Synergistic factors for stem cell proliferation: further studies of the target stem cells and the mechanism of stimulation by interleukin-1, interleukin-6, and granulocyte colony-stimulating factor

Serial observations of blast cell colony development from spleen cells of mice treated with 5-fluorouracil (5-FU) four days earlier revealed that either form of human interleukin-1 (IL-1 alpha or IL-1 beta) hastens the emergence of interleukin-3 (IL-3)-dependent blast cell colonies. This activity was essentially indistinguishable from the effect of interleukin-6 (IL-6) or granulocyte colony-stimulating factor (G-CSF) in the same system, an effect that we have ascribed previously to a shortening of the G0 period of the dormant stem cells. We also analyzed the time courses of colony formation from cultures of day-2 post-5-FU marrow cells supported by IL-1 alpha, IL-6, or G-CSF alone or in combination with IL-3. In the presence of IL-3, G-CSF and IL-6 but not IL-1 alpha hastened the development of colonies and increased the numbers of multilineage colonies relative to cultures of IL-3 alone. This observation, together with our previous data from the human system, suggests that the synergistic effect of IL-1 is likely due to induction of secondary growth factors, including IL-6 and G-CSF, by accessory cells in culture. The effect of IL-6 on G0 was confirmed by analysis of the cycling status of progenitor cells in short-term culture. While neither IL-3 nor IL-6 alone had any effect on the cycling status, the combination of factors resulted in a rapid recruitment of quiescent cells into cell cycle (within 48 hours) as represented by a twofold increase in the numbers of multipotential progenitors and a significant increase in the sensitivity of these cells to 3H-thymidine with high specific activity. Combinational testing of all of these synergistic factors revealed that the target cell populations for the IL-1, IL-6, and G-CSF overlap considerably, suggesting that they all may act through a common mechanism. This is further supported by our finding that cells from blast cell colonies grown in the presence of a combination of any one of the synergistic factors with IL-3 replate with higher efficiency and yield more multilineage secondary colonies than those from colonies grown in IL-3 alone. These findings provide further evidence that IL-1, IL-6, and G- CSF serve to integrate the immediate host responses to infection through augmentation of effector cells and antibody production as well as the longer term host responses by recruitment of dormant hemopoietic stem cells into active cell cycling.     

Antidepressants differentially related to 1,25-(OH)2 vitamin D3 and 25-(OH) vitamin D3 in late-life depression

A low plasma 25-OH vitamin D₃ level is a universal risk factor for a wide range of diseases and has also been implicated in late-life depression. It is currently unknown whether the biologically active form of vitamin D, that is, 1,25-(OH)₂ vitamin D₃, is also decreased in late-life depression, or whether vitamin D levels correlate with specific depression characteristics. We determined plasma 25-OH vitamin D₃, 1,25-(OH)₂ vitamin D₃ and parathormone levels in 355 depressed older persons and 124 non-depressed comparison subjects (age⩾60 years). Psychopathology was established with the Composite International Diagnostic Interview 2.1, together with potential confounders and depression characteristics (severity, symptom profile, age of onset, recurrence, chronicity and antidepressant drug use). Adjusted for confounders, depressed patients had significantly lower levels of 25-OH vitamin D₃₃ (Cohen''s d =0.28 (95% confidence interval: 0.07–0.49), P=0.033) as well as 1,25-(OH)₂ vitamin D₃ (Cohen''s d =0.48 (95% confidence interval: 0.27–0.70), P<0.001) than comparison subjects. Of all depression characteristics tested, only the use of tricyclic antidepressants (TCAs) was significantly correlated with lower 1,25-(OH)₂ vitamin D₃ levels (Cohen''s d =0.86 (95% confidence interval: 0.53–1.19), P<0.001), but not its often measured precursor 25-OH vitamin D₃. As vitamin D levels were significantly lower after adjustment for confounders, vitamin D might have an aetiological role in late-life depression. Differences between depressed and non-depressed subjects were largest for the biologically active form of vitamin D. The differential impact of TCAs on 25-OH vitamin D₃ and 1,25-(OH)₂ vitamin D₃ levels suggests modulation of 1-α-hydroxylase and/or 24-hydroxylase, which may in turn have clinical implications for biological ageing mechanisms in late-life depression.     

Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis

Mastocytosis is an emerging differential diagnosis in patients with more or less specific mediator‐related symptoms. In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established. In other cases, however, skin lesions are absent, which represents a diagnostic challenge. In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis. In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration. In adults without skin lesions who suffer from mediator‐related or other typical symptoms, the basal tryptase level is an important parameter. In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful. In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25–30 ng/ml) and/or (iii) other clinical or laboratory features suggest the presence of ‘occult’ mastocytosis or another haematologic neoplasm, a BM investigation is recommended. In the absence of KIT D816V and other signs or symptoms of mastocytosis or another haematopoietic disease, no BM investigation is required, but the clinical course and tryptase levels are monitored in the follow‐up. In paediatric patients, a BM investigation is usually not required, even if the tryptase level is increased. Although validation is required, it can be expected that the algorithm proposed herein will facilitate the management of patients with suspected mastocytosis and help avoid unnecessary referrals and investigations.     

