Circulating microRNA as a Potential Biomarker for Skeletal Disease in Primary Hyperparathyroidism: A Case-control Study.

OBJECTIVE: The goal of this study was to characterize the microRNA (miRNA) expression signatures in patients with PHPT and identify miRNA biomarkers of bone homeostasis. SUMMARY BACKGROUND DATA: Primary hyperparathyroidism (PHPT) is associated with increased bone turnover and decreased bone mass. miRNA are markers of bone remodeling. METHODS: We performed a prospective case-control study of post-menopausal females with PHPT and control subjects matched for race, age, and BMD. We collected clinical and biochemical data, assessed BMD by dual-energy X-ray absorptiometry, and measured 27 serum miRNAs related to bone remodeling. We used linear regression to assess the correlation between miRNA levels, conventional biochemical markers and BMD. RESULTS: A total of 135 subjects were evaluated, including 49 with PHPT (discovery group), 47 control patients without PHPT, and an independent validation cohort of 39 PHPT patients. Of 27 miRNAs evaluated, nine (miR-335-5p, miR-130b-3p, miR-125b-5p, miR-23a-3p, miR-152-3p, miR-582-5p, miR-144-5p, miR-320a and miR-19b-3p) were differentially expressed in PHPT compared to matched control subjects. All nine differentially expressed miRNAs significantly correlated with levels of serum parathyroid hormone (PTH), and eight of the nine correlated with calcium levels. No differentially expressed miRNAs were consistently correlated with markers of BMD. Subjects with PHPT segregate from controls based on the signature of these nine miRNAs on principle component analysis. CONCLUSIONS: These data suggest that PHPT is characterized by a unique miRNA signature that is distinct from postmenopausal and idiopathic osteoporosis. Levels of specific miRNAs significantly correlate with PTH, suggesting that bone remodeling in PHPT may be mediated in part by PTH-induced changes in miRNA.

The radiological interpretation of possible microbleeds after moderate or severe traumatic brain injury: a longitudinal study.

INTRODUCTION: In order to augment the certainty of the radiological interpretation of "possible microbleeds" after traumatic brain injury (TBI), we assessed their longitudinal evolution on 3-T SWI in patients with moderate/severe TBI. METHODS: Standardized 3-T SWI and T1-weighted imaging were obtained 3 and 26 weeks after TBI in 31 patients. Their microbleeds were computer-aided detected and classified by a neuroradiologist as no, possible, or definite at baseline and follow-up, separately (single-scan evaluation). Thereafter, the classifications were re-evaluated after comparison between the time-points (post-comparison evaluation). We selected the possible microbleeds at baseline at single-scan evaluation and recorded their post-comparison classification at follow-up. RESULTS: Of the 1038 microbleeds at baseline, 173 were possible microbleeds. Of these, 53.8% corresponded to no microbleed at follow-up. At follow-up, 30.6% were possible and 15.6% were definite. Of the 120 differences between baseline and follow-up, 10% showed evidence of a pathophysiological change over time. Proximity to extra-axial injury and proximity to definite microbleeds were independently predictive of becoming a definite microbleed at follow-up. The reclassification level differed between anatomical locations. CONCLUSIONS: Our findings support disregarding possible microbleeds in the absence of clinical consequences. In selected cases, however, a follow-up SWI-scan could be considered to exclude evolution into a definite microbleed.

Effect of isolation method on human corneal stromal cell behaviour.

Current research on healthy corneal stromal cells will typically use primary cells as they are the most representative of in vivo behaviour. Primary cells are normally isolated from the limbus of discarded donor peripheral corneal tissue left over from transplantation (due to its relative abundance). Therefore, the central part of the cornea is less used in research as this tissue is usually used for transplantation. In some cases, although rare, the whole cornea, can become available for research. It is important to keep in mind that these corneas often have longer storage time, but the use of the central tissue for research is even more interesting, as knowing what cells are being transplanted into recipients would be highly relevant. To this end, stromal cells were extracted from both the limbus and central button of healthy corneas donated for research. This allowed for important comparison between central and limbal cells in culture. Of interest here was the extraction method of stromal cells from the donor tissue. The two most common methods of extraction are enzyme digestion and explant migration. However, no work has been done to understand how each method relatively affects the extracted cells. The extraction method and location from which stromal cells are harvested seems to have a significant effect on the cell adherence, survival, and gene expression of the stromal cells in culture. Enzyme digested cells showed that limbal and central cells had different gene expressions prior to culture, with gene such as ALDH3A1 being much more expressed in limbal cells. Enzyme digesting the limbal ring seems to yield the hardiest populations of stromal cells, a desirable trait in the culture of primary cells.

