Striosomes Mediate Value-Based Learning Vulnerable in Age and a Huntington's Disease Model.

Learning valence-based responses to favorable and unfavorable options requires judgments of the relative value of the options, a process necessary for species survival. We found, using engineered mice, that circuit connectivity and function of the striosome compartment of the striatum are critical for this type of learning. Calcium imaging during valence-based learning exhibited a selective correlation between learning and striosomal but not matrix signals. This striosomal activity encoded discrimination learning and was correlated with task engagement, which, in turn, could be regulated by chemogenetic excitation and inhibition. Striosomal function during discrimination learning was disturbed with aging and severely so in a mouse model of Huntington's disease. Anatomical and functional connectivity of parvalbumin-positive, putative fast-spiking interneurons (FSIs) to striatal projection neurons was enhanced in striosomes compared with matrix in mice that learned. Computational modeling of these findings suggests that FSIs can modulate the striosomal signal-to-noise ratio, crucial for discrimination and learning.

Cutaneous soft tissue tumors: diagnostically disorienting epithelioid tumors that are not epithelial, and other perplexing mesenchymal lesions.

Cutaneous soft tissue tumors with epithelioid features present a diagnostic challenge given that many entities in this category are rare, and they show morphologic overlap with significantly more common cutaneous epithelial and melanocytic neoplasms. The challenge is compounded by overlapping expression of epithelial or melanocytic markers in some of these entities. A broad spectrum of primary cutaneous epithelioid soft tissue tumors exists, including benign and malignant counterparts of tumors with various differentiation including melanocytic, peripheral nerve sheath, angiomatous, fibrohistiocytic, and myoid or myoepithelial, in addition to translocation-associated tumors lacking a derivative tissue type. Given this spectrum, an initial targeted immunohistochemical panel for epithelioid dermal and subcutaneous neoplasms is recommended, covering a broad spectrum of differentiation. In diagnostically challenging cases, select molecular studies can be employed to make critical distinctions between entities sharing morphologic and immunohistochemical properties. Due to sometimes marked differences in prognosis and treatment, knowledge and familiarity with epithelioid soft tissue tumors is key for any surgical pathologist who evaluates skin and subcutaneous biopsies and excision specimens. This concise review provides brief descriptions, key diagnostic features, and important modern ancillary studies for the diagnosis of non-epithelial, non-melanocytic cutaneous tumors that can exhibit a prominent degree of epithelioid morphology.

The sensory features of a food cue influence its ability to act as an incentive stimulus and evoke dopamine release in the nucleus accumbens core.

The sensory properties of a reward-paired cue (a conditioned stimulus; CS) may impact the motivational value attributed to the cue, and in turn influence the form of the conditioned response (CR) that develops. A cue with multiple sensory qualities, such as a moving lever-CS, may activate numerous neural pathways that process auditory and visual information, resulting in CRs that vary both within and between individuals. For example, CRs include approach to the lever-CS itself (rats that "sign-track"; ST), approach to the location of reward delivery (rats that "goal-track"; GT), or an "intermediate" combination of these behaviors. We found that the multimodal sensory features of the lever-CS were important to the development and expression of sign-tracking. When the lever-CS was covered, and thus could only be heard moving, STs not only continued to approach the lever location but also started to approach the food cup during the CS period. While still predictive of reward, the auditory component of the lever-CS was a much weaker conditioned reinforcer than the visible lever-CS. This plasticity in behavioral responding observed in STs closely resembled behaviors normally seen in rats classified as "intermediates." Furthermore, the ability of both the lever-CS and the reward-delivery to evoke dopamine release in the nucleus accumbens was also altered by covering the lever-dopamine signaling in STs resembled neurotransmission observed in rats that normally only GT. These data suggest that while the visible lever-CS was attractive, wanted, and had incentive value for STs, when presented in isolation, the auditory component of the cue was simply predictive of reward, lacking incentive salience. Therefore, the specific sensory features of cues may differentially contribute to responding and ensure behavioral flexibility.

Incidence and prevalence of hypertension in 18-40-year-old patients referred for palpitations with normal cardiac monitor findings.

