Pilot dose-ranging of rhIGF-1/rhIGFBP-3 in a preterm lamb model of evolving bronchopulmonary dysplasia.

BACKGROUND: Low levels of insulin-like growth factor-1 (IGF-1) protein in preterm human infants are associated with bronchopulmonary dysplasia (BPD). We used our preterm lamb model of BPD to determine (1) dosage of recombinant human (rh) IGF-1 bound to binding protein-3 (IGFBP-3) to reach infant physiologic plasma levels; and (2) whether repletion of plasma IGF-1 improves pulmonary and cardiovascular outcomes. METHODS: Group 1: normal, unventilated lambs from 128 days gestation through postnatal age 5 months defined normal plasma levels of IGF-1. Group 2: continuous infusion of rhIGF-1/rhIGFBP-3 (0.5, 1.5, or 4.5 mg/kg/day; n = 2) for 3 days in mechanically ventilated (MV) preterm lambs determined that 1.5 mg/kg/day dosage attained physiologic plasma IGF-1 concentration of ~125 ng/mL, which was infused in four more MV preterm lambs. RESULTS: Group 1: plasma IGF-1 protein increased from ~75 ng/mL at 128 days gestation to ~220 ng/L at 5 months. Group 2: pilot study of the optimal dosage (1.5 mg/kg/day rhIGF-1/rhIGFBP-3) in six MV preterm lambs significantly improved some pulmonary and cardiovascular outcomes (p < 0.1) compared to six MV preterm controls. RhIGF-1/rhIGFBP-3 was not toxic to the liver, kidneys, or lungs. CONCLUSIONS: Three days of continuous iv infusion of rhIGF-1/rhIGFBP-3 at 1.5 mg/kg/day improved some pulmonary and cardiovascular outcomes without toxicity. IMPACT: Preterm birth is associated with rapid decreases in serum or plasma IGF-1 protein level. This decline adversely impacts the growth and development of the lung and cardiovascular system. For this pilot study, continuous infusion of optimal dosage of rhIGF-1/rhIGFBP-3 (1.5 mg/kg/day) to maintain physiologic plasma IGF-1 level of ~125 ng/mL during mechanical ventilation for 3 days statistically improved some structural and biochemical outcomes related to the alveolar formation that would favor improved gas exchange compared to vehicle-control. We conclude that 3 days of continuous iv infusion of rhIGF-1/rhIGFBP-3 improved some physiological, morphological, and biochemical outcomes, without toxicity, in mechanically ventilated preterm lambs.

mTORC1 Controls Phase Separation and the Biophysical Properties of the Cytoplasm by Tuning Crowding.

Macromolecular crowding has a profound impact on reaction rates and the physical properties of the cell interior, but the mechanisms that regulate crowding are poorly understood. We developed genetically encoded multimeric nanoparticles (GEMs) to dissect these mechanisms. GEMs are homomultimeric scaffolds fused to a fluorescent protein that self-assemble into bright, stable particles of defined size and shape. By combining tracking of GEMs with genetic and pharmacological approaches, we discovered that the mTORC1 pathway can modulate the effective diffusion coefficient of particles ≥20 nm in diameter more than 2-fold by tuning ribosome concentration, without any discernable effect on the motion of molecules ≤5 nm. This change in ribosome concentration affected phase separation both in vitro and in vivo. Together, these results establish a role for mTORC1 in controlling both the mesoscale biophysical properties of the cytoplasm and biomolecular condensation.

Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials.

Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.

Predictors for the progression of geographic atrophy in patients with age-related macular degeneration: fundus autofluorescence study with modified fundus camera.

PURPOSE: We examined the association between abnormal fundus autofluorescence (FAF) features on images obtained by a modified fundus camera (mFC) and geographic atrophy (GA) progression in patients with age-related macular degeneration (AMD). METHODS: Serial FAF images of 131 eyes from 131 patients with GA were included in the study. All FAF images were obtained with an mFC (excitation, ∼ 500-610 nm; emission, ∼ 675-715 nm). The GA area was quantified at baseline and 1 year later using a customized segmentation program. The yearly GA enlargement rate was then calculated. Abnormal FAF patterns in the junctional zone of GA were classified as None or Minimal change, Focal, Patchy, Banded, or Diffuse according to previously published classification based on confocal scanning laser ophthalmoscopy (cSLO). The relationship between GA enlargement and abnormal FAF was evaluated. RESULTS: The mean rate of GA enlargement was the fastest in eyes with Diffuse pattern (1.74 mm(2) per year), followed by eyes with the Banded pattern (1.69 mm(2) per year). Binary logistic regression analysis revealed that eyes with the Banded and Diffuse pattern had significantly higher risk for GA enlargement compared with eyes with the other patterns. CONCLUSIONS: FAF image obtained by mFC appears to be acceptable for evaluating GA in accordance with an established cSLO-based classification. Eyes with the Banded or the Diffuse patterns of abnormal FAF at baseline indicate a high risk for GA progression. Identifying patients at high risk for GA progression using an mFC is broadly available method that can provide additional information to help predict disease course.

