EUS vs. ERCP-guided primary drainage of inoperable distal malignant biliary obstruction: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Several randomized controlled trials (RCTs) compared endoscopic ultrasound-guided biliary drainage (EUS-BD) to endoscopic retrograde cholangiopancreatography (ERCP) as first-line interventions in distal malignant biliary obstruction (DMBO). We assessed the efficacy and safety of these two approaches. METHODS: A PubMed/Medline, Embase and Cochrane databases bibliographic search until 01/12/2023 was performed to identify RCTs comparing EUS-BD to ERCP for primary biliary drainage in inoperable patients with DMBO. Primary outcome was technical success. Secondary outcomes were clinical success, adverse events (AEs), mean procedure time, 1-year stent patency, and overall survival. Relative risk (RR) with 95% confidence interval (CI) were calculated using random-effect model. RESULTS: Five studies (519 patients) were included. The RR for pooled technical success in EUS-BD was 1.06 ([0.96-1.17]; P=0.27) and 1.02 [0.97-1.08]; P=0.45) for clinical success. 1-year stent patency was similar among the two groups (RR 1.15; [0.94-1.42], P=0.17), with lower reintervention in the EUS-BD group (RR 0.58; [0.37-0.9]; P=0.01). The RR of AEs rate was 0.85 [0.49-1.46]; P=0.55) and severe AEs of 0.97 [0.10-0.17]; P=0.98). On subgroup analysis, EUS-lumen apposing metal stents (LAMS) outperformed ERCP in term of technical success (RR 1.17; [1.01-1.35]; P=0.03). Procedure time was lower in EUS-BD (standardized mean difference -2.36 minutes; [-2.68 to -2.05]; P<0.001). CONCLUSIONS: EUS-BD showed a statistically significant lower re-intervention rate compared to ERCP, but with similar technical success rate, stent patency, clinical success rate and safety profile, while in the subgroup of EUS-LAMS, the technical success was better than ERCP Keywords: distal; biliary obstruction; efficacy; safety.

The additive diagnostic value of cytology in fine needle biopsy of pancreatic adenocarcinoma: A tertiary center experience.

OBJECTIVE: Endoscopic ultrasound guide fine needle biopsy (EUS-FNB) is the main diagnostic tool for pancreatic adenocarcinoma. In most instances, only histology is obtained via FNB, without sending cytological slides. The aim of our study was to assess the additive diagnostic yield of cytology performed through FNB. METHODS: We conducted a retrospective study of all patients with histological diagnosis of pancreatic adenocarcinoma who were diagnosed by EUS-FNB. RESULTS: Overall, 80 patients were included in the study period. The overall concordance between cytology and histology all FNB needles was 78.2%. Notably, cytological assessment improved the diagnostic yield for malignancy by 12.8%. The overall kappa coefficient correlation between histology and cytology was .501, 95% CI 0.361-0.641. However, the kappa correlation for suspicious of malignancy and malignant was excellent of .872, 95% CI 0.733-1, suggesting that cytology is crucial when histology is inconclusive. Further analysis showed that the Acquire and Sharkcore needles outperformed the Procore needle in term of concordance between cytology and histology (kappa correlation of .527, 95% CI 0.331-0.724, .515, 95% CI 0.265-0.764, and .297, 95% CI -0.051-0.646), respectively. CONCLUSION: Performing cytology specimen when using FNB improves the diagnostic yield in pancreatic adenocarcinoma.

Obesity Is Associated with Distal Migration of Pancreatic Adenocarcinoma to Body and Tail: A Multi-Center Study.

(1) Background: Pancreatic adenocarcinoma (PAC) is one of the most lethal types of cancer. Most cases of PAC occur in the head of the pancreas. Given the proximity of the pancreatic head to the bile duct, most patients present clinically during early stages of the disease, while distally located PAC could have delayed clinical presentation. (2) Aims: To assess predictors of non-head PAC. (3) Methods: A retrospective multicenter study was conducted, including all patients who had endoscopic ultrasound (EUS) for pancreatic masses and who had histologic confirmation of PAC. (4) Results: Of the 151 patients included, 92 (60.9%) had pancreatic head cancer, and 59 (39.1%) had distal pancreatic cancer. PAC at body was the most common location in the distal PAC group (31 patients (52.5%)). Logistic regression analysis demonstrated a significant association of obesity with distal migration of PAC (OR 4.44, 95% CI 1.15-17.19, p = 0.03), while none of the other assessed parameters showed a significant association. Notably, abdominal pain was more significantly associated with distal PAC vs. head location (OR 2.85, 95% CI 1.32-6.16, p = 0.008). (5) Conclusions: Obesity shows a significant association as a clinical predictor of distal PAC. Further studies are needed to better explore this association.

