Chimerism studies in HLA-identical nonmyeloablative hematopoietic stem cell transplantation point to the donor CD8(+) T-cell count on day + 14 as a predictor of acute graft-versus-host disease.

Chimerism analysis of hematopoietic cells has emerged as an essential tool in nonmyeloablative hematopoietic stem cell transplantation. We have investigated the development of donor chimerism in granulocytes and CD4(+) and CD8(+) T cells in blood and bone marrow of 24 patients with hematologic malignancies who received HLA-identical sibling peripheral blood stem cell grafts after conditioning with fludarabine and 2 Gy of total body irradiation. The T-cell chimerism of blood and bone marrow was tightly correlated. Complete donor chimerism was reached earlier in the granulocytes than in the T cells. Mixed T-cell chimerism was common at the time of onset of acute graft-versus-host disease (aGVHD), and both CD4(+) and CD8(+) donor T-cell chimerism increased with the occurrence of aGVHD grades II to IV (P =.0002 and P =.019, respectively). The rate of disappearance of recipient CD8(+) T cells was faster in patients with aGVHD grades II to IV than in patients without clinically significant aGVHD (P =.016). This observation indicates a role of graft-versus-lymphohematopoietic tissue reactions in creating complete donor T-cell chimerism. A donor CD8(+) T-cell count above the median on day +14 increased the risk of subsequent development of aGVHD grades II to IV (P =.003).     

Terbutaline Depot Tablets in Asthma

A sustained release preparation of terbutaline sulphate has been formulated (Bricanyl® depot tablets) in order to extend the duration and accordingly change the dosage regimen to twice a day. This presentation gives a summary of a clinical trial performed in order to study effect and side effects of terbutaline depot tablets 7.5 mg twice a day compared to terbutaline tablets 5 mg three times a day.
Patients suffering from perennial asthma and with daily requirement of asthma medicine were accepted for the study. The trial was a double-blind cross-over, double dummy and randomized. The tablets were given in two consecutive periods of 7 day's duration each. The effect of terbutaline depot tablets was equal to the effect of the ordinary terbutaline tablets. The indication for using depot tablets in the basic treatment of bronchial asthma is a better patient compliance due to medication twice a day. Furthermore in patients with unstable bronchial asthma and in patients with morning dips in PEF the more stable plasma concentration may perhaps keep the patients in a more steady state.     

Hypercalcemia After Cosmetic Oil Injections: Unraveling Etiology,Pathogenesis, and Severity

Intramuscular injections of paraffin oil can cause foreign body granuloma formation and hypercalcemia. Macrophages with the ability to produce high levels of 1,25(OH)₂D₃ may induce the mineral disturbance, but no major series of patients have been published to date. Here, medical history, physical evaluation, biochemical, and urinary analysis for calcium homeostasis were obtained from 88 males, who 6 years previously had injected paraffin or synthol oil into skeletal muscle. Moreover, granuloma tissue from three men was cultured for 48 hours ex vivo to determine 1,25(OH)₂D₃ production supported by qPCR and immunohistochemistry of vitamin D metabolism and immune cell populations after treatment with 14 different drugs. The 88 men were stratified into men with hypercalcemia (34%), whereas normocalcemic men were separated into men with either normal (42%) or suppressed parathyroid hormone (PTH) (24%). All men had high calcium excretion, and nephrolithiasis was found in 48% of hypercalcemic men, 22% of normocalcemic men with normal PTH, and 47% of normocalcemic men with suppressed PTH. Risk factors for developing hypercalcemia were oil volume injected, injection of heated oil, high serum interleukin-2 receptor levels, and high urine calcium. High 1,25(OH)₂D₃/25OHD ratio, calcium excretion, and low PTH was associated with nephrolithiasis. The vitamin D activating enzyme CYP27B1 was markedly expressed in granuloma tissue, and 1,25(OH)₂D₃ was released in concentrations corresponding to 40% to 50% of the production by human kidney specimens. Dexamethasone, ketoconazole, and ciclosporin significantly suppressed granulomatous production of 1,25(OH)₂D₃. In conclusion, this study shows that injection of large oil volumes alters calcium homeostasis and increases the risk of nephrolithiasis. Hypercalciuria is an early sign of disease, and high granulomatous 1,25(OH)₂D₃ production is part of the cause. Prospective clinical trials are needed to determine if ciclosporin, ketoconazole, or other drugs can be used as prednisolone-sparing treatment. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Workplace bullying and risk of suicide and suicide attempts: A register-based prospective cohort study of 98 330 participants in Denmark

ObjectivesThe aim of this study was to analyze whether individuals reporting exposure to workplace bullying had a higher risk of suicidal behavior, including both suicide attempt and death by suicide, than those not reporting such exposure.MethodsUsing a prospective cohort study design, we linked data from nine Danish questionnaire-based surveys (2004–2014) to national registers up to 31 December 2016. Exposure to workplace bullying was measured by a single item. Suicide attempts were identified in hospital registers and death by suicide in the Cause of Death Register. Among participants with no previous suicide attempts, we estimated hazard ratios (HR) and 95% confidence intervals (CI), adjusting for sex, age, marital status, socioeconomic status, and history of psychiatric morbidity.ResultsThe sample consisted of 98 330 participants (713 798 person-years), 63.6% were women, and the mean age was 44.5 years. Of these participants, 10 259 (10.4%) reported workplace bullying. During a mean follow-up of 7.3 years, we observed 184 cases of suicidal behavior, including 145 suicide attempts, 35 deaths by suicide and 4 cases that died by suicide after surviving a suicide attempt. The fully-adjusted HR for the association between workplace bullying and suicidal behavior was 1.65 (95% CI 1.06–2.58). The HR for suicide attempts and death by suicide were 1.65 (1.09–2.50) and 2.08 (0.82–5.27), respectively. Analyses stratified by sex showed a statistically significant association between workplace bullying and suicidal behavior among men but not women.ConclusionsThe results suggest that exposure to workplace bullying is associated with an elevated risk of suicidal behavior among men.     

