Age-related dysfunction of the lacrimal gland and oxidative stress: evidence from the Cu,Zn-superoxide dismutase-1 (Sod1) knockout mice

An imbalance between free radical generation and radical scavenging antioxidant systems results in oxidative stress, which has been associated with cell injury observed in many age-related diseases. The superoxide dismutase (SOD) family is a major antioxidant system, and deficiency of Cu,Zn-superoxide dismutase-1 (Sod1) in mice leads to many different phenotypes that resemble accelerated aging. In this study we examined the morphologic features and the secretory functions of the lacrimal glands in Sod1(-/-) mice. Lacrimal glands showed atrophy of acinar units; fibrosis; infiltration with CD4(+) T cells, monocytes, and neutrophils; increased staining with both 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine; increases in apoptotic cells; and the presence of the epithelial-mesenchymal transition in senescent Sod1(-/-) mice. Electron microscopy findings revealed evidence of epithelial-mesenchymal transition, presence of swollen and degenerated mitochondria, and the presence of apoptotic cell death in the lacrimal glands of senescent Sod1(-/-) mice. These alterations were also associated with the accumulation of secretory vesicles in acinar epithelial cells, decreased production of both stimulated and nonstimulated tears, and a decline in total protein secretion from the lacrimal glands. Our results suggest that Sod1(-/-) mice may be a good model system in which to study the mechanism of reactive oxygen species-mediated lacrimal gland alterations.     

A robust algorithm of intensity modulated proton therapy for critical tissue sparing and target coverage

Intensity modulated proton therapy (IMPT) offers the possibility of generating excellent target coverage while sparing the neighbouring organs at risk. However, treatment plans optimized for IMPT may be very sensitive to range and setup uncertainties. We developed a method to deal with these uncertainties in the dose optimization. This method aims at two objectives: one for maintaining the dose coverage within the target, and the other for preventing undesired exposure to organs at risk. The former objective was achieved by the algorithm described in our previous paper to suppress the in-field dose gradient within the target. In this study, the latter objective was achieved by a novel algorithm in which we suppressed pencil beams with high risk to deliver undesired doses to organs at risk under conditions where range and setup uncertainties occur. We defined the risk index that quantifies the likelihood of each pencil beam delivering high doses to organs at risk, and introduced it into the objective function of dose optimizations. In order to test the algorithm's performance, this method was applied to an RTOG benchmark phantom geometry and to a cervical chordoma case. These simulations demonstrated that our method provides IMPT plans that are more robust against range and setup errors compared to conventional IMPT plans. Compared to the conventional IMPT plan, the optimization time for the robust plan increased by a factor of only 3, from 4 to 11 min.     

Identification of independent risk loci for Graves' disease within the MHC in the Japanese population

To identify genetic variants that confer the risk of Graves' disease (GD) in the Japanese population, we conducted a two-stage genome-wide association study (GWAS) using 1119 Japanese individuals with GD and 2718 unrelated controls, and a subsequent replication study using independent 432 GD cases and 1157 controls. We identified 34 single nucleotide polymorphisms (SNPs) to be significantly associated with GD in the GWAS phase. Twenty-two out of 34 SNPs remained positive in the replication study. All 22 SNPs were located within the major histocompatibility complex (MHC) locus on chromosome 6p21. No strong long-range linkage disequilibrium (LD) was observed among the 22 SNPs, indicating independent involvement of multiple loci within the MHC with the risk of GD. Multivariate stepwise logistic regression analysis selected rs3893464, rs4313034, rs3132613, rs4248154, rs2273017, rs9394159 and rs4713693, as markers for independent risk loci for GD. The analysis of LD between these seven SNPs and tagging SNPs for GD-associated human leukocyte antigen (HLA) alleles in the Japanese population (HLA-DPB1(*)0501 and HLA-A(*)0206) demonstrated that all of and five of seven SNPs were not in strong LD with HLA-DPB1(*)0501 and HLA-A(*)0206, respectively. Although causal variants remain to be identified, our results demonstrate the existence of multiple GD susceptibility loci within the MHC region.     

Kinetics of cytokine and chemokine responses in patients with primary human herpesvirus 6 infection

BackgroundCytokines and chemokines induced by human herpesvirus 6 (HHV-6) infection may play an important role in the observed HHV-6-associated clinical complications. However, basic data for cytokine and chemokine synthesis in primary HHV-6 infected patient without complication is lacking.ObjectiveAim of this study was to elucidate basic kinetic data for expressions of cytokines and chemokines in patients with primary HHV-6 infection without complication.Study designTwenty-six patients suffering from fever were enrolled in this study. Fourteen biomarkers were measured in 74 serially collected sera samples from 26 patients. Additionally, serum samples obtained from 14 healthy children were used for control.ResultsTwenty of the 26 patients were diagnosed with primary HHV-6 infection based on viral isolation and serological analysis. The mean age (P = 0.1289) and proportion of males to females (P = 0.9999) between the patients with and without primary HHV-6 infection were not statistically different. At the acute phase of the disease, three cytokines (IFN-γ; P = 0.0046, IL-2; P = 0.0366, and IL-4; P = 0.0255) and one chemokine (MCP-1; P = 0.0019) were significantly higher in patients with primary HHV-6 infection compared to those without infection. Interleukin-5 levels during the convalescent period were significantly higher in patients with HHV-6 infection (P = 0.0205). By 1 month post-infection, cytokine and chemokine expression had returned to almost basal levels.ConclusionAs suggested by the previous in vitro studies, present in vivo analysis also suggests that HHV-6 has potency for induction of cytokines and chemokines.     

