Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) has various extra-pancreatic actions, in addition to its enhancement of insulin secretion from pancreatic beta cells. The GLP-1 receptor is produced in kidney tissue. However, the direct effect of GLP-1 on diabetic nephropathy remains unclear. Here we demonstrate that a GLP-1 receptor agonist, exendin-4, exerts renoprotective effects through its anti-inflammatory action via the GLP-1 receptor without lowering blood glucose. METHODS: We administered exendin-4 at 10 µg/kg body weight daily for 8 weeks to a streptozotocin-induced rat model of type 1 diabetes and evaluated their urinary albumin excretion, metabolic data, histology and morphometry. We also examined the direct effects of exendin-4 on glomerular endothelial cells and macrophages in vitro. RESULTS: Exendin-4 ameliorated albuminuria, glomerular hyperfiltration, glomerular hypertrophy and mesangial matrix expansion in the diabetic rats without changing blood pressure or body weight. Exendin-4 also prevented macrophage infiltration, and decreased protein levels of intercellular adhesion molecule-1 (ICAM-1) and type IV collagen, as well as decreasing oxidative stress and nuclear factor-κB activation in kidney tissue. In addition, we found that the GLP-1 receptor was produced on monocytes/macrophages and glomerular endothelial cells. We demonstrated that in vitro exendin-4 acted directly on the GLP-1 receptor, and attenuated release of pro-inflammatory cytokines from macrophages and ICAM-1 production on glomerular endothelial cells. CONCLUSIONS/INTERPRETATION: These results indicate that GLP-1 receptor agonists may prevent disease progression in the early stage of diabetic nephropathy through direct effects on the GLP-1 receptor in kidney tissue.

Morphological approach for the functional improvement of an artificial myocardial assist device using shape memory alloy fibres.

The authors have been developing a mechano-electric artificial myocardial assist system (artificial myocardium) which is capable of supporting natural contractile functions from the outside of the ventricle without blood contacting surface. In this study, a nano-tech covalent type shape memory alloy fibre (Biometal, Toki Corp, Japan) was employed and the parallel-link structured myocardial assist device was developed. And basic characteristics of the system were examined in a mechanical circulatory system as well as in animal experiments using goats. The contractile functions were evaluated with the mock circulatory system that simulated systemic circulation with a silicone left ventricular model and an aortic afterload. Hemodynamic performance was also examined in goats. Prior to the measurement, the artificial myocardial assist device was installed into the goat's thoracic cavity and attached onto the ventricular wall. As a result, the system could be installed successfully without severe complications related to the heating, and the aortic flow rate was increased by 15% and the systolic left ventricular pressure was elevated by 7% under the cardiac output condition of 3L/min in a goat. And those values were elevated by the improvement of the design which was capable of the natural morphological myocardial tissue streamlines. Therefore it was indicated that the effective assistance might be achieved by the contraction by the newly-designed artificial myocardial assist system using Biometal. Moreover it was suggested that the assistance gain might be obtained by the optimised configuration design along with the natural anatomical myocardial stream line.

Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats.

AIMS/HYPOTHESIS: Recent studies have shown that the inflammatory process is involved in the pathogenesis of diabetic nephropathy. Fourteen-membered ring macrolides, including erythromycin, have anti-inflammatory, as well as antibacterial effects. The aim of this study was to investigate the renoprotective effects of erythromycin in streptozotocin (STZ)-induced diabetic rats. METHODS: STZ-induced diabetic rats were treated orally with erythromycin (5 mg/kg body weight) or vehicle every day for 8 weeks. To evaluate the effect of erythromycin treatment, we measured urinary albumin excretion, and examined the following in the kidney: histological changes, the expression of intercellular adhesion molecule-1 (ICAM-1), macrophage infiltration, and nuclear factor-kappa B (NF-kappaB) activity. RESULTS: Erythromycin significantly reduced urinary albumin excretion without affecting blood glucose levels and blood pressure. Erythromycin also attenuated glomerular hypertrophy, mesangial expansion, macrophage infiltration and ICAM-1 expression in renal tissues. The expression of the gene encoding TGFB1 (also known as TGF-beta1), type IV collagen protein production and NF-kappaB activity in renal tissues were increased in diabetic rats and reduced by erythromycin treatment. CONCLUSIONS/INTERPRETATION: Erythromycin prevented renal injuries without changes of blood glucose levels and blood pressure in experimental diabetic rats. These results suggest that the renoprotective effects of erythromycin are based on its anti-inflammatory effect via suppression of NF-kappaB activation. Modulation of microinflammation with erythromycin may provide a new approach for diabetic nephropathy.

