ABSTRACT
Healthcare-acquired infections and multi-drug resistance in pathogens pose a major crisis for the healthcare industry. Novel antibiotics which are effective against resistant strains and unlikely to elicit strong resistance are sought after in these settings. We have previously developed synthetic mimics of ubiquitous antimicrobial peptides and have worked to apply a lead compound, CSA-131, to the crisis. We aimed to generate a system of CSA-131-containing coatings for medical devices that can be adjusted to match elution and compound load for various environments and establish their efficacy in preventing the growth of common pathogens in and around these devices. Peripherally inserted central catheter (PICC) lines were selected for our substrate in this work, and a polyurethane-based system was used to establish coatings for evaluation. Microbial challenges by methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans were performed and SEM was used to evaluate coating structure and colonization. The results indicate that selected coatings show activity against selected planktonic pathogens that extend between 16 and 33 days, with similar periods of biofilm prevention.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Catheters , BiofilmsABSTRACT
AIM: Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by deficient tripeptidyl peptidase 1 (TPP1) enzyme, leading to progressive deterioration of neurological functions commonly occurring in children aged 2-4 years and culminating in early death. Atypical cases associated with earlier or later symptom onset, or even protracted course, have already been reported. Such variable manifestations may constitute an additional challenge to early diagnosis and initiation of appropriate treatment. The present work aimed to analyse clinical data from a cohort of Latin American CLN2 patients with atypical phenotypes. METHODS: Experts in inborn errors of metabolism from Latin America selected patients from their centres who were deemed by the clinicians to have atypical forms of CLN2, according to the current literature on this topic and their practical experience. Clinical and genetic data from the medical records were retrospectively revised. All cases were presented and analysed by these experts at an Advisory Board Meeting in São Paulo, Brazil, in October 2018. RESULTS: Seizures, language abnormalities and behavioural disorders were found as the first manifestations, appearing at the median age of 6 years, an older age than classically described for the late infantile form. Three novel mutations were also identified. CONCLUSION: Our findings reinforce the inclusion of CLN2 in the differential diagnosis of children presenting with seizures, behavioural disorders and language abnormalities. Early diagnosis will allow early initiation of specific therapy.
Subject(s)
Neuronal Ceroid-Lipofuscinoses , Aged , Brazil , Child , Child, Preschool , Humans , Neuronal Ceroid-Lipofuscinoses/diagnosis , Neuronal Ceroid-Lipofuscinoses/genetics , Phenotype , Retrospective Studies , Tripeptidyl-Peptidase 1ABSTRACT
Asthma remains a significant health problem in the United States. Adults with poorly controlled asthma can affect their community in a number of ways, from lost productivity in the workplace to health care costs to premature death. Asthma self-management education helps individuals achieve better control of their asthma and is critical for the overall health and well-being of individuals with asthma. While there are numerous programs and initiatives targeting children with asthma, there is a lack of comparable focus on the needs of adults with asthma. The American Lung Association developed Breathe Well, Live Well, an adult asthma self-management education program, and launched it nationwide in 2007. The program for adults has a flexible delivery format for community-based implementation. This article describes the development, dissemination, and transformation of the program. Each stage of implementation showed positive changes in asthma self-management practices that contribute to better asthma control, and one local implementation additionally showed decreased reports of missed work and unscheduled health care visits among participants. The findings from the three evaluations support the use of Breathe Well, Live Well for broad community-based implementation to improve asthma self-management efficacy and behaviors.
Subject(s)
Asthma , Self-Management , Adult , Asthma/drug therapy , Health Behavior , Humans , Self Care , United StatesABSTRACT
Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive condition caused by variants in the TPP1 gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase I (TPP1). We update on the spectrum of TPP1 variants associated with CLN2 disease, comprising 131 unique variants from 389 individuals (717 alleles) collected from the literature review, public databases, and laboratory communications. Previously unrecorded individuals were added to the UCL TPP1-specific database. Two known pathogenic variants, c.509-1 G>C and c.622 C>T (p.(Arg208*)), collectively occur in 60% of affected individuals in the sample, and account for 50% of disease-associated alleles. At least 86 variants (66%) are private to single families. Homozygosity occurs in 45% of individuals where both alleles are known (87% of reported individuals). Atypical CLN2 disease, TPP1 enzyme deficiency with disease onset and/or progression distinct from classic late-infantile CLN2, represents 13% of individuals recorded with associated phenotype. NCBI ClinVar currently holds records for 37% of variants collected here. Effective CLN2 disease management requires early diagnosis; however, irreversible neurodegeneration occurs before a diagnosis is typically reached at age 5. Timely classification and public reporting of TPP1 variants is essential as molecular testing increases in use as a first-line diagnostic test for pediatric-onset neurological disease.