Sixteen percent of patients referred for cardiology evaluation are found to have no cause for palpitations. Studies show that hypertension intricately influences "heart rate" and "contractility,?" the key components of "palpitation." While the prevalence of hypertension is 22.4% in 18-39-year-olds, the relationship between palpitations and hypertension remains unknown in this age group. In our study, we assessed the incidence and prevalence of hypertension over 5 years in 18-40-year-olds referred for palpitations who had no known arrhythmic cause for palpitations between January 1, 206 and December 31, 2017. We found that over a period of 2.2 (0.7-4.1) years, an additional 56% patients were diagnosed with stage 1 (65/130) and stage 2 (28/130) hypertension, increasing the prevalence from 16% at the start of the study period to 72% at the end of the study period (p < .0001). Hypertensive patients were obese (BMI: 29 [24-36] kg/m2 vs. 25 [22-31] kg/m2; p = .03), used nonsteroidal anti-inflammatory drugs (NSAIDs) (62 vs. 35%; p = .04), had a stronger family history of hypertension (55 vs. 4%; p < .0001) and exhibited higher systolic (124[120-130] mmHg vs. 112[108-115] mmHg; p < .0001) and diastolic (80[76-83] mmHg vs. 72[69-75] mmHg; p < .0001) blood pressures. Hypertension is commonly diagnosed in 18-40-year-old predominantly white female patients referred for palpitations without a known arrhythmic cause. The possibility of untreated hypertension causing palpitations in this cohort needs further evaluation.

Complementary and Inducible creERT2 Mouse Models for Functional Evaluation of Endothelial Cell Subtypes in the Bone Marrow.

In the adult bone marrow (BM), endothelial cells (ECs) are an integral component of the hematopoietic stem cell (HSC)-supportive niche, which modulates HSC activity by producing secreted and membrane-bound paracrine signals. Within the BM, distinct vascular arteriole, transitional, and sinusoidal EC subtypes display unique paracrine expression profiles and create anatomically-discrete microenvironments. However, the relative contributions of vascular endothelial subtypes in supporting hematopoiesis is unclear. Moreover, constitutive expression and off-target activity of currently available endothelial-specific and endothelial-subtype-specific murine cre lines potentially confound data analysis and interpretation. To address this, we describe two tamoxifen-inducible cre-expressing lines, Vegfr3-creERT2 and Cx40-creERT2, that efficiently label sinusoidal/transitional and arteriole endothelium respectively in adult marrow, without off-target activity in hematopoietic or perivascular cells. Utilizing an established mouse model in which cre-dependent recombination constitutively-activates MAPK signaling within adult endothelium, we identify arteriole ECs as the driver of MAPK-mediated hematopoietic dysfunction. These results define complementary tamoxifen-inducible creERT2-expressing mouse lines that label functionally-discrete and non-overlapping sinusoidal/transitional and arteriole EC populations in the adult BM, providing a robust toolset to investigate the differential contributions of vascular subtypes in maintaining hematopoietic homeostasis.

Therapeutic Carbohydrate Restriction as a Metabolic Modality for the Prevention and Treatment of Abnormal Uterine Bleeding.

Therapeutic carbohydrate restriction diets have been becoming increasingly popular over the years, resulting in dramatic weight loss and an improvement in metabolic disorders. Obesity, insulin resistance, and diabetes are the risk factors for many gynecologic morbidities such as uterine leiomyoma, endometrial polyps, and polycystic ovarian syndrome. There is evidence suggesting that the pathogenesis of cardiovascular disease is similar to that seen in many causes of abnormal uterine bleeding. We aim to explain how cardiovascular disease risk factor reduction with the use of therapeutic carbohydrate restriction may prevent and potentially treat these gynecologic disorders.

A case of niraparib PARP-Inhibitor induced Sweet Syndrome in gynecologic cancer.

Sweet Syndrome, or acute febrile neutrophilic dermatosis, is a rare inflammatory dermatologic disorder that can be spontaneous, associated with malignancy, or drug-induced. Reports of Sweet Syndrome in gynecologic oncology patients are sparse, and the majority are thought to be malignancy-associated. The case presented here represents the third case of drug-induced Sweet Syndrome in a gynecologic oncology patient. To the best of our knowledge, this is the first report of Sweet Syndrome after initiation of a poly (ADP-ribose) polymerase inhibitor (PARPi) for maintenance therapy in the treatment of high grade serous ovarian carcinoma (HGSOC). This represents one of the most severe dermatologic adverse effects of treatment with PARPi reported to date, requiring treatment discontinuation.

Diabetic ketoacidosis diagnosis in a hospital setting.

