4) 77 The higher aspect ratios of rod-shaped particles affected t

4).77 The higher aspect ratios of rod-shaped particles affected the cell functions, such as cellular uptake and apoptosis, in higher extent than sphere-shaped particles. Figure 4. (A) Quantification of cellular uptake and apoptosis of different shaped PSiO2 by flow cytometry analysis of different prepared PSiO2 nanoparticles: sphere-shaped, NS (100 nm), short rod-shaped, NSR Tofacitinib Citrate order (240 nm) and long rod-shaped, NLR (450 … Cellular uptake and trafficking In order to understand the response of biological cells to nanoparticles, it is crucial to learn about the mechanisms of cellular uptake and intracellular trafficking.10 The cell membrane is a complex system consisting of lipids, proteins, cholesterol and receptors, which presents a net negative surface charge.

16 Hence, the surface potential of the nanocarrier as well as the receptors attached to the cell membrane are the features that define cell uptake and trafficking in animal cells. Moreover, it has been demonstrated that the cell uptake of nanoparticles, besides depending on the dosage and time, also depends on the cell type,80 particle size,81 shape,77 surface charge45 and surface chemistry.82 Concerning the size of the nanoparticles, there are some studies that link the size of different vehicles with cell uptake and from which it can be deduced that depending on the cell line, the size limits for endocytosis of particles may vary.45,83-86 Particles smaller than 200 nm are internalized by cells through endocytic mechanisms, while bigger particles when internalized they are uptaked by either endocytosis or phagocytosis.

Regarding the PSiO2 nanoparticles, several studies have been reported describing the relationship between particle size, surface modifications and targeting moieties, and cellular uptake.23 PSiO2 nanoparticle uptake was found to take place via a clarthrin-mediated endocytosis, but the surface modifications of the particles led to different endocytosis mechanisms, e.g., amine- and guanidinium-functionalized PSiO2 nanoparticles suffered a clarthrin and caveolae-independent endocytosis, while folic acid (FA)-functionalized PSiO2 nanoparticles experienced a FA receptor-mediated endocytosis, which increased particles�� uptake by cancer cells.24,53,87 In addition, it has been demonstrated that FITC-PSiO2 nanoparticle internalization is also cell type-, concentration- and time-dependent.

80,87 Lu et al. further demonstrated the energy dependency of the uptake process by showing the higher particle uptake efficiency of cells at 37��C compared with 4��C, and the effect of some metabolic inhibitors in surpressing the PSiO2 nanoparticle uptake in human pancreatic cells.46 PSiO2 nanoparticle endocytosis Anacetrapib and intracellular trafficking pathways have been followed by confocal fluorescence microscopy.45,80,88 The endocytosis led to the formation of a vesicle which captured the particles and internalized them into the cytosol rendering an endosome.

The outcomes of treatment with the epidural butorphanol plus cort

The outcomes of treatment with the epidural butorphanol plus corticosteroid were compared with those of treatment with the epidural corticosteroid alone with the use of parametric and nonparametric analyses as appropriate for the data. The independent-sample Student t tests, Fisher’s exact tests, Pearson Chi-square selleck products tests, Mann?CWhitney U test were performed with the use of SAS statistical package (SAS institute, Cary, NC, USA). A P value of <0.05 was considered to be statistically significant. RESULTS Study group Between October 2007 and September 2010, 120 patients who satisfy the inclusion and exclusion criteria were enrolled in the study, with 60 patients in the butorphanol plus corticosteroid group and 60 in the corticosteroid group.

Randomization was done after we had taken written informed consent from the study participants and obtained baseline information. There were no significant differences between the 2 groups with regard to baseline characteristics [Table 1]. Table 1 Baseline characteristics of 120 patients with sciatica randomly assigned to receive butorphanol plus corticosteroid or corticosteroid alone Withdrawals A total of 18 of the 120 patients did not complete the 3 follow-up visits. In the butorphanol plus corticosteroid group, 2 patients did not come after the first injection, 5 patients did not come after the first visit and 3 patients did not come after the second visit. In the corticosteroid group, 2 patients did not come after the first injection, 4 patients did not come after the first visit and 3 patients did not come after the second visit.

