A pilot randomized trial of adjuvanted influenza vaccine in adult allogeneic hematopoietic stem cell transplant recipients.

The annual influenza vaccine is recommended for hematopoietic stem cell transplant (HSCT) patients although studies have shown suboptimal immunogenicity. Influenza vaccine containing an oil-in-water emulsion adjuvant (MF59) may lead to greater immunogenicity in HSCT recipients. We randomized adult allogeneic HSCT patients to receive the 2015-2016 influenza vaccine with or without MF59 adjuvant. Preimmunization and 4-week post-immunization sera underwent strain-specific hemagglutination inhibition assay. We randomized 73 patients and 67 (35 adjuvanted; 32 non-adjuvanted) had paired samples available at follow-up. Median age was 54 years (range 22-74) and time from transplant was 380 days (range 85-8107). Concurrent graft-versus-host disease was seen in 42/73 (57.5%). Geometric mean titers increased significantly after vaccination in both groups. Seroconversion to at least one of three influenza antigens was present in 62.9% vs 53.1% in adjuvanted vs non-adjuvanted vaccine (P=0.42). Factors associated with lower seroconversion rates were use of calcineurin inhibitors (P<0.001) and shorter duration from transplantation (P=0.001). Seroconversion rates were greater in patients who got previous year influenza vaccination (82.6% vs 45.5%, P=0.03). Adjuvanted vaccine demonstrated similar immunogenicity to non-adjuvanted vaccine in the HSCT population and may be an option for some patients.

Clinical course of abducens nerve palsy associated with skull base tumours.

BACKGROUND: The clinical course of abducens nerve palsy associated with skull base tumour is rarely reported. In this study, we examined the post-operative course of abducens nerve palsies associated with various skull base tumours. METHOD: Between January 2003 and December 2006, 240 patients with various skull base tumours underwent surgery at Kyushu University Hospital. Among them, nine patients presented with abducens nerve palsies (ten nerves) following surgery. The conditions included two pituitary adenomas, two trigeminal schwannomas and five meningiomas. We evaluated the function of the abducens nerves in these patients on admission, at discharge, and periodically in the outpatient clinic. FINDINGS: Four of the abducens nerve palsies already existed prior to surgery, and six of them developed post-operatively. In the four patients with pituitary adenomas and trigeminal schwannomas, all nerves were anatomically preserved and showed complete recovery of function within 6 months after surgery. In contrast, only two of the six palsies in patients with skull base meningiomas showed complete recovery. In three patients with petro-clival meningiomas, the abducens nerves were completely transected during surgery, and one was reconstructed using fibrin glue. This patient remarkably recovered from the abducens nerve palsy within 2 years. CONCLUSIONS: The abducens nerve palsies in pituitary adenomas and trigeminal schwannomas showed a better clinical course compared to those in skull base meningiomas. The abducens nerve palsies that occur with skull base meningiomas are less likely to recover. Nevertheless, it is important to preserve the nerves and to perform surgical repair if the nerve is transected.

New highly potent and specific E6 and E7 siRNAs for treatment of HPV16 positive cervical cancer.

Persistent infection by high-risk types of human papillomaviruses (HPV) is a necessary cause of cervical cancer, with HPV16 the most prevalent, accounting for more than 50% of reported cases. The virus encodes the E6 and E7 oncoproteins, whose expression is essential for maintenance of the malignant phenotype. To select efficacious siRNAs applicable to RNAi therapy for patients with HPV16+ cervical cancer, E6 and E7 siRNAs were designed using siDirect computer software, after which 10 compatible with all HPV16 variants were selected, and then extensively examined for RNAi activity and specificity using HPV16+ and HPV16-cells. Three siRNAs with the highest RNAi activities toward E6 and E7 expression, as well as specific and potent growth suppression of HPV16+ cancer cells as low as 1 nM were chosen. Growth suppression was accompanied by accumulation of p53 and p21(WAF1/CIP1), as well as morphological and cytochemical changes characteristic of cellular senescence. Antitumor activity of one of the selected siRNAs was confirmed by retarded tumor growth of HPV16+ cells in NOD/SCID mice when locally injected in a complex with atelocollagen. Our results demonstrate that these E6 and E7 siRNAs are promising therapeutic agents for treatment of virus-related cancer.

