Advanced Glycation End Products Stimulate Osteoblast Apoptosis Via the MAP Kinase and Cytosolic Apoptotic Pathways

We have previously shown that diabetes significantly enhances apoptosis of osteoblastic cells in vivo and that the enhanced apoptosis contributes to diabetes impaired new bone formation. A potential mechanism is enhanced apoptosis stimulated by advanced glycation end products (AGEs). To investigate this further, an advanced glycation product, carboxymethyl lysine modified collagen (CML-collagen), was injected in vivo and stimulated a 5-fold increase in calvarial periosteal cell apoptosis compared to unmodified collagen. It also induced apoptosis in primary cultures of human or neonatal rat osteoblastic cells or MC3T3-E1 cells in vitro. Moreover, the apoptotic effect was largely mediated through RAGE receptor. CML-collagen increased p38 and JNK activity 3.2- and 4.4-fold, respectively. Inhibition of p38 and JNK reduced CML-collagen stimulated apoptosis by 45% and 59% and by 90% when used together (P \u3c 0.05). The predominant apoptotic pathway induced by CML-collagen involved caspase-8 activation of caspase-3 and was independent of NF-κB activation. When osteoblastic cells were exposed to a long-term low dose incubation with CML-collagen, there was a higher degree of apoptosis compared to short-term incubation. In more differentiated osteoblastic cultures, apoptosis was enhanced even further. These results indicate that advanced glycation end products, which accumulate in diabetic and aged individuals, may promote apoptosis of osteoblastic cells and contribute to deficient bone formation

Like gold dust these days’: domestic violence fact-finding hearings in child contact cases

Fact-finding hearings may be held to determine disputed allegations of domestic violence in child contact cases in England and Wales, and can play a vital role for mothers seeking protection and autonomy from violent fathers. Drawing on the author’s empirical study, this article examines the implications for the holding of fact-finding hearings of judges’ and professionals’ understandings of domestic violence and the extent to which they perceive it to be relevant to contact. While more judges and professionals are developing their understanding of domestic violence, the ambit of when and how it is considered relevant to contact has grown increasingly narrow, which suggests that many disputed allegations of domestic violence are disregarded and women and children continue to be put at risk from violent fathers. This bifurcated approach is likely to have significant implications for recent developments in this area of family law which are considered in this article

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Osteoblast apoptosis is induced by an advanced glycation enproduct

PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact [email protected] (MSD)--Boston University, Goldman School of Dental Medicine, 2006 (Endodontics).Includes bibliographical references: leaves 55-66.The present study was carried out to determine whether an advanced glycation product, carboxymethyl lysine modified collagen (CML-collagen), could stimulate apoptosis of osteoblastic cells. In vitro CML-collagen stimulated a dose- and time-dependent increase in apoptosis in primary human adult osteoblastic cells. It also stimulated apoptosis to a similar degree in primary cultures of rat calvarial osteoblastic and MC3T3-E1 cells. However,the maximum induction was less than that induced by TNF-[alpha]. When primary neonatal calvarial osteoblasts or MC3T3E-1 cells were incubated under conditions that promote differentiation, the level of apoptosis stimulated by CML-collagen was higher in differentiated compared to less differentiated osteoblasts. CML-collagen stimulated a significant increase in caspase-3 and -8 activities and to a lesser extent, caspase-9 activity.That the predominant apoptotic pathway invoIved caspase-8 activation of caspase-3 was shown by use of specific inhibitors. When osteoblastic cells were exposed to a chronic low dose exposure to CML-collagen there was a higher degree of apoptosis than exposure to a short-term incubation at a higher dose. Given the impact of premature osteoblast apoptosis on limiting bone formation, these results suggest that AGEs could contribute to diabetic complications associated with inadequate bone formation including diabetic osteopenia, impaired fracture repair and diabetes aggravated periodontal disease

A jewel here on earth, a jewel for heaven;

voiceMrs. Coy Boyd Buckner, Arkansas May 7, 1951 Collected by Irene Carlisle Reel 117 Item 3 'WAY BACK IN THE HILLS 'Way back in the hills, a girlie once wandered; Deep down in the grave lies the one that I love; She was called from this earth, a jewel for heaven, More precious than diamonds, more precious than gold. A jewel here on earth, a jewel for heaven; She will brighten the kingdom around God's great throne; May the angels have peace; God bless her in heaven; She's broken my heart and she's left me to roam. A girl of sixteen; we courted each other; She promised some day to become my sweet wife; I bought her a ring to wear on her finger, But the angels, they called her to heaven one night. (Repeat chorus) This world holds its wealth, its troubles and sorrows; Mother Earth holds her treasures of diamonds and gold; But it cannot hold one soul of one precious jewel; She's restin' in peace in the heavenly fold. (Chorus)Funding for digitization provided by the Arkansas Humanities Council and the Happy Hollow Foundation

Come, a l l you young companions, and listen to me

voiceMrs. Coy Boyd Buckner, Arkansas May 7, 1951 Collected by Irene Carlisle Reel 117 Item 2 BAD COMPANIONS Come, a l l you young companions, and l i s t e n unto me; I'll tell you a l l a story of some bad company. I was borned in Pennsylvania, among those beautiful h i l l s; And the memories of my childhood that dwells within me s t i ll I did not like my harsh l i f e ; I did not like my home; I had a view for ramblin', and far away did roam. I had a dear old mother, that often would plead with me; The l a s t words that she gave me was, "Shun bad company." I had two lovin' sisters, who were kind and good to me; Down on their knees before me they'd pray and wept for me. I did not refuse to love them, but the home I bade farewell; I landed in Chicago, the very depths of h e l l. It was there I took to drinking; I sinned both night and day And always in my bosom a feeble voice would say, "So fare you well, my loved ones; may God protect ray boy, And gladness that dwell ever with him throughout his manhood j o y ." I courted a f a i r maiden; her name I w i l l not t e l l; I never would disgrace her, but although I'm bound f o r h e l l. It was on one beautiful evenin', when the stars were shinin' bright, I took a fatal dagger, and I bade her s p i r i t f l y. So now I'm on the s c a f f o l d ; my moments are not long; You may forget the singer, but don't forget the song.Funding for digitization provided by the Arkansas Humanities Council and the Happy Hollow Foundation