Regulation of the glucose supply from capillary to tissue examined by developing a capillary model

A new glucose transport model relying upon diffusion and convection across the capillary membrane was developed, and supplemented with tissue space and lymph flow. The rate of glucose utilization (J _util) in the tissue space was described as a saturation function of glucose concentration in the interstitial fluid (C _glu,isf), and was varied by applying a scaling factor f to J _max. With f = 0, the glucose diffusion ceased within ~20 min. While, with increasing f, the diffusion was accelerated through a decrease in C _glu,isf, but the convective flux remained close to resting level. When the glucose supplying capacity of the capillary was measured with a criterion of J _util /J _max = 0.5, the capacity increased in proportion to the number of perfused capillaries. A consistent profile of declining C _glu,isf along the capillary axis was observed at the criterion of 0.5 irrespective of the capillary number. Increasing blood flow scarcely improved the supplying capacity.     

Prognostic value of metabolic tumor volume of pretreatment <Superscript>18</Superscript>F-FAMT PET/CT in non-small cell lung Cancer

Background

This study aimed to determine the prognostic value of positron emission tomography (PET) metabolic parameters—namely metabolic tumor volume (MTV), total lesion glycolysis (TLG), and total lesion retention (TLR)—on fluorine-18 (¹⁸F) fluorodeoxyglucose (FDG) and L- [3-¹⁸F]-α-methyltyrosine (¹⁸F-FAMT) PET/CT in patients with non-small-cell lung cancer (NSCLC).

Methods

The study group comprised 112 NSCLC patients who underwent ¹⁸F-FDG and ¹⁸F-FAMT PET/CT prior to any therapy. The MTV, TLG, TLR, and maximum standardized uptake value (SUV_max) of the primary tumors were determined. Automatic MTV measurement was performed using PET volume computer assisted reading software. (GE Healthcare). Cox proportional hazards models were built to assess the prognostic value of MTV, TLG (for ¹⁸F-FDG), TLR (for ¹⁸F-FAMT), SUV_max, T stage, N stage, M stage, clinical stage, age, sex, tumor histological subtype, and treatment method (surgery or other therapy) on overall survival (OS).

Results

Higher TNM, higher clinical stage, inoperable status, and higher values for all PET parameters (both ¹⁸F-FAMT and ¹⁸F-FDG PET) were significantly associated (P?<?0.05) with shorter OS. Multivariate analysis revealed that a higher MTV of ¹⁸F-FAMT (hazard ratio [HR]: 2.88, CI: 1.63–5.09, P?<?0.01) and advanced clinical stage (HR: 5.36, CI: 1.88–15.34, P?<?0.01) were significant predictors of shorter OS.

Conclusions

MTV of ¹⁸F-FAMT is of prognostic value for OS in NSCLC cases and can help guide decision-making during patient management.

     

Central mucoepidermoid carcinoma arising from glandular odontogenic cyst confirmed by analysis of MAML2 rearrangement: A case report

Central mucoepidermoid carcinoma (MEC) poses a diagnostic challenge because of its rarity and histological overlap with glandular odontogenic cyst (GOC). In MEC of both salivary glands and jaws, MAML2 arrangement has been well known as the specific gene alteration. We report a case of central MEC arising from GOC diagnosed by MAML2 fusion gene. A 57‐year‐old male presented a multilocular cystic lesion in left molar region of the mandible. Histopathologically, multiple cysts lined by thin cuboidal or non‐keratinized squamous epithelium with small duct‐like structures, mucous cells and ciliated cells were present. It was diagnosed as GOC. The recurrent lesion after nine years showed the proliferation of many cystic and solid nests composed of epidermoid, mucous and intermediated cells. Nested PCR revealed CRTC3‐MAML2 fusion gene in the recurrent lesion, but not in the primary one. Similarly, MAML‐2 rearrangement by FISH analysis was positive in the recurrent lesion, while negative for the primary one, thus confirming the diagnosis of central MEC arising from GOC. Analysis of MAML2 rearrangement can be used as a supportive evidence to distinguish central MEC from GOC.     

