Acute shoulder injuries: A clinical review of diagnosis and management in the deployed Naval environment.

Musculoskeletal injuries of the shoulder are a common presentation in primary care. Injuries to this highly mobile region can have a profound impact on the range of movement, resulting in severe functional limitation. The shoulder can also be one of the more complicated regions to examine due to its high mobility, poor localisation of pain and numerous supporting structures. This article aims to review the anatomy of the shoulder, examination technique and the pathology underlying common acute injuries in order to provide guidance to medical personnel deployed with the Royal Navy and Royal Marines.

The acutely swollen knee. Part two--management of traumatic pathology.

The acutely swollen knee is a common presentation of knee pathology in the emergency department and the primary care setting, whether on board ship, in a Regimental Aid Post, or in a Medical Centre. The swollen knee has both traumatic and atraumatic (systemic) causes, all of which can be accurately diagnosed with an understanding of the underlying injury patterns and patho-anatomy. In Part 2 of this paper we consider the traumatic causes and also suggest a combined approach to managing an acutely swollen knee. The taking of a detailed history combined with thorough clinical examination will establish the diagnosis or at least the narrow differential diagnosis in the majority of cases. The use of specialist examination techniques, diagnostic imaging and arthrocentesis can further assist the clinician in confirming the correct diagnosis and thus prescribing the appropriate treatment. This review will endeavour to give a consensus of opinion and structured guidelines in the diagnosis and initial management of patients presenting with acute or recent onset swelling of the knee.

The acutely swollen knee. Part 1: Management of atraumatic pathology.

The acutely swollen knee is a common presentation of knee pathology in the Emergency Department and the primary care setting whether on board ship, a Regimental Aid Post or Medical Centre. The swollen knee has both traumatic and atraumatic (systemic) causes, all of which can be accurately diagnosed with an understanding of the underlying injury patterns and patho-anatomy. In Part One, we will be examining the management of non-traumatic causes, followed by Part Two, looking at traumatic causes, in the next issue of the Journal. A detailed clinical history combined with thorough clinical examination will establish the diagnosis, or at least the narrow differential diagnosis in the majority of cases. The uses of specialist examination techniques, diagnostic imaging and arthrocentesis can further assist the clinician in confirming the correct diagnosis and thus prescribing the appropriate treatment. This review will endeavour to give a consensus of opinion and structured guidelines in the diagnosis and initial management of patients presenting with acute or recent-onset swelling of the knee related to atraumatic pathology.

A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.

Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF. Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.

Oral morphine in cancer pain: influences on morphine and metabolite concentration.

One hundred fifty-one patients with chronic cancer pain were studied during chronic treatment with oral morphine. Plasma concentrations of morphine and metabolites (M3G and M6G) were measured. The ratio of plasma morphine to metabolites was not affected by dose. Generalized linear interactive modeling analysis using morphine dose, age, sex, renal and hepatic dysfunction, and concomitant medication as explanatory variables accounted for 70% of the variance in plasma concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Increasing morphine dose was a significant factor for increased plasma concentrations of morphine, M3G, and M6G. Other significant factors were: age greater than 70 years (increased M3G and M6G plasma concentrations), plasma creatinine greater than 150 mumol/L (increased M3G and M6G plasma concentrations), male sex (decreased morphine and M6G plasma concentrations), raised creatinine plus coadministration of tricyclic antidepressants (increased M3G plasma concentrations), ranitidine (increased morphine plasma concentrations), and raised creatinine plus coadministration of ranitidine (increased M6G plasma concentrations).

Morphine and ibuprofen compared using the cold pressor test.

The analgesic efficacy of single doses of oral morphine sulphate solution (10 mg) and ibuprofen 600 mg was compared in 12 volunteers using a double-blind, double-dummy, placebo-controlled design on the cold pressor experimental pain model. Measurement of pain intensity was made before medication and then at 30, 60, 90, 120 and 180 min; blood samples were taken at these times for measurement of morphine and glucuronide metabolites by radioimmunoassay. Sessions were at least 5 days apart. Correlations were sought between analgesic effect and plasma concentrations of either morphine or morphine-6-glucuronide. Morphine produced significant reduction in both peak pain intensity and area under the pain intensity curve compared with placebo; the threshold time was significantly increased by morphine compared with placebo. Ibuprofen was statistically indistinguishable from placebo on all three measures of analgesia. Analgesic effect and plasma concentrations of morphine showed significant correlation (P = 0.053). The study confirmed reports of the opiate sensitivity of the cold pressor model, and the apparent insensitivity of the model to non-steroidal anti-inflammatory drugs.

The mucin antigens: what are we measuring?

