To evaluate respiratory motion of a patient by generating four-dimensional digital tomosynthesis (4D DTS), extracting respiratory signal from patients' on-board projection data, and ensuring the feasibility of 4D DTS as a localization tool for the targets which have respiratory movement.
Methods and Materials
Four patients with lung and liver cancer were included to verify the feasibility of 4D-DTS with an on-board imager. CBCT acquisition (650–670 projections) was used to reconstruct 4D DTS images and the breath signal of the patients was generated by extracting the motion of diaphragm during data acquisition. Based on the extracted signal, the projection data was divided into four phases: peak-exhale phase, mid-inhale phase, peak-inhale phase, and mid-exhale phase. The binned projection data was then used to generate 4D DTS, where the total scan angle was assigned as ±22.5° from rotation center, centered on 0° and 180° for coronal “half-fan” 4D DTS, and 90° and 270° for sagittal “half-fan” 4D DTS. The result was then compared with 4D CBCT which we have also generated with the same phase distribution.
The motion of the diaphragm was evident from the 4D DTS results for peak-exhale, mid-inhale, peak-inhale and mid-exhale phase assignment which was absent in 3D DTS. Compared to the result of 4D CBCT, the view aliasing effect due to arbitrary angle reconstruction was less severe. In addition, the severity of metal artifacts, the image distortion due to presence of metal, was less than that of the 4D CBCT results.
We have implemented on-board 4D DTS on patients data to visualize the movement of anatomy due to respiratory motion. The results indicate that 4D-DTS could be a promising alternative to 4D CBCT for acquiring the respiratory motion of internal organs just prior to radiotherapy treatment.
Renal allograft tolerance has been achieved in MHC-mismatched primates via nonmyeloablative conditioning beginning 6 days prior to planned kidney and donor bone marrow (DBM) transplantation. To extend the applicability of this approach to deceased donor transplantation, we recently developed a novel conditioning regimen, the “delayed protocol” in which DBM is transplanted several months after kidney transplantation. However, activation/expansion of donor-reactive CD8+ memory T cells (TMEM) occurring during the interval between kidney and DBM transplantation impaired tolerance induction using this strategy. In the current study, we tested whether, Alefacept, a fusion protein which targets LFA-3/CD2 interactions and selectively depletes CD2highCD8+ effector memory T cells (TEM) could similarly induce long-term immunosuppression-free renal allograft survival but avoid the deleterious effects of anti-CD8 mAb treatment. We found that Alefacept significantly delayed the expansion of CD2high cells including CD8+ TEM while sparing naïve CD8+ T and NK cells and achieved mixed chimerism and long-term immunosuppression-free renal allograft survival. In conclusion, elimination of CD2high T cells represents a promising approach to prevent electively the expansion/activation of donor-reactive TEM and promotes tolerance induction via the delayed protocol mixed chimerism approach.
kidney transplantation; tolerance; non-human primates; mixed hematopoietic chimerism; memory T cells
We report the findings of 18F-fluorodeoxyglocese positron emission tomography (FDG-PET) and diffusion tensor tractography (DTT) in a right-handed patient presenting with callosal disconnection syndrome, including alien hand syndrome, after an anterior communicating artery aneurysmal rupture. The 49-year-old patient had right hemiparesis and unintended movement of the right hand during action of the left hand. A brain magnetic resonance imaging revealed lesions in the upper part of the genu and body in the corpus callosum as well as hemorrhage in the inter-hemispheric fissure. We observed extensive disruption of corpus callosum fibers in the upper genu and trunk by DTT for the evaluation of inter-hemispheric connection. FDG-PET revealed severe hypometabolism in the left cerebral hemisphere, including basal ganglia and thalamus, and hypermetabolism in the right cerebral hemisphere. Based on findings of FDG-PET and DTT, the callosal disconnection syndrome presented in the patient could be the result of loss of transcallosal inhibition in the contralateral hemisphere.
