Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Patients with maternally-inherited mutations develop pseudohypoparathyroidism type 1A (PHP1A) with ...multi-hormone resistance and aberrant craniofacial and skeletal development among other abnormalities. Chiari malformation type 1 (CM1), a condition in which brain tissue extends into the spinal canal when the skull is too small, has been reported in isolated cases of PHP1A. It has been hypothesized to be associated with growth hormone (GH) deficiency. Given the adverse clinical sequelae that can occur if CM1 goes unrecognized, we investigated the previously undetermined prevalence of CM1, as well as any potential correlations with GH status, given the known increased prevalence of GH deficiency in PHP1A. We also investigated these metrics for low lying cerebellar tonsils (LLCT), defined as tonsillar descent less than 5 mm below the foramen magnum. In addition, we investigated possible correlations of CM1/LLCT with advanced hand/wrist bone ages and craniofacial abnormalities known to occur in PHP1A to determine whether premature chondrocyte differentiation and/or aberrant craniofacial development could be potential etiologies of CM1/LLCT through both human studies and investigations of our AHO mouse model.
We examined patients with PHP1A in our clinic and noticed CM1 more frequently than expected. Therefore, we set out to determine the true prevalence of CM1 and LLCT in a cohort of 54 mutation-confirmed PHP1A participants who had clinically-indicated brain imaging. We examined potential correlations with GH status, clinical features, biological sex, genotype, and hand/wrist bone age determinations. In addition, we investigated the craniofacial development in our mouse model of AHO (Gnas E1+/-m) by histologic analyses, dynamic histomorphometry, and micro-computerized tomographic imaging (MCT) in order to determine potential etiologies of CM1/LLCT in PHP1A.
In our cohort of PHP1A, the prevalence of CM1 is 10.8%, which is at least 10-fold higher than in the general population. If LLCT is included, the prevalence increases to 21.7%. We found no correlation with GH status, biological sex, genotype, or hand/wrist bone age. Through investigations of our Gnas E1+/-m mice, the correlate to PHP1A, we identified a smaller cranial vault and increased cranial dome angle with evidence of hyperostosis due to increased osteogenesis. We also demonstrated that there was premature closure of the spheno-occipital synchondrosis (SOS), a cartilaginous structure essential to the development of the cranial base. These findings lead to craniofacial abnormalities and could contribute to CM1 and LLCT development in PHP1A.
The prevalence of CM1 is at least 10-fold higher in PHP1A compared to the general population and 20-fold higher when including LLCT. This is independent of the GH deficiency that is found in approximately two-thirds of patients with PHP1A. In light of potential serious consequences of CM1, clinicians should have a low threshold for brain imaging. Investigations of our AHO mouse model revealed aberrant cranial formation including a smaller cranium, increased cranial dome angle, hyperostosis, and premature SOS closure rates, providing a potential etiology for the increased prevalence of CM1 and LLCT in PHP1A.
Wells syndrome, also referred to as eosinophilic cellulitis, is a rare and often sporadic inflammatory skin condition whose aetiology remains uncertain. Clinically, this condition presents as a ...collection of erythematous, oedematous, and tender skin lesions most often affecting the extremities and trunk that can mimic cellulitis. Histologically, Wells syndrome is characterised by inflammatory changes and eosinophilic infiltration of the dermis with the absence of underlying infection, thereby distinguishing it from cellulitis. Due to the rarity of this syndrome and its ambiguous presentation, there remains to be a definitive strategy for treatment. Recent case reports have documented varying success and recurrence with the use of oral and topical corticosteroids, antifungals, antibiotics, immunosuppressants and antihistamines. Here, we report a unique case of progressively worsening neutrophilic‐rich Wells syndrome on the vertex of the scalp that was successfully treated with a combination of dupilumab and oral corticosteroids.
We report a unique case of progressively worsening neutrophilic‐rich Wells syndrome on the vertex of the scalp that was successfully treated with a combination of dupilumab and oral corticosteroids.
