bluuebunny/crossref_metadata_2025 huggingface dataset:
Development assistance for global tobacco control
Authors: Ross Hana , Stoklosa Michal
Published: June 2011

Background

By 2030, the tobacco epidemic will be responsible for over eight million deaths worldwide per year, with 80% of those deaths occurring in low-resource countries. Despite the magnitude of the problem, little is known about the funding for global tobacco control.

Methods

To estimate the amount of tobacco control funding, we created an integrated database based on information provided by tobacco control donors. We focus on resources available to low-income and middle-income countries provided as Development Assistance to Control Tobacco (DACT).

Results

Global DACT grew from US$1.2 million in 2000 to US$44.2 million in 2009, primarily due to contributions from private philanthropies. Average annual 2000–2009 funding amounted to about US$0.003 per adult (US$0.0003 per adult in 2000 and US$0.011 per adult in 2009). DACT has been supplemented by domestic public funding that reached US$0.009 per adult in 2008. 28% of emerging and developing countries received zero DACT and 15% of those countries reported no funding at all. Out of US$21.8 billion disbursed in 2007 for health-related development assistance, DACT represented only US$0.02 billion, or 0.09%.

Conclusions

Since the funding for both infectious and non-communicable diseases in low-resourced countries is inadequate, the solution for global tobacco control is not to shift resources from other public health priorities, but rather to generate additional tobacco control funding. Several mechanisms to achieve this goal are proposed.
Clinical audit – learning from the medical profession
Authors: Viner B. P. , Jenner C. S.
Published: June 2011

Clinical audit – a process of improving patient care by reviewing performance against a set of criteria and bringing in changes where they are indicated – has become increasingly important in human medical practice over the past two decades. Bradley Viner and Chris Jenner argue that its application in veterinary practice could have many advantages, and that vets can benefit from doctors’ experience
A VENDOR MANAGED TWO-ECHELON INVENTORY SYSTEM FOR AN INTEGRATED PRODUCTION PROCUREMENT CASE
Authors: SINGH ABHIJEET , KOUL SAROJ , AGRAWAL ANIL K.
Published: June 2011

Joint economic lot size models for purchasers and vendors are more economical than when considering their inventory problems independently. It requires vendors to have a complete knowledge of their purchaser's demands. In such a situation, the vendor shall manage the supply with comparatively more inventory at its end. The operational cost can further decrease provided supply is in sub-batches and logistics cost does not increase substantially. However, determining the right size for these sub-batches becomes an issue. Sub-batches of varying size may cause planning and control problems, but supply in sub-batches of uniform size will not.

In this paper, joint economic lot size models are presented for the two supply situations, namely staggered supply and uniform supply. Cases are employed that describe the inventory situation of a single vendor supplying an item to a manufacturer that is further processed before it is supplied to the end-user. Using illustrative examples, the comparative advantages of the uniform sub-batch supply over the staggered alternative are investigated. From the analysis, uniform supply models are found to be comparatively more beneficial and robust than the staggered sub-batch supply.
Porphyrin containing isoindoline nitroxides as potential fluorescence sensors of free radicals
Authors: Yan Guo-Ping , Fairfull-Smith Kathryn E. , Smith Craig D. , Hanson Graeme R. , Bottle Steven E.
Published: June 2011

A series of new spin-labeled porphyrin containing isoindoline nitroxide moieties were synthesized and characterized as potential free radical fluorescence sensors. Fluorescence-suppression was observed in the free-base monoradical porphyrins, whilst the free-base biradical porphyrins exhibited highly suppressed fluorescence about three times greater than the monoradical porphyrins. The observed fluorescence-suppression was attributed to enhanced intersystem crossing resulting from electronexchange between the doublet nitroxide and the excited porphyrin fluorophore. Notably, fluorescencesuppression was not as strong in the related metalated porphyrins, possibly due to insufficient spin coupling between the nitroxide and the porphyrin. Continuous wave EPR spectroscopy of the diradical porphyrins in fluid solution suggests that the nitroxyl-nitroxyl interspin distance is long enough and tumbling is fast enough not to detect dipolar coupling.
Myosin Va plays a key role in nitrergic neurotransmission by transporting nNOSα to enteric varicosity membrane
Authors: Chaudhury Arun , He Xue-Dao , Goyal Raj K.
Published: June 2011

Nitrergic neurotransmission at the smooth muscle neuromuscular junctions requires nitric oxide (NO) release that is dependent on the transport and docking of neuronal NO synthase (nNOS) α to the membrane of nerve terminals. However, the mechanism of translocation of nNOSα in actin-rich varicosities is unknown. We report here that the processive motor protein myosin Va is necessary for nitrergic neurotransmission. In wild-type mice, nNOSα-stained enteric varicosities colocalized with myosin Va and its tail constituent light chain 8 (LC8). In situ proximity ligation assay showed close association among nNOSα, myosin Va, and LC8. nNOSα was associated with varicosity membrane. Varicosities showed nitric oxide production upon stimulation with KCl. Intracellular microelectrode studies showed nitrergic IJP and smooth muscle hyperpolarizing responses to NO donor diethylenetriamine-NO (DNO). In contrast, enteric varicosities from myosin Va-deficient DBA (for dilute, brown, non-agouti) mice showed near absence of myosin Va but normal nNOSα and LC8. Membrane-bound nNOSα was not detectable, and the varicosities showed reduced NO production. Intracellular recordings in DBA mice showed reduced nitrergic IJPs but normal hyperpolarizing response to DNO. The nitrergic slow IJP was 9.1 ± 0.7 mV in the wild-type controls and 3.4 ± 0.3 mV in the DBA mice ( P < 0.0001). Deficiency of myosin Va resulted in loss of nitrergic neuromuscular neurotransmission despite normal presence of nNOSα in the varicosities. These studies reveal the critical importance of myosin Va in nitrergic neurotransmission by facilitating transport of nNOSα to the varicosity membrane.
Local heating, but not indirect whole body heating, increases human skeletal muscle blood flow
Authors: Heinonen Ilkka , Brothers R. Matthew , Kemppainen Jukka , Knuuti Juhani , Kalliokoski Kari K. , Crandall Craig G.
Published: June 2011

