Effect of a model consultation informed by guidelines on recorded quality of care of osteoarthritis (MOSAICS): a cluster randomised controlled trial in primary care.

OBJECTIVE: To determine the effect of a model osteoarthritis (OA) consultation (MOAC) informed by National Institute for Health and Care Excellence (NICE) recommendations compared with usual care on recorded quality of care of clinical OA in general practice. DESIGN: Two-arm cluster randomised controlled trial. SETTING: Eight general practices in Cheshire, Shropshire, or Staffordshire UK. PARTICIPANTS: General practitioners and nurses with patients consulting with clinical OA. INTERVENTION: Following six-month baseline period practices were randomised to intervention (n = 4) or usual care (n = 4). Intervention practices delivered MOAC (enhanced initial GP consultation, nurse-led clinic, OA guidebook) to patients aged ≥45 years consulting with clinical OA. An electronic (e-)template for consultations was used in all practices to record OA quality care indicators. OUTCOMES: Quality of OA care over six months recorded in the medical record. RESULTS: 1851 patients consulted in baseline period (1015 intervention; 836 control); 1960 consulted following randomisation (1118 intervention; 842 control). At baseline wide variations in quality of care were noted. Post-randomisation increases were found for written advice on OA (4-28%), exercise (4-22%) and weight loss (1-15%) in intervention practices but not controls (1-3%). Intervention practices were more likely to refer to physiotherapy (10% vs 2%, odds ratio 5.30; 95% CI 2.11, 13.34), and prescribe paracetamol (22% vs 14%, 1.74; 95% CI 1.27, 2.38). CONCLUSIONS: The intervention did not improve all aspects of care but increased core NICE recommendations of written advice on OA, exercise and weight management. There remains a need to reduce variation and uniformly enhance improvement in recorded OA care. TRIAL REGISTRATION NUMBER: ISRCTN06984617.

Development and preclinical evaluation of a trivalent, formalin-inactivated Shigella whole-cell vaccine.

Studies were undertaken to manufacture a multivalent Shigella inactivated whole-cell vaccine that is safe, effective, and inexpensive. By using several formalin concentrations, temperatures, and incubation periods, an optimized set of inactivation conditions was established for Shigella flexneri 2a, S. sonnei, and S. flexneri 3a to produce inactivated whole cells expressing a full repertoire of Ipa proteins and lipopolysaccharide (LPS). The inactivation conditions selected were treatment with 0.2% formalin (S. flexneri 2a and 3a) or 0.6% formalin (S. sonnei) for 48 h at 25°C. Vaccine formulations prepared under different inactivation conditions, in different doses (10E5, 10E7, and 10E9 cells), and with or without the inclusion of double-mutant heat-labile toxin (dmLT) were evaluated in mice. Two intranasal immunizations with ≥10E7 inactivated whole cells resulted in high levels of anti-Invaplex and moderate levels of LPS-specific IgG and IgA in serum and in lung and intestinal wash samples. Addition of dmLT to the vaccine formulations did not significantly enhance humoral immunogenicity. Minimal humoral responses for IpaB, IpaC, or IpaD were detected after immunization with inactivated whole Shigella cells regardless of the vaccine inactivation conditions. In guinea pigs, monovalent formulations of S. flexneri 2a of 3a or S. sonnei consisting of 10E8, 10E9, or 10E10 cells were protective in a keratoconjunctivitis assay. A trivalent formulation provided protection against all three serotypes (S. flexneri 2a, P = 0.018; S. flexneri 3a, P = 0.04; S. sonnei, P < 0.0001). The inactivated Shigella whole-cell vaccine approach incorporates an uncomplicated manufacturing process that is compatible with multivalency and the future development of a broadly protective Shigella vaccine.

Influence of imaging on touch imprint cytology of breast lesions.

