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Anemia affects a third of the world's population and contributes to increased morbidity and mortality, decreased work productivity, and impaired neurological development. In recent years, many studies have found a possible association between anemia and sensorineural hearing loss (SNHL), especially in various types of nutritional deficiency and hemoglobin disorders anemia. Anemia may affect hearing through various mechanisms, including affecting microcirculation in the ear, causing tissue hypoxia in the ear, and through inflammatory and oxidative stress pathways. This review aims to comprehensively analyze the association between various types of anemia and SNHL, including possible biological mechanisms, clinical features, and treatment strategies, and clarify the importance of anemia treatment and management in preventing SNHL., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Incidence of cognitive impairment and its consequences have not been fully examined in heart failure (HF)., Objective: The aim of this study was to examine associations of HF with cognitive decline, frequencies and risks of, and time-to-develop mild cognitive impairment (MCI) or dementia during 15-year follow-up., Methods: For this retrospective cohort study, data were retrieved from the National Alzheimer's Coordinating Center. Cognitive decline was assessed using the Uniform Data Set neuropsychological battery. Development of MCI and dementia was assessed using clinically diagnosed cognitive status., Results: Compared with participants without HF (n = 12 904), participants with HF (n = 256) had more decline in attention, executive function, and memory while controlling for covariates including apolipoprotein E4. Participants with HF developed MCI or dementia more frequently (44.9% vs 34.4%), developed dementia faster from normal cognition, and had a lower risk of dementia from MCI after controlling for covariates (hazard ratio, 0.71) than participants without HF., Conclusions: Heart failure was associated with accelerated cognitive decline., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To investigate the effectiveness of two regimens of ranibizumab-assisted pars plana vitrectomy in the treatment of patients with proliferative diabetic retinopathy., Methods: This is a prospective, 6-month, randomized controlled trial. Eighty patients with 87 eyes requiring pars plana vitrectomy treatment for proliferative diabetic retinopathy were included and randomly divided into a 1.0-mg injection group and a 0.5-mg injection group. The ranibizumab was delivered intraoperatively, at the close of surgery. The vitreous hemorrhage grade, best-corrected visual acuity, central macular thickness, and safety data were assessed to Month 6., Results: The 1.0-mg injection group had a milder grade and a lower reoccurrence rate of early postoperatively vitreous hemorrhage than the 0.5-mg injection group (35.0% and 63.4%, respectively, P = 0.0195). The mean best-corrected visual acuity of two groups was significantly improved from baseline to 6 months after surgery, 1.60 ± 0.72 Logarithm of the Minimum Angle of Resolution (LogMAR) (<20/200) to 0.47 ± 0.49 LogMAR (20/59) for the 1.0-mg injection group and 1.51 ± 0.69 LogMAR (<20/200) to 0.50 ± 0.31 LogMAR (20/63) for the 0.5-mg injection group, but there was no significant difference between the two groups ( P = 0.74). There was no significant difference in the mean decrease in central macular thickness and probability of postoperative adverse events between the two groups., Conclusion: Intravitreal injection of 1.0 mg of ranibizumab after pars plana vitrectomy compared with the recommended dose of 0.5 mg significantly reduced the recurrence and severity of early postoperative vitreous hemorrhage in patients with proliferative diabetic retinopathy. It also contributed to the early recovery of visual acuity after surgery and did not increase postoperative adverse events., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Background: Hypoxia is a major cause and promoter of pulmonary hypertension (PH), a representative vascular remodeling disease with poor prognosis and high mortality. However, the mechanism underlying how pulmonary arterial system responds to hypoxic stress during PH remains unclear. Endothelial mitochondria are considered signaling organelles on oxygen tension. Results from previous clinical research and our studies suggested a potential role of posttranslational SUMOylation (small ubiquitin-like modifier modification) in endothelial mitochondria in hypoxia-related vasculopathy., Methods: Chronic hypoxia mouse model and Sugen/hypoxia rat model were employed as PH animal models. Mitochondrial morphology and subcellular structure were determined by transmission electron and immunofluorescent microscopies. Mitochondrial metabolism was determined by mitochondrial oxygen consumption rate and extracellular acidification rate. SUMOylation and protein interaction were determined by immunoprecipitation., Results: The involvement of SENP1 (sentrin-specific protease 1)-mediated SUMOylation in mitochondrial remodeling in the pulmonary endothelium was identified in clinical specimens of hypoxia-related PH and was verified in human pulmonary artery endothelial cells under hypoxia. Further analyses in clinical specimens, hypoxic rat and mouse PH models, and human pulmonary artery endothelial cells and human embryonic stem cell-derived endothelial cells revealed that short-term hypoxia-induced SENP1 translocation to endothelial mitochondria to regulate deSUMOylation (the reversible process of SUMOylation) of mitochondrial fission protein FIS1 (mitochondrial fission 1), which facilitated FIS1 assembling with fusion protein MFN2 (mitofusin 2) and mitochondrial gatekeeper VDAC1 (voltage-dependent anion channel 1), and the membrane tethering activity of MFN2 by enhancing its oligomerization. Consequently, FIS1 deSUMOylation maintained the mitochondrial integrity and endoplasmic reticulum-mitochondria calcium communication across mitochondrial-associated membranes, subsequently preserving pulmonary endothelial function and vascular homeostasis. In contrast, prolonged hypoxia disabled the FIS1 deSUMOylation by diminishing the availability of SENP1 in mitochondria via inducing miR (micro RNA)-138 and consequently resulted in mitochondrial dysfunction and metabolic reprogramming in pulmonary endothelium. Functionally, introduction of viral-packaged deSUMOylated FIS1 within pulmonary endothelium in mice improved pulmonary endothelial dysfunction and hypoxic PH development, while knock-in of SUMO (small ubiquitin-like modifier)-conjugated FIS1 in mice exaggerated the diseased cellular and tissue phenotypes., Conclusions: By maintaining endothelial mitochondrial homeostasis, deSUMOylation of FIS1 adaptively preserves pulmonary endothelial function against hypoxic stress and consequently protects against PH. The FIS1 deSUMOylation-SUMOylation transition in pulmonary endothelium is an intrinsic pathogenesis of hypoxic PH., Competing Interests: Disclosures None.

