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Biomedical subjects

M Weir

Publications and source records attributed to M Weir.

At least 37 records · Page 2Linked to original sources

Suspecting lumbar spondylolysis in adolescent low back pain.

Spondylolysis in the athletic adolescent and preadolescent is common enough that primary care practitioners should be familiar with its frequency and its progression from pars interarticularis stress fracture to spondylolysis and to spondylolisthesis. One-half of all pediatric back pain in athletic patients is related to disturbances of the posterior elements including spondylolysis, which presents as low back pain aggravated by activity, frequently with minimal physical findings. Failure to suspect, hence to diagnosis, a pars stress fracture or early spondylolysis is common and a misdiagnosis of lumbosacral strain is often made. A complicating factor in early diagnosis is the fact that plain radiographs, even with oblique films, may not be helpful at the stress fracture stage, and other imaging techniques (bone scan possibly with single photon emission computed tomography [SPECT]) must be used early in the diagnostic process. In the primary care setting, an early diagnosis of posterior element involvement in low back pain either at the stage of pars stress fracture or early spondylolysis can prevent progression of the disease and the need for aggressive intervention for a more significant defect. We present three adolescent and preadolescent athletes with low back pain in whom a high index of suspicion led to the early diagnosis of pars stress fracture or spondylolysis. All three had different stages of spondylolysis, and one illustrates the clinical utility of the one-legged hyperextension test. The ease with which early disease may be treated further supports efforts by primary care practitioners to suspect and diagnose pars stress fracture and early spondylolysis.

Adolescent↗

The vascular architecture of renal cell carcinoma in fine-needle aspiration biopsies. An aid in its distinction from hepatocellular carcinoma.

BACKGROUND: The morphologic similarities between renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) can cause diagnostic difficulty in fine-needle aspiration biopsy (FNAB) specimens. In the authors' prior study of liver FNAB, peripherally wrapping endothelium (PE) and arborizing transgressing endothelium (TE) were 100% specific for HCC relative to metastatic tumors, which included only three RCCs. In this study, the vascular patterns of RCC in FNAB were reviewed for comparison with HCC, to determine their usefulness in the differential diagnosis of HCC and RCC. METHODS: FNAB of 49 RCCs (26 primary and 23 metastatic) from 46 patients were reviewed. Four vascular patterns were assessed: PE, TE, papillary endothelium (PAP) in fibrovascular cores of papillary fragments, and short nonbranching endothelium (SE) in small cell clusters. Each pattern was given a semiquantitative score: absent (0), focal (1), or extensive (2). Cellularity was categorized as low (< 20 groups), moderate (20-50 groups), or high (> 50 groups). RESULTS: Vessels were present in 19 of 26 (73%) primary and 9 of 23 (39%) secondary RCC. PE was not identified. TE was observed in 11 primary (42%) and 7 metastatic (30%) RCC. SE was present in 5 primary (19%) and 1 metastatic (4%) RCC. The TE and SE patterns were distributed among the clear cell, granular cell, and chromophobe RCC. PAP was observed in all four papillary RCC. The majority of the TE and all of the PAP were present in moderately to highly cellular FNABs, whereas SE was usually observed in FNABs with low cellularity. CONCLUSIONS: FNAB specimens of RCC commonly contain TE, as in HCC, but lack PE. TE was less frequent in metastatic than primary RCC. Other vascular patterns (SE, PAP), absent in HCC, were observed infrequently. Vascular patterns, especially PE, are useful in distinguishing HCC from RCC.

Biopsy, Needle↗

Antihypertensive effects of mibefradil: a double-blind comparison with diltiazem CD.

