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Purpose: Dietary fats with an abundance of phytonutrients have garnered public attention beyond fatty acids per se. This study was set to investigate the impact of consuming diets with red palm olein (RPOO), extra virgin coconut oil (EVCO) and extra virgin olive oil (EVOO, as a control) on cardiometabolic risk biomarkers and lipid profile. Methods: We recruited a total of 156 individuals with central obesity, aged 25–45 years, with waist circumference ≥ 90 cm for men and ≥ 80 cm for women in a parallel single-blind 3-arm randomised controlled trial. The participants consumed isocaloric diets (~ 2400 kcal) enriched with respective test fats (RPOO, EVCO or EVOO) for a 12-week duration. Results: The mean of the primary outcome plasma high sensitivity C-reactive protein was statistically similar between the three diets after a 12-week intervention. EVOO resulted in significantly lower mean LDL cholesterol compared with RPOO and EVCO, despite similar effects on LDL and HDL cholesterol subfractions. The RPOO diet group showed elevated mean α and β -carotenes levels compared with EVCO and EVOO diet groups (P < 0.05), corresponding with the rich carotenoid content in RPOO. Conclusion: The three oils, each of which has unique phytonutrient and fatty acid compositions, manifested statistically similar cardiometabolic effects in individuals with central obesity at risk of developing cardiovascular diseases with distinct circulating antioxidant properties. Clinical trial registration: ClinicalTrials.gov (NCT05791370). [ABSTRACT FROM AUTHOR]

Cardiomyopathies (CMP) represent a significant health problem as they have a poor long-term prognosis and often require transplantation. Heavy metals are known to have cardiotoxic effects and some of them, such as cadmium (Cd), are found to be elevated in the urine and blood of individuals with heart diseases; nevertheless, direct measurement of metals (e.g. zinc (Zn) which is necessary for normal heart function), in the myocardium of individuals with CMP has not been performed. Here, we aimed to analyze the levels of a group of metals in the myocardium of the left ventricle in individuals with CMP. At the Institute of Pathology, we collected 52 samples of left ventricle post-mortem, out of which 19 subjects had been diagnosed with CMP (mean age: 72 y ± 10), and 33 subjects had not suffered from any heart disease (mean age: 67 y ± 15). We found out that individuals with CMP had a significantly higher concentrations of lead, nickel, manganese and copper than non-CMP subjects (p = 0.002, p < 0.001, p = 0.011, and p = 0.002). Interestingly, zinc was significantly lower in CMP subjects than in n-CMP individuals (p = 0.017). Our results indicated the involvement of an increased lead, nickel, copper and manganese heart load in individuals with CMP coupled with lower concentrations of zinc. [ABSTRACT FROM AUTHOR]

Elevated serum uric acid (SUA)—hyperuricemia—is caused by overproduction of urate or by its decreased renal and/or intestinal excretion. This disease, which is increasing in prevalence worldwide, is associated with both gout and metabolic diseases. Several studies have reported relationships between apolipoprotein E (APOE) haplotypes and SUA levels in humans; however, their results remain inconsistent. This prompted us to investigate the relationship between APOE polymorphisms and SUA levels. Our subjects were 5,272 Japanese men, premenopausal women, and postmenopausal women. Multiple linear regression analyses revealed the ε2 haplotype of APOE to be independently associated with higher SUA in men (N = 1,726) and postmenopausal women (N = 1,753), but not in premenopausal women (N = 1,793). In contrast, the ε4 haplotype was little related to SUA levels in each group. Moreover, to examine the effect of Apoe deficiency on SUA levels, we conducted animal experiments using Apoe knockout mice, which mimics ε2/ε2 carriers. We found that SUA levels in Apoe knockout mice were significantly higher than those in wild-type mice, which is consistent with the SUA-raising effect of the ε2 haplotype observed in our clinico-genetic analyses. Further analyses suggested that renal rather than intestinal underexcretion of urate could be involved in Apoe deficiency-related SUA increase. In conclusion, we successfully demonstrated that the ε2 haplotype, but not the ε4 haplotype, increases SUA levels. These findings will improve our understanding of genetic factors affecting SUA levels. [ABSTRACT FROM AUTHOR]

Purpose: We present a unique opportunity to compare standard neck injury criteria (used by the automotive industry to predict injury) with real-life injuries. The injuries sustained during, and the overall kinematics of, a television demonstration of whiplash mechanics were used to inform and validate a vertebral level model of neck mechanics to examine the relevance of current injury criteria used by the automotive industry. Methods: Frontal and rear impact pulses, obtained from videos of sled motion, were used to drive a MADYMO human model to generate detailed segmental level biomechanics. The maximum amplitude of the frontal and rear crash pulses was 166 ms−2 and 196 ms−2, respectively, both with a duration of 0.137 s. The MADYMO model was used to predict standard automotive neck injury criteria as well as detailed mechanics of each cervical segment. Results: Whilst the subject suffered significant upper neck injuries, these were not predicted by conventional upper neck injury criteria (Nij and Nkm). However, the model did predict anterior accelerations of C1 and C2 of 40 g, which is 5 times higher than the threshold of the acceleration for alar ligament injury. Similarly, excessive anterior shear displacement (15 mm) of the skull relative to C2 was predicted. Predictions of NIC, an injury criterion relevant to the lower neck, as well as maximum flexion angles for the lower cervical segments (C3–T1) exceeded injury thresholds. Conclusion: The criteria used by the automotive industry as standard surrogates for upper neck injury (Nij and Nkm) did not predict the significant cranio-cervical junction injury observed clinically. [ABSTRACT FROM AUTHOR]

Objective: This cross-sectional study determined whether acute sensory irritative or (sub)chronic inflammatory effects of the eyes, nose or respiratory tract are observed in employees who are exposed to naphthalene at the workplace. Methods: Thirtynine healthy and non-smoking male employees with either moderate (n = 22) or high (n = 17) exposure to naphthalene were compared to 22 male employees from the same plants with no or only rare exposure to naphthalene. (Sub)clinical endpoint measures included nasal endoscopy, smell sensitivity, self-reported work-related complaints and the intensity of naphthalene odor and irritation. In addition, cellular and soluble mediators in blood, nasal lavage fluid (NALF) and induced sputum (IS) were analysed. All measurements were carried out pre-shift on Monday and post-shift on Thursday. Personal air monitoring revealed naphthalene shift concentrations up to 11.6 mg/m3 with short-term peak concentrations up to 145.8 mg/m3 and 1- and 2-naphthol levels (sum) in post-shift urine up to 10.1 mg/L. Results: Acute sensory irritating effects at the eyes and upper airways were reported to occur when directly handling naphthalene (e.g., sieving pure naphthalene). Generally, naphthalene odor was described as intense and unpleasant. Habituation effects or olfactory fatigue were not observed. Endoscopic examination revealed mild inflammatory effects at the nasal mucosa of exposed employees in terms of reddening and swelling and abnormal mucus production. No consistent pattern of cellular and soluble mediators in blood, NALF or IS was observed which would indicate a chronic or acute inflammatory effect of naphthalene in exposed workers. Conclusions: The results suggest that exposure to naphthalene induces acute sensory irritative effects in exposed workers. No (sub)chronic inflammatory effects on the nasal epithelium or the respiratory tract could be observed under the study conditions described here. [ABSTRACT FROM AUTHOR]