CONTEXT: Diabetic ketoacidosis (DKA) is an endocrine emergency that can occur in people with diabetes. Its incidence is estimated to be 220,340 hospital admissions each year. Treatment algorithms include fluid resuscitation, intravenous (IV) insulin infusion, and scheduled electrolyte and glucose monitoring. The misdiagnosis of DKA in the setting of hyperglycemic emergencies results in overtreatment and unnecessary increases in healthcare utilization and costs. OBJECTIVES: The aims of this study were to determine how often DKA is overdiagnosed in the context of other acute hyperglycemic emergencies, to describe the baseline characteristics of patients, to determine the hospital treatments for DKA, and to identify the frequency of endocrinology or diabetology consultation in the hospital setting. METHODS: A retrospective chart review was conducted utilizing charts from three different hospitals within a hospital system. Charts were identified utilizing ICD-10 codes for admissions to the hospital for DKA. If the patient was over 18 and had one of the diagnostic codes of interest, the chart was reviewed for further details regarding the criteria for DKA diagnosis as well as admission and treatment details. RESULTS: A total of 520 hospital admissions were included for review. DKA was incorrectly diagnosed in 28.4 % of the hospital admissions reviewed, based on a review of the labs and DKA diagnostic criteria. Most patients were admitted to the intensive care unit (ICU) and treated with IV insulin infusion (n=288). Consultation of endocrinology or diabetology occurred in 40.2 % (n=209) of all hospital admissions, and 128 of those consults occurred in ICU admissions. The diagnosis of DKA was incorrect in 92 of the patients admitted to the medical surgical unit (MSU) and in 49 of patients admitted to the ICU. CONCLUSIONS: Almost one third of hospital admissions for hyperglycemic emergencies were misdiagnosed and managed as DKA. DKA diagnostic criteria are specific; however, other diagnoses like hyperosmolar hyperglycemic syndrome (HHS), hyperglycemia, and euglycemic DKA can make an accurate diagnosis more complicated. Education directed at improving the diagnostic accuracy of DKA among healthcare providers is needed to improve diagnostic accuracy, ensure the appropriate use of hospital resources, and potentially reduce costs to the healthcare system.

Recognizing Ethyl Chloride Neurotoxicity: Inhalant Abuse Hidden in Plain Sight.

Ethyl chloride is a common topical anesthetic. However, when abused as an inhalant, effects can range from headaches and dizziness to debilitating neurotoxicity requiring intubation. While previous case reports describe the short-term reversible neurotoxicity of ethyl chloride, ours show chronic morbidity and mortality outcome. During the initial evaluation, it is essential to consider the rising trend of commercially available inhalants being used as recreational drugs. We present a case of a middle-aged man presenting with subacute neurotoxicity due to repeated abuse of ethyl chloride.

Prenylcysteine oxidase 1 like protein is required for neutrophil bactericidal activities.

The bactericidal function of neutrophils is dependent on a myriad of intrinsic and extrinsic stimuli. Using systems immunology approaches we identify microbiome- and infection-induced changes in neutrophils. We focus on investigating the Prenylcysteine oxidase 1 like (Pcyox1l) protein function. Murine and human Pcyox1l proteins share ninety four percent aminoacid homology revealing significant evolutionary conservation and implicating Pcyox1l in mediating important biological functions. Here we show that the loss of Pcyox1l protein results in significant reductions in the mevalonate pathway impacting autophagy and cellular viability under homeostatic conditions. Concurrently, Pcyox1l CRISPRed-out neutrophils exhibit deficient bactericidal properties. Pcyox1l knock-out mice demonstrate significant susceptibility to infection with the gram-negative pathogen Psuedomonas aeruginosa exemplified through increased neutrophil infiltrates, hemorrhaging, and reduced bactericidal functionality. Cumulatively, we ascribe a function to Pcyox1l protein in modulation of the prenylation pathway and suggest connections beween metabolic responses and neutrophil functionality.

Atrial Flutter Masquerading as an ST-segment-elevation Myocardial Infarction in a Patient with Dextrocardia.

Electrocardiogram (ECG) findings suggestive of an ST-segment-elevation myocardial infarction (STEMI) often lead to emergent left heart catheterization. Occasionally, non-coronary conditions mimic ECG findings of STEMI, resulting in an increased risk and expenses from emergent transportation and procedures. In this report, we describe diagnostic and management strategies for a case of 1:1 atrial flutter in a patient with dextrocardia presenting as a STEMI.

Multiplexed action-outcome representation by striatal striosome-matrix compartments detected with a mouse cost-benefit foraging task.

Learning about positive and negative outcomes of actions is crucial for survival and underpinned by conserved circuits including the striatum. How associations between actions and outcomes are formed is not fully understood, particularly when the outcomes have mixed positive and negative features. We developed a novel foraging ('bandit') task requiring mice to maximize rewards while minimizing punishments. By 2-photon Ca++ imaging, we monitored activity of visually identified anterodorsal striatal striosomal and matrix neurons. We found that action-outcome associations for reward and punishment were encoded in parallel in partially overlapping populations. Single neurons could, for one action, encode outcomes of opposing valence. Striosome compartments consistently exhibited stronger representations of reinforcement outcomes than matrix, especially for high reward or punishment prediction errors. These findings demonstrate multiplexing of action-outcome contingencies by single identified striatal neurons and suggest that striosomal neurons are particularly important in action-outcome learning.

