External Nasal Neuralgia: an Update

Purpose of Review

External nasal neuralgia is a rare syndrome of atypical facial pain for which there is limited reports in the scientific literature. We aim to review diagnosis and provide an update on treatments for this rare condition.

Recent Findings

Etiology has been documented as post-traumatic due to direct trauma to the nose area and in few case reports, idiopathic. Sensory innervation of the nose arises from the ophthalmic and maxillary divisions of the trigeminal nerve. Direct injury to the nerve appears to be the etiology of post-traumatic external nasal neuralgia. Pathophysiology for idiopathic nasal neuralgia is poorly understood but it appears to be of a central etiology given lack of response to intranasal anesthetics. Pain can be episodic with episodes of tingling sensation lasting up to 30 min, two to three times per day, but for some patients it can be constant bruised sensation of mild to moderate pain. Diagnostic workup including magnetic resonance imaging of brain and computerized tomography of the sinuses are usually negative, but there have been few cases of a nasal contact point. Routine blood work including erythrocyte sedimentation rate is negative.

Summary

Treatment for this rare condition is varied with very few patients responding to tricyclic antidepressants, specifically amitriptyline. Another medication used as prevention is pregabalin with good results as well. Most patients respond to nerve blockade with local anesthetic to the external nasal nerve and sphenopalatine ganglion block and radiofrequency ablation. More reports of this condition need to be published in the scientific literature to assist with proper diagnosis and treatment of this condition.

     

Effects of acute and chronic aripiprazole treatment on choice between cocaine self-administration and food under a concurrent schedule of reinforcement in rats

Rationale  Dopamine D2-like partial agonists such as aripiprazole have received some attention as potential pharmacotherapies for the treatment of psychostimulant addiction. However, the preclinical evaluations so far have focused on acute effects of aripiprazole. Objectives  We tested the hypothesis that aripiprazole, both as acute and as chronic treatment, would preferentially decrease cocaine self-administration while sparing behavior maintained by a natural reinforcer, resulting in a shift in the allocation of behavior from cocaine-taking towards the alternative reinforcer. Materials and methods  Rats were trained to self-administer intravenous cocaine in a concurrent choice procedure, with a palatable food as the competing reinforcer, under a fixed ratio (FR) 1 FR 5 chain schedule. Aripiprazole was then administered as continuous infusion by osmotic minipumps for 5 days, during which performance in the choice procedure was assessed daily. Results  An intermediate dose of aripiprazole decreased cocaine self-administration and shifted the cocaine choice curve to the right as an acute treatment. However, as a chronic treatment, aripiprazole failed to decrease cocaine self-administration or cocaine choice, despite a dose-dependent decrease in overall response rates and food-maintained behavior. Conclusions  Our results confirm and extend earlier findings and indicate that acute administration of aripiprazole can decrease cocaine self-administration. However, based on the present data, chronic treatment with aripiprazole does not show much promise as a potential pharmacotherapy for cocaine addiction. Both acute and chronic treatment data are in agreement with published clinical findings, suggesting that the concurrent choice procedure in rats has predictive validity of efficacy in humans.     

Culturing patient-derived malignant hematopoietic stem cells in engineered and fully humanized 3D niches

Human malignant hematopoietic stem and progenitor cells (HSPCs) reside in bone marrow (BM) niches, which remain challenging to explore due to limited in vivo accessibility and constraints with humanized animal models. Several in vitro systems have been established to culture patient-derived HSPCs in specific microenvironments, but they do not fully recapitulate the complex features of native bone marrow. Our group previously reported that human osteoblastic BM niches (O-N), engineered by culturing mesenchymal stromal cells within three-dimensional (3D) porous scaffolds under perfusion flow in a bioreactor system, are capable of maintaining, expanding, and functionally regulating healthy human cord blood-derived HSPCs. Here, we first demonstrate that this 3D O-N can sustain malignant CD34⁺ cells from acute myeloid leukemia (AML) and myeloproliferative neoplasm patients for up to 3 wk. Human malignant cells distributed in the bioreactor system mimicking the spatial distribution found in native BM tissue, where most HSPCs remain linked to the niches and mature cells are released to the circulation. Using human adipose tissue-derived stromal vascular fraction cells, we then generated a stromal-vascular niche and demonstrated that O-N and stromal-vascular niche differentially regulate leukemic UCSD-AML1 cell expansion, immunophenotype, and response to chemotherapy. The developed system offers a unique platform to investigate human leukemogenesis and response to drugs in customized environments, mimicking defined features of native hematopoietic niches and compatible with the establishment of personalized settings.