The utility of IgG,IgM, and CD138 immunohistochemistry in the evaluation of autoimmune liver diseases

Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) present with distinct clinical features. The term “PBC–AIH overlap syndrome (OS)” has been adopted to describe the condition characterized by occurrence of both PBC and AIH, although this clinical entity is difficult to define. This study aimed to assess the utility of IgG, IgM, and CD138 immunohistochemistry in the evaluation of AIH, PBC, and OS. Immunohistochemistry was performed with anti-human IgG, IgM, and CD138 to detect specific plasma cells in the liver. Predominant IgG staining was observed in AIH (85.7 %), while equivocal (46.1 %) or predominant (38.5 %) IgM staining was observed in PBC. In OS, equivocal (20 %) or predominant (80 %) IgG staining was observed. The IgM/IgG ratio was significantly higher in PBC than in AIH or OS (P < 0.005). Histological findings revealed significantly higher IgM expression in PBC at cholangitis activity grades 2–3 compared to those at cholangitis activity grades 0–1. In contrast, a significantly higher IgG expression was observed in PBC at hepatitis activity and fibrosis grades 2–3 compared to those at hepatitis activity and fibrosis grades 0–1. Taken together, periportal plasmacytic infiltrates with variable immunohistochemistry patterns of IgG and IgM expression characterized different autoimmune liver diseases.     

Muscle Fiber Population and Biochemical Properties of Whole Body Muscles in Thoroughbred Horses

We examine the muscle fiber population and metabolic properties of skeletal muscles from the whole body in Thoroughbred horses. Postmortem samples were taken from 46 sites in six Thoroughbred horses aged between 3 and 6 years. Fiber type population was determined on muscle fibers stained with monoclonal antibody to each myosin heavy chain isoform and metabolic enzyme activities were determined spectrophotometrically. Histochemical analysis demonstrated that most of the muscles had a high percentage of Type IIa fibers. In terms of the muscle characteristic in several parts of the horse body, the forelimb muscles had a higher percentage of Type IIa fiber and a significantly lower percentage of Type IIx fiber than the hindlimb muscles. The muscle fiber type populations in the thoracic and trunk portion were similar to those in the hindlimb portion. Biochemical analysis indicated high succinate dehydrogenase activity in respiratory‐related muscle and high phosphofructokinase activity in hindlimbs. We suggested that the higher percentage of Type IIa fibers in Thoroughbred racehorses is attributed to training effects. To consider further the physiological significance of each part of the body, data for the recruitment pattern of each muscle fiber type during exercise are needed. The muscle fiber properties in this study combined with the recruitment data would provide fundamental information for physiological and pathological studies in Thoroughbred horses. Anat Rec, 2009. © 2009 Wiley‐Liss, Inc.     

Virulence of Mycobacterium avium complex strains isolated from immunocompetent patients

Mycobacterium avium complex (MAC) disease has been increasing worldwide not only in immunocompromised but also in immunocompetent humans. However, the relationship between mycobacterial strain virulence and disease progression in immunocompetent humans is unclear. In this study, we isolated 6 strains from patients with pulmonary MAC disease. To explore the virulence, we examined the growth in human THP-1 macrophages and pathogenicity in C57BL/6 mice. We found that one strain, designated 198, which was isolated from a patient showing the most progressive disease, persisted in THP-1 cells. In addition, strain 198 grew to a high bacterial load with strong inflammation in mouse lungs and spleens 16 weeks after infection. To our knowledge, strain 198 is the first isolated MAC strain that exhibits hypervirulence consistently for the human patient, human macrophages in vitro, and even for immunocompetent mice. Other strains showed limited survival and weak virulence both in macrophages and in mice, uncorrelated to disease progression in human patients. We demonstrated that there is a hypervirulent clinical MAC strain whose experimental virulence corresponds to the serious disease progression in the patients. The existence of such strain suggests the involvement of bacterial virulence in the pathogenesis of pulmonary MAC disease in immunocompetent status.     

Virological significance of low-level hepatitis B virus infection in patients with hepatitis C virus associated liver disease

Cytomegalovirus (CMV) infection is an important cause of morbidity in solid organ recipients. Early markers to identify the progress of the infection and patients at high risk are required in order to apply a strategy of pre-emptive therapy. The efficacy of pre-emptive therapy relies on accurate laboratory tests to monitor CMV infection. The evaluation of CMV DNA kinetics by the polymerase chain reaction (PCR) is widely used for the management of CMV infection but markers predicting the progression of the infection and standardization of the technique are essential for the clinical interpretation of PCR results. A commercially available PCR system, the COBAS AMPLICOR Monitor (Roche Diagnostics, Brachburg, NJ), was used for the quantitation of CMV DNA in weekly blood samples (n = 504) from 47 solid organ recipients in the first 6 months after transplantation. PCR results were evaluated according to the development of clinical disease in order to find a DNA threshold and time points predicting the progression of CMV infection. Week 4 from transplantation was the earliest time point to note a significant difference between those patients who eventually developed CMV disease (n = 30) and those who remained asymptomatically infected (n = 17). At week 4, viral loads were significantly higher in patients who developed CMV disease than in asymptomatic infections (median value: 4 log(10)/10(6) leukocytes vs. 2.8, P < 0.0001). At week 4, a DNA level >/=4 log(10)/10(6) leukocytes was associated with a 45.37 odds ratio for CMV disease. Any increase >/=1 log from the first DNA detection to week 4 correlated with the clinical progression of CMV infection (odds ratio 1.74). In those patients who were treated with anti-CMV therapy, a >97% reduction of the baseline viral load was associated with a complete therapeutic success. In conclusion, CMV infection is a highly dynamic process and the quantitation of CMV DNA by PCR is a powerful marker to control successfully the infection, but a strict follow-up of the recipient and standardized PCR tests are mandatory for the best management of the infection.     

