The Role of Aryl Hydrocarbon Receptor in the Endothelium: A Systematic Review.

Activation of the aryl hydrocarbon receptor (AhR) has been shown to be important in physiological processes other than detoxification, including vascular homeostasis. Although AhR is highly expressed in the endothelium, its function has been poorly studied. This systematic review aims to summarise current knowledge on the AhR role in the endothelium and its cardiovascular implications. We focus on endogenous AhR agonists, such as some uremic toxins and other agonists unrelated to environmental pollutants, as well as studies using AhR knockout models. We conclude that AhR activation leads to vascular oxidative stress and endothelial dysfunction and that blocking AhR signalling could provide a new target for the treatment of vascular disorders such as cardiovascular complications in patients with chronic kidney disease or pulmonary arterial hypertension.

Restless legs-like syndrome as an emergent adverse event of CGRP monoclonal antibodies: A report of two cases.

BACKGROUND: One of the advantages of CGRP monoclonal antibodies is their excellent safety and tolerability. However, postmarketing surveillance, is essential to detect potential rare emergent adverse events. OBJECTIVES: To report two patients who developed restless legs syndrome symptoms after treatment with CGRP antibodies. METHODS AND RESULTS: Two women with chronic refractory migraine, with no significant medical antecedents, developed typical restless legs syndrome symptoms 1.5 and 4 months after starting erenumab 140 mg, respectively. In case 1 symptoms resolved when erenumab was stopped for two months but reappeared on galcanezumab. In both patients migraine attacks had dramatically decreased and no iron deficiency was found. CONCLUSIONS: Even though caution is needed before establishing a causal relationship, these cases suggest that restless legs-like symptoms might be an emergent adverse event of CGRP antibodies, regardless of the mechanism of action. We propose that plastic changes in CGRP sensory fibers, which are very abundant in legs, induced by CGRP monoclonal antibodies could be the reason for restless legs syndrome development.

The presence of chemosensory cues transmitted through the mother's milk increases the search and ingestion responses toward bitter and sour solutions.

Olfaction is of major importance during early stages of life in altricial species. This sense allows newborns to develop different behaviors that will allow them to survive. Odors tend to be associated to contextual stimuli (such as warmth); this, in turn, enables the pups to recognize when to withdraw or approach. At the same time, olfaction modulates the acceptance of aversive flavors. The increase of approach responses toward a bitter substance during early life is enhanced by stimulation with familiar, pre-exposed odors. Newborn rats exhibit heightened grasp responses toward an artificial nipple dispensing quinine, and drink more of this bitter solution, in the presence of a pre-exposed odor (lemon or the mother's odor). The present research assessed the replicability of previous results by pre-exposing the subjects to the scent through maternal milk and using solutions with different aversive tastes. Half of the subjects (3 day-old Wistar rats) were pre-exposed to lemon odor through the maternal milk (the mother had previously ingested the lemon essence via an intragastric injection); 4 h later, all the rats were evaluated in the presence of the lemon odor with an artificial nipple containing quinine, citric acid, saline solution, or water. The results showed enhanced seeking and intake of the bitter (quinine) and sour solution (citric acid). However, this did not occur when the nipple contained water or saline solution. The evidence suggests that: During the early stages of development, familiar odors regulate the acceptance of non-palatable, otherwise rejected, flavors; and that the route of transmission of the pre-exposed odor can be through air, or through food (amniotic fluid in previous studies and, in this case, breast milk), that is, via the retronasal and orthonasal routes.

Central oxytocin signaling inhibits food reward-motivated behaviors and VTA dopamine responses to food-predictive cues in male rats.

