Objectives

To evaluate the accuracy of the Root ZX in teeth with simulated root perforation in the presence of gel or liquid type endodontic irrigants, such as saline, 5.25% sodium hypochlorite (NaOCl), 2% chlorhexidine liquid, 2% chlorhexidine gel, and RC-Prep, and also to determine the electrical conductivities of these endodontic irrigants.

Materials and Methods

A root perforation was simulated on twenty freshly extracted teeth by means of a small perforation made on the proximal surface of the root at 4 mm from the anatomic apex. Root ZX was used to locate root perforation and measure the electronic working lengths. The results obtained were compared with the actual working length (AWL) and the actual location of perforations (AP), allowing tolerances of 0.5 or 1.0 mm. Measurements within these limits were considered as acceptable. Chi-square test or the Fisher's exact test was used to evaluate significance. Electrical conductivities of each irrigant were also measured with an electrical conductivity tester.

Results

The accuracies of the Root ZX in perforated teeth were significantly different between liquid types (saline, NaOCl) and gel types (chlorhexidine gel, RC-Prep). The accuracies of electronic working lengths in perforated teeth were higher in gel types than in liquid types. The accuracy in locating root perforation was higher in liquid types than gel types. 5.25% NaOCl had the highest electrical conductivity, whereas 2% chlorhexidine gel and RC-Prep gel had the lowest electrical conductivities among the five irrigants.

Conclusions

Different canal irrigants with different electrical conductivities may affect the accuracy of the Root ZX in perforated teeth.

All cellular phenomena and developmental events, including inner ear development, are modulated through harmonized signaling networks. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor, is a major signaling component involved in cross talk with key regulators of development; i.e., Wnt, Notch, and bone morphogenetic proteins. Although Pten function has been studied in various systems, its role in inner ear development is poorly understood. Here, we used inner ear-specific Pten conditional knockout mice and examined the characteristics of the inner ear. In a detailed analysis of the phenotype, reduced cochlear turning and widened epithelia were observed. Phalloidin staining of sensory epithelium revealed that hair cell patterns were disturbed; i.e., additional rows of hair cells were discovered. The neural abnormality revealed a reduction in and disorganization of nerve fibers, including apoptosis at the neural precursor stage. Pten deficiency induced increased phosphorylation of Akt at Ser473. The elevation of inhibitory glycogen synthase kinase 3β Ser9 phosphorylation (pGSK3β) was sustained until the neuronal differentiation stage at embryonic day 14.5, instead of pGSK3β downregulation. This is the first report on the influence of Pten/Akt/GSK3β signaling on the development of spiral ganglia. These results suggest that Pten is required for the maintenance of neuroblast number, neural precursors, and differentiation in the inner ear.

Background

Genome-wide association studies (GWAS) have identified approximately three dozen single nucleotide polymorphisms (SNPs) consistently associated with prostate cancer (PCa) risk. Despite the reproducibility of these associations, the molecular mechanism for most of these SNPs has not been well elaborated as most lie within non-coding regions of the genome. Androgens play a key role in prostate carcinogenesis. Recently, using ChIP-on-chip technology, 22,447 androgen receptor (AR) binding sites have been mapped throughout the genome, greatly expanding the genomic regions potentially involved in androgen-mediated activity.

Methodology/Principal findings

To test the hypothesis that sequence variants in AR binding sites are associated with PCa risk, we performed a systematic evaluation among two existing PCa GWAS cohorts; the Johns Hopkins Hospital and the Cancer Genetic Markers of Susceptibility (CGEMS) study population. We demonstrate that regions containing AR binding sites are significantly enriched for PCa risk-associated SNPs, i.e. more than expected by chance alone. In addition, compared with the entire genome, these newly observed risk-associated SNPs in these regions are significantly more likely to overlap with established PCa risk-associated SNPs from previous GWAS. These results are consistent with our previous finding from a bioinformatics analysis that one-third of the 33 known PCa risk-associated SNPs discovered by GWAS are located in regions of the genome containing AR binding sites.

