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Apparent resistant hypertension (aTRH) is a significant public health issue. Once low adherence to antihypertensive treatment has been ruled out and true resistant hypertension is diagnosed, aldosterone-direct-renin-ratio (ADRR) aids in the screening of an aldosterone-producing adenoma (APA) and primary aldosteronism (PA). Once PA and other secondary causes have been ruled out, the values of aldosterone and renin allow patients to be classified into phenotypes such as low renin hypertension (LRH), Liddle's-like (LLph), and primary hyperaldosteronism (PAph). These classifications could aid in the treatment decision-making process. However, optimal cut-off points for these classifications remain uncertain. This study aims to assess the prevalence of these phenotypes and the behavior of different cut-offs of the ADRR in an Afro-Colombian population with apparent resistant hypertension, as well to describe their sodium consumption. Afro-descendant individuals 18 years of age or older, diagnosed with resistant hypertension and attending to a primary care center in Colombia were recruited as volunteers. As part of the study, their plasma renin concentration (PRC) and plasma aldosterone concentration (PAC) were measured. The phenotypes were categorized into three groups based on multiple cut-off points from different authors: low renin and low aldosterone phenotype (LLph), low renin and high aldosterone phenotype (PAph), and high renin and high aldosterone phenotype, referred to as the renal phenotype (Rph). The prevalence of ADRR values exceeding the cut-off and phenotypes were calculated. A linear regression model was derived to assess the effect of sodium consumption with PAC, PRC and ADRR. A total of 88 patients with aTRH were included. Adherence to at least 3 antihypertensive medications was 62.5%. The median age was 56 years (IQR 48-60), 44% were female, and 20% had diabetes. The study found that the prevalence of ADRR values exceeding the cut-off ranged from 4.5 to 23%, while low-renin hypertension (LRH) varied from 15 to 74%, Rph was found in approximately 30 to 34% of patients, PAph in 30 to 51%, and the LLph in 15 to 41%, respectively, depending on the specific cut-off value by different authors. Notably, sodium consumption was associated with lower aldosterone (β - 0.15, 95% CI [- 0.27, - 0.03]) and renin concentrations (β - 0.75, 95% CI [- 1.5, - 0.02]), but ADRR showed no significant association with sodium consumption. There were no significant differences in prevalences between the groups taking < 3 vs ≥ 3 antihypertensive medications. Altered aldosterone-direct-renin-ratio, low renin hypertension, Liddle's-like, and primary hyperaldosteronism are prevalent phenotypes in patients within Afro-Colombian patients with apparent treatment-Resistant hypertension., (© 2024. The Author(s).)

Due to a lack of controlled, prospective trials examining the pathophysiology and treatment of catatonia, current guidelines vary regarding how and when to best use antipsychotics in the presence of catatonia and what factors to consider in a thorough risk-benefit analysis. The literature is especially limited in describing the risks and benefits of using long-acting injectable antipsychotics in the presence of catatonia. We describe four cases where patients with preexisting catatonia received long-acting injectable first generation antipsychotics and experienced severe adverse effects (three experienced worsening of catatonia and one experienced neuroleptic malignant syndrome). The evidence base for managing comorbid catatonia and psychosis remains underdeveloped and inconsistent, but there are numerous known risk factors for adverse antipsychotic reactions, which we describe in relation to these cases. Finally, we present best practices to consider when managing comorbid psychosis and catatonia, especially when considering the use of long-acting injectable antipsychotics., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Introduction: The association of APOL1 risk variants with cardiovascular risk and cardiovascular disease (CVD) in observational and clinical trials has had inconsistent results. We aim to assess the relationship between the presence of APOL1 risk variants and the CVD risk in Afro-descendant patients with end-stage renal disease (ESRD)., Methods: We performed an observational, cross-sectional study of Afro-descendant adult patients with ESRD who were on the waitlist for a kidney transplant. Associations of APOL1 genotypes (high-risk [HR] = 2 alleles; low-risk [LR] = 0 or 1 allele) with cardiovascular risk were the primary clinical endpoint. The relation was evaluated using univariate and multivariate analysis., Results: We enrolled a total of 102 patients with ESRD; 37% (38 patients) had APOL1 HR status with two alleles in homozygous (G1/G1 = 21 and G2/G2 = 3) or compound heterozygote (G1/G2 = 14) form and 63% (64 patients) had APOL1 LR status. No significant association was found between HR APOL1 genotypes and high cardiovascular risk (in adjusted Colombia Framingham Risk Score). APOL1 HR versus LR variants were not independently associated with left ventricular hypertrophy or systolic dysfunction. No cardiovascular deaths occurred during the follow-up., Conclusion: In Afro-descendent patients with ESRD, APOL1 HR status is not associated with the increase in cardiovascular risk profile and metabolic disturbances., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: The COVID-19 pandemic has reduced access to endomyocardial biopsy (EMB) rejection surveillance in heart transplant (HT) recipients. This study is the first in Canada to assess the role for noninvasive rejection surveillance in personalizing titration of immunosuppression and patient satisfaction post-HT., Methods: In this mixed-methods prospective cohort study, adult HT recipients more than 6 months from HT had their routine EMBs replaced by noninvasive rejection surveillance with gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) testing. Demographics, outcomes of noninvasive surveillance score, hospital admissions, patient satisfaction, and health status on the medical outcomes study 12-item short-form health survey (SF-12) were collected and analyzed, using t tests and χ 2 tests. Thematic qualitative analysis was performed for open-ended responses., Results: Among 90 patients, 31 (33%) were enrolled. A total of 36 combined GEP/dd-cfDNA tests were performed; 22 (61%) had negative results for both, 10 (27%) had positive GEP/negative dd-cfDNA results, 4 (11%) had negative GEP/positive dd-cfDNA results, and 0 were positive on both. All patients with a positive dd-cfDNA result (range: 0.19%-0.81%) underwent EMB with no significant cellular or antibody-mediated rejection. A total of 15 cases (42%) had immunosuppression reduction, and this increased to 55% in patients with negative concordant testing. Overall, patients' reported satisfaction was 90%, and on thematic analysis they were more satisfied, with less anxiety, during the noninvasive testing experience., Conclusions: Noninvasive rejection surveillance was associated with the ability to lower immunosuppression, increase satisfaction, and reduce anxiety in HT recipients, minimizing exposure for patients and providers during a global pandemic., (© 2022 The Authors.)

