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A MacDonald

Publications and source records attributed to A MacDonald.

At least 37 records · Page 2Linked to original sources
PubMed2003

Administration of protein substitute and quality of control in phenylketonuria: a randomized study.

Uneven administration of an L-amino acid protein substitute is an important contributing factor in variability in plasma phenylalanine concentrations over the 24-hour period in patients with phenylketonuria under treatment. The aim of this study was to determine whether manipulating the timing of protein substitution would reduce variability in plasma phenylalanine over 24 h. Sixteen children (aged 1-11 years) with well-controlled phenylketonuria were entered into a randomized crossover study in which four protocols of the same daily dose of protein substitute administration were compared. In protocol A, three equal, divided doses were given with meals over 10 h; in protocol B, three equal doses over 14 h; in protocol C, four equal doses over 14 h; and in protocol D, six equal doses over 24 h (3 subjects only). Four-hourly skin puncture blood specimens were collected for 48 h in each study protocol. In protocols A, B and C, but not in protocol D, there was wide variability in 24 h plasma phenylalanine. The median daily differences (micromol/L) between highest and lowest phenylalanine concentrations were: for protocol A, 140; for protocol B, 100; for protocol C, 120; and for protocol D, 40. In protocol D, 97% of all phenylalanine concentrations were below 120 micromol/L and no concentration fell below 40 micromol/L. Administration of protein substitute overnight as well as during daytime produces stable and lower plasma phenylalanine concentrations and may lead to improved dietary phenylalanine tolerance.

Amino Acids↗
PubMed2003

Are tablets a practical source of protein substitute in phenylketonuria?

BACKGROUND: A phenylalanine-free amino acid based protein substitute is necessary to provide the major source of protein in phenylketonuria (PKU). Protein substitutes in PKU are usually given as drinks. These are unpalatable and compliance is often poor. Tablets containing a suitable mixture of phenylalanine-free amino acids (Aminogran Food Supplement, UCB) are now available. AIMS: To compare the effectiveness and acceptability of these tablets with conventional protein substitute drinks. METHODS: Twenty one subjects with PKU, aged 8-25 years, participated in a randomised crossover study. During one phase, subjects received at least 40% of their protein substitute requirements from the amino acid tablets and the rest from their usual protein substitute tablets. During the other phase, they received their usual protein substitute. Each period lasted 12 weeks. Blood phenylalanine concentrations were measured at least once every two weeks and other plasma amino acids were measured at the beginning, at crossover, and at the end of the study. The subjects kept a diary of all protein substitute taken. RESULTS: Compliance appeared to be better with the new tablets than with patients' usual protein substitutes. Ninety per cent (18/20) recorded that they took the tablets as prescribed, compared with 65% (13/20) fully compliant with their usual protein substitute. Moreover, plasma phenyalanine was lower on the amino acid tablets, and the median difference in blood concentrations between the two groups was 46 micro mol/l (95% CI 14.8 to 89.0, p = 0.02). Tyrosine increased by a median of 16 micro mol/l daily on the amino acid tablets (95% CI 7.1 to 40.5, p = 0.01). Most subjects (70%) preferred incorporating the new tablets into their usual protein substitute regimen. CONCLUSIONS: Amino acid tablets are an effective and relatively popular protein substitute in older children, teenagers, and adults with PKU.

Adolescent↗
PubMed2003

Is breast best? Is early solid feeding harmful?

The health benefits of breastfeeding for babies and mothers have long been recognised and it is now globally recommended that it be continued exclusively for six months. Although there are few controlled trials to support this recommendation, the most important advantage is less morbidity from gastrointestinal infection in developing countries. There is also evidence that respiratory tract infections and atopic dermatitis is reduced, and the maternal risk of breast cancer decreases, particularly with a longer duration of breastfeeding and a high parity. There is little to suggest that exclusive breastfeeding for six months adversely affects infant growth, nutritional status or infant feeding skills, but more studies are needed. Equally, there is no evidence that introduction of solids from 17 weeks is harmful in developed countries. However, in the UK breastfeeding prevalence is low and solids are introduced early for the majority of infants and much can be done to positively encourage and support all mothers to continue breastfeeding for a longer period.

