Parasitic infestations of the biliary tract

Parasitic infestations of the biliary tract are a common cause of biliary obstruction in tropical countries and can lead to such serious complications as cholangitis and cholangiocarcinoma. Endoscopic therapy has helped in the management of biliary complications caused by these parasites. Ascaris lumbricoides organisms, which normally reside in the jejunum, are actively motile and can invade the papilla, thus migrating into the bile duct and causing biliary obstruction. Endoscopic retrograde cholangiopancreatography is a useful diagnostic tool with potential for therapeutic management of biliary ascariasis. Infestation with Clonorchis sinensis organisms can cause such complications as intrahepatic stones, recurrent pyogenic cholangitis, cirrhosis, cholelithiasis, pancreatitis, and cholangiocarcinoma. Opisthorchis viverrini, Opisthorchis felineus, and Dicrocoelium dendriticum are closely related to C. sinensis and can also cause serious biliary complications. Fascioliasis, caused by Fasciola hepatica and F. gigantica, is a zoonotic helminthiasis that can present as acute hepatic or chronic biliary tract infection. CT, MRI, and ultrasound guidance are useful imaging tools for identifying these parasites and their complications.     

Serological investigations of flavivirus prevalence in Khammouane Province, Lao People's Democratic Republic, 2007-2008

A large-scale cross-sectional seroprevalence study of dengue (DEN) and Japanese encephalitis (JE) was conducted in Khammouane province, Lao PDR, as part of the initial baseline health impact assessment of the Nam Theun 2 hydroelectric dam construction project. Health surveys were performed between May 2007 and February 2008 with serum samples collected from healthy individuals involved in the resettlement program of 16 villages (total surveyed population 4,369). Hemagglutination inhibition assay using flavivirus antigens (DENV1, DENV3, and JEV) performed on 1,708 plasma specimens revealed 30.4% (519) cross-reactive positives, and 10% (172) and 1.3% (22) positives to JEV or DENV, respectively. Entomological surveys conducted during the rainy season of 2008 indicated the presence of competent flavivirus vectors (Culex vishnui group and Aedes albopictus), although Aedes aegypti was not found. Continued surveillance and investigation is warranted to assess the clinical disease burden of flaviviruses in this area that is undergoing rapid ecological and demographic change.     

Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells

mTOR-generated signals play critical roles in growth of leukemic cells by controlling mRNA translation of genes that promote mitogenic responses. Despite extensive work on the functional relevance of rapamycin-sensitive mTORC1 complexes, much less is known on the roles of rapamycin-insensitive (RI) complexes, including mTORC2 and RI-mTORC1, in BCR-ABL-leukemogenesis. We provide evidence for the presence of mTORC2 complexes in BCR-ABL-transformed cells and identify phosphorylation of 4E-BP1 on Thr37/46 and Ser65 as RI-mTORC1 signals in primary chronic myelogenous leukemia (CML) cells. Our studies establish that a unique dual mTORC2/mTORC1 inhibitor, OSI-027, induces potent suppressive effects on primitive leukemic progenitors from CML patients and generates antileukemic responses in cells expressing the T315I-BCR-ABL mutation, which is refractory to all BCR-ABL kinase inhibitors currently in clinical use. Induction of apoptosis by OSI-027 appears to negatively correlate with induction of autophagy in some types of BCR-ABL transformed cells, as shown by the induction of autophagy during OSI-027-treatment and the potentiation of apoptosis by concomitant inhibition of such autophagy. Altogether, our studies establish critical roles for mTORC2 and RI-mTORC1 complexes in survival and growth of BCR-ABL cells and suggest that dual therapeutic targeting of such complexes may provide an approach to overcome leukemic cell resistance in CML and Ph+ ALL.     

Functions of tumorigenic and migrating cancer progenitor cells in cancer progression and metastasis and their therapeutic implications

The in vitro and in vivo characterization of adult stem cells has allowed researchers to identify certain specific functional features to each tissue-specific stem cell. Moreover, recent studies revealed that their malignant counterparts, the cancer progenitor cells with stem cell-like properties, may assume a crucial role for the initiation and progression of locally invasive cancers into disseminated and incurable disease states. Therefore, a new direction in cancer research appears necessary in considering the critical functions of cancer progenitor cells. In this review, we discuss recent concepts on the critical roles of tumorigenic and migrating cancer progenitor cells in carcinogenesis. Particularly, we describe the tumorigenic cascades that are frequently activated through the interplay of diverse hormones, growth factors, cytokines and integrins in cancer progenitor cells versus their further differentiated progeny. The emphasis is on the oncogenic signaling pathways activated during the localized cancer progression and micrometastatic events involved in tumor formation at distant sites such as bone marrow. Of therapeutic interest, important information for the selective molecular targeting of cancer progenitor cells, which must now be considered in developing new effective diagnostic and prognostic methods and curative treatments against the most locally advanced and metastatic cancers, is also described.     

