MED: Medicine Papers

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ICAT: a novel algorithm to robustly identify cell states following perturbations in single cell transcriptomes
(2022-05-29) Hawkins, Dakota Y.; Zuch, Daniel T.; Huth, James; Rodriguez-Sastre, Nahomie; McCutcheon, Kelley R.; Glick, Abigail; Lion, Alexandra T.; Thomas, Christopher F.; Descoteaux, Abigail E.; Johnson, W. Evan; Bradham, Cynthia A.
Associations of accelerometer-measured physical activity and sedentary time with chronic kidney disease: The Framingham Heart Study
(2020) Lee, Joowon; Walker, Maura E.; Gabriel, Kelley P.; Vasan, Ramachandran S.; Xanthakis, Vanessa
BACKGROUND: Few studies examined the individual and conjoint associations of accelerometer-measured physical activity (PA) and sedentary times with the prevalence of chronic kidney disease (CKD) among older adults. METHODS: We evaluated 1,268 Framingham Offspring Study participants (mean age 69.2 years, 53.8% women) between 2011 and 2014. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.732 and/or urine albumin-to-creatinine ratio (UACR) ≥25/35 μg/mg (men/women). We used multivariable logistic regression models to relate time spent being sedentary and active with the odds of CKD. We then performed compositional data analysis to estimate the change in the eGFR and UACR when a fixed proportion of time in one activity behavior (among the following: moderate to vigorous physical activity [MVPA], light intensity physical activity [LIPA], and sedentary) is reallocated to another activity behavior. RESULTS: Overall, 258 participants had prevalent CKD (20.4%; 120 women). Higher total PA ([MVPA+LIPA], adjusted-odds ratio [OR] per 30 minutes/day increase, 0.86; 95% CI, 0.78-0.96) and higher LIPA (OR per 30 minutes/day increase, 0.87; 95% CI, 0.76-0.99) were associated with lower odds of CKD. Additionally, higher sedentary time (OR per 30 minutes/day increase, 1.16; 95% CI, 1.04-1.29) was associated with higher odds of CKD. Reallocating 5% of the time from LIPA to sedentary was associated with the largest predicted difference in eGFR (-1.06 ml/min/1.73m2). Reallocating 1% of time spent in MVPA to sedentary status predicted the largest difference in UACR (14.37 μg/mg). CONCLUSION: The findings suggest that increasing LIPA and maintaining MVPA at the expense of sedentary time may be associated with a lower risk of CKD in community-based older adults.
Klotho pathways, myelination disorders, neurodegenerative diseases, and epigenetic drugs
(Mary Ann Liebert, Inc., 2020) Moos, Walter H.; Faller, Douglas V.; Glavas, Ioannis P.; Harpp, David N.; Kanara, Iphigenia; Mavrakis, Anastasios N.; Pernokas, Julie; Pernokas, Mark; Pinkert, Carl A.; Powers, Whitney R.; Sampani, Konstantina; Steliou, Kosta; Vavvas, Demetrios G.; Zamboni, Robert J.; Kodukula, Krishna; Chen, Xiaohong
In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.
Epigenetic treatment of persistent viral infections
(Wiley, 2017-02-01) Moos, Walter H.; Pinkert, Carl A.; Irwin, Michael H.; Faller, Douglas V.; Kodukula, Krishna; Glavas, Ioannis P.; Steliou, Kosta
Approximately 2,500 years ago, Hippocrates used the word herpes as a medical term to describe lesions that appeared to creep or crawl on the skin, advocating heat as a possible treatment. During the last 50 years, pharmaceutical research has made great strides, and therapeutic options have expanded to include small molecule antiviral agents, protease inhibitors, preventive vaccines for a handful of the papillomaviruses, and even cures for hepatitis C virus infections. However, effective treatments for persistent and recurrent viral infections, particularly the highly prevalent herpesviruses, continue to represent a significant unmet medical need, affecting the majority of the world’s population. Exploring the population diversity of the human microbiome and the effects its compositional variances have on the immune system, health, and disease are the subjects of intense investigational research and study. Among the collection of viruses, bacteria, fungi, and single-celled eukaryotes that comprise the human microbiome, the virome has been grossly understudied relative to the influence it exerts on human pathophysiology, much as mitochondria have until recently failed to receive the attention they deserve, given their critical biomedical importance. Fortunately, cellular epigenetic machinery offers a wealth of druggable targets for therapeutic intervention in numerous disease indications, including those outlined above. With advances in synthetic biology, engineering our body’s commensal microorganisms to seek out and destroy pathogenic species is clearly on the horizon. This is especially the case given recent breakthroughs in genetic manipulation with tools such as the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated) gene-editing platforms. Tying these concepts together with our previous work on the microbiome and neurodegenerative and neuropsychiatric diseases, we suggest that, because mammalian cells respond to a viral infection by triggering a cascade of antiviral innate immune responses governed substantially by the cell’s mitochondria, small molecule carnitinoids represent a new class of therapeutics with potential widespread utility against many infectious insults.