Breast Feeding↗
PubMed2003

Transanal endoscopic microsurgery: a viable operative alternative in selected patients with rectal lesions.

BACKGROUND: Local excision of rectal lesions is being increasingly undertaken, especially in those unfit for major surgery. The traditional transanal approach is often cumbersome and limited to low and mid rectal lesions. Transanal endoscopic microsurgery (TEMS) is being used to excise both benign and malignant rectal lesions, including those in the upper rectum. METHODS: Prospective analysis of all patients undergoing a TEMS excision between January 1997 and December 2000 in a specialized colorectal unit. RESULTS: Forty patients underwent a TEMS resection, with a mean age of 72 years (SD, 10 years). The mean distance of the lesions from the anal verge was 9.8 cm (SD, 3.1 cm). In 24 patients, the lesion was located >or=10 cm from the anal verge, making them unsuitable for traditional transanal resection. The mean operative time was 91 minutes (SD, 34 minutes), and the mean postoperative stay was 3 days (SD, 1.5 days). No mortality was associated with the procedure, and there was minimal morbidity in 15%. There has been no recurrence in the 18 patients who had a malignant lesion excised. CONCLUSIONS: The TEMS operating system provides the surgeon with a suitable alternative for the resection of benign and malignant rectal neoplasms in selected patients. It has the advantage of providing visual clarity of the operative field, allowing more precise dissection and a minimally invasive approach to mid and upper rectal lesions. There has been no mortality and minimal morbidity. We advocate its inclusion as part of a colorectal surgeon's operative armamentarium for these selected cases.

Aged↗
PubMed2003

Pilot study: quality of life assessment of postnatal fatigue and other physical morbidity.

Postnatal morbidity is increasingly recognized, but standard assessments may not capture what is most important to the woman with such morbidity in terms of her quality of life. The Mother-Generated Index (MGI) is a proposed postnatal quality-of-life instrument which allows the mother to determine both content and scoring. In this pilot study we found that although a degree of psychological and physical morbidity (including tiredness) is common, and may be very significant, for most women these factors are low-grade, and other aspects of their lives are more important. A quality-of-life approach allows the mother to determine her own postnatal assessment, and encourages practitioners to view her more holistically.

Adolescent↗
PubMed2002

How practical are recommendations for dietary control in phenylketonuria?

In patients with phenylketonuria, blood phenylalanine concentration during childhood is the major determinant of cognitive outcome. Guidelines provide age-related recommendations for treatment. To ascertain the extent to which these aims are achievable, we audited results from four centres for the years 1994-2000. The median proportion of samples with phenylalanine concentrations above those recommended was less than 30% for those younger than age 10 years but almost 80% for those aged 15 years and older. Similarly, the median frequency of blood sampling, expressed as a proportion of that recommended, was more than 80% for patients younger than 10 years but less than 50% by age 15 years. Our results indicate the difficulty of maintaining control in phenylketonuria, especially in older rather than younger children.

Adolescent↗
PubMed2002

The measurement of engagement in the homeless mentally ill: the Homeless Engagement and Acceptance Scale--HEAS.

BACKGROUND: Much of the difficulty in helping the homeless mentally ill arises as a consequence of their resistance to engagement. A refused intervention can seldom influence a client's problems and engagement status can be argued as being an important independent predictor of outcome. No instrument could be identified which systematically measured the factors involved. This paper describes the development and psychometric properties of a new scale, the Homeless Engagement and Acceptance Scale (HEAS). METHOD: Staff from an established project for the homeless mentally ill helped to identify relevant questions used to develop a five-item rating scale for completion by an informant. After piloting, the instrument was tested in a study in which subjects were assessed twice over 12 months by informants. Item analysis was undertaken and predictive validity was assessed. RESULTS: Item analysis indicated a good facility index signifying all items were able to differentiate subjects according to the characteristic being measured, and a high discrimination index demonstrating that all items were measuring the same concept. Predictive validity and internal consistency coefficients were both good. The 3 month HEAS score was found to be a significant predictor of accommodation status and adequacy of a support network at 12 months. CONCLUSIONS: The good psychometric properties and predictive validity of the scale suggest the HEAS is likely to be a useful tool in assessing engagement status. One of the five questions (Q4) can be omitted for those who are not homeless and the scale termed the Engagement and Acceptance Scale (EAS).