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Background: The potential treatment effects and safety of Yu ping feng san (YPFS) for pediatric allergic rhinitis (PAR) patients have yet to be studied systematically., Objectives: To assess the effects and safety of YPFS for treat pediatric patients, allergic rhinitis., Methods: We systematically searched PubMed, EMBASE (Excerpta Medical Database), Cochrane library, Chinese Cochrane Centre's Controlled Trials Register platform, Wanfang Chinese Digital Periodical and Conference Database, China National Knowledge Infrastructure Database, and VIP Chinese Science, from inception dates to November 1, 2019. Randomized controlled trials (RCTs) were included. The risk of bias in the trials was assessed in accordance with the Cochrane Handbook, version 5.1.0. RevMan 5.3 software was used to perform a meta-analysis. Grading of Recommendations Assessment, Development and Evaluation methodology was applied to evaluate the evidence quality for each outcome. The quality of evidence for each outcome measurement was low for 4 outcomes and very low for 5 outcomes., Results: A total of 10 RCTs involving 1069 participants (3-15 years old) fulfilled the inclusion criteria. After exclusion, 8 RCTs were pooled for efficacy assessment. The overall efficacy evaluation result did not show benefit for the experimental group (relative risk 0.32, CI 95% 0.24-0.45; P = .98;) Investigation of variation of serum IgA, immunoglobulin E, IgG in three studies in 2 groups returned no statistical significance. YPFS gave relatively better safety (relative risk 0.29, CI 95% 0.14-0.58; P = .0005; Fig. S8, http://links.lww.com/MD/F751) and lower recurrence rates than did Western medical therapy., Conclusions: Current evidence cannot support the routine use of YPFS for treatment of PAR. This may be due to poor-quality study-design limitations of the included YPFS studies. Our data showed that the use of YPFS for PAR is relatively safe compared to Western medical therapy, but a conclusion could not be drawn because only 5 studies were analyzed. Every study suffered from some methodological limitation. Therefore, further large, rigorously-designed studies are necessary to determine conclusively the utility of YPFS in PAR., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To investigate to what extent low-frequency genetic variants (with minor allele frequencies <5%) affect the risk of intracranial aneurysms (IAs)., Methods: One thousand fifty-six patients with IA and 2,097 population-based controls from the Netherlands were genotyped with the Illumina HumanExome BeadChip. After quality control (QC) of samples and single nucleotide variants (SNVs), we conducted a single variant analysis using the Fisher exact test. We also performed the variable threshold (VT) test and the sequence kernel association test (SKAT) at different minor allele count (MAC) thresholds of >5 and >0 to test the hypothesis that multiple variants within the same gene are associated with IA risk. Significant results were tested in a replication cohort of 425 patients with IA and 311 controls, and results of the 2 cohorts were combined in a meta-analysis., Results: After QC, 995 patients with IA and 2,080 controls remained for further analysis. The single variant analysis comprising 46,534 SNVs did not identify significant loci at the genome-wide level. The gene-based tests showed a statistically significant association for fibulin 2 ( FBLN2 ) (best p = 1 × 10 -6 for the VT test, MAC >5). Associations were not statistically significant in the independent but smaller replication cohort ( p > 0.57) but became slightly stronger in a meta-analysis of the 2 cohorts (best p = 4.8 × 10 -7 for the SKAT, MAC ≥1)., Conclusion: Gene-based tests indicated an association for FBLN2 , a gene encoding an extracellular matrix protein implicated in vascular wall remodeling, but independent validation in larger cohorts is warranted. We did not identify any significant associations for single low-frequency genetic variants., (© 2019 American Academy of Neurology.)

Background: Primary osteoporosis (POP) is one kind of global disease, as a serious threat to human health. Liuwei Dihuang Decoction (LWDHD) has been recommended to treat osteoporosis alone or combined with medicine in China; however, its efficacy is unclear. The object of this systematic review and meta-analysis is to evaluate the efficacy and safety of LWDHD in the management of POP., Methods: We will search The Cochrane Library, Medline, PubMed, Elsevier, Springer, Web of Science, Ovid, WHO ICTRP, CNKI, CBM, VIP, and WanFang Database from their inception to February 2019. All randomized controlled trials (RCTs) of LWDHD for the treatment of POP will be included. The language is limited to Chinese and English. The fracture incidence will be accepted as the primary outcomes. Data synthesis, subgroup analysis, sensitivity analysis will be performed by using RevMan V.5.3.5 software., Results: A high-quality synthesis of current evidence for the treatment of POP with LWDHD will be provided from efficacy and safety., Conclusion: This systematic review will generate evidence for judging whether LWDHD is an effective and safe intervention for POP or not., Prospero Registration Number: PROSPERO CRD 4201926066.

