ABSTRACT
The complement system is an evolutionarily ancient arm of the innate immune system. It remains, however, one of the last major pathways in immunology for which specific pharmaceutical antagonists have been developed. In recent years, a fundamental role for complement has been described in many different renal diseases, including both pauci-immune as well as immune-complex diseases. Since the 2011 FDA approval of eculizumab, the only marketed complement antagonist, no new therapeutics have entered clinical practice. There are now multiple new agents in clinical trials, from oral molecules to small inhibitory RNA, that target the classical, lectin, and alternative pathways. Herein we summarize several potential renal diseases in which complement inhibitors may provide a therapeutic benefit, as well as specific complement inhibitors in development.
Subject(s)
Complement Inactivating Agents , Complement System Proteins/immunology , Kidney Diseases , Complement Inactivating Agents/immunology , Complement Inactivating Agents/pharmacology , Humans , Kidney Diseases/drug therapy , Kidney Diseases/immunology , Molecular Targeted Therapy/trendsABSTRACT
BACKGROUND: In February 2015, two unlinked culture-confirmed cases of Neisseria meningitidis serogroup B (MenB) disease occurred at a local college in Rhode Island ("college X") within 3 days. This represented a 489-fold increase in the incidence of MenB disease, and an outbreak was declared. For the first time, bivalent rLP2086 (Trumenba) was selected as a mandatory intervention response. A mass vaccination clinic was coordinated, which provided a unique opportunity to collect safety data in a real-world population of college-age participants. Though the Advisory Committee on Immunization Practices recommends MenB vaccination for college-age individuals (16-23 year olds), there is limited quantifiable safety data available for this population. METHODS: The Dillman total design survey method was used. Adverse events of bivalent rLP2086 were solicited and quantified retrospectively 2-4 months following each dose of vaccine. Safety data from six clinical trials were used as comparison tools. RESULTS: The most commonly reported adverse event following vaccination was injection site pain. Reported rates of injection site pain, fatigue, myalgia, fever, and chills were similar than those reported in clinical trials. Reported rates of headache were lower than in clinical trials. CONCLUSIONS: This study is the first to examine adverse events of bivalent rLP2086 in a real-world setting where more than 90% of a college-age population was vaccinated.
Subject(s)
Disease Outbreaks/prevention & control , Drug-Related Side Effects and Adverse Reactions/epidemiology , Mass Vaccination/adverse effects , Meningitis, Meningococcal/prevention & control , Meningococcal Vaccines/adverse effects , Adolescent , Adult , Antigens, Bacterial , Bacterial Proteins , Disease Outbreaks/statistics & numerical data , Female , Humans , Longitudinal Studies , Male , Mass Vaccination/statistics & numerical data , Meningitis, Meningococcal/epidemiology , Meningococcal Vaccines/administration & dosage , Rhode Island/epidemiology , Young AdultABSTRACT
OBJECTIVE: To outline the reasoning behind use of bivalent rLP2086 in a Rhode Island college meningococcal B disease outbreak, highlighting the timeline from outbreak declaration to vaccination clinic, emphasizing that these two time points are <3 days apart. PARTICIPANTS: Staff, faculty, and students at College X eligible for vaccination. METHODS: An outbreak response was initiated, advantages/disadvantages of available MenB vaccines were discussed, and a vaccination clinic was coordinated. RESULTS: Bivalent rLP2086 was chosen as the vaccination intervention. We achieved a 94% coverage rate for the first dose. To date, this intervention has prevented further cases of Neisseria meningitidis serogroup B disease at College X. CONCLUSIONS: The close, efficient collaboration of public health stakeholders and College X led 94% of the eligible population to be safely vaccinated with at least one dose of bivalent rLP2086. This outbreak marked the first time bivalent rLP2086 was effectively used as an intervention response.
