Cessation and resuming of alglucosidase alfa in Pompe disease: a retrospective analysis.

Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) in late-onset Pompe disease is moderately effective. Little is known about the clinical course after treatment termination and the resumption of ERT. In Switzerland, rhGAA therapy for Pompe disease was temporarily withdrawn after the federal court judged that the treatment costs were greatly out of proportion compared to the benefits. Re-treatment was initiated after the therapy was finally licensed. We retrospectively analysed seven Pompe patients, who underwent cessation and resumption of ERT (median age 43 years). The delay from first symptoms to final diagnosis ranged from 4 to 20 years. The demographics, clinical characteristics, assessments with the 6-min walking test (6-MWT), the predicted forced vital capacity (FVC) and muscle strength were analysed. Before initiation of ERT, all patients suffered from proximal muscle weakness of the lower limbs; one was wheelchair-bound and two patients received night-time non-invasive ventilation. Initial treatment stabilised respiratory function in most patients and improved their walking performance. After treatment cessation, upright FVC declined in most and the 6-MWT declined in all patients. Two patients needed additional non-invasive ventilatory support. Twelve months after resuming ERT, the respiratory and walking capacity improved again in most patients. However, aside for one patient, none of the patients reached the same level of respiratory function or distance walked in 6 min, as at the time of ERT withdrawal. We conclude that cessation of ERT in Pompe disease causes a decline in clinical function and should be avoided. Resuming treatment only partially recovers respiratory function and walking capacity.

Nosocomial infections in dialysis access.

Nosocomial infections in patients requiring renal replacement therapy have a high impact on morbidity and mortality. The most dangerous complication is bloodstream infection (BSI) associated with the vascular access, with a low BSI risk in arteriovenous fistulas or grafts and a comparatively high risk in central venous catheters. The single most important measure for preventing BSI is therefore the reduction of catheter use by means of early fistula formation. As this is not always feasible, prevention should focus on educational efforts, hand hygiene, surveillance of dialysis-associated events, and specific measures at and after the insertion of catheters. Core measures at the time of insertion include choosing the optimal site of insertion, the use of maximum sterile barrier precautions, adequate skin antisepsis, and the choice of catheter type; after insertion, access care needs to ensure hub disinfection and regular dressing changes. The application of antimicrobial locks is reserved for special situations. Evidence suggests that bundling a selection of the aforementioned measures can significantly reduce infection rates. The diagnosis of central line-associated BSI (CLABSI) is based on clinical signs and microbiological findings in blood cultures ideally drawn both peripherally and from the catheter. The prompt installation of empiric antibiotic treatment covering the most commonly encountered organisms is key regarding CLABSI treatment. Catheter removal is recommended in complicated cases or if cultures yield Staphylococcus aureus, enterococci, Pseudomonas or fungi. In other cases, guide wire exchange or catheter salvage strategies with antibiotic lock solutions may be acceptable alternatives.

Disparities in treatment rates of paediatric end-stage renal disease across Europe: insights from the ESPN/ERA-EDTA registry.

BACKGROUND Considerable disparities exist in the provision of paediatric renal replacement therapy (RRT) across Europe. This study aims to determine whether these disparities arise from geographical differences in the occurrence of renal disease, or whether country-level access-to-care factors may be responsible. METHODS Incidence was defined as the number of new patients aged 0-14 years starting RRT per year, between 2007 and 2011, per million children (pmc), and was extracted from the ESPN/ERA-EDTA registry database for 35 European countries. Country-level indicators on macroeconomics, perinatal care and physical access to treatment were collected through an online survey and from the World Bank database. The estimated effect is presented per 1SD increase for each indicator. RESULTS The incidence of paediatric RRT in Europe was 5.4 cases pmc. Incidence decreased from Western to Eastern Europe (-1.91 pmc/1321 km, P < 0.0001), and increased from Southern to Northern Europe (0.93 pmc/838 km, P = 0.002). Regional differences in the occurrence of specific renal diseases were marginal. Higher RRT treatment rates were found in wealthier countries (2.47 pmc/€10 378 GDP per capita, P < 0.0001), among those that tend to spend more on healthcare (1.45 pmc/1.7% public health expenditure, P < 0.0001), and among countries where patients pay less out-of-pocket for healthcare (-1.29 pmc/11.7% out-of-pocket health expenditure, P < 0.0001). Country neonatal mortality was inversely related with incidence in the youngest patients (ages 0-4, -1.1 pmc/2.1 deaths per 1000 births, P = 0.10). Countries with a higher incidence had a lower average age at RRT start, which was fully explained by country GDP per capita. CONCLUSIONS Inequalities exist in the provision of paediatric RRT throughout Europe, most of which are explained by differences in country macroeconomics, which limit the provision of treatment particularly in the youngest patients. This poses a challenge for healthcare policy makers in their aim to ensure universal and equal access to high-quality healthcare services across Europe.