Background and Objective: Glucocorticoids are the standard treatment for idiopathic sudden sensorineural hearing loss (ISSNHL), but whether intratympanic or systemic therapy is superior remains controversial. Previous meta-analyses of this question have omitted key clinical trials or included observational studies., Methods: English-language randomized controlled trials in OvidSP, PubMed, Embase, CINAHL, and the Cochrane Library comparing intratympanic versus systemic glucocorticoid therapy for ISSNHL were meta-analyzed using RevMan 5.3. The primary outcome of interest was improvement in pure tone average (PTA) threshold., Results: Six trials involving 248 patients receiving intratympanic steroids and 236 receiving systemic steroids were meta-analyzed. PTA thresholds were similar between the 2 groups at 3 months after therapy initiation (mean difference, 0.24; 95% confidence interval [CI] -2.43 to 2.91, P = .86; I = 54%, P = .07, random-effects model). PTA thresholds were also similar at 6 months (mean difference, 4.69, 95% CI -5.84 to 15.22, P = .38), although the results showed extremely high heterogeneity (I = 98%). Sensitivity analysis indicated that a single trial containing 250 patients provided the strongest evidence for equivalence between the 2 types of therapy. Rates of recovery within 3 months (defined as PTA improvement >10 dB) were similar between the 2 types of therapy (odds ratio 0.92, 95% CI 0.59-1.43, P = .70), with no significant heterogeneity in the pooled data (I = 1%, P = .40)., Conclusion: Intratympanic and systemic steroids' therapies appear to show similar short-term efficacy for restoring hearing in patients with ISSNHL. Intratympanic therapy may reduce systemic side effects associated with steroid use., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Basal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored., Design: Animal research., Setting: University research laboratory., Subjects: Male wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice., Interventions: The cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used., Measurements and Main Results: Photostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor-α and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-α and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti-inflammation., Conclusions: These results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti-inflammatory effect in sepsis.

Background: Activated patients have the skills, knowledge, and confidence to manage their care, resulting in positive outcomes such as lower hospital readmission and fewer adverse consequences due to poor communication with providers. Despite extensive evidence on patient activation, little is known about activation in the home hospice setting, when family caregivers assume more responsibility in care management., Objective: We examined caregiver and nurse communication behaviors associated with caregiver activation during home hospice visits of patients with advanced cancer using a prospective observational design., Methods: We adapted Street's Activation Verbal Coding tool to caregiver communication and used qualitative thematic analysis to develop codes for nurse communications that preceded and followed each activation statement in 60 audio-recorded home hospice visits., Results: Caregiver communication that reflected activation included demonstrating knowledge regarding the patient/care, describing care strategies, expressing opinions regarding care, requesting explanations of care, expressing concern about the patient, and redirecting the conversation toward the patient. Nurses responded by providing education, reassessing the patient/care environment, validating communications, clarifying care issues, updating/revising care, and making recommendations for future care. Nurses prompted caregiver activation through focused care-specific questions, open-ended questions/statements, and personal questions., Conclusions: Few studies have investigated nurse/caregiver communication in home hospice, and, to our knowledge, no other studies focused on caregiver activation. The current study provides a foundation to develop a framework of caregiver activation through enhanced communication with nurses., Implications for Practice: Activated caregivers may facilitate patient-centered care through communication with nurses in home hospice, thus resulting in enhanced outcomes for patients with advanced cancer.

Background: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute-sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms., Methods: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety., Results: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] -0.6 to 2.5; P =0.238), collateral count (0.9±0.6 arteries; 95% CI, -0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, -0.8 to 0.8; P =0.978), and capillary perfusion (-0.2±0.6%; 95% CI, -1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1-2.9; P =0.047) in participants with completely occluded femoral arteries., Conclusions: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097., (© 2017 American Heart Association, Inc.)

Background: Different adenosine stress imaging protocols have not been systemically validated for absolute myocardial perfusion and coronary flow reserve (CFR) by positron emission tomography, where submaximal stress precludes assessing physiological severity of coronary artery disease., Methods and Results: In 127 volunteers, serial rest-stress positron emission tomography scans using rubidium-82 with various adenosine infusion protocols identified (1) the protocol with maximum stress perfusion and CFR, (2) test-retest precision in same subject, (3) stress perfusion and CFR after adenosine compared with dipyridamole, (4) heterogeneity of coronary flow capacity combining stress perfusion and CFR, and (5) potential relevance for patients with risk factors or coronary artery disease. The adenosine 6-minute infusion with rubidium-82 injection at 3 minutes caused CFR that was significantly 15.7% higher than the 4-minute adenosine infusion with rubidium-82 injection at 2 minutes and significantly more homogeneous by Kolmogorov-Smirnov analysis for histograms of 1344 pixel range of perfusion in paired positron emission tomographies. In a coronary artery disease cohort separate from volunteers of this study, compared with the 3/6-minute protocol, the 2/4-minute adenosine protocol would potentially have changed 332 of 1732 (19%) positron emission tomographies at low-risk physiological severity CFR ≥2.3 to CFR <2.0, thereby implying high-risk quantitative severity potentially appropriate for interventions but because of suboptimal stress of the 2/4 protocol in some patients., Conclusions: The 6-minute adenosine infusion with rubidium-82 activation at 3 minutes produced CFR that averaged 15.7% higher than that in the 2/4-minute protocol, thereby potentially providing essential information for personalized management in some patients., (© 2017 American Heart Association, Inc.)