Subject(s)
Aminopeptidases/genetics , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Genetic Predisposition to Disease , Mutation , Neuronal Ceroid-Lipofuscinoses/genetics , Serine Proteases/genetics , Alleles , Aminopeptidases/chemistry , Animals , Biomarkers , Databases, Genetic , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/chemistry , Disease Models, Animal , Genetic Association Studies , Genotype , Humans , Molecular Dynamics Simulation , Neuronal Ceroid-Lipofuscinoses/diagnosis , Neuronal Ceroid-Lipofuscinoses/metabolism , Phenotype , Protein Conformation , Serine Proteases/chemistry , Structure-Activity Relationship , Tripeptidyl-Peptidase 1ABSTRACT
BACKGROUND: Biallelic variants in the major facilitator superfamily domain containing 8 gene (MFSD8) are associated with distinct clinical presentations that range from typical late-infantile neuronal ceroid lipofuscinosis type 7 (CLN7 disease) to isolated adult-onset retinal dystrophy. Classic late-infantile CLN7 disease is a severe, rare neurological disorder with an age of onset typically between 2 and 6 years, presenting with seizures and/or cognitive regression. Its clinical course is progressive, leading to premature death, and often includes visual loss due to severe retinal dystrophy. In rare cases, pathogenic variants in MFSD8 can be associated with isolated non-syndromic macular dystrophy with variable age at onset, in which the disease process predominantly or exclusively affects the cones of the macula and where there are no neurological or neuropsychiatric manifestations. METHODS: Here we present longitudinal studies on four adult-onset patients who were biallelic for four MFSD8 variants. RESULTS: Two unrelated patients who presented with adult-onset ataxia and had macular dystrophy on examination were homozygous for a novel variant in MFSD8 NM_152778.4: c.935T>C p.(Ile312Thr). Two other patients presented in adulthood with visual symptoms, and one of these developed mild to moderate cerebellar ataxia years after the onset of visual symptoms. CONCLUSIONS: Our observations expand the knowledge on biallelic pathogenic MFSD8 variants and confirm that these are associated with a spectrum of more heterogeneous clinical phenotypes. In MFSD8-related disease, adult-onset recessive ataxia can be the presenting manifestation or may occur in combination with retinal dystrophy.
Subject(s)
Macular Degeneration , Humans , Adult , Male , Female , Macular Degeneration/genetics , Macular Degeneration/pathology , Age of Onset , Ataxia/genetics , Ataxia/pathology , Alleles , Middle Aged , Mutation , Membrane Transport Proteins/genetics , PhenotypeABSTRACT
Objective: Analyze our long-term experience with a less-popularized but stalwart approach, the stapled end-to-side ileocolic anastomosis. Background: The choice of technical approach to ileocolic anastomosis after ileocecal resection for Crohn's disease affects surgical outcomes and recurrence. Yet, despite heterogeneous data from different anastomotic configurations, there remains no clear guidance as to the optimal technique. Methods: In a retrospective cohort design, patients undergoing ileocolic anastomosis in the setting of Crohn's disease between 2016 and 2021 at two institutions were identified. Patient characteristics and surgical outcomes in terms of recurrence (surgical, clinical, and endoscopic) were studied. Results: In total, 211 patients were included. Before surgery, 80% were exposed to at least 1 cycle of systemic steroids and 71% had at least 1 biologic agent; 60% exhibited penetrating disease and 38% developed an intra-abdominal abscess. After surgery, one anastomosis leaked (0.5%). Over 2.4 years of follow-up (IQR = 1.3-3.9), surgical recurrence was 0.9%. Two-year overall recurrence-free and endoscopic recurrence-free survivals were 74% and 85% (95% CI = 68-81 and 80-91), respectively. The adjusted hazard ratio of endoscopic recurrence was 3.0 (95% CI = 1.4-6.2) for males and 5.2 (1.2-22) for patients who received systemic steroids before the surgery. Conclusion: The stapled end-to-side anastomosis is an efficient, reliable, and reproducible approach to maintain bowel continuity after ileocecal resection with durable outcomes. Our outcomes demonstrate low rates of disease recurrence and stand favorably in comparison to other more technically complex or protracted anastomotic approaches. This anastomosis is an ideal reconstructive approach after ileocecal resection for Crohn's disease.
