Genetic Epidemiology and Associated Diseases of APOL1: A Narrative Review.

BACKGROUND: The Apolipoprotein 1 (APOL1) protein is a product of the human APOL1 gene located on chromosome 22q13.1 and performs functions including lipid transport and metabolism, programmed cell death, autophagy and innate immunity against intracellular pathogens. It is unique among its gene family in its possession of a signal peptide that confers on it the ability for export out of the cell and into the blood stream. The aim of this review is to explore the genetic epidemiology and biology of the APOL1 gene, describe its association with different renal and extra-renal disorders and highlight the timelines of the discoveries of the various associations. METHODS: A literature search was carried out using combination of terms including "apolipoproteins", "apolipoprotein L", "APOL1", "genetics of APOL1", "Chronic Kidney Disease (CKD) and APOL1"," APOL1 and associated diseases" covering the period January 1990 to April 2020. RESULTS: High frequency of the APOL1 gene arose as a result of natural selection in East and West Africa, regions endemic for Trypanosoma brucei infection. High frequencies are also reported among individuals of African ancestry in North America. APOL1 G1 and G2 variants protect against Trypanosoma brucei rhodesiense having overcome their virulence through the serum trypanolytic factor. Although protective against infection from trypanosomes, these alleles have also been shown to increase the risk of several disorders including various forms of chronic kidney diseases, schizophrenia, stroke, cancer, and pre - eclampsia. CONCLUSION: The elucidation of the APOL1 gene has deepened understanding of racial disparities in health and disease. Growing understanding of the genetics and functions of APOL1 has potential to enhance translational benefits for development of new biomarkers, preventive and therapeutic interventions in the context of precision medicine.

RÉSUMÉ: La protéine Apolipoprotéine 1 (APOL1) est un produit du gène humain APOL1 situé sur le chromosome 22q13.1 et remplit des fonctions telles que le transport et le métabolisme des lipides, la mort cellulaire programmée, l'autophagie et l'immunité innée contre les agents pathogènes intracellulaires. Il est unique parmi sa famille de gènes en ce qu'il possède un peptide signal qui lui confère la capacité de s'exporter hors de la cellule et dans la circulation sanguine. L'objectif de cette revue est d'explorer l'épidémiologie génétique et la biologie du gène APOL1, de décrire son association avec différentes maladies rénales et extra-rénales et de mettre en évidence la chronologie des découvertes des différentes associations. MÉTHODES: Une recherche bibliographique a été effectuée en utilisant une combinaison de termes comprenant « apolipoprotéines ¼, « apolipoprotéine L ¼, « APOL1 ¼, « génétique d'APOL1 ¼, « Maladie rénale chronique (CKD) et APOL1 ¼, « APOL1 et maladies associées ¼ période de janvier 1990 à avril 2020. RÉSULTATS: La fréquence élevée du gène APOL1 est apparue à la suite de la sélection naturelle en Afrique de l'Est et de l'Ouest, régions endémiques pour l'infection à Trypanosoma brucei. Des fréquences élevées sont également signalées chez les individus d'ascendance africaine en Amérique du Nord. Les variants APOL1 G1 et G2 protègent contre Trypanosoma brucei rhodesiense après avoir surmonté leur virulence grâce au facteur trypanolytique sérique. Bien qu'ils protègent contre l'infection par les trypanosomes, il a également été démontré que ces allèles augmentent le risque de plusieurs troubles, notamment diverses formes de maladies rénales chroniques, la schizophrénie, les accidents vasculaires cérébraux, le cancer et la pré-éclampsie. CONCLUSION: L'élucidation du gène APOL1 a approfondi la compréhension des disparités raciales en matière de santé et de maladie. La compréhension croissante de la génétique et des fonctions d'APOL1 a le potentiel d'améliorer les avantages translationnels pour le développement de nouveaux biomarqueurs, d'interventions préventives et thérapeutiques dans le contexte de la médecine de précision. MOTS-CLÉS: APOL1 ; La génétique; Épidémiologie; La biologie; Maladies associées.

Specific class of intrapartum antibiotics relates to maturation of the infant gut microbiota: a prospective cohort study.