Rationale: Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, selected patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear., Objective: The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size after ST-segment-elevation-myocardial infarction., Methods and Results: This prospective study comprised patients consecutively enrolled in the CCTRN TIME (Cardiovascular Cell Therapy Research Network Timing in Myocardial Infarction Evaluation) trial who agreed to have their BMCs stored and analyzed at the CCTRN Biorepository. Change in infarct size between baseline (3 days after percutaneous coronary intervention) and 6-month follow-up was measured by cardiac MRI. Infarct-size measurements and BMC phenotype and function data were obtained for 101 patients (mean age, 56.5 years; mean screening ejection fraction, 37%; mean baseline cardiac MRI ejection fraction, 45%). At 6 months, 75 patients (74.3%) showed a reduction in infarct size (mean change, -21.0±17.6%). Multiple regression analysis indicated that infarct size reduction was greater in patients who had a larger percentage of CD31(+) BMCs (P=0.046) and in those with faster BMC growth rates in colony-forming unit Hill and endothelial-colony forming cell functional assays (P=0.033 and P=0.032, respectively)., Conclusions: This study identified BMC characteristics associated with a better clinical outcome in patients with segment-elevation-myocardial infarction and highlighted the importance of endothelial precursor activity in regenerating infarcted myocardium. Furthermore, it suggests that for these patients with segment-elevation-myocardial infarction, myocardial repair was more dependent on baseline BMC characteristics than on whether the patient underwent intracoronary BMC transplantation., Clinical Trial Registration Information Url: http://www.clinicaltrials.gov. Unique identifier: NCT00684021., (© 2014 American Heart Association, Inc.)

Background and Purpose: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk., Methods: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest., Results: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0×10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14×10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91×10(-10))., Conclusions: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA., (© 2014 American Heart Association, Inc.)

Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI)., Objective: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction., Methods and Results: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34(+) cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%-2.7% in other cohorts; P<0.05). BM-derived endothelial colonies were significantly decreased (P<0.05). Increased BM CD11b(+) cells associated with worse LV ejection fraction (LVEF) after AMI (P<0.05). Increased BM CD34(+) percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P=0.03, for patients with AMI and +6.6% versus -0.02%; P=0.021 for patients with chronic IHD). In addition, decreased BM CD34(+) percentage in patients with chronic IHD correlated with decrement in LVEF (-2.9% versus +0.7%; P=0.0355)., Conclusions: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment., Clinical Trial Registrations Url: http://www.clinicaltrials.gov. Unique identifiers: NCT00684021, NCT00684060, and NCT00824005., (© 2014 American Heart Association, Inc.)

Background: Genomewide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA., Method: We utilized 2 complementary samples, one recruited on the basis of a dense family history of IA (discovery sample 1: 388 IA cases and 397 controls) and the other without regard to family history (discovery sample 2: 1095 IA cases and 1286 controls). Imputation was used to generate a common set of single nucleotide polymorphisms (SNP) across samples, and a logistic regression model was used to test for association in each sample. Results from each sample were then combined in a metaanalysis., Results: There was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genomewide significance. However, the metaanalysis yielded genomewide significance for SNP on chromosome 9p (CDKN2BAS; rs6475606; P=3.6×10(-8)) and provided further evidence to support the previously reported association of IA with SNP in SOX17 on chromosome 8q (rs1072737; P=8.7×10(-5)). Analyses suggest that the effect of smoking acts multiplicatively with the SNP genotype, and smoking has a greater effect on risk than SNP genotype., Conclusions: In addition to replicating several previously reported loci, we provide further evidence that the association on chromosome 9p is attributable to variants in CDKN2BAS (also known as ANRIL, an antisense noncoding RNA).

Rationale: Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) have been implicated in the generation of arrhythmias and cardiac muscle nuclear signaling. However, in the mammalian sinoatrial node (SAN), where the heart beat originates, the expression and functional activity of IP(3)Rs have not been investigated., Objectives: To determine whether SAN express IP(3)Rs and which isoforms are present. To examine the response of the SAN to IP(3)R agonists and antagonist, and the potential role played by IP(3)Rs in cardiac pacemaking., Methods and Results: The expression and distribution of IP(3)Rs were studied by reverse-transcription polymerase chain reaction, Western blotting, and immunolabeling. Ca(2+) signaling and electric activity in intact mouse SAN were measured with Ca(2+)-sensitive fluorescent dyes. We found that although the entire SAN expressed three IP(3)R mRNA isoforms, the type II IP(3)R (IP(3)R2) was the predominant protein isoform detected by Western blot using protein extracts from the SAN, atrioventricular node, and atrial tissue. Immunohistochemistry studies also showed that IP(3)R2 was expressed in the central SAN region. Studies using isolated single pacemaker cells revealed that IP(3)R2 (but not IP(3)R1) was located with a similar distribution to the sarcoplasmic reticulum marker protein SERCA2a with some labeling adjacent to the surface membrane. The application of membrane-permeable IP(3) (IP(3)-butyryloxymethyl ester) increased Ca(2+) spark frequency and the pacemaker firing rate in single isolated pacemaker cells. In intact SAN preparations, IP(3)R agonists, endothelin-1 and IP(3)-butyryloxymethyl ester both increased intracellular Ca(2+) and the pacemaker firing rate, whereas the IP(3)R antagonist, 2-aminoethoxydiphenyl borate decreased Ca(2+) and the firing rate. Both of these effects were absent in the SAN from transgenic IP(3)R2 knockout mice., Conclusions: This study provides new evidence that functional IP(3)R2s are expressed in the mouse SAN and could serve as an additional Ca(2+)-dependent mechanism in modulating cardiac pacemaker activity as well as other Ca(2+)-dependent processes.

