Clinical and experimental studies of intraperitoneal lipolysis and the development of clinically relevant pancreatic fistula after pancreatic surgery.

BACKGROUND: Visceral obesity is one of the risk factors for clinically relevant pancreatic fistula after pancreatic resection. The objective of this study was to evaluate the impact of intraperitoneal lipolysis on postoperative pancreatic fistula. METHODS: The degree of intraperitoneal lipolysis was investigated by measuring the free fatty acid concentration in drain discharge in patients after pancreatic resection. An experimental pancreatic fistula model was prepared by pancreatic transection, and the impact of intraperitoneal lipolysis was evaluated by intraperitoneal administration of triolein (triglyceride) with, or without orlistat (lipase inhibitor). RESULTS: Thirty-three patients were included in the analysis. The free fatty acid concentration in drain discharge on postoperative day 1 was significantly associated with the development of a clinically relevant pancreatic fistula (P = 0·004). A higher free fatty acid concentration in drain discharge was associated with more visceral adipose tissue (P = 0·009). In the experimental model that included 98 rats, intraperitoneal lipolysis caused an increased amount of pancreatic juice leakage and multiple organ dysfunction. Intraperitoneal administration of a lipase inhibitor reduced lipolysis and prevented deterioration of the fistula. CONCLUSION: Intraperitoneal lipolysis significantly exacerbates pancreatic fistula after pancreatic resection. Inhibition of lipolysis by intraperitoneal administration of a lipase inhibitor could be a promising therapy to reduce clinically relevant postoperative pancreatic fistula. Surgical relevance Clinically, there are two types of pancreatic fistula after pancreatic resections: harmless biochemical leak and harmful clinically relevant pancreatic fistula. Visceral obesity is one of the known risk factors for clinically relevant pancreatic fistula; however, the underlying mechanisms remained to be elucidated. Patients with clinically relevant pancreatic fistula had a higher free fatty acid concentration in the drain discharge, suggesting a relationship between intraperitoneal lipolysis and pancreatic fistula. The experimental model of pancreatic fistula demonstrated that intraperitoneal lipolysis caused deterioration in pancreatic fistula, suggesting that intraperitoneal lipolysis is one of the mechanisms that drives biochemical leakage to clinically relevant pancreatic fistula. Intraperitoneal administration of a lipase inhibitor prevented lipolysis as well as pancreatic fistula deterioration in the experimental model, suggesting a future clinical application for lipase inhibitors in prevention of clinically relevant pancreatic fistula.

Measuring differences in compositional properties of bone tissue by confocal Raman spectroscopy.

The full range of fracture risk determinants arise from each hierarchical level comprising the organization of bone. Raman spectroscopy is one tool capable of characterizing the collagen and mineral phases at a near submicron-length scale, but the ability of Raman spectra to distinguish compositional differences of bone is not well defined. Therefore, we analyzed multiple Raman peak intensities and peak ratios to characterize their ability to distinguish between the typically less mineralized osteonal tissue and the more mineralized interstitial tissue in intracortical human bone. To further assess origins of variance, we collected Raman spectra from embedded specimens and for two orientations of cut. Per specimen, Raman peak intensities or ratios were averaged among multiple sites within five osteons and five neighboring interstitial tissue. The peak ratios of ν(1) phosphate (PO(4)) to proline or amide III detected the highest increases of 15.4 or 12.5%, respectively, in composition from osteonal to interstitial tissue. The coefficient of variance was less than 5% for each as opposed to a value of ~8% for the traditional ν(1)PO(4)/amide I, a peak ratio that varied the most between transverse and longitudinal cuts for each tissue type. Although embedding affected Raman peaks, it did not obscure differences in most peak ratios related to mineralization between the two tissue types. In studies with limited sample size but sufficient number of Raman spectra per specimen for spatial averaging, ν(1)PO(4)/amide III or ν(1)PO(4)/proline is the Raman property that is most likely to detect a compositional difference between experimental groups.

