Management of Hyperleukocytosis in Childhood Acute Leukemia Without Leukapheresis and Rasburicase Prophylaxis.

Indications of leukapheresis (LPh) and the prophylactic use of rasburicase in tumor lysis syndrome (TLS) of patients with acute leukemia with hyperleukocytosis are not clear. In this retrospective single-center pediatric study, the outcomes of patients with hyperleukocytosis were reviewed. There were 48 patients with acute lymphoblastic leukemia (ALL) and 13 patients with acute myeloblastic leukemia (AML). The treatment strategies included hyperhydration, allopurinol administration, strict monitoring, and early initiation of induction chemotherapy (CT). No patient underwent LPh because it was not available. Rasburicase was used only in 3 ALL patients with hyperuricemia when the drug was available. Laboratory and clinical TLS developed in 54.16% and 14.58% of patients with ALL, respectively. Laboratory and clinical TLS developed in 76.92% and 15.38% of patients with AML, respectively. No patient developed grade III to V TLS requiring dialysis. Thirteen patients (21.3%) had pulmonary leukostasis on admission, but recovered with CT and nasal oxygen. During the first 14 days of presentation, cerebral leukostasis/coagulopathy-related early death (ED) was 4.2% and 7.7% in patients with ALL and AML, respectively, and all of these patients had a white blood cell count ≥400,000/µL. There was also 1 infection-related death. Patients with hyperleukocytosis can be treated without LPh and liberal use of rasburicase. Renal failure is no longer a cause of ED. Intracranial hemorrhage is the main cause of ED, especially in patients already presenting with this complication. LPh may be performed in patients with leukostasis, if it is not possible to start induction CT early. When resources are limited, rasburicase should be administered in patients presenting with or developing hyperuricemia and/or renal dysfunction.

Histological Evidence of Wound Healing Improvement in Rats Treated with Oral Administration of Hydroalcoholic Extract of Vitis labrusca.

Plant extracts rich in phenolic compounds have been demonstrated to accelerate wound healing, but their use by oral route has been poorly studied. The leaves of Vitis labrusca are rich in phenolic acids and flavonoids. The goal of this study was to assess the healing properties of the oral administration of hydroalcoholic extract of V. labrusca leaves (HEVL) in a murine model. HEVL was obtained by Soxhlet and dynamic maceration, and their yield and phenolic acids and flavonoid contents were determined. For the wound healing assay, 8 mm wounds were performed on the back of 48 Wistar rats, assigned into four groups (n = 12): CTR (distilled water), HEVL100, HEVL200, and HEVL300 (HEVL at 100, 200, and 300 mg/kg, respectively). On days 7 and 14, wound closure rates were assessed, and the healing wounds were subjected to histological analysis. Soxhlet-obtained extract was selected for the wound healing assay because it provided a higher yield and phenolic acid and flavonoid contents. HEVL significantly reduced leukocytosis in the peripheral blood (p < 0.05), accelerated wound closure (p < 0.05), and improved collagenization (p < 0.05) on day 7, as well as enhanced the epidermal tissue thickness (p < 0.001) and elastic fiber deposition on day 14 (p < 0.01). Furthermore, HEVL promoted an increase in the histological grading of wound healing on both days 7 and 14 (p < 0.01). The doses of 200 and 300 mg/kg provided better results than 100 mg/Kg. Our data provide histological evidence that the oral administration of HEVL improves wound healing in rodents. Therefore, the extract can be a potential oral medicine for healing purposes.

Neuroprotective effects of low-dose G-CSF plus meloxicam in a rat model of anterior ischemic optic neuropathy.

Non-arteritic anterior ischemic optic neuropathy (NAION) causes a sudden loss of vision and lacks effective treatment. Granulocyte colony-stimulating factor (G-CSF) provides neuroprotection against the experimental optic nerve injuries but also induce leukocytosis upon typical administration. We found synergetic neuroprotective effects of meloxicam and low dose G-CSF without leukocytosis in a rat model of anterior ischemic optic neuropathy (rAION). The WBC counts in the low-dose G-CSF-plus meloxicam-treated group were similar to the sham-operated group. Combination treatment of low-dose G-CSF plus meloxicam preserved RGCs survival and visual function, reduced RGC apoptosis and the macrophages infiltration, and promote more M2 phenotype of macrophage/microglial transition than the low-dose GCSF treatment or the meloxicam treatment. Moreover, the combination treatment induced higher serine/threonine kinase 1 (Akt1) expression. The combination treatment of low-dose G-CSF plus meloxicam lessened the leukocytotic side effect and provided neuroprotective effects via Akt1 activation in the rAION model. This approach provides crucial preclinical information for the development of alternative therapy in AION.