Rationale: The cardiac gene regulatory network (GRN) is controlled by transcription factors and signaling inputs, but network logic in development and it unraveling in disease is poorly understood. In development, the membrane-tethered signaling ligand Neuregulin (Nrg)1, expressed in endocardium, is essential for ventricular morphogenesis. In adults, Nrg1 protects against heart failure and can induce cardiomyocytes to divide., Objective: To understand the role of Nrg1 in heart development through analysis of null and hypomorphic Nrg1 mutant mice., Methods and Results: Chamber domains were correctly specified in Nrg1 mutants, although chamber-restricted genes Hand1 and Cited1 failed to be activated. The chamber GRN subsequently decayed with individual genes exhibiting decay patterns unrelated to known patterning boundaries. Both trabecular and nontrabecular myocardium were affected. Network demise was spatiotemporally dynamic, the most sensitive region being the central part of the left ventricle, in which the GRN underwent complete collapse. Other regions were partially affected with graded sensitivity. In vitro, Nrg1 promoted phospho-Erk1/2-dependent transcription factor expression, cardiomyocyte maturation and cell cycle inhibition. We monitored cardiac pErk1/2 in embryos and found that expression was Nrg1-dependent and levels correlated with cardiac GRN sensitivity in mutants., Conclusions: The chamber GRN is fundamentally labile and dependent on signaling from extracardiac sources. Nrg1-ErbB1/4-Erk1/2 signaling critically sustains elements of the GRN in trabecular and nontrabecular myocardium, challenging our understanding of Nrg1 function. Transcriptional decay patterns induced by reduced Nrg1 suggest a novel mechanism for cardiac transcriptional regulation and dysfunction in disease, potentially linking biomechanical feedback to molecular pathways for growth and differentiation.

Rationale: Recent studies have highlighted important roles of CaMKII in regulating Ca(2+) handling and excitation-contraction coupling. However, the cardiac effect of chronic CaMKII inhibition has not been well understood., Objective: We have tested the alterations of L-type calcium current (I(Ca)) and cardiac function in CaMKIIdelta knockout (KO) mouse left ventricle (LV)., Methods and Results: We used the patch-clamp method to record I(Ca) in ventricular myocytes and found that in KO LV, basal I(Ca) was significantly increased without changing the transmural gradient of I(Ca) distribution. Substitution of Ba(2+) for Ca(2+) showed similar increase in I(Ba). There was no change in the voltage dependence of I(Ca) activation and inactivation. I(Ca) recovery from inactivation, however, was significantly slowed. In KO LV, the Ca(2+)-dependent I(Ca) facilitation (CDF) and I(Ca) response to isoproterenol (ISO) were significantly reduced. However, ISO response was reversed by beta2-adrenergic receptor (AR) inhibition. Western blots showed a decrease in beta1-AR and an increase in Ca(v)1.2, beta2-AR, and Galphai3 protein levels. Ca(2+) transient and sarcomere shortening in KO myocytes were unchanged at 1-Hz but reduced at 3-Hz stimulation. Echocardiography in conscious mice revealed an increased basal contractility in KO mice. However, cardiac reserve to work load and beta-adrenergic stimulation was reduced. Surprisingly, KO mice showed a reduced heart rate in response to work load or beta-adrenergic stimulation., Conclusions: Our results implicate physiological CaMKII activity in maintaining normal I(Ca), Ca(2+) handling, excitation-contraction coupling, and the in vivo heart function in response to cardiac stress.

Background and Purpose: The purpose of this study was to replicate the previous association of single nucleotide polymorphisms (SNPs) with risk of intracranial aneurysm (IA) and to examine the relationship of smoking with these variants and the risk of IA., Methods: White probands with an IA from families with multiple affected members were identified by 26 clinical centers located throughout North America, New Zealand, and Australia. White control subjects free of stroke and IA were selected by random digit dialing from the Greater Cincinnati population. SNPs previously associated with IA on chromosomes 2, 8, and 9 were genotyped using a TaqMan assay or were included in the Affymetrix 6.0 array that was part of a genomewide association study of 406 IA cases and 392 control subjects. Logistic regression modeling tested whether the association of replicated SNPs with IA was modulated by smoking., Results: The strongest evidence of association with IA was found with the 8q SNP rs10958409 (genotypic P=9.2x10(-5); allelic P=1.3x10(-5); OR=1.86, 95% CI: 1.40 to 2.47). We also replicated the association with both SNPs on chromosome 9p, rs1333040 and rs10757278, but were not able to replicate the previously reported association of the 2 SNPs on chromosome 2q. Statistical testing showed a multiplicative relationship between the risk alleles and smoking with regard to the risk of IA., Conclusions: Our data provide complementary evidence that the variants on chromosomes 8q and 9p are associated with IA and that the risk of IA in patients with these variants is greatly increased with cigarette smoking.

Background and Purpose: Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is thought to be heritable with mounting evidence for genetic predisposition. The concept of shared risk for these conditions is challenged by differences in age of diagnosis and demographic characteristics. We performed a genomewide linkage analysis in multiplex families with both IA and AA from the Familial Intracranial Aneurysm study., Methods: Available medical records of subjects who reported IA or abdominal/thoracic AA were reviewed with adjudication as definite/probable, possible, or not a case. To identify genes contributing to the susceptibility for IA and AA, genomewide linkage analysis was performed in the 26 multiplex IA families who had members who also had thoracic or abdominal AA. Individuals (n=91) were defined as affected if they had an IA (definite/probable) or an aortic or thoracic AA (definite/probable)., Results: Maximum logarithm of odds (LOD) scores were found on chromosomes 11 (144 cM; LOD=3.0) and 6 (33 cM; LOD=2.3). In both chromosomal regions, analyses of these same 26 families considering only IA as the disease phenotype produced LOD scores of 1.8 and 1.6, respectively., Conclusions: Our linkage analysis in these 26 families using the broadest disease phenotype, including IA, abdominal AA, and thoracic AA, supports the concept of shared genetic risk. The chromosome 11 locus appears to confirm earlier independent associations in IA and AA. The chromosome 6 finding is novel. Both warrant further investigation.

Background and Purpose: Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA., Methods: Multiplex families having at least 2 individuals with "definite" or "probable" IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene x smoking (pack-years) interaction., Results: The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P=0.03), 7 (LOD=4.1; P=0.01) and 12 (LOD=3.6; P=0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking., Conclusions: We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene x smoking interaction with 3 of the loci.

