Effect of postoperative proton pump inhibitor therapy on voice outcomes following phonomicrosurgery for vocal fold polyp: a randomized controlled study.

OBJECTIVE: To determine the effect of a postoperative proton pump inhibitor (PPI) on voice outcomes after phonomicrosurgery in patients with vocal fold polyp. STUDY DESIGN: This is a prospective, randomized controlled study. SETTINGS: This study was carried out in a tertiary care referral medical centre. PARTICIPANTS: A total of 48 patients underwent phonomicrosurgery for vocal fold polyps. After surgery, patients were randomized to the PPI group (lansoprazole 15 mg twice daily for 2 months) and the non-PPI group. MAIN OUTCOME MEASURES: Voice handicap index (VHI) and perceptual and acoustic voice analysis were evaluated at baseline and 2 months after surgery. RESULTS: Among 48 enrolled patients, a total of 42 patients [non-PPI group (n = 23), PPI group (n = 19)] completed the study. The VHI, perceptual and most acoustic parameters significantly improved in both groups after surgery. However, there was no significant difference in the per cent of change in those parameters. CONCLUSION: Postoperative PPI treatment did not significantly influence voice outcomes after phonomicrosurgery in patients with vocal fold polyp.

Synergistic effect of surface modification with poly(ethylene glycol) and immunosuppressants on repetitive pancreatic islet transplantation into antecedently sensitized rat.

BACKGROUND: Polymeric modification of islet surface is highly effective in preventing transplanted islets against host immune reactions. However, grafted islets are eventually rejected by the host immune reaction. Thus, repetitive islet transplantation is needed to treat type 1 diabetic patients experiencing graft rejection. We explored whether using poly(ethylene glycol) (PEG) as surface camouflage of islets (PEGylation) can be an affordable immunoprotective remedy for repeated islet transplantation. METHODS: The surface coverage of PEG was evaluated in vitro. The viability of PEGylated islets cocultured with sensitized or nonsensitized splenocytes was evaluated using lactate dehydrogenase assay. In addition, the effect of surface modification on immunoprotection for repetitively transplanted islets was evaluated in a sensitized rat model. RESULTS: Unmodified islets transplanted in combination with Cyclosporine (CsA) and anti-CD4 monoclonal antibody (OX-38) into the sensitized recipients did not maintain a normal level of blood glucose over 20 days. Interestingly, however, three of the five recipients became normoglycemic up to 30 days when PEGylated islets were transplanted in combination with CsA and OX-38. CONCLUSION: These results demonstrated that PEGylation alone was not an affordable immunoprotective method, but the combination of CsA and OX-38 along with PEGylation showed a highly improved a synergic effects on the inhibition of sensitized host immune reactions.

Plating of humeral shaft fractures: comparison of standard conventional plating versus minimally invasive plating.

PURPOSE: This study compared clinical outcomes and complications in patients with humeral shaft fractures treated using two methods of fixation by plating. METHODS: Minimally invasive plate osteosynthesis (MIPO, n=29) was prospectively performed from around the middle of the study period, while open reduction and plate osteosynthesis (ORPO, n=30) had been the original standard method. Locking compression plate was used in these two groups. Major characteristics of the two groups were similar in terms of fracture type, fracture location, age, associated injuries and numbers of open fractures. RESULTS: Primary union was achieved in 28 of 29 in the MIPO and in 27 of 30 in the ORPO. Mean time to union was similar in the two groups. Mean operation time in the MIPO (110min) was shorter than in the ORPO (169min) (P<0.05). Bone grafting was performed in five patients of in the ORPO, but in no patient in the MIPO (P<0.0001). There was one case of deep infection in the ORPO. Functional outcome was satisfactory in both groups. CONCLUSIONS: Minimally invasive plate osteosynthesis may achieve comparable results with the open plate osteosynthesis method in simple as well as complex fractures of humeral shaft. Although MIPO potentially has the radiation hazard, it may reduce the perioperative complications with a shortened operation time. LEVEL OF EVIDENCE: Level III. Case-control study.

