Extended dosing of etanercept 25 mg can be effective in patients with ankylosing spondylitis: a retrospective analysis
As a measure of healthcare cost containment, the total number of vials of entanercept (25 mg) that can be prescribed for patients with inflammatory arthritis is restricted in Korea. Consequently, attempts to extend the dosing interval while maintaining the efficacy have not been an uncommon clinical practice. The aim of this study was to determine if extended doing interval of etanercept can be effective in patients with ankylosing spondylitis (AS). We performed a retrospective analysis using medical records at a single tertiary hospital. One hundred and nine patients with AS and 79 patients with rheumatoid arthritis (RA) started on etanercept between November 2004 and November 2009 were indentified. Etanercept (25 mg) was started with twice-weekly dosing schedule. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), C-reactive protein (CRP), and etanercept dosing interval for AS patients at 0, 3, 9, 15, 21 months were reviewed. Dosing interval for RA patients was analyzed for comparison. In AS, mean dosing interval was 4.7 ± 2.1 days at 3 months and was increased to 12.1 ± 7.0 days at 21 months. Despite the progressive increase in the dosing interval, the mean BASDAI declined rapidly at 3 months, and continued to decrease over 21 months. Mean CRP declined after 3 months of therapy and remained low thereafter. In RA, mean dosing interval was 4.0 ± 1.2 days at 3 months and 5.1 ± 1.8 days at 21 months. In conclusion, in AS, extended dosing of etanercept can be effective without compromising clinical and laboratory markers of disease activity as measured by BASDAI and CRP, respectively. Tapering of etanercept was less accommodating in RA when compared to AS.

title: MRI findings in Kirner deformity: normal insertion of the flexor digitorum profundus tendon without soft-tissue enhancement
abstract: Kirner deformity is characterized by volar and radial incurvature of the distal phalanx of the 5th finger. A proposed causative mechanism includes abnormal distal insertion of the flexor digitorum profundus tendon along the volar surface of the distal phalanx of the 5th finger. A chronic inflammatory process or altered vascularisation of the soft tissues has also been suggested as the underlying causative mechanism based on MRI findings. We present a teenage boy with Kirner deformity, along with supplementary imaging of his father who also has the deformity, to illustrate MRI findings that dispute the above hypotheses. MRI in both son and father show normal insertion of the deep flexor tendon and no signs of inflammation.

title: CIP2A expression is associated with synovial hyperplasia and invasive function of fibroblast-like synoviocytes in rheumatoid arthritis
abstract: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that leads to cellular proliferation in cancer cells. We aim to investigate CIP2A expression in fibroblast-like synoviocytes (FLS) and its association with the histopathological grade of synovitis and the invasive function of FLS in rheumatoid arthritis (RA). CIP2A protein expression was measured in 8 RA FLS and 8 OA FLS using Western blot analysis. CIP2A mRNA expression from 19 RA FLS and 7 OA FLS was measured using real-time PCR. Synovitis score of RA FLS-matched synovial tissues was semiquantitatively measured by two independent pathologists. An in vitro cell invasion assay was performed using RA FLS treated with CIP2A small interfering RNA (siRNA) or with control vector. Western blot analysis showed that CIP2A is more frequently overexpressed in RA FLS compared with OA FLS. CIP2A mRNA expression was higher in RA FLS compared with those in OA FLS, but did not reach statistical significance (P = 0.076). In RA, total synovitis score was strongly correlated with FLS CIP2A mRNA expression (rs = 0.849, P = 0.043). TNF-α treatment induced a robust increase in the invasive function of control FLS (P = 0.0021), but no significant effect was observed in CIP2A siRNA-treated FLS. Our data demonstrate that CIP2A expression is closely associated with the histopathological score of synovitis and invasive function of FLS in RA. These results suggest that CIP2A may play a critical role in the destructive process in RA and warrant further investigation of CIP2A as a therapeutic target.

title: Successful cyclophosphamide therapy with complete resolution of pulmonary artery aneurysm in Hughes–Stovin syndrome patient
abstract: Hughes–Stovin syndrome is an exceedingly rare disorder of unknown etiology, and it is characterized by multiple pulmonary artery aneurysms and peripheral venous thrombosis. We report a case of Hughes–Stovin syndrome with complete resolution of pulmonary artery aneurysm after treatment with cyclophosphamide. A 48-year-old man presented with massive hemoptysis, fever, and weight loss of 4-month duration. Computed tomography angiography revealed multiple pulmonary arterial aneurysms of variable sizes in both lung fields. Inferior vena caval thrombosis was also noted. Despite multiple surgical procedures including embolectomy and lobectomy combined with steroid therapy, new aneurysms continued to appear with persistent hemoptysis. Thorough history and physical examination did not suggest any evidence of Behcet’s disease. Hughes–Stovin syndrome was subsequently diagnosed. High-dose prednisolone combined with oral cyclophosphamide therapy was initiated. Chest radiography follow-up in 3 months revealed complete resolution of pulmonary aneurysm. No new aneurysm was detected at 15 months of follow-up.

title: Underlying venous pathology causing perimesencephalic subarachnoid hemorrhage.
abstract: Perimesencephalic subarachnoid hemorrhage (PSH) is a relatively benign clinical entity with a low risk of recurrent bleeding. The precise etiology of PSH has not yet been determined. We report here three cases of PSH with clinical and radiological features that support a venous system as a cause.