Oxytocin potently reduces food intake and is a potential target system for obesity treatment. A better understanding of the behavioral and neurobiological mechanisms mediating oxytocin's anorexigenic effects may guide more effective obesity pharmacotherapy development. The present study examined the effects of central (lateral intracerebroventricular [ICV]) administration of oxytocin in rats on motivated responding for palatable food. Various conditioning procedures were employed to measure distinct appetitive behavioral domains, including food seeking in the absence of consumption (conditioned place preference expression), impulsive responding for food (differential reinforcement of low rates of responding), effort-based appetitive decision making (high-effort palatable vs. low-effort bland food), and sucrose reward value encoding following a motivational shift (incentive learning). Results reveal that ICV oxytocin potently reduces food-seeking behavior, impulsivity, and effort-based palatable food choice, yet does not influence encoding of sucrose reward value in the incentive learning task. To investigate a potential neurobiological mechanism mediating these behavioral outcomes, we utilized in vivo fiber photometry in ventral tegmental area (VTA) dopamine neurons to examine oxytocin's effect on phasic dopamine neuron responses to sucrose-predictive Pavlovian cues. Results reveal that ICV oxytocin significantly reduced food cue-evoked dopamine neuron activity. Collectively, these data reveal that central oxytocin signaling inhibits various obesity-relevant conditioned appetitive behaviors, potentially via reductions in food cue-driven phasic dopamine neural responses in the VTA.

Evaluation of the Diagnostic Accuracy of an Online Artificial Intelligence Application for Skin Disease Diagnosis.

Artificial intelligence (AI) algorithms for automated classification of skin diseases are available to the consumer market. Studies of their diagnostic accuracy are rare. We assessed the diagnostic accuracy of an open-access AI application (Skin Image Search™) for recognition of skin diseases. Clinical images including tumours, infective and inflammatory skin diseases were collected at the Department of Dermatology at the Sahlgrenska University Hospital and uploaded for classification by the online application. The AI algorithm classified the images giving 5 differential diagnoses, which were then compared to the diagnoses made clinically by the dermatologists and/or histologically. We included 521 images portraying 26 diagnoses. The diagnostic accuracy was 56.4% for the top 5 suggested diagnoses and 22.8% when only considering the most probable diagnosis. The level of diagnostic accuracy varied considerably for diagnostic groups. The online application demonstrated low diagnostic accuracy compared to a dermatologist evaluation and needs further development.

Sensitive period for the acceptance of unpalatable flavors in the presence of a preexposed odor in infant rats.

It has been shown that exposure to familiar odors facilitate the acceptance of bitter flavors in preweanling rats, yet it unknown how long this phenomenon persists. This study assessed, in 9- or 15-day-old Wistar rats, the influence of a familiar scent (i.e., lemon) on the intake of and behavioral responsiveness (i.e., mouthing, paw lick, chin rub, head shake, among other taste reactivity responses) elicited by a 0.1% quinine solution. The results showed heightened quinine intake in 9-day-old rats that had been preexposed to the odor, when compared to non-preexposed controls. This result was replicated in Experiment 2, which also documented no alterations in behavioral responsiveness toward quinine in the 9-day-old rats, as a function of the pre-exposure. More importantly, 15-day-old rats exhibited no alterations in intake or behavioral responsiveness toward quinine as a function of odor pre-exposure. These results suggest that the effects of odor pre-exposure upon acceptance of bitter tastes may occur within a sensitive period for the acceptance of bitter food.

Environmental enrichment during adolescence heightens ethanol intake in female, but not male, adolescent rats that are selectively bred for high and low ethanol intake during adolescence.

Background: Discriminating between adolescents who will eventually have ethanol use problems from those who do not is important. Environmental enrichment is a promising approach to reduce drug-related problems, but its impact on ethanol's effects and intake is being scrutinized. Objective: We tested the effects of environmental enrichment on ethanol intake, preference, and anxiety-like response as well as shelter seeking and risk-taking behaviors. Methods: Experiment 1 examined ethanol intake, preference, and anxiety-like responses in 46 male and 54 female Wistar rats that were derived from a short-term breeding program that selected for high and low ethanol drinking during adolescence (ADHI2 and ADLO2 lines, respectively). Shelter-seeking and risk-taking behaviors were assessed (Experiment 2) in ADHI2 and ADLO2 rats (73 males, 76 females) reared under environmental enrichment or standard housing conditions and given doses of ethanol (2.5 g/kg, intraperitoneal) for 3 weeks. Environmental enrichment was applied on postnatal days 21-42. Ethanol intake was measured on postnatal days 42-68. Anxiety-like behavior and exploratory responses were assessed using the light-dark box and multivariate concentric square field test. Results: In Experiment 1, environmental enrichment increased ethanol intake in female, but not male, ADHI2 and ADLO2 rats (p < 0.05). In the baseline measurement of Experiment 2, ADHI2 rats exhibited reduced risk-taking and increased anxiety-like behavior (p < .05). After exposure to environmental enrichment the ADHI and ADLO rats, both males and females, exhibited increased risk-taking and exploratory behavior (p < 0.05). Conclusions: Environmental enrichment appears to increase ethanol intake in female rats by promoting the exploration of new environments or stimuli. The findings indicate that environmental enrichment increased ethanol intake in female, but not male, rats. Clinical programs that treat alcohol use disorder by emphasizing environmental stimulation should be designed with caution.