Competing Interests: All the other authors confirm that there are no relationships with industry or financial associations that might pose a conflict of interest.

Introduction: Urinary tract injuries (UTI) are a frequent complication of morbidly adherent placenta (MAP) management. In this study, we aim to characterize the type of UTI that occurs and to define if their incidence varies after establishing a fixed interdisciplinary group for the protocolized management of patients with MAP., Methodology: All patients with confirmed MAP attended between 2011 and 2019 in our institution, were included. We analyzed the effect of a change in the surgical protocol including rigid ureteral catheters, vesicouterine dissection before hysterotomy and interdisciplinary planning, in the bladder or ureteral injuries incidence., Results: The study included 65 women. UTI was identified in 27.7% of patients and was associated with a greater volume of blood loss, transfusion requirement, hospital stay, and the need for additional surgeries. There was a high frequency of UTI in patients without protocolized management. The use of rigid ureteral catheters and retrovesical dissection before hysterotomy were associated with a less ureteral injury., Conclusions: Developing expertise among the members of the surgical team is essential to improve results. Using rigid ureteral catheters, performing retrovesical dissection before hysterotomy, and performing less extensive surgeries in selected patients are associated with a low frequency of ureteral injuries.

Case Presentation . Distal renal tubular acidosis (dRTA) is characterized by impaired hydrogen ion secretion in the distal nephron resulting either from decreased net activity of the proton pump or from increased luminal membrane hydrogen ion permeability. Typical complications of dRTA include severe hypokalemia, normal anion gap metabolic acidosis, nephrolithiasis, and nephrocalcinosis. The patient is a 25-year-old woman in immediate puerperium with hypokalemia leading to paralysis, and the laboratory findings in this patients were concerning for dRTA. It is rare to encounter this entity during pregnancy, and the impact of this pathology is unknown., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Carlos E. Duran et al.)