Is breast cancer risk the same for all progestogens?

The population-based case–control study CECILE investigated the impact of various menopausal hormone therapy (MHT) products on breast cancer (BC) risk in 1,555 postmenopausal women [1]. The case group (n = 739) included incident cases of in situ (!) or invasive BC in postmenopausal women. The control group (n = 816) included women from the general population within predefined quotas by age and socio-economic status (SES). While quotas by age were applied to obtain similar distributions by age among controls and among cases, quotas by SES in control women were applied to reflect the distribution by SES of women in the general population in the study area. Data of participants were obtained by a structured questionnaire during in-person interviews, and from pathology reports if applicable, respectively. Women were divided into current and past MHT user. MHTs were classified in estrogen-only therapy (ET), estrogen combined with progestin therapy (EPT) and tibolone. EPT was subdivided in three subtypes according to the progestogen constituent: natural micronized progesterone, progesterone derivatives, and testosterone derivatives. In comparison to never MHT users, any current or past MHT use (ET, EPT, tibolone) was not associated with an increased BC risk. However, in subanalysis BC risk was significantly increased for current use of EPT for 4 or more years (n = 73 cases and n = 56 controls, adjusted OR 1.55; 95 % CI 1.02–2.36). Within the group of current EPT users for 4 or more years, 14 cases had used estrogens combined with micronized progesterone (n = 17 controls), and 55 a combination with a synthetic progestogen (n = 34 controls), respectively. Compared to never MHT use, current use of EPT containing a synthetic progestogen for 4 or more years was associated with a significantly increased BC risk (adjusted OR 2.07; 95 % CI 1.26–3.39), but EPT containing micronized progesterone was not (adjusted OR 0.79; 95 % CI 0.37–1.71). 73 % of current MHT users started treatment within the first year of onset of menopause. Early EPT (n = 52 cases and n = 38 controls, adjusted OR 1.65; 95 % CI 1.02–2.69), but not early ET, starters had a significantly higher BC risk compared to never MHT users. In contrast, MHT initiation beyond 1 year after menopause was not associated with an increased BC risk. The authors concluded that: (1) ET and EPT containing natural progesterone did not increase BC risk whereas, (2) BC risk was increased in users of tibolone or EPT containing a synthetic progestogen, respectively, and that (3) MHT use early after onset of menopause was associated with an increased BC risk as compared to women who delay MHT beyond 1 or more years.

Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: analysis of the GenOSept cohort.

INTRODUCTION Patients admitted to intensive care following surgery for faecal peritonitis present particular challenges in terms of clinical management and risk assessment. Collaborating surgical and intensive care teams need shared perspectives on prognosis. We aimed to determine the relationship between dynamic assessment of trends in selected variables and outcomes. METHODS We analysed trends in physiological and laboratory variables during the first week of intensive care unit (ICU) stay in 977 patients at 102 centres across 16 European countries. The primary outcome was 6-month mortality. Secondary endpoints were ICU, hospital and 28-day mortality. For each trend, Cox proportional hazards (PH) regression analyses, adjusted for age and sex, were performed for each endpoint. RESULTS Trends over the first 7 days of the ICU stay independently associated with 6-month mortality were worsening thrombocytopaenia (mortality: hazard ratio (HR) = 1.02; 95% confidence interval (CI), 1.01 to 1.03; P <0.001) and renal function (total daily urine output: HR =1.02; 95% CI, 1.01 to 1.03; P <0.001; Sequential Organ Failure Assessment (SOFA) renal subscore: HR = 0.87; 95% CI, 0.75 to 0.99; P = 0.047), maximum bilirubin level (HR = 0.99; 95% CI, 0.99 to 0.99; P = 0.02) and Glasgow Coma Scale (GCS) SOFA subscore (HR = 0.81; 95% CI, 0.68 to 0.98; P = 0.028). Changes in renal function (total daily urine output and renal component of the SOFA score), GCS component of the SOFA score, total SOFA score and worsening thrombocytopaenia were also independently associated with secondary outcomes (ICU, hospital and 28-day mortality). We detected the same pattern when we analysed trends on days 2, 3 and 5. Dynamic trends in all other measured laboratory and physiological variables, and in radiological findings, changes inrespiratory support, renal replacement therapy and inotrope and/or vasopressor requirements failed to be retained as independently associated with outcome in multivariate analysis. CONCLUSIONS Only deterioration in renal function, thrombocytopaenia and SOFA score over the first 2, 3, 5 and 7 days of the ICU stay were consistently associated with mortality at all endpoints. These findings may help to inform clinical decision making in patients with this common cause of critical illness.