Conclusions/Significance

The results to date provide novel statistical evidence suggesting an androgen-mediated mechanism by which some PCa associated SNPs act to influence PCa risk. However, these results are hypothesis generating and ultimately warrant testing through in-depth molecular analyses.

Nanotechnology has been extensively explored for drug delivery. Here, we introduce the concept of a nanodrug based on synergy of photothermally-activated physical and biological effects in nanoparticle-drug conjugates. To prove this concept, we utilized tumor necrosis factor-alpha coated gold nanospheres (Au-TNF) heated by laser pulses. To enhance photothermal efficiency in near-infrared window of tissue transparency we explored slightly ellipsoidal nanoparticles, its clustering, and laser-induced nonlinear dynamic phenomena leading to amplification and spectral sharpening of photothermal and photoacoustic resonances red-shifted relatively to linear plasmonic resonances. Using a murine carcinoma model, we demonstrated higher therapy efficacy of Au-TNF conjugates compared to laser and Au-TNF alone or laser with TNF-free gold nanospheres. The photothermal activation of low toxicity Au-TNF conjugates, which are in phase II trials in humans, with a laser approved for medical applications opens new avenues in the development of clinically relevant nanodrugs with synergistic antitumor theranostic action.

Background

Parasite peptidases have been actively studied as vaccine candidates or drug targets for prevention or treatment of parasitic diseases because of their important roles for survival and/or invasion in the host. Like other parasites, the facultative histophagous ciliate Miamiensis avidus would possess peptidases that are closely associated with the invasion into the host tissue and survival in the host.

Results

The 17 genes encoding peptidases, including seven cathepsin-like cysteine peptidases, four serine carboxypeptidases, a eukaryotic aspartyl protease family protein, an ATP-dependent metalloprotease FtsH family protein, three leishmanolysin family proteins and a peptidase family M49 protein were identified from a Miamiensis avidus cDNA library by BLAST X search. Expression of genes encoding two cysteine peptidases, three leishmanolysin-like peptidases and a peptidase family M49 protein was up-regulated in the cell-fed ciliates compared to the starved ciliates. Especially, one cysteine peptidase (MaPro 4) and one leishmanolysin-like peptidase (MaPro 14) were transcribed more than 100-folds in the cell-fed ciliates.

Conclusions

The genetic information and transcriptional characteristics of the peptidases in the present results would be helpful to elucidate the role of peptidases in the invasion of scuticociliates into their hosts.

Background

If a chronically infected abdominal wound develops, complications such as peritonitis and an abdominal wall defect could occur. This could prolong the patient's hospital stay and increase the possibility of re-operation or another infection as well. For this reason, a solution for infection control is necessary. In this study, surgery using a rectus abdominis muscle myofascial splitting flap was performed on an abdominal wall defect.

Methods

From 2009 to 2012, 5 patients who underwent surgery due to ovarian rupture, cesarean section, or uterine myoma were chosen. In each case, during the first week after operation, the wound showed signs of infection. Surgery was chosen because the wounds did not resolve with dressing. Debridement was performed along the previous operation wound and dissection of the skin was performed to separate the skin and subcutaneous tissue from the attenuated rectus muscle and Scarpa's fascial layers. Once the anterior rectus sheath and muscle were adequately mobilized, the fascia and muscle flap were advanced medially so that the skin defect could be covered for reconstruction.

Results

Upon 3-week follow-up after a rectus abdominis myofascial splitting flap operation, no major complication occurred. In addition, all of the patients showed satisfaction in terms of function and esthetics at 3 to 6 months post-surgery.

Conclusions

Using a rectus abdominis myofascial splitting flap has many esthetic and functional benefits over previous methods of abdominal defect treatment, and notably, it enabled infection control by reconstruction using muscle.

