Nationwide study of surgery for primary infected abdominal aortic and common iliac artery aneurysms.

BACKGROUND: Primary infected aneurysms of the abdominal aorta and iliac arteries are potentially life-threatening. However, because of the rarity of the disease, its pathogenesis and optimal treatment strategy remain poorly defined. METHODS: A nationwide retrospective cohort study investigated patients who underwent surgical treatment for a primary infected abdominal aortic and/or common iliac artery (CIA) aneurysm between 2011 and 2017 using a Japanese clinical registry. The study evaluated the relationships between preoperative factors and postoperative outcomes including 90-day and 3-year mortality, and persistent or recurrent aneurysm-related infection. Propensity score matching was used to compare survival between patients who underwent in situ prosthetic grafting and those who had endovascular aneurysm repair (EVAR). RESULTS: Some 862 patients were included in the analysis. Preceding infection was identified in 30.2 per cent of the patients. The median duration of postoperative follow-up was 639 days. Cumulative overall survival rates at 30 days, 90 days, 1 year, 3 years and 5 years were 94.0, 89.7, 82.6, 74.9 and 68.5 per cent respectively. Age, preoperative shock and hypoalbuminaemia were independently associated with short-term and late mortality. Compared with open repair, EVAR was more closely associated with persistent or recurrent aneurysm-related infection (odds ratio 2.76, 95 per cent c.i. 1.67 to 4.58; P < 0.001). Propensity score-matched analyses demonstrated no significant differences between EVAR and in situ graft replacement in terms of 3-year all-cause and aorta-related mortality rates (P = 0.093 and P =0.472 respectively). CONCLUSION: In patients undergoing surgical intervention for primary infected abdominal aortic and CIA aneursyms, postoperative survival rates were encouraging. Eradication of infection following EVAR appeared less likely than with open repair, but survival rates were similar in matched patients between EVAR and in situ graft replacement.

Impairment of host resistance to helminthes with age in murine small intestine.

Age-associated alterations of Th2 immune responses against nematode parasites are largely unknown. We investigated primary and memory responses against two types of gastrointestinal nematode parasites, Heligmosomoides polygyrus (Hp) and Nippostrongylus brasiliensis (Nb), in aged mice. The small intestinal gene expression of Th2 cytokines was almost unchanged after primary (Nb and Hp) and secondary infection (Hp) in aged mice in contrast to strongly increased small intestinal gene expression of Th2 cytokines in young (3-month-old) mice. Mucus production decreased (Nb), and worm expulsion was impaired (Nb and Hp) compared with the young mice. Immunofluorescent staining revealed that after Hp infection, the number of alternatively activated macrophages, which are induced by Th2 cytokines, was lower in the aged mice. On the other hand, the number of CD4(+) T cells recruited to the worm cysts was normal compared with the young mice. These results suggest that migration of CD4(+) T cells to the host-parasite interface is not affected by ageing. Alterations in Th2 immune responses in aged mice might be due to inappropriate or insufficient activation of CD4(+) T cells in the submucosa.

Factors influencing wound healing of critical ischaemic foot after bypass surgery: is the angiosome important in selecting bypass target artery?

OBJECTIVES: The aim of the study is to determine factors affecting ischaemic wound healing and role of the angiosome concept in bypass surgery. DESIGN: Single-centre, retrospective clinical study. MATERIALS AND METHODS: A total of 249 consecutive critical ischaemic limbs with tissue loss in 228 patients who underwent distal bypasses from 2003 to 2009 were reviewed. A total of 81% of patients were diabetic, and 49% of patients had dialysis-dependent renal disease (end-stage renal disease, ESRD). Distal targets of bypasses were the crural artery (57%) and the pedal artery (43%). RESULTS: The complete healing of ischaemic wounds was achieved in 211 limbs (84.7%). ESRD (odds ratio (OR) 0.127, p < 0.001), diabetes (OR 0.216, p = 0.030), Rutherford category 6 (R6) with heel ulcer/gangrene (OR 0.134, p < 0.001), R6 except heel (OR 0.336, p = 0.025) and low albuminaemia (OR 0.387, p = 0.049) were negative predictors of wound healing. Regarding the angiosome, the healing rate in the indirect revascularisation (IR) group was slower than in the direct revascularisation (DR) group, especially in patients with ESRD (p < 0.001). However, the healing rates of the DR and IR groups were similar after minimising background differences with propensity score methods (p = 0.185). CONCLUSIONS: In the field of bypass surgery, the angiosome concept seems unimportant, at least in non-ESRD cases. The location and extent of ischaemic wounds as well as co-morbidities may be more relevant than the angiosome in terms of wound healing.

