Kawasaki Disease in a Father and Son

The pathogenesis and etiology of Kawasaki disease are unknown, but some studies suggest increased genetic susceptibility. The case is presented of an infant with Kawasaki disease whose father suffered from the same illness 21 years previously. The A, B and C loci of the HLA antigens were examined.     

Clinicopathologic Study of Angiogenesis in Japanese Patients with Breast Cancer

p = 0.0007) and tumor necrosis (TN) (HMC: p = 0.0050). Univariate analysis showed that AMC or HMC was a statistically significant predictor of overall survival in all patients ( p = 0.0086 and p = 0.0307, respectively). Multivariate analysis showed that AMC was an independent predictor of node status when we fitted a model with node status, BVI, and either AMC or HMC; but HMC was not independent. However, when we fitted a model including all 11 of the other indicators and AMC or HMC, the node status, HG, and LI were independent predictors, but AMC and HMC were not. Although AMC was a better method than HMC for evaluating angiogenesis, we cannot confirm angiogenesis as a significant independent prognostic factor associated with long-term survival in Japanese breast cancer patients.     

Novel Fluorinated Hybrid Polymer by Radical Polyaddition of Bis(α‐trifluoromethyl‐β,β‐difluorovinyl) Terephthalate onto Dialkoxydialkylsilanes

To develop the radical polyaddition of bisperfluoroisopropenyl esters, the reactions of bis(α‐trifluoromethyl‐β,β‐difluorovinyl) terephthalate [CF₂?C(CF₃)OCOC₆H₄COOC(CF₃)?CF₂] (BFP) with dialkoxydialkylsilane were examined to prepare fluorinated hybrid polymers bearing dialkylsilyl groups in the main chain. Prior to polyaddition, the radical addition reaction of 2‐benzoyloxypentafluoropropene [CF₂?C(CF₃)OCOC₆H₅] (BPFP) has been investigated to afford the results that diethoxydimethylsilane (DEOMS) or dimethoxydimethylsilane with BPFP initiated by oxo radical are the best combination for the preparation of polymers. The mechanism of the addition reaction was proposed. Radical polyaddition of BFP with DEOMS initiated by benzoyl peroxide or di‐tert‐butyl peroxide has yielded polymers of up to molecular weight 1 × 10⁶ with rather broad molecular weight distribution. A mechanism for the polyaddition reaction is proposed based on the radical addition reaction between BPFP and DEOMS. The step‐growth polymerization is initiated by hydrogen abstraction of DEOMS to add a perfluoroisopropenyl group, followed by a 1,7‐shift of the radical in the intermediate. The relationship between addition reaction mechanism and polyaddition mechanism was also discussed.

     

An application of a patient-specific cardiac simulator for the prediction of outcomes after mitral valve replacement: a pilot study

Journal of Artificial Organs - Despite advancements in preoperative prediction of patient outcomes, determination of the most appropriate surgical treatments for patients with severely impaired...     

Feeding Administration of Daikenchuto Suppresses Colitis Induced by Naive CD4+ T Cell Transfer into SCID Mice

Background and Aims

Daikenchuto, a traditional Japanese herbal medicine, suppresses bacterial translocation by improvement of gastrointestinal motility and blood flow. As Daikenchuto reportedly reduces gastrointestinal inflammatory activity by these mechanisms, we analyzed whether Daikenchuto suppresses experimental colitis and reduces inflammatory cytokine expression in a mouse model.

Methods

Colitis was induced by transfer of naive CD4⁺ T cells of BALB/c mice into SCID mice, and mice were given either control or 2.7?% Daikenchuto-containing feed. We investigated body weight, clinical symptoms, histological changes, and Th1- and Th17-cytokine expression. Cytokine mRNA expression was analyzed using real-time RT-PCR. The ratio of IL-17⁺ and IFN-γ⁺ CD4⁺ T cells were analyzed by flow cytometry.

Results

Daikenchuto delayed the development of colitis and significantly reduced the histological inflammation scores. Analyses of cytokine mRNA revealed that Th17 cytokines were significantly decreased in colons of mice that received Daikenchuto. Absolute numbers of IL-17⁺ or IFN-γ⁺ CD4⁺ T cells per colon were less in mice receiving Daikenchuto than in mice that received control feed, as both groups received naive CD4⁺ T cells to induce colitis.

