Harnessing zebrafish for the study of white blood cell development and its perturbation

Considerable progress has been made in understanding the molecular basis of normal white blood cell development and its perturbation in disease through the use of clinical studies and traditional animal and cell line models. Despite this, however, many questions are still being answered and white blood cell disorders, including leukemia and lymphoma, remain a significant health problem. The zebrafish (Danio rerio) has emerged as a powerful alternative vertebrate model for the study of development and disease. We review the recent application of zebrafish to the study of white blood cell development and its disruption, particularly leukemogenesis. Such studies have highlighted the overall conservation of these processes throughout vertebrates, and establish zebrafish as a useful experimental model. This organism is now poised to make an important contribution to our understanding of the underlying genetic control of white blood cell development and its disruption, as well as the identification of new therapeutic agents.

Blood pressure response to dietary modifications in free-living individuals 1,2

A diet rich in fruits, vegetables, and low-fat dairy foods has been shown to lower blood pressure (BP) when all foods are provided. We compared the effect on BP (measured at home) of 2 different self-selected diets: a low-sodium, high-potassium diet, rich in fruit and vegetables (LNAHK) and a high-calcium diet rich in low-fat dairy foods (HC) with a moderate-sodium, high-potassium, high-calcium DASH-type diet, high in fruits, vegetables and low-fat dairy foods (OD). Subjects were randomly allocated to 2 test diets for 4 wk, the OD and either LNAHK or HC diet, each preceded by a 2 wk control diet (CD). The changes in BP between the preceding CD period and the test diet period (LNAHK or HC) were compared with the change between the CD and the OD periods. Of the 56 men and 38 women that completed the OD period, 43 completed the LNAHK diet period and 48 the HC diet period. The mean age was 55.6 ± 9.9 (±SD) years. There was a fall in systolic pressure between and the CD and OD [-1.8 ± 0.5 mm Hg (P < 0.001)]. Compared with OD, systolic and diastolic BPs fell during the LNAHK diet period [-3.5 ± 1.0 (P < 0.001) and -1.9 ± 0.7 (P < 0.05) mmHg, respectively] and increased during the HC diet period [+3.1 ± 0.9 (P < 0.01) and +0.8 ± 0.6 (P = 0.15) mm Hg, respectively]. A self-selected low-sodium, high-potassium diet resulted in a greater fall in BP than a multifaceted OD, confirming the beneficial effect of dietary intervention on BP in a community setting.

The relationship between patient blood pathology values and patient falls in an acute-care setting : a retrospective analysis

Few studies have investigated the relationship between patient falls and patient blood pathology values, which can reveal objective information about the health and nutritional status of a patient. It could be that some abnormal values are associated with patients that fall. The objectives of the current study were to determine whether blood pathology values were different in patients who fell compared to patients who did not fall, and whether there was a difference in the type and number of currently documented risk factors for falls found for patients who fell compared to patients who did not fall. A retrospective audit of patient incident reports and medical records was conducted in an acute-care hospital for 220 patients who fell and who did not fall. Faller and non-faller patients were matched by casemix type and length of stay. Findings revealed a significant relationship between patients who fell and the variables of age, confusion status and alkaline phosphatase blood values.

Blood pressure change with weight loss is affected by diet type in men

Background: Weight loss reduces blood pressure, and the Dietary Approaches to Stop Hypertension (DASH) diet has also been shown to lower blood pressure.

Objective: Our goal was to assess the effect on blood pressure of 2 weight-reduction diets: a low-fat diet (LF diet) and a moderate-sodium, high-potassium, high-calcium, low-fat DASH diet (WELL diet).

Design: After baseline measurements, 63 men were randomly assigned to either the WELL or the LF diet for 12 wk, and both diet groups undertook 0.5 h of moderate physical activity on most days of the week.

Results: Fifty-four men completed the study. Their mean (±SD) age was 47.9 ± 9.3 y (WELL diet, n = 27; LF diet, n = 27), and their mean baseline home systolic and diastolic blood pressures were 129.4 ± 11.3 and 80.6 ± 8.6 mm Hg, respectively. Body weight decreased by 4.9 ± 0.6 kg (±SEM) in the WELL group and by 4.6 ± 0.6 kg in the LF group (P < 0.001 for both). There was a greater decrease in blood pressure in the WELL group than in the LF group [between-group difference (week 12 –baseline) in both SBP (5.5 ± 1.9 mm Hg; P = 0.006) and DBP (4.4 ± 1.2 mm Hg; P = 0.001)].

Conclusions: For a comparable 5-kg weight loss, a diet high in low-fat dairy products, vegetables, and fruit (the WELL diet) resulted in a greater decrease in blood pressure than did the LF diet. This dietary approach to achieving weight reduction may confer an additional benefit in reducing blood pressure in those who are overweight.