Factors related to postoperative delirium in patients with lower limb ischaemia: a prospective cohort study.

OBJECTIVES: To preoperatively determine candidates at definitive risk of postoperative delirium (POD), we identified relevant factors in patients with arteriosclerosis obliterans who underwent bypass surgery. DESIGN: A prospective cohort study. PATIENTS AND METHODS: 299 patients (age ≥ 60 years) who underwent bypasses in 1995-2006 were enrolled. Cognitive impairment was assessed by the Revised Hasegawa Dementia Scale, the Confusion Assessment Method was also used, and severity was graded as Grade I-III (mild to severe) based on the Delirium Rating Scale. All patients were followed for 3 years. RESULTS: POD occurred in 88 patients (29%), with a median age of 75 (10) years (IQR). Onset was 2 (1) days postoperatively, and a duration of 2 (2) days was observed. POD was hyperactive in 89% and was Grade I, II, and III in 11%, 68%, and 21% respectively. Multiple logistic regression analysis identified the following risk factors for POD: age ≥ 72 years (<0.0001), end-stage renal failure (0.001), multiple occlusive lesions (<0.0001), cognitive impairment (0.003), and critical limb ischaemia (0.034). The 3-year survival rate was similar when comparing POD and non-POD patients (84% vs. 88%, NS). CONCLUSIONS: This study identified 5 risk factors for POD in patients undergoing bypasses for limb ischaemia. Long-term outcomes were similar when comparing the patients who experienced POD with those who did not.

Isotype-specific selection of high affinity memory B cells in nasal-associated lymphoid tissue.

Mucosal immunoglobulin (Ig)A dominance has been proposed to be associated with preferential class switch recombination (CSR) to the IgA heavy chain constant region, Calpha. Here, we report that B cell activation in nasal-associated lymphoid tissue (NALT) upon stimulation with the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken gamma globulin caused an anti-NP memory response dominated by high affinity IgA antibodies. In the response, however, NP-specific IgG(+) B cells expanded and sustained their number as a major population in germinal centers (GCs), supporting the view that CSR to IgG heavy chain constant region, Cgamma, operated efficiently in NALT. Both IgG(+) and IgA(+) GC B cells accumulated somatic mutations, indicative of affinity maturation to a similar extent, suggesting that both types of cell were equally selected by antigen. Despite the selection in GCs, high affinity NP-specific B cells were barely detected in the IgG memory compartment, whereas such cells dominated the IgA memory compartment. Taken together with the analysis of the V(H) gene clonotype in GC and memory B cells, we propose that NALT is equipped with a unique machinery providing IgA-specific enrichment of high affinity cells into the memory compartment, facilitating immunity with high affinity and noninflammatory secretory antibodies.

High-resolution record of Northern Hemisphere climate extending into the last interglacial period.

Two deep ice cores from central Greenland, drilled in the 1990s, have played a key role in climate reconstructions of the Northern Hemisphere, but the oldest sections of the cores were disturbed in chronology owing to ice folding near the bedrock. Here we present an undisturbed climate record from a North Greenland ice core, which extends back to 123,000 years before the present, within the last interglacial period. The oxygen isotopes in the ice imply that climate was stable during the last interglacial period, with temperatures 5 degrees C warmer than today. We find unexpectedly large temperature differences between our new record from northern Greenland and the undisturbed sections of the cores from central Greenland, suggesting that the extent of ice in the Northern Hemisphere modulated the latitudinal temperature gradients in Greenland. This record shows a slow decline in temperatures that marked the initiation of the last glacial period. Our record reveals a hitherto unrecognized warm period initiated by an abrupt climate warming about 115,000 years ago, before glacial conditions were fully developed. This event does not appear to have an immediate Antarctic counterpart, suggesting that the climate see-saw between the hemispheres (which dominated the last glacial period) was not operating at this time.