A case of progressive digital ischemia after early withdrawal of gemcitabine and S-1 in a patient with systemic sclerosis.

The safety of chemotherapy for patients with systemic sclerosis is unclear, and there are few published reports documenting the side effects of chemotherapy in patients with this condition. Here, we report the case of a patient with systemic sclerosis who developed severe digital ischemia during combination gemcitabine/S-1 chemotherapy for pancreatic cancer. In spite of aggressive treatment, the digital ischemia progressively worsened and gangrenous changes developed in multiple fingers and toes. In this patient, the systemic sclerosis had been well controlled, with no digital ischemic symptoms for the previous 6 years, so this progressive clinical course in spite of aggressive treatment strongly suggests that the chemotherapy triggered or aggravated the digital necrosis. To the best of our knowledge, this is only the third reported case of a patient with systemic sclerosis developing digital necrosis after gemcitabine-based chemotherapy. The incidence of digital necrosis during chemotherapy in patients with systemic sclerosis is unknown, and the mechanism by which it occurs is unclear, but the three reports published to date, including the present case, suggest that physicians should be very cautious about administering gemcitabine-based chemotherapy to patients with systemic sclerosis. Any resulting digital ischemia might be refractory to treatment and worsen progressively, even if chemotherapy is withdrawn in the early stages of digital ischemia.

Nano-meter-sized domain formation in lipid membranes observed by small angle neutron scattering.

Using a contrast matching technique of small angle neutron scattering (SANS), we have investigated a phase separation to liquid-disordered and liquid-ordered phases on ternary small unilamellar vesicles (SUVs) composed of deuterated-saturated, hydrogenated-unsaturated phosphatidylcholine lipids and cholesterol, where the equilibrium size of these domains is constrained to less than 10nm by the system size. Below a miscibility temperature, we observed characteristic scattering profiles with a maximum, indicating the formation of nano-meter-sized domains on the SUVs. The observed profiles can be described by a multi-domain model rather than a mono-domain model. The nano-meter-sized domain is agitated by thermal fluctuations and eventually ruptured, which may result in the multi-domain state. The kinetically trapped nano-meter-sized domains grow to a mono-domain state by decreasing temperature. Furthermore, between the miscibility and disorder-order transition temperature of saturated lipid, the integrated SANS intensity increased slightly, indicating the formation of nano-meter-sized heterogeneity prior to the domain nucleation.

Isotopic fingerprint of electron-phonon coupling in high-Tc cuprates.

Angle-resolved photoemission spectroscopy with low-energy tunable photons along the nodal direction of oxygen isotope substituted Bi(2)Sr(2)CaCu(2)O(8+delta) reveals a distinct oxygen isotope shift near the electron-boson coupling "kink" in the electronic dispersion. The magnitude (a few meV) and direction of the kink shift are as expected due to the measured isotopic shift of phonon frequency, and are also in agreement with theoretical expectations. This demonstrates the participation of the phonons as dominant players, as well as pinpointing the most relevant of the phonon branches.

Nationwide survey on the prevalence of anti-tuberculosis drug resistance in the Republic of Yemen, 2004.

OBJECTIVES: To determine the prevalence of resistance to the four major anti-tuberculosis drugs, isoniazid, rifampicin, streptomycin and ethambutol, in Yemen. METHODS: Cluster sampling with probability proportionate to size was applied. Susceptibility to four major anti-tuberculosis drugs was examined. The proportion method using Löwenstein-Jensen medium or Ogawa medium was carried out. RESULTS: A total of 790 primary culture isolates from tuberculosis (TB) cases enrolled at the National Tuberculosis Institute, Yemen, were examined. In the confirmation culture at the supranational reference laboratory, 227 of them failed to grow on the secondary culture or were proved to be mycobacteria other than Mycobacterium tuberculosis and were excluded from further analysis. Among 563 cultures, 510 were obtained from new cases and 53 from previously treated cases. The prevalence of resistance to any four drugs was 9.8% (95%CI 7.0-12.5) among new cases and 17.4% (95%CI 12.0-33.5) among previously treated cases. The prevalence of multidrug-resistant TB was 3.0% (95%CI 1.5-4.5) among new cases and 9.4% (95%CI 0.2-18.7) among previously treated cases. CONCLUSION: The first nationwide prevalence survey on resistance to the four major anti-tuberculosis drugs in Yemen showed a relatively low prevalence of drug-resistant cases, but a high prevalence of multidrug resistance among new cases.