Pneumothorax as a complication of dry needling technique.

Post-dry needling pneumothorax is not extremely rare. Patients and referring doctors should be aware of this. Informed consent should mention pneumothorax as a considerable risk of dry needling procedures in the neck, shoulder or chest region. https://bit.ly/49YYNR8.

Occult solitary fibrous tumour of the pleura presenting as recurrent spontaneous pneumothorax.

A woman in her 30s, non-smoker, presented at the emergency department two times because of spontaneous pneumothorax. The first episode was treated with small bore catheter drainage, while during the second episode-occurring only 1 week later-thoracoscopic talcage was attempted. The postoperative course was characterised by slow clinical and radiological resolution, and recurrence 3 days after discharge. Eventually, multiportal video-assisted thoracoscopic exploration identified an interfissural solid mass. Resection and further work-up revealed the diagnosis of 'low-risk' solitary fibrous tumour (SFT) stage pT1N0M0. The interdisciplinary tumour board advised no adjuvant therapy. A CT thorax was scheduled in 1 year for follow-up. The patient was discharged without complications and has had no recurrences of pneumothorax at 6 months of follow-up. This report shows that SFT can easily be missed on initial presentation and should be considered in the differential diagnosis of pneumothorax, especially when frequently recurring.

ABCB5+ Limbal Epithelial Stem Cells Inhibit Developmental but Promote Inflammatory (Lymph) Angiogenesis While Preventing Corneal Inflammation.

The limbus, the vascularized junction between the cornea and conjunctiva, is thought to function as a barrier against corneal neovascularization. However, the exact mechanisms regulating this remain unknown. In this study, the limbal epithelial stem cell (LESC) marker ABCB5 was used to investigate the role of LESCs in corneal neovascularization. In an ABCB5KO model, a mild but significant increase of limbal lymphatic and blood vascular network complexity was observed in developing mice (4 weeks) but not in adult mice. Conversely, when using a cornea suture model, the WT animals exhibited a mild but significant increase in the number of lymphatic vessel sprouts compared to the ABCB5KO, suggesting a contextual anti-lymphangiogenic effect of ABCB5 on the limbal vasculature during development, but a pro-lymphangiogenic effect under inflammatory challenge in adulthood. In addition, conditioned media from ABCB5-positive cultured human limbal epithelial cells (ABCB5+) stimulated human blood and lymphatic endothelial cell proliferation and migration. Finally, a proteomic analysis demonstrated ABCB5+ cells have a pro(lymph)angiogenic as well as an anti-inflammatory profile. These data suggest a novel dual, context-dependent role of ABCB5+ LESCs, inhibiting developmental but promoting inflammatory (lymph)angiogenesis in adulthood and exerting anti-inflammatory effects. These findings are of high clinical relevance in relation to LESC therapy against blindness.

Allogeneic Hematopoietic Stem Cell Transplantation After Prior Lung Transplantation for Hereditary Pulmonary Alveolar Proteinosis: A Case Report.

Pulmonary alveolar proteinosis (PAP) is a rare, diffuse lung disorder characterized by surfactant accumulation in the small airways due to defective clearance by alveolar macrophages, resulting in impaired gas exchange. Whole lung lavage is the current standard of care treatment for PAP. Lung transplantation is an accepted treatment option when whole lung lavage or other experimental treatment options are ineffective, or in case of extensive pulmonary fibrosis secondary to PAP. A disadvantage of lung transplantation is recurrence of PAP in the transplanted lungs, especially in hereditary PAP. The hereditary form of PAP is an ultra-rare condition caused by genetic mutations in genes encoding for the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, and intrinsically affects bone marrow derived-monocytes, which differentiate into macrophages in the lung. Consequently, these macrophages typically display disrupted GM-CSF receptor-signaling, causing defective surfactant clearance. Bone marrow/hematopoietic stem cell transplantation may potentially reverse the lung disease in hereditary PAP. In patients with hereditary PAP undergoing lung transplantation, post-lung transplant recurrence of PAP may theoretically be averted by subsequent hematopoietic stem cell transplantation, which results in a graft-versus-disease (PAP) effect, and thus could improve long-term outcome. We describe the successful long-term post-transplant outcome of a unique case of end-stage respiratory failure due to hereditary PAP-induced pulmonary fibrosis, successfully treated by bilateral lung transplantation and subsequent allogeneic hematopoietic stem cell transplantation. Our report supports treatment with serial lung and hematopoietic stem cell transplantation to improve quality of life and prolong survival, without PAP recurrence, in selected patients with end-stage hereditary PAP.