Lipoblastomas and liposarcomas in paediatric patients: A case series.

Lipoblastomas and liposarcomas are rare causes of soft tissue masses in paediatric patients. In this retrospective clinical case series we identified 11 patients from our paediatric database (10 with a lipoblastoma and one with a liposarcoma) who had attended our hospital between 1998 and 2019. The median age of patients with lipoblastoma was 29 months. All lipoblastoma cases were managed with surgical excision and histological examination. The 18-year old patient with liposarcoma presented with a metastatic and unresectable tumour that was unresponsive to chemotherapy and radiation. Our experience demonstrates the importance of differentiating the type of soft tissue mass in children.

Long-term Comparison of Retrograde and Antegrade Femoral Nailing.

Antegrade or retrograde nailing for femoral shaft fractures remains the gold standard, but long-term data on functional outcomes after intramedullary nailing are lacking. In a retrospective review of prospectively collected patient registry data, patients with an isolated femoral shaft fracture treated with antegrade or retrograde femoral nailing from 1997 to 2012 were interviewed and their medical records analyzed. Functional reported outcome data were obtained via the visual analog scale (VAS) for pain and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 5 to 17 years postoperatively. Antegrade and retrograde intramedullary nailing of diaphyseal femur shaft fractures demonstrated a mean WOMAC of 23.5%±23.6% (range, 0%-82.3%) and 29.7%±24.0% (range, 0%-88%), respectively (P=.23). The mean VAS scores of the antegrade vs retrograde intramedullary nailing groups were 2.5±2.6 (range, 0-8) and 3.4±2.8 (range, 0-10), respectively (P=.11). Location of pain differed between groups as well, with the antegrade group noting an increased rate of hip pain (25.6% vs 7.0%, P=.01), but a nonsignificant difference in the rate of thigh pain (27.9% vs 15.5%, P=.15) and knee pain (18.6% vs 26.7%, P=.49) as compared with the retrograde group. Diaphyseal femur fractures are successfully treated with either antegrade or retrograde intramedullary nails without significantly differing long-term functional outcomes, which correlates with other reported findings in the literature at short-term follow-up. [Orthopedics. 2020;43(4):e278-e282.].

Important Recently Characterized Non-Ewing Small Round Cell Tumors.

Round cell sarcomas morphologically similar to Ewing sarcoma, but lacking the classic immunohistochemical features, EWSR-ETS family fusions, and other signs of differentiation, are classified as Ewing-like sarcomas. Recent molecular advances led to the discovery and characterization of two recurrent oncogenic fusion rearrangements, CIC-DUX4 and BCOR-CCNB3, in a significant subset of Ewing-like sarcomas. Uncovered alternate fusion partners broadened the proposed classification of these tumors to CIC-rearranged sarcomas and BCOR-rearranged sarcomas. This article summarizes the clinicopathologic and molecular features of these entities, with particular attention paid to those features that overlap with and distinguish these sarcomas from other round cell sarcomas.

Ossifying Fibromyxoid Tumor: A Review With Emphasis on Recent Molecular Advances and Differential Diagnosis.

CONTEXT.­: Ossifying fibromyxoid tumor (OFMT) is a rare, slow-growing mesenchymal neoplasm of uncertain histogenesis with intermediate malignant potential. OBJECTIVE.­: To highlight the most important diagnostic features, including morphologic, immunohistochemical, and molecular findings; to provide comparisons to other entities in the differential diagnosis; and to provide a summary of the clinical features and outcomes in cases reported to date. DATA SOURCES.­: The data sources include recently published literature encompassing OFMT and tumors in the histologic differential diagnosis, and cases from institutional files. CONCLUSIONS.­: Ossifying fibromyxoid tumor is important to recognize because of its low-grade morphology but potential for recurrence and metastasis. Recent molecular analysis has expanded the morphologic spectrum of OFMT, with additional cases discovered that are enriched for aggressive behavior. The diagnosis can often be rendered through a combination of morphology and coexpression of S100 protein and desmin, although only a minority of cases described contain all of these primary features. In cases that do not have all of these features, a high index of suspicion guided by morphology and exclusion of other tumors in the histologic differential diagnosis can lead to the correct diagnosis. Growing access to molecular genetic testing will become increasingly important for correct diagnosis of tumors at the ends of the morphologic spectrum.

Cellular Spindled Histiocytic Pseudotumor: A Benign Mimic of Spindle Cell Neoplasia of the Breast.