This study was to determine whether the proportion of death due to breast cancer changed over time in different cohorts of women diagnosed with breast cancer. We identified 316,149 women with breast cancer at age 20 or older during 1975-2003 from the Surveillance, Epidemiology, and End Results 9 tumor registries in the United States. Logistic regression models were used to assess the effects of time period on the likelihood of dying because of breast cancer as underlying cause of death, adjusting for other factors. Overall, underlying cause of death was 52.8% due to breast cancer, 17.8% due to heart disease, and 4.9% due to stroke. Percentage of death due to breast cancer did not change significantly from 1975 to 2003 in those who died < 12 months after diagnosis, but decreased significantly in women who died between 1 and 15 years. Risk of death due to breast cancer in women diagnosed during 1995-1998 was significantly lower than those in 1975-1979 (odds ratio = 0.79, 95% confidence interval = 0.70-0.89), after adjusting for age, race, ethnicity, and tumor stage. Percentage of death due to breast cancer decreased significantly with age from 87.5% in women < 40% to 30.7% in those 80 or older, which was not significantly affected by year of diagnosis. Proportion of death due to breast cancer increased with advanced tumor stage and was similar in various racial/ethnic groups of population. The findings demonstrated that the impact of breast cancer on overall death was reduced after 1 year of diagnosis, but suggested the need for continued cancer surveillance.

Store-operated Ca(2+) entry was investigated in isolated mouse sinoatrial nodes (SAN) dissected from right atria and loaded with Ca(2+) indicators. Incubation of the SAN in Ca(2+)-free solution caused a substantial decrease in resting intracellular Ca(2+) concentration ([Ca(2+)](i)) and stopped pacemaker activity. Reintroduction of Ca(2+) in the presence of cyclopiazonic acid (CPA), a sarcoplasmic reticulum Ca(2+) pump inhibitor, led to sustained elevation of [Ca(2+)](i), a characteristic of store-operated Ca(2+) channel (SOCC) activity. Two SOCC antagonists, Gd(3+) and SKF-96365, inhibited 72+/-8% and 65+/-8% of this Ca(2+) influx, respectively. SKF-96365 also reduced the spontaneous pacemaker rate to 27+/-4% of control in the presence of CPA. Because members of the transient receptor potential canonical (TRPC) gene family may encode SOCCs, we used RT-PCR to examine mRNA expression of the 7 known mammalian TRPC isoforms. Transcripts for TRPC1, 2, 3, 4, 6, and 7, but not TRPC5, were detected. Immunohistochemistry using anti-TRPC1, 3, 4, and 6 antibodies revealed positive labeling in the SAN region and single pacemaker cells. These results indicate that mouse SAN exhibits store-operated Ca(2+) activity which may be attributable to TRPC expression, and suggest that SOCCs may be involved in regulating pacemaker firing rate.

Background: We evaluate the effect of reconstructing huge defects (mean, 15.8 cm) of the distal femur with Ilizarov's distraction osteogenesis and free twin-barreled vascularized fibular bone graft (TVFG)., Methods: We retrospectively reviewed a consecutive series of five patients who had cases of distal femoral fractures with huge defects and infection that were treated by the Ilizarov's distraction osteogenesis. After radical debridement, two of the five cases had free TVFG and monolocal distraction osteogenesis, and another two cases had multilocal distraction osteogenesis with knee fusion because of loss of the joint congruity. The other case with floating knee injury had bilocal distraction osteogenesis and a preserved knee joint. The mean defect of distal femur was 15.8 cm (range, 14-18 cm) in length., Results: The mean length of distraction osteogenesis by Ilizarov's apparatus was 8.2 cm. The mean length of TVFG was 8 cm. The average duration from application of Ilizarov's apparatus to achievement of bony union was 10.2 months (range, 8-13 months). At the end of the follow-up, ranges of motion of three knees were 0 to 45 degrees, 0 to 60 degrees, and 0 to 90 degrees. Two cases had knee arthrodesis with bony fusion because of loss of the joint congruity. There were no leg length discrepancies in all five patients. In addition, three patients had pin tract infections and one case had a 10 degree varus deformity of the femur., Conclusions: Juxta-articular huge defect (>10 cm) of distal femur remains a challenge to orthopedic surgeons. Ilizarov's technique provides the capability to maintain stability, eradicate infection, restore leg length, and to perform adjuvant reconstructive procedure easily. In this study, we found that combining Ilizarov's distraction osteogenesis with TVFG results in improved patient outcome for patients with injuries such as supracondylar or intercondylar infected fractures or nonunion of distal femur with huge bone defect.

Purpose: To examine the associations between physical activity and body mass index (BMI) among females aged 14 to 17 yr., Methods: A convenience sample of 65 Mexican American, 58 African American, and 49 non-Hispanic white girls in an urban high school in Texas participated in this study. Physical activity was assessed by ankle actigraphy. Average activity per period (before, during and after school) of the day and total activity were derived by a software program as movements per minute. The Center for Disease Control and Prevention 2000 BMI charts were used to calculate overweight status. Pearson correlation coefficient and analysis of variance were used to determine the strength of association and to compare activity levels by BMI status., Results: There was a statistically significant inverse association between total diurnal physical activity level and BMI (r=-0.37; P<0.05); and a statistically significant association between after-school activity and BMI (r= -0.28; P<0.05). After adjusting for the effects of age, race, and sexual maturity, total diurnal activity level was 10% less (P=0.03) for overweight females; for females at risk of overweight, diurnal activity level was 6% less (P=0.04) than for normal-weight females. Ethnic differences showed an 8% lower activity level among African American than for non-Hispanic white and 6% lower than for Mexican American females., Conclusion: The study indicated that adolescent females in schools are at risk for inactivity at certain times of the day. Schools in partnership with their communities should assume a major role to promote participation in physical activity among adolescents through innovative activity programs in schools.