Background: As patients with advanced heart failure are living longer, defining the impact of left ventricular assist devices (LVADs) on outcomes in an aging population is of great importance. We describe overall survival, rates of adverse events (AEs), and post-AE survival in patients age ≥ 70 years vs age 50-69 years after destination-therapy (DT) LVAD implantation., Methods: A retrospective analysis was conducted with the use of the International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support (IMACS) registry. All adults age ≥ 50 years with a continuous-flow DT LVAD from 2013 to 2017 were included. The primary outcome was all-cause mortality. The secondary outcomes were the incidence of and survival after gastrointestinal (GI) bleeding, infection, stroke, pump thrombosis, pump exchange, and right-side heart failure. Mortality and AEs were assessed with the use of competing risk models., Results: At total of 5,572 patients were included: 3,700 aged 50-69 and 1,872 aged ≥ 70. All-cause mortality by 42 months was 55.8% in patients aged ≥ 70 and 44.8% in patients aged 50-69 (P = 0.001). Patients aged ≥ 70 had a 37.8% higher risk of death after DT LVAD implantation (hazard ratio 1.378, 95% CI 1.251-1.517). Patients aged ≥ 70 had higher risk of GI bleeding but lower risk of right-side heart failure. There was no difference between age groups for risk of infection or stroke. Experiencing any AE was associated with an increased risk of death that did not vary with age., Conclusions: Patients aged ≥ 70 years have reduced survival after DT LVAD, in part because of increased GI bleeding, while the incidence of other AEs is similar to that of patients aged 50-69 years. Careful patient selection beyond age alone may allow for optimal outcomes after DT LVAD implantation., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Introduction: New-onset diabetes after transplantation (NODAT) is associated with immunosuppression. Its complications can negatively influence patients' quality of life, which is why it is important to study the associated risk factors and expand the possible therapies in this particular group of patients. Materials and methods . Case-control study nested in a retrospective cohort. It included patients who received kidney transplantation at the high complexity University Hospital Fundación Valle del Lili in Cali, Colombia, between 1995 and 2014. Two controls were assigned for each case, depending on the type of donor and the date of the surgery. Information was collected from clinical records and the institutional TRENAL registry. We carried out a descriptive analysis of the selected variables and identified the risk factors with conditional logistic regression., Results: 122 cases were identified to which 224 controls were assigned. The median age was 44 years (IQR: 34-55), and 54% were men. Having >50 years of age at the time of transplantation (OR: 3.18, 95% CI: 1.6-6.3, p = 0.001), body mass index >30 kg/m 2 (OR: 3.6, 95% CI: 1.3-9.7, p = 0.010) and being afro-descendant (OR: 2.74, 95% CI: 1.1-6.5, p = 0.023) were identified as risk factors for the development of NODAT. Pretransplant fasting plasma glucose >100 mg/dl (OR: 2.9, 95% CI: 1.4-6.4, p = 0.005) and serum triglycerides >200 mg/dl (OR: 2.5, 95% CI: 1.4-4.4, p = 0.002) were also reported as independent risk factors., Conclusion: We ratify some risk factors for the development of this important disease, which include certain modifiable characteristics. Interventions aimed at changes in lifestyle could be established in a timely manner before transplant surgery., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 Guillermo E. Guzmán et al.)

Risk prediction scores have been developed to predict survival following heart transplantation (HT). Our objective was to systematically review the model characteristics and performance for all available scores that predict survival after HT. Ovid Medline and Epub Ahead of Print and In-Process & Other Non-Indexed Citations, Ovid Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Clinical Trials were searched to December 2018. Eligible articles reported a score to predict mortality following HT. Of the 5392 studies screened, 21 studies were included that derived and/or validated 16 scores. Seven (44%) scores were validated in external cohorts and 8 (50%) assessed model performance. Overall model discrimination ranged from poor to moderate (C-statistic/area under the receiver operating characteristics 0.54-0.77). The IMPACT score was the most widely validated, was well calibrated in two large registries, and was best at discriminating 3-month survival (C-statistic 0.76). Most scores did not perform particularly well in any cohort in which they were assessed. This review shows that there are insufficient data to recommend the use of one model over the others for prediction of post-HT outcomes., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Previous evidence suggests that cardiologists and family doctors have limited accuracy in predicting patient prognosis. Predictive models with satisfactory accuracy for estimating mortality in patients with heart failure (HF) exist; physicians, however, seldom use these models. We evaluated the relative accuracy of physician vs model prediction to estimate 1-year survival in ambulatory patients with HF., Methods: We conducted a single-centre cross-sectional study involving 150 consecutive ambulatory patients with HF >18 years of age with a left ventricular ejection fraction ≤40%. Each patient's cardiologist and family doctor provided their predicted 1-year survival, and predicted survival scores were calculated using 3 models: HF Meta-Score, Seattle Heart Failure Model (SHFM), and Meta-Analysis Global Group in Chronic HF (MAGGIC) score. We compared accuracy between physician and model predictions using intraclass correlation (ICC)., Results: Median predicted survival by HF cardiologists was lower (median 80%, interquartile range [IQR]: 61%-90%) than that predicted by family physicians (median 90%, IQR 70%-99%, P = 0.08). One-year median survival calculated by the HF Meta-Score (94.6%), SHFM (95.4%), and MAGGIC (88.9%,) proved as high or higher than physician estimates. Agreement among HF cardiologists (ICC 0.28-0.41) and family physicians (ICC 0.43-0.47) when compared with 1-year model-predicted survival scores proved limited, whereas the 3 models agreed well (ICC > 0.65)., Conclusions: HF cardiologists underestimated survival in comparison with family physicians, whereas both physician estimates were lower than calculated model estimates. Our results provide additional evidence of potential inaccuracy of physician survival predictions in ambulatory patients with HF. These results should be validated in longitudinal studies collecting actual survival., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Introduction: In Colombia, the genetic background of the populations was shaped by different levels of admixture between Natives, European, and Africans. Approximately 35.363 patients have diagnosed chronic kidney disease and according to population studies, 10.4% of these patients are Afro-descendant. We aim to assess the frequency of APOL1 variants G1 and G2 in Afro-descendant patients with ESRD treated at la Fundacion Valle del Lili University Hospital in Cali, Colombia., Methods: This is an observational cross-sectional study. Afro-descendant patients with ESRD in waitlist or recipients of kidney transplant were evaluated. Clinical data were collected from the electronic medical records. Genotyping was carried out by amplification of the exon 7 of the APOL1 gene. For the identification of risk genotypes, the bioinformatics tool BLAST was used., Results: We enrolled 102 participants. The frequency of APOL1 risk variants was 67.2%, in which 24.5% ( n  = 25) were G1 heterozygous and 5.8% ( n  = 6) were G2 heterozygous and 37% of the patients had high-risk status with two alleles in homozygous (G1/G1 = 21 and G2/G2 = 3) or compound heterozygote (G1/G2 = 14) form., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2019 Carlos E. Duran et al.)

