Renal arteriolar hyalinosis, not intimal thickening in large arteries, is associated with cardiovascular events in people with biopsy-proven diabetic nephropathy.

AIMS: Diabetic nephropathy, a pathologically diagnosed microvascular complication of diabetes, is a strong risk factor for cardiovascular events, which mainly involve arteries larger than those affected in diabetic nephropathy. However, the association between diabetic nephropathy pathological findings and cardiovascular events has not been well studied. We aimed to investigate whether the pathological findings in diabetic nephropathy are closely associated with cardiovascular event development. METHODS: This retrospective cohort study analysed 377 people with type 2 diabetes and biopsy-proven diabetic nephropathy, with a median follow-up of 5.9 years (interquartile range 2.0 to 13.5). We investigated how cardiovascular events were impacted by two vascular diabetic nephropathy lesions, namely arteriolar hyalinosis and arterial intimal thickening, and by glomerular and interstitial lesions. RESULTS: Of the 377 people with diabetic nephropathy, 331 (88%) and 295 (78%) had arteriolar hyalinosis and arterial intimal thickening, respectively. During the entire follow-up period, those with arteriolar hyalinosis had higher cardiovascular event rates in the crude Kaplan-Meier analysis than those without these lesions (P = 0.005, log-rank test). When fully adjusted for clinically relevant confounders, arteriolar hyalinosis independently predicted cardiovascular events [hazard ratio (HR) 1.99; 95% confidence interval (CI) 1.12, 3.86], but we did not find any relationship between arterial intimal thickening and cardiovascular events (HR 0.89; 95% CI 0.60, 1.37). Additionally, neither glomerular nor interstitial lesions were independently associated with cardiovascular events in the fully adjusted model. CONCLUSIONS: Arteriolar hyalinosis, but not intimal thickening of large arteries, was strongly associated with cardiovascular events in people with diabetic nephropathy.

A single-center experience of preemptive anticoagulation for patients with risk factors for allograft thrombosis in renal transplantation.

AIMS: to review our single-center experience of preemptive anticoagulation for the prevention of allograft thrombosis in patients with hypercoagulable states. MATERIAL AND METHODS: this is a retrospective cohort study. Included subjects were first-time kidney allograft recipients transplanted between 2003 and 2007 at a single center, with hypercoagulable states: prior venous thromboembolism, multiple vascular access thromboses, or identifiable thrombophilia. The predictor variable was preemptive anticoagulation and outcome variable was allograft thrombosis. Other risk factors for allograft thrombosis, characteristics of transplantation, and hemorrhagic complications were also examined. RESULTS: among this high-risk cohort (n = 48), 16 received preemptive anticoagulation and 32 did not. The anticoagulated group included significantly more subjects with identifiable thrombophilia (50.0% vs. 0%; p < 0.001). One subject (6.3%) in the anticoagulated group and 6 (18.8%) without anticoagulation developed allograft thrombosis (p = 0.40). A perinephric hematoma was observed in 5 (31.3%) and 2 (6.3%) with and without anticoagulation, respectively (p = 0.03). CONCLUSIONS: preemptive anticoagulation was associated with a non-significant trend towards decreased allograft thrombosis. It may be associated with increased risk of hemorrhage and should be considered cautiously in high-risk patients.

Removal of gadolinium by peritoneal dialysis.

An association between gadolinium-containing contrast and the development of nephrogenic systemic fibrosis (NSF) has been increasingly recognized. For patients receiving hemodialysis (HD) who are exposed to gadolinium, the Federal Drug Administration (FDA) recommends HD to remove this contrast agent in order to minimize the risk of NSF. This study examines if gadolinium can be removed by frequent exchanges by peritoneal dialysis (PD). Following administration of 0.1 mmol/kg of gadodiamide to a patient with end-stage renal disease, the serum clearance of this contrast agent by automated PD was examined. 10 and 15 exchanges of PD using an automated cycler were respectively performed during the first and second 24-hour periods after gadolinium exposure. Serum gadolinium levels were measured 1 hour after the gadolinium administration, then at 24 and 48 hours after PD was initiated. 90% of the gadolinium was removed from the circulation in 2 days with a regimen of 10-15 exchanges per day of PD. For patients on chronic maintenance PD who receive gadolinium, our case suggests that a temporary intensive automated PD regimen, aimed at maximizing clearance of this contrast agent immediately after exposure, could be an effective alternative when institution of HD is problematic.

Entire course and distinct phases of day-lasting depression of miniature EPSC amplitudes in cultured Purkinje neurons.