Adult bone marrow (BM) stem cell niches are natural blood factories in which BM mesenchymal stromal cells (MSC-BM) and their extracellular matrices interact with hematopoietic stem and progenitor cells (HSPCs) to ensure their maintenance, self-renewal, and differentiation (1, 2). The composition of these BM niches is critical to determine HSPC function. In the murine system, quiescent HSPCs were originally found close to bone surfaces in osteoblastic niches (3–5), but subsequent studies showed that the vast majority of HSPCs locate in niches close to the sinusoidal vasculature (6). These so-called perivascular niches host active HSPCs that circulate between the BM and the bloodstream (7, 8). BM microenvironments also contribute to the development of hematopoietic malignancies (9, 10). Acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN) are clonal hematopoietic malignancies characterized by overproduction of neoplastic hematopoietic cells (11, 12), which evolve and hijack BM microenvironments to create supportive niches for leukemic stem cells (13–19). In contrast to their murine counterparts, human adult BM niches (20) have remained largely unexplored due to the limited accessibility.Multiple humanized animal models have been generated in the last years to model hematological disorders (21), including recently developed patient-derived xenograft models with human BM niche-forming cells (22). Alternatively, human MSC-BM–coated scaffolds have been implanted in mice to generate humanized bone organs capable of hosting healthy murine and human HSPCs (23–26), but also patient-derived leukemic cells (27–30). Nevertheless, none of these in vivo approaches allows studying human malignant HSPCs over prolonged time under controlled settings. In vitro models mimicking the complexity of human BM would represent a solution to investigate the mechanisms of leukemogenesis, while bypassing the ethical concerns associated with the use of experimental animals (31). Some two-dimensional (2D) coculture systems were reported to maintain self-renewing AML progenitor cells for several weeks (from 3 up to 24 wk); these are based on cocultures with either murine (MS-5) or human (Saos-2, HS-5) cell lines (32–34), or human undifferentiated/adipogenic MSC-BM (35, 36). However, they do not recapitulate the complex, specialized signals and cell interactions of native human BM microenvironments. Recently, a three-dimensional (3D) hydrogel triculture system including primary AML cells, MSC-BM, and human umbilical vein endothelial cells (HUVEC) was proposed to model cell–cell interactions in the AML vascular niche (37). Despite introducing the vascular component, this system is based on undifferentiated MSC-BM and thus lacks important features from mature BM niches (e.g., osteoblastic cells and matrix). Although few 3D systems have been developed to model multiple myeloma (38, 39), they are based on classic static cultures and thus, they cannot recapitulate features such as BM interstitial flow and hematopoietic cell circulation. Therefore, 3D multicellular niches mimicking the complexity of human BM niches are not available to culture patient-derived malignant HSPCs for at least 1 wk.We have previously developed a bioreactor-based 3D culture system for MSC-BM that can be used to model in vitro human BM stem cell niches (40). The system enables perfusion in alternate directions of MSC-BM suspensions directly through the pores of 3D hydroxyapatite scaffolds, mimicking the mineral component of trabecular bone. The resulting constructs, recapitulating features of a native human osteoblastic BM niche (O-N), can be further perfused with umbilical cord blood (CB) HSPCs, which establish direct interactions with the O-N and thereby maintain functional properties (41). The culture model offers the unprecedented opportunity to investigate in an in vitro system not only the growth/differentiation of HSPCs within a solid 3D niche, but also the exit of defined subpopulations of HSPCs or their differentiated progenies from the niche. Indeed, hematopoietic cells distributed differentially in the two compartments: while HSPCs remained within the O-N, committed blood cells were released into the liquid phase (supernatant) (41). This system could thus be used to investigate the effects of extrinsic factors (noncell autonomous) on HSPCs, as well as for disease modeling (42).In this study, we aimed at exploiting 3D biomimetic niches engineered in perfusion bioreactors for culturing patient-derived blood cancer cells in fully human microenvironments. First, we assessed the culture of patient-derived AML and MPN CD34⁺ cells in engineered O-N niches for up to 3 wk. We investigated the impact of O-N on cell expansion, immunophenotype, gene expression, and distribution between the bioreactor compartments. Then, we tested the customization potential of our approach by engineering a stromal-vascular niche (SV-N) using human adipose tissue-derived stromal vascular fraction (SVF) cells, leading to stromal tissues enriched in endothelial cells and pericytes (43). We compared O-N and SV-N for culturing leukemic UCSD-AML1 cells and studied the influence of the different microenvironments on leukemic cell expansion, immunophenotype, gene expression, and response to gold-standard chemotherapy (Ara-C; cytarabine), the latter in comparison to classic 2D cultures.     