Background: While it is well known that heart failure patients presenting to the emergency room (ER) have high short-term mortality after discharge, the outcomes of patients with heart failure with repeated ER visits within a short time are not known. In this study, we aimed to determine whether clustering is associated with an increased risk of death., Methods and Results: This is a retrospective, population-based cohort study with an accrual window between 2003 and 2014 and maximal follow-up up to and including March 31, 2015. Data were obtained from administrative databases from Ontario, Canada. Clustering was defined a priori as 3 or more ER visits within a 6-month period. The main outcome of interest was time to death conditional on 6-month survival. A total of 72 810 patients with an index hospitalization for acute heart failure were evaluated. ER clustering was observed in 15.1% of the population. Increased burden of comorbidities, primary rural residence, and lack of primary care provider were identified as factors associated with ER clustering. Age- and sex-adjusted mortality for clustered patients was higher than for nonclustered (hazard ratio [HR] 1.51; 95% confidence interval, 1.47-1.55, P <0.0001). Adjusted mortality risk was also higher for patients with clustered ER visits (HR 1.42; 95% confidence interval 1.38-1.46; P <0.0001)., Conclusions: Clustering, as defined by 3 or more ER visits for any reason within 6 months of index heart failure hospitalization reflects a novel risk factor associated with increased mortality. Future research into the strategies to better manage complex patients with heart failure with recurrent ER visits are warranted., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