The cerebellar long-term depression (LTD) is the long-lasting reduction of transmission efficacy at the granule neuron-Purkinje neuron (G-P) synapses and is a candidate mechanism for the motor learning. Despite extensive studies on its induction and expression mechanisms, it has not been known how long the LTD lasts. The LTD is accompanied by the decrease in the postsynaptic responsiveness to glutamate, the transmitter at G-P synapses. Therefore, during the LTD, the amplitude of miniature EPSCs (mEPSCs) at G-P synapses should decrease. We studied the depression of mEPSC amplitudes (DME) as a possible contributing factor for the LTD and found that the conditioning treatment of cultured cerebellar neurons with 50 mM K(+) and 100 microM glutamate, an analogous condition used to induce the LTD, induced the long-lasting DME. The mEPSC amplitudes recovered to the original level 48 hr after the 5 min conditioning treatment. Changing the duration of the conditioning revealed that the DME consisted of two distinct phases: the early phase lasting for a few hours and the late phase for >1 d. The latter was distinguished from the former by its requirement of prolonged conditioning treatment and syntheses of mRNA and protein for the induction. There were critical periods for mRNA and protein syntheses. The critical period for protein synthesis was much longer than that for mRNA synthesis. These results demonstrate that the DME lasts for 1-2 d and that it consists of two phases, whose induction and maintenance mechanisms are distinct.

Characterization of neocortical non-pyramidal neurons expressing preprotachykinins A and B: a double immunofluorescence study in the rat.

Neurons expressing preprotachykinin A and preprotachykinin B, which are the precursor prepropeptides of substance P and neurokinin B (neuromedin K), respectively, were characterized immunocytochemically in the rat neocortex. Antibodies raised against C-terminal portions of preprotachykinins were used for labeling cell bodies of preprotachykinin-producing neurons. Neurons immunoreactive for preprotachykinin B were encountered four times more frequently in the neocortex than those immunoreactive for preprotachykinin A. Preprotachykinin A-immunoreactive neurons were scattered more frequently in the deep cortical layers (layers IV-VI) than in the superficial layers (layers I-III), whereas preprotachykinin B-immunoreactive neurons were distributed more frequently in the superficial layers than in the deep layers. Almost all preprotachykinin-expressing neurons were immunoreactive for GABA, suggesting that they were non-pyramidal cells. However, co-expression of the two preprotachykinin immunoreactivities in single neurons was not found. Preprotachykinin-expressing neocortical neurons were further examined with markers for subpopulations of GABAergic cortical neurons. Immunoreactivities for parvalbumin, calbindin and somatostatin were found in 69%, 27% and 11%, respectively, of preprotachykinin A-immunoreactive neurons. Conversely, preprotachykinin A-immunoreactive neurons constituted only 6% of parvalbumin-immunoreactive neurons, 4% of calbindin-immunoreactive neurons and 1% of somatostatin-immunoreactive neurons. Immunoreactivities for calretinin, choline acetyltransferase, vasoactive intestinal polypeptide, corticotropin-releasing factor and cholecystokinin were detected in 13-39% of preprotachykinin B-immunoreactive neurons. Preprotachykinin B immunoreactivity was seen in 33% of calretinin-positive neurons, 45% of cholinergic neurons, 47% of vasoactive intestinal polypeptide-positive neurons, 59% of corticotropin-releasing factor-positive neurons and 83% of cholecystokinin-positive neurons. These results indicate that preprotachykinin A- and preprotachykinin B-expressing neurons constitute separate populations of GABAergic non-pyramidal neurons in the neocortex. Since receptors for substance P and neurokinin B are expressed in GABAergic neurons [Kaneko T. et al. (1994) Neuroscience 60, 199-211] and pyramidal neurons [Ding Y. Q. et al. (1996) J. comp. Neurol. 364, 290-310], respectively, cortical neurons may use two separate lines of tachykinin signals; substance P serves as a signal between GABAergic non-pyramidal neurons, whereas neurokinin B acts as a signal of GABAergic neurons to pyramidal neurons.

Primary pulmonary non-Hodgkin's lymphoma in a Japanese renal transplant recipient.

Pulmonary non-Hodgkin's lymphoma (NHL) developed in a 31-year-old renal transplant recipient 3 years after transplantation. Chest roentgenogram showed rapidly progressive multiple nodules in both lungs. The pleural fluid obtained by needle aspiration contained many atypical cells with surface B cell antigen and abnormal karyotype. The patient died of pulmonary edema shortly after combination chemotherapy was begun without regression of the tumors. Autopsy revealed diffuse large cell NHL confined to both lungs. Immunological examination and DNA analysis of the tumor showed monoclonal B cell NHL.

Treatment of acute myeloid leukemia and myelodysplastic syndrome with orally administered cytarabine ocfosfate and granulocyte colony-stimulating factor.

