Preliminary study: Measurement of ion beam energy spreads produced by a Penning ionization gauge-type ion source using electromagnets for a mega-electron volt compact ion microbeam system.

The energy spreads of ion beams generated from a penning ionization gauge-type ion source with electromagnets were measured using a parallel electrostatic analyzer. The ion source was developed to be installed in a mega-electron volt (MeV) compact ion microbeam system. A gaseous ion beam of expectedly high brightness and narrow energy spread was generated from the ion source to form a microbeam. To produce such an ion beam, a high-density plasma with a small volume was generated using a strong magnetic field in the ion source. The beam energy spread width was of particular importance because it forms an ion microbeam by reducing the chromatic aberration at a focusing lens. In this report, the energy spread was investigated by changing the parameters of the ion source, e.g., extraction voltage, excitation current of electromagnets, vacuum, and anode voltage. The investigation showed that spread widths are influenced by the extraction voltage, vacuum, and anode voltage. The minimum width of ∼5.0 ± 0.1 eV was obtained at a beam energy of 200 eV. This value is acceptable for the MeV compact ion microbeam system.

Investigation of the time interval of plasma generation for a high repetition rate laser ion source.

To apply a laser ion source that generates a high-intensity pulsed beam to high-dose applications, such as ion implantation, a high repetition rate operation with a short pulse interval is required. However, when the pulse interval is shortened, there is a concern that a plasma, which is different from a single pulse plasma generation, may be formed due to the interaction between the preceding and following pulses. We investigated the time interval in which plasma pulses are generated without pulse-to-pulse interaction using a laser ion source with two lasers. In the experiment, a graphite target was irradiated by two laser beams (1064-nm wavelengths) with the same pulse widths (5.4 ns) and energies (15 mJ, 30 mJ, and 45 mJ) at different time intervals ranging from 1000 µs to 0 µs, and the time integrated value corresponding to the total charge amount was calculated from the measured time-of-flight signal of the generated carbon ion current. It was observed that the total charge did not change when the time interval was as low as approximately 100 µs, and the total charge rapidly decreased when the time interval was below approximately 100 µs. Thus, it was determined that the interaction occurs within a time interval of approximately 100 µs.

Low-charge-state ion production by a laser ion source for the TIARA ion implanter.

Ion implanters require various kinds of heavy-ion beams in low-charge states for material science experiments. For this purpose, a laser ion source has been developed for the ion implanter at Takasaki Ion Accelerators for Advanced Radiation Application. In this study, we investigated the particle number of ions per laser pulse for each charge state in the laser-produced carbon plasma. In the experiment, the carbon plasma was generated from a graphite target using a Nd:YAG laser (1064 nm wavelength, 5 ns pulse width) at a laser energy of 37.5 mJ, 28.3 mJ, or 15.6 mJ. The particle number of ions in the plasma was evaluated from the time-integrated value of each ion-charge-state's current signal by placing the focusing lens at various positions. We found that the particle number of carbon ions was the highest for singly charged ions at all laser energies, with particle number in the order of 1010 ions obtained at a 1-m distance from the target surface.

A unique phenotype of acquired Glanzmann thrombasthenia due to non-function-blocking anti-αIIbß3 autoantibodies.

Essentials Acquired Glanzmann thrombasthenia (aGT) is generally caused by function-blocking antibodies (Abs). We demonstrated a unique aGT case due to marked reduction of αIIbß3 with anti-αIIbß3 Abs. The anti-αIIbß3 Abs of the patient did not inhibit platelet function but reduced surface αIIbß3. Internalization of αIIbß3 induced by the Abs binding may be responsible for the phenotype. SUMMARY: Background Acquired Glanzmann thrombasthenia (aGT) is a bleeding disorder generally caused by function-blocking anti-αIIbß3 autoantibodies. Aim We characterize an unusual case of aGT caused by marked reduction of surface αIIbß3 with non-function-blocking anti-αIIbß3 antibodies (Abs). Methods A 72-year-old male suffering from immune thrombocytopenia since his 50s showed exacerbation of bleeding symptom despite mild thrombocytopenia. Platelet aggregation was absent with all agonists but ristocetin. Analysis of αIIbß3 expression and genetic analysis were performed. We also analyzed effects of anti-αIIbß3 Abs of the patient on platelet function and αIIbß3 expression. Results Surface αIIbß3 expression was markedly reduced to around 5% of normal, whereas his platelets contained αIIbß3 to the amount of 40-50% of normal. A substantial amount of fibrinogen was also detected in his platelets. There were no abnormalities in ITGA2B and ITGB3 cDNA. These results indicated that reduced surface αIIbß3 expression caused a GT phenotype, and active internalization of αIIbß3 was suggested. Anti-αIIbß3 IgG Abs were detected in platelet eluate and plasma. These Abs did not inhibit PAC-1 binding, indicating that the Abs were non-function-blocking. Surface αIIbß3 expression of a megakaryocytic cell line and cultured megakaryocytes tended to be impaired by incubation with the patient's Abs. After 2 years of aGT diagnosis, his bleeding symptom improved and surface αIIbß3 expression was recovered to 20% of normal with reduction of anti-αIIbß3 Abs. Conclusion We demonstrated a unique aGT phenotype due to marked reduction of surface αIIbß3. Internalization induced by anti-αIIbß3 Abs may be responsible in part for the phenotype.

