Extinction times in the subcritical stochastic SIS logistic epidemic

Many real epidemics of an infectious disease are not straightforwardly super- or sub-critical, and the understanding of epidemic models that exhibit such complexity has been identified as a priority for theoretical work. We provide insights into the near-critical regime by considering the stochastic SIS logistic epidemic, a well-known birth-and-death chain used to model the spread of an epidemic within a population of a given size $N$. We study the behaviour of the process as the population size $N$ tends to infinity. Our results cover the entire subcritical regime, including the "barely subcritical" regime, where the recovery rate exceeds the infection rate by an amount that tends to 0 as $N \to \infty$ but more slowly than $N^{-1/2}$. We derive precise asymptotics for the distribution of the extinction time and the total number of cases throughout the subcritical regime, give a detailed description of the course of the epidemic, and compare to numerical results for a range of parameter values. We hypothesise that features of the course of the epidemic will be seen in a wide class of other epidemic models, and we use real data to provide some tentative and preliminary support for this theory.Comment: Revised; 34 pages; 6 figure

Lack of microbiological concordance between bone and non-bone specimens in chronic osteomyelitis: an observational study

BACKGROUND: Prognosis of chronic osteomyelitis depends heavily on proper identification and treatment of the bone-infecting organism. Current knowledge on selecting the best specimen for culture is confusing, and many consider that non-bone specimens are suitable to replace bone cultures. This paper compares the microbiology of non-bone specimens with bone cultures, taking the last as the diagnostic gold standard. METHODS: Retrospective observational analysis of 50 patients with bacterial chronic osteomyelitis in a 750-bed University-based hospital. RESULTS: Concordance between both specimens for all etiologic agents was 28%, for Staphylococcus aureus 38%, and for organisms other than S. aureus 19%. The culture of non-bone specimens to identify the causative organisms in chronic osteomyelitis produced 52% false negatives and 36% false positives when compared against bone cultures. CONCLUSIONS: Diagnosis and therapy of chronic osteomyelitis cannot be guided by cultures of non-bone specimens because their microbiology is substantially different to the microbiology of the bone

Surgical impact on brain tumor invasion: A physical perspective

It is conventional strategy to treat highly malignant brain tumors initially with cytoreductive surgery followed by adjuvant radio- and chemotherapy. However, in spite of all such efforts, the patients' prognosis remains dismal since residual glioma cells continue to infiltrate adjacent parenchyma and the tumors almost always recur. On the basis of a simple biomechanical conjecture that we have introduced previously, we argue here that by affecting the 'volume-pressure' relationship and minimizing surface tension of the remaining tumor cells, gross total resection may have an inductive effect on the invasiveness of the tumor cells left behind. Potential implications for treatment strategies are discussed

Effect of simulated dawn on quality of sleep – a community-based trial

BACKGROUND: Morning light exposure administered as simulated dawn looks a promising method to treat Seasonal Affective Disorder, but it may moreover help with resetting the inaccurate organisation of body clock functions relative to sleep occurring in winter among people in general. Disturbances in sleep patterns are common and may compromise wellbeing even in the short term. Our hypothesis was that simulated dawn could improve the subjective quality of sleep during winter. METHODS: A community-based trial with 100 volunteer subjects provided with dawn simulators. Study period lasted for eight weeks, and subjects used the dawn simulators for two weeks at a time, each subject acting as his own control (ABAB-design). Main outcome measure was subjective quality of sleep recorded each morning with Groningen Sleep Quality Scale. RESULTS: 77 subjects completed the trial. Quality of sleep improved while subjects were using dawn simulator-devices (p = 0.001). The treatment became beneficial after six days' use of dawn simulator, but the effect did not last after the use was ceased. CONCLUSION: Dawn simulation may help to improve the subjective quality of sleep, but the benefits are modest. Further research is needed to verify these findings and to elucidate the mechanism by which dawn simulation acts on the sleep-wake pattern

Mobility and other predictors of hospitalization for urinary tract infection: a retrospective cohort study

Abstract Background Many hospitalizations for residents of skilled nursing facilities are potentially avoidable. Factors that could prevent hospitalization for urinary tract infection (UTI) were investigated, with focus on patient mobility. Methods A retrospective cohort study was conducted using 2003–2004 data from the Centers for Medicare and Medicaid Services. The study included 408,192 residents of 4267 skilled nursing facilities in California, Florida, Michigan, New York, and Texas. The patients were followed over time, from admission to the skilled nursing facility to discharge or, for those who were not discharged, for 1 year. Cox proportional hazards regression was conducted with hospitalization for UTI as the outcome. Results The ability to walk was associated with a 69% lower rate of hospitalization for UTI. Maintaining or improving walking ability over time reduced the risk of hospitalization for UTI by 39% to 76% for patients with various conditions. For residents with severe mobility problems, such as being in a wheelchair or having a missing limb, maintaining or improving mobility (in bed or when transferring) reduced the risk of hospitalization for UTI by 38% to 80%. Other potentially modifiable predictors included a physician visit at the time of admission to the skilled nursing facility (Hazard Ratio (HR), 0.68), use of an indwelling urinary catheter (HR, 2.78), infection with Clostridium difficile or an antibiotic-resistant microorganism (HR, 1.20), and use of 10 or more medications (HR, 1.31). Patient characteristics associated with hospitalization for UTI were advancing age, being Hispanic or African-American, and having diabetes mellitus, renal failure, Parkinson's disease, dementia, or stroke. Conclusion Maintaining or improving mobility (walking, transferring between positions, or moving in bed) was associated with a lower risk of hospitalization for UTI. A physician visit at the time of admission to the skilled nursing facility also reduced the risk of hospitalization for UTI.http://deepblue.lib.umich.edu/bitstream/2027.42/112369/1/12877_2008_Article_125.pd

