Experimental headache in humans

The need for valid human experimental models of headache is obvious. Several compounds have been proposed as headache-inducing agents, but only the nitroglycerin (NTG) model has been validated. In healthy subjects, intravenous infusions of the nitric oxide (NO) donor NTG induce a dose-dependent headache and dilatation of the temporal, radial and middle cerebral artery. NTG-induced headache, although less intense, resembles migraine in pain characteristics, but the accompanying symptoms are rarely present. Cephalic large arteries are dilated during migraine headache as well as during NTG headache. N-acetylcysteine enhances the formation of NO and potentiates NTG-induced headache, whereas mepyramine, a H1 -antagonist capable of blocking histamine-induced headache, has no effect. Thus, the headache is dependent on NO or other steps in the NO cascade. The model is useful for pharmacological interventions and sumatriptan reduced the NTG-induced headache. The NTG model may be a valuable tool in the development of future migraine drugs.     

Neutrophil dermatosis of the dorsal hands

Neutrophil dermatosis of the dorsal hands (NDDH) is a recently described skin manifestation regarded as a subset of acute febrile neutrophilic dermatotis (Sweet syndrome). We describe 5 cases with pustular and ulcerative plaques and/or bullae and vesicles of the dorsal hands. Three of the patients also had skin changes at sides other than the hands. Associated conditions were found in two patients, one patient treated with hemo-dialysis for chronic glomerulonephritis, and one patient had suffered from a streptococcal tonsillitis prior to the eruption. Two of the patients had fever, two had neutrophil leucocytosis in peripheral blood and two had elevated sedimentation rates. Histological findings showed signs of vasculitis in biopsies from two of the patients. NDDH is discussed on the basis of prior case reports concerning the subject, and it is concluded that Neutrophil dermatosis of the dorsal hands should be regarded as a localized variety of Sweet syndrome.     

Headache induced by a nitric oxide donor (nitroglycerin) responds to sumatriptan. A human model for development of migraine drugs

Experimental "vascular" headache in humans may be used in characterizing new migraine drugs. The effects of sumatriptan on nitroglycerin-(NTG)-induced headache and arterial responses were therefore studied. Following a double-blind randomized crossover design, 10 healthy volunteers received sumatriptan 6 mg s.c. or placebo succeeded by 20 min NTG (0.12 mg/kg/min) infusion. Headache was rated on a 10 points scale. Temporal and radial artery diameters and velocity in the middle cerebral artery (MCA) were measured with ultrasound. Sumatriptan reduced the NTG-induced headache, median score 1.5 versus 4 after placebo ( p <0.01) and decreased temporal and radial artery diameters 75±3 and 86±3% of baseline respectively ( p <0.05), Blood velocity in the MCA was unaffected. The NTG model may prove to be a valuable tool in the development of future migraine drugs. The results suggest that NTG headache in non-migraineurs may share mechanisms with migraine headache.     

16层螺旋CT血管造影对冠状动脉狭窄的评价

目的:分析16层螺旋CT血管造影(MSCTA)无创性评价冠状动脉(冠脉)狭窄的价值.方法:80例临床初诊疑为冠心病,既往无冠脉成形术和搭桥术史的患者,行冠脉16层MSCTA后(其中9例在CT扫描前心率超过80次/min的患者应用了β受体阻滞剂),回顾性重建心电门控轴位图像,并分别采用容积成像、多平面重建、曲面重建、最大密度投影等后处理方法,对所有冠脉及其分支进行重建,统计可供临床评价的、管径≥1.5 mm的冠脉段,以选择性冠脉造影(SCA)为标准,对比分析MSCTA诊断冠脉显著性狭窄(管腔平均直径缩小>50%)的准确性.结果:94%(989/1056)的冠脉节段和94%(290/310)的冠脉主支可供评价,(6%)67/1056段不能评价的主要原因分别为:心脏运动伪影39段,致密钙化20段和管腔显影不良8段.除外不能评价的冠脉,按节段和主支分类,与SCA相比,MSCTA诊断冠脉显著性狭窄的差异无统计学意义,其敏感性、特异性、阳性和阴性预期值分别为93%、99%、87%、99%和95%、98%、91%及99%.结论:在患者心率<80次/min时,16层MSCTA即可获得较好的图像质量用于评价冠脉并判断其狭窄程度,是一种值得临床医生信赖的检查冠脉有无狭窄的无创伤性方法.     

