Trajectory and magnitude of response in adults with anxiety disorders: a Bayesian hierarchical modeling meta-analysis of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and benzodiazepines.

BACKGROUND: How the trajectory of response to medication (and placebo response) varies among selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), benzodiazepines and across anxiety disorders is unknown. METHODS: We performed a meta-analysis using weekly symptom severity data from randomized, parallel-group, placebo-controlled trials of SSRIs, SNRIs, and benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in anxiety using Bayesian hierarchical models. RESULTS: Across 122 trials (N=15,760), SSRIs, SNRIs, and benzodiazepines produced significant improvement in anxiety compared to placebo. Benzodiazepines produced faster improvement by the first week of treatment (p < 0.001). By week 8, the response for benzodiazepines and SSRIs (p = 0.103) and SNRIs (p = 0.911) did not differ nor did SSRIs and SNRIs differ (p = 0.057), although for patients with generalized anxiety disorder (GAD), the benzodiazepines produced greater improvement than SNRIs at week 8 (difference - 12.42, CrI: -25.05 to -0.78, p = 0.037). Medication response was similar across anxiety disorders except for benzodiazepines, which produced greater improvement over the first 4 weeks compared to SSRIs and SNRIs in panic disorder. For SSRIs and SNRIs, women improved more than men, and for benzodiazepines, older patients improved more compared to younger patients. Finally, placebo response plateaued by week 4 of treatment, and, at week 8, social anxiety disorder trials had lower placebo response compared to other anxiety disorders. CONCLUSIONS: Benzodiazepines show early improvement compared to SSRIs and SNRIs. However, by week 8, all treatments yield similar results. Patient characteristics influence the improvement trajectory and magnitude, suggesting potential for personalized medication selection.

Early diastolic heart sounds caused by the atrial kick.

An 81-year-old male with a history of coronary artery disease, hypertension, paroxysmal atrial fibrillation and chronic kidney disease presents with asymptomatic bradycardia. Examination was notable for an early diastolic heart sound. 12-lead electrocardiogram revealed sinus bradycardia with a markedly prolonged PR interval and second-degree atrioventricular block, type I Mobitz. We review the differential diagnosis of early diastolic heart sounds and present a case of Wenckebach associated with a variable early diastolic sound on physical exam.

Persistent hepatic encephalopathy secondary to portosystemic shunt occluded with Amplatzer device.

Hepatic encephalopathy is a frequent complication of cirrhosis, when this event becomes persistent, treatment compliance should be verified and any precipitating factor need to be identified. Also the presence of portosystemic shunts, which are a rare cause of decompensation or persistence hepatic encephalopathy need to be ruled out. In this paper we report the case of a 57 year old man with persistent hepatic encephalopathy secondary to the presence of a porto-onfalo-femoral shunt successfully closed with the placement of an Amplatzer device.

The Impact of Development on Antidepressant and Placebo Response in Anxiety Disorders: A Bayesian Hierarchical Meta-Analytic Examination of Randomized Controlled Trials in Children, Adolescents, and Adults.

Background: Understanding how development influences medication and placebo responses in anxiety disorders could inform treatment decisions, including age-specific first- versus second-line psychopharmacological interventions. Objective: To meta-analytically compare the trajectory of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and placebo response in youth and adults with anxiety disorders. Methods: Weekly symptom severity data were extracted from prospective, randomized, parallel-group, placebo-controlled trials of SSRIs and SNRIs in children, adolescents, and adults with anxiety disorders (generalized, separation, and social anxiety disorders as well as panic disorder). Treatment response was modeled for the standardized change in continuous measures of anxiety using a Bayesian hierarchical model. Change in symptom severity was evaluated as a function of time, and post hoc analyses were conducted to determine the sensitivity of these results across sample heterogeneity and alternative functional forms. Results: Data were included from 11 trials of youth (SSRI, κ = 7; SNRI, κ = 4) and 71 studies of adults (SSRI, κ = 46; SNRI, κ = 25). In total, 1067 youth participated in SSRI trials and 1024 in SNRI trials. In total, 10,826 adults participated in SSRI trials (placebo, n = 5367; SSRI n = 5,459) and 6232 in SNRI trials (placebo, n = 3,128; SNRI n = 3,094). A logarithmic model best described the response. Placebo response was similar in youth and adults (mean difference = -1.98 ± 6.21, 95% credible interval [CrI]: -10.2 to 14.2, p = 0.750), and statistically significant improvement from baseline emerged by week 2 in both adults (mean difference: -18.34 + 1.017, 95% CrI: -20.3 to 16.3, p < 0.001) and youth (mean difference: -23.74 + 3.736, 95% CrI: -31.1 to -16.4, p < 0.001). SSRIs produced similar improvements for youth and adults (p = 0.129), but SNRIs produced slower improvement in youth than adults (p = 0.018). Conclusions: Antidepressant-related improvement occurs early in youth and adults with anxiety disorders. SSRI response is similar in adults and youth; however, SNRIs produce greater responses in adults than youth, potentially representing a developmental effect.