Keratoconus at a Molecular Level: A Review.

Keratoconus is the most common ectatic disease of the cornea. The disease is usually detected between ages 15 and 25. Incidence is estimated at one out of every 2000 individuals, with some specific ethnic groups being more at risk. Keratoconus manifests itself as a progressive stromal thinning and deformation of the corneal tissue into a conical shape. The etiology of keratoconus is uncertain, although several studies have associated the disease to environmental factors, behavioral conditions and certain genetic disorders. In an effort to better understand how the corneal stroma becomes compromised, multiple experiments have been conducted over the last few years looking at the cells themselves and the factors they produce. The secretion pathways and levels of inflammatory molecules, growth factors, digestive enzymes, and apoptotic factors are all relevant to keratoconus. This review describes the current knowledge of keratoconic pathological signaling pathways within the cornea that may help future developments in disease prevention, treatment and modeling. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.

Single subunit chimeric integrins as mimics and inhibitors of endogenous integrin functions in receptor localization, cell spreading and migration, and matrix assembly.

The ability of single subunit chimeric receptors containing various integrin beta intracellular domains to mimic and/or inhibit endogenous integrin function was examined. Chimeric receptors consisting of the extracellular and transmembrane domains of the small subunit of the human interleukin-2 receptor connected to either the beta 1, beta 3, beta 3B, or beta 5 intracellular domain were transiently expressed in normal human fibroblasts. When expressed at relatively low levels, the beta 3 and beta 5 chimeras mimicked endogenous ligand-occupied integrins and, like the beta 1 chimera (LaFlamme, S. E., S. K. Akiyama, and K. M. Yamada. 1992. J. Cell Biol. 117:437), concentrated with endogenous integrins in focal adhesions and sites of fibronectin fibril formation. In contrast, the chimeric receptor containing the beta 3B intracellular domain (a beta 3 intracellular domain modified by alternative splicing) was expressed diffusely on the cell surface, indicating that alternative splicing can regulate integrin receptor distribution by an intracellular mechanism. Furthermore, when expressed at higher levels, the beta 1 and beta 3 chimeric receptors functioned as dominant negative mutants and inhibited endogenous integrin function in localization to fibronectin fibrils, fibronectin matrix assembly, cell spreading, and cell migration. The beta 5 chimera was a less effective inhibitor, and the beta 3B chimera and the reporter lacking an intracellular domain did not inhibit endogenous integrin function. Comparison of the relative levels of expression of the transfected beta 1 chimera and the endogenous beta 1 subunit indicated that in 10 to 15 h assays, the beta 1 chimera can inhibit cell spreading when expressed at levels approximately equal to the endogenous beta 1 subunit. Levels of chimeric receptor expression that inhibited cell spreading also inhibited cell migration, whereas lower levels were able to inhibit alpha 5 beta 1 localization to fibrils and matrix assembly. Our results indicate that single subunit chimeric integrins can mimic and/or inhibit endogenous integrin receptor function, presumably by interacting with cytoplasmic components critical for endogenous integrin function. Our results also demonstrate that beta intracellular domains, expressed in this context, display specificity in their abilities to mimic and inhibit endogenous integrin function. Furthermore, the approach that we have used permits the analysis of intracellular domain function in the processes of cell spreading, migration and extracellular matrix assembly independent of effects due to the rest of integrin dimers. This approach should prove valuable in the further analysis of integrin intracellular domain function in these and other integrin-mediated processes requiring the interaction of integrins with cytoplasmic components.