[Klinik und Diagnose von Hypogonadismus und Andropause]

Diagnosis and therapy of male hypogonadism is still a challenge because of the unspecific clinical signs and symptoms. The clinical presentation of a androgen deficiency is age-related. In the adult men, one can often observe fatigue, decrease in physical capacity, loss of libido and erectile dysfunction. At the physical examination, genitalia have always to be assessed in search of a testes/penis atrophy. Two fasting measurements of total testosterone concentrations by a reliable assay are needed to confirm the diagnosis. By assessing gonadotropines the origin of hypogonadism can be determined (central/secondary or peripheral/primary). Exogenous administration of androgens should be considered in young, sportive, healthy and muscular males. Patients with metabolic syndrome should only be screened for hypogonadism in the presence of suggestive symptoms. Prostate disease, hematocrit higher than 50 %, uncontrolled heart failure and severe obstructive sleep apnea are contraindications of a testosterone replacement therapy. Patients with metabolic-syndrome-associated low testosterone levels should firstly benefit from a lifestyle intervention that can normalize clinical and biochemical hypogonadism. So far, there is no clear evidence for a possible benefit of testosterone therapy in patients with the metabolic syndrome. Similarly, in patients with PADAM (partial androgen deficiency of the aging male) testosterone therapy is not established or recommended.

Cisplatin Nephrotoxicity and Longitudinal Growth in Children With Solid Tumors: A Retrospective Cohort Study

Cisplatin, a major antineoplastic drug used in the treatment of solid tumors, is a known nephrotoxin. This retrospective cohort study evaluated the prevalence and severity of cisplatin nephrotoxicity in 54 children and its impact on height and weight.We recorded the weight, height, serum creatinine, and electrolytes in each cisplatin cycle and after 12 months of treatment. Nephrotoxicity was graded as follows: normal renal function (Grade 0); asymptomatic electrolyte disorders, including an increase in serum creatinine, up to 1.5 times baseline value (Grade 1); need for electrolyte supplementation <3 months and/or increase in serum creatinine 1.5 to 1.9 times from baseline (Grade 2); increase in serum creatinine 2 to 2.9 times from baseline or need for electrolyte supplementation for more than 3 months after treatment completion (Grade 3); and increase in serum creatinine ≥3 times from baseline or renal replacement therapy (Grade 4).Nephrotoxicity was observed in 41 subjects (75.9%). Grade 1 nephrotoxicity was observed in 18 patients (33.3%), Grade 2 in 5 patients (9.2%), and Grade 3 in 18 patients (33.3%). None had Grade 4 nephrotoxicity. Nephrotoxicity patients were younger and received higher cisplatin dose, they also had impairment in longitudinal growth manifested as statistically significant worsening on the height Z Score at 12 months after treatment. We used a multiple logistic regression model using the delta of height Z Score (baseline-12 months) as dependent variable in order to adjust for the main confounder variables such as: germ cell tumor, cisplatin total dose, serum magnesium levels at 12 months, gender, and nephrotoxicity grade. Patients with nephrotoxicity Grade 1 where at higher risk of not growing (OR 5.1, 95% CI 1.07-24.3, P=0.04). The cisplatin total dose had a significant negative relationship with magnesium levels at 12 months (Spearman r=-0.527, P=<0.001).

Nierenersatzverfahren – gestern, heute und morgen

Die Nierenersatztherapie ist eine der erfolgreichsten Geschichten eines künstlichen Organersatzes. Der vorliegende Artikel beschreibt die wichtigsten Schritte in der Evolution zur modernen Therapie mit Peritonealdialyse und Hämodialyse. Aktuelle Fragen im Bereich der Nierenersatztherapie werden diskutiert und zukünftige Entwicklungen aufgezeigt. Dem Patienten stehen heute diverse Therapiemöglichkeiten offen. Allerdings nur, wenn er mindestens ein halbes Jahr vor der Notwendigkeit eines Therapiebeginns die für ihn ideale Therapieform auswählen kann. Verspätete Zuweisungen und die Notwendigkeit eines akuten Dialysebeginns führen nicht nur zu einer erhöhten Mortalität, sondern auch dazu, dass eine präemptive Lebendnierentransplantation verunmöglicht wird. Zudem bleiben diese Patienten in der Regel im Dialysezentrum und können für eine Heimbehandlung, sei es nun in Form einer Peritonealdialyse oder Heimhämodialyse, nicht mehr motiviert werden.

