Regional Disparity in First-in-Class Anticancer Drug Development in the US, EU, and Japan.

A cancer diagnosis is devastating for both patients and their caregivers. With high morbidity and mortality, cancer is a serious disease area with unmet medical needs. Thus, innovative anticancer drugs are in high demand worldwide but are unequally available. Our study focused on first-in-class (FIC) anticancer drugs and investigated their actual development situation in the United States (US), European Union (EU), and Japan over the last two decades to obtain fundamental information for understanding how the aforementioned demands are met, especially to eliminate drug lags among regions. We identified FIC anticancer drugs using pharmacological classes for the Japanese drug pricing system. Most FIC anticancer drugs were first approved in the US. The median approval time for anticancer drugs in new pharmacological classes during the last two decades in Japan (5072 d) was significantly different (p = 0.043) from that in the US (4253 d), though it was not significantly different from that in the EU (4655 d). Submission and approval lags between the US and Japan were more than 2.1 years, and those between the EU and Japan were more than 1.2 years. However, those between the US and the EU were less than 0.8 years. The development rate of FIC anticancer drugs in Japan is slower than in other regions. Even among developed countries, FIC anticancer drug lags exist. Considering the high impact of FIC anticancer drugs on society worldwide, we should work together to reduce drug lag among regions using an improved international cooperative framework.

Who's challenging who training for staff empathy towards adults with challenging behaviour: cluster randomised controlled trial.

BACKGROUND: One in five adults with intellectual disabilities (ID) known to services display challenging behaviours (CBs), and these individuals are at risk for restrictive practices and poor care. Staff attitudes may contribute to the development and/or maintenance of CBs. We investigated the effectiveness of co-produced Who's Challenging Who? training delivered by people with ID to staff. METHOD: This study involved a cluster randomised controlled trial (RCT) of Who's Challenging Who? training with follow-up at six and 20 weeks post-randomisation. PARTICIPANTS: two staff from each of 118 residential care settings for adults with ID at least one of whom displayed aggressive CB. PRIMARY OUTCOME: Self-reported Staff Empathy for people with Challenging Behaviour Questionnaire. ANALYSIS: intention to treat of all randomised settings. ISCRTN registration: ISRCTN53763600. RESULTS: 118 residential settings (including 236 staff) were randomised to either receive training (59 settings) or to receive training after a delay (59 settings). The primary analysis included data from 121 staff in 76 settings (51% of staff, 64% of settings). The adjusted mean difference on the transformed (cubed) Staff Empathy for people with Challenging Behaviour Questionnaire score at the primary end point was 1073.2 (95% CI: -938.1 to 3084.5, P = 0.296) in favour of the intervention group (effect size Cohen's d = .19). CONCLUSIONS: This is the first large-scale RCT of a co-produced training course delivered by people with ID. Findings indicated a small positive (but statistically non-significant) effect on increased staff empathy at 20 weeks, and small to moderate effects for staff reported secondary outcomes in favour of the intervention group.

Metabolomic analysis of human plasma reveals that arginine is depleted in knee osteoarthritis patients.

OBJECTIVE: To identify novel biomarker(s) for knee osteoarthritis (OA) using a metabolomics approach. METHOD: We utilized a two-stage case-control study design. Plasma samples were collected from knee OA patients and healthy controls after 8-h fasting and metabolically profiled using a targeted metabolomics assay kit. Linear regression was used to identify novel metabolic markers for OA. Receiver operating characteristic (ROC) analysis was used to examine diagnostic values. Gene expression analysis was performed on human cartilage to explore the potential mechanism for the novel OA marker(s). RESULTS: Sixty-four knee OA patients and 45 controls were included in the discovery stage and 72 knee OA patients and 76 age and sex matched controls were included in the validation stage. We identified and confirmed six metabolites that were significantly associated with knee OA, of which arginine was the most significant metabolite (P < 3.5 × 10(-13)) with knee OA patients having on average 69 µM lower than that in controls. ROC analysis showed that arginine had the greatest diagnostic value with area under the curve (AUC) of 0.984. The optimal cutoff of arginine concentration was 57 µM with 98.3% sensitivity and 89% specificity. The depletion of arginine in OA patients was most likely due to the over activity of arginine to ornithine pathway, leading to imbalance between cartilage repair and degradation. CONCLUSION: Arginine is significantly depleted in refractory knee OA patients. Further studies within a longitudinal setting are required to examine whether arginine can predict early OA changes.