A protonic biotransducer controlling mitochondrial ATP synthesis.

In nature, protons (H+) play an important role in biological activities such as in mitochondrial ATP synthesis, which is driven by a H+ gradient across the inner membrane, or in the activation of acid sensing ion channels in neuron cells. Bioprotonic devices directly interface with the H+ concentration (pH) to facilitate engineered interactions with these biochemical processes. Here we develop a H+ biotransducer that changes the pH in a mitochondrial matrix by controlling the flow of H+ between a conductive polymer of sulfonated polyaniline and solution. We have successfully modulated the rate of ATP synthesis in mitochondria by altering the solution pH. Our H+ biotransducer provides a new way to monitor and modulate pH dependent biological functions at the interface between the electronic devices and biological materials.

A novel triple secured technique for pancreatic reconstruction following pancreaticoduodenectomy for a soft pancreas.

BACKGROUND/AIMS: Soft pancreases are susceptible to developing pancreatic fistula following pancreaticoduodenectomy. To reduce the incidence of pancreatic fistula after pancreaticoduodenectomy in patients with a soft pancreas, we developed a triple secured technique. In this study, we describe the details of this technique and also report on the postoperative outcomes. METHODOLOGY: The triple secured technique employed an ultrasonic dissector for pancreatic transection with skeletonizing and ligating of the small pancreatic branch ducts, duct-invagination or duct-to-mucosa anastomosis for main pancreatic duct management, and, finally, four large stitches between the pancreatic stump parenchyma and the jejunal seromuscular layer to prevent minor pancreatic leakage. A total of 28 consecutive patients with a soft pancreas who underwent pancreaticoduodenectomy using our technique were included in this study. RESULTS: Postopetrative complications occurred in 16 patients. Grade B pancreatic fistula developed in 6 patients. However, no grade C pancreatic fistula occurred in this series. Neither any reoperation nor in-hospital mortality was observed in this series. CONCLUSIONS: Our triple secured technique after pancreaticoduodenectomy was feasible and safe, with an acceptable rate of grade B pancreatic fistula and no grade C pancreatic fistula for patients with a soft pancreas.

A transverse emittance and acceptance measurement system in a low-energy beam transport line.

A transverse beam emittance and acceptance measurement system has been developed to visualize the relationship between the injected beam emittance and the acceptance of a cyclotron. The system is composed of a steering magnet, two pairs of slits to limit the horizontal and vertical phase-space, a beam intensity detector just behind the slits for the emittance measurement, and a beam intensity detector in the cyclotron for the acceptance measurement. The emittance is obtained by scanning the slits and measuring the beam intensity distribution. The acceptance is obtained by measuring the distribution of relative beam transmission by injecting small emittance beams at various positions in a transverse phase-space using the slits. In the acceptance measurement, the beam from an ion source is deflected to the defined region by the slits using the steering magnet so that measurable acceptance area covers a region outside the injection beam emittance. Measurement tests were carried out under the condition of accelerating a beam of (16)O(6+) from 50.2 keV to 160 MeV. The emittance of the injected beam and the acceptance for accelerating and transporting the beam to the entrance of the extraction deflector were successfully measured. The relationship between the emittance and acceptance is visualized by displaying the results in the same phase-plane.

Immunohistochemical study of the muscularis externa of the esophagus in achalasia patients.

The etiology of achalasia is believed to be the neuropathy associated with chronic inflammation of the nerve plexus, but the cause of plexus inflammation is unknown. The purpose of this study was to evaluate the pathophysiology of achalasia by examining the muscularis externa of the esophagus. We used the muscularis externa of the esophagus of 62 patients with achalasia (median 44 years, male : female 32:30) who underwent surgical treatment (achalasia group) and of 10 patients (median 65.5 years, male : female 9:1) who underwent esophagectomy for thoracic esophageal cancer (control group) to perform immunohistochemical staining with S-100, CD43, c-kit (CD117), n-NOS, vasoactive intestinal polypeptide (VIP), and ubiquitin. The cell counts that were positive for S-100, n-NOS, VIP, and ubiquitin were significantly lower in the achalasia group compared with the control group (P < 0.001, P= 0.001, P < 0.001, and P= 0.001, respectively). There were no statistically significant differences with respect to CD43 and c-kit staining (P= 0.586 and P= 0.209, respectively). In conclusion, the pathophysiology of achalasia is therefore considered to be an impaired production of NO and VIP, which both affect interstitial cell of Cajal and smooth muscles, and this impairment is therefore considered to play a role in the pathophysiology of achalasia.