Breeding system, colony and population structure in the weaver ant Oecophylla smaragdina.

Weaver ants (Oecophylla smaragdina) are dominant ants in open forests from India, Australia, China and Southeast Asia, whose leaf nests are held together with larval silk. The species, together with its sole congener O. longinoda, has been important in research on biological control, communication, territoriality and colony integration. Over most of the range, only one queen has been found per colony, but the occurrence of several queens per nest has been reported for the Australian Northern Territory. The number of males mating with each queen is little known. Here we report on the colony structure of O. smaragdina using published and new microsatellite markers. Worker genotype arrays reflect the occurrence of habitual polygyny (more than one queen per colony) in 18 colonies from Darwin, Northern Australia, with up to five queens inferred per colony. Monogyny (one queen per colony) with occasional polygyny was inferred for 14 colonies from Queensland, Australia, and 20 colonies from Java, Indonesia. Direct genotyping of the sperm carried by 77 Queensland queens and worker genotypic arrays of established colonies yielded similar results, indicating that less than half of the queens mate only once and some mate up to five times. Worker genotype arrays indicated that queens from Java and the Northern Territory also often mate with more than one male, but less often than those from Queensland. A strong isolation-by-distance effect was found for Queensland samples. The variation uncovered means that O. smaragdina is a more versatile study system than previously supposed.

Hepatocyte growth factor as a key to modulate anti-ulcer action of prostaglandins in stomach.

Although the clinical efficacy of prostaglandins (PGs), especially on gastric mucosal injuries induced by nonsteroidal antiinflammatory drugs, is widely appreciated, their mechanism of action, apart from acid suppression, is quite unclear. In this study, we have established a primary culture system of human gastric fibroblasts and clearly demonstrated that PGs strongly induce the expression of hepatocyte growth factor (HGF) in the fibroblasts, which is mediated by PGE specific receptor, EP2 or EP4. Since HGF facilitates repair and protection of gastric epithelial cells in a paracrine manner, it is assumed that some of the beneficial effects of PGs may be mediated by HGF. To confirm this assumption, we established a simplified in vitro culture gastric mucosal model which consists of gastric epithelial cells and gastric fibroblasts. Using the model, we performed a round wound restitution assay. PGE1 remarkably accelerated restitution which was completely inhibited by anti-HGF antibody, indicating that the action was mediated by HGF. To confirm these in vitro data, we further demonstrated that HGF mRNA expression is downregulated at the edges of nonsteroidal antiinflammatory drug-induced gastric ulcers where PGs should be depleted. In summary, we proposed that gastric fibroblasts are newly recognized targets of PGs, and HGF produced by human gastric fibroblasts may be a key factor for anti-ulcer action of PGs in the stomach.

Distinct roles for the small GTPases Cdc42 and Rho in endothelial responses to shear stress.

Shear stress, the tangential component of hemodynamic forces, plays an important role in endothelial remodeling. In this study, we investigated the role of Rho family GTPases Cdc42 and Rho in shear stress-induced signal transduction and cytoskeleton reorganization. Our results showed that shear stress induced the translocation of Cdc42 and Rho from cytosol to membrane. Although both Cdc42 and Rho were involved in the shear stress-induced transcription factor AP-1 acting on the 12-O-tetradecanoyl-13-phorbol-acetate-responsive element (TRE), only Cdc42 was sufficient to activate AP-1/TRE. Dominant-negative mutants of Cdc42 and Rho, as well as recombinant C3 exoenzyme, attenuated the shear stress activation of c-Jun NH2-terminal kinases (JNKs), suggesting that Cdc42 and Rho regulate the shear stress induction of AP-1/TRE activity through JNKs. Shear stress-induced cell alignment and stress fiber formation were inhibited by the dominant-negative mutants of Rho and p160ROCK, but not by the dominant-negative mutant of Cdc42, indicating that the Rho-p160ROCK pathway regulates the cytoskeletal reorganization in response to shear stress.