Monitoring differentiated thyroid cancer patients with negative serum thyroglobulin. Diagnostic implication of TSH-stimulated antithyroglobulin antibody.

AIM: Serum antithyroglobulin antibody (TgAb) has been reported as a surrogate marker for differentiated thyroid cancer (DTC) in some conditions. We investigated changes in serum TgAb levels after stimulation with thyroid-stimulating hormone (TSH) and the clinical implications for monitoring DTC. PATIENTS, METHODS: We retrospectively enrolled 53 DTC patients who had undergone total thyroidectomy and were negative for serum Tg and positive for TgAb. Patients underwent high-dose radioactive iodine treatment, and serum TgAb was measured before (TgAbBAS) and after TSH stimulation (TgAbSTIM). TgAb was followed up 6 to 12 months later (TgAbF/U). The change in TgAb after TSH stimulation (∆TgAbSTIM) was calculated as a percentage of the baseline level. Patient disease status was classified into no residual disease (ND) and residual or recurred disease (RD) by follow-up imaging studies and pathologic data. The characteristics and diagnostic value of serum TgAb levels and ∆ TgAbSTIM were investigated with respect to disease status. RESULTS: 38 patients were in the ND group and 15 were in the RD group. TgAbBAS, TgAbSTIM and TgAbF/U were significantly higher in the RD compared to the ND group (p = 0.0008, 0.0002, and < 0.0001, respectively). ∆TgAbSTIM was also significantly higher in the RD group (p = 0.0009). In the patients who presented with obviously high (≥ 50%) or low (< -50%) ∆ TgAbSTIM, the proportions in the RD group were markedly different at 100% and 7%, respectively. ∆ TgAbSTIM had significant diagnostic value for RD (p < 0.001). CONCLUSION: The change in serum TgAb level after TSH stimulation is different between the RD and ND groups, and thus, it may be used as a surrogate diagnostic marker for DTC when the serum Tg is negative and TgAb is positive.

Complementary treatment of siTERT for improving the antitumor effect of TERT-specific I-131 therapy.

Sodium iodide symporter (NIS)-based radionuclide therapy provides an effective means of treating malignant tumors. However, it is sometimes inadequate because of limited effects on radio-resistant tumors, and thus, combination therapies with other therapeutic options have been requested to enhance its efficacy. Human telomerase reverse transcriptase (hTERT) has been reported to be involved in the progression of most cancers and also been viewed as a good candidate for targeting tumor. Application of TERT-specific radionuclide therapies using NIS gene transfer have been reported to treat TERT-positive tumors, but this approach only demonstrated tumor regression rather than eradication. As inhibiting TERT expression by introducing the hTERT-specific shRNA (siTERT) has been suggested as a therapeutic option, we investigated the complementary role of siTERT treatment after the TERT-specific I-131 therapy and its possibility as a novel anticancer therapeutic strategy. Retroviruses containing TERT promoter/NIS for TERT specific Radionuclide therapy and siTERT for TERT targeting antisense therapy were produced. Hep3B cells expressing TERT specific NIS (Hep3B-TERT/NIS) were xenografted into nude mouse and visualized with micro-SPECT/CT for monitoring NIS activity. The levels of hTERT mRNA, protein and its activity were confirmed by RT-PCR, Western blotting and Telomerase repeat amplification protocol assay. Cell proliferation was monitored by MTT assay and induced apoptosis was confirmed by Annexin-V-PI staining. Therapeutic effects of I-131 and/or siTERT were evaluated by clonogenic assay and mouse tumor model. Reduction of hTERT mRNA, protein and TERT activity by siTERT were observed in Hep3B-TERT/NIS cells. The viabilities of the infected cells were significantly decreased to 50% versus siScramble treated controls. The early apoptotic cell population was increased by siTERT. The survival rates of cells treated with siTERT or I-131 alone were 72.4±7.6% and 56.2±5.2%, respectively. However, the survival rate of cells treated with I-131 and siTERT were decreased to 22.1±2.8%. From mouse xenograft model, we also found that the siTERT gene therapy showed synergism to the radioiodine therapy for reducing tumor growth in vivo. Our Results suggested that complementary siTERT gene therapy offers a novel strategy of cancer therapy to improve the therapeutic efficacy of TERT-specific I-131.