Separate vertical wiring for the fixation of comminuted fractures of the inferior pole of the patella.

Comminuted and displaced fractures of the inferiorole of the patella are not easy to reduce and it is difficult to fix the fragments soundly enough to allow early movement of the knee. We have evaluated the clinical effectiveness of the separate vertical wiring technique in acute comminuted fractures of the inferior pole of the patella. A biomechanical study was also performed using ten pairs of embalmed cadaver knees. A four-part fracture was made on the inferior pole of the patella and fixed by two separate vertical wires on one side and two pull-out sutures after partial patellectomy on the other. The ultimate load to failure in the first group was significantly higher than in the second (250.1+/- 109.7 N v 69.7 +/- 18.9 N, p < 0.002), as was the stiffness (279.9 +/- 76.4 N/mm v 23.2 +/- 11.4 N/mm, p < 0.001). The separate wire technique was used in 25 patients with comminuted fractures of the inferior pole of the patella who were followed up for a mean period of 22 months (10 to 50). All the fractures healed at a mean of seven weeks (6 to 10). No breakage of a wire or infection occurred. The mean grading at the final follow-up was 29.5 points (27 to 30) using the Böstman method. This technique preserved the length of the patella, fixed the comminuted fragments of the inferior pole and avoided long-term immobilisation of the knee.

Metalloprotease-specific poly(ethylene glycol) methyl ether-peptide-doxorubicin conjugate for targeting anticancer drug delivery based on angiogenesis.

This article proposes a novel cancer-targeting drug-delivery system based on angiogenesis, in which the enzymatic activity of type IV collagenases is used to cleave the inactive drug conjugate, thereby activating drug fragments. In this study, the amount and distribution of metalloprotease (MMP)-2 and MMP-9 secreted from Lewis lung carcinoma (LCC) cells and the formation of blood vessels were evaluated by gelatin zymography, in situ film zymography and immunostaining. LLC cells secreted MMP-2 and MMP-9, thereby distributing large amounts of MMPs around a solid tumor. The newly developed blood vessels were also found in a solid LLC tumor. The anticancer drug conjugate (mPEG-GPLGV-DOX) was synthesized by conjugating doxorubicin with Gly-Pro-Leu-Gly-Val (GPLGV) peptide and poly(ethylene glycol) methyl ether (mPEG). GPLGV pentapeptide was used as a substrate for MMP-2 and MMP-9, where the cleavage of Gly-Val bond by MMP was expected. In addition, mPEG was grafted to peptide-doxorubicin conjugate to increase the circulation time in the body and to reduce the cytotoxicity of the anticancer drug. The mPEG-GPLGV-DOX conjugate formed a micelle structure in aqueous solution, with a critical micelle concentration (CMC) of about 0.25 mg/ml and a diameter of 73.1 +/- 12.7 nm at 1 mg/ml. In an in vivo experiment, mPEG-GPLGV-DOX showed 20% chemotherapeutic activity compared with free doxorubicin. Although a 50 mg/kg dose of mPEG-GPLGV-DOX showed similar therapeutic effects to a 10 mg/kg dose of doxorubicin, the life span of mice in the conjugate group was significantly increased. Therefore, an efficient anticancer drug-delivery system could be created by increasing therapeutic efficiency and decreasing drug-toxicity by optimizing the degradation rate of the peptide link by MMP and circulation time in the body.

Inhibition effect of new farnesol derivatives on all-trans-retinoic acid metabolism.

All-trans-retinoic acid (atRA) is a promising anticancer and antiwrinkle drug. However, its clinical application is limited because it is rapidly metabolized by the induced cytochrome P450 (P450). In this study, farnesol derivatives are proposed as new inhibitors to prevent P450-mediated metabolism. The farnesol derivatives were suc-farnesol and mal-farnesol, which were synthesized by the chemical conjugation of farnesol with succinic anhydride and maleic anhydride, respectively. The inhibition effects of farnesol, farnesoic acid, and farnesol derivatives on the atRA metabolism were evaluated in microsome and in AMC-HN-6 cells. In the microsome experiment, suc-farnesol and mal-farnesol strongly inhibited atRA metabolism at 10(minus;4) mol/L concentration by as much as 61% and 77%, respectively. In the cell experiment, the inhibition effects of farnesol derivatives on the atRA metabolism showed similar tendency as the results in the microsome experiment, even if the effect was somewhat decreased. Effects of farnesoic acid and farnesol, however, were not significant. This research suggests that carboxylic end groups, such as atRA and hydrophobicity, might be important factors causing the higher inhibition effect, and that derivatization of farnesol can be 1 method to develop new inhibitors of atRA metabolism.