Defense Mechanisms↗
PubMed2002

Relaxation to bradykinin in bovine pulmonary supernumerary arteries can be mediated by both a nitric oxide-dependent and -independent mechanism.

1. The aim of the present study was to determine the relative contribution of prostanoids, nitric oxide and K(+) channels in the bradykinin-induced relaxation of bovine pulmonary supernumerary arteries. 2. In endothelium-intact, but not denuded rings, bradykinin produced a concentration-dependent relaxation (pEC(50), 9.6+/-0.1), which was unaffected by the cyclo-oxygenase inhibitor indomethacin. The nitric oxide scavenger hydroxocobalamin (200 micro M, pEC(50), 8.5+/-0.2) and the nitric oxide synthase inhibitor L-NAME (100 micro M, pEC(50), 8.9+/-0.1) and the combination of L-NAME and hydroxocobalamin (pEC(50), 8.1+/-0.2) produced rightward shifts in the bradykinin concentration response curve. 3. The guanylyl cyclase inhibitor ODQ (10 micro M, pEC(50), 9.6+/-0.4) did not affect the response to bradykinin. 4. Elevating the extracellular [K(+)] to 30 mM did not affect the response to bradykinin but abolished the response when ODQ or L-NAME was present. 5. The K(+) channel blocker apamin (100 nM), combined with charybdotoxin (100 nM), produced a small reduction in the maximum response to bradykinin but they abolished the response to bradykinin when ODQ, L-NAME or hydroxocobalamin were present. Apamin (100 nM) combined with iberiotoxin (100 nM) also reduced the response to bradykinin in the presence of hydroxocobalamin or L-NAME. 6. The concentration response curve for sodium nitroprusside-induced relaxation was abolished by ODQ (10 micro M) and shifted to the right by apamin and charybdotoxin. 7. These studies suggest that in bovine pulmonary supernumerary arteries bradykinin can stimulate the formation of nitric oxide and activate an EDHF-like mechanism and that either of these pathways alone can mediate the bradykinin-induced relaxation. In addition nitric oxide, acting through guanylyl cyclase, can activate an apamin/charbydotoxin-sensitive K(+) channel in this tissue.

Animals↗
PubMed2002

Involvement of gap junctions in bradykinin-induced relaxation of bovine pulmonary supernumerary arteries before and after inhibition of nitric oxide/guanylate cyclase.

This study evaluated the possible contribution of gap junctions to the nitric oxide (NO)- and endothelium-derived hyperpolarizing factor (EDHF)-mediated responses elicited by bradykinin in bovine pulmonary supernumerary arteries. In artery rings with an intact endothelium and treated with the cyclo-oxygenase inhibitor indomethacin (10 microM), bradykinin (100 pM-1 microM) produced a concentration-dependent relaxation [-logEC(50) (pEC(50)), 9.6+/-0.2; maximum relaxation ( R (max)), 89.7+/-14.8%; n =6]. The NO synthase inhibitor N (G)-nitro-L-arginine methyl ester (L-NAME; 100 microM) and the NO scavenger hydroxocobalamin (200 microM) each produced a rightward shift in the bradykinin concentration-response curve [pEC(50): L-NAME, 8.9+/-0.1 ( n =6; P <0.01); hydroxocobalamin, 8.3+/-0.2, ( n =6; P <0.001)]. However, the soluble guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 10 microM) did not significantly alter the response to bradykinin (pEC(50) 9.4+/-0.2; n =9). The gap junction inhibitor carbenoxolone (100 microM) did not affect the relaxation produced by bradykinin (pEC(50), 9.7+/-0.1; R (max), 100+/-3.2%; n =6), but it significantly depressed R (max) when L-NAME, hydroxocobalamin or ODQ was present. Further, carbenoxolone produced a rightward shift in the bradykinin concentration-response curve in the presence of ODQ (8.4+/-0.1; n =6, P <0.01). The data suggest that, in bovine pulmonary supernumerary arteries, gap junctions may, in part, facilitate the EDHF-mediated response, but not the NO-mediated response, to bradykinin. However, the additional involvement of an unidentified endothelial relaxing factor cannot be excluded.