Subject(s)
Civil Defense/organization & administration , Disease Outbreaks , Meningococcal Vaccines/therapeutic use , Universities/trends , Antigens, Bacterial/pharmacology , Antigens, Bacterial/therapeutic use , Bacterial Proteins/pharmacology , Bacterial Proteins/therapeutic use , Civil Defense/methods , Faculty/statistics & numerical data , Humans , Meningococcal Infections/drug therapy , Meningococcal Infections/epidemiology , Meningococcal Infections/immunology , Meningococcal Vaccines/pharmacology , Neisseria meningitidis, Serogroup B/pathogenicity , Public Health/methods , Public Health/trends , Rhode Island/epidemiology , Students/statistics & numerical data , Universities/statistics & numerical dataABSTRACT
PURPOSE: Women with higher body mass index (BMI) following breast cancer (BC) treatment are at higher risk of BC recurrence and death than women of normal weight. African American (AA) BC patients have the highest risk of BC recurrence and gain more weight after diagnosis than their white counterparts. The purpose of this study was to evaluate the association between a mindful eating intervention and weight loss in AA women following chemotherapy for BC. METHODS: A single-group 24-week longitudinal pilot study with repeated measures was conducted. AA women (N = 22, BMI = 35.13 kg/m(2), range = 27.08-47.21) with stage I-III BC who had finished active cancer treatment received a 12-week mindful eating intervention with individual dietary counseling and group mindfulness sessions, followed by bi-weekly telephone follow-up for 12 weeks. Linear mixed models were used to evaluate the effects of the intervention and of baseline mindfulness on the weight change over time. RESULTS: In the overall group (N = 22), MEQ scores increased over time (p = 0.001) while weight decreased over time (-0.887 kg, p = 0.015). Weight loss over time was associated with higher T1 MEQ scores (p = 0.043). Participants in the higher MEQ group (n = 11) at T1 experienced significant weight loss over time (-1.166 kg, p = 0.044), whereas those in the low MEQ (n = 11) did not lose weight. Participants who were diagnosed with stage 1 BC experienced significant weight loss over time (-7.909 kg, p = 0.014). CONCLUSIONS: This study suggests that a mindful weight loss program may be effective for weight reduction and maintenance in some AA women who have completed treatment for BC, particularly those diagnosed with stage 1 BC and with initially higher mindful eating behaviors. Mindful weight loss program is proposed as a promising way in which to reduce obesity-related conditions in AA BC survivors.
Subject(s)
Breast Neoplasms/therapy , Obesity/therapy , Weight Loss , Adult , Black or African American , Aged , Body Mass Index , Breast Neoplasms/psychology , Diet , Female , Humans , Longitudinal Studies , Middle Aged , MindfulnessABSTRACT
On February 2, 2015, the Rhode Island Department of Health was notified of a case of meningococcal disease in a male undergraduate student at Providence College. Three days later, a second case was reported in a male undergraduate with no contact with the first student, indicating an attack rate of 44 cases per 100,000 students, nearly 500 times higher than the national incidence of 0.15 cases per 100,000 among persons aged 17-22 years (Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, CDC, unpublished data, 2013). Both cases were caused by a rare outbreak strain of Neisseria meningitidis serogroup B (ST-9069); neither case was fatal. In response to the outbreak, potential contacts received antibiotic chemoprophylaxis, and a mass vaccination campaign with a recently licensed serogroup B meningococcal (MenB) vaccine was implemented. In collaboration with CDC, the first phase of a meningococcal carriage evaluation was undertaken.
Subject(s)
Carrier State/epidemiology , Disease Outbreaks/prevention & control , Meningococcal Infections/epidemiology , Meningococcal Infections/microbiology , Neisseria meningitidis, Serogroup B/isolation & purification , Universities , Adolescent , Anti-Bacterial Agents/therapeutic use , Ciprofloxacin/therapeutic use , Female , Humans , Incidence , Male , Mass Vaccination , Meningococcal Infections/prevention & control , Meningococcal Vaccines/administration & dosage , Rhode Island/epidemiology , Young AdultABSTRACT
OBJECTIVES/HYPOTHESIS: To evaluate the outcome of cochlear implantation (CI) in patients with vestibular schwannoma (VS). STUDY DESIGN: A retrospective case series from a tertiary auditory implant center. METHODS: A retrospective case note review was carried out to evaluate patients with bilateral profound hearing loss and VS who underwent unilateral CI within the Auditory Implant Centre at St. Thomas' Hospital, London, between 2000 and 2012. This included both bilateral VS with neurofibromatosis type 2 (NF2) and unilateral sporadic VS. Outcome measures included speech perception with Bamford-Kowal-Bench and City University of New York sentences, sound-field thresholds with warble tones, and the subjective benefits reported by patients. RESULTS: The study included five patients with NF2 and bilateral VS and two patients with sporadic unilateral VS. The standard preoperative audiologic assessment for CI often could not be carried out in NF2 patients. Preoperative testing was more complete in the two patients with sporadic VS. The audiologic outcome was variable. Open-set speech perception was achieved in three out of five NF2 patients, and another reported significant improvement in environmental sound perception and ease of communication. The outcome was overall better in patients with sporadic VS, both of whom were able to use the telephone in their implanted ear. CONCLUSIONS: Good speech perception can be achieved in some cases, and CI should be considered as an option for auditory rehabilitation in patients with VS.
