Collection of peripheral blood stem cells in newly diagnosed myeloma patients without any prior cytoreductive therapy: the first step towards an 'operational cure'?

We have shown that primary therapy with non-myeloablative (140 mg/m(2)) high-dose melphalan (HDM) without hematopoietic support results in high response rates in untreated myeloma and very long-term survival of some patients. This study was designed to see if sufficient CD34 (+) cells can be harvested at presentation in newly diagnosed patients to administer myeloablative HDM (200 mg/m(2); HDM200) with autograft as primary therapy. This may improve outcome by rapid achievement of complete remission (CR) and possible avoidance of late myelodysplasia as a consequence of non-transplant induction chemotherapy. Thirty untreated patients received 1 g/m(2) methylprednisolone daily (days 1-6) and 12-16 micro g/kg G-CSF daily (days 3-6), and underwent leukapheresis on days 6 and 7. The median CD34(+) cell yield was 1.31 x10(6)/kg (range, 0.23-5.63), and was > or =1 x10(6)/kg in 73%. Cell yields were significantly lower than in 82 historical controls apheresed after completion of induction chemotherapy (median 2.16 x 10(6)/kg), and improved in patients who were apheresed again after induction chemotherapy. Three patients received primary therapy with HDM200 and autograft using these cells and attained CR. We conclude that it is possible to harvest stem cells in three-quarters of untreated myeloma patients. Increasing the number of apheresis procedures is needed to improve the number of CD34(+) cells collected.     

Impact of previous high-dose therapy on outcome after allografting for multiple myeloma

We describe a single centre experience of 33 patients allografted for multiple myeloma, of which 28 received matched sibling marrow, one haploidentical family donor marrow and four matched but unrelated donor marrow. Median follow-up after transplant is 27 months, and 13 patients are currently alive. One out of four patients with an unrelated donor survives and 12 out of 28 (42.8%) with matched sibling donors. Four patients were unevaluable because of early death (相似文献   

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission - long-term follow-up

From 1984 to 1996, 31 consecutive children without sibling donors, aged 5-19 years (median 8) with acute lymphoblastic leukaemia (ALL) in second complete remission (CR), received unpurged autologous bone marrow transplantation (ABMT) after melphalan and single fraction total body irradiation (TBI). ABMT was performed using fresh unmanipulated marrow harvested after standard reinduction and consolidation therapy 2-11 months (median 5) after relapse. With a median survival of 2.9 years the probability of survival for all patients in continuing second CR was 45.1% (95% CI, 24%-62%) after 5 years. Regimen-related and non-leukaemia mortality was 7% (95% CI, 2%-26%). The longest time to second relapse from ABMT was 3.1 years. Pituitary and gonadal dysfunction requiring hormonal replacement therapy occurred in the majority of long-term survivors. Twelve patients developed cataracts. ABMT with melphalan/single fraction TBI has proved an effective anti-leukaemia treatment with low regimen-related mortality but significant long-term morbidity. The current approach of allogeneic BMT from an unrelated donor when no sibling donor is available, following conditioning with cyclophosphamide/ fractionated TBI has resulted in a reduced relapse rate and improved short-term overall survival in the treatment of relapsed childhood ALL. However, long-term results are awaited.     

The psychometric properties of the Evaluation of Daily Activity Questionnaire in seven musculoskeletal conditions

Purpose: The purpose of this study is to psychometrically test the Evaluation of Daily Activity Questionnaire in seven musculoskeletal conditions.

Materials and methods: One thousand and two hundred people with ankylosing spondylitis; osteoarthritis; systemic lupus erythematosus; systemic sclerosis; chronic pain; chronic upper limb disorders; or Primary Sjögren’s syndrome completed the Evaluation of Daily Activity Questionnaire, Health Assessment Questionnaire and Short-Form Health Survey v2. We examined internal construct validity using Rasch analysis, internal consistency, concurrent validity with the Health Assessment Questionnaire and Short-Form Health Survey v2. Participants repeated the Evaluation of Daily Activity Questionnaire to assess test–retest reliability.

Results: The 12 domains satisfied Rasch model expectations for fit, local dependency, unidimensionality and invariance by age and gender, in each musculoskeletal condition. Internal consistency was consistent with individual use (Cronbach’s α?>?0.90); concurrent validity was strong (Health Assessment Questionnaire:?r_s?=?0.60–0.92; Short-Form Health Survey v2 Physical Function:?r_s?=??0.61 to ?0.91) and test–retest reliability excellent (Intra-Class Correlation Coefficient(2,1)?=?0.77–0.96).