Granulomatous hepatitis caused by Q fever: a differential diagnosis of fever of unknown origin.

The differential diagnosis of fever of unknown origin (FUO) includes infectious, neoplastic, rheumaticinflammatory and miscellaneous diseases. We report the case of a 35-year-old man with FUO caused by Q fever. A liver biopsy showed the characteristic fibrin-ring lipogranulomas compatible with Q fever. The serologic tests confirmed the diagnosis of acute infection by Coxiella burnetii. The therapeutic response was excellent. In conclusion, we described a patient with acute Q fever and granulomatous hepatitis.

What Is the Added Benefit of Combining Cognitive Behavioral Therapy and Selective Serotonin Reuptake Inhibitors in Youth with Obsessive Compulsive Disorder? A Bayesian Hierarchical Modeling Meta-Analysis.

Background: Treatment of obsessive-compulsive disorder (OCD) in children and adolescents frequently involves cognitive behavioral therapy (CBT), selective serotonin reuptake inhibitors (SSRIs), or their combination. However, how adding CBT to SSRIs affects the trajectory and magnitude of improvement has not been evaluated meta-analytically. Methods: We performed a meta-analysis using weekly data from prospective randomized parallel group trials of CBT and SSRIs in pediatric patients with OCD. Response was modeled for the change in the Child Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) using a Bayesian hierarchical model over 12 weeks. Results: Fourteen studies included pharmacotherapy arms, 4 studies included combined pharmacotherapy and psychotherapy, and 10 studies included a placebo or control arm. The studies included 1146 patients (mean age 12.7 ± 1.3 years, mean 42.1% female). In the logarithmic model of response, statistically significant differences in treatment effects for CBT+SSRI and SSRI monotherapy were observed compared with placebo (SSRI ß = -3.59, credible interval [95% CrI]: -4.13 to -3.02, p < 0.001; SSRI+CBT ß = -4.07, 95% CrI: -5.05 to -3.04, p < 0.001). Adding CBT to an SSRI produced numerically (but not statistically significantly) greater improvement over 12 weeks. Greater improvement was observed in studies with more boys (p < 0.001), younger patients (p < 0.001), and in studies with greater baseline symptom severity (p < 0.001). Conclusions: In children and adolescents with OCD, compared with placebo, both SSRIs and SSRI+CBT produced early and sustained improvement over 12 weeks, although the improvement was also related to sample characteristics. Longer term studies are needed to determine when the additive benefit of CBT emerges relative to SSRI monotherapy.

[Primary sclerosing cholangitis presenting as recurrent cholangitis and right hepatic duct outpouching]. / Quiste de la vía biliar y colangitis de repetición como manifestaciones iniciales de colangitis esclerosante primaria.

Primary sclerosing cholangitis (PSC) may have an atypical mode of presentation with recurrent cholangitis and diverticulum-like outpouchings of the hepatic ducts; a high clinical suspicion is required to confirm the diagnosis instead of ascribing cirrhosis to a secondary cause as a result of the biliary stasis propitiated by the biliary cysts. We describe the case of a 63-year old woman with a one-year history of episodes of cholangitis and a persistent elevation of alkaline phosphatase. The endoscopic retrograde cholangiopancreatography and a magnetic resonance cholangiography showed strictures of the intrahepatic biliary tract compatible with PSC and a diverticulum-like outpouching of the right hepatic duct. A liver biopsy revealed cirrhosis. Initial management consisted of antibiotics, a sphincterotomy and the placement of a biliary plastic stent, however, the patient continued to have recurrent cholangitis and finally, the cyst was resected.