OBJECTIVE: To evaluate the potential impact of intrapartum antibiotics, and their specific classes, on the infant gut microbiota in the first year of life. DESIGN: Prospective study of infants in the New Hampshire Birth Cohort Study (NHBCS). SETTINGS: Rural New Hampshire, USA. POPULATION OR SAMPLE: Two hundred and sixty-six full-term infants from the NHBCS. METHODS: Intrapartum antibiotic use during labour and delivery was abstracted from medical records. Faecal samples collected at 6 weeks and 1 year of age were characterised by 16S rRNA sequencing, and metagenomics analysis in a subset of samples. EXPOSURES: Maternal exposure to antibiotics during labour and delivery. MAIN OUTCOME MEASURE: Taxonomic and functional profiles of faecal samples. RESULTS: Infant exposure to intrapartum antibiotics, particularly to two or more antibiotic classes, was independently associated with lower microbial diversity scores as well as a unique bacterial community at 6 weeks (GUnifrac, P = 0.02). At 1 year, infants in the penicillin-only group had significantly lower α diversity scores than infants not exposed to intrapartum antibiotics. Within the first year of life, intrapartum exposure to penicillins was related to a significantly lower increase in several taxa including Bacteroides, use of cephalosporins was associated with a significantly lower rise over time in Bifidobacterium and infants in the multi-class group experienced a significantly higher increase in Veillonella dispar. CONCLUSIONS: Our findings suggest that intrapartum antibiotics alter the developmental trajectory of the infant gut microbiome, and specific antibiotic types may impact community composition, diversity and keystone immune training taxa. TWEETABLE ABSTRACT: Class of intrapartum antibiotics administered during delivery relates to maturation of infant gut microbiota.

Infection of Small-Bore Tunneled Central Venous Catheters.

OBJECTIVE. The purpose of this study is to evaluate the association of common clinical variables with small-bore tunneled central venous catheter (CVC) infection. MATERIALS AND METHODS. Retrospective data were collected from all small-bore (6-French) tunneled CVCs placed by the interventional radiology service between 2012 and 2015. Only patients who had a documented reason for tunneled CVC removal were included in the analysis to capture all events. Transfemoral, transhepatic, and translumbar placements were excluded to reduce cohort heterogeneity. Multiple clinical variables were collected from a review of the medical record. The t test and Fisher exact test were used for two-group comparisons for continuous variables and categoric variables, respectively. Logistic regression analyses were further used to identify variables that were associated with catheter infection. RESULTS. One hundred eighty-two patients (105 women [57.7%] and 77 men [42.3%]) with a mean (± SD) age of 49.7 ± 16 years were included. Thirty-two catheters (17.6%) were removed because of infection. Noninfected lines were removed at a mean of 39 (SD, 57.3) days, whereas infected lines were removed at a mean of 95.9 (SD, 113.4) days after placement (p < 0.001). There was a statistically significant difference in the number of tunneled CVCs removed for infection when the indication for tunneled CVC placement was the administration of IV antibiotics (p = 0.04). By multivariate analysis, only time to removal (p = 0.002; odds ratio, 0.992; 95% CI, 0.986-0.998) and a history of tunneled CVC (p = 0.01; odds ratio, 0.306; 95% CI, 0.121-0.772) were associated with catheter removal for infection. CONCLUSION. Time to catheter removal and history of tunneled CVC were associated with an increased risk of tunneled CVC removal because of infection.

Exposure to household air pollution from biomass-burning cookstoves and HbA1c and diabetic status among Honduran women.

Household air pollution from biomass cookstoves is estimated to be responsible for more than two and a half million premature deaths annually, primarily in low and middle-income countries where cardiometabolic disorders, such as Type II Diabetes, are increasing. Growing evidence supports a link between ambient air pollution and diabetes, but evidence for household air pollution is limited. This cross-sectional study of 142 women (72 with traditional stoves and 70 with cleaner-burning Justa stoves) in rural Honduras evaluated the association of exposure to household air pollution (stove type, 24-hour average kitchen and personal fine particulate matter [PM2.5 ] mass and black carbon) with glycated hemoglobin (HbA1c) levels and diabetic status based on HbA1c levels. The prevalence ratio (PR) per interquartile range increase in pollution concentration indicated higher prevalence of prediabetes/diabetes (vs normal HbA1c) for all pollutant measures (eg, PR per 84 µg/m3 increase in personal PM2.5 , 1.49; 95% confidence interval [CI], 1.11-2.01). Results for HbA1c as a continuous variable were generally in the hypothesized direction. These results provide some evidence linking household air pollution with the prevalence of prediabetes/diabetes, and, if confirmed, suggest that the global public health impact of household air pollution may be broader than currently estimated.

