeopardizes the use of assessment of α-synuclein in the peripheral tissue for confirmation of an ongoing cerebral α-synucleinopathy.

Heat-Mitigated Design and Lorentz Force-Based Steering of an MRI-Driven Microcatheter toward Minimally Invasive Surgery.

Catheters integrated with microcoils for electromagnetic steering under the high, uniform magnetic field within magnetic resonance (MR) scanners (3-7 Tesla) have enabled an alternative approach for active catheter operations. Achieving larger ranges of tip motion for Lorentz force-based steering have previously been dependent on using high power coupled with active cooling, bulkier catheter designs, or introducing additional microcoil sets along the catheter. This work proposes an alternative approach using a heat-mitigated design and actuation strategy for a magnetic resonance imaging (MRI)-driven microcatheter. A quad-configuration microcoil (QCM) design is introduced, allowing miniaturization of existing MRI-driven, Lorentz force-based catheters down to 1-mm diameters with minimal power consumption (0.44 W). Heating concerns are experimentally validated using noninvasive MRI thermometry. The Cosserat model is implemented within an MR scanner and results demonstrate a desired tip range up to 110° with 4° error. The QCM is used to validate the proposed model and power-optimized steering algorithm using an MRI-compatible neurovascular phantom and ex vivo kidney tissue. The power-optimized tip orientation controller conserves as much as 25% power regardless of the catheter's initial orientation. These results demonstrate the implementation of an MRI-driven, electromagnetic catheter steering platform for minimally invasive surgical applications without the need for camera feedback or manual advancement via guidewires. The incorporation of such system in clinics using the proposed design and actuation strategy can further improve the safety and reliability of future MRI-driven active catheter operations.

Meta-Analysis of Circulating Cell-Free DNA's Role in the Prognosis of Pancreatic Cancer.

INTRODUCTION: The analysis of cell-free DNA (cfDNA) for genetic abnormalities is a promising new approach for the diagnosis and prognosis of pancreatic cancer patients. Insights into the molecular characteristics of pancreatic cancer may provide valuable information, leading to its earlier detection and the development of targeted therapies. MATERIAL AND METHODS: We conducted a systematic review and a meta-analysis of studies that reported cfDNA in pancreatic ductal adenocarcinoma (PDAC). The studies were considered eligible if they included patients with PDAC, if they had blood tests for cfDNA/ctDNA, and if they analyzed the prognostic value of cfDNA/ctDNA for patients' survival. The studies published before 22 October 2020 were identified through the PubMED, EMBASE, Web of Science and Cochrane Library databases. The assessed outcomes were the overall (OS) and progression-free survival (PFS), expressed as the log hazard ratio (HR) and standard error (SE). The summary of the HR effect size was estimated by pooling the individual trial results using the Review Manager, version 5.3, Cochrane Collaboration. The heterogeneity was assessed using the Cochran Q test and I2 statistic. RESULTS: In total, 48 studies were included in the qualitative review, while 44 were assessed in the quantitative synthesis, with the total number of patients included being 3524. Overall negative impacts of cfDNA and KRAS mutations on OS and PFS in PDAC (HR = 2.42, 95% CI: 1.95-2.99 and HR = 2.46, 95% CI: 2.01-3.00, respectively) were found. The subgroup analysis of the locally advanced and metastatic disease presented similar results (HR = 2.51, 95% CI: 1.90-3.31). In the studies assessing the pre-treatment presence of KRAS, there was a moderate to high degree of heterogeneity (I2 = 87% and I2 = 48%, for OS and PFS, respectively), which was remarkably decreased in the analysis of the studies measuring post-treatment KRAS (I2 = 24% and I2 = 0%, for OS and PFS, respectively). The patients who were KRAS positive before but KRAS negative after treatment had a better prognosis than the persistently KRAS-positive patients (HR = 5.30, 95% CI: 1.02-27.63). CONCLUSION: The assessment of KRAS mutation by liquid biopsy can be considered as an additional tool for the estimation of the disease course and outcome in PDAC patients.

Decreased ERß expression and high cyclin D1 expression may predict early CRC recurrence in high-risk Duke's B and Duke's C stage.