For decades it was believed that direct and indirect heating (the latter of which elevates blood and core temperatures without directly heating the area being evaluated) increases skin but not skeletal muscle blood flow. Recent results, however, suggest that passive heating of the leg may increase muscle blood flow. Using the technique of positron-emission tomography, the present study tested the hypothesis that both direct and indirect heating increases muscle blood flow. Calf muscle and skin blood flows were evaluated from eight subjects during normothermic baseline, during local heating of the right calf [only the right calf was exposed to the heating source (water-perfused suit)], and during indirect whole body heat stress in which the left calf was not exposed to the heating source. Local heating increased intramuscular temperature of the right calf from 33.4 ± 1.0°C to 37.4 ± 0.8°C, without changing intestinal temperature. This stimulus increased muscle blood flow from 1.4 ± 0.5 to 2.3 ± 1.2 ml·100 g−1·min−1 ( P < 0.05), whereas skin blood flow under the heating source increased from 0.7 ± 0.3 to 5.5 ± 1.5 ml·100 g−1·min−1 ( P < 0.01). While whole body heat stress increased intestinal temperature by ∼1°C, muscle blood flow in the calf that was not directly exposed to the water-perfused suit (i.e., indirect heating) did not increase during the whole body heat stress (normothermia: 1.6 ± 0.5 ml·100 g−1·min−1; heat stress: 1.7 ± 0.3 ml·100 g−1·min−1; P = 0.87). Whole body heating, however, reflexively increased calf skin blood flow (to 4.0 ± 1.5 ml·100 g−1·min−1) in the area not exposed to the water-perfused suit. These data show that local, but not indirect, heating increases calf skeletal muscle blood flow in humans. These results have important implications toward the reconsideration of previously accepted blood flow distribution during whole body heat stress.
Pharmacokinetics ofp-Aminohippuric Acid and Inulin in Rabbits with Aristolochic Acid Nephropathy
Authors: Tseng Chiao-Shih , Chen Shih-Ming , Chien Shu-Chen , Hsu Kuang-Yang
Published: June 2011

The characteristics of aristolochic acid nephropathy (AAN) are interstitial fibrosis and atrophy of the proximal tubules, but with no change in glomeruli. To investigate the effects of AA on renal functions and the pharmacokinetics (PKs) ofp-aminohippuric acid (PAH) and inulin, New Zealand white rabbits were used in this study. The plasma concentrations of PAH and inulin were determined by validated HPLC methods. After a single intravenous administration of 0.5 mg/kg aristolochic acid sodium (AANa), rabbits exhibited mild to moderate nephrotoxicity on the 7th day. Significant tubulointerstitial damage to kidney specimens was found, but there were no remarkable glomerular changes. Clearance rates of PAH and inulin both significantly decreased in AANa-treated rabbits. In addition, there was a significant correlation among the degree of tubulointerstitial changes and PK parameters of PAH after AANa administration, but no correlation was noted with the PKs of inulin. With mild to moderate AAN in rabbits, the renal plasma flow significantly decreased by 55%, and the glomerular filtration rate also significantly decreased by 85%. In conclusion, major renal lesions were found on proximal tubules after AANa administration. The PKs of PAH and inulin significantly changed, and kidney functions, including the RPF and GFR, were reduced.
Single-port Laparoscopic Reversal of Hartmann's Procedure: Technique and Results
Authors: Carus Th. , Emmert A.
Published: June 2011

In general, reversal of Hartmann's procedure is associated with a high morbidity and therefore leads to a low rate of intestinal restoration. Reversal of Hartmann's procedure has to be seen as a complex abdominal operation with the same possible complications as in other colorectal resections. By using the laparoscopic technique, operative access trauma by laparotomy can be minimized. After introducing single-port access into laparoscopic surgery beginning with cholecystectomies and sigmoid resections, we started with the first single-port laparoscopic reversal of Hartmann's procedure in January 2010. After excision of the colostoma, mobilization, and reponing into the abdominal cavity, the single-port trocar was placed at the stoma incision without any extra scar. We investigated whether the single-port laparoscopic reversal is as safely feasible as the “conventional” laparoscopic procedure. Till December 2010, single-port reversal operation was performed in 8 patients 2–4 months after Hartmann's procedure because of complicated diverticulitis. No conversion to “conventional” laparoscopic or open procedure was necessary in 1 patient one extra 5 mm trocar was used. The average operation time was 74 min. Except for one wound complication, the postoperative course was uncomplicated. The patients were discharged after 4 to 8 postoperative days. Single-port reversal of Hartmann's procedure has showed as a new method for minimizing the access trauma even further than “conventional” laparoscopic surgery.
Extrinsic Factors Involved in the Differentiation of Stem Cells into Insulin-Producing Cells: An Overview
Authors: Wong Rebecca S. Y.
Published: June 2011

