Pyoderma gangrenosum on varicella lesions.
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Adult↗
Biomedical subjects
A St John
Publications and source records attributed to A St John.
HIV evolution: CTL escape mutation and reversion after transmission.
Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.
Adult↗
The value of blood lactate measurements in ICU: an evaluation of the role in the management of patients on haemofiltration.
In response to clinical demand some point-of-care analysers now provide blood lactate measurements, but recently concern has been expressed about the value and interpretation of these measurements. We undertook this study to evaluate blood lactate measurements in patients with acute renal failure undergoing haemofiltration (HF) with lactate replacement fluid. At baseline, 27 patients had base deficits of >5 mmol/l and 14 (52%) had blood lactates of >3.5 mmol/l. Lactate 'tolerance' was monitored by peak changes in these parameters during the procedure. There was a worsening of base deficit in only three of the patients in whom lactate rises exceeded 10 mmol/l with one survivor. Twelve patients with rises of blood lactate greater than 5 mmol/l improved their base deficit (+1 to +17) with eight (67%) survivors. Of the remaining 12 patients with improved base deficit (+2 to +20), 10 (83%) survived. Lactate tolerance was compromised in patients with co-incidental liver disease, those on inotropic support, and in patients with initial blood lactate measurements of >10 mmol/l and large base deficits. The data suggest that blood lactate and simultaneous acid-base response measurements during HF help to assign correct buffer replacement and should be performed on all patients.
Acute Kidney Injury↗
A connectivity standard for point-of-care testing.
A software standard has been designed that will facilitate the linking of all point-of-care testing (POCT) devices to information systems. This standard will replace the myriad of proprietary and incompatible solutions that currently exist. The standard is expected to be a feature of new POCT instruments by 2002.
Computer Communication Networks↗
Regulated gene expression in Staphylococcus aureus for identifying conditional lethal phenotypes and antibiotic mode of action.
Selectively regulating gene expression in bacteria has provided an important tool for studying gene function. However, well-regulated gene control systems have been restricted primarily for use in laboratory non-pathogenic strains of bacteria (e.g. Escherichia coli, Bacillus subtilis). The development of analogous systems for use in bacterial pathogens such as Staphylococcus aureus would significantly enhance our ability to examine the contribution of any given gene product to pathogen growth and viability. In this report, we adapt, examine and compare three regulated gene expression systems in S. aureus, which had previously been used in B. subtilis. We demonstrate that all three systems function and exhibit titratable induction, together covering a dynamic range of gene expression of approximately 3000-fold. This dynamic range correlates well with the physiological expression levels of cellular proteins. Importantly, we show that one of these systems, the Spac system, is particularly useful for examining gene essentiality and creating specific conditional lethal phenotypes. Moreover, we find that titration of selective target gene products using this system allows direct demonstration of antibiotic mode of action.
Anti-Bacterial Agents↗
Antiphospholipid syndrome with proliferative vasculopathy and bowel infarction.
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Adult↗
Secondary hyperparathyroidism in patients from Western Australia with hip fracture: relationship to type of hip fracture, renal function, and vitamin D deficiency.
OBJECTIVES: To determine the frequency of vitamin D deficiency and secondary hyperparathyroidism in Australian hip fracture patients living in the community. PATIENTS: A total of 283 consecutive patients with hip fracture admitted over a 15-month period to a university teaching hospital in Western Australia. Included were residents of hostels for the elderly, and excluded were nursing home residents and those with malignant fractures. METHOD: Data collected included biochemistry (25 hydroxyvitamin D, parathyroid hormone and creatinine levels), measurements of function and disability (Barthel Index, Frenchay Activity Index), sunshine exposure, and basic demographics. RESULTS: Vitamin D deficiency occurred in 31.7% and secondary hyperparathyroidism occurred in 17.7% of cases. The major determinants of vitamin D deficiency were outdoor sunshine exposure, ambient daily sunshine, and disability (low Frenchay Activity Index or ADL difficulty). Secondary hyperparathyroidism was related to older age, renal dysfunction, and vitamin D deficiency. Secondary hyperparathyroidism was associated with an excess of trochanteric over subcapital hip fractures. CONCLUSIONS: Secondary hyperparathyroidism appears to be a heterogeneous condition, caused in approximately equal proportions by vitamin D deficiency and renal dysfunction, that may confer increased cortical bone fragility and trochanteric fractures. Renal dysfunction in old age may be an important additional determinant of senile osteoporosis, which has implications for preventive therapy. Vitamin D deficiency occurs in disabled and, presumably, housebound older people despite near optimal climatic conditions.
