bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbiota-immune interactions: from gut to brain
Authors: Salvo-Romero Eloisa , Stokes Patricia , Gareau Mélanie G. 
Published: January 2020

The vast diversity of bacteria that inhabit the gastrointestinal tract strongly influence host physiology, not only nutrient metabolism but also immune system development and function. The complexity of the microbiota is matched by the complexity of the host immune system, where they have coevolved to maintain homeostasis ensuring the mutualistic host-microbial relationship. Numerous studies in recent years investigating the gut-brain axis have demonstrated an important role for the gut microbiota in modulating brain development and function, with the immune system serving as an important coordinator of these interactions. Gut bacteria can modulate not only gut-resident immune cells but also brain-resident immune cells. Activation of the immune system in the gut and in the brain are implicated in responses to neuroinflammation, brain injury, as well as changes in neurogenesis and plasticity. Impairments in this bidirectional communication are implicated in the etiopathogenesis of psychiatric and neurodevelopmental diseases and disorders, including autism spectrum disorders, or comorbidities associated with Gastrointestinal diseases, including inflammatory bowel diseases, where dysbiosis is commonly seen. Consequently, probiotics, or beneficial microbes, are being recognized as promising therapeutic targets to modulate behavior and brain development by modulating the gut microbiota. Here we review the role of microbiota-immune interactions in the gut and the brain during homeostasis and disease and their impact on gut-brain communication, brain function, and behavior as well as the use of probiotics in central nervous system alterations.Statement of novelty: The microbiota-gut-brain axis is increasingly recognized as an important physiological pathway for maintaining health and impacting the brain and central nervous system. Increasing evidence suggests that the immune system is crucial for gut-brain signaling. In this review, we highlight the critical studies in the literature that identify the key immune pathways involved.
Denosumab-induced hypocalcaemia in metastatic castrate-resistant prostate cancer
Authors: Gunawan Florence , George Elizabeth , Kotowicz Mark 
Published: January 2020

Summary
Denosumab is a fully human MAB that acts as a potent anti-resorptive by inhibiting activation of osteoclasts by inhibiting the receptor activator of nuclear factor-kappa B (RANK) ligand. Hypocalcaemia has been reported as one of the serious adverse sequelae of use of denosumab. We present a case of refractory hypocalcaemia following administration of a single dose of denosumab in a patient with metastatic castrate-resistant prostate cancer. The patient’s serum calcium and vitamin D concentrations and renal function were normal prior to denosumab administration. Serum alkaline phosphatase (ALP) level was however elevated pre-morbidly consistent with known bone metastases. The patient was treated with high-dose oral and IV calcium without any appreciable response in serum calcium. During his 30-day hospital admission, he demonstrated disease progression with development of new liver metastases and bone marrow involvement. Normocalcaemia was not achieved despite 1 month of aggressive therapy. Given the patient was asymptomatic and prognosis guarded, he was eventually discharged for ongoing supportive care under the palliative care team.

Learning points:

Denosumab is a potent anti-resorptive therapy and hypocalcaemia is one of the known adverse effects.

Serum calcium and vitamin D concentrations must be replete prior to administration of denosumab to reduce the risk of hypocalcaemia.

Denosumab has been proven to be more effective than zoledronic acid in preventing skeletal-related adverse effects in patients with metastatic castrate-resistant prostate cancer.
Misdiagnosis of Mullerian agenesis in a patient with 46, XX gonadal dysgenesis: a missed opportunity for prevention of osteoporosis
Authors: Thewjitcharoen Yotsapon , Veerasomboonsin Veekij , Nakasatien Soontaree , Krittiyawong Sirinate , Himathongkam Thep 
Published: January 2020

Summary
Primary amenorrhea could be caused by disorders of four parts: disorders of the outflow tract, disorders of the ovary, disorders of the anterior pituitary, and disorders of hypothalamus. Delay in diagnosis and hormone substitution therapy causes secondary osteoporosis. Herein, we report a case of a 23-year-old phenotypical female who presented with primary amenorrhea from 46, XX gonadal dysgenesis but had been misdiagnosed as Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome or Mullerian agenesis. The coexistence of gonadal dysgenesis and MRKH was suspected after laboratory and imaging investigations. However, the vanishing uterus reappeared after 18 months of hormone replacement therapy. Therefore, hormone profiles and karyotype should be thoroughly investigated to distinguish MRKH syndrome from other disorders of sex development (DSD). Double diagnosis of DSD is extremely rare and periodic evaluation should be reassessed. This case highlights the presence of estrogen deficiency state, the uterus may remain invisible until adequate exposure to exogenous estrogen.

Learning points:

An early diagnosis of disorders of sex development (DSD) is extremely important in order to promptly begin treatment, provide emotional support to the patient and reduce the risks of associated complications.