Purpose: Synaptic abnormalities are associated with many brain disorders. Recently, we developed a novel synaptic vesicle glycoprotein 2A (SV2A) radiotracer [18F]SynVesT-1 and demonstrated its excellent imaging and binding properties in nonhuman primates. The aim of this study was to perform dosimetry calculations in nonhuman primates and to evaluate this tracer in humans and assess its test-retest reliability in comparison with [11C]UCB-J. Methods: Three rhesus monkeys underwent whole body dynamic PET scanning to estimate the absorbed dose. PET scans in six healthy human subjects were acquired. Time-activity curves (TACs) were generated with defined regions of interest (ROI). Reproducibility of distribution volume (VT) values and its sensitivity to scan duration were assessed with the one-tissue compartment (1TC) model. Non-displaceable binding potential (BPND) was calculated using centrum semiovale as the reference region. Results: The dosimetry study showed high uptake in the urinary bladder and brain. In humans, [18F]SynVesT-1 displayed high uptake with maximum SUV of ~10 and appropriate kinetics with a quick rise in tracer uptake followed by a gradual clearance. Mean 1TC VT values (mL/cm3) ranged from 3.4 (centrum semiovale) to 19.6 (putamen) and were similar to those of [11C]UCB-J. Regional BPND values were 2.7–4.7 in gray matter areas, and mean BPND values across all ROIs were ~ 21% higher than those of [11C]UCB-J. The absolute test-retest variability of VT and BPND was excellent (< 9%) across all brain regions. Conclusions: [18F]SynVesT-1 demonstrates outstanding characteristics in humans: fast and high brain uptake, appropriate tissue kinetics, high levels of specific binding, and excellent test-retest reproducibility of binding parameters. As such, [18F]SynVesT-1 is proved to be a favorable radiotracer for SV2A imaging and quantification in humans. [ABSTRACT FROM AUTHOR]

Purpose: In diffusion MRI (dMRI), it remains unclear to know how much increase of b-value is conveying additional biological meaning. We tested the correlations between cortical microarchitecture and diffusion metrics computed from standard (1000 s/mm2), high (3000 s/mm2), to very high (5000 s/mm2) b-value dMRI. Methods: Healthy volunteers were scanned with a dMRI pulse sequence that was first optimized together with a T1-WI and T2-WI. Averaged cortical surface map of estimated myelin (T1-WI/T2-WI) was compared with surface maps of mean diffusivity (MD) computed from each b-value (MD1000, MD3000, and MD5000) and to surface map of mean kurtosis (MK computed from the 0-, 1000-, to 3000-s/mm2 shells) in 360 cortical parcels using Spearman correlations, multiple linear regressions, and Akaike information criteria (AIC). Results: Surface map from MD1000 showed variations not related to myelin but the MD3000 and MD5000 maps inversely mirrored estimated myelin map; lower MD values being observed in more myelinated cortical areas. MK mirrored myelinated cortical areas. Quantitatively, Spearman correlations between myelin and MD became more and more negative as long as b-values increased while the correlation was positive between myelin and MK. Multiple regression models confirmed negative associations between myelin and MD that were significantly better from MD1000 to MD3000 and MD5000 (R2 = 0.33, p < 0.001; R2 = 0.43, p < 0.001; and R2 = 0.50, p < 0.001) and positive association between myelin and MK (R2 = 0.53, p < 0.001). Comparisons of the 3 statistical models showed the best performances with MK and MD5000 (AICMK < AICMD5000 < AICMD3000 < AICMD1000). Conclusion: Higher b-values are more closely related to subtle cellular variations of the cortical microarchitecture. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we investigated the absorption and excretion kinetics of antioxidant dietary phytochemicals (vitamin E, γ-oryzanol, and ferulic acid) in healthy humans after the ingestion of an oatmeal porridge supplemented with rice bran extract (RBE) prepared with water or with whole milk, and we compared it with the intake of an equivalent dose of the rice bran content, in the form of RBE oil. Methods: Twelve healthy volunteers (6 men and 6 women) orally ingested RBE oil (2 g) or RBE-enriched porridge (35 g, including 2-g RBE) with water or with milk, in a three-armed, crossover trial. Blood and urine samples were collected at baseline and up to 24 h after intake. Vitamin E (α-, β-, γ-, and δ-tocopherols and tocotrienols), ferulic acid (FA), and γ-oryzanol (ORY) were quantified by HPLC. Results: The ingestion of RBE-fortified oatmeal porridge and RBE oil significantly increased FA concentrations in plasma, showing faster absorption and higher maximum plasma concentrations after the intake of the porridges, irrespective of the addition of water or milk. At least part of the FA could have been hydrolyzed from ORY. However, plasma vitamin E concentrations did not increase from baseline, and no intact FA esters (cycloartenyl ferulate, 24-methylenecycloartanyl ferulate, campesteryl ferulate, and β-sitosteryl ferulate) were detected in plasma or urine with any of the meal treatments. Conclusions: Rice bran extract-enriched porridge and, to a lesser extent, RBE oil, provide relevant sources of bioaccessible and bioavailable ferulic acid, and could be further developed into functional foods with health potential. [ABSTRACT FROM AUTHOR]

Acrylamide (AA) is a heat-induced food contaminant considered as genotoxic carcinogen. The present study investigated the influence of nutritional and lifestyle preferences on human AA exposure. A 10-day human study was performed with ten volunteers without nutritional preferences (omnivores) and ten vegans. Volunteers self-reported their daily routine and dietary habits. Overall mean AA intake, calculated from contents of diet duplicates, was 0.32 ± 0.19 µg/kg body weight (bw)/day with marked inter-day and inter-volunteer variabilities. Vegans ingested more AA (0.38 ± 0.23 µg/kg bw/day) than omnivore volunteers without dietary restrictions (0.26 ± 0.10 µg/kg bw/day). Excretion kinetics of urinary AA-related mercapturic acids N-acetyl-S-(2-carbamoylethyl)-l-cysteine and N-acetyl-S-(2-hydroxy-2-carbamoylethyl)-l-cysteine were essentially concordant with the respective dietary AA intake. Disproportionately enhanced AA-related biomarker excretion could be traced back to reportedly inadvertent, passive exposure to tobacco and/or fire smoke, as evidenced by the respective urinary exposure biomarkers, cotinine and N-acetyl-S-(2-cyanoethyl)-l-cysteine. Although the study is based on the comparison of small volunteer groups, the results confirm the association of AA exposure biomarkers with documented dietary preferences and lifestyle factors. Some additional contribution of endogenous background AA exposure was demonstrated individually. Disproportionately enhanced AA exposure is suggested to result from passive exposure to tobacco and/or barbecue smoke. [ABSTRACT FROM AUTHOR]

