New Reconstructive Procedure After Intestinal Resection for Crohn’s Disease: Modified Side-to-Side Isoperistaltic Anastomosis With Double Heineke-Mikulicz Procedure

Although side-to-side isoperistaltic anastomosis is a useful strictureplasty technique when long segments of intestinal stenosis complicate Crohns disease, concerns have been raised regarding disease recurrence adjacent to the anastomosis. We performed side-to-side isoperistaltic anastomosis without spatulated intestinal ends as a method of reconstruction after intestinal resection for Crohns disease; both intestinal ends were transversely closed like a Heineke-Mikulicz-type strictureplasty. With this procedure, the luminal diameter proximal and distal to the anastomosis became wider than the original diameter of the intestine. This new procedure, which we refer to as the modified side-to-side isoperistaltic anastomosis with double Heineke-Mikulicz procedure could become an alternative operation after intestinal resection in persons with Crohns disease, although long-term outcome analysis is necessary.     

T-gamma delta large granular lymphocyte leukemia preceded by pure red cell aplasia and complicated with hemophagocytic syndrome caused by Epstein-Barr virus infection

A 51-year-old man developed anemia, and was diagnosed with pure red cell aplasia through the absence of erythroid progenitors. Initially, he was treated with cyclosporine and prednisolone for 6 months but they were ineffective. Large granular lymphocyte (LGL) leukemia with the T-cell gamma delta phenotype evolved after 6 months showing CD2+, CD3+, CD8- and CD56- with the T-cell receptor beta gene rearrangement, clonalities of gamma and delta genes and complex chromosome abnormality simultaneously with hemophagocytic syndrome (HPS). Epstein-Barr virus (EBV) genomic DNA was detected in the bone marrow cells. Administration of bolus methylprednisolone was ineffective, and the patient died one month later. In the present patient, it seemed that lymphoproliferative disease of large granular lymphocytes (LDGL) manifested initially as PRCA, gammadelta LGL leukemia evolved, and finally fatal HPS become complicated, presumably caused by the EBV reactivation in the immunodeficiency state with the administration of immunosuppressants.     

Regulatory effects of macrolides on bacterial virulence: potential role as quorum-sensing inhibitors

Pseudomonas aeruginosa is an opportunistic pathogen, and this organism is a major cause of pulmonary damage and mortality in patients with cystic fibrosis (CF), diffuse panbronchiolitis (DPB) and other forms of bronchiectasis. A break-through in the treatment of DPB and associated chronic P. aeruginosa pulmonary infection was realized when a patient with DPB improved dramatically after treatment with erythromycin for years. Now, long-term macrolide therapy has become a first line of treatment in DPB patients, and the immunomodulatory properties have now been extended to other clinical settings, including CF. An important factor in the pathogenesis of chronic P. aeruginosa infection is a bacterial cell-to-cell signaling mechanism, referred to as "quorum sensing", which enables bacteria to coordinately turn on and off specific virulence genes through the production of autoinducer molecules. Interference or blocking of quorum-sensing systems has been considered an attractive therapeutic strategy. Clinical and basic science data suggests the potential of macrolides as relevant inhibitors of the Pseudomonas quorum-sensing system. In fact, certain macrolides strongly suppressed quorum-sensing associated genes and autoinducer production, in addition to inhibition of a variety of virulence factors. In this review, clinical efficacy of macrolides on DPB and CF patients will be briefly summarized. Additionally, the mechanisms of action of macrolides will be discussed from the standpoint of sub-MIC macrolide effects on P. aeruginosa, particularly the ability of this antibiotic to suppress quorum-sensing systems, which may be crucial in the pathogenesis of chronic P. aeruginosa infection.     

ERBIN associates with p0071, an armadillo protein,at cell-cell junctions of epithelial cells

BACKGROUND: ERBIN, an ErbB2 receptor-interacting protein, belongs to a recently described family of proteins termed the LAP [leucine-rich repeats and PSD-95/dLg-A/ZO-1 (PDZ) domains] family which has essential roles in establishment of cell polarity. RESULTS: To identify new ERBIN-binding proteins, we screened a yeast two-hybrid library, using the carboxyl-terminal fragment of ERBIN containing PDZ domain as the bait, and we isolated p0071 (also called plakophilin-4) as an ERBIN-interacting protein. p0071 is a member of the p120 catenin family, which are defined as proteins with 10 armadillo repeats, and localizes along the cell-cell border. The ERBIN PDZ domain binds the COOH-terminus of p0071 containing the PDZ domain-binding sequence. Endogenous ERBIN was co-immunoprecipitated with p0071. In fully polarized Madin-Darby canine kidney (MDCK) cells, ERBIN co-localized largely with beta-catenin and partly with desmoplakin along the lateral plasma membrane domain. At these cell-cell contact regions, ERBIN co-localizes with p0071. Over-expression of the dominant active forms of Cdc42, Rac1 or RhoA, Rho family small GTPases, resulted in a marked accumulation of ERBIN at the cell-cell contacts of MDCK and HeLa cells. CONCLUSION: These results show that ERBIN interacts in vivo with p0071 and that it may be involved in the organization of adherens junctions and the desmosomes of epithelia. In addition, we demonstrated that the subcellular localization of ERBIN might be regulated by Rho family small GTPases.     