Noble 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-isoindolinone derivatives. part I: synthesis and SAR studies for the inhibition of TNF-alpha production.

This study describes the synthesis and in vitro evaluation of noble 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-isoindolinone derivatives for the inhibition of TNF-alpha production. Among these compounds, 2-[3-(cyclopentyloxy)-4-methoxyphenyll-3-methyl-1-isoindolinone (5) was the most potent in inhibitory activity of TNF-alpha production in LPS-stimulated RAW264.7 cells.

Effects of ethylene oxide gas sterilization on physical properties of poly(L-lactide)-poly(ethylene glycol)-poly(L-lactide) microspheres.

The aggregation of poly(alpha-hydroxy acid) microspheres during ethylene oxide (EO) gas sterilization makes it difficult for the microspheres to be used in clinical applications. In this study, six kinds of PLLA-PEG-PLLA triblock copolymers (TriPLE) were synthesized with various composition ratios of PEG/PLLA in the range of 0.012 to 0.103. TriPLE microspheres were prepared by the oil-in-water emulsion method. TriPLE microspheres were characterized by using 1H-NMR, gel permeation chromatography (GPC), and differential scanning calorimetry (DSC). After sterilization by EO gas at 55 degrees C, the microspheres were analyzed by scanning electron microscope (SEM), laser diffractometry, standard sieves, X-ray diffraction (XRD), GPC, and DSC. When the composition ratio of PEG/PLLA was above 0.02, the initial crystallinity of TriPLE in microspheres was as high as 50%, and the microspheres were suitable to be sterilized by EO gas. On the other hand, TriPLE microspheres, which had composition ratios of PEG/PLLA below 0.02, had low initial crystallinities of about 30%, and aggregated during EO gas sterilization. For these microspheres, crystallinity increased up to 50% during the sterilization, whereas other TriPLE microspheres did not show any changes in crystallinity. Therefore, the aggregation of TriPLE microspheres during EO gas sterilization was markedly reduced as the initial crystallinity of TriPLE in the microspheres was increased.

Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis.

Caspases are key mediators of apoptosis. Using a novel expression cloning strategy we recently developed to identify cDNAs encoding caspase substrates, we isolated the intermediate filament protein vimentin as a caspase substrate. Vimentin is preferentially cleaved by multiple caspases at distinct sites in vitro, including Asp85 by caspases-3 and -7 and Asp259 by caspase-6, to yield multiple proteolytic fragments. Vimentin is rapidly proteolyzed by multiple caspases into similar sized fragments during apoptosis induced by many stimuli. Caspase cleavage of vimentin disrupts its cytoplasmic network of intermediate filaments and coincides temporally with nuclear fragmentation. Moreover, caspase proteolysis of vimentin at Asp85 generates a pro-apoptotic amino-terminal fragment whose ability to induce apoptosis is dependent on caspases. Taken together, our findings suggest that caspase proteolysis of vimentin promotes apoptosis by dismantling intermediate filaments and by amplifying the cell death signal via a pro-apoptotic cleavage product.

Poly(ethylene glycol)-poly(L-lactide) diblock copolymer prevents aggregation of poly(L-lactide) microspheres during ethylene oxide gas sterilization.