Predictors of spontaneous passage of ingested foreign bodies in adults: twelve years of experience.

BACKGROUND: Foreign body ingestion in adults is commonly encountered in clinical practice. The therapeutic approach of whether to follow-up or extract is often controversial. AIM: We aimed to explore predictors for spontaneous passage of ingested foreign bodies by focusing on foreign body type, length, and location of impaction. METHODS: We performed a 12-year retrospective single-center study. Logistic regression analysis was done to identify predictors of spontaneous passage. RESULTS: Overall, 365 patients with foreign body ingestion were included. The rate of spontaneous passage was 53.7% in general, while the spontaneous passage rate was 47.9% in food impaction, 44.3% in sharp objects, 88.7% in blunt objects and only 22.2% in long blunt objects (> 6 cm). On regression analysis, esophageal location was associated with a higher impaction rate and lower spontaneous passage vs. stomach and small and large intestine (OR 0.15, 95% CI 0.07-0.31, OR 0.18, 95% CI 0.09-0.37 and OR 0.02, 95% CI 0.003-0.14), respectively. Performing Receiver operating characteristics (ROC) analysis found that the maximal length above which the foreign body will fail to pass spontaneously was 3.5 cm in the stomach and 3 cm in the small intestine, with area under the curve (AUC) of 0.8509 in stomach and 0.8073 in small intestine. CONCLUSION: Endoscopic removal was needed for all esophageal foreign bodies, and all foreign bodies more than 3.5 cm above the duodenum. Spontaneous passage of ingested foreign body in a selected cohort of patients depends on foreign body type, location, and length.

Clinical Predictors of Gastrointestinal Bleeding Source before Computed Tomography Angiography.

BACKGROUND: Acute gastrointestinal bleeding (GIB) is a commonly encountered medical emergency. In cases of negative endoscopic evaluations, computed tomography angiography (CTA) is usually the next diagnostic step. To date, data regarding positive CTA examinations are lacking. We aimed to assess the clinical and laboratory parameters that predict a positive CTA examination, as demonstrated by the extravasation of contrast material into the bowel lumen. METHODS: We performed a single-center retrospective study, including all patients who were admitted with GIB and who underwent CTA. Analysis was performed to compare patients' characteristics, and logistic regression was used to explore parameters associated with a positive CTA. RESULTS: We included 154 patients. Of them, 25 patients (16.2%) had active GIB on CTA vs. 129 patients (83.8%) who did not. On univariate analysis, several parameters were positively associated with active GIB, including congestive heart failure (OR 2.47, 95% CI 1.04-5.86, p = 0.04), warfarin use (OR 4.76, 95% CI 1.49-15.21, p = 0.008), higher INR (OR 1.33, 1.04-1.69, p = 0.02), and low albumin level (OR 0.37, 95% CI 0.17-0.79, p = 0.01). On multivariate logistic regression analysis, only high INR (OR 1.34, 95% CI 1.02-1.76, p = 0.03) and low albumin (OR 0.3, 95% CI 0.12-0.7, p = 0.005) kept their positive association with active bleeding, while a high ASA score was negatively associated with an active GIB. CONCLUSIONS: We could identify high INR and low albumin as strong predictors of active GIB, as demonstrated by positive CTA. On the other hand, comorbid patients classified by a high ASA score did not experience a higher rate of active GIB.

Liver Fat Storage Is a Better Predictor of Coronary Artery Disease than Visceral Fat.