Mutation analysis is a well-studied, fault-based testing technique. It requires testers to design tests based on a set of artificial defects. The defects help in performing testing activities by measuring the ratio that is revealed by the candidate tests. Unfortunately, applying mutation to real-world programs requires automated tools due to the vast number of defects involved. In such a case, the effectiveness of the method strongly depends on the peculiarities of the employed tools. Thus, when using automated tools, their implementation inadequacies can lead to inaccurate results. To deal with this issue, we cross-evaluate four mutation testing tools for Java, namely PIT, MUJAVA, Major and the research version of PIT, PITRV, with respect to their fault-detection capabilities. We investigate the strengths of the tools based on: a) a set of real faults and b) manual analysis of the mutants they introduce. We find that there are large differences between the tools’ effectiveness and demonstrate that no tool is able to subsume the others. We also provide results indicating the application cost of the method. Overall, we find that PITRV achieves the best results. In particular, PITRV outperforms the other tools by finding 6% more faults than the other tools combined. [ABSTRACT FROM AUTHOR]

Purpose: Chronic low-level systemic and adipose tissue inflammation has been identified as a major etiologic factor in many chronic diseases, including hypertension and cardiovascular diseases. Evidence from experimental studies suggests anti-inflammatory effects of dietary flavonols such as quercetin. Methods: We investigated the effects of regular intake of quercetin on leptin, adiponectin, biomarkers of inflammation, glucose and insulin in overweight-to-obese patients with pre- and stage 1 hypertension. Another objective was to assess the safety of daily quercetin supplementation measured by parameters of liver and kidney function and of hematology. Subjects ( n = 70) were randomized to receive a supra-nutritional dose of 162 mg/d quercetin or placebo in a double-blinded, placebo-controlled crossover trial with 6-week treatment periods separated by a 6-week washout period. Two subjects dropped out for personal reasons. Only data from the remaining 68 subjects were included in the analysis. Results: Compared to placebo, quercetin did not significantly affect serum concentrations of leptin and adiponectin, HOMA-AD or the ratios of leptin/adiponectin and adiponectin/leptin. Neither quercetin nor placebo significantly changed serum C-reactive protein and plasma tumor necrosis factor alpha. Compared to placebo, quercetin did not significantly affect glucose, insulin, HOMA-IR, blood biomarkers of liver and renal function, hematology and serum electrolytes. Conclusion: A supra-nutritional dose of 162 mg/d quercetin from onion skin extract for 6 weeks is safe but without significant effects on parameters of systemic and adipose tissue inflammation as well as glucose and insulin in overweight-to-obese subjects with (pre-)hypertension. This trial was registered at and as DRKS00000555. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the plasma kinetics of quercetin derived from hard capsules filled with onion skin extract powder or quercetin dihydrate in humans. Methods: In a randomized, single-blind, diet-controlled crossover study, 12 healthy subjects (six men and six women) aged 21-33 years were administered a single oral supra-nutritional dose of approximately 163 mg quercetin derived from onion skin extract powder (containing 95.3 % of total flavonoids as quercetin aglycone) or quercetin dihydrate (134 mg quercetin aglycone equivalent). Blood samples were collected before and during a 24-h period after quercetin administration. The concentrations of quercetin and its two monomethylated derivatives, isorhamnetin (3′- O-methyl quercetin), and tamarixetin (4′- O-methyl quercetin), were measured using HPLC with fluorescence detection after plasma enzymatic treatment. Results: The systemic availability, determined by comparing the plasma concentration-time curves of quercetin, was 4.8 times higher, and the maximum plasma concentration ( C ) was 5.4 times higher after ingestion of the onion skin extract than after ingestion of pure quercetin dihydrate. By contrast, t did not differ significantly between the two formulations. The C values for isorhamnetin and tamarixetin were 3.8 and 4.4 times higher, respectively, after administration of onion skin extract than after pure quercetin dihydrate. The plasma kinetics of quercetin were not significantly different in men and women. Conclusion: Quercetin aglycone derived from onion skin extract powder is significantly more bioavailable than that from quercetin dihydrate powder filled hard capsules. [ABSTRACT FROM AUTHOR]

Objective: To asses the fate of the costochondral graft (CCG) used to stimulate mandibular growth in the management of Temporomandibular joint (TMJ) reconsrtuction in ankylosis-histologically. Materials and Methods: Ten patients who had undergone CCG grafting for TMJ ankylosis between 1994-2009 in the department of Oral & Maxillofacial Surgery, Tamil Nadu Govt Dental College and Hospital, Chennai and had come back with reankylosis, were surgically explored and the graft along with the ankylotic mass was excised and evaluated histologically. There is no documented human study and clinically it is not possible. Results: Histological evaluation revealed the presence of osseous tissue, fibrous tissue and osteocytes but no evidence of any chondroid tissue. Conclusion: Our study showing the absence of chondroid tissue raises the question on the rationale of CCG in TMJ reconstruction when other interpositional gap arthroplasty can achieve a disease free joint. [ABSTRACT FROM AUTHOR]

Although monosodium glutamate (MSG) is classified as a causative substance of headache in the International Classification of Headache Disorders 3rd edition (ICHD-III beta), there is no literature in which causal relationship between MSG and headache was comprehensively reviewed. We performed systematic review of human studies which include the incidence of headache after an oral administration of MSG. An analysis was made by separating the human studies with MSG administration with or without food, because of the significant difference of kinetics of glutamate between those conditions (Am J Clin Nutr 37:194-200, 1983; J Nutr 130:1002S-1004S, 2000) and there are some papers which report the difference of the manifestation of symptoms after MSG ingestion with or without food (Food Chem Toxicol 31:1019-1035, 1993; J Nutr 125:2891S-2906S, 1995). Of five papers including six studies with food, none showed a significant difference in the incidence of headache except for the female group in one study. Of five papers including seven studies without food, four studies showed a significant difference. Many of the studies involved administration of MSG in solution at high concentrations (>2 %). Since the distinctive MSG is readily identified at such concentrations, these studies were thought not to be properly blinded. Because of the absence of proper blinding, and the inconsistency of the findings, we conclude that further studies are required to evaluate whether or not a causal relationship exists between MSG ingestion and headache. [ABSTRACT FROM AUTHOR]

