Mitral Regurgitation Augments Post-Myocardial Infarction Remodeling: Failure of Hypertrophic Compensation Ronen Beeri, Chaim Yosefy, J. Luis Guerrero, Francesca Nesta, Suzan Abedat, Miguel Chaput, ...Federica del Monte, Mark D. Handschumacher, Robert Stroud, Suzanne Sullivan, Thea Pugatsch, Dan Gilon, Gus J. Vlahakes, Francis G. Spinale, Roger J. Hajjar, Robert A. Levine Mitral regurgitation (MR) doubles mortality after myocardial infarction (MI), but its additive contribution to left ventricular remodeling is debated and has not been addressed in a controlled fashion. In a sheep model with apical MI and a standard moderate MR, we observed excess remodeling as compared with MI without MR, as manifested by increased gross remodeling morphology by 3-dimensional echocardiography, reduced intrinsic contractility at the global and cellular levels, exhaustion of pro-hypertrophic signaling in the cardiomyocytes, and increased extracellular matrix turnover. Hence, MR worsens post-MI remodeling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We examined whether mitral regurgitation (MR) augments post-myocardial infarction (MI) remodeling.
MR doubles mortality after MI, but its additive contribution to left ventricular (LV) remodeling is ...debated and has not been addressed in a controlled fashion.
Apical MIs were created in 12 sheep, and 6 had an LV-to-left atrial shunt implanted, consistently producing regurgitant fractions of approximately 30%. The groups were compared at baseline, 1, and 3 months.
Left ventricular end-systolic volume progressively increased by 190% with MR versus 90% without MR (p < 0.02). Pre-load-recruitable stroke work declined by 82 +/- 13% versus 25 +/- 16% (p < 0.01) with MR, with decreased remote-zone sarcoplasmic reticulum Ca(2+)-ATPase levels (0.56 +/- 0.03 vs. 0.76 +/- 0.02, p < 0.001), and decreased isolated myocyte contractility. In remote zones, pro-hypertrophic Akt and gp130 were upregulated in both groups at 1 month, but significantly lower and below baseline in the MR group at 3 months. Pro-apoptotic caspase 3 remained high in both groups. Matrix metalloproteinase (MMP)-13 and membrane-type MMP-1 were increased in remote zones of MR versus infarct-only animals at 1 month, then fell below baseline. The MMP tissue inhibitors rose from baseline to 3 months in all animals, rising higher in the MI + MR-group border zone.
In this controlled model, moderate MR worsens post-MI remodeling, with reduced contractility. Pro-hypertrophic pathways are initially upregulated but subsequently fall below infarct-only levels and baseline; with sustained caspase 3 elevation, transformation to a failure phenotype occurs. Extracellular matrix turnover increases in MR animals. Therefore, MR can precipitate an earlier onset of dilated heart failure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neonatal drug withdrawal Hudak, Mark L; Tan, Rosemarie C
Pediatrics,
02/2012, Volume:
129, Issue:
2
Journal Article
Peer reviewed
Open access
Maternal use of certain drugs during pregnancy can result in transient neonatal signs consistent with withdrawal or acute toxicity or cause sustained signs consistent with a lasting drug effect. In ...addition, hospitalized infants who are treated with opioids or benzodiazepines to provide analgesia or sedation may be at risk for manifesting signs of withdrawal. This statement updates information about the clinical presentation of infants exposed to intrauterine drugs and the therapeutic options for treatment of withdrawal and is expanded to include evidence-based approaches to the management of the hospitalized infant who requires weaning from analgesics or sedatives.
Manzamine A and related derivatives isolated from a common Indonesian sponge, Acanthostrongylophora, have been identified as a new class of GSK-3β inhibitors. The semisynthesis of new analogues and ...the first structure–activity relationship studies with GSK-3β are also reported. Moreover, manzamine A proved to be effective in decreasing tau hyperphosphorylation in human neuroblastoma cell lines, a demonstration of its ability to enter cells and interfere with tau pathology. Inhibition studies of manzamine A against a selected panel of five different kinases related to GSK-3β, specifically CDK-1, PKA, CDK-5, MAPK, and GSK-3α, show the specific inhibition of manzamine A on GSK-3β and CDK-5, the two kinases involved in tau pathological hyperphosphorylation. These results suggest that manzamine A constitutes a promising scaffold from which more potent and selective GSK-3 inhibitors could be designed as potential therapeutic agents for Alzheimer’s disease.
