Embolization using hydrogel-coated coils for pulmonary arteriovenous malformations.

PURPOSE: To prospectively evaluate the efficacy and safety of embolization using hydrogel-coated coils for the treatment of pulmonary arteriovenous malformations (PAVMs). MATERIALS AND METHODS: The outcomes of 21 PAVMs in 19 patients (3 men and 16 women; mean age, 58.8±15.2 [SD] years; age range 14-78 years) treated by venous sac embolization (VSE) with additional feeding artery embolization were prospectively evaluated. For VSE, using one or more 0.018-inch hydrogel-coated coils was mandatory. Recanalization and/or reperfusion were evaluated by pulmonary arteriography 1 year after embolization. RESULTS: The mean feeding artery and venous sac sizes were 4.0mm and 8.5mm, respectively. Embolization was successfully completed in 20/21 PAVMs, yielding a technical success rate of 95%. The feeding artery was also embolized in 17/20 successful PAVMs (85%). A technical failure occurred in one PAVM, where embolization was abandoned because of migration of one bare coil to the left ventricle. The mean numbers of hydrogel-coated coils and bare platinum detachable coils used for VSE were 3.3±2.1 (SD) (range, 1-8) and 4.4±3.9 (SD) (range, 1-17), respectively. The mean percentages of hydrogel-coated coils in number, length, and estimated volume were 42.9%, 33.3%, and 72.7% respectively. One patient with one PAVM was lost to follow-up after 3 months. Neither recanalization nor reperfusion was noted in the remaining 19 PAVMs (success rate, 19/19 [100%]). One grade 4 (coil migration) adverse event occurred, and it was treated without any sequelae. CONCLUSION: VSE using hydrogel-coated coils with additional feeding artery embolization is a safe and effective treatment for PAVM.

CT fluoroscopy-guided core needle biopsy of anterior mediastinal masses.

OBJECTIVE: To retrospectively evaluate the safety, diagnostic yield, and risk factors of diagnostic failure of computed tomography (CT) fluoroscopy-guided biopsies of anterior mediastinal masses. MATERIALS AND METHODS: Biopsy procedures and results of anterior mediastinal masses in 71 patients (32 women/39 men; mean [±standard deviation] age, 53.8±20.0years; range, 14-88years) were analyzed. Final diagnoses were based on surgical outcomes, imaging findings, or clinical follow-up findings. The biopsy results were compared with the final diagnosis, and the biopsy procedures grouped by pathologic findings into diagnostic success and failure groups. Multiple putative risk factors for diagnostic failure were then assessed. RESULTS: Seventy-one biopsies (71 masses; mean size, 67.5±27.3mm; range 8.6-128.2mm) were analyzed. We identified 17 grade 1 and one grade 2 adverse events (25.4% overall) according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Sixty-nine biopsies (97.2%) provided samples fit for pathologic analysis. Diagnostic failure was found for eight (11.3%) masses; the 63 masses diagnosed successfully included thymic carcinoma (n=17), lung cancer (n=14), thymoma (n=12), malignant lymphoma (n=11), germ cell tumor (n=3), and others (n=6). Using a thinner needle (i.e., a 20-gauge needle) was the sole significant risk factor for diagnostic failure (P=0.039). CONCLUSION: CT fluoroscopy-guided biopsy of anterior mediastinal masses was safe and had a high diagnostic yield; however, using a thinner biopsy needle significantly increased the risk of a failed diagnosis.

Radiofrequency ablation of pulmonary tumors near the diaphragm.