Changes in antibiotic usage and susceptibility in nosocomial Enterobacteriaceae and Pseudomonas isolates following the introduction of ertapenem to hospital formulary.

There is concern that widespread usage of ertapenem may promote cross-resistance to other carbapenems. To analyse the impact that adding ertapenem to our hospital formulary had on usage of other broad-spectrum agents and on susceptibilities of nosocomial Enterobacteriaceae and Pseudomonas isolates, we performed interrupted time-series analyses to determine the change in linear trend in antibiotic usage and change in mean proportion and linear trend of susceptibility pre- (March 2004-June 2005) and post- (July 2005-December 2008) ertapenem introduction. Usage of piperacillin-tazobactam (P=0·0013) and ampicillin-sulbactam (P=0·035) declined post-ertapenem introduction. For Enterobacteriaceae, the mean proportion susceptible to ciprofloxacin (P=0·016) and piperacillin-tazobactam (P=0·038) increased, while the linear trend in susceptibility significantly increased for cefepime (P=0·012) but declined for ceftriaxone (P=0·0032). For Pseudomonas, the mean proportion susceptible to cefepime (P=0·011) and piperacillin-tazobactam (P=0·028) increased, as did the linear trend in susceptibility to ciprofloxacin (P=0·028). Notably, no significant changes in carbapenem susceptibility were observed.

Bilateral cataract surgery: a controlled clinical trial.

PURPOSE: To evaluate the efficacy and safety of simultaneous bilateral cataract surgery with respect to patient satisfaction, outcomes, and complication rates. METHODS: We conducted a prospective study of consecutive patients who had simultaneous bilateral cataract surgery on the same day or separate bilateral cataract surgery with an interval of 2 days between operations. The changes in refraction, visual acuity, degree of anisometropia, and complication rates were compared between the simultaneous bilateral cataract surgery and separate bilateral cataract surgery groups. Patient satisfaction was assessed with a questionnaire. RESULTS: Ninety-four patients who had simultaneous bilateral cataract surgery and 100 patients who had separate bilateral cataract surgery were enrolled in this study. The preoperative best-corrected visual acuity (logMAR) was 0.31 +/- 0.17 in the simultaneous bilateral cataract surgery group and 0.29 +/- 0.16 in the separate bilateral cataract surgery group, and it improved postoperatively to 0.11 +/- 0.12 in the simultaneous bilateral cataract surgery group and to 0.10 +/- 0.11 in the separate bilateral cataract surgery group. There was no significant difference between the two groups (P = 0.061). In addition, 96.8% of eyes in the simultaneous bilateral cataract surgery group and 97.0% of eyes in the separate bilateral cataract surgery group were within 1.0 diopters of the mean absolute error, and there were no sight-threatening intraoperative or postoperative complications in the two groups. CONCLUSIONS: Simultaneous bilateral cataract surgery may be an effective and safe bilateral cataract surgery option with a high degree of patient satisfaction.

Restoration of patency in iliofemoral deep vein thrombosis with catheter-directed thrombolysis does not always prevent post-thrombotic damage.

