Regional over-representations on chromosomes 1q, 3q and 7q in the progression of hepatitis B virus-related hepatocellular carcinoma.

Hepatocellular carcinoma is a highly malignant tumor that is prevalent in Southeast Asia and China, where hepatitis B viral infection is the main etiologic factor. Despite a high incidence of hepatocellular carcinoma developing in patients with viral hepatitis B-induced liver cirrhosis, the molecular events underlying the malignant liver progression remain largely unclear. In an effort to characterize the genetic abnormalities involved in the hepatitis B-related liver carcinogenesis, we performed genome-wide explorations by the technique of comparative genomic hybridization (CGH) on 100 hepatocellular carcinoma tumors that arose from hepatitis B-induced liver cirrhosis. According to the American Joint Committee on Cancer staging, four cases were classified as stage I, 69 as stage II, 23 as stage III and four as stage IV. CGH analysis indicated chromosomal instability in both early (stages I/II) and advanced (stages III/IV) stage tumors, with common gains on 1q, 8q and 17q23-q25, and losses on 4q22-q35, 8p21-p22, 13q14-q21, 16q and 17p identified in both groups (P>0.05). Nevertheless, preferential sites of chromosomal defects in relation to hepatocellular carcinoma progression were also identified. Statistical correlations suggested a higher incidence of regional 1q21-q22, 3q22-q28, 7q21-q22 and 7q34-q36 over-representations in association with the advanced stage tumors (P<0.05). In this study, our novel identification of specific chromosomal aberrations in relation to the advanced stage tumors may represent a first step towards mapping genes linked to the progression of hepatocellular carcinoma.     

RESEARCH REPORT Pre- and in-treatment predictors of retention in methadone treatment using survival analysis

Abstract Aims. To determine the effects of pre- and in-treatment variables on patient retention in methadone treatment. Design. Retrospective longitudinal study of an admission cohort sample for up to 3 years of treatment or until discharge. Setting. Six methadone maintenance programs operating 15 clinics in New York City. Participants. A sample of 1206 admissions to these clinics during 1989-90. Measurements. Data were abstracted from patients' medical charts. Time in treatment for up to 3 years was the dependent variable, analyzed as a survival function. Pretreatment variables were: gender, race/ethnicity, age at admission, employment, education, marital status, living arrangements, child care responsibility, criminal justice status, life-time arrests, referral source, age at first heroin use, polydrug use, route of drug administration, mental health status and methadone treatment history. In-treatment variables were: patient problems during treatment, clinic response to patient problems, patient treatment strengths, methadone dosage, heroin use and cocaine use. Findings. The estimated median treatment duration was 23 months. Cox proportional hazards modeling determined that two pretreatment variables (older age and no criminal justice involvement) were associated with longer retention in treatment. Among in-treatment variables, constructive clinic responses to patient problems, higher methadone dosage, more patient treatment strengths and less heroin and cocaine use during treatment were associated with longer retention. Conclusions. Events during treatment are crucial for patient retention in methadone treatment. Only two of 16 pretreatment variables, compared with five of six during-treatment variables, had significant effects on length of stay in a multivariate model.     

Surface expression of CD3 in the absence of T cell receptor (TcR): evidence for sorting of partial TcR/CD3 complexes in a post-endoplasmic reticulum compartment

The T cell receptor (TcR) for antigen, on the majority of T cells, is a disulfide-linked heterodimer composed of the alpha and beta chains, noncovalently associated with the CD3 complex of polypeptides (gamma, delta, epsilon and zeta). In this report, two murine thymoma cell lines are described which synthesized incomplete TcR/CD3 complexes and expressed low levels of CD3 on their surface in the absence of the TcR chains. The partial TcR/CD3 complexes were composed primarily of the inherently metabolically stable CD3 gamma and epsilon subunits. These results were in contrast to previous studies, which suggested that synthesis of all of the component chains of the TcR/CD3 complex is required for the successful transport of any of the chains to the cell surface. The efficiency of transport of the partial TcR/CD3 complexes from the endoplasmic reticulum (ER) to medial Golgi in the two thymomas was similar to complete complexes. However, the transport of the incomplete receptors was impaired at some point between the medial Golgi and the plasma membrane. Taken together with previous studies, these results suggested that T cells have mechanisms to retain partial TcR/CD3 complexes intracellularly both in the ER and in an undefined post-ER compartment. However, the transport of low levels of partial TcR/CD3 complexes to the cell surface in some T cell lines implied that the retention mechanisms may not always be completely efficient. Cross-linking of the surface, partial TcR/CD3 complexes with anti-CD3 epsilon antibodies did not stimulate interleukin 2 (IL 2) production. It is possible, however, that the partial TcR/CD3 complexes have some function which is unrelated to the stimulation of IL 2 production.     

Modulation of cancer cell survival pathways using multivalent liposomal therapeutic antibody constructs

Various methods have been explored to enhance antibody-based cancer therapy. The use of multivalent antibodies or fragments against tumor antigens has generated a great deal of interest, as various cellular signals, including induction of apoptosis, inhibition of cell growth/survival, or internalization of the surface molecules, can be triggered or enhanced on extensive cross-linking of the target/antibody complex by the multivalent form of the antibody. The goal of the studies reported here was to develop multivalent antibody constructs via grafting of antibody molecules onto liposome membranes to enhance antibody activity. Using trastuzumab and rituximab as examples, up to a 25-fold increase in the antibody potency in cell viability assay was observed when the antibodies were presented in the multivalent liposome formulation. Key cell survival signaling molecules, such as phosphorylated Akt and phosphorylated p65 nuclear factor-kappaB, were down-regulated on treatment with multivalent liposomal trastuzumab and liposomal rituximab, respectively. Potent in vivo antitumor activity was shown for liposomal trastuzumab. The data presented here showed the potential of liposome technology to enhance the therapeutic effect of antibodies via a mechanism that modulates cell survival through clustering of the target/antibody complex.     