Nitric oxide control of lower vertebrate blood vessels by vasomotor nerves

In mammals, much is understood about the endothelial and neural NO control mechanisms in the vasculature. In contrast, NO control of blood vessels in lower vertebrates is poorly understood, with the majority of research focusing on the presence of an endothelial NO system; however, its presence remains controversial. This study examined the mechanisms by which NO regulates the large blood vessels of non-mammalian vertebrates. In all species examined, the arteries and veins contained a plexus of NOS-positive perivascular nerves that included nerve bundles and fine, varicose nerve terminals. However, in the large arteries and veins of various species of fishes and amphibians, no anatomical evidence was found for endothelial NOS using both NADPH-diaphorase and eNOS immunohistochemistry. In contrast, perinuclear NOS staining was readily apparent in blue-tongue lizard, pigeon and rat, which suggested that eNOS first appeared in reptiles. Physiological analysis of NO signalling in the vascular smooth muscle of short-finned eel and cane toad could not find any evidence for endothelial NO signalling. In contrast, it appears that activation of the nitrergic vasomotor nerves is responsible for NO control of the blood vessels.

Dietary patterns throughout adult life are associated with body mass index, waist circumference, blood pressure, and red cell folate

Dietary patterns are important in the prevention of chronic disease; however, there are few studies that include repeat measures of dietary patterns. The objective of this study was to assess the relations between dietary patterns during adult life (at ages 36, 43, and 53 y) and risk factors for chronic disease at age 53 y. Participants of a longitudinal study of health completed a 5-d food diary at 3 occasions during adult life (n = 1265). Factor analysis was used to identify dietary patterns and a pattern score was calculated from the consumption of the food items in each dietary pattern. Means and 95% CI for dietary pattern scores were calculated for each risk factor category using random effects models adjusted for socio-demographic and health-related behaviors. In women, the fruit, vegetables, and dairy pattern was inversely associated with BMI (P < 0.004), waist circumference (P = 0.0007), blood pressure (P = 0.02), and was positively associated with red cell folate (P < 0.03). The ethnic foods and alcohol pattern was also inversely associated with blood pressure (P = 0.008), whereas the meat, potatoes and sweet foods pattern was positively associated with glycated hemoglobin (P = 0.01). In men, a mixed pattern was inversely associated with waist circumference (P = 0.02) and blood pressure (P = 0.01), whereas there were no significant associations with the ethnic foods and alcohol pattern. Specific dietary patterns throughout adult life were associated with chronic disease risk factors.

Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimers disease, across the blood-brain

Cryptotanshinone (CTS), a major constituent from the roots of Salvia miltiorrhiza (Danshen), is widely used in the treatment of coronary heart disease, stroke and less commonly Alzheimer's disease. Our recent study indicates that CTS is a substrate for Pglycoprotein (PgP/MDR1/ABCB1). This study has investigated the nature of the brain distribution of CTS across the brain-blood barrier (BBB) using several in vitro and in vivo rodent models. A polarized transport of CTS was found in rat primary microvascular endothelial cell (RBMVEC) monolayers, with facilitated efflux from the abluminal side to luminal side. Addition of a PgP (e.g. verapamil and quinidine) or multi-drug resistance protein 1/2 (MRP1/2) inhibitor (e.g. probenecid and MK-571) in both luminal and abluminal sides attenuated the polarized transport. In a bilateral in situ brain perfusion model, the uptake of CTS into the cerebrum increased from 0.52 ± 0.1% at 1 min to 11.13 ± 2.36 ml/100 g tissue at 30 min and was significantly greater than that of sucrose. Co-perfusion of a PgP/MDR1 (e.g. verapamil) or MRP1/2 inhibitor (e.g. probenecid) significantly increased the brain distribution of CTS by 35.1-163.6%. The brain levels of CTS were only about 21% of those in plasma, and were significantly increased when coadministered with verapamil or probenecid in rats. The brain levels of CTS in rats subjected to middle cerebral artery occlusion and rats treated with quinolinic acid (a neurotoxin) were about 2- to 2.5-fold higher than the control rats. Moreover, the brain levels in mdr1a(-/-) and mrp1(-/-) mice were 10.9- and 1.5-fold higher than those in the wild-type mice, respectively. Taken collectively, these findings indicate that PgP and Mrp1 limit the brain penetration of CTS in rodents, suggesting a possible role of PgP and MRP1 in limiting the brain penetration of CTS in patients and causing drug resistance to Danshen therapy and interactions with conventional drugs that are substrates of PgP and MRP1. Further studies are needed to explore the role of other drug transporters in restricting the brain penetration of CTS and the clinical relevance.

Blood cells of Murray cod maccullochella peelii peelii (Mitchell)

Analysis of the peripheral blood cells of Murray cod Maccullochella peelii peelii identified seven distinct subpopulations including a novel basophilic cell. Haematological reference ranges were established to facilitate future diagnostic blood sampling of this fish.