BACKGROUND AND HYPOTHESIS: Mibefradil is the first compound of a new class of calcium antagonists with a unique chemical structure and mechanism of action. This trial compared mibefradil with diltiazem CD, a widely prescribed calcium antagonist for the treatment of hypertension. METHODS: In all, 201 patients with uncomplicated, mild-to-moderate essential hypertension with a baseline sitting diastolic blood pressure (SDBP) of > or = 95 and < or = 114 mmHg were evenly randomized to receive either mibefradil (100 mg) or diltiazem CD (360 mg) daily for 12 weeks. To determine whether antihypertensive effects persisted after 12 weeks, patients then entered a 4-week withdrawal period during which they remained on active treatment or were switched to placebo. RESULTS: Efficacy variables were the changes from baseline in SDBP to the end of the treatment period (Week 12) and during the randomized withdrawal period (Week 16). At Week 12, the reduction from baseline in SDBP at trough was significantly greater (p < 0.001) in the mibefradil group (-14.0 +/- 7.8 mmHg) than in the diltiazem CD group (-9.5 +/- 7.5 mmHg). Significantly more patients (72%) on mibefradil achieved SDBP normalization by Week 12 than did patients on diltiazem (51%) (p < 0.01). Patients maintained on mibefradil or diltiazem CD during the withdrawal period had a significantly larger reduction in trough SDBP at Week 16 than those switched to placebo. The incidence of side effects was similar in both treatment groups. CONCLUSIONS: Once-daily mibefradil was equally well tolerated as diltiazem CD, but was more effective in lowering blood pressure at the doses studied than the extended-release formulation of diltiazem.

Adult↗

The effects of oral versus written instructions on parents' recall and satisfaction after pediatric appointments.

This study explored the differential effects of written versus oral instructions on parents' recall of information and satisfaction after pediatric appointments. Ninety-six parents completed descriptive information and satisfaction ratings, and four pediatricians completed ratings concerning the complexity level of the appointment. After the appointment, parents were randomly assigned to the Written condition (to receive a transcription of the pediatrician's instructions) or Oral condition (verbal instruction only). Parents were telephoned 5 to 7 days later to report their recall of instructions and satisfaction with the appointment. For the Oral condition parents only, more previous appointments with a given pediatrician were associated with greater parental satisfaction and recall of instructions, and more previous appointments and more time spent with the pediatrician were related to fewer forgotten instructions. Parental characteristics, such as age, number of children, and occupational status, were associated with satisfaction and accurate recall. Implications of these findings are discussed.

Adolescent↗

Drosophila Paired regulates late even-skipped expression through a composite binding site for the paired domain and the homeodomain.

The even-skipped (eve) pair-rule gene plays a key role in the establishment of the anterior-posterior segmental pattern of the Drosophila embryo. The continuously changing pattern of eve expression can be resolved into two phases. Early expression consists of seven broad stripes in the blastoderm embryo, while late expression, which occurs after cellularization, consists of narrow stripes with sharp anterior borders that coincide with the odd-numbered parasegment boundaries. Previous studies have shown that these two phases are controlled by separate classes of cis elements in the eve promoter. Early stripes are expressed by multiple stripe-specific elements under the control of maternal-effect genes and gap genes, while late stripes are expressed by a single regulatory element, the 'late element', under the control of pair-rule genes including eve itself. We report here that paired (prd), a pair-rule gene which had been considered to be below eve in the regulatory hierarchy of pair-rule genes, in fact plays a critical role in the regulation of late eve expression. Transgenic analysis shows that this regulation is largely mediated by an evolutionarily conserved sequence within the late element termed PTE (Paired Target Element). In vitro analysis shows that the Prd protein binds strongly to this sequence. Interestingly, PTE contains juxtaposed binding sites for the two DNA-binding domains of the Prd protein, the paired domain and the homeodomain. Mutagenesis of either binding site leads to significant reduction in the activity of the late element, indicating that both DNA-binding domains in the Paired protein are required for regulation.

Animals↗

Both the paired domain and homeodomain are required for in vivo function of Drosophila Paired.

