Primate maternal placental angiography.

BACKGROUND: In humans, it is known that blood flow is directed to the gravid uterus from two (right and left) pelvic uterine arteries. The extent of supply from the tubo-ovarian anastomosis (joining of the ovarian and uterine arteries) is unknown. The aim of this study was to delineate the arterial blood supply to the placenta via systematic angiography in normal pregnancies in a non-human primate, the baboon (Papio hamadryas). METHODS: The assessment of the distribution of blood supply with single-shot 3-vessel angiography (aorta, right and left common iliac arteries), allowed assessment of bilateral supply and possible ovarian supply (n=9). In 2-vessel pictures (aorta and left or right iliac), the contralateral supply was determined by subtraction of the ipsilateral supply from the total supply (n=7). The studies were all approved by the Institutional animal welfare committee and were conducted as part of a broader project investigating preeclampsia. RESULTS: The animals were 9 years of age and 140 days of gestation for the 3 vessel study and 154 days of gestation for the 2 vessel study. The angiograms were more likely to have cotyledons perfused by the left uterine artery (p=0.012) than the right. Overall, 55% of placentae had 5-44% of supply overlapping and 22% had 10-15% ovarian contribution to blood supply. DISCUSSION: This study demonstrates the variation in primate uteroplacental blood flow including the contribution of ovarian arteries and left and right collateralization. Similarity to human vascular anatomy strengthens the use of primate species as a model of human placentation.

Uteroplacental blood flow and placental vascular endothelial growth factor in normotensive and pre-eclamptic pregnancy.

OBJECTIVE: To determine whether placental vascular endothelial growth factor (VEGF) is increased in pre-eclampsia. DESIGN: Prospective cohort study. SETTING: Royal Prince Alfred Hospital, Sydney, Australia. SAMPLE: Eleven normotensive women and eight women with pre-eclampsia matched for age and gestation. METHODS: Uterine artery Doppler ultrasound flow velocity profiles were recorded in the third trimester and resistance index calculated as (Vs-Vd)/Vs (Vs = peak systolic flow velocity, Vd = end diastolic flow velocity). Placental tissue at delivery was examined for VEGF distribution with avidin-biotin-peroxidase immunohistochemistry. RESULTS: Uterine resistance index [median (range)] was significantly increased in pre-eclamptic women (normotensive: 0.42 (0.36-0.51); pre-eclampsia: 0.59 (0.40-0.75); P = 0.005). Notching of the uterine artery waveform, consistent with a high resistance circulation, was evident in early diastole in five women with pre-eclampsia but only one normotensive woman (P = 0.013). Placental VEGF was increased in women with pre-eclampsia in the decidual trophoblast (normotensive: 34% (4-59) cells stained for VEGF; pre-eclampsia: 58% (15-95); P = 0.033) and in the villous syncytiotrophoblast (normotensive: VEGF count 1.4 arbitrary units (1.1-2.1); pre-eclampsia: 1.8 arbitrary units (1.4-2.2); P = 0.041). Analysis indicated that uterine artery resistance index was directly correlated with placental VEGF staining, mean arterial pressure and birthweight. CONCLUSIONS: Abnormal uterine artery Doppler ultrasound flow velocity profiles in pre-eclampsia indicate increased uteroplacental resistance. The associated increase in placental VEGF may represent a compensatory mechanism attempting to restore blood flow towards normal.

Functional and structural abnormalities in the nerves of type I diabetic baboons: aminoguanidine treatment does not improve nerve function.