Tetrahydrobiopterin (BH4) deficiency is a genetic disorder associated with a variety of metabolic syndromes such as phenylketonuria (PKU). In this article, the signaling pathway by which BH4 deficiency inactivates mTORC1 leading to the activation of the autophagic pathway was studied utilizing BH4-deficient Spr-/- mice generated by the knockout of the gene encoding sepiapterin reductase (SR) catalyzing BH4 synthesis. We found that mTORC1 signaling was inactivated and autophagic pathway was activated in tissues from Spr-/- mice. This study demonstrates that tyrosine deficiency causes mTORC1 inactivation and subsequent activation of autophagic pathway in Spr-/- mice. Therapeutic tyrosine diet completely rescued dwarfism and mTORC1 inhibition but inactivated autophagic pathway in Spr-/- mice. Tyrosine-dependent inactivation of mTORC1 was further supported by mTORC1 inactivation in Pahenu2 mouse model lacking phenylalanine hydroxylase (Pah). NIH3T3 cells grown under the condition of tyrosine restriction exhibited autophagy induction. However, mTORC1 activation by RhebQ64L, a positive regulator of mTORC1, inactivated autophagic pathway in NIH3T3 cells under tyrosine-deficient conditions. In addition, this study first documents mTORC1 inactivation and autophagy induction in PKU patients with BH4 deficiency.

Quantification of quality of life (QOL) related to disease severity is important in patients with atopic dermatitis (AD), because the assessment provides additional information to the traditional objective clinical scoring systems. To document the impact of AD on QOL for both children and adults as well as to quantify the relationship with disease severity, QOL assessments were performed over a 6-month period on 415 patients with AD. A questionnaire derived from the Infants' Dermatitis Quality of Life Index (IDQOL), the Children's Dermatology Life Quality Index (CDLQI) and the Dermatology Life Quality Index (DLQI) was used to determine the QOL for 71 infants, 197 children and 147 adults, respectively. To measure AD severity, both the Rajka & Langeland scoring system and the Scoring of Atopic Dermatitis (SCORAD) index were used. The mean scores were as follows: 7.7 ± 5.5 for IDQOL, 6.6 ± 6.3 for CDLQI, and 10.7 ± 7.9 for DLQI. In conclusion, these QOL scores are correlated with AD severity scores as estimated by the Rajka & Langeland severity score and the SCORAD. The outcome of the QOL instruments in this study demonstrates that atopic dermatitis of both children and adults affects their QOL.

Objectives

The purpose of this study was to enhance curing light penetration through resin inlays by modifying the thicknesses of the dentin, enamel, and translucent layers.

Materials and Methods

To investigate the layer dominantly affecting the power density of light curing units, resin wafers of each layer with 0.5 mm thickness were prepared and power density through resin wafers was measured with a dental radiometer (Cure Rite, Kerr). The dentin layer, which had the dominant effect on power density reduction, was decreased in thickness from 0.5 to 0.1 mm while thickness of the enamel layer was kept unchanged at 0.5 mm and thickness of the translucent layer was increased from 0.5 to 0.9 mm and vice versa, in order to maintain the total thickness of 1.5 mm of the resin inlay. Power density of various light curing units through resin inlays was measured.

Results

Power density measured through 0.5 mm resin wafers decreased more significantly with the dentin layer than with the enamel and translucent layers (p < 0.05). Power density through 1.5 mm resin inlays increased when the dentin layer thickness was reduced and the enamel or translucent layer thickness was increased. The highest power density was recorded with dentin layer thickness of 0.1 mm and increased translucent layer thickness in all light curing units.

Conclusions

To enhance the power density through resin inlays, reducing the dentin layer thickness and increasing the translucent layer thickness would be recommendable when fabricating resin inlays.

Background

Patients who have undergone enucleation during infancy due to retinoblastoma can develop microorbitalism due to the decreased growth stimulation from the eyeball and the surrounding soft tissues. Anatomically, the orbit consist of parts of the frontal bone superiorly, the maxilla inferiorly, the ethmoid bone medially, and the zygoma laterally. Considering the possibility of surgically expanding the orbit using tripod osteotomy, in this study we conducted tripod osteotomy on adult patients with microorbitalism of retinoblastoma.

Methods

Tripod osteotomy was conducted to expand the orbital volume in adult patients with microorbitalism due to enucleation in infancy for retinoblastoma. The orbital volume was measured using the Aquarius Workstation ver. 4.3.6 and the orbit width was measured with preoperative and postoperative 3-dimensional facial bone computed tomography (CT) imaging. Preoperative and postoperative photographs were used to visualize the difference produced by the surgery.