Hepatitis B virus DNA in liver, serum, and peripheral blood mononuclear cells after the clearance of serum hepatitis B virus surface antigen

The integration of hepatitis B virus (HBV) DNA in the liver of chronic HBV carriers has been documented extensively. However, the status of the viral genome during acute infection has not been assessed conclusively. While HBV DNA sequences are detected often in serum, liver, and peripheral blood mononuclear cells (PBMCs) after the clearance of serum the hepatitis B virus surface antigen (HBsAg), the precise status of the viral genome, and in particular the possible persistence of integrated genomes in PBMCs, has not been established. A highly sensitive PCR-derived assay (Alu-PCR) was employed to re-examine liver and PBMC specimens obtained from patients with acute (n = 19) and chronic (n = 22) hepatitis in whom serum HBsAg was present (n = 12) (HBV-related chronic active hepatitis) or absent with anti-HCV (n = 10) (HCV-related chronic active hepatitis). Viral integration was demonstrated in 3 out of 19 liver specimens from patients with acute hepatitis and 12 out of 12 specimens from patients with chronic hepatitis. Viral integration was also observed in 4 out of 7 PBMC samples from HBV-related chronic active hepatitis patients and 2 out of 10 liver and PBMC samples from HCV-related chronic active hepatitis patients. In one liver specimen from an acute hepatitis patient, HBV DNA was found integrated in the intronic sequence of the tumour necrosis factor (TNF)-induced protein gene; viral integration into cellular sequences was also found in the PBMCs of four HBV-related chronic active hepatitis and two HCV-related chronic active hepatitis. The results demonstrate the early integration of HBV genome during acute viral infections and the persistence of the viral genome in an integrated form in PBMCs.     

Excitatory neurotoxic properties of pontamine sky blue make it a useful tool for examining the functions of focal brain parts

Pontamine sky blue (PSB) is used in brain studies to mark the position of microelectrode and micropipette tips. However, few studies have been made on the effects of PSB on neurons; therefore we examined these effects. When puffed on isolated sensory ganglion cells of rats, PSB increased membrane conductance, depolarized membrane potential, and reduced the amplitude of action potentials. When dripped on frog sympathetic ganglion, much like hexamethonium, PSB decreased the amplitude of compound action potentials of the postganglionic strand. A bath application of PSB to sartorius muscle fibers that had been treated with tetrodotoxin depolarized the membrane potential and increased the frequency and amplitude of miniature end-plate potentials. All these effects were reversible. When injected into the rat's pontine part corresponding to the location of the canine pontine defecation reflex center, PSB produced repetitive colorectal contractions and irreversibly abolished them in response to anal-canal stimulation. The excitatory and blocking effects of PSB and its staining ability make it a useful tool for examining the functions of focal brain parts.     

The tetraspanin CD9 is preferentially expressed on the human CD4(+)CD45RA+ naive T cell population and is involved in T cell activation

Human CD4+ T cells can be divided into reciprocal memory and naive T cell subsets based on their expression of CD45 isoforms and CD29/integrin beta1 subunit. To identify unique cell surface molecules on human T cells, we developed a new monoclonal antibody termed anti5H9. Binding of anti5H9 triggers a co-stimulatory response in human peripheral blood T cells. Retrovirus-mediated expression cloning has revealed that the antigen recognized by anti5H9 is identical to the tetraspanin CD9. We now show that human CD9 is preferentially expressed on the CD4(+)CD45RA+ naive T cell subset, and that CD9(+)CD45RA+ T cells respond preferentially to the recombinant beta2-glycoprotein I, compared to CD9-CD45RA+ T cells. Furthermore, anti5H9 inhibits both the recombinant beta2-glycoprotein I- and the recall antigen tetanus toxoid-specific T cell proliferation. These results suggest that the tetraspanin CD9 plays an important role in T cell activation.