Detection and avoiding ventricular suction of ventricular assist devices.

Continuous flow blood pumps, such as axial flow and centrifugal pumps, have been gaining interest as circulatory devices for total artificial hearts (TAHs) and a biventricular assist device (BVAD) because of their smaller size and simpler structure compared to pulsatile pumps. However, continuous flow pumps are more prone to suction of the left ventricle than pulsatile pumps are. Sudden increases in flow rate to meet changes in physiological demand, especially in the left pump, often cause ventricle suction. In this study, a control algorithm to prevent suction from occurring in the left ventricle by controlling the rotational speed of the right pump, instead of reducing the cardiac output of the left pump, was developed and investigated. The method was tested in acute animal experiments with calves. The results indicate that this proposed method is capable of preventing suction and could simultaneously maintain circulatory control. A key advantage of this control system is that flow rates can be maximized while avoiding ventricle suction conditions particularly when the circulatory system is unstable such as in a the first few days after operation.

Development of an Artificial Myocardium using a Covalent Shape-memory Alloy Fiber and its Cardiovascular Diagnostic Response.

The authors have been developing a newly-designed totally-implantable artificial myocardium using a covalent shape-memory alloy fibre (Biometal®, Toki Corporation), which is attached onto the ventricular wall and is also capable of supporting the natural ventricular contraction. This mechanical system consists of a contraction assistive device, which is made of Ti-Ni alloy. And the phenomenon of the martensitic transformation of the alloy was employed to achieve the physiologic motion of the device. The diameter of the alloy wire could be selected from 45 to 250μm. In this study, the basic characteristics of the fiber of 150μm was examined to design the sophisticated mechano-electric myocardium. The stress generated by the fiber was 400gf under the pulsatile driving condition (0.4W, 1Hz). Therefore it was indicated that the effective assistance might be achieved by using the Biometal shape-memory alloy fiber.

Dynamic response of the pulmonary circulation in continuous flow artificial heart systems.

Pulmonary circulation dynamics is important when considering bi-ventricular assist devices (BiVAD) or total artificial heart (TAH) systems and in investigating the mechanism of atrial collapse in order to design better control algorithms. In this study, we investigated pulmonary circulation dynamics in a continuous flow artificial heart system by performing acute tests on a mature goat. By varying the right pump speed, we were able to observe the dynamic response of the left atrial pressure (LAP) and simulate conditions that result in atrial suction. The results showed a time constant characteristic of a compliance lag in LAP response to changes in right pump output in the TAH configuration. These results may prove useful in the design of a new mock circulatory system that incorporates the dynamics of the pulmonary circulation, and in the improvement of existing control algorithms that prevent atrial wall collapse.

Preventive effect of sulphated colominic acid on P-selectin-dependent infiltration of macrophages in experimentally induced crescentic glomerulonephritis.

Leucocytes infiltrate into renal tissue and are involved in the pathogenesis of crescentic glomerulonephritis. The initial event in the process of leucocyte infiltration is characterized by selectin-mediated leucocyte rolling on endothelial surface. Role of selectins in pathogenesis of glomerulonephritis has still been controversial. Sulphated glycolipids and sulphated polysaccharides interfere with the binding of P- and L-selectin with carbohydrate ligands on endothelial cells or on leucocytes. Here we evaluated the role of selectins and the preventive effects of sulphated colominic acid (SCA), a synthetic sulphated polysaccharide, on experimental crescentic glomerulonephritis in Wistar-Kyoto (WKY) rats. Crescentic glomerulonephritis was induced by injection of nephrotoxic serum (NTS) in WKY rats. Rats subsequently received intraperitoneal injection of saline, neutralizing or non-neutralizing monoclonal antibody (mAb) to rat P-selectin and L-selectin, SCA (5 or 10mg/kg/day) or nonsulphated colominic acid (CA) (10mg/kg/day) for 2 weeks. Localization of P-, E-selectin, ligands for L-selectin and intraglomerular leucocytes was examined by immunohistochemistry. Gene expression of platelet-derived growth factor (PDGF) B chain in glomeruli was quantified using real-time RT-PCR. P-selectin was highly expressed on glomerular endothelial cells after injection of NTS, whereas E-selectin and L-selectin ligands were not detected. Anti-P-selectin mAb, but not anti-L-selectin mAb, significantly reduced glomerular infiltration of macrophages, crescent formation, and proteinuria. SCA also reduced proteinuria, macrophage infiltration, and crescent formation in a dose-dependent manner. Furthermore, SCA suppressed gene expression of PDGF B chain in glomeruli. Our results indicate that P-selectin partially mediates glomerular infiltration of macrophage in experimental crescentic glomerulonephritis. Moreover, SCA may inhibit intraglomerular infiltration of macrophages by interfering with P-selectin-dependent adhesion pathway, and progression of experimental crescentic glomerulonephritis.