The RAR-RXR as well as the RXR-RXR pathway is involved in signaling growth inhibition of human CD34+ erythroid progenitor cells

Previous studies have shown that retinoic acid (RA), similar to tumor necrosis factor-alpha (TNF-alpha), can act as a bifunctional regulator of the growth of bone marrow progenitors, in that it can stimulate granulocyte-macrophage colony-stimulating factor (GM-CSF)- or interleukin-3 (IL-3)-induced GM colony formation, but potently inhibit G-CSF-induced growth. The present study, using highly enriched human CD34+ as well as Lin- murine bone marrow progenitor cells, demonstrates a potent inhibitory effect of 9-cis-RA on burst-forming unit-erythroid (BFU-E) colony formation regardless of the cytokine stimulating growth. Specifically, 9-cis-RA potently inhibited the growth of BFU-E response to erythropoietin (Epo) (100%), stem cell factor (SCF) + Epo (92%), IL- 3 + Epo (97%), IL-4 + Epo (88%), and IL-9 + Epo (100%). Erythroid colony growth was also inhibited when CD34+ progenitors were seeded at one cell per well, suggesting a direct action of RA. Using synthetic ligands to retinoic acid receptors (RARs) and retinoid X receptors (RXRs) that selectively bind and activate RAR-RXR or RXR-RXR dimers, respectively, we dissected the involvement of the two retinoid response pathways in the regulation of normal myeloid and erythroid progenitor cell growth. Transactivation studies showed that both the RAR (Ro 13- 7410) and RXR (Ro 25-6603 and Ro 25-7386) ligands were highly selective at 100 nmol/L. At this concentration, Ro 13-7410 potently inhibited G- CSF-stimulated myeloid as well as SCF + Epo-induced erythroid colony growth. At the same concentration, Ro 25-6603 and Ro 25-7386 had little or no effect on G-CSF-induced colony formation, whereas they inhibited 75% and 53%, respectively, of SCF + Epo-stimulated BFU-E colony growth. Thus, the RAR-RXR response pathway can signal growth inhibition of normal bone marrow myeloid and erythroid progenitor cells. In addition, we demonstrate a unique involvement of the RXR-RXR pathway in mediating growth inhibition of erythroid but not myeloid progenitor cells.     

Serial Echocardiographic Characteristics,Novel Biomarkers and Cachexia Development in Patients with Stable Chronic Heart Failure

Little is known regarding objective predictors of cachexia affecting patients with heart failure (HF). We studied 108 stable chronic systolic HF patients with serial echocardiography and biomarker measurements over 10 months. Cachexia was defined as weight loss ≥5 % from baseline or final BMI <20 kg/m²; 18.5 % developed cachexia. While there were no significant differences in baseline or serial echocardiographic measures in those developing cachexia, we found significant differences in baseline amino-terminal pro-B type natriuretic peptide (NT-proBNP), highly sensitive troponin I, sST2, and endothelin-1. Baseline log NT-proBNP (hazard ratio (HR)?=?2.57, p?=?0.004) and edema (HR?=?3.36, p?=?0.04) were predictive of cachexia in an adjusted analysis. When serial measurement of biomarkers was considered, only percent time with NT-proBNP ≥1000 pg/mL was predictive of cachexia. Thus, a close association exists between baseline and serial measurement of NT-proBNP and HF cachexia.     

Plastic-adherent progenitor cells in mobilized peripheral blood progenitor cell collections

The use of peripheral blood progenitor cells (PBPC) to reconstitute hematopoiesis after high-dose chemoradiotherapy is now commonplace in the treatment of malignancies. Attempts to characterize these cells have concentrated primarily on their phenotype and their content of clonogenic colony-forming cells (CFC). We have used a plastic-adherent delta (P delta) assay system to evaluate the quantity and quality of more primitive cells in addition to the conventional measurements of CFC and CD34-positive cells. The leukapheresis products from 20 patients mobilized using cyclophosphamide (Cy) and granulocyte colony- stimulating factor (G-CSF) were examined for progenitor cell content. The mean number of mononuclear cells (MNC), colony-forming units- granulocyte/macrophage (CFU-GM), and CD34-positive cells from two leukaphereses per patients were 7.9 x 10(8)/kg, 47.3 x 10(4)/kg, and 10.5 x 10(6)/kg, respectively. The mean number of P delta progenitors was 9.3 x 10(4)/kg. Limiting dilution analyses showed the frequency of P delta progenitors in PBPC to be between 1 and 5.3 per 10(5) MNC and that each P delta progenitor has the proliferative capability to generate an overall mean of 4.5 CFU-GM. Of the 20 patients, 16 underwent autografting with PBPC alone. Fifteen patients engrafted neutrophils and platelets within 16 days. One patient had delayed engraftment associated with inadequate etoposide clearance. Statistical analysis showed a strong correlation between numbers of CFU-GM and CD34 positivity. The numbers of plastic-adherent P delta progenitor cells did not correlate with CFU-GM or CD34-positive cells. We conclude that the plastic-adherent P delta progenitor cell assay is capable of measuring primitive hematopoietic cells and that it may be useful for the investigation of primitive progenitors in PBPC harvests.     