The global burden of pulmonary hypertension in sickle cell disease: a systematic review and meta-analysis.

Elevated tricuspid regurgitant jet velocity (TRJV) is a surrogate measure of pulmonary hypertension (PH) in persons with sickle cell disease (SCD). We sought to estimate the burden of PH in people living with sickle cell disease based on TRJV. From 2000 to 2015, we searched electronic databases for eligible publications and included 29 studies (n = 5358 persons). We used random effects modeling to determine the pooled estimate of elevated TRJV. The overall pooled prevalence of elevated TRJV was 23.5 %(95 % CI 19.5-27.4) in persons with SCD. The pooled prevalence of elevated TRJV in children and adults with SCD was 20.7 % (95 % CI 15.7--25.6) and 24.4 % (95 % CI 18.4-30.4), respectively. TRJV is prevalent among adults and children with SCD. Our finding support international recommendations that call for screening for PH in SCD patients.

The Translational Science Conundrum for Junior Investigators.

KNOWLEDGE TRANSFER STATEMENT: The challenges and recommendations outlined in this commentary will serve as steppingstones to process the concepts of translational science, facilitate training for future scientists, and serve as an approach for the early investigators in the field of translational science.

Impact of DHCWs' Safety Perception on Vaccine Acceptance and Adoption of Risk Mitigation Strategies.

OBJECTIVES: To estimate the association between safety perception on vaccine acceptance and adoptions of risk mitigation strategies among dental health care workers (DHCWs). METHODS: A survey was emailed to DHCWs in the New Jersey area from December 2020 to January 2021. Perceived safety from regular SARS-CoV-2 testing of self, coworkers, and patients and its association with vaccine hesitancy and risk mitigation were ascertained. Risk Mitigation Strategy (RiMS) scores were computed from groupings of office measures: 1) physical distancing (reduced occupancy, traffic flow, donning of masks, minimal room crowding), 2) personal protective equipment (fitted for N95; donning N95 masks; use of face shields; coverings for head, body, and feet), and 3) environmental disinfection (suction, air filtration, ultraviolet, surface wiping). RESULTS: SARS-CoV-2 testing of dental professionals, coworkers, and patients were perceived to provide safety at 49%, 55%, and 68%, respectively. While dentists were least likely to feel safe with regular self-testing for SARS-CoV-2 (P < 0.001) as compared with hygienists and assistants, they were more willing than hygienists (P = 0.004; odds ratio, 1.79 [95% CI, 1.21 to 2.66]) and assistants (P < 0.001; odds ratio, 3.32 [95% CI, 1.93 to 5.71]) to receive the vaccine. RiMS scores ranged from 0 to 19 for 467 participants (mean [SD], 10.9 [2.9]). RiMS scores did not significantly differ among groups of DHCWs; however, mean RiMS scores were higher among those who received or planned to receive the COVID-19 vaccine than those with who did not (P = 0.004). DHCWs who felt safer with regular testing had greater RiMS scores than those who did not (11.0 vs. 10.3, P = 0.01). CONCLUSIONS: Understanding DHCWs' perception of risk and safety is crucial, as it likely influences attitudes toward testing and implementation of office risk mitigation policies. Clinical studies that correlate risk perception and RiMS with SARS-CoV-2 testing are needed to demonstrate the effectiveness of RiMS in dental care settings. KNOWLEDGE TRANSFER STATEMENT: Educators, clinicians, and policy makers can use the results of this study when improving attitudes toward testing and implementation of risk mitigation policies within dental offices, for current and future pandemics.

Who tells the story of burns in low-and-middle income countries? - A bibliometric study.