Conclusion: The Evaluation of Daily Activity Questionnaire satisfied Rasch model requirements for construct validity and has good reliability and validity in each MSC. The Evaluation of Daily Activity Questionnaire can be used as a measure of everyday activity in practice and research with people with musculoskeletal conditions.

• Implications for rehabilitation

• The Evaluation of Daily Activity Questionnaire evaluates users’ ability to perform common daily activities (in 12 domains) that were identified as problematic by people with seven musculoskeletal conditions (i.e., osteoarthritis, systemic lupus, ankylosing spondylitis, chronic pain, chronic upper limb conditions, systemic sclerosis, Sjogren’s syndrome).

• Most patients considered the Evaluation of Daily Activity Questionnaire was the right length and would be helpful for discussing everyday problems with an occupational therapist.

• The 12 domains have good reliability and validity and can be combined into two components: Self-Care and Mobility.

• The Evaluation of Daily Activity Questionnaire is suitable for use both in clinical practice and research and a User Manual is available for therapists and researchers.

     

Antiphospholipid antibodies in critically ill COVID-19 patients with thromboembolism: cause of disease or epiphenomenon?

Coronavirus 2019 disease (COVID-19) is associated with coagulation dysfunction that predisposes patients to an increased risk for both arterial (ATE) and venous thromboembolism (VTE) and consequent poor prognosis; in particular, the incidence of ATE and VTE in critically ill COVID-19 patients can reach 5% and 31%, respectively. The mechanism of thrombosis in COVID-19 patients is complex and still not completely clear. Recent literature suggests a link between the presence of antiphospholipid antibodies (aPLs) and thromboembolism in COVID-19 patients. However, it remains uncertain whether aPLs are an epiphenomenon or are involved in the pathogenesis of the disease.

     

The quantitative distribution of cytosolic androgen receptors in microdissected areas of the male rat brain: effects of estrogen treatment

Estrogen and androgen synergize in the regulation of various neuroendocrine functions. To determine a potential cellular basis of this synergism, we measured androgen receptor (AR) in the cytosol of 16 hypothalamic and limbic nuclei and subregions in castrated male rats and castrated rats treated with estradiol. Androgen receptor was measured by a previously validated in vitro binding assay using the synthetic androgen methyltrienolone [( 3H]R1881). Male Sprague-Dawley rats (250-350 g) were castrated 2 weeks before the implantation of a 2.5-cm Silastic capsule filled with crystalline 17 beta-estradiol. Control rats were sham implanted. Estrogen treatment lasted for 1 week, after which time the animals were killed, their brains were frozen and sectioned, and individual nuclei and subregions were removed by a tissue punch technique. Tissue from six rats were combined for each determination. The highest levels of AR were found in the ventromedial nucleus (16.5 +/- 1.4 fmol/mg protein), medial preoptic area (12.1 +/- 1.4 fmol/mg protein), bed nucleus of the stria terminalis (11.6 +/- 1.4 fmol/mg protein), lateral septum (11.4 +/- 1.4 fmol/mg protein), arcuate nucleus-median eminence (10.9 +/- 2.1 fmol/mg protein), and medial amygdala (10.3 +/- 0.9 fmol/mg protein). Estrogen treatment resulted in significant increases in AR in medial preoptic area (14.8 +/- 0.6 fmol/mg protein; P less than 0.05) and medial amygdala (14.6 +/- 1.2 fmol/mg protein; P less than 0.02). Subsequent studies using block-dissected hypothalamus-preoptic area, anterior pituitary, and prostate revealed significant estrogen-mediated elevations in AR in anterior pituitary cytosol [42.2 +/- 3.0 vs. 26.4 +/- 1.6 fmol/mg protein (control); P less than 0.01], but not in hypothalamus-preoptic area or prostate cytosols. Estrogen treatment had no effect on AR affinity. The binding of [3H]R1881 was specific for AR and was not affected by the addition of radioinert progesterone to the incubation tube. Estimates of AR concentration were similar regardless of whether [3H]R1881 or [3H]dihydrotestosterone was used as the ligand. In this study, we describe the distribution of AR throughout the hypothalamus and limbic areas using biochemical techniques. In addition, we have identified some cellular events that may mediate the synergistic actions of estrogen and androgen on the neuroendocrine system.     

Diet and exercise in type 2 diabetes mellitus.