Serum of breast cancer patients contains high molecular weight, mucin-like glycoproteins which are held to be differentiation markers for certain types of normal epithelia, in particular mammary epithelium. These components have primarily been identified using monoclonal antibodies raised against human milk fat globule membranes, tumour extracts or purified mucins. Even so, many of the antibodies produced react with a discrete region of the mucin protein core involving the hydrophilic turn domain APDTRPAP. The present investigation using the anti-urinary mucin antibody, C595, illustrates both the clinical potential of the mucin antigens in breast cancer studies as well as the exquisite specificity of immune recognition of a complex polymorphic glycoprotein at the level of the individual amino acids.

Experimental spinal cord injury: imaging the acute lesion.

In order to obtain high resolution images of fixed excised rat spinal cords we have developed a technique using a 6-mm bore, two-turn saddle coil, with a usable imaging length of approximately 4 cm. MR imaging is performed on a prototype 31-cm bore, 1.9-T system with a 1.5-mm section thickness and 7.6-mm field of view.

Postmortem magnetic resonance imaging of experimental spinal cord injury: magnetic resonance findings versus in vivo functional deficit.

The relationship between the severity of the posttraumatic functional deficit and findings on magnetic resonance imaging (MRI) was investigated in a rat model of experimental spinal cord trauma. Thirty Sprague-Dawley rats were subjected to an identical, moderate, contusion injury of the spinal cord. Control animals underwent laminectomy without cord injury. The severity of the functional deficit was assessed with the Combined Behavioral Score (CBS). Animals were killed at 3, 7, 14, 21, or 28 days after injury, and the fixed, excised spinal cords were studied with MRI at 1.9 T. The lesion length was measured on sagittal spin-echo MRI. The lesion length measured on MRI was highly correlated with the CBS functional score (r = 0.56, P = 0.002). There were significant correlations between lesion length as determined by MRI and by histological morphometry (r = 0.44, P = 0.02), between histological morphometric lesion length and CBS functional deficit (r = 0.76, P < 0.001), and between the area of residual white matter at the lesion epicenter, determined by histological techniques, and the severity of functional deficit (r = -0.59, P = 0.001). A qualitative estimate of the area of preserved white matter, derived from MRI, was significantly correlated with the severity of functional deficit (r = -0.56, P = 0.006). A multiple regression of MRI-determined lesion length and MRI estimate of residual white matter versus CBS explained more than 42% of the variability of the functional deficit among these animals subjected to the same weight drop injury. We conclude that MRI parameters are reliable predictors of the severity of neurological deficit in experimental spinal cord trauma.

Histological characteristics and expression of acidic and basic fibroblast growth factor genes in intracerebral xenogeneic transplants of human glioma cells.

Eleven athymic nude rats had stereotactic intracerebral inoculation of cells from one of three established human glioma cell lines (A172, A1207, and A1235). The implants grew progressively in 9 of 11 instances, which led to spontaneous death of the host in 14 to 37 days. For comparison, two Sprague-Dawley normal albino rats were implanted with the rat C6 glioma cell line. One rat died at 14 days, and the other was killed at Day 16. The human glioma cells developed into partially (A172, A1235) or totally (A1207) circumscribed tumor masses. Invasion, when present, was manifested as infiltrating prongs of cells rather than as individual cell infiltration. The growth of the human glioma cells was accompanied by a small zone of surrounding edema and marked central necrosis. These features were not encountered in the C6 implants. Inflammatory changes were minimal to nonexistent in all cases. All tumor lines produced internal cerebral herniation and neuraxis spread with implants seeded throughout the ventricular system, often associated with ventricular dilation. In situ hybridization, by the use of isotopic and nonisotopic detection methods, was used to study the cellular expression of the acidic fibroblast growth factor and basic fibroblast growth factor genes in A172 glioma xenografts. The expression of these genes was not seen in normal rat brain, but the genes were selectively overexpressed by the glioma cell implants, with especially high signal in the tumor periphery.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphine and morphine-6-glucuronide plasma concentrations and effect in cancer pain.

The relationships between plasma morphine and metabolite (M3G and M6G) concentrations and analgesic efficacy were investigated in an open study of 39 cancer pain patients receiving chronic oral morphine therapy with either morphine sulfate solution or controlled-release morphine tablets. There were no differences in morphine, metabolite kinetics, or analgesic efficacy between equivalent doses of conventional or controlled-release formulations. The increase in morphine plasma concentration after a dose (1 hr for normal release, 2 hr for controlled release) was correlated significantly with the dose of morphine (r = 0.914, P < 0.001). There was a significant reduction in pain intensity (P < 0.05) and increase in pain relief (P < 0.001) after the dose of morphine administration, when compared with the predose score. One-half of the patients had mild and tolerable adverse effects. Patients were classified by mean pain relief between doses as having optimal, moderate, or poor pain control. No simple relationship was found between morphine plasma concentration and pain control. Morphine plus M6G concentrations in the "optimal control" group (751.2 +/- 194 nmol/L), however, were more than twice those found in the "moderate control" group (276.9 +/- 41.9 nmol/L) (P < 0.05), and no patient in the moderate control group had a morphine plus M6G concentration greater than 405 nmol/L. These results support the importance of M6G in morphine analgesia. For these hospitalized patients, there appeared to be a therapeutic range of morphine plus M6G plasma concentrations for optimal pain control with a lower limit of 400 nmol/L predose.

