Change in fiber type in partially-denervated soleus muscle of the rat

In 30% or less partially denervated muscle, the reinnervation of denervated muscle fiber may give rise to a change in motor unit size or number of muscle fibers innervated by a single motor neuron. This study was designed to evaluate changes in fiber type and contractibility of partially denervated rat soleus muscle. Partial denervation (by 30% or less) of the soleus nerve does not cause a decrease in the number of muscle fibers. A histochemical study was performed on frozen sections of the muscle. The total number of muscle fibers, atrophied fibers and type II fibers were counted. In the muscle 4 weeks after partial denervation, the number of type II fibers was fewer with a decrease of about 40% which was not significant. The twitch time to peak and half-relaxation time were not changed. The number of type II fibers was significantly decreased (p less than 0.01) after 8 weeks. There was a prolongation of contraction time. The decrease of type II fibers was extensive involving not only the denervated area but also the rest of the muscle area. The transformation of fiber type observed in partially denervated muscle may be attributed to a possible diminution of neurotrophic substances in intact motor neurons.     

Gene therapy for intraperitoneally disseminated pancreatic cancers by Escherichia coli uracil phosphoribosiltransferase (UPRT) gene mediated by restricted replication-competent adenoviral vectors

Although patients with unresectable pancreatic tumors have been treated with 5-fluorouracil (5FU)-based combination chemotherapy, the drug resistance of cancer cells presents a crucial therapeutic problem. It was reported that UPRT overcomes 5FU resistance. UPRT catalyzes the synthesis of 5-fluorouridine monophosphate (FUMP) from Uracil and phosphoribosylpyrophosphate (PRPP). The antitumor effect of 5FU is enhanced by augmenting 5-fluorodeoxyuridine monophosphate (FdUMP) converted from FUMP, which inhibits thymidylate synthetase (TS). We first demonstrated that injecting an E1-deficient adenoviral vector (Adv) expressing UPRT (AxCAUPRT) followed by 5-FU treatment resulted in a volume reduction of xenotransplanted human tumors. In examining the therapeutic effect of AxCAUPRT/5-FU against peritoneal dissemination, we found that non-selective gene transduction of AxCAUPRT caused severe adverse effects arising from the increase of F-dUMP in normal intestine. Because the therapeutic gene delivered by a restricted replication-competent Adv lacking 55 kDa E1B protein (AxE1AdB) is speculated to be expressed selectively in tumors, mice with established tumors were injected with AxE1AdB and E1-deleted Adv expressing the lacZ reporter gene (AxCAlacZ). The expression of the reporter gene (lacZ) was selectively enhanced in disseminated tumors. The therapeutic advantage of restricted replication competent Adv that expresses UPRT (AxE1AdB-UPRT) was evaluated in an intraperitoneal disseminated tumor model. To study the anti-tumor effect of AxE1AdB-UPRT/5FU, mice with disseminated AsPC-1 tumors were administered the Adv, followed by the 5FU treatment. It was shown that the treatment with AxE1AdB-UPRT/5FU caused a dramatic reduction of the disseminated tumor burden without toxicity in normal tissues. Our results showed that the AxE1AdB-UPRT/5FU system is a promising tool for intraperitoneal disseminated pancreatic cancer.     

Neoadjuvant Chemotherapy with Gemcitabine and S-1 for Resectable and Borderline Pancreatic Ductal Adenocarcinoma: Results from a Prospective Multi-institutional Phase 2 Trial

Background

Surgical resection is the only curative strategy for pancreatic ductal adenocarcinoma (PDAC), but recurrence rates are high even after purported curative resection. First-line treatment with gemcitabine and S-1 (GS) is associated with promising antitumor activity with a high response rate. The aim of this study was to assess the feasibility and efficacy of GS in the neoadjuvant setting.

Methods

In a multi-institutional single-arm phase 2 study, neoadjuvant chemotherapy (NAC) with gemcitabine and S-1, repeated every 21 days, was administered for two cycles (NAC-GS) to patients with resectable and borderline PDAC. The primary end point was the 2-year survival rate. Secondary end points were feasibility, resection rate, pathological effect, recurrence-free survival, and tumor marker status.

Results

Of 36 patients enrolled, 35 were eligible for this clinical trial conducted between 2008 and 2010. The most common toxicity was neutropenia in response to 90 % of the relative dose intensity. Responses to NAC included radiological tumor shrinkage (69 %) and decreases in CA19-9 levels (89 %). R0 resection was performed for 87 % in resection, and the morbidity rate (40 %) was acceptable. The 2-year survival rate of the total cohort was 45.7 %. Patients who underwent resection without metastases after NAC-GS (n = 27) had an increased median overall survival (34.7 months) compared with those who did not undergo resection (P = 0.0017).

Conclusions

NAC-GS was well tolerated and safe when used in a multi-institutional setting. The R0 resection rate and the 2-year survival rate analysis are encouraging for patients with resectable and borderline PDAC.     