Recent advances and future prospects in choroideremia.

Choroideremia is a complex and rare disease that is frequently misdiagnosed due to its similar appearance to classic retinitis pigmentosa. Recent advances in genetic testing have identified specific genetic mutations in many retinal dystrophies, and the identification of the mutation of the CHM gene on the X chromosome 25 years ago has paved the way for gene replacement therapy with the first human trials now underway. This article reviews the epidemiological and pathological features of choroideremia and new prospects in imaging to monitor disease progression, as well as potential treatment approaches for choroideremia.

Life style habits such as alcohol consumption and physical activity in relation to serum apoB / apoA-I ratio amongst 64-year-old women with varying degrees of glucose tolerance.

OBJECTIVES To investigate how life style factors such as alcohol consumption and physical activity relate to the serum apoB / apoA-I ratio in a cohort of middle-aged women with varying degrees of glucose tolerance. DESIGN Observational, cross-sectional cohort study. SETTING Research laboratory at a University Hospital. SUBJECTS A screened cohort of 64-year-old postmenopausal women with varying degrees of glucose tolerance, ranging from diabetes (n = 232), impaired (n = 212) and normal (n = 191) glucose tolerance. MAIN OUTCOME MEASURE ApoB / apoA-I ratio in relation to alcohol consumption and physical activity as assessed by questionnaires. RESULTS Alcohol consumption and regular physical activity at high levels were inversely associated with the serum apoB / apoA-I ratio independently of confounding factors such as obesity, lipid-lowering treatment, degree of glucose tolerance and hormone replacement therapy. Alcohol seemed related to the apoB / apoA-I ratio mainly through increasing apoA-I, whereas physical activity seemed mainly related to lowering of apoB. Alcohol consumption above a daily intake of 8.9 g, i.e. less than a glass of wine was accompanied by a decrease in apoB / apoA-I ratio. CONCLUSIONS Amongst these 64-year-old women with varying degrees of glucose tolerance, a moderate alcohol intake and regular physical exercise leading to sweating were associated with lower apoB / apoA-I ratio and these effects seem to be additive.

Abdominal aortic calcification and risk of fracture among older women - The SOF study

Data concerning the link between severity of abdominal aortic calcification (AAC) and fracture risk in postmenopausal women are discordant. This association may vary by skeletal site and duration of follow-up. Our aim was to assess the association between the AAC severity and fracture risk in older women over the short- and long term. This is a case-cohort study nested in a large multicenter prospective cohort study. The association between AAC and fracture was assessed using Odds Ratios (OR) and 95% confidence intervals (95%CI) for vertebral fractures and using Hazard Risks (HR) and 95%CI for non-vertebral and hip fractures. AAC severity was evaluated from lateral spine radiographs using Kauppila's semiquantitative score. Severe AAC (AAC score 5+) was associated with higher risk of vertebral fracture during 4 years of follow-up, after adjustment for confounders (age, BMI, walking, smoking, hip bone mineral density, prevalent vertebral fracture, systolic blood pressure, hormone replacement therapy) (OR=2.31, 95%CI: 1.24-4.30, p<0.01). In a similar model, severe AAC was associated with an increase in the hip fracture risk (HR=2.88, 95%CI: 1.00-8.36, p=0.05). AAC was not associated with the risk of any non-vertebral fracture. AAC was not associated with the fracture risk after 15 years of follow-up. In elderly women, severe AAC is associated with higher short-term risk of vertebral and hip fractures, but not with the long-term risk of these fractures. There is no association between AAC and risk of non-vertebral-non-hip fracture in older women. Our findings lend further support to the hypothesis that AAC and skeletal fragility are related.

Racial Disparities in Access to and Outcomes of Kidney Transplantation in Children, Adolescents, and Young Adults: Results From the ESPN/ERA-EDTA (European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association) Registry.