A 60-year-old woman with a history of dilated cardiomyopathy underwent heart transplantation. One month post discharge, she presented to clinic with low-grade fever and productive cough. Her chest radiograph showed air-fluid levels in the pericardial silhouette. Transthoracic echocardiogram showed a large complex pericardial collection with no evidence of cardiac tamponade. The patient was urgently taken to the operating room for exploration. A large "egg-shaped" mass in the pericardium measuring 10 × 12 cm with gaseous material was aspirated. As the posterior wall of the mass was firmly adhered to the right atrium, the capsule was incompletely excised. We present the case of a potentially life-threatening complication post transplantation that required surgical debridement and life-long antibiotic suppressive therapy. To our knowledge, this is the first report of purulent pericardial collection caused by Enterobacter cancerogenous. Further research is required to better understand the biology of this microorganism and the role it may play as a pathogen in immunocompromised patients following solid organ transplantation., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Clinicians have strong opinions about whether they should be provided the clinical history before or after bedside testing. We hypothesized that diagnostic accuracy is improved when a concordant clinical history is provided before a diagnostic test. To investigate whether the timing (before or after) and the consistency (concordant vs discordant) of the clinical history in the setting of focused bedside echocardiography affects clinician diagnostic accuracy and management decisions. Thirty-two cardiology residents were asked to perform a bedside echocardiogram on a Vimedix 3D mannequin. Half of the histories were provided before echocardiography and half after echocardiography. Half were consistent with the echocardiographic diagnosis (concordant), and half were suggestive of a plausible alternative diagnosis (discordant). Participants were asked for a diagnosis and management plan. The primary outcome was the diagnostic accuracy of the echocardiographic images. The secondary outcome was the management plan. Overall diagnostic accuracy was 63%. If the clinical history was provided before the bedside testing, it significantly improved diagnostic accuracy if it was concordant and it diminished accuracy if it was discordant (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.16-0.80; P = 0.001). Clinical history, whether concordant or discordant, had no significant impact if provided after the images were obtained. Appropriate management was chosen 77% of the time and was chosen less often with discordant compared with concordant histories (OR, 0.25; 95% CI, 0.11-0.57; P = 0.001). Our study suggests a significant downside to clinical information received before echocardiography when the information is discordant, raising the possibility that receiving clinical information after echocardiography may be superior for diagnostic accuracy., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Frailty assessment has become an integral part of the evaluation of potential candidates for heart transplantation and ventricular assist device (HTx/VAD). The impact of frailty, as a heart failure risk factor or to identify those who will derive the greatest benefit with HTx/VAD remains unclear. The aim of this study was to evaluate the independent prognostic relevance of frailty assessment from peak oxygen consumption (peak VO 2 ) or B-type natriuretic peptide (BNP) on mortality in patients referred for advanced heart failure therapies. Frailty was measured using modified Fried frailty criteria. In 201 consecutive patients, during a median follow-up of 17.5 months (IQR 11-29.2), there were 25 (12.4%) deaths. One-year survival was 100%, 94%, and 78% in nonfrail, prefrail, and frail patients, respectively (log rank P = .0001). Frailty was associated with a twofold increase risk of death (HR 2.01, P < .0001, 95% CI 1.42-2.84). When adjusted for BNP or peak VO 2 , frailty was not associated with a significant risk of all-cause death. However, when peak VO 2 is stratified into two categories (≥12 mL/kg/min vs <12 mL/kg/min), frailty was associated with increased mortality in patients with a lower peak VO 2 (HR 1.72, P = .006)., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background Lupus nephritis (LN) is one of the most frequent complications of SLE and occurs in up to 50% of cases depending on the studied population. Of these, approximately 20% progress to end-stage renal disease (ESRD), with the treatment of choice being a kidney transplant. Objective The objective of this study was to describe the clinical outcome of patients transplanted due to LN, compared with patients transplanted for other causes, in a Latin American population from the Fundación Valle del Lili in Cali, Colombia. Methods Observational, retrospective case study with controls matched by age, sex and type of donor in a single center between 1996 and 2014. Results Sixty-five kidney transplants were performed in patients with LN and ESRD. The survival of patients with LN was 98% at 1, 10 and 15 years ( p = .99). For controls by age and sex, survival was also 98% at 15 years post-transplant, and for controls by donor, the survival rate was 100% at 5 years and 98% at 15 years. Graft survival in patients with LN to 1, 5 and 15 years was 92%, 83% and 71%, respectively; for controls by age and sex, it was 90%, 84% and 64%, respectively, and for the controls by donor, it was 89%, 86% and 79%, respectively ( p = .7718). There were no statistically significant differences found in the cumulative incidence of acute graft rejection in the first year, but it was found that acute rejection is a factor that relates to the loss of function of the renal graft ( p = .032). Of the patients transplanted for LN, two (3.1%) experienced a recurrence of the disease. One patient died after a diagnosis of recurrence of LN due to an infection. Conclusions Kidney transplantation is a good option for patients with ESRD due to LN. In this Hispanic population, the survival of patients, graft survival, and cumulative incidence of graft rejection are not different from those of other transplanted patients. In addition, recurrence of LN was rare, showing the benefits of renal transplantation in LN patients with ESRD.

BACKGROUND En-bloc transplantation is a surgical procedure in which multiple organs are transplanted simultaneously. It has some similarities with multi-organ transplantation but offers certain advantages. This report highlights the experience of our interdisciplinary group regarding the treatment and follow-up of patients who received en-bloc transplantation, with the aim of encouraging the development of this surgical technique. CASE REPORT The first case is a 38-year-old patient with type 1 diabetes mellitus, liver cirrhosis, and chronic kidney failure who received an en-bloc transplant of the liver, pancreas, and kidney with no intraoperative complications. He had a prolonged hospital stay due to anemia and systemic inflammatory response syndrome, which were resolved successfully. At follow-up, he had no requirement for insulin or for dialysis, or for new interventions. The second case describes a 48-year-old patient with type 2 diabetes mellitus, renal failure, and liver cirrhosis who received an en-bloc transplant of the liver, pancreas, and kidney with no complications. During the postoperative period, the patient suffered a possible episode of acute tubular necrosis, which evolved towards improvement, with a tendency to normal metabolic and renal functioning, with no additional events. The patient is currently in follow-up and is insulin-independent. CONCLUSIONS En-bloc transplantation is a safe procedure, which is technically simple and which achieves excellent results. This procedure is indicated in patients with end-stage renal disease, cirrhosis, and diabetes mellitus that is difficult to control., Competing Interests: Conflicts of Interest: None declared Statement All authors certify that they have no conflict of interest.

Infection with polyomavirus (BK virus) is the cause of renal graft losses in more than 50% of the infected cases. There should be a high index of suspicion about this disease, although the incidence is only between 2% and 5% as the future of renal graft depends on the early and appropriate management of the same. Herein, we describe three clinical cases: Two were those of kidney transplant and the third, a combined kidney-pancreas transplant. In these cases, by reducing immunosuppression and, in one case, replacing the calcineurin inhibitor by MTOR (mammalian target of rapamycin) in addition, we were able to preserve of the normal function of the transplanted organs.