Cytarabine ocfosfate (SPAC) was administered orally to 19 patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). SPAC was administered at doses of 200-300 mg/day for more than 14 days with granulocyte colony-stimulating factor (G-CSF). Four of the 12 patients with AML and 1 of the 7 patients with MDS achieved complete remission (CR) after one cycle of SPAC treatment. Especially, 3 of the 6 patients with newly diagnosed AML achieved CR. Major side effects of SPAC were myelosuppression and tolerable gastrointestinal disorders. The treatment with SPAC is a therapeutic option in elderly patients or patients with organ failure.

Periodontitis in the house musk shrew (Suncus murinus): a potential animal model for human periodontal disease.

BACKGROUND: Our understanding of periodontal diseases has been facilitated greatly by the use of animal models. However, no animal model has been identified that truly reflects the disease seen in humans. Suncus murinus, a rat-sized laboratory house musk shrew, has received attention as a valuable animal model due to ease of handling. In the studies described here, periodontal conditions in Suncus murinus were evaluated to determine the usefulness of the shrew as an experimental model for understanding various aspects of periodontal diseases. METHODS: Periodontal tissues of 34 Suncus murinus (18 to 430 days old) were examined macroscopically, morphometrically, histologically, and ultrastructurally. RESULTS: Dentition pattern is I3/1, C1/1, P2/1, M3/3. Spontaneous gingival swelling with accumulation of plaque was observed in more than two-thirds of animals older than 200 days. Morphometric analysis of alveolar bone demonstrated a pattern of bone loss that correlated closely with animal age. Histologically, periodontal lesions varying from gingivitis to periodontitis, similar to those observed in humans, were noted. Marked infiltration of lymphocytes and plasma cells in the connective tissue was noted, usually not seen in periodontal lesions of rodents. Although osteoclastic alveolar bone resorption was noted, active bone resorption was not a frequent feature in specimens obtained from chronic inflammatory lesions. Ultrastructurally, degradation of collagen fibers in the inflamed area and ingestion of collagen fibrils by fibroblasts in the deeper connective tissue were often seen. CONCLUSIONS: These results indicate the potential utility of Suncus murinus as a model to study periodontal disease; e.g., chronic nature of the inflammatory periodontal lesions, similar to those in humans, as well as other advantages including size and ease of handling and housing of these animals.

[Chemotherapy of aggressive non-Hodgkin's lymphomas: a retrospective analysis of a single institution].

In order to assess the curability of diffuse non-Hodgkin's lymphoma, a total of 93 patients who had entered into protocol studies in our institution was analysed retrospectively. Between 1977 and 1988, 53 large cell lymphoma (DL), 16 mixed cell lymphoma (DMx), and 24 medium-sized cell lymphoma (DM) patients with advanced disease were treated with CHOP, CHOP-Bleo, or CHOP-Bleo alternating with POEM-Bleo (5-drug combination of mitoxantrone, etoposide, vincristine, bleomycin, and prednisolone). The complete response rate was 70% for DL, 69% for DMx, and 54% for DM. The response was most durable in DL, compared with DMx and DM: the relapse-free survival rate at 5-year was 71% for DL, both 38% for DMx and DM. Almost all the relapses had occurred within 2 years in DL, DMx and DM, as well, thus responding patients over 2 years after cessation of chemotherapy appeared to have been cured. Relapse-free survival rate was almost the same for T- and B-lymphoma, however, the 5-year survival rate of T-lymphoma was lower than that of B-lymphoma, reflecting the poor complete response rate of the former. Finally, the disease-free survival rate at 5-year was 39% for all the 93 patients, with a trend favoring for DL histology with a rate of 51%. The alternating CHOP-Bleo/POEM-Bleo regimen appears beneficial compared with conventional regimens such as CHOP and CHOP-Bleo on the basis of response rate and response durability, and these results warrant further clinical trials.

[Current status of chemotherapy in the treatment of malignant lymphomas].

Chemotherapy of malignant lymphomas has accomplished a significant progress during the two decades. Cure can be expected in a significant proportion of patients, even those with advanced disease. The major obstacle for cure is selection and overgrowth of a drug-resistant tumor cell population. For this reason, a number of investigators have tested the efficacy of intensive chemotherapy including non-cross-resistant alternating regimens and hybrid regimens. Today, with intensive combination chemotherapy, at least 60% of patients with advanced Hodgkin's disease and 50% of those with diffuse large cell lymphoma can be curable. The authors update the review of the chemotherapy for malignant lymphomas, and also report outcomes of chemotherapy in our own patients.

[Salvage chemotherapy of non-Hodgkin's lymphoma with a four-drug combination of mitoxantrone, etoposide, cisplatin and prednisolone (MEPP)].