Transcerebellomedullary fissure approach with special reference to methods of dissecting the fissure.

OBJECT: The purpose of the present study was to refine the transcerebellomedullary fissure approach to the fourth ventricle and to clarify the optimal method of dissecting the fissure to obtain an appropriate operative view without splitting the inferior vermis. METHODS: The authors studied the microsurgical anatomy by using formalin-fixed specimens to determine the most appropriate method of dissecting the cerebellomedullary fissure. While dissecting the spaces around the tonsils and making incisions in the ventricle roof, the procedures used to expose each ventricle wall were studied. Based on their findings, the authors adopted the best approach for use in 19 cases of fourth ventricle tumor. The fissure was further separated into two slit spaces on each side: namely the uvulotonsillar and medullotonsillar spaces. The floor of the fissure was composed of the tela choroidea, inferior medullary velum, and lateral recess, which form the ventricle roof. In this approach, the authors first dissected the spaces around the tonsils and then incised the taenia with or without the posterior margin of the lateral recess. These precise dissections allowed for easy retraction of the tonsil(s) and uvula and provided a sufficient view of the ventricle wall such that the deep aqueductal region and the lateral region around the lateral recess could be seen without splitting the vermis. The dissecting method could be divided into three different types, including extensive (aqueduct), lateral wall, and lateral recess, depending on the location of the ventricle wall and the extent of surgical exposure required. CONCLUSIONS: When the fissure is appropriately and completely opened, the approach provides a sufficient operative view without splitting the vermis. Two key principles of this opening method are sufficient dissection of the spaces around the tonsil(s) and an incision of the appropriate portions of the ventricle roof. The taenia(e) with or without the posterior margin of the lateral recess(es) should be incised.

Surgery on a saccular vertebral artery-posterior inferior cerebellar artery aneurysm via the transcondylar fossa (supracondylar transjugular tubercle) approach or the transcondylar approach: surgical results and indications for using two different lateral skull base approaches.

OBJECT: The authors report on the surgical results they achieved in caring for patients with vertebral artery-posterior inferior cerebellar artery (VA-PICA) saccular aneurysms that were treated via either the transcondylar fossa (supracondylar transjugular tubercle) approach or the transcondylar approach. In this report they clarify the characteristics of and differences between these two lateral skull base approaches. They also present the techniques they used in performing the transcondylar fossa approach, especially the maneuver used to remove the jugular tubercle extradurally without injuring the atlantooccipital joint. METHODS: Eight patients underwent surgery for VA-PICA saccular aneurysms (six ruptured and two unruptured ones) during which one of the two approaches was performed. Clinical data including neurological and radiological findings and reports of the operative procedures were analyzed. The Glasgow Outcome Scale was used to estimate the activities of daily living experienced by the patients. In all cases the aneurysm was successfully clipped and no permanent neurological deficits remained, except for one case of severe vasospasm. In seven of the eight patients, the transcondylar fossa approach provided a sufficient operative field for clipping the aneurysm without difficulty. In the remaining patient, in whom the aneurysm was located at the midline on the clivus at the level of the hypoglossal canal, the aneurysm could not be found by using the transcondylar fossa approach; thus, the route was changed to the transcondylar approach, and clipping was performed below the hypoglossal nerve rootlets. CONCLUSIONS: Both approaches offer excellent visualization and a wide working field, with ready access to the lesion. This remarkably reduces the risk of development of postoperative deficits. These approaches should be used properly; the transcondylar fossa approach is indicated for aneurysms located above the hypoglossal canal and the transcondylar approach is indicated for those located below it.

[Infratemporal fossa approach for mid-skull base lesion: its usefulness, surgical anatomy, and intraoperative device].

The usefulness of the infratemporal fossa type C approach is reported through a presentation of a case of clival chordoma, which was successfully treated by this approach. Although it is complicated and includes some demerits, this approach gives a shorter and wider access to mid-skull base pathology than other approaches. Among the demerits, deformity of the temporal region caused by extensive drilling of the bone could be minimized by cosmetic mastoidectomy, which was first applied during this approach by the authors. The surgical anatomy for this approach is demonstrated using a cadaver specimen.

Surgical treatment of glossopharyngeal neuralgia as vascular compression syndrome via transcondylar fossa (supracondylar transjugular tubercle) approach.