Automated Fetal Head Detection and Circumference Estimation from Free-Hand Ultrasound Sweeps Using Deep Learning in Resource-Limited Countries.

Ultrasound imaging remains out of reach for most pregnant women in developing countries because it requires a trained sonographer to acquire and interpret the images. We address this problem by presenting a system that can automatically estimate the fetal head circumference (HC) from data obtained with use of the obstetric sweep protocol (OSP). The OSP consists of multiple pre-defined sweeps with the ultrasound transducer over the abdomen of the pregnant woman. The OSP can be taught within a day to any health care worker without prior knowledge of ultrasound. An experienced sonographer acquired both the standard plane-to obtain the reference HC-and the OSP from 183 pregnant women in St. Luke's Hospital, Wolisso, Ethiopia. The OSP data, which will most likely not contain the standard plane, was used to automatically estimate HC using two fully convolutional neural networks. First, a VGG-Net-inspired network was trained to automatically detect the frames that contained the fetal head. Second, a U-net-inspired network was trained to automatically measure the HC for all frames in which the first network detected a fetal head. The HC was estimated from these frame measurements, and the curve of Hadlock was used to determine gestational age (GA). The results indicated that most automatically estimated GAs fell within the P2.5-P97.5 interval of the Hadlock curve compared with the GAs obtained from the reference HC, so it is possible to automatically estimate GA from OSP data. Our method therefore has potential application for providing maternal care in resource-constrained countries.

Complaints about dental practitioners: an analysis of 6 years of complaints about dentists, dental prosthetists, oral health therapists, dental therapists and dental hygienists in Australia.

BACKGROUND: Previous research has found dental practitioners at elevated risk of complaint compared with other health professions. This study aimed to describe the frequency, nature and risk factors for complaints involving dental practitioners. METHODS: We assembled a national dataset of complaints about registered health practitioners in Australia between January 2011 and December 2016. We classified complaints into 23 issues across three domains: health, performance and conduct. We compared rates of complaints about dental practitioners and other health practitioners. We used negative binomial regression analysis to identify factors associated with complaints. RESULTS: Dental practitioners made up 3.5% of health practitioners, yet accounted for approximately 10% of complaints. Dental practitioners had the highest rate of complaints among fourteen health professions (42.7 per 1000 practitioners per year) with higher rates among dentists and dental prosthetists than allied dental practitioners. Male practitioners were at a higher risk of complaints. Most complaints about dentists related to treatments and procedures (59%). Around 4% of dentists received more than one complaint, accounting for 49% of complaints about dentists. In 60% of closed cases no regulatory action was required. Around 13% of complaints resulted in restrictive actions, such as conditions on practice. CONCLUSION: Improved understanding of patterns may assist regulatory boards and professional associations to ensure competent practice and protect patient safety.

Automated measurement of fetal head circumference using 2D ultrasound images.

In this paper we present a computer aided detection (CAD) system for automated measurement of the fetal head circumference (HC) in 2D ultrasound images for all trimesters of the pregnancy. The HC can be used to estimate the gestational age and monitor growth of the fetus. Automated HC assessment could be valuable in developing countries, where there is a severe shortage of trained sonographers. The CAD system consists of two steps: First, Haar-like features were computed from the ultrasound images to train a random forest classifier to locate the fetal skull. Secondly, the HC was extracted using Hough transform, dynamic programming and an ellipse fit. The CAD system was trained on 999 images and validated on an independent test set of 335 images from all trimesters. The test set was manually annotated by an experienced sonographer and a medical researcher. The reference gestational age (GA) was estimated using the crown-rump length measurement (CRL). The mean difference between the reference GA and the GA estimated by the experienced sonographer was 0.8 ± 2.6, -0.0 ± 4.6 and 1.9 ± 11.0 days for the first, second and third trimester, respectively. The mean difference between the reference GA and the GA estimated by the medical researcher was 1.6 ± 2.7, 2.0 ± 4.8 and 3.9 ± 13.7 days. The mean difference between the reference GA and the GA estimated by the CAD system was 0.6 ± 4.3, 0.4 ± 4.7 and 2.5 ± 12.4 days. The results show that the CAD system performs comparable to an experienced sonographer. The presented system shows similar or superior results compared to systems published in literature. This is the first automated system for HC assessment evaluated on a large test set which contained data of all trimesters of the pregnancy.