A survey on the referral of tuberculosis patients at the National Tuberculosis Institute, Yemen.

The study aims to determine whether the tuberculosis (TB) patients referred from the National Tuberculosis Institute (NTI), Sana'a City, actually present themselves, are registered and initiate treatment at the health facilities to which they are referred. In 2004, 591 smear-positive TB cases were diagnosed, 481 cases were referred back to health centres, 75 cases were registered at the NTI and 35 cases could not be retrieved. Among the 481 referred cases, 427 cases actually presented themselves and were registered at the health centres (88.8%). The average number of days between the day of referral and that of registration was 2.5 days (median 1 day).

Multiple gap symmetries for the order parameter of cuprate superconductors from penetration depth measurements.

The temperature dependence of the London penetration depth lambda was measured for an untwinned single crystal of YBa_{2}Cu_{3}O_{7-delta} along the three principal crystallographic directions (a, b, and c). Both in-plane components (lambda_{a};{-2} and lambda_{b};{-2}) show an inflection point in their temperature dependence which is absent in the component along the c direction (lambda_{c};{-2}). The data provide convincing evidence that the in-plane superconducting order parameter is a mixture of (s+d)-wave symmetry whereas it is mainly s wave along the c direction. In conjunction with previous results it is concluded that coupled s+d-order parameters are universal and intrinsic to cuprate superconductors.

Interplay of electron-lattice interactions and superconductivity in superconductivity in Bi2Sr2CaCu2O8+delta.

Formation of electron pairs is essential to superconductivity. For conventional superconductors, tunnelling spectroscopy has established that pairing is mediated by bosonic modes (phonons); a peak in the second derivative of tunnel current d2I/dV2 corresponds to each phonon mode. For high-transition-temperature (high-T(c)) superconductivity, however, no boson mediating electron pairing has been identified. One explanation could be that electron pair formation and related electron-boson interactions are heterogeneous at the atomic scale and therefore challenging to characterize. However, with the latest advances in d2I/dV2 spectroscopy using scanning tunnelling microscopy, it has become possible to study bosonic modes directly at the atomic scale. Here we report d2I/dV2 imaging studies of the high-T(c) superconductor Bi2Sr2CaCu2O8+delta. We find intense disorder of electron-boson interaction energies at the nanometre scale, along with the expected modulations in d2I/dV2 (refs 9, 10). Changing the density of holes has minimal effects on both the average mode energies and the modulations, indicating that the bosonic modes are unrelated to electronic or magnetic structure. Instead, the modes appear to be local lattice vibrations, as substitution of 18O for 16O throughout the material reduces the average mode energy by approximately 6 per cent--the expected effect of this isotope substitution on lattice vibration frequencies. Significantly, the mode energies are always spatially anticorrelated with the superconducting pairing-gap energies, suggesting an interplay between these lattice vibration modes and the superconductivity.

ALDH2 polymorphisms and bone mineral density in an elderly Japanese population.