Diabetes mellitus is a chronic disease with many debilitating complications. Treatment of diabetes mellitus mainly revolves around conventional oral hypoglycaemic agents and insulin replacement therapy. Recently, scientists have turned their attention to the generation of insulin-producing cells (IPCs) from stem cells of various sources. To date, many types of stem cells of human and animal origins have been successfully turned into IPCsin vitroand have been shown to exert glucose-lowering effectin vivo. However, scientists are still faced with the challenge of producing a sufficient number of IPCs that can in turn produce sufficient insulin for clinical use. A careful choice of stem cells, methods, and extrinsic factors for induction may all be contributing factors to successful production of functional beta-islet like IPCs. It is also important that the mechanism of differentiation and mechanism by which IPCs correct hyperglycaemia are carefully studied before they are used in human subjects.
The LLNA: A Brief Review of Recent Advances and Limitations
Authors: Anderson Stacey E. , Siegel Paul D. , Meade B. J.
Published: June 2011

Allergic contact dermatitis is the second most commonly reported occupational illness, accounting for 10% to 15% of all occupational diseases. This highlights the importance of developing rapid and sensitive methods for hazard identification of chemical sensitizers. The murine local lymph node assay (LLNA) was developed and validated for the identification of low molecular weight sensitizing chemicals. It provides several benefits over other tests for sensitization because it provides a quantitative endpoint, dose-responsive data, and allows for prediction of potency. However, there are also several concerns with this assay including: levels of false positive responses, variability due to vehicle, and predictivity. This report serves as a concise review which briefly summarizes the progress, advances and limitations of the assay over the last decade.
Primary Omental Torsion in an Old Woman: Imaging Techniques Can Prevent Unnecessary Surgical Interventions
Authors: Modaghegh Mohhamad-Hadi Saeed , Jafarzadeh Reza
Published: June 2011

Torsion and/or infarction of the greater omentum are rare but well-recognized clinical situations which present as an acute abdomen. The etiology is unknown and speculative. In most cases, the pathology is right sided and clinical presentation consists of an acute or subacute flank pain with mild peritonism usually evoking appendicitis or cholecystitis. Nevertheless, knowledge concerning these two problems can help the surgeon in proper diagnosis and treatment. Since the first report on primary torsion by Eitel in 1899, a few hundred more have been reported and some collective reviews published to date. Recently, ultra sonography and computed tomography have proved to provide sufficiently typical, consistent, and well-recognizable features to avoid unnecessary surgery. In this study, we will present a case diagnosed as primary omental torsion based on computed tomography, which underwent successful conservative management.
Age-Related Changes in the Hepatic Pharmacology and Toxicology of Paracetamol
Authors: Mitchell Sarah J. , Kane Alice E. , Hilmer Sarah N.
Published: June 2011

Optimal pharmacotherapy is determined when the pharmacokinetics and pharmacodynamics of the drug are understood. However, the age-related changes in pharmacokinetics and pharmacodynamics, as well as the increased interindividual variation mean optimal dose selection are a challenge for prescribing in older adults. Poor understanding of how hepatic clearance and toxicity are different with age results in suboptimal dose selection, poor efficacy, and/or increased toxicity. Of particular concern is the analgesic paracetamol which has been in use for more than 50 years and is consumed by a large proportion of older adults. Paracetamol is considered to be a relatively safe drug; however, caution must be taken because of its potential for toxicity. Paracetamol-induced liver injury from accidental overdose accounts for up to 55% of cases in older adults. Better understanding of how age affects the hepatic clearance and toxicity of drugs will contribute to evidence-based prescribing for older people, leading to fewer adverse drug reactions without loss of benefit.
Inner Functions in Lipschitz, Besov, and Sobolev Spaces
Authors: Girela Daniel , González Cristóbal , Jevtić Miroljub
Published: June 2011

We study the membership of inner functions in Besov, Lipschitz, and Hardy‐Sobolev spaces, finding conditions that enable an inner function to be in one of these spaces. Several results in this direction are given that complement or extend previous works on the subject from different authors. In particular, we prove that the only inner functions in either any of the Hardy‐Sobolev spaces with 1/p ≤ α < ∞ or any of the Besov spaces
with
0 < p, q ≤ ∞ and
α ≥ 1/p, except when
p = ∞,
α = 0, and 2 < q ≤ ∞ or when
0 < p < ∞,
q = ∞, and α = 1/p are finite Blaschke products. Our assertion for the spaces
,
0 < q ≤ 2, follows from the fact that they are included in the space
VMOA. We prove also that for 2 < q < ∞, VMOA is not contained in and that this space contains infinite Blaschke products. Furthermore, we obtain distinct results for other values of α relating the membership of an inner function
I in the spaces under consideration with the distribution of the sequences of preimages
{I−1(a)},
|a | < 1. In addition, we include a section devoted to Blaschke products with zeros in a Stolz angle.
Effects of a Visual Distracter Task on the Gait of Elderly versus Young Persons
Authors: Bock Otmar , Beurskens Rainer
Published: June 2011