Corpus callosum; Positron emission tomography; Diffusion tensor imaging
As PI3K/Akt signaling is frequently deregulated in a wide variety of human tumors, PI3K inhibitors are an emerging class of drugs for cancer treatment. The monitoring of the drug behavior and distribution in the biological system can play an important role for targeted therapy and provide information regarding the response or resistance to available therapies. In this study, therefore, we have developed a family of xanthine derivatives, serving as a dual function exhibiting fluorescence, as well as inhibiting PI3K. Among them, HS-133 showed anti-proliferative effects and was monitored for its subcellular localization by a fluorescence microscopy. HS-133 suppressed the PI3K/Akt pathway and induced cell cycle arrest at the G0/G1 phase. The induction of apoptosis by HS-133 was confirmed by the increases of the cleaved PARP, caspase-3, and caspase-8. Furthermore, HS-133 decreased the protein expression of HIF-1α and VEGF, as well inhibited the tube formation and migration of the human umbilical vein endothelial cells. In vivo imaging also showed that tumors were visualized fluorescent with HS-133, and its oral administration significantly inhibited the growth of tumor in SkBr3 mouse xenograft models. Thus, we suggest that HS-133 may be used as a fluorescent anticancer agent against human breast cancer.
Anticancer; Targeted therapy; PI3K; Fluorescence; Imaging; Apoptosis
[Purpose] The purpose of this study was to investigate the changes in pain, dysfunction,
and grip strength of patients with acute lateral epicondylitis and to suggest the
appropriate treatment frequency and period. [Subjects] The subjects were divided into
three: 2 days per week group (n=12), 3 days per week group (n=15), and 6 days per week
group (n=13). [Methods] All groups received conventional physical therapy for 40 minutes
and therapeutic exercises for 20 minutes per session during 6 weeks. The outcome
measurements were the visual analogue scale (VAS), Patient-Rated Tennis Elbow Evaluation
(PRTEE), and grip strength. [Results] The results of this study were as follows: at 3
weeks, there were no significant differences in VAS and PRTEE in the 3 groups, but at 6
weeks, 6 days per week group significantly decreased these two outcomes. Grip strength was
significantly increased in 3 and 6 days per week groups at 6 weeks. [Conclusion] In
conclusion, physical therapy is needed 3 days per week for 3 weeks in patients with acute
lateral epicondylitis. After 3 weeks, 6 days per week is the most effective treatment
Dysfunction; Frequency of physical therapy; Lateral epicondylitis
Hematopoiesis is a complex process requiring multiple regulators for hematopoietic stem/progenitor cells (HSPC) and differentiation to multi-lineage blood cells. TC1(C8orf4) is implicated in cancers, hematological malignancies and inflammatory activation. Here, we report that Tc1 regulates hematopoiesis in mice. Myeloid and lymphoid cells are increased markedly in peripheral blood of Tc1–deleted mice compared to wild type controls. Red blood cells are small-sized but increased in number. The bone marrow of Tc1−/− mice is normocellular histologically. However, Lin−Sca-1+c-Kit+ (LSK) cells are expanded in Tc1−/− mice compared to wild type controls. The expanded population mostly consists of CD150−CD48+ cells, suggesting the expansion of lineage-restricted hematopoietic progenitor cells. Colony forming units (CFU) are increased in Tc1−/− mice bone marrow cells compared to controls. In wild type mice bone marrow, Tc1 is expressed in a limited population of HSPC but not in differentiated cells. Major myeloid transcriptional regulators such as Pu.1 and Cebpα are not up-regulated in Tc1−/− mice bone marrow. Our findings indicate that TC1 is a novel hematopoietic regulator. The mechanisms of TC1-dependent HSPC regulation and lineage determination are unknown.
Mild traumatic brain injury (mTBI) is frequently associated with psychiatric symptoms and cognitive dysfunction, as well as with the receipt of workers' compensation, as many mTBIs occur due to work-related accidents. We hypothesized that depression and insufficient cognitive effort mediate the relationship between sociodemographic variables and cognitive dysfunction in mTBI.
A retrospective chart review study was conducted using 115 records of patients with mTBI. Cognitive effort was measured based on scores on the Rey 15-Item Test. Multivariate linear regression analysis was performed to examine factors predictive of cognitive functions. Path analysis was subsequently performed to investigate the mediating effects of depression and cognitive effort in relation to receipt of workers' compensation and demographic variables.