Inhibition of JAK2 Suppresses Myelopoiesis and Atherosclerosis in Apoe-/- Mice.

OBJECTIVE: Increased myelopoiesis has been linked to risk of atherosclerotic cardiovascular disease (ACD). Excessive myelopoiesis can be driven by dyslipidemia and cholesterol accumulation in hematopoietic stem and progenitor cells (HSPC) and may involve increased signaling via Janus kinase 2 (JAK2). Constitutively activating JAK2 mutants drive biased myelopoiesis and promote development of myeloproliferative neoplasms (MPN) or clonal hematopoiesis, conditions associated with increased risk of ACD. JAK2 inhibitors have been developed as a therapy for MPNs. The potential for JAK2 inhibitors to protect against atherosclerosis has not been tested. We therefore assessed the impact of JAK2 inhibition on atherogenesis. METHODS: A selective JAK2 inhibitor TG101348 (fedratinib) or vehicle was given to high-fat high-cholesterol Western diet (WD)-fed wild-type (WT) or Apoe-/- mice. Hematopoietic cell profiles, cell proliferation, and atherosclerosis in WT or Apoe-/- mice were assessed. RESULTS: TG101348 selectively reversed neutrophilia, monocytosis, HSPC, and granulocyte-macrophage progenitor (GMP) expansion in Apoe-/- mice with decreased cellular phosphorylated STAT5 and ERK1/2 and reduced cell cycling and BrdU incorporation in HSPCs, indicating inhibition of JAK/STAT signaling and cell proliferation. Ten-week WD feeding allowed the development of marked aortic atherosclerosis in Apoe-/- mice which was substantially reduced by TG101348. CONCLUSIONS: Selective JAK2 inhibition reduces atherogenesis by suppressing excessive myelopoiesis in hypercholesterolemic Apoe-/- mice. These findings suggest selective JAK2 inhibition as a potential therapeutic approach to decrease ACD risk in patients with increased myelopoiesis and leukocytosis.

Umbelliferone prevents oxidative stress, inflammation and hematological alterations, and modulates glutamate-nitric oxide-cGMP signaling in hyperammonemic rats.

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication that occurs as a result of liver failure. Umbelliferone (UMB; 7-hydroxycoumarin) is a natural product with proven hepatoprotective activity; however, nothing has yet been reported on its protective effect against hyperammonemia, the main culprit behind the symptoms of HE. Here, we evaluated the effect of UMB against ammonium chloride (NH4Cl)-induced hyperammonemia, oxidative stress, inflammation and hematological alterations in rats. We demonstrated the modulatory role of UMB on the glutamate-nitric oxide (NO)-cGMP pathways in the cerebrum of rats. Rats received intraperitoneal injections of NH4Cl (3 times/week) for 8 weeks and concomitantly received 50 mg/kg UMB. NH4Cl-induced rats showed significantly elevated blood ammonia and liver function markers. Lipid peroxidation and NO were increased in the liver and cerebrum of rats while the antioxidant defenses were declined. UMB significantly reduced blood ammonia, liver function markers, lipid peroxidation and NO, and enhanced the antioxidant defenses in NH4Cl-induced rats. UMB significantly prevented anemia, leukocytosis, thrombocytopenia and prolongation of PT and aPTT. Hyperammonemic rats showed elevated levels of cerebral TNF-α, IL-1ß and glutamine as well as increased activity and expression of Na+/K+-ATPase, effects that were significantly reversed by UMB. In addition, UMB down-regulated nitric oxide synthase and soluble guanylate cyclase in the cerebrum of hyperammonemic rats. In conclusion, this study provides evidence that UMB protects against hyperammonemia via attenuation of oxidative stress and inflammation. UMB prevents hyperammonemia associated hematological alterations and therefore represents a promising protective agent against the deleterious effects of excess ammonia.