OBJECTIVE: These are the first reported cases in whom the transcondylar fossa approach was applied for the treatment of glossopharyngeal neuralgia (GPN) as a vascular compression syndrome. CASES PRESENTATION: All three cases presented with severe paroxysmal pharyngeal pain which could not be controlled by medical treatment. The patients all underwent microvascular decompression surgery (MVD) via transcondylar fossa approach. The posterior inferior cerebellar artery or the anterior inferior cerebellar artery was clearly verified to be compressing the glossopharyngeal nerve and then was safely and completely moved and fixed to the dura mater by the sling retraction technique to effect decompression. No patient has since experienced any further pain or permanent neurological deficit after surgery. TECHNICAL ADVANTAGE: The transcondylar fossa approach is one of the lateral approaches which is different from the transcondylar approach. In this approach, the posterior part of the jugular tubercle is extradurally removed without injuring the atlanto-occipital joint. The entire course of the cisternal portion of the glossopharyngeal nerve can be sufficiently seen with gentle retraction of the cerebellar hemisphere, when using this approach. CONCLUSION: This approach makes the MVD for GPN both effective and safe.

Huge hamartoma with inverted papilloma in the nasal cavity.

We report clinical experience in managing a 46-year-old Japanese man with long-standing nasal obstruction resulting from a huge left nasal mass. Computed tomography, magnetic resonance imaging and biopsy were used to make a provisional diagnosis of inverted papilloma. The mass was resected via a frontal approach combined with rhinotomy. Histopathologic examination of the resected specimen was consistent with a hamartoma that included an inverted papilloma on a portion of its surface. In addition to being rare tumors in the nasal cavity, we believe that our patient's tumor the largest nasal hamartoma ever reported.

Analysis of the fatty acid components in a perchloric acid-soluble protein.

We had previously found that a perchloric acid-soluble protein (PSP1) occurs in rat liver, and that this novel protein inhibits protein synthesis in a rabbit reticulocyte lysate system (T. Oka, H. Tsuji, C. Noda, K. Sakai, Y.-H. Hong, I. Suzuki, S. Muñoz, Y. Natori, J. Biol. Chem. 270 (1995) 30060-30067). In the present study, we analyzed lipid components bound to PSP1. Native PSP1 was purified from rat liver using Sephadex G-75, DE-52 cellulose and IgGPSP-affinity chromatography, and the lipid components were extracted. The components obtained from the purified PSP1 were shown to be free fatty acids by thin-layer chromatography. By GC-MS, six major fatty acids were identified as 14:0, 16:0, 18:0, 18:1, 18:2 and 20:4. 1 mol of PSP1 contained 1.26 mol of total fatty acid components. The fatty acid-binding assay of PSP1 showed that the Bmax was 1.25 mol fatty acid/mol PSP1 and the Kd value for palmitic acid was 6.03 microM. The concentration of PSP1 mRNA in rat liver increased 2.3-fold by the administration of peroxisome proliferator, bezafibrate. These findings show that PSP1 is a fatty acid-binding protein-like protein, which is involved in the intracellular metabolism of fatty acid and is quite different from the known fatty acid-binding proteins.

A historical cohort mortality study of workers exposed to asbestos in a refitting shipyard.

To investigate the risks of developing asbestos-related diseases we conducted a historical cohort mortality study on 249 ship repair workers (90 laggers and 159 boiler repairers) in a single U.S. Navy shipyard in Japan. We successfully identified the vital status of 87 (96.7%) laggers and 150 (94.3%) boiler repairers, and, of these, 49 (56.3%) and 65 (43.3%) died, respectively, during the follow-up period from 1947 till the end of 1996. Our in-person interviews with some of the subjects clarified that asbestos exposure was considered to be substantially high in the 1950-60s, decreased thereafter gradually but remained till 1979 in the shipyard. The laggers, who had handled asbestos materials directly, showed a significantly elevated SMR of 2.75 (95% C.I.: 1.08-6.48) for lung cancer. The risk developing the disease was greater in the laggers after a 20-year latency (SMR = 3.42). Pancreatic cancer yielded a greater SMR than unity (7.78, 90% C.I.: 2.07-25.19) in a longer working years group. Four laggers died from asbestosis. The boiler repairers, who had many chances for secondary exposure to asbestos and a few for direct exposure, showed no elevation of the SMR of lung cancer overall, but there was a borderline statistically significant SMR of 2.41 (90% C.I.: 1.05-5.45) in a longer working years group. One boiler repairer died from mesothelioma and four from asbestosis.

