The Pharmacological Treatment of Neuropathic Pain in Children.

The International Association for the Study of Pain (IASP) defines neuropathic pain as pain caused by a lesion or disease of the somatosensory nervous system. It is characterized as a clinical condition in which diagnostic studies reveal an underlying cause of an abnormality in the peripheral or central nervous system. Many common causes of neuropathic pain in adults are rare in children. The purpose of this focused narrative review is, to 1) provide an overview of neuropathic pain in children, 2) highlight unique considerations related to the diagnosis and mechanisms of neuropathic pain in children, and 3) perform a comprehensive analysis of the pharmacological treatments available. We emphasize that data for routine use of pharmacological agents in children with neuropathic pain are largely inferred from adult literature with little research performed on pediatric populations, yet have clear evidence of harms to pediatric patients. Based on these findings, we propose risk mitigation strategies such as utilizing topical treatments whenever possible, assessing pain phenotyping to guide drug class choice, and considering pharmaceuticals in the broader context of the multidisciplinary treatment of pediatric pain. Furthermore, we highlight important directions for future research on pediatric neuropathic pain treatment.

Telemedicine Applications for the Evaluation of Patients with Non-Acute Headache: A Narrative Review.

The COVID-19 pandemic has spurred a hasty transition to virtual care but also an abundance of new literature highlighting telehealth's capabilities and limitations for various healthcare applications. In this review, we aim to narrate the current state of the literature on telehealth applied to migraine care. First, telemedicine in the context of non-acute headache management has been shown to produce non-inferior patient outcomes when compared to traditional face-to-face appointments. The assignment of patients to telehealth appointments should be made after referring more urgent cases to dedicated in-person clinics. During the virtual appointment, physicians can ask their patients about the "3 F's" in order to perform a thorough assessment of their headaches: frequency of headache days, frequency of acute medication usage and functional impairment. Clinical assessment scores that have been studied and deemed feasible for telemedicine, safe and efficient include the HIT-6, VAS and MIDAS scores. Although MIDAS was found to be redundant and inadequate to use on a daily basis, we suggest that it can be useful in periodic remote follow-up appointments. Additionally, several mobile health apps have been studied including Migraine Buddy, Migraine Coach and Migraine Monitor. All of these are appropriate for use in telemedicine when combined with an adequate trial period with Migraine Buddy being rated the highest, as it captures the most detailed clinical picture. High satisfaction rates have been reported for virtual headache management which were shown to be equal to in-person consults. These are based on patients' perceived increase in convenience due to avoided travel time, less disruption of their daily routine and feeling more comfortable in the environment of their choice. Despite this, limitations such as technological knowledge, access to videoconferencing modalities and having a more impersonal consultation with the physician may hinder some patients from adopting this service.

Nursing and medical students near-peer activity in the anatomy laboratory: format for success.

BACKGROUND/AIMS: An anatomy interprofessional near-peer learning activity (AIP-NPLA) between nursing and medical students was piloted to assess its implementability. This study aimed to: (1) identify key factors of feasibility and (2) describe student-group perceptions of their experience of the interprofessional education (IPE) activity. METHODS: A total of 59 medical and 179 nursing students participated in the AIP-NPLA whereby medical students were asked to facilitate and lead group discussions with their nursing students colleagues on an anatomical topic using a donor cadaver. Each AIP-NPLA session lasted a total of two hours. A mixed methods approach was employed using both quantitative and qualitative means of assessment. Variables such as Readiness for Interprofessional Learning, Professional Self-Identity, Clinical Teaching Preference, and Near-Peer Teaching and Learning Experience were assessed quantitatively using validated surveys. Qualitative measures included thematic content analysis of focus group interviews conducted following the AIP-NPLA to capture the perceptions of the student groups' experience in the IPE activity. RESULTS: The results of this investigation demonstrated that there are key factors to consider when designing successful and sustainable IPE activities; the level of clinical exposure and therefore student-group pairing based on professional self-identify scores, optimal tutor-to-tutee group ratios and an activity format that maintained an informal, flexible and free forum for discussion on a topic of common knowledge. Focus group interviews also revealed reflections on professional stereotypes. CONCLUSION: These findings suggest that early implementation of IPE activities outside of a clinical setting are beneficial and can foster both learning from one another and positive perceptions of interprofessional roles when carefully designed.

Homozygous Calcium-Sensing Receptor Polymorphism R544Q Presents as Hypocalcemic Hypoparathyroidism.

Context: Autosomal dominant hypocalcemia type 1 (ADH1) is caused by heterozygous activating mutations in the calcium-sensing receptor gene (CASR). Whether polymorphisms that are benign in the heterozygous state pathologically alter receptor function in the homozygous state is unknown. Objective: To identify the genetic defect in an adolescent female with a history of surgery for bilateral cataracts and seizures. The patient has hypocalcemia, hyperphosphatemia, and low serum PTH level. The parents of the proband are healthy. Methods: Mutation testing of PTH, GNA11, GCM2, and CASR was done on leukocyte DNA of the proband. Functional analysis in transfected cells was conducted on the gene variant identified. Public single nucleotide polymorphism (SNP) databases were searched for the presence of the variant allele. Results: No mutations were identified in PTH, GNA11, and GCM2 in the proband. However, a germline homozygous variant (c.1631G>A; p.R544Q) in exon 6 of the CASR was identified. Both parents are heterozygous for the variant. The variant allele frequency was near 0.1% in SNP databases. By in vitro functional analysis, the variant was significantly more potent in stimulating both the Ca2+i and MAPK signaling pathways than wild type when transfected alone (P < 0.05) but not when transfected together with wild type. The overactivity of the mutant CaSR is due to loss of a critical structural cation-π interaction. Conclusions: The patient's hypoparathyroidism is due to homozygosity of a variant in the CASR that normally has weak or no phenotypic expression in heterozygosity. Although rare, this has important implications for genetic counseling and clinical management.