Epigenetic treatment of dermatologic disorders
(Wiley, 2019-09) Moos, Walter H.; Faller, Douglas V.; Glavas, Ioannis P.; Harpp, David N.; Kanara, Iphigenia; Pinkert, Carl A.; Powers, Whitney R.; Sampani, Konstantina; Steliou, Kosta; Vavvas, Demetrios G.; Kodukula, Krishna; Zamboni, Robert J.
Healthy skin protects us against a multitude of insults but injured or maladapted skin can lead to infection, inflammation or worse. Fortunately, naturally occurring bioactive products, many commonly found in olive oil and other plant and vegetable extracts,have shown utility in treating skin and related diseases as well as conditioning the skin to maintain its healthy function. Powerful agents targeting nuclear regulatory pathways continue to hold promise as new or repurposed therapies for a wide variety of ills and skin conditions. Epigenetic approaches that activate Nrf2 to effect detoxification, redox balance, DNA repair and mitochondrial function are noteworthy. Some of the disease applications being actively investigated range from eczema and psoriasis to skin cancer and diabetes-related wound healing to name just a few
Epigenetic treatment of neurodegenerative disorders: Alzheimer and Parkinson diseases
(Wiley-Blackwell, 2016-05-01) Irwin, Michael H.; Moos, Walter H.; Faller, Douglas V.; Steliou, Kosta; Pinkert, Carl A.
In this review we expand our discussion of epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt–Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy.
Epigenetic treatment of neuropsychiatric disorders: autism and schizophrenia
(John Wiley & Sons, Inc., 2016-03-01) Moos, Walter H.; Maneta, Eleni; Pinkert, Carl A.; Irwin, Michael H.; Hoffman, Michelle E.; Faller, Douglas V.; Steliou, Kosta
Neuropsychiatric disorders are a heterogeneous group of conditions that often share underlying mitochondrial dysfunction and biological pathways implicated in their pathogenesis, progression, and treatment. To date, these disorders have proven notoriously resistant to molecular-targeted therapies, and clinical options are relegated to interventional types, which do not address the core symptoms of the disease. In this review, we discuss emerging epigenetic-driven approaches using novel acylcarnitine esters (carnitinoids) that act on master regulators of antioxidant and cytoprotective genes and mitophagic pathways. These carnitinoids are actively transported, mitochondria-localizing, biomimetic coenzyme A surrogates of short-chain fatty acids, which inhibit histone deacetylase and may reinvigorate synaptic plasticity and protect against neuronal damage. We outline these neuroprotective effects in the context of treatment of neuropsychiatric disorders such as autism spectrum disorder and schizophrenia.
Butyrate histone deacetylase inhibitors.
(2012-08) Steliou, Kosta; Boosalis, Michael S.; Perrine, Susan P.; Sangerman, José; Faller, Douglas V.
In addition to being a part of the metabolic fatty acid fuel cycle, butyrate is also capable of inducing growth arrest in a variety of normal cell types and senescence-like phenotypes in gynecological cancer cells, inhibiting DNA synthesis and cell growth in colonic tumor cell lines, suppressing hTERT mRNA expression and telomerase activity in human prostate cancer cells, and inducing stem cell differentiation and apoptosis by DNA fragmentation. It regulates gene expression by inhibiting histone deacetylases (HDACs), enhances memory recovery and formation in mice, stimulates neurogenesis in the ischemic brain, promotes osteoblast formation, selectively blocks cell replication in transformed cells (compared to healthy cells), and can prevent and treat diet-induced obesity and insulin resistance in mouse models of obesity, as well as stimulate fetal hemoglobin expression in individuals with hematologic diseases such as the thalassemias and sickle-cell disease, in addition to a multitude of other biochemical effects in vivo. However, efforts to exploit the potential of butyrate in the clinical treatment of cancer and other medical disorders are thwarted by its poor pharmacological properties (short half-life and first-pass hepatic clearance) and the multigram doses needed to achieve therapeutic concentrations in vivo. Herein, we review some of the methods used to overcome these difficulties with an emphasis on HDAC inhibition.
