Respiratory infection and otitis media visits in relation to pneumococcal conjugate vaccine use in Saskatchewan

BACKGROUND:

In Saskatchewan, pneumococcal conjugate vaccination (PCV) was offered to high-risk children in 2002 and to all infants in 2005.

OBJECTIVE:

To describe trends in the frequency of medical visits for lower respiratory tract infection (LRI) and otitis media (OM) in relation to PCV use during the period 1990 to 2008.

METHODS:

Statistics regarding the number of children covered by the health insurance plan, PCV administration, and medical visits with a diagnostic code associated with LRI and OM were provided by Saskatchewan Health. Monthly rates were analyzed using dynamic state space models.

RESULTS:

In all series, there was a marked seasonal cycle and some higher-than-expected winter peak values, possibly associated with epidemics of specific respiratory viruses. Three abrupt decreases in baseline rate were observed for LRI and the final one, in February 2007, could be related to the increased proportion of children vaccinated with PCV. There was no statistical correlation between PCV use and OM visit frequency.

CONCLUSION:

Many environmental, biological and administrative factors may influence health services use, and an effect of low magnitude of a particular vaccine pertaining to nonspecific outcomes could be obscured in time-series analyses.     

Origin of correlated activity between parasol retinal ganglion cells

Cells throughout the CNS have synchronous activity patterns; that is, a cell's probability of generating an action potential depends both on its firing rate and on the occurrence of action potentials in surrounding cells. The mechanisms producing synchronous or correlated activity are poorly understood despite its prevalence and potential effect on neural coding. We found that neighboring parasol ganglion cells in primate retina received strongly correlated synaptic input in the absence of modulated light stimuli. This correlated variability appeared to arise through the same circuits that provide uncorrelated synaptic input. In addition, ON, but not OFF, parasol cells were coupled electrically. Correlated variability in synaptic input, however, dominated correlations in the parasol spike outputs and shared variability in the timing of action potentials generated by neighboring cells. These results provide a mechanistic picture of how correlated activity is produced in a population of neurons that are critical for visual perception.     

Pesticide poisoning of farm workers-implications of blood test results from Vietnam

Information on the health impacts of pesticides is quite limited in many developing countries, with many surveys relying solely on farmer self-assessments of their health status. To test the reliability of self-reported data, an acetyl cholinesterase enzyme (AChE) blood test was conducted for 190 rice farmers in the Mekong Delta, Vietnam. Results reveal a high prevalence of pesticide poisoning by organophosphate and carbamate exposure, where over 35% of test subjects experienced acute pesticide poisoning (a reduction of AChE >25%), and 21% chronically poisoned (>66% AChE reduction). Using the medical test results as benchmarks, we find that farmers' self-reported symptoms have very weak associations with actual poisoning. To investigate the possible determinants of pesticide poisoning, a probit model was constructed with pesticide amount, toxicity, training, and the use of protective measures as explanatory variables. The results indicate that although the absolute amount of pesticides used does not increase the probability of poisoning, a 1% increase in the use of highly hazardous pesticides (WHO Ia or Ib) increases the probability of poisoning by 3.9% and an increased use of protective measures decreases the probability of poisoning by 44.3%. We also find significant provincial differences in poisoning incidence after we control for individual factors. The provincial effects highlight the potential importance of negative externalities, and suggest that future research on pesticide-related damage should include information on local water, air and soil contamination.     

Retrocaval ureter in a 10-year-old boy

Retrocaval ureter is an uncommon abnormality of the inferior vena cava, which is rarely detected in the child due to its non-specific symptomatology. Despite a varying state of severity, chronic ureteral obstruction generally leads to the deterioration of renal function during adulthood. Treatment depends on the symptomatology in question, and surgical management should be as conservative as possible.     