Evaluation of Dynamic Carpal Arch Stability following Carpal Tunnel Release Using Four-Dimensional Computed Tomography

Introduction  This study aimed to assess the carpal arch dynamics during active finger and wrist motion following carpal tunnel release using four-dimensional computed tomography (4D-CT). Materials and Methods  Four patients who diagnosed with bilateral carpal tunnel syndrome and underwent unilateral carpal tunnel release were prospectively included. 4D-CT of the bilateral wrists during active finger and wrist motion was performed for 10 seconds at five frames per second. The distances between the tip of tuberosity of the scaphoid and the volar ridge of the pisiform (S–P distance) and volar ridge of trapezium and the tip of hook of hamate (T–H distance) were measured at each position and the values of S–P and T–H distances were compared between the postoperative and contralateral wrists. Results  During finger motion, the S–P and T–H distances were not different at any position between the postoperative side and contralateral side. Conversely, S–P and T–H distances gradually increased in the postoperative wrists. The differences between the sides of S–P distance were significant, with >0 degrees of wrist extension, and differences of T–H distance were significant with >15 degrees of wrist extension. Conclusion  This study demonstrated the carpal arch dynamics using 4D-CT and revealed that the carpal arch was widened with the wrist in extension after carpal tunnel release. This study suggests that the transverse carpal ligament plays an important role in maintaining carpal arch stability.     

Evaluation of Retrievability of the Gunther Tulip Vena Cava Filter

Purpose To evaluate the feasibility and safety of withdrawal of a Gunther tulip retrievable vena cava filter (GTF). Methods Between June 2001 and December 2005, at our institution 86 GTFs were implanted for temporary caval filtration in 59 patients (37 women, 22 men; mean age 59.3 years, range 18–87 years). For GTFs retrieved thereafter, we retrospectively reviewed the following parameters: rate of success in retrieval, degree of trapped thrombus in the filter, and complications during retrieval. Results Worsening of or new development of pulmonary embolism after filter implantation did not occur in any patient. Of the 86 GTFs implanted, retrieval of 80 was attempted. Among those 80 filters, 77 (96%) were successfully retrieved (with the standard method, n = 72; with the modified method, n = 5) without any complication. The period of implantation of the retrieved filters was 13.4 ± 4.2 days. In the 5 filters that were filled to a height of ≥ 1/4 with trapped thrombus, retrieval was performed after attempts were made to decrease trapped thrombi. In addition, a temporary filter or another GTF was temporarily placed at the cephalad level of the GTF during this removal procedure. Conclusion GTFs can be retrieved in the majority of cases. Even when encountering situations in which the filter could not be removed using the standard method, withdrawal was possible in a high frequency of cases through various trials using modified methods.     

Additive effects of spironolactone and candesartan on cardiac sympathetic nerve activity and left ventricular remodeling in patients with congestive heart failure.

The activation of the renin-angiotensin-aldosterone system prevents the uptake of norepinephrine in the myocardium. However, the additive effects of combined spironolactone and candesartan on cardiac sympathetic nerve activity (CSNA) have not been determined. We investigated the effects of the angiotensin-receptor blocker candesartan alone and in combination with spironolactone on CSNA in patients with congestive heart failure (CHF). METHODS: Fifty patients with CHF (left ventricular ejection fraction [LVEF] < 45%) were randomly assigned to candesartan plus spironolactone (group A; n = 25) or to candesartan alone (group B; n = 25). All patients were also treated with a loop diuretic. The delayed percent denervation, delayed heart-to-mediastinum count (H/M) ratio, and washout rate (WR) were determined from (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, and plasma brain natriuretic peptide (BNP) concentration was measured before and 6 mo after treatment. The LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LVEF were also determined by echocardiography. RESULTS: After 6 mo, all of these parameters were improved in both groups. However, the degree of change in the percent denervation was -14 +/- 12 in group A and -7 +/- 10 in group B (P < 0.05); the change in the H/M ratio was 0.19 +/- 0.18 in group A and 0.08 +/- 0.14 in group B (P < 0.05), the change in WR was -12% +/- 8% in group A and -5% +/- 13% in group B (P < 0.05), and the change in plasma BNP was -100 +/- 83 pg/mL in group A and -43 +/- 97 pg/mL in group B (P < 0.05). The degree of change in LVEDV, LVESV, and LVEF in group A tended to be better than that in group B, but these changes were not statistically significant. Moreover, there were significant correlations between changes in the (123)I-MIBG scintigraphic findings and changes in the LVEDV (% denervation, r = 0.692, P < 0.001; H/M ratio, r = -0.437, P < 0.05; and WR, r = 0.505, P < 0.01) or the LVESV (% denervation, r = 0.663, P < 0.001; H/M ratio, r = -0.438, P < 0.05; and WR, r = 0.532, P < 0.01) in group A. In contrast, there was no relationship between these parameters in group B. CONCLUSION: These findings indicate that the combination of spironolactone and candesartan may be more beneficial for CSNA and LV performance than candesartan alone in patients with CHF.     