Conclusions

We demonstrated that feeding administration of Daikenchuto suppresses colitis induced by naive CD4⁺ T cell transfer into SCID mice. Daikenchuto may show clinical benefit in the treatment of human inflammatory bowel disease and further studies are warranted.     

Improved techniques for double-balloon-enteroscopy-assisted endoscopic retrograde cholangiopancreatography

AIM: To investigate the clinical outcome of double balloon enteroscopy (DBE)-assisted endoscopic retrograde cholangiopancreatography (DB-ERCP) in patients with altered gastrointestinal anatomy.METHODS: Between September 2006 and April 2011, 47 procedures of DB-ERCP were performed in 28 patients with a Roux-en-Y total gastrectomy (n = 11), Billroth II gastrectomy (n = 15), or Roux-en-Y anastomosis with hepaticojejunostomy (n = 2). DB-ERCP was performed using a short-type DBE combined with several technical innovations such as using an endoscope attachment, marking by submucosal tattooing, selectively applying contrast medium, and CO₂ insufflations.RESULTS: The papilla of Vater or hepaticojejunostomy site was reached in its entirety with a 96% success rate (45/47 procedures). There were no significant differences in the success rate of reaching the blind end with a DBE among Roux-en-Y total gastrectomy (96%), Billroth II reconstruction (94%), or pancreatoduodenectomy (100%), respectively (P = 0.91). The total successful rate of cannulation and contrast enhancement of the target bile duct in patients whom the blind end was reached with a DBE was 40/45 procedures (89%). Again, there were no significant differences in the success rate of cannulation and contrast enhancement of the target bile duct with a DBE among Roux-en-Y total gastrectomy (88 %), Billroth II reconstruction (89%), or pancreatoduodenectomy (100%), respectively (P = 0.67). Treatment was achieved in all 40 procedures (100%) in patients whom the contrast enhancement of the bile duct was successful. Common endoscopic treatments were endoscopic biliary drainage (24 procedures) and extraction of stones (14 procedures). Biliary drainage was done by placement of plastic stents. Stones extraction was done by lithotomy with the mechanical lithotripter followed by extraction with a basket or by the balloon pull-through method. Endoscopic sphincterotomy was performed in 14 procedures with a needle precutting knife using a guidewire. The mean total duration of the procedure was 93.6 ± 6.8 min and the mean time required to reach the papilla was 30.5 ± 3.7 min. The mean time required to reach the papilla tended to be shorter in Billroth II reconstruction (20.9 ± 5.8 min) than that in Roux-en-Y total gastrectomy (37.1 ± 4.9 min) but there was no significant difference (P = 0.09). A major complication occurred in one patient (3.5%); perforation of the long limb in a patient with Billroth II anastomosis.CONCLUSION: Short-type DBE combined with several technical innovations enabled us to perform ERCP in most patients with altered gastrointestinal anatomy.     

Locking versus non-locking neutralization plates for treatment of lateral malleolar fractures: a randomized controlled trial

Purpose

The reduction of periosteal compression through the use of a locking plate may minimize disturbances of bone blood supply and may improve the rate of bone union. A single-centre, assessor blinded randomized controlled trial was conducted to compare the clinical effectiveness of a locking plate and a non-locking plate.

Methods

A total of 52 patients with AO/OTA 44B lateral malleolar fractures were included in this study. All patients underwent surgical fixation using a lag screw and neutralization plate. An identical treatment protocol was used in all patients, with exception of plate selection. The rate of radiographic bone union, defined as the complete disappearance of fracture lines confirmed through anteroposterior, lateral, and internal oblique views was compared at three, six, and 12 months following surgery. In addition, the Medical Outcomes 36-Item Short-Form Health Survey (SF-36) score, the time required for resolution of tenderness at the fracture site and the complication rate were evaluated.

Results

Twenty-three patients were randomly assigned to undergo fixation using a locking plate, and 29 patients were assigned to undergo fixation using a non-locking plate. Intention-to-treat analysis showed no difference in the radiographic bone union rate of fibula, SF-36 score, the time for resolution of tenderness at the fracture site and complication rates.

Conclusion

No differences were observed in patients with AO/OTA 44B lateral malleolar fractures undergoing fixation with a locking versus non-locking neutralization plate.     