Fifteen of the 115 participants (13.0%) received failing scores on the Rey 15-Item Test, which indicated insufficient cognitive effort. Path analysis indicated that cognitive effort mediated the effects of age and workers' compensation on cognitive functions.
Given the significant mediating effects of cognitive effort on cognitive performance, it is important to address patient motivation and encourage mTBI patients covered by workers' compensation to perform tests with authentic effort.
Neuropsychological test; Brain concussion; Depression; Mental process; Compensation
The NF-κB pathway transcriptionally controls a large set of target genes that play important roles in cell survival, inflammation, and immune responses. While many studies showed anti-tumorigenic and pro-survival role of NF-κB in cancer cells, recent findings postulate that NF-κB participates in a senescence-associated cytokine response, thereby suggesting a tumor restraining role of NF-κB. In this review, we discuss implications of the NF-κB signaling pathway in cancer. Particularly, we emphasize the connection of NF-κB with cellular senescence as a response to chemotherapy, and furthermore, present examples how distinct oncogenic network contexts surrounding NF-κB produce fundamentally different treatment outcomes in aggressive B-cell lymphomas as an example.
cancer; chemotherapy; NF-κB; senescence
Pulmonary lesions from active tuberculosis patients are thought to contain persistent, nonreplicating bacilli that arise from hypoxic stress. Metronidazole, approved for anaerobic infections, has antituberculosis activity against anoxic bacilli in vitro and in some animal models and may target persistent, nonreplicating bacilli. In this double-blind, placebo-controlled trial, pulmonary multidrug-resistant tuberculosis subjects were randomly assigned to receive metronidazole (500 mg thrice daily) or placebo for 8 weeks in addition to an individualized background regimen. Outcomes were measured radiologically (change on high-resolution computed tomography [HRCT]), microbiologically (time to sputum smear and culture conversion), and clinically (status 6 months after stopping therapy). Enrollment was stopped early due to excessive peripheral neuropathies in the metronidazole arm. Among 35 randomized subjects, 31 (15 metronidazole, 16 placebo) were included in the modified intent-to-treat analysis. There were no significant differences by arm in improvement of HRCT lesions from baseline to 2 or 6 months. More subjects in the metronidazole arm converted their sputum smear (P = 0.04) and liquid culture (P = 0.04) to negative at 1 month, but these differences were lost by 2 months. Overall, 81% showed clinical success 6 months after stopping therapy, with no differences by arm. However, 8/16 (50%) of subjects in the metronidazole group and 2/17 (12%) of those in the placebo group developed peripheral neuropathy. Subjects who received metronidazole were 4.3-fold (95% confidence interval [CI], 1.1 to 17.1) more likely to develop peripheral neuropathies than subjects who received placebo. Metronidazole may have increased early sputum smear and culture conversion but was too neurotoxic to use over the longer term. Newer nitroimidazoles with both aerobic and anaerobic activity, now in clinical trials, may increase the sterilizing potency of future treatment regimens.
Pedicled transverse rectus abdominis musculocutaneous flaps typically sacrifice the entire muscle. In our experience, the lateral strip of the rectus abdominis muscle can be spared in an attempt to maintain function and reduce morbidity. When the intercostal nerves are injured, muscle atrophy appears with time. The severed intercostal nerve was reinserted into the remnant lateral strip of the rectus abdominis muscle to reduce muscle atrophy.
The authors retrospectively reviewed 9 neurotized cases and 10 non-neurotized cases. Abdominal computed tomography was performed to determine the area of the rectus muscles. Electromyography (EMG) was performed to check contractile function of the remnant muscle. A single investigator measured the mean areas of randomly selected locations (second lumbar spine) using ImageJ software in a series of 10 cross-sectional slices. We compared the Hounsfield unit (HU) pre- and postoperatively to evaluate regeneration quality.
In the neurotization group, 7 of 9 cases maintained the mass of remnant muscle. However, in the non-neurotization group, 8 of 10 lost their mass. The number of totally atrophied muscles in each of the two groups was significantly different (P=0.027). All of the remnant muscles showed contractile function on EMG. The 9 remaining remnant rectus abdominis muscles showed declined the HU value after surgery but also within a normal range of muscle.