Exposure to maternal odor enhances intake of a taste that mimicks the sensory attributes of ethanol.

Early exposure to ethanol increases subsequent acceptance of this drug. Little attention, however, has been devoted to the interaction of the taste of the drug with other, familiar or non-familiar, odors contingent with ethanol access, particularly early in ontogeny. This study assessed the influence of exposure to maternal odor on intake and grasp responses to an artificial nipple providing a solution (a sucrose-quinine mix) that emulates the taste of alcohol, in 4-day-old rat pups. The results showed that the mother's odor enhanced intake from and seeking responses to an artificial nipple that provided the solution that mimicked the taste of alcohol (Experiment 1). This pattern of results was not evoked by the odor of an unrelated dam (Experiment 2), nor was it observed when the nipple delivered water. The main new finding of the present study is that 4-day-old rats tested in the presence of the mother (and hence exposed to her odor cues) exhibited enhanced seeking and intake of a solution that mimics the chemosensory properties of ethanol.

Cutaneous cytomegalovirus manifestations, diagnosis, and treatment: a review.

The possible presentations of cytomegalovirus (CMV) are vast not only in its systemic manifestations, but also in the various cutaneous lesions that may result. Cutaneous cytomegalovirus is rarely reported in the literature because the clinical and pathologic features can be difficult to identify. Its identification, however, is vital as cutaneous human CMV infection can signal systemic disease and an unfavorable prognosis. The objective of this study is to aid in recognition, diagnosis, and treatment of CMV according to dermatological evidence. A complete literature search was performed within PubMed, resulting in the inclusion of 58 patient cases. The most common dermatologic manifestation was perianal or oral ulcers, but the locations and types of lesions noted throughout the review were numerous. Treatment is often simple, yet incorrect diagnoses along with concurrent illnesses can often complicate management. It is imperative for CMV to be detected early in its course to prevent mortality, especially in the immunocompromised. Dermatological presentations are often the first sign of this deadly virus' activity and it is essential that these diagnoses are made more efficient and accurate.

Consummatory succesive positive contrast produced by the downshift of an aversive solution in infant rats.

Subjects trained in successive positive contrast are usually given an appetitive stimulus of relatively low quality during a pre-shift, followed by exposure to a significantly greater quality of the same stimulus. Enhanced responsiveness to the high-quality stimulus during the post-shift phase, compared to a control group that receives the superior reward in both phases, is taken as an index of successive positive contrast. Successive positive contrast reports are rare, probably due to performance limitations inherent to the experimental protocols available. We exposed infant rats (14 days old at the start of training) to .1% or .01% quinine during 4, 10 min, trials (pre-shift phase). All animals were then given two trials of exposure to .01% quinine (post-shift phase). During the pre-shift the level of intake was greater in pups stimulated with the relatively less aversive .01% quinine solution. These animals also exhibited, compared to those stimulated with .1% quinine, lower emission of the aversive response paw treading. During the post-shift phase, the group that had been exposed to .1% quinine exhibited significantly greater intake of .01% quinine, along with a reduction in the emission of paw treading and an enhancement in paw licking, an ingestive, appetitive response. Altogether, the evidence is suggestive of the emergence of consummatory successive positive contrast during the second week of life of the rat. To our knowledge, this is the first evidence of positive contrast using an aversive solution.

Inflamed Actinic Keratoses After Pemetrexed.

