Intranuclear Neuronal Inclusions in Huntington''s Disease and Dentatorubral and Pallidoluysian Atrophy: Correlation between the Density of Inclusions andIT15CAG Triplet Repeat Length

Huntington's disease (HD) is caused by CAG triplet repeat expansion inIT15which leads to polyglutamine stretches in the HD protein product, huntingtin. The pathological hallmark of HD is the degeneration of subsets of neurons, primarily those in the striatum and neocortex. Specific morphological markers of affected cells have not been identified in patients with HD, although a unique intranuclear inclusion was recently reported in neurons of transgenic animals expressing a construct encoding the N-terminal part (including the glutamine repeat) of huntingtin (Davieset al., 1997). In order to understand the importance of this finding, we sought for comparable nuclear abnormalities in autopsy material from patients with HD. In all 20 HD cases examined, anti-ubiquitin and N-terminal huntingtin antibodies identified intranuclear inclusions in neurons and the frequency of these lesions correlated with the length of the CAG repeat inIT15. In addition, examination of material from the related HD-like triplet repeat disorder, dentatorubral and pallidoluysian atrophy, also revealed intranuclear neuronal inclusions. These findings suggest that intranuclear inclusions containing protein aggregates may be a common feature of the pathogenesis of glutamine repeat neurodegenerative disorders.     

Organization of TNIK in dendritic spines

Tumor necrosis factor receptor‐associated factor 2 (TRAF2)‐ and noncatalytic region of tyrosine kinase (NCK)‐interacting kinase (TNIK) has been identified as an interactor in the psychiatric risk factor, Disrupted in Schizophrenia 1 (DISC1). As a step toward deciphering its function in the brain, we performed high‐resolution light and electron microscopic immunocytochemistry. We demonstrate here that TNIK is expressed in neurons throughout the adult mouse brain. In striatum and cerebral cortex, TNIK concentrates in dendritic spines, especially in the vicinity of the lateral edge of the synapse. Thus, TNIK is highly enriched at a microdomain critical for glutamatergic signaling. J. Comp. Neurol. 523:1913–1924, 2015 © 2015 Wiley Periodicals, Inc.     

Predicting Clostridium difficile Stool Cytotoxin Results in Hospitalized Patients with Diarrhea

OBJECTIVE: To validate a model for the prediction of Clostridium difficile cytotoxin assay results, and to identify a subgroup of patients with a very low likelihood of C. difficile-associated disease in whom the yield of routine cytotoxin testing is low. DESIGN: Prospective cohort study. Relevant clinical symptoms, signs, and antibiotic exposure were recorded before reporting of assay results. Each predictor was assigned a score based on regression coefficients, and patients were stratified according to their total score. SETTING: Two urban, tertiary care, university hospitals. PATIENTS: A total of 609 consecutive adult inpatients who received testing for C. difficile cytotoxin during a 3-month period in 1994. MEASUREMENTS AND MAIN RESULTS: The prevalence of positive cytotoxin assays was 8% in the validation set, compared with 14% in the derivation set. Defining patients without both prior antibiotic use and at least one symptom predictor (significant diarrhea or abdominal pain) as a low-risk subgroup, the misclassification rate was 2.8% (5/177) for assay results; of the five misclassified cases patients, only one was judged to have C. difficile-associated disease. Use of this rule to identify low-risk patients could have potentially averted 29% of all cytotoxin assays. CONCLUSIONS: Exposure to role models in a particular clinical field is strongly associated with medical students' choice of clinical field for residency training. Knowing which characteristics students look for in their role models should help identify the physicians who may be most influential in medical students' career choice.     

Avoiding collateral damage in the war on hypertension

• When performed by experienced clinicians, renal nerve denervation (RND) can be done with very low risk of complication and/or acute renal injury
• Renal function seems to remain unchanged in this small series over 3 years
• More studies are needed to establish the role of renal biomarkers in assessment of acute renal injury in this setting and larger series of RND in azotemic patients should be done before the procedure indications can be expanded

     

The Ubiquitin-Proteasome Reporter GFPu Does Not Accumulate in Neurons of the R6/2 Transgenic Mouse Model of Huntington's Disease