Ciprofloxacin in the treatment of pneumonia.

The use of ciprofloxacin as the sole agent in the treatment of 25 patients with pneumonias caused by susceptible organisms resulted in rapid cure. No side effects, superinfections, or recurrences were observed.     

Sentinel site community surveillance of mortality and nutritional status in southwestern Central African Republic, 2010

ABSTRACT: BACKGROUND: During 2010, a community-based, sentinel site prospective surveillance system measured mortality, acute malnutrition prevalence, and the coverage of a Medecins Sans Frontieres (MSF) intervention in four sous-prefectures of Lobaye prefecture in southwestern Central African Republic. We describe this surveillance system and its evaluation. METHODS: Within 24 randomly selected sentinel sites, home visitors performed a census, weekly demographic surveillance of births, deaths, and in- or out-migration, and weekly anthropometry on a sample of children. We evaluated the system through various methods including capture-recapture analysis and repeat census. RESULTS: The system included 18,081 people at baseline. Over 32 weeks, the crude death rate was 1.0 (95% confidence interval [CI]: 0.8-1.2) deaths per 10,000 person-days (35 deaths per 1,000 person-years), with higher values during the rainy season. The under-5 death rate was approximately double. The prevalence of severe acute malnutrition (SAM) was 3.0% (95% CI: 2.3-4.0), almost half featuring kwashiorkor signs. The coverage of SAM treatment was 29.1%. The system detected >90% of deaths, and >90% of death reports appeared valid. However, demographic surveillance yielded discrepancies with the census and an implausible rate of population growth, while the predictive value of SAM classification was around 60%. DISCUSSION: We found evidence of a chronic health crisis in this remote region. MSF's intervention coverage improved progressively. Mortality data appeared valid, but inaccuracies in population denominators and anthropometric measurements were noted. Similar systems could be implemented in other remote settings and acute emergencies, but with certain technical improvements.     

An unmasking phenomenon in an observational post-licensure safety study of adolescent girls and young women

Our recent experience in a post-licensure safety study of autoimmune conditions following the quadrivalent human papillomavirus vaccine in 189,629 girls and young women ages 9-26 years led us to question the adequacy of the exclusion of Day 0 events to prevent the erroneous association of prevalent conditions with vaccination. Of the 18 confirmed cases of Graves' disease diagnosed in days 1-60 following vaccination, only 6 cases appeared to be truly new onset. Among the remaining 12 cases, 2 cases had abnormal thyroid stimulating hormone or thyroxine labs drawn prior to or on Day 0 but had no documented pre-existing symptoms. The other 10 cases had mention of symptoms of hyperthyroidism referencing a period prior to first HPV-4 dose. This 'unmasking' phenomenon, due to health care visits that include vaccination and new workups of preexisting symptoms, may not be adequately controlled through the exclusion of Day 0 events.     

Nitric oxide and central antihypertensive drugs: one more difference between catecholamines and imidazolines

NO is known to be involved in the peripheral and central regulation of the cardiovascular function. It plays a neuromodulatory role via a direct action on presynaptic nerve terminals, stimulating the release of gamma-aminobutyric acid, glutamate, and norepinephrine. Our aim was to study the possible role of NO in the cardiovascular effects of the central antihypertensive drugs clonidine, rilmenidine, and alpha-methyl-norepinephrine (alpha-MNA). Sites and mechanisms of the hypotensive action of these drugs were different; clonidine and rilmenidine acted on imidazoline receptors in the nucleus reticularis lateralis, whereas alpha-MNA acted upon alpha(2)-adrenoceptors in the nucleus tractus solitarius. The influence of N:(G)-nitro-L-arginine, an NO synthase inhibitor, on the central hypotensive effects of these drugs was investigated in pentobarbital-anesthetized rabbits. The intracisternal (IC) administration of alpha-MNA (30 microg/kg) induced hypotension (79+/-2 versus 103+/-4 mm Hg) and bradycardia (222+/-8 versus 278+/-4 bpm) (P:<0.05) (n=5). Clonidine (0.07 microg/kg IC) also induced hypotension (69+/-5 versus 99+/-4 mm Hg) and bradycardia (266+/-7 versus 306+/-10 bpm) (P:<0.05) (n=5). In addition to clonidine, rilmenidine (1 microg/kg IC) induced hypotension (64+/-4 versus 97+/-4 mm Hg) and bradycardia (264+/-11 versus 310+/-4 bpm) (P:<0.05) (n=5). Pretreatment with N:(G)-nitro-L-arginine (900 microg/kg IC) completely prevented the hypotensive effect of alpha-MNA but influenced the cardiovascular effects of neither clonidine nor rilmenidine. These results confirm that imidazoline drugs, such as clonidine, rilmenidine, and the catecholamine alpha(2)-adrenoceptor agonist alpha-MNA, have distinct mechanisms of action.