INTRODUCTION: Low- and middle-income countries (LMICs) remain drastically underrepresented in health research, with African countries producing less than 1% of the global output. This work investigates authorship patterns of publications on burns in LMICs. Original research studies addressing burn injuries in LMICs and published between 1st January 2015 and 31st December 2020 were included in the review. Descriptive statistics were performed for country affiliations of authors, World Bank Country Income Groups, WHO group, study-focus and country studied. Of the 458 results, 426 studies met the inclusion criteria. Nearly a quarter of papers on burns in LMICs had both first and senior authors from high-income countries (HICs, n = 95, 24.4%), more than half of the papers had both first and senior authors from upper middle- income countries (upper MICs, n = 222, 57.2%), while less than 1% (n = 3) had first and senior authors exclusively from lower-income countries (LICs). Eleven percent (n = 41/388) of all papers were written without either first nor senior author being from the country studied, and 17 of them (41%) had both first and senior authors from the USA. Twenty-five (6%) of the papers had the first author and not the senior author from the country of focus, while six (2%) had the senior and not the first author from the country of interest. To overcome global health challenges such as burns, locally led research is imperative. The maximum benefit of HIC-LMIC collaborations is achieved when LMICs play an active role in leading the research. When LMICs direct the research being conducted in their country, the harm of inherently inequitable relationships is minimized.

Immune status, and not HIV infection or exposure, drives the development of the oral microbiota.

Even with antiretroviral therapy, children born to HIV-infected (HI) mothers are at a higher risk of early-life infections and morbidities including dental disease. The increased risk of dental caries in HI children suggest immune-mediated changes in oral bacterial communities, however, the impact of perinatal HIV exposure on the oral microbiota remains unclear. We hypothesized that the oral microbiota of HI and perinatally HIV-exposed-but-uninfected (HEU) children will significantly differ from HIV-unexposed-and-uninfected (HUU) children. Saliva samples from 286 child-participants in Nigeria, aged ≤ 6 years, were analyzed using 16S rRNA gene sequencing. Perinatal HIV infection was significantly associated with community composition (HI vs. HUU-p = 0.04; HEU vs. HUU-p = 0.11) however, immune status had stronger impacts on bacterial profiles (p < 0.001). We observed age-stratified associations of perinatal HIV exposure on community composition, with HEU children differing from HUU children in early life but HEU children becoming more similar to HUU children with age. Our findings suggest that, regardless of age, HIV infection or exposure, low CD4 levels persistently alter the oral microbiota during this critical developmental period. Data also indicates that, while HIV infection clearly shapes the developing infant oral microbiome, the effect of perinatal exposure (without infection) appears transient.

A monocentric pilot study of an antioxidative defense and hsCRP in pediatric patients with glycogen storage disease type IA and III.

BACKGROUND AND AIMS: Patients with glycogen storage disease type Ia (GSD Ia) and III (GSD III) do not develop premature atherosclerosis despite hyperlipidemia. The aim of the study was to investigate the oxidative-antioxidative conditions and high sensitivity C-reactive protein (hsCRP) levels in patients with glycogen storage disease type Ia and III. METHODS: We measured lipid profile and lipid peroxidation products in comparison with hsCRP and antioxidative status: trolox equivalent antioxidant capacity, total antioxidant activity, proteinaceous antioxidant enzymes (catalase, superoxide dismutase, paraoxonase, arylesterase), aqueous antioxidants (vitamin C, uric acid, bilirubin, total protein) and lipid-soluble antioxidants (alpha-tocopherol, beta-carotene). The study included 50 individuals: 22 with GSD Ia, 9 with GSD III, and 19 healthy subjects. RESULTS: GSD Ia patients showed a marked hypertriglyceridemia, whereas GSD III patients demonstrated hypercholesterolemia with elevated LDL-cholesterol and decreased HDL-cholesterol levels. Lipid peroxidation levels increased in both GSD groups. The antioxidant activity elevated in GSD Ia group. No significant differences were found in the activities of antioxidant enzymes. Uric acid and alpha-tocopherol levels increased, however, vitamin C and beta-carotene reduced in both GSD groups. The hsCRP levels did not differ among the groups. CONCLUSIONS: In summary our study revealed normal levels of hsCRP in spite of the dyslipidemic status in both GSD patients. The increased plasma antioxidative defense in GSD Ia might be attributed not only to the elevated uric acid but also to the supplemented vitamin E levels. These findings should motivate further investigations in the area of atherosclerotic escape of GSDs.