PURPOSE: To retrospectively evaluate the feasibility, safety, and efficacy of radiofrequency ablation (RFA) of lung tumors located near the diaphragm. MATERIALS AND METHODS: A total of 26 patients (15 men, 11 women; mean age, 61.5 years±13.0 [SD]) with a total of 29 lung tumors near the diaphragm (i.e., distance<10mm) were included. Mean tumor diameter was 11.0mm±5.3 (SD) (range, 2-23mm). Efficacy of RFA, number of adverse events and number of adverse events with a grade≥3, based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, were compared between patients with lung tumors near the diaphragm and a control group of patients with more distally located lung tumors (i.e., distance≥10mm). RESULTS: RFA was technically feasible for all tumors near the diaphragm. Four grade 3 adverse events (1 pneumothorax requiring pleurodesis and 3 phrenic nerve injuries) were observed. No grade≥4 adverse events were reported. The median follow-up period for tumors near the diaphragm was 18.3 months. Local progression was observed 3.3 months after RFA in 1 tumor. The technique efficacy rates were 96.2% at 1 year and 96.2% at 2 years and were not different, from those observed in control subjects (186 tumors; P=0.839). Shoulder pain (P<0.001) and grade 1 pleural effusion (P<0.001) were more frequently observed in patients with lung tumor near the diaphragm. The rates of grade≥3 adverse events did not significantly differ between tumors near the diaphragm (4/26 sessions) and the controls (7/133 sessions) (P=0.083). CONCLUSION: RFA is a feasible and effective therapeutic option for lung tumors located near the diaphragm. However, it conveys a higher rate of shoulder pain and asymptomatic pleural effusion by comparison with more distant lung tumors.

Simultaneous biopsy and radiofrequency ablation of T1a renal cell carcinoma.

OBJECTIVE: The goal of this study was to retrospectively evaluate the outcome, including feasibility, safety, diagnostic yield, and factors affecting the success of computed tomography fluoroscopy-guided biopsy when performed during the same procedure than radiofrequency ablation (RFA) in renal tumors strongly suspected of being T1a renal cell carcinoma (RCC). MATERIALS AND METHODS: Nineteen patients (13 men, 6 women; mean age, 66.7 years) with a total of 19 suspected renal tumors (mean diameter, 1.8cm) underwent computed tomography fluoroscopy-guided biopsy during (n=6) or immediately after (n=13) RFA. All patients were strongly suspected of having RCC on the basis of patient's medical histories and/or the results of imaging investigations. All procedures were divided into diagnostic and non-diagnostic biopsies. Various variables were compared between the 2 groups using univariate analysis. RESULTS: In all tumors, biopsy procedures were technically feasible. No major complications were observed, except for 8 minor post-procedural bleedings. All but one tumor was completely ablated. Local recurrence in the ablation zone as well as tumor seeding in retroperitoneal fat occurred in 1 patient 8.5months after the procedure and were successfully treated with further percutaneous cryoablation. Thirteen tumors were diagnosed as RCC, whereas 6 were ultimately found to contain normal renal tissue (n=5) or connective tissue (n=1). Univariate analysis revealed that none of the variables were significantly different between the diagnostic and non-diagnostic biopsies. CONCLUSION: The performance of renal tumor biopsy and RFA in the same session is feasible and safe. Although pre-treatment pathological diagnosis would be generally desirable, simultaneous biopsy with RFA can be an option for the patients who are not amenable to pre-treatment biopsy.

A case of upper gingiva carcinoma with chronic graft-versus-host disease after allogenic bone marrow transplantation.

Oral squamous cell carcinoma (OSCC) is one of the most common solid tumours occurring after haematopoietic stem cell transplantation (HSCT), especially in patients with chronic graft-versus-host-disease (cGVHD). We describe a case of OSCC that developed in a 51-year-old male 22 years after he had received allogeneic HSCT from his human leukocyte antigen-identical sister as a treatment for acute myelocytic leukaemia. The patient had presented with multiple white patchy lesions on the palatal gingiva and mucosa 16 years after HSCT; these lesions were consistent with the clinical features of cGVHD. Six years later, oral examination and biopsy revealed upper gingival squamous cell carcinoma (SCC) in areas of cGVHD, and he underwent tumour excision. Follow-up examination at 2 years and 4 months after the operation revealed no evidence of recurrence of local SCC or metastasis of the cervical lymph node. The current case highlights the susceptibility of patients with cGVHD to the development of OSCC even two decades after HSCT. Therefore, we recommend careful long-term follow-up of the oral cavity for patients with cGVHD.

Generation of dyspeptic symptoms by direct acid and water infusion into the stomachs of functional dyspepsia patients and healthy subjects.