Activities of Daily Living↗
The effect of estrogen deficiency on bone mineral density, renal calcium and phosphorus handling and calcitropic hormones in the rat.
The oophorectomized (OOX) rat has been proposed as a good model of postmenopausal osteoporosis in women. The aim of this study was to compare the effect of OOX in 6-month-old rats to the effects of menopause in women with respect to bone mass, the renal handling of calcium and phosphorus, and calcitropic hormones. To more closely replicate the human situation the rats were pair fed a 0.1% calcium diet. Thirty four, 6-month-old rats were randomized to sham operation or OOX. Whole body and regional bone density was performed at baseline and 6 weeks postoperation. Blood and 24-hour urine samples were obtained at baseline, 1, 3, and 6 weeks and assayed for various biochemical variables, parathyroid hormone (PTH), and calcitriol. The OOX rats lost significantly more bone than the sham-operated rats (change in global bone mineral density, sham -1.7 +/- 2.0%, OOX -3.9 +/- 2.6%, P < 0.001). In the OOX animals, an increase in the 24-hour urine calcium was observed at 1 and 3 weeks, which had returned to sham-operated levels by 6 weeks. In the whole group, the increase in urine calcium at 1 week was negatively correlated with the change in bone mass at 6 weeks (r = -0.39, P = 0. 029). OOX resulted in an increased filtered load of calcium and phosphorus. There was an increase in the maximal renal tubular reabsorption of phosphorus (TmP-GFR) but no clear change in renal calcium handling. Neither calcitriol nor parathyroid hormone showed a significant change as a result of OOX. As in postmenopausal women, following oophorectomy in the rat, there was significant generalized bone loss and a negative calcium balance. This was associated with an initial rise in urine calcium due to a rise in the filtered calcium load; plasma phosphorus and TmP-GFR also rose. The rat model may differ from postmenopausal bone loss in that the initial rise in urine calcium was not present at later time points as occurs in natural menopause in women. Calcitropic hormone levels did not change. This study has shown that the 6-month-old OOX rat fed a 0.1% calcium diet has many similarities of calcium and phosphorus homeostasis to that seen at menopause in women.
Absorptiometry, Photon↗
The effects of menopause and age on calcitropic hormones: a cross-sectional study of 655 healthy women aged 35 to 90.
Although women lose 30% of their skeletal mass after the menopause, the mechanism of this loss is uncertain. Clearly estrogen deficiency is important but whether this works only through direct effects on the skeleton is uncertain. To examine these mechanisms further we have evaluated calcium-related metabolic factors in 655 healthy women. Fasting blood samples were collected from all subjects who were up to 35 years past the menopause, and fasting urine and 24-h urine samples were collected in 365 women who were up to 25 years past the menopause. In the first 15 years postmenopause, there was a rise in total plasma calcium due to a rise in albumin. Bone resorption (hydroxyproline creatinine ratio), bone formation (alkaline phosphatase), and the urine calcium creatinine ratio all rose at menopause and remained elevated for the next 25 years. There was a transient further rise in bone resorption for the 10 years following menopause. Neither PTH nor the free calcitriol index changed for the first 10 years following menopause. Ten years past the menopause, although total calcitriol rose, the free calcitriol index fell due to a rise in vitamin D binding protein. PTH began to rise at 15 years past menopause. GFR fell gradually over the 25 years following menopause. Thus following menopause there is an increase in bone turnover and increased urine calcium loss independent of any effect of PTH or calcitriol, suggesting a direct effect of estrogen deficiency on bone and kidney.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The metabolism of platelet-activating factor in severe and cerebral malaria.