Results

The orbital volume of the affected side was 10.3 cm3 before and 12.5 cm3 after the surgery, showing an average increase in volume of 2.2 cm3 (21.4%). The increase in the obital width was confirmed by the preoperative and postoperative 3-dimensional facial CT images and aesthetic improvement was observed by the preoperative and postoperative photographs.

Conclusions

Tripod osteotomy, which realigns the orbital bone, zygoma, and maxilla, is used to correct posttraumatic malunion as well as non-traumatic congenital abnormalities such as that seen in facial cleft. We applied this procedure in microorbitalism secondary to enucleation for retinoblastoma to allow orbital expansion and correct asymmetry.

Intestinal giant-cystic disease (IGCD) of the Israel carp (Cyprinus carpio nudus) has been recognized as one of the most serious diseases afflicting inland farmed fish in the Republic of Korea, and Thelohanellus kitauei has been identified as the causative agent of the disease. Until now, studies concerning IGCD caused by T. kitauei in the Israel carp have been limited to morphological and histopathological examinations. However, these types of diagnostic examinations are relatively time-consuming, and the infection frequently cannot be detected in its early stages. In this study, we cloned the full-length 18S rRNA gene of T. kitauei isolated from diseased Israel carps, and carried out molecular identification by comparing the sequence with those of other myxosporeans. Moreover, conventional PCR and real-time quantitative PCR (qPCR) using oligonucleotide primers for the amplification of 18S rRNA gene fragment were established for further use as methods for rapid diagnosis of IGCD. Our results demonstrated that both the conventional PCR and real-time quantitative PCR systems applied herein are effective for rapid detection of T. kitauei spores in fish tissues and environmental water.

Background

The aim of this study was to analyze clinical situations requiring rigid bronchoscopy and evaluate usefulness of rigid bronchoscopic intervention in benign or malignant airway disorders.

Methods

We retrospectively reviewed 29 patients who underwent rigid bronchoscopy from November 2007 to February 2011 at St. Paul's Hospital, The Catholic University of Korea School of Medicine.

Results

Of the 29 patients, the most frequent underlying etiology was benign stenosis of trachea (n=20). Of those 20 patients, 16 had post-intubation tracheal stenosis (PITS), 2 had tracheal stenosis due to inhalation burn (IBTS) and other 2 had obstructive fibrinous tracheal pseudomembrane (OFTP). Other etiologies were airway malignancy (n=6), endobronchial stenosis due to tuberculosis (n=2), and foreign body (n=1). For treatment, silicone stent insertion was done in 16 cases of PITS and IBTS and mechanical removal was performed in 2 cases of OFTP. In 6 cases of malignant airway obstruction mechanical debulking was performed and silicone stents were inserted additionally in 2 cases. Balloon dilatation and electrocautery were used in 2 cases of endobronchial stenosis due to tuberculosis. In all cases of stent, airway obstructive symptom improved immediately. Granulation tissue formation was the most common complication.

Conclusion

Tracheal stenosis was most common indication and silicone stenting was most common procedure of rigid bronchoscopy in our center. Rigid bronchoscopic procedures, at least tracheal silicone stenting, should be included in pulmonary medicine fellowship programs because it is a very effective and indispensable method to relieve critical airway obstruction which needs training to learn.

Background

Orbital roof fractures are frequently associated with a high energy impact to the craniofacial region, and displaced orbital roof fractures can cause ophthalmic and neurologic complications and occasionally require open surgical intervention. The purpose of this article was to investigate the clinical features and treatment outcomes of orbital root fractures combined with neurologic injuries after early reconstruction.

Methods

Between January 2006 and December 2008, 45 patients with orbital roof fractures were admitted; among them, 37 patients were treated conservatively and 8 patients underwent early surgical intervention for orbital roof fractures. The type of injuries that caused the fractures, patient characteristics, associated fractures, ocular and neurological injuries, patient management, and treatment outcomes were investigated.