BACKGROUND: The mechanisms of the development of symptoms in functional dyspepsia (FD) patients have not been fully elucidated. We previously reported that acid directly infused into the stomach causes dyspeptic symptoms in asymptomatic healthy controls (HCs); however, the response to acid infusion of FD patients was not determined. AIM: To investigate the severity of dyspeptic symptoms induced by direct acid infusion in FD subjects and HCs. METHODS: This was a multi-centre, cross-over, randomised, double-blind study in 23 FD subjects and 32 HCs. FD was defined using the Rome III criteria. All subjects were Helicobacter pylori negative. Each subject received two tests; 0.1 mol/L hydrochloric acid and water infused into the stomach. The presence and severity of 12 dyspeptic symptoms were assessed using a visual analogue scale. RESULTS: The proportion of subjects developing symptoms by acid or water infusion was significantly greater in FD subjects than HCs. All of the FD subjects experienced at least one symptom by water or acid infusion. In the FD subjects, the severity of symptoms was significantly greater with acid infusion than water infusion. The severity of symptoms in total and the scores for eight of the 12 symptoms induced by acid infusion was significantly greater in FD subjects than in HCs. CONCLUSIONS: The severity of dyspeptic symptom generation induced by direct acid infusion into the stomach was significantly greater in functional dyspepsia subjects than in healthy controls, suggesting that hypersensitivity to acid is one of the important mechanisms of the development of symptoms in functional dyspepsia patients.

NK-1 receptor is involved in the decreased movement in a rat chronic acid reflux oesophagitis model.

BACKGROUND: We previously reported that rats with reflux oesophagitis (RE) show a decrease in voluntary movement, which could be used as a measure of chronic visceral symptoms. However, what mediates these symptoms is still unknown, and pain-related neuropeptides or their receptors in oesophageal mucosa are possibly related to the symptom generation of oesophagitis. In the present study, we investigated the role of NK-1 receptor (NK-1R) as a mediator of oesophagitis symptoms. METHODS: Chronic RE was surgically induced using rats. The degree or severity of oesophageal symptoms was evaluated by assessing voluntary movement, which was monitored using an infrared sensor system. The NK-1R antagonist, L-732,138, was administered and changes in voluntary movement were assessed. Ten days after surgery, the rats were killed to examine the oesophagus. NK-1R and tachykinin-1 mRNA were detected by real-time RT-PCR. NK-1R protein expression was examined by Western blotting. KEY RESULTS: Voluntary movement of the oesophagitis model rats was significantly lower than that of the sham-operated rats on day 10. The size of oesophageal mucosal erosion did not correlate with the amount of voluntary movement. The amount of NK-1R protein and mRNA in the oesophageal tissue was significantly higher at both the erosion and non-erosion sites. The amount of tachykinin-1 mRNA in oesophageal tissue at the non-erosion sites was significantly higher in oesophagitis rats. The voluntary movement of oesophagitis rats was significantly increased by the administration of L-732,138. CONCLUSIONS & INFERENCES: The NK-1R and related neuropeptides are possibly involved in the decrease in voluntary movement of RE.

Transient receptor potential A1 mediates gastric distention-induced visceral pain in rats.

BACKGROUND: Transient receptor potential (TRP)A1, a member of the TRP family of ion channels, has been proposed to function in diverse sensory processes, including thermosensation and pain. However, TRPA1 has not been directly implicated in stomach mechanosensation, and its contribution to acute visceral pain from this organ is unknown. Here, we investigated the expression of TRPA1 in primary sensory afferents and its involvement in visceral hypersensitivity in rats. METHODS: We examined TRPA1 expression in the dorsal root ganglion (DRG), nodose ganglion (NG), and stomach of rats by using immunohistochemistry. Electromyographic responses to gastric distention (GD) were recorded from the acromiotrapezius muscle in TRPA1 knockdown rats and in control rats. RESULTS: TRPA1 was predominantly expressed with sensory neuropeptides in DRG and NG neurons, and in nerve fibres in the rat stomach. Gastric distention induced the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) in DRG and NG neurons 2 min after stimulation, and most of the phosphorylated-ERK1/2-labelled DRG neurons were TRPA1-positive neurons. Intrathecal injection of TRPA1 antisense attenuated the visceromotor response, and suppressed ERK1/2 activation in the DRG, but not NG, neurons produced by GD. Furthermore, intrathecal and intraperitoneal injections of the TRPA1 inhibitor HC-03003 suppressed the response to noxious GD. CONCLUSIONS: The activation of TRPA1 in DRG neurons by noxious GD may be involved in acute visceral pain. Our findings point to the potential blockade of TRPA1 in primary afferents as a new therapeutic target for the reduction of visceral hypersensitivity.

