Bone marrow transplantation for patients with Philadelphia chromosome- positive acute lymphoblastic leukemia

We report the treatment outcome of allogeneic bone marrow transplantation in ten patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Six patients are alive and well for 6 to 30 months (median 19 months) after transplantation. Four patients died with transplant related complications. In view of the poor prognosis associated with this disease, marrow ablation followed by allogeneic or syngeneic marrow grafting may be the preferred treatment modality if a suitable marrow donor is available.     

The effect of lithium on growth factor production in long-term bone marrow cultures

We have previously reported that lithium chloride (LiCl) stimulates the production of granulocyte-macrophage colony-forming cells (GM-CFC), pluripotent stem cells (CFU-S), and differentiated granulocytes, macrophages and megakaryocytes in murine Dexter marrow cultures and that this effect appears to be mediated indirectly by a radioresistant adherent marrow cell. In this study we have established that exposure of murine Dexter cultures to LiCl (4 mEq/L) causes an increase of colony-forming cell megakaryocytes (CFU-meg) over 1 to 6 weeks of culture in both supernatant (188% to 611%) and stromal phases (123% to 246%). Moreover, we have shown that lithium treatment of either irradiated (1,100 rad) or unirradiated stromal cells increased production of activities stimulating formation of megakaryocyte, granulocyte, macrophage, and mixed lineage colonies and proliferation of the factor-dependent cell line, FDC-P1. This FDC-P1 stimulatory activity was completely blocked by an antibody to purified recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF). The baseline or lithium-induced--stromal-derived bone marrow colony stimulating activity was partially blocked by the antibody to rGM-CSF and by an antibody to purified colony stimulating factor I (CSF-1); the two antibodies combined resulted in greater than 90% inhibition of the lithium-induced marrow stimulatory activity. In addition, radioimmunoassay (RIA) showed that although CSF-1 was detectable in supernatants of these cultures, exposure to lithium did not increase CSF-1 levels. These data indicate that Dexter stromal cells produce CSF- 1 and GM-CSF and that lithium appears to exert its stimulatory effects on in vitro myelopoiesis by inducing production of GM-CSF.     

Soluble Guanylate Cyclase Stimulators and Activators: Novel Therapies for Pulmonary Vascular Disease or a Different Method of Increasing cGMP?

Pulmonary arterial hypertension (PAH) is a progressively worsening disorder characterized by increased pulmonary vascular resistance leading to increased afterload, right ventricular hypertrophy, and ultimately right heart failure and death. Current pharmacologic treatments primarily act to reduce pulmonary vascular resistance (PVR) and provide some benefit but do not cure PAH. Canonical vasodilator therapy involving the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP pathway has demonstrated efficacy, but in pathologic states, endothelial dysfunction within the pulmonary vasculature leads to the reduced synthesis and bioavailability of NO. Acting downstream of NO, sGC stimulators and activators restore the endogenous functions of NO and exploit the positive effects of sGC stimulation on various organ systems, including the heart. Riociguat (BAY 63-2521) is the first agent in a class of sGC stimulators to receive FDA approval for the treatment of PAH and chronic thromboembolic hypertension (CTEPH). Riociguat has demonstrated significant benefit as assessed by 6MWD, PVR, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, time to clinical worsening, World Health Organization (WHO) functional class, and other quality of life measures in clinical trials as a monotherapy and in combination with endothelin receptor antagonists or non-intravenous prostanoids. Riociguat is the first FDA-approved treatment option for inoperable or persistent CTEPH and adds a new effective drug to available treatment options for pulmonary hypertension (PH). The question of whether riociguat is superior to other available treatment options is unanswered at the present time and requires further study.     

High-dose atorvastatin therapy in severe heterozygous familial hypercholesterolaemia