High salt intake does not exacerbate murine autoimmune thyroiditis.

Recent studies have shown that high salt (HS) intake exacerbates experimental autoimmune encephalomyelitis and have raised the possibility that a HS diet may comprise a risk factor for autoimmune diseases in general. In this report, we have examined whether a HS diet regimen could exacerbate murine autoimmune thyroiditis, including spontaneous autoimmune thyroiditis (SAT) in non-obese diabetic (NOD.H2(h4)) mice, experimental autoimmune thyroiditis (EAT) in C57BL/6J mice challenged with thyroglobulin (Tg) and EAT in CBA/J mice challenged with the Tg peptide (2549-2560). The physiological impact of HS intake was confirmed by enhanced water consumption and suppressed aldosterone levels in all strains. However, the HS treatment failed to significantly affect the incidence and severity of SAT or EAT or Tg-specific immunoglobulin (Ig)G levels, relative to control mice maintained on a normal salt diet. In three experimental models, these data demonstrate that HS intake does not exacerbate autoimmune thyroiditis, indicating that a HS diet is not a risk factor for all autoimmune diseases.

Development of a core outcome set for the evaluation of interventions to enhance trial participation decisions on behalf of adults who lack capacity to consent: a mixed methods study (COnSiDER Study).

BACKGROUND: Trials involving adults who lack capacity to provide consent rely on proxy or surrogate decision-makers, usually a family member, to make decisions about participation. Interventions to enhance proxy decisions about trial participation are now being developed. However, a lack of standardised outcome measures limits evaluation of these interventions. The aim of this study was to establish an agreed standardised core outcome set (COS) for use when evaluating interventions to improve proxy decisions about trial participation. METHODS: We used established methods to develop the COS including a consensus study with key stakeholder groups comprising those who will use the COS in research (researchers and healthcare professionals) and patients or their representatives. Following a scoping review to identify candidate items, we used a modified two-round Delphi survey to achieve consensus on core outcomes, with equivocal items taken to a consensus meeting for discussion. The COS was finalised following an online consensus meeting in October 2020. RESULTS: A total of 28 UK stakeholders (5 researchers, 10 trialists, 3 patient/family representatives, 7 recruiters and 3 advisors/approvers) participated in the online Delphi survey to rank candidate items from the scoping review (n = 36) and additional items proposed by participants (n = 1). Items were broadly grouped into three categories: how family members make decisions, their experiences of making decisions, and the personal aspects that influence the decision. Following the Delphi survey, 27 items were included and ten items exhibited no consensus which required discussion at the consensus meeting. Sixteen participants attended the meeting, including additional patient/family representatives invited to increase representation from this key group (n = 2). We reached consensus for the inclusion of 28 outcome items, including one selected at the consensus meeting. CONCLUSIONS: The study identified outcomes that should be measured as a minimum in all evaluations of interventions to enhance proxy decisions about trials. These relate to the process of decision-making, proxies' experience of decision-making, and factors that influence decision-making such as understanding. Further work with people with impairing conditions and their families is needed to explore their views about the COS and to identify appropriate outcome measures and timing of measurement. TRIAL REGISTRATION: The study is registered on the COMET database ( https://www.comet-initiative.org/Studies/Details/1409 ).

Impact of a pharmaceutical care intervention on blood pressure control in a chain pharmacy practice.

BACKGROUND: Hypertension affects over 50 million Americans, with only 50% of patients being adequately controlled. Several pharmacist counseling and pharmacist-physician comanagement studies have documented that community pharmacist interventions improve blood pressure (BP) management. OBJECTIVE: To determine whether community pharmacists can improve clinical endpoints including hypertension control, drug therapy dosing, adherence to prescribed regimens, adverse drug reaction incidence, patient understanding, response to therapy, and quality-of-life. METHODS: The program included the education and training of a group of 18 chain community pharmacists in hypertension therapies, monitoring, and management. Protocols and documentation tools were based on nationally accepted clinical practice guidelines for hypertension in place at the time of the study. Pharmaceutical care (PC) was then compared with usual care (UC) over a 12-month period. RESULTS: The study initially enrolled 180 PC and 196 UC patients, with 44% (PC) and 32% (UC) of the patients reporting a final BP measurement. A larger proportion (50%) of PC patients who had poorly controlled hypertension at baseline (>140/90 mm Hg) were controlled compared with UC patients (22%). The average reduction in systolic BP was 9.9 mm Hg in PC patients compared with 2.8 mm Hg in UC patients (p < 0.05). Changes in diastolic BP were similar in the PC and UC groups. Based on patient self-report, PC patients were more likely to say that they take their medicines as prescribed compared with UC patients (p < 0.05). The 1- to 6-month antihypertensive adherence rate was higher in PC patients (0.91 +/- 0.15) compared to UC patients (0.78 +/- 0.30) (p = 0.02); there was no significant difference in adherence rate during the 7- to 12-month period. CONCLUSIONS: Community pharmacists can positively affect patient medication adherence during the 6-month period following counseling by a pharmacist along with an improvement in patient BP. However, there is much room for improvement in PC programs and in the number of patients who properly adhere to their medications.

