BCL-2 family proteins in peripheral T-cell lymphomas: correlation with tumour apoptosis and proliferation

The present study investigated expression levels of the anti-apoptotic proteins BCL-2, BCL-XL and MCL-1 and the pro-apoptotic proteins BAX and BCL-XS in a series of 112 peripheral T-cell lymphomas (PTCLs) classified according to the WHO classification. Using immunohistochemical methods and a 10% cut-off, each protein was detected in a subset of PTCLs: BCL-2 in 46%, BCL-XS in 49%, BAX in 57%, BCL-XL in 57%, and MCL-1 in 65%. The mean percentage of positive cells for these proteins varied significantly among the PTCL types. Only two types of PTCL, ALK-positive anaplastic large cell lymphoma (ALCL) and enteropathy-type T-cell lymphoma, had a distinctive pattern of expression; all were BCL-2-negative and MCL-1-positive. The mean percentage of BAX-positive and BCL-XS-positive tumour cells was higher in ALK-positive ALCL than in ALK-negative ALCL or other types of PTCL (p = 0.06 and p = 0.01, respectively, Kruskal-Wallis test). MCL-1 was detected significantly more frequently (p = 0.01, chi-square test) and at higher levels (p = 0.0001, Kruskal-Wallis test) in ALK-positive ALCL and ALK-negative ALCL than in other PTCL types. The apoptotic rate, evaluated by the TUNEL assay, correlated inversely with BCL-2 expression (p = 0.035). The proliferation index, assessed by the MIB-1 antibody, correlated with expression levels of MCL-1 (R = 0.42, p = 0.003), BCL-2 (R = 0.32, p = 0.027), BAX (R = 0.33, p = 0.014), and BCL-XL (R = 0.34, p = 0.015) (Spearman rank). In conclusion, BCL-2 family proteins are expressed by a subset of PTCLs and their levels correlate with some histological types, apoptotic rate, and proliferation index. Expression of these proteins may explain the poor response of many types of PTCL to standard chemotherapy. These proteins may also provide novel targets for experimental therapy.     

Fatal pulmonary thromboembolism after a second course of high-dose chemotherapy with autologous peripheral blood stem cell transplantation

We describe a 4-yr-old boy with an occult primitive neuroectodermal tumor, who suffered fatal PTE after a second course of HDC with autologous PBSCT. On day + 52 after a second PBSCT, he was admitted because of respiratory distress. Respiratory failure rapidly progressed and he died within 4 days. The diagnosis of PTE was confirmed by a lung perfusion study with technetium-99m macroaggregated albumin, but too late to allow treatment. Although rare, PTE must be recognized as an important differential diagnosis when respiratory symptoms are observed after HDC with PBSCT.     

Acute ventilatory and circulatory reactions evoked by nicotine: are they excitatory or depressant?

Either excitatory or inhibitory cardio-respiratory responses induced by nicotine have been reported. We evaluated the joint and separate contributions of peripheral arterial chemoreceptors and pulmonary vagal afferences to nicotine-induced cardio-respiratory responses in 11 pentobarbitone-anaesthetized cats. Nicotine, given i.v. in doses of from 1 to 200 microg/kg, evoked dose-dependent transient increases in tidal volume (VT) and arterial blood pressure (BP), but the highest doses evoked brief apnoea, immediately followed by intense hyperventilation, as well as discrete early hypotension followed by late hypertension. Bilateral section of the aortic and carotid nerves abolished all hyperventilatory responses to nicotine, giving way to apnoea followed by few cycles of reduced VT and profound hypotension followed by slight hypertension in response to intermediate doses (50-100 microg/kg). Subsequent bilateral vagotomy (BV) suppressed apnoeic and hypotensive responses. In other cats initially subjected to BV, only increases in VT and BP were observed in response to nicotine, effects which were no longer observed after additional carotid and aortic deafferentation. These data suggest that excitatory effects of nicotine on respiration and BP are reflexes evoked by stimulation of peripheral arterial chemoreceptors, while inhibitory effects are also reflex responses but evoked from stimulation of pulmonary vagal afferences.     

