Abstract Infections, and the resulting immune response to these infections, have recently received increased recognition as pathogenic mechanisms for neuropsychiatric disorders. Sydenham’s chorea ...(SC), a widely recognized post-streptococcal autoimmune disorder, represents a model for this proposed pathogenesis. In SC, a dysregulated immune response to a streptococcal infection is hypothesized to result in inflammation of neuronal networks, particularly the basal ganglia nuclei. The resulting dysfunction in the basal ganglia nuclei are hypothesized to lead to a constellation of adventitious movements and psychiatric symptoms, which investigations have shown are amenable to immunomodulatory therapies. PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections) has been proposed as a variant of SC, and is hypothesized to share a pathogenic mechanism, despite a unique symptom profile of predominantly psychiatric symptoms. In this review, we present the clinical aspects of both disorders, the data for potential shared etiopathogenesis between them, and the evidence for the therapeutic use of immunomodulatory therapies for the symptoms of SC and PANDAS. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.
Obsessive compulsive disorder is prevalent, disabling, incompletely understood, and often resistant to current therapies. Established treatments consist of specialized cognitive-behavioral ...psychotherapy and pharmacotherapy with medications targeting serotonergic and dopaminergic neurotransmission. However, remission is rare, and more than a quarter of OCD sufferers receive little or no benefit from these approaches, even when they are optimally delivered. New insights into the disorder, and new treatment strategies, are urgently needed. Recent evidence suggests that the ubiquitous excitatory neurotransmitter glutamate is dysregulated in OCD, and that this dysregulation may contribute to the pathophysiology of the disorder. Here we review the current state of this evidence, including neuroimaging studies, genetics, neurochemical investigations, and insights from animal models. Finally, we review recent findings from small clinical trials of glutamate-modulating medications in treatment-refractory OCD. The precise role of glutamate dysregulation in OCD remains unclear, and we lack blinded, well-controlled studies demonstrating therapeutic benefit from glutamate-modulating agents. Nevertheless, the evidence supporting some important perturbation of glutamate in the disorder is increasingly strong. This new perspective on the pathophysiology of OCD, which complements the older focus on monoaminergic neurotransmission, constitutes an important focus of current research and a promising area for the ongoing development of new therapeutics.
Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for ...the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.
Microglia, the brain's resident immune cells, are phagocytes of the macrophage lineage that have a key role in responding to inflammation and immune challenge in the brain. More recently, they have ...been shown to have a number of important roles beyond immune surveillance and response, including synaptic pruning during development and the support of adult neurogenesis. Microglial abnormalities have been found in several neuropsychiatric conditions, though in most cases it remains unclear whether these are causative or are a reaction to some other underlying pathophysiology. Here we summarize postmortem, animal, neuroimaging, and other evidence for microglial pathology in major depression, schizophrenia, autism, obsessive-compulsive disorder, and Tourette syndrome. We identify gaps in the existing literature and important areas for future research. If microglial pathology proves to be an important causative factor in these or other neuropsychiatric diseases, modulators of microglial function may represent a novel therapeutic strategy.
Skin of color (SoC) remains an understudied and under taught area of dermatology despite its rising importance. Race and ethnicity play a particularly important role in dermatology as skin ...pigmentation can affect the manifestation and presentation of many common dermatoses. With this review, we seek to review pertinent differences in SoC histology, as well as highlight the histopathology of conditions more common in SoC and address inherent bias that may affect accurate dermatopathology sign out.
Alginates gel rapidly under ambient conditions and have widely documented potential to form protective matrices for sensitive bioactive cargo. Most commonly, alginate gelation occurs via calcium ...mediated electrostatic crosslinks between the linear polyuronic acid polymers. A recent breakthrough to form crosslinked alginate microcapsules (CLAMs) by in situ gelation during spray drying ("CLAMs process") has demonstrated applications in protection and controlled delivery of bioactives in food, cosmetics, and agriculture. The extent of crosslinking of alginates in CLAMs impacts the effectiveness of its barrier properties. For example, higher crosslinking extents can improve oxidative stability and limit diffusion of the encapsulated cargo. Crosslinking in CLAMs can be controlled by varying the calcium to alginate ratio; however, the choice of alginates used in the process also influences the ultimate extent of crosslinking. To understand how to select alginates to target crosslinking in CLAMs, we examined the roles of alginate molecular properties. A surprise finding was the formation of alginic acid gelling in the CLAMs that is a consequence of simultaneous and rapid pH reduction and moisture removal that occurs during spray drying. Thus, spray dried CLAMs gelation is due to calcium crosslinking and alginic acid formation, and unlike external gelation methods, is insensitive to the molecular composition of the alginates. The 'extent of gelation' of spray dried CLAMs is influenced by the molecular weights of the alginates at saturating calcium concentrations. Alginate viscosity correlates with molecular weight; thus, viscosity is a convenient criterion for selecting commercial alginates to target gelation extent in CLAMs.