Tuberculosis in the Circumpolar Region, 2006-2012.

SETTING: The northern circumpolar jurisdictions Canada (Northwest Territories, Nunavik, Nunavut, Yukon), Finland, Greenland, Norway, Russian Federation (Arkhangelsk), Sweden and the United States (Alaska). OBJECTIVE: To describe and compare demographic, clinical and laboratory characteristics, including drug resistance and treatment completion, of tuberculosis (TB) cases in the northern circumpolar populations. DESIGN: Descriptive analysis of all active TB cases reported from 2006 to 2012 for incidence rate (IR), age and sex distribution, sputum smear and diagnostic site characteristics, drug resistance and treatment completion rates. RESULTS: The annual IR of TB disease ranged from a low of 4.3 per 100 000 population in Northern Sweden to a high of 199.5/100 000 in Nunavik, QC, Canada. For all jurisdictions, IR was higher for males than for females. Yukon had the highest proportion of new cases compared with retreatment cases (96.6%). Alaska reported the highest percentage of laboratory-confirmed cases (87.4%). Smear-positive pulmonary cases ranged from 25.8% to 65.2%. Multidrug-resistant cases ranged from 0% (Northern Canada) to 46.3% (Arkhangelsk). Treatment outcome data, available up to 2011, demonstrated >80% treatment completion for four of the 10 jurisdictions. CONCLUSION: TB remains a serious public health issue in the circumpolar regions. Surveillance data contribute toward a better understanding and improved control of TB in the north.

Binding of rat serum phosphorylcholine binding protein to platelets.

Rat serum phosphorylcholine binding protein (PCBP), a normal component of rat serum, inhibits in vitro aggregation of rat, rabbit and human platelets by interacting with platelets. In the present study, we have demonstrated the calcium-dependent, specific and saturable binding of 125I-PCBP to rat, rabbit and human platelets. Scatchard analysis of the binding data reveal a class of specific high-affinity binding sites with Kd values of 45.2 +/- 14.9, 26.1 +/- 8.3 and 32.2 +/- 9.9 nM on rat, rabbit and human platelets, respectively. These platelets also expressed a high capacity for binding to 125I-PCBP. The binding of 125I-PCBP to platelets was calcium- and time-dependent, and could be inhibited by phosphorylcholine (IC50 = 5.6 microM). Occupation of these binding sites by PCBP may be responsible for inhibition of platelet aggregation.

Evidence for phosphatidylcholine hydrolysis by phospholipase C in rat platelets.

Production of [3H]1,2-dipalmitoylglycerol ([3H]DAG) from 1-palmitoyl-2-[9,10-3H]palmitoyl-sn-glycero-3-phosphocholine and [3H]phosphorylcholine from 1,2-dipalmitoyl-sn-glycero-3-[Me-3H]phosphocholine was studied using sonicated rat platelets. The formation of [3H]DAG and [3H]phosphorylcholine occurred at a comparable rate. [3H]Phosphorylcholine formation was dependent on the concentration of the substrate, platelet sonicates and calcium in the incubation medium. The [3H]phosphorylcholine formation increased in presence of 0.01% deoxycholate and 0.01% Triton X-100. The phosphatidylcholine-phospholipase C (PC-PLC) in the platelet sonicates was recovered in both the supernatant and particulate fractions obtained after ultracentrifugation at 105,000 x g for 1 h. The PC-PLC activity in both fractions was inhibited by 2 mM EDTA. In the presence of 0.01% deoxycholate and 0.01% Triton X-100 the activity in the particulate fraction increased compared to the activity in the supernatant, which was inhibited by 0.01% Triton X-100. The pH optima for PC-PLC in both fractions was between pH 7.2 and 7.6. PC-PLC activity was also found in rabbit and human platelet sonicates, but the activity was significantly lower than in rat platelet sonicates. There was no evidence to suggest presence of phosphatidylcholine-specific phospholipase D activity in rat sonicated platelets. This data, therefore, provides direct evidence for the presence of PC-PLC activity in rat platelets.

