mic Efficiency and Pareto Optimality in a Stochastic OLG Model with Production and Social Security

We analyze the interaction between risk sharing and capital accumulation in a stochastic OLG model with production. We give a complete characterization of interim Pareto optimality. Our characterization also subsumes equilibria with a PAYG social security system. In a competitive equilibrium interim Pareto optimality is equivalent to intergenerational exchange efficiency, which in turn implies dynamic efficiency. Furthermore, dynamic efficiency does not rule out a Pareto-improving role for a social security system. Social security can provide insurance against macroeconomic risk, namely aggregate productivity risk in the second period of life (old age) through dynamic risk sharing. We briefly relate our results to models without uncertainty where the notions of exchange efficiency, dynamic efficiency and interim Pareto optimality are all equivalent in a competitive equilibrium.Stochastic OLG Model, Dynamic Efficiency, Interim Pareto Optimality, Social Security, Risk Sharing

An adverse selection model of optimal unemployment insurance

We derive the shape of optimal unemployment insurance (UI) contracts when agents can exert search effort but face different search costs and have private information about their type. We derive a recursive solution of our dynamic adverse selection problem with repeated moral hazard. Conditions under which the UI agency should always offer separating contracts are identified. We show that the good searcher receives an information rent and that the bad searcher receives the minimal entitlement. From a methodological point of view, we achieve a precise characterization of the sets of jointly feasible entitlements. This allows us to map our analytical results one-toone to a numerical algorithm. According to our results the contract for the good searcher has a decreasing benefit profile, as the one he would be offered in a pure moral hazard environment. In contrast, the contract of the bad searcher is distorted by an adverse selection effect, so that it tends to have an upward-sloping benefit profile. We provide a comparative static analysis of changes in various parameters of our model. --Unemployment Insurance,Adverse Selection,Moral Hazard

Molecular mechanisms of neuroinvasion by monocytes-macrophages in HIV-1 infection

HIV associated neurocognitive disorders and their histopathological correlates largely depend on the continuous seeding of the central nervous system with immune activated leukocytes, mainly monocytes/macrophages from the periphery. The blood-brain-barrier plays a critical role in this never stopping neuroinvasion, although it appears unaltered until the late stage of HIV encephalitis. HIV flux that moves toward the brain thus relies on hijacking and exacerbating the physiological mechanisms that govern blood brain barrier crossing rather than barrier disruption. This review will summarize the recent data describing neuroinvasion by HIV with a focus on the molecular mechanisms involved

CXCL12-induced neurotoxicity critically depends on NMDA receptor-gated and L-type Ca2+ channels upstream of p38 MAPK.

BackgroundThe chemokine receptor CXCR4 (CD184) and its natural ligand CXCL12 contribute to many physiological processes, including decisions about cell death and survival in the central nervous system. In addition, CXCR4 is a co-receptor for human immunodeficiency virus (HIV)-1 and mediates the neurotoxicity of the viral envelope protein gp120. However, we previously observed that CXCL12 also causes toxicity in cerebrocortical neurons but the cellular mechanism remained incompletely defined.MethodsPrimary neuronal-glial cerebrocortical cell cultures from rat were exposed to a neurotoxicity-inducing CXCL12 concentration for different times and the activity of the stress-associated mitogen-activated protein kinase p38 (p38 MAPK) was assessed using an in vitro kinase assay. Neurotoxicity of CXCL12 and cellular localization of p38 MAPK was analyzed by immunofluorescence microscopy. Pharmacological inhibition of NMDA-type glutamate receptor-gated ion channels (NMDAR) of L-type Ca2+ channels was employed during 12- and 24-h exposure to neurotoxic amounts of CXCL12 to study the effects on active p38 MAPK and neuronal survival by Western blotting and microscopy, respectively. Neurotoxicity of CXCL12 was also assessed during pharmacological inhibition of p38 MAPK.ResultsHere, we show that a neurotoxic amount of CXCL12 triggers a significant increase of endogenous p38 MAPK activity in cerebrocortical cells. Immunofluorescence and Western blotting experiments with mixed neuronal-glial and neuron-depleted glial cerebrocortical cells revealed that the majority of active/phosphorylated p38 MAPK was located in neurons. Blockade of NMDAR-gated ion channels or L-type Ca2+ channels both abrogated an increase of active p38 MAPK and toxicity of CXCL12 in cerebrocortical neurons. Inhibition of L-type Ca2+ channels with nimodipine kept the active kinase at levels not significantly different from baseline while blocking NMDAR with MK-801 strongly reduced phosphorylated p38 MAPK below baseline. Finally, we confirmed that directly blocking p38 MAPK also abrogated neurotoxicity of CXCL12.ConclusionsOur findings link CXCL12-induced neuronal death to the regulation of NMDAR-gated ion channels and L-type Ca2+ channels upstream of p38 MAPK activation

Risk adapted dose-intensified postoperative radiation therapy in prostate cancer patients using a simultaneous integrated boost technique applied with helical Tomotherapy