Structural and biochemical basis for the inhibition of cell death by APIP,a methionine salvage enzyme

APIP, Apaf-1 interacting protein, has been known to inhibit two main types of programmed cell death, apoptosis and pyroptosis, and was recently found to be associated with cancers and inflammatory diseases. Distinct from its inhibitory role in cell death, APIP was also shown to act as a 5-methylthioribulose-1-phosphate dehydratase, or MtnB, in the methionine salvage pathway. Here we report the structural and enzymatic characterization of human APIP as an MtnB enzyme with a K_m of 9.32 μM and a V_max of 1.39 μmol min⁻¹ mg⁻¹. The crystal structure was determined at 2.0-Å resolution, revealing an overall fold similar to members of the zinc-dependent class II aldolase family. APIP/MtnB exists as a tetramer in solution and exhibits an assembly with C4 symmetry in the crystal lattice. The pocket-shaped active site is located at the end of a long cleft between two adjacent subunits. We propose an enzymatic reaction mechanism involving Glu139* as a catalytic acid/base, as supported by enzymatic assay, substrate-docking study, and sequence conservation analysis. We explored the relationship between two distinct functions of APIP/MtnB, cell death inhibition, and methionine salvage, by measuring the ability of enzymatic mutants to inhibit cell death, and determined that APIP/MtnB functions as a cell death inhibitor independently of its MtnB enzyme activity for apoptosis induced by either hypoxia or etoposide, but dependently for caspase-1-induced pyroptosis. Our results establish the structural and biochemical groundwork for future mechanistic studies of the role of APIP/MtnB in modulating cell death and inflammation and in the development of related diseases.The programmed death of dangerous cells, either infected or transformed, has critical importance for the survival of the multicellular organism and therefore is also of great medical relevance. APIP, Apaf-1 interacting protein, was initially identified as an inhibitor of apoptotic cell death induced by hypoxia/ischemia and cytotoxic drugs (1). Recently APIP was also shown to inhibit pyroptosis, an inflammatory form of cell death, induced by Salmonella infection (2). Thus, APIP has been implicated in two major types of programmed cell death: apoptosis and pyroptosis. In apoptosis, APIP inhibits the mitochondrial pathway involving caspase-9 but not the receptor pathway involving caspase-8 (1, 3). In pyroptosis, APIP’s inhibitory function was recently revealed in a functional genetic screen for the SNP associated with increased caspase-1–mediated cell death in response to Salmonella infection (2) and subsequently confirmed by cell viability assays (2, 4). Intriguingly, other SNPs near APIP were found in patients suffering from systemic inflammatory response syndrome (2), which further implicates APIP in inflammation.Distinct from its inhibitory role in the programmed cell death, APIP was recently shown to act as an enzyme in the methionine salvage pathway (2, 4). The amino acid sequence of human APIP exhibits 23–26% identity to the previously characterized Bacillus and yeast 5-methylthioribulose-1-phosphate dehydratase (MtnB) (4). The methionine salvage pathway converts MTA (5-methylthioadenosine) to methionine through six enzymatic reaction steps, and MtnB is the third enzyme in the pathway and catalyzes the dehydration of MTRu-1-P (5-methylthioribulose-1-phosphate) to DK-MTP-1-P (2,3-diketo-5-methylthiopentyl-1-phosphate) (Fig. 1B) (4, 5). In the absence of methionine, cells supplemented with MTA exhibit decreased viability when APIP expression is reduced (2, 4). These studies indicate that APIP is an MtnB enzyme in the methionine salvage pathway.Open in a separate windowFig. 1.APIP as an MtnB enzyme in the methionine salvage pathway. (A) Initial reaction rate was plotted at seven different concentrations of the substrate MTRu-1-P for Michaelis-Menten kinetic analysis. Data represent mean values with SE from three independent measurements. (B) Methionine salvage pathway characterized in Homo sapiens and Saccharomyces cerevisiae converts MTA to methionine (Met) through the common six enzymatic reactions. Dashed line represents B. subtilis methionine salvage reaction steps distinct from H. sapiens and S. cerevisiae. Gray colored enzymatic steps and metabolites represent biochemical links that are not conceptually part of the methionine salvage pathway. AdoMet, S-adenosyl-l-methionine; dAdoMet, decarboxylated AdoMet; DHK-MTPene, 1,2-dihydroxy-3-keto-5-methylthiopentene; HK-MTPenyl-1-P, 2-hydroxy-3-keto-5-methylthiopentenyl-1-phosphate; Met, l-methionine; MTOB, 4-methylthio-2-oxobutyrate; MTR, 5-methylthioribose.The methionine salvage pathway is found in all organisms, from bacteria to plants and animals (6). The role of this pathway is to recycle MTA, which is a by-product of the polyamine synthetic process, back to methionine (Fig. 1B). The methionine salvage pathway is beneficial as a means of recycling the sulfur present in MTA because assimilation of sulfur is thermodynamically costly (6). The metabolic importance of the pathway is underscored in humans because methionine is one of the essential amino acids needed to be provided through the diet, in which it is one of the most limiting amino acids (6). Recently, the methionine salvage pathway attracted medical interest because it was implicated in cell death and inflammation and diseases associated with these processes. For example, metabolites such as MTA and 2-keto-4-methylthiobutyrate (KMTB) have effects of apoptosis induction (6–9). MTA was also shown to induce caspase-1–dependent pyroptosis in the inflammatory response to bacterial infection (2). In addition, the 5-methylthioadenosine phosphorylase (MTAP, which catalyzes the first step) is a tumor suppressor implicated in a various human cancers (6, 10), and aci-reducton dioxygenase 1 (ADI1, also called MtnD, which catalyzes the fifth step) has a similar role in prostate cancer (11, 12). Human APIP/MtnB, which is the focus of the present study, is another example of a methionine salvage enzyme that is implicated in cell death and inflammation. APIP/MtnB was recently reported to be up-regulated in squamous carcinoma cells from tongue and larynx (13) and down-regulated in the cells and tumors of non–small-cell lung carcinoma (14). In addition, APIP/MtnB is implicated in inflammatory conditions that likely involve caspase-1–dependent pyroptosis, such as systemic inflammatory response syndrome (2).Studies of APIP/MtnB to date have focused mainly on its functional role either in cell death or in methionine salvage. To gain a better understanding of APIP/MtnB at a molecular and biochemical level, we carried out a structural and biochemical characterization in this study. The MtnB enzyme activity of APIP was verified by an in vitro enzyme assay. In addition, the crystal structure was determined at 2.0-Å resolution, which revealed details of the active site architecture and led to a proposed catalytic mechanism. Furthermore, we explored the relationship between two distinct functions of APIP/MtnB, cell death inhibition, and methionine salvage, by testing its enzymatic mutants derived from the crystal structure for their ability to inhibit two main types of programmed cell death: pyroptosis and apoptosis.     