A phase II study of weekly paclitaxel combined with carboplatin for elderly patients with advanced non-small cell lung cancer

We conducted this phase II study to explore the efficacy and safety of weekly paclitaxel combined with carboplatin in elderly patients with advanced non-small cell lung cancer (NSCLC). Elderly patients (> or = 70 years old) of stage IIIB, IV, or recurrent NSCLC with PS 0 or 1 were enrolled. Patients received paclitaxel at a dose of 70 mg/m2 on Days 1, 8, 15, and carboplatin at the target dose of the area under the curve (AUC) of six on Day 1 every 28 days for at least two cycles. Forty-two patients were enrolled and 40 patients were treated with a median of three cycles (range, 1-5). The overall response rate (ORR) was 45% (95% confidence interval, 30-60%). The median survival time (MST) was 14 months and the 1-year survival rate was 62%. Twenty-eight patients (70%) had grade 3/4 neutropenia and two patients (5%) experienced grade 3 febrile neutropenia. Non-hematological toxicities were generally mild to moderate and grade 3 peripheral neuropathy was seen in one patient (3%). There was one treatment-related death by infection due to neutropenia. Weekly paclitaxel and carboplatin combination chemotherapy was an effective and safe regimen in elderly patients with advanced NSCLC. A randomized trial comparing this treatment with the conventional tri-weekly regimen of paclitaxel and carboplatin is warranted.     

Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization

Hematopoietic stem cells (HSCs) are maintained in a specific bone marrow (BM) niche in cavities formed by osteoclasts. Osteoclast-deficient mice are osteopetrotic and exhibit closed BM cavities. Osteoclast activity is inversely correlated with hematopoietic activity; however, how osteoclasts and the BM cavity potentially regulate hematopoiesis is not well understood. To investigate this question, we evaluated hematopoietic activity in three osteopetrotic mouse models: op/op, c-Fos-deficient, and RANKL (receptor activator of nuclear factor kappa B ligand)-deficient mice. We show that, although osteoclasts and, by consequence, BM cavities are absent in these animals, hematopoietic stem and progenitor cell (HSPC) mobilization after granulocyte colony-stimulating factor injection was comparable or even higher in all three lines compared with wild-type mice. In contrast, osteoprotegerin-deficient mice, which have increased numbers of osteoclasts, showed reduced HSPC mobilization. BM-deficient patients and mice reportedly maintain hematopoiesis in extramedullary spaces, such as spleen; however, splenectomized op/op mice did not show reduced HSPC mobilization. Interestingly, we detected an HSC population in osteopetrotic bone of op/op mice, and pharmacological ablation of osteoclasts in wild-type mice did not inhibit, and even increased, HSPC mobilization. These results suggest that osteoclasts are dispensable for HSC mobilization and may function as negative regulators in the hematopoietic system.     

Efficacy of intravenous immune globulin therapy combined with dexamethasone for the initial treatment of acute Kawasaki disease

We studied the effects of a new regimen consisting of intravenous immune globulin (IVIG) combined with dexamethasone (DEX) on clinical outcome and serum levels of vascular endothelial growth factor (VEGF) in the initial treatment of Kawasaki disease (KD). A total of 46 KD patients received 0.3 mg/kg per day DEX plus heparin i.v. for 3 consecutive days, together with 2 g/kg IVIG over 4 to 5 days (DEX group). Low-dose acetylsalicylic acid was started after completion of DEX therapy. The control group consisted of 46 KD patients retrospectively treated earlier with 2 g/kg IVIG over 4 to 5 days plus higher dose acetylsalicylic acid (CONTROL group). No serious adverse effect was noted in either group. There were no differences in baseline and post-treatment laboratory data except for C-reactive protein between the groups. Post-treatment C-reactive protein in the DEX group (median 0.9 mg/dl, range 0.0 to 24.7 mg/dl) was lower than that (1.2 mg/dl, range 0.2 to 19.5 mg/dl) in the CONTROL group ( P =0.033 by Mann-Whitney U test). In addition, the mean duration of fever after the first IVIG infusion was 2.2 days (median 1 day, range 1 to 12 days) in the DEX group and 2.8 days (2 days, 1 to 16 days) in the CONTROL group ( P =0.015 by Mann-Whitney U test). The new regimen did not reduce VEGF levels. Two patients in each group developed small- or medium-sized coronary artery aneurysms. Conclusion:although this regimen did not affect coronary outcome, intravenous immune globulin therapy combined with dexamethasone for the initial treatment of Kawasaki disease was safe and may accelerate the resolution of systemic inflammation.Abbreviations CAA coronary artery aneurysms - DEX dexamethasone - IVIG intravenous immune globulin - KD Kawasaki disease - VEGF vascular endothelial growth factor     