Terminal differentiation of B cells and hypergammaglobulinemia are hallmarks of B-cell hyperactivity in HIV disease. Plasmablasts are terminally differentiating B cells that circulate transiently in the blood following infection or vaccination; however, in HIV infection, they arise early and are maintained at abnormally high levels in viremic individuals. Here we show that only a small fraction of plasmablasts in the blood of viremic individuals is HIV specific. Assessment of plasmablast immunoglobulin isotype distribution revealed increased IgG(+) plasmablasts in early and most prominently during chronic HIV viremia, contrasting with a predominantly IgA(+) plasmablast profile in HIV-negative individuals or in aviremic HIV-infected individuals on treatment. Of note, IgG is the predominant immunoglobulin isotype of plasmablasts that arise transiently in the blood following parenteral immunization. Serum immunoglobulin levels were also elevated in HIV-infected viremic individuals, especially IgG, and correlated with levels of IgG(+) plasmablasts. Several soluble factors associated with immune activation were also increased in the sera of HIV-infected individuals, especially in viremic individuals, and correlated with serum immunoglobulin levels, particularly IgG. Thus, our data suggest that while plasmablasts in the blood may contribute to the HIV-specific immune response, the majority of these cells are not HIV specific and arise early, likely from indirect immune-activating effects of HIV replication, and reflect over time the effects of chronic antigenic stimulation. Such B-cell dysregulation may help explain why the antibody response is inadequate in HIV-infected individuals, even during early infection.

CD27(+) memory B cells are reduced in the blood of patients with chronic granulomatous disease (CGD) for reasons and consequences that remain unclear. Here we confirm not only decreased CD27(+) but also IgG(+) B cells in the blood of CGD patients compared with healthy donors (HDs). However, among IgG(+) B cells, the ratio of CD27(-) to CD27(+) was significantly higher in CGD patients compared with HDs. Similar to conventional memory B cells, CD27(-)IgG(+) B cells of CGD patients expressed activation markers and had undergone somatic hypermutation, albeit at levels lower than their CD27(+) counterparts. Functional analyses revealed slight reductions in frequencies of total IgG but not influenza-specific memory B-cell responses, as measured by Elispot in CGD patients compared with HDs. Serum IgG levels and influenza-specific antibodies were also normal in these CGD patients. Finally, we provide evidence that influenza-specific memory B cells can be present within the CD27(-)IgG(+) B-cell compartment. Together, these findings show that, despite reduced circulating CD27(+) memory B cells, CGD patients maintain an intact humoral immunologic memory, with potential contribution from CD27(-) B cells.

Chronic immune activation in HIV-infected individuals leads to accumulation of exhausted tissue-like memory B cells. Exhausted lymphocytes display increased expression of multiple inhibitory receptors, which may contribute to the inefficiency of HIV-specific antibody responses. Here, we show that downregulation of B cell inhibitory receptors in primary human B cells led to increased tissue-like memory B cell proliferation and responsiveness against HIV. In human B cells, siRNA knockdown of 9 known and putative B cell inhibitory receptors led to enhanced B cell receptor-mediated (BCR-mediated) proliferation of tissue-like memory but not other B cell subpopulations. The strongest effects were observed with the putative inhibitory receptors Fc receptor-like-4 (FCRL4) and sialic acid-binding Ig-like lectin 6 (Siglec-6). Inhibitory receptor downregulation also led to increased levels of HIV-specific antibody-secreting cells and B cell-associated chemokines and cytokines. The absence of known ligands for FCRL4 and Siglec-6 suggests these receptors may regulate BCR signaling through their own constitutive or tonic signaling. Furthermore, the extent of FCLR4 knockdown effects on BCR-mediated proliferation varied depending on the costimulatory ligand, suggesting that inhibitory receptors may engage specific pathways in inhibiting B cell proliferation. These findings on HIV-associated B cell exhaustion define potential targets for reversing the deleterious effect of inhibitory receptors on immune responses against persistent viral infections.

