Biomedical subjects
Publications and source records attributed to J M Goddard.
Primary erythromelalgia is a rare condition, which is characterised by redness, burning pain, and increased temperature of the extremities. We describe a 6 year old boy with symptoms of erythromelalgia and the difficulty surrounding treatment of this condition. Severe pain responded to the use of regional anaesthetic blocks.
BACKGROUND: Oral midazolam is widely used for preoperative sedation in children. We have studied the pharmacokinetics (PK) of both midazolam and its active 1-hydroxy metabolite and their contributions to sedative effect in 45 children attending for day surgery. METHODS: Blood samples (two per individual) were collected at the beginning and end of the surgical procedure. Plasma midazolam and 1-hydroxymidazolam (1-OHMDZ) were measured by HPLC. Sedation score (score: 1 = awake, 2 = drowsy/asleep) was recorded at the same time as the first blood sample. The population-PK software P-Pharm was used to analyse the data. Age, weight, sex, concomitant drugs, and the metabolic ratio, 1-OHMDZ/midazolam were investigated as co-variates of the PK of midazolam and 1-OHMDZ. The pharmacokinetic-pharmacodynamic (PK-PD) modelling of the score in relation to plasma midazolam and 1-OHMDZ was performed using logistic regression analysis. RESULTS: A median dose of 0.5 mg kg-1 was given to the children, median age 5 yr (range from 9 months to 12 yr) and weight 21 kg (range 8-75 kg). Average concentrations of midazolam 150 ng ml-1 and 1-OHMDZ 90 ng ml-1 were observed in the first plasma samples. These concentrations resulted in an odds ratio of 4 in favour of score 2 vs 1. The best PK-PD model included both midazolam and 1-OHMDZ as active moieties and predicted correct scores in 86% of cases. CONCLUSION: Studies of midazolam should evaluate the contribution of 1-OHMDZ to the overall PD effect. The metabolite 1-OHMDZ has approximately half the activity of the parent drug and can compensate for at least part of the decreased effect due to increased midazolam metabolism.
This study investigated the effect of diclofenac on the lung function of 70 children aged 6-15 years with a diagnosis of asthma, recruited from a hospital respiratory clinic. Peak flow and a forced expiratory flow-volume loop were measured and the patients were then given 1-1.5 mg.kg-1 effervescent diclofenac orally. Spirometry was repeated at 10, 20 and 30 min, a 15% decrease in results being considered a significant reduction in lung function. No patient demonstrated a consistent reduction in lung function of > 15% during the study and there were no reports of wheezing or increased bronchodilator use after completion of the spirometry. In conclusion, we studied a group of genuine asthmatics and found no clinically significant incidence of bronchospasm with the use of a single therapeutic dose of diclofenac.
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Targeted disruption of the Hoxd-10 gene, a 5' member of the mouse HoxD linkage group, produces mice with hindlimb-specific defects in gait and adduction. To determine the underlying causes of this locomotor defect, mutant mice were examined for skeletal, muscular and neural abnormalities. Mutant mice exhibit alterations in the vertebral column and in the bones of the hindlimb. Sacral vertebrae beginning at the level of S2 exhibit homeotic transformations to adopt the morphology of the next most anterior vertebra. In the hindlimb, there is an anterior shift in the position of the patella, an occasional production of an anterior sesamoid bone, and an outward rotation of the lower part of the leg, all of which contribute to the defects in locomotion. No major alterations in hindlimb musculature were observed, but defects in the nervous system were evident. There was a decrease in the number of spinal segments projecting nerve fibers through the sacral plexus to innervate the musculature of the hindlimb. Deletion of a hindlimb nerve was seen in some animals, and a shift was evident in the position of the lumbar lateral motor column. These observations suggest a role for the Hoxd-10 gene in establishing regional identity within the spinal cord and imply that patterning of the spinal cord may have intrinsic components and is not completely imposed by the surrounding mesoderm.
An audit project was designed to assess and improve the provision of postoperative analgesia in a children's hospital. Pain assessment for all children and analgesia standards for our institution were introduced prior to data collection. Data were collected on consecutive samples of 316 and 325 children undergoing surgery as inpatients during 10-week periods. Change was initiated between the two periods in response to our findings; our action plan involved education, changes to documentation, the widespread use of diclofenac in children over 2 years of age and recommendations for the prescription of analgesia. The initial prescription of analgesia increased from 95% to 98% (p = 0.019), administration of analgesia to children experiencing bad or severe pain increased from 57% to 71% (p = 0.032) and the number of children experiencing severe pain reduced from 17% to 11% (p = 0.050). Application of audit, by a clinical nurse specialist, enabled us to achieve and demonstrate improvements in the prescription, administration and effectiveness of postoperative analgesia.
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The function of scavenging equipment is to remove waste anaesthetic gases from the operating theatre and thus reduce the potentially harmful effects these agents may have on staff. However, these systems can pose a serious risk to patients which is not well recognised. We describe two cases where harm to patients could have occurred as a result of faulty or inappropriate equipment being used and inadequate checking of scavenging systems.