A 66-year-old man presented with a 1-day history of a mildly pruritic eruption on the face, chest, arms, and upper part of the back. The dermatitis began 3 weeks after receiving an initial infusion of pemetrexed (500 mg/m2) as induction chemotherapy for non-small cell lung cancer. Physical examination revealed numerous erythematous, scaly papules over the face, extensor surface of the arms, hands, and upper aspects of the chest and back, sparing sun-protected areas (Figure). He acknowledged that in the past he frequently went shirtless outdoors and rarely wore sunscreen or sun protective clothing during the many years he worked at construction sites. Results from a biopsy specimen from a typical lesion on the forearm revealed an inflamed actinic keratosis. Systemic chemotherapy was continued, and only emollients and mid-potency topical steroids were used to treat the skin eruption. At 2-week follow-up, the patient's eruption was greatly diminished with loss of significant erythema and scale, as well as absence of pruritus.

Clinical and dermoscopic features of combined cutaneous squamous cell carcinoma (SCC)/neuroendocrine [Merkel cell] carcinoma (MCC).

BACKGROUND: Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma, associated with Merkel cell polyomavirus. MCC admixed with squamous cell carcinoma (SCC) is unassociated with polyomavirus, and is genetically distinct. OBJECTIVE: We sought to distinguish clinically and dermoscopically between MCC and SCC/MCC. METHODS: We compared patient data for SCC/MCC (n = 26) and MCC (n = 20), and reviewed clinical and dermoscopic images (n = 9) of SCC/MCC. RESULTS: Patients with SCC/MCC were older (median 76.5 vs 69 years) and more often male (77% vs 60%), and had more nonmelanoma skin cancer (85% vs 25%), malignant extracutaneous tumors (25% vs 5%), lymphoproliferative disorders (23% vs 10%), and immunodeficient/proinflammatory states (77% vs 35%). In all, 58% of SCC/MCC versus 10% of MCC were clinically diagnosed nonmelanoma skin cancer. Patients with SCC/MCC had more metastases (77% vs 40%), more treatment failures (53% vs 45%), shorter survival (41 vs 54 months), and more death from disease (50% vs 40%). SCC/MCC demonstrated marked scale (7/9), and telangiectasia (1/9). Dermoscopically, small dotted and short linear irregular peripheral vessels and central milky-red areas with large-diameter arborizing vessels were seen. LIMITATIONS: The rarity of SCC/MCC limits available data. CONCLUSIONS: SCC/MCC is aggressive, arising within elderly patients' chronically ultraviolet-exposed skin, often in the setting of immunosuppression or inflammation. Dermoscopically, polymorphous vessels in lesions suspicious for nonmelanoma skin cancer are suggestive.

Post-radiation atypical vascular proliferation on the head of a young woman: a diagnostic challenge.

With improved outcomes associated with radiotherapy (RT), post-irradiation tumors are increasingly seen in long-term cancer survivors. We report a case of a young woman who presented with a three-year history of a vascular lesion on the temple, previously irradiated for a childhood brain tumor. The history of radiation, the clinical appearance, and the biopsy findings of an atypical vascular proliferation in the dermis, were worrisome for a malignant vascular neoplasm and prompted surgical excision. However, further tissue analysis of the excised specimen confirmed a benign atypical vascular lesion (AVL) overlying a banal pilar cyst. Distinguishing post-radiation benign from malignant vascular lesions can be difficult because they share overlapping clinical and histopathologic features. Thus, any vascular lesion that occurs in a previously irradiated field should be excised completely with tumor-free margins and examined histologically.

Viral cyclins mediate separate phases of infection by integrating functions of distinct mammalian cyclins.

Gammaherpesvirus cyclins have expanded biochemical features relative to mammalian cyclins, and promote infection and pathogenesis including acute lung infection, viral persistence, and reactivation from latency. To define the essential features of the viral cyclin, we generated a panel of knock-in viruses expressing various viral or mammalian cyclins from the murine gammaherpesvirus 68 cyclin locus. Viral cyclins of both gammaherpesvirus 68 and Kaposi's sarcoma-associated herpesvirus supported all cyclin-dependent stages of infection, indicating functional conservation. Although mammalian cyclins could not restore lung replication, they did promote viral persistence and reactivation. Strikingly, distinct and non-overlapping mammalian cyclins complemented persistence (cyclin A, E) or reactivation from latency (cyclin D3). Based on these data, unique biochemical features of viral cyclins (e.g. enhanced kinase activation) are not essential to mediate specific processes during infection. What is essential for, and unique to, the viral cyclins is the integration of the activities of several different mammalian cyclins, which allows viral cyclins to mediate multiple, discrete stages of infection. These studies also demonstrated that closely related stages of infection, that are cyclin-dependent, are in fact genetically distinct, and thus predict that cyclin requirements may be used to tailor potential therapies for virus-associated diseases.

