For the past two decades, hematopoietic cell transplantation (HCT) has been used as effective therapy for selected inherited metabolic diseases (IMD) including Hurler (MPS IH) and Maroteaux-Lamy (MPS ...VI) syndromes, childhood-onset cerebral X-linked adrenoleukodystrophy (X-ALD), globoid-cell leukodystrophy (GLD), metachromatic leukodystrophy (MLD), alpha-mannosidosis, osteopetrosis, and others. Careful pre-HCT evaluation is critical and coordinated, multidisciplinary follow-up is essential in this field of transplantation. The primary goals of HCT for these disorders have been to promote long-term survival with donor-derived engraftment and to optimize the quality of life. Guidelines for HCT and monitoring are provided; a brief overview of long-term results is also presented.
COVID-19 is a serious and potentially deadly disease. Early diagnosis of infected individuals will play an important role in stopping its further escalation. The present gold standard for sampling is ...the nasopharyngeal swab method. However, several recent papers suggested that saliva-based testing is a promising alternative that could simplify and accelerate COVID-19 diagnosis.
Our aim was to conduct a meta-analysis on the reliability and consistency of SARS-CoV-2 viral RNA detection in saliva specimens.
We have reported our meta-analysis according to the Cochrane Handbook. We searched the Cochrane Library, Embase, Pubmed, Scopus, Web of Science and clinical trial registries for eligible studies published between 1 January and 25 April 2020. The number of positive tests and the total number of tests conducted were collected as raw data. The proportion of positive tests in the pooled data were calculated by score confidence-interval estimation with the Freeman-Tukey transformation. Heterogeneity was assessed using the
measure and the χ
-test.
The systematic search revealed 96 records after removal of duplicates. Twenty-six records were included for qualitative analysis and 5 records for quantitative synthesis. We found 91% (CI 80-99%) sensitivity for saliva tests and 98% (CI 89-100%) sensitivity for nasopharyngeal swab (NPS) tests in previously confirmed COVID-19 patients, with moderate heterogeneity among the studies. Additionally, we identified 18 registered, ongoing clinical trials of saliva-based tests for detection of the virus.
Saliva tests offer a promising alternative to NPS for COVID-19 diagnosis. However, further diagnostic accuracy studies are needed to improve their specificity and sensitivity.
Tamoxifen is an estrogen receptor (ER) ligand with widespread use in clinical and basic research settings. Beyond its application in treating ER-positive cancer, tamoxifen has been co-opted into a ...powerful approach for temporal-specific genetic alteration. The use of tamoxifen-inducible Cre-recombinase mouse models to examine genetic, molecular, and cellular mechanisms of development and disease is now prevalent in biomedical research. Understanding off-target effects of tamoxifen will inform its use in both clinical and basic research applications. Here, we show that prenatal tamoxifen exposure can cause structural birth defects in the mouse. Administration of a single 200 mg/kg tamoxifen dose to pregnant wildtype C57BL/6J mice at gestational day 9.75 caused cleft palate and limb malformations in the fetuses, including posterior digit duplication, reduction, or fusion. These malformations were highly penetrant and consistent across independent chemical manufacturers. As opposed to 200 mg/kg, a single dose of 50 mg/kg tamoxifen at the same developmental stage did not result in overt structural malformations. Demonstrating that prenatal tamoxifen exposure at a specific time point causes dose-dependent developmental abnormalities, these findings argue for more considerate application of tamoxifen in Cre-inducible systems and further investigation of tamoxifen's mechanisms of action.
The osteopetroses are caused by reduced activity of osteoclasts which results in defective remodelling of bone and increased bone density. They range from a devastating neurometabolic disease, ...through severe malignant infantile osteopetrosis (OP) to two more benign conditions principally affecting adults autosomal dominant OP (ADO I and II). In many patients the disease is caused by defects in either the proton pump the a3 subunit of vacuolar‐type H(+)‐ATPase, encoded by the gene variously termed ATP6i or TCIRG1 or the ClC‐7 chloride channel (ClCN7 gene). These pumps are responsible for acidifying the bone surface beneath the osteoclast. Although generally thought of as bone diseases, the most serious consequences of the osteopetroses are seen in the nervous system. Cranial nerves, blood vessels and the spinal cord are compressed by either gradual occlusion or lack of growth of skull foramina. Most patients with OP have some degree of optic atrophy and many children with severe forms of autosomal recessive OP are rendered blind; optic decompression is frequently attempted to prevent the latter. Auditory, facial and trigeminal nerves may also be affected, and hydrocephalus can develop. Stenosis of both arterial supply (internal carotid and vertebral arteries) and venous drainage may occur. The least understood form of the disease is neuronopathic OP OP and infantile neuroaxonal dystrophy, MIM (Mendelian inheritance in man) 600329 which causes rapid neurodegeneration and death within the first year. Although characterized by the finding of widespread axonal spheroids and accumulation of ceroid lipofuscin, the biochemical basis of this disease remains unknown. The neurological complications of this disease and other variants are presented in the context of the latest classification of the disease.
Microinvasive tumor cells, which are not detected on conventional imaging, contribute to poor prognoses for patients diagnosed with glioblastoma multiforme (GBM, WHO grade IV). Diffusion tensor ...imaging (DTI) shows promise in being able to detect this infiltration. This study aims to detect a difference in diffusion properties between GBM (infiltrative) and brain metastases (noninfiltrative).
For 49 tumors (30 GBM, 19 metastases), DTI measures (p, q, L, and fractional anisotropy FA) were calculated for regions of gross tumor (excluding hemorrhagic and necrotic core), peritumoral edema, peritumoral margin (edema most adjacent to tumor), adjacent normal-appearing white matter (NAWM), and contralateral white matter. Parametric and nonparametric statistical tests were used to determine significance, and receiver operating characteristic (ROC) curve analyses were performed.