Antibodies specific for a segment of human membrane IgE deplete IgE-producing B cells in humanized mice

IgE-mediated hypersensitivity is central to the pathogenesis of asthma and other allergic diseases. Although neutralization of serum IgE with IgE-specific antibodies is in general an efficacious treatment for allergic asthma, one limitation of this approach is its lack of effect on IgE production. Here, we have developed a strategy to disrupt IgE production by generating monoclonal antibodies that target a segment of membrane IgE on human IgE-switched B cells that is not present in serum IgE. This segment is known as the M1′ domain, and using genetically modified mice that contain the human M1′ domain inserted into the mouse IgE locus, we demonstrated that M1′-specific antibodies reduced serum IgE and IgE-producing plasma cells in vivo, without affecting other immunoglobulin isotypes. M1′-specific antibodies were effective when delivered prophylactically and therapeutically in mouse models of immunization, allergic asthma, and Nippostrongylus brasiliensis infection, likely by inducing apoptosis of IgE-producing B cells. In addition, we generated a humanized M1′-specific antibody that was active on primary human cells in vivo, as determined by its reduction of serum IgE levels and IgE plasma cell numbers in a human PBMC-SCID mouse model. Thus, targeting of human IgE-producing B cells with apoptosis-inducing M1′-specific antibodies may be a novel treatment for asthma and allergy.     

Cyclooxygenase-2 Expression Increases with the Stage and Grade in Transitional Cell Carcinoma of the Urinary Bladder

Objectives: Experimental models of carcinogenesis show that non-steroidal anti-inflammatory drugs (NSAIDs) increase apoptosis, inhibit angiogenesis and reduce metastases. A linkage between the activity of prostaglandin synthase enzyme cyclooxygenase-2 (COX-2), a known mediator of inflammation, and cancer angiogenesis is implicated. We investigated the expression of COX-2 in bladder cancer tissue specimens using immunohistochemistry. Methods: The immunohistochemical expression of COX-2 in bladder cancer was evaluated by scoring the intensity of immunoreactivity from 0 to 3. Further, the degree of COX-2 expression was correlated with the tumor grade and depth of invasion (T stage). Result: Fifty eight percent patients (n=22) had superficial bladder tumors, while 42% (n=16) were invasive bladder cancers. Overall, COX-2 immuno-positivity was seen in 84.2% (32/38) patients. COX-2 expression was positive in 76.4% (13/17) cases with pTa tumors, 100% (5/5) of pT1 tumors, 86.6% (13/15) of pT2 tumors and in 100% (1/1) of pT3 tumor. The higher stage tumors stained more intensely; this correlation wassignificant(p=0.01987; χ2=19.6977). With reference to the grade of tumors, a positive expression was seen in 81.25% (13/16) of the low-grade tumors and 89% (17/19) of the high-grade tumors. The differential COX-2 expression relative to the grade of tumor was found to be statistically significant (p=0.05; χ2=15.8612). Conclusion: The degree of COX-2 expression is significantly increased with advancing grade and T stage of disease (p < 0.05).     

Transmission modes of severe acute respiratory syndrome coronavirus 2 and implications for infection control: a review

The complete picture regarding transmission modes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unknown. This review summarises the available evidence on its transmission modes, our preliminary research findings and implications for infection control policy, and outlines future research directions. Environmental contamination has been reported in hospital settings occupied by infected patients, and is higher in the first week of illness. Transmission via environmental surfaces or fomites is likely, but decontamination protocols are effective in minimising this risk. The extent of airborne transmission is also unclear. While several studies have detected SARS-CoV-2 ribonucleic acid in air samples, none has isolated viable virus in culture. Transmission likely lies on a spectrum between droplet and airborne transmission, depending on the patient, disease and environmental factors. Singapore’s current personal protective equipment and isolation protocols are sufficient to manage this risk.     

Outbreak of Acinetobacter spp septicemia in a neonatal ICU

An outbreak of Acinetobacter spp infection in the neonatal unit at Lok Nayak Hospital, New Delhi, India, is described. During a 6-month period, 68 strains of Acinetobacter baumannii were isolated from the blood and CSF of 47 neonates admitted to the intensive care unit. Diagnosis of clinically significant bacteremia was made in 36 patients. On environmental/personnel sampling, Acinetobacter spp isolates with similar antibiogram were recovered from intravenous catheter and washbasin. Control of the outbreak was possible only after strict infection control practices in the unit. It was concluded that any clinical multidrug resistant A. baumannii isolate can be a potential nosocomial outbreak strain.