Comparison Study of Low-Cost Ultrasound Devices for Estimation of Gestational Age in Resource-Limited Countries.

We investigated how accurately low-cost ultrasound devices can estimate gestational age (GA) using both the standard plane and the obstetric sweep protocol (OSP). The OSP can be taught to health care workers without prior knowledge of ultrasound within one day and thus avoid the need to train dedicated sonographers. Three low-cost ultrasound devices were compared with one high-end ultrasound device. GA was estimated with the head circumference (HC), abdominal circumference (AC) and femur length (FL) using both the standard plane and the OSP. The results revealed that the HC, AC and FL can be used to estimate GA using low-cost ultrasound devices in the standard plane within the inter-observer variability presented in the literature. The OSP can be used to estimate GA by measuring the HC and the AC, but not the FL. This study shows that it is feasible to estimate GA in resource-limited countries with low-cost ultrasound devices using the OSP. This makes it possible to estimate GA and assess fetal growth for pregnant women in rural areas of resource-limited countries.

Development of a Low-Cost Medical Ultrasound Scanner Using a Monostatic Synthetic Aperture.

OBJECTIVE: In this paper, we present the design of low-cost medical ultrasound scanners aimed at the detection of maternal mortality risk factors in developing countries. METHOD: Modern ultrasound scanners typically employ a high element count transducer array with multichannel transmit and receive electronics. To minimize hardware costs, we employ a single piezoelectric element, mechanically swept across the target scene, and a highly cost-engineered single channel acquisition circuit. Given this constraint, we compare the achievable image quality of a monostatic fixed focus scanner (MFFS) with a monostatic synthetic aperture scanner (MSAS) using postfocusing. Quantitative analysis of image quality was carried out using simulation and phantom experiments, which were used to compare a proof-of-concept MSAS prototype with an MFFS device currently available on the market. Finally, in vivo experiments were performed to validate the MSAS prototype in obstetric imaging. RESULTS: Simulations show that the achievable lateral resolution of the MSAS approach is superior at all ranges compared to the fixed focus approach. Phantom experiments verify the improved resolution of the MSAS prototype but reveal a lower signal to noise ratio. In vivo experiments show promising results using the MSAS for clinical diagnostics in prenatal care. CONCLUSION: The proposed MSAS achieves superior resolution but lower SNR compared to an MFFS approach, principally due to lower acoustic energy emitted. SIGNIFICANCE: The production costs of the proposed MSAS could be an order of magnitude lower than any other ultrasound system on the market today, bringing affordable obstetric imaging a step closer for developing countries.

Dental prosthesis aspiration: An uncommon cause of respiratory distress.

We present a case of a 66-year-old Caucasian man with acute respiratory distress. The patient had a history of multiple cerebrovascular accidents which resulted in left hemiplegia, swallowing problems, and aphasia. He was tentatively diagnosed with aspiration pneumonia. However, because of clinical deterioration further investigations concluded to the aspiration of a dental prosthesis. After intubation and stabilization, the prosthesis could be manually extracted. However, the patient developed a Staphylococcus epidermidis sepsis and despite adequate antibiotic therapy, he eventually died. Dental prosthesis aspiration is a medical situation associated with a higher morbidity and mortality rate compared to ingested foreign bodies. It requires a high level of suspicion to ensure a timely diagnosis and life-saving treatment. Thorough history taking is of great importance in case of tracheobronchial aspiration, which is in the adult population mostly secondary to an underlying disorder. In impaired adults with missing dental prostheses there should be extra awareness for this problem. This case report illustrates the importance of a detailed history in case of tracheobronchial aspiration and shows the limitations in the diagnostic usefulness of bedside chest radiography.

Rehabilitation in patients with radically treated respiratory cancer: A randomised controlled trial comparing two training modalities.