Seniors show deficits of dual-task walking when the second task has high visual-processing requirements. Here, we evaluate whether similar deficits emerge when the second task is discrete rather than continuous, as is often the case in everyday life. Subjects walked in a hallway, while foot proprioception was either perturbed by vibration or unperturbed. At unpredictable intervals, they were prompted to turn their head and perform a mental-rotation task. We found that locomotion of young subjects was not affected by this distracter task with or without vibration. In contrast, seniors moved their legs after the distraction at a slower pace through smaller angles and with a higher spatiotemporal variability; the magnitude of these changes was vibration independent. We conclude that the visual distracter task degraded the gait of elderly subjects but completely spared young ones, that this effect is not due to degraded proprioception, and that it rather might reflect the known decline of executive functions in the elderly.
A Generalization of Suzuki′s Lemma
Authors: Panyanak B. , Cuntavepanit A.
Published: June 2011

Let {zn}, {wn}, and {vn} be bounded sequences in a metric space of hyperbolic type
(X, d), and let {αn} be a sequence in [0, 1] with 0 < lim  inf n αn ≤ lim  sup n αn < 1. If zn+1 = αnwn ⊕ (1 − αn)vn for all n ∈ ℕ, lim n d(zn, vn) = 0, and lim  sup n (d(wn+1, wn) − d(zn+1, zn)) ≤ 0, then lim n d(wn, zn) = 0. This is a generalization of Lemma 2.2 in (T. Suzuki, 2005). As
a consequence, we obtain strong convergence theorems for the modified Halpern iterations
of nonexpansive mappings in CAT(0) spaces.
Design of Robust Current Controller for Two-Level 12-Pulse VSC-based STATCOM
Authors: Janaki M. , Thirumalaivasan R. , Prabhu Nagesh
Published: June 2011

The static synchronous compensator (STATCOM) is a shunt connected voltage source converter (VSC) based FACTS controller using GTOs employed for reactive power control. A typical application of a STATCOM is for voltage regulation at the midpoint of a long transmission line for the enhancement of power transfer capability and/or reactive power control at the load centre. The PI controller-based reactive current controller can cause oscillatory instability in inductive mode of operation of STATCOM and can be overcome by the nonlinear feedback controller. The transient response of the STATCOM depends on the controller parameters selected. This paper presents a systematic method for controller parameter optimization based on genetic algorithm (GA). The performance of the designed controller is evaluated by transient simulation. It is observed that the STATCOM with optimized controller parameters shows excellent transient response for the step change in the reactive current reference. While the eigenvalue analysis and controller design are based on D-Q model, the transient simulation is based on both D-Q and 3-phase models of STATCOM (which considers switching action of VSC).
Gamma Kernel Estimators for Density and Hazard Rate of Right‐Censored Data
Authors: Bouezmarni T. , El Ghouch A. , Mesfioui M.
Published: June 2011

The nonparametric estimation for the density and hazard rate functions for right‐censored data using the kernel smoothing techniques is considered. The “classical” fixed symmetric kernel type estimator of these functions performs well in the interior region, but it suffers from the problem of bias in the boundary region. Here, we propose new estimators based on the gamma kernels for the density and the hazard rate functions. The estimators are free of bias and achieve the optimal rate of convergence in terms of integrated mean squared error. The mean integrated squared error, the asymptotic normality, and the law of iterated logarithm are studied. A comparison of gamma estimators with the local linear estimator for the density function and with hazard rate estimator proposed by Müller and Wang (1994), which are free from boundary bias, is investigated by simulations.
Recent Advances in p53 Research and Cancer Treatment
Authors: Suzuki Kazufumi , Matsubara Hisahiro
Published: June 2011

TP53, encoding p53, is one of the most famous tumor suppressor genes. The majority of human cancers demonstrate the inactivation of the p53 pathway. Mutant p53 not only, no longer, functions as a tumor suppressor but can also exert tumor‐promoting effects. The basic function of p53 is to respond to cellular stress. We herein review the recent advances in p53 research and focus on apoptosis, cell cycle arrest, and senescence in response to stress. We also review the clinical applications of p53‐based therapy for human cancer.
Distribution and Diversity of the Cryptic Ant GenusOxyepoecus(Hymenoptera: Formicidae: Myrmicinae) in Paraguay with Descriptions of Two New Species
Authors: Delsinne T. , Mackay W. , Wild A. , Roisin Y. , Leponce M.
Published: June 2011

We discuss the diversity and distribution of the ant genusOxyepoecusin Paraguay.Oxyepoecus inquilinusis recorded for the first time, and new distribution data are given forO. rastratusandO. vezenyii. Published data forO. bruchi,O. rastratus,O. reticulatus,andO. vezenyiiare summarized. Two new species are described (O. bidentatusn. sp. andO. striatusn. sp.), and a key to the workers of the seven ParaguayanOxyepoecusspecies is provided. At Teniente Enciso National Park, four species cooccur. This locality appears as a promising site for studies documenting the biology of this poorly known ant genus, and because of the IUCN “vulnerable“ Red List classification ofO. inquilinus, the importance of the Teniente Enciso National Park for biological conservation is clearly established.
Immunotherapy for Prostate Cancer: Recent Advances, Lessons Learned, and Areas for Further Research
Authors: Gulley James L. , Drake Charles G.
Published: June 2011