Sterilization procedure is one of the most important obstacles in the clinical applications of biodegradable microspheres. The microspheres prepared with poly(alpha-hydroxy acid) were severely aggregated during ethylene oxide (EO) gas sterilization, and could not be used in clinical applications. In this study, the effects of EO gas sterilization on the poly(L-lactide) (PLLA) microspheres were analyzed by nuclear magnetic resonance spectroscopy (1H-NMR), differential scanning calorimetry (DSC), gel permeation chromatography (GPC), scanning electron microscope (SEM) and size fractionation. The aggregation between the microspheres might be stimulated by high mobility of amorphous regions of PLLA on the microsphere surfaces since both water vapor and gas mixture can reduce glass transition temperature (Tg) of PLLA below the sterilization temperature. During EO gas sterilization, there were no changes in the molecular structure and the molecular weight of PLLA in microspheres, but there were changes in the crystallinity of PLLA in microspheres. In this study, poly(L-lactide)-poly(ethylene glycol) diblock copolymers (PLE) were blended with PLLA homopolymers in various ratios to design the microsphere suitable for EO gas sterilization. Aggregation of PLLA microspheres was markedly prevented when more than 4wt% of PLE was blended in the microspheres. This inhibition effect on aggregation may be due to the increased initial crystallinity of the microspheres, which help to maintain the microsphere morphology during EO gas sterilization.

Retroperitoneoscopy assisted live donor nephrectomy: the Yonsei experience.

PURPOSE: Retroperitoneoscopy assisted live donor nephrectomy has become standard based on our experience with 103 consecutive cases operated on between January 1993 and May 2000. We describe the advantages of retroperitoneoscopy assisted compared to laparoscopic live donor nephrectomy. MATERIALS AND METHODS: After performing more than 1,200 cases of open live donor nephrectomy (S. C. Y.), we combined our experience with open and laparoscopic surgery to develop a specific technique of minilaparotomy live donor nephrectomy. Operations were performed by 1 senior surgeon and 1 assistant, with the help of specially designed piercing abdominal and peritoneal retractors. A 5 to 7 cm. transverse pararectal skin incision is made at the level of 10th rib and the abdominal muscles are split without division. A 10 mm. port is placed at the lower abdomen to allow for the telescope. The procedure is performed extraperitoneally, combining open and laparoscopic instruments under direct vision. Renal pedicles and ureters are ligated using laparoscopic clips and sutures. The kidney is removed via laparotomy and the wound is closed. RESULTS: Average operating time for the 103 live donor nephrectomies was 130 minutes (range 85 to 210), and there was no case of kidney loss, open surgical conversion or blood transfusion. Mean warm ischemia time was 2.3 +/- 1.2 minutes and average incision length was 6.5 cm. (range 5.1 to 7.0). Postoperative pain was minimal and analgesics were generally not required by postoperative day 2. Patients were fully ambulatory a mean 1.5 days (range 1 to 3.5) postoperatively. CONCLUSIONS: Retroperitoneoscopy assisted live donor nephrectomy is not only feasible, but reproducible. Any surgeon with previous experience with conventional open live donor nephrectomy can perform this hybrid, minimally invasive procedure.

Long-term delivery of all-trans-retinoic acid using biodegradable PLLA/PEG-PLLA blended microspheres.

All-trans-retinoic acid (atRA) has been proved to be effective against several malignancies in human clinical trials. However, in many patients who were treated with atRA, the cancer relapsed after a brief remission. One reason for such relapse is that atRA is metabolized by specific P450s that are induced in the liver during prolonged atRA treatments. In order to overcome such a drawback of atRA, we prepared biodegradable microspheres to provide continuous release of atRA for a long period of time. These biodegradable microspheres were prepared by poly(L-lactide) (PLLA) and polyethylene glycol (PEG)-PLLA diblock copolymers (PLE) in various blending ratios to control the release rate of atRA. As the PLE content in microsphere was increased, the density of the hydrophilic PEG block of PLE on microsphere surfaces increased and the microspheres were dispersed well in PBS without any surfactants. Various release patterns of atRA were obtained according to PLE and atRA contents in the microspheres. Especially, the pseudo-zero-order release profiles were observed for 5 weeks when the contents of PLE and atRA in the microspheres were above 4 wt.%.

Synthesis and structure-activity relationships of novel compounds for the inhibition of TNF-alpha production.