Intraoperative superficial femoral artery balloon angioplasty and popliteal to distal bypass graft: an option for combined open and endovascular treatment of diabetic gangrene.

PURPOSE: The purpose of this study was to evaluate the results of combining intraoperative balloon angioplasty (IBA) of the superficial femoral artery (SFA) with distal bypass graft originating from the popliteal artery as a method of lower extremity revascularization in diabetic patients with gangrene. METHODS: Among 380 infrainguinal bypass grafts performed over a 6-year period, there were 110 reversed saphenous vein bypass grafts to the tibial or pedal arteries to treat diabetic patients with gangrene. Diffuse infrainguinal disease was treated with femoral-distal bypass graft (long; n = 46). Popliteal-distal bypass graft was performed when the inflow femoral artery was not significantly diseased (short; n = 52). Focal SFA stenosis and severe infrageniculate disease were treated with combined IBA of the SFA and distal bypass graft originating from the popliteal artery (combined; n = 12). Follow-up was performed with duplex scan surveillance of both the bypass graft and IBA sites. Treatment groups were compared with life-table analysis. RESULTS: There were no perioperative graft failures or amputations. The perioperative mortality rate was 1% (1 of 110). The 2-year primary patency rates were similar in the three groups: 72% in the long bypass graft group, 82% in the short bypass graft group, and 76% in the combined group (P =.8, log-rank test). SFA IBA sites developed recurrent stenosis in two patients, at 7 and 48 months; both were detected with surveillance and treated with percutaneous transluminal balloon angioplasty. The overall 5-year rate of primary patency was 63%, secondary patency was 78%, limb salvage was 81%, and survival was 35%. There were no significant differences among the three treatment groups with respect to these outcomes. CONCLUSION: Results with the combined procedure were similar to those achieved with either femoral-distal bypass graft or popliteal-distal bypass graft without SFA IBA. These data suggest that IBA of the inflow SFA may be combined with popliteal to distal bypass graft and that this technique is a reasonable alternative to longer, femoral-origin bypass graft in selected diabetic patients with gangrene.

Posture-related changes in the pressure environment of the ventriculoperitoneal shunt system.

OBJECT: The purpose of this study is to clarify the whole pressure environment of the ventriculoperitoneal (VP) shunt system in patients with successfully treated hydrocephalus and to determine which factor of the pressure environment has a preventive effect on overdrainage. METHODS: Thirteen patients with hydrocephalus who had been treated with VP shunt therapy by using a Codman-Hakim programmable valve without incidence of overdrainage were examined. The authors evaluated intracranial pressure (ICP), intraabdominal pressure (IAP), hydrostatic pressure (HP), and the perfusion pressure (PP) of the shunt system with the patients both supine and sitting. With patients supine, ICP, IAP, and HP were 4.6 +/- 3 mm Hg, 5.7 +/- 3.3 mm Hg, and 3.3 +/- 1 mm Hg, respectively. As a result, the PP was only 2.2 +/- 4.9 mm Hg. When the patients sat up, the IAP increased to 14.7 +/- 4.8 mm Hg, and ICP decreased to-- 14.2 +/- 4.5 mm Hg. The increased IAP and decreased ICP offset 67% of the HP (42.9 +/- 3.5 mm Hg), and consequently the PP (14 +/- 6.3 mm Hg) corresponded to only 33% of HP. CONCLUSIONS: The results observed in patients indicated that IAP as well as ICP play an important role in VP shunt therapy and that the increased IAP and the decreased ICP in patients placed in the upright position allow them to adapt to the siphoning effect and for overdrainage thereby to be avoided.

Isolated dilation of the trigono-inferior horn--four case reports.

Four patients presented with isolated dilation of the trigono-inferior horn associated with either mass lesion at the trigone of the lateral ventricle or with shunt over-drainage. We investigated clinical symptoms, course, and neuroradiological findings of these cases. The pressure of the isolated ventricle was measured or estimated at surgery in all cases. The common symptoms were recent memory disturbance and contralateral homonymous hemianopia. Contralateral hemiparesis was observed occasionally. Rapid deterioration of the isolation caused uncal herniation in one case. Comma-shaped dilation of the inferior horn was observed in all cases. Midline shift was not conspicuous except in one case. Intraventricular pressure at surgery was 18 cmH2O, 35 cmH2O, 3 cmH2O, and within normal range. These cases had very similar clinical symptoms and neuroradiological findings. The pathophysiology of isolation suggested three types of isolation (high-, normal-, and low-pressure isolation), depending on the pressure of the isolated ventricle. The isolation of trigono-inferior horn is an important clinical entity as it may cause uncal herniation in patients with high-pressure lesions.