Drosophila paired, a homolog of mammalian Pax-3, is key to the coordinated regulation of segment-polarity genes during embryogenesis. The paired gene and its homologs are unusual in encoding proteins with two DNA-binding domains, a paired domain and a homeodomain. We are using an in vivo assay to dissect the functions of the domains of this type of molecule. In particular, we are interested in determining whether one or both DNA-binding activities are required for individual in vivo functions of Paired. We constructed point mutants in each domain designed to disrupt DNA binding and tested the mutants with ectopic expression assays in Drosophila embryos. Mutations in either domain abolished the normal regulation of the target genes engrailed, hedgehog, gooseberry and even-skipped, suggesting that these in vivo functions of Paired require DNA binding through both domains rather than either domain alone. However, when the two mutant proteins were placed in the same embryo, Paired function was restored, indicating that the two DNA-binding activities need not be present in the same molecule. Quantitation of this effect shows that the paired domain mutant has a dominant-negative effect consistent with the observations that Paired protein can bind DNA as a dimer.

Animals↗

The effects of nonsteroidal anti-inflammatory drugs on blood pressures of patients with hypertension controlled by verapamil.

BACKGROUND: Nonsteroidal anti-inflammatory drugs may attenuate the antihypertensive effects of diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, central alpha-agonists, and other vasodilators. Their effects on the antihypertensive efficacy of calcium channel blockers are inadequately studied in small numbers of patients but appear to be minimal. METHODS: A three-phase, randomized, double-blind, placebo-controlled multicenter study included 162 patients aged 18 to 75 years with essential hypertension. After diastolic blood pressure was controlled to 90 mm Hg or less with once-daily verapamil hydrochloride, patients received ibuprofen, naproxen, or placebo matching capsules for 3 weeks, and blood pressure, heart rate, weight, and adverse effects were evaluated. A general linear model with 95% confidence intervals was used to compare each nonsteroidal anti-inflammatory drug treatment group with the placebo group. RESULTS: No significant differences in sitting, standing, or supine blood pressure were noted with naproxen or ibuprofen compared with placebo. The percentages of patients in each treatment group with increases of 10 mm Hg or more in either systolic or diastolic blood pressure were similar. Statistically significant increases in weight were seen with both nonsteroidal anti-inflammatory drug therapies. Changes in pulse rate were not significant. The incidence of adverse effects was similar across all three treatment groups. CONCLUSIONS: The addition of naproxen or ibuprofen to the treatment of hypertensive patients in whom blood pressure is controlled by once-daily verapamil does not cause an increase in blood pressure. Verapamil may therefore offer considerable advantages in maintaining control of blood pressure in patients who regularly receive nonsteroidal anti-inflammatory drug therapy.

Adolescent↗

PdbAlign, PdbDist and DistAlign: tools to aid in relating sequence variability to structure.

Many sequence analysis problems involve consideration of a multiple sequence alignment where the 3-dimensional structure of one (or more) of the aligned sequences is known. In such cases, it is useful to map the sequence variability onto the atomic co-ordinates of known structure. If the structure also includes a bound ligand (or the location of the active site is known), each column position in the multiple sequence alignment may be annotated with its 'distance' from the binding site. These annotations, together with a measure of sequence variability, provide additional insights into drug specificity, for example among viral mutants. This paper describes several useful programs that automate this analysis.

Amino Acid Sequence↗

Synthesis of a mixture of cyclic peptides based on the Bowman-Birk reactive site loop to screen for serine protease inhibitors.

A peptide mixture containing 21 peptide sequences has been constructed to test the Bowman-Birk inhibitor reactive-site loop motif as the basis of inhibition for a range of serine proteases. The 21 peptides are all based on an 11 amino acid sequence designed from a Bowman-Birk like inhibitor reactive-site loop. Variation has been introduced at the P1 site of the loop, which has been randomised to include all the natural L-amino acids (except for cysteine), plus the non-natural L-amino acids ornithine and norleucine, The mixture of peptides was screened for specific binding to immobilised porcine pancreatic elastase, subtilisin BPN', alpha-chymotrypsin, trypsin, anhydro-alpha-chymotrypsin and anhydrotrypsin. Five peptides from the mixture bind to alpha-chymotrypsin, two of which also bind to anhydro-alpha-chymotrypsin, and two peptides bind trypsin, neither of which binds to anhydro-trypsin. The competitive inhibition constants (K(i)) and the rates of proteolytic hydrolysis of the individual peptides with their respective enzymes were determined. The rates of hydrolysis were found to vary widely and show little correlation with the K(i) values. In the case of the alpha-chymotrypsin inhibitors, the peptides with the lowest K(i) (0.1-0.05 mM) were the only peptides that bound to anhydro-alpha-chymotrypsin. However, no peptides bound to anhydrotrypsin, suggesting a fundamental difference in the way that alpha-chymotrypsin and trypsin are inhibited by these cyclic peptides.