[Clinical experience of image-guided neurosurgery with a frameless navigation system (StealthStation)].

We have applied the frameless navigation system (StealthStation) to various neurosurgical procedures to examine its usefulness. The system consists of a UNIX based workstation that creates triplanar and 3-dimensional images; an infrared optical digitizer with camera array; a reference-light-emitting diode (LED) array (e.g., reference array); and pointer probe modified by the addition of LEDs. This system was used to assist in placing a minimal skin incision and craniotomy in 4 cases, to determine the tumor/brain interface in 2 cases, to target the subcortical lesion in one case, and to correlate bony structure with a skull base tumor in 3 cases. The combined use with magnetic source imaging of the somatosensory cortex allowed a fast orientation of eloquent areas in 2 cases with peri-Rolandic tumor. This system, thus, was proved to be a useful adjunct to open-tumor biopsy or resection.

Induction of cytokines in a human colon epithelial cell line by Shiga toxin 1 (Stx1) and Stx2 but not by non-toxic mutant Stx1 which lacks N-glycosidase activity.

Stx1 and Stx2 produced by Shiga toxin-producing Escherichia coli are cytotoxic due to their N-glycosidase activity on 28S rRNA. In this study, we have shown that proinflammatory cytokine mRNAs, especially IL-8, were induced by Stx1 and Stx2 in Caco-2 cells. A non-toxic mutant of Stxl which lacks N-glycosidase activity did not induce cytokine mRNAs. IL-8 production at the protein level was enhanced by Stx1 and Stx2, but not by the mutant Stx1. These results demonstrate that Shiga toxins induce expression and synthesis of cytokines in Caco-2 cells and their N-glycosidase activity is essential for the induction.

A simple procedure for the isolation of rat kidney lysosomes.

BACKGROUND: A procedure for the isolation of highly purified lysosomes from normal rat kidney is described. METHODS: The method depends on the swelling of mitochondria when the postnuclear supernatant fraction is incubated with 2 mM Ca2+. The lysosomes can then be separated from the swollen mitochondria by Percoll density gradient centrifugation. RESULTS: The lysosomal fraction obtained by our method was enriched more than 30-fold in terms of marker enzymes with a yield of about 11%. Electron microscopic examination and the measurement of the activities of marker enzymes for various subcellular organelles indicated that our lysosomal preparation was essentially free from contamination by other organelles. CONCLUSION: We believe that this procedure for isolating kidney lysosome will be useful in the study of the mechanisms of specific modification, processing and catabolism of proteins.

cDNA cloning, expression, and characterization of the human bifunctional ATP sulfurylase/adenosine 5'-phosphosulfate kinase enzyme.

A cDNA encoding the human bifunctional ATP sulfurylase/adenosine 5'-phosphosulfate (APS) kinase was cloned and sequenced. The enzyme contains an APS kinase domain in its N-terminal portion and an ATP sulfurylase domain in its C-terminal portion. Recombinant full-length enzyme and its constituent APS kinase and ATP sulfurylase domains were individually expressed, purified, and shown to have their respective enzymatic activities.

Purification, characterization and differentiation-dependent expression of a perchloric acid soluble protein from rat kidney.

We have recently reported the presence of a novel perchloric acid soluble protein in rat liver (PSP1) that inhibits cell-free protein synthesis in a rabbit reticulocyte system. While studying the perchloric acid soluble proteins from different tissues of rats, we found that the kidney protein cross-reacted with antibody against the PSP1. In this investigation, we have purified a perchloric acid soluble protein from the rat kidney and studied its characterization and expression. The protein extracted from the postmitochondrial supernatant fraction with 5% perchloric acid was purified by ammonium sulfate fractionation and CM-Sephadex chromatography. By immunoscreening with the rabbit antisera against the PSP1, we detected a cDNA that contained an open reading frame of 411 bp, encoding a 137 amino-acid protein with a molecular mass of 14,149 daltons. The deduced amino acid sequence was completely identical with that of PSP1 from rat liver. The perchloric acid soluble protein from rat kidney (K-PSP1) also inhibited cell-free protein synthesis in the rabbit reticulocyte lysate system in a different manner than RNase A. Immunohistochemistry showed that the expression of K-PSP1 increased from fetal 17th day to postnatal 4th week, and it remained almost the same until the 7th week of postnatal age. Furthermore, the expression of K-PSP1 in the kidney of the nephrotic rat model was shown to be differentiation dependent. On the other hand, the expression of K-PSP1 in renal tumor cells was downregulated as compared with intact tissue. These results suggest that the expression of K-PSP1 is regulated in a differentiation-dependent manner in the kidney.