A surge of interest in therapeutic cancer vaccines has arisen in the wake of recent clinical trials suggesting that such vaccines can result in statistically significant and clinically meaningful improvements in overall survival—with substantially limited side effects compared with chemotherapy—in patients with metastatic castration-resistant prostate cancer. One of these trials led to the registration of sipuleucel-T, the first therapeutic vaccine to be approved for cancer patients. In this review we highlight emerging patterns from clinical trials that suggest a need for more-appropriate patient populations (i.e., with lower tumor volume and less-aggressive disease) and endpoints (i.e., overall survival) for studies of immunotherapy alone, as well as biologically plausible explanations for these findings. We also explore the rationale for ongoing and planned studies combining therapeutic vaccines with other modalities. Finally, we attempt to put these findings into a practical clinical context and suggest fertile areas for future study. Although our discussion focuses on prostate cancer, the concepts we address most likely have broad applicability to immunotherapy for other cancers as well. Clin Cancer Res; 17(12); 3884–91. ©2011 AACR.
Targeting Continued Androgen Receptor Signaling in Prostate Cancer
Authors: Massard Christophe , Fizazi Karim
Published: June 2011

Prostate cancer is the most common cancer and the second leading cause of death from cancer in males in most Western countries. Prostate cancer has an exquisite sensitivity to androgen deprivation therapy and is the most endocrine-sensitive solid neoplasm, although advanced disease eventually progresses to castration-resistant prostate cancer (CRPC). Recent evidence has shown that cancer progression at the CRPC stage is often mediated by androgen receptor signaling, so that subsequent androgen receptor targeting may further contribute to disease control and, eventually, survival improvement. Abiraterone acetate, an androgen biosynthesis inhibitor, was tested in patients with CRPC pretreated with docetaxel in a phase III trial with demonstration of an overall survival benefit, confirming that CRPC remains hormone driven, even in advanced stages of the disease. Several novel agents also targeting androgen receptor signaling are currently being evaluated, including MDV3100 and orteronel (TAK-700). With the availability of newer endocrine treatments and also nonendocrine treatments (e.g., chemotherapy, immunotherapy, and bone-targeting agents), data supporting a more rational use of therapeutic agents are urgently required in patients with CRPC. It is likely that molecular characterization of prostate cancer will lead to the identification of different subsets of prostate cancer disease with a different natural history, sensitivity, and resistance to treatment; efforts to develop, validate, and implement predictive biomarkers in clinical trials and eventually in routine care should now be strongly supported. Clin Cancer Res; 17(12); 3876–83. ©2011 AACR.
Statin Use and Colorectal Cancer Risk According to Molecular Subtypes in Two Large Prospective Cohort Studies
Authors: Lee Jung Eun , Baba Yoshifumi , Ng Kimmie , Giovannucci Edward , Fuchs Charles S. , Ogino Shuji , Chan Andrew T.
Published: June 2011

Use of statins is hypothesized to reduce colorectal cancer risk but the evidence remains inconsistent. This may be partly explained by differential associations according to tumor location or molecular subtypes of colorectal cancer. We examined the association between statin use and colorectal cancer risk according to tumor location, KRAS mutation status, microsatellite instability (MSI) status, PTGS2 (COX-2) expression, or CpG island methylator phenotype (CIMP) status in two large prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study. We applied Cox regression to a competing risks analysis. We identified 1,818 colorectal cancers during 1990 to 2006. Compared with nonusers, current statin use was not associated with colorectal cancer [relative risk (RR) = 0.99, 95% CI = 0.86–1.14] or colon cancer (RR = 1.10, 95% CI = 0.94–1.29) but was inversely associated with rectal cancer (RR = 0.59, 95% CI = 0.41–0.84, Pheterogeneity < 0.001). When we examined the association within strata of KRAS mutation status, we found no association with KRAS-mutated cancers (RR = 1.20, 95% CI = 0.87–1.67) but did observe a possible inverse association among KRAS wild-type cancers (RR = 0.80, 95% CI = 0.60–1.06, Pheterogeneity = 0.06). The association did not substantially differ by PTGS2 expression, MSI status, or CIMP status. Current statin use was not associated with risk of overall colorectal cancer. The possibility that statin use may be associated with lower risk of rectal cancer or KRAS wild-type colorectal cancer requires further confirmation. Cancer Prev Res; 4(11); 1808–15. ©2011 AACR.
Relationship of lipoprotein cholesterol concentrations to experimental atherosclerosis in baboons.
Authors: McGill H C , McMahan C A , Kruski A W , Mott G E
Published: June 2011

For 26 months, we fed baboons a high saturated fat, high cholesterol diet that contained very low concentrations of four common pesticides (chlordane, parathion, diazinon, and carbofuran). We detected no effect of pesticides on body weight, serum lipid, or lipoprotein cholesterol concentrations, or experimental atherosclerosis. We then examined the associations of serum lipid and lipoprotein cholesterol concentrations (predictor variables) with arterial lesions (response variables). Among predictor variables, very low density lipoprotein plus low density lipoprotein cholesterol concentration showed a positive association with fatty streaks in the aorta and its major branches, including the coronary arteries, while high density lipoprotein cholesterol concentration showed a consistently negative association. The very low density lipoprotein plus low density lipoprotein/high density lipoprotein cholesterol ratio was more highly associated with lesions than was either value alone. These results are consistent with epidemiologic evidence suggesting that high density lipoprotein cholesterol concentration is inversely related to probability of developing clinically manifest atherosclerotic disease.
Transfer of plasma lipoprotein components and of plasma proteins into aortas of cholesterol-fed rabbits. Molecular size as a determinant of plasma lipoprotein influx.
Authors: Stender S , Zilversmit D B
Published: June 2011