In order to examine the effects of platelet-activating factor (PAF) in complicated Plasmodium falciparum infections, plasma concentrations of lyso-PAF, stable metabolite and principal precursor of PAF, were measured in 25 Vietnamese adults with severe malaria. The concentration of PAF in the cerebrospinal fluid (CSF) was determined in a sub-group of 23 comatose patients and, together with that of lyso-PAF, in the plasma of 20 patients on recovery of consciousness. The concentration of lyso-PAF in the plasma was depressed on admission to hospital (median [range]; 21 [8-143] vs. 293 [215-410] ng/ml in 10 controls; P < 0.001). There was, however, no change in plasma activity of acetylhydrolase which converts PAF to lyso-PAF (P > 0.01 vs. controls) while simultaneous reduction in the concentration of lipoproteins associated with lyso-PAF were less than those of lyso-PAF per se in the plasma. The plasma concentration of lyso-PAF on admission was associated with parasitaemia and the concentration of serum triglycerides (rs = -0.42, P = 0.04 in each case), the latter being consistent with hepatic effects of PAF reported in previous studies. CSF concentrations of PAF on admission were low (2.3 [0.5-7.7] vs. 0.9 [0-2.5] ng/ml after recovery, P < 0.01) compared with values reported previously in bacterial meningitis. Plasma concentrations of lyso-PAF after recovery lay between admission and control values. While increased availability of PAF may reflect parasite burden and may modulate liver-mediated metabolic disturbances such as hypoglycaemia and lactic acidosis, the role of PAF in cerebral malaria is uncertain.
Adult↗
Dynamic assessment of the electrocardiographic QT interval during citrate infusion in healthy volunteers.
OBJECTIVE: To investigate changes in the electrocardiographic QT interval during rapidly induced, sustained hypocalcaemia in healthy volunteers. DESIGN: Serial rate corrected QT measurements were made during and after a variable rate trisodium citrate infusion designed to "clamp" the whole blood ionised calcium concentration 0.20 mmol/l below baseline for 120 min. SUBJECTS: 12 healthy teetotallers aged 19- 36 years who were not receiving medication known to influence calcium homoeostasis. MAIN OUTCOME MEASURES: Whole blood ionised calcium concentration and QaTc intervals (onset of the Q wave to T wave apex divided by the square root of the RR interval). RESULTS: Mean (SD) ionised calcium concentration decreased from 1.18 (0.03) mmol/l preinfusion to values close to target (0.98 mmol/l) between 10 and 120 min. The QaTc interval lengthened from a baseline of 0.309 (0.021) to a maximum 0.343 (0.024) s0.5 at 10 min before returning to a stable level from 15 to 120 min (0.334 (0.023) and 0.330 (0.023) s0.5 respectively). The change from baseline of both variables expressed as a ratio (delta QaTc/ delta [Ca2+]) was greater during rapid induction of hypocalcaemia (at 5 and 10 min) than at other times during and after the infusion (P < 0.02). CONCLUSIONS: The disproportionate prolongation of QaTc interval during prompt induction of hypocalcaemia suggests rate dependency which can be represented by a hysteresis relation between (ionised calcium, QaTc) coordinates. This finding may have clinical implications.
Adult↗
Serum parathyroid hormone concentrations in patients with HIV infection.
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Acquired Immunodeficiency Syndrome↗
Mineral homoeostasis in acute renal failure complicating severe falciparum malaria.