Animals↗
PubMed2002

An observational study to evaluate micronutrient status during enteral feeding.

BACKGROUND: There are few data on the optimal micronutrient composition of paediatric enteral feeds. The recent European Directive on Foods for Special Medical Purposes (1999/21/EC) did not distinguish between the composition of adult and paediatric feeds. AIMS: To evaluate, in an open, observational study, the long term nutritional biochemistry of 12 children aged 1-6 years and/or 8-20 kg. METHODS: The children were receiving at least 50% of their estimated average requirement (EAR) for energy from paediatric enteral formulae: 1.0 kcal/ml (Nutrison Paediatric Standard) or 1.5 kcal/ml (Nutrison Paediatric Energy Plus). Venous blood samples for trace elements, vitamins, and minerals were taken at study entry and six months later. Parents kept three day food and feed records every month. RESULTS: Despite a median energy intake of only 75% EAR (range 52-158%), 67% (n = 8) achieved their reference nutrient intake (RNI) for all micronutrients. No significant micronutrient deficiencies were seen on blood analysis after six months. Eighty three per cent (n = 10) had vitamin B(12) and 92% (n = 11) had copper intake >150% RNI. Fifty eight per cent (n = 7) had high plasma B(12) (>733 micromol/l) and 75% (n = 9) had high serum copper (>22 micromol/l) concentrations. CONCLUSIONS: Children without excess losses maintain adequate micronutrient status on long term enteral feeding. Subjects had high blood concentrations of vitamin B(12) and copper, and had high dietary intakes of these micronutrients. We suggest that the maximum nutrient guidelines for paediatric enteral feeds should be more clearly defined.

Body Weight↗
PubMed2001

Improving tolerability of immunosuppressive regimens.

CNIs and corticosteroids are associated with adverse effects that can diminish quality of life and detrimentally affect long-term allograft and patient survival. Nephrotoxicity is the major side effect of CNI therapy. A search has been ongoing for improved immunosuppressive regimens that will provide adequate protection against acute allograft rejection, while decreasing the nephrotoxic and other effects associated with CNIs. This paper reviewed the immunosuppressive agent sirolimus as a potential new option in transplantation, focusing on its mechanism of action and clinical efficacy as well as potential antiproliferative and antineoplastic properties. The findings and lessons learned from key clinical studies in which sirolimus was used to augment or replace CNIs and/or corticosteroids were highlighted, and the importance of clinical pharmacokinetics and therapeutic drug monitoring in these regimens were discussed. Preliminary studies of combination therapy with sirolimus and tacrolimus in solid organ transplantation indicate that sirolimus/tacrolimus combination therapy may provide strong protection against acute rejection and diminish the nephrotoxicity associated with CNI-based therapy. Other studies suggest that sirolimus can be used as base immunosuppressive therapy, thereby completely avoiding the nephrotoxicity associated with CNI-based therapies, while continuing to provide powerful protection against rejection. With patients surviving longer with functional allografts, quality of life is becoming an increasing important clinical endpoint in transplantation. The studies reviewed here suggest that sirolimus might be used to improve quality of life significantly without increasing the risk of allograft rejection or shortening patient survival.

Adrenal Cortex Hormones↗
PubMed2001

The alpha(1A)-adrenoceptor subtype mediates contraction in rat femoral resistance arteries.