OBJECTIVES: To evaluate the long-term results of catheter-directed thrombolysis (CDT) and the feasibility of stent placement for lower extremity deep vein thrombosis (DVT). DESIGN & METHODS: Retrospective study of 34 patients (10 men and 24 women, mean age 55, S.D. 13 years) with lower extremity DVT underwent CDT at Seoul National University Hospital from January 1999 to October 2003. Patient characteristics, risk factors of DVT, extent of thrombosis, and short-term and long-term results of CDT and/or stent placement were analysed. RESULTS: Mean follow-up times were 47 S.D. 16 months. The primary technical success rate was 97% (complete lysis 68%, partial 29%). During the follow-up periods 11 (32%) patients showed re-thrombosis. Sixteen (47%) of 34 patients showed chronic change of vessels during the follow-up periods. By Cox Proportional Hazard analysis, extent of thrombolysis was a statistically significant factor affecting the freedom of re-thrombosis and chronic change (P=0.008 and P=0.001). Nine (44%) of 21 deployed stents were obstructed, and the overall stent patency at 3 years was 56.7%. The only factor affecting the stent patency was stent length more than 6 cm (P=0.002, HR 13, 95% CI 2.7-59). CONCLUSION: Long-term results of CDT are not satisfactory because of the high recurrence rate of DVT and it cannot prevent chronic post-thrombotic damage to the affected vessels despite long-term anticoagulation therapy. Careful long-term surveillance of the venous function is highly recommended after CDT.

Combined endovenous laser treatment and ambulatory phlebectomy for the treatment of saphenous vein incompetence.

OBJECTIVES: The aim of this retrospective study is to assess the safety and effectiveness of endovenous laser treatment (EVLT) combined with ambulatory phlebectomy (AP) as a single procedure for treating saphenous vein incompetence. METHODS: The study enrolled 148 patients with saphenofemoral or saphenopopliteal junction reflux associated with saphenous vein incompetence and enlarged branch veins. Patients were treated with EVLT (135 great saphenous veins, 41 small saphenous veins) concomitantly with AP as a single procedure. All patients were followed up by clinical assessment and duplex ultrasound at one week and 12 weeks after the procedure. RESULTS: No postprocedural deep vein thrombosis and pulmonary embolism occurred. Saphenous vein recanalization rate at three months was 5.7%. Residual varicosities were found in 11.4% of the patients at three months after procedure, but only 2.3% of those required subsequent interventions. CONCLUSION: Combined EVLT and AP could be a safe and effective treatment modality for the saphenous vein incompetence.

Absorbed radiation dose of the female breast during diagnostic multidetector chest CT and dose reduction with a tungsten-antimony composite breast shield: preliminary results.

AIM: To determine the absorbed radiation dose to the female breast during chest computed tomography (CT), and whether a custom-designed breast shield can reduce that dose. MATERIALS AND METHODS: Bilateral breast phantoms were combined with an anthropomorphic torso phantom. Each breast phantom contained 20 thermoluminescent dosimeter (TLD) cavities. Eight cavities were used per phantom. Absorbed radiation was measured using TLD 100 s. Three-stacked TLDs comprised a set. Three sets of three TLDs were positioned at eight designated locations and three depths (surface; 1 cm; 4 cm). One set of three TLDs was positioned at eight additional designations, 1cm deep. Each breast was divided anatomically into quadrants. In total, 32 TLD sets/96 TLDs were deployed. The breast-torso phantom was consecutively imaged using a 16-detector array CT machine. Subsequently, 32 new TLD sets were similarly placed, the phantom re-imaged in a likewise manner, but with the application of a tungsten-antimony composite breast shield. TLD readings were averaged and calculated. RESULTS: Average absorbed radiation doses for unshielded right and left breast phantoms ranged from 13.83-19.36 mGy, and 14-20.47 mGy, respectively. The absorbed dose in the shielded right and left breast was reduced to 6.64-8.12 mGy, and 6.7-8.03 mGy, respectively. Average absorbed radiation doses based on the depth for the unshielded breasts ranged from 15.4-18.3 mGy. Shielding reduced this dose to 7-7.9 mGy. Unshielded absorbed radiation doses based on anatomic quadrants ranged from 17.5-18.9 mGy. Shielding reduced this dose to 7-7.5 mGy. CONCLUSIONS: The average absorbed radiation dose to the unshielded female breast phantom is approximately 14-20 mGy. An externally applied shield can reduce this absorbed dose by 56-61%.

Congenital sudoriferous cyst within the orbit followed by esotropia.