Experimental oesophagitis in the rat is associated with decreased voluntary movement.

Growing interest has arisen regarding the mechanism of dyspeptic symptom generation. However, no evaluation system of these symptoms in animals has been developed. In this study, we examined whether voluntary movement of rats could be a measure to assess visceral symptoms of reflux oesophagitis. A chronic acid reflux oesophagitis model was made using rats, and the size of erosions was measured. Omeprazole was administered to the oesophagitis rats for 10 days. The amount of voluntary movement was measured by an infrared sensor. Intracellular spaces in oesophageal epithelium were also measured using a emission electron microscope. NP-40 soluble and insoluble fractions of claudins were examined by Western blot. Voluntary movement was significantly lower in the oesophagitis model rats than in the sham-operated rats (P < 0.01). Although omeprazole reduced the size of erosions, it did not significantly affect the total amount of voluntary movement (r = -0.033, P = 0.916). Intracellular spaces were significantly dilated in the oesophagitis model rats and claudin-3 showed a significantly lower relative quantity in the NP-40 insoluble fraction. Omeprazole significantly increased voluntary movement of oesophagitis model rats and the relative quantity of claudin-3 in the insoluble fraction (P < 0.05). Dilated intercellular spaces and the lower level of claudin-3 may relate to the voluntary movement of oesophagitis model rats. Decreases in voluntary movement of oesophagitis model rats may reflect visceral symptoms and be able to serve as an index of chronic abdominal symptoms.

Involvement of tumour necrosis factor-alpha in Clostridium perfringens beta-toxin-induced plasma extravasation in mice.

BACKGROUND AND PURPOSE: Clostridium perfringens beta-toxin, an important agent of necrotic enteritis, causes plasma extravasation due to the release of a tachykinin NK(1) receptor agonist in mouse skin. In this study, we investigated the role of cytokines in beta-toxin-induced plasma extravasation. EXPERIMENTAL APPROACH: Male Balb/c, C3H/HeN and C3H/HeJ mice were anaesthetized with pentobarbitone and beta-toxin was injected i.d. into shaved dorsal skin. SR140333, capsaicin, chlorpromazine and pentoxifylline were given as pretreatment when required before the injection of the toxin. Cytokines in the dorsal skin were measured by ELISA. KEY RESULTS: Injection (i.d.) of beta-toxin induced a dose-dependent increase in dermal TNF-alpha and interleukin (IL)-1beta levels with a concomitant increase in plasma extravasation, but not the release of IL-6. SR140333 and capsaicin significantly inhibited the toxin-induced release of TNF-alpha and IL-1beta. The plasma extravasation and the release of TNF-alpha induced by beta-toxin were significantly inhibited by chlorpromazine and pentoxifylline which inhibit the release of TNF-alpha. The toxin-induced plasma extravasation in mouse skin was attenuated by pretreatment with a monoclonal antibody against TNF-alpha, but not anti-IL-1beta. Furthermore, the toxin caused an increase in plasma extravasation in both C3H/HeN (TLR4-intact) and C3H/HeJ (TLR4-deficient) mice. In C3H/HeN mice, the toxin-induced leakage was not inhibited by pretreatment with anti-TLR4/MD-2 antibody. CONCLUSIONS AND IMPLICATIONS: These observations show that beta-toxin-induced plasma extravasation in mouse skin is related to the release of TNF-alpha via the mechanism involving tachykinin NK(1) receptors, but not via TLR4.

Modification of the hepatic mitochondrial proteome in response to ischemic preconditioning following ischemia-reperfusion injury of the rat liver.