Low cost extraction and isothermal amplification of DNA for infectious diarrhea diagnosis
(Public Library of Science, 2013-03-28) Huang, Shichu; Do, Jaephil; Mahalanabis, Madhumita; Fan, Andy; Zhao, Lei; Jepeal, Lisa; Singh, Satish K.; Klapperich, Catherine M.
In order to counter the common perception that molecular diagnostics are too complicated to work in low resource settings, we have performed a difficult sample preparation and DNA amplification protocol using instrumentation designed to be operated without wall or battery power. In this work we have combined a nearly electricity-free nucleic acid extraction process with an electricity-free isothermal amplification assay to detect the presence of Clostridium difficile (C. difficile) DNA in the stool of infected patients. We used helicase-dependent isothermal amplification (HDA) to amplify the DNA in a low-cost, thermoplastic reaction chip heated with a pair of commercially available toe warmers, while using a simple Styrofoam insulator. DNA was extracted from known positive and negative stool samples. The DNA extraction protocol utilized an air pressure driven solid phase extraction device run using a standard bicycle pump. The simple heater setup required no electricity or battery and was capable of maintaining the temperature at 65°C±2°C for 55 min, suitable for repeatable HDA amplification. Experiments were performed to explore the adaptability of the system for use in a range of ambient conditions. When compared to a traditional centrifuge extraction protocol and a laboratory thermocycler, this disposable, no power platform achieved approximately the same lower limit of detection (1.25×10−2 pg of C. difficile DNA) while requiring much less raw material and a fraction of the lab infrastructure and cost. This proof of concept study could greatly impact the accessibility of molecular assays for applications in global health.
LITAF mediation of increased TNF-α secretion from inflamed colonic lamina propria macrophages.
(2011) Bushell, Kristen N.; Leeman, Susan E.; Gillespie, Earl; Gower, Adam C.; Reed, Karen L.; Stucchi, Arthur F.; Becker, James M.; Amar, Salomon
Dysregulation of TNF-α in lamina propria macrophages (LPM) is a feature of inflammatory bowel diseases (IBD). LPS-Induced-TNF-Alpha-Factor (LITAF) is a transcription factor that mediates TNF-α expression. To determine whether LITAF participates in the mediation of TNF-α expression in acutely inflamed colonic tissues, we first established the TNBS-induced colonic inflammation model in C57BL/6 mice. LPM were harvested from non-inflamed and inflamed colonic tissue and inflammatory parameters TNF-α and LITAF mRNA and protein levels were measured ex-vivo. LPM from TNBS-treated mice secreted significantly more TNF-α at basal state and in response to LPS than LPM from untreated mice (p<0.05). LITAF mRNA and protein levels were elevated in LPM from TNBS compared with untreated animals and LPS further increased LITAF protein levels in LPM from inflamed tissue (P<0.05). To further confirm the role of LITAF in acutely inflamed colonic tissues, TNBS-induced colonic inflammation was produced in LITAF macrophage specific knockout mice (LITAF mac -/- mice) and compared to wild type (WT) C57BL/6. Twenty four hours following TNBS administration, colonic tissue from LITAF mac -/- mice had less MPO activity and reduced colonic TNF-α mRNA then WT C57BL/6 mice (p<0.05). LPM harvested from LITAF mac -/- secreted significantly less TNF-α in response to LPS than wild type (WT) C57BL/6 (p<0.05). This study provides evidence that LITAF contributes to the regulation of TNF-α in LPM harvested following acute inflammation or LPS treatment paving the way for future work focusing on LITAF inhibitors in the treatment of TNF-α-mediated inflammatory conditions.