Twenty-two patients with non-Hodgkin's lymphoma were treated with a four-drug combination of mitoxantrone, etoposide, cisplatin and prednisolone (MEPP) after their disease had failed to respond to, or had relapsed after, induction chemotherapy consisting of cyclophosphamide, adriamycin, vincristine and prednisolone with/without bleomycin (CHOP/CHOP-bleo). Of 18 evaluable patients, four (22%) achieved complete remission and six (33%) responded partially. The median duration of response was 29 weeks (range, 9 to 54 weeks). The median survival time was 45 weeks for responders and 22 weeks for non-responders. Gastrointestinal toxicity was common, but well tolerated. Myelosuppression was the major dose-limiting toxicity: 11 patients (61%) experienced a febrile episode during periods of neutropenia and two patients, both of whom had massive bone marrow involvement of the disease, succumbed to infection. Despite the moderate to severe myelotoxicity, these results provide evidence that MEPP is an effective regimen for non-Hodgkin's lymphoma resistant to CHOP or CHOP-bleo.

[Combination chemotherapy of diffuse large-cell non-Hodgkin's lymphoma--superiority of the adriamycin combination].

In patients with diffuse large-cell non-Hodgkin's lymphoma, the results of combination chemotherapy containing adriamycin (ADM) were compared with those of combination chemotherapy without ADM. None of the patients had had any prior therapy and there was no difference in any other background factors for these two treatment groups. Of 32 patients treated without ADM, 19 (59%) achieved complete response (CR) and 12 (38%) achieved partial response (PR). Of 20 patients treated with ADM. 14 (70%) achieved CR and 6 (30%) achieved PR. For patients treated without ADM, median duration of CR was 9 months, projected 5-year relapse-free rate was 27%, median survival time was 1 year 6 months and projected 5-year survival rate was 27%. For patients treated with ADM, median duration of CR was not reached, projected 5-year relapse-free rate was 85%, median survival time was 2 years 2 months and projected 5-year survival rate was 49%. Combination of ADM was superior and therefore should be used for the initial treatment of this type of non-Hodgkin's lymphoma.

Change in the pattern of adrenal venous sampling over time in patients with primary aldosteronism.

We report six patients with primary aldosteronism who had serial adrenal venous sampling. Patients with contralateral suppression of aldosterone to cortisol ratio compared with that in inferior vena cava developed lateralization over time whereas patients without contralateral suppression remained with a bilateral pattern.

[A case of slowly progressing interstitial pneumonia associated with idiopathic thrombocytopenic purpura].

A 72-year-old man had been taking 10 mg/day of prednisone since idiopathic thrombocytopenic purpura (ITP) was diagnosed when he was 60 years old. An interstitial lung shadow was observed on chest X-ray films when he was about 62 years old, and interstitial pneumonia (IP) (chronic-type), etiology unknown was diagnosed. With the progression of honey-comb shadows on the dorsal side of the lower lung fields, cystic changes on the anterior side of the upper lung fields also became more obvious. Slowly progressing IP associated with ITP is very rare. In addition, the chest CT findings of cystic changes on the dorsal side in the lower lung fields and on the anterior side in the upper lung fields are quite interesting.

Salvage chemotherapy for non-Hodgkin's lymphoma with a combination of mitoxantrone, etoposide, cisplatin, and prednisolone.

We tested the combination of mitoxantrone, etoposide, cisplatin, and prednisolone as salvage treatment for patients with advanced aggressive non-Hodgkin's lymphoma. Among 18 evaluable patients, four complete and seven partial responses were observed, for an overall response rate of 61%. The median duration of response was 36 weeks (range, 11-58). The median survival time from the beginning of the regimen was 52 weeks for responders and 24 weeks for nonresponders. Myelosuppression was the major dose-limiting toxic effect; however, it was generally well-tolerated. These results indicate that the combination regimen can play a role in the treatment of relapsed or resistant non-Hodgkin's lymphoma.

[Mitoxantrone in the treatment of relapsed and refractory malignant lymphoma].

Mitoxantrone is an anthracenedione with structural similarities to adriamycin but without the amino-sugar moiety on the parent molecule. The compound attracted attention on the basis of animal tumor studies in which it showed equal or superior efficacy compared to adriamycin, but with diminished cardiotoxicity; and it was not fully cross-resistant to adriamycin. Our in vitro studies using human small cell lung cancer cell line (SBC-3) disclosed the absence of cross-resistance between mitoxantrone and adriamycin: SBC-3/ADM, which had developed resistance by continuous exposure to increasing concentration of adriamycin, was as equally sensitive to mitoxantrone as SBC-3 was when tested by clonogenic assay. A phase II study conducted in our Department revealed that mitoxantrone was active to malignant lymphoma refractory to conventional agents including adriamycin: 6 (33%) of 18 patients responded to the agent. Based on the results of our phase II studies of mitoxantrone, etoposide, and cisplatin in malignant lymphoma, we have conducted a phase III study of a 4-drug combination of these 3 drugs plus prednisolone in relapsed or refractory lymphoma: Out of 14 patients, 3 responded completely and 4 did partially, so far. The regimen would appear useful as a salvage therapy for refractory lymphoma.