In this study, alpha(1)-adrenoceptor subtypes were characterised in rat femoral resistance arteries mounted on a small vessel myograph. A-61603 was found to be more potent than noradrenaline and phenylephrine in these arteries. Brimonidine (UK 14304) could not evoke any contractile responses and the sensitivity to noradrenaline and phenylephrine was not affected by (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine (RS 79948), ruling out the presence of alpha(2)-adrenoceptors. Prazosin, 5-methyl-urapidil and 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB 4101) produced rightward shifts in the sensitivity to noradrenaline, giving pA(2) values of 9.6, 9.4 and 10.4, respectively, in agreement with the presence of alpha(1A)-adrenoceptors. (8-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY 7378; 1 microM) produced a small shift in the sensitivity of noradrenaline giving a pK(B) of 7.2. In the presence of 300 nM 5-methyl-urapidil, sensitivity to noradrenaline was not further shifted by 1 microM BMY 7378. Responses to noradrenaline were unaffected by the alpha(1B)-adrenoceptor alkylating agent chloroethylclonidine (1 microM). These results suggest alpha(1A)-adrenoceptors mediate contractile responses to noradrenaline in rat femoral resistance arteries.

Adrenergic alpha-1 Receptor Agonists↗
PubMed2001

Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia.

BACKGROUND: Previously we proposed that dorsolateral prefrontal cortex (PFC) supports a specific working memory (WM) subcomponent: the ability to represent and maintain context information necessary to guide appropriate task behavior. By context, we mean prior task-relevant information represented in such a form that it supports selection of the appropriate behavioral response. Furthermore, we hypothesized that WM deficits in schizophrenia reflect impaired context processing due to a disturbance in dorsolateral PFC. We use functional magnetic resonance imaging to examine PFC activation in medication-naive, first-episode patients with schizophrenia during a WM, task-isolating context processing. METHODS: Fourteen first-episode, medication-naive patients with schizophrenia and 12 controls similar in age, sex, and parental education underwent functional magnetic resonance imaging during performance of an A-X version of the Continuous Performance Test. RESULTS: Patients with schizophrenia demonstrated deficits in dorsolateral PFC activation in task conditions requiring context processing but showed intact activation of posterior and inferior PFC. In addition, patients demonstrated intact activation of the primary motor and somatosensory cortex in response to stimulus processing demands. CONCLUSIONS: These results demonstrate selectivity in dorsolateral PFC dysfunction among medication-naive first-episode patients with schizophrenia, suggesting that a specific deficit in PFC function is present at illness onset, prior to the administration of medication or the most confounding effects of illness duration. Furthermore, these results are consistent with the hypothesis that WM deficits in patients with schizophrenia reflect an impairment in context processing due to a disturbance in dorsolateral PFC function.

Adult↗
PubMed2001

Increased alpha(1)- and alpha(2)-adrenoceptor-mediated contractile responses of human skeletal muscle resistance arteries in chronic limb ischemia.

OBJECTIVE: Recently, we have shown augmented contractile responses of skeletal muscle resistance arteries to noradrenaline in patients with critical limb ischemia. We investigated whether this increased sensitivity in skeletal muscle resistance arteries is due to either alpha(1)- or alpha(2)-adrenoceptor-mediated responses or both. METHODS: Skeletal muscle resistance arteries were isolated from the proximal (non-ischemic) and distal (ischemic) parts of limbs amputated for critical limb ischemia and mounted on a small vessel wire myograph. Cumulative concentration response curves of the vessel segments to noradrenaline, phenylephrine and brimonidine were obtained in the presence or the absence of the selective antagonists, prazosin and RS79948. RESULTS: Noradrenaline and phenylephrine produced almost equal maximal contractile responses. Brimonidine responses were smaller and were almost abolished by 0.1 microM RS 79948 while those of phenylephrine and noradrenaline were not affected. Prazosin reduced the maximum responses to brimonidine, shifted the concentration response curves of noradrenaline and phenylephrine rightwards giving pK(B) values of 9.86 and 9.33, respectively. Maximum responses produced by all three agonists in distal vessels were significantly higher than those obtained in proximal vessels. CONCLUSIONS: Noradrenaline contractile responses in skeletal muscle resistance arteries are predominantly mediated by alpha(1)-adrenoceptors. Both alpha(1)- and alpha(2)-adrenoceptor-mediated responses are increased in the arteries from ischemic regions that may aggravate the decreased blood flow to the limbs due to arterial occlusion.