Bleeding tendency and impaired platelet function in a patient carrying a heterozygous mutation in the thromboxane A2 receptor.

BACKGROUND: Thromboxane A(2) receptor (TXA(2)R) abnormality appears to dominantly disturb platelet function. OBJECTIVES: To reveal a molecular genetic defect in a patient with TXA(2)R abnormality and investigate the mechanism for the impaired response to TXA(2). PATIENT: The proband (OSP-2, PT) was a 7-year-old Japanese girl, suffering from repeated mucocutaneous bleeding. METHODS AND RESULTS: U46619 (2.5 and 10 µm)-induced platelet aggregation was remarkably impaired in the proband and her father. Immunoblots showed that TXA(2)R expression levels in their platelets were approximately 50% of controls, and nucleotide sequence analysis revealed that they were heterozygous for a novel mutation, c.167dupG in the TXA(2)R cDNA. Expression studies using Chinese hamster ovary (CHO) cells indicated that the mutation is responsible for the expression defect in TXA(2)R. We then examined α(IIb)ß(3) activation by employing an initial velocity analysis and revealed that U46619 failed to induce a sustained α(IIb)ß(3) and Rap1B activation in the proband. In addition, platelet secretion as monitored by P-selectin expression was markedly impaired in response to U46619 but not to ADP. The interaction between secreted ADP and P2Y(12) has been shown to play a critical role in the sustained α(IIb)ß(3) activation (Kamae et al. J Thromb Haemost 2006; 4: 1379). As expected, small amounts of exogenous ADP (0.5 µm) partially restored the sustained α(IIb)ß(3) activation induced by U46619. CONCLUSION: Our present data strongly suggest that the impaired platelet activation in response to U46619 in the heterozygous subject for the TXA(2)R mutation is, at least in part, as a result of the decrease in ADP secretion.

[Anti-reflux procedure].

We introduced surgical indication, laparoscopic technique and procedure, management after surgery, and postoperative complication for gastroesophageal reflux diseases (GERD). Several points of laparoscopic fundoplication for GERD are shown below. 1) Exposure of abdominal esophagus: downward exposure is recommended in order to avoid postoperative dysphagia like achalasia. 2) Dissection of short gastric vessels: this procedure warrant free tension of gastric fundus at fundoplication. 3) Crural repair: create appropriate size of hiatus. 4) Fundoplication: we should do shoe shine maneuver and drop test to confirm free tension of fundus. 5) Shoulder stitch and anchor stitch: this procedure are needed to avoid dislocation of gastric fundus.

Roles of prostanoids in the pathogenesis of cardiovascular diseases.

The roles of prostanoids in the pathogenesis of cardiovascular diseases and in the development of pathological conditions have been examined using mice lacking the individual, specific prostanoid receptor. Prostaglandin (PG) I2 protected the heart from ischemia-reperfusion injury in a model of acute myocardial infarction. In addition, PGI2 suppressed the development of pressure overload-induced cardiac hypertrophy. Aside from its potent vasodilatory action, PGI2 contributed critically to the development of renovascular hypertension via the activation of the renin-angiotensin-aldosterone system. Thromboxane (TX) A2 and PGF2alpha were found to be the mediators of inflammatory tachycardia under a systemic inflammatory condition induced by lipopolysaccharide. Under a septic condition leading to a vascular hypo-responsive state, TXA2 worked to maintain vascular tone by inhibiting the induction of inducible nitric oxide synthase in vascular smooth muscle cells. Mice lacking the PGE2 receptor subtype EP3 had a bleeding tendency and were resistant to thromboembolism, due to a defective activation of platelets. From these studies, the important and novel roles of prostanoids in the pathogenesis of cardiovascular diseases have been clarified.

A novel nonsecosteroidal VDR agonist (CH5036249) exhibits efficacy in a spontaneous benign prostatic hyperplasia beagle model.

To date, there have been no reports showing the efficacy of nonsecosteroidal vitamin D receptor (VDR) agonists in a benign prostatic hyperplasia (BPH) animal model. To examine the efficacy of CH5036249, a novel nonsecosteroidal VDR agonist, we orally administered the compound at 0.03 microg/kg to a beagle model with spontaneous BPH. Prostate volume was checked by rectal ultrasonic probe periodically during 11 months of administration and the prostate tissues histologically examined. CH5036249 inhibited prostate growth in two out of three dogs compared with vehicle-treated dogs. In the prostate specimens, substantial atrophy of the epithelium was observed in all dogs administered CH5036249. At the dose given, serum calcium levels slightly increased in the CH5036249-treated dogs but stayed within a normal range. We next examined the cell growth inhibition of CH5036249 using human prostate stromal cells and found the cell growth inhibitory activity of CH5036249 to be comparable to that of 1alpha,25(OH)2D3. The bioavailability from oral administration in rats was 95.1% with a t1/2 of 17.6 h. Both micro-AMES and micronucleus tests were negative. Although the results are still preliminary, we consider the novel nonsecosteroidal VDR agonist CH5036249 to be a possible new drug candidate for the treatment of BPH in humans.