Antiallergic and antihistaminic actions of Ceasalpinia bonducella seeds: Possible role in treatment of asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Seed kernel of the plant Ceasalpinia bonducella Linn (Caesalpiniacaeae) are used for the treatment of asthma in folk medicine and ancient books. AIM OF STUDY: To assess the pharmacological efficacy of the plant in asthma and to confine and describe the synthetic constituents from the seeds that are in charge of the action. MATERIAL AND METHODS: The viability of petroleum ether, ethanol extract and ethyl acetate fraction from ethanol extract of C. bonducella seeds were screened for the treatment of asthma by various methods viz. effect of test drug on clonidine and haloperidol induced catalepsy, milk-induced leukocytosis and eosinophilia, mast cell stabilizing activity in mice and studies on smooth muscle preparation of guinea pig ileum (in-vitro). Column chromatography of active extract was done to pinpoint the active compound followed by structure elucidation by FTIR, GCMS and NMR spectroscopic methods. RESULTS: Ethyl acetate fraction from ethanol extract of C. bonducella seeds exhibited antihistaminic activity at the dose of 50 and 100 mg/kg, inhibited clonidine-induced catalepsy but not haloperidol-induced catalepsy. Ethyl acetate fraction from ethanol extract significantly inhibited increased leukocyte and eosinophil count due to milk allergen and showed maximum protection against mast cell degranulation by clonidine. The results of guinea pig ileum indicated that the compound 2 methyl, 1 hexadecanol isolated from ethyl acetate fraction of ethanol extract relaxed significantly the ileum muscle strips pre-contracted by which suggests the involvement of ß2-agonists on the relaxation of the tissue. All the results are dose dependent. Active ethyl acetate fraction from ethanol extract showed presence of anti-asthmatic compound, 2-methyl, 1-hexadecanol. CONCLUSION: The ethyl acetate fraction from ethanol extract of seeds of the plant C. bonducella can inhibit parameters linked to asthma disease.

Resistance exercise attenuates skeletal muscle oxidative stress, systemic pro-inflammatory state, and cachexia in Walker-256 tumor-bearing rats.

The aim of this study was to investigate the effects of resistance exercise training (RET) on oxidative stress, systemic inflammatory markers, and muscle wasting in Walker-256 tumor-bearing rats. Male (Wistar) rats were divided into 4 groups: sedentary controls (n = 9), tumor-bearing (n = 9), exercised (n = 9), and tumor-bearing exercised (n = 10). Exercised and tumor-bearing exercised rats were exposed to resistance exercise of climbing a ladder apparatus with weights tied to their tails for 6 weeks. The physical activity of control and tumor-bearing rats was confined to the space of the cage. After this period, tumor-bearing and tumor-bearing exercised animals were inoculated subcutaneously with Walker-256 tumor cells (11.0 × 107 cells in 0.5 mL of phosphate-buffered saline) while control and exercised rats were injected with vehicle. Following inoculation, rats maintained resistance exercise training (exercised and tumor-bearing exercised) or sedentary behavior (control and tumor-bearing) for 12 more days, after which they were euthanized. Results showed muscle wasting in the tumor-bearing group, with body weight loss, increased systemic leukocytes, and inflammatory interleukins as well as muscular oxidative stress and reduced mTOR signaling. In contrast, RET in the tumor-bearing exercised group was able to mitigate the reduced body weight and muscle wasting with the attenuation of muscle oxidative stress and systemic inflammatory markers. RET also prevented loss of muscle strength associated with tumor development. RET, however, did not prevent the muscle proteolysis signaling via FBXO32 gene messenger RNA expression in the tumor-bearing group. In conclusion, RET performed prior tumor implantation prevents cachexia development by attenuating tumor-induced systemic pro-inflammatory condition with muscle oxidative stress and muscle damage.

[Very Severe Differentiation Syndrome in Low Risk Acute Promyelocytic Leukemia - A Peril of Differentiating Therapy]. / Sehr schweres Differenzierungssyndrom bei Niedrigrisiko akuter Promyelozytenleukämie ­ eine Tücke der differenzierenden Therapie.