BACKGROUND Racial disparities in kidney transplantation in children have been found in the United States, but have not been studied before in Europe. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS Data were derived from the ESPN/ERA-EDTA Registry, an international pediatric renal registry collecting data from 36 European countries. This analysis included 1,134 young patients (aged ≤19 years) from 8 medium- to high-income countries who initiated renal replacement therapy (RRT) in 2006 to 2012. FACTOR Racial background. OUTCOMES & MEASUREMENTS Differences between racial groups in access to kidney transplantation, transplant survival, and overall survival on RRT were examined using Cox regression analysis while adjusting for age at RRT initiation, sex, and country of residence. RESULTS 868 (76.5%) patients were white; 59 (5.2%), black; 116 (10.2%), Asian; and 91 (8.0%), from other racial groups. After a median follow-up of 2.8 (range, 0.1-3.0) years, we found that black (HR, 0.49; 95% CI, 0.34-0.72) and Asian (HR, 0.54; 95% CI, 0.41-0.71) patients were less likely to receive a kidney transplant than white patients. These disparities persisted after adjustment for primary renal disease. Transplant survival rates were similar across racial groups. Asian patients had higher overall mortality risk on RRT compared with white patients (HR, 2.50; 95% CI, 1.14-5.49). Adjustment for primary kidney disease reduced the effect of Asian background, suggesting that part of the association may be explained by differences in the underlying kidney disease between racial groups. LIMITATIONS No data for socioeconomic status, blood group, and HLA profile. CONCLUSIONS We believe this is the first study examining racial differences in access to and outcomes of kidney transplantation in a large European population. We found important differences with less favorable outcomes for black and Asian patients. Further research is required to address the barriers to optimal treatment among racial minority groups.

Obesity and risk of multiple myeloma: A case-control study

Introduction. Several studies have reported a positive association of body mass index (BMI) with multiple myeloma; however, the period of adulthood where BMI is most important remains unclear. In addition, it is well known that body fat is associated with both sex-steroid hormone storage and with increasing insulin levels; therefore, it was hypothesized that the association between obesity and multiple myeloma may be attributed to increased aromatization of androgen in adipose tissue. Objective. The overall objective of this case-control study was to determine whether multiple myeloma cases had higher BMI and greater adult weight gain relative to healthy controls. In addition, we tested the hypothesis that hormone replacement therapy use among women will further increase the association between BMI and risk of multiple myeloma. This study used data from a pilot case-control study at M.D. Anderson Cancer Center (MDACC), entitled Etiology of multiple myeloma, directed by Dr. Sara Strom and Dr. Sergio Giralt. Methods. The pilot study recruited a total of 122 cases of histopathologically confirmed multiple myeloma from MDACC. Controls (n=183) were selected from a database of random digit dialing controls accrued in the Department of Epidemiology at MDACC and were frequency matched to the cases on age (±5 years), gender, and race/ethnicity. Demographic and risk factor information were obtained from all participants who completed a self-administered questionnaire. Items included in the questionnaire include demographic information, height and weight at age 25, 40 and current/diagnosis, medical history, family history of cancer, smoking and alcohol use. Statistical analysis. Initial descriptive analysis included Student's t-test and Pearson's chi-squared tests. Odds ratios and 95% confidence intervals were calculated to quantify the association between the variables of interest and multiple myeloma. A multivariable model will be developed using unconditional logistic regression. Results. MM cases were 1.79 times (95% CI=0.99-3.32) more likely to have been overweight or obese (BMI > 25 kg/m2) at age 25 relative to healthy controls after controlling for age, gender, race/ethnicty, education and family history of cancer. Being overweight or obese at age 40 was not significantly associated with mutliple myeloma risk (OR=1.42, 95% CI=0.86-2.34) nor was being overweight or obses at diagnosis (OR=1.43, 95% CI=0.78, 2.63). We observed a statistically significant 2-fold increased odds of multiple myeloma in individuals who gained more than 4.7 kg during between 25 and 40 years (OR=1.97, 95% CI=1.15-3.39). When assessing HRT as a modifier of the BMI and multiple myeloma association among women (N=123), no association between obesity and MM status was observed among women who have never used HRT (OR=0.60, 95% CI=0.23-1.61; n=73). Yet among women who have ever used HRT (n=50), being overweight or obese was associated with an increase in MM risk (OR=2. 93, 95% CI=0.81-10.6) after adjusting for age; however, the association was not statistically significant. Significance. This study provides further evidence that increased BMI increases the risk of multiple myeloma. Furthermore, among women, HRT use may modify risk of disease. ^