Typically, colonic absorption of a drug is mandatory for a sustained release formulation to hold the drug's plasma level for more than 12 or 24 h above the minimum therapeutic plasma concentration (efficacy). According to Drugs@FDA, only 7.4% of the oral drugs are extended release forms probably showing colonic absorption. Therefore an early determination of a drug's colonic absorption using the IntelliCap® in animals or humans will provide the mandatory information to initiate or stop a SR form development. Diltiazem (60 mg) is used in the oral swallowable IntelliCap® and the marketed SR form from Mylan (coated beads). A human study with 14 healthy volunteers compared the Mylan formulation with the IntelliCap® device that releases the drug identical to the in-vitro dissolution of the Mylan product. The plasma profiles of IntelliCap® and Mylan formulation are highly similar. The mean AUC (bioequivalence fulfilled) and mean Cmax of IntelliCap® shows only a difference of +15% and −12%, respectively. But the PK profile of the Mylan formulation shows a broader peak around Cmax. About 81.8% diltiazem was absorbed in the colon (IntelliCap®) comparable to former publications. The Mylan is a SR diffusion coated beads form whereas the IntelliCap® is a monolithic capsule. The beads are transported in the gut and spread which results in a longer Tmax and a broader Cmax peak. The IntelliCap® device can quantitatively measure the colonic absorption of a drug in excellent accordance to a standard oral SR dosage form. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Orexin A (OXA) modulates food intake, energy expenditure, and lipid and glucose metabolism. OXA regulates the secretion of insulin and glucagon, while glucose regulates OXA release. Here, we evaluate the role of glucagon in regulating OXA release both in vivo and in vitro. Methods: In a double-blind crossover study, healthy volunteers and type 1 diabetic patients received either intramuscular glucagon or placebo. Patients newly diagnosed with type 2 diabetes underwent hyperinsulinaemic-euglycaemic clamp experiments, and insulin-hypoglycaemia tests were performed on healthy volunteers. The primary endpoint was a change in OXA levels after intramuscular glucagon or placebo administration in healthy participants and patients with type 1 diabetes. Secondary endpoints included changes in OXA in healthy participants during insulin tolerance tests and in patients with type 2 diabetes under hyperinsulinaemic-euglycaemic conditions. Participants and staff conducting examinations and taking measurements were blinded to group assignment. OXA secretion in response to glucagon treatment was assessed in healthy and obese mice, the streptozotocin-induced mouse model of type 1 diabetes, and isolated rat pancreatic islets. Results: Plasma OXA levels declined in lean volunteers and in type 1 diabetic patients injected with glucagon. OXA levels increased during hyperinsulinaemic hypoglycaemia testing in healthy volunteers and during hyperinsulinaemic euglycaemic conditions in type 2 diabetic patients. Plasma OXA concentrations in healthy lean and obese mice and in a mouse model of type 1 diabetes were lower after glucagon treatment, compared with vehicle control. Glucagon decreased OXA secretion from isolated rat pancreatic islets at both low and high glucose levels. OXA secretion declined in pancreatic islets exposed to diazoxide at high and low glucose levels, and after exposure to an anti-insulin antibody. Glucagon further reduced OXA secretion in islets pretreated with diazoxide or an anti-insulin antibody. Conclusions/interpretation: Glucagon inhibits OXA secretion in humans and animals, irrespective of changes in glucose or insulin levels. Through modifying OXA secretion, glucagon may influence energy expenditure, body weight, food intake and glucose metabolism. [ABSTRACT FROM AUTHOR]

Burn wound healing is a complicated process including inflammation, re-epithelialization, granulation, neovascularization and wound contraction. Several biochemicals are involved in burn healing process including antioxidants, cytokines and liver and kidney damage biomarkers. Although several preparations are available for the management of burn wound, there is still a necessity of researching for efficacious medicine. The aim of the present study was to evaluate herbal preparations and their phytochemical constituents for burn wound management. For this purpose, electronic databases including Pubmed, Scirus, Scopus and Cochrane library were searched from 1966 to July 2013 for in vitro, in vivo or clinical studies which examined the effect of any herbal preparation on different types of burn wound. Only 3 human studies were found to include in this review. In contrast, there were 62 in vivo and in vitro studies that show the need for more clinical trials to prove the plant's potential to cure burn wound. Among single herbal preparations, Allium sativum, Aloe vera, Centella asiatica and Hippophae rhamnoides showed the best burn wound healing activity. Flavonoids, alkaloids, saponins and phenolic compounds were active constituents present in different herbs facilitating wound closure. Glycosides including madecassoside and asiaticoside and proteolytic enzymes were among the main active components. Phytochemicals represented positive activity at different stages of burn wound healing process by various mechanisms including antimicrobial, anti-inflammatory, antioxidant, collagen synthesis stimulation, cell proliferative and angiogenic effect. Overall, several herbal medicaments have shown marked activity in the management of wounds-especially burn wounds-and therefore can be considered as an alternative source of treatment. Furthermore, various natural compounds with verified burn-induced wound healing potential can be assumed as future natural drugs. [ABSTRACT FROM AUTHOR]