Administration of Exogenous Melatonin After the Onset of Systemic Inflammation Is Hardly Beneficial

Melatonin improves survival and functional impairment including hemolysis, thrombocytopenia, and hypotension when administered in a prophylactic manner or early after initiation of sepsis or endotoxemia. In the present study, melatonin was given not before first symptoms of systemic inflammation became manifest. Lipopolysaccharide was infused at a rate of 0.5 mg/kg × h to induce systemic inflammation in male Wistar rats. Melatonin (single dose 3 mg/kg × 15 min) was intravenously administered 180 and 270 min after starting of the lipopolysaccharide infusion. Systemic and vital parameters (e.g., systemic blood pressure and breathing rate) as well as blood and plasma parameters (acid-base parameters; electrolytes; parameters of tissue injury such as glucose concentration, lactate concentration, hemolysis, and aminotransferase activities; parameters of thromboelastometry; and platelet count) were determined in regular intervals. Infusion of lipopolysaccharide led to characteristic symptoms of severe systemic inflammation including hypotension, metabolic acidosis and hypoglycemia, electrolyte and hemostatic disturbances, thrombocytopenia, and hemolysis. Melatonin neither decreased mortality nor reduced lipopolysaccharide-dependent changes to vital, blood, and plasma parameters. Even though melatonin may have a beneficial effect in early stages of systemic inflammation, it can hardly be an option in therapy of manifest sepsis or endotoxemia in an intensive care unit.     

安徽省青少年留守状况的流行病学调查

目的:描述安徽省青少年的留守状况,探索不同类型青少年留守率的差异.方法:采用分层整群抽样的方法抽取皖南、皖北城乡普通中学7所,获得样本3 421人,其中留守青少年682人.自行设计流行病学凋查表对研究对象的一般人口学特征和留守状况进行问卷调查.结果:安徽省10 ～ 18岁青少年的留守率为19.94％.不同类型青少年留守...     

Fibrin glue obliteration is safe,effective and minimally invasive as first line treatment for pilonidal sinus disease in children

Background / PurposeSacrococcygeal pilonidal sinus disease (PSD) has an incidence of 1.2–2.5/1000 in children. Onset is around puberty. Symptoms of recurrent abscess and chronic suppuration may interfere with education and social integration. Treatments should cause minimal disruption while having good cure and recurrence rates. Curettage and Fibrin glue obliteration (FGO) show promising results in adults. We present our experience of its use in children.MethodsReview of all pediatric patients receiving FGO of pilonidal sinus performed by a single surgeon from September 2014 to February 2018.ResultsEighteen patients were identified. Median age was 16 (range 15–17), 55.6% were male. All procedures were completed as day cases. Median operative duration was 14 .1 (6–29) min. Twelve patients required only 1 procedure, 4 required 2 procedures, 1 required 5 procedures and 1 elected for formal excision after 2 FGO treatments. Median return to normal activities was 3 days, with 1 day school absence. Two patients developed minor surgical site infections. Median follow-up was 52 weeks (17–102), during which time there was 1 recurrence (5.6%).ConclusionThis study demonstrates FGO is a safe, effective procedure for pediatric PNS, with results comparable to off-midline flap techniques and without the need for extensive tissue excision and the associated morbidity.Level of evidenceIV     

Outcome of obstetric anal sphincter injuries in terms of persisting endoanal ultrasonographic defects and defecatory symptoms

Objective

To determine the prevalence of persisting endoanal ultrasonographic defects among women with obstetric anal sphincter injuries (OASIS), and the incidence of defecatory symptoms.

Methods

In a prospective study in Enschede, Netherlands, women with OASIS were enrolled between 2007 and 2012. Three months after surgical repair, all women had an endoanal ultrasound, and data were collected on gas and fecal incontinence, soiling, and fecal urgency.

Results

Overall, 99 women were included. At follow-up, 35 (35.4%) women had a persisting defect of the external anal sphincter on ultrasound, and 5 women (5.1%) also had a persisting defect of the internal anal sphincter. Overall, 35 (35.4%) women had one or more defecatory complaints—predominantly involuntary loss of gas and fecal urgency. Overall, 22 of 35 (63.0%) women with and 13 of 64 (20.3%) women without a persisting defect on ultrasound had defecatory complaints. The number of defecatory symptoms showed a positive correlation with severity of injury. Women with a persisting defect had a threefold higher risk of defecatory complaints as compared with women who had a successful repair (odds ratio, 6.6; 95% confidence interval, 2.6–16.6).

Conclusion

The results emphasize the importance of adequate repair of OASIS and demonstrate that repair can be difficult or underestimated.