Background Postoperative adjuvant radiation therapy (ART) in T3 and R1 prostate cancer as well as salvage radiation therapy (SRT) in case of postoperative biochemical failure (BF) are established treatments. Dose- intensified postoperative radiation therapy (RT) schemes have shown superior biochemical control accompanied by increased toxicity rates. In our study we evaluate a novel risk adapted dose-intensified postoperative RT scheme. Methods A consecutive series of prostate cancer patients receiving postoperative RT after radical prostatectomy using helical Tomotherapy between 04/2012 and 04/2015 was analyzed retrospectively. RT was administered using a simultaneous integrated boost (SIB) to the area at risk (37 fractions of 1.9 Gy, total dose: 70.3 Gy) being defined based on histopathological findings (T3/R1 region) and in few cases according to additional diagnostic imaging. The whole prostate bed was treated with a dose of 66.6 Gy (37 fractions of 1.8 Gy). Primary endpoints were acute and late genitourinary (GU) and gastrointestinal (GI) toxicities. Secondary endpoints included patient reported outcome as assessed by the International Prostate Symptom Score (IPSS), the International Consultation on Incontinence questionnaire (ICIQ) and prostate cancer specific Quality of Life questionnaire QLQ-PR25, as well as rates of BF. Results A total of 69 patients were analyzed. Sixteen patients underwent ART and 53 patients SRT, respectively. The median follow-up was 20 months (range, 8–41 months). Seven (10.1%) and four (5.8%) patients experienced acute grade 2 GU and GI toxicity. Two patients (2.9%) had late grade 2 GU toxicity, whereas no late grade 2 GI nor any grade 3 acute or late GU or GI events were observed. When compared to the baseline IPSS scores (p = 1.0) and ICIQ scores (p = 0.87) were not significantly different at the end of follow-up. Patient reported Quality of life (QoL) showed also no significant difference. A total of seven patients (10.1%) experienced a biochemical recurrence with the 2-year biochemical progression-free survival (bPFS) being 91%. Conclusions Postoperative RT for prostate cancer patients with a risk adapted dose-intensified SIB using helical tomotherapy is feasible and associated with favorable acute and late GU and GI toxicity rates, no significant change of IPSS-, ICIQ scores and patient reported QoL and results in promising bPFS rates

Radiotherapeutic treatment options for oligotopic malignant liver lesions

Background: Several radiotherapeutic approaches for patients with oligotopic malignant liver lesions unfit for surgical resection exist. The most advanced competitive techniques are high-dose-rate (HDR) brachytherapy, Cyberknife, volume-modulated-arc therapy (VMAT) and Tomotherapy. We evaluated the optimal technique by a planning study for a single ablative dose with different lesion sizes. :Methods We compared dose distributions of HDR-brachytherapy with stereotactic ablative radiotherapy using the Cyberknife, VMAT or Tomotherapy. Tumor-control-probabilities (TCP), normal-tissue-complication-probabilities (NTCP) were determined in a theoretical framework applying a single dose of 20 Gy (demanding 95% coverage) for intrahepatic lesions of 1-5 cm in size. We evaluated therapeutic ratios by TCP (mean dose in the lesion) relative to high-dose (conformality) or low-dose liver exposition in dependency on the lesion size for each technique. In addition, we considered treatment times and accuracy (clinical target volume vs planning target volume). Results: HDR-brachtherapy has the highest therapeutic ratios with respect to high-dose as well as low-dose liver exposition even for extended lesions, and the Cyberknife being suited second best. However, for lesions >= 3 cm diameter the therapeutic ratios of all ablative techniques are increasingly converging, and better tolerance and shorter treatment times of noninvasive external techniques become more important. On the other hand, mean tumor doses of HDR-brachytherapy of near 60 Gy are unattainable by the other techniques gaining only 22-34 Gy, and the conformality of HDR-brachytherapy is still rather good for lesions >= 3 cm diameter. Conclusions: HDR-brachytherapy is by far the most effective technique to treat intrahepatic lesions by a single fraction, but sparing of the surroundings declines with increasing lesion size and approaches the benchmarks of external beam radiosurgery techniques. External beam radiotherapy has the advantage to use suitable fractionation schedules

Lack of Detectable HIV-1–Specific CD8+ T Cell Responses in Zambian HIV-1–Exposed Seronegative Partners of HIV-1–Positive Individuals

Human immunodeficiency virus type 1 (HIV-1)–specific T cell responses were characterized in a blinded study involving infected individuals and their seronegative exposed uninfected (EU) partners from Lusaka, Zambia. HIV-1–specific T cell responses were detected ex vivo in all infected individuals and amplified, on average, 27-fold following in vitro expansion. In contrast, no HIV-1–specific T cell responses were detected in any of the EU partners ex vivo or following in vitro expansion. These data demonstrate that the detection of HIV-1–specific T cell immunity in EU individuals is not universal and that alternative mechanisms may account for protection in these individuals