Adrenergic alpha-Agonists↗
PubMed2001

Functional characterization of alpha(1)-adrenoceptor subtypes in human skeletal muscle resistance arteries.

alpha(1)-adrenoceptor subtypes in human skeletal muscle resistance arteries were characterized using agonists noradrenaline (non-selective) and A61603 (alpha(1A)-selective), the antagonists prazosin (non-selective), 5-methyl-urapidil (alpha(1A)-selective) and BMY7378 (alpha(1D)-selective) and the alkylating agent chloroethylclonidine (preferential for alpha(1B)). Small arteries were obtained from the non-ischaemic skeletal muscle of limbs amputated for critical limb ischaemia and isometric tension recorded using wire myography. Prazosin antagonized responses to noradrenaline with a pA(2) value of 9.18, consistent with the presence of alpha(1)-adrenoceptors, although the Schild slope (1.32) was significantly different from unity. 5-Methyl-urapidil competitively antagonized responses to noradrenaline with a pK(B) value of 8.48 and a Schild slope of 0.99, consistent with the presence of alpha(1A)-adrenoceptors. In the presence of 300 nM 5-methyl-urapidil, noradrenaline exhibited biphasic concentration response curves, indicating the presence of a minor population of a 5-methyl-urapidil-resistant subtype. Contractile responses to noradrenaline were not affected by 1 microM chloroethylclonidine suggesting the absence of alpha(1B)-adrenoceptors. Maximum responses to noradrenaline and A61603 were reduced to a similar extent by 10 microM chloroethylclonidine, suggesting an effect of chloroethylclonidine at alpha(1A)-adrenoceptors at the higher concentration. BMY7378 (10 and 100 nM) had no effect on responses to noradrenaline. BMY7378 (1 microM) poorly shifted the potency of noradrenaline giving a pA(2) of 6.52. These results rule out the presence of the alpha(1D)-subtype. These results show that contractile responses to noradrenaline in human skeletal muscle resistance arteries are predominantly mediated by the alpha(1A)-adrenoceptor subtype with a minor population of an unknown alpha(1)-adrenoceptor subtype.

Adrenergic alpha-Agonists↗
PubMed2001

Insulin-mediated vasorelaxation in pregnancy.

OBJECTIVE: To investigate insulin-mediated vasorelaxation in pregnancy, and the role of nitric oxide in this response. DESIGN: In vitro study of isolated subcutaneous resistance arteries from pregnant and non-pregnant women. METHODS: Small arteries (mean vessel diameter <300 microm) were isolated from biopsies of subcutaneous fat from 14 pregnant and seven non-pregnant women. Insulin-mediated attenuation of the vasoconstriction response to noradrenaline, before and after nitric oxide synthase inhibition, was studied in isolated arteries using wire myography. Vessel responses to noradrenaline following incubation with insulin were also tested after endothelial denudation. Maximum responses were compared using one-way ANOVA and Bonferroni's post hoc test for multiple comparisons. RESULTS: In pregnancy, the maximum vasoconstriction produced by noradrenaline was increased (P < 0.01). Insulin significantly reduced this response in pregnant women (P < 0.01), while inhibition of nitric oxide synthase with Nomega-nitro-L-arginine methyl ester (L-NAME) resulted in potentiation (P < 0.05). Following inhibition of nitric oxide synthase with L-NAME, addition of the insulin was still able to produce a significant attenuation in maximum vasoconstriction to noradrenaline in pregnant women (P < 0.01). Furthermore, the absence of functioning endothelium did not abolish the attenuating effect of the insulin on noradrenaline-induced vasoconstriction in pregnant women (P < 0.01). CONCLUSIONS: The vasodilatory effect of insulin is not diminished in pregnancy, despite the development of insulin resistance. Furthermore, the attenuation of vasoconstrictor tone is via an endothelium-independent mechanism. This suggests that the vascular dysfunction associated with diabetes mellitus does not occur with physiological insulin resistance.

Adult↗