Fatty liver is one aspect of metabolic syndrome. The roles and contributions of fatty liver and visceral fat storage to coronary artery disease (CAD) are not clear. This study measured associations among visceral fat storage, fatty liver, insulin resistance, atherosclerosis, and CAD. Patients were divided into three groups: excess visceral fat (visceral fat area >330 ± 99 cm2), non-alcoholic fatty liver disease (NAFLD), and a control group. The definition of fatty liver is liver minus spleen density greater than or equal to -10. We defined early atherosclerosis as intima-media thickness of the common carotid artery >7 mm in men and >0.65 mm in women, measured with Doppler ultrasound. Visceral fat area was defined using CT (>330 ± 99 cm2). Insulin-resistance biomarkers (HOMA), CRP, and oxidant-antioxidant status (MDA-Paraoxonase) were also measured. Patients with high liver or visceral fat showed higher coronary plaque prevalence (50% (p < 0.001), 38% (p < 0.01), respectively vs. 25% in the control group), higher prevalence of coronary stenosis (30% (p < 0.001), 22% (p < 0.01) vs. 11% in the control group), higher intimal thickening (0.98 ± 0.3 (p< 0.01), 0.86 ± 0.1 (p < 0.01) vs. 0.83 ± 0.1 in the control group), higher HOMA (4.0 ± 3.0 (p < 0.005), 3.0 ± 1.0 (p < 0.001) vs. 1.5 ± 1.2 in the control group), and higher triglyceride levels (196.8 ± 103 (p < 0.005), 182.6 ± 90.87 (p < 0.005) vs. 145 ± 60 in the control group). Multiple logistic regression analysis showed that fatty liver predicted CAD (OR 2.7, 95% CI 2.3-4.9, p < 0.001) independently of visceral fat storage (OR 2.01, 95% CI 1.2-2.8, p < 0.001). Liver fat storage is a strong independent risk factor for CAD and carotid atherosclerosis and contributes more than visceral fat storage.

Neurosarcoidosis: The Presentation, Diagnosis and Treatment Review of Two Cases.

Sarcoidosis is a chronic granulomatous disease of unknown cause characterized by the presence of non-caseating granulomas. The disease can affect any organ including the nervous system. Neurosarcoidosis occurs in about 5% patients with sarcoidosis. The clinical presentation of neurosarcoidosis is varied, and it can involve the brain, spinal cord and peripheral nervous system, separately or in different combinations. The diagnosis of neurosarcoidosis is challenging, as biopsies from the nervous system are not readily available. Anti-TNFα agents are becoming one of the cornerstone treatments for neurosarcoidosis. In this case-based review, we discuss two cases of neurosarcoidosis with different clinical presentations. The first patient presented with confusion, while the second presented with walking difficulty and neurogenic bladder. Both patients were treated with methylprednisolone pulse therapy with rapid, but non-complete, improvement. Therefore, infliximab was initiated in both cases with subsequent improvement in the clinical manifestations and imaging findings, emphasizing the effectiveness and safety of infliximab in cases of severe neurosarcoidosis. In conclusion, the goal of neurosarcoidosis management is to prevent organ system damage and minimize the toxic cumulative adverse effects of glucocorticoid use. In this case-based review we discuss the various presentations, the diagnosis and the treatment of neurosarcoidosis.

Nonalcoholic Fatty Liver Disease-A Concise Review of Noninvasive Tests and Biomarkers.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with a continuously growing prevalence. The pathophysiology of the disease is complex and includes several mechanisms, with metabolic syndrome and insulin resistance playing a major role. It is crucial to diagnose NAFLD before it advances to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis, presented by its complications which include ascites, portal hypertension, bleeding varices and encephalopathy. Another important complication of NAFLD and cirrhosis is hepatocellular carcinoma (HCC), a cancer with increasing incidence and poor prognosis. Even with the growing prevalence of NAFLD, diagnosis via liver biopsies is unrealistic, considering the costs and complications. Noninvasive tests, including serum biomarkers and elastography, are cost-effective and convenient, thereby replacing liver biopsies in diagnosing and excluding liver fibrosis. However, currently, these noninvasive tests have several limitations, such as variability, inadequate accuracy and risk factors for error. The limitations and variability of these tests comet the investigator to propose combining them in diagnostic algorithms to produce more accurate tools. Identifying patients with significant fibrosis is important for targeted therapies to prevent disease progression. Effective screening using noninvasive tests can be crucial for patient risk stratification and early diagnosis.

Regen-COV-2 Antibody Cocktail Mediated Clearance of SARS-COV-2 in an Immunocompromised Patient.