Acid–base transporters modulate cell migration,growth and proliferation: Implications for structure development and remodeling of resistance arteries?

Disturbed acid–base transport across the plasma membrane affects intracellular pH control and has been shown—primarily based on studies with non-vascular cells—to interfere with a number of fundamental cell functions including cell migration, growth and proliferation. Here, we evaluate the effects of acid–base transport and intracellular pH on the morphology of the resistance artery wall, which is altered in a number of physiological and pathological conditions and is an independent predictor of cardiovascular risk. The current evidence supports that disturbed function and/or expression of acid–base transporters can alter resistance artery morphology—and potentially atherosclerosis-prone conduit arteries—and hence should be considered as possible mechanistic components and targets for treatment in cardiovascular disease. More experimental evidence is required, however, to evaluate the cell biological effects of acid–base transport in vascular cells, the roles of specific acid–base transporters in artery remodeling, the relative mechanistic importance of acid–base transporters in the vascular wall compared to other organs, and the therapeutic potential of modifying acid–base transport activity pharmacologically or genetically.     

Mortality and causes of death in Crohn's disease: follow-up of a population-based cohort in Copenhagen County,Denmark

BACKGROUND & AIMS: A population-based cohort comprising 374 patients with Crohn's disease diagnosed in Copenhagen County between 1962 and 1987 was observed until 1997 for mortality and causes of death. METHODS: Observed deaths were compared with expected deaths calculated by using individually computed person-years at risk and 1995 rates for Copenhagen County. Cumulative survival curves were calculated. RESULTS: A total of 84 deaths occurred vs. 67 expected (standardized mortality ratio [SMR], 1.3; 95% confidence interval [CI], 1.01-1.56): 45 women vs. 31.8 expected (SMR, 1.4; 95% CI, 1.03-1.89) and 39 men vs. 35.2 expected (SMR, 1.1; 95% CI, 0.79-1.51). An excess mortality was observed among women observed for 21-25 years after diagnosis. Among women aged <50 years at diagnosis, 25 deaths were observed vs. 7.3 expected (SMR, 3.42; 95% CI, 2.21-5.04). Fourteen (31%) of the observed deaths among women and 8 (21%) among men had a certain or possible connection to Crohn's disease. Among causes of death unrelated to Crohn's disease, an overrepresentation of gastrointestinal diseases, infections, and diseases of the urinary organs was observed. CONCLUSIONS: An increased mortality was observed late in the disease course that was most pronounced among women younger than 50 years at diagnosis and was attributed to death associated with severe Crohn's disease.     

Abnormalities of Megakaryocytes in W/Wv Mice

Megakaryocytopoiesis was evaluated ingenetically anemic mice of the W/W^v genotype and was found to be abnormal.Concentration and size of blood plateletswere normal. Megakaryocytes were decreased in number in tibial marrow andspleen, and the size of mature megakaryocytes was increased.

Submitted on April 9, 1973 Revised on May 31, 1973 Accepted on June 12, 1973     

Survival and cause-specific mortality in ulcerative colitis: follow-up of a population-based cohort in Copenhagen County

BACKGROUND & AIMS: A population-based cohort from Copenhagen County comprising 1160 patients diagnosed with ulcerative colitis between 1962 and 1987 was followed-up until 1997 to describe survival and cause-specific mortality. METHODS: Observed vs. expected deaths were presented as standardized mortality ratio (SMR) with exact 95% confidence intervals (CI) calculated by using individually registered person-years at risk and Danish 1995 mortality rates. Cumulative survival curves were calculated. RESULTS: A total of 261 deaths occurred, not significantly different from the expected number of 249 (SMR, 1.05; 95% CI, 0.92-1.19). The median age at death among men was 70 years (range, 6-96 years) and among women 74 years (range, 25-96 years). Twenty-five deaths (9.6%) were caused by complications to ulcerative colitis, mostly infectious and cardiovascular postoperative complications. Patients older than 50 years of age at diagnosis and with extensive colitis showed an increased mortality within the first 2 years because of ulcerative colitis-associated causes. The mortality from colorectal cancer was not increased and that of cancer in general was significantly lower than expected: 50 vs. 71 (SMR, 0.70; 95% CI, 0.52-0.93). A significantly increased mortality from pulmonary embolism and pneumonia was found. Among women only, death from genitourinary tract diseases and suicide was significantly increased. CONCLUSIONS: Despite an overall normal life expectancy for patients with ulcerative colitis, patients >50 years of age and with extensive colitis at diagnosis had increased mortality within the first 2 years after diagnosis, owing to colitis-associated postoperative complications and comorbidity.