Hormone profiles and karyotype should be investigated in all cases of the presumptive diagnosis of Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome or Mullerian agenesis.

The association between 46, XX gonadal dysgenesis and Mullerian agenesis has been occasionally reported as a co-incidental event; however, reassessment of the presence of uterus should be done again after administration of exogenous estrogen replacement for at least 6–12 months.

A multidisciplinary approach is necessary for patients presenting with DSD to ensure appropriate treatments and follow-up across the lifespan of individuals with DSD.
Primary aldosteronism in Klinefelter’s syndrome: two cases
Authors: Seki Yasufumi , Morimoto Satoshi , Yoshida Naohiro , Bokuda Kanako , Sasaki Nobukazu , Yatabe Midori , Yatabe Junichi , Watanabe Daisuke , Morita Satoru , Hata Keisuke , Yamamoto Tomoko , Nagashima Yoji , Ichihara Atsuhiro 
Published: January 2020

Summary
Primary aldosteronism (PA) is more common than expected. Aberrant adrenal expression of luteinizing hormone (LH) receptor in patients with PA has been reported; however, its physiological role on the development of PA is still unknown. Herein, we report two unique cases of PA in patients with untreated Klinefelter’s syndrome, characterized as increased serum LH, suggesting a possible contribution of the syndrome to PA development. Case 1 was a 39-year-old man with obesity and hypertension since his 20s. His plasma aldosterone concentration (PAC) and renin activity (PRA) were 220 pg/mL and 0.4 ng/mL/h, respectively. He was diagnosed as having bilateral PA by confirmatory tests and adrenal venous sampling (AVS). Klinefelter’s syndrome was suspected as he showed gynecomastia and small testes, and it was confirmed on the basis of a low serum total testosterone level (57.3 ng/dL), high serum LH level (50.9 mIU/mL), and chromosome analysis. Case 2 was a 28-year-old man who had untreated Klinefelter’s syndrome diagnosed in his childhood and a 2-year history of hypertension and hypokalemia. PAC and PRA were 247 pg/mL and 0.3 ng/mL/h, respectively. He was diagnosed as having a 10 mm-sized aldosterone-producing adenoma (APA) by AVS. In the APA, immunohistochemical analysis showed co-expression of LH receptor and CYP11B2. Our cases of untreated Klinefelter’s syndrome complicated with PA suggest that increased serum LH levels and adipose tissues, caused by primary hypogonadism, could contribute to PA development. The possible complication of PA in hypertensive patients with Klinefelter’s syndrome should be carefully considered.

Learning points:

The pathogenesis of primary aldosteronism is still unclear.

Expression of luteinizing hormone receptor has been reported in aldosterone-producing adenoma.

Serum luteinizing hormone, which is increased in patients with Klinefelter’s syndrome, might contribute to the development of primary aldosteronism.
Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease
Authors: Newell-Price John , Pivonello Rosario , Tabarin Antoine , Fleseriu Maria , Witek Przemysław , Gadelha Mônica R , Petersenn Stephan , Tauchmanova Libuse , Ravichandran Shoba , Gupta Pritam , Lacroix André , Biller Beverly M K 
Published: January 2020

Objective
Monitoring of patients with Cushing’s disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing’s disease.

Design
Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing’s disease (clinicaltrials.gov: NCT01374906).

Methods
Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time.

Results
At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman’s correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN.

Conclusion
mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing’s disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.
Long-term outcome of partial P450 side-chain cleavage enzyme deficiency in three brothers: the importance of early diagnosis
Authors: Kallali Wafa , Gray Ewan , Mehdi Muhammad Zain , Lindsay Robert , Metherell Louise A , Buonocore Federica , Suntharalingham Jenifer P , Achermann John C , Donaldson Malcolm 
Published: January 2020

Objective
CYP11A1 mutations cause P450 side-chain cleavage (scc) deficiency, a rare form of congenital adrenal hyperplasia with a wide clinical spectrum. We detail the phenotype and evolution in a male sibship identified by HaloPlex targeted capture array.

Family study
The youngest of three brothers from a non-consanguineous Scottish family presented with hyperpigmentation at 3.7 years. Investigation showed grossly impaired glucocorticoid function with ACTH elevation, moderately impaired mineralocorticoid function, and normal external genitalia. The older brothers were found to be pigmented also, with glucocorticoid impairment but normal electrolytes. Linkage studies in 2002 showed that all three brothers had inherited the same critical regions of the maternal X chromosome suggesting an X-linked disorder, but analysis of NR0B1 (DAX-1, adrenal hypoplasia) and ABCD1 (adrenoleukodystrophy) were negative.
In 2016, next-generation sequencing revealed compound heterozygosity for the rs6161 variant in CYP11A1 (c.940G>A, p.Glu314Lys), together with a severely disruptive frameshift mutation (c.790_802del, K264Lfs*5). The brothers were stable on hydrocortisone and fludrocortisone replacement, testicular volumes (15–20 mL), and serum testosterone levels (24.7, 33.3, and 27.2 nmol/L) were normal, but FSH (41.2 µ/L) was elevated in the proband. The latter had undergone left orchidectomy for suspected malignancy at the age of 25 years and was attending a fertility clinic for oligospermia. Initial histology was reported as showing nodular Leydig cell hyperplasia. However, histological review using CD56 staining confirmed testicular adrenal rest cell tumour (TART).