The multiple hit hypothesis for Gulf War illness: self-reported chemical/biological weapons exposure and mild traumatic brain injury
(MDPI, 2018-11-01) Janulewicz, Patricia; Krengel, Maxine; Quinn, Emily; Heeren, Timothy; Toomey, Rosemary; Killiany, Ronald; Zundel, Clara; Ajama, Joy; O'Callaghan, James; Steele, Lea; Klimas, Nancy; Sullivan, Kimberly
The Gulf War Illness Consortium (GWIC) was designed to identify objective biomarkers of Gulf War Illness (GWI) in 1991 Gulf War veterans. The symptoms of GWI include fatigue, pain, cognitive problems, gastrointestinal, respiratory, and skin problems. Neurotoxicant exposures during deployment, such as pesticides, sarin, and pyridostigmine bromide pills have been identified as contributors to GWI. We have also found an association between mild traumatic brain injury (mTBI) and increased rates of GWI. However, the combined impact of these physical and chemical exposures has not yet been explored in GWI. The objective of this study was to examine both self-reported mTBI and exposure to chemical/biological weapons (CBW) as a multiple or two hit model for increased risk of GWI and other chronic health conditions. The study population included 125 Gulf War (GW) veterans from the Boston GWIC. Exposure to CBW was reported in 47.2% of the study population, and 35.2% reported sustaining a mTBI during the war. Results confirmed that those with both exposures (mTBI and CBW) had higher rates of comorbid chronic health conditions while rates of GWI were equivalent for mTBI and CBW or mTBI alone. The timing of exposure to mTBI was found to be strikingly different between those with GWI and those without it. Correspondingly, 42.3% of GWI cases reported experiencing a mTBI during military service while none of the controls did (p = 0.0002). Rates of mTBI before and after the war did not differ between the cases and controls. In addition, 54% of cases compared to 14.3% of controls (p = <0.001) reported being exposed to CBW during military service. The current study examined the relation of the separate and combined effects of exposure to mTBI and CBW in 1991 GW veterans. The findings from this study suggest that both exposure to mTBI and CBW are associated with the development of GWI and multiple chronic health conditions and that combined exposure appears to lead to higher risk of chronic health effects.
Epigenetic treatment of neurodegenerative ophthalmic disorders: an eye toward the future.
(2017) Moos, Walter H.; Faller, Douglas V.; Glavas, Ioannis P.; Harpp, David N.; Irwin, Michael H.; Kanara, Iphigenia; Pinkert, Carl A.; Powers, Whitney R.; Steliou, Kosta; Vavvas, Demetrios G.; Kodukula, Krishna
Eye disease is one of the primary medical conditions that requires attention and therapeutic intervention in ageing populations worldwide. Further, the global burden of diabetes and obesity, along with heart disease, all lead to secondary manifestations of ophthalmic distress. Therefore, there is increased interest in developing innovative new approaches that target various mechanisms and sequelae driving conditions that result in adverse vision. The research challenge is even greater given that the terrain of eye diseases is difficult to landscape into a single therapeutic theme. This report addresses the burden of eye disease due to mitochondrial dysfunction, including antioxidant, autophagic, epigenetic, mitophagic, and other cellular processes that modulate the biomedical end result. In this light, we single out lipoic acid as a potent known natural activator of these pathways, along with alternative and potentially more effective conjugates, which together harness the necessary potency, specificity, and biodistribution parameters required for improved therapeutic outcomes.
Interactive single cell RNA-Seq analysis with Single Cell Toolkit (SCTK)
(2019-05) Johnson, W. Evan; Jenkins, David; Khan, Mohammed Muzamil; Faits, Tyler; Zhang, Yuqing; McFarlane, Ada; Zhao, Yue; Campbell, Joshua David; Yajima, Masanao
I will present the Single Cell Toolkit (SCTK), an R package and interactive single cell RNA-sequencing (scRNA-Seq) analysis package that provides the first complete workflow for scRNA-Seq data analysis and visualization using a set of R functions and an interactive web interface. Users can perform analysis with modules for filtering raw results, clustering, batch correction, differential expression, pathway enrichment, and scRNA-Seq study design. The toolkit supports command line or pipeline data processing, and results can be loaded into the GUI for additional exploration and downstream analysis. We demonstrate the effectiveness of the SCTK on multiple scRNA-seq examples, including data from mucosal-associated invariant T cells, induced pluripotent stem cells, and breast cancer tumor cells. While other scRNA-Seq analysis tools exist, the SCTK is the first fully interactive analysis toolkit for scRNA-Seq data available within the R language.