Introduction: In 1992, we published a report on the effect of positive end-expiratory pressure (PEEP) on right ventricular (RV) function in humans. Results: We measured RV volumes and pressures and pericardial pressure (Ppc) as PEEP was increased from zero to 15 cm H20 in 12 patients after thoracotomy, using a pulmonary arterial catheter equipped with a rapid responding thermistor that allowed measurement of RV ejection fraction (RVef), while Ppc was measured via a pericardial balloon catheter. RV end-diastolic volume (EDV) was estimated as the ratio of stroke volume (SV) to RVef, whereas RV end-systolic volume (ESV) were estimated as RV EDV-SV. PEEP increased Ppc and Pra, but RVef unaltered. There was no relation between either RV filling pressure (Pra-Ppc) and EDV or the change in RV filling pressure and EDV, although EDV varied significantly with PEEP ( p < 0.05). The relations between EDV and both SV and RVef were weak ( r = 0.54 and 0.55, respectively). RVef varied inversely with ESV ( r = −0.77), although it showed no relation to transmural peak pulmonary artery pressure ( r = 0.28). However, both absolute and relative changes in EDV corresponded closely with respective ESV values ( r = 0.94). We concluded that EDV varies independently of changes in filling pressure and that changes in ESV occur independently of changes in ejection pressure. These data can be explained by assuming that the RV shape changes can dissociate changes in RV EDV from changes in RV wall stress (preload). Thus, changes in RV EDV may or may not alter SV but should proportionately change ESV to a degree dependent on election pressure and contractility. Conclusions: Subsequent studies confirmed our findings which can be summarized as 1) RV filling is independent of Pra; thus central venous pressure cannot be used to estimate RV preload; and 2) for cardiac output to increase by the Starling mechanism the RV must dilate increasing RV ESV. Since the pericardium limits absolute biventricular volume, there is a finite limit to which cardiac output can increase by the Starling mechanism defined not by left ventricular contractility but by RV function. And 3) if fluid loading causes Pra to increase without increasing cardiac output, then resuscitation should stop as the patient is going into acute cor pulmonale. These truths help bedside clinicians understand the echocardiographic and hemodynamic signatures of both RV failure and volume responsiveness. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this 'first-in-man' study was to investigate the safety of a novel vascular polyester prosthesis coated with a resorbable polymer and free of any animal-based coating agents such as gelatin or collagen. Methods: In a nonrandomized first-in-man multicenter safety study, the frequency of perigraft seroma (PGS) as the primary endpoint was studied in consecutive patients undergoing aortic reconstructions. The follow-up control to study the primary endpoint was intended at 3 months under routine clinical conditions. Pre- and postoperative white blood cell counts (WBC), C-reactive protein (CRP), and liver enzyme levels to characterize the systemic inflammation response and possible metabolic consequences were determined at different postoperative time points (secondary endpoints). Additionally, the primary unassisted patency rate, perioperative complications and serious adverse events, as well as intraoperative handling properties of the graft based on a semiquantitative scale were assessed. Magnetic resonance angiography (MRA) follow-up investigations were scheduled postoperatively at 3 months to determine graft tissue integration and the presence of PGS. Results: A total of 24 patients with comorbidities such as coronary artery disease (8.3 %, 2/24), chronic occlusive pulmonary disease (COPD, 8.3 %, 2/24), Fontaine III/IV (20.8 %, 5/24), and diabetes (20.8 %, 5/24) were enrolled from June 2011 to September 2012. Due to two early nongraft-related deaths, there were 22 patients that had a follow-up. In these 22 patients, the freedom from PGS was 90.9 % (20/22) suggesting that the graft/tissue integration was comparable to other vascular grafts described in the relevant literature. WBC counts were not significantly different (pre (8.67 ± 2.98 1/nl) vs. follow-up (7.97 ± 2.24 1/nlI, p = 0.203). Likewise, preoperative CRP serum levels (6.47 ± 11.59 mg/l) were not different from those at follow-up (7.87 ± 12.81 mg/l, p = 0.769). There were two patients with a documented coagulation disorder and two premature deaths (cardiac failure, cerebral bleeding). The primary unassisted patency at follow-up was 77.3 % (17/22) in all patients who reached the follow-up (85.0 % or 17/20 if two cases with documented coagulation disorders are excluded). The reasons for occlusions were technical/surgical difficulties (2/5) and documented coagulation disorders (2/5). In one occlusion, the cause was unknown. There were no graft infections. Intraoperative graft handling properties were evaluated less favorable as compared to the routinely used gelatin- or collagen-coated polyester grafts in each investigator's clinical practice. Conclusions: Our results suggest that Uni-Graft® Synthetic is a promising prosthetic vascular graft to reduce PGS. Our findings should be interpreted with caution noting the limitation of the lack of a control group. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Glucagon reduces body weight by modifying food intake, glucose/lipid metabolism and energy expenditure. All these physiological processes are also controlled by fibroblast growth factor 21 (FGF-21), a circulating hepatokine that improves the metabolic profile in obesity and type 2 diabetes. Animal experiments have suggested a possible interaction between glucagon and FGF-21 however, the metabolic consequences of this crosstalk are not understood. Methods: The effects of exogenous glucagon on plasma FGF-21 levels and lipolysis were evaluated in healthy volunteers and humans with type 1 diabetes, as well as in rodents with streptozotocin (STZ)-induced insulinopenic diabetes. In vitro, the role of glucagon on FGF-21 secretion and lipolysis was studied using isolated primary rat hepatocytes and adipocytes. Fgf-21 expression in differentiated rat pre-adipocytes was suppressed by small interfering RNA and released FGF-21 was immunoneutralised by polyclonal antibodies. Results: Glucagon induced lipolysis in healthy human volunteers, patients with type 1 diabetes, mice and rats with STZ-induced insulinopenic diabetes, and in adipocytes isolated from diabetic and non-diabetic animals. In addition, glucagon increased circulating FGF-21 in healthy humans and rodents, as well as in patients with type 1 diabetes, and insulinopenic rodents. Glucagon stimulated FGF-21 secretion from isolated primary hepatocytes and adipocytes derived from animals with insulinopenic diabetes. Furthermore, FGF-21 stimulated lipolysis in primary adipocytes isolated from non-diabetic and diabetic rats. Reduction of Fgf-21 expression (by approximately 66%) or immunoneutralisation of released FGF-21 markedly attenuated glucagon-stimulated lipolysis in adipocytes. Conclusions/interpretation: These results indicate that glucagon increases circulating FGF-21 independently of endogenous insulin levels. FGF-21 participates in glucagon-induced stimulation of lipolysis. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the influence of dietary proteins (casein, soy protein) and skimmed milk on the plasma kinetics of green tea (GT) catechins. Methods: In a randomized cross-over design with one-week intervals, 24 healthy normal-weight women consumed a test drink containing 1.75 g GT extract with or without the addition of different proteins. Treatments were GT (control), GT with skimmed milk (GT + M), GT with caseinate (GT + CS), or GT with soy protein (GT + S). Venous blood samples were taken before and several times during a period of 4.5 h after consumption of the test drink. Plasma concentrations of catechins were analyzed by HPLC with electrochemical detection. Results: Compared to control, consumption of GT with milk, caseinate, or soy protein significantly reduced the bioavailability (mean area under the plasma concentration-time curve) of total catechins (means ± SEM; GT + M, 87 ± 5%; GT + CS, 79 ± 5%; GT + S, 88 ± 4%), epigallocatechin gallate (GT + M, 68 ± 4%; GT + CS, 63 ± 5%; GT + S, 76 ± 5%), and epicatechin gallate (GT + M, 68 ± 5%; GT + CS, 66 ± 6%; GT + S, 77 ± 6%), while the bioavailability of non-galloylated catechins such as epigallocatechin (GT + M, 134 ± 9%; GT + CS, 118 ± 9 %; GT + S, 123 ± 8%) and epicatechin (GT + M, 125 ± 10%; GT + CS, 114 ± 11%; GT + S, 110 ± 8%) significantly increased. No significant differences in bioavailability of GT catechins were observed between the treatments GT + M, GT + CS, or GT + S. Conclusion: Simultaneous ingestion of dietary proteins reduces the bioavailability of galloylated catechins from GT in humans. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to assess the feasibility of using 4-[F]-ADAM as a brain SERT imaging agent in humans. Methods: Enrolled in the study were 19 healthy Taiwanese subjects (11 men, 8 women; age 33 ± 9 years). The PET data were semiquantitatively analyzed and expressed as specific uptake ratios (SUR) and distribution volume ratios (DVR) using the software package PMOD. The SUR and DVR of 4-[F]-ADAM in the raphe nucleus (RN), midbrain (MB), thalamus (TH), striatum (STR) and prefrontal cortex (PFC) were determined using the cerebellum (CB) as the reference region. Results: 4-[F]-ADAM bound to known SERT-rich regions in human brain. The order of the regional brain uptake was MB (RN) > TH > STR > PFC > CB. The DVR ( n = 4, t* = 60 min) in the RN, TH, STR and PFC were 3.00 ± 0.50, 2.25 ± 0.45, 2.05 ± 0.31 and 1.40 ± 0.13, respectively. The optimal time for imaging brain SERT with 4-[F]-ADAM was 120-140 min after injection. At the optimal imaging time, the SURs ( n = 15) in the MB, TH, STR, and PFC were 2.25 ± 0.20, 2.28 ± 0.20, 2.12 ± 0.18 and 1.47 ± 0.14, respectively. There were no significant differences in SERT availability between men and women ( p < 0.05). Conclusion: The results of this study showed that 4-[F]-ADAM was safe for human studies and its distribution in human brain appeared to correlate well with the known distribution of SERT in the human brain. In addition, it had high specific binding and a reasonable optimal time for imaging brain SERT in humans. Thus, 4-[F]-ADAM may be feasible for assessing the status of brain SERT in humans. [ABSTRACT FROM AUTHOR]