Role of liposome and peptide in the synergistic enhancement of transfection with a lipopolyplex vector

Lipopolyplexes are of widespread interest for gene therapy due to their multifunctionality and high transfection efficiencies. Here we compared the biological and biophysical properties of a lipopolyplex formulation with its lipoplex and polyplex equivalents to assess the role of the lipid and peptide components in the formation and function of the lipopolyplex formulation. We show that peptide efficiently packaged plasmid DNA forming spherical, highly cationic nanocomplexes that are taken up efficiently by cells. However, transgene expression was poor, most likely due to endosomal degradation since the polyplex lacks membrane trafficking properties. In addition the strong peptide-DNA interaction may prevent plasmid release from the complex and so limit plasmid DNA availability. Lipid/DNA lipoplexes, on the other hand, produced aggregated masses that showed poorer cellular uptake than the polyplex but contrastingly greater levels of transgene expression. This may be due to the greater ability of lipoplexes relative to polyplexes to promote endosomal escape. Lipopolyplex formulations formed spherical, cationic nanocomplexes with efficient cellular uptake and significantly enhanced transfection efficiency. The lipopolyplexes combined the optimal features of lipoplexes and polyplexes showing optimal cell uptake, endosomal escape and availability of plasmid for transcription, thus explaining the synergistic increase in transfection efficiency

Impact of therapy on quality of life, neurocognitive function and their correlates in glioblastoma multiforme: a review

The maintenance of quality of life (QoL) in patients with high-grade glioma is an important endpoint during treatment, particularly in those with glioblastoma multiforme (GBM) given its dismal prognosis despite limited advances in standard therapy. It has proven difficult to identify new therapies that extend survival in patients with recurrent GBM, so one of the primary aims of new therapies is to reduce morbidity, restore or preserve neurologic functions, and the capacity to perform daily activities. Apart from temozolomide, cytotoxic chemotherapeutic agents do not appear to significantly impact response or survival, but produce toxicity that is likely to negatively impact QoL. New biological agents, such as bevacizumab, can induce a clinically meaningful proportion of durable responses among patients with recurrent GBM with an acceptable safety profile. Emerging evidence suggests that bevacizumab produces an improvement or preservation of neurocognitive function in GBM patients, suggestive of QoL improvement, in most poor-prognosis patients who would otherwise be expected to show a sudden and rapid deterioration in QoL

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia can findings from animal models be translated to humans?

Background: Cachexia is a multi-factorial, systemic syndrome that especially affects patients with cancer of the gastrointestinal tract, and leads to reduced treatment response, survival and quality of life. The most important clinical feature of cachexia is the excessive wasting of skeletal muscle mass. Currently, an effective treatment is still lacking and the search for therapeutic targets continues. Even though a substantial number of animal studies have contributed to a better understanding of the underlying mechanisms of the loss of skeletal muscle mass, subsequent clinical trials of potential new drugs have not yet yielded any effective treatment for cancer cachexia. Therefore, we questioned to which degree findings from animal studies can be translated to humans in clinical practice and research. Discussion: A substantial amount of animal studies on the molecular mechanisms of muscle wasting in cancer cachexia has been conducted in recent years. This extensive review of the literature showed that most of their observations could not be consistently reproduced in studies on human skeletal muscle samples. However, studies on human material are scarce and limited in patient numbers and homogeneity. Therefore, their results have to be interpreted critically. Summary: More research is needed on human tissue samples to clarify the signaling pathways that lead to skeletal muscle loss, and to confirm pre-selected drug targets from animal models in clinical trials. In addition, improved diagnostic tools and standardized clinical criteria for cancer cachexia are needed to conduct standardized, randomized controlled trials of potential drug candidates in the future

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production.

Microglial priming and enhanced reactivity to secondary insults cause substantial neuronal damage and are hallmarks of brain aging, traumatic brain injury and neurodegenerative diseases. It is, thus, of particular interest to identify mechanisms involved in microglial priming. Here, we demonstrate that priming of microglia with interferon-γ (IFN γ) substantially enhanced production of reactive oxygen species (ROS) following stimulation of microglia with ATP. Priming of microglial ROS production was substantially reduced by inhibition of p38 MAPK activity with SB203580, by increases in intracellular glutathione levels with N-Acetyl-L-cysteine, by blockade of NADPH oxidase subunit NOX2 activity with gp91ds-tat or by inhibition of nitric oxide production with L-NAME. Together, our data indicate that priming of microglial ROS production involves reduction of intracellular glutathione levels, upregulation of NADPH oxidase subunit NOX2 and increases in nitric oxide production, and suggest that these simultaneously occurring processes result in enhanced production of neurotoxic peroxynitrite. Furthermore, IFNγ-induced priming of microglial ROS production was reduced upon blockade of Kir2.1 inward rectifier K+ channels with ML133. Inhibitory effects of ML133 on microglial priming were mediated via regulation of intracellular glutathione levels and nitric oxide production. These data suggest that microglial Kir2.1 channels may represent novel therapeutic targets to inhibit excessive ROS production by primed microglia in brain pathology