Projections from the nucleus reticularis magnocellularis to the rat cervical cord using electrical stimulation and iontophoretic injection methods

The aim of this study is to clarify the fiber distribution of the nucleus reticularis magnocellularis (NRMC) and adjacent areas in the rat spinal cord. Biotinylated dextran amine was injected iontophoretically through a glass capillary into the areas, in which a single cell responded to noxious electrical stimulation of the sciatic nerve and to a pinch of the thigh skin with multiple spikes. Labeled fibers descended bilaterally through the ventral funiculi of the medulla oblongata and then through the ventral and lateral funiculi of the cervical cord with an ipsilateral predominance, and terminated in the spinal gray (laminae I–2X). A single fiber sometimes ran through several laminae while bifurcating many short branches with axon varicosities and terminal buttons in one transverse section, that is, through laminae V, VII and X, through laminae V, III–IV and I-II, and through laminae VII to I–II. The present study showed that the wide distribution of a single fiber and a mass of fibers descending from the NRMC and adjacent areas might modulate not only somatic sensory and motor functions but also autonomic functions in the spinal cord.     

The psychosocial aspects of donating blood stem cells: the sibling donor perspective

The collection of peripheral blood progenitor cells (PBPC) by apheresis has become common in related allogeneic donors. However, the acceptability of the procedure to donors has not been documented. The purpose of this baseline case series study was to evaluate the psycho-social dimensions of apheresis from the perspective of healthy sibling donors and to explore issues surrounding fully informed consent including voluntary donation. At the first interview to discuss donation, 17 consecutive human leucocyte antigens (HLA) identical sibling donors who chose to donate PBPC were recruited to the study. They then completed both scales of the State-Trait Anxiety Inventory. The state scale was completed again immediately before first apheresis. At the end of the final apheresis, the donors were interviewed again by an independent researcher using a standardised questionnaire. All aspects of the procedure were well tolerated, including levels of anxiety and pain. Donors donated even if the relationship with their sibling was poor. However, some areas for improvement were highlighted. Eight (47%) donors were asked to donate by their sibling or another close relative, and this gave them no real volunteer status. Written information was judged important by 11 (65%) donors, but the material used was limited. The possibility of a poor outcome for the recipient was not well understood. The content of the written documentation and the management of confidentiality in terms of donor volunteer status needed to be addressed. A further study regarding the follow-up needs of donors, including those where the outcome is poor, is underway.     

Cytokine production by human milk cells and peripheral blood mononuclear cells from the same mothers

Samples of milk (n = 80) and venous blood were collected at 5 weeks postpartum from 82 lactating mothers. Human milk cells and peripheral blood mononuclear cells were isolated and the production of interleukin-1, interleukin-6, and tumor necrosis factor- in the absence and presence of lipopolysaccharide was determined by enzyme-linked immunosorbent assay. Human milk cells spontaneously produced significantly less interleukin-1, interleukin-6, and tumor necrosis factor- than peripheral blood mononuclear cells in the absence of stimulation. In vitro stimulation of human milk cells with lipopolysaccharide (500 ng/ml) for 24 hr increased cytokine production by approximately 40–50%, whereas peripheral blood mononuclear cells responded to lipopolysaccharide (200 ng/ml) with increased cytokine production of up to 350%. These observations suggest that cells in milk are capable of active involvement in the production of the interleukin-1, interleukin-6, and tumor necrosis factor- in the mammary gland and have the capacity to respond to further stimulation after leaving the breast.     

Skin microvascular dilatation response to acetylcholine and sodium nitroprusside in peripheral arterial disease

The relative magnitude of endothelial versus non‐endothelial vasodilatation in the skin of limbs of patients with peripheral arterial occlusive disease (PAOD) is not known. We therefore investigated the effects of iontophoretically administered sodium nitroprusside (SNP) and acetylcholine (Ach) on the skin microvascular blood flow measured by laser‐Doppler fluxmetry. Methods: Blood flow changes in the skin was measured on the dorsal side of the foot in three different groups: (i) 11 patients (mean age 73 years) with PAOD, with a mean ankle‐brachial index of 0·46, (ii) eight age‐matched elderly healthy volunteers (mean age 73 years) and (iii) young healthy group (n=15; mean age 34 years). For drug administration with iontophoretic technique we used a Periont Micropharmacology System. Results: In patients with PAOD, Ach produced a vasodilatation, which was directly correlated to the strength of iontophoretic stimulation. The difference between the patients and the elderly healthy group was significant after the highest stimulation (160 s, P<0·05). The same pattern was found during stimulation with SNP. In comparison with the young healthy group there was a statistically significant difference (P<0·001) with a slower and less pronounced response in patients with PAOD. Conclusion: In patients with PAOD it is possible to achieve local vasodilatation from a baseline level by delivering Ach or SNP through the skin. The two vasodilators, acting by different mechanisms, produced the same vasodilatation response, suggesting that the impaired vasodilatation capacity in patients with peripheral arterial disease may not emanate primarily from local endothelial dysfunction in the skin microcirculation.     