Homozygosity mapping and linkage analysis demonstrate that autosomal recessive congenital hereditary endothelial dystrophy (CHED) and autosomal dominant CHED are genetically distinct.

BACKGROUND: Congenital hereditary endothelial dystrophy (CHED) is a corneal dystrophy characterised by diffuse bilateral corneal clouding resulting in impaired vision. It is inherited in either an autosomal dominant (AD) or autosomal recessive (AR) manner. The AD form of CHED has been mapped to the pericentromeric region of chromosome 20. Another endothelial dystrophy, posterior polymorphous dystrophy (PPM), has been linked to a larger but overlapping region on chromosome 20. A large, Irish, consanguineous family with AR CHED was investigated to determine if there was linkage to this region. METHODS: The technique of linkage analysis with polymorphic microsatellite markers amplified by polymerase chain reaction (PCR) was used. In addition, a DNA pooling approach to homozygosity mapping was employed to demonstrate the efficiency of this method. RESULTS: Conventional genetic analysis in addition to a pooled DNA strategy excludes linkage of AR CHED to the AD CHED and larger PPMD loci. CONCLUSION: This demonstrates that AR CHED is genetically distinct from AD CHED and PPMD.

Analysis of morphine and its major metabolites by differential radioimmunoassay.

The analysis of morphine, morphine-3-glucuronide (M-3-G) morphine-6-glucuronide (M-6-G) by differential radioimmunoassay using iodinated label and three different antisera is described. These methods were used to measure concentrations of morphine and its conjugated metabolites in human plasma, over a 3-h period, following a single 10 mg intravenous dose. In 13 patients peak concentrations of M-3-G (739 nmol/L +/- 73.7 SEM) were approximately 10 times greater than those of M-6-G (71.3 nmol/L +/- 8.6 SEM). Times to reach these peaks were similar for both metabolites. Decay of morphine from plasma followed a biexponential pattern with a mean terminal half-life of 59.3 min (+/- 8.1 SEM, n = 11). Accurate determination of the half-lives of the glucuronides was not possible due to the short sampling period, but M-6-G seemed to have a similar half-life to morphine, while M-3-G was eliminated more slowly.

Radioimmunoassay of buprenorphine with iodine label: analysis of buprenorphine and metabolites in human plasma.

Quantitative analysis of potent opiate drugs in plasma by radioimmunoassay is potentially inaccurate because of the occurrence of cross-reacting metabolites. This paper describes the chemical synthesis of buprenorphine-3-O-glucuronide, a metabolite of buprenorphine, and an extraction procedure coupled with radioimmunoassay which allows the sensitive and specific measurement of buprenorphine using an iodinated buprenorphine derivative. The measurement of extracted and unextracted samples using two different antisera allowed investigation of the metabolism of buprenorphine. In four patients who had taken sublingual buprenorphine for at least one month, N-dealkyl buprenorphine was present in similar concentrations to those of buprenorphine, while buprenorphine-3-O-glucuronide was present in two to three times those concentrations.

A founder mutation in French-Canadian families with X-linked hereditary neuropathy.

BACKGROUND: The aim of the present study was to identify the mutations in the connexin 32 gene in French-Canadian families with X-linked Charcot-Marie-Tooth disease (CMTX). METHODS: Molecular analysis was performed by nonisotopic single strand conformation polymorphism (SSCP) analysis and sequencing. Clinical evaluation was carried out according to the scale defined by the European Hereditary Motor and Sensory Neuropathy Consortium. RESULTS: In one family, the mutation Arg142Trp was located in the transmembrane domain III whereas, in four other families we identified a novel mutation (Ser26Trp) located in the transmembrane domain I of the connexin 32 gene. Haplotype analysis revealed that these four families are related and suggests a founder mutation. Sixteen patients from these four families were studied. As expected, all the affected males were more clinically affected than the females and all affected patients exhibited some electrophysiological characteristics of demyelination. CONCLUSION: Our study suggests that the Ser26Trp mutation may cause a primary demyelinating neuropathy that is not associated with a specific clinical phenotype. We also find evidence that the majority of kindreds share a common ancestor.

The development and reliability of the Royal College of General Practitioners' questionnaire for measuring senior house officers' satisfaction with their hospital training.