Medial prefrontal cortex neuronal activation and synaptic alterations after stress-induced reinstatement of palatable food seeking: a study using c-fos-GFP transgenic female rats

Relapse to maladaptive eating habits during dieting is often provoked by stress and there is evidence for a role of ovarian hormones in stress responses and feeding. We studied the role of these hormones in stress-induced reinstatement of food seeking and medial prefrontal cortex (mPFC) neuronal activation in c-fos-GFP transgenic female rats, which express GFP in strongly activated neurons. Food-restricted ovariectomized or sham-operated c-fos-GFP rats were trained to lever-press for palatable food pellets. Subsequently, lever-pressing was extinguished and reinstatement of food seeking and mPFC neuronal activation was assessed after injections of the pharmacological stressor yohimbine (0.5-2 mg/kg) or pellet priming (1-4 noncontingent pellets). Estrous cycle effects on reinstatement were also assessed in wild-type rats. Yohimbine- and pellet-priming-induced reinstatement was associated with Fos and GFP induction in mPFC; both reinstatement and neuronal activation were minimally affected by ovarian hormones in both c-fos-GFP and wild-type rats. c-fos-GFP transgenic rats were then used to assess glutamatergic synaptic alterations within activated GFP-positive and nonactivated GFP-negative mPFC neurons following yohimbine-induced reinstatement of food seeking. This reinstatement was associated with reduced AMPA receptor/NMDA receptor current ratios and increased paired-pulse facilitation in activated GFP-positive but not GFP-negative neurons. While ovarian hormones do not appear to play a role in stress-induced relapse of food seeking in our rat model, this reinstatement was associated with unique synaptic alterations in strongly activated mPFC neurons. Our paper introduces the c-fos-GFP transgenic rat as a new tool to study unique synaptic changes in activated neurons during behavior.     

Retroperitoneal abscess from dropped appendicolith complicating laparoscopic appendectomy.

Abscesses can occur after appendectomy. With the increasing use of laparoscopy, this risk has increased in the same way as the incidence of abscesses related to dropped gallstones increased after laparoscopic cholecystectomy. However, this occurrence has been rarely reported. We describe here the case of a young patient who developed retroperitoneal abscess one year after laparoscopic appendectomy.     

Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils

Expansion of myeloid cells associated with solid tumor development is a key contributor to neoplastic progression. Despite their clinical relevance, the mechanisms controlling myeloid cell production and activity in cancer remains poorly understood. Using a multistage mouse model of breast cancer, we show that production of atypical T cell-suppressive neutrophils occurs during early tumor progression, at the onset of malignant conversion, and that these cells preferentially accumulate in peripheral tissues but not in the primary tumor. Production of these cells results from activation of a myeloid differentiation program in bone marrow (BM) by a novel mechanism in which tumor-derived granulocyte-colony stimulating factor (G-CSF) directs expansion and differentiation of hematopoietic stem cells to skew hematopoiesis toward the myeloid lineage. Chronic skewing of myeloid production occurred in parallel to a decrease in erythropoiesis in BM in mice with progressive disease. Significantly, we reveal that prolonged G-CSF stimulation is both necessary and sufficient for the distinguishing characteristics of tumor-induced immunosuppressive neutrophils. These results demonstrate that prolonged G-CSF may be responsible for both the development and activity of immunosuppressive neutrophils in cancer.Cancer is a systemic disease. Tumors secrete a variety of factors that not only regulate their local microenvironment, but also regulate peripheral tissues to promote metastasis (1–3). The tumor-promoting role of the immune system has long been recognized (4–7), and emerging evidence suggests that accumulation of circulating myeloid cells at peripheral sites promotes a permissive macro-environment for systemic tumor outgrowth.In cancer patients with solid tumors, aberrant myeloid cells with T cell-suppressive activity are significantly increased in the circulation compared with healthy individuals and are highest in number in patients with extensive metastatic tumor burden (8). In murine transplantation models that mainly mimic the late stages of tumor development, T cell-suppressive myeloid cells expand in the circulation and also in the tumor, spleen, and premetastatic lungs (9). Of particular interest, these myeloid cells promote tumor progression by impairing adaptive immune responses (10, 11), modulating cytokine production by macrophages (12), and stimulating angiogenesis and remodeling of the extracellular matrix (13). In addition, expansion of these T cell-suppressive myeloid cells in premetastatic lung is associated with a local decrease in IFNγ production, the major antitumor cytokine, and an increase in several protumor cytokines, along with vascular remodeling leading to abnormal leaky vessels (14, 15).This population of myeloid cells that acquires the ability to suppress T-cell function in cancer is heterogeneous and includes monocytes, myeloid precursors, and neutrophils, leading to the collective term myeloid-derived suppressor cells (MDSCs) (16). The T cell-suppressive phenotype is mediated by increased arginase activity and the production of reactive oxygen species (ROS) (16). These cells share common myeloid surface markers with their naïve healthy counterparts (CD11b⁺Gr1⁺ in mice or CD11b⁺CD33⁺HLADR⁻ in humans), but differ in activity and gene expression. Although a link between poor prognosis in breast cancer and an increase in circulating myeloid cells in humans is well documented (17), how tumors regulate myeloid cell development remains largely unknown.Hematopoietic cells are all produced from a rare population of self-renewing hematopoietic stem cells (HSCs), which reside in the bone marrow (BM) cavity (18). In mice, the lineage^neg Sca-1⁺c-Kit⁺ (LSK) cell compartment contains the most immature hematopoietic stem and progenitor cells (HSPCs) and include HSCs (defined as LSK Flk2^negCD150⁺CD48^neg) along with non–self-renewing multipotent progenitors (MPPs), which can be further divided into LSK Flk2⁺ (MPP^F+) and a less characterized LSK Flk2^negCD48⁺ (MPP^F−) subset (19). MPPs give rise to lineage-committed common lymphocyte progenitors (CLPs) and common myeloid progenitors (CMPs, defined as lineage^negSca-1⁺c-Kit^negFcγR^negCD34⁺), which support the production of all circulating mature lymphoid and myeloid cells, respectively. CLPs give rise to distinct subsets of B cells, T cells, natural killer cells, and dendritic cells (DCs), whereas CMPs differentiate into granulocyte/macrophage progenitors (GMPs, defined as lineage^negSca-1⁺c-Kit^negFcγR⁺CD34⁺) to support the production of monocytic (macrophage) and granulocytic (neutrophils, eosinophils, and basophils) cells, as well as myeloid-derived DCs. CMPs also differentiate into megakaryocyte/erythrocyte progenitors (MEPs, defined as lineage^negSca-1⁺c-Kit^negFcγR^negCD34^neg) to give rise to red blood cells (RBCs) and megakaryocytes (platelets). Within this well-established hematopoietic tree, the origin of tumor-associated T cell-suppressive CD11b⁺Gr1⁺ myeloid cells is still a matter of debate.The current model suggests that these cells arise from myeloid progenitors (MPs) that are past the GMP stage in a two-step process that includes a block in differentiation, resulting in an expansion of CD11b⁺Gr1⁺ myeloid precursors and an induction of T cell-suppressive activity (9). Tumor-derived myeloid differentiation cytokines including granulocyte (G)-colony stimulating factor (G-CSF), macrophage (M)-colony stimulating factor (CSF), and GM-CSF are thought to induce accumulation of immature myeloid progenitors, in combination with tumor-associated proinflammatory factors (e.g., IL-1β, IL-6, S100A8, S100A9). In addition, T cell-derived cytokines (IFNγ, IL-4, IL-10, and IL-13) likely commit T cell-suppressive activity to these cells (9). Epigenetic silencing of the gene that encodes the protein for Retinoblastoma-1 (Rb1) is also associated with the aberrant myeloid cell expansion that occurs in solid tumor cancers, and knockdown of Rb1 in the absence of tumor development is sufficient to induce the overproduction of similar myeloid cells, but without T cell-suppressive activity (20). Although these results provide a mechanism for the expansion of tumor-associated CD11b⁺Gr1⁺ myeloid cells, it remains unknown which tumor-secreted factors inhibit Rb1 expression, at which stage during myeloid commitment loss of Rb1 occurs, and how T cell-suppressive activity is acquired. Moreover, it remains unclear whether this effect is limited to MPs or also involves more immature HSPCs.Our goal was to determine the driving factor(s) and identify the cell populations responsible for expansion of T cell-suppressive myeloid cells in cancer. We conducted a comprehensive in vivo evaluation of the HSPC and MP regulation in an autochthonous multistage mouse model of breast cancer. We identified a previously unidentified pathway of myeloid differentiation in cancer in which tumor-derived G-CSF directs myeloid differentiation at the primitive HSC to generate activated, Rb1^low, T cell-suppressive neutrophils.