Mean values of p, L, and FA from regions of signal-intensity abnormality differed from those of normal brain in both tumors. The mean q value did not differ significantly compared with that in normal brain in any region in metastases or in adjacent NAWM of GBM. For GBM compared with metastases, q and FA were significantly lower in gross tumor (P < .001) and q was significantly lower in peritumoral margin (P < .001), which may be due to tumor infiltration. Significant overlap was present, which was reflected in the ROC curve analyses (area under the curve values from 0.732 to 0.804).
DTI may be used to help differentiate between GBM and brain metastases. The results also suggest that DTI has the potential to assist in detecting infiltrative tumor cells in surrounding brain.
In many species the pancreatic duct epithelium secretes HCO3- ions at a concentration of around 140 mM by a mechanism that is only partially understood. We know that HCO3- uptake at the basolateral ...membrane is achieved by Na+-HCO3- cotransport and also by a H+-ATPase and Na+/H+ exchanger operating together with carbonic anhydrase. At the apical membrane, the secretion of moderate concentrations of HCO3- can be explained by the parallel activity of a Cl-/HCO3- exchanger and a Cl- conductance, either the cystic fibrosis transmembrane conductance regulator (CFTR) or a Ca2+-activated Cl- channel (CaCC). However, the sustained secretion of HCO3- into a HCO- -rich luminal fluid cannot be explained by conventional Cl-/HCO3- exchange. HCO3- efflux across the apical membrane is an electrogenic process that is facilitated by the depletion of intracellular Cl-, but it remains to be seen whether it is mediated predominantly by CFTR or by an electrogenic SLC26 anion exchanger.
Key points
The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO3− concentrations as high as 140 mm during hormonal stimulation.
A computational model has been ...constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea‐pig pancreatic ducts.
The model was readily able to secrete 140 mm HCO3−. Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers.
We conclude that the main requirement for secreting high HCO3− concentrations is to minimize the secretion of Cl− ions.
These findings help to clarify the mechanism responsible for pancreatic HCO3− secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease.
A computational model of guinea‐pig pancreatic duct epithelium was developed to determine the transport mechanism by which HCO3− ions are secreted at concentrations in excess of 140 mm. Parameters defining the contributions of the individual ion channels and transporters were estimated by least‐squares fitting of the model predictions to experimental data obtained from isolated ducts and intact pancreas under a range of experimental conditions. The effects of cAMP‐stimulated secretion were well replicated by increasing the activities of the basolateral Na+‐HCO3− cotransporter (NBC1) and apical Cl−/HCO3− exchanger (solute carrier family 26 member A6; SLC26A6), increasing the basolateral K+ permeability and apical Cl− and HCO3− permeabilities (CFTR), and reducing the activity of the basolateral Cl−/HCO3− exchanger (anion exchanger 2; AE2). Under these conditions, the model secreted ∼140 mm HCO3− at a rate of ∼3 nl min−1 mm−2, which is consistent with experimental observations. Alternative 1:2 and 1:1 stoichiometries for Cl−/HCO3− exchange via SLC26A6 at the apical membrane were able to support a HCO3−‐rich secretion. Raising the HCO3−/Cl− permeability ratio of CFTR from 0.4 to 1.0 had little impact upon either the secreted HCO3− concentration or the volume flow. However, modelling showed that a reduction in basolateral AE2 activity by ∼80% was essential in minimizing the intracellular Cl− concentration following cAMP stimulation and thereby maximizing the secreted HCO3− concentration. The addition of a basolateral Na+‐K+‐2Cl− cotransporter (NKCC1), assumed to be present in rat and mouse ducts, raised intracellular Cl− and resulted in a lower secreted HCO3− concentration, as is characteristic of those species. We conclude therefore that minimizing the driving force for Cl− secretion is the main requirement for secreting 140 mm HCO3−.
Key points
The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO3− concentrations as high as 140 mm during hormonal stimulation.
A computational model has been constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea‐pig pancreatic ducts.
The model was readily able to secrete 140 mm HCO3−. Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers.
We conclude that the main requirement for secreting high HCO3− concentrations is to minimize the secretion of Cl− ions.
These findings help to clarify the mechanism responsible for pancreatic HCO3− secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease.
TRPM7 plays an important role in cellular Ca
, Zn
and Mg
homeostasis. TRPM7 channels are abundantly expressed in ameloblasts and, in the absence of TRPM7, dental enamel is hypomineralized. The ...potential role of TRPM7 channels in Ca
transport during amelogenesis was investigated in the HAT-7 rat ameloblast cell line. The cells showed strong TRPM7 mRNA and protein expression. Characteristic TRPM7 transmembrane currents were observed, which increased in the absence of intracellular Mg
(Mg
), were reduced by elevated Mg
, and were inhibited by the TRPM7 inhibitors NS8593 and FTY720. Mibefradil evoked similar currents, which were suppressed by elevated Mg
, reducing extracellular pH stimulated transmembrane currents, which were inhibited by FTY720. Naltriben and mibefradil both evoked Ca
influx, which was further enhanced by the acidic intracellular conditions. The SOCE inhibitor BTP2 blocked Ca
entry induced by naltriben but not by mibefradil. Thus, in HAT-7 cells, TRPM7 may serves both as a potential modulator of Orai-dependent Ca
uptake and as an independent Ca
entry pathway sensitive to pH. Therefore, TRPM7 may contribute directly to transepithelial Ca
transport in amelogenesis.
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