PURPOSE: To report a case of congenital sudoriferous cyst of the orbit with esotropia. METHODS: A 20-day-old male, born prematurely presented with a palpable lump on left upper lid. Orbital ultrasonography including color doppler image and orbital magnetic resonance image were performed to evaluate the lid lesion. The mass was excised and histologically examined. Complete ocular examination including visual acuity, duction, version, and the presence of strabismus were performed. RESULTS: A well circumscribed round cystic mass, measuring 1.4 x 1.3 cm was noted at medial superior aspect of the left orbit. It compressed and displaced the left globe to inferior posterior position with intact optic nerve. Histopathologic examination showed the lesion to be a solitary sudoriferous cyst lined by two layers of cuboidal epithelial cells with eosinophilic cytoplasm. After the excision of the mass, limitations of extraocular muscle movements, esotropia, and amblyopia were noted. CONCLUSIONS: If an orbital cyst affects the globe or extraocular muscles, it should be excised as soon as possible to prevent strabismus and amblyopia especially in infant.

Anorexiant-induced transient myopia after myopic laser in situ keratomileusis.

We report a case of acute transient myopia associated with ciliochoroidal effusion induced by anorexiants. The patient had had myopic laser in situ keratomileusis 7 years earlier. Acute bilateral myopia associated with anterior chamber shallowing, intraocular pressure elevation, diffuse ciliochoroidal effusion, and perimacular retinal folds was relieved 14 days after discontinuation of anorexiant medications. Tropicamide and atropine were used to deepen the anterior chamber. Sympathomimetic drugs such as phendimetrazine and ephedrine are used as anorexiants and may induce transient myopia associated with ciliochoroidal effusion, shallow anterior chamber, and acute angle-closure glaucoma.

Laser photocoagulation combined with intravitreal triamcinolone acetonide injection in proliferative diabetic retinopathy with macular edema.

PURPOSE: To evaluate therapeutic effects and usefulness of a combination treatment of intravitreal injection of triamcinolone acetonide (IVTA) and panretinal photocoagulation (PRP) in patients with clinically significant macular edema secondary to proliferative diabetic retinopathy (PDR). METHODS: Visual acuity test, fundoscopy, fluorescein angiography, and optical coherence tomography (OCT) were taken in 20 patients (20 eyes) of macular edema and PDR. A combination of intravitreal injection of triamcinolone acetonide and PRP was performed in 10 patients (10 eyes) and a combination of focal or grid laser photocoaqulation and PRP in the remaining 10 eyes. The postoperative outcomes were compared between the two combination treatments by best corrected visual acuity (BCVA), tonometry, fluorescein angiography, and OCT at 2 weeks, 1, 2, and 3 months. RESULTS: Average BCVA (log MAR) significantly improved from preoperative 0.56-/+0.20 to 0.43-/+0.08 at 1 month (P=0.042) and it was maintained until 3 months after a combination of IVTA and PRP in 10 eyes (P=0.007). The thickness of fovea decreased from average 433.3-/+114.9 micrometer to average 279.5-/+34.1 micrometer at 2 weeks after combined treatment of IVTA and PRP (P=0.005), which was significantly maintained until 3 months, but there was a transient visual disturbance and no significant difference in thickness of the fovea before and after treatment in the groups with PRP and focal or grid laser photocoagulation. CONCLUSIONS: A combination of IVTA and PRP might be an effective treatment modality in the treatment of macular edema and PDR and prevent the subsequent PRP-induced macular edema result in visual dysfunction. In combination with PRP, IVTA might be more effective than focal or grid laser photocoagulation and PRP for reducing diabetic macular edema and preventing aggravation of macular edema without transient visual disturbance in patients requiring immediate PRP.

Artisan phakic intraocular lens implantation after retinal detachment surgery.

PURPOSE: To report three cases of Artisan phakic intraocular lens (PIOL) implantation to correct myopic refractive error after previous retinal detachment surgery treated with scleral encircling. METHODS: Artisan PIOLs were implanted in a 29-year-old man with -21.0 -2.0 x 180 manifest refraction and best spectacle-corrected visual acuity (BSCVA) of 20/40 (case 1), a 28-year-old woman with BSCVA of 20/20 and -8.5 -1.0 x 180 manifest refraction (case 2), and a 44-year-old man with BSCVA of 20/32 and -11.75 -1.75 x 10 manifest refraction (case 3). RESULTS: In case 1, 24 months after implantation of the Artisan PIOL, uncorrected visual acuity (UCVA) was 20/40. In case 2, 24 months after surgery, UCVA was 20/32. In case 3, 3 months after surgery, UCVA was 20/32. There was no formation of new breaks, progressive vitreoretinal traction, or complications. CONCLUSIONS: The Artisan PIOL may provide an alternative method to correct high myopia after retinal detachment surgery.