The question is no longer whether diet and exercise can benefit the individual with type 2 diabetes. Rather, the type and duration of exercise the magnitude of the effects on glycemic control, insulin sensitivity, and on risk factors for cardiovascular disease must be considered in determining the feasibility and acceptability of an intervention program. It is now clear that regular physical exercise is important in both the prevention and treatment of type 2 diabetes. The benefits of exercise are many and include increased energy expenditure, which, combined with dietary restriction, leads to decreased body fat, increased insulin sensitivity, improved long-term glycemic control, improved lipid profiles, lower blood pressure, and increased cardiovascular fitness. Persons with type 2 diabetes often find it difficult to exercise and are at increased risk for injury or exacerbation of underlying diseases or diabetic complications. Therefore, before starting an exercise program, all patients with type 2 diabetes should have a complete history and physical examination, with particular attention to evaluation of cardiovascular disease, medications that may affect glycemic control during or after exercise, and diabetic complications including retinopathy, nephropathy, and neuropathy. Exercise programs should be designed to start slowly, build up gradually, and emphasize moderately intense exercise performed at least three times a week and preferably five to seven times a week for best results.     

A 12-lipoxygenase product of arachidonate metabolism is involved in angiotensin action on renin release

Angiotensin II (AII) action is coupled to the hydrolysis of phospholipids resulting in the formation of arachidonic acid, the precursor of both prostaglandins, and hydroxyeicosatetraenoic acids (HETEs). Since 12-HETE is not only a major arachidonate lipoxygenase (LO) product in the kidney, but is also a potent inhibitor of renin release, we studied the role of AII on renin inhibition and 12-HETE formation using rat renal cortical slices and isolated juxtaglomerular-like cells. In both preparations, 12-HETE was produced in a basal state. AII significantly inhibited renin release (control 100 +/- 3%, AII (10(8) M) 79 + 4%, P less than 0.01) and stimulated 12-HETE formation in slices (control 106 +/- 6%, AII 10(-8) M 177 +/- 18%, P less than 0.01) and in an enriched juxtaglomular cell preparation (control 96 +/- 3%, AII 10(-8) M 130 +/- 6%, P less than 0.001). A specific cyclooxygenase blocker, meclofenomate, or 5-LO blocker, U60,257, did not alter basal or AII-induced renin inhibition or 12-HETE formation by slices. The LO blockers BW755c, at 10(-5) M, or baicalein, 10(-6) M, did not significantly alter basal renin or 12-HETE levels, but BW755c at 10(-4) M, significantly stimulated basal renin (131 +/- 4%) and decreased basal 12-HETE levels (72 +/- 5%). However, both BW755c and baicalein blunted AII-induced renin inhibition (AII, 10(-8) M 70 +/- 3%, AII + BW755c, 10(-5) M 85 +/- 4%, P less than 0.02, AII + baicalein, 10(-6) M, 90 +/- 4%, P less than 0.005) and AII mediated 12-HETE formation (AII, 10(-8) M 150 +/- 5%, AII + BW755c, 10(-5) M 117 +/- 8%, P less than 0.02, AII + baicalein, 10(-6) M 110 +/- 3%, P less than 0.005). These results suggest that AII inhibition of renin is not mediated by the cyclooxygenase or 5-LO pathway, but rather by the 12-LO pathway. These findings reveal a new action for 12-LO products which may play a pivotal role in stimulus secretion coupling of renin secretion.     

Thalidomide after allogeneic haematopoietic stem cell transplantation: activity in chronic but not in acute graft-versus-host disease

Thalidomide was used to treat acute (n=21) or chronic (n=59) graft-vs-host disease (GVHD) in 80 haematopoietic stem cell allograft recipients after failure to respond to the combination of cyclosporine and corticosteroids with or without other agents. The median time to onset of acute GVHD was 11 days, and thalidomide was started at a median of 48 days post transplant. In addition to corticosteroids and cyclosporine, 13 patients had also received other agents before thalidomide. None of the patients responded and all died of acute GVHD. For chronic GVHD (limited in 13, extensive in 46), thalidomide was started at a median of 385 days post transplant. In addition to corticosteroids and cyclosporine, 34 patients received azathioprine concomitantly. In all patients, thalidomide was added to the ongoing immunosuppressive regimen. The median duration of therapy with thalidomide was 60 days (range, 11-1210; <2 weeks in 11). In total, 13 patients (22%) had complete response, eight (14%) partial response and 38 (64%) no response. Response rates were comparable for limited (39%) and extensive (33%) chronic GVHD. At a median of 53 months, 19 patients are alive, 13 without evidence of chronic GVHD. Survival was significantly better in patients who responded to thalidomide. The principal causes of death were progressive chronic GVHD (n=29) and relapsed leukaemia (n=7). In conclusion, thalidomide has no activity in acute GVHD, but has some activity in chronic GVHD in combination with other agents.