BACKGROUND: Coronavirus disease 2019 (COVID-19) affects different people in different ways. Most infected people develop mild to moderate illness and recover without hospitalization. This case report presents a patient who had difficulty eradicating the corona virus due to being treated with rituximab, which depletes B lymphocytes and therefore disables the production of neutralizing antibodies. The regen-COV-2 antibody cocktail consists of two monoclonal antibodies, casirivimab and imdevimab. This cocktail successfully helped the patient's immune system eradicate the virus without auto specific severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody production. In vitro studies confirm that eradication of the intact the virus. This case report emphases the importance of providing external antiviral antibodies regularly, like the regen-COV-2 antibody cocktail, as post- and even pre- SARS-CoV-2 infection prophylaxis in patients treated with rituximab.

Cytokine Patterns in COVID-19 Patients: Which Cytokines Predict Mortality and Which Protect Against?

(1) Background/Aim: People infected with SARS-CoV-2 may develop COVID-19 in a wide range of clinical severity. Pulmonary fibrosis is characterized by several grades of chronic inflammation and collagen deposition in the interalveolar space. SARS-CoV-2 infection has been demonstrated to cause lung fibrosis without a currently elucidated mechanism. Some studies emphasize the role of proinflammatory cytokines. This research studies the correlation of the released cytokines with mortality or lung injury in COVID-19 patients. (2) Methods: Electronic medical record data from 40 patients diagnosed with COVID-19 in the COVID-19 Department, Galilee Medical Center, Nahariya, Israel, were collected. Epidemiological, clinical, laboratory, and imaging variables were analyzed. The cytokine levels were measured upon admission and discharge. A correlation between cytokine levels and severity and mortality or lung involvement was undertaken. (3) Results: IFN-gamma and IL-10 are the most powerful risk factors for mortality in the COVID-19 patient groups in a multivariate analysis. However, in a univariate analysis, TGF-ß, CXCL-10, IFN gamma, and IL-7 affected mortality in COVID-19 patients. MMP-7 was significantly correlated with a cytokine storm and a high 4-C (severity) score in COVID-19 patients. MMP-7, TGF-ß, IL-10, IL-7, TNF-α, and IL-6 were correlated with high lung involvement in COVID-19 patients. Serum concentrations of IGF-1 were significantly increased upon discharge, but MMP-7 was decreased. (4) Conclusions: Proinflammatory cytokines predict clinical severity, lung fibrosis, and mortality in COVID-19 patients. High concentrations of TGF-ß, CXCL-10, IL-10, IL-6, and TNF-α are correlated to severity and lung injury. However, certain cytokines have protective effects and higher levels of these cytokines increase survival levels and lower lung damage. High levels of INF-γ, IL-7, MMP-7, and IGF-1 have protection probabilities against lung injury and severity.

Convalescent Plasma Reduces Mortality and Decreases Hospitalization Stay in Patients with Moderate COVID-19 Pneumonia.

Humans infected with SARS-CoV-2 may develop COVID-19, which manifests across a wide spectrum of clinical severity ranging from mild upper respiratory tract illnesses to diffuse viral pneumonia, causing acute respiratory failure. Many therapies have been tested for their efficacy in treating COVID-19. Controversy surrounds convalescent plasma transfusions as an effective treatment for COVID-19. This study discusses the efficacy of this treatment on COVID-19 patients. Electronic medical record data were collected from patients diagnosed with COVID-19, from November 2020 to August 2021, in the Galilee Medical Center's COVID-19 departments. Epidemiological, clinical, laboratory and imaging variables were analyzed. Multivariate stepwise regression and discriminant analyses were used to identify and validate the correlation between convalescent treatment and either death or time to negative PCR and hospitalization length. The study population included 270 patients, 100 of them treated with convalescent plasma. The results show that convalescent plasma therapy significantly prevented mortality in moderate patients, reduced hospitalization length and time to negative PCR. Additionally, high BMI, elderly age, high CRP and 4C-scores correlated with the severity and mortality of COVID-19 patients. Convalescent plasma also significantly reduced inflammatory markers, especially in moderate COVID-19 patients. In non-critical hospitalized patients, convalescent plasma therapy reduces morbidity and mortality in moderate COVID-19 patients and hospitalization length. Identifying patients who could benefit from this treatment could reduce the risk of death and shorten their hospitalization stay.

Clinical Predictors of Mortality and Critical Illness in Patients with COVID-19 Pneumonia.