FDG uptake and glucose transporter type 1 expression in lymph nodes of non-small cell lung cancer.

AIMS: FDG uptake in NSCLC is related to glucose transporter type 1 (Glut-1) expression. Here, we investigated the direct causal relationship between FDG uptake and Glut-1 expression to determine the role of Glut-1 in FDG uptake by malignant and benign lymph nodes (LNs). METHODS: Fifty-five curative lung resections in 53 NSCLC patients (male:female=36:17, age=62.0+/-11.8 years) were included. Maximum standardized uptake values (maxSUVs) of LNs in preoperative whole body FDG-PET and Glut-1 immunostaining results were compared. RESULTS: Of 316 pathologically confirmed LNs, 12.3% (39/316) were malignant, and in malignant LNs, FDG positive LNs were no different from FDG negative LNs in terms of size (15.0+/-6.7 mm vs 10.0+/-6.1mm, p>0.05), or in terms of the proportion of LNs occupied by tumor (60.0+/-28.8% vs 39.2+/-38.4%, p>0.05), but had greater percentages of Glut-1 positive cells in tumors (74.1+/-31.8% vs 22.7+/-18.7%, p<0.01), and Glut-1 staining intensities (3.4+/-0.9 vs 1.8+/-1.3, p<0.01). FDG negative malignant LNs featured cytoplasmic Glut-1 expression and adenocarcinoma. Glut-1 staining intensities were found to be significantly correlated with the maxSUVs of malignant LNs (rho=0.516, p<0.05), but the percentages of Glut-1 positive cells in tumors were not (r=0.2072, p>0.05). Analysis of FDG positive benign LNs showed that maxSUV was not correlated with degree of follicular hyperplasia, or Glut-1 expression (p>0.05). CONCLUSIONS: Intense Glut-1 immunoreactivity was found to be proportionally related to the degree of FDG uptake by malignant LNs in NSCLC. However, the finding that Glut-1 expression in lymphoid hyperplasia showed no correlation with FDG uptake in benign LNs requires further investigation.

Structure-activity relationship of neuropeptide gamma derived from mammalian and fish.

This study of relationship between structure and biologic activity was performed using five neuropeptide gammas [NPgamma; mammalian-NPgamma (M-NPgamma), trout-NPgamma (T-NPgamma), goldfish-NPgamma (G-NPgamma), bowfin-NPgamma (B-NPgamma), and shark-NPgamma (S-NPgamma)]. Circular dichroism (CD) spectra showed that all peptides took random structure in buffer solution. In neutral and acidic liposomes, M-NPgamma, T-NPgamma, B-NPgamma, and S-NPgamma still adopted random structure, while G-NPgamma had an alpha-helical structure. The biologic activity of NPgammas has been estimated by their effects on the intestinal motility and arterial relaxation. The intestinal motility was investigated with rat duodenum (RD), carp intestine (CI), and guinea-pig ileum (GPI). The arterial relaxing effect was tested with guinea-pig aorta (GPA) and rat mesenteric artery (RMA). In RD, the order of potency compared with the EC50 value was M-NPgamma >> S-NPgamma >> B-NPgamma >> G-NPgamma >> T-NPgamma. G-NPgamma was the most contractile agent in CI. S-NPgamma was the most contractile agent in GPI. Using an arterial relaxing test, the order of potency was G-NPgamma >> T-NPgamma >> B-NPgamma >> S-NPgamma >> M-NPgamma in GPA, and all NPgammas remarkably reduced relaxing activity in RMA. Despite their structural similarities to NPgammas, G-NPgamma has high affinity to tachykinin receptor-binding sites in GPA and CI, indicating an alpha-helical structure may have a critical role for receptor binding. However, an alpha-helical structure does not play a critical role in recognizing receptor-binding sites in RD and GPI.

Detection of response-predicting mutations in the kinase domain of the epidermal growth factor receptor gene in cholangiocarcinomas.