Identification of pathognomonic purine synthesis biomarkers by metabolomic profiling of adolescents with obesity and type 2 diabetes.

The incidence of type 2 diabetes is increasing more rapidly in adolescents than in any other age group. We identified and compared metabolite signatures in obese children with type 2 diabetes (T2D), obese children without diabetes (OB), and healthy, age- and gender-matched normal weight controls (NW) by measuring 273 analytes in fasting plasma and 24-hour urine samples from 90 subjects by targeted LC-MS/MS. Diabetic subjects were within 2 years of diagnosis in an attempt to capture early-stage disease prior to declining renal function. We found 22 urine metabolites that were uniquely associated with T2D when compared to OB and NW groups. The metabolites most significantly elevated in T2D youth included members of the betaine pathway, nucleic acid metabolism, and branched-chain amino acids (BCAAs) and their catabolites. Notably, the metabolite pattern in OB and T2D groups differed between urine and plasma, suggesting that urinary BCAAs and their intermediates behaved as a more specific biomarker for T2D, while plasma BCAAs associated with the obese, insulin resistant state independent of diabetes status. Correlative analysis of metabolites in the T2D signature indicated that betaine metabolites, BCAAs, and aromatic amino acids were associated with hyperglycemia, but BCAA acylglycine derivatives and nucleic acid metabolites were linked to insulin resistance. Of major interest, we found that urine levels of succinylaminoimidazole carboxamide riboside (SAICA-riboside) were increased in diabetic youth, identifying urine SAICA-riboside as a potential biomarker for T2D.

Beta blockers in portal hypertension. Are they really a good option?

Non-selective beta blockers are very useful drugs in preventing first variceal bleeding and re-bleeding in patients with cirrhosis. These drugs work in two ways: 1) by blocking beta1 receptors and reducing cardiac output, and 2) by blocking beta2 receptors, producing splanchnic vasoconstriction and reducing portal flow. Consequently, they reduce portal pressure. In primary prophylaxis, beta blockers reduced the bleeding risk from 30 to 15%; in secondary prophylaxis, this risk decreased from 60 to 42% in the first year. Heart rate decrease does not necessary correlate with reduction in hepatic venous pressure gradient (HVPG). When this gradient is reduced to less than 12 mmHg, the patient will not bleed; when this is reduced > 20% from basal values bleeding risk is extremely low, estimated at 9% at 2 years. The only way to know whether the patient has become a responder is to measure the HVPG. Additionally, by means of this method we also can identify the non-responders, who have a higher rate of re-bleeding, between 54 and 64%, and can attempt to utilize a more aggressive therapy, such as adding isosorbide mononitrate to the beta blocker or combining the beta blocker with endoscopic ligation. These options are discussed in the present review.

Pregnancy and portal hypertension a pathology view of physiologic changes.

The coexistent of pregnancy and liver disease represent a complex clinical situation, besides the liver complications that present in pregnancy with a previous health liver, like intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy or HELLP syndrome with bleeding disorders and viral hepatitis, the previous liver damage with portal hypertension associated represent a clear stated of hemodynamic changes which increased risk of variceal bleeding. The portal hypertension syndrome has a splanchnic blood flow increase. During pregnancy an hypervolemic stated developed as consequence there is an increased in portal flow that contributed to more portal pressure transmitted to the collaterals veins which increase variceal bleeding risk in this group of patients. The present review will focus on treatment options to prevent variceal bleeding in this clinical situation.

Early experience of Budd-Chiari syndrome treatment with transjugular intrahepatic portosystemic shunt.