Hormonal exposure and risk of pancreatic cancer in the United States

Background. In the United States, the incidence of pancreatic cancer has increased; more than 37,000 new cases of pancreatic cancer were diagnosed in the year 2007. Overall, the five-year survival rate is about 5% and pancreatic cancer ranks the fourth leading cause of cancer-related mortality among men and women. Despite the observed progress in cancer diagnosis and treatment, pancreatic cancer remains an unresolved significant public health problem in the United States. Familial pancreatic cancer has been confirmed to be responsible for approximately 10% of pancreatic cancer cases. However, 90% are still without known inherited predisposition. Until now, the role of oral contraceptive pills (OCPs) and hormonal replacement therapy (HRT) among women with pancreatic cancer remain unclear. We examined the association of exogenous hormonal uses in US women with risk of pancreatic cancer. ^ Methods. This was an active hospital-based case-control study which is conducted at the department of gastrointestinal medical oncology in The University of Texas M.D. Anderson Cancer Center. Between January 2005 and December 2007, a total of 287 women with pathologically confirmed pancreatic cancer (cases) and 287 healthy women (controls) were included in this investigation. Both cases and controls were frequency matched by age and race. Information about the use of hormonal contraceptives and hormonal replacement therapy (HRT) preparations as well as information about several risk factors of pancreatic cancer were collected by personal interview. Univariate and multivariate analyses were performed in this study to analyze the data. ^ Results. We found a statistical significant protective effect for use of exogenous hormone preparations on pancreatic cancer development (adjusted odds ratio [AOR], 0.4; 95% confidence interval [CI], 0.2–0.8). In addition, a 40% reduction in pancreatic cancer risk was observed among women who ever used any of the contraceptive methods including oral contraceptive pills (AOR, 6; 95% CI, 0.4–0.9). ^ Conclusions. Consistent with previous studies, the use of exogenous hormone preparations including oral contraceptive pills may confers a protective effect for pancreatic cancer development. More studies are warranted to explore for the underlying mechanism of such protection.^

Antibody chemical reactivity: Beneficial and pathogenic roles

Antibodies (Abs) to autoantigens and foreign antigens (Ags) mediate, respectively, various pathogenic and beneficial effects. Abs express enzyme-like nucleophiles that react covalently with electrophiles. A subpopulation of nucleophilic Abs expresses proteolytic activity, which can inactivate the Ag permanently. This thesis shows how the nucleophilicity can be exploited to inhibit harmful Abs or potentially protect against a virus. ^ Inactivation of pathogenic Abs from Hemophilia A (HA) patients by means of nucleophile-electrophile pairing was studied. Deficient factor VIII (FVIII) in HA subjects impairs blood coagulation. FVIII replacement therapy fails in 20-30% of HA patients due to production of anti-FVIII Abs. FVIII analogs containing electrophilic phosphonate group (E-FVIII and E-C2) were hypothesized to inactivate the Abs by reacting specifically and covalently with nucleophilic sites. Anti-FVIII IgGs from HA patients formed immune complexes with E-FVIII and E-C2 that remained irreversibly associated under conditions that disrupt noncovalent Ab-Ag complexes. The reaction induced irreversible loss of Ab anti-coagulant activity. E-FVIII alone displayed limited interference with coagulation. E-FVIII is a prototype reagent suitable for further development as a selective inactivator of pathogenic anti-FVIII Abs. ^ The beneficial function of Abs to human immunodeficiency virus type 1 (HIV-1) was analyzed. HIV-1 eludes the immune system by rapidly changing its coat protein structure. IgAs from noninfected subjects hydrolyzed gp120 and neutralized HIV-1 with modest potency by recognizing the gp120 421-433 epitope, a conserved B cell superantigenic region that is also essential for HIV-1 attachment to host cell CD4 receptors. An adaptive immune response to superantigens is generally prohibited due to their ability to downregulate B cells. IgAs from subjects with prolonged HIV-1 infection displayed improved catalytic hydrolysis of gp120 and exceptionally potent and broad neutralization of diverse CCR5-dependent primary HIV isolates attributable to recognition of the 421-433 epitope. This indicates that slow immunological bypass of the superantigenic character of gp120 is possible, opening the path to effective HIV vaccination. ^ My research reveals a novel route to inactivate pathogenic nucleophilic Abs using electrophilic antigens. Conversely, naturally occurring nucleophilic Abs may help impede HIV infection, and the Abs could be developed for passive immunotherapy of HIV infected subjects. ^