Advances in Causal Chain Development and Testing in Alcohol Research: Mediation, Suppression, Moderation, Mediated Moderation, and Moderated Mediation

Background:  While causal modeling is generally well known to alcohol researchers, several causal structures (including suppression, mediated moderation, and moderated mediation) are often poorly understood and seldom employed when investigators seek to model the complex mechanisms of behavior change, despite their widespread applicability to the field.
Methods:  This paper compares and contrasts five basic structures of causal modeling in the context of contemporary alcohol research and demonstrates how mechanisms of behavior change can be conceptualized and tested as parallel and serial sequences of these basic causal structures, forming causal chains.
Conclusion:  Recent methodological developments, while representing an important advancement for the field, fail to adequately address the complexities of alcohol dependence phenomena. A differentiation between frequently combined forms of these causal structures is proposed that would better address the needs of the field.     

Thalamic and cortical projections to middle suprasylvian cortex of cats: constancy and variation

 We investigated the constancy and variability in the numbers of thalamic and cortical neurons projecting to cat middle suprasylvian (MS) visual cortex. Retrograde pathway tracers were injected at a single anatomically and physiologically defined locus in MS cortex. Counts of labeled neurons showed that the visual thalamic projections to MS cortex consistently arose from a fixed set of nuclei in relatively constant proportions. In contrast, counts of cortical neurons revealed that transcortical inputs to MS cortex were much more variable. This differential variability may be linked to the developmental program, which affords greater influence of experiential factors on cortical pathway development than on thalamocortical pathway development. These results have implications for the development of models of cerebral connectivity that include measures of pathway variability. Received: 29 March 1996 / Accepted: 3 September 1996     

In Situ Thermal Denaturation of Proteins in Dunning AT-1 Prostate Cancer Cells: Implication for Hyperthermic Cell Injury

The in situ thermal protein denaturation and its correlation with direct hyperthermic cell injury in Dunning AT-1 prostate tumor cells were investigated in this study. The in situ thermal protein denaturation was studied using both Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The FTIR spectra at different temperatures show changes in protein secondary structure (from alpha helix to extended beta sheet) during in situ thermal protein denaturation within AT-1 cells. Calorimetric studies using DSC show that endothermic heat release is associated with the in situ thermal protein denaturation. Furthermore, both the secondary structure changes detected by FTIR and the calorimetric changes detected by DSC were quantified and the kinetics of the overall in situ thermal protein denaturation was derived under different heating conditions. The onset temperature where the overall in situ thermal protein denaturation is first detectable was found to be scanning rate dependent (approximately 41 degrees C at 2 degrees C min(-1) and approximately 44 degrees C at 5 degrees C min(-1)). The kinetics of the overall in situ thermal protein denaturation was derived from both DSC and FTIR measurements and was fit using kinetic and statistical models. The kinetic data determined by FTIR and DSC under the same heating conditions match well with each other. The activation energy of the overall in situ thermal protein denaturation is found to be strongly dependent on the temperature range considered (the activation energy ranges from approximately 110 kJ mol(-1) between 44 and 90 degrees C to approximately 750 kJ mol(-1) between 44 and 50 degrees C). However, its dependence on heating rate is negligible. Several denaturation peaks, including a dominant one between approximately 62 and 65 degrees C, are identifiable from both the DSC and the FTIR results. To investigate directly the relationship between thermally induced cell injury and the in situ thermal protein denaturation, both acute (propidium iodide dye exclusion, assessed 3-h postthermal treatment) and chronic (clonogenics, assessed 7-day postthermal treatment) cell injury were quantified using AT-1 cells prepared under the same conditions as for the DSC protein studies. Comparisons of the results from the cell injury studies and the DSC protein denaturation studies show that the overall in situ thermal protein denaturation correlates well with both the acute and the chronic cell injury, which suggests that overall in situ thermal protein denaturation is an important mechanism of direct hyperthermic cell injury in AT-1 cells at the macromolecular level.     

Remodeling of the ICF: A commentary

Since its publication in 2001 the International Classification of Functioning, Disability and Health (ICF) has attracted debate about the content and the model presented. After almost 20 years use, regular updating since 2008 and with the prospect of a new edition in 2020 there is increasing interest in the ICF as a tool to meet contemporary information requirements. Information on functioning is important across not only health systems, but all areas where change in functioning is important: education, employment, and social welfare for example. This commentary responds to the issues raised in a commentary by Mitra & Shakespeare in 2019 and supports review of the ICF in the current context by informing users and providers of data on human functioning how they might engage in the maintenance, updating, and modernisation of the ICF.     

Noninvasive loading of the rat ulna in vivo induces a strain-related modeling response uncomplicated by trauma or periostal pressure

Adaptive changes in bone modeling in response to noninvasive, cyclic axial loading of the rat ulna were compared with those using 4-point bending of the tibia. Twenty cycles daily of 4-point bending for 10 days were applied to rat tibiae through loading points 23 and 11 mm apart. Control bones received nonbending loads through loading points 11 mm apart. As woven bone was produced in both situations, any strain-related response was confounded by the response to direct periosteal pressure. Four-point bending is not, therefore, an ideal mode of loading for the investigation of strain-related adaptive modeling. The ulna's adaptive response to daily axial loading over 9 days was investigated in 30 rats. Groups 1–3 were loaded for 1200 cycles: Group 1 at 10 Hz and 20 N, Group 2 at 10 Hz and 15 N, and Group 3 at 20 Hz and 15 N. Groups 4 and 5 received 12,000 cycles of 20 N and 15 N at 10 Hz. Groups 1 and 4 showed a similar amount of new bone formation. Group 4 showed the same pattern of response but in reduced amount. The responses in Groups 2 and 3 were either small or absent. Strains were measured with single-element, miniature strain gauges bonded around the circumference of dissected bones. The 20 N loading induced peak strains of 3500–4500 strain. The width of the periosteal new bone response was proportional to the longitudinal strain at each point around the bone's circumference. It appears that when a bone is loaded in a normal strain distribution, an osteogenic response occurs when peak physiological strains are exceeded. In this situation the amount of new bone formed at each location is proportional to the local surface strain. Cycle numbers between 1200 and 12,000, and cycle frequencies between 10 and 20 Hz have no effect on the bone's adaptive response.     