This study describes the synthesis, in vitro evaluation and molecular modeling study of novel compounds for the inhibition of TNF-alpha production. Among these compounds, 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-isoindolinone (9) was selected as a lead compound and its pyridine derivative 10 was more potent in activity and safer than rolipram.

Low molecular weight protamine: a potent but nontoxic antagonist to heparin/low molecular weight protamine.

To avoid bleeding complications, protamine is routinely used after cardiovascular surgery to neutralize the anticoagulant function of heparin. However, its clinical use is associated with adverse and sometimes fatal reactions. Based on literature review of the mechanism of heparin neutralization and protamine induced immunologic toxicity, we propose the following hypothesis: If a chain shortened low molecular weight protamine (LMWP) containing the heparin neutralizing domain could be derived from native protamine, it could be a potent and yet nontoxic heparin antagonist. In this study, we present results to validate this hypothesis. LMWP fragments containing an intact arginine sequence and an average molecular weight of approximately 1,100 daltons were successfully prepared by enzymatic digestion of protamine with thermolysin. In vitro studies show that such LMWP fragments completely neutralized the anticoagulant functions of heparin and LMWH, based on the anti-Xa chromogenic and aPTT clotting time assays. In vivo results reveal that although injection of protamine to mice led to obvious production of anti-protamine antibodies, injection of LMWP did not elicit any detectable immunogenic responses. In addition, these LMWP fragments exhibited a markedly reduced antigenicity and cross-reactivity toward the mice anti-protamine antibodies.

Inflammatory pseudotumor of the urinary bladder in a child.

The inflammatory pseudotumor of the urinary bladder is rare, especially in children. It is a benign proliferative lesion of the submucosal stroma easily mistaken for a sarcoma clinically, so it should be differentiated from a malignant neoplasm. We report the case of bladder inflammatory pseudotumor in a 7-year-old girl.

Inflammatory pseudotumor of urinary bladder.

A previously healthy 44-year-old male was admitted with the chief complaint of intermittent gross hematuria. On initial ultrasonographic and CT examination, a grossly protruding intravesical tumor was noted and, under the impression of a malignant bladder tumor, transurethral resection was performed. The histological findings were spindle cells with elongated cytoplasm with rare mitotic figures distributed in myxoid stroma, consistent with diagnosis of inflammatory pseudotumor of the bladder. The benign nature of this tumor warrants conservative surgical management, usually consisting of transurethral resection or partial cystectomy. No reports of metastasis have been reported following complete excision. Therefore, any suspicion and recognition of this entity is imperative to avoid performing an irreversible radical procedure.

Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo.

Myocardial ischemia and reperfusion lead to myocyte cell death, at least in part, by an apoptotic mechanism. Caspases are a conserved family of proteases that play an essential role in the execution of apoptosis; however, their potential contribution to ischemic myocardial cell death is largely unknown. To examine their role in this process, we subjected rabbits to 30 min of coronary artery occlusion followed by 3 h of reperfusion. Immunoblot analyses revealed that caspases-2, -3 and -7 were proteolytically activated during myocardial ischemia and reperfusion in vivo. In addition, the well-characterized caspase substrate poly(ADP-ribose) polymerase (PARP) was selectively cleaved into its signature apoptotic fragment in ischemic/reperfused myocardium. Systemic administration of the broad-spectrum caspase inhibitor acetyl-Tyr-Val-Ala-Asp chloromethylketone (YVAD-cmk, 4.8 mg/kg) partially blocked caspase activation and dramatically reduced the percentage of terminal dUTP deoyxynucleotidyl-transferase nick end-labeling (TUNEL)-positive myocyte nuclei in the infarct region (3.9+/-0.8%v 13.0+/-2.2% in control animals, P=0.012). Moreover, YVAD-cmk reduced myocardial infarct size by approximately 31% (31.1+/-3.3%v 45.3+/-4.9% in control animals, P=0.032). These results indicate that caspases are critical mediators of myocardial injury induced by ischemia and reperfusion in vivo, and they suggest that caspase inhibition may be therapeutically beneficial in myocardial infarction.