Amino Acid Sequence↗

Gonococcal serovar patterns in Glasgow: 1990-1992.

Using monoclonal antibodies directed against protein 1 (major outer membrane protein) in the cell wall of Neisseria gonorrhoeae it is possible to serotype the gonococcus into different sub-groups. This study was designed to analyse the distribution of such serovars in Glasgow, Scotland, and report associations between serovars and clinical features of infection. N. gonorrhoeae isolated from all patients with a diagnosis of gonorrhoea attending genitourinary medicine clinics in Glasgow were serotyped between January 1990 and December 1992. The results were then correlated with sexual orientation of patients, penicillin sensitivity, site of infection, location of acquisition of infection and presence of symptoms. Six hundred and four episodes of gonococcal infection were analysed and an association between certain serovars with sexual orientation, penicillin sensitivity and asymptomatic infection was found. No association between serovar type and locality of acquisition of infection was apparent. Although there was a decreasing trend in the incidence of gonorrhoea overall, infections in homosexual men increased over the three-year study period. The associations between serovars and other features of gonococcal infection are discussed. The observed increase in homosexually-acquired infection has implications with regard to the spread of human immunodeficiency virus infection in this area, and suggests that attempts to promote safer sex in this group are failing.

Adolescent↗

Pyridoxine as therapy in theophylline-induced seizures.

Theophylline-induced seizures have significant morbidity and mortality and are difficult to treat. Theophylline therapy for asthma has been observed to depress plasma pyridoxal 5'-phosphate (PLP) levels which may decrease gamma-aminobutyric acid (GABA) synthesis and thereby contribute to seizures. We hypothesized that treatment with pyridoxine might prove beneficial in theophylline-induced seizures. One hundred thirty-nine mice were injected with 250 mg theophylline/kg ip and 89 mice were injected with 250-750 mg pyridoxine/kg ip as treatment. Decreased rates of seizure (42 vs 70%, p < 0.002) and death (29 vs 56%, p < 0.002) were observed. Six New Zealand White rabbits were given 115 mg theophylline/kg iv over 50 min followed by treatment with an iv bolus of 115 mg pyridoxine/kg, with subsequent continuous drip infusion of 230 mg/kg over 50 min. Serum theophylline levels and plasma PLP levels showed significant negative correlation prior to pyridoxine infusion with a mean peak theophylline level of 182 micrograms/ml and a mean low PLP level of 64 nM/L. Electroencephalogram (EEG) tracings were obtained before infusions, during theophylline infusion and during pyridoxine infusion. All 6 rabbits developed abnormal EEGs during theophylline infusion and all 6 rabbit EEG patterns returned to baseline during treatment with pyridoxine. These findings suggest that pyridoxine may partially reverse theophylline-induced central nervous system toxicity.

Aminophylline↗

Dissection of the Drosophila paired protein: functional requirements for conserved motifs.

The Drosophila paired gene encodes three conserved motifs: a homeodomain, paired domain and PRD (his/pro) repeat. To investigate the functional importance of the PRD repeat and paired domain, we tested deletion mutants using an ectopic expression assay in embryos. Our results suggest that the PRD repeat is not required for the in vivo regulation of the target genes, engrailed and gooseberry. However, the PRD repeat appears to be embedded within a proline-rich transcriptional activation domain required for the regulation of these genes. Our analysis of the paired domain indicated that its N-terminal half, which is required for DNA binding in vitro, is also required for in vivo function, whereas surprisingly, the C-terminal half is dispensable for the regulation of engrailed and gooseberry.

Amino Acid Sequence↗