Effect of rat phosphorylcholine-binding protein on platelet aggregation.

Rat serum phosphorylcholine-binding protein (PCBP), also referred to as rat C-reactive protein, is present in serum under normal physiological conditions. In the present study, PCBP is shown to inhibit, in a dose-dependent manner, ADP- and platelet-activating factor (PAF)-induced platelet aggregation, using either washed rat platelets or platelet-rich plasma from rats or humans. Rat platelets, as expected, were refractory to aggregation by PAF. However, when rabbit antiserum against PCBP was added to rat platelet-rich plasma, it resulted in aggregation of platelets by PAF. PCBP also inhibited the PAF-induced aggregation of human platelets in a dose-dependent manner. The inhibition of ADP-induced platelet aggregation by PCBP was reversed by adding phosphorylcholine. Our results suggest that PCBP present in rat serum could be the cause of the refractory response of rat plasma to PAF. It is possible that PCBP inhibits platelet aggregation by binding to the platelet surface phospholipids.

Modulation by iron loading and chelation of the uptake of non-transferrin-bound iron by human liver cells.

Hepatic non-transferrin-bound Fe (NTBI) flux and its regulation were characterized by measuring the uptake of Fe from [59Fe]/nitrilotriacetate (NTA) complexes in control and Fe-loaded cultures of human hepatocellular carcinoma cells (HepG2). Exposure to ferric ammonium citrate (FAC) for 1 to 7 days resulted in a time- and dose-dependent increase in the rate of NTBI uptake. In contrast to previous studies showing a dependence of the rate of Fe uptake on extracellular Fe, this was positively correlated with total cellular Fe content. The Fe3+ chelating agents deferoxamine (DFO), 1,2-dimethyl-3-hydroxypyrid-4-one (CP 020) and 1,2-diethyl-3-hydroxypyrid-4-one (CP 094) prevented or diminished the increase in NTBI transport when present during Fe loading and reversed the stimulation in pre-loaded cells in relation to their abilities to decrease intracellular iron. Although saturation of the Fe uptake process was not achieved in control cells, kinetic modelling to include linear diffusion-controlled processes yielded estimated parameters of Km = 4.3 microM and Vmax = 2.6 fmol/micrograms protein/min for the underlying process. There was a significant increase in the apparent Vmax (31.2 fmol/micrograms protein per min) for NTBI uptake in Fe-loaded cells, suggesting that Fe loading increases the number of a rate-limiting carrier site for Fe. Km also increased to 15.2 microM, comparable to values reported when whole liver is perfused with FeSO4. We conclude that HepG2 cells possess a transferrin-independent mechanism of Fe accumulation that responds reversibly to a regulatory intracellular Fe pool.

Measurement of methylglyoxal in rat tissues by electrospray ionization mass spectrometry and liquid chromatography.

INTRODUCTION: Increased methylglyoxal formation due to insulin resistance has been implicated in the development of essential hypertension and in type-2 diabetic complications in animal models. Methylglyoxal is a highly reactive aldehyde, which binds sulfhydryl and amino groups of membrane proteins forming conjugates, advanced glycation end products (AGEs), which alter membrane function, leading to increased blood pressure and oxidative stress. We have shown elevated aldehyde conjugates in tissues of hypertensive rats which may be formed primarily from methylglyoxal. Our objective was to develop a specific method to measure methylglyoxal in rat tissues. METHOD: This method involves preparation of plasma, blood and tissue homogenates, solid phase extraction of methylglyoxal, derivitization using o-phenylenediamine, further purification of derivatized products by solid phase extraction and quantification by electrospray ionization liquid chromatography mass spectrometry (ESI/LC/MS). RESULTS: Methylglyoxal was highest in aorta followed by heart, liver, kidney and blood in that order in Sprague-Dawley rats. Levels of methylglyoxal in plasma were about an order of magnitude lower than that in tissues, but above the concentration used for the lowest calibration standard. DISCUSSION: We have successfully developed an ESI/LC/MS method for quantification of methylglyoxal in rat tissues. The high selectivity of this method offers an advantage over other methods based on fluorescence. This method will allow the evaluation of methylglyoxal in essential hypertension and type-2 diabetes.