PURPOSE: Touch imprint cytology (TIC) facilitates rapid diagnosis of breast diseases in women attending triple assessment clinics. Some pathologists, in our centre, feel that pathological interpretation of TIC slides is contentious when the lesions are radiologically indeterminate (R3), as these can lead to potentially higher false positive or false negative cytology results. We hypothesised that: '(R3) lesions are more likely to have higher false positive or false negative TIC and/or be inadequate for TIC assessment'. In other words, 'imaging influences cytological classification especially when indeterminate'. METHODS: Review of the data collected in our centre between December 2003 and July 2005. All patients who attended the one stop symptomatic breast clinic and had a TIC performed following an ultrasound (US) guided core biopsy (CB) were included. Demographic, radiological, cytological and core biopsy grading data were collected. Cytology grading was correlated with radiology classification to assess our hypothesis. RESULTS: A total of 248 patients underwent 254 CB/TIC. The average patient's age of the group was 54 years (range of 29-95). On TIC, 186 (73%) were deemed malignant, 23(9%) benign while 33(13%) were inadequate for assessment. There was no false positive or false negative TIC. There was good correlation between TIC and CB results (p<0.0001). Thirty-three cases were inadequate (C1) for cytology assessment, of these 16 (48.5%) were indeterminate on imaging. R3 lesions were 6 times more prone to have C1 cytology (p<0.0001). CONCLUSION: Touch imprint cytology is a reliable and efficient method in running a one stop breast clinic, with the backup of full tissue diagnosis. Careful selection of cases that would benefit from this technique is highly recommended as a significant number of radiologically indeterminate lesions are likely to be insufficient for cytological assessment. Further prospective trials are required to assess this further. Until then the diagnosis in this sub-group should depend on core biopsy.

Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function.

BACKGROUND: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. OBJECTIVE: To characterise genetic and clinical findings in patients with SIX3 mutations. METHODS: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. RESULTS: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. CONCLUSIONS: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models.

The usefulness of tyrosinase in the immunohistochemical assessment of melanocytic lesions: a comparison of the novel T311 antibody (anti-tyrosinase) with S-100, HMB45, and A103 (anti-melan-A).

AIM: To compare the sensitivity and staining pattern of the new immunohistochemical antibody to tyrosinase (T311) with S-100, HMB45, and the recently evaluated antibody to melan-A (A103) in a range of melanocytic lesions. METHOD: Archival, formalin fixed, paraffin wax embedded sections from 50 benign and malignant melanocytic lesions were stained immunohistochemically with anti-tyrosinase, A103, S-100, and HMB45. They were scored semiquantitatively for the distribution and intensity of staining. RESULTS: All melanomas, with the exception of desmoplastic melanoma, showed some staining with all four antibodies. Overall, T311 and A103 showed an intermediate sensitivity compared with that of S-100 and HMB45. T311 stained most benign and malignant lesions strongly and diffusely with minimal background staining. Immunoreactivity was found to be patchy in some naevi, with weak or absent staining of the mature melanocytes. A103 showed strong and diffuse staining of all benign lesions and most melanomas with minimal background staining. S-100 was the most sensitive, with diffuse staining of most lesions, including desmoplastic and metastatic melanoma, but lacked specificity. HMB45 was the least sensitive antibody, frequently demonstrating patchy staining with absent staining in some benign naevi. CONCLUSIONS: S-100 remains the most sensitive marker of melanocytes. However, because of its lack of specificity, it should be used with at least one other more specific antibody. HMB45 is more specific, but lacks sensitivity; T311 is a reliable marker of melanocytes in paraffin wax embedded sections and is worth consideration for use in a staining panel, although it shows no additional benefit over A103.

Split hand/split foot malformation with hearing loss: first report of families linked to the SHFM1 locus in 7q21.