Results

The patients underwent frontal craniotomy and free bone fragment removal, their orbital roofs were reconstructed with titanium micromesh, and associated fractures were repaired. The mean follow up period was 11 months. There were no postoperative neurologic sequelae. Postoperative computed tomography scans showed anatomically reconstructed orbital roofs. Two of the five patients with traumatic optic neuropathy achieved full visual acuity recovery, one patient showed decreased visual acuity, and the other two patients completely lost their vision due to traumatic optic neuropathy. Preoperative ophthalmic symptoms, such as proptosis, diplopia, upper eyelid ptosis, and enophthalmos were corrected.

Conclusions

Early recognition and treatment of orbital roof fractures can reduce intracranial and ocular complications. A coronal flap with frontal craniotomy and orbital roof reconstruction using titanium mesh provides a versatile method and provides good functional and cosmetic results.

This paper investigates the issue of interference avoidance in body area networks (BANs). IEEE 802.15 Task Group 6 presented several schemes to reduce such interference, but these schemes are still not proper solutions for BANs. We present a novel distributed TDMA-based beacon interval shifting scheme that reduces interference in the BANs. A design goal of the scheme is to avoid the wakeup period of each BAN coinciding with other networks by employing carrier sensing before a beacon transmission. We analyze the beacon interval shifting scheme and investigate the proper back-off length when the channel is busy. We compare the performance of the proposed scheme with the schemes presented in IEEE 802.15 Task Group 6 using an OMNeT++ simulation. The simulation results show that the proposed scheme has a lower packet loss, energy consumption, and delivery-latency than the schemes of IEEE 802.15 Task Group 6.

Aquagenic urticaria is a rare form of physical urticaria, in which contact with water evokes wheals. A 19-year-old man and a 4-year-old boy complained of recurrent episodes of urticaria. Urticaria appeared while taking a bath or a shower, in the rain, or in a swimming pool. Well-defined pin head to small pea-sized wheals surrounded by variable sized erythema were provoked by contact with water on the face, neck, and trunk, regardless of its temperature or source. Results from a physical examination and a baseline laboratory evaluation were within normal limits. Treatment of the 19-year-old man with 180 mg fexofenadine daily was successful to prevent the wheals and erythema. Treatment with 5 ml ketotifen syrup bid per day resulted in improvement of symptoms in the 4-year-old boy.

A 35-year-old man with infertility was referred for chromosomal analysis. In routine cytogenetic analysis, the patient was seen to have additional material of unknown origin on the terminal region of the short arm of chromosome 4. To determine the origin of the unknown material, we carried out high-resolution banding, comparative genomic hybridization (CGH), and FISH. CGH showed a gain of signal on the region of 4q32→q35. FISH using whole chromosome painting and subtelomeric region probes for chromosome 4 confirmed the aberrant chromosome as an intrachromosomal insertion duplication of 4q32→q35. Duplication often leads to some phenotypic abnormalities; however, our patient showed an almost normal phenotype except for congenital dysfunction in spermatogenesis.

Hepatocellular carcinoma (HCC) is a common cancer and hepatitis B virus (HBV) is a major etiological agent. Convincing epidemiological and experimental evidence also links HCC to aflatoxin, a naturally occurring mycotoxin that produces a signature p53-249ser mutation. Recently, we have reported that tumor-derived HBx variants encoded by HBV exhibited attenuated transactivation and pro-apoptotic functions, but retained their ability to block p53-mediated apoptosis. These results indicate that mutations in HBx may contribute to the development of HCC. In this study, we determined whether tumor-derived HBx mutants along, or in cooperation with p53-249ser, could alter cell proliferation and chromosome stability of normal human hepatocytes. To test this hypothesis, we established a telomerase immortalized normal human hepatocycte line HHT4 that exhibited a near diploid karyotype and expressed many hepatocyte-specific genes. We found that over-expression one of the tumor-derived HBx mutants, CT, significantly increased colony forming efficiency (CFE) while its corresponding wild-type allele CNT significantly decreased CFE in HHT4 cells. p53-249ser rescued CNT-mediated inhibition of colony formation. While HHT4 cells lacked an anchorage independent growth capability as they did not form any colonies in soft agar, the CT-expressing HHT4 cells could form colonies, which could be significantly enhanced by p53-249ser. Induction of aneuploidy could be observed in HHT4 cells expressing CT but additional recurring chromosome abnormalities could only be detected in cells coexpressing CT and p53-249ser. Our results are consistent with the hypothesis that certain mutations in HBx and p53 at codon 249 may cooperate in contributing to liver carcinogenesis.