AIMS/HYPOTHESIS: To improve understanding of the pathophysiology of diabetic neuropathy and to establish a primate model for experimental studies, we examined nerve changes in baboons with Type I (insulin-dependent) diabetes mellitus. We also examined the effect of aminoguanidine (an inhibitor of the formation of advanced glycation end products) on nerve function. METHODS: Male baboons (Papio hamadryas) were assigned to four groups; control, diabetic, control and diabetic treated with aminoguanidine. Diabetes was induced with streptozotocin (60 mg/kg, intravenous). Insulin and aminoguanidine (10 mg/kg) were injected subcutaneously daily. Motor and sensory nerve conduction velocity was measured using standard techniques. Autonomic function was examined by measuring heart rate response to positional change. Sural nerve morphometry was analysed in the diabetic group (mean duration 5.5 years) along with their age-matched controls. RESULTS: The diabetic groups were smaller in size with a mean HbA1c of 8.9 +/- 1.2%. The nerve conduction velocity and heart rate response was reduced in the diabetic groups. Morphometric analysis of the diabetic sural nerve showed smaller axon diameter (2.99 +/- 0.06 microns vs 3.29 +/- 0.06 microns; p < 0.01) accompanied by thinner myelin (1.02 +/- 0.02 microns vs 1.15 +/- 0.02 microns, p < 0.01) with no change in the axon density. Treatment with aminoguanidine for 3 years had no effect on glycaemic control and did not restore conduction velocity or autonomic dysfunction in the diabetic animals, contrary to the studies in rats. CONCLUSIONS/INTERPRETATION: These results show that the primate is a good model to study diabetic neuropathy and suggest that the accumulation of advanced glycation end products are not an early mechanism of nerve damage in this disorder.

The effects of the menstrual cycle, pregnancy and early lactation on haematology and plasma biochemistry in the baboon (Papio hamadryas).

The changes in the haematology and clinical biochemistry associated with the different stages of the menstrual cycle, gestation and lactation in the baboon (Papio hamadryas) were evaluated in a prospective longitudinal study. Serial EDTA and heparin blood samples were collected from 12 baboons. Haemoglobin concentration, haematorcrit, red blood cell and white blood cell counts were decreased in the luteal compared to the follicular phase (P<0.001); the reverse effect was observed for platelet count, total protein and albumin concentrations. The changes in plasma concentrations of sodium, potassium, urea, creatinine and cholesterol and plasma osmolality were characterized by reductions (P<0.01) in early pregnancy which were maintained throughout gestation. Plasma concentrations of total protein, albumin and alkaline phosphatase, as well as haemoglobin, haematocrit and red cell count were reduced (P<0.001) from mid-gestation. Platelet count and plasma calcium concentration fell continuously throughout gestation (P<0.001). Plasma triglycerides were lower and plasma iron was higher (P<0.01) in gestation compared to the phases of the menstrual cycle and lactation. By 1 week post partum, all parameters except haemaglobin had returned to pre-conception levels.

End-stage renal disease in aboriginals in New South Wales: a very different picture to the Northern Territory.

OBJECTIVES: To compare the incidence of end-stage renal disease (ESRD) among Aboriginals in New South Wales with the incidence among Aboriginals in the Northern Territory, and to compare the patterns of ESRD among Aboriginals and non-Aboriginals in NSW. DESIGN: Secondary data analysis of information from unpublished and published Australia and New Zealand Dialysis and Transplant Registry reports. MAIN OUTCOME MEASURES: Average annual incidence of ESRD (persons per million); form of renal replacement therapy; mortality at 31 March 1998; patient and graft survival one and five years after transplant. RESULTS: Each year in NSW, 5-17 new Aboriginal patients are treated for ESRD. There was no increase in the average annual incidence of ESRD among NSW Aboriginals (118 per million in 1988-1989 and 111 per million in 1996-1997), whereas incidence in the NT increased from 255 per million to 800 per million. In NSW, ESRD was attributed to diabetes in 32% of Aboriginal patients, compared with 13% of non-Aboriginal patients (P < 0.001). In NSW, Aboriginal patients were younger and more likely to be female, a pattern similar to that in the NT. The outcome of ESRD treatment is not significantly different between Aboriginals and non-Aboriginals in NSW. CONCLUSION: There is a different pattern of incidence of ESRD and of outcomes with treatment among Aboriginals in NSW compared with those in the NT. A possible explanation is that the lower incidence in NSW reflects less profound socioeconomic disadvantage and better access to primary and specialist care.

Low-dose nitro-L-arginine administration in baboon (Papio hamadryas) pregnancy.