Health-Related QOL and Economic Burden of Chronic Pruritus Whang, Katherine A.; Khanna, Raveena; Williams, Kyle A. ...
Journal of investigative dermatology,
April 2021, 2021-Apr, 2021-04-00, 20210401, Volume:
141, Issue:
4
Journal Article
Peer reviewed
Open access
Chronic pruritus (CP) has considerable implications for QOL. However, its impact on health-related QOL and economic burden is not fully characterized. We administered a cross-sectional survey on 132 ...patients with CP using the Health Utilities Index Mark 3 instrument. Normative data from healthy adults (n = 4,187) were obtained from the Joint Canada/US Survey of Health. Quality-adjusted life-year loss and economic costs were estimated on the basis of Health Utilities Index Mark 3 scores of patients with CP versus controls. Patients with CP had lower overall health performance than the control (0.56 ± 0.03 vs. 0.86 ± 0.003, P < 0.001). In multivariable regression, CP was associated with worse overall health performance (coefficient = −0.30, 95% confidence interval = −0.33 to −0.27), most accentuated in the domains of pain (coefficient = −0.24, confidence interval = −0.28 to −0.21) and emotion (coefficient = −0.11, confidence interval = −0.13 to −0.10). The reduced Health Utilities Index Mark 3 score correlated with 5.5 average lifetime quality-adjusted life-years lost per patient. Using conservative estimates for willingness to pay, the quality-adjusted life-year loss translated to an individual lifetime economic burden of $274,921 and a societal burden of $88.8 billion. CP is associated with significant QOL impairment. The economic burden of CP highlights the necessity for further research into management options.
Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene
.
encodes neurofibromin, a negative ...regulator of the Ras signaling pathway. Individuals with NF1 often develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage, some of which progress further to malignant peripheral nerve sheath tumors (MPNSTs). Treatment options for neurofibromas and MPNSTs are extremely limited, relying largely on surgical resection and cytotoxic chemotherapy. Identification of novel therapeutic targets in both benign neurofibromas and MPNSTs is critical for improved patient outcomes and quality of life. Recent clinical trials conducted in patients with NF1 for the treatment of symptomatic plexiform neurofibromas using inhibitors of the mitogen-activated protein kinase (MEK) have shown very promising results. However, MEK inhibitors do not work in all patients and have significant side effects. In addition, preliminary evidence suggests single agent use of MEK inhibitors for MPNST treatment will fail. Here, we describe the preclinical efforts that led to the identification of MEK inhibitors as promising therapeutics for the treatment of NF1-related neoplasia and possible reasons they lack single agent efficacy in the treatment of MPNSTs. In addition, we describe work to find targets other than MEK for treatment of MPNST. These have come from studies of RAS biochemistry, in vitro drug screening, forward genetic screens for Schwann cell tumors, and synthetic lethal screens in cells with oncogenic
gene mutations. Lastly, we discuss new approaches to exploit drug screening and synthetic lethality with
loss of function mutations in human Schwann cells using CRISPR/Cas9 technology.
Summary
Modular construction practices are used in many countries as an alternative to conventional on‐site construction for residential homes. While modular home construction has certain advantages ...in terms of material and time efficiency, it requires a different infrastructure than conventional home construction, and the overall environmental trade‐offs between the two methods have been unclear. This study uses life cycle assessment to quantify the environmental impacts of constructing a typical residential home using the two methods, based on data from several modular construction companies and conventional homebuilders. The study includes impacts from material production and transport, off‐site and on‐site energy use, worker transport, and waste management. For all categories considered, the average impacts of building the home are less for modular construction than for conventional construction, although these averages obscure significant variation among the individual projects and companies.
Increasing evidence has suggested the systemic nature of atopic dermatitis (AD), a common inflammatory skin condition in children. However, comprehensive analyses of real-world comorbidities in ...pediatric AD are limited.
To characterize comorbidity burden in patients with AD aged <18 years old.
The MarketScan commercial claims database was queried from January 1, 2017, to December 31, 2017. Age- and sex-matched analyses were used to compare patients with AD with general population controls.
A total of 86,969 pediatric patients with AD and 116,564 matched controls were identified. Increased anxiety (odds ratio OR, 1.20) and attention-deficit hyperactivity disorder (OR, 1.11) were noted in patients with AD. In addition to dermatologic/allergic diseases, AD was also associated with infections, including methicillin-resistant Staphylococcus aureus (OR, 3.76), and autoimmune conditions, including vitiligo (OR, 2.98) and alopecia areata (OR, 4.32). Pediatric patients with AD had higher likelihoods of lymphoid/hematologic malignancies (OR, 1.94), ocular disorders (OR, 1.37-2.02), metabolic syndrome (OR, 1.61), and obesity (OR, 1.81). For all the ORs mentioned above, P was <.001.
Retrospective analysis of health care claims data.
AD in pediatric patients was associated with a wide range of psychologic and systemic comorbidities. Increased awareness can help minimize its negative effects on the quality of life and prevent long-term health consequences in young patients with AD.
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