INTRODUCTION: Osteoporosis is a multifactorial genetic disease which greatly increases the risk of bone fracture in elderly persons. METHODS: Four hundred and three recipients of a community health screening program were examined for the presence/absence of osteoporosis and 11 kinds of gene polymorphisms as a means of determining the relation between these gene polymorphisms and osteoporosis. The gene polymorphisms screened were: alcohol sensitivity-associated polymorphisms of alcohol dehydrogenase (ADH2) Arg47His, aldehyde dehydrogenase (ALDH2) Glu487Lys, smoking sensitivity-associated polymorphisms of glutathione S transferase (GST) M1, (GST)T1, NAD(P)H quinone oxidoreductase 1 (NQO1) C609T, inflammation-associated polymorphisms of interleukin-1beta (IL-1B)T-31C, tumor necrosis factor alpha (TNF-alpha) T-1031C, endothelial constitutive nitric oxide synthase (ecNOS) Glu298Asp, longevity-associated polymorphism of mitochondrial DNA (mtDNA) 5178 A/C, allergy-associated polymorphism of interleukin-4 (IL-4), and immunity-associated polymorphism of CD14. RESULTS: A significant association was found between the ALDH2Glu478Lys gene polymorphisms and osteoporosis. In the osteoporosis group of patients, a significant difference was noted between the Lys/Lys group and the group comprising Glu/Lys and Glu/Glu groups (namely, the genotypes including Glu alleles). In the Lys/Lys group, after age, sex, BMI, smoking history and alcohol consumption history had been adjusted for, the morbidity rate was significantly elevated [odds ratio (OR): 3.33; 95% confidence interval (95% CI): 1.28-8.71; p=0.014], and the effect was even more evident in the sub-group of women with osteoporosis (OR: 4.31; 95% CI: 1.24-14.92; p=0.021). CONCLUSIONS: The present results suggest that active prophylactic interventions such as dietary, exercise, and pharmacological therapies should be offered to non-carriers of the Glu allele (Lys/Lys).

Negative quantum interference between the electronic Raman scattering processes of CuO chains and CuO2 planes of heavily overdoped (Y, Ca)Ba2Cu3O(7-delta).

We found a strong X-Y anisotropy of the pair-breaking peak in the Raman scattering of heavily overdoped (Y, Ca)Ba2Cu3O(7-delta) (T(c) = 65 K). The pair-breaking peak is radically suppressed in the YY-polarized spectrum. We ascribe this anomaly to the effect of quantum interference between the Raman processes of the CuO-chain and the CuO2-plane electronic excitations that might take place as a result of the increase in the transfer matrix due to overdoping.

Muon spin relaxation studies of magnetic-field-induced effects in high-Tc superconductors.

Muon spin relaxation measurements in high transverse magnetic fields [FORMULA: SEE TEXT] revealed strong field-induced quasistatic magnetism in the underdoped and Eu-doped (La,Sr)2CuO4 and La1.875Ba0.125CuO4, existing well above Tc and TN. The susceptibility counterpart of Cu spin polarization, derived from the muon spin relaxation rate, exhibits a divergent behavior towards T approximately 25 K. No field-induced magnetism was detected in overdoped La1.81Sr0.19CuO4, optimally doped Bi2212, and Zn-doped YBa2Cu3O7.

Mott gap excitations in twin-free YBa2Cu3O7-delta (Tc=93 K) studied by resonant inelastic x-ray scattering.

Mott gap excitations in the optimally doped high-T(c) superconductor YBa(2)Cu(3)O(7-delta) (T(c)=93 K) have been studied by the resonant inelastic x-ray scattering method. Anisotropic spectra in the ab plane are observed in a twin-free crystal. The excitation from the one-dimensional CuO chain is enhanced at 2 eV near the zone boundary of the b* direction, while the excitation from the CuO2 plane is broad at 1.5-4 eV and almost independent of the momentum transfer. Theoretical calculations based on the one-dimensional and two-dimensional Hubbard model reproduces the observed spectra when different values of the on-site Coulomb energy are assumed. The Mott gap of the CuO chain site is found to be much smaller than that of the CuO2 plane site.

Dispersion of magnetic excitations in optimally doped superconducting YBa2Cu3O6.95.