Background

Type B insulin resistance syndrome is a manifestation of autoantibodies to the insulin receptor that results in severe hyperglycemia and acanthosis nigricans. However, the mechanisms by which these autoantibodies induce hypoglycemia are largely unknown. In this paper, we report the case of patient with type B insulin resistance syndrome who presented with frequent severe fasting hypoglycemia and acanthosis nigricans.

Methods

To evaluate the mechanism of hypoglycemia, we measured the inhibition of insulin binding to erythrocytes and IM9 lymphocytes in a sample of the patient's dialyzed serum before and after immunosuppressive therapy.

Results

In the patient's pre-treatment serum IgG, the binding of 125I-insulin to erythrocytes was markedly inhibited in a dose-dependent manner until the cold insulin level reached 10-9 mol/L. We also observed dose-dependent inhibition of insulin binding to IM9 lymphocytes, which reached approximately 82% inhibition and persisted even when diluted 1:20. After treatment with glucocorticoids, insulin-erythrocyte binding activity returned to between 70% and 80% of normal, while the inhibition of insulin-lymphocyte binding was reduced by 17%.

Conclusion

We treated a patient with type B insulin resistance syndrome showing recurrent fasting hypoglycemia with steroids and azathioprine. We characterized the patient's insulin receptor antibodies by measuring the inhibition of insulin binding.

In vivo multicolor photoacoustic (PA) flow cytometry for ultra-sensitive molecular detection of the CD44+ circulating tumor cells (CTCs) is demonstrated on a mouse model of human breast cancer. Targeting of CTCs with stem-like phenotype, which are naturally shed from parent tumors, was performed with functionalized gold and magnetic nanoparticles. Results in vivo were verified in vitro with a multifunctional microscope, which integrates PA, photothermal (PT), fluorescent and transmission modules. Magnet-induced clustering of magnetic nanoparticles in individual cells significantly amplified PT and PA signals. The novel noninvasive platform, which integrates multispectral PA detection and PT therapy with a potential for multiplex targeting of many cancer biomarkers using multicolor nanoparticles, may prospectively solve grand challenges in cancer research for diagnosis and purging of undetectable yet tumor-initiating cells in circulation before they form metastasis.

The retinal pigment epithelium (RPE) is indispensable for photoreceptor function, not only because it provides functional photopigments to photoreceptors, but also because it eliminates oxidatively damaged materials from photoreceptors. Maintaining homeostatic antioxidative programs that support a healthy RPE is therefore important for the normal functioning of the eye. These homeostatic mechanisms, however, often fail in aged RPE cells that have been exposed repeatedly to excessive oxidative stress. When RPE cells succumb to oxidative stress, their death contributes to the development of retinal degenerative diseases such as age-related macular degeneration. Recent studies have highlighted the importance of reciprocal phosphoinositide signaling events orchestrated by phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) in the homeostatic programs that protect RPE cells against oxidative stress. Here, we discuss the role of PI3K signaling pathways in RPE cells and suggest that they might be crucial targets of oxidative molecules that initiate early pathological events in retinal degenerative diseases.

Although it is well known that multiple genes may influence prostate cancer risk, most current efforts at identifying prostate cancer risk variants rely on single-gene approaches. In previous work using mostly single-gene approaches, we observed significant associations (P < 0.05) for 6 of 46 polymorphisms in five genes in a Swedish prostate cancer case-control study population. We now report on the higher-order gene-gene interactions among those 46 genetic variants and the combined effect of the six polymorphisms with significant main effects for association with prostate cancer risk in 795 controls and 1,461 cases. Classification and regression tree analysis was used to evaluate higher-order gene-gene interactions. No interactions were confirmed by the result from logistic regressions. For the combined analysis, we tested the hypothesis that individuals carrying multiple copies of risk variants are at increased risk for prostate cancer. Individuals carrying more than eight copies of any risk variant were almost twofold more likely to get prostate cancer (OR = 1.99, P = 0.0014). A significant trend relationship was observed (P < 0.0001). In the present study, additive effects but not multiplicative effects among these six polymorphisms with significant main effects were observed.