Interphotoreceptor retinoid-binding protein (IRBP) plays a major role in the visual cycle and is essential to the maintenance of photoreceptors. The aim of this study was to determine whether a decrease in IRBP production exists in the early stages of diabetic retinopathy. Vitreous samples from diabetic patients with proliferative and non-proliferative diabetic retinopathy (PDR, NPDR), and from non-diabetic patients with macular hole (control group) were selected for IRBP quantitative assessment by proteomic analysis (fluorescence-based difference gel electrophoresis) and western blot. Human post mortem eyes ( n = 16) from diabetic donors without clinically detectable retinopathy and from non-diabetic donors ( n = 16) were used to determine IRBP (also known as RBP3) mRNA levels (RT-PCR) and protein content (western blot and confocal microscopy). Retinal neurodegeneration was assessed by measuring glial fibrillar acidic protein (GFAP) and the apoptotic rate. Y79 human retinoblastoma cells were used to test the effects of glucose, TNF-α and IL-1β on IRBP expression and IRBP levels. Intravitreous IRBP concentration was significantly lower in PDR < NPDR < control in proteomic and western blot analysis. IRBP mRNA levels and IRBP protein content were significantly lower in the retinas from diabetic donors than in those from non-diabetic donors. Increased GFAP and a higher degree of apoptosis were observed in diabetic retinas compared with non-diabetic retinas. A dose-dependent downregulation of IRBP mRNA expression and IRBP content was detected with glucose, TNF-α and IL-1β in cultures of Y79 human retinoblastoma cells. Underproduction of IRBP is an early event in the human diabetic retina and is associated with retinal neurodegeneration. The mechanisms leading to this deficit deserve further investigation. [ABSTRACT FROM AUTHOR]

The possibility of using microbes to maintain health, and to prevent or treat disease is a topic as old as microbiology. The research of novel probiotic strains is important in order to satisfy the increasing request of the market and to obtain functional products in which the probiotic cultures are more active and with better probiotic characteristics than those already present on the market. In this study, the probiotic potential of Lactobacillus strains isolated from Italian elderly human faeces was investigated. The Lactobacillus strains were identified and examined for resistance to gastric acidity and bile toxicity, adhesion to HT-29 cells, antimicrobial activities, antibiotic susceptibility and plasmid profile. Survival of the strains through human intestine was examined in a 3 months human feeding trial. Two strains, Lactobacillus rhamnosus IMC 501 and Lactobacillus paracasei IMC 502, tolerated well low pH and bile acids. In antimicrobial activity assays, both strains showed inhibitory properties towards selected potential harmful microorganisms, particularly against Candida albicans. The two selected strains expressed high in vitro adherence to HT-29 cells increasing this characteristic when they are used in combination and they were resistant to vamcomycin, colistin sulphate, gentamicin, oxolinic acid and kanamycin. Moreover, the two strains could be recovered from stools of volunteers after the feeding trials. Lactobacillus rhamnosus IMC 501 and L. paracasei IMC 502 present favourable strain-specific properties for their utilisation as probiotics in functional foods and the high adhesion ability of the L. rhamnosus IMC 501 and L. paracasei IMC 502 used in combination, confirmed by both in vitro and in vivo study, indicate that the two bacterial strains could be used as health-promoting bacteria. [ABSTRACT FROM AUTHOR]

Previous human studies on the effect of dietary calcium supplementation on faecal excretion of bile acids (BA) and faecal water concentrations of animal neutral sterols (NSt, cholesterol and its metabolites) lack detailed information about single BA and NSt. We investigated whether single BA and NSt in faeces and especially in faecal water are affected by calcium supplementation and whether this affects genotoxicity of faecal water. In addition, we differentiated between men and women with regard to the concentrations of BA and NSt in faecal water. Thirty-one healthy volunteers consumed a calcium supplemented bread (1.0 g/day) and a placebo bread, respectively, for 4 weeks in a double-blind, randomised cross-over trial. Faeces were collected quantitatively for 5 days in the last week of each period. NSt and BA were analysed by GC–MS. Due to calcium supplementation faecal concentrations of lithocholic acid (LCA, 14%, P = 0.008), deoxycholic acid (DCA, 19%, P < 0.001) and 12keto-deoxycholic acid (12keto DCA, 29%, P = 0.049) significantly increased whereas BA concentrations in faecal water were only marginally affected. In contrast, concentrations of cholesterol (30%, P = 0.020) and its metabolites coprostanol (43%, P = 0.004), coprostanone (36%, P = 0.003), cholestanol (44%, P = 0.001) and cholestenone (32%, P = 0.038) in faecal water significantly decreased. Total NSt concentration in faecal water was found to be significantly higher in women compared to men ( P = 0.018). The genotoxicity of faecal water was neither affected by calcium supplementation nor were there gender-specific differences. Dietary calcium supplementation diversely affects BA and NSt in faeces and in faecal water but does not influence the genotoxicity of faecal water in healthy adults. [ABSTRACT FROM AUTHOR]

We assessed tissue O2 saturation (StO2) and total hemoglobin (HbT) changes during a vascular occlusion test (VOT) as markers of O2 consumption and cardiovascular reserve. Using the non-invasive InSpectra® near infrared spectrometer, we studied the effect of VOT to StO2 < 40% then release on thenar eminence StO2 and HbT in 15 normal volunteers (controls) and 10 trauma patients. We repeated the VOT four times in controls and twice in patients, with controls exercising during the last VOT, and correlated StO2 with HbT changes by linear regression analysis. StO2 started to decrease 3–28 s post-occlusion (latency) in controls and then decreased in a linear fashion (−0.18 ± 0.04% O2/s, mean ± SD), while post-occlusion StO2 recovery was rapid (5.20 ± 1.19% O2/s). Exercise decreased latency (0–5 s) and increased desaturation rate (−0.18 and −0.69% O2/s, P < 0.005) without altering recovery. Trauma patients showed similar StO2 desaturation rates, but slower recovery (5.20 ± 1.19 vs. 2.88 ± 1.71%/s, P < 0.0001). Repeated VOT gave similar recovery results within study groups. The hyperemic response was variable in both groups and, if present, was associated with an increased HbT. HbT pre- and post-VOT were significantly different within each subject. Although HbT slope of recovery correlated significantly with StO2 recovery in trauma patients (rho 0.76), it was not in controls. One VOT defines StO2 deoxygenation and recovery. That StO2 and HbT recovery co-vary only in trauma patients suggests that pre-existing vasoconstriction was unmasked by the ischemic challenge consistent with increased sympathetic tone. [ABSTRACT FROM AUTHOR]