A transitional opioid program to engage hospitalized drug users
(J Gen Intern Med., 2010-08) Shanahan, Christopher W.; Beers, D.; Alford, Daniel P.; Brigandi, E.; Samet, Jeffrey H.
BACKGROUND: Many opioid-dependent patients do not receive care for addiction issues when hospitalized for other medical problems. Based on 3 years of clinical practice, we report the Transitional Opioid Program (TOP) experience using hospitalization as a "reachable moment" to identify and link opioid-dependent persons to addiction treatment from medical care. METHODS: A program nurse identified, assessed, and enrolled hospitalized, out-of-treatment opioid-dependent drug users based on their receipt of methadone during hospitalization. At discharge, patients transitioned to an outpatient interim opioid agonist program providing 30-day stabilization followed by 60-day taper. The nurse provided case management emphasizing HIV risk reduction, health education, counseling, and medical follow-up. Treatment outcomes included opioid agonist stabilization then taper or transfer to long-term opioid agonist treatment. RESULTS: From January 2002 to January 2005, 362 unique hospitalized, opioid-dependent drug users were screened; 56% (n = 203) met eligibility criteria and enrolled into the program. Subsequently, 82% (167/203) presented to the program clinic post-hospital discharge; for 59% (119/203) treatment was provided, for 26% (52/203) treatment was not provided, and for 16% (32/203) treatment was not possible (pursuit of TOP objectives precluded by medical problems, psychiatric issues, or incarceration). Program patients adhered to a spectrum of medical recommendations (e.g., obtaining prescription medications, medical follow-up). CONCLUSIONS: The Transitional Opioid Program (TOP) identified at-risk hospitalized, out-of-treatment opioid-dependent drug users and, by offering a range of treatment intensity options, engaged a majority into addiction treatment. Hospitalization can be a "reachable moment" to engage and link drug users into addiction treatment.
Inhibitory Effects of Robo2 on Nephrin: A Crosstalk between Positive and Negative Signals Regulating Podocyte Structure
(Elsevier, 2012-07-26) Fan, Xueping; Li, Qinggang; Pisarek-Horowitz, Anna; Rasouly, Hila Milo; Wang, Xiangling; Bonegio, Ramon G.; Wang, Hang; McLaughlin, Margaret; Mangos, Steve; Kalluri, Raghu; Holzman, Lawrence B.; Drummond, Iain A.; Brown, Dennis; Salant, David J.; Lu, Weining
Robo2 is the cell surface receptor for the repulsive guidance cue Slit and is involved in axon guidance and neuronal migration. Nephrin is a podocyte slit- diaphragm protein that functions in the kidney glomerular filtration barrier. Here, we report that Robo2 is expressed at the basal surface of mouse podocytes and colocalizes with nephrin. Biochemical studies indicate that Robo2 forms a complex with nephrin in the kidney through adaptor protein Nck. In contrast to the role of nephrin that promotes actin polymerization, Slit2-Robo2 signaling inhibits nephrin-induced actin polymerization. In addition, the amount of F-actin associated with nephrin is increased in Robo2 knockout mice that develop an altered podocyte foot process structure. Genetic interaction study further reveals that loss of Robo2 alleviates the abnormal podocyte structural pheno- type in nephrin null mice. These results suggest that Robo2 signaling acts as a negative regulator on neph- rin to influence podocyte foot process architecture.