生物合成调控的青霉素发酵数学模型与过程优化

青霉素生物合成受溶解氧、溶解二氧化碳、pH、氨氮、碳源(特别是葡萄糖)等的调控，这些调控反应的产生不仅与基础培养基配方有关，更受发酵过程通气、搅拌条件及补料方案的影响。为此，笔者通过把握发酵过程中产生菌生长和青霉素生物合成代谢流的元素平衡、能量平衡以及传递与反应速度平衡的方法，结合生产经验和数据资料，建立了一种能够模拟青霉素发酵过程工艺学参数和经济学参数变化的数学模型。应用这一模型，在充分考虑生物合成代谢调控的基础上，对青霉素发酵过程进行优化，即通过补水维持上述平衡，避免因环境条件、初始条件和约束条件的变化及人为的失误造成的过程波动，使生产不断趋向最优状态。模拟运行表明，这种优化可显著提高发酵生产的经济效益。     

癌因性疲劳动物模型的研究进展

癌因性疲劳(CRF)是一种与癌症本身或癌症治疗相关的常见症状,它不仅会中断患者的治疗,还会严重影响患者生存质量.目前,CRF具体的机制仍不明确,且缺乏公认的有效治疗.建立规范的相关动物模型并进一步探讨CRF的产生机制是找寻有效治疗途径的前提条件.本文综述国内外CRF的动物模型,以期找寻合适的临床前实验的造模方法,并区分...     

Understanding the in vivo performance of enteric coated tablets using an in vitro-in silico-in vivo approach: Case example diclofenac

Individual pharmacokinetics after administration of enteric coated tablets are often highly variable and this has been ascribed to the interaction of the dosage form with the physiology of the gastrointestinal tract. This research aimed to explore the influence of interactions between enteric coated tablets and physiological factors such as gastric and intestinal pH as well as gastric emptying on the release of drug from the dosage form and the subsequent plasma profile, using diclofenac as a case example.A physiologically based pharmacokinetic (PBPK) model for monolithic enteric coated dosage forms was designed and coupled with biorelevant dissolution results to predict PK profiles of diclofenac from Voltaren® tablets in both fasted and fed humans. The paddle method was used to obtain the dissolution profiles of diclofenac in biorelevant media. The Noyes–Whitney model was employed to describe the dissolution kinetics. The PBPK model was set up using STELLA® software. A single unit enteric coated tablet was assumed to be emptied from stomach only with the house-keeping wave. Timing of the emptying was simulated using a random number generator to statistically estimate gastric emptying times after ingestion. The lag times and the dissolution rate used as input parameters in the STELLA® model were adjusted according to the pre-exposure period. The oral PK profiles were predicted for each virtual subject individually, and then the mean profiles and standard deviations were calculated.The dissolution profiles were highly affected by the period of pre-exposure in FaSSGF. A long period of pre-exposure of the tablet prolonged the lag time and decreased the dissolution rate. The results of the pharmacokinetic simulations showed that not only the mean profiles in the fasted state but also the variability could be predicted successfully using data generated for the individual virtual subjects. The results emphasize the importance of accounting for the range of pH profiles and gastrointestinal transit in the target population when predicting plasma profiles of enteric coated dosage forms and point to problems in demonstrating bioequivalence for dosage forms of this type.     

Impact of metabolic surgery on cost and long-term health outcome: a cost-effectiveness approach

BackgroundThe increase in obesity has become a major public health concern. Morbid obesity is associated with co-morbidities, reduced quality-of-life, and death. Metabolic surgery (MS) is the most effective treatment for obesity.ObjectivesThe aim of this study was to evaluate the costs and outcomes of MS compared with no surgery in patients with a body mass index ≥30 kg/m².SettingHealth care system, AustriaMethodsA total of 177 patients who underwent MS were documented retrospectively, based on the hospital records of 2 specialized centers in Austria, over a 1-year period. At baseline 26.0% of patients exhibited type 2 diabetes (T2D), 52.5% cardiovascular disease (CVD), 23.2% hyperlipidemia, and 23.7% depression. Following the observation period, a Markov chain simulation model was developed to analyze the long-term consequences of T2D, including diabetic complications, CVD, hyperlipidemia, depression, non-alcoholic steatohepatitis (NASH), myocardial infarction, and stroke, over a total of 20 years. Direct medical costs were expressed in 2017 euros from the payer’s perspective. Quality-adjusted life years (QALYs), life years (LYs), and costs were discounted.ResultsMS led to costs of €40,427 and 9.58 QALYs (15.58 LYs) per patient over 20 years. No MS was associated with €64,819 and 6.33 QALYs (13.92 LYs). Total cost-savings amounted to €24,392, which offset the cost of the procedure including re-operations. Over 20 years MS saved –6.7 patient-years per patient with T2D, –5.8 patient-years with CVD, –1.5 patient-years with hyperlipidemia, –1.8 patient-years with depression, and –3.8 patient-years with NASH.ConclusionMS is associated with substantial savings in long-term costs, expected health benefits, and reduced onset of complications. MS significantly increases quality of life.