β-Cryptoxanthin displays a unique anabolic effect on bone calcification. In women with osteoporosis, serum β-cryptoxanthin and 25-OH-vitamin D3 showed a weak but significant correlation and exhibited a complementary seasonal distribution. The potential role of β-cryptoxanthin as a nutritional approach to improving bone health deserves further evaluation. Dietary intake and serum levels of β-cryptoxanthin have been inversely related to different bone and joint disorders and in vitro and animal studies have shown that β-cryptoxanthin displays a unique anabolic effect on bone calcification. Due to the emerging role of β-cryptoxanthin in bone biology, we aimed to assess the serum distribution and variability of β-cryptoxanthin and their potential relation to 25-OH-vitamin D3 in women with osteoporosis. Serum concentrations of α- and β-cryptoxanthin and 25-OH- D3 in women with osteoporosis ( N = 644) were analyzed using a quality-controlled high-performance liquid chromatography (HPLC) method. Overall, significant seasonal variations were found for the three analytes and inter-individual variation was also high (60–73%). β-cryptoxanthin and 25-OH-vitamin D3 exhibited a marked complementary seasonal distribution in serum, with vitamin D displaying the highest values in summer and β-cryptoxanthin in winter. Given the anabolic effect of β-cryptoxanthin on bone calcification and its complementary seasonal distribution with respect to 25-OH-vitamin D3, the potential role of β-cryptoxanthin as a sustainable nutritional approach to improving bone health deserves to be further evaluated. [ABSTRACT FROM AUTHOR]

Bioavailability is a critical feature in the assessment of the role of micronutrients in human health. Although postprandial behaviour does not predict long-term responses and acute responses, it is accepted that the study of triglyceride-rich lipoprotein fractions reflects newly absorbed lipids from recent meals. To assess the predictive value of a 3-point versus 7-point post-prandial response (area under the curve) in nutrient bioavailability studies in humans. We used results from a human bioavailability study ( n = 19) that consisted of a single-dose pharmacokinetic assay involving three types of commercially available vitamin A and E fortified milk. Correlation coefficients between 3-point AUC (AUCp, predictive) versus 7-point AUC (AUCc, conventional) ranged between r = 0.81 ( P < 0.001) for vitamin A-fortified skim milk and r = 0.95 ( P < 0.001) for whole milk. Bland-Altman representations showed a good agreement between the two methods with 95% of the differences within the concordance limits. More than 90% of the subjects were correctly classified in the same or adjacent quartiles and he calculated relative absorption of vitamin A from the foods was, on average, <5% lower using the AUCp compared to that estimated using AUCc. The use of the 3-point approach may be a reliable alternative to assess the relative postprandial lipid response in human bioavailability studies. Nevertheless, since this approach has been studied considering one nutrient (i.e. preformed vitamin A) and one type of food (i.e. milk), its applicability to other nutrients and foods should be tested. [ABSTRACT FROM AUTHOR]

Amalgam is still one of the most frequently used dental filling materials. However, the possible adverse effects especially that of the mercuric component have led to continued controversy. Considering that mercury may be released from amalgam fillings into the oral cavity and also reach the circulating blood after absorption and resorption, it eventually may contribute to tumorigenesis in a variety of target cells. The present investigation focuses on genotoxic effects below a cytotoxic dose level of mercuric dichloride (HgCl2) in human samples of salivary glands and lymphocytes to elucidate a possible role in tumor initiation. DNA migration due to single strand breaks, alkali labile sites and incomplete excision repair was quantified with the aid of the single cell microgel electrophoresis (Comet) assay. The concepts of Olive Tail Moment, percentage of DNA in the Tail and Tail Length were used as measures of DNA damage. To control for cytotoxic effects, the trypan blue exclusion test was applied. Human samples of the parotid salivary gland and lymphocytes of ten donors were exposed to HgCl2 concentrations from 1 to 50 μM. N-methyl- N′-nitro- N-nitrosoguanidine (MNNG) and dimethyl sulfoxide (DMSO) served as controls. Increasing dose-dependent DNA migration could be demonstrated after exposure to HgCl2 in cells of the salivary glands and lymphocytes. In both cell types a significant increase in DNA migration could be shown starting from HgCl2 concentrations of 5 μM in comparison to the negative control. The viability of the cell systems was not affected except at the highest concentration (50 μM) tested. These data indicate genotoxic effects of mercuric dichloride in human salivary glands and lymphocytes at concentrations not leading to cytotoxic effects or cell death. Consequently, a contributory role in oral salivary gland tumor initiation warrants further investigation. [ABSTRACT FROM AUTHOR]

Background Consumption of fruit and vegetables is associated with a decreased risk of heart disease and cancer. This has been ascribed in part to antioxidants in these foods inactivating reactive oxygen species involved in initiation or progression of these diseases. Non-nutritive anthocyanins are present in significant amounts in the human diet. However, it is unclear whether they have health benefits in humans. Aim To determine whether daily consumption of anthocyanin-rich cranberry juice could alter plasma antioxidant activity and biomarkers of oxidative stress. Methods 20 healthy female volunteers aged 18–40 y were recruited. Subjects consumed 750 ml/day of either cranberry juice or a placebo drink for 2 weeks. Fasted blood and urine samples were obtained over 4 weeks. The total phenol, anthocyanin and catechin content of the supplements and plasma were measured. Anthocyanin glycosides were identified by tandem mass spectrometry (MS-MS). Vitamin C, homocysteine (tHcy) and reduced glutathione (GSH) were measured by HPLC. Total antioxidant ability was determined using electron spin resonance (ESR) spectrometry and by the FRAP assay. Plasma total cholesterol, high density lipoprotein (HDL), and low density lipoprotein (LDL) cholesterol and triglycerides (TG) were measured. Glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) activities were measured in erythrocytes. Urine was collected for analysis of malondialdehyde (MDA) by HPLC and 8-oxo deoxyguanosine (8-oxo-dG) by ELISA. Endogenous and induced DNA damage were measured by single cell gel electrophoresis (SCGE) in lymphocytes. Results Vitamin C, total phenol, anthocyanin and catechin concentrations and FRAP and ESR values were significantly higher in the cranberry juice compared with the placebo. Cyanidin and peonidin glycosides comprised the major anthocyanin metabolites [peonidin galactoside (29.2%) > cyanidin arabinoside (26.1%) > cyanidin galactoside (21.7%) > peonidin arabinoside (17.5%) > peonidin glucoside (4.1%) > cyanidin glucoside (1.4 %)]. Plasma vitamin C increased significantly (P < 0.01) in volunteers consuming cranberry juice. No anthocyanins (plasma) or catechins (plasma or urine) were detectable and plasma total phenols, tHcy, TC, TG, HDL and LDL were unchanged. The antioxidant potential of the plasma, GSH-Px, CAT and SOD activities, and MDA were similar for both groups. Supplementation with cranberry juice did not affect 8-oxo-deoxyguanosine in urine or endogenous or H2O2-induced DNA damage in lymphocytes. Conclusions Cranberry juice consumption did not alter blood or cellular antioxidant status or several biomarkers of lipid status pertinent to heart disease. Similarly, cranberry juice had no effect on basal or induced oxidative DNA damage. These results show the importance of distinguishing between the in vitro and in vivo antioxidant activities of dietary anthocyanins in relation to human health. [ABSTRACT FROM AUTHOR]