Obstructive fibrinous tracheal pseudomembrane is a rare, but potentially fatal complication associated with endotracheal intubation. It has been known that the formation of tracheal pseudomembrane is related with intracuff pressure during endotracheal intubation or infectious cause. But in the patient described in this case, pseudomembrane formation in the trachea was associated with subglottic epithelial trauma or caustic injuries to the trachea caused by aspirated gastric contents during intubation rather than tracheal ischemia due to high cuff pressure. We report a patient with obstructive fibrinous tracheal pseudomembrane after endotracheal intubation who presented with dyspnea and stridor and was treated successfully with mechanical removal using rigid bronchoscopy.

Background/Aims

Based on the results of well designed clinical studies, intensive insulin therapy has been established to improve glycemic control in newly diagnosed diabetes. However, discrepancies exist between the findings of clinical trials and experiences in general practice. Furthermore, the efficacy of an early insulin therapy (EIT) - commonly used in general practice - on long-term glycemic control has not been established. Therefore, we evaluated the effects of EIT on pancreatic β-cell function and glycemic control using insulin-based methods widely employed in general practice.

Methods

We performed a retrospective cohort study that initially involved reviewing patients' medical records. Following a thorough review, 61 patients who received either biphasic or prandial EIT at the time of diagnosis were enrolled. We then evaluated changes in β-cell function and glycemic control during a 48-month follow-up period.

Results

Mean HbA1c decreased significantly as a result of EIT from 10.7 ± 1.8% to 6.2 ± 1.1% (p < 0.001). On average, 2.6 months was required to achieve an HbA1c value < 7%. EIT significantly improved the insulinogenic index. Glycemic control was well maintained for 48 months. More than 70% of patients were able to maintain glycemic control following lifestyle modifications or treatment with oral antidiabetic drugs. No significant differences were identified between patients receiving biphasic EIT and prandial EIT in terms of glycemic control or pancreatic β-cell function.

Conclusions

Our results suggest that regardless of the method of delivery, EIT significantly improves β-cell function and facilitates long-term glycemic control in patients with newly diagnosed type 2 diabetes mellitus.

Background

Cancer cells recurrently develop into acquired resistance to the administered drugs. The iatrogenic mechanisms of induced chemotherapy-resistance remain elusive and the degree of drug resistance did not exclusively correlate with reductions of drug accumulation, suggesting that drug resistance may involve additional mechanisms. Our aim is to define the potential targets, that makes drug-sensitive MCF-7 breast cancer cells turn to drug-resistant, for the anti-cancer drug development against drug resistant breast cancer cells.

Methods

Doxorubicin resistant human breast MCF-7 clones were generated. The doxorubicin-induced cell fusion events were examined. Heterokaryons were identified and sorted by FACS. In the development of doxorubicin resistance, cell-fusion associated genes, from the previous results of microarray, were verified using dot blot array and quantitative RT-PCR. The doxorubicin-induced expression patterns of pro-survival and pro-apoptotic genes were validated.

Results

YB-1 and ABCB5 were up regulated in the doxorubicin treated MCF-7 cells that resulted in certain degree of genomic instability that accompanied by the drug resistance phenotype. Cell fusion increased diversity within the cell population and doxorubicin resistant MCF-7 cells emerged probably through clonal selection. Most of the drug resistant hybrid cells were anchorage independent. But some of the anchorage dependent MCF-7 cells exhibited several unique morphological appearances suggesting minor population of the fused cells maybe de-differentiated and have progenitor cell like characteristics.

Conclusion

Our work provides valuable insight into the drug induced cell fusion event and outcome, and suggests YB-1, GST, ABCB5 and ERK3 could be potential targets for the anti-cancer drug development against drug resistant breast cancer cells. Especially, the ERK-3 serine/threonine kinase is specifically up-regulated in the resistant cells and known to be susceptible to synthetic antagonists.