Atrial septal defect (ASD) is a common congenital heart disease (CHD) occurring in 5 to 7 per 10,000 live births. Mutations in 5 human genes (NKX2.5, TBX5, GATA4, MYHC, ACTC) are known to cause dominant ASD, but these account for a minority of cases. Human and mouse data suggest that ASD exists in an anatomical continuum with milder septal variants patent foramen ovale (PFO) and atrial septal aneurysm, strongly associated with ischemic stroke and migraine. We have previously shown in inbred mice that the incidence of PFO strongly correlates with length of the interatrial septum primum, defining a quantitative trait underlying PFO risk. To better understand genetic causation of atrial septal abnormalities, we mapped quantitative trait loci (QTL) influencing septal morphology using mouse strains (QSi5 and 129T2/SvEms) maximally informative for PFO incidence and 3 quantitative septal anatomical traits including septum primum length. [QSi5x129T2/SvEms]F2 intercross animals (n=1437) were phenotyped and a whole genome scan performed at an average 17-cM interval. Statistical methodology scoring PFO as a binary phenotype was developed as a confirmatory mapping technique. We mapped 7 significant and 6 suggestive QTL modifying quantitative phenotypes, with 4 supported by binary analysis. Quantitative traits, although strongly associated with PFO (P<0.001), correlated poorly with each other and in all but 1 case QTL for different traits were nonoverlapping. Thus, multiple anatomical processes under separate genetic control contribute to risk of PFO. Our findings demonstrate the feasibility of modeling the genetic basis of common CHD using animal genetic and genomic technologies.

Background: Malignancies, a well-known complication of immunosuppressive therapy in renal transplant recipients, represent an important cause of long-term morbidity and mortality. One approach to addressing this problem is identifying agents that display antineoplastic properties concomitant with their immunosuppressive effects., Methods: We examined the neoplasms among 1008 renal transplant recipients treated at a single center with sirolimus-cyclosporine +/- prednisone., Results: Clinical and laboratory data, including 62.3+/-26.1 months follow-up (range 27.1-131), revealed 36 tumors in 35 patients (3.6%) presenting at 32.5+/-29.8 months. The 2.4% incidence of skin tumors, the most common neoplasms, was 1.58-fold greater than the general U.S. population. In addition to a 0.4% incidence of posttransplant lymphoproliferative disorders (PTLD) and a 0.2% incidence of renal cell carcinomas, we observed single cases of breast, bladder, endometrial, lung, and brain neoplasms as well as leukemia. The mean trough drug concentrations at the time of diagnosis in affected recipients were within our putative target ranges. In addition to eleven graft losses due to death with a functioning kidney, two were related to chronic rejection following reduced immunosuppression, and one, therapeutic nephrectomy for PTLD. Five of twelve deaths were caused by malignancies; four others among 1008 patients over the entire follow-up were attributed to cardiovascular events; one, to respiratory failure; and two, at distant locations to unknown causes., Conclusions: The sirolimus-cyclosporine +/- prednisone combination appears likely to be associated with a reduced incidence of tumors.

We used the potential gains in life expectancy to quantify the impact of eliminating HIV/AIDS,heart disease and malignant neoplasms on the life expectancy of the population of the USA from 1987 to 1999 by race and sex groups. We previously reported the results from 1987 to 1992,with a focus on the year 1992. This report gives an update to 1999, showing the impact of improvements in the care and treatment of HIV/AIDS in recent years.

Objective: To assess hearing in patients with essential tremor (ET) vs patients with Parkinson disease (PD) and normal controls., Methods: The authors assessed demographic and clinical information including use of hearing aids in 250 patients with ET, 127 patients with PD, and 127 normal controls. The authors administered the Nursing Home Hearing Handicap Index (NHHI), a validated measure of hearing disability. Regression techniques were used to adjust for factors such as age and sex. The authors assessed a complete audiologic evaluation in a subset of patients with ET., Results: Patients with ET had worse adjusted NHHI scores when compared to patients with PD (p < 0.001), controls (p < 0.001), and both (p < 0.001). A higher percentage of patients with ET also used hearing aids (p < 0.0001). In the ET group, hearing loss was associated with tremor severity (p = 0.02) and tended to be associated with older age (p = 0.06), male sex (p = 0.06), and the absence of dystonia (p = 0.18). Audiology testing was consistent with high-frequency sensorineural hearing loss. Central processing was not disproportionally greater than peripheral loss., Conclusion: Patients with ET have increased hearing disability compared to patients with PD and normal controls, which correlates with tremor severity.

Objective: To determine whether the Nurr1 gene, which is critical for the development and maintenance of nigral dopaminergic neurons, is a risk factor associated with PD., Background: The Nurrl gene is highly expressed in the dopaminergic neurons in the midbrain. Knockout of the gene results in agenesis of nigral dopaminergic neurons and heterozygous knockout mice increases 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity., Methods: This study included 105 patients with familial PD (fPD) and 120 patients with sporadic PD (sPD) and 221 age-matched healthy control subjects. The polymorphisms and mutations of the Nurr1 gene in patients with PD were initially examined by heteroduplex analysis and sequencing analysis from PCR-amplified Nurr1 gene fragments. A polymorphism in the BseRI restriction site was identified, and a relatively large-scale analysis then was conducted by three independent investigators who were blinded to the clinical status of the subjects., Results: A homozygous 7048G7049 polymorphism was found in intron 6 of the Nurr1 gene, which was significantly higher in fPD (10/105; 9.5%) and in sPD (5/120; 4.2%) compared with healthy control subjects (2/221; 0.9%). The mean age and the SD at onset of these homozygote patients with PD was 52 +/- 15 years for fPD and 46 +/- 7 years for sPD. The clinical features of these homozygote patients with PD did not differ from those of typical PD., Conclusions: The homozygote polymorphism of 7048G7049 in intron 6 of the Nurr1 gene is associated with typical PD.

