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Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is caused by heterozygous germ-line mutations in either PKD1 (85%) or PKD2 (15%). It is characterised by the formation of numerous fluid-filled renal cysts and leads to adult-onset kidney failure in ~50% of patients by 60 years. Kidney cysts in ADPKD are focal and sporadic, arising from the clonal proliferation of collecting-duct principal cells, but in only 1–2% of nephrons for reasons that are not clear. Previous studies have demonstrated that further postnatal reductions in PKD1 (or PKD2) dose are required for kidney cyst formation, but the exact triggering factors are not clear. A growing body of evidence suggests that DNA damage, and activation of the DNA damage response pathway, are altered in ciliopathies. The aims of this review are to: (i) analyse the evidence linking DNA damage and renal cyst formation in ADPKD; (ii) evaluate the advantages and disadvantages of biomarkers to assess DNA damage in ADPKD and finally, (iii) evaluate the potential effects of current clinical treatments on modifying DNA damage in ADPKD. These studies will address the significance of DNA damage and may lead to a new therapeutic approach in ADPKD.
OBJECTIVES/SPECIFIC AIMS: Objective: Approximately 86 million people in the US have prediabetes, but only a fraction of them receive proven effective therapies to prevent diabetes. Further, the effectiveness of these therapies varies with individual risk of progression to diabetes. We estimated the value of targeting those individuals at highest diabetes risk for treatment, compared to treating all individuals meeting inclusion criteria for the Diabetes Prevention Program (DPP). METHODS/STUDY POPULATION: METHODS: Using a micro-simulation model, we estimated total lifetime costs and quality-adjusted life expectancy (QALE) for individuals receiving: (1) lifestyle intervention involving an intensive program focused on healthy diet and exercise, (2) metformin administration, or (3) no intervention. The model combines several components. First a Cox proportional hazards model predicted onset of diabetes from baseline characteristics for each pre-diabetic individual and yielded a probability distribution for each alternative. We derived this risk model from the Diabetes Prevention Program (DPP) clinical trial data and the follow-up study DPP-OS. The Michigan Diabetes Research Center Model for Diabetes then estimated costs and outcomes for individuals after diabetes diagnosis using standard of care diabetes treatment. Based on individual costs and QALE, we evaluated NMB of the two interventions at population and individual levels, stratified by risk quintiles for diabetes onset at 3 years. RESULTS/ANTICIPATED RESULTS: Results: Compared to usual care, lifestyle modification conferred positive benefits for all eligible individuals. Metformin’s NMB was negative for the lowest population risk quintile. By avoiding use among individuals who would not benefit, targeted administration of metformin conferred a benefit of $500-$800 per person, depending on duration of treatment effect. When treating only 20% of the population (e.g., due to capacity constraints), targeting conferred a NMB of $14,000-$18,000 per person for lifestyle modification and $16,000-$20,000 for metformin. DISCUSSION/SIGNIFICANCE OF IMPACT: Conclusions: Metformin confers value only among higher risk individuals, so targeting its use is worthwhile. While lifestyle modification confers value for all eligible individuals, prioritizing the intervention to high risk patients when capacity is constrained substantially increases societal benefits.
This article reviews and reflects on the use of the geographic information system (GIS) as a tool, or geographic information science (GIScience) as a research methodology, and associated techniques of analysis in an empirical study-in-progress on the law and history of early twentieth century British Hong Kong. The article begins by introducing the study and its objectives, as well as the rationale for adopting GIS/GIScience as one of its research methodologies. It then highlights the preliminary findings of the current project and compares them with those of earlier research on the legal history of early twentieth century Beijing using GIS. The article also discusses the difficulties involved in adopting such a digital tool and methodology in historical research. It concludes by reflecting on what GIS can help scholars understand about the social history of law in Hong Kong, beyond what is already known, and how specialists in law, history, and geography can collaborate in a digital law and history project involving the use of GIS. This article also gives an overview of the use of GIS in conducting empirical research in the humanities (including but not limited to history and legal history research) and points to digital sources and web sites useful to researchers who may need tools and data to launch a GIS study in law and history.
During panendoscopy, the anesthesiologist and surgeon must share the airway, with different objectives. The anesthesiologist must deliver oxygen, remove carbon dioxide, provide anesthesia and protect the airway from soiling or aspiration. The surgeon requires an immobile, unobstructed surgical field and adequate time for diagnostic evaluation and intervention. Some patients requiring panendoscopy will present with critical airway obstruction and in these circumstances the safest approach is to proceed to elective tracheostomy under local anesthesia prior to any further endoscopic evaluation. Ventilation techniques can be considered in terms of open and closed systems. A closed system implies ventilation via a cuffed endotracheal tube (ETT). An open system without an ETT is more commonly used for panendoscopy. Panendoscopy is a brief yet highly stimulating procedure that requires deep anesthesia, obtunded hemodynamic reflexes, an immobile surgical field and rapid emergence with early return of protective airway reflexes.
Olanzapine, an atypical antipsychotic, has a broad receptor binding profile, which may account for its pharmacological effects in schizophrenia. In vitro receptor binding studies showed a high affinity for dopamine D2, D3, and D4 receptors; all 5-HT2 receptor subtypes and the 5-HT6 receptor; muscarinic receptors, especially the M1 subtype; and α1-adrenergic receptors. In vivo studies showed that olanzapine had potent activity at D2 and 5 -HT2A receptors, but much less activity at D1 and muscarinic receptors, and that it inhibited dopaminergic neurons in the A10 but not the A9 tract, suggesting that this agent will not cause extrapyramidal side-effects (EPS). Microdialysis studies showed that olanzapine increased the extracellular levels of norepinephrine and dopamine, but not 5-HT, in the prefrontal cortex, and increased extracellular dopamine levels in the neostriatum and nucleus accumbens, areas ofthe brain associated with schizophrenia. Studies of gene expression showed that olanzapine 10 mg/kg also increased Fos expression in the prefrontal cortex, the dorsolateral striatum, and the nucleus accumbens. These findings are consistent with the effectiveness of olanzapine on both negative and positive symptoms and suggest that, with careful dosing, olanzapine should not cause EPS.
The chemical structure of fluoxetine, (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine, as shown in Fig. 1, lacks the three-fused ring system contained in tricyclic antidepressant drugs (TCAs) such as imipramine and amitriptyline. The p-trifluoromethyl substituent on the phenoxy ring of fluoxetine is an important determinant of its potency and its specificity as a serotonin-uptake inhibitor, e.g. the analogue having an o-trifluoromethyl substituent on that ring is only about one-hundredth as potent as fluoxetine in inhibiting serotonin uptake (Wong et al, 1975a). Nisoxetine (Wong et al, 1975b) and tomoxetine (Wong et al, 1982) are analogues differing from fluoxetine only in having an o-methoxy or an o-methyl substituent respectively, in place of the p-trifluoromethyl substituent on the phenoxy ring. Nisoxetine (LY94939) and tomoxetine (LY 139603) are potent and highly selective inhibitors of norepinephrine uptake (Wong et al, 1975b, 1982), differing strikingly from fluoxetine in specificity of uptake inhibition.
Fluoxetine has been shown to be a potent and selective inhibitor of serotonin uptake in laboratory animals; it is orally effective and has a long duration of action. This compound has been a valuable pharmacological tool to study the mechanisms of serotonergic neurotransmission and physiological functions of brain serotonin neurons (Fuller & Wong, 1977; Wong et al, 1985a; Fuller & Wong, 1987). The present paper summarises some of the pre-clinical studies which have characterised fluoxetine as a selective inhibitor of serotonin uptake.
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