Developmental anomalies of the appendicular skeleton are among the most common and easily ascertained birth defects. Split hand/split foot malformations, distinctive in having deficiency of the central rays, occur as isolated anomalies and as one component of multisystem syndromes. The clinical and molecular characterization of a new syndrome, found in two unrelated families, consisting of split foot with hearing loss, is presented here. As in other split hand/split foot conditions, variable expression and reduced penetrance is notable. In the larger family, variably expressed split foot malformations were found in 6 of 11 gene carriers. and mild-to-moderate sensorineural hearing loss in 4. Split hand and cleft lip/palate in one individual and tibial deficiency in another suggest that these malformations are uncommon components of the syndrome. Ectodermal abnormalities did not occur. In the second family, variable split foot was observed in 3 of 4 gene carriers, and sensorineural deafness was present in 3. Split hand was only seen in a gene carrier who also had split foot and deafness. One gene carrier only had deafness. The gene for split hand split foot with sensorineural hearing loss was linked to markers in 7q21 in both families, with a combined (maximum LOD score of 4.37 at theta = 0.0 for locus D7S527) at 80% penetrance. Efforts to identify the responsible gene have not yet been successful.

Ischiospinal dysostosis with rib gaps and nephroblastomatosis.

Rib gaps, vertebral ossification defects, hypoplastic ischial bones and large kidneys were present in a newborn. A renal biopsy showed nephroblastomatosis . The observation links two recently described conditions - 'ischiospinal dysostosis' and 'a new syndrome comprising vertebral anomalies and multicystic kidneys' - and shows that nephroblastomatosis may be a manifestation of ischiospinal dysostosis. Ischiospinal dysostosis with nephroblastomatosis is one of a group of disorders characterized by developmental defects of the axial skeleton. It must be added to the conditions predisposing to Wilms tumor formation.

Representation and classification of breath sounds recorded in an intensive care setting using neural networks.

OBJECTIVE: Develop and test methods for representing and classifying breath sounds in an intensive care setting. METHODS: Breath sounds were recorded over the bronchial regions of the chest. The breath sounds were represented by their averaged power spectral density, summed into feature vectors across the frequency spectrum from 0 to 800 Hertz. The sounds were segmented by individual breath and each breath was divided into inspiratory and expiratory segments. Sounds were classified as normal or abnormal. Different back-propagation neural network configurations were evaluated. The number of input features, hidden units, and hidden layers were varied. RESULTS: 2127 individual breath sounds from the ICU patients and 321 breaths from training tapes were obtained. Best overall classification rate for the ICU breath sounds was 73% with 62% sensitivity and 85% specificity. Best overall classification rate for the training tapes was 91% with 87% sensitivity and 95% specificity. CONCLUSIONS: Long term monitoring of lung sounds is not feasible unless several barriers can be overcome. Several choices in signal representation and neural network design greatly improved the classification rates of breath sounds. The analysis of transmitted sounds from the trachea to the lung is suggested as an area for future study.

Effects of clonidine on prolonged postoperative sympathetic response.

OBJECTIVE: Surgical trauma results in diffuse sympathoadrenal activation which is thought to contribute to perioperative cardiovascular complications in high-risk patients. Regional anesthetic and analgesic techniques can attenuate this "stress response" and reduce the occurrence rate of adverse perioperative events; however, their use in the postoperative period is logistically difficult and costly. The present study was undertaken to evaluate whether transdermal administration of the alpha2 adrenergic-receptor agonist, clonidine, can be used as a pharmacologic means of blunting the stress response throughout the perioperative period. DESIGN: Double-blind, placebo-controlled clinical trial in patients undergoing pancreatico-biliary surgery. SETTING: Operating rooms and surgical intensive care unit of a major university teaching hospital. PATIENTS: Forty patients scheduled for major upper abdominal surgery. INTERVENTIONS: Patients received either clonidine (0.2 mg orally and a clonidine TTS-3 patch the evening before surgery and 0.3 mg orally on call to the operating room) or matched oral and transdermal placebo. MEASUREMENTS AND MAIN RESULTS: Heart rate, systemic arterial blood pressure, plasma catecholamine, clonidine, interleukin-6 concentrations, and 24-hr urine cortisol and nitrogen excretion were measured the day before surgery and daily thereafter for 72 hrs postoperatively. Preoperative transdermal (and oral) clonidine administration resulted in therapeutic plasma clonidine concentrations throughout the perioperative period (1.54 +/- .07 [SEM] microg/mL). Clonidine reduced preoperative epinephrine and norepinephrine concentrations by 65%. Plasma catecholamine concentrations increased in both groups following surgery but were markedly lower throughout the postoperative period in patients receiving clonidine. Patients receiving clonidine had a reduced frequency rate of postoperative hypertension. Clonidine had no effect on plasma interleukin-6 concentration, urine cortisol excretion, or urine nitrogen excretion. No adverse effects of clonidine administration were observed. CONCLUSIONS: The combined administration of oral and transdermal clonidine effectively attenuated the catecholamine response to surgical stress throughout the postoperative study period. Clonidine administration produced specific sympatholytic effects, since other elements of the stress response were not attenuated. Undesirable side effects were not noted. The sustained sympatholytic effects we observed suggest that alpha2 adrenergic-receptor agonists may offer a pharmacologic means of modifying the sympathoadrenal response to injury, and may be useful in reducing perioperative complications.