Giant umbilical cord and hypoglycemia in an infant with Proteus syndrome

Proteus syndrome (PS) is characterized by the progressive, segmental, or patchy overgrowth of the skin, and other tissues. This is the first case report of recurrent severe insulin‐independent hypoglycemia in an infant with PS. Somatic p.E17K of AKT1 mutation was confirmed. The patient also had a giant umbilical cord, which has not yet been reported in PS.     

Association of a single nucleotide polymorphism in the WISP1 gene with spinal osteoarthritis in postmenopausal Japanese women

The Wnt-β-catenin signaling pathway that regulates bone density is also involved in cartilage development and homeostasis in vivo. Here, we assumed that genetic variation in Wnt-β-catenin signaling genes can affect the pathogenesis of cartilage related diseases, such as osteoarthritis. Wnt-1-induced secreted protein 1 (WISP1) is a target of the Wnt pathway and directly regulated by β-catenin. In the present study, we analyzed the association of a single nucleotide polymorphism (SNP) in the WISP1 3′-UTR region with the development of radiographically observable osteoarthritis of the spine. For this purpose, we evaluated the presence of osteophytes, endplate sclerosis, and narrowing of disc spaces in 304 postmenopausal Japanese women. We compared those who carried the G allele (GG or GA, n = 184) with those who did not (AA, n = 120). We found that the subjects without the G allele (AA) were significantly over-represented in the subjects having higher endplate sclerosis score (P = 0.0069; odds ratio, 2.91; 95% confidence interval, 1.34–6.30 by logistic regression analysis). On the other hand, the occurrence of disc narrowing and osteophyte formation did not significantly differ between those with and without at least one G allele. Thus, we suggest that a genetic variation in the WISP1 gene locus is associated with spinal osteoarthritis, in line with the involvement of the Wnt-β-catenin-regulated gene in bone and cartilage metabolism.     

Propofol reduces the incidence of emergence agitation in preschool-aged children as well as in school-aged children: a comparison with sevoflurane

Purpose Young age is considered as one of the factors associated with emergence agitation (EA) following sevoflurane anesthesia. The relationship between EA following propofol anesthesia and young age has not yet been examined. This study was designed to compare the incidence of EA in younger children and older children following either propofol or sevoflurane anesthesia. Methods Ninety-six preschool-aged (2–5 years) children and 90 school-aged (6–11 years) children (American Society of Anesthesiologists [ASA] I or II) scheduled to undergo otorhinolaryngological surgery were randomly assigned to receive either propofol or sevoflurane. These children were divided into the following four groups: propofol-preschool (P-pre), sevoflurane-preschool (S-pre), propofol-school (P-school), and sevoflurane-school (S-school) groups. Recovery times and incidence of EA were compared among the four groups. Results We observed that the recovery times were similar in the four groups. After extubation, the incidence of EA in the S-pre group was significantly higher than that in the other groups. After eye opening, the incidence of EA in the S-pre and S-school groups was significantly higher than that in the P-pre or P-school groups. At all recovery times, no difference was observed in the incidence of EA between the P-pre and P-school groups. Conclusion Propofol, in comparison with sevoflurane, resulted in a lower incidence of EA, with no relation to age.     

Pancreatic Hamartoma Difficult to Diagnose Preoperatively

Abdominal ultrasonography in a 70-year-old woman showed a hypoechoic mass, 14 mm in diameter, in the pancreatic body. Computed tomography showed a mass with contrast effect in the pancreatic body. Test results for endocrine factors or tumor markers were normal. The initial consideration was nonfunctional pancreatic neuroendocrine tumor. Over 8 years of monitoring, the tumor diameter increased to 18 mm, until pancreatic tumor enucleation was performed. The postoperative diagnosis was pancreatic hamartoma, a rare type of benign pancreatic tumor. The preoperative diagnosis of pancreatic hamartoma is difficult, but consideration must be given to the possibility of hamartoma when encountering pancreatic tumors.     

Association of HTRA1 promoter polymorphism with spinal disc degeneration in Japanese women

HTRA1 (high-temperature requirement A1) has been implicated in the modulation of various disease pathologies. HTRA1 expression is upregulated in osteoarthritic joints, suggesting that it may contribute to the development of this debilitating disease. Moreover, recent reports have shown that the rs11200638, a single nucleotide polymorphism (SNP) in the promoter region of the HTRA1 gene, is strongly associated with an increased prevalence of age-related macular degeneration (AMD). In the present study, we examined the expression of the HTRA1 in human primary chondrocytes and an association between the rs11200638 SNP and radiographic features of spinal disc degeneration in 513 postmenopausal Japanese women. HTRA1 mRNA was detected and increased by TGF-β treatment in human primary chondrocytes. As an association study of rs11200638 SNP in the HTRA1 gene, the subjects without the G allele (AA; n = 89) had a significantly higher spinal disc space narrowing score than the subjects bearing at least one G allele (GG + GA; n = 424) (P = 0.0292). We found that subjects without the G allele (AA) were significantly overrepresented in the subjects having a higher (≥4) disc space narrowing score (P = 0.013; odds ratio 1.97; 95% confidence interval 1.15–3.37 by logistic regression analysis). A genetic variation at the HTRA1 gene promoter locus is associated with spinal disc degeneration, suggesting an involvement of the HTRA1 gene in osteoarthritis.