The first patient, a 72-year-old woman, had PSH and venous hemorrhagic infarct in the left thalamus on non-contrast CT. Subsequent cerebral angiography revealed widespread thrombosis in the cerebral venous system, a potential cause for reflux overflow hemorrhage. The second patient, a 55-year-old man with an established diagnosis of neuro-Behçet's disease, a well-known cause for cerebral venulitis, presented with PSH one year later. The third patient, a 39-year-old female, with incomplete Behçet's disease was admitted with PSH.



Current concepts on the anatomic origin and the possible pathophysiologic mechanism leading to PSH are discussed. The underlying pathological conditions in the venous system in our cases provide theoretical clues to the anatomic origin of PSH in general.

title: Underexpression of TIM-3 and Blunted Galectin-9-Induced Apoptosis of CD4+ T Cells in Rheumatoid Arthritis
abstract: The aim of this study is to compare the expression of TIM-3 from CD4+ T cells from rheumatoid arthritis (RA) patients and healthy controls and to evaluate the effect of galectin-9 (Gal-9) on apoptosis of CD4+ T cells in these patients. CD4+ T cells from RA patients and healthy controls were isolated from peripheral blood mononuclear cells and were activated. The expression of TIM-3 mRNA in CD4+ T cells was measured using real-time polymerase chain reaction. CD4+ T cells were activated in the presence of graded doses of Gal-9 or control, and Gal-9-induced cytotoxicity and apoptotic activity of CD4+ T cells were analyzed using MTT assays and annexin-V staining, respectively. TIM-3 mRNA expression was significantly lower in CD4+ T cells from RA patients compared with those in healthy controls (p = 0.028). CD4+ T cell survival as measured by MTT assay when incubated with Gal-9 (15 nM) was significantly higher in RA patients than in healthy controls (p = 0.002). Apoptotic activity of CD4+ T cells from healthy controls as measured by annexin staining increased with graded doses of Gal-9 (0 nM vs. 30 nM, 0 nM vs. 90 nM, p = 0.016 each). However, apoptotic activity of CD4+ T cells from RA patients did not change despite the stimulation with Gal-9. Gal-9-mediated apoptosis of CD4+ T cells is dysfunctional in RA patients. Blunted Gal-9-mediated apoptosis may be exerted through underexpression of TIM-3 that negatively regulates Th1 response. Our data suggest that TIM-3 and its interaction with Gal-9 may play an important role in the pathogenesis of RA and may represent a potential therapeutic target.

title: Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells.
abstract: Genomic imprinting is an epigenetic mechanism that causes functional differences between paternal and maternal genomes, and plays an essential role in mammalian development. Stage-specific changes in the DNA methylation patterns of imprinted genes suggest that their imprints are erased some time during the primordial germ cell (PGC) stage, before their gametic patterns are re-established during gametogenesis according to the sex of individuals. To define the exact timing and pattern of the erasure process, we have analyzed parental-origin-specific expression of imprinted genes and DNA methylation patterns of differentially methylated regions (DMRs) in embryos, each derived from a single day 11.5 to day 13.5 PGC by nuclear transfer. Cloned embryos produced from day 12.5 to day 13.5 PGCs showed growth retardation and early embryonic lethality around day 9.5. Imprinted genes lost their parental-origin-specific expression patterns completely and became biallelic or silenced. We confirmed that clones derived from both male and female PGCs gave the same result, demonstrating the existence of a common default state of genomic imprinting to male and female germlines. When we produced clone embryos from day 11.5 PGCs, their development was significantly improved, allowing them to survive until at least the day 11.5 embryonic stage. Interestingly, several intermediate states of genomic imprinting between somatic cell states and the default states were seen in these embryos. Loss of the monoallelic expression of imprinted genes proceeded in a step-wise manner coordinated specifically for each imprinted gene. DNA demethylation of the DMRs of the imprinted genes in exact accordance with the loss of their imprinted monoallelic expression was also observed. Analysis of DNA methylation in day 10.5 to day 12.5 PGCs demonstrated that PGC clones represented the DNA methylation status of donor PGCs well. These findings provide strong evidence that the erasure process of genomic imprinting memory proceeds in the day 10.5 to day 11.5 PGCs, with the timing precisely controlled for each imprinted gene. The nuclear transfer technique enabled us to analyze the imprinting status of each PGC and clearly demonstrated a close relationship between expression and DNA methylation patterns and the ability of imprinted genes to support development.