A polymorphism in the integrin ��V subunit gene affects the progression of primary biliary cirrhosis in Japanese patients

Background

Accumulating evidence indicates that multiple genetic factors are involved in the pathogenesis of primary biliary cirrhosis (PBC). The aim of this study was to investigate whether polymorphisms of the integrin ??V subunit gene (ITGAV), a component of integrin ??V??6, which plays an important role in the process of fibrosis, are associated with susceptibility to the onset and/or progression of PBC.

Methods

In the primary study, eight tag single nucleotide polymorphisms (SNPs) in ITGAV were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, direct DNA sequencing, or high-resolution melting curve analysis in 309 Japanese patients with PBC who were registered in the National Hospital Organization Study Group for Liver Disease in Japan (PBC cohort I) and 293 gender-matched healthy Japanese volunteers (control subjects). For the replication study, 35 PBC patients who progressed to end-stage hepatic failure and underwent liver transplantation (PBC cohort II) were also analyzed.

Results

Three tag SNPs (rs3911238, rs10174098, and rs1448427) in ITGAV were significantly associated with the severe progression of PBC, but not with susceptibility to the onset of PBC, in the primary study (PBC cohort I). Among these SNPs, rs1448427 was also significantly associated with the severe progression to end-stage hepatic failure in the replication study of PBC patients who underwent liver transplantation (PBC cohort II).

Conclusions

ITGAV is a genetic determinant for the severe progression of PBC in Japanese patients. Genetic polymorphisms of ITGAV may be useful for identifying high-risk Japanese PBC patients, including those who will require liver transplantation, at the time of initial diagnosis.     

Evaluation of cortical processing of language by use of positron emission tomography in hearing loss children with congenital cytomegalovirus infection

Objective

To predict cochlear implant efficacy and investigate the cortical processing of the visual component of language in profoundly deafened patients with asymptomatic congenital cytomegalovirus (CMV) infection.

Methods and cases

The cortical activity of two children with CMV-related hearing loss was evaluated with fluorodeoxyglucose-positron emission tomography (FDG-PET) with a visual language task before cochlear implantation. Total development and auditory perception ability were assessed one year after implantation.

Results

The two children with CMV-related hearing loss showed activation in the auditory association area where no activation was found in the controls, and exhibited nearly identical cortical activation patterns to those seen in patients with profound congenital hearing loss. In contrast, differences in total development in verbal ability and discrimination of sentences between the two cases were revealed one year after implantation.

Conclusion

These results might indicate that the differences of cortical activities according to hearing abilities could have been influenced by CMV infection that involves higher function of the brain directly and/or affects the cochlea peripherally. Additionally, if CMV infection might have affected only the cochlea, these cortical activation patterns were influenced secondary by the time course of hearing loss characterized by CMV infection, which had varied manifestations.Accurate diagnosis and cochlear implantation at the appropriate time are important for successful speech development, and each patient needs a personalized habilitation program based on their etiology and brain function.     

Pulmonary metastasectomy for metachronous metastasis of esophageal cancer after esophagectomy

Background and objective

Pulmonary metastasectomy is a standard therapy for some types of metastatic lesions in the lung. Although the prognosis for esophageal cancer patients with pulmonary metastasis is poor, it has been reported that some post-esophagectomy patients have good prognosis after pulmonary metastasectomy. We investigated the role of resecting pulmonary metastases arising from esophageal cancer at our institution.

Patients and methods

Seven patients with primary squamous cell carcinoma or adenocarcinoma of the thoracic esophagus who underwent resection of metachronous pulmonary metastases at our institution between 2006 and 2012 were identified from a retrospective database. All patients had undergone curative resection of their primary esophageal carcinoma.

Results

Six patients had unilateral and solitary lung metastasis. One patient presented with one metastatic lesion on each side, and he underwent 4 metastasectomy for pulmonary metastasis 3 times. There was no perioperative morbidity or mortality. The disease-free interval after esophagectomy ranged from 191 to 559 days (median, 463 days). Survival after pulmonary metastasectomy ranged from 357 to 3191 days (median, 1803 days). Three patients received systemic chemotherapy before metastasectomy. Currently, 5 patients are alive without evidence of recurrent disease.

Conclusion

Pulmonary metastasectomy may be acceptable as a part of multimodal treatment for solitary metachronous pulmonary metastasis in esophageal carcinoma.