Subject(s)
Cochlear Implantation/methods , Hearing Loss/therapy , Neuroma, Acoustic/surgery , Adolescent , Adult , Female , Humans , Male , Middle Aged , Retrospective Studies , Treatment Outcome , United Kingdom , Young AdultABSTRACT
CONCLUSION: The bone-anchored hearing aid (BAHA) system can offer significant benefits to patients with single-sided deafness (SSD), primarily by lifting the head shadow effect. OBJECTIVE: To evaluate the efficacy of BAHA for SSD by comparing pre- and postoperative speech, spatial and qualities of hearing scale (SSQ) scores. METHODS: This was a prospective study conducted within a tertiary auditory implant department. The inclusion criteria were unilateral profound hearing loss with normal or mild high frequency hearing loss in the hearing ear (pure tone average better than or equal to 25 dBHL measured at 0.5, 1, 2 and 3 kHz) and subjective benefits reported by patients following a home trial with a BAHA Softband. Patients who met the above criteria and opted for surgery were asked to complete the SSQ questionnaire. The postoperative SSQ response was collected after at least 6 months of consistent BAHA usage. RESULTS: This study included 25 adult patients (mean age at implantation 57.5 years). There was a statistically significant improvement in the average SSQ score in all three sections of the questionnaire with the use of the BAHA. Our patients experienced most marked benefits in speech hearing in challenging listening situations. All patients remain consistent users and there has been no explantation to date.
Subject(s)
Hearing Aids , Hearing Loss, Unilateral/rehabilitation , Adult , Aged , Female , Follow-Up Studies , Hearing Loss, Unilateral/physiopathology , Hearing Loss, Unilateral/psychology , Humans , Male , Middle Aged , Patient Satisfaction , Prospective Studies , Sound Localization/physiology , Speech Perception/physiology , Suture Anchors , Treatment Outcome , Young AdultABSTRACT
This article discusses hearing impairment and the frequency with which it occurs in older adults. Anatomy and physiology of the ear are examined. Categories of hearing loss, causes, assessment and management are explored, including hearing aids, auditory implants and approaches to communication with hearing-impaired patients.
Subject(s)
Hearing Loss/nursing , Hearing Loss/therapy , Aged , Cochlear Implants , Ear/anatomy & histology , Hearing Aids , Hearing Loss/etiology , Humans , Middle Aged , Surveys and QuestionnairesABSTRACT
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent life- threatening, hereditary disease. ADPKD is more common than sickle cell anemia, cystic fibrosis, muscular dystrophy, hemophilia, Down's syndrome, and Huntington's disease combined. ADPKD is a multisystemic disorder characterized by the progressive development of renal cysts and marked renal enlargement. Structural and functional renal deterioration occurs in ADPKD patients and is the fourth leading cause of end-stage renal disease (ESRD) in adults. Aside from the renal manifestations, extrarenal structural abnormalities, such as liver cysts, cardiovascular abnormalities, and intracranial aneurysms may lead to morbidity and mortality. Recent studies have identified prognostic factors for progressive renal impairment including gender, race, age, proteinuria, hematuria, hypertension and increased left ventricular mass index (LVMI). Early diagnosis and better understanding of the pathophysiology of the disease provides the opportunity to aggressivly treat hypertension with renin-angiotensin-aldosterone system inhibitors and thereby potentially reduce LVMI, prevent cardiovascular morbidity and mortality and slow progression of the renal disease.
ABSTRACT
BACKGROUND: At the University of Colorado Health Sciences Center, on detailed questioning, approximately 10% of patients with autosomal dominant polycystic kidney disease (ADPKD) gave no family history of ADPKD. There are several explanations for this observation, including occurrence of a de novo pathogenic sequence variant or extreme phenotypic variability. To confirm de novo sequence variants, we have undertaken clinical and genetic screening of affected offspring and their parents. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 24 patients with a well-documented ADPKD phenotype and no family history of polycystic kidney disease (PKD) and both parents of each patient. OUTCOME: Presence or absence of PKD1 or PKD2 pathogenic sequence variants in parents of affected offspring. MEASUREMENTS: Abdominal ultrasound of affected offspring and their parents for ADPKD diagnosis. Parentage testing by genotyping. Complete screening of PKD1 and PKD2 genes by using genomic DNA from affected offspring; analysis of genomic DNA from both parents to confirm the absence or presence of all DNA variants found. RESULTS: A positive diagnosis of ADPKD by means of ultrasound or genetic screening was made in 1 parent of 4 patients (17%). No PKD1 or PKD2 pathogenic sequence variants were identified in 10 patients (42%), whereas possible pathological DNA variants were identified in 4 patients (17%) and 1 of their respective parents. Parentage was confirmed in the remaining 6 patients (25%), and de novo sequence variants were documented. LIMITATIONS: Size of patient group. No direct examination of RNA. CONCLUSION: Causes other than de novo pathogenic sequence variants may explain the negative family history of ADPKD in certain families.