Neurotization was found to be effective in maintaining the mass of remnant muscle. Neurotized remnant muscle had contractile function on EMG and no fatty degeneration by HU value.
Rectus abdominis; Nerve transfer; Electromyography; Multidetector computed tomography
Spinal accessory neuropathy is commonly caused by iatrogenic injury or secondary to trauma or infection. Nevertheless, the tumor related palsy is rare. We present a case of an 18-year-old male patient suffering from paralysis of his right trapezius and sternocleidomastoid muscle. An electrophysiologic diagnostic study confirmed the spinal accessory neuropathy of the proximal segment. In addition, magnetic resonance imaging showed the location of tumor on the jugular foramen. However, the type of the tumor was not confirmed through biopsy because the patient refused surgical procedure. Based on the study, it is hypothesized that the tumor located on the jugular foramen should be considered as a cause of the spinal accessory nerve of the proximal segment.
Accessroy nerve; Glomus jugulare; Neoplasms
Ischiofemoral impingement syndrome is known as one of the causes of hip pain due to impingement of ischium and femur, and usually correlated with trauma or operation. We report a rare case of ischiofemoral impingement syndrome that has no history of trauma or surgery. A 48-year-old female patient was referred for 2 months history of the left hip pain, radiating to lower extremity with a hip snapping sensation. She had no history of trauma or surgery at or around the hip joint and femur. The magnetic resonance imaging (MRI) of the lumbar spine showed no abnormality, except diffuse bulging disc without cord compression at the lumbosacral area. Electrophysiologic study was normal, and there were no neurologic abnormalities compatible with the lumbosacral radiculopathy or spinal stenosis. Hip MRI revealed quadratus femoris muscle edema with concurrent narrowing of the ischiofemoral space. The distance of ischiofemoral space and quadratus femoris space were narrow. It was compatible with ischiofemoral impingement syndrome. After treatment with nonsteroidal anti-inflammatory drugs, physical therapy, and exercise program, the patient's pain was relieved and the snapping was improved. To our knowledge, this is the first reported case of a nontraumatic, noniatrogenic ischiofemoral impingement syndrome, and also the first case to be treated by a nonsurgical method in the Republic of Korea.
Ischiofemoral; Impingement; Impingement syndrome
Mesoporous silica (MPS) nanoparticles (NPs), which have a unique pore structure and extremely large surface area and pore volume, have received much attention because of their biomedical application potential. Using MPS NPs for biomedical devices requires the verification of their biocompatibility because the surface area of NPs is one of the most important determinants of toxicity, including the cellular uptake and immune response. We have previously reported that the cytotoxicity and inflammation potential of MPS NPs have been shown to be lower than those of general amorphous colloidal silica (Col) NPs in macrophages, but the low cytotoxicity does not guarantee high biocompatibility in vivo. In this study, we compared the in vivo immunotoxicity of MPS and Col NPs in the mouse model to define the effects of pore structural conditions of silica NPs.
Materials and methods
Both MPS and Col NPs (2, 20, and 50 mg/kg/day) were intraperitoneally administered in female BALB/c mice for 4 weeks, and clinical toxicity, lymphocyte population, serum IgG/IgM levels, and histological changes were examined.
There was no overt sign of clinical toxicity in either MPS- or Col-treated mice. However, MPS NPs led to significant increases in liver and spleen weight and splenocyte proliferation. Mice treated with MPS NPs showed altered lymphocyte populations (CD3+, CD45+, CD4+, and CD8+) in the spleen, increased serum IgG and IgM levels, and histological changes. Despite slight changes in lymphocyte populations in the spleen, Col NPs did not alter other immunological factors.