1. The purpose of the present study was to examine the effect of nitric oxide (NO) inhibition on mean arterial pressure (MAP), endothelin (ET) and the renin-aldosterone system in pregnancy in the non-human primate (baboon). 2. Twenty pregnant baboons (Papio hamadryas) were examined prospectively after the administration of an oral NO inhibitor in different phases of pregnancy. Haemodynamic responses to NO inhibition, evidence of pre-eclampsia and the renin-aldosterone system were examined under anaesthesia. 3. Oral NL-nitro-L-arginine (NOLA; 5 or 10 mg/kg) was given for 1 week in early (6-8 weeks gestation), middle (14-16 weeks gestation) and late (22-24 weeks gestation) pregnancy and while non-pregnant. Mean arterial pressure, heart rate, haematology, biochemistry, ET, plasma renin activity (PRA) and aldosterone were measured. Foetal effects of NOLA were also examined by ultrasound and neonatal measurements. 4. Nitric oxide inhibition led to an increase in MAP in non-pregnant animals (9 mmHg) and in middle and later pregnancy (6 and 7 mmHg, respectively). Mean arterial pressure in early pregnancy was not affected. A reduction in PRA occurred after NO inhibition in all stages of pregnancy. Significant proteinuria occurred only in late pregnancy. 5. Nitric oxide is involved in the maintenance of lower blood pressure in late pregnancy and inhibition leads to an increase in blood pressure and proteinuria in the baboon. Nitric oxide insufficiency may contribute to the clinical manifestations of human pre-eclampsia. Nitric oxide was not involved in the normal vasodilation of early primate pregnancy.

Anti-RNA polymerase III antibodies in the diagnosis of scleroderma renal crisis sine scleroderma.

We describe the use of antibodies to RNA polymerase III in the diagnosis of scleroderma in 2 patients who presented with renal crisis without other clinical features of the condition. Both presented with accelerated hypertension, rapidly progressive acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. One patient developed digital infarcts in the course of his initial illness. Neither showed evidence of skin thickening at presentation. Nailfold capillaroscopy was normal in one patient and showed capillary dropout in the other. Renal biopsy showed findings consistent with thrombotic microangiopathy and both had anti-RNA polymerase III antibodies.

Biochemistry and haematology values for the baboon (Papio hamadryas): the effects of sex, growth, development and age.

A retrospective study evaluated the influence of sex and age on plasma biochemistry and haematology parameters in a captive-bred colony of baboons. Over 1,140 ETDA and heparin blood samples were obtained from 160 clinically normal baboons between the ages of 11 months and 11 years. Data for these blood tests were analysed for the effects of sex, age and sex age interactions. Sex, age and sex age interactions were detected for many plasma biochemistry and haematological parameters. The reference range values for platelets, white-blood cells and mean corpuscular volume and plasma chloride, glucose, total protein and iron were higher (P < 0.01) and red blood cell, plasma sodium, potassium, total CO2, creatinine, urea, total bilirubin, albumin, alkaline phosphate, gamma glutamyl transpeptidase and phosphate were lower (P < 0.01) in the female compared to the male population. Sex age interactions (P < 0.05) were seen with haemoglobin, white blood cells, haematocrit, mean corpuscular volume, sodium, creatinine, urea, calcium, phosphate, total bilirubin, total protein alkaline phosphatase, the liver enzymes and triglycerides. Plasma alkaline phosphatase was highest ( > 800 micro/l) in young juveniles of both sexes; creatinine was higher in older ( > 4 years) compared to younger baboons of the same sex (P < 0.05). Plasma cholesterol and triglycerides were greater (P < 0.01) in young baboons compared to older animals.

Changes of extracellular matrix in a baboon (Papio hamadryas) model of insulin dependent diabetes: studies using electron microscopy and X-ray diffraction techniques.

Extracellular matrix plays an important role in many physiological functions and its abnormalities are thought to play a key role in the pathogenesis of diabetic complications. In this paper we used the techniques of electron microscopy, immunostaining and X-ray diffraction to document some of the early events in the changes of extracellular matrix in a model of insulin dependent diabetes in baboons. Our results show that thickening of basement membrane and enlargement of mesangium are demonstrable in the glomeruli of prepubertal diabetic baboons within 2 years from the onset of diabetes. Concomitant with this was the accumulation of type IV collagen and laminin in the mesangium. By contrast, even the very sensitive technique of X-ray diffraction failed to demonstrate changes in the equatorial direction of collagen molecules of the skin and tendon. We conclude that changes of glomerular extracellular matrix are demonstrable early in insulin dependent diabetes even in prepubertal baboons. These can be used as endpoints in evaluating the efficacy of pharmacological agents such as aminoguanidine in preventing diabetic complications.