ABSTRACT
Background: Rates of return to preinjury level of play after anterior cruciate ligament (ACL) reconstruction (ACLR) remain unsatisfactory, particularly for patients who undergo revision surgery. Psychological readiness is associated with successful return to sport (RTS) and self-perceived preinjury sport performance. Purpose: To compare psychological readiness at RTS between patients who underwent revision ACL autograft reconstruction and matched controls who underwent primary ACL autograft reconstruction. Study Design: Cohort study; Level of evidence, 3. Methods: Data were gathered using a single orthopaedic surgeon database of patients who underwent ACLR between 2015 and 2018. Patients who underwent revision ACLR and met the study criteria (N = 92) were matched by age, sex, graft type, and rehabilitation protocol to a control group of patients who underwent primary ACLR (n = 92). Functional assessment at release to play was examined using passive knee range of motion, single-leg squat, and single-leg hop testing. Self-reported outcomes included the International Knee Documentation Committee subjective function survey and the ACL-Return to Sport after Injury (ACL-RSI) psychological readiness scale. Time to release to play was recorded as the number of months needed to reach a ≥90% limb symmetry index from the date of the index ACLR. Data were assessed for normality using the Shapiro-Wilk test, and univariate general linear models were utilized with an alpha level of .05. Results: The overall mean patient age was 29.9 ± 10 years, and 40% of patients were women. No significant differences between groups were noted in any of the baseline patient characteristics or surgical findings. At RTS, the mean ACL-RSI score was significantly lower in the revision surgery group (77.4 ± 19.4 vs 85.3 ± 17.4; P = .011). In addition, the revision surgery group returned to play significantly later than the primary surgery group (9.4 ± 2 vs 8.1 ± 1.3 months, respectively; P < .001). Conclusion: When compared with primary ACL autograft reconstruction, revision reconstruction patients exhibited lower psychological readiness scores and a longer time to meet the objective criteria for RTS. Registration: NCT03704376 (ClinicalTrials.gov identifier).
ABSTRACT
Effective stroke recovery therapeutics remain limited. Stem cell therapies have yielded promising results, but the harsh ischemic environment of the post-stroke brain reduces their therapeutic potential. Previously, we developed a conductive polymer scaffold system that enabled stem cell delivery with simultaneous electrical modulation of the cells and surrounding neural environment. This wired polymer scaffold proved efficacious in optimizing ideal conditions for stem cell mediated motor improvements in a rodent model of stroke. To further enable preclinical studies and enhance translational potential, we identified a method to improve this system by eliminating its dependence upon a tethered power source. We have herein developed a wirelessly powered, electrically conductive polymer system that eases therapeutic application and enables full mobility. As a proof of concept, we demonstrate that the wirelessly powered scaffold is able to stimulate neural stem cells in vitro, as well as in vivo in a rodent model of stroke. This system modulates the stroke microenvironment and increases the production of endogenous stem cells. In summation, this novel, wirelessly powered conductive scaffold can serve as a mobile platform for a wide variety of therapeutics involving electrical stimulation.
ABSTRACT
Stroke is a leading cause of long-term disability worldwide, intensifying the need for effective recovery therapies. Stem cells are a promising stroke therapeutic, but creating ideal conditions for treatment is essential. Here we developed a conductive polymer system for stem cell delivery and electrical modulation in animals. Using this system, electrical modulation of human stem cell transplants improve functional stroke recovery in rodents. Increased endogenous stem cell production corresponds with improved function. Transcriptome analysis identified stanniocalcin 2 (STC2) as one of the genes most significantly upregulated by electrical stimulation. Lentiviral upregulation and downregulation of STC2 in the transplanted stem cells demonstrate that this glycoprotein is an essential mediator in the functional improvements seen with electrical modulation. Moreover, intraventricular administration of recombinant STC2 post-stroke confers functional benefits. In summation, our conductive polymer system enables electrical modulation of stem cells as a potential method to improve recovery and identify important therapeutic targets.