INTRODUCTION: The evidence on the effectiveness of rehabilitation in lung cancer patients is limited. Whole body vibration (WBV) has been proposed as an alternative to conventional resistance training (CRT). METHODS: We investigated the effect of radical treatment (RT) and of two rehabilitation programmes in lung cancer patients. The primary endpoint was a change in 6-min walking distance (6MWD) after rehabilitation. Patients were randomised after RT to either CRT, WBVT or standard follow-up (CON). Patients were evaluated before, after RT and after 12 weeks of intervention. RESULTS: Of 121 included patients, 70 were randomised to either CON (24), CRT (24) or WBVT (22). After RT, 6MWD decreased with a mean of 38m (95% CI 22-54) and increased with a mean of 95m (95% CI 58-132) in CRT (p<0.0001), 37m (95% CI -1-76) in WBVT (p=0.06) and 1m (95% CI -34-36) in CON (p=0.95), respectively. Surgical treatment, magnitude of decrease in 6MWD by RT and allocation to either CRT or WBVT were prognostic for reaching the minimally clinically important difference of 54m increase in 6MWD after intervention. CONCLUSIONS: RT of lung cancer significantly impairs patients' exercise capacity. CRT significantly improves and restores functional exercise capacity, whereas WBVT does not fully substitute for CRT.

Genetic regulation of light damage to photoreceptors.

Albino mice of different inbred strains have been exposed to constant fluorescent lighting at an illuminance level of 115-130 ft-c for intervals of 1-6 weeks. Under these conditions the photoreceptors in retinas of albino BALB/cByJ mice rapidly degenerate, whereas the photoreceptors in retinas of albino C57BL/6J-c2J mice are remarkably more resistant to light damage. F1 heterozygotes produced from these two strains display an intermediate degree of light-induced degeneration. These findings demonstrate that phenotypically identical populations with different genetic constitutions can show markedly different sensitivities to light, and that genetic factors must now be included as a determinant for the severity of light damage.

The role of prostaglandins in feline experimental cholecystitis.

The arachidonic acid metabolites are recognized as important biochemical mediators of inflammation in a wide variety of disease processes. Also the ability to change prostaglandin formation by inhibition of prostaglandin synthetase activity with aspirin and other nonsteroidal anti-inflammatory agents is important in the treatment of many diseases with an inflammatory component. Although gallbladder disease is primarily related to the development of cholesterol stones, inflammation is an important contributor to the subsequent symptoms and accompanying illness. This research evaluates the formation of prostaglandins E and F by gallbladder tissue. Gallbladder mucosal cells and muscle tissue were maintained in tissue culture medium. Production of prostaglandins E and F was determined by quantitation by radioimmunoassay of these substances in culture media and mucosal cell and muscle tissue homogenates. Prostaglandin production by normal gallbladder tissue in a variety of species including man was consistently demonstrated in the nanogram per milligram mucosal cell or muscle tissue protein range. In cats, inflammation was produced by placing a 4% carrageenan-soaked sponge in the gallbladder, and prostaglandin synthetase inhibition was produced by indomethacin administration. The feline gallbladder increased prostaglandin F production in inflamed gallbladder mucosal cells and E production by inflamed gallbladder muscle tissue, and indomethacin inhibited these increases. A positive, significant correlation existed between the increased prostaglandin E and prostaglandin F production by inflamed gallbladder tissue and the amount of inflammation present as determined by a histologic score. The histologic score of the amount of gallbladder inflammation present was decreased significantly by indomethacin when compared with inflamed gallbladders from cats not receiving indomethacin. Prostaglandins may play a role in the inflammatory processes occurring in acute cholecystitis.

Acute reactive hepatitis in pregnancy induced by alpha-methyldopa.

BACKGROUND: Alpha-methyldopa is an antihypertensive medication used commonly in pregnancy. Reactive hepatitis is a severe, uncommon reported side effect of this medication. To our knowledge, there has been only one other reported case of alpha-methyldopa-induced hepatitis associated with pregnancy in the United States. CASE: A patient at 17 weeks' estimated gestational age was evaluated for elevated maternal serum alpha-fetoprotein, which is used generally as a screening test for birth defects. A thorough history, physical examination, and laboratory evaluation were performed, and alpha-methyldopa-induced maternal hepatitis was diagnosed. CONCLUSION: The astute clinician should include maternal hepatic dysfunction in the differential diagnosis of an elevated maternal serum alpha-fetoprotein and should consider obtaining aminotransferase levels after initiation of alpha-methyldopa therapy during pregnancy.