There were no significant differences between Cilengitide the 2 groups with regard to withdrawals [Table 2]. Mean number of follow-up visits in the butorphanol plus corticosteroid group (2.68 ?? 0.77) was not significantly different from that in the corticosteroid group (2.71?? 0.74) (independent sample Student t test, P = 0.83). Table 2 Withdrawals of the 120 patients with sciatica randomly assigned to receive butorphanol plus corticosteroid or corticosteroid alone Complications Twelve patients in the butorphanol plus corticosteroid group (20%) and 16 patients in the corticosteroid group (26.67%) experienced a fleeting headache within 24 h after at least one of the epidural injections (Fisher’s exact test, P = 0.52). Response to treatment In the butorphanol plus corticosteroid group, 25 (41.

67%) patients received 1 injection, 28 (46.67%) patients received 2 injections, and only 7 (11.67%) patients received 3 injections, as compared with 14 (23.33%), 20 (33.33%), and 26 (43.33%) patients, respectively, in sellckchem the corticosteroid group. Mean number of injections in the butorphanol group (1.7 ?? 0.67) was significantly different from that of the corticosteroid group (2.2 ?? 0.8) (independent sample Student t test, P = 0.0003). At each follow-up visit, patients were re-evaluated by recording the various outcome measures.

The odds ratios for any frequency of moderate exercise were 0 61

The odds ratios for any frequency of moderate exercise were 0.61 (95% CI 0.43 to 0.88; P = 0.008) for midlife (age of 50 to 65 years) and 0.68 (95% CI 0.49 to 0.93; P = 0.02) for late selleck products life. A recent meta-analysis reported by Hamer and Chida [34] included 16 studies with exercise measures, including 163,797 controls at baseline and 3,219 incident cases of dementia or PD. The authors found that the relative risks in the highest physical activity category compared with the lowest were 0.72 (95% CI 0.60 to 0.86; P < 0.001) for dementia, 0.55 (95% CI 0.36 to 0.84; P = 0.006) for AD, and 0.82 (95% CI 0.57 to 1.18; P = 0.28) for PD. While this provides support that exercise may be protective against dementia, there is less support of its being protective against dementia in PD.

Aarsland and colleagues [28] completed a meta-analysis evaluating whether exercise might protect against VaD and found five studies that met criteria for meta-analysis, including 10,108 nondemented control subjects and 374 individuals with VaD. The meta -analysis demonstrated a significant association between physical exercise and a reduced risk of developing VaD (odds ratio 0.62, 95% CI 0.42 to 0.92). 3. Randomized control trials A recent Cochrane systematic review of 11 studies of aerobic exercise programs for healthy older persons [35] indicated that 8 of the studies reported cognitive improvement associated with fitness improvement. According to the review, the largest and most consistent cognitive effects in meta-analyses were observed on measures of cognitive speed and attention.

Changes across other cognitive domains (for example, memory, language, and visuospatial) were also present but varied across individual studies. In a single-blind study [6] from Australia, moderate exercise (50 minutes three times per week for 6 months) was shown to enhance cognition in cognitively normal older persons as well as in individuals Anacetrapib who complained of memory difficulty. This was a randomized controlled trial of a 24-week physical activity intervention with a total of 170 participants, and 138 participants completed the 18-month assessment. The main outcome measure was the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) at 18 months. The investigators found that, in an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% CI -0.

89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% CI 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. This showed a modest improvement at 18 months after 6 months of exercise intervention. In a randomized control trial by Erikson and colleagues [36], 120 cognitively normal sedentary adults from 55 to 80 years old were randomly selleck bio assigned to aerobic exercise (building up to walking 40 minutes four times per week) or toning and stretching.

Of particular note, while there were dramatic decreases in cerebe

Of particular note, while there were dramatic decreases in cerebellar white matter PlsEtns, there were no changes in cerebellar gray matter PlsEtns even in late stage AD [9]. PlsEtn changes were also shown to be specific in that phosphatidylethanolamines, serine glycerophospholipids and inositol glycerophospholipids were unaltered [8-10] (nomenclature and structures are presented in Figure ?Figure11). Vorinostat MK0683 Figure 1 Chemical structures of glycerophospholipids. Phosphatidyl glycerophospholipids are diacyl lipids in which fatty acids are the substituents at sn-1 and sn-2 and charged bases (PEtn, PCh, PSer or PIn) at sn-3. Ether lipids possess a fatty alcohol at sn-1 … Figure 2 Inter-relationships of ethanolamine glycerophospholipid and sphingolipid pathways.