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IJS, KILJ, NUK, PNG, UL, UM
The passage of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act has collectively resulted in an improvement in rational prescribing for children, including more than ...500 labeling changes. However, off-label drug use remains an important public health issue for infants, children, and adolescents, because an overwhelming number of drugs still have no information in the labeling for use in pediatrics. The purpose of off-label use is to benefit the individual patient. Practitioners use their professional judgment to determine these uses. As such, the term "off-label" does not imply an improper, illegal, contraindicated, or investigational use. Therapeutic decision-making must always rely on the best available evidence and the importance of the benefit for the individual patient.
Of patients with pneumonia coming from the community, 18% are immunocompromised. Specific immunocompromised states are associated with specific microbiology, which has to be taken into consideration ...when choosing empirical therapy.
Abstract
Background
The correct management of immunocompromised patients with pneumonia is debated. We evaluated the prevalence, risk factors, and characteristics of immunocompromised patients coming from the community with pneumonia.
Methods
We conducted a secondary analysis of an international, multicenter study enrolling adult patients coming from the community with pneumonia and hospitalized in 222 hospitals in 54 countries worldwide. Risk factors for immunocompromise included AIDS, aplastic anemia, asplenia, hematological cancer, chemotherapy, neutropenia, biological drug use, lung transplantation, chronic steroid use, and solid tumor.
Results
At least 1 risk factor for immunocompromise was recorded in 18% of the 3702 patients enrolled. The prevalences of risk factors significantly differed across continents and countries, with chronic steroid use (45%), hematological cancer (25%), and chemotherapy (22%) the most common. Among immunocompromised patients, community-acquired pneumonia (CAP) pathogens were the most frequently identified, and prevalences did not differ from those in immunocompetent patients. Risk factors for immunocompromise were independently associated with neither Pseudomonas aeruginosa nor non–community-acquired bacteria. Specific risk factors were independently associated with fungal infections (odds ratio for AIDS and hematological cancer, 15.10 and 4.65, respectively; both P = .001), mycobacterial infections (AIDS; P = .006), and viral infections other than influenza (hematological cancer, 5.49; P < .001).
Conclusions
Our findings could be considered by clinicians in prescribing empiric antibiotic therapy for CAP in immunocompromised patients. Patients with AIDS and hematological cancer admitted with CAP may have higher prevalences of fungi, mycobacteria, and noninfluenza viruses.
As a component of comprehensive pediatric care, adolescents should receive appropriate guidance regarding substance use during routine clinical care. This statement addresses practitioner challenges ...posed by the spectrum of pediatric substance use and presents an algorithm-based approach to augment the pediatrician's confidence and abilities related to substance use screening, brief intervention, and referral to treatment in the primary care setting. Adolescents with addictions should be managed collaboratively (or comanaged) with child and adolescent mental health or addiction specialists. This statement reviews recommended referral guidelines that are based on established patient-treatment-matching criteria and the risk level for substance abuse.
Autism spectrum disorders are not rare; many primary care pediatricians care for several children with autism spectrum disorders. Pediatricians play an important role in early recognition of autism ...spectrum disorders, because they usually are the first point of contact for parents. Parents are now much more aware of the early signs of autism spectrum disorders because of frequent coverage in the media; if their child demonstrates any of the published signs, they will most likely raise their concerns to their child's pediatrician. It is important that pediatricians be able to recognize the signs and symptoms of autism spectrum disorders and have a strategy for assessing them systematically. Pediatricians also must be aware of local resources that can assist in making a definitive diagnosis of, and in managing, autism spectrum disorders. The pediatrician must be familiar with developmental, educational, and community resources as well as medical subspecialty clinics. This clinical report is 1 of 2 documents that replace the original American Academy of Pediatrics policy statement and technical report published in 2001. This report addresses background information, including definition, history, epidemiology, diagnostic criteria, early signs, neuropathologic aspects, and etiologic possibilities in autism spectrum disorders. In addition, this report provides an algorithm to help the pediatrician develop a strategy for early identification of children with autism spectrum disorders. The accompanying clinical report addresses the management of children with autism spectrum disorders and follows this report on page 1162 available at www.pediatrics.org/cgi/content/full/120/5/1162. Both clinical reports are complemented by the toolkit titled "Autism: Caring for Children With Autism Spectrum Disorders: A Resource Toolkit for Clinicians," which contains screening and surveillance tools, practical forms, tables, and parent handouts to assist the pediatrician in the identification, evaluation, and management of autism spectrum disorders in children.
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