Conclusion
This kinship with partial P450scc deficiency demonstrates the importance of precise diagnosis in primary adrenal insufficiency to ensure appropriate counselling and management, particularly of TART.
High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature
Authors: Stavber L , Hovnik T , Kotnik P , Lovrečić L , Kovač J , Tesovnik T , Bertok S , Dovč K , Debeljak M , Battelino T , Avbelj Stefanija M 
Published: January 2020

Context
Defining the underlying etiology of idiopathic short stature (ISS) improves the overall management of an individual.

Objective
To assess the frequency of pathogenic ACAN variants in selected individuals.

Design
The single-center cohort study was conducted at a tertiary university children’s hospital. From 51 unrelated patients with ISS, the 16 probands aged between 3 and 18 years (12 females) with advanced bone age and/or autosomal dominant inheritance pattern of short stature were selected for the study. Fifteen family members of ACAN-positive probands were included. Exome sequencing was performed in all probands, and additional copy number variation (CNV) detection was applied in selected probands with a distinct ACAN-associated phenotype.

Results
Systematic phenotyping of the study cohort yielded 37.5% (6/16) ACAN-positive probands, with all novel pathogenic variants, including a 6.082 kb large intragenic deletion, detected by array comparative genomic hybridization (array CGH) and exome data analysis. All variants were co-segregated with short stature phenotype, except in one family member with the intragenic deletion who had an unexpected growth pattern within the normal range (−0.5 SDS). One patient presented with otosclerosis, a sign not previously associated with aggrecanopathy.

Conclusions
ACAN pathogenic variants presented a common cause of familial ISS. The selection criteria used in our study were suggested for a personalized approach to genetic testing of the ACAN gene in clinical practice. Our results expanded the number of pathogenic ACAN variants, including the first intragenic deletion, and suggested CNV evaluation in patients with typical clinical features of aggrecanopathy as reasonable. Intra-familial phenotypic variability in growth patterns should be considered.
Clinicopathological features of colorectal polyps and risk of colorectal cancer in acromegaly
Authors: Ochiai Yorinari , Inoshita Naoko , Iizuka Toshiro , Nishioka Hiroshi , Yamada Shozo , Kitagawa Masanobu , Hoteya Shu 
Published: January 2020

Objective
Patients with acromegaly are at increased risk of colorectal polyps. However, their risk of colorectal cancer remains unclear. This study aimed to identify the histopathological features of colorectal polyps in patients with acromegaly and compare their risk of colorectal cancer with that in healthy controls.

Methods
The study participants were 178 patients who underwent Hardy’s operation and perioperative colonoscopy at our hospital between April 2008 and September 2016. For the control group, we randomly selected 356 age- and sex-matched patients who underwent colonoscopy at our hospital during the same period. The incidence, size, location, and histology of the colorectal polyps detected were compared between the groups.

Results
Colorectal polyps were detected in 66.8% of the acromegaly group and 24.2% of the control group (P < 0.001). The average number and size of the polyps were 2.44 and 4.74 mm, respectively, in the acromegaly group and 1.77 and 3.89 mm in the control group (P = 0.001). Polyps in the acromegaly group were more likely to be in the rectosigmoid region (P = 0.006). In the acromegaly group, the frequency of polyps ≥5 mm was 34.3% and that for polyps ≥10 mm was 15.2%; the respective values were 7.6% and 2.2% in the control group (P < 0.001). We found no evidence of between-group histopathological differences in the polyp specimens resected by endoscopy.

ConclusionsPatients with acromegaly are at an increased risk of colorectal polyps, especially in the rectosigmoid region. However, there is no pathological evidence that they are at greater risk of colorectal cancer than the general population.
Perchance to Read: Developing an Augmented Reality Game to Increase Student Engagement with Hamlet
Authors: MISAK JOHN R , LaGrandeur Kevin 
Published: January 2020

Hamlet (and similar texts) can be difficult for students to follow initially. Often when students read, they may gloss over the text, missing key contexts. These problems lead to a lack of engagement in the literature classroom. The use of videos can help, but this often deters reading. This dilemma prompted the development of an Augmented Reality (AR) application to enhance Hamlet. By ‘zooming in’ on specific elements of Hamlet—Act I Scenes IV and V (the ghost scenes)— students explore and gain valuable information on the context behind these scenes. Students discover their perspective on a key question in the play; is the ghost real, or is it coinage from Hamlet’s brain? Students can arrive at a more concrete understanding of their own thoughts and take away a better grasp of both the context of the scene and the character of Hamlet through their active participation in the application.