A unique design for ease of access and movement of captive Papio hamadryas.

Baboons are widely used in biomedical research but their size and behaviour present potential problems with accessibility. A unique system has been developed that ensures ease of access to all animals in a colony of Papio hamadryas. Two distinct caging complexes were linked by a network of overhead races, that are connected to a physical restraint area where individual animals could be separated, restrained and weighed without being handled. Access to and separation of individual family groups was achieved in this manner. This race system proved to be time effective, simple, sturdy, safe and hygienic.

Cyclical changes in the renin-angiotensin-aldosterone system during the menstrual cycle of the baboon (Papio hamadryas).

This study characterizes the renin-angiotensin-aldosterone system during the normal menstrual cycle in the baboon. Ten animals received a daily dose of an ACE inhibitor or placebo in a randomized blind cross-over design. Data were obtained during the mid-follicular and early luteal phases of normal non-pregnant menstrual cycles. All examinations and blood collections were performed with ketamine sedation: 7-kg by im injection. Blood pressure was recorded by sphygmomanometer. Serum ACE activity was measured by spectrophotometry. Aldosterone (ALDO), angiotensin I (AI), and angiotensin II (AII) were measured by radioimmunoassay. Plasma renin activity (PRA) was measured by AI generation. The renin-angiotensin-aldosterone system was found to be activated in the follicular phase and suppressed during the luteal phase of the normal non-pregnant menstrual cycle in the baboon.

Reproductive and neonatal outcomes in captive bred baboons (Papio hamadryas).

Baboons are widely used in biomedical research. Although it is widely held that Papio hamadryas breed well in captivity, each established colony has a different reproductive success often hypothesised to be due to husbandry practices. The National Baboon Colony in Australia is a unique colony that houses Papio hamadryas to mimic that structure seen in the wild. In this article; we have analysed their reproductive parameters and neonatal outcomes. The success of the colony husbandry practices was demonstrated by lack of maternal mortality, low foetal morbidity, and known maternal and paternal linage.

Maternal and neonatal outcome of patients classified according to the Australasian Society for the Study of Hypertension in Pregnancy Consensus Statement.

OBJECTIVE: To outline the maternal and perinatal features and outcome of patients referred to a tertiary referral obstetric hospital for management of their hypertension. SETTING AND PATIENTS: 205 consecutive public patients admitted for assessment of hypertension (either full admission or day-stay) to King George V Hospital's Hypertension in Pregnancy Unit, between February 1993 and January 1994. DESIGN: A prospective study in which patients were classified according to the Australasian Society for the Study of Hypertension in Pregnancy (ASSHP) Consensus Statement classification. RESULTS: Of the 205 patients, 25% did not meet the criteria for pre-eclampsia or chronic hypertension, 33% had mild pre-eclampsia, 34% had severe pre-eclampsia and the remainder had chronic hypertension. The mean gestation at delivery for those with mild pre-eclampsia was 38.3 weeks and for severe pre-eclampsia 35.3 weeks. For the mild and severe groups respectively, the rate of elective delivery for raised blood pressure was 56% and 53%; for caesarean section, 17% and 61%; and for perinatal death, 2% and 4%. In the severe group, 49% had fetal problems and 25% required intravenous antihypertensives. CONCLUSIONS: The multisystem nature of pre-eclampsia makes comparison of management protocols difficult. Ongoing audit is needed of maternal and perinatal outcomes and features of disease in patients with hypertension in pregnancy under a universal classification. The ASSHP classification system successfully identifies patients who require more intensive management and intervention.

A baboon (Papio hamadryas) model of insulin-dependent diabetes.