Lipid targets can be difficult to attain in familial hypercholesterolaemia. To compare atorvastatin with simvastatin- fenofibrate and simvastatin-cholestyramine therapy, we studied 54 patients with familial hypercholesterolaemia over periods of 2-6 months on each therapeutic regimen. The atorvastatin regimen reduced total cholesterol by 41.2 +/- 11.2%, LDL by 45.6 +/- 15.5%, triglycerides by 33.8 +/- 24.8%, and increased HDL by 2.3 +/- 37.0%. Simvastatin- fenofibrate therapy achieved reductions of 33.9 +/- 8.5% in cholesterol, 42.0 +/- 12.2% in LDL, 34.7 +/- 38.3% for triglycerides, and a 25.4 +/- 55.1% increase in HDL. Simvastatin-cholestyramine gave a reduction of 31.3 +/- 11.8% in cholesterol, 36.0 +/- 14.4% in LDL, 13.7 +/- 36.3% in triglycerides, and a 1.1 +/- 30.3% rise in HDL. The atorvastatin regimen was marginally but not significantly better than simvastatin-fenofibrate in improving the LDL:HDL ratio, LDL:apoB and and apolipoprotein B:A1 ratios. Eleven patients (20.4%) had side- effects: two discontinued atorvastatin due to side-effects; two patients had rashes; six had myalgia and two had diarrhoea. Gastrointestinal side-effects were described in 16 (30.1%) patients on simvastatin-cholestyramine therapy and four cases of myalgia (11.2%) were seen with simvastatin-fenofibrate. In nine patients on atorvastatin (20.4%) a 30% or greater fall in HDL was observed, compared to five patients with resin therapy (9.2%) and two with fibrate therapy (5.5%). There were no significant differences in liver or muscle biochemistry between the regimens, but atorvastatin did raise transaminase and creatine kinase concentrations significantly compared to pre-treatment values (p = 0.001). Atorvastatin significantly improves the lipid profile in most patients compared with other regimens. It has a comparable incidence of side-effects to combination therapy regimens.      

The provision of renal replacement therapy for adults in England and Wales: recent trends and future directions

We assessed the level of provision of renal replacement therapy for adults in England and Wales. All autonomous main renal units in England (n = 52) and Wales (n = 5) were surveyed in 1996. Data for England were compared to the 1993 National Renal Review. The acceptance rate in England 1995 was 82 (80-85) per million population (p.m.p.) compared with 67 (65-70) p.m.p. in 1991-2. The rate in 1995 in Wales was 109 (98- 122) p.m.p. The prevalence rate in England was 476 p.m.p. at end-1995 compared to 393 p.m.p. in 1993, in Wales it was 487 p.m.p. The number of main renal units in England did not rise between 1993 and 1995; capacity was increased by use of more treatment shifts and temporary haemodialysis stations, and by opening more satellite units. The main growth was in hospital haemodialysis. There was an uneven geographical distribution of services. Patients accepted were older with more comorbidity. The use of better-quality processes of dialysis increased. The steady-state position for RRT will not be reached for over a decade. Health authorities will face continued pressure to fund increases in quantity and quality improvements. A stronger evidence base of the effectiveness of therapies, and a national registry to monitor the equity and cost-effectiveness of services are needed.      

Nociceptin Has Vasodilator Activity in the Pulmonary Vascular Bed of the Rat

BACKGROUND: Recent studies have shown that the newly discovered endogenous opioid-like peptide, nociceptin, has vasodilator activity in the peripheral vascular bed. However, little if anything is known about the effects of the peptide in the pulmonary vascular bed. Therefore, responses to nociceptin in the pulmonary vascular bed were investigated and compared with responses in the hindlimb and systemic vascular beds of the rat. METHODS AND RESULTS: Responses to nociceptin were investigated in the pulmonary and hindquarters vascular beds in the rat under constant flow conditions and were compared with decreases in systemic vascular resistance. Under conditions of constant flow, injections of nociceptin in doses of 3-30 nM induced dose-related decreases in pulmonary arterial perfusion pressure when baseline tone was increased to a high steady level with U46619. Pulmonary vasodilator responses to nociceptin were not modified by the opioid receptor antagonist naloxone, and the newly discovered ligand was 10-fold less potent than adrenomedullin in decreasing pulmonary vascular resistance when decreases in pulmonary hind quarters and systemic vascular resistances were compared, nociceptin was significantly more potent in decreasing hindquarters and systemic vascular resistance than in reducing pulmonary vascular resistance. CONCLUSIONS: The results of the present study indicate that nociceptin decreases pulmonary vascular resistance by a naloxone-insensitive mechanism, and that the peptide is less potent in decreasing pulmonary vascular resistance than in decreasing systemic vascular resistance in the rat.     