Effects of live weight and processing on the sensory traits, androstenedione concentration and 5-alpha-androst-16-en-3-one (androstenone) concentration in boar meat.

Twenty-nine crossbred boars were used to evaluate the effects of live weight and processing on the sensory attributes and concentrations of androstenedione and androstenone (boar taint) in boar meat. Boars were stratified by litter across six weight group endpoints (90.9, 95.5, 100.0, 104.5, 109.1, and 113.6kg). Back fat and longissimus muscle from the lumbar region were used for androstenone determination, proximate analysis and sensory evaluation. Hams were cured for sensory analysis and were used to determine androstenone concentrations. Androstenone as an off-flavor did not differ (P>0.05) among treatments for longissimus lean or cured hams and was found to be in the "threshold" to "none detected" range. Back fat androstenone concentration was positively correlated (P<0.05) to hot carcass weight, however, lean androstenone concentration was not (P>0.05). No relationship was found (P>0.05) between androstenone concentration and days on feed, average daily gain or androstenedione concentration. Additionally, further processing decreased androstenone concentration by approximately 29%.

An analysis of potential predictors of tunneled hemodialysis catheter infection or dysfunction.

PURPOSE: To assess the ability of various clinical factors to predict infection or dysfunction of tunneled hemodialysis catheters. METHODS: A retrospective review of all adult patients who had a tunneled hemodialysis catheter placed between 2012 and 2016 was performed. Tunneled hemodialysis catheters were considered infected based on clinical suspicion or culture-positive bacteremia. Dysfunction was defined as all other non-infectious causes for line failure. Time-to-removal or exchange was recorded. Clinical parameters analyzed as potential predictors of tunneled hemodialysis catheter infection or dysfunction, included the following: age, sex, site of placement, inpatient versus outpatient status at time of placement, body mass index, Charlson Comorbidity Index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, platelet count, white blood cell count, international normalized ratio, and partial thromboplastin time. RESULTS: A total of 177 patients (95: female, 82: male; 71.7%: African American; mean age: 54.9 years) qualified for inclusion. The internal jugular vein was the site of placement in 97.1% of patients with 79.7% of lines being placed on the right side. One patient (0.5%) had minor bleeding after catheter insertion but no other complications were recorded. A total of 17 patients (9.6%) had lines removed or exchanged due to infection at a median of 86 (range: 13-626) days, while 68 patients (38.4%) had lines removed or exchanged due to dysfunction at a median of 42 (range: 1-531) days. A total of 92 patients (51.9%) had lines removed due to completion of therapy at a median of 68 (range: 7-433) days. Dysfunctional lines had a shorter time-to-removal than successful lines (p = 0.007). No difference was seen in time-to-removal between infected lines and successful lines (p = 0.16). Multivariate analysis showed that female sex (p = 0.003) and left-sided line placement (p = 0.007) were independent predictors of line dysfunction. No evaluated factors were predictive of tunneled hemodialysis catheter infection. CONCLUSION: Female sex and left-sided line placement were independent predictors of tunneled hemodialysis catheter dysfunction, but none of the evaluated parameters predicted tunneled hemodialysis catheter infection.

Renal involvement as a rare complication of Dorfman-Chanarin syndrome: a case report.

Dorfman-Chanarin syndrome is a rare, autosomal recessive inherited lipid storage disease with congenital ichthyotic erythroderma due to an acylglycerol recycling defect. It is characterized by accumulation of neutral lipids in different tissues. Liver, muscle, ear, eye, and central nervous system are generally involved, so we presented a patient with severe ichthyosis, lipid vacuoles in neutrophils, and multiorgan involvement including a very rare complication, renal involvement. A 7-month-old girl was presented with frequent respiratory infection, congenital ichthyotic erithroderma and suspicion for immune deficiency. On her physical examination hepatomegaly, developmental delay, palmar and plantar hyperkeratosis and increased deep tendon reflexes with clonus and high tonus were found. Laboratory investigations revealed elevation at transaminases levels, hypoalbuminemia, hypergammaglobulinemia, presence of autoantibodies and eosinophilia. Vacuolization in leukocytes confirmed Dorfman-Chanarin syndrome, whereas no mutation at RAG1-2 and ARTEMIS genes ruled-out immune deficient status of the patient. At the age of eight months the patient died from severe renal failure. Her necropsies demonstrated microvesicular lipid accumulation not only at the liver but also at the renal species. The variability of involvement of different systems in Dorfman-Chanarin syndrome is well described, however the renal findings has not been reported previously at the literature.