History, examinations and diagnosis A young patient consulted the hospital because of spontaneous hematomas. The combination of pancytopenia and coagulopathy in the blood and the proving cytogenetic and moleculargenetic examinations of the bone marrow lead to the diagnosis of low-risk acute promyelocytic leukemia (APL). Therapy and clinical course During the combination therapy with ATRA and ATO, the patient developed a severe differentiation syndrome and hyperleukocytosis. Management of the condition was only possible due to clinical expertise and massive substitution of blood products and clotting factors. Conclusion The case illustrates the difficulty and dangers of APL induction therapy even with a favorable initial clinical presentation despite the generally low toxicity of new therapies.

Hematopoietic arginase 1 deficiency results in decreased leukocytosis and increased foam cell formation but does not affect atherosclerosis.

BACKGROUND AND AIMS: Arginase1 (Arg1), an M2 macrophage marker, plays a critical role in a number of immunological functions in macrophages, which are the main cell type facilitating atherosclerotic lesion development. Arg1 uses the substrate l-arginine to create l-ornithine, a precursor molecule required for collagen formation and vascular smooth muscle cell differentiation. By reducing l-arginine availability, Arg1 limits the production of nitric oxide (NO), a pro-atherogenic factor in macrophages. In endothelial cells, conversely, NO is strongly anti-atherogenic. However, until now, the role of Arg1 in atherosclerosis is largely unknown. The aim of this study is to specifically investigate the effect of Arg1 deletion in hematopoietic cells on atherosclerosis susceptibility. METHODS: Ldlr KO mice were transplanted with Arg1flox/flox;Tie2-Cre (Arg1 KO) bone marrow (BM) or wildtype (WT) BM. After 8 weeks of recovery on chow diet, recipients mice were fed a Western-Type Diet (WTD) for 10 weeks to induce atherosclerosis. RESULTS: After 10-week WTD challenge, blood leukocyte counts were decreased by 25% (p < 0.001), and spleen leukocytes were decreased by 35% (p = 0.05) in Ldlr KO mice transplanted with Arg1 KO BM compared to mice transplanted with WT BM. The decrease in leukocytes was due to lower B lymphocyte counts. However, oxLDL-specific antibodies were increased in plasma of Ldlr KO mice transplanted with Arg1 KO BM compared to WT BM transplanted controls, whereas oxLDL-specific IgM was not affected. On the other hand, peritoneal foam cells in Arg1 KO BM recipients were increased 3-fold (p < 0.001) compared to WT BM recipients. No change in blood cholesterol was found. Despite changes in leukocyte counts and macrophage foam cell formation, we did not observe differences in atherosclerotic plaque size or plaque macrophage content in the aortic root. Surprisingly, there was also no difference in plaque collagen content, indicating that absence of macrophage Arg1 function does not reduce plaque stability. CONCLUSIONS: Deletion of Arg1 in hematopoietic cells adversely affects blood leukocyte counts and increases foam cell formation. However, no effects on atherosclerosis could be demonstrated, indicating that hematopoietic Arg1 function is not a decisive factor in atherosclerotic plaque formation.

A randomized controlled trial of prophylactic antibiotics in the prevention of electrocoagulation syndrome after colorectal endoscopic submucosal dissection.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is currently commonly performed, but colorectal ESD has a substantial risk of adverse events, including post-ESD electrocoagulation syndrome (PEECS). We investigated whether the use of prophylactic antibiotics can reduce the occurrence of PEECS. METHODS: Patients who underwent colorectal ESD were randomly assigned to 1 of 2 treatment regimens. Ampicillin and/or sulbactam mixed with normal saline solution was administered 1 hour before ESD in group 1 then additionally injected every 8 hours twice more. In group 2, normal saline solution without antibiotics was administered following the same schedule. We investigated the characteristics of the patients and tumors, the incidence of PEECS, laboratory findings, and the visual analog scale (VAS) score for abdominal pain measured on the morning after ESD. RESULTS: A total of 100 cases (50 per group) were finally analyzed, and 97 tumors were successfully resected en bloc. The number of patients having C-reactive protein (CRP) levels ≥1 mg/dL and the number of patients having VAS scores for abdominal pain ≥1 were greater in group 2 than in group 1 (P = .008 and .023, respectively). The incidence of PEECS in group 2 also was higher than that in group 1 (1 and 8 in groups 1 and 2, respectively; P = .031). CONCLUSIONS: The prophylactic use of ampicillin and/or sulbactam in colorectal ESD is associated with reduced risk of PEECS, decreased CRP levels, and decreased abdominal pain. The use of prophylactic antibiotics in colorectal ESD may be an effective tool for reducing the risk of PEECS. (Clinical trial registration number: KCT0001102.).