Impairment of the ubiquitin-proteasome system (UPS) has long been considered an attractive hypothesis to explain the selective dysfunction and death of neurons in polyglutamine disorders such as Huntington's disease (HD). The fact that inclusion bodies in HD mouse models and patient brains are rich in ubiquitin and proteasome components suggests that the UPS may be hindered directly or indirectly by inclusion bodies or their misfolded monomeric or oligomeric precursors. However, studies into UPS function in various polyglutamine disease models have yielded conflicting results, suggesting mutant polyglutamine tracts may exert different effects on the UPS depending on protein context, expression level, subcellular localisation and cell-type. To investigate UPS function in a well-characterised mouse model of HD, we have crossed R6/2 HD mice with transgenic UPS reporter mice expressing the GFPu construct. The GFPu construct comprises GFP fused to a constitutive degradation signal (CL-1) that promotes its rapid degradation under conditions of a healthy UPS. Using a combination of immunoblot analysis, fluorescence and immunofluorescence microscopy studies, we found that steady-state GFPu levels were not detectably different between R6/2 and non-R6/2 brain. We observed no correlation between inclusion body formation and GFPu accumulation, suggesting no direct relationship between protein aggregation and global UPS inhibition in R6/2 mice. These findings suggest that while certain branches of the UPS can be impaired by mutant polyglutamine proteins, such proteins do not necessarily cause total blockade of UPS-dependent degradation. It is therefore likely that the relationship between mutant polyglutamine proteins and the UPS is more complex than originally anticipated.     

Health Care Equity in the Use of Advanced Analytics and Artificial Intelligence Technologies in Primary Care

The integration of advanced analytics and artificial intelligence (AI) technologies into the practice of medicine holds much promise. Yet, the opportunity to leverage these tools carries with it an equal responsibility to ensure that principles of equity are incorporated into their implementation and use. Without such efforts, tools will potentially reflect the myriad of ways in which data, algorithmic, and analytic biases can be produced, with the potential to widen inequities by race, ethnicity, gender, and other sociodemographic factors implicated in disparate health outcomes. We propose a set of strategic assertions to examine before, during, and after adoption of these technologies in order to facilitate healthcare equity across all patient population groups. The purpose is to enable generalists to promote engagement with technology companies and co-create, promote, or support innovation and insights that can potentially inform decision-making and health care equity.

Primary care has a critical role to play in ensuring that mission-driven values aimed at eliminating health care disparities are prioritized in the development, selection, clinical implementation, and use of advanced analytics and AI technologies. Because the application of these technologies in primary care is in its infancy, primary care professionals have a unique opportunity to guide the growth of fair, transparent, and ethical AI and analytics applications that embody health equity principles that meet the needs of diverse populations.Today, clinical decision-making in primary care is influenced by the ongoing integration of advanced analytics and AI technologies into the practice of medicine.¹ Examples include patient risk stratification, predictive modeling for disease progression,^2,3 decision-support applications,^4,5 and population health management tools for cancer screenings,^6,7 diabetes,^8,9 cardiovascular disease,^10–12 and other chronic disease conditions.¹³ These and other similar tools may or may not explicitly address the needs of diverse patient populations in primary care. Unless explicit strategies are used to promote equity, advanced analytics may inadvertently perpetuate inequities in primary care delivery, such as the use of algorithms that erroneously treat race categories as biological rather than social attributes in clinical decision making.¹⁴The importance of articulating equity as a specific goal for integrating AI into care is described in the 2019 National Academy of Medicine (NAM) report, Artificial Intelligence in Health Care: The Hope, The Hype, The Promise, The Peril. The report describes a quintuple aim to improve population health, reduce costs, improve the patient experience, promote care team well-being and achieve health care equity.¹⁵ Specifically, the report suggests that embracing health care equity would challenge a siloed approach to health care by addressing the diversity of patient needs using varied sources of data that include social determinants of health and psychosocial risk factors (Fig. ​(Fig.1).1). Equity, integral to the quintuple aim, would also require engaging diverse stakeholders to inform the design of AI applications and to monitor the impact of these technologies. The NAM report underscores the need for explicit strategies to actively embrace health care equity; without such strategies, AI applications are likely to reflect human biases in ways that will widen inequities by race/ethnicity, gender identity, sexual orientation, disability status, age, social class, geography, and other dimensions of social identity.^15,16 Open in a separate windowFigure 1Building on the quintuple aims of equity and inclusion in health and healthcare (National Academy of Medicine).¹⁴Indifference to technology and passive acceptance of biased tools pose risks to health care equity among diverse groups. To prevent this, we must be willing to articulate the priorities for successful AI and advanced analytics implementation and adopt strategies and processes that lead to equitable outcomes. To further these aims, we propose the following series of questions that should be considered before and during the adoption of an AI technology or advanced analytic strategy into practice. First, what needs of diverse patient populations can be better served by applying advanced analytics and AI technology? How can novel and diverse data sources be leveraged to enhance equity in AI implementations? How can patients and community members engage with stakeholders involved in shaping the use of AI in the delivery of health care? And finally, how are principles of diversity and inclusion reflected among those who are involved in the development, selection, and use of technology solutions to enable equitable health care?     

