Usefulness of three-dimensional CT cholangiography for patients prior to laparoscopic cholecystectomy

PURPOSE: The aim of this study was to demonstrate three-dimensional biliary anatomy by using spiral CT scanning for patients prior to laparoscopic cholecystectomy. MATERIALS AND METHODS: We studied 22 patients (11 men, 11 women; mean age, 60 years) with preoperative imaging. All patients had normal serum bilirubin levels. Either 50 ml (in 10 cases) or 100 ml (in 12 cases) of meglumine iotroxate was infused intravenously over 30 minutes. Spiral CT scanning was started immediately after the infusion was finished. Volumetric data through the entire biliary tracts were obtained during one breath-hold. The data were reconstructed by using a maximum intensity projection algorithm and three-dimensional shaded surface rendering. RESULTS: In all patients, the anatomical relationship between the cystic duct and the common bile duct was clearly depicted, including one with junctional anomaly. The intrahepatic biliary ducts and the confluence of the hepatic ducts were displayed from all angles. The third or higher intrahepatic branches were delineated in 11 of the 12 (92%) patients with the use of 100 ml of the cholangiographic agent and in seven of the 10 (70%) with 50 ml. CONCLUSION: Three-dimensional CT cholangiography was able to provide adequate information about precise biliary anatomy.     

The involvement of neuropeptide Y in the antimuricide action of noradrenaline injected into the medial amygdala of olfactory bulbectomized rats

The present study was designed to clarify the functional role of neuropeptide Y (NPY) in the regulation of muricide induced by olfactory bulbectomy (OB) in relation to that of noradrenaline (NA) in the medial amygdala (AME). NA injected into AME inhibited muricide dose-dependently in OB rats. NPY at doses of 5 and 10 micrograms/microliter injected alone into AME failed to suppress muricide. When NPY 10 micrograms was injected into AME in combination with the maximal non-effective dose of NA, which was determined in each rat, muricide was suppressed in 80% of OB rats. The present study has provided the first evidence suggesting that NPY may be involved in the regulation of OB-induced muricide.     

In Vitro System to Evaluate Oral Absorption of Poorly Water-Soluble Drugs: Simultaneous Analysis on Dissolution and Permeation of Drugs

Purpose. The aim of the present work was to develop a new in vitro system to evaluate oral absorption of poorly water-soluble drugs by utilizing Caco-2 monolayers. Methods. Caco-2 monolayer was mounted between side-by-side chambers, which enabled the simultaneous assay of dissolution and permeation of drugs (dissolution/permeation system; D/P system). Apical and basal sides of the chamber were filled with buffer solutions. Drugs were applied to the apical side as powder, suspension, or solution, and then, the permeated amounts into the basal side were monitored for 2 h. At the same time, dissolved amounts of drugs at the apical side were detected. The amount of drug applied to the D/P system was based on its in vivo clinical dose. Results. Sodium taurocholate (5 mM, apical side) and bovine serum albumin (4.5% w/v, basal side) increased the permeated amount of poorly water-soluble drugs. Both additives were considered to be effective at mimicking in vivo conditions of intestinal drug absorption. From the correlation between the permeated amount of 13 drugs (% dose/2 h) in the D/P system and their percentage dose absorbed in humans in vivo, this system was found to be useful in evaluating oral absorption of poorly water-soluble drugs. Conclusions. With attempts made to mimic the physiologic conditions of the human GI tract, in vivo oral absorption of drugs was quantitatively assessed in the D/P system in vitro. This system is quite useful to predict the oral absorption of poorly water-soluble drugs after administration as solid dosage forms.     

How Can We Identify Very High-Risk Heterozygous Familial Hypercholesterolemia?

Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder that elevates low-density lipoprotein cholesterol and increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). However, despite their atherogenic lipid profiles, the cardiovascular risk of HeFH varies in each individual. Their variety of phenotypic features suggests the need for better risk stratification to optimize their therapeutic management. The current review summarizes three potential approaches, including (1) definition of familial hypercholesterolemia (FH)-related risk scores, (2) genetic analysis, and (3) biomarkers. The International Atherosclerosis Society has recently proposed a definition of severe FH to identify very high-risk HeFH subjects according to their clinical characteristics. Furthermore, published studies have shown the association of FH-related genetic phenotypes with ASCVD, which indicates the genetic analysis’s potential to evaluate individual cardiovascular risks. Biomarkers reflecting disease activity have been considered to predict the formation of atherosclerosis and the occurrence of ASCVD in HeFH subjects. Incorporating these risk stratifications will be expected to allocate adequate intensity of lipid-lowering therapies in HeFH subjects, which ultimately improves cardiovascular outcomes.     

Significant accumulation of KRAS mutations in bronchiolar metaplasia-associated honeycomb lesions of interstitial pneumonia

Interstitial pneumonia (IP) is a major risk factor for lung adenocarcinoma (LADC). IP-related LADC predominantly develops in the bronchiolar metaplasia lining in honeycomb lesions. Kirsten rat sarcoma virus (KRAS) is the most common oncogene mutated in IP-related LADC. The present study examined the metaplastic epithelia in honeycomb lesions for KRAS mutations using digital droplet polymerase chain reaction (ddPCR), a sensitive method used to detect infrequent mutations. Significantly higher KRAS mutation variant allele frequencies (VAFs) were detected in the metaplastic lung epithelia from 13 patients with IP compared with those in 46 non-lesioned lung samples from patients without IP (G12V, P=0.0004, G12C, P=0.0181, and G12A, P=0.0234; Mann Whitney U test). Multivariate analyses revealed that higher KRAS G12V (logistic regression model; P=0.0133, odds ratio=7.11) and G12C (P=0.0191, odds ratio=5.81) VAFs in patients with IP were independent of confounding variables, such as smoking and age. In patients with IP, metaplastic epithelia exhibited significantly higher KRAS G12V and G12C VAFs compared with the non-lesioned counterparts (paired t-test; G12V, P=0.0158, G12C, P=0.0465). These results suggested that IP could increase KRAS mutations and supported the hypothesis that bronchiolar metaplasia could be a precursor for IP-related LADC.     

TP53 variants in p53 signatures and the clonality of STICs in RRSO samples

ObjectivePrecursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer.MethodsWe analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease.Results TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer.ConclusionThe sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.     

CD1-dependent natural killer (NK1.1(+)) T cells are required for oral and portal venous tolerance induction

BACKGROUND: Local antigen presentation via either the oral (PO) or the portal venous (PV) routes results in suppression of systemic delayed-type hypersensitivity (DTH). The responsible cell populations are not well defined. Because NK1.1(+) T cells express the Fas ligand and produce high levels of the immunosuppressive cytokine, IL-4, they may play a role in both activated T-cell apoptosis and a Th1 to Th2 immune shift, thus promoting tolerance induction. METHODS: C57BL/6 mice were tolerized to BALB/c alloantigen by PV or PO spleen cells (25 x 10(6)) on Day 0. Subcutaneous (SQ) challenge with 10 x 10(6) BALB/c cells on Day 7 was followed by footpad injection of 10 x 10(6) BALB/c cells on Day 14. Footpad swelling was measured 24 h later. A single injection of the NK1.1(+) cell-depleting antibody, PK-136, was given IP (10 mg/kg) 2 days prior to PV or PO antigen. Flow cytometry evaluated NK1.1(+) cell depletion. CD1 knockout (KO) mice, lacking NK1.1(+) T cells, were also challenged with PV and PO Balb/c in parallel experiments. RESULTS: The DTH to BALB/c antigen was markedly suppressed in C57BL/6 mice when this alloantigen was given by either PO or PV routes (P < 0.001, P < 0.001). The maintenance of an unaltered response to third-party C3H/HeJ demonstrated alloantigenic specificity. Administration of the anti-NK1.1 T cell monoclonal antibody, PK-136, resulted in complete restoration of in vivo DTH responsiveness in PO tolerance (P < 0.01), and partial restoration in PV tolerance (P < 0.05) in C57BL/6 mice. FACS confirmed virtually complete depletion of liver, splenic, Peyer's patch, and mesenteric lymph node NK1.1(+) lymphocytes. Development of both PO and PV tolerance was prevented in CD1 KO mice. CONCLUSION: NK1.1(+) T cells play an essential role in antigen-specific suppression of the DTH response mediated by both oral and portal venous tolerance.     