Early identification of patients with COVID-19 who will develop severe or critical disease symptoms is important for delivering proper and early treatment. We analyzed demographic, clinical, immunological, hematological, biochemical and radiographic findings that may be of utility to clinicians in predicting COVID-19 severity and mortality. Electronic medical record data from patients diagnosed with COVID-19 from November 2020 to June 2021 in the COVID-19 Department in the Galilee Medical Center, Nahariya, Israel, were collected. Epidemiologic, clinical, laboratory and imaging variables were analyzed. Multivariate stepwise regression analyses and discriminant analyses were used to identify and validate powerful predictors. The main outcome measure was invasive ventilation, or death. The study population included 390 patients, with a mean age of 61 ± 18, and 51% were male. The non-survivors were mostly male, elderly and overweight and significantly suffered from hypertension, diabetes mellitus type 2, lung disease, hemodialysis and past use of aspirin. Four predictive factors were found that associated with increased disease severity and/or mortality: age, NLR, BUN, and use of high flow oxygen therapy (HFNC). The AUC or diagnostic accuracy was 87%, with a sensitivity of 97%, specificity of 60%, PPV of 87% and NPP of 91%. The cytokine levels of CXCL-10, GCSF, IL-2 and IL-6 were significantly reduced upon the discharge of severely ill COVID-19 patients. The predictive factors associated with increased mortality include age, NLR, BUN, and use of HFNC upon admission. Identifying those with higher risks of mortality could help in early interventions to reduce the risk of death.

Pulmonary Embolism in Autosomal Dominant Polycystic Kidney Patient Induced by Inferior Vena Cava Mechanical Compression.

INTRODUCTION: Autosomal dominant polycystic kidney disease is a common syndrome. Renal and hepatic cysts can cause discomfort, bleeding, rupture, infection, hypertension and a mass effect with compression of adjacent organs. CASE PRESENTATION: A 48-year-old man with polycystic kidney disease and hypertension presented to the emergency department for bilateral flank pain. An abdominal computed tomography scan with contrast showed a 7 cm heterogeneous process posteriorly and laterally to the right kidney. It appeared to be a renal cyst associated with bleeding and bilateral pulmonary artery filling defects, apparently due to pulmonary embolism. Cavography following inferior vena cava filter insertion did not show any deep vein thrombosis. DISCUSSION AND CONCLUSION: The pulmonary embolism was probably caused by extrinsic inferior vena cava compression by a liver cyst. Virchow's triad of stasis, vessel damage and hypercoagulability probably resulted in a thrombus which moved on the right side to the pulmonary artery. LEARNING POINTS: Autosomal dominant polycystic kidney disease is a common syndrome.Renal and hepatic cysts can compress adjacent organs.The mass effect of a large cyst on the right side compressed the inferior vena cava, resulting in Virchow's triad of stasis, vessel damage and hypercoagulability, which can cause pulmonary embolism.

Clearance of the SARS-CoV-2 Virus in an Immunocompromised Patient Mediated by Convalescent Plasma without B-Cell Recovery.

Coronavirus disease (COVID-19) is a contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This case report presents a patient who had difficulty eradicating the corona virus due to being treated with Rituximab, which depletes B lymphocyte cells and therefore disables the production of neutralizing antibodies. The combined use of external anti-viral agents like convalescent plasma, IVIG and Remdesivir successfully helped the patient's immune system to eradicate the virus without B-cell population recovery. In vitro studies showed that convalescent plasma is the main agent that helped in eradicating the virus.

Isolation and expansion of high yield of pure mesenchymal stromal cells from fresh and cryopreserved placental tissues.

The injection of placental stromal cells isolated from fetal human tissues (f-hPSC) was reported to indirectly induce tissue regeneration in different animal models. A procedure of f-hPSC isolation from fragments of both selected fresh or cryopreserved bulk placental neonate tissues is proposed, based on their high migratory potential,. The fragments of the desired fetal placental tissues are adhered to a culture dish by traces of diluted fibrin and covered with culture medium. Spontaneous migration of pure f-hPSC from the tissue fragments to the cell culture dishes is followed by their rapid expansion by numerous passages. The isolated f-hPSC express typical mesenchymal surface antigens, including CD29, CD105, CD166 and CD146, with negative expression of white blood cell lineage and endothelial cells markers. Optimal yields of f-hPSC cultures can also be obtained from tissue samples cryopreserved in medium composed of 10% dimethyl sulfoxide (M2SO) and 50% fetal calf serum. Slightly better yields are obtained with media supplemented with 1% human albumin. Medium with 5% M2SO and/or 0.25 mg/ml PEG yielded inferior results. The f-hPSC from fresh or cryopreserved tissues express similar cell markers and growth kinetics. The proposed isolation protocol may also be applied for high yield isolation of stromal cells from fresh and cryopreserved tissue of other organs.