Over a period of four years, streptozocin has been used to induce diabetes in 10 baboons, all of whom are insulin dependent. We describe our experience with their husbandry, induction of diabetes, insulin therapy, metabolic control and growth rate. Streptozocin dosage of 60 mg/kg readily induces hyperglycemia with minimal hepatic or renal toxicity. Using a once daily injection of mixed short and intermediate acting insulins at a dosage of 2-4 U/kg, it is possible to maintain a degree of metabolic control similar to that attained in patients.

The use of nebulized opioids for breathlessness: a chart review.

Breathlessness secondary to both cancer and non-malignant disease is a distressing, exhausting symptom which, to date, has been difficult to control. This paper reports a chart review undertaken on patients referred to the Ottawa Civic Hospital's Palliative Care Service over the 18-month period from 1 January 1992 to 30 June 1993. The intent of the review was to assess the recorded efficacy and safety of nebulized opioid use on patients with complaints of dyspnoea. Fifty-four patients were treated and subjective data have been compiled. The treatment was found to be effective, safe and convenient for the majority of the patients studied. In addition, nebulized opioids have been demonstrated as a treatment modality which is feasible for self-administration by the patient at home.

Maintenance of high risk pregnancies: role of prostaglandins and other mediators.

The initiation of a complex cascade of events resulting in the delivery of a healthy newborn appears to involve the integrated actions of the fetus, mother and the placenta. Many putative factors have already been extensively reviewed. Instead of concentrating on the action of estrogen and progesterone, the role of regulators of myometrial activity such as prostaglandins as well as the fetal pituitary-adrenal system, oxytocin, corticosteroids, leukotrienes, platelet activating factor, endotoxin and cytokines to name a few, will be discussed. Nevertheless, there is an increasing weight of evidence suggesting that many of the above agonists converge upon a final pathway of prostaglandin production which subsequently increases myometrial responsiveness. Prostaglandins are involved at levels of myometrial regulation such as myometrial gap junction formation, intracellular calcium flux modulation, synchronisation of myometrial contraction via interaction with oxytocin thus having stimulatory effects on uterine contractility, as well as cervical maturation (via PGE2). Importantly, there has been clinical benefit of a more thorough understanding of the physiology of myometrial regulation at the time of partuition. The approach to the treatment of preterm delivery has improved, eventhough the exact mechanism(s) and cause(s) of this phenomenon remain an enigma. Current tocolytic therapy is not generally prophylactic but commences after labour, contractions and cervical dilatation are underway. Key regulatory pathways have been pin-pointed that present opportunity for tocolysis including:-c-AMP inhibition of contraction by beta-mimetic agents, inhibition of calmodulin-calcium function, inhibition of calcium influx by calcium channel blockers, inhibition of prostaglandin production, modulation of myometrial function by peptide hormones or antagonists (e.g. relaxin, VIP and oxytocin antagonists).(ABSTRACT TRUNCATED AT 250 WORDS)

Protein restriction sequentially induces new urea transport processes in rat initial IMCD.

We reported that feeding rats 8% protein for 4 wk induces two new urea transport processes in initial inner medullary collecting ducts (IMCD); neither is present in rats fed 18% protein. In this study, we measured the time course of induction of these transporters in perfused initial IMCD segments from rats fed 8% protein. Net urea flux was induced after 3 wk, whereas vasopressin-stimulated passive urea permeability (P(urea)) was induced after 2 wk. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) significantly increased P(urea)); adding vasopressin did not increase P(urea) further. In fact, there was no difference in vasopressin-stimulated cAMP production in initial or terminal IMCD segments from rats fed 18% or 8% protein, suggesting that the adaptive response was not due to increased cAMP production. Glucagon did not change cAMP production or P(urea). Specificity of the response was suggested because neither aldose reductase nor sorbitol dehydrogenase activity changed with feeding 8% protein. Thus 1) in initial IMCD segments, vasopressin-stimulated P(urea) is induced after 2 wk, but net urea flux requires 3 wk of feeding 8% protein; 2) this adaptation is not solely due to a higher rate of cAMP production; and 3) specificity of the adaptive response is suggested because activities of enzymes responding to decreases in concentrating ability are unchanged. These results suggest that two distinct urea transporters may be involved in the adaptation to a low-protein diet.

The urease inhibitor acetohydroxamic acid is transported by the urea pathway in rat terminal IMCD.