Red Wine Prevents the Acute Negative Vascular Effects of Smoking.

BACKGROUND: Moderate consumption of red wine is associated with fewer cardiovascular events. We investigated whether red wine consumption counteracts the adverse vascular effects of cigarette smoking. METHODS: Participants smoked 3 cigarettes alone or after drinking a titrated volume of red wine. Clinical chemistry, blood counts, plasma cytokine enzyme-linked immunosorbent assays, immunomagnetic separation of CD14+ monocytes for gene expression analysis, fluorescence-activated cell sorting for microparticles, and isolation of circulating mononuclear cells to measure telomerase activity were performed, and urine cotinine levels were quantified. RESULTS: Compared with baseline, leukocytosis (P = .019), neutrophilia (P <.001), lymphopenia (P <.001), and eosinopenia (P = .008) were observed after only smoking. Endothelial and platelet-, monocyte-, and leukocyte-derived microparticles (P <.001 each) were elevated. In monocytes, messenger RNA expression of interleukin (IL)-6 (2.6- ± 0.57-fold), tumor necrosis factor alpha (2.2- ± 0.62-fold), and IL-1b (2.3- ± 0.44-fold) were upregulated, as was IL-6 (1.2 ± 0.12-fold) protein concentration in plasma. Smoking acutely inhibited mononuclear cell telomerase activity. Markers of endothelial damage, inflammation, and cellular aging were completely attenuated by red wine consumption. CONCLUSION: Cigarette smoke results in acute endothelial damage, vascular and systemic inflammation, and indicators of the cellular aging processes in otherwise healthy nonsmokers. Pretreatment with red wine was preventive. The findings underscore the magnitude of acute damage exerted by cigarette smoking in "occasional lifestyle smokers" and demonstrate the potential of red wine as a protective strategy to avert markers of vascular injury.

Selenium Pretreatment for Mitigation of Ischemia/Reperfusion Injury in Cardiovascular Surgery: Influence on Acute Organ Damage and Inflammatory Response.

Ischemia/reperfusion injury (IRI) contributes to morbidity and mortality after cardiovascular surgery requiring cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). Multi-organ damage is associated with substantial decreases of blood selenium (Se) levels in patients undergoing cardiac surgery with CPB. We compared the influence of a dietary surplus of Se and pretreatment with ebselen, a mimic of the selenoenzyme glutathione peroxidase, on IRI-induced tissue damage and inflammation. Male Wistar rats were fed either a Se-adequate diet containing 0.3 ppm Se or supplemented with 1 ppm Se (as sodium selenite) for 5 weeks. Two other groups of Se-adequate rats received intraperitoneal injection of ebselen (30 mg/kg) or DMSO (solvent control) before surgery. The animals were connected to a heart-lung-machine and underwent 45 min of global ischemia during circulatory arrest at 16 °C, followed by re-warming and reperfusion. Selenite and ebselen suppressed IRI-induced leukocytosis and the increase in plasma levels of tissue damage markers (AST, ALT, LDH, troponin) during surgery but did not prevent the induction of proinflammatory cytokines (IL-6, TNF-α). Both Se compounds affected phosphorylation and expression of proteins related to stress response and inflammation: Ebselen increased phosphorylation of STAT3 transcription factor in the heart and decreased phosphorylation of ERK1/2 MAP kinases in the lungs. Selenite decreased ERK1/2 phosphorylation and HSP-70 expression in the heart. Pretreatment with selenite or ebselen protected against acute IRI-induced tissue damage during CPB and DHCA. Potential implications of their different actions with regard to molecular stress markers on the recovery after surgery represent promising targets for further investigation.

Absceso hepático secundario a una perforación duodenal por espina de pescado: descripción de un caso / Liver abscess secondary to duodenal perforation by fishbone: report of a case

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Hemoperitoneo secundario a tumor miofibroblástico inflamatorio perforado. Presentación de una complicación inusual / Hemoperitoneum secondary to perforated inflammatory myofibroblastic tumor: a case report of an unusual complication

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Antitussive, expectorant, and anti-inflammatory activities of four caffeoylquinic acids isolated from Tussilago farfara.