Pseudomalabsorption of levothyroxine: a case report.

A 51-year-old woman who had been treated with levothyroxine sodium because of hypothyroidism after total thyroidectomy for thyroidal cancer was admitted to our hospital for persistent hypothyroidism despite large dose administration of levothyroxine (600 microg/day). The patient complained of severe general fatigue and body weight gain. Free thyroxine, free triiodothyronine and thyrotropin levels were 0.97 ng/dl, 1.55 pg/ml and 24.51 microU/ml, respectively, under oral administration of levothyroxine. Levothyroxine loading test performed by liquid form, pulverized tablets via nasogastric tube and intravenous administration revealed no evidence of malabsorption or metabolic disorder of levothyroxine, although oral intake of tablets was ineffective due to her factitiousness. We report here a possible case of "pseudomalabsorption of levothyroxine" to emphasize the clinical recognition of this disorder in patients with resistant hypothyroidism.

Cytotoxic mechanisms of inhibitor of RNA synthesis, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106).

We investigated the molecular mechanisms of cell death induced by 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106: Figure 1), a potent inhibitor of RNA synthesis, using mouse mammary tumor FM3A cells and human fibrosarcoma HT1080 cells. ECyd induced the characteristics of apoptosis on these cells, such as morphological changes, DNA fragmentations and caspase-3-like protease activation. General caspases inhibitor (Z-Asp-CH2-DCB) inhibited cell death. Interestingly, we also found that ECyd induced rRNA fragmentation with the size of 3.2, 2.8 and 1.5 kb, and which might be caused by inhibition of RNA synthesis. rRNA fragmentation was mainly occurred in D8 domain of 28 S rRNA, and the end of 5'-terminal sequence of 1.5 kb fragment was C3220pC3221p or C3221pG3222p, that was identical to the recognition sequence of RNase L. Furthermore, the fragmentation patterns of rRNA digested with RNase L resembled that of ECyd treated cells in shape. These results indicate that antitumor mechanisms of ECyd are involved in activation of RNase L. rRNA fragmentation may be one of the death events as a result of inhibition of RNA synthesis and play an important role in the antitumor activity of ECyd.

Lung cancer associated with pulmonary bulla. case report and review of literature.

A few reports have suggested the possible association between lung cancer and bullous disease. We report a surgical case of lung adenocarcinoma located in close proximity to pulmonary bullae. A 48-year-old nonsmoker, asymptomatic male was found to have a pulmonary tumor mass and giant bulla in the right lung. Thoracotomy identified a tumor arising from a firm, scarred and contracted area close to the bulla wall. Based on this report and review of other cases in the literature, we emphasize the need for physicians to be aware of the potential development of lung cancer in patients with pulmonary bulla.

Integrins mediate the inhibitory effect of focal adhesion on angiotensin II-induced p44/42 mitogen-activated protein (MAP) kinase activity in human mesangial cells.

Previously, we reported that the formation of focal adhesion accelerated by accumulation of extracellular matrices may inhibit the angiotensin II-stimulated proliferation of human mesangial cells (HMCs). The process is regulated by p44/42 MAP kinase activity through the mediation of paxillin and GTPase activating proteins. In this report, we investigated the effect of integrin molecules on the angiotensin II-induced p44/42 MAP kinase activation in non-adherent HMCs. The results demonstrated that incubation of cells with both antibody to integrin beta(1) chain (K20) and GRGDS peptide induced integrin clustering, paxillin aggregation, and marked suppression of angiotensin II-induced p44/42 MAP kinase activation. On the other hand, incubation of cells with K20 alone induced integrin clustering without paxillin aggregation and the suppressive effect on angiotensin II-stimulated p44/42 MAP kinase activity. Our results strongly suggest the pivotal role of integrins in the inhibitory effect of focal adhesion on p44/42 MAP kinase activity, the checking system against angiotensin II-induced MAP kinase overactivation.

A clinical survey of hydrocephalus and current treatment for hydrocephalus in Japan: analysis by nationwide questionnaire.