Effect on vein graft intimal hyperplasia of nuclear factor-kB decoy transfection using the second generation of HVJ vector.

AIM: Vein graft stenosis due to intimal hyperplasia (IH) is the main cause of graft failure. We examined possibilities of nuclear factor-kB (NF-kB) expression in vein grafts, and inhibitive effects of NF-kB decoy on the gene expression and subsequent vein graft IH. METHODS: Fifteen mongrel dogs underwent femoral artery replacement with autogenous vein grafts. Group I: grafts were retrieved at a predetermined time and subjected to NF-kB binding activity assay; Groups II and III: grafts were transfected with scrambled (II-a, III-a) or NF-kB (II-b, III-b) decoy using hemagglutinating virus of Japan envelope before implantation. Grafts were retrieved 7 days after implantation for evaluation of intercellular adhesion molecule-1 (ICAM-1) mRNA expression (Group II) and 4 weeks after implantation for comparison of IH by morphometric analysis (Group III). RESULTS: NF-kB binding activity was increased in a time-dependent manner, with a peak 2 days after implantation. The ratio between ICAM-1 and glyceraldehyde-3-phosphate dehydrogenase mRNA expression in II-b was significantly lower than that in II-a (0.347 +/- 0.07 versus 0.612+/-0.08; P = 0.047). The ratio of intimal cross-section area to luminal cross-section area of III-b was significantly lower than that of the III-a (0.096+/-0.03 versus 0.461+/-0.11; P = 0.048). CONCLUSION: NF-kB binding activity in vein grafts increases after implantation, and transfection of NF-kB decoy before implantation may reduce IH through the inhibition of ICAM-1 expression.

[Vacuum-assisted wound closure in the management of deep sternal wound infection].

We herein present a case who underwent vacuum-assisted wound closure (VAC) therapy for post-sternotomy mediastinitis. A 71-year-old female with chronic renal failure on dialysis underwent a graft replacement of the ascending aortic aorta for the treatment of an acute aortic dissection. After she was discharged from the hospital, a purulent discharge was noted to occur from the median sternal wound. The wound was therefore reopened and all sternal wires were removed. Thereafter, polyurethane foam which was shaped to fit the defect was placed within the cavity. The area was covered with adhesive drape and suction drainage was carried out at -100 mmHg. The polyurethane foam was replaced every few days. The wound was finally closed using a muscle flap at 49 days after surgery. VAC therapy is therefore considered to be a useful treatment modality for deep sternal wound infections.

Effect of paroxetine on marble-burying behavior in mice.

The present study was undertaken to investigate the effect of paroxetine, a selective serotonin reuptake inhibitor (SSRI), on marble-burying behavior in mice in comparison with those of fluvoxamine and clomipramine. Marble-burying test is extensively used as an animal model for obsessive/compulsive disorder. A significant inhibition in marble-burying behavior was observed with paroxetine, at a dose of 10 mg/kg. The earlier SSRI, fluvoxamine, also significantly inhibited marble-burying behavior at a dose of 30 mg/kg. Although clomipramine, a tricyclic antidepressant, caused an inhibition in marble-burying behavior, a high dose of 100 mg/kg was needed to show a significant effect. On the other hand, all the drugs used in the present study showed no significant changes in spontaneous locomotor activity at doses inhibiting marble-burying behavior. In conclusion, it was confirmed that paroxetine has a potent inhibitory effect on marble-burying behavior in mice, and could have a similar antiobsessive/anticompulsive activity in human beings.

Expression of type II collagen at the middle stages of chick embryonic and human fetal skin development.

Using in situ hybridization techniques and RNase protection assays, type II collagen mRNA was transiently detected in the epidermis of chick embryonic skins during days 9-15 after fertilization, with a maximum expression at day 11. Immunohistochemical studies demonstrated that deposition of type II collagen was also transiently localized at the subepidermal region during days 10-15. Type II collagen gene and gene product concomitantly started to decline preferentially at the region where feather buds were being formed on day 12, and thereafter diminished at the region between feather buds. Using immunohistochemical methods, type II collagen was also detected in human fetal scalp skin at 17-23 fetal weeks at the subepidermal region, excluding the region beneath the hair follicles. These results indicate that the lack of type II collagen expression is related to the development of feather and hair at a certain stage of chick embryonic and human fetal skin development.