The boxed reactions are conducted in peroxisomes while the other reactions are mainly in the endoplasmic reticulum. Red lipids are decreased in Alzheimer’s disease brain … Subsequent research demonstrated disease severity-dependent decreases in circulating DHA and PlsEtns, particularly PlsEtns containing DHA at sn-2 [11,12]. While plasma DHA is derived both from the diet and from peroxisome-dependent synthesis by the liver and gastrointestinal epithelium, peroxisomes are obligatory for PlsEtn synthesis [13]. Based on these data, a peroxisomal deficit in AD was proposed [11] and was soon demonstrated in AD liver [14] and AD brain [15,16]; however, these data do not also preclude a contribution of lipid peroxidation in plasmalogen decrements or potential drug-induced liver toxicity.

Brain and liver DHA is decreased in AD tissues and pristanic acid, a metabolite of dietary phytanic acid that is metabolized exclusively by peroxisomes [17], is elevated in AD liver [14]. Decreases in AD brain PlsEtn levels are accompanied by accumulation of very long chain fatty acids (VLCFAs): behenic acid (C22:0), lignoceric acid (C24:0) and hexacosanoic Batimastat acid (C26:0) [15]. These VLCFAs are all metabolized by peroxisomes [13,15], again supporting peroxisomal dysfunction in AD. Furthermore, the decrements in brain [9], liver [14] and plasma [11,12] DHA-containing plasmalogens and the accumulation of VLCFAs in the cortex [15] correlate with cognitive deficit in AD patients. In contrast, decreases in white matter PlsEtns occur early in the disease process and do not correlate with cognitive status [9].

Supply of PlsEtn building blocks to the central nervous system (CNS) is complicated in that a number of lipid transport mechanisms are involved. DHA (omega-3) and arachidonic acid (omega-6), which are long chain polyunsaturated fatty acids essential make it clear for PlsEtn synthesis, comprise 8% and 6% of brain dry weight, respectively [1]. Fatty acid binding proteins [18] are major determinants of fatty acid transport into and within the CNS.

Abbreviations ARBD: alcohol-related brain damage; ARD: alcohol-re

Abbreviations ARBD: alcohol-related brain damage; ARD: alcohol-related dementia; DSM-IV: Diagnostic and Statistical choose size Manual of Mental Disorders: 4th edition; EFNS: European Federation of Neurological Societies; KS: Korsakoff syndrome; WE: Wernicke’s encephalopathy; WKS: Wernicke-Korsakoff syndrome. Competing interests The authors declare that they have no competing interests.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which patients typically lose cognitive faculties, struggle to carry out activities of daily living (ADLs), and experience behavioural and neuropsychiatric problems. At present, AD cannot be cured, any improvements produced by pharmacotherapy are often temporary, and no treatments have been demonstrated to be disease-modifying.

Consequently, alleviating symptoms, and delaying or reducing clinical worsening (that is, symptom progression), without modifying the underlying pathophysiology, are realistic and meaningful treatment goals [1] that can be termed disease-course-modifying effects [2]. Achieving these goals allows patients to spend more time in the milder, more functional, stages of AD than they would without treatment [1]. Memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors, is approved in the EU and US for the treatment of patients with moderate to severe AD (Mini-Mental State Examination [MMSE] [3] score < 20). Donepezil, Dacomitinib a cholinesterase inhibitor (ChEI), is approved for the treatment of mild to moderate AD in the EU, and for mild, moderate, and severe AD in the US and some other countries.

As monotherapy, both memantine and donepezil have demonstrated efficacy for treating the symptoms of AD within their respective approved inhibitor Brefeldin A indications [4-12]. In addition, the incidence of clinical worsening, as defined by concurrent deterioration in three domains (cognitive, functional, and global) over time, is reduced by memantine treatment in patients with moderate to severe AD [6], and by donepezil treatment in patients with mild to moderate AD [13]. Since memantine and donepezil have different and complementary mechanisms of action, together they potentially offer additional benefits to the patient [14]. Pharmacokinetic and pharmacodynamic data in healthy volunteers provided initial evidence that memantine and donepezil may be safely used in combination [15]. The addition of memantine to stable ChEI therapy has also been associated with a good safety profile in patients with AD [16,17]. Two 24-week, randomised, double-blind, placebo-controlled trials (RCTs) have investigated the efficacy and safety of memantine 20 mg/day in combination with a ChEI.