Acetohydroxamic acid (AHA), a urea analogue, is used clinically to dissolve struvite stones because it inhibits the urease produced by Proteus mirabilis. To be effective, the concentration of AHA must be high in the collecting duct system and final urine. Because AHA is structurally similar to urea, we investigated whether AHA is transported by the urea carrier found in the terminal inner medullary collecting duct (IMCD) and the erythrocyte. We examined AHA transport under four conditions known to affect urea movement across the terminal IMCD, i.e., stimulation by vasopressin (AVP) and hyperosmolality, and inhibition by phloretin and urea analogues. The AHA permeability was determined with a 10 mM bath-to-lumen AHA gradient. AHA was measured by ultramicrocolorimetry. Addition of 1 nM AVP to the bath increased the AHA permeability of the perfused terminal IMCD. Increasing perfusate and bath osmolality from 290 to 690 mosmol/kgH2O (by adding NaCl) also increased tubule permeability to AHA. Addition of either 0.25 mM phloretin to the bath or 200 mM thiourea to the lumen reversibly inhibited the AVP-stimulated AHA permeability. AHA-induced osmotic lysis of erythrocytes was inhibited by phloretin or thionicotinamide; AHA inhibited the osmotic lysis induced by the urea analogue acetamide. Thus, in the rat terminal IMCD, both urea and AHA transport are stimulated by AVP and hyperosmolality, and both are inhibited by phloretin and thiourea. In erythrocytes, both urea and AHA transport are inhibited by phloretin or thionicotinamide. Thus AHA is transported by the urea carrier in the terminal IMCD and erythrocyte.(ABSTRACT TRUNCATED AT 250 WORDS)

Osmolarity-stimulated urea transport in rat terminal IMCD: role of intracellular calcium.

We showed previously that both increasing osmolality by adding NaCl or manitol (hyperosmolarity) or adding vasopressin can stimulate urea permeability in rat terminal inner medullary collecting ducts (IMCD). Vasopressin acts via adenosine 3',5'-cyclic monophosphate (cAMP), but the mechanism by which hyperosmolarity acts is unknown. To study the mechanism, we determined the effect of varying osmolality (with NaCl) on two potential second messenger systems, i.e., cAMP and intracellular calcium. There was no significant difference in cAMP production among tubules incubated at 290, 490, 690, or 890 mosmol/kg. In contrast, cAMP did increase significantly after vasopressin (10(-8) M) addition. Intracellular calcium increased significantly when osmolality was increased from 290 to 490 mosmol/kg in the absence of vasopressin. To examine whether changes in intracellular calcium affect urea permeability, we added thapsigargin (and removed bath calcium) while maintaining osmolality at 290 mosmol/kg. Both intracellular calcium and urea permeability increased significantly. Next, we buffered intracellular calcium by pretreatment with the acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA, 50 microM). BAPTA completely blocked the increase in urea permeability occurring when osmolality was increased from 290 to 490 mosmol/kg, but did not block the increase in urea permeability occurring when vasopressin (10(-8) M) was added. In summary, 1) hyperosmolarity increases intracellular calcium, but has no effect on cAMP accumulation; 2) thapsigargin increases intracellular calcium and urea permeability; and 3) BAPTA blocks the hyperosmolarity-stimulated increase in urea permeability, but not vasopressin-stimulated urea permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

Urea transport in the kidney.

Urea transport within the kidney is regulated and varies dramatically between different nephron segments. The terminal IMCD displays very high rates of transepithelial urea transport enabling delivery of large amounts of urea into the deepest portions of the inner medulla to maintain a high interstitial osmolality for concentrating the urine maximally. Urea in the terminal IMCD is transported by a specific urea transporter that is stimulated by vasopressin and hyperosmolarity. Although the urea transporter has not been cloned, individuals have been identified who lack the urea transporter. Individuals who lacked the Kidd antigen (a minor blood group antigen) also lacked carrier-mediated urea transport in their erythrocytes (and presumably in their kidneys). These same subjects were unable to concentrate their urine above 800 mOsm following overnight water deprivation. This experiment of nature illustrates the critical importance of the urea transporter to concentrating ability in humans.