Seeds of a putative 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicide–resistant tall waterhemp biotype from Henry County, IA, were collected from a seed corn field in fall 2009 after ...plants were not controlled following a POST application of mesotrione plus atrazine. The response of this biotype to various herbicide modes of action was evaluated in greenhouse and field tests. Under greenhouse conditions, the suspect biotype showed an eightfold decrease in sensitivity to mesotrione with a 50% control rate of 21 g ha−1 compared with 2.7 g ha−1 for the susceptible biotype. The biotype also had a 10-fold decrease in sensitivity to atrazine and a 28-fold decrease in sensitivity to thifensulfuron. Under field conditions, tall waterhemp was not controlled POST at the label rate of 1,100 g ha−1 of atrazine. Tall waterhemp control was less than 60% at the label rates of three commonly used POST HPPD-inhibiting herbicides in seed corn: 105 g ha−1 of mesotrione, 92 g ha−1 of tembotrione, or 18 g ha−1 of topramezone. Thus, this new tall waterhemp biotype is resistant to three herbicide modes of action: HPPD inhibitors, photosystem-II inhibitors, and acetolactate synthase (ALS) inhibitors. Nomenclature: Atrazine; mesotrione; tembotrione; thifensulfuron, topramezone, tall waterhemp, Amaranthus tuberculatus (Moq.) Sauer AMATU; corn, Zea mays L. ZEAMX
Background The optimal treatment for acute stroke attributable to isolated cervical internal carotid artery occlusion without intracranial target is unclear. The purpose of our study was to examine ...whether endovascular therapy for acute stroke attributable to isolated cervical internal carotid artery occlusion was associated with improved clinical outcome. Methods We identified patients from 2 comprehensive stroke centers during the period January 2009 to December 2019, with acute ischemic stroke attributable to cervical internal carotid artery occlusion without an intracranial occlusion. We categorized patients into 2 groups: endovascular therapy and medical therapy. Clinical outcome (modified Rankin scale score at 90 days poststroke) was compared between the 2 groups. Results Seventy‐three patients were included (26 women 36%; median age, 69 interquartile range (IQR), 60–80 years; median National Institutes of Health Stroke Scale score, 11 IQR, 5–16). Of these, 40 patients received endovascular therapy, and 33 patients were managed with medical therapy alone. The endovascular therapy group had a significantly higher median National Institutes of Health Stroke Scale score on presentation (13 versus 3; P <0.0001). Rates of thrombolysis were also significantly higher in the endovascular group (50% versus 15%; P =0.002). There were no other significant differences in baseline characteristics between the 2 groups. Good clinical outcome (modified Rankin scale score 0–2 at 90 days or no decline in modified Rankin scale score from baseline at 90 days) was seen in 73% of the endovascular therapy group compared with the 61% of the medical management group (odds ratio OR for good outcome, 1.7 95% CI, 0.64–4.6), despite the large discrepancy in baseline stroke severity. When restricted to patients with presenting National Institutes of Health Stroke Scale score ≥6, endovascular therapy was associated with higher rates of good clinical outcome (66% versus 18%; OR for good outcome, 9.0 95% CI, 1.65–49.0). Conclusions Endovascular therapy in isolated cervical internal carotid artery occlusion may be associated with improved outcome when compared with medical therapy. However, the significant differences in baseline characteristics between the groups limit interpretation. Randomized controlled trials are necessary.
Background: In India, 50-65% of the population face difficulties in accessing medicines. The Health Impact Fund (HIF) is a novel proposal whereby pharmaceutical companies would be paid based on the ...measured global health impact of their drugs. We conducted a key stakeholder analysis to explore access to medicines in India, acceptability of the HIF and potential barriers and facilitators at policy level.
Objectives: To conduct a stakeholder analysis of the HIF in India: to determine key stakeholder views regarding access to medicines in India; to evaluate acceptability of the HIF; and to assess potential barriers and facilitators to the HIF as a policy.
Methods: In New Delhi, we conducted semi-structured interviews. There was purposive recruitment of participants with snowball sampling. Transcribed data were analysed using stakeholder analysis frameworks and directed content analysis.
Results: Participation rate was 29% (14/49). 14 semi-structured interviews were conducted among stakeholders in New Delhi. All participants highlighted access to medicines as a problem in India. There were mixed views about the HIF in terms of relevance and scaleability. Stakeholders felt it should focus on diseases with limited or no market and potentially incorporate direct investment in research.
Conclusions: First, access to medicines is perceived to be a major problem in India by all stakeholders, but affordability is just one factor. Second, stakeholders despite considerable support for the idea of the HIF, there are major concerns about scaleability, generalisability and impact on access to medicines. Third, the HIF and other novel drug-related health policies can afford to be more radical, e.g. working outside the existing intellectual property rights regime, targeting generic as well as branded drugs, or extending to research and development. Further innovations in access to medicines must involve country-specific key stakeholders in order to increase the likelihood of their success.
Purpose of Review
This review highlights the impact of
Gnas
inactivation on both bone remodeling and the development of heterotopic subcutaneous ossifications in Albright hereditary osteodystrophy ...(AHO). Here we discuss recent advancements in understanding the pathophysiologic mechanisms of the aberrant bone development in AHO as well as potential translational implications.
Recent Findings
Gnas
inactivation can regulate the differentiation and function of not only osteoblasts but also osteoclasts and osteocytes. Investigations utilizing a mouse model of AHO generated by targeted disruption of
Gnas
have revealed that bone formation and resorption are differentially affected based upon the parental origin of the
Gnas
mutation. Data suggest that
Gnas
inactivation leads to heterotopic bone formation within subcutaneous tissue by changing the connective tissue microenvironment, thereby promoting osteogenic differentiation of tissue-resident mesenchymal progenitors.
Summary
Observed variations in bone formation and resorption based upon the parental origin of the
Gnas
mutation warrant future investigations and may have implications in the management and treatment of AHO and related conditions. Additionally, studies of heterotopic bone formation due to
Gnas
inactivation have identified an essential role of sonic hedgehog signaling, which could have therapeutic implications not only for AHO and related conditions but also for heterotopic bone formation in a wide variety of settings in which aberrant bone formation is a cause of significant morbidity.
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