Detailed neutron scattering measurements of YBa2Cu3O6.95 found that the resonance peak and incommensurate magnetic scattering induced by superconductivity represent the same physical phenomenon: two dispersive branches that converge near 41 meV and the in-plane wave vector q(AF)=(pi/a,pi/a) to form the resonance peak. One branch has a circular symmetry around q(AF) and quadratic downward dispersion from approximately 41 meV to the spin gap of 33+/-1 meV. The other, of lower intensity, disperses from approximately 41 meV to at least 55 meV. Our results exclude a quartet of vertical incommensurate rods in q-omega space expected from spin waves produced by dynamical charge stripes as an origin of the observed incommensurate scattering in optimally doped YBCO.

Observation of structures of chain vortices inside anisotropic high- Tc superconductors.

In order to elucidate the formation mechanism of unconventional arrangements of vortices in high- Tc superconducting thin films at an inclined magnetic field to the layer plane, we investigated the structures of vortex lines inside the films by Lorentz microscopy using our 1-MV field-emission electron microscope. Our observation results concluded that vortex lines are tilted to form linear chains in YBaCu3O(7,8). Vortex lines in the chain-lattice state in Bi2Sr2CaCu2O(8+delta), on the other hand, are all perpendicular to the layer plane, and therefore only vortices lined up along Josephson vortices form chains.

Immunolocalization of hepatocyte growth factor and its receptor (c-Met) during mouse liver development.

Although hepatocyte growth factor (HGF) was discovered as a potent hepatotrophic factor responsible for liver regeneration and may involve some organ development in embryogenesis, it remains to be revealed what roles HGF plays in liver development. The present study was undertaken to determine which cells express HGF and its receptor c-Met and when c-Met is activated in mouse liver development by using immunoblotting and immunohistochemical techniques. HGF was detected in hepatocytes and non-parenchymal cells, including biliary epithelial cells, periportal connective tissue cells, megakaryocytes, endothelial cells, and sinusoidal cells, throughout liver development. Positive HGF immunostaining in hepatocytes increased during postnatal development, and reached the maximal level in the adult stage. c-Met protein was also expressed in hepatocytes throughout liver development, but maximal staining was obtained in 1- or 2-week-old livers. Phosphorylation of tyrosine residues in the c-Met beta chain also occurred in these stages. These results suggest that HGF signaling is implicated in hepatocyte growth during postnatal liver development, and its action could be in a paracrine mode; HGF produced by non-parenchymal cells such as sinusoidal cells acts on hepatocytes expressing c-Met receptors. Positive immunostaining in adult and postnatal hepatocytes may be derived from their blood clearance of HGF.

Expression of METH-1 and METH-2 in pancreatic cancer.

PURPOSE: METH-1/hADAMTS-1 and METH-2/hADAMTS-8 are recently identified genes that inhibit angiogenesis, and the murine homologue, ADAMTS-1, shows metalloproteinase function. Because the significance of METH-1 and METH-2 has not been determined in solid tumors, we examined the mRNA expressions of these molecules in pancreatic cancer and hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: METH-1 and METH-2 mRNA expressions were identified in six pancreatic cancer cell lines and were quantified by TaqMan reverse transcription-PCR in 18 paired samples of pancreatic cancer and surrounding noncancerous pancreas, and in 14 samples of pancreatic cancer. METH-1 mRNA expression was also examined in 16 pairs of HCC and cirrhotic liver. Vascularity was estimated by CD34 staining. The correlation between clinicopathological factors and METH-1 expression was additionally analyzed. RESULTS: Four of six pancreatic cancer cell lines expressed METH-1, and 1/6 expressed METH-2. METH-1 was substantially expressed in both pancreatic cancer and noncancerous pancreas, but METH-2 was not. METH-1 expression in pancreatic cancer tissue was significantly lower than that in noncancerous pancreas (P = 0.002), and a similar result was obtained between HCC and cirrhotic liver (P = 0.003). METH-1 expression did not show a significant correlation with vascularity in pancreatic cancer or in HCC. However, pancreatic cancer with higher expression of METH-1 showed significantly severe lymph node metastasis or retroperitoneal invasion (P = 0.033 and P = 0.018, respectively) and worse prognosis (P = 0.038). CONCLUSIONS: METH-1, which was initially reported to have a potent antiangiogenic effect, does not seem to be a predominant determinant of tumor vascularity in pancreatic cancer. Rather, METH-1 seems to be involved in progression of pancreatic cancer through local invasion and lymph node metastasis.