PURPOSE: Epidermal growth factor receptor (EGFR) signalings have recently been implicated in the genesis and progression of cholangiocarcinomas. Thus, the EGFR kinase inhibitor appears to be promising in the treatment of this cancer. The response-predicting mutations in the tyrosine kinase domain of EGFR gene have recently been detected in non-small cell lung cancers. This study was, therefore, to investigate if these mutations are also found in cholangiocarcinomas. METHODS: Twenty-two consecutive cholangiocarcinoma patients who underwent surgical resection were enrolled. Their resected paraffin-embedded cholangiocarcinoma specimens were used for mutation analysis, which was performed by DNA sequencing of exons 18, 19 and 21 in the EGFR gene. Clinical characteristics were compared between each group according to the presence or absence of mutations. RESULTS: Three patients (13.6%) harbored EGFR mutations. All the mutations found were deletions in exon 19. Mutations were more common in intra-hepatic or poorly differentiated tumors. Differences in age, sex, stage at diagnosis and survival were not observed between mutation-positive and -negative patients. CONCLUSIONS: This study, for the first time, demonstrates that a subset of cholangiocarcinoma patients has response-predicting EGFR mutations. Therefore, a highly selected application of the EGFR kinase inhibitor would be therapeutically effective in these patients.

Parametric image of myocardial blood flow generated from dynamic H2(15)O PET using factor analysis and cluster analysis.

Algorithm-based parametric imaging of myocardial blood flow (MBF), as measured by H2(15)O PET, has been the goal of many research efforts. A method for generating parametric images of regional MBF by factor and cluster analysis on H2(15)O dynamic myocardial PET was validated by its comparison with gold-standard MBF values determined invasively using radiolabelled microspheres. Right and left ventricular blood pool activities and their factor images were obtained by the application of factor analysis to dynamic frames. By subtraction of the factor images multiplied by their corresponding values on the factors from the original dynamic images for each frame, pure tissue dynamic images were obtained, from which arterial blood activities were excluded. Cluster analysis that averaged pixels having time-activity curves with the same shape was applied to pure tissue images to generate parametric MBF images. The usefulness of this method for quantifying regional MBF was evaluated using canine experiment data. H2(15)O PET scans and microsphere studies were performed on seven dogs at rest and after pharmacological stress. The image qualities and the contrast of parametric images obtained using the proposed method were significantly improved over either the tissue factor images or the parametric images obtained using a conventional method. Regional MBFs obtained using the proposed method correlated well with those obtained by the region of interest method (r = 0.94) and by the microsphere technique (r = 0.90). A non-invasive method is presented for generating parametric images of MBF from H2(15)O PET, using factor and cluster analysis.

Comparison of [18F]fluorodeoxyglucose uptake with glucose transporter-1 expression and proliferation rate in human glioma and non-small-cell lung cancer.

To clarify the biological significance of [18F]fluorodeoxyglucose (18F-FDG) accumulation in patients with cancer, we assessed the relationships between 18F-FDG uptake and glucose transporter-1 (GLUT-1) expression and proliferation rate in human glioma and lung cancer. We obtained FDG PET images and measured standardized uptake values (SUVs) of primary tumours in 13 patients with brain glioma and 25 patients with non-small-cell lung cancer. After surgery, portions of respected tumours were obtained, and the proliferation rate was measured as proliferation index (per cent of (S+G2+M)/(G0+G1+S+G2+M)) using DNA flow cytometry. The expression of GLUT-1 in a tumour was evaluated by using immunostaining. We classified GLUT-1 expression as grade 0 (no positive cell), grade 1 (< 10% cells positive), grade 2 (11-50% cells positive) and grade 3 (51-100% cells positive). Based on the expression of GLUT-1, cases with grades 0, 1, 2 and 3 showed SUVs of 6.1 +/- 2.8, 5.0 +/- 3.2, 8.3 +/- 3.3 and 10.4 +/- 6.6, respectively (P < 0.05). Non-small-cell lung cancer showed higher FDG uptake (SUV, 8.5 +/- 5.1) and higher GLUT-1 expression (grade, 2.0 +/- 1.0) than did brain glioma (SUV, 4.7 +/- 2.5; grade, 0.8 +/- 0.8). Based on the total number of cases, SUVs did not relate to proliferation index (r = 0.19). In non-small-cell lung cancer, SUVs did not correlate with proliferation index, whereas in glioma, SUVs were strongly related to proliferation index (r = 0.79, P < 0.01). In conclusion, FDG uptake generally correlated with GLUT-1 expression in non-small-cell lung cancer and glioma. In the case of glioma, FDG uptake also indicated increased cellular proliferation, which was not demonstrated in non-small-cell lung cancer.