Blood-nourishing and hard-softening capsule costs less in the management of osteoarthriticknee pain : A randomized controlled trial

The blood-nourishing and hard-softening (BNHS) capsule is a traditional Chinese formula used in the symptomatic treatment of inflammation and pain. We conducted this randomized controlled trial to compare the efficacy of BNHS with other commonly prescribed drugs. We recruited 120 patients from two teaching hospitals; 30 patients in each hospital were randomly assigned to receive BNHS. In one hospital, the 30 controls were given another traditional Chinese drug; whereas a Western medicine (chondroprotection drug/Viartril-s) was used as the control in the other hospital. Intervention was carried out over a period of 4 weeks. Primary outcome measures included self-reported pain level, and changes in stiffness and functional ability as measured by the Western Ontario McMaster Universities Osteoarthritis (WOMAC) index. Mixed models were used for statistical analysis. Substantial improvements in disease-specific symptoms were observed, after 4 weeks of treatment, in patients taking BNHS capsules. As assessed by the WOMAC index, pain level of the BNHS group decreased by 57% [95% confidence interval (CI) = 50, 63], stiffness by 63% (95% CI = 55, 71) and functional ability increased by 56% (95% CI = 50, 63). No significant differences were found in any of the outcome measures between the BNHS group and either of the comparison groups. No severe adverse effects were reported. However, this study lacked a placebo group; therefore, we conclude that BNHS appears to be as effective as commonly prescribed medicines for the relief of pain and dysfunction in knee osteoarthritis patients, but costs a lot less than other Western and herbal drugs in the study.

Optimal H∞ insulin injection control for blood glucose regulation in diabetic patients

The theory of H/sup /spl infin// optimal control has the feature of minimizing the worst-case gain of an unknown disturbance input. When appropriately modified, the theory can be used to design a "switching" controller that can be applied to insulin injection for blood glucose (BG) regulation. The "switching" controller is defined by a collection of basic insulin rates and a rule that switches the insulin rates from one value to another. The rule employed an estimation of BG from noisy measurements, and the subsequent optimization of a performance index that involves the solution of a "jump" Riccati differential equation and a discrete-time dynamic programming equation. With an appropriate patient model, simulation studies have shown that the controller could correct BG deviation using clinically acceptable insulin delivery rates.

Splanchnic blood flow and hepatic glucose production in exercising humans : role of renin-angiotensin system

The study examined the implication of the renin-angiotensin system (RAS) in regulation of splanchnic blood flow and glucose production in exercising humans. Subjects cycled for 40 min at 50% maximal O2 consumption (VO2 max) followed by 30 min at 70% VO2 max either with [angiotensin-converting enzyme (ACE) blockade] or without (control) administration of the ACE inhibitor enalapril (10 mg iv). Splanchnic blood flow was estimated by indocyanine green, and splanchnic substrate exchange was determined by the arteriohepatic venous difference. Exercise led to an ~20-fold increase (P < 0.001) in ANG II levels in the control group (5.4 ± 1.0 to 102.0 ± 25.1 pg/ml), whereas this response was blunted during ACE blockade (8.1 ± 1.2 to 13.2 ± 2.4 pg/ml) and in response to an orthostatic challenge performed postexercise. Apart from lactate and cortisol, which were higher in the ACE-blockade group vs. the control group, hormones, metabolites, VO2, and RER followed the same pattern of changes in ACE-blockade and control groups during exercise. Splanchnic blood flow (at rest: 1.67 ± 0.12, ACE blockade; 1.59 ± 0.18 l/min, control) decreased during moderate exercise (0.78 ± 0.07, ACE blockade; 0.74 ± 0.14 l/min, control), whereas splanchnic glucose production (at rest: 0.50 ± 0.06, ACE blockade; 0.68 ± 0.10 mmol/min, control) increased during moderate exercise (1.97 ± 0.29, ACE blockade; 1.91 ± 0.41 mmol/min, control). Refuting a major role of the RAS for these responses, no differences in the pattern of change of splanchnic blood flow and splanchnic glucose production were observed during ACE blockade compared with controls. This study demonstrates that the normal increase in ANG II levels observed during prolonged exercise in humans does not play a major role in the regulation of splanchnic blood flow and glucose production.

