Fecoflowmetric Analysis of Anorectal Motor Function in Postoperative Anal-Preserving Surgery Patients With Low Rectal Cancer Comparison With the Wexner Score and Anorectal Manometry

The aim of this study was to elucidate whether fecoflowmetry (FFM) could evaluate more detailed evacuative function than anorectal manometry by comparing between FFM or anorectal manometric findings and the clinical questionnaires and the types of surgical procedure in the patients who received anal-preserving surgery. Fifty-three patients who underwent anal-preserving surgery for low rectal cancer were enrolled. The relationships between FFM or the manometric findings and the clinical questionnaires and the types of procedure of anal-preserving surgery were evaluated. There were significant differences between FFM markers and the clinical questionnaire and the types of the surgical procedure, whereas no significant relationship was observed between the manometric findings and the clinical questionnaire and the types of the surgical procedure. FFM might be feasible and useful for the objective assessment of evacuative function and may be superior to manometry for patients undergoing anal-preserving surgery.Key words: Anorectal manometry, Anal-preserving surgery, Fecoflowmetry, Incontinence, Rectal cancerSphincter preservation has been one of the key issues of rectal cancer surgery. Low anterior resection (LAR)¹ and internal and external sphincter resection (ISR and ESR) are anal-preserving surgeries.^2,3 The aim of these procedures is to restore the normal process of defecation, along with its function, and to improve the quality of life of patients by avoiding permanent colostomy. However, anal-preserving surgery is often associated with evacuative dysfunction and various degrees of incontinence.^4–7Most studies that have assessed the evacuation function have used clinical questionnaires, which are subjective and may vary according to the patient perception.⁷ There are many factors that can affect the evacuative function, such as the stool consistency, rectal capacity, anal sphincters, pelvic floor muscles, and intra-abdominal pressure. Although manometry with or without the clinical score has also commonly been used, fecoflowmetry (FFM) has been reported to be more accurate and useful for assessing the postoperative anorectal motor function.^8–13 FFM was first introduced by Shafik and is a dynamic method for examining the anorectal motor activity that simulates the natural act of defecation.¹⁴ Some studies have shown its usefulness in postoperative patients with anorectal disease,^8–11 but only a few studies have been performed to examine the evacuative function following anal-preserving surgery.^12,13 The aim of this study was to evaluate the evacuative function in the postoperative period following anal-preserving surgery in patients with low rectal cancer using FFM, and to compare the results with the Wexner score and anorectal manometry.¹⁵     

Activation of eNOS in rat portal hypertensive gastric mucosa is mediated by TNF-alpha via the PI 3-kinase-Akt signaling pathway

Activation of endothelial nitric oxide synthase (eNOS) in portal hypertensive (PHT) gastric mucosa leads to hyperdynamic circulation and increased susceptibility to injury. However, the signaling mechanisms for eNOS activation in PHT gastric mucosa and the role of TNF-alpha in this signaling remain unknown. In PHT gastric mucosa we studied (1) eNOS phosphorylation (at serine 1177) required for its activation; (2) association of the phosphatidylinositol 3-kinase (PI 3-kinase), and its downstream effector Akt, with eNOS; and, (3) whether TNF-alpha neutralization affects eNOS phosphorylation and PI 3-kinase-Akt activation. To determine human relevance, we used human microvascular endothelial cells to examine directly whether TNF-alpha stimulates eNOS phosphorylation via PI 3-kinase. PHT gastric mucosa has significantly increased (1) eNOS phosphorylation at serine 1177 by 90% (P <.01); (2) membrane translocation (P <.05) and phosphorylation (P <.05) of p85 (regulatory subunit of PI 3-kinase) by 61% and 85%, respectively; (3) phosphorylation (P <.01) and activity (P <.01) of Akt by 40% and 52%, respectively; and (4) binding of Akt to eNOS by as much as 410% (P <.001). Neutralizing anti-TNF-alpha antibody significantly reduced p85 phosphorylation, phosphorylation and activity of Akt, and eNOS phosphorylation in PHT gastric mucosa to normal levels. Furthermore, TNF-alpha stimulated eNOS phosphorylation in human microvascular endothelial cells. In conclusion, these findings show that in PHT gastric mucosa, TNF-alpha stimulates eNOS phosphorylation at serine 1177 (required for its activation) via the PI 3-kinase-Akt signal transduction pathway.     