The results indicate that in vivo exposure to MPS NPs caused more damage to systemic immunity than that of Col NPs through the dysregulation of the spleen. The results for in vivo data are inconsistent with those for in vitro data, which show lower cytotoxicity for MPS NPs. These results suggest the importance of verifying biocompatibility both in vitro and in vivo during the design of new nanomaterials.
immunotoxicity; mesoporous silica nanoparticle; colloidal silica nanoparticle; spleen
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder that presents with hemolytic anemia, marrow failure and thrombophilia. During acute attacks, corticosteroid can alleviate the hemolytic paroxysm, but the prolonged administration induces serious toxicity including immunosuppression. So American thoracic society (ATS) for tuberculosis (TB) recommends prophylactic anti-TB medication in patients with a long-term steroid therapy. However, in the patient who was treated for active TB in the past, there are no guidelines of the test for determining patients who have latent TB infection (LTBI) and no recommendations of TB prophylaxis if there is no evidence of reactivation at present. A 40-year-old male patient presented with fever and aggravated weakness for a week. He was diagnosed with PNH a month ago and took corticosteroid for 3 weeks. In the past, he was diagnosed with pulmonary TB and completely cured after treatment. According to guideline, he was not indicated with TB prophylaxis. However, he caught miliary TB, progressed to acute respiratory distress syndrome. We experience this embarrassing case, and emphasize the need to investigate multicentral TB prevalence and to make the guidelines of anti-TB medication in subgroups of hematologic diseases including PNH.
Paroxysmal nocturnal hemoglobinuria; Miliary tuberculosis (TB); Tuberculosis (TB) prophylaxis
Central cord syndrome (CCS) is extremely rare as a direct consequence of generalized epileptic seizure. CCS is associated with hyperextension of the spinal cord and has characteristic radiologic findings including posterior ligamentous injury and prevertebral hyperintensity following magnetic resonance imaging (MRI). We experienced the case of a 25-year-old man who suffered CCS after status epilepticus. Cervical spinal MRI revealed high signal intensity at the C1 level but with no signal or structural changes in other sites. After rehabilitation management, the patient significantly improved on the ASIA (American Spinal Injury Association) motor scale and bladder function. We proposed that epilepsy related CCS may be caused by muscle contractions during generalized seizure, which can induce traction injury of the spinal cord or relative narrowing of spinal canal via transient herniated nucleus pulposus or transient subluxation of vertebra. We also suggest CCS without radiologic findings of trauma has good prognosis compared with other CCS.
Central cord syndrome; Status epilepticus
The purpose of the present study was to develop reliable and valid parent and teacher scales for measurement of functional impairment in children and adolescents in order to assist the diagnosis of attention-deficit/hyperactivity disorder (ADHD).
Seventy-two children with ADHD fulfilling the Diagnostic and Statistical Manual of Mental Disorder, 4th Edition criteria and forty-two normal controls were enrolled in this study. Parents and teachers of the subjects completed the parent and teacher form of the preliminary items of Child and Adolescent Functioning Impairment Scale (CAFIS) made up by the authors. Based on the reliability and factor analysis, the final parent (CAFIS-parent form) and teacher version (CAFIS-teacher form) were constructed. Scales were analyzed for reliability and validity. Relative operating characteristics curve was drawn to calculate the cutoff scores of these scales for children with ADHD.
The CAFIS-parent and CAFIS-teacher forms consist of four and three factors, respectively. Internal consistency and test-retest correlation of the scales were satisfactory. The CAFIS and Children's Global Assessment Scale were significantly correlated. All scores of subscales of CAFIS in ADHD group were significantly higher than those of control group. The sensitivity and specificity of the subscales were mostly at an appropriate level.
The CAFIS is a brief layperson-administered scale to assess functional impairment of children and adolescents. It can be a useful tool for parents and teachers to objectively measure the functions of children at home and in school. This scale was found to be reliable and valid, and it appears to be a valuable instrument in Korean language.
Attention-deficit/hyperactivity disorder; Child and adolescent; Impairment; Scale; Reliability; Validity
This multicenter, randomized, open-label, parallel trial aimed to provide a detailed dose-response profile for atomoxetine in Korean pediatric outpatients with attention-deficit/hyperactivity disorder (ADHD).