We analyzed current treatment for hydrocephalus in Japan by means of a nationwide questionnaire. Ventriculoperitoneal (VP) shunting was the most common form of cerebrospinal fluid (CSF) shunting, and in 66% of cases the ventricular catheter was inserted via the anterior horn. Various types of flow-control valves were used in 46% of CSF shunting procedures, and the proportion of cases in which such valves are used seems to be increasing. The Codman-Hakim valve was used most frequently, followed by the Sophy valve. The initial pressure setting of programmable pressure valves was selected in 82% of institutes on the basis of the CSF pressure obtained during the shunt operation. Most flow-control valves were implanted in the retroauricular region; however, Sophy valves were implanted in the chest wall in a high percentage of cases. The rate of shunt complications was significantly lower among VP shunt cases with flow-control valves than in those without flow-control valves. The most common cause of shunt complications was trouble with the abdominal catheter. These results will contribute to progress in the treatment for hydrocephalus.

Lower extremity revascularization without contrast arteriography: a prospective study of operation based upon duplex mapping.

This study prospectively assessed the results of lower extremity surgical revascularization, which was performed on the basis of duplex arterial mapping in selected patients without preoperative contrast arteriography. Criteria were developed for patient selection. Among 158 patients requiring surgery for lower extremity ischemia over a 24-month period, 24 (15%) were selected for operation without current preoperative arteriography. Aorto-iliac and infrainguinal duplex arterial mapping were performed in an laboratory that was accredited by the Intersocietal Commission for Accreditation of Vascular Laboratories. Indications for surgery were minor gangrene (11), rest pain (7), or claudication (6). Operations included femoropopliteal bypass (14), femoral endarterectomy (9) and femoral-femoral bypass (1). Mean length of stay was 4.5 +/- 2.0 days. Ankle-brachial index improved from 0.49 +/- 0.12 to 0.80 +/- 0.15 (P < 0.05). Primary patency was 91.7 +/- 9.4% and assisted primary patency was 100% at 18 months. There was no graft occlusion or limb loss. Mean follow-up was 16.7 +/- 7.0 months. These preliminary data support the safety and durability of duplex-guided lower extremity surgical revascularization without arteriography in selected cases. Success in a broader application of this approach requires the continuing development of patient selection criteria.

Is routine preoperative aortoiliac arteriography necessary in the treatment of lower extremity ischemia?

PURPOSE: To determine whether preoperative aortoiliac arteriography can be replaced with noninvasive evaluation in the management of some patients with chronic lower extremity ischemia. METHODS: Preoperative evaluation was performed on 184 ischemic limbs (119 patients) over 19 months by means of aortoiliac arteriography with runoff and noninvasive studies, which included common femoral artery duplex scanning, waveform and acceleration time (normal <140 msec), and aortoiliac duplex scanning. An algorithm was proposed for combining indirect (common femoral artery evaluation) and direct (aortoiliac evaluation) noninvasive studies to decrease the need for aortoiliac arteriography when possible. RESULTS: Aortoiliac occlusive disease (> or =50% stenosis to occlusion) was present at arteriography in 48 limbs (30%), and there was no inflow disease in 114 (70%). Aortoiliac lesions were identified by means of noninvasive studies. The accuracies of femoral waveform, acceleration time, and aortoiliac duplex studies were 85%, 89% and 87%. The negative predictive values were 92%, 94% and 100%. The acceleration time results were not affected by runoff status but were significantly different for various categories of stenosis (p < 0.05). The algorithm was applied to the data obtained. When acceleration time and waveform were normal, 84 of 86 patients (98%) had no stenosis at arteriography. When aortoiliac duplex findings were normal, the arteriographic findings were normal in all examinations. CONCLUSION: A combination of indirect and direct noninvasive studies can be used reliably to rule out clinically significant inflow occlusive disease and allows selective use of aortoiliac arteriography in patients with lower extremity ischemia.

Stent-graft repair of mycotic superficial femoral artery aneurysm using a Palmaz stent and autologous saphenous vein.

Developing endoluminal technology has permitted the management of selected aneurysms using stent-grafts, but the applicability and durability of these new devices has not yet been proven. Standard treatment of mycotic aneurysms generally requires arterial ligation, excision and debridement, and autologous or extraanatomic synthetic bypass. A saphenous vein-covered stent was used to exclude an expanding, mycotic, superficial femoral artery aneurysm in a critically ill patient. Although stent-graft exclusion was intended as a bridge to standard therapy, the mass resolved, the superficial femoral artery remains patent, and the patient is symptom-free at 1 year without further intervention. Additional experience is required to determine whether stent-grafts have a role in the management of mycotic aneurysms.