Colorectal cancer screening in Australia: an economic evaluation of a potential biennial screening program using faecal occult blood tests

Objective: To evaluate whether the introduction of a national, co-ordinated screening program using the faecal occult blood test represents 'value-for-money' from the perspective of the Australian Government as third-party funder.  Methods: The annual equivalent costs and consequences of a   biennial screening program in 'steady-state' operation were estimated for the Australian population using 1996 as the reference year. Disability-adjusted life years (DALYs) and the years of life lost (YLLs) averted, and the health service costs were modelled, based on the epidemiology and the costs of colorectal cancer in Australia together with the mortality reduction achieved in randomised controlled trials. Uncertainty in the model was examined using Monte Carlo simulation methods. Results: We estimate a minimum or 'base program' of screening those aged 55 to 69 years could avert 250 deaths per annum (95% uncertainty interval 99–400), at a gross cost of $A55 million (95% UI $A46 million to $A96 million) and a gross incremental cost-effectiveness ratio of $A17,000/DALY (95% UI $A13,000/DALY to $A52,000/DALY). Extending the program to include 70 to 74-year-olds is a more effective option (cheaper and higher health gain) than including the 50 to 54-year-olds. Conclusions: The findings of this study support the case for a national program directed at the 55 to 69-year-old age group with extension to 70 to 74-year-olds if there are sufficient resources. The pilot tests recently announced in Australia provide an important opportunity to consider the age range for screening and the sources of uncertainty, identified in the modelled evaluation, to assist decisions on implementing a full national program.

Adiponectin in umbillcal cord blood is inversely related to low-density lipoprotein cholesteril but not ethnicity

Context: Adiponectin is a recognized protective risk marker for cardiovascular disease in adults and is associated with an optimal lipid profile. The role of adiponectin at birth is not well understood, and its relationship with the neonatal lipid profile is unknown. Because ethnic disparities in cardiovascular risk have been attributed to low adiponectin and its associated low high-density lipoprotein cholesterol (HDL-C), investigation at birth may help determine the etiology of these risk patterns.

Objective: Our objective was to investigate the relationship between neonatal adiponectin and lipid profile at birth in two ethnic groups in cord blood.

Design, Setting, and Participants: Seventy-four healthy mothers and their newborns of South Asian and White European origin were studied in this cross-sectional study at St. Mary’s Hospital, Manchester, United Kingdom.

Main Outcome Measures: Serum adiponectin, total cholesterol, HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels were measured in umbilical venous blood at birth and in maternal blood collected at 28 wk gestation.

Results: Cord adiponectin was significantly inversely associated with cord LDL-C (r = –0.32; P = 0.005) but not HDL-C. In a multiple regression analysis, cord LDL-C remained the most significant association of cord adiponectin (ß = –0.13; P < 0.001). We did not find any significant ethnic differences in cord adiponectin or lipids with the exception of triglycerides, which were significantly lower in South Asian newborns (P < 0.05).

Conclusion: This is the first report of an inverse relationship between cord adiponectin and LDL-C at birth. In contrast to adult studies, we found no significant association between adiponectin and HDL-C in cord blood. Our results and the strong independent association between adiponectin and HDL-C observed in adult studies suggest a role for adiponectin in lipid metabolism. Ethnic differences in adiponectin may arise after birth.

Increased blood pressure later in life may be associated with perinatal n-3 fatty acid deficiency

Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Previous work in both animals and humans with high blood pressure has demonstrated the antihypertensive effects of n−3 polyunsaturated fatty acids (PUFA), although it is not known whether these nutrients are effective in preventing hypertension. The predominant n−3 PUFA in the mammalian nervous system, docosahexaenoic acid (DHA), is deposited into synaptic membranes at a high rate during the perinatal period, and recent observations indicate that the perinatal environment is important for the normal development of blood pressure control. This study investigated the importance of perinatal n−3 PUFA supply in the control of blood pressure in adult Sprague-Dawley rats. Pregnant rat dams were fed semisynthetic diets that were either deficient in (DEF) or supplemented with (CON) n−3 PUFA. Offspring were fed the same diets as their mothers until 9 wk; then, half of the rats from each group were crossed over to the opposite diet, creating four groups, i.e., CON-CON; CON-DEF; DEF-DEF, DEF-CON. Mean arterial blood pressures (MAP) were measured directly, at 33 wk of age, by cannulation of the femoral artery. The phospholipid fatty acid profile of the hypothalamic region was determined by capillary gas-liquid chromatography. The tissue phospholipid fatty acid profile reflected the diet that the rats were consuming at the time of testing. Both groups receiving DEF after 9 wk of age (i.e., DEF-DEF and CON-DEF) had similar profiles with a reduction in DHA levels of 30%, compared with rats receiving CON (i.e., CON-CON and DEF-CON). DEF-DEF rats had significantly raised MAP compared with all other groups, with differences as great as 17 mm Hg. DEF-CON rats had raised MAP compared with CON-CON rats, and DEF-DEF rats had higher MAP than CON-DEF rats, despite the fact that their respective fatty acid profiles were not different. These findings indicate that inadequate levels of DHA in the perinatal period are associated with altered blood pressure control in later life. The way in which these long-term effects are produced remains to be elucidated.