Rehabilitation Referral for Patients With Irreversible Vision Impairment Seen in a Public Safety-Net Eye Clinic.

Importance: The prevalence of irreversible vision impairment in the United States is expected to increase by 2050. Vision rehabilitation is the primary treatment option. Clinical trials have established its efficacy in improving quality of life. Yet studies indicate that patients experience many barriers to accessing low-vision care. Objectives: To examine the rate of referral for low-vision rehabilitation services by resident and attending ophthalmologists for adults with irreversible vision impairment and to assess the knowledge, attitudes, and beliefs of patients about vision rehabilitation. Design, Setting, and Participants: Cross-sectional study with enrollment from June 20, 2016, to January 31, 2017, of 143 adults 18 years or older seen in a publicly funded, comprehensive eye clinic in Jefferson County, Alabama, and having 1 or both eyes with irreversible vision impairment (visual acuity was defined as 20/60 or worse) per the electronic health record. Exposures: Demographic characteristics; patient questionnaire on knowledge, attitudes, and beliefs about vision rehabilitation; general cognitive status (Short Orientation-Memory-Concentration test); depressive symptoms (Patient Health Questionnaire-9); health literacy (Rapid Estimate of Adult Literacy in Medicine, Revised [REALM-R]); and self-reported difficulty in everyday activities. Main Outcomes and Measures: Proportion of patients with irreversible vision impairment who were referred by ophthalmologists to low-vision rehabilitation services per the electronic health record. Results: Of 143 patients enrolled with irreversible vision impairment in 1 or both eyes, the mean (SD) age was 55.4 (11.1) years and 68 (47.6%) were women. Most patients were African American (123 [86.0%]), uninsured (88 [61.5%]), and unemployed (92 [64.3%]); on average, they had normal cognitive status, minor depressive symptoms, and limited health literacy. As noted in the electronic health record, the rate of referral for low-vision rehabilitation services was 11.4% for patients with irreversible bilateral vision impairment (4 of 35 patients) and 1.9% for those with unilateral impairment (2 of 108). Most patients with bilateral (31 of 34 [91.2%]) and unilateral (90 of 97 [92.8%]) impairment indicated that they were bothered by their vision impairment, and most reported difficulty with reading (33 of 34 patients [97.1%] who were bilaterally impaired vs 85 of 104 [81.7%] who were unilaterally impaired). Conclusions and Relevance: Results of this study suggest a need to better educate ophthalmologists and residents in ophthalmology about referrals to low-vision rehabilitation services for patients with irreversible vision impairment.

Preliminary Screening Results of Fabry Disease in Kidney Transplantation Patients: A Single-Center Study.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by the deficiency of alfa-galactosidase A (AGALA) and leads to progressive impairment of renal function in almost all male patients and in a significant proportion of female patients. FD is underdiagnosed or even misdiagnosed in patients undergoing kidney transplantation. We initiated a selective screening study for FD among kidney transplant patients in our center. In this study, 1095 male and female patients were included. Dried blood samples on Guthrie papers were used to analyze galactosidase A enzyme for male patients. Genetic analyses were performed in all female and male patients with low enzyme activity. In total, 648 female and 447 male patients with functioning grafts were evaluated. Among 1095 patients, 5 male patients had AGALA activity below threshold and 3 female patients had galactosidase alpha gene DNA variations. One male patient had a disease-causing mutation. The other 4 patients had polymorphisms causing low enzyme activity. All the 3 female patients had mutations that were associated with FD according to Human Gene Mutation Database (ID: CM025441). In contrast, these mutations were reported as unknown clinical significance in Clinvar (rs149391489). The patients with clinical findings suggesting FD were planned to be analyzed for Lyso Gb3. In our selective screening study, 8 variations were found among 1095 kidney transplantation patients, which needs further investigation to determine causes of FD. Clinical findings, physical examination, and family history are also necessary to evaluate the genetic changes as a mutation in this selected population.