Albright hereditary osteodystrophy and del(2) (q37.3) in four unrelated individuals.

Albright hereditary osteodystrophy (AHO) is a condition with characteristic physical findings (short stature, obesity, round face, brachydactyly) but variable biochemical changes (pseudohypoparathyroidism, pseudopseudohypoparathyroidism). Most patients with AHO have decreased activity of the guanine nucleotide-binding protein (GS protein) that stimulates adenylyl cyclase. The gene encoding the alpha subunit of the GS protein (GNAS1) has been mapped to the long arm of chromosome 20. We describe 4 unrelated individuals with apparent AHO, associated with small terminal deletions of chromosome 2. All 4 patients had normal serum calcium levels consistent with pseudopseudohypoparathyroidism. Del(2) (q37) is the first consistent karyotypic abnormality that has been documented in AHO [Phelan et al., 1993: Am J Hum Genet 53:484]. The finding of the same small terminal deletion in 4 unrelated individuals with a similar phenotype suggests that a gene locus in the 2q37 region is important in the pathogenesis of Albright syndrome. The association of Albright syndrome and the GNAS1 locus on chromosome 20 is well documented. The observation of a second potential disease locus on chromosome 2 may help explain the heterogeneity observed in this disorder.

Atypical beta-adrenoceptor in bovine adrenal medulla.

Bovine adrenal medullary membranes were incubated with [125I]cyanopindolol to assess beta-adrenoceptor binding. Binding was saturable and specific; a single low affinity site (Kd = 750 pM) was identified. [125I]Cyanopindolol binding was displaced by micromolar concentrations of classic beta-adrenoceptor antagonists and by sodium-4-[-2-[2-hydroxy-2-(-3-chloro-phenyl) ethylamino] propyl] phenoxyacetate. These data are similar to reported binding of beta 3-adrenoceptors and may explain beta-adrenoceptor agonist modulation of chromaffin cell degranulation in this catecholamine rich environment.

A behavioral measure of hand preference as opposed to hand skill.

Twenty-five self-professed left-handers and 21 self-professed right-handers were given a variety of performance tests to assess handedness, along with a preference inventory and a dichotic listening test of language lateralization. The performance tests included the Annett pegboard task, that Tapley and Bryden dot-filling tasks, and two procedures, the long pegboard and long dots tasks, that were intended to assess the point in space at which a particular unimanual movement became sufficiently awkward for one to shift to the other hand. All four of these performance tests differentiated between left-handers and right-handers, although the differences between handedness groups were somewhat larger when handedness was defined in terms of the preference inventory rather than on the basis of self-report. When the difference between preferred and non-preferred hands was examined, the best predictor of hand preference was the long pegboard task. Such a finding is consistent with the view that the long pegboard provides a behavioral measure of hand preference, while the pegs and dots tasks are more closely linked to specific skills. In addition, the correlations between individual preference items and the dichotic right-ear advantage suggest that language lateralization is related to rather different handedness measures than those usually used to define handedness. This finding would suggest that handedness and language lateralization are determined by somewhat different mechanisms.

Adrenal blood flow and secretory effects of adrenergic receptor stimulation.