Subject(s)
Rodentia , Stroke , Animals , Recovery of Function/physiology , Stem Cell Transplantation/methods , Stroke/therapyABSTRACT
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults. They share some similar clinical features and the accumulation of autofluorescent storage material. Since the discovery of the first causative genes, more than 530 mutations have been identified across 13 genes in cases diagnosed with NCL. These genes encode a variety of proteins whose functions have not been fully defined; most are lysosomal enzymes, or transmembrane proteins of the lysosome or other organelles. Many mutations in these genes are associated with a typical NCL disease phenotype. However, increasing numbers of variant disease phenotypes are being described, affecting age of onset, severity or progression, and including some distinct clinical phenotypes. This data is collated by the NCL Mutation Database which allows analysis from many perspectives. This article will summarise and interpret current knowledge and understanding of their genetic basis and phenotypic heterogeneity.
ABSTRACT
C1q/TNF-related protein 3 (CTRP3) is a cytokine known to regulate a variety of metabolic processes. Though previously undescribed in the context of bone regeneration, high throughput gene expression experiments in mice identified CTRP3 as one of the most highly upregulated genes in fracture callus tissue. Hypothesizing a positive regulatory role for CTRP3 in bone regeneration, we phenotyped skeletal development and fracture healing in CTRP3 knockout (KO) and CTRP3 overexpressing transgenic (TG) mice relative to wild-type (WT) control animals. CTRP3 KO mice experienced delayed endochondral fracture healing, resulting in abnormal mineral distribution, the presence of periosteal marrow compartments, and a nonunion-like state. Decreased osteoclast number was also observed in CTRP3 KO mice, whereas CTRP3 TG mice underwent accelerated callus remodeling. Gene expression profiling revealed a broad impact on osteoblast/osteoclast lineage commitment and metabolism, including arrested progression toward mature skeletal lineages in the KO group. A single systemic injection of CTRP3 protein at the time of fracture was insufficient to phenocopy the chronic TG healing response in WT mice. By associating CTRP3 levels with fracture healing progression, these data identify a novel protein family with potential therapeutic and diagnostic value. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:00-19966, 2020.
Subject(s)
Adipokines/physiology , Bone Remodeling , Fracture Healing , Animals , Bony Callus/growth & development , Cell Line , Humans , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
OBJECTIVES: We revised the Danger Assessment to predict reassault in abusive female same-sex relationships. METHODS: We used focus groups and interviews to evaluate the assessment tool and identify new risk factors and telephone interviews at baseline and at 1-month follow-up to evaluate the revised assessment. RESULTS: The new assessment tool comprised 8 original and 10 new items. Predictors included increase in physical violence (relative risk ratio [RRR]=1.95; 95% confidence interval [CI]=0.84, 4.54), constant jealousy or possessiveness of abuser (RRR = 4.07; 95% CI = 0.61, 27.00), cohabitation (RRR = 1.96; 95% CI = 0.54, 7.12), threats or use of gun by abuser (RRR=1.93; 95% CI=0.79, 4.75), alcoholism or problem drinking of abuser (RRR=1.47; 95% CI=0.79, 2.71), illegal drug use or abuse of prescription medications by abuser (RRR = 1.33; 95% CI = 0.72, 2.46), stalking by abuser (RRR=1.39; 95% CI=0.70, 2.76), failure of individuals to take victim seriously when she sought help (RRR=1.66; 95% CI=0.90, 3.05), victim's fear of reinforcing negative stereotypes (RRR=1.42; 95% CI=0.73, 2.77), and secrecy of abuse (RRR=1.72; 95% CI=0.74, 3.99). Both unweighted (P < .005) and weighted (P < .004) versions of the revised assessment were significant predictors of reassault. CONCLUSIONS: The revised Danger Assessment accurately assesses risk of re-assault in abusive female relationships.
Subject(s)
Aggression , Battered Women/psychology , Homosexuality, Female , Adult , Female , Focus Groups , Humans , Interviews as Topic , Predictive Value of Tests , RiskABSTRACT
Identification, protection, and management of patellofemoral articular cartilage lesions continue to remain on the forefront of sports medicine rehabilitation. Due to high-level compression forces that are applied through the patellofemoral (PF) joint, managing articular cartilage lesions is challenging for sports medicine specialists. Articular cartilage damage may exist in a wide spectrum of injuries ranging from small, single areas of focal damage to wide spread osteoarthritis involving large chondral regions. Management of these conditions has evolved over the last two centuries, most recently using biogenetic materials and cartilage replacement modalities. The purpose of this clinical commentary is to discuss PF articular cartilage injuries, etiological variables, and investigate the evolution in management of articular cartilage lesions. Rehabilitation of these lesions will also be discussed with a focus on current trends and return to function criteria. LEVEL OF EVIDENCE: 5.