The arterial influx of esterified and free cholesterol from low density lipoproteins and very low density lipoproteins in 20 hypercholesterolemic rabbits was measured simultaneously by the use of lipoproteins labeled in vivo with [3H]- and [14C]-cholesterol. The simultaneous arterial influx of either [3H]-leucine-labeled very low density lipoproteins, low density lipoproteins, high density lipoproteins, or plasma proteins was also measured in each rabbit. The arterial influx was calculated as intimal clearance, i.e., the influx of a given fraction divided by its plasma concentration. The intimal clearance of low density lipoprotein esterified cholesterol was equal to that for the apolipoproteins of that fraction, which is compatible with an arterial influx of intact low density lipoprotein molecules. The intimal clearance of very low density apolipoprotein or cholesteryl ester was less than that for low density lipoprotein, whereas high density lipoprotein and albumin clearances exceeded low density lipoprotein clearance by 1.5- to 3-fold. The intimal clearances of plasma proteins, high density, low density, and very low density lipoproteins decreased linearly with the logarithm of the macromolecular diameter. This indicates that the arterial influx of three plasma lipoprotein fractions and of plasma proteins proceeds by similar mechanisms. Apparently the relative intimal clearances of lipoproteins are more dependent on their size relative to pores or vesicular diameters at the plasma-artery interface than on specific interactions between lipoproteins and the arterial intimal surface.
Proaggregatory effect of fasting on platelet aggregation in the microcirculation of mice with streptozotocin diabetes.
Authors: Rosenblum W I , El-Sabban F , Loria R M
Published: June 2011

This study investigates whether experimental diabetes alters the ease with which platelet aggregation can be initiated in pial and mesenteric microvessels of the mouse. Aggregation was elicited by exposing microvessels to radiant energy from a mercury lamp in the presence of sodium fluorescein. The time required for this noxious stimulus to initiate aggregation was similar in fed or fasted alloxan diabetics and their controls, and in fed streptozotocin diabetics and their controls, but was significantly shortened in streptozotocin mice fasted for 18 to 24 hours when these animals were compared with either fed or fasted controls. Aggregation was also elicited by puncture of microvessels or by micropunture plus locally applied adenosine 5'-diphosphate. No differences in aggregability were found between either fed or fasted diabetics and their respective controls. In the light plus dye model of injury, the capacity to enhance aggregation at will by fasting streptozotocin diabetics may provide a means by which some of the factors controlling aggregation in this model of diabetes can be identified, enhanced aggregation in other species or in other types of diabetes.
Flow studies in a model carotid bifurcation.
Authors: LoGerfo F W , Nowak M D , Quist W C , Crawshaw H M , Bharadvaj B K
Published: June 2011

Boundary layer separation in a plexiglass model carotid bifurcation was investigated in relation to the origin of atherosclerotic plaque clinically found in this region. Our model was comparable to a human carotid in both dimensions and geometry. Water flowed through the model at Reynolds numbers from 200 to 1200 under steady and pulsatile flow conditions, with outflow through the external and internal branches varied. The near-wall flow was visualized by slow injection of dye through ports machined in the model. Under steady flow at a physiological Reynolds number of 500 and a flow split at the bifurcation similar to that of a human carotid at rest, boundary layer separation was found to occur in a carotid sinus across from the external carotid origin, forming a shell of slowly moving fluid around the bifurcation. The rapidly moving mainstream impinged directly on the flow divider. The location of atherosclerotic plaque correlates best with the low shear region of separation and not with the region of high shear at the flow divider. Preliminary studies with pulsatile flow demonstrated little change from the steady flow results.
Hormone receptors of the baboon cardiovascular system. Biochemical characterization of aortic cytoplasmic androgen receptors.
Authors: Lin A L , McGill H C , Shain S A
Published: June 2011

Cytoplasmic androgen receptors were identified in the aorta of the baboon (Papio sp.). Using the synthetic androgen R1881 (17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-trien-3-one) as probe, androgen receptors were demonstrated only when the incubation mixtures contained 1.0 microM triamcinolone acetonide (TA). The relative binding affinity of selected steroids for the aortic androgen receptor was R1881, 100%; 5 alpha-dihydrotestosterone, 46.1%; testosterone, 60.7% progesterone, 9.1%; R5020, 3.1%; and estradiol-17 beta, 7.5%. THe androgen receptor migrated on low-ionic-strength linear sucrose density gradients as a macromolecule with a sedimentation coefficient of 8.0S. Saturation analysis performed at 2 degrees C (available sites) showed that the androgen receptor content a baboon aortic cytoplasmic extracts was 12.9 +/- 2.4 fmoles/mg protein and that the dissociation constant for R1881 was 1.47 +/- 0.07 nM. The observation that TA was required in the cytoplasmic extracts in order to identify androgen receptors indicates the presence of progesterone receptor-like binding components. These aortic cytoplasmic androgen receptors are indicated to be physiologically functional by previous autoradiographic studies that showed localization of radioisotope in the nuclei of aortic smooth muscle cells following injection of baboons with 5 alpha-dihydrotestosterone.
Studies of blood pressure in hyperlipidemic school children.
Authors: Khoury P , Morrison J A , Kelly K , Mellies M J , Glueck C J
Published: June 2011