Subject(s)
Mutation , Polycystic Kidney, Autosomal Dominant/genetics , Adult , Aged , Aged, 80 and over , Female , Genetic Testing , Humans , Male , Middle Aged , TRPP Cation Channels/genetics , Young AdultABSTRACT
BACKGROUND: Heterogeneity manifest as more severe disease in successive generations has been attributed to genetic anticipation in patients with autosomal dominant polycystic kidney disease (ADPKD). We evaluated variation in age at end-stage renal disease (ESRD) in ADPKD families for evidence of anticipation. STUDY DESIGN: Retrospective. SETTING & PARTICIPANTS: 413 families with ADPKD seen at our single center between 1985 and 2004 (including 95 families with documented polycystic disease type 1 [PKD1] and 213 ADPKD families with parents born before 1930). PREDICTOR: Generational status. OUTCOME: Age at ESRD onset. MEASUREMENTS: Time to ESRD was evaluated by using survival analysis, Cox regression, and descriptive statistics. Unstable trinucleotide repeat expansion was evaluated by means of genotyping in 6 PKD1 families. RESULTS: We analyzed 413 ADPKD families (1,391 parent-offspring pairs) with known age at ESRD or last known age without ESRD (informative pairs). There was no difference in age at ESRD between parents and offspring by means of Cox regression after adjusting for correlations among family members and sex (hazard ratio, 1.019; 95% confidence interval, 0.919 to 1.13; P = 0.7). Similar analysis of PKD1 informative pairs and those with parents born before 1930 showed no differences in age at ESRD. Male ADPKD patients were 42% more likely to reach ESRD (P < 0.001), and male patients with documented PKD1 were 41% more likely to reach ESRD (P = 0.01) than female patients. LIMITATIONS: Hypertension treatment unknown. CONCLUSIONS: We found no evidence for anticipation of ESRD in patients with ADPKD; thus, the observed variation in age at ESRD may result from other genetic, sex, or environmental causes.
Subject(s)
Kidney Failure, Chronic/physiopathology , Polycystic Kidney, Autosomal Dominant/complications , Polycystic Kidney, Autosomal Dominant/genetics , Adult , Age of Onset , Aged , Female , Genomic Instability , Genotype , Humans , Kidney Failure, Chronic/genetics , Kidney Failure, Chronic/mortality , Male , Middle Aged , Proportional Hazards Models , Retrospective Studies , Sex Factors , Survival Analysis , Trinucleotide RepeatsABSTRACT
Polycystic kidney diseases (autosomal dominant and autosomal recessive) are progressive renal tubular cystic diseases, which are characterised by cyst expansion and loss of normal kidney structure and function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common life- threatening, hereditary disease. ADPKD is more prevalent than Huntington's disease, haemophilia, sickle cell disease, cystic fibrosis, myotonic dystrophy and Down's syndrome combined. Early diagnosis and treatment of hypertension with inhibitors of the renin-angiotensin-aldosterone system (RAAS) and its potential protective effect on left ventricular hypertrophy has been one of the major therapeutic goals to decrease cardiac complications and contribute to improved prognosis of the disease. Advances in the understanding of the genetics, molecular biology and pathophysiology of the disease are likely to facilitate the improvement of treatments for these diseases. Developments in describing the role of intracellular calcium ([Ca(2+)](i)) and its correlation with cellular signalling systems, Ras/Raf/mitogen extracellular kinase (MEK)/extracellular signal-regulated protein kinase (ERK), and interaction of these pathways with cyclic adenosine monophosphate (cAMP) levels, provide new insights on treatment strategies. Blocking the vasopressin V(2) receptor, a major adenylyl cyclase agonist, demonstrated significant improvements in inhibiting cytogenesis in animal models. Because of activation of the mammalian target of rapamycin (mTOR) pathway, the use of sirolimus (rapamycin) an mTOR inhibitor, markedly reduced cyst formation and decreased polycystic kidney size in several animal models. Caspase inhibitors have been shown to decrease cytogenesis and renal failure in rats with cystic disease. Cystic fluid secretion results in cyst enlargement and somatostatin analogues have been shown to decrease renal cyst progression in patients with ADPKD. The safety and efficacy of these classes of drugs provide potential interventions for experimental and clinical trials.