Male and female outpatients aged 6-18 years with ADHD meeting symptom severity criteria of 1.5 standard deviations above age and gender norms on the ADHD Rating Scale-IV-Parent: Investigator-Administered and Scored (ADHDRS-IV-Parent: Inv), and a Clinical Global Impression-ADHD-Severity score ≥4 were randomized to atomoxetine (mg/kg/day) 0.2 fixed, 0.5 fixed or 0.5 (7 days), 0.8 (7 days) then 1.2 for 28 days. The primary efficacy measure was change in ADHDRS-IV-Parent: Inv total score after 6 weeks of atomoxetine treatment.
Of 153 randomized patients, 83.7% were male and mean age was 9.8 (SD±2.4) years. The completion rate was 86.9%. A graded dose response was apparent with mean change in ADHDRS-IV-Parent: Inv total scores of -9.6, -12.3 and -14.5 with atomoxetine 0.2, 0.5 and 1.2 mg/kg/day, respectively (p=0.024 - F-test). Moreover, a greater reduction in ADHD symptoms, as assessed by mean change from baseline to endpoint CGI-S and mean CGI-ADHD-Improvement at endpoint, was also observed with increasing atomoxetine dose. More patients receiving atomoxetine 1.2 mg/kg/day reported ≥1 treatment-emergent adverse event/s (58.3%) compared with 0.5 (40.7%; p=0.11) or 0.2 mg/kg/day (29.4%; p=0.005). These were generally mild to moderate.
Atomoxetine was found to be safe and well tolerated at all doses administered in Korean pediatric ADHD patients, and 1.2 mg/kg/day was an efficacious dose in this population.
ADHD; Atomoxetine; Dose response; Korea; Pediatric
The human herpes simplex virus (HSV) host cell factor HCF-1 is a transcriptional coregulator that associates with both histone methyl- and acetyltransferases, and a histone deacetylase and regulates cell proliferation and division. In HSV-infected cells, HCF-1 associates with the viral protein VP16 to promote formation of a multiprotein–DNA transcriptional activator complex. The ability of HCF proteins to stabilize this VP16-induced complex has been conserved in diverse animal species including Drosophila melanogaster and Caenorhabditis elegans suggesting that VP16 targets a conserved cellular function of HCF-1.
To investigate the role of HCF proteins in animal development, we have characterized the effects of loss of the HCF-1 homolog in C. elegans, called Ce HCF-1. Two large hcf-1 deletion mutants (pk924 and ok559) are viable but display reduced fertility. Loss of Ce HCF-1 protein at reduced temperatures (e.g., 12°C), however, leads to a high incidence of embryonic lethality and early embryonic mitotic and cytokinetic defects reminiscent of mammalian cell-division defects upon loss of HCF-1 function. Even when viable, however, at normal temperature, mutant embryos display reduced levels of phospho-histone H3 serine 10 (H3S10P), a modification implicated in both transcriptional and mitotic regulation. Mammalian cells with defective HCF-1 also display defects in mitotic H3S10P status.
These results suggest that HCF-1 proteins possess conserved roles in the regulation of cell division and mitotic histone phosphorylation.
The human herpes simplex virus (HSV) protein VP16 induces formation of a transcriptional regulatory complex with two cellular factors—the POU homeodomain transcription factor Oct-1 and the cell proliferation factor HCF-1—to activate viral immediate-early-gene transcription. Although the cellular role of Oct-1 in transcription is relatively well understood, the cellular role of HCF-1 in cell proliferation is enigmatic. HCF-1 and the related protein HCF-2 form an HCF protein family in humans that is related to a Caenorhabditis elegans homolog called CeHCF. In this study, we show that all three proteins can promote VP16-induced-complex formation, indicating that VP16 targets a highly conserved function of HCF proteins. The resulting VP16-induced complexes, however, display different transcriptional activities. In contrast to HCF-1 and CeHCF, HCF-2 fails to support VP16 activation of transcription effectively. These results suggest that, along with HCF-1, HCF-2 could have a role, albeit probably a different role, in HSV infection. CeHCF can mimic HCF-1 for both association with viral and cellular proteins and transcriptional activation, suggesting that the function(s) of HCF-1 targeted by VP16 has been highly conserved throughout metazoan evolution.