Carboxymethylcellulose (CMC) and sodium alginate (ALG) gave incon

Carboxymethylcellulose (CMC) and sodium alginate (ALG) gave inconsistent results, suggesting these polymers may interfere with binding, since it was the association rate constant kon that had the largest variability. Of the polymers tested, only HA has significant intrinsic biological activities, promoting cell motility and acting as cell assay a damage-associated molecular pattern upon degradation.36 Further research will be necessary to understand the influence of polymer chemistry and biochemistry on conjugate activities, but the approach utilizing negatively charged polymers in conjunction with antibody-based inhibitors appears to be quite general. Prospectus Challenges in developing antibody-polymer conjugates include validating them for use in treatment of autoimmune diseases that present with local manifestations of persistent inflammatory states, such as psoriasis and Crohn��s disease.

In addition, injuries in healing-impaired models, such as rodent models of diabetes, will provide an important test of whether intrinsic healing responses are sufficient to repair injuries if intense inflammation is modulated. Finally, a better understanding of the interplay between intrinsic biochemical activities of polymers and biopolymers used to conjugate to antibodies and their degradation rates will provide insight into the pharmacokinetics of this drug-delivery strategy and its overall biological activities. Ultimately, this therapeutic approach will need to be tested in humans to determine whether local cytokine neutralization is an effective treatment strategy.

Inhibitors of TNF-�� are currently the most promising formulation, but rapid development of next-generation inhibitors of mediators of inflammation could allow even more targeted treatment. Combined with improvements in polymer delivery vehicles, potentially offering time-dependent or stimulus-responsive delivery, and this approach could treat conditions for which there are very few effective options currently. Acknowledgments This work was supported by the Armed Forces Institute of Regenerative Medicine (W81XWH-08-2-0032), the National Institutes of Health (R43GM085897), and the Department of Defense (W81XWH-13-C-0050). NRW gratefully acknowledges support from a 3M Non-Tenured Faculty Grant, the Wallace H. Coulter Foundation Translational Research Award program, and the Heinz Endowments (C1747).

Disclosure of Potential Conflicts of Interest Disclosure of Potential Conflicts of Interest NRW has started a company to commercialize aspects of this research and acknowledges a potential conflict of interest. Footnotes Previously published online: www.landesbioscience.com/journals/biomatter/article/25597
Zinc oxide (ZnO) is a widely utilized commercial material that has recently garnered interest by medical and nanotechnology researchers due to its considerable antimicrobial1 and UV protection properties.2 In a review Cilengitide by Lansdown et al.

This evidence seems to be especially important for the N-Exp grou

This evidence seems to be especially important for the N-Exp group. The non-experienced participants demonstrated a poorer adaptation to 6 vs. 6 + GKs, explained by differences recorded in the results of offensive sequences and especially by the greater number of unsuccessful offensive sequences in this game format. Our data suggested that the game AZD9291? format clearly affects the quantity and quality of performed actions and, consequently, the offensive sequences�� characteristics. Katis and Kellis (2009) argued also that SSGs can serve several purposes as specific means of training. According to Reilly (2005), since young players need to develop physical abilities, technical skills and decision making in specific performance contexts, it makes sense to use SSGs depending on the age of the participants.

However, youth soccer coaches should be aware that age is not a very precise variable to use in the organization of the training task. Even within the same age group, it is possible to note considerable differences in individual and collective performance of players with well distinct skill and experience levels. In summary, the present paper has evidenced that the deliberate practice experience (individual constraint) and the SSG format (task constraint) do not depend of each other (interaction effect) to influence the offensive performance of young soccer players. Both factors affected independently the characteristics of the offensive sequences. Findings confirm that SSGs can serve several purposes as specific means of training.