Five cases of contralateral pneumothorax after lung resection

Contralateral pneumothorax is one of severe complications after lung resection. We present our experiences with surgical treatment of 5 cases [case 4 is under the percutaneous cardiopulmonary support (PCPS) assistance] of contralateral pneumothorax after lung resection. All cases were men and not able to stop smoking, the disease caused by lung resection was lung cancer 3 and tuberculosis 2. Operative procedure was lobectomy 4 and pneumonectomy 1. Tracheal intubation was done before radiological confirmation of pneumothorax in 4 cases. Immediately after diagnosis all patients underwent chest drainage. Because the contralateral pneumothorax after lung resection is severe complication, we thought that surgical treatment is necessary. Though the thoracoscopic surgery under the PCPS assistance is also possible, it seems that a small thoracotomy with adjusting ventilation by anesthetist are more favorable. Accurate diagnosis and treatment is the key for success of treatment. The patient who receives lung resection due to lung cancer often has emphysema, and the risk of contralateral pneumothorax after the operation should also be explained.     

Manipulation of the anabolic and catabolic responses with BMP-2 and zoledronic acid in a rat femoral fracture model

Bone repair involves a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone matrix at the fracture site. It has been reported that the optimal time point for single-dose zoledronic acid (ZA) administration systemically increased the strength of bone morphogenetic protein (BMP)-7-mediated callus. However, its repair mechanism during bone fracture healing remains unknown. We aimed to investigate the synergic effect of recombinant human (rh) BMP-2 and ZA in a rat femoral fracture model. Fifty-eight rats were divided into 4 groups. Group I (n = 14) animals were implanted with a carrier alone. Group II (n = 15) animals were implanted with a carrier containing 1-μg rhBMP-2. Group III (n = 14) animals were implanted with a carrier and a subcutaneous systemic ZA injection 2 weeks after surgery. Group IV (n = 15) animals were implanted with a carrier containing 1-μg rhBMP-2 and ZA subcutaneous injection 2 weeks after surgery. The rats were euthanized after 6 weeks and their fractured femurs were explanted and assessed by manual palpation, radiographs, and high-resolution micro-computerized tomography (micro-CT) and were subjected to biomechanical and histological analysis. The fusion rates in Group IV (93.3%) were considerably higher than those in Groups I (28.6%), II (53.3%), and III (57.1%). Additionally, the radiographic scores of Group IV were higher than those in Groups I, II, and III. In micro-CT analysis, the tissue volume (TV) of the callus was higher in Group IV than in Groups I and II (p < 0.05). New bone volume (BV) and trabecular spacing (Tb.Sp) also showed essentially the same trend as that of TV. The ratio of BV to TV (BV/TV), the trabecular number (Tb.N), and the trabecular thickness (Tb.Th) was higher in Groups III and IV than in Groups I and II (p < 0.05). In biomechanical analysis, the ultimate loads at failure and stiffness in Groups III and IV were on average higher than those in Groups I and II (p < 0.05), while the energy absorption of Group IV was higher than those of Groups I and II (p < 0.05). The synergic effect of rhBMP-2 and ZA given systemically as a single dose at the optimal time was efficacious for fracture repair and significantly enhanced bone fusion. Our results suggest that this combination facilitates bone healing and has potential clinical application.