The Mineralization Regulator ANKH Mediates Cellular Efflux of ATP,Not Pyrophosphate

The plasma membrane protein ankylosis homologue (ANKH, mouse ortholog: Ank) prevents pathological mineralization of joints by controlling extracellular levels of the mineralization inhibitor pyrophosphate (PPi). It was long thought that ANKH acts by transporting PPi into the joints. We recently showed that when overproduced in HEK293 cells, ANKH mediates release of large amounts of nucleoside triphosphates (NTPs), predominantly ATP, into the culture medium. ATP is converted extracellularly into PPi and AMP by the ectoenzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We could not rule out, however, that cells also release PPi directly via ANKH. We now addressed the question of whether PPi leaves cells via ANKH using HEK293 cells that completely lack ENPP1. Introduction of ANKH in these ENPP1-deficient HEK293 cells resulted in robust cellular ATP release without the concomitant increase in extracellular PPi found in ENPP1-proficient cells. Ank activity was previously shown to be responsible for about 75% of the PPi found in mouse bones. However, bones of Enpp1^−/− mice contained <2.5% of the PPi found in bones of wild-type mice, showing that Enpp1 activity is also a prerequisite for Ank-dependent PPi incorporation into the mineralized bone matrix in vivo. Hence, ATP release precedes ENPP1-mediated PPi formation. We find that ANKH also provides about 25% of plasma PPi, whereas we have previously shown that 60% to 70% of plasma PPi is derived from the NTPs extruded by the ABC transporter, ABCC6. Both transporters that keep plasma PPi at sufficient levels to prevent pathological calcification therefore do so by extruding NTPs rather than PPi itself. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Overweight/Obesity and Monoclonal Gammopathy of Undetermined Significance

BackgroundObesity and high body mass index (BMI) are associated with increased incidence of multiple myeloma (MM). MM usually evolves from a precursor asymptomatic disease, namely monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a 1% annual rate; however, risk factors predisposing to MGUS are not completely understood. We conducted a systematic review to assess the relationship between obesity and high BMI with MGUS prevalence and progression to MM. To our knowledge, this is the first systematic review evaluating the role of obesity in MGUS.Patients and MethodsWe searched the Medline database and ClinicalTrials.gov for studies investigating BMI and obesity association with MGUS incidence and progression. The algorithm consisted of a predefined combination of the words “obesity,” “obese,” “body mass index,” “overweight,” “diet,” “nutrition,” “food,” “dietary,” “adiponectin,” “monoclonal gammopathy,” and “MGUS”.ResultsOverall, 12 articles were retrieved, including 11 eligible articles and 1 clinical trial. More than 57,068 patients were evaluated in this systematic review. Discrepancies between the identified studies were noted. Multiple studies support the notion that obesity or high BMI are positively linked to MGUS prevalence and transition to MM. In contrast, other studies revealed no such association. Visceral adipose tissue metabolic activity and decreased adiponectin concentrations were identified as biomarkers of MGUS progression to MM.ConclusionObesity and increased BMI seem to be implicated both in MGUS development and progression to MM. Further studies should be designed to confirm this hypothesis.     

The effects of the skull on CT imaging of the brain: a skull and brain phantom study

Objective:To investigate the effects of beam hardening by the skull on the measured radiodensity of the brain. To test a hypothesis that these effects of beam hardening are decreased using a monochromatic energy source.Methods:Selected clinical cases were reviewed in illustration. An anthropomorphic skull and brain phantom was created and scanned in a clinical CT scanner with skull, without skull, and with hemicraniectomy. The effects of beam hardening were illustrated by scanning the phantom with mono- and poly-chromatic X-ray sources.Results:In clinical cases, the HU values of the brain were consistently lower when the X-ray beam traversed the skull than when it did not. An anthropomorphic skull-and-brain phantom further demonstrated these effects, which were evident with a polychromatic energy source and absent with a virtual monochromatic energy source.Conclusions:Beam hardening by the skull lowers the measured HU values of the brain. The effects, which can impact quantitative imaging, may be mitigated by a virtual monochromatic energy source.Advances in knowledge:Beam hardening by the skull lowers the measured radiodensity of the brain. The effects may be mitigated by a virtual monochromatic energy source.

It has long been known that the skull filters polychromatic X-ray energy with a resulting increase in the mean energy of X-rays reaching the brain. Modern scanners attempt beam hardening correction;¹ however, as the brain is rarely imaged in the absence of the skull, residual effects of this phenomenon are not well characterized. Observations made from clinical cases of hemicraniectomy show that brain in the absence of intervening skull has consistently higher mean HU measure than in the presence of skull. CT scanning of an anthropomorphic skull-and-brain phantom shows similar findings. As expected, these effects are mitigated with a virtual monochromatic energy source. These observations may have significance for quantitative methods in head CT imaging.     

Interferon gamma release assay in the diagnosis of tuberculous mastitis

Tuberculous mastitis is rare, especially in Western countries. We describe a case where the interferon gamma release assay blood test led to diagnosis and successful treatment of the disease.     

Aetiological factors for oral manifestations of HIV

OBJECTIVES: Describe the oral diseases in HIV-infected individuals in London, UK and identify social and medical factors related to the presence of specific oral diseases.
DESIGN: Cross-sectional analytic study.
SETTING: Dental clinics.
SUBJECTS: Consecutive sample of 456 patients with HIV infection.
METHODS: Social and medical history and clinical examinations. Univariate and logistic regression analysis.
OUTCOMES: Presence of HIV-associated oral disease.
RESULTS: 80% of patients with AIDS and 50% of patients with HIV had a specific oral disease. The most common diseases were hairy leukoplakia (30%), erythematous candidiasis (24%), pseudomembranous candidiasis (14%), angular chielitis (6%), necrotising periodontal disease (8%) and non-recurrent ulceration (6%).
CONCLUSIONS: The presence of erythematous candidiasis was not related to advanced HIV disease. Pseudomembranous candidiasis, hairy leukoplakia and mucosal ulceration were significantly associated with advanced HIV disease. Smoking was also identified as a strong aetiological factor in oral diseases. Longitudinal studies are required to further explore the prognostic significance of oral diseases in HIV infection.