Chemokine expression and leucocyte infiltration in Sjogren's syndrome

OBJECTIVE: To investigate the expression and source of chemokines in minor salivary gland biopsies (MSGs) in patients with Sjogren's syndrome (SS). METHODS: Immunohistochemical analysis was used to determine the pattern of chemokine expression in MSGs from patients with (n=6) and without (n=5) SS, as well as to examine the phenotype of both resident and infiltrating cells expressing chemokines. RESULTS: Significant differences in the number of infiltrating mononuclear (MN) cells in patients with and without SS were noted. Ductal epithelial cells of SS biopsies expressed significantly increased levels of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, interleukin-8 (IL-8) and RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted). Biopsies from patients with SS showed that MIP-1beta was expressed by 51% of infiltrating cells, while 41% expressed MIP-1alpha, whereas 22 and 7% expressed RANTES and IL-8, respectively. CONCLUSION: Chemokines expressed by ductal epithelial cells may attract circulating leucocytes, in particular CD4+ T cells, towards the site of inflammation, thereby orchestrating the influx of MN cells characteristically seen in MSGs in SS. Chemokines may be induced directly by a putative triggering agent for SS, or secondary to the release of pro-inflammatory cytokines produced by epithelial cells. These findings further implicate epithelial cells as playing a major role in the pathogenesis of SS and implicate chemokines in the leucocyte recruitment in this setting.      

Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelial-derived hyperpolarizing factors, and prostaglandins

Under resting conditions the arterial vasculature exists in a vasoconstricted state referred to as vascular tone. Physiological dilatation in response to increased flow, a function of normal endothelium is necessary to maintain normal blood pressure. Endothelial dysfunction in vascular smooth muscle cells thus results in loss of normal vasorelaxant function and the inability of arteries to appropriately dilate in response to increased blood flow in either a systemic or regional vascular bed, resulting in increased blood pressure, a sequence that may represent a common pathway to hypertension. Normal vasorelaxation is mediated by a number of endothelial systems including nitric oxide (NO), prostaglandins (PGI2 and PGE2), and a family of endothelial-derived hyperpolarizing factors (EDHF). In response to hemodynamic shear stress, endothelium continuously releases NO, EDHF, and PGI2 to provide vasodilatation. EDHF, not a single molecule but rather a group of molecules that includes epoxyeicosatrienoic acids, hydrogen peroxide, carbon monoxide, hydrogen sulfide, C-natriuretic peptide, and K+ itself, causes vasodilatation by activation of vascular smooth muscle cell K+ channels, resulting in hyperpolarization and thus vasorelaxation. The understanding and effective management of blood pressure requires an understanding of both physiologic and pathophysiologic regulation of vascular tone. This review describes molecular mechanisms underlying normal endothelial regulation and pathological states, such as increased oxidative stress, which cause loss of vasorelaxation. Possible pharmacological interventions to restore normal function are suggested.     

Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice [see comments]

We report the successful long-term engraftment of normal male donor bone marrow (BM) transfused into noncytoablated female mice, challenging the assumption that "niches" need to be created for marrow to engraft. We have used chromosomal banding and Southern blot analysis to identify transplanted male marrow cells, and shown the long-term stability of the chimeric marrows. Balb/C, BDF1, or CBA-J female hosts (no irradiation) received for 5 consecutive days 40 x 10(6) male cells (per day) of the same strain, and repopulation patterns were observed. Parallel studies were performed using tibia/femur equivalents of normal marrow or marrow from Balb/C mice pretreated 6 days previously with 150 mg/kg 5-fluorouracil (5-FU). Chromosome banding techniques showed that 5% to 46% of marrow cells were male 3 to 9 months posttransplant with normal donor marrow. Southern blot analysis, using the pY2 probe, showed continued engraftment at 21 to 25 months posttransplant, ranging from 15% to 42% male engrafted cells in marrow. Normal donor male marrow engrafted significantly better than 5-FU-pretreated male marrow as shown 1 to 12 months posttransplant in non-cytoablated female recipients. Percentages of male engrafted cells in BM ranged from 23% to 78% for recipients of normal donor marrow and from 0.1% to 39% for recipients of 5-FU marrow. Mean engraftment for 6 mice receiving normal marrow was 38%, whereas that for 6 mice receiving post-5-FU marrow was 8%, as assayed 1 to 3 months posttransplant. At 10 to 12 months, mean engraftment for the normal donor group was 46%, compared with 16% for the 5-FU group. The patterns of engraftment with normal and 5-FU marrow were similar for spleen and thymus. These results show that long-term chimerism can be established after transplantation of normal donor marrow to normal nonirradiated host mice and indicate that marrow spaces do not have to be created for successful engraftment. They suggest that transplanted marrow competes equally with host marrow for marrow space. Finally, these data show that post-5-FU Balb/C male marrow is markedly inferior in the repopulation of Balb/C female host marrow, spleen, and thymus, and suggest that this population of cells may not be the ideal population for gene transfer studies.