Endobronchial metastasis from stomach cancer.

A young woman presented with a dry cough present during the previous 4 weeks. A chest radiograph demonstrated diffuse interstitial infiltration in both lower lung fields. Fibreoptic bronchoscopic examination revealed multiple 2-3 mm elevated nodules on the bronchial surface and a mucosal biopsy showed extensive subepithelial infiltration of poorly differentiated adenocarcinoma without definite precancerous alteration in the overlying epithelium. Studies for the evaluation of primary tumour focus were performed. Oesophagogastroduodenoscopy showed advanced gastric cancer of Borrmann type III, and mucosal biopsy of the stomach showed poorly differentiated adenocarcinoma. The patient was treated three times with systemic chemotherapy, but her condition deteriorated. Three months after diagnosis, she died of complicated pneumonia. This is a rare case of endobronchial metastasis from stomach cancer. The stomach is an unusual site of endobronchial metastasis from extrathoracic primary malignancy.

Low molecular weight protamine: a potential nontoxic heparin antagonist.

Protamine sulfate is the universal clinical antagonist to heparin and is used routinely after cardiovascular surgery to neutralize the anticoagulant function of heparin. Its clinical use, however, is associated with adverse effects including idiosyncratic fatal reactions. An examination of the mechanism of heparin neutralization and protamine toxicity suggests that the reversal of heparin anticoagulation may only require a small arginine-rich fragment of protamine to electrostatically dissociate antithrombin III from its binding to a specific pentasaccharide sequence in heparin. A review of literature indicates that chain-shortened peptide fragments derived from their parent proteins are normally accompanied with significantly reduced antigenicity and immunogenicity, which are two primary contributing factors to protamine-induced life-threatening toxic effects via an immunoglobulin-mediated pathway. Based on these observations, we propose our general hypothesis: if a chain-shortened low molecular weight protamine fragment containing the heparin-neutralizing domain could be derived directly from a native protamine, it could be a potent and nontoxic heparin antagonist. In this article, we present our experimental results to support the above hypothesis. LMWP fragments containing an intact arginine sequence and an average molecular weight of approximately 1.1 kDa were prepared successfully by enzymatic digestion of native protamine with thermolysin. In vitro studies demonstrated that such LMWP fragments completely neutralized the anticoagulant functions of heparin, based on the anti-Xa chromogenic assay and aPTT clotting time assay. Our in vivo results indicated that while administration of protamine to mice led to obvious production of antiprotamine antibodies, injection of LMWP did not elicit any detectable immunogenic responses. In addition, the LMWP fragments showed a significantly reduced antigenicity or, in other words, cross-reactivity towards the mice antiprotamine antibodies produced by the administration of protamine.

Laparoscopy-assisted urologic surgery through minilaparotomy.

Minimally invasive surgery has gained wide acceptance as a method of reducing postoperative pain and curtailing the convalescence period. We have devised a modified surgical technique of laparoscopy-assisted surgery through minilaparotomy. It is a hybridized form of conventional open and laparoscopic surgery and it combines the benefits of both techniques by reducing postoperative pain and scarring as in laparoscopy, but at the same time maintaining the safety of conventional open surgery. From January 1992 to September 1999, we performed laparoscopy-assisted surgery through minilaparotomy in 167 patients. The operative time for laparoscopy-assisted surgery through minilaparotomy ranged from 79 to 290 minutes (mean 125). There was no conversion to open surgery, no peri- or postoperative complications, and only 3 patients needed a blood transfusion at any stage. Pain was significant on the first day but resolved quickly. All patients resumed consistent oral intake on the second day. All patients commenced ambulation by the second postoperative day and were able to resume full ambulatory activity by the fourth postoperative day. The final would size did not exceed 10 cm in size and all patients expressed satisfaction with their wounds. In conclusion, we believe that laparoscopy-assisted minilaparotomy surgery is a truly minimally invasive technique maintaining the advantages of conventional surgery. Our method could become a first-line approach for simple nephrectomy, living donor nephrectomy and radical nephrectomy, as well as surgery for kidney and ureter stones.