The Budd-Chiari syndrome is a heterogeneous group of disorders characterized by obstruction of hepatic venous outflow at any level from the small hepatic veins to the junction of the inferior vena cava with the right atrium. We present two cases of Budd- Chiari syndrome with severe ascites associated with polycythemia vera in first case and protein C deficiency in the second, in both cases transjugular intrahepatic portosystemic shunt were placed, with excellent control of symptoms, no mortality were observed, and just one episode of pulmonary venous thrombosis was observed. To our knowledge this is the first time that transjugular intrahepatic portosystemic shunt are used and reported in Budd-Chiari syndrome in Mexico.

A 57 year old man with chronic renal failure and cardiac tamponade who developed ischemic hepatitis.

Ischemic hepatitis is an infrequent entity, usually associated with low cardiac out put. We present a case of a 57 year-old man with chronic renal failure and cardiac tamponade who developed elevation of serum alanine transferase level of 5,054 U/L, aspartate transferase level of 8,747 U/L and lactate dehydrogenasa level of 15,220 U/L. The patient developed hepatic encephalopathy and hypoglycemia. Liver Doppler ultrasound was normal. He was seronegative for HBV and HCV, drugs list was scrutinized for the names of known hepatotoxins. Ischemic hepatitis was diagnosed. The hypoglycemia and encephalopathy were solved and the patient was discharged with normal transaminase levels. Ischemic hepatitis is typically preceded by hypotension, hypoxemia, or both. As one would expect, the most common cause of sustained systemic hypotension is cardiovascular disease. Liver biopsy is usually not necessary. The best treatment is support measures and correct the underlying condition.

[Renal hemodynamics and its correlation with the Child-Pugh stage in cirrhotic patients and their controls]. / Hemodinámica renal y su correlación con el estadio de Child-Pugh en pacientes cirróticos y controles sanos.

INTRODUCTION: Portal hypertension is associated with splanchnic vasodilatation and baroreceptors activation with secondary renal vasoconstriction. OBJECTIVE: To measure the pulsatility and resistance index in the renal arteries: Segmentaries and arcuates of both kidneys in cirrhotic patients Child-Pugh A, B, C classes and compared them with healthy controls. PATIENTS AND METHODS: Thirty patients with cirrhosis were included: Ten patients Child A, 10 were Child B and 10 Child C class and 10 healthy patients, we measured the resistance index (RI = [systolic peak velocity-minimum diastolic velocity]/systolic peak velocity) and the pulsatility index (PI = [systolic peak velocity-minimum diastolic velocity]/medium velocity) with Doppler spectral analysis. RESULTS: The RI in controls had an average of 0.55 +/- 0.11. In child A: 0.79 +/- 0.114, in Child B 0.77 +/- 0.104 and in Child C 0.85 +/- 0.037. For the pulsatility index the values were: 0.98 +/- 0.21, 1.4 +/- 0.105, 1.72 +/- 0.206, and 2.04 +/- 0.346, respectively. The resistances and pulsatility index were higher in patients with cirrhosis at the time to be compared with healthy controls, which represent a diminishment in blood flow. At the time to compare each one of the Child stages with controls, both index resulted higher in cirrhotic patients, but when we compared the cirrhotic patients between them, only difference for RI in child B vs. C was evident. The differences in PI were evident between each one of the Child classes. DISCUSSION: The present study proved that a non invasive method like Doppler ultrasound is useful in the evaluation of the renal hemodynamic changes in cirrhotic patients with a good correlation between Child class and IP.

Biliary stricture caused by portal biliopathy: case report and literature review.

Portal biliopathy is a rare condition that is usually not diagnosed and only in few cases causes symptoms. Those symptoms are caused by vascular obstruction of the biliary tree in patients with portal hypertension. We report a case of a 29 years man who presented with history of intermittent jaundice, persistent elevation of hepatic function test and hematemesis as a manifestation of portal hypertension without liver damage. We present the clinical, radiological and pathological characteristics and literature review of the cases that had been reported, their diagnoses, treatment and clinical implication.

[Therapeutic options for portal hypertensive biliopathy: case series and literature review]. / Opciones terapéuticas de la biliopatía por hipertensión portal: serie de casos y revisión de la bibliografía.