Noninvasive Assessment of Antenatal Hydronephrosis in Mice Reveals a Critical Role for Robo2 in Maintaining Anti-Reflux Mechanism
(PLoS ONE, 2011-09-20) Wang, Hang; Li, Qinggang; Liu, Juan; Mendelsohn, Cathy; Salant, David J.; Lu, Weining
Antenatal hydronephrosis and vesicoureteral reflux (VUR) are common renal tract birth defects. We recently showed that disruption of the Robo2 gene is associated with VUR in humans and antenatal hydronephrosis in knockout mice. However, the natural history, causal relationship and developmental origins of these clinical conditions remain largely unclear. Although the hydronephrosis phenotype in Robo2 knockout mice has been attributed to the coexistence of ureteral reflux and obstruction in the same mice, this hypothesis has not been tested experimentally. Here we used noninvasive high- resolution micro-ultrasonography and pathological analysis to follow the progression of antenatal hydronephrosis in individual Robo2-deficient mice from embryo to adulthood. We found that hydronephrosis progressed continuously after birth with no spontaneous resolution. With the use of a microbubble ultrasound contrast agent and ultrasound-guided percutaneous aspiration, we demonstrated that antenatal hydronephrosis in Robo2-deficient mice is caused by high-grade VUR resulting from a dilated and incompetent ureterovesical junction rather than ureteral obstruction. We further documented Robo2 expression around the developing ureterovesical junction and identified early dilatation of ureteral orifice structures as a potential fetal origin of antenatal hydronephrosis and VUR. Our results thus demonstrate that Robo2 is crucial for the formation of a normal ureteral orifice and for the maintenance of an effective anti-reflux mechanism. This study also establishes a reproducible genetic mouse model of progressive antenatal hydronephrosis and primary high- grade VUR.
Translation of artemether-lumefantrine treatment policy into paediatric clinical practice: an early experience from Kenya
(Blackwell Publishing Ltd, 2008-01) Zurovac, D.; Njogu, J.; Akhwale, W.; Hamer, D.H.; Snow, R.W.
OBJECTIVE. To describe the quality of outpatient paediatric malaria case-management approximately 4-6 months after artemether-lumefantrine (AL) replaced sulfadoxine-pyrimethamine (SP) as the nationally recommended first-line therapy in Kenya. METHODS. Cross-sectional survey at all government facilities in four Kenyan districts. Main outcome measures were health facility and health worker readiness to implement AL policy; quality of antimalarial prescribing, counselling and drug dispensing in comparison with national guidelines; and factors influencing AL prescribing for treatment of uncomplicated malaria in under-fives. RESULTS. We evaluated 193 facilities, 227 health workers and 1533 sick-child consultations. Health facility and health worker readiness was variable: 89% of facilities stocked AL, 55% of health workers had access to guidelines, 46% received in-service training on AL and only 1% of facilities had AL wall charts. Of 940 children who needed AL treatment, AL was prescribed for 26%, amodiaquine for 39%, SP for 4%, various other antimalarials for 8% and 23% of children left the facility without any antimalarial prescribed. When AL was prescribed, 92% of children were prescribed correct weight-specific dose. AL dispensing and counselling tasks were variably performed. Higher health worker's cadre, in-service training including AL use, positive malaria test, main complaint of fever and high temperature were associated with better prescribing. CONCLUSIONS. Changes in clinical practices at the point of care might take longer than anticipated. Delivery of successful interventions and their scaling up to increase coverage are important during this process; however, this should be accompanied by rigorous research evaluations, corrective actions on existing interventions and testing cost-effectiveness of novel interventions capable of improving and maintaining health worker performance and health systems to deliver artemisinin-based combination therapy in Africa.
Brief screening for co-occurring disorders among women entering substance abuse treatment
(BioMed Central, 2006-9-7) Lincoln, Alisa K.; Liebschutz, Jane M.; Chernoff, Miriam; Nguyen, Dana; Amaro, Hortensia
BACKGROUND. Despite the importance of identifying co-occurring psychiatric disorders in substance abuse treatment programs, there are few appropriate and validated instruments available to substance abuse treatment staff to conduct brief screen for these conditions. This paper describes the development, implementation and validation of a brief screening instrument for mental health diagnoses and trauma among a diverse sample of Black, Hispanic and White women in substance abuse treatment. With input from clinicians and consumers, we adapted longer existing validated instruments into a 14 question screen covering demographics, mental health symptoms and physical and sexual violence exposure. All women entering treatment (methadone, residential and out-patient) at five treatment sites were screened at intake (N = 374). RESULTS. Eighty nine percent reported a history of interpersonal violence, and 70% reported a history of sexual assault. Eighty-eight percent reported mental health symptoms in the last 30 days. The screening questions administered to 88 female clients were validated against in-depth psychiatric diagnostic assessments by trained mental health clinicians. We estimated measures of predictive validity, including sensitivity, specificity and predictive values positive and negative. Screening items were examined multiple ways to assess utility. The screen is a useful and valid proxy for PTSD but not for other mental illness. CONCLUSION. Substance abuse treatment programs should incorporate violence exposure questions into clinical use as a matter of policy. More work is needed to develop brief screening tools measures for front-line treatment staff to accurately assess other mental health needs of women entering substance abuse treatment
Effects of revised diagnostic recommendations on malaria treatment practices across age groups in Kenya
(Blackwell Publishing Ltd, 2008-06) Zurovac, D.; Njogu, J.; Akhwale, W.; Hamer, D.H.; Larson, B.A.; Snow, R.W.