CONTEXT: The flower bud of Tussilago farfara L. (Compositae) (FTF) is one of the traditional Chinese medicinal herbs used to treat cough, phlegm, bronchitic, and asthmatic conditions. OBJECTIVE: The objective of this study is to isolate four caffeoylquinic acids from the ethyl acetate extract (EtE) of FTF and to evaluate their antitussive, expectorant, and anti-inflammatory activities. MATERIALS AND METHODS: The structures of compounds 1-4 isolated from EtE were determined by spectral analysis. Mice were orally treated with these compounds and their mixture (in a ratio of 5:28:41:26 as in EtE) at doses of 10 and 20 mg/kg once daily for 3 d. The antitussive and expectorant activities were evaluated separately with the ammonia liquor-induced model and the phenol red secretion model. The anti-inflammation activity was evaluated using leukocyte count in the bronchoalveolar lavage fluid after ammonia liquor-induced acute airway inflammation. RESULTS: The four compounds were identified as chlorogenic acid (1), 3,5-dicaffeoylquinic acid (2), 3,4-dicaffeoylquinic acid (3), and 4,5-dicaffeoylquinic acid (4). All compounds, especially compound 4 (58.0% inhibition in cough frequency), showed a significant antitussive effect. However, the mixture was the most effective to inhibit the cough frequency by 61.7%. All compounds also showed a significant expectorant effect, while compound 2 was the most potent to enhance the phenol red secretion by 35.7%. All compounds significantly alleviated inflammation, but compound 4 showed the strongest effect to inhibit the leukocytosis by 49.7%. DISCUSSION AND CONCLUSION: The caffeoylquinic acids and their mixture, exhibiting significant antitussive, expectorant, and anti-inflammatory effects, could be considered as the main effective ingredients of FTF, and they may act in a collective and synergistic way.

Mercuric chloride induced hepatotoxic and hematologic changes in rats: The protective effects of sodium selenite and vitamin E.

This study focuses on investigating the possible protective effect of sodium selenite (Na2SeO3) and/or vitamin E against mercuric chloride (HgCl2)-induced hepatotoxicity in rat. Male rats were given HgCl2 (1 mg/kg body weight (bw)) and HgCl2 plus Na2SeO3 (0.25 mg/kg bw) and/or vitamin E (100 mg/kg bw) daily via gavage for 4 weeks. HgCl2-treated groups had significantly higher white blood cell and thrombocyte counts than the control group. Serum activities of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl-transferase, and lactate dehydrogenase significantly increased and serum levels of total protein, albumin, triglyceride, total cholesterol, and low-density lipoprotein cholesterol significantly decreased in the HgCl2-treated groups compared with control group. Malondialdehyde level significantly increased and superoxide dismutase, catalase, and glutathione peroxidase activities decreased in liver tissue of HgCl2-treated rats. Also, HgCl2 exposure resulted in histopathological changes. Supplementation of Na2SeO3 and/or vitamin E provided partial protection in hematological and biochemical parameters that were altered by HgCl2 As a result, Na2SeO3 and/or vitamin E significantly reduced HgCl2-induced hepatotoxicity, but not protected completely.

The plant hormone zeatin riboside inhibits T lymphocyte activity via adenosine A2A receptor activation.

Cytokinins are plant hormones that play an integral role in multiple aspects of plant growth and development. The biological functions of cytokinins in mammalian systems are, however, largely uncharacterized. The naturally occurring cytokinin zeatin riboside has recently been demonstrated to activate the mammalian adenosine A(2A) receptor, which is broadly expressed by various cell types including immune system cells, with the activation of the A(2A)R playing a role in the regulation of cells involved in both innate and adaptive immunity. We show for the first time that zeatin riboside modulates mammalian immune system activity via an A(2A)R-dependent mechanism. Specifically, zeatin riboside treatment induces the production of cyclic adenosine monophosphate (cAMP) by T lymphocytes and inhibits the production by CD3(+)CD4(+) T cells of interferon (IFN)-γ, IL-2, tumor-necrosis factor (TNF)-α, IL-4 and IL-13, and the production by CD3(+)CD8(+) T cells of IFN-γ, IL-2 and TNF-α. Additionally, the upregulation of CD25, CD69 and CD40L by activated T lymphocytes is modulated by zeatin riboside. Zeatin riboside treatment also potently inhibits thioglycollate-induced peritoneal leukocytosis. The immunomodulatory activities of zeatin riboside are blocked by co-treatment with the selective A(2A)R antagonist ZM241385. These data suggest that zeatin riboside possesses therapeutic potential as a mammalian immunomodulatory agent.