BACKGROUND: Portal hypertensive biliopathy is an underdiagnosed condition because only some patients have symptoms. The major clinical manifestations include cholestasis and cholangitis. The aim of this study is to present a series of cases evaluated, treated and followed at a tertiary-care public institution. CLINICAL CASE: Four patients with portal hypertensive biliopathy were exposed to different therapeutic approaches focused on the management of portal hypertension and biliary decompression. They were followed for ~5 years. Three cases achieved a favorable outcome with symptom remission, but one patient died while attempting dilatation of the bile duct. Finally, we carried out a literature review about actual portal hypertensive biliopathy therapeutics. CONCLUSIONS: There is currently no consensus on the optimal treatment for this condition. The goal is to decompress the biliary tree. Each case should be individually evaluated to choose the best treatment option.

Antecedentes: la biliopatía por hipertensión portal es poco diagnosticada debido a que sólo algunos pacientes experimentan síntomas. Las manifestaciones clínicas más importantes son la colestasis y la colangitis. Objetivo: comunicar una serie de casos evaluados, tratados y seguidos en una institución pública de tercer nivel. Casos clínicos: cuatro pacientes con biliopatía por hipertensión portal se expusieron a diferentes métodos para tratar la hipertensión portal y la descompresión de la vía biliar. Se realizó seguimiento durante casi cinco años. Tres casos mostraron adecuada evolución, con remisión de los síntomas; un paciente falleció al intentar dilatarle la vía biliar. Finalmente, se revisa la bibliografía en relación con la terapéutica de la biliopatía por hipertensión portal. Conclusiones: no existe consenso para el tratamiento óptimo de este padecimiento, aunque el objetivo es descomprimir la vía biliar; cada caso plantea particularidades que guían el tratamiento.

Technical aspects of spinal cord injections for cell transplantation. Clinical and translational considerations.

Spinal cord injections may be used to transplant cellular suspensions for the experimental treatment of spinal cord injury. These injections cause some additional injury due to needle penetration, spinal cord motion during injection, creation of intraparenchymal pressure gradients and hydrodynamic dissection, instillation of a deforming cell mass and possible cord ischemia. It is important to understand these variables to maximize the safety of injections and avoid injury to spared structures. Surprisingly little knowledge exists regarding these variables. Further complicating spinal cord injections is the fact that intraparenchymal events are not evident during injections. As cell injections for spinal cord injury enter extensive clinical testing it is important to both optimize the procedures, and reduce the probability of technical failures. In this review current knowledge and key areas for knowledge advance are identified. These include a need for a more thorough understanding of how the spinal cord is affected by needle entry and dwell, needle-cord relative motion, instillation of highly concentrated cellular volumes, compliance of intact and damaged spinal cord tissue, radial tensile stresses and hydrodynamic forces created by injection, and the rates of pressure gradient dissipation in damaged and intact tissue. We propose that if the variables associated with injury can be identified, injection injury may be reduced and we illustrate the use of ultrasound to monitor injection in a spinal cord model. We also suggest that injectate backout or extrusion be reinterpreted as a clear indicator of excessive intraparenchymal pressure. The strengths and weaknesses of alternatives to direct intraparenchymal injection are also discussed.

Liver failure after an uncovered TIPS procedure associated with hepatic infarction.

Transjugular intrahepatic portosystemic shunt (TIPS) is a safe and effective procedure for the treatment of complications of liver cirrhosis, such as refractory ascites, hepatic hydrothorax and refractory variceal bleeding. The aim of this paper is to describe a rare case of liver failure after a TIPS procedure. A 38-year-old diabetic male with Child-Pugh C liver cirrhosis due to chronic hepatitis C infection who had developed refractory ascites was scheduled for a TIPS procedure. Within 24 h following TIPS placement, the patient developed distributive shock, jaundice, persistentgrade 3 hepatic encephalopathy, severe coagulopathy and acute renal failure. He was treated with lactulose enemas, broad-spectrum antibiotics and blood-derived products. Laboratory data revealed a 100-fold increase in aminotransferases and a non-enhanced computed tomography showed an irregular hypodense area in the right posterior segment of the liver. Despite being initially being in a stable condition, the patient developed progressive liver failure and died 2 mo later. Hepatic infarction is an uncommon phenomenon after a TIPS procedure; however, it can greatly complicate the course of a disease in a patient with an already compromised liver function.