Disturbances in calcium metabolism in acute renal failure (ARF) remain incompletely understood. Most data are from patients with rhabdomyolysis. As renal impairment commonly accompanies severe malaria in the absence of rhabdomyolysis, falciparum malaria provides an alternative model of mineral homoeostasis in ARF. We studied 25 Vietnamese subjects, aged 18-63 yr, with severe malaria and 10 controls. Fourteen patients had a serum creatinine level of 250 mumol/L or less during treatment (group 1), five developed ARF but were not dialyzed (group 2a), and six required dialysis (group 2b). Group 1 patients presented with mild hypocalcemia (mean +/- SD serum ionized calcium, 1.18 +/- 0.05 vs. 1.23 +/- 0.02 mmol/L in controls; P = 0.01) that persisted until discharge in the presence of normal serum phosphate, PTH, and vitamin D metabolite levels. Group 2 patients were more hypocalcemic on admission (1.10 +/- 0.08 mmol/L; P < 0.0001 vs. controls), especially those in group 2b whose serum ionized calcium fell to 0.88 +/- 0.13 mmol/L when renal dysfunction was maximal. In group 2 patients, the admission serum PTH level was raised (5.4 +/- 3.8 vs. 2.7 +/- 0.9 pmol/L in controls; P < 0.02) and changed reciprocally with calcemia. Significant rises in serum phosphate occurred only in group 2b patients who had depressed serum free 1,25-dihydroxyvitamin D levels throughout. Hypercalcemia did not accompany the diuretic phase of ARF. These data suggest that parathyroid gland dysfunction is a cause of hypocalcemia in severe malaria without ARF, as seen in group 1 patients; in patients with ARF, the effect of the combination of phosphate retention and altered vitamin D metabolism on skeletal PTH sensitivity is of prime significance.
Acute Kidney Injury↗
Secondary hyperparathyroidism, vitamin D deficiency and hip fracture: importance of sampling times after fracture.
There is controversy about how often elevated parathyroid hormone (PTH) levels are found in hip fracture patients. The aim of this study was to determine whether changes in PTH levels after fracture and surgery could explain some of the variation in published data. Blood samples were obtained from 24 elderly patients with hip fracture before surgery, immediately after surgery and at 2 weeks and 3 months after fracture. PTH levels were elevated (> 5.5 pmol) in 33% initially and then fell significantly at 2 weeks in virtually all subjects (P < 0.001) and remained significantly lower after 3 months (n = 17). Although 25-hydroxyvitamin D levels were low (< 30 nmol) in 44% of the patients, the fall in PTH was not explained by alterations in vitamin D metabolites or other measured parameters. The cause of the variation in PTH levels is unknown but measurements immediately after fracture could overestimate the incidence of secondary hyperparathyroidism. Vitamin D deficiency is common in our hip fracture population and is not influenced by hospitalisation.
Aged↗
Serum vitamin A and E concentrations in acute falciparum malaria: modulators or markers of severity?
1. To assess the association between vitamin A, vitamin E and the clinical course of severe malaria, serial morning blood samples were taken from 24 Vietnamese patients, aged 18-62 years, receiving intensive treatment for complicated Plasmodium falciparum infections. A single fasting blood sample was also taken from 10 control subjects aged 22-45 years. Serum retinol, carotene and vitamin E concentrations were measured by h.p.l.c. 2. Admission serum retinol concentration was depressed relative to that of the control subjects (0.69 +/- 0.35 versus 1.86 +/- 0.41 mumol/l mean +/- SD, P < 0.001) and correlated inversely with indices of hepatic function, but positively with the simultaneous serum creatinine concentration (P < 0.05). During the first week of treatment, serum retinol concentration increased in parallel with improving liver function, whereas serum creatinine concentration remained elevated in the majority of patients. Serum alpha- and beta-carotene concentrations remained depressed throughout. 3. Serum vitamin E concentration, corrected for total serum cholesterol concentration in the form of a ratio, was also depressed at presentation (3.1 +/- 1.8 x 10(3) versus 4.2 +/- 0.8 x 10(3) in control subjects; P < 0.05), but tended to be higher than the control value at the time of discharge (0.1 > P > 0.05); there was a significant correlation between admission ratio and parasite clearance time (P = 0.04). 4. On the basis of this and previous studies, vitamin A replacement could be considered in selected severely ill patients without renal impairment. As found previously in animal models, depressed vitamin E levels may have a beneficial effect on the course of malarial infection.
Acute Disease↗
Parathyroid function in mild to moderate renal failure: evaluation by oral calcium suppression test.