The hemodynamic response to constant dobutamine infusion: the effect of ADRB1 389 polymorphism and sex.

OBJECTIVES: Prolonged activation of the ß-1 adrenergic receptor (ADRB1) is associated with receptor desensitization. This process has been suggested to have important pathophysiological and clinical implications in conditions such as congestive heart failure. The contribution of genetic factors to this process is a subject of ongoing research. We have previously shown that the ADRB1 389 polymorphism affects the response to incremental dose infusion of the ADRB agonist dobutamine. The aim of the current study was to determine whether the ADRB1 389 polymorphism affects the hemodynamic response to constant dose infusion of dobutamine in healthy patients. PATIENTS AND METHODS: Healthy patients were recruited according to their ADRB1 49 and 389 genotypes [15 Arg389Arg, 10 Gly389Arg, and 10 Gly389Gly patients (all Ser49Ser), 21 men and 14 women]. Following a standardized protocol of dose increase, 6 mcg/kg/min dobutamine was infused over 2 h. Heart rate (HR), blood pressure (BP), and active plasma renin (PR) were measured. Standardized exercise (1 min) was performed at three time points during infusion. RESULTS: In all patients, resting systolic BP was significantly decreased during infusion [144.4±11.5 vs. 140.3±12.2 mmHg (mean±SD), P=0.007]. There was no change in HR, and PR following 120 min of dobutamine infusion. ADRB1 389 genotypes were not associated with HR, systolic BP, and PR changes during dobutamine infusion (all P>0.05, repeated measures analysis of variance). Sex was associated with response to dobutamine. Among women, but not in men, resting HR significantly increased, and diastolic blood pressure (DBP) significantly decreased during dobutamine infusion [HR: 76.0±7.3 to 86.3±17.5 beats per minute (P=0.023), and DBP 78.5±8.49 mmHg to 72.36±6.16 (P=0.041) (repeated measures analysis of variance)]. CONCLUSION: In healthy patients, the ADRB1 389 genotype was not associated with hemodynamic changes during constant dobutamine infusion. In women, but not in men, HR significantly increased and DBP decreased during 2 h of infusion.

Effects of sex and the common ADRB1 389 genetic polymorphism on the hemodynamic response to dobutamine.

INTRODUCTION: The ADRB1 389 polymorphism affects responses to the ß-1 adrenergic receptor (ß1AR) agonist in vitro. Previous studies on its effect on the response to dobutamine stress echocardiography were conflicting. In addition, sex differences in the response to dobutamine have been suggested. The aim of this study was to determine whether the ADRB1 389 polymorphism affects the hemodynamic response to dobutamine in healthy individuals including men and women. PARTICIPANTS AND METHODS: Healthy individuals were recruited according to their ADRB1 49 and 389 genotypes [15 Arg389Arg, 10 Gly389Arg, and 10 Gly389Gly individuals, (all Ser49Ser), 21 men and 14 women]. Dobutamine was infused at 2, 4, and 6 mcg/kg/min. Standardized exercise was performed during the last minute of each infusion. RESULTS: Resting heart rate (HR) response to 6 mcg/kg/min dobutamine (ΔHR) was 4.7-fold larger in Arg389Arg than in Gly389Gly [(mean ± SD) 12.95 ± 6.99, 2.75 ± 1.65 bpm, respectively, PANOVA=0.012]. Renin response to dobutamine (ΔRenin) was 3.9-fold greater in Arg389Arg than in Gly389Gly (PANOVA=0.032). Among Arg389Gly heterozygotes, ΔHR and ΔRenin were not significantly different from either homozygote group. In multivariate analysis for ΔHR variance, significant contributions were observed for genotype (P=0.011), baseline HR (P=0.011), and borderline effect for sex (P=0.049). CONCLUSION: In healthy individuals, HR and renin responses to dobutamine were more than three-fold greater among ADRB1 Arg389 compared with Gly389 homozygotes. Future studies on the effect of the ADRB1 389 polymorphism on dobutamine stress echocardiography should compare Arg389 and Gly389 homozygotes.

Levels of sirolimus in saliva and blood following oral topical sustained-release varnish delivery system application.