BACKGROUND: The training provided for senior house officers (SHOs) has been the subject of debate, and variable satisfaction with training has been reported. The reliability of the instruments used for measuring satisfaction has not been adequately addressed. AIM: To develop a reliable questionnaire to measure SHO satisfaction with hospital training. METHOD: A 42-item questionnaire with eight scales was developed using criteria from the joint hospital visiting guidelines of the Royal College of General Practitioners. The questionnaire was sent to SHOs in Anglia before monitoring visits from the royal colleges, the postgraduate dean and the Joint Committee on Postgraduate Training for General Practice. RESULTS: Response rates varied from 37.0% to 100%, with an overall response rate of 58.8%. The internal reliability of the whole questionnaire was 0.82. Levels of internal reliability for the individual scales were satisfactory, Cronbach's alpha coefficient being 0.75 or more in all but two of the scales. Test-retest reliability using Pearson's product moment correlation coefficient was greater than 0.82 for six of the scales. There were significant differences in total satisfaction between SHOs reporting on posts accredited by the different royal colleges and also between SHOs training for general practice and those training to be specialists. CONCLUSION: A reliable questionnaire has been developed to measure SHO satisfaction with hospital training that is acceptable to doctors and feasible to administer. National acceptance of a single questionnaire for monitoring SHO posts would enable standards to be monitored regularly at a time of considerable change in hospital training.

Comparison of whole blood and plasma morphine.

Thirty paired samples of plasma and whole hemolyzed blood were obtained from patients undergoing surgery. Morphine concentrations were measured with the DPC serum morphine kit without prior treatment. In a regression analysis, the equation to the regression line was blood = 1.02 plasma + 1.0 ng/mL, and the correlation coefficient was 0.994. Radioimmunoassay screening of postmortem blood samples can be performed without prior sample treatment.

Development and validation of a nonisotopic immunoassay for the detection of LSD in human urine.

A microplate enzyme immunoassay (EIA) for the detection of lysergic acid diethylamide (LSD) in human urine was developed. The assay kit is designed around an LSD derivative coated on the wall of microplate wells with preservatives and stabilizers. Sample and rabbit anti-LSD are added to the microplate well. The immobilized LSD and LSD present in specimens compete for the opportunity to bind to the anti-LSD antibodies. An anti-rabbit antibody labeled with horseradish peroxidase is used to provide the assay signal, which is inversely proportional to the concentration of LSD in the sample. The assay requires a 25-microL urine sample and three consecutive incubation periods of 60, 30, and 30 min at room temperature. The assay was tested with a variety of drugs, including ergot alkaloids spiked into drug-free urine at up to 100,000 ng/mL without cross-reaction. Nor-LSD was shown to cross-react between 16% and 28%, depending on its concentration. Of the other compounds tested, only ergonovine demonstrated slight cross-reactivity at approximately 0.0008%. The assay is designed to be used with a qualitative cutoff of 0.5 ng/mL. Precision testing at 0.5 ng/mL gave a coefficient of variation (CV) of 6% based on 20 replicates. The CV at 0.375 ng/mL (cutoff, -25%) was 5.2% and at 0.625 ng/mL was 6.6%. Precision at other concentrations within the range of the calibration curve gave similar results both intra- and interassay. Clinical performance of the assay was compared with that of a commercial radioimmunoassay (RIA). Comparable performance was observed with both methods, each screening a total of 458 samples as negative and 17 samples as positive relative to a 0.5 ng/mL cutoff. The EIA found an additional three positive samples that were negative by RIA. The EIA is suitable for the screening of urine samples for the presence of LSD. Preliminary indications are that the assay is also suitable for use with whole blood specimens. The assay can be performed manually or be fully automated and without the need for radioactivity; it can be used in any laboratory.

Radioimmunoassay of buprenorphine in urine: studies in patients and in a drug clinic.

A radioimmunoassay kit (DPC buprenorphine double antibody) was evaluated with clinical samples and samples from a drug clinic. Urine samples were collected over a 2-day period from 5 hospital in-patients receiving sublingual buprenorphine, 400 to 2000 micrograms/day, for the relief of chronic pain. Samples were measured before and after enzymatic hydrolysis. Urine buprenorphine concentrations were measurable at all doses studied (minimum value 5.6 ng/mL) and were greater with larger doses. The increase in concentration after hydrolysis averaged 49% and was similar for all doses studied. The authors conclude that the method has extensive cross-reactivity with glucuronides of buprenorphine and its metabolites and that samples may be analyzed without prior hydrolysis. The prevalence of buprenorphine use in 97 patients attending a drug clinic was also studied. Sixty (62%) had measurable urinary buprenorphine concentrations of 1 ng/mL or more by direct assay. The buprenorphine users were significantly younger and reported significantly greater use of opiates than nonusers.