To assess determinants of blood pressure and racial differences in blood pressure in hyperlipidemic children, and to compare blood pressure in hyperlipidemic and random recall groups of children, studies were carried out on 513 school children (ages 6 through 19 years), and 309 adults (ages 20 through 64), recalled by virtue of elevated cholesterol or triglyceride levels in the Cincinnati Lipid Research Clinic's Princeton School prevalence study. For systolic and diastolic blood pressure in children, there were positive simple correlations with plasma triglyceride and inverse correlations with plasma high density lipoprotein cholesterol. Race did not enter the multiple regression equations as a significant explanatory variable for children's systolic or diastolic blood pressures, but was a significant variable for adults' blood pressures; blacks had higher pressures. Major explanatory variables for systolic blood pressure in children included weight, pulse, and age; 46% of the variance was explained. Major variables for diastolic blood pressure in children included age, pulse, and Quetelet index; 25% of the variance was explained. After covariance adjusting for Quetelet index, blood pressures within race did not differ between the hyperlipidemic and the random recall groups. Quetelet index was the covariable that related positively to blood pressure and plasma triglycerides, and negatively to high density lipoprotein cholesterol. Although relative ponderosity does not appear to be an independent coronary heart disease risk factor variable, its inverse relationship to high density lipoprotein cholesterol and positive association with triglyceride and blood pressure in school children should provide a basis for prudent, early, therapeutic approaches to overweight children and those with persistently elevated blood pressure. (Arteriosclerosis 1981; 1:280-286).
Declining mortality in coronary heart disease.
Authors: Levy R I
Published: June 2011

Since 1968, there has been a dramatic, unprecedented decline in mortality from cardiovascular disease in the United States, especially from coronary heart disease and stroke. The decline has now been confirmed as real and has been observed in all age, sex, and race groups. Possible causes of the decline in coronary heart disease mortality include the development of the concept of acute coronary care, new drugs, sophisticated surgical techniques such as coronary artery bypass, noninvasive diagnostic methods for earlier disease detection, and the identification of specific cardiovascular risk factors. The decline has been temporally related to risk factor awareness and modification (cigarette smoking cessation, hypertension control, diet change and reduction in cholesterol). Thus, both primary prevention through lifestyle changes and improved treatment regimes have played a role in the decline.
Platelet function and survival in patients wit severe hypercholesterolemia.
Authors: Corash L , Andersen J , Poindexter B J , Schaefer E J
Published: June 2011

Platelet aggregation and survival were measured in twelve subjects with severe hypercholesterolemia. There was a small increase in sensitivity to epinephrine and adenosine diphosphate among the most hypercholesterolemic patients, but this did not correlate with reduced platelet lifespan. Platelet survival was normal or only moderately reduced in the markedly hypercholesterolemic homozygous subjects. However, the incidence of reduced platelet survival was significantly increased (p less than 0.05) among the older patients with more extensive atherosclerotic vascular disease compared to the younger patients with limited vascular disease. Marked hypercholesterolemia in the absence of atherosclerosis does not appear to accelerate platelet destruction, although a modest increased aggregability is present.
Cannabinoids impair the formation of cholesteryl ester in cultured human cells.
Authors: Cornicelli J A , Gilman S R , Krom B A , Kottke B A
Published: June 2011

The ability of cultured human fibroblasts to form cholesteryl esters from 14C-oleate is impaired by delta'-tetrahydrocannabinol, cannabidiol, and cannabinol, a group of natural products isolated from Cannabis sativa. This inhibition is compound and dose-related; 30 microM cannabidiol reduced esterification to less than 20% of the control values. The esterification of endogenous and exogenous cholesterol was affected, since inhibition was seen with either low density lipoproteins (200 micrograms/ml) or 25-hydroxycholesterol (5 micrograms/ml) as esterification stimuli. Cells treated with these compounds at doses of from 1 to 30 microM showed no impairment of protein synthesis, triglyceride or phospholipid formation, or ability to metabolize 125I-low density lipoproteins. An inhibition of cholesterol esterification was seen in human aortic medial cells. With increasing doses of these compounds, low density lipoproteins (25 micrograms/ml) became progressively less effective in suppressing HMG-CoA reductase in cultured human fibroblasts; with 30 microM cannabidiol the enzyme suppression was only 24% of that found in cells incubated with low density lipoproteins in the absence of drugs. Based on these data, we conclude that the cannabinoids "compartmentalize" cholesterol and, thus, make is unavailable for regulating cellular cholesterol metabolism. This may occur as a result of enhanced sterol efflux.
Longitudinal study (32 years) of exercise tolerance, breathing response, blood pressure, and blood lipids in young men.
Authors: Gillum R F , Taylor H L , Anderson J , Blackburn H
Published: June 2011