The individual differences in alcohol pharmacokinetics were studied using the one-compartment model with first-order absorption and zero-order elimination kinetics in humans. The blood alcohol concentrations (BACs) were simulated by obtained parameters, absorption rate constant (ka), and climination rate constant (β). The 81 healthy young Japanese volunteers, who had been divided into those without alcohol-induced facial flushing (nonflushers) and those with facial flushing (flushers) according to alcohol patch test results and a questionnaire beforehand, ingested 0.50 g/kg ethanol within 1 minute. Breath alcohol concentrations (BrACs) were measured during absorption and during the elimination period. BACs were obtained based on BrACs. Fifteen percent of subjects exhibited low BAC profile (below 0.4 mg/mL) (first-pass effect [FPE] group), although the majority showed normal BAC profile (normal group). The ka was approximately 5 to 8 (h−1) in the normal group without significant difference between nonflushers and flushers, whereas that in the FPE group was significantly smaller than in the normal group. For the normal group, peak BACs were well simulated by the one-compartment model with first-order absorption and zero-order elimination kinetics. A considerable portion of subjects exhibited FPE. Absorption of alcohol from the intestine plays an important role in alcohol pharmacokinetics in humans. [ABSTRACT FROM AUTHOR]

A sensitive and precise dexamethasone radioimmunoassay method was applied to the determination of dexamethasone levels in the plasma and urine of human subjects who had received small doses of the drug by mouth. While the method can be applied directly to plasma, urine has to be diluted before assay. Very little cross-reaction was observed with two possible metabolites of dexamethasone. Both in the healthy subjects and in the group of patients investigated rapid absorption of dexamethasone from the gastrointestinal tract was observed. However, there appeared to be a large individual variation in the plasma concentration of the drug obtained after doses of the same size. [ABSTRACT FROM AUTHOR]

The effects of intravenous human atrial natriuretic factor ANF(99-126) administration on anterior pituitary hormone secretion have not been extensively investigated in humans. We repeatedly studied 10 healthy volunteers (5 female, 5 male, aged 28±2 years) on 2 occasions, 3 days apart. In randomized, single blind order, subjects received pretreatment with either placebo or intravenous ANF(99-126) (bolus 100 μg/kg, 30-min infusion of 0.1 μg/kg-min). Subsequently, on both occasions subjects received a combined intravenous bolus injection of pituitary releasing hormones (200 pg thyrotropin releasing hormone, 100 μg gonadotropin releasing hormone, 50 μg growth hormone releasing hormone and 100 μg human adrenocorticotropin releasing hormone; Bissendorf, Hannover, FRG). Plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), thyrotropin (TSH), prolactin, ANF and cyclic guanosine monophosphate (GMP) were determined by radioimmunoassay. ANF(99-126) treatment induced a significant reduction in basal ACTH plasma concentrations and tended to decrease basal plasma cortisol. The TSH response to combined releasing hormone administration was significantly diminished after ANF(99-126) pretreatment. In women, the releasing hormone induced prolactin increase was reduced after ANF(99-126) pretreatment. With the present study design, ANF(99-126) did not alter the basal or releasing hormone stimulated plasma concentrations of cortisol, LH, FSH and GH. Releasing hormone administration did not affect ANF and cyclic GMP plasma levels. In humans, effects of natriuretic peptides on anterior pituitary hormone secretion may have to be considered with investigational or therapeutic administration of ANF analogues or agents interfering with the ANF metabolism. [ABSTRACT FROM AUTHOR]

Proliferation indices are used, along with other parameters, to estimate the risk of recurrence of breast cancer for individual patients. Because it is unlikely one index will be practical for all patients, it is important to understand the relationship between various indices of proliferation. For this reason, we compared a proliferation index based on in vivo labeling of S-phase tumor cells with the thymidine analog bromodeoxyuridine (BrdUrd), to a proliferation index based on an estimate of the growth fraction with the MIB-1 antibody to the Ki-67 antigen. With informed consent, we gave 145 patients 200 mg/m2 BrdUrd intravenously just prior to surgical removal of breast cancer. On histology sections, we visually counted S-phase cells which had incorporated BrdUrd using the Br-3 antibody which is specific to DNA-incorporated BrdUrd, and we counted cells in the growth fraction using the MIB-1 antibody to the Ki-67 antigen. We found that both indices were positively correlated with tumor size, number of positive nodes, and tumor grade, and both were negatively correlated with age and estrogen-progesterone receptor positivity. Using a linear functional relationship model, we found that the best (i.e. the maximal) fit between the two indices (correlation coefficient 0.79; p < 0.0001) occurred when each index was square root transformed, as is appropriate when counts follow a Poisson distribution. When we used the median as a cutpoint for each index, the classification of 19 percent of data pairs changed depending upon which index was used. We also estimated that the Ki-67 intercept (1.02 ± 0.25) was significantly greater than zero. We conclude that the BrdUrd index of DNA synthesis in S-phase correlates highly with the MIB-1 index of the growth fraction, and both indices correlate well with other parameters of tumor aggressiveness. Because this correlation is driven by concordance of the extremes of high and low counts, clinical comparison will be necessary to determine which is the better prognostic marker for human breast cancer. [ABSTRACT FROM AUTHOR]

Polyethylene sponge (Plastipore TM) prostheses were clinically implanted in the middle ear for periods varying from 2 weeks to 6 years. Revision surgery allowed removal of 98 of these prostheses for histological examinations. Local foreign body reactions and/or microscopic breakdown of the polyethylene were found to varying degrees in 95 of the 98 prostheses. The remaining 3 prostheses showed only fibrous tissue ingrowth without other changes. We compared the histopathology present with the length of time of implantation, and found that the changes noted were more frequent and marked in those prostheses implanted for long periods of time. [ABSTRACT FROM AUTHOR]

Diltiazem, a benzothiazepine calcium channel antagonist, was given to six healthy men as a single 60 mg oral dose 120 min before IV injection of cocaine (0.2 mg/kg) in a double-blind, placebo-controlled, two-session study. Diltiazem alone produced no significant effects. Cocaine increased blood pressure, heart rate, pupil size and subjective 'high' ratings, and decreased skin temperature. Diltiazem pretreatment diminished the cocaine effect on skin temperature, but did not otherwise alter the response to cocaine. Calcium channel antagonists diminish the effects of cocaine in vitro and in animals. Dosage considerations may be critical because of the differential sensitivity of various tissues to calcium channel antagonists. [ABSTRACT FROM AUTHOR]