Alterations of PTH secretion in patients with mild to moderate chronic renal failure were evaluated using an oral calcium suppression test. Ionized calcium and PTH were measured at 0, 30, 60, 120, and 180 min after ingestion of 2 g elemental calcium in 18 patients and 15 control subjects. The mean glomerular filtration rate was significantly lower in the patients compared to the controls (58 +/- 18 vs. 100 +/- 12 mL/min, P < 0.01) but the basal ionized calcium and PTH were not significantly different. After ingestion of calcium there was a similar rise in ionized calcium with time in both patients and controls. However the mean PTH concentration in the patients was significantly higher than the controls at all equivalent ionized calcium concentrations. Overall the patients showed significantly less percentage suppression of PTH compared to control subjects, 63 +/- 10% vs. 74 +/- 9%, P < 0.01. The minimum PTH value was also higher in the patients than the controls, 1.2 +/- 0.7 vs. 0.7 +/- 0.3 pmol/L, P < 0.01. Thus although the majority of patients had PTH levels within the conventional reference range they demonstrated abnormal suppression of PTH secretion. The data from this study would further support the view that treatment for secondary hyperparathyroidism should be started early on in the course of chronic renal failure.
Administration, Oral↗
Relationship between calcitrophic hormones and blood pressure in elderly subjects.
The relationship between calcitrophic hormones and blood pressure has been investigated in 583 elderly subjects who were untreated for hypertension. Univariate analysis demonstrated that serum parathyroid hormone, calcitriol, albumin and calcium were correlated significantly with mean blood pressure (r = +0.15, +0.10, +0.14 and +0.11, respectively), as were body mass index and age (r = +0.19 and +0.10, respectively). Parathyroid hormone also was correlated positively with both age and calcitriol (r = +0.34 and +0.15, respectively) and negatively with plasma calcium and albumin (r = -0.09 and -0.09, respectively). Multivariate analysis demonstrated that when allowing for age and body mass index, parathyroid hormone and calcitriol were both significant independent determinants of the mean blood pressure. When other independent variables were included in the analysis, parathyroid hormone but not calcitriol remained a significant predictor of mean blood pressure. This study has demonstrated a weak but significant relationship between blood pressure and calcitrophic hormones in a group of elderly people. The data are consistent with the hypothesis that hypertension may be due in part to calcium deficiency.
Age Factors↗
A comparison between estimates of GFR using [99mTc]DTPA clearance and the approximation of Cockcroft and Gault.
BACKGROUND: The formula of Cockcroft and Gault, relating age, weight, sex and plasma creatinine is widely used to estimate glomerular function. Its ability to predict [99mTc]DTPA clearance, an accepted measure of GFR, is therefore of interest. AIM: To test prospectively the reliability of the formula in predicting the [99mTc]DTPA clearance in subjects with normal and sub-normal renal function. METHODS: The 24 hour creatinine clearance (Ccr), the derived clearance using the formula (Cder), and the [99mTc]TPA clearance have been compared in 47 male and 47 female subjects, aged between 15 and 71 years. Obese and non-obese subjects (males > 90 kg, females > 80 kg body weight) were considered separately. RESULTS: Across the range of [99mTc]DTPA clearance studied (14 to 125 mL/minute), in non-obese subjects, both Ccr and Cder were correlated similarly with [99mTc]DTPA clearance in males and females. In obese subjects as a group, Cder was also closely correlated with [99mTc]DTPA clearance but the scatter of data was wider. Among non-obese subjects, correlations were high between either Ccr or Cder and [99mTc]DTPA clearance values < 101 mL/minute but were not significant at [99mTc]DTPA clearance values > 100 mL/minute. For [99mTc]DTPA clearance values between 14 and 100 mL/minute, Cder was a more direct and more precise predictor of [99mTc]DTPA clearance [DTPA clearance = 1.01 (Cder) + 2.34, with 95% confidence limits of +/- 18 mL/minute] than of Ccr [Ccr = 1.34(CderC)-10.86, confidence limits +/- 28 mL/minute]. CONCLUSION: For very mild through to moderate renal failure, the formula of Cockcroft and Gault can evidently be used as a reasonable estimate of GFR.
Adolescent↗