Can we say farewell to monitoring minimal residual disease in acute promyelocytic leukaemia?

Molecularly targeted therapies have transformed the management of PML-RARA+ acute promyelocytic leukaemia (APL), with survival rates now exceeding 80% in clinical trials. This raises questions about the relevance of post-remission monitoring for PML-RARA transcripts, which has been widely used to predict relapse, guiding early intervention to prevent disease progression and the inherent risk of fatal bleeding. Given the treatability of haematological relapse, survival benefits would only be seen if monitoring could identify patients who could be salvaged if treated early but not later on, although it could be argued that early deployment of arsenic trioxide (ATO) can avoid inducing hyperleucocytosis and the associated differentiation syndrome, which frequently complicate treatment of frank relapse. However, given the low rates of relapse now observed in patients presenting with standard risk disease (i.e. presenting WBC<10×10(9)/l) who achieve early molecular remission, subsequent sequential minimal residual disease (MRD) monitoring confers only a marginal benefit, so could be avoided in this group. However, sequential MRD monitoring may still be of value in patients with high risk APL, although evidence tends to come from historically controlled studies. Therefore, there may remain a role for MRD monitoring in the most clinically challenging subsets of APL, but the continuing debate highlights the need for robust evidence in developing a more individualized approach to management of other subtypes of acute leukaemia.

Low-dose combination of alendronate and atorvastatin reduces ligature-induced alveolar bone loss in rats.

BACKGROUND AND OBJECTIVE: Atorvastatin (ATV) has bone anabolic properties, and alendronate (ALD) is an important antiresorptive drug. This study aimed to evaluate the effects of the combination of ALD and ATV on ligature-induced alveolar bone loss in rats. MATERIAL AND METHODS: Periodontitis was induced by ligature in 78 Wistar rats. Groups of six rats prophylactically received 0.9% saline (SAL), ALD (0.01 or 0.25 mg/kg subcutaneously) or ATV (0.3 or 27 mg/kg by gavage). Then, groups of six rats received the combination of ALD+ATV (0.25 mg/kg + 27 mg/kg, 0.01 mg/kg + 0.3 mg/kg, 0.25 mg/kg + 0.3 mg/kg or 0.01 mg/kg + 27 mg/kg) prophylactically. An extra group of six rats received therapeutic SAL or a lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) therapeutically. Three extra groups of six rats each received SAL or a lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) prophylactically or therapeutically for histometric and immunohistochemical analyses. The rats were killed on day 11 after ligature placement, and the maxillae were removed and processed for macroscopic, histomorphometric and TRAP immunohistochemical analyses. Gingival samples were collected to evaluate myeloperoxidase (MPO) activity. Blood samples were collected to measure serum bone-specific alkaline phosphatase (BALP) and transaminase levels and for hematological studies. Rats were weighed daily. RESULTS: All combined therapies prevented alveolar bone loss when compared with SAL or low doses of monotherapy (ALD or ATV) (p < 0.05). The lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively), administered either prophylactically (39.0%) or therapeutically (53.5%), prevented alveolar bone loss. Decreases in bone and cementum resorption, in leukocyte infiltration and in immunostaining for TRAP and MPO activity corroborated the morphometric findings. The lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) prevented BALP reduction (p < 0.05) and did not alter the level of serum transaminases. Moreover, the lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) also reduced neutrophilia and lymphomonocytosis and did not cause weight loss when compared with administration of SAL. CONCLUSION: The lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) demonstrated a protective effect on alveolar bone loss.

Cardiac critical care after transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) is a new therapy for severe aortic stenosis now available in the United States. Initial patients eligible for TAVR are defined by high operative risk, with advanced age and multiple comorbidities. Following TAVR, patients experience acute hemodynamic changes and several possible complications, including hypotension, vascular injury, anemia, stroke, new-onset atrial fibrillation, conduction disturbances and kidney injury, requiring an acute phase of intensive care. Alongside improvements in TAVR technology and technique, improvements in care after TAVR may contribute to improved outcomes. This review presents an approach to post-TAVR critical care and identifies directions for future research.