BACKGROUND/AIM: Ischemic preconditioning (IPC) may reduce hepatic ischemia-reperfusion (IR) injury, but efficacy of IPC on mitochondrial proteome is not demonstrated. We investigated how IPC modifies the mitochondrial proteome after IR injury. METHODS: Rats were subjected to 25 min of portal triad crossclamping (IR group, n = 8). In the IPC group (n = 8), 10 min of temporal portal triad clamping was performed before 25 min of portal clamping. Samples were obtained after 24 h. The mitochondrial inner-membrane potential was measured by the uptake of a lipophilic cationic carbocyanine probe and mitochondrial proteome was also investigated using 2-dimensional differential in-gel electrophoresis and liquid chromatography-tandem mass spectrometry. RESULTS: Mitochondrial inner-membrane potential and glutathione were lower and serum transaminase was higher in the IPC group than in the IR group. The mitochondrial precursor of aldehyde dehydrogenase 2 and alpha-methylacyl-CoA-racemase were upregulated in the IPC group in comparison to the IR group. In contrast, protein disulfide-isomerase A3 precursor, 60S acid ribosomal protein P0, carbonic anhydrase 3 and superoxide dismutase were significantly more downregulated in the IPC group than in the IR group. CONCLUSIONS: A hepatoprotective effect by IPC was not shown; however, IPC caused significant up- or downregulation of several mitochondrial proteins.

Protective effects of MnM2Py4P and Mn-salen against small bowel ischemia/reperfusion injury in rats using an in vivo and an ex vivo electron paramagnetic resonance technique with a spin probe.

BACKGROUND: Reperfusion of ischemic tissues results in the formation of toxic reactive oxygen species (ROS), such as superoxide anion, hydroxyl radicals, hydroperoxide, and peroxynitrite. ROS are potent oxidizing agents, capable of damaging cellular membranes by lipid peroxidation. In the present study, we applied an in vivo electron paramagnetic resonance (EPR)/spin probe and an ex vivo EPR technique to provide direct evidence of ROS following experimentally induced small bowel ischemia/reperfusion (I/R) injury. MATERIALS AND METHODS: We used a rat model of small bowel I/R injury to explore the possibility that MnM2Py4P or Mn-salen can prevent the accumulation of ROS species following experimentally induced I/R injury. We examined the ability of MnM2Py4P and Mn-salen to scavenge radicals in living Sprague-Dawley (SD) rats using an in vivo and an ex vivo EPR technique with a spin probe. RESULTS: The CP decay rates in the MnM2Py4P- and Mn-salen-treated rats were significantly higher than those in the untreated rats and almost equal to those in sham group rats. There were no significant differences between the MnM2Py4P-treated group and the Mn-salen-treated group. Superoxide scavenging activities (SSA) in the MnM2Py4P- and EUK-8-treated group were higher than those in the untreated group and almost equal to the sham group. CONCLUSION: The present study suggested that the protective effects of MnM2Py4P and Mn-salen against small bowel IR injury were mediated by the inhibition of O2, H2O2, and NO production.

Differential expression of the glycosylated forms of MUC1 during lung development.

Human MUC1 mucin is a high-molecular weight transmembrane glycoprotein expressed on the apical surface of the simple epithelia of many different tissues. Previous investigations suggest the involvement of MUC1 in epithelial cytodifferentiation and glandular morphogenesis. However, the role of MUC1 in the development of the fetal respiratory tracts has so far been poorly investigated. To obtain more information on the roles of MUC1 during fetal lung development, we examined the expression and distribution of MUC1 by immunohistochemical staining of postmortem lung specimens from fetuses and neonates of various gestational ages. Three monoclonal antibodies, HMFG1, HMFG2, and anti-KL-6, which bind different glycosylation variants, were used. Each monoclonal antibody has been shown to recognize heavily-glycosylated MUC1, sparsely-glycosylated MUC1, and sialylated carbohydrate side chains of MUC1, respectively. At 13 weeks of gestation, the terminal respiratory tracts were diffusely stained with HFMG1 and anti-KL-6. Sparsely-glycosylated MUC1, as recognized by HMFG2, was detected only in the distal portions of the terminal bronchioles that divided into respiratory bronchioles. As such development continued, MUC1, recognized by HMFG1 and anti-KL-6, was detected throughout the bronchioles and terminal sacs, although HMFG1 immunoreactivity decreased in intensity towards the terminal sacs. Sparsely-glycosylated MUC1, as recognized by HMFG2, was mainly observed in the terminal portions. In the adult lungs, both the alveolar spaces and the respiratory bronchioles stained with HFMG1 and anti-KL-6. However, the distribution of sparsely-glycosylated MUC1 was limited in the alveolar epithelial cells. Our investigation demonstrated that variants of MUC1 were expressed in the fetal respiratory tracts as early as 13 weeks of gestation, and its expression persisted even after lung maturation. The precise roles of MUC1 were not determined in the present study; however, different glycosylation variants of MUC1 may be associated with the development of different regions of the terminal respiratory tract.