Mice were generated with targeted disruptions in the hoxb-1 gene. Two separate mutations were created: the first disrupts only the homeodomain and the second inactivates the first exon as well as the homeodomain. The phenotypes associated with these two mutant alleles are indistinguishable in surviving adult mice. The predominant defect in these mutant mice is a failure to form the somatic motor component of the VIIth (facial) nerve, possibly through a failure to specify these neurons. The phenotype of hoxb-1 mutant homozygotes closely resembles features of the clinical profile associated with humans suffering from Bell's Palsy or Moebius Syndrome. These animals should therefore provide a useful animal model for these human diseases.
Mammals produce two isozymes of angiotensin-converting enzyme (ACE). Somatic ACE plays an important role in the control of blood pressure. The function of testis ACE, produced by male and germ cells, is not known. To examine the roles of these isozymes, we used targeted homologous recombination to introduce a modified ACE allele into a mouse line. Mice homozygous for this mutant allele lack both ACE isozymes and have markedly reduced blood pressures. Contrary to a previous report, we found heterozygous male mice to have normal blood pressures. Homozygous mutant mice also have severe renal disease. The renal papilla is markedly reduced, and the intrarenal arteries exhibit vascular hyperplasia associated with a perivascular inflammatory infiltrate. These animals cannot effectively concentrate urine. They also have an abnormally low urinary sodium to potassium ratio despite reduced levels of aldosterone. Homozygous mutant male mice sire significantly smaller litters than wild-type male mice; however, no defect in sperm number, morphology, or motility was detected. ACE-deficient animals demonstrate the role of this enzyme in systemic blood pressure, renal development and function, and male fertility.
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We derived mice that carry a targeted insertion of a neor gene in the int-2 (Fgf-3) proto-oncogene coding sequences. The mutation was found to be recessive and mice that were homozygous for the insertion did not often survive to adulthood. The mutant mice had defects in the development of the tail and inner ear that could be correlated with disruption of int-2 expression in the posterior primitive streak and hindbrain or otic vesicle. While the tail phenotype was 100% penetrant, we found that the inner ear phenotype had reduced penetrance and variable expressivity. The variable expressivity could not be attributed to variability in the genetic background of the mutant allele or to leaky expression from the mutant allele. Thus, we conclude that even in a uniform genetic background, stochastic variation in the expression of a developmental circuit can result in dramatic differences in phenotypic consequences.
Targeted disruption of the murine hox-A1 gene results in severe defects in the formation of the hindbrain and associated cranial ganglia and nerves. Carbocyanine dye injections were used to trace afferent and efferent projections to and from the hindbrain in hox-A1-/hox-A1- mutant mice. Defects were observed in the position of efferent neurons in the hindbrain and in their projection patterns. In situ hybridization was used to analyze the transcription pattern of genes expressed within specific rhombomeres. Krox-20, int-2 (fgf-3), and hox-B1 all display aberrant patterns of expression in hox-A1- mutant embryos. The observed morphological and molecular defects suggest that there are changes in the formation of the hindbrain extending from rhombomere 3 through rhombomere 8 including the absence of rhombomere 5. Also, motor neurons identified by their axon projection patterns which would normally be present in the missing rhombomere appear to be respecified to or migrate into adjacent rhombomeres, suggesting a role for hox-A1 in the specification of cell identity and/or cell migration in the hindbrain.
A frequent dilemma facing the anaesthetist is the child with respiratory tract symptoms. The risks of anaesthesia and surgery in these patients have not been clearly established. We present three cases which illustrate a potentially serious complication which may arise. Our patients each had symptoms of cough, but were systemically healthy. Two of the children had absent clinical signs, whilst the third had a normal chest X ray. However, during surgery and anaesthesia each child developed significant pulmonary collapse, associated with desaturation on oximetry.
OBJECTIVE: To validate Pediatric Risk of Mortality (PRISM) scoring in infants and children admitted for intensive care. DESIGN: Validation cohort. SETTING: A five-bed pediatric ICU and three cots providing intensive care for surgical neonates, within a 159-bed tertiary care children's hospital. PATIENTS: All patients admitted for intensive care during an 18-month period, January 1990 to July 1991. METHODS: Admission (first 24 hrs) PRISM scoring was introduced as a routine procedure. Discretion was allowed in requesting arterial blood gas measurements and clotting studies. All other parameters were intended to be measured on all patients. MEASUREMENTS AND MAIN RESULTS: PRISM scores were obtained on 380 (88%) of 433 patients. Median age was 15 months. A complete PRISM score was obtained in 24% of cases and a score as intended (i.e., allowing discretionary omissions) was obtained in 56% of patients. Comparison of observed and predicted mortality rates using chi square goodness-of-fit tests showed a significantly better observed outcome for all patients (chi 2(5) = 12.04, p < .05). In-depth analysis indicates that the model works well for children (chi 2(5) = 1.80, p > .75), but that observed outcome is significantly better than predicted for infants (chi 2(5) = 17.46, p < .01). Underscoring of children is not the cause of this finding. CONCLUSIONS: In our center, PRISM scoring overestimates severity of illness in infants. PRISM scoring is not institutionally independent and therefore, at present, a comparison between units may not be justified. A reappraisal of the parameter ranges for infants is suggested.
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