Immunohistochemical analysis of KBA.62 in 18 neurothekeomas: a potential marker for differentiating neurothekeoma, but a marker that may lead to confusion with melanocytic tumors.

BACKGROUND: Neurothekeoma represents a neoplasm of uncertain histogenesis that often occurs on the head and neck of younger individuals. Distinguishing neurothekeoma from other tumors, particularly malignancies such as melanoma, can be difficult given the variable presence of nuclear atypia, mitoses and extension into fat or skeletal muscle. KBA.62 represents an anti-melanoma monoclonal antibody that marks approximately 93% of melanomas. This study sought to evaluate KBA.62 expression in neurothekeomas, both as means of affirming the diagnosis and as a potential confounding factor in excluding a melanocytic process. METHODS: Eighteen neurothekeomas from 17 patients were analyzed by light microscopy and immunohistochemistry. Immunohistochemistry was performed with KBA.62, S100 and CD10 antibodies. The diagnosis of neurothekeoma was confirmed by at least two dermatopathologists. RESULTS: All cases showed similar light microscopic and immunohistochemical features. With the exception of two cases, cells expressed CD10 and exhibited morphologic features consistent with neurothekeoma. All 18 cases were S100 immunonegative. The epithelioid cells of all neurothekeomas were KBA.62 immunopositive, including both of two neurothekeomas occurring in the same patient. CONCLUSIONS: In this study 100% of neurothekeomas tested were KBA.62 positive, admittedly to varying degrees, suggesting the utility of this reagent as being supportive of the diagnosis of neurothekeoma.

Ontogeny of consummatory successive negative contrast in rats.

Consummatory successive negative contrast (cSNC) occurs when organisms repeatedly exposed to a high-magnitude reward are suddenly given a low-magnitude reward. This results in a significant reduction in the consumption of the devalued reinforcer, at a level even below that of a group which had been always exposed to the low-magnitude reinforcer. A scarcity of animal studies assessed the expression of this phenomenon during early development. Three experiments assessed age of cSNC onset in preweanling rats. Percent body weight gained (%BWG) and taste reactions associated with reinforcement devaluation were measured. A reduction in %BWG and a significant increase in emission of aversive hedonic behaviors, indicative of cSNC, occurred on postnatal day 18 (PD 18; Experiments 1 and 2), but not on PD 14 or PD 17 (Experiments 3a and 3b). The neurobiological mechanisms underlying these effects and theoretical implications are discussed.

Injection preparation filtration and health concerns among indigenous people who inject methamphetamine.

Introduction: Injecting methamphetamine poses significant health risks, but little is known about how methamphetamine injectors filter their injection preparations and experience related health concerns. Methods: A chain-referral sample of Indigenous people who inject methamphetamine (n = 30) was recruited and semistructured interviews were conducted to collect information on filtration practices and health concerns. Results: Filtration of the injection preparation was described by 53% of injectors. Elevated levels of concern for kidney disease, cancer and heart disease were observed among those who filtered their preparations (ranging from 50 to 56.3%). Concern about liver disease was the most frequent concern among those who filtered their preparations (62.5%) and was elevated in comparison to those who did not use filters (7.1%). Grouped logistic regression revealed a positive association between filtration of the injection preparation and overall health concerns expressed by injectors, after adjusting for gender and age. The marginal posterior distribution of the adjusted odds ratio for filtration of the injection preparation had a posterior median = 35.7, and 95% HPD interval = (5.1, 512.4). Discussion: Results illustrate a positive relationship between filtration of the injection preparation and health concerns among Indigenous people who inject methamphetamine. This likely reflects the use of filtration to reduce harms, and further research is needed to understand the full scope of prevention that may be associated with filtration of methamphetamine injection preparations.

Levamisole Impairs Vascular Function by Blocking α-Adrenergic Receptors and Reducing NO Bioavailability in Rabbit Renal Artery.