Objective: To assess the humoral immune response to low-dose AS03-adjuvanted and standard-dose nonadjuvanted 2009 pandemic H1N1 influenza A vaccine in HIV-infected aviremic individuals receiving antiretroviral therapy and in uninfected individuals., Design: A three-arm study., Setting: Two clinics: one at the National Institutes of Health in Bethesda, Maryland, USA; and the other at the Maple Leaf Medical Clinic in Toronto, Ontario, Canada., Participants: HIV-infected and HIV-uninfected adults., Intervention: Single intramuscular 15 μg dose of the monovalent inactivated 2009 pandemic H1N1 influenza A vaccine without adjuvant or 3.75 μg dose of the same strain with adjuvant AS03., Main Outcomes: Immunogenicity, as measured by hemagglutination inhibition (HAI) antibody titers and vaccine-specific memory B-cell responses., Results: A total of 74 participants were enrolled. Twenty-one HIV-infected individuals received the low-dose adjuvanted 2009 pandemic H1N1 influenza A vaccine. Twenty-nine HIV-infected and 24 HIV-uninfected individuals received the standard-dose nonadjuvanted vaccine. There were no significant differences in antibody responses at 9 weeks postvaccination among the three groups studied. However, the IgG memory B-cell response against the vaccine was significantly higher in the HIV-infected group that received the low-dose adjuvanted vaccine when compared to the HIV-infected and uninfected groups that received the standard-dose nonadjuvanted vaccine. Conclusions remained unchanged after regression adjustment for age, gender, CD4 T-cell count, and baseline HAI titer., Conclusion: These data suggest that adjuvants could be used to expand coverage through dose sparing and improve humoral immune responses in immunocompromised individuals.

Characterization of lymphocytes including B cells during early versus chronic HIV infection is important for understanding the impact of chronic viremia on immune cell function. In this setting, we investigated B cells before and after reduction of HIV plasma viremia by antiretroviral therapy (ART). At baseline, peripheral blood B-cell counts were significantly lower in both early and chronic HIV-infected individuals compared with uninfected controls. Similar to CD4(+) but not CD8(+) T cells, B-cell numbers in both groups increased significantly after ART. At baseline, B cells of early HIV-infected individuals were composed of a higher percentage of plasmablasts and resting memory B cells compared with chronic HIV-infected individuals whose B cells were composed of a higher percentage of immature/transitional and exhausted B cells compared with their early infection counterparts. At 1 year after ART, the percentage of resting memory B cells remained higher in early compared with chronic HIV-infected individuals. This difference translated into a better functional profile in that memory B-cell responses to HIV and non-HIV antigens were superior in early- compared with chronic-treated HIV infected individuals. These findings provide new insights on B cells in HIV infection and how early initiation of ART may prevent irreversible immune system damage.

The database of patients who underwent laparoscopic gastric bypass at our institution from 2002 to 2008 was reviewed. Five patients with kidney transplants were found. The impact of the laparoscopic gastric bypass on their comorbidities and the grafts and patients' survival were studied. The five patients of the group are between 36 and 66 years old, three men and two women. Preoperative body mass index ranged between 35 and 42 kg/m(2). The first patient was operated on 4 years ago and presented an anastomotic leak at the gastrojejunal anastomosis that healed with medical treatment. The remaining four patients did not present postoperative complications. At the moment of analysis, the five patients were healthy and enjoying a good quality of life. All the patients had dyslipidemia which reached normal levels after surgery. Three of the patients had diabetes and achieved good control after the surgery. Most importantly, the absorption of immune suppressors was not altered; while some of the patients were even able to reduce their doses. Patients with renal terminal renal diseases and those with renal transplants with severe or morbid obesity are a group that can particularly benefit from a gastric bypass. The laparoscopic gastric bypass is feasible in severely or morbidly obese patients with kidney transplantation. The absorption of the immune-suppressive medication is not altered after a gastric bypass.

A peristaltic gradient insures that chyme normally removed from the jejunal feeding site continues to be propelled caudad. The trigger for iatrogenic "feeding intolerance" is the inadvertently overwhelming of the jejunum's peristaltic outflow, even momentarily. Even minimum local stasis can stimulate a vagal reflex response. Motility of the sluggish gut further slows, leading to generalized abdominal distention, malaise, immobility, and impaired respiratory mechanics. Vagal vascular reflexes could explain the 1:1000 incidence of bowel necrosis for jejunally fed patients. We developed a clinical regimen that continuously "checks for residual" at the enteral feeding site, monitoring the adequacy of emptying. The jejunal inflow automatically is titrated to match peristaltic outflow if the latter cannot keep up. Intermittent suction aspirates the feeding catheter into a plastic chamber for 30 s. All swallowed air is removed efficiently within the close confines of the jejunal segment, without wasting digestive juices. The degassed aspirate is returned by gravity with the feedings during the second half of the 1-min cycle, unless incipient excess (>or=20 mL) fluid overflows. Only this relatively small volume of potentially excess fluid is discarded, forestalling the local distention. All patients tolerated immediate feeding without discomfort or abdominal distention, including three that had esophageal resection (including vagotomy) for carcinoma. Postoperative full enteral nutrition can be achieved quickly and safely with minimum attention, despite initially marginal gastrointestinal function.