Endothelial nitric oxide synthase gene is positively associated with essential hypertension.

Essential hypertension has a genetic basis. Accumulating evidence, including findings of elevation of arterial blood pressure in mice lacking the endothelial nitric oxide synthase (eNOS) gene, strongly suggests that alteration in NO metabolism is implicated in hypertension. There are, however, no reports indicating that polymorphism in the eNOS gene is associated with essential hypertension. We have identified a missense variant, Glu298Asp, in exon 7 of the eNOS gene and demonstrated that it is associated with both coronary spastic angina and myocardial infarction. To explore the genetic involvement of the eNOS gene in essential hypertension, we examined the possible association between essential hypertension and several polymorphisms including the Glu298Asp variant, variable number tandem repeats in intron 4 (eNOS4b/4a), and two polymorphisms in introns 18 and 23. We performed a large-scale study of genetic association using two independent populations from Kyoto (n=458; 240 normotensive versus 218 hypertensive subjects) and Kumamoto (n=421; 223 normotensive versus 187 hypertensive subjects), Japan. In both groups, a new coding variant, Glu298Asp, showed a strong association with essential hypertension (Kyoto: odds ratio, 2.3 [95% confidence interval, 1.4 to 3.9]; Kumamoto: odds ratio, 2.4 [95% confidence interval, 1.4 to 4.0]). The allele frequencies of 298Asp in hypertensive subjects were significantly higher than those in normotensive subjects in both groups (Kyoto: 0.103 versus 0.050, P<0.0017; Kumamoto: 0.120 versus 0.058, P<0.0013, respectively). No such disequilibrium between genotypes was significantly associated with any other polymorphisms we examined; the Glu298Asp variant was also not linked to any other polymorphisms. In conclusion, the Glu298Asp missense variant was significantly associated with essential hypertension, which suggests that it is a genetic susceptibility factor for essential hypertension.

Missense mutation at the C terminus of the PAX6 gene in ocular anterior segment anomalies.

PURPOSE: To report a rare case of ocular anterior segment anomalies including uveal ectropion of the iris, invasion of the conjunctival epithelia into the cornea, and posterior embryotoxon with a missense mutation of the PAX6 gene. METHODS: The authors performed polymerase chain reaction-single-strand conformation polymorphism analysis and sequencing of the PAX6 gene using genomic DNA of family members and more than 100 control subjects. RESULTS: The A to G transition at nucleotide 1682 in exon 13 in the patient was identified in an allele that resulted in a Gln to Arg substitution (Q422R) at the C terminus of the protein. The mutation was not found in the parents, a sibling, or control subjects. CONCLUSIONS: The mutation indicates that the proline-serine-threonine-rich domain at the C terminus of the PAX6 protein plays a role in ocular anterior segment morphogenesis.

Missense mutations in the PAX6 gene in aniridia.

PURPOSE: Aniridia is caused by a mutation of the PAX6 gene. Haploinsufficiency of the gene product is thought to result in the aniridia phenotype, because most mutations thus far detected have been large deletions encompassing the entire gene and nonsense, frameshift, or splice errors that result in premature translational termination on one of the alleles. Only two missense mutations have been detected in aniridia pedigrees, each of which occurs in its paired domain or homeodomain. In this study, four novel missense mutations were found in three aniridia pedigrees. METHODS: Polymerase chain reaction-single-strand conformation polymorphism analysis and sequencing of the PAX6 gene were performed using genomic DNA of three aniridia pedigrees and more than 100 healthy control subjects. RESULTS: Three mutations occurred in the N-terminal subdomain of the paired domain, namely N17S, I29V, and R44Q, the first two of which were detected on the same allele of one patient. The other mutation (Q178H) was in the linking portion of the paired domain and homeodomain. CONCLUSIONS: These missense mutations give rise to haploinsufficiency by another route, because the missense mutations presented here resulted in an aniridia phenotype indistinguishable from that caused by a heterozygous deletion of the entire PAX6 gene.