Tachykinins via Tachykinin NK(2) receptor activation mediate ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs

1. Acute exposure to ozone is known to cause airway hyperresponsiveness, which, at least in part, seems to result from an increase in the permeability of the airway mucosa. Recently, we demonstrated that depletion of sensory neuropeptides inhibits the ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs. The aim of this study was to determine whether tachykinins mediate ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs. 2. Anaesthetized guinea-pigs were exposed to either 3 p.p.m. ozone or filtered air for 30 min. Immediately after exposure, a tracheal segment was isolated in vivo and administered with horseradish peroxidase (HRP). The permeability was assessed by monitoring the appearance of HRP in the blood. 3. A low dose of NKA increased the permeability of the tracheal mucosa, whereas a low dose of SP was without effect. Low and high doses of the selective NK(3) receptor agonist, senktide, were also without effect. The effect of a low dose of NKA was abolished by the NK(2) receptor antagonist, SR-48,968. A high dose of SP increased the permeability in a manner reversible by the NK(1) receptor antagonist, CP-96,345. 4. Pretreatment with SR-48,968 completely inhibited the ozone-induced increase in the permeability, whereas CP-96,345 had no effect. 5. It is thus concluded that endogenous tachykinins mediate the ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs mainly via NK(2) receptor activation.     

Profound sinus bradycardia after intravenous nicardipine

IMPLICATIONS: Nicardipine-induced bradycardia has been reported in experimental animals but not in clinical patients. We report a clinical case of unexpected bradycardia caused by nicardipine. The mechanism of this bradycardia was not clear, and depression of sympathetic tone by epidural anesthesia, hypothermia, and paroxysmal atrial fibrillation might have been contributory.