A psychometric evaluation of an advanced pharmacy practice experience clinical competency framework.

OBJECTIVE: To assess the psychometric properties of the clinical competency framework known as the System of Universal Clinical Competency Evaluation in the Sunshine State (SUCCESS), including its internal consistency and content, construct, and criterion validity. METHODS: Sub-competency items within each hypothesized competency pair were subjected to principal components factor analysis to demonstrate convergent and discriminant validity. Varimax rotation was conducted for each competency pair (eg, competency 1 vs competency 2, competency 1 vs competency 3, competency 2 vs competency 3). Internal consistency was evaluated using Cronbach alpha. RESULTS: Of the initial 78 pairings, 44 (56%) demonstrated convergent and discriminant validity. Five pairs of competencies were unidimensional. Of the 34 pairs where at least 1 competency was multidimensional, most (91%) were from competencies 7, 11, and 12, indicating modifications were warranted in those competencies. After reconfiguring the competencies, 76 (94%) of the 81 pairs resulted in 2 factors as required. A unidimensional factor emerged when all 13 of the competencies were entered into a factor analysis. The internal consistency of all of the competencies was satisfactory. CONCLUSION: Psychometric evaluation shows the SUCCESS framework demonstrates adequate reliability and validity for most competencies. However, it also provides guidance where improvements are needed as part of a continuous quality improvement program.

Kousseff syndrome caused by deletion of chromosome 22q11-13.

Kousseff syndrome was originally described by Boris Kousseff in 1984: Pediatrics 74:395-398 in three siblings whose main features were conotruncal heart defects, neural tube defects, and dysmorphic features. The proband is a white male who has spina bifida, shunted hydrocephalus, cleft palate, short stature, cognitive impairment, and the typical craniofacial features of velo-cardio-facial syndrome (VCFS), including low-set and dysplastic ears, broad base of the nose, narrow alae nasi, and retrognathia. The family history is significant for a brother who died at 2 weeks of age with myelomeningocele, hydrocephalus, transposition of the great vessels, and unilateral renal agenesis, and a sister who died at 11 days of age with myelomeningocele, truncus arteriosus, hypocalcemia, and autopsy findings of absent thymus and parathyroid glands, consistent with DiGeorge anomaly. Given the clinical findings, family history, and recent knowledge that open neural tube defects can occur in VCFS/DiGeorge anomaly, FISH analysis for 22q11-13 deletion was performed on the proband. A deletion was detected in him and subsequently confirmed in his father. Molecular analysis on autopsy material confirmed the deletion in the proband's deceased brother. We suggest that individuals with neural tube defects associated with other anomalies such as congenital heart defects or cleft palate be evaluated for 22q deletions.

An automated enzymatic method on the Roche COBAS MIRA S for monitoring phenylalanine in dried blood spots of patients with phenylketonuria.

OBJECTIVE: To describe and evaluate a phenylalanine dehydrogenase-coupled enzymatic assay for blood-spot phenylalanine (Phe) automated on the COBAS MIRA S analyzer for monitoring Phe in phenylketonuria (PKU) patients, as part of a home testing program. METHODS AND RESULTS: This method required a four-point calibration with each run and the useful range was 9.3 to 3500 micromol/L Phe. The within-run precision (CV%) was 8.8% at a mean of 77 micromol/L Phe and 5.3% at 787 micromol/L Phe. The between-run precision was 15% and 5.6% for 104 micromol/L and 748 micromol/L Phe, respectively. Blood-spot Phe determinations by this method were compared with plasma Phe determined by the Beckman system 7300 HPLC analyzer using 152 samples collected from PKU patients and 56 samples from patients without PKU. Linear regression analysis revealed the equation y = 0.933x + 14.9. The standard error of estimate (Sy.x) was 82.9 and the correlation coefficient (r) was 0.98. A positive bias, observed for the blood-spot Phe assay with specimens containing Phe concentrations below 200 micro mol/L, was not due to carryover or tyrosine. CONCLUSION: The results indicate that this method is acceptable for monitoring blood Phe levels in PKU patients.