Intimal hyperplasia of experimental autologous vein graft in hyperlipidemic rabbits with poor distal run-off

Poor distal runoff and hyperlipidemia are factors affecting the fate of an implanted graft. In the present study, combined effects of poor distal runoff and hyperlipidemia on intimal hyperplasia (IH) of the vein graft were examined in a newly developed poor distal runoff model in rabbits. A poor distal runoff model was prepared in the right hindlimb of 30 rabbits. These animals were divided into two groups, depending on the diet provided; normolipidemic diet group (Group NL, n = 14) and hyperlipidemic 1% cholesterol diet group (Group HL, n = 16). Four weeks after preparing the poor runoff model, the femoral vein was implanted into the ipsilateral femoral artery. At 2, 4 and 6 weeks, the grafts were harvested. IH of the graft was measured and macrophages in the IH were examined immunohistochemically. Intimal cell proliferation was also determined by bromodeoxyuridine (BrdU) incorporation. IH of the vein graft was significantly accelerated in cases of poor distal runoff and hyperlipidemia. There were no macrophages in the IH in the NL group. In the HL group, macrophages infiltrated the outer layer of IH, sometimes just above the internal elastic lamina, and increased with time. In the poor distal runoff limbs at 6 weeks, macrophages also appeared in the subendothelial layer but were absent in that layer in the controls. Intimal cell proliferation expressed as the Brd U labeling index (LI) was maximum at 2 weeks. In the HL group, BrdU LI of 1H in the poor distal runoff limb was higher than in the control at 2 and 4 weeks. Throughout the experiments, BrdU Us in the HL group were significantly higher than in the NL. Hyperlipidemia accelerates intimal cell proliferation to a greater extent, then does 1H. In cases of a poor distal runoff, the enhancement of cell proliferation by hyperlipidemia is augmented. These responses, in the presence of a hyperlipidemia, may be closely related to the migration of macrophages.     

Acute myeloid leukaemia with myelodysplastic features in children: a report of Japanese Paediatric Leukaemia/Lymphoma Study Group

The clinical characteristics and prognostic relevance of acute myeloid leukaemia (AML) with myelodysplastic features remains to be clarified in children. We prospectively examined 443 newly diagnosed patients in a multicentre clinical trial for paediatric de novo AML, and found ‘AML with myelodysplasia‐related changes’ (AML‐MRC) according to the 2008 World Health Organization classification in 93 (21·0%), in whom 59 were diagnosed from myelodysplasia‐related cytogenetics alone, 28 from multilineage dysplasia alone and six from a combination of both. Compared with 111 patients with ‘AML, not otherwise specified’ (AML‐NOS), patients with ‘AML‐MRC’ presented at a younger age, with a lower white blood cell count, higher incidence of 20–30% bone marrow blasts, unfavourable cytogenetics and a lower frequency of Fms‐like tyrosine kinase 3 internal tandem duplication (FLT3‐ITD), NPM1 and CEBPA mutations. Complete remission rate and 3‐year probability of event‐free survival were significantly worse in ‘AML‐MRC’ patients (67·7 vs. 85·6%, P < 0·01, 37·1% vs. 53·8%, P = 0·02, respectively), but 3‐year overall survival and relapse‐free survival were comparable with ‘AML‐NOS’ patients. By multivariate analysis, FLT3‐ITD was solely associated with worse overall survival. These results support the distinctive features of the category ‘AML‐MRC’ even in children.     

Protein disulfide isomerase homolog PDILT is required for quality control of sperm membrane protein ADAM3 and male fertility [corrected

A disintegrin and metalloproteinase 3 (ADAM3) is a sperm membrane protein critical for both sperm migration from the uterus into the oviduct and sperm primary binding to the zona pellucida (ZP). Here we show that the testis-specific protein disulfide isomerase homolog (PDILT) cooperates with the testis-specific calreticulin-like chaperone, calsperin (CALR3), in the endoplasmic reticulum and plays an indispensable role in the disulfide-bond formation and folding of ADAM3. Pdilt(-/-) mice were male infertile because ADAM3 could not be folded properly and transported to the sperm surface without the PDILT/CALR3 complex. Peculiarly we find that not only Pdilt(-/-), but also Adam3(-/-), spermatozoa effectively fertilize eggs when the eggs are surrounded in cumulus oophorus. These findings reveal that ADAM3 requires testis-specific private chaperones to be folded properly and that the principle role of ADAM3 is for sperm migration into the oviduct but not for the fertilization event. Moreover, the importance of primary sperm ZP binding, which has been thought to be a critical step in mammalian fertilization, should be reconsidered.     

Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development

It has been hypothesized that respiration defects caused by accumulation of pathogenic mitochondrial DNA (mtDNA) mutations and the resultant overproduction of reactive oxygen species (ROS) or lactates are responsible for aging and age-associated disorders, including diabetes and tumor development. However, there is no direct evidence to prove the involvement of mtDNA mutations in these processes, because it is difficult to exclude the possible involvement of nuclear DNA mutations. Our previous studies resolved this issue by using an mtDNA exchange technology and showed that a G13997A mtDNA mutation found in mouse tumor cells induces metastasis via ROS overproduction. Here, using transmitochondrial mice (mito-mice), which we had generated previously by introducing G13997A mtDNA from mouse tumor cells into mouse embryonic stem cells, we provide convincing evidence supporting part of the abovementioned hypothesis by showing that G13997A mtDNA regulates diabetes development, lymphoma formation, and metastasis--but not aging--in this model.