Identification of axonal involvement in Hallervorden-Spatz disease with magnetic resonance spectroscopy.

Hallervorden-Spatz disease is a neurodegenerative disorder associated with cysteine-iron complex accumulation typically seen as bilateral symmetrical hypointense signal changes in the medial globus pallidus on magnetic resonance imaging. We used magnetic resonance spectroscopy to identify and quantify neuronal damage in two siblings with Hallervorden-Spatz disease. The first patient presenting with a rapidly progressive extrapyramidal syndrome had markedly decreased N-acetylaspartate (NAA) to creatinine (Cr) ratios in the globus pallidi and the periatrial white matter. He also had increased myoinositol (mI) to creatinine (Cr) ratios implying glial proliferation in the affected regions. However the second patient who had the initial presentation of disease had normal NAA/Cr and mI/Cr ratios. These findings indicate that the quantification of NAA:Cr and mI:Cr ratios might be used to predict the extent of neuronal axonal loss and glial proliferation in patients with Hallervorden-Spatz disease respectively.

Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor.

BACKGROUND: The mechanisms responsible for tumor necrosis factor (TNF)-induced LV structural remodeling in the adult heart are not known. METHODS AND RESULTS: We generated a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF that develop progressive LV dilation/remodeling from 4 to 12 weeks of age. During the early phases of LV structural remodeling, there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded to a decrease in total myocardial fibrillar collagen content. As the MHCsTNF mice aged, there was a significant decrease in total MMP zymographic activity that was accompanied by an increase in total fibrillar collagen content. The changes in total MMP activity and myocardial fibrillar collagen content were related to a time- dependent increase in myocardial tissue inhibitor of metalloproteinases (TIMP)-1 levels, resulting in a significant time-dependent decrease in the MMP activity/TIMP level ratio in the MHCsTNF mice. To determine a possible mechanism for the increase in myocardial fibrosis, we also measured levels of TGF-beta(1) and TGF-beta(2) protein levels, which were shown to be significantly elevated in the hearts of the MHCsTNF mice. CONCLUSIONS: Our results suggest that progressive time-dependent changes in the balance between MMP activity and TIMP activity are responsible, at least in part, for the spectrum of TNF-induced changes in the myofibrillar collagen content that occur during LV structural remodeling in the MHCsTNF mice.

Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure.

BACKGROUND: Matrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing LV failure. METHODS AND RESULTS: LV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 months (n=10), (2) SHHF at 13 months (n=12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg. kg(-1). d(-1) PO; n=14), (4) normotensive Wistar-Furth rats (WF) at 9 months (n=12), and (5) WF at 13 months (n=12). Plasma concentrations of the MMP inhibitor (116+/-11 micromol/L) reduced in vitro LV myocardial MMP-2 activity by approximately 100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months was reduced in the SHHF group compared with WF (3578+/-477 versus 5983+/-109 mm Hg/s, P

A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure.

BACKGROUND: Matrix metalloproteinases (MMPs) contribute to matrix remodeling in disease states such as tumor metastases. Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to increase MMP expression, and membrane-type MMP or MT1-MMP has been implicated to activate MMPs. The present study examined whether and to what degree EMMPRIN and MT1-MMP were expressed in human left ventricular (LV) myocardium as well as the association with MMP activity and expression in dilated cardiomyopathy (DCM). METHODS AND RESULTS: LV myocardial zymographic MMP activity increased by >2-fold with both nonischemic DCM (n=21) and ischemic DCM (n=16) compared with normal (n=13). LV myocardial abundance of MMP-9 was increased with both forms of DCM. MMP-2 and MMP-3 were increased with nonischemic DCM. MMP-1 levels were decreased with both forms of DCM. EMMPRIN increased by >250% and MT1-MMP increased by >1000% with both forms of DCM. CONCLUSIONS: Increased LV myocardial MMP activity and selective upregulation of MMPs with nonischemic and ischemic forms of DCM occurred. Moreover, a local MMP induction/activation system was identified in isolated normal human LV myocytes that was upregulated with DCM. The control of MMP activation and expression in the failing human LV myocardium represents a new and potentially significant therapeutic target for this disease process.