A novel protein-repellent dental composite containing 2-methacryloyloxyethyl phosphorylcholine

Secondary caries due to biofilm acids is a primary cause of dental composite restoration failure.To date,there have been no reports of dental composites that can repel protein adsorption and inhibit bacteria attachment.The objectives of this study were to develop a protein-repellent dental composite by incorporating 2-methacryloyloxyethyl phosphorylcholine(MPC) and to investigate for the first time the effects of MPC mass fraction on protein adsorption,bacteria attachment,biofilm growth,and mechanical properties.Composites were synthesized with 0(control),0.75%,1.5%,2.25%,3%,4.5%and 6%of MPC by mass.A commercial composite was also tested as a control.Mechanical properties were measured in three-point flexure.Protein adsorption onto the composite was determined by the microbicinchoninic acid method.A human saliva microcosm biofilm model was used.Early attachment at 4 h,biofilm at 2 days,live/dead staining and colony-forming units(CFUs) of biofilms grown on the composites were investigated.Composites with MPC of up to 3%had mechanical properties similar to those without MPC and those of the commercial control,whereas 4.5%and 6%MPC decreased the mechanical properties(P<0.05).Increasing MPC from 0 to 3%reduced the protein adsorption on composites(P<0.05).The composite with 3%MPC had protein adsorption that was 1/12 that of the control(P<0.05).Oral bacteria early attachment and biofilm growth were also greatly reduced on the composite with 3%MPC,compared to the control(P<0.05).In conclusion,incorporation of MPC into composites at 3%greatly reduced protein adsorption,bacteria attachment and biofilm CFUs,without compromising mechanical properties.Protein-repellent composites could help to repel bacteria attachment and plaque build-up to reduce secondary caries.The protein-repellent method might be applicable to other dental materials.     

Allogeneic bone marrow transplantation with a fixed low number of T cells in the marrow graft [see comments]

Despite prophylaxis with immunosuppressive drugs, severe acute graft- versus-host disease (GVHD) remains a major cause of morbidity and mortality in patients transplanted with unmodified bone marrow (BM) grafts from HLA-identical siblings. Although T-cell depletion of the BM graft has evolved as the most effective method to prevent severe acute GVHD, this beneficial effect is counterbalanced by an increased rate of graft failure and relapse of the disease. To find an approach to T-cell depletion that may avoid these extreme risks, we gave BM recipients a fixed low number of 1 x 10(5) donor T cells per kilogram of recipient's body weight in the graft. This corresponds with 99% T-cell depletion and is achieved by the addition of T cells to the graft that was previously depleted of T cells. A total of 70 patients with hematologic malignancies or aplastic anemia, including 40 patients with standard- risk leukemias, received BM grafts, depleted of T cells according to this approach, from HLA-identical siblings. The preparative regimen consisted of cyclophosphamide and total body irradiation. The patients also received a short course of cyclosporine posttransplant. Graft failure did not occur. Acute GVHD, only grade I or II, was seen in 70% of the patients and was limited to the skin in all patients. Chronic GVHD occurred in 31% of the patients and, with the exception of 1 patient, was limited to the skin as well. Relapse occurred in 3 of 40 (8%) patients with standard-risk leukemias, resulting in a projected survival at 5 years of 80%. Patients with standard-risk diseases had a procedure-related mortality of 11%. Quality of life, determined 1 year after BM transplant, was good in almost all patients with standard-risk diseases. Thus, this approach of T-cell depletion may be an approach that avoids the development of severe acute and chronic GVHD without damaging the function or antileukemic effect of the graft and that has a low transplant-related morbidity and mortality.     

Stem cell factor and interleukin-7 synergize to enhance early myelopoiesis in vitro

Interleukin-7 (IL-7) has been shown to be a critical factor in murine lymphoid development. It stimulates pre-B cells to divide in the absence of stroma cells and it is an important growth regulator of immature and mature T cells. IL-7 has been shown to synergize with stem cell factor (SCF) to provide a potent growth stimulus for pre-B cells. However, the combined effects of IL-7 and SCF on murine primitive hematopoietic cells in vitro have not been established. In the present study, the effects of recombinant rat (rr) SCF and recombinant human (rh) IL-7 on primitive murine bone marrow progenitors (Lin-Sca1+) were investigated in single-cell cloning experiments. rhIL-7 alone had no proliferative effect on Lin-Sca1+ cells, but in a dose-dependent manner directly enhanced rrSCF-induced colony formation, with an average increase in colony numbers of 2.7-fold. Interestingly, the cells formed in response to SCF and IL-7 were predominantly mature granulocytes. Thus, SCF and IL-7 synergize to stimulate early myelopoiesis in vitro.