Clostridium perfringens epsilon-toxin increases permeability of single perfused microvessels of rat mesentery.

Epsilon-toxin, the primary virulence factor of Clostridium perfringens type D, causes mortality in livestock, particularly sheep and goats, in which it induces an often-fatal enterotoxemia. It is believed to compromise the intestinal barrier and then enter the gut vasculature, from which it is carried systemically, causing widespread vascular endothelial damage and edema. Here we used single perfused venular microvessels in rat mesentery, which enabled direct observation of permeability properties of the in situ vascular wall during exposure to toxin. We determined the hydraulic conductivity (L(p)) of microvessels as a measure of the response to epsilon-toxin. We found that microvessels were highly sensitive to toxin. At 10 microg ml(-1) the L(p) increased irreversibly to more than 15 times the control value by 10 min. At 0.3 microg ml(-1) no increase in L(p) was observed for up to 90 min. The toxin-induced increase in L(p) was consistent with changes in ultrastructure of microvessels exposed to the toxin. Those microvessels exhibited gaps either between or through endothelial cells where perfusate had direct access to the basement membrane. Many endothelial cells appeared necrotic, highly attenuated, and with dense cytoplasm. We showed that epsilon-toxin, in a time- and dose-dependent manner, rapidly and irreversibly compromised the barrier function of venular microvessel endothelium. The results conformed to the hypothesis that epsilon-toxin interacts with vascular endothelial cells and increases the vessel wall permeability by direct damage of the endothelium.

Effects of single and long-term administration of wheat albumin on blood glucose control: randomized controlled clinical trials.

OBJECTIVE: To examine the effects of single and long-term administration of wheat albumin (WA) on blood glucose levels and blood glucose control, respectively. DESIGN: Randomly arranged crossover trial for single administration in healthy subjects and double-blinded randomized controlled trial for long-term administration (3 months) in diabetic patients. In vitro alpha-amylase inhibitory activity of WA was also determined. SETTING: Central Research Laboratories of Nisshin Flour Milling Co. Ltd. (Saitama, Japan) for single administration and Aiwa Clinic (Saitama, Japan) for long-term administration. SUBJECTS: A total of 12 healthy adult male volunteers for the single administration and 24 type II outpatient diabetics with mild hyperglycemia for the long-term administration. INTERVENTIONS: Subjects took soups containing 0, 0.25, 0.5, and 1.0 g WA before test meals for single administration, and patients took soups with or without 0.5 g WA before every meal for the long-term (3 months) administration. RESULTS: In vitro alpha-amylase inhibitory activity of WA was 150 times that of wheat flour. In the single administration experiment, WA suppressed peak postprandial blood glucose levels in a dose-dependent manner: 31, 47, and 50% reduction after 0.25, 0.5, and 1.0 g administrations, respectively. In the long-term administration, 0.5 g of WA did not affect fasting blood glucose levels, whereas it reduced hemoglobin A1c levels. No significant adverse effects such as hypoglycemia or gastrointestinal disturbances were observed in the two experiments. CONCLUSION: In the treatment of type II diabetic patients, WA might be a useful functional food, which, with diet and exercise, could help to improve blood glucose control without any critical adverse effects.

[Stickler syndrome with rapidly progressive mitral valve regurgitation: report of a case].

A 36-year-old man with Stickler syndrome who underwent mitral valve replacement for rapidly progressive mitral regurgitation due to prolapse of an anterior leaflet. Stickler syndrome is a relatively rare condition caused by a defective collagen gene and characterized by high myopia, sensorineural-hearing deficit and flattened facial features. The prevalence of mitral valve prolapse in Stickler syndrome is reported to be much higher than in the general population because of its connective tissue dysplasia. Mitral regurgitation rapidly and refractorily progresses. Prompt surgical treatment should be recommended to mitral regurgitation in Stickler syndrome, and mitral valve replacement with a prosthetic valve is a better selection than mitral valve plasty for tissue fragility.