Management of end hole in placement of port-catheter system for continuous hepatic arterial infusion chemotherapy using the fixed catheter tip method

OBJECTIVE: The purpose of our study was to compare persistent hepatofugal blood flow in the gastroduodenal artery after implanting a port-catheter system for repeated hepatic arterial infusion chemotherapy using either the original or the modified fixed catheter tip method. With the original method the lumen of the catheter tip is closed with a microcoil; with the modified method it is left open. Persistent hepatofugal blood flow can induce reactive gastric or duodenal mucosal lesions. MATERIALS AND METHODS: A port-catheter system with the catheter tip fixed to the gastroduodenal artery by embolic agents was percutaneously implanted in 156 patients (102 men, 54 women; mean age, 63.2 years) with unresectable liver cancer. In 98 patients the original method was used, and in 58 patients the modified method was used. Existence of persistent blood flow beyond the indwelling catheter tip as shown on arteriography via the port performed immediately and 2-10 days after port-catheter placement was compared between these two groups. RESULTS: In all cases, percutaneous port-catheter placement was successfully performed. In one (1.0%) of 98 procedures involving the original method, the gastroduodenal artery was detected on arteriography just after implantation, compared with 23 (39.7%) of 58 procedures using the modified method. However, arteriography performed 2-10 days (mean, 5.02 days) after implantation detected the gastroduodenal artery in only one case. CONCLUSION: This retrospective study indicates that closure of the end hole appears to occur spontaneously shortly after implantation. Thus, such closure is not always necessary to avoid persistent hepatofugal blood flow in the gastroduodenal artery.     

Influence of extrahepatic arterial inflow into the posterior segment or caudate lobe of the liver on repeated hepatic arterial infusion chemotherapy

PURPOSE: For therapeutic effectiveness of repeated hepatic arterial infusion chemotherapy (HAIC) for unresectable advanced liver malignancies, distribution of anticancer drugs via an indwelling catheter should be uniform throughout the entire liver. It was investigated how an extrahepatic artery entering the posterior segment or caudate lobe of the liver influences performance of repeated HAIC. MATERIALS AND METHODS: One hundred ninety-five patients with unresectable advanced liver cancer underwent placement of a percutaneously implantable port-catheter system and were followed arteriographically with and without computed tomography (CT). The frequency of poor distribution in the posterior segment or caudate lobe of the liver was observed on CT during arteriography via the port for HAIC. The correlation between poor distribution and various factors including the number of intrahepatic arteries was studied, and the management of such poor distribution is described. RESULTS: In 34 of 195 patients (17.4%), poor distribution was observed in the posterior segment and/or caudate lobe of the liver. The rate of poor distribution was significantly higher in those with two or more hepatic arteries than in those with one (13 of 35 vs 21 of 160; P = .0007, chi2 test). Other evaluated factors were not significantly correlated with such poor distribution. The right inferior phrenic artery was successfully embolized in 22 patients with tumors in segments with poor distribution. Good distribution throughout the entire liver was achieved in 21 patients (95.5%). CONCLUSION: Inflow of the right inferior phrenic artery into the liver occasionally prevents distribution of anticancer drugs throughout the entire liver during performance of long-term HAIC.     

Gunther Tulip Inferior Vena Cava Filter Placement During Treatment for Deep Venous Thrombosis of the Lower Extremity

Purpose To evaluate the efficacy and safety of Gunther tulip retrievable vena cava filter (GTF) implantation to prevent pulmonary embolism during intravenously administered thrombolytic and anticoagulation therapy and interventional radiological therapy for occlusive or nonocclusive deep venous thrombosis (DVT) of the lower extremity.Methods We evaluated placement of 55 GTFs in 42 patients with lower extremity DVT who had undergone various treatments including those utilizing techniques of interventional radiology.Results Worsening of pulmonary embolism in patients with existing pulmonary embolism or in those without pulmonary embolism at the time of GTF insertion was avoided in all patients. All attempts at implantation of the GTF were safely accomplished. Perforation and migration experienced by one patient was the only complication. Mean period of treatment for DVT under protection from pulmonary embolism by the GTF was 12.7 ± 8.3 days (mean ± SD, range 4–37 days). We attempted retrieval of GTFs in 18 patients in whom the venous thrombus had disappeared after therapy, and retrieval in one of these 18 cases failed. GTFs were left in the vena cava in 24 patients for permanent use when the DVT was refractory to treatment.Conclusion The ability of the GTF to protect against pulmonary embolism during treatment of DVT was demonstrated. Safety in both placement and retrieval was clarified. Because replacement with a permanent filter was not required, use of the GTF was convenient when further protection from complicated pulmonary embolism was necessary.