PURPOSE: Despite many known risk factors for the colorectal cancer (CRC) recurrence, significant differences in disease-free survival (DFS) impose the need to look for new explanations. This study aimed to determine the degree of expression of ERα, ERß, PR, Cyclin D1, and Bcl-2 and their association with early CRC relapse. METHODS: This retrospective study included 101 radically operated CRC patients in high-risk Duke's B and Duke's C stage. Tissue samples were retrieved from paraffin blocks and clinical and diagnostic data from medical records obtained during further clinical treatment and follow up. Patients were divided into DFS≤24 months group and DFS≥48 months group. Immunostaining of ERα, ERß, PR, Cyclin D1, and Bcl-2 was performed and analyzed. RESULTS: ERα was not expressed in all patients. ERß moderate expression was present in 25% of all patients, more often in the DFS≥48 group (p=0.001). PR and Bcl-2 showed only moderate expression in 1/5 and 1/3 of the patients, respectively, without significant difference between groups (p=0.145;p=0.566). Cyclin D1 was expressed in the whole sample of patients with strong expression statistically more often in DFS≤24 group (p=0.011) and had 5.2 higher odds of having DFS˂24 months. Moderate expression of ERß was joined with 79.2% smaller odds for shorter DFS. Advanced T stage had 11.3 times higher odds of having DFS˂24 months. CONCLUSION: Early recurrence of CRC in high-risk Duke's B and Duke's C stage relates with reduced ERß expression and the high cyclin D1 expression, so they could be considered independent prognostic factors, especially in patients in advanced T stage.

The routine use of platelet function tests in elective coronary artery bypass grafting: A prospective observational trial.

BACKGROUND: Preoperative use of platelet function tests contributes to the decrease of re-intervention rate due to bleeding and the necessity of transfusion in coronary artery bypass grafting (CABG) patients. The aim was to investigate the predictive value and to justify routine preoperative use of multiple electrode aggregometry in these patients. METHODS: A prospective observational trial which included 416 consecutive patients subjected to elective isolated CABG was conducted. The Multiplate® test was used to assess platelet function. Platelet function test results, postoperative blood loss, and transfusion requirements were compared between high and low bleeding risk patients. Receiver operating characteristic analysis was performed to assess the sensitivity and specificity of the arachidonic acid (ASPI) and adenosine di-phosphate high sensitive (ADPHS) tests. RESULTS: ADPHS and ASPI test results significantly predicted total bleeding > 1000 ml (AUC, 0.685, p < .001; 0.695, p = .039). Sensitivity and specificity were 62.9% and 40.0%, for ADPHS ≤602, and 70.8% and 41.8%, for ASPI ≤ 453. The sensitivity and specificity of cut-off values recommended by the manufacturer were 84.2% and 40.0% for ADPHS ≤ 500, while for ASPI < 600 the values were 54.7% and 62.2%. More platelets and cryoprecipitate were transfused in patients with ADPHS ≤ 602.5 (p < .001; p = .035). Patients with ADPHS ≤ 500 had a higher rate of red blood count, platelet and cryoprecipitate transfusion (p<.001p<.001; p = .013). The manufacturer's ASPI test cut-off values showed no statistically significant prediction for a higher transfusion rate. CONCLUSION: Preoperative platelet function tests should be conducted systematically for all elective CABG patients who were on dual antiplatelet therapy after adjusting test cut-off values for each population.

The Prospects of Secondary Moderate Mitral Regurgitation after Aortic Valve Replacement -Meta-Analysis.

Aortic valve replacement for aortic stenosis represents one of the most frequent surgical procedures on heart valves. These patients often have concomitant mitral regurgitation. To reveal whether the moderate mitral regurgitation will improve after aortic valve replacement alone, we performed a systematic review and meta-analysis. We identified 27 studies with 4452 patients that underwent aortic valve replacement for aortic stenosis and had co-existent mitral regurgitation. Primary end point was the impact of aortic valve replacement on the concomitant mitral regurgitation. Secondary end points were the analysis of the left ventricle reverse remodeling and long-term survival. Our results showed that there was significant improvement in mitral regurgitation postoperatively (RR, 1.65; 95% CI 1.36-2.00; p < 0.00001) with the average decrease of 0.46 (WMD; 95% CI 0.35-0.57; p < 0.00001). The effect is more pronounced in the elderly population. Perioperative mortality was higher (p < 0.0001) and long-term survival significantly worse (p < 0.00001) in patients that had moderate/severe mitral regurgitation preoperatively. We conclude that after aortic valve replacement alone there are fair chances but for only slight improvement in concomitant mitral regurgitation. The secondary moderate mitral regurgitation should be addressed at the time of aortic valve replacement. A more conservative approach should be followed for elderly and high-risk patients.

Identification of ALK in Thinness.

There is considerable inter-individual variability in susceptibility to weight gain despite an equally obesogenic environment in large parts of the world. Whereas many studies have focused on identifying the genetic susceptibility to obesity, we performed a GWAS on metabolically healthy thin individuals (lowest 6th percentile of the population-wide BMI spectrum) in a uniquely phenotyped Estonian cohort. We discovered anaplastic lymphoma kinase (ALK) as a candidate thinness gene. In Drosophila, RNAi mediated knockdown of Alk led to decreased triglyceride levels. In mice, genetic deletion of Alk resulted in thin animals with marked resistance to diet- and leptin-mutation-induced obesity. Mechanistically, we found that ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis. Our genetic and mechanistic experiments identify ALK as a thinness gene, which is involved in the resistance to weight gain.