PURPOSE: Sirolimus (rapamycin) is a mammalian target of rapamycin pathway blocker. The efficacy of sirolimus is currently studied for its antiproliferative properties in various malignancies and particularly in squamous cell carcinoma and other oral disorders. Topical application at the oral cavity can augment sirolimus availability at the site of action by increasing sirolimus levels in saliva and hence efficacy, along with improved safety (low levels in the blood to avoid side effects) and compliance. Our purpose was to evaluate the release profile and safety of a topical sirolimus sustained-release varnish drug delivery system. SUBJECTS AND METHODS: Sirolimus sustained-release varnish drug delivery system containing a total of 0.5 mg of the drug was applied to nine healthy male volunteers. Saliva and blood levels were determined utilizing mass spectrometry and chemiluminescent microparticle immunoassay, respectively. The prolonged release profile and safety were evaluated for the oral topical delivery system. RESULTS: After the application of the drug delivery system, a sustained-release profile was observed in the oral cavity. We have measured moderate sirolimus levels for up to 12 h. The safety was confirmed, and systemic sirolimus blood levels were negligible. CONCLUSIONS: After an application of sirolimus sustained-release varnish drug delivery system, prolonged drug levels can be achieved in the saliva. The oral topical sirolimus concentrations were potentially therapeutic along with minimal systemic exposure. These results broaden the potential clinical use of sustained-release oral topical rapalogs.

Blood pressure modulation following activation of mast cells by cationic cell penetrating peptides.

Short cell penetrating peptides (CPP) are widely used in vitro to transduce agents into cells. But their systemic effect has not been yet studied in detail. We studied the systemic effect of the cell penetrating peptides, penetratin, transportan and pro-rich, on rat hemodynamic functions. Intra-arterial monitoring of blood pressure showed that injection of the positively charged penetratin and transportan in a wide range of concentrations (2.5-320 µg/kg) caused highly significant transient decrease in the systolic and diastolic blood pressure in a dose dependent manner (p<0.01). Pretreatment with histamine receptors blockers or with cromolyn, a mast cell stabilizing agent, significantly attenuated this effect. Furthermore, in vitro incubation of these both peptides with mast cells line, LAD2, caused a massive mast cell degranulation. In vitro studies showed that these CPP in a wide range of concentrations were not cytotoxic without any effect on the survival of LAD2 mast cell line. In contrast, the less positively charged and proline-rich CPP, pro-rich, had no systemic effects with no effect on mast cell degranulation. Our results indicate that intravenously administrated positively charged CPP may have deleterious consequences due to their induced BP drop, mediated by mast cell activation. Therefore, the major effect of mast cell activation on BP should be considered in developing possible future drug therapies based on the injection of membrane-permeable and positively charged CPP. Nevertheless, lower levels of such CPP may be considered as a treatment of systemic high BP through moderate systemic mast cell activation.

Mast cell activation by fibrinogen-related homologous c-terminal peptides (haptides) modulates systemic blood pressure.

BACKGROUND: Haptides are a family of short peptides homologous to C-termini sequences of fibrinogen chains ß and γ (haptides Cß and preCγ, respectively) which were previously shown to penetrate and bind cells. OBJECTIVES: This work investigates the systemic effect of the haptides with possible clinical implications. METHODS: Intra-arterial monitoring in rats recorded the haptides' effects on systemic blood pressure. In parallel, their effect was also tested in vitro on isolated rat peritoneal mast cells and on human mast cells. RESULTS: Intra-arterial monitoring in rats showed that intravenous administration of low haptides concentrations (35-560 µg/kg rat) caused a shocklike behavior with transient decrease in the systolic and diastolic blood pressure by up to 55% (P < .05) in a dose-dependent manner and a minor increase in their heart rate. Randomly scrambled sequences of the haptides had no such effect, suggesting a specific interaction with receptors. Intravenous administration of blockers to histamine receptors H1 and H2 before haptides administration attenuated this effect. Furthermore, in vitro incubation of human LAD2 mast cell line or isolated rat peritoneal mast cells with the haptides caused degranulation of the mast cells. We found that the haptides Cß and preCγ activated mast cells causing histamine release, resulting in a steep decrease in blood pressure, comparable to anaphylactic shock. CONCLUSION: In treating vascular occlusive diseases, massive fibrinolysis is induced, and haptide-containing sequences are released. We suggest that treatment with histamine receptor blockers or with mast cell stabilizing agents in such pathological conditions may overcome this effect.