Laser ion source: a direct plasma injection scheme for two-beam type interdigital-H radio frequency quadrupole linac.

We developed a laser ion source using a direct plasma injection scheme (DPIS) as an injection system for a two-beam type radio frequency quadrupole (RFQ) linac with an interdigital-H (IH) type cavity. The laser ion source in the DPIS is directly connected to the RFQ cavity without the low energy beam transport system. We achieved a high current C(2+) beam above 60 mA per beam channel from the ion source. The beam will be injected to the two-beam type IH-RFQ linac, and the linac will generate a beam current of approximately 44 mA per beam channel.

Drift distance survey in direct plasma injection scheme for high current beam production.

In a laser ion source, plasma drift distance is one of the most important design parameters. Ion current density and beam pulse width are defined by plasma drift distance between a laser target and beam extraction position. In direct plasma injection scheme, which uses a laser ion source and a radio frequency quadrupole linac, we can apply relatively higher electric field at beam extraction due to the unique shape of a positively biased electrode. However, when we aim at very high current acceleration such as several tens of milliamperes, we observed mismatched beam extraction conditions. We tested three different ion current at ion extraction region by changing plasma drift distance to study better extraction condition. In this experiment, C(6+) beam was accelerated. We confirmed that matching condition can be improved by controlling plasma drift distance.

Particle simulation for direct plasma injection in a radio frequency quadrupole matching section.

We have been investigating direct plasma injection scheme (DPIS) for high-intensity heavy-ion beam acceleration. In the DPIS, laser-produced plasma is directly injected into a radio frequency quadrupole (RFQ) linac. To study the beam dynamics of the ion injection in the DPIS, we tracked particle motions in the RFQ matching section using three-dimensional particle-in-cell method. As a result of the numerical simulation, we found that the electrostatic field generated by the extraction electrode reduces the transmission efficiency. To avoid the radially defocusing force, the input beam into the RFQ has to be initially convergent. In the DPIS, further optimization of the plasma density is required for better matching.

Presence of platelet-associated anti-glycoprotein (GP)VI autoantibodies and restoration of GPVI expression in patients with GPVI deficiency.

BACKGROUND: Glycoprotein (GP)VI deficiency is a rare platelet disorder with a mild bleeding tendency. However, its pathophysiology remains unclear. OBJECTIVES: We characterized a novel GPVI-deficient patient with immune thrombocytopenic purpura and searched for the presence of anti-GPVI autoantibodies in this and another patient with GPVI deficiency. METHODS AND RESULTS: A 12-year-old Japanese girl (case 1) with moderate thrombocytopenia and mild bleeding showed selectively impaired collagen-induced platelet aggregation. Flow cytometric analysis indicated that the patient had a defect in the expression of GPVI-FcRgamma. An eluate of her platelet-associated IgG contained anti-alpha(IIb)beta3 autoantibodies. Moreover, using GPVI-FcRgamma-transfected cells, we unexpectedly identified anti-GPVI antibodies against the soluble ectodomain of GPVI in the eluate, despite the patient's GPVI deficiency. In contrast, anti-GPVI antibodies were not detectable in her plasma. In another case of GPVI deficiency (case 2) without detectable plasma anti-GPVI antibodies, we again detected platelet-associated anti-GPVI antibodies. In a 2-year follow-up of case 1, the platelet count increased to within the normal range and the bleeding tendency improved. Interestingly, GPVI was again expressed on her platelets, in association with a decrease in the relative amount of anti-GPVI antibodies. CONCLUSIONS: This is the first demonstration of platelet-associated anti-GPVI antibodies in GPVI-deficient subjects, in one case with spontaneous restoration of GPVI expression. These results strongly suggest an autoimmune mechanism in GPVI deficiency.

Direct plasma injection scheme in accelerators.

The idea of direct plasma injection scheme (DPIS) was proposed in 2000. This new technique has been studied and proven to accelerate intense ion beams. To provide medium mass ions with highly charged states, small tabletop solid lasers were used for plasma production. Based on the measured plasma properties, aluminum and carbon ions were accelerated with more than 60 mA of current. The next experiments will use an radio frequency quadrupole designed for q/m=1/6 and explore beam productions using targets up to silver, and future work will explore production up to uranium. The DPIS has been established and is ready to be used with various accelerators which require pulsed high current, high charge state ion beams.