CONTEXT.­: Cellular spindled histiocytic pseudotumor (CSHPT) is an exuberant, dense histiocytic proliferation seen in the setting of mammary fat necrosis. CSHPT has a broad histologic differential diagnosis, including benign, malignant, and inflammatory etiologies. OBJECTIVES.­: To highlight the most important histologic and immunohistochemical findings of CSHPT and provide comparisons to entities within the broad differential diagnosis. DATA SOURCES.­: Recently published literature regarding CSHPT and other diagnostic considerations. CONCLUSIONS.­: CSHPT is a benign histiocytic proliferation with a broad differential diagnosis, for which comprehensive ancillary studies may be required to exclude malignant and infectious entities.

Multiclonality and Marked Branched Evolution of Low-Grade Endometrioid Endometrial Carcinoma.

The molecular events driving low-grade endometrioid endometrial carcinoma (LGEC) development-like in many cancers-are incompletely understood. Hence, here we performed multiregion, comprehensive somatic molecular profiling of routinely processed formalin-fixed, paraffin-embedded (FFPE) material from 13 cases of LGEC totaling 64 minute, spatially defined cell populations ranging from presumed precursor lesions through invasive LGEC. Shared driving PTEN, PIK3R1, or PIK3CA mutations support clonal origin of the samples in each case, except for two cases with two clonally distinct neoplastic populations, consistent with unexpected multiclonality in LGEC development. Although substantial heterogeneity in driving somatic alterations was present across populations in nearly all cases, these alterations were usually clonal in a given population, supporting continued selection and clonal sweeping of driving alterations in populations with both precursor and LGEC histology. Importantly, CTNNB1 mutational status, which has been proposed as both prognostic and predictive in LGEC, was frequently heterogeneous and subclonal, occurring both exclusively in precursor or cancer populations in different cases. Whole-transcriptome profiling of coisolated RNA from 12 lesions (from 5 cases) was robust and confirmed histologic and molecular heterogeneity, including activated Wnt signaling in CTNNB1-mutant versus wild-type populations. Taken together, we demonstrate clinically relevant multiclonality and intratumoral heterogeneity during LGEC development with important implications for diagnosis, prognosis, and therapeutic prediction. More broadly, our methodology is broadly scalable to enable high-throughput genomic and transcriptomic characterization of precursor and invasive cancer populations from routine FFPE specimens. IMPLICATIONS: Multiregion profiling of LGEC populations using a highly scalable approach demonstrates clinically relevant multiclonality and intratumoral heterogeneity.

Biphenotypic Sinonasal Sarcoma: A Review and Update.

CONTEXT.­: Biphenotypic sinonasal sarcoma (BSNS) is a rare, slow-growing soft tissue sarcoma of the sinonasal tract, typically presenting with nonspecific obstructive nasal symptoms. Although recurrences are common, no metastases have been reported, and only 1 patient has died of disease thus far. It characteristically demonstrates rearrangements of PAX3 with multiple fusion partners, the most common of which is MAML3. OBJECTIVES.­: To highlight the most important diagnostic features, including morphologic, immunohistochemical, and molecular findings, and to provide comparisons to other entities in the differential diagnosis. We also aim to provide a summary of the clinical features and outcomes in cases reported to date. DATA SOURCES.­: Recently published literature encompassing BSNS and its synonym, low-grade sinonasal sarcoma with neural and myogenic differentiation. CONCLUSIONS.­: BSNS is a sinonasal tumor that is important to recognize because its biologic behavior differs from most of the entities in the differential diagnosis. The diagnosis can typically be rendered through a combination of morphology, immunohistochemical stains, and ancillary testing for characteristic PAX3 rearrangements.

Atypical Ductal Lesions of the Breast: Criteria, Significance, and Laboratory Updates.

CONTEXT.­: Atypical ductal hyperplasia (ADH) is a challenging diagnosis defined by cytologic and architectural features that carries an increased risk of subsequent carcinoma when diagnosed in isolation. In addition, ADH may secondarily involve benign breast lesions, wherein it carries variable clinical significance. OBJECTIVES.­: To review the diagnostic criteria and clinical significance of ADH in isolation and as it involves benign breast lesions, and to review the evolving literature on its molecular signature. DATA SOURCES.­: Recently published studies that collectively examine ADH were reviewed. CONCLUSIONS.­: Atypical ductal hyperplasia carries an increased risk of subsequent carcinoma in isolation and when it involves most benign breast lesions. Identifying which cases of ADH will be upgraded to carcinoma has been challenging, and new laboratory developments, such as EZH2 overexpression, may have a future role.