Changes in exercise tolerance, blood lipids, and blood pressure from youth to middle age was studied in 106 subjects followed 32 years. In addition, the responses to cold pressor and CO2 stress were studied as correlates of future lipids and blood pressure. Treadmill exercise test, cold pressor test, response to breathing a mixture of 6% CO2, and 21% O2, for 5 minutes, blood pressure, and lipid measurements were performed in 1947 when subjects were 20 +/- 2 years old. Exercise, blood pressure and lipid tests were repeated in 1979. Tracking of blood pressure and pulse response to exercise over the period was demonstrated. Baseline exercise response correlated with future blood pressure, cholesterol, triglycerides, and high density lipoproteins. Change in exercise pulse rate over the period correlated with change in cholesterol. Cold pressor systolic blood pressure response correlated with future systolic blood pressure and triglycerides. Pulse and blood pressure response to CO2 breathing correlated with cholesterol, triglyceride and high density lipoprotein 32 years later. These correlations were independent of baseline values of the variables and body mass index. Individuals who were judged "fit" (exercise pulse rise less than median) at both baseline and follow-up had the best cardiovascular risk profile (blood pressure and lipids). Blood pressure and pulse response to exercise tracked between ages 20 and 50. Exercise, cold pressor, and CO2 responses in youth correlated with blood lipid levels in middle age.
Growth characteristics and cytoskeletal organization of cultured smooth muscle cells from human primary stenosing and restenosing lesions.
Authors: Dartsch P C , Voisard R , Bauriedel G , Höfling B , Betz E
Published: June 2011

Growth characteristics of human plaque cells selectively extracted from advanced primary stenosing and fresh restenosing lesions by percutaneous transluminal atherectomy were studied in vitro. Cells were isolated either by explant technique or by enzymatic disaggregation, and they were identified as smooth muscle cells (SMC) by positive reaction with antibodies against alpha-smooth muscle actin. Endothelial cells were not found in the atherectomized tissue. The cells of primary stenosing tissue (ps-SMC) exhibited a significantly low growth rate (0.16 +/- 0.04 population doublings per day) in comparison to the cells of restenosing lesions (re-SMC, 0.64 +/- 0.15 population doublings per day). Furthermore, ps-SMC became senescent and remained quiescent after two passages, whereas re-SMC retained a high proliferative activity and became quiescent by passage 8 to 10. Both types of cells responded to increasing serum concentrations in a dose-dependent manner. Ps-SMC failed to respond to purified platelet-derived growth factor (PDGF) and a mitogen mixture isolated from bovine brain (ECGF), but their proliferative activity was increased by the addition of re-SMC-conditioned culture medium. Despite their high basic growth rate, the proliferative activity of re-SMC was significantly stimulated by PDGF and ECGF in a dose-dependent manner. PS-SMC and re-SMC populations consisted of two distinct subpopulations, which could be discriminated by cell size measurements and cell adhesion: 1) relatively small (cell diameter, 18.6 +/- 5 microns), low-adhesive, predominant cells, and 2) enlarged (cell diameter, 27.1 +/- 3 microns), high-adhesive, fibroblast-like cells with abundant microfilaments. Neither ps-SMC or re-SMC stained with antibodies against desmin, but did express vimentin. The organization patterns of vimentin and tubulin were unaltered in comparison to each other and to smooth muscle cells cultured from the media of nonatherosclerotic human arteries.
Use of synthetic peptide analogues to localize lecithin:cholesterol acyltransferase activating domain in apolipoprotein A-I.
Authors: Anantharamaiah G M , Venkatachalapathi Y V , Brouillette C G , Segrest J P
Published: June 2011

The major protein of high density lipoprotein (HDL), apolipoprotein (apo) A-I, is the major activator of the plasma enzyme lecithin:cholesterol acyltransferase (LCAT). A consensus amino acid sequence has been defined for the eight, 22-residue long, tandem amphipathic helical repeats located in the carboxy-terminal region of apo A-I. A series of 22 and 44mer synthetic peptide analogues of the consensus domain, differing only in their 13th amino acid residue, were prepared and tested for LCAT activation. One of the peptides was found to equal apo A-I in LCAT activation. This is the first time a peptide activator for LCAT that rivals the activity of apo A-I in the vesicular and discoidal egg phosphatidylcholine assay systems has been synthesized. Based on these results, we propose that the major LCAT-activating domain of apo A-I resides in the 22mer tandem repeats, each containing Glu at the 13th residue and located between residues 66 and 121 in the native apolipoprotein.
Dietary lipids and thrombosis. Relationships to atherosclerosis.
Authors: Nordøy A , Goodnight S H
Published: June 2011

A high intake of saturated fatty acids and cholesterol is associated with a high incidence of occlusive arterial lesions involving both atherosclerosis and thrombosis. The evidence is based on epidemiological, experimental, and clinical studies. Such dietary habits increase serum low density lipoprotein cholesterol, a main risk factor for atherosclerosis. The mechanisms by which dietary saturated fatty acids are connected to arterial thrombogenesis are only partly known. Experimental and epidemiological studies also indicate an association between dietary saturated fatty acids and venous thrombosis; however, the chain of evidence lacks documentation from prospective clinical studies. When unsaturated fatty acids of the (n-9), (n-6), or (n-3) families replace saturated fatty acids in the diet, risk factors related to atherosclerosis may be reduced and the development of atherosclerosis, inhibited. This potential is related both to the reduction of saturated fatty acids and, in varying degrees, to the individual unsaturated fatty acids. The very long-chain fatty acids of the (n-3) family and probably also linoleic acid of the (n-6) family have the potential to inhibit thrombogenesis. In this respect, the effect of the individual fatty acids seems even more important. To obtain an optimal dietary lipid composition for the prevention of atherosclerosis and thrombosis, it is important to appreciate the metabolic and structural effects of the individual fatty acids. The interaction between the various dietary fatty acids and their effects on lipid biosynthesis is still only partly known. The present nutritional recommendations include a low intake of saturated fatty acids and cholesterol and a balanced content of the unsaturated fatty acids and represent a well-documented approach to the prevention of both processes.