Effects of prenatal protein malnutrition on hippocampal CA1 pyramidal cells in rats of four age groups

The present study was undertaken to investigate the effect of prenatal protein deprivation on area CA1 hippocampal pyramidal cells on postnatal (P) days 15, 30, 90 and 220 using Golgi techniques. Age related changes in both groups and diet related changes between groups were assessed. There were significant diet effects at all four ages, with one of 12 different measurements showing a significant diet effect on P15, five on P30, one on P90, and seven on P220. The most marked effect of the diet was on pyramidal cell dendrite spine density in the stratum moleculare and stratum radiatum, with a different pattern of diet effects in the two strata. In pyramidal cell dendrites in the stratum moleculare, there was a deficit in spine density that was significant at three of the four ages and there were similar age-related changes in the two diet groups. Spines on pyramidal cell dendrites in the stratum radiatum showed a lack of synchrony of age-related changes in the two diet groups, with an increased spine density in the malnourished rats on P30 and a widening deficit in this parameter on P90 and P220. The bimodal distribution to these changes, with most marked deficits occurring on P30 and P220, with an intervening period of apparent “catch-up” on P90, is of interest and may be a significant brain adaptation to malnutrition. The present study is the final of three morphometric studies on the effect of prenatal protein restriction on three key neurons in the hippocampal trisynaptic circuit. When compared to our previous studies on the dentate granule cell and the CA3 pyramidal cell, it is noted that there is an effect of the low protein diet on all these neurons, with the most marked effect on the predominantly postnatally generated dentate granule cells. Hippocampus 7:192–203, 1997. © 1997 Wiley-Liss, Inc.     

Impact of the Front-of-Pack Label Nutri-Score on the Nutritional Quality of Food Choices in a Quasi-Experimental Trial in Catering

The front-of-pack labelling Nutri-Score has recently been implemented as a policy measure to improve the healthiness of food choices. The aim of this study was to investigate the impact of the Nutri-Score label in catering. A quasi-experimental trial was conducted in France between 16 December 2019 and 13 March 2020 in two staff restaurants (one intervention and one control site) from the same company. After a control period of seven weeks, the Nutri-Score label was affixed on all proposed products in the intervention site. Overall effects of the intervention were investigated using a difference in difference approach with generalised linear models. Over the 13 weeks of the study, 2063 participants who frequented the restaurant cafeteria at least once were included (1268 and 795 in the intervention and control site, respectively), representing 36,114 meals. Overall, the intervention led to a significant improvement in the nutritional quality of meals (p = 0.008) and a significant reduction in the intake of calories, sugars and saturated fat (p < 0.0001). Mixed effects models showed a qualitative improvement of food choices initially, and an adaptation of the quantities consumed over time, suggesting for the first time longer-term effects of the label on dietary behaviour.