To evaluate effects of adrenergic receptor stimulation on regional adrenal blood flow and secretion, pentobarbital-anesthetized dogs (n = 5-6/group) received the beta-agonist isoproterenol (group I), the alpha 1-agonist phenylephrine (group II), or the alpha 2-agonist dexmedetomidine (group III). Measurements of adrenal cortical (CQ) and medullary (MQ) blood flow (radiolabeled microspheres) and catecholamine secretion were made before and during agonist infusion. Isoproterenol increased catecholamine secretion but had no direct effect on MQ or CQ. In contrast, phenylephrine increased MQ and CQ four- and twofold, respectively. Dexmedetomidine had no effect on MQ or catecholamine secretion. To evaluate whether blood flow effects of phenylephrine were due to increases in mean arterial blood pressure (MAP) or related to activation of alpha 1-adrenergic receptors, two additional groups of animals received phenylephrine; group IV had MAP maintained at baseline by controlled hemorrhage into a pressurized bottle; group V received prazosin before phenylephrine. Prevention of MAP increase did not prevent the vasodilation response to phenylephrine, but it was completely blocked by prazosin. Canine adrenal homogenates incubated with the alpha 1-adrenoceptor ligand, 125I-labeled 2-[beta-(4-hydroxyphenyl)ethlaminomethyl]tetralone, demonstrated specific and saturable binding, supporting the presence of alpha 1-adrenergic receptors. We conclude that increases in MQ and CQ elicited by phenylephrine appear to be due to alpha 1-receptor stimulation. The mechanism responsible for this vasodilation is not known.

Gastric cancer and Helicobacter pylori infection.

AIMS: To identify differences in the prevalence of Helicobacter pylori infection in different groups of patients with gastric cancer. METHODS: In total 224 cases of gastric cancer were studied: 120 (53.6%) intestinal; 69 (30.8%) diffuse; and 35 (15.6%) unclassified. Site of tumour, presence and severity of gastritis, presence and extent of intestinal metaplasia, and age and sex were also recorded. Infection by H pylori was assessed using modified Giemsa staining. RESULTS: H pylori infection was found in 96 (43%) cases. There was no significant association between infection and histological type of tumour, nor was there any significant association between infection and site of tumour, the presence of intestinal metaplasia, age, or sex. The only significant association identified was between infection and gastritis. CONCLUSIONS: These results are in broad agreement with those of other similar studies, although the overall prevalence of infection, at 43%, was lower than has been reported in some series. The findings do not support a role for H pylori in any particular subgroup of patients with gastric cancer but do not exclude a role for the organism in the pathogenesis of gastric cancer as a whole.

A comparative evaluation of propofol and midazolam as sedative agents in fiberoptic bronchoscopy.

Propofol, a new intravenous sedative agent, was investigated in 41 asthmatic patients undergoing day-case (outpatient) fiberoptic bronchoscopy. The study design was a randomized comparison between propofol and midazolam, which is a well-established intravenous sedative agent. The age, weight, and American Society of Anesthesiologists physical status and lung function of the two groups were not significantly different. Mean (SD) induction dose of propofol was 104.7 (30.1) mg with a maintenance dose of 121.9 (38.5) mg. Corresponding values of midazolam were 9.3 (3.1) mg and 3.7 (2.3) mg. The required level of sedation was achieved significantly faster with propofol, mean (SD) 125.4 (39.8) s, compared with midazolam, 179.4 (55.2) s (p < 0.001). Significantly faster recovery was noted with propofol compared with midazolam in terms of time to recall name and date of birth 2.3 (1.7) min vs 6.3 (8.6) min, (p < 0.045). Alertness scored with the digital symbol substitution test (DSST) returned to prebronchoscopy values in the propofol group at 30 min, DSST score = 35.9 (18.2) vs 13.4 (9.1), in the midazolam group (p < .0001) and was still significantly higher at 90 min-39.4 (17.9) and 23.1 (13.8) (p < 0.01). We conclude that propofol is a useful sedating agent in fiberoptic bronchoscopy with similar efficacy to midazolam but with a faster onset of action and a more rapid recovery. These represent significant advantages for day-case procedures.