Subject(s)
Polycystic Kidney Diseases/drug therapy , Animals , Humans , Polycystic Kidney Diseases/diagnosis , Polycystic Kidney Diseases/metabolism , Renin-Angiotensin SystemABSTRACT
BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) often develop hypertension before any abnormalities in renal function are detected clinically. Therefore, standard screening (serum creatinine and urinalysis) of young individuals with unexplained hypertension to exclude renal parenchymal disease would rarely detect ADPKD. METHODS: Data from 516 subjects with ADPKD (217 male and 299 female), aged newbornto 55 years with a normal serum creatinine and no proteinuria based on urine dipstick, studied between 1985 and 2000, were compared with data from similar subjects from the National Health and Nutrition Examination Survey (NHANES) III (1988-1994) and NHANES IV (1999-2000) data, by gender. RESULTS: There was a highly significant occurrence of hypertension in young patients with ADPKD when compared to patients aged 20 to 34 years in the U.S. population. The hypertension in patients with ADPKD occurred in the absence of abnormal renal function or abnormal urinalysis. CONCLUSIONS: These data indicate that renal ultrasound screening of young hypertensive individuals (aged 20 to 34 years) should be considered when searching for causes of secondary hypertension. Identifying affected ADPKD individuals early in their disease will permit aggressive blood pressure treatment and early inhibition of the renin-angiotensin-aldosterone system, which has been shown to reverse left ventricular hypertrophy, an important cardiovascular risk factor. In the present era of renal replacement therapy, cardiovascular complications are the main cause of death in patients with ADPKD.
Subject(s)
Hypertension/epidemiology , Polycystic Kidney, Autosomal Dominant/epidemiology , Adolescent , Adult , Child , Child, Preschool , Creatinine/blood , Female , Humans , Hypertension/diagnosis , Hypertension/etiology , Incidence , Infant , Infant, Newborn , Male , Middle Aged , Polycystic Kidney, Autosomal Dominant/complications , Polycystic Kidney, Autosomal Dominant/diagnosis , Proteinuria/diagnosis , Proteinuria/etiology , Ultrasonography , United States/epidemiology , Urinalysis/methodsABSTRACT
This study examines the effects of a home health intervention designed to standardize nursing care, strengthen nurses' support for patient self-management and yield better CHF patient outcomes. Participants were 371 Medicare CHF patients served by 205 nurses randomized to intervention and control groups in a large urban home healthcare agency (HHA). The intervention consisted of an evidence-based nursing protocol, patient self-care guide, and training to improve nurses'teaching and support skills. Outcome measures included home care,physician and emergency department (ED) use, hospital admission, condition-specific quality of life (QoL), satisfaction with home care services and survival at 90 days. The intervention was associated with a marginally significant reduction in the volume of skilled nursing visits (p = .074), and a reduction variation in the typical number of visits provided (p < .05), without a significant increase in physician or ED use or patient mortality. Hypothesized improvement in other outcomes did not occur.
Subject(s)
Community Networks , Heart Failure/therapy , Home Care Services/organization & administration , Aged , Female , Health Services Research , Home Care Services/standards , Humans , Male , Outcome Assessment, Health Care , Patient Satisfaction , Quality of LifeABSTRACT
Normal reabsorption of glomerular filtrate proteins probably requires recycling of the endocytic receptors megalin (gp330) and cubilin. Both receptors are located on the luminal surface of the renal proximal tubule epithelium. Whether abnormal amounts of receptor are present in the urine of patients with Dent's disease, Lowe's syndrome, or autosomal dominant idiopathic Fanconi syndrome was explored. They are all forms of the renal Fanconi syndrome and are associated with tubular proteinuria. Urine samples of equal creatinine contents were dialyzed, lyophilized, and subjected to electrophoresis on nonreducing sodium dodecyl sulfate-5% polyacrylamide gels. Proteins were blotted and probed with anti-megalin IgG, anti-cubilin IgG, or receptor-associated protein. Megalin and cubilin levels detected by immunochemiluminescence were measured as integrated pixels and expressed as percentages of the normal mean values. A striking deficiency of urinary megalin, compared with normal individuals (n = 42), was observed for eight of nine families with Dent's disease (n = 10) and for the two families with Lowe's syndrome (n = 3). The family with autosomal dominant idiopathic Fanconi syndrome (n = 2) exhibited megalin levels within the normal range. The measured levels of cubilin were normal for all patients. These results are consistent with defective recycling of megalin to the apical cell surface of the proximal tubules and thus decreased loss into urine in Dent's disease and Lowe's syndrome. This defect would interfere with the normal endocytic function of megalin, result in losses of potential ligands into the urine, and produce tubular proteinuria.