Synthesis, Liposomal Formulation, and Immunological Evaluation of a Minimalistic Carbohydrate-α-GalCer Vaccine Candidate.

Fully synthetic glycan-based vaccines hold great potential as preventive and therapeutic vaccines against infectious diseases as well as cancer. Here, we present a two-component platform based on the facile conjugation of carbohydrate antigens to α-galactosylceramide (α-GalCer) to yield fully synthetic vaccine candidates. Formulation of the cancer-associated Tn antigen glycolipid model vaccine candidate into liposomes of different sizes and subsequent immunization of mice generated specific, high-affinity antibodies against the carbohydrate antigen with characteristics of T cell-dependent immunity. Liposome formulation elicited more reproducible glycan immunity than a conventional glycoconjugate vaccine bearing the same glycan antigen did. Further evaluation of the immune response revealed that the size of the liposomes influenced the glycan antibody responses toward either a cellular (Th1) or a humoral (Th2) immune phenotype. The glycolipid vaccine platform affords strong and robust antiglycan antibody responses in vivo without the need for an external adjuvant.

Rhamnose glycoconjugates for the recruitment of endogenous anti-carbohydrate antibodies to tumor cells.

Immunotherapy is a promising strategy for targeting tumors. One emerging approach is to harness the immune effector functions of natural antibodies to destroy tumor cells. Dinitrophenyl (DNP) and the galactose-α-1,3-galactose (αGal) epitope are two haptens that bind endogenous antibodies. One potential alternative is the deoxysugar L-rhamnose. We compared these candidates by using a biosensor assay to evaluate human sera for endogenous antibody concentration, antibody isotype distribution, and longevity of antibody-hapten interactions. Antibodies recognizing α-rhamnose are of equal or greater abundance and affinity as those recognizing αGal. Moreover, both rhamnose and αGal epitopes are more effective than DNP at recruiting the IgG antibody subtype. Exposure of tumor cells to rhamnose-bearing glycolipids and human serum promotes complement-mediated cytotoxicity. These data highlight the utility of α-rhamnose-containing glycoconjugates to direct the immune system to target cells.

Synthetic antigens reveal dynamics of BCR endocytosis during inhibitory signaling.

B cells detect foreign antigens through their B cell antigen receptor (BCR). The BCR, when engaged by antigen, initiates a signaling cascade. Concurrent with signaling is endocytosis of the BCR complex, which acts to downregulate signaling and facilitate uptake of antigen for processing and display on the cell surface. The relationship between signaling and BCR endocytosis is poorly defined. Here, we explore the interplay between BCR endocytosis and antigens that either promote or inhibit B cell activation. Specifically, synthetic antigens were generated that engage the BCR alone or both the BCR and the inhibitory co-receptor CD22. The lectin CD22, a member of the Siglec family, binds sialic acid-containing glycoconjugates found on host tissues, inhibiting BCR signaling to prevent erroneous B cell activation. At low concentrations, antigens that can cocluster the BCR and CD22 promote rapid BCR endocytosis; whereas, slower endocytosis occurs with antigens that bind only the BCR. At higher antigen concentrations, rapid BCR endocytosis occurs upon treatment with either stimulatory or inhibitory antigens. Endocytosis of the BCR, in response to synthetic antigens, results in its entry into early endocytic compartments. Although the CD22-binding antigens fail to activate key regulators of antigen presentation (e.g., Syk), they also promote BCR endocytosis, indicating that inhibitory antigens can be internalized. Together, our observations support a functional role for BCR endocytosis in downregulating BCR signaling. The reduction of cell surface BCR levels in the absence of B cell activation should raise the threshold for BCR subsequent activation. The ability of the activating synthetic antigens to trigger both signaling and entry of the BCR into early endosomes suggests strategies for targeted antigen delivery.

Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist.

1,25-dihydroxyvitamin D(3) (1,25D) regulates gene expression by signaling through the nuclear vitamin D receptor (VDR) transcription factor and exhibits calcium homeostatic, anticancer, and immunomodulatory properties. Histone deacetylase inhibitors (HDACis) alter nuclear and cytoplasmic protein acetylation, modify gene expression, and have potential for treatment of cancer and other indications. The function of nuclear receptor ligands, including 1,25D, can be enhanced in combination with HDACi. We designed triciferol, a hybrid molecule in which the 1,25D side chain was replaced with the dienyl hydroxamic acid of HDACi trichostatin A. Triciferol binds directly to the VDR, and functions as an agonist with 1,25D-like potency on several 1,25D target genes. Moreover, unlike 1,25D, triciferol induces marked tubulin hyperacetylation, and augments histone acetylation at concentrations that largely overlap those where VDR agonism is observed. Triciferol also exhibits more efficacious antiproliferative and cytotoxic activities than 1,25D in four cancer cell models in vitro. The bifunctionality of triciferol is notable because (i) the HDACi activity is generated by modifying the 1,25D side chain without resorting to linker technology and (ii) 1,25D and HDACi have sympathetic, but very distinct biochemical targets; the hydrophobic VDR ligand binding domain and the active sites of HDACs, which are zinc metalloenzymes. These studies demonstrate the feasibility of combining HDAC inhibition with nuclear receptor agonism to enhance their therapeutic potential.