Genes and metabolic pathway of sarcoidosis: identification of key players and risk modifiers.

INTRODUCTION: Sarcoidosis is a rare multisystem granulomatous disease with unknown etiology. The interplay of vitamin D deficiency and genetic polymorphisms in genes coding for the proteins relevant for metabolism of vitamin D is an important, but unexplored area. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in CYP2R1 (rs10741657), CYP27B1 (rs10877012), DBP (rs7041; rs4588), and VDR (rs2228570) genes and sarcoidosis, as well as the association between these SNPs and 25(OH)D levels in sarcoidosis patients. MATERIAL AND METHODS: For that purpose we genotyped 86 sarcoidosis patients and 50 healthy controls using the PCR-RFLP method. RESULTS: Subjects carrying the CC genotype of CYP27B1 rs10877012 have 10 times lower odds of suffering from sarcoidosis. Moreover, DBP rs4588 AA genotype was shown to be a susceptibility factor, where carriers of this genotype had eight times higher odds for developing sarcoidosis. In addition, the A allele of the DBP gene (rs4588) was associated with lower levels of 25(OH)D in sarcoidosis patients. CONCLUSIONS: These results suggest that patients with vitamin D deficiency should be regularly tested for genetic modifiers that are related to sarcoidosis in order to prevent development of serious forms of sarcoidosis.

Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy.

Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti-angiogenic treatment has limited efficacy due to therapy-induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy-induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid-derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti-angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor-induced metastases, and high Apelin levels correlate with poor prognosis of anti-angiogenic therapy patients. These data identify a druggable anti-angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases.

Long Term Outcomes of The Off-Pump and On-Pump Coronary Artery Bypass Grafting In A High-Volume Center.

Coronary artery bypass grafting (CABG) remains the most frequent surgery in the practice of an adult cardiac surgeon and the most frequently performed cardiac surgical procedure worldwide. Despite the ongoing debates regarding the superiority or inferiority of off-pump coronary artery bypass grafting, it still comprises 15-30% of all CABG cases varying in different national registries. We performed a propensity matched study of 302 consecutive CABG patients,143 off -pump cases performed by the four experienced off-pump surgeons and the on-pump CABG cases performed by those surgeons and four other experienced coronary surgeons. The five year follow up was performed and data collected comprised of mortality, rehospitalization due to cardiac origin, repeated revascularization, myocardial infarction and cerebrovascular accident. Overall, the off-pump group of patients had a higher risk profile than the patients in the on-pump group. After matching, fewer differences were found between the groups. Propensity score matching analysis showed no difference in long-term survival as well as MACCE and repeated revascularization. The higher risk profile of the patients subjected to OPCAB and the comparable survival to lower risk CPB patients in this series indicate that in experienced hands, OPCAB is a valuable option in this important subgroup of patients.

Relevance of TNF-α, IL-6 and IRAK1 gene expression for assessing disease severity and therapy effects in tuberculosis patients.

INTRODUCTION: Tuberculosis (TBC) is a contagious chronic respiratory disease which despite the known cause, Mycobacterium tuberculosis (Mtb), and many decades of successful therapy, remains one of the leading global health problems. Immune responses against Mtb infection involve both of types of immunity, but cellular immunity, in which certain cytokines and Th1 cells play a key role, is crucial. A better understanding of the functions of the cytokine network involved in the state and progression of TBC could identify specific molecular markers for monitoring of disease activity as well as therapy outcomes in TBC patients. METHODOLOGY: We investigated expression of TNF-α, IL-6 and IRAK1 genes using an RT-qPCR technique in peripheral blood mononuclear cells of 33 TBC patients and 10 healthy individuals. RESULTS: Comparison between TBC patients and healthy individuals revealed statistically significant differences for all analyzed genes. The levels of expression of TNF-α and IL-6 mRNA were higher, while the level of IRAK1 mRNA was lower in the TBC group compared to controls. Moreover, a strong positive correlation was observed between TNF-α and IL-6 gene expression. When clinical parameters were analyzed, increased levels of TNF-α mRNA were detected in patients with a longer duration of therapy (>2 months) compared to those with a shorter therapy duration (< 2 months), and in patients without anemia. CONCLUSIONS: Our results indicate that the inflammatory genes we examined play a crucial role in the pathogenesis of tuberculosis, and that the expression of the TNF-α gene could be a marker for monitoring the clinical effect of the ant-tuberculosis drugs during therapy.