Interleukin-6 inhibits radiation induced apoptosis in pancreatic cancer cells.

We have examined the relationship between the expression and activation of the IL-6 receptor and the possible involvement of IL-6 in the resistance of radiation-induced apoptosis in pancreatic cancer cells. Levels of IL-6 in the incubation media measured with ELISA were 1900 pg/ml in CFPAC-1, 54 pg/ml in HPAC and less than 0.2 pg/ml in MIAPaCa-2 and AsPC-1. Western blot demonstrated gp80 protein (IL-6 receptor a subunit) in all pancreatic cancer cell lines except in AsPC-1. When immunoprecipitation was performed, the bands indicating phosphorylated gp130 (IL-6Rbeta) were observed in CFPAC-1 and HPAC, however, no band was found in MIAPaCa-2 or in AsPC-1 cells. RT-PCR and Western blot demonstrated that mRNA and protein expression for Bcl-2 and Bcl-XL was substantially increased by the IL-6 treatment in CEPAC-1 cells, but not in AsPC-1 cells. Neither exogenous IL-6 nor neutralizing anti-IL-6 mAb affected the proliferation of CFPAC-1 and AsPC-1 cells. However, the IL-6 treatment significantly attenuated the susceptibility to radiation in CFPAC-1 cells but not in AsPC-1 cells, and the neutralizing anti-IL-6 mAb significantly increased the radiosensitivity of CFPAC-1 cells. The results indicated that IL-6 might be produced in a paracrine and/or autocrine fashion in pancreatic cancer cells. In-6 inhibits radiation-induced apoptosis and enhances the survival of the cells through a functional receptor system, which is associated with the up-regulation of anti-apoptotic Bcl-2 family proteins, especially Bcl-XL.

Fat-suppressed T2-weighted MRI of the liver: comparison of respiratory-triggered fast spin-echo, breath-hold single-shot fast spin-echo, and breath-hold fast-recovery fast spin-echo sequences.

The purpose of our study was to compare the value of respiratory-triggered fast spin-echo, breath-hold single-shot fast spin-echo, and breath-hold fast-recovery fast spin-echo sequences in detecting hepatic lesions. Fat-suppressed T2-weighted magnetic resonance (MR) images obtained with the three sequences in 36 patients with 138 lesions and nine patients without lesions were prospectively analyzed. Quantitative and qualitative analyses, including receiver operating characteristic (ROC) analyses, were performed. The mean lesion-to-liver contrast-to-noise ratio (CNR) for hepatic lesions was highest with the respiratory-triggered fast spin-echo sequence. On the basis of receiver-operating characteristic analyses, tumor detection rates were higher with the breath-hold fast-recovery fast spin-echo sequence (Az = 0.94) than with the respiratory-triggered fast spin-echo sequence (AZ = 0.80, P < 0.0001) or the single-shot fast spin-echo sequence (Az = 0.77, P < 0.0001). The image quality with the breath-hold fast-recovery fast spin-echo sequence was acceptable in all patients. The breath-hold fast-recovery fast spin-echo sequence provided the highest tumor detection in a short imaging time, although the mean lesion-to-liver CNRs were inferior to those of the respiratory-triggered fast spin-echo and the breath-hold single-shot fast spin-echo sequences.