Differential graft-versus-leukaemia effect by CD28 and CD40 co-stimulatory blockade after graft-versus-host disease prophylaxis.

Co-stimulatory blockade may be a promising strategy for tolerance induction in transplantation. In allogeneic bone marrow transplantation (BMT) for leukaemia treatment, however, preservation of the graft-versus-leukaemia (GVL) effect is another critical requirement for clinical application. In this study, we have compared the effect on GVL of using CD28 and CD40 co-stimulatory blockades as graft-versus-host disease (GVHD) prophylaxis in a murine allogeneic BMT model with simultaneous transfer of BCL1 leukaemia. Despite the relative improvement of GVHD as assessed by survival and body weight in both treatment regimes, treatment with anti-CD154 moAb clearly diminished the GVL effect, whereas treatment with anti-CD80 and CD86 MoAbs maintained this effect. Although T cell-mediated effector function at 14 days post-BMT assessed by IFNgamma expression and cytotoxicity against host alloantigen was comparable between both co-stimulatory blockades, IL-12 mRNA expression was preferentially reduced by CD40 blockade. Our results suggest the differential involvement of the CD28 and CD40 co-stimulatory pathways in the development of GVHD and GVL effects. CD28 blockade may be a favourable strategy for tolerance induction in leukaemia patients undergoing BMT.

A novel renal carcinoma predisposing gene of the Nihon rat maps on chromosome 10.

A novel rat model of hereditary renal cell carcinoma (RC) was found in a rat colony of the Sprague-Dawley (SD) strain in Japan, and named the "Nihon" rat in 2000. This study was designed to map the RC susceptibility gene in the Nihon rat using 113 backcross animals. Our present data clearly show that the Nihon gene is genetically linked to interleukin-3 (IL3) gene (chi(2) = 93.6, Lod score = 25.16), lethal (2) giant larvae (LLGL1) locus (chi(2) = 109.0, Lod score = 31.56) and myosin heavy chain, embryonic skeletal muscle (MYHSE) gene (chi(2) = 90.6, Lod score = 23.87), which are located on the distal part of rat chromosome 10. The order of the genes is the Eker (Tsc2) gene (located on the proximal part of rat chromosome 10; human chromosome 16p 13.3)--21.3 cM--IL3 gene (human 5q23-31)--4.4 cM--Nihon gene--0.9 cM--LLGL1 locus (human 17p11.2)--4.4 cM--MYHSE gene (human 17p13.1). We also detected loss of the wild-type allele at the MYHSE locus, fitting Knudson's "two hit" model. Thus, the Nihon rat should have a mutation of a novel tumor suppressor gene related to renal carcinogenesis.

Preferential blockade of CD8(+) T cell responses by administration of anti-CD137 ligand monoclonal antibody results in differential effect on development of murine acute and chronic graft-versus-host diseases.

We investigated the effect of CD137 costimulatory blockade in the development of murine acute and chronic graft-vs-host diseases (GVHD). The administration of anti-CD137 ligand (anti-CD137L) mAb at the time of GVHD induction ameliorated the lethality of acute GVHD, but enhanced IgE and anti-dsDNA IgG autoantibody production in chronic GVHD. The anti-CD137L mAb treatment efficiently inhibited donor CD8(+) T cell expansion and IFN-gamma expression by CD8(+) T cells in both GVHD models and CD8(+) T cell-mediated cytotoxicity against host-alloantigen in acute GVHD. However, a clear inhibition of donor CD4(+) T cell expansion and activation has not been observed. On the contrary, in chronic GVHD, the number of CD4(+) T cells producing IL-4 was enhanced by anti-CD137L mAb treatment. This suggests that the reduction of CD8(+) T cells producing IFN-gamma promotes Th2 cell differentiation and may result in exacerbation of chronic GVHD. Our results highlight the effective inactivation of CD8(+) T cells and the lesser effect on CD4(+) T cell inactivation by CD137 blockade. Intervention of the CD137 costimulatory pathway may be beneficial for some selected diseases in which CD8(+) T cells are major effector or pathogenic cells. Otherwise, a combinatorial approach will be required for intervention of CD4(+) T cell function.