Primarily, this article will highlight the dramatic effect student experience, both real and perceived, had on the development and execution of the application. The goal is to convey the pedagogical questions addressed when conceptualizing the application: the desired learning outcomes, the perceived student audience, and the need to connect game actions to the text of the play. It is one thing to speculate what students may want/need in such an environment from an instructor’s perspective. It’s another to analyze student and instructor feedback to help highlight critical areas more effectively. Students not only learn through their actions in the app; they help create the design of the application through their feedback. The article will detail the development of the application through this user input and the impact of praxis on its iteration.
Spatio-seasonal variations in the faecal bacterial community of Zulu sheep grazing in communally managed rangeland
Authors: Xulu Thembinkosi G. , Ezeokoli Obinna T. , Gupta Arvind K. , Mienie Charlotte , Bezuidenhout Cornelius C. , Kunene Nokuthula W. 
Published: January 2020

The adaptation of Zulu (Nguni) sheep (Ovis aries) to environmental stress and survival under extensive conditions makes them uniquely important to rural Nguni farmers of South Africa. Here, the faecal bacterial community of five Zulu sheep populations managed under extensive conditions across summer and winter seasons was investigated in order to understand the influence of prevailing seasonal factors. Bacterial operational taxonomic units (OTUs)/species (at 97% 16S rRNA gene similarity) in Zulu sheep faeces were more diverse in winter than in summer at most (80%) sites and varied between seasons at specific sites. Firmicutes was the most abundant phyla in both summer and winter seasons, while the relative abundance of Actinobacteria reduced in 80% of sites from summer to winter. The genera (or family) such as Akkermansia, Eubacterium coprostanoligenes group, Intestinibacter, R-7 group (family Christensenellaceae), Ruminococcus, Ruminoclostridium, Treponema and UCG-005 (family Ruminococcaceae) were relatively more abundant and belonged to a ‘core microbiome’ of Zulu sheep faeces. Between seasons, Acinetobacter, Jeotgalicoccus, Methanobrevibacter, Phascolarctobacterium and Planomicrobium were differentially abundant. Overall, results suggest increased richness and diversity of bacteria from summer to winter which may be related to spatio-seasonal variations in grazing management, forage types and availability. This observation serves as baseline evidence, justifying further controlled studies investigating, amongst other factors, effects of forage type and availability across seasons on ruminal microbiota of Zulu sheep grazing in communally managed rangelands.
Significance:

Spatio-seasonal dynamics in the bacterial community of Zulu sheep faeces suggest differences in forage type and availability across sites potentially influence faecal bacteria of Zulu sheep.
The study provides a basis for further controlled studies investigating the influence of environmental factors on rumen and faecal microbiomes of Zulu sheep.

Open data set:
https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA356736
Demonstrate observe assist perform versus video assisted teaching in teaching deep tendon reflexes to medical students: a comparative study
Authors: S. Sundeep , Pillai Swapna K. 
Published: January 2020

Background: Clinical examination of Deep tendon reflexes is a skilled technique that should be taught in an interesting way. Newer teaching learning methods like Video assisted teaching can be utilized to facilitate self-directed and long term learning and to cultivate enhanced interest in the study.Method: Among 120 students are divided into 6 groups. Each group is divided into two batches of 10 members each. 6 batches are taught deep tendon reflexes separately by DOAP. 6 batches are taught deep tendon reflexes separately by video assisted teaching. At the end of teaching and 2 weeks later, each batch is assessed by OSCE . Objective Structured Clinical Examination checklist marks are systematically entered in an excel sheet and was analysed using unpaired t-test .The perception to each teaching learning method was assessed by feedback Questionnaire using Likert Scale.Results: On comparing between the effectiveness of video assisted teaching and clinical demonstration of the examination of deep tendon reflexes , students taught by video assisted teaching scored higher marks in the evaluation after two weeks, which was statistically significant. Regarding perception, students favoured both teaching methods for their effectiveness. For clarifying doubts, students favoured DOAP method. For reproducibility and better retaining of memory, students favoured video assisted teaching.Conclusion: Video assisted teaching was equally effective as DOAP in teaching deep tendon reflexes to medical students. For reproducibility and better retaining of memory, Video assisted teaching was perceived better as reflected in the better mean scores two weeks after the teaching sessions.