Diaziquone, an aziridinylbenzoquinone currently in phase II-III trials, is an alkylating agent, the major toxic effect of which is myelosuppression. We report here on six cases of hypersensitivity attributable to diaziquone. In five patients an acute reaction characterized by hypotension, bronchospasm, and urticaria was observed. In one patient a delayed urticarial rash was noted. Resolution was rapid in all patients but one, who responded to standard treatment over a period of hours. No reaction was fatal. Approximately 2000 patients have been treated with diaziquone in clinical trials sponsored by the National Cancer Institute. It is suggested that the reaction may not be to the drug itself but to the vehicle (dimethylacetamide) in which diaziquone is formulated. Studies to elucidate the relative contribution of drug and vehicle are warranted.

Semustine is an investigational cancer chemotherapeutic agent in widespread use. This agent has now been documented to produce nephrotoxicity and renal failure with long-term administration. We collected 29 cases of semustine nephrotoxicity from the literature and six unpublished cases brought to the attention of the National Cancer Institute. Using these 35 cases as a data base, we have analyzed the incidence, dose and treatment duration relationships, clinical and histologic manifestations, and clinical course of semustine nephrotoxicity. In addition, we discuss the possible mechanisms of this nephrotoxicity based upon ongoing laboratory work. We conclude that there is a high risk of severe nephrotoxicity from semustine when the cumulative dose exceeds 1200 mg/m2 and that there may be considerable delay in onset of the renal dysfunction.

Fifty-one patients with advanced ovarian carcinoma were treated with a combination of cyclophosphamide, hexamethylmelamine, and 5-fluorouracil, CHF. Compared to the hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil (Hexa-CAF) regimen, the omission of methotrexate in CHF did not detract from its antitumor activity and it was well tolerated with only mild to moderate toxicity. The CHF combination was as effective as Hexa-CAF and was particularly active in patients who had nonmeasurable/residual disease, classified as less than 2 cm in its greatest diameter at the initiation of chemotherapy. In future studies, CHF should be prospectively compared to other combination using Adriamycin and cis-platinum that with extended use can cause renal and cardiac damage in long-term survivors.

Amsacrine is an antileukemia drug being widely used in North America, Europe, Australia, and New Zealand. In the initial clinical trials, patients treated with amsacrine developed occasional instances of acute cardiac arrhythmias and cardiomyopathy. We review and analyze the features of cardiac abnormalities associated with amsacrine in 82 patients, 27 of whom have not been previously reported. The rest have been reported in the literature, but we have included a large amount of additional information about these patients in our analysis. We conclude that amsacrine-related cardiac events are less common than those related to anthracycline chemotherapeutic agents. Manifestations of such toxicity include ECG abnormalities, ventricular and atrial arrhythmias, sudden death, and congestive heart failure. There is little or no cumulative dose effect. Hypokalemia may be a risk factor for development of serious tachyarrhythmias, but such problems can occur despite a normal serum potassium level. Amsacrine appears to affect depolarization and repolarization of the heart, but the mechanism is unknown.

Diaziquone is an aziridinylbenzoquinone with properties suggestive of an alkylating agent. The drug has shown broad antitumor activity against numerous transplantable murine tumors including curative activity against several intracerebrally implanted tumors. Parent diaziquone appears to have a t1/2 beta of approximately 30 min. The drug is rapidly and widely distributed to tissues as evidenced by a t1/2 alpha of approximately 1-3 min and a volume of distribution exceeding that of total body water. In addition, it rapidly penetrates the central nervous system, reaching peak concentrations (30-50%) of corresponding plasma levels) in approximately one hour. Diaziquone is rapidly and extensively metabolized by the liver. Diaziquone is a potent marrow suppressive agent inducing significant degrees of leukopenia, granulocytopenia, and thrombocytopenia in humans. Thrombocytopenia is often severe. Although myelosuppression is for the most part dose related, many patients had significant toxicity even at lower doses. Most investigators have attributed this to the extent of prior therapy. Diaziquone demonstrates a very steep dose-response relationship. Myelosuppression was the dose-limiting toxicity in all phase I trials. No nonhematologic dose-limiting toxicity has been identified to date. In phase I and preliminary phase II trials, diaziquone has demonstrated activity against primary brain tumors. Little activity has been seen in other tumor categories. It should be noted, however, that all studies to date have been carried out in heavily pretreated patients. Because of the broad spectrum of antitumor activity in experimental murine tumors, the lack of nonhematologic dose-limiting toxicity, the ability of this drug to attain significant levels in the central nervous system, and the activity of the drug in primary brain tumors, further studies examining its role in the management of patients with cancer are warranted. These studies should be conducted in patients who have had little or no prior therapy in order to better evaluate the efficacy of the drug.