However, for effective skill acquisition and performance enhancing in youth soccer, the manipulation of pitch size and number of players should always consider the players�� individual constraints. In this sense, smaller game formats seems to be particularly suitable for novice athletes (e.g., children/youngsters without experience and/or with a lower skill level), since they constrain the development of sport-specific skills based on a major involvement with the ball. On the other hand, in larger SSG formats, the number of actions that each player performs on the ball tends to decrease, increasing the number of ��off-the-ball�� movements and the need to form an effective unit of cooperation with teammates. Such game formats may be useful to practice the specific movement requirements of competitive situations (Hill-Haas et al.

, 2009), and should be carefully considered as young players improve game understanding and specific motor skills. Further studies should continue to verify how the GSK-3 task constraints imply the efficacy of the learning process in soccer, aggregating different contexts and players�� experiences. The functional impact, as far as technical and tactical behavioral changes in consequence of pitch size and number of players�� modifications are concerned, should be clarified. Acknowledgments The results of this paper were previously published in the Book of abstracts (pp.

Consider a flat cell-ECM interface on the boundary of a linear

.. Consider a flat cell-ECM interface on the boundary of a linear tubule (Fig. 3B). For simplicity, we use a 1-D topology to represent the surface of the tubule. The surface area is then the integral of arc length of the tubule. The length of the tubule is confined as S0 by the surrounding thoroughly matrix environment. After a certain amount of time, the number of cells increases and the proliferation pressure pushes the tubule to reach a new equilibrium length S, which is not allowed due to the confinement, leading to the formation of buckles (i.e., bending cells into the matrix, Fig. 3A). To analyze branching pattern formation, let��s use coordinate r? = (x, y) to describe the surface of the tubule (initial y = 0 everywhere on the tubule surface).

Adapting the equations from reference 52, the simplest 2-D free energy function F that ,takes into account both the bending energy and the confinement of tubule length is: F=��2��x=0x=S0ds(d2r?ds2)2+��2[��x=0x=S0ds?S]2.(1) Here, �� is the bending stiffness, �� is the intracellular pressure to push the extension of the tubule, and ds = (dx2 + dy2)1/2 is the arc length along the tubule surface. Following the variation procedure introduced in reference 52 we can perform a variation of F with respect to the coordinates r?, which gives the equation of motion of r?: ��dr?dt=?��F��r?.(2) Here, �� is the viscosity of the tubule surface when cells move into the ECM space. To investigate how branching patterns emerge on the tubule surface, consider a small perturbation of the tubule surface, i.e., y < < S0. Expanding Eqn.

2 to the first order of y, we have: ��dydt=?��d4ydx4?��[S?S0]d2ydx2+O(y2).(3) Using mode analysis with y(k) = y0(k) exp[��(k)t] where k is the wavenumber, we have a dispersion relation: �Ǧ�(k) = ?��k4 + ��[S ? S0]k2.(4) Eqn. 4 indicates that the tubule surface is marginally stable. It also predicts that instability occurs (i.e., ��(k) > 0) when S > S0. The wavenumber with the maximal growth rate, kmax, and the corresponding spacing between branched sites, L, are: kmax=��[S?S0]2��,(5) L=2��kmax=2��2�ʦ�[S?S0].(6) This model predicts that the spacing between branched sites along the tubule surface, L, decreases with the increment of cell number [Fig. 3C (i)], which is controlled by the dosage of growth factors, while L increases with the bending stiffness (i.e., the tension at cell-ECM interface) [Fig.

3C (ii)]. Branching pattern formation by surface tension and cell scattering Besides bending stiffness, another possible effect due to the tension on the cell-ECM interface is to minimize the surface area of epithelial tubules and to confine the motion Brefeldin_A of cells on the surface. To investigate how such effect can lead to branching pattern formation, consider a group of cells that escape or scatter from a preexisting tubule surface into the surrounding ECM (Fig. 4A). In vivo and In vitro, such scattering can be induced by stimulating cells with scattering factors such as hepatocyte growth factor.

1996) When examining

1996). When examining afatinib cancer the relative contributions of conduct problems, depressive affect, and the interaction of conduct problems and depressive affect on AOD use, depressive affect is not as powerful a predictor as are conduct problems. However, the interaction of the two variables (i.e., high levels of both) is a relatively powerful predictor of alcohol use, especially for younger adolescents (Maslowsky and Schulenberg, in press). Drinking Attitudes and Reasons for Using Alcohol Attitudes regarding alcohol use and reasons for use are powerful correlates and predictors of drinking behavior. Indeed, disapproval of binge drinking is one of the strongest protective factors against heavy drinking (Patrick and Schulenberg 2010).