OBJECTIVE. The recent change of treatment policy for uncomplicated malaria from sulfadoxine-pyrime-thamine to artemether-lumefantrine (AL) in Kenya was accompanied by revised malaria diagnosis recommendations promoting presumptive antimalarial treatment in young children and parasitological diagnosis in patients 5 years and older. We evaluated the impact of these age-specific recommendations on routine malaria treatment practices 4-6 months after AL treatment was implemented. METHODS. Cross-sectional, cluster sample survey using quality-of-care assessment methods in all government facilities in four Kenyan districts. Analysis was restricted to the 64 facilities with malaria diagnostics and AL available on the survey day. Main outcome measures were antimalarial treatment practices for febrile patients stratified by age, use of malaria diagnostic tests, and test result. RESULTS. Treatment practices for 706 febrile patients (401 young children and 305 patients =5 years) were evaluated. 43.0% of patients =5 years and 25.9% of children underwent parasitological malaria testing (87% by microscopy). AL was prescribed for 79.7% of patients =5 years with positive test results, for 9.7% with negative results and for 10.9% without a test. 84.6% of children with positive tests, 19.2% with negative tests, and 21.6% without tests were treated with AL. At least one antimalarial drug was prescribed for 75.0% of children and for 61.3% of patients =5 years with a negative test result. CONCLUSIONS. Despite different recommendations for patients below and above 5 years of age, malaria diagnosis and treatment practices were similar in the two age groups. Parasitological diagnosis was under-used in older children and adults, and young children were still tested. Use of AL was low overall and alternative antimalarials were commonly prescribed; but AL prescribing largely followed the results of malaria tests. Malaria diagnosis recommendations differing between age groups appear complex to implement; further strengthening of diagnosis and treatment practices under AL policy is required.
Role of Viral Hemagglutinin Glycosylation in Anti-Influenza Activities of Recombinant Surfactant Protein D
(Respiratory Research, 2008-9-23) Hartshorn, Kevan L.; Webby, Richard; White, Mitchell R.; Tecle, Tesfaldet; Pan, Clark; Boucher, Susan; Moreland, Rodney J.; Crouch, Erika C.; Scheule, Ronald K.
BACKGROUND. Surfactant protein D (SP-D) plays an important role in innate defense against influenza A viruses (IAVs) and other pathogens. METHODS. We tested antiviral activities of recombinant human SP-D against a panel of IAV strains that vary in glycosylation sites on their hemagglutinin (HA). For these experiments a recombinant version of human SP-D of the Met11, Ala160 genotype was used after it was characterized biochemically and structurally. RESULTS. Oligosaccharides at amino acid 165 on the HA in the H3N2 subtype and 104 in the H1N1 subtype are absent in collectin-resistant strains developed in vitro and are important for mediating antiviral activity of SP-D; however, other glycans on the HA of these viral subtypes also are involved in inhibition by SP-D. H3N2 strains obtained shortly after introduction into the human population were largely resistant to SP-D, despite having the glycan at 165. H3N2 strains have become steadily more sensitive to SP-D over time in the human population, in association with addition of other glycans to the head region of the HA. In contrast, H1N1 strains were most sensitive in the 1970s-1980s and more recent strains have become less sensitive, despite retaining the glycan at 104. Two H5N1 strains were also resistant to inhibition by SP-D. By comparing sites of glycan attachment on sensitive vs. resistant strains, specific glycan sites on the head domain of the HA are implicated as important for inhibition by SP-D. Molecular modeling of the glycan attachment sites on HA and the carbohydrate recognition domain of SPD are consistent with these observations. CONCLUSION. Inhibition by SP-D correlates with presence of several glycan attachment sites on the HA. Pandemic and avian strains appear to lack susceptibility to SP-D and this could be a contributory factor to their virulence.

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