Identification and characterization of a Streptococcus pyogenes operon involved in binding of hemoproteins and acquisition of iron

The hemolytic Streptococcus pyogenes can use a variety of heme compounds as an iron source. In this study, we investigate hemoprotein utilization by S. pyogenes. We demonstrate that surface proteins contribute to the binding of hemoproteins to S. pyogenes. We identify an ABC transporter from the iron complex family named sia for streptococcal iron acquisition, which consists of a lipoprotein (siaA), membrane permease (siaB), and ATPase (siaC). The sia transporter is part of a highly conserved, iron regulated, 10-gene operon. SiaA, which was localized to the cell membrane, could specifically bind hemoglobin. The operon's first gene encodes a novel bacterial protein that bound hemoglobin, myoglobin, heme-albumin, and hemoglobin-haptoglobin (but not apo-haptoglobin) and therefore was named Shr, for streptococcal hemoprotein receptor. PhoZ fusion and Western blot analysis showed that Shr has a leader peptide and is found in both membrane-bound and soluble forms. An M1 SF370 strain with a polar mutation in shr was more resistant to streptonigrin and hydrogen peroxide, suggesting decreased iron uptake. The addition of hemoglobin to the culture medium increased cell resistance to hydrogen peroxide in SF370 but not in the mutant, implying the sia operon may be involved in hemoglobin-dependent resistance to oxidative stress. The shr mutant demonstrated reduced hemoglobin binding, though cell growth in iron-depleted medium supplemented with hemoglobin, whole blood, or ferric citrate was not affected, suggesting additional systems are involved in hemoglobin utilization. SiaA and Shr are the first hemoprotein receptors identified in S. pyogenes; their possible role in iron capture is discussed.     

Reed‐sternberg cells in breast FNA of a patient with left breast mass

Hodgkin's lymphoma is a potentially curable malignancy of the lymphatic system characterized by a variable number of scattered and large mononucleated and multinucleated tumor cells, the Hodgkin and Reed‐Sternberg cells residing in an abundant heterogeneous admixture of non‐neoplastic inflammatory cells. It represents approximately 30% of all lymphomas according to the World Health Organization (WHO). Patients with Hodgkin's lymphoma typically present with painless peripheral adenopathy, fever, night sweats, and weight loss. We report a rare case of Hodgkin's lymphoma presented as a breast mass in a 23‐year‐old woman diagnosed on fine needle aspiration (FNA). At presentation, she had no B symptoms, or palpable lymphadenopathy. Diagn. Cytopathol. 2010;38:663–668. © 2010 Wiley‐Liss, Inc.     

The Estimation of Lung Mechanics Parameters in the Presence of Pathology: A Theoretical Analysis

Mechanical lung function is frequently assessed in terms of lung resistance (R _L), lung elastance (E _L), and airway resistance (R _aw). These quantities are determined by measuring input impedance at various oscillation frequencies, and allow lung tissue resistance (R _t) to be estimated as the difference between R _L and R _aw. These various parameters change in characteristic ways in the presence of lung pathology. In particular, the ratio R _t/E _L (known as hysteresivity, (η) has been shown both experimentally and in numerical simulations to increase when regional heterogeneities in mechanical function develop throughout the lung. In this study, we performed an analytical investigation of a two-compartment lung model and showed that while heterogeneity always leads to an increase in E _L, η will increase only initially. When heterogeneity becomes extreme, η stops increasing and starts to decrease. However, there are no experimental reports of η decreasing under conditions in which heterogeneity would be expected to exist. We speculate that this is because liquid bridges invariably form across airway lumen that narrow to a certain point, thereby preventing them from achieving arbitrarily small non-zero radii. We also show that recruitment of closed lung units during lung inflation may lead to variables responses in both η and E _L.