A long-standing focus of the MTF study has been to show how, at the population level, changes in perceptions of risk about and disapproval of substance use precede changes in substance use (Bachman et al. 1998; Johnston et al. 2012; Keyes et al. 2011). A recent analysis assessed the effects of age, period (i.e., the year in which data were obtained), and cohort effects of population-based social norms regarding heavy alcohol use (i.e., level of disapproval of heavy use) on individual-level heavy drinking during adolescence. The study found that cohort effects predominated, indicating that being part of a birth cohort that reported higher disapproval of heavy drinking set the stage for lower alcohol use (Keyes et al. 2012). Motivations or reasons for drinking also are associated with alcohol use behaviors and may serve as a marker for the development of problematic behavioral patterns.

The reasons for alcohol use typically change across adolescence and into adulthood. MTF study investigators have assessed reasons for drinking using MTF study panel data following high-school seniors into young adulthood. (MTF survey questions regarding motivations are not included in the 8th- and 10th-grade surveys.) Of particular interest here, 12th-grade adolescents tend to report higher motivation for drinking to get drunk (as well as other social and coping reasons for drinking) than do young adults. Conversely, 12th graders report lower motivations to use alcohol to relax, to sleep, and because it tastes good, all of which increase across the transition to adulthood (Patrick and Brefeldin_A Schulenberg 2011; Patrick et al. 2011). It is important to understand the reasons for alcohol use among adolescents, because the reasons for use reported in 12th grade, when adolescents are about 18, show long-term longitudinal associations with alcohol use and symptoms of alcohol use disorders decades later (Patrick et al. 2011; Schulenberg et al. 1996).

Life expectancy and mortality, all causes and related to cannabis

Life expectancy and mortality, all causes and related to cannabis use General information about age-specific mortality and life expectancy are readily available (e.g. for Belgium, see http://statbel.fgov.be/). The causes of mortality in Belgium can be found in the ‘Nationale Databank Mortaliteit’ Gemcitabine HCl (National Database Mortality), but caution is needed when interpreting this Inhibitors,Modulators,Libraries information, due to likely miscoding [57]. Besides, the definition of ‘drug related death’ does not include all deaths caused by drug use. For example, deaths caused by lung cancer, which in turn may partially be caused by smoking cannabis, are not recognised as drug related. It should be noted again though, that there is no known fatal dose of cannabis, and no death has ever been attributed solely to the use of cannabis.

Inhibitors,Modulators,Libraries For these reasons, Inhibitors,Modulators,Libraries it is difficult, if not impossible, to express the effects of prevention of cannabis use in terms of mortality measurements. Intervention costs To map out the direct costs of personnel and material, a process evaluation will be necessary [58]. In doing so, resource use will fall into two parts, namely volume (time, manpower, allocated fixed costs and the like) and price (cost per attributable unit of volume). More specifically, the coordinators and/or the staff members of the intervention programme should be asked for information about the issues mentioned in Table Table33 and documents, relevant to the cost structure of these interventions should be studied. Considering the nature of most drug prevention interventions, it will be almost impossible to assign the prevention costs to one specific drug.

It is difficult, if not impossible, to disentangle specific prevention efforts of cannabis use from interventions that, among other things, try to prevent or reduce cannabis use. Direct treatment costs Direct treatment Inhibitors,Modulators,Libraries costs can be obtained through surveys questioning workers in the health care sector and patients, and probably also in several databases (e.g. databases of the Rijksinstituut voor ziekte- en invaliditeitsverzekering [RIZIV, the National Institute for Health and Disability Insurance] or the Sickness Funds). However, it needs to be noted that Inhibitors,Modulators,Libraries Belgium trails behind in making publicly available anonymous in-formation with regard to the costs for specific treatments.

This arrear is caused by the fragmented character of the Belgian health care sector and the budget administrators, as well as competition between sickness funds, which provide (mandatory basic and additional) health insurance [59]. Indirect productivity costs Indirect productivity Drug_discovery costs also fall into two parts: the volume and price component. On the basis of the average gross labour costs, the price component can be calculated. The volume component, however, is more problematic.