Background: The purpose of this investigation was to study mitral valve 3D geometry and dynamics by using a coordinate-free system in normal and ischemic hearts to gain mechanistic insight into normal valve function, valve dysfunction during ischemic mitral regurgitation (IMR), and the treatment effects of ring annuloplasty., Methods and Results: Radiopaque markers were implanted in sheep: 9 in the ventricle, 1 on each papillary tip, 8 around the mitral annulus, and 1 on each leaflet edge midpoint. One group served as a control (n=7); all others underwent flexible Tailor partial (n=5) or Duran complete (n=6) ring annuloplasty. After an 8+/-2-day recovery, 3D marker coordinates were measured with biplane videofluoroscopy before and during posterolateral left ventricular ischemia, and MR was assessed by color Doppler echocardiography. Papillary to annular distances remained constant throughout the cardiac cycle in normal hearts, during ischemia, and after ring annuloplasty with either type of ring. Papillary to leaflet edge distances similarly remained constant throughout ejection. During ischemia, however, the absolute distances from the papillary tips to the annulus changed in a manner consistent with leaflet tethering, and IMR was observed. In contrast, during ischemia in either ring group, those distances did not change from preischemia, and no IMR was observed., Conclusions: This analysis uncovered a simple pattern of relatively constant intracardiac distances that describes the 3D geometry and dynamics of the papillary tips and leaflet edges from the dynamic mitral annulus. Ischemia perturbed the papillary-annular distances, and IMR occurred. Either type of ring annuloplasty prevented such changes, preserved papillary-annular distances, and prevented IMR.

Nail-patella syndrome (NPS), also known as hereditary onycho-osteodysplasia, is an autosomal dominant pleiotropic disorder characterized by nailbed dysplasia or hypoplasia, absent or hypoplastic patellae, iliac horns and deformation or luxation of the radial head. Nephropathy is a known serious complication associated with NPS. In this report, we describe an adult Chinese woman with the clinical and radiological features of NPS who presented with the nephrotic syndrome. Renal biopsy disclosed focal segmental glomerulosclerosis on light microscopy, while immunofluorescence revealed predominant staining for IgA in the glomerular mesangium and along some capillary walls. Ultrastructural study confirmed the presence of paramesangial deposits as well as subendothelial collagen fibrils in the glomeruli. The histological findings were those of combined NPS and IgA disease, an association which has rarely been described.

Objectives: The potential gains in life expectancy of the US population by the partial and total elimination of deaths from HIV/AIDS were compared with that of deaths from heart disease and malignant neoplasms., Methods: The data from the 1992 advanced mortality report and detailed information provided by the National Center for Health Statistics were analysed by using the partial multiple decrement life-table technique., Results: For the total population of the United States in 1992, the gains in future life expectancy through the elimination of deaths from HIV/AIDS, heart disease and malignant neoplasms were 0.34, 3.25 and 3.21 years, respectively. The gains in life expectancy in those of working age 15-64 years) through the elimination of deaths from these three causes of deaths were 0.20, 0.40 and 0.55 years, respectively. Race/sex-specific calculations indicate that the total elimination of deaths from HIV/AIDS, heart disease and malignant neoplasms in white men of working age resulted in increased life expectancy of 0.28, 0.54 and 0.53, respectively, whereas the corresponding figures for black men were 0.82, 0.90 and 0.76 years, respectively. Although the impact of the elimination of the other causes remained relatively stable from 1987 to 1992, the potential gains in life expectancy for black men of working age by eliminating HIV/AIDS rose from 0.36 years in 1987 to 0.82 years in 1992. For the total US population of working age, the elimination of HIV/AIDS deaths resulted in increased life expectancy similar to that observed for a 50% reduction of heart disease or malignant neoplasms, whereas among black men of working age, the increased years of life expectancy from the elimination of HIV/AIDS deaths were virtually the same as those observed for the elimination of heart disease or malignant neoplasms., Conclusions: The potential gains in life expectancy by reduction of deaths from heart disease and malignant neoplasms are more heavily influenced by increasing years after the working ages (15-64 years), whereas the potential gains in life expectancy by reducing deaths from HIV/AIDS make a greater contribution to those of working age. Hence, in terms of the economic costs and benefits, these results indicate that in evaluating policy issues regarding allocation of research funds, studies of life expectancy are far more important than the simple approach which allocates funds on the basis of the number of deaths due to various diseases.

Back pain is a common condition and in most cases is not disabling. We have investigated disabling back pain that leads to health care utilization, time lost from work, and high costs. Disabling back pain remains of obscure origin because the focus in studying it has been too narrow. Our indicator of disability is the industrial insurance claim rate for back sprain by county (N = 39) in the State of Washington. After controlling for the size of the labor force and the proportion of workers in occupations that are particularly at risk of back sprain, we determined the effect of 3 socioeconomic factors on the claim rate: the unemployment rate, percentage receiving food stamps, and per capita income. For 2 of the 3 years studied, socioeconomic factors accounted for about one-third of the variance in the claim rate. Even though claimants of industrial insurance are employed, the unemployment rate was significantly related to the claim rate in the 3 years studied. Our interpretation is that disability is a symptom of distress. Where there is a rise in job insecurity and an attendant rise in economic insecurity, there is a greater likelihood that back pain will become disabling.