Operative approaches to the pineal region tumors.

Until the introduction of microsurgery, the surgical treatment of pineal region tumors had very poor results with high mortality and morbidity. However, there have been remarkable improvements with modern surgical technology and advanced knowledge. Now the main surgical approaches to pineal region tumors are the occipital transtentorial approach and the infratentorial supracerebellar approach. Recently the neuroendoscopic approach has been added. The surgical approach and any supplementary treatment should be selected in each case according to the nature of the individual tumor. The forms of treatment practiced by ourselves, including neuroendoscopic surgery, are presented, and the surgical treatments now applied are discussed.

Microsurgical anatomy for lateral approaches to the foramen magnum with special reference to transcondylar fossa (supracondylar transjugular tubercle) approach.

Microsurgical anatomy for lateral approaches to the foramen magnum, especially for transcondylar fossa (supracondylar transjugular tubercle) approach, was studied using cadavers. The transcondylar fossa approach is an approach in which extradural removal of the posterior portion of the jugular tubercle through the condylar fossa is added to the far lateral approach. Some differences between this approach and the transcondylar approach are demonstrated. The atlanto-occipital joint and the jugular tubercle are obstacles for the lateral approaches. The condylar fossa forming the external occipital surface of the jugular tubercle is located supero-posterior to the occipital condyle. The fossa is limited laterally by the sigmoid sulcus and the jugular foramen. The posterior condylar canal communicating anteriorly with the distal end of the sigmoid sulcus, the jugular foramen, or the hypoglossal canal opens at the bottom of the fossa. The condyle is situated inferior to the posterior condylar and hypoglossal canals, and the jugular tubercle is located superior to them. In the transcondylar fossa approach the posterior part of the jugular tubercle is extradurally removed, but the condyle and the atlanto-occipital joint are untouched. On the other band, in the transcondylar approach the medial parts of the condyle and the lateral mass of Cl are removed. The latter approach offers better visualization of the inferior part of the foramen magnum. The essential difference of the two approaches is in the direction of looking and the extent of resection of the atlanto-occipital joint. Both approaches offer excellent view of the ventral dural space in the lower clivus and the foramen magnum, but the level of exposure differs somewhat between them. In the lateral approaches to the foramen magnum, the condylar fossa, the posterior condylar canal, and the posterior condylar emissary vein all play an important role as intraoperative anatomical landmarks.

Surgery of angiomas in the brainstem with a stress on the presence of telangiectasia.

This report deals with the surgery of angiomas other than arteriovenous malformation in the brainstem. The surgical cases were three cavernomas, two telangiectasias, and two venous malformations. We performed surgery when an angioma bled and the resulting hematoma was situated near the surface of the brainstem or the fourth ventricle. The cases were operated on at the subacute or chronic stages after hemorrhage. Although a magnetic resonance (MR) image showed a subacute or chronic localized hematoma with a low intensity rim, the case was not always a cavernoma, but a telangiectasia. Cavernomas could be totally removed, but telangiectasia could not. In the cases of medullary venous malformation the diagnosis was obtained radiologically, and when the hematoma was large, only hematoma evacuation was performed. In all cases the postoperative Karnofsky scores were improved or unchanged. Postoperative rebleeding in the hematoma cavity continued insidiously in a case of telangiectasia. The abnormal vessels of telangiectasia in the brainstem were preoperatively not visualized by cerebral angiography or MR imaging, but became visualized by enhanced MR imaging after evacuation of hematoma in two cases. It is stressed that an angioma with a hematoma intensity core surrounded by a low intensity rim on MR images is not always a cavernoma, but possibly is a telangiectasia.