Interference in glucose and other clinical chemistry assays by thiocyanate and cyanide in a patient treated with nitroprusside.

A 3-year-old patient treated with nitroprusside for congestive heart failure had 6.5 mmol/L thiocyanate (toxic, >1.5 mmol/L) and 110 micromol/L cyanide (toxic, >5 micromol/L) present in her blood. At this time a whole-blood glucose concentration assayed on the Nova Stat Profile 5 Plus (Stat Profile) was 25.1 mmol/L. Plasma from that specimen analyzed on a Kodak Ektachem 700 analyzer (E700) indicated 5.2 mmol/L glucose. We investigated the potential interference of dissolved thiocyanate or cyanide on glucose and other routine assays. Toxic concentrations of thiocyanate increased Stat Profile glucose values and E700 total calcium, chloride, and creatinine values. Stat Profile ionized calcium values were decreased by toxic concentrations of thiocyanate. Cyanide (100 micromol/L) decreased alanine aminotransferase activity measured on the E700. Interference with the Stat Profile glucose assay may have been caused by thiocyanate oxidation at the glucose electrode.

Interaction between rat serum phosphorylcholine binding protein and platelet activating factor.

The binding of rat serum phosphorylcholine binding protein (PCBP) to platelet activating factor (PAF) has been demonstrated using a HPLC-gel filtration technique. The bulk of the bound [3H]-PAF eluted with a higher molecular weight species of PCBP, possibly an aggregated form of PCBP. A smaller amount of [3H]-PAF co-eluted with the major monomeric species of PCBP. Formation of the PCBP-PAF complex was calcium dependent and could be inhibited by phosphorylcholine, suggesting the involvement of the phosphorylcholine binding site on PCBP. Binding of albumin and alpha 1-acid glycoprotein to PAF was not affected by phosphorylcholine or calcium. The specificity of this binding may explain the inhibitory effect of PCBP and related phosphorylcholine binding proteins on PAF induced aggregation of platelets.

In vitro inhibition of rat platelet aggregation by ochratoxin A.

The mycotoxin ochratoxin A (OA) consists of 5-chloro-3-methyl-3,4-dihydro-8-hydroxyisocoumarin moiety linked by an amide bond to beta-L-phenylalanine. When added to washed rat platelets in vitro, OA caused a dose-dependent inhibition of aggregation induced by agonists such as adenosine diphosphate (ADP) or thrombin. The aggregatory response induced by prior addition of an agonist was also reversed in a dose-dependent manner by OA. Inhibition of aggregation appeared to be irreversible since exposure of platelets to OA followed by several washings removed most of the mycotoxin associated with the platelets but did not diminish the inhibitory response. Serotonin secretion from dense granules and arachidonic acid release from membrane phospholipid (especially phosphatidylcholine) as well as its further metabolism were also inhibited by OA. These results suggest that a disruption of the platelet plasma membrane structure by OA is probably responsible for inhibition of the primary and secondary phases of aggregation.

Changes in serum carbohydrate-deficient transferrin and gammaglutamyl transferase after moderate wine consumption in healthy males.

Serum carbohydrate-deficient transferrin (CDT) concentrations and gammaglutamyl transferase (GGT) activities were measured in the fasting serum of healthy male subjects before and after 4 weeks consumption each day of 375 ml wine or 500 ml grape juice. After wine consumption, serum CDT concentrations rose in 38 of 48 individual test procedures, and the mean +/- SEM increased from 17.8 +/- 0.86 u/l to 20.9 +/- 1.14 u/l (t0 = 4.66; P < 0.001). Serum GGT activity rose in 35 of these test procedures, and the mean +/- SEM increased from 19.6 +/- 1.40 u/l to 22.3 +/- 1.79 u/l (t0 = 3.58; P < 0.001). When wine consumption was followed by 2 weeks of abstinence from alcohol, significant reductions in both CDT and GGT were noted, virtually reaching baseline levels. No significant change in either index occurred after 4 weeks of consuming grape juice. The correlation between CDT and GGT was rather low, suggesting that their responses to alcohol occur by different mechanisms. The results indicate that the response of CDT to alcohol dose is continuous, and that even moderate consumption can cause significant elevations in a healthy population.