title: Quantitative measures of facial expression for patients with head and neck cancer
abstract: In addition to changes in facial morphology, head and neck cancer treatment can impact the facial expression. Quantification of changes in facial expression, particularly of smiling, would enable a deeper understanding of the relationship between physical changes and psychosocial adjustment in patients being treated for facial cancer. This study proposes 48 quantitative facial expression measures, which consist of the length normalized distances and slopes between 27 manually annotated fiducial points on standard 2D clinical photographs of patients with head and neck cancer. Using the proposed measures, the maximum intensity of smiling for patients with head and neck cancer prior to their treatments was compared to that of a sample from a healthy population. A total of 7 facial expression measures captured statistically significant differences between patients with head and neck cancer and healthy individuals. These measures suggest that patients with head and neck cancer are less expressive than people without head and neck cancer. This study is the first attempt to quantify the facial expression of patients with head and neck cancer and to build a foundation for studying how surgical interventions may affect their facial expressions. Moreover, this study lays the groundwork for future investigation of the relationship between facial expression and psychosocial adjustment in cancer patients.

title: Multidrug-resistant tuberculosis in a lung transplant recipient.
abstract: Tuberculosis infection has been a relatively rare complication after lung transplantation. However, as more countries in which Mycobacterium tuberculosis infection remains endemic embark on lung transplant programs, the occurrence of multidrug-resistant tuberculosis after transplantation is a genuine threat. We report the first case of multidrug-resistant tuberculosis in a double-lung transplant recipient who probably acquired the disease from the donor. We discuss the problems in clinical management of post-transplant tuberculosis infection and of drug-resistance.

title: Conditional deletion of the focal adhesion kinase FAK alters remodeling of the blood-brain barrier in glioma.
abstract: Gliomas generally infiltrate the surrounding normal brain parenchyma, a process associated with increased vascular permeability (VP) and dysregulation of the blood-brain barrier (BBB). However, the molecular mechanisms underlying glioma-induced VP in the brain remain poorly understood. Using a conditional, endothelium-specific deletion of the focal adhesion kinase (FAK) in the mouse (FAK CKO), we show that FAK is critical for destabilization of the tumor endothelium in tumor-bearing mice, with mutant mice exhibiting a relatively normalized vasculature compared with wild-type mice (FAK WT). Tumor vessels in the FAK CKO mice displayed reduced VP compared with FAK WT mice, resulting in reduced tumor growth. Additionally, FAK CKO mice displayed partial restoration of cell-cell junction proteins in the tumor vessels and astrocyte-endothelium interactions in tumors, revealing an additional role of astrocytes in mediating tumor-induced VP. Together, these results provide genetic evidence that FAK is a mediator of tumor-induced VP in the brain. Our findings may help understand how therapeutics might be used to regulate specific cell-type interactions to restore BBB structure/function in cancer and perhaps other pathologic conditions.

title: Is partial colectomy the operation of choice in pediatric Clostridium difficile colitis?
abstract: PurposeThis study examined the national trends in incidence and surgical management of pediatric Clostridium difficle colitis (CDC) hospitalizations.MethodsThis was a cross-sectional Nationwide Inpatient Sample (NIS) analysis of pediatric CDC from 2000 to 2008. Data analysis included patient demographics, procedures, length of stay (LOS), total hospital charges (THC), and in-hospital mortality.ResultsDuring the 9-year study period, the total number of CDC hospitalizations per year increased almost twofold, from 2,513 in 2000 to 4,817 in 2008. The rate per 100,000 discharges followed a similar trend, increasing from 38.08 in 2000 to 72.57 in 2008. Abdominal colectomy was performed in 0.35 %, with partial colectomy performed more often than total colectomy. Mortality, mean LOS, and mean THC were not statistically different between partial versus total colectomy. Children with ulcerative colitis were more likely to undergo total colectomy, (OR 35.700, CI 11.025–115.98, P < 0.001). Infants under the age of 1 year were less likely to undergo total colectomy (OR 0.568, 0.477–0.677, P < 0.001).ConclusionPediatric hospitalizations for CDC are on the rise. Partial colectomy is performed more often than total colectomy without statistical compromise of mortality, length of stay, and total hospital charges. Further studies are needed to determine the standard surgical management of pediatric CDC.