Use of a non-depleting anti-CD4 antibody to modulate the immune response to coagulation factors VIII and IX

The generation of antibodies to therapeutic factors VIII or IX is a major problem in the management of haemophilia and places potential limitations on the application of gene therapy. We have investigated the administration of a non-depleting anti-CD4 antibody for modulation of the immune response to human recombinant coagulation factors VIII and IX. In mice given these clotting factors, co-administration of anti-CD4 antibody significantly reduced the appearance of factor-specific antibodies. These data provide evidence that the neutralizing antibody response to exogenous coagulation factors may be controllable if non-depleting anti-CD4 antibody is co-administered at the time of initial replacement therapy.     

Effects of long-term propranolol and octreotide on postprandial hemodynamics in cirrhosis: a randomized, controlled trial

BACKGROUND & AIMS: Postprandial increases in portal pressure may influence esophageal variceal rupture. The effects of chronic propranolol and octreotide (100 and 200 microg subcutaneously in a single dose) on postprandial hemodynamics were evaluated. METHODS: FIRST STUDY: 36 cirrhotic patients were studied at baseline and 30 and 60 minutes after a standard meal and then treated with propranolol (139 +/- 9 mg/d during 39 +/- 2 days). SECOND STUDY: After baseline measurements, patients were randomized into 3 groups: (1) placebo, (2) octreotide (100 microg), or (3) octreotide (200 microg) (n = 12 for each group). Thirty minutes postinjection a new baseline was established and measurements were repeated 30 and 60 minutes after the meal. RESULTS: First study: Baseline portal pressure was 18.1 +/- 1.2 mm Hg, 30 and 60 minutes after the meal it was 21.5 +/- 0.8 mm Hg and 20.5 +/- 0.8 mm Hg, respectively (both P < 0.01 vs. baseline). Cardiac index (CI) was 4.5 +/- 0.2, 4.8 +/- 0.2, and 4.9 +/- 0.2 L x min(-1) x m(-2), respectively (both P < 0.05 vs. baseline). Peripheral vascular resistance was 1012 +/- 56, 902 +/- 51 (P = NS), and 884 +/- 49 dynes x sec x cm(-5) (P< 0.05 vs. baseline), respectively. Second study: Propranolol and placebo did not blunt postprandial increase in portal pressure. Octreotide (100 microg) partially ameliorated postprandial increase in portal pressure. Octreotide (200 microg) significantly enhanced the portal hypotensive effect of propranolol and blunted the postprandial increase in portal pressure. CONCLUSIONS: Octreotide blunts postprandial increase in portal pressure not prevented by long-term propranolol administration.     

pQCT bone strength index may serve as a better predictor than bone mineral density for long bone breaking strength

Bone mineral density (BMD) is commonly used to predict osteoporotic fracture risk without considering the geometry of the bone. However, geometric parameters are also important in determination of bone strength. An index including both material and geometric properties may be therefore more relevant in prediction of fracture risk. We studied the correlation between parameters measured by noninvasive peripheral quantitative computed tomography (pQCT) and bone bending strength of the diaphysis of 45 fresh goat humeri and 27 femora. Multislice pQCT was used for measuring volumetric diaphyseal cortical BMD, total BMD, diaphyseal and cortical cross-sectional area (CSA), and cross-sectional moment of inertia (CSMI) and their derived bone strength indices (BSIs), including BSI_CSMI (cortical BMD × CSMI) and BSI_CSA (cortical BMD × cortical CSA). Conventional dual-energy absorptiometry (DXA) was also conducted to measure areal BMD of diaphysis for comparison. Ultimate fracture load was obtained via three-point bending test. Results showed that for femora, fracture load was correlated better with BSI_CSA (r = 0.697, P 0.001) than cortical BMD (r = 0.304, P 0.05) and total BMD (r = 0.387, P 0.05) measured using pQCT and areal BMD (r = 0.612, P 0.001) measured using DXA. For humeri, fracture load was also correlated with BSI_CSA (r = 0.579, P 0.001) but not with other pQCT parameters including cortical BMD and total BMD (r = 0.282 and 0.305, respectively; P 0.05, both). The best correlation was found with areal BMD measured by DXA (r = 0.760, P 0.001). In conclusion, pQCT noninvasive BSI_CSA derived from cortical BMD (material) and its cortical CSA (bone geometry or distribution) may serve as an important noninvasive index for predicting long bone bending strength. The bending strength was also predicted by bone mass (areal BMD) measured by DXA, an integration of bone mineral and geometry. Further clinical studies are needed to validate the predictive value of BSI in long bone osteoporotic fracture.