Levamisole is an anthelmintic drug restricted to veterinary use but is currently detected as the most widely used cocaine cutting agent in European countries. Levamisole-adulterated cocaine has been linked to acute kidney injury, marked by a decrease in glomerular filtration rate, which involves reduced renal blood flow, but data on the alteration of renovascular response produced by levamisole are scarce. Renal arteries were isolated from healthy rabbits and used for isometric tension recording in organ baths and protein analysis. We provide evidence that depending on its concentration, levamisole modulates renovascular tone by acting as a non-selective α-adrenergic receptor blocker and down-regulates α1-adrenoceptor expression. Furthermore, levamisole impairs the endothelium-dependent relaxation induced by acetylcholine without modifying endothelial nitric oxide synthase (eNOS) expression. However, exposure to superoxide dismutase (SOD) partially prevents the impairment of ACh-induced relaxation by levamisole. This response is consistent with a down-regulation of SOD1 and an up-regulation of NADPH oxidase 4 (Nox4), suggesting that endothelial NO loss is due to increased local oxidative stress. Our findings demonstrate that levamisole can interfere with renal blood flow and the coordinated response to a vasodilator stimulus, which could worsen the deleterious consequences of cocaine use.

Sodium valproate treatment reverses endothelial dysfunction in aorta from rabbits with acute myocardial infarction.

Sodium valproate (VPA), a histone deacetylase (HDAC) inhibitor, could be a promising candidate to treat acute myocardial infarction (AMI). In this study, AMI was induced in New Zealand White rabbits by occluding the left circumflex coronary artery for 1 h, followed by reperfusion. The animals were distributed into three experimental groups: the sham-operated group (SHAM), the AMI group and the AMI + VPA group (AMI treated with VPA 500 mg/kg/day). After 5 weeks, abdominal aorta was removed and used for isometric recording of tension in organ baths or protein expression by Western blot, and plasma for the determination of nitrate/nitrite (NOx) levels by colorimetric assay. Our results indicated that AMI induced a reduction of the endothelium-dependent response to acetylcholine without modifying the endothelium-independent response to sodium nitroprusside, leading to endothelial dysfunction. VPA treatment reversed AMI-induced endothelial dysfunction and even increased NO sensitivity in vascular smooth muscle. This response was consistent with an antioxidant effect of VPA, as it was able to reverse the superoxide dismutase 1 (SOD 1) down-regulation induced by AMI. Our experiments also ruled out that the VPA mechanism was related to eNOS, iNOS, sGC and arginase expression or changes in NOx plasma levels. Therefore, we conclude that VPA improves vasodilation by increasing NO bioavailability, likely due to its antioxidant effect. Since endothelial dysfunction was closely related to AMI, VPA treatment could increase aortic blood flow, making it a potential agent in reperfusion therapy that can prevent the vascular damage.

Immunomodulation with AM3 and antioxidants creates an adequate framework for skin repair and decreases the monocyte proinflammatory stage in smoker women.

Smoking has been considering a crucial factor in promoting skin and systemic aging that is associated with the development of a low-level, systemic, chronic inflammation known as "inflammaging" in which monocytes play a pivotal role. Our aim was to investigate the effects of AM3 plus antioxidants vs placebo in the activation status, function of monocytes and cutaneous aging parameters in healthy smoker middle-aged women. A total of 32 women were 1:1 randomly assigned to AM3 plus antioxidants or placebo for three months. Peripheral mononuclear blood cells and cutaneous biopsy were obtained and flow cytometry and immunohistological studies, respectively, were performed before and after the treatment. AM3 plus antioxidants treatment compared with placebo significantly reduced the monocyte production of the proinflammatory interleukin 1 (IL-1), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) cytokines as well as increased the regulatory IL-10 in middle-aged smoker women. Furthermore, AM3 and antioxidants did not modify ROS production by monocytes and granulocytes but increased their phagocytic activity. The active combination also stimulated a significative increase in reticular dermis depth as well as an increase in the expression of CD117 and CD31. Thus, AM3 and antioxidants treatment reduces the systemic proinflammatory monocyte disturbance of heathy smoker middle-aged women and encourage skin repair mechanisms.