Mild End Research Articles

Collapse of geometrically imperfect stainless steel tubes under external hydrostatic pressure

This paper reports on an investigation into the buckling behaviour of 5 geometrically imperfect duplex stainless steel tube models, subjected to external hydrostatic pressure. The research was partly experimental and partly theoretical, where in the latter case; both analytical & numerical theoretical analyses were carried out.The experiments were carried out on five stainless steel tube models of different lengths, using two mild steel end bungs to seal the models. The experimental results showed that the Duplex stainless steel specimens behaved similarly to other isotropic materials tested by other researchers.The theoretical calculations and analyses were made by MisesNP, a DOS-based computer program, together with the ANSYS finite element structural analysis software.Combining the results of the present series of models, together with the results of other experimenters, a design chart was produced, which can be used for designing full-scale vessels. It should be emphasised that this design chart has been extended to those from previous studies, so that shorter and thicker vessels can now be designed.

Tracheobronchomalacia in children

Tracheobronchomalacia disorders present a considerable diagnostic challenge and workload to tertiary pediatrics. Bronchoscopy is the definitive way of confirming these diagnoses. Quantification of the size of lesions with a reference point is important to the decision-making processes for management, yet this aspect of assessment has been left to subjective visual estimates of size, even though there are now methods available for quantitative measurement. There is a wide range of bronchoscopic appearances and clinical manifestations of these disorders, and a spectrum of resultant diseases. At the mild end of the spectrum of illnesses, the clinical profiles are worse than similar respiratory illnesses in normal children. At the moderate and severe ends of the spectrum, invasive interventions, operative approaches and intensive care management are often necessary. Generally, these disorders are thought to improve with increasing age, but exactly which types and to what extent these disorders actually do improve or resolve are not known. Research is necessary to establish a true definition of these disorders to establish an improved understanding of the clinical profiles of the various appearance and types of malacia. Randomized, controlled studies of the management of malacia disorders, including research on potentially curative medical molecular genetic therapies, will be beneficial to pediatric respiratory medicine and ultimately the care of children with these disorders.

Conversational treatment in mild aphasia: A case study

Background: The literature suggests that mild aphasia negatively affects everyday experiences, social life, and identity. However, while mild word‐finding problems and difficulty understanding abstract or grammatically complex language are typical clinical characteristics, their impact on everyday discourse and conversation partners remains relatively unexplored. Similarly, treatment studies addressing conversational difficulties have predominantly included those with moderate to severe aphasia, rather than those at the mild end of the severity scale. Aims: The current study examines conversational difficulties in mild aphasia and their accessibility to a conversational treatment procedure. Methods & Procedures: A woman with mild aphasia and her husband participated in the study. They underwent 14 sessions of conversational therapy, based on the procedures of Boles (1998) and Boles and Lewis (2003). Outcome measures included subjective ratings by the couple regarding conversational parameters they deemed important, ratings of their interactions by independent judges on the Measure of skill in Supported Conversation (MSC) and the Measure of Participation in Conversation (MPC) (Kagan et al., 2004), independent judgments of whether interactions were pre or post‐treatment, as well as a series of behavioural measures related to specific goals collaboratively set by the couple and the clinician. Outcomes & Results: Improvements were noted in both the participants’ ratings and the independent judges’ ratings. While some changes were noted on behavioural measures, clear patterns were not always evident. Conclusions: The study suggests that conversational treatment may be beneficial to couples dealing with mild aphasia as well as those at the more severe end of the continuum as reported previously. However, measures of the effects of treatment need to be further explored in terms of sensitivity to conversational changes in mild aphasia.

Treatment strategies in mild asthma

More than 10 years ago the category of mild asthma was split into mild intermittent and mild persistent asthma and maintenance therapy with low dose inhaled corticosteroids (ICS) was recommended for mild persistent asthma. The threshold for instituting regular ICS therapy was arbitrarily chosen, in the absence of clinical studies specifically addressing this issue. The results of recent trials have questioned the assumption that all patients at the mild end of the asthma severity spectrum should be committed to regular anti-inflammatory treatment with inhaled corticosteroids. As a consequence, the identification of the relevant outcomes for the treatment of mild persistent asthma has become a matter of discussion, which has provided the rationale to test the efficacy and well tolerance of new strategies, other than guidelines-recommended regular low-dose ICS, for the treatment of mild persistent asthma. Several approaches have been evaluated with some promising results, to include the combination of ICS and long-acting b2-agonists, oral leukotriene antagonists, and the intermittent or as-needed use of ICS in the absence of regular treatment. Conversely, little effort has been made to evaluate therapeutic options other than as-needed bronchodilation in mild intermittent asthma.

The role of cannabis use within a dimensional approach to cannabis use disorders

Context Cannabis consumption is central to diagnosis of cannabis use disorders; yet, most research on cannabis disorders has focused just on diagnosis or criteria. The present study examines the ability of a frequency and quantity measure of cannabis use as well as cannabis abuse and dependence criteria to discriminate between individuals across the cannabis use disorder continuum. Method A representative sample of USA adults in 2001–2002 ( N = 43,093) were queried about the past year frequency of cannabis use and each Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) cannabis abuse and dependence criterion. Factor analysis and item response theory (IRT) models were used to define the relationship between observed responses and the underlying unobserved latent trait (cannabis use disorder severity) among past year cannabis users ( n = 1603). Results Factor analyses demonstrated a good fit for a one-factor model both with and without the cannabis use criterion and no differential criterion functioning was demonstrated across sex. The IRT model including the cannabis use criterion had discriminatory power comparable to the model without the cannabis use criterion and exceeded the informational value of the model without the cannabis use criterion in mild and moderate ranges of the severity continuum. Discussion Factor and IRT analyses disprove the validity of the DSM-IV abuse and dependence distinction: A single dimension represented the criteria rather than the two implied by the separate abuse/dependence categories. IRT models identified some dependence criteria to be among the mildest and some abuse criteria to be among the most severe—results inconsistent with the interpretation of DSM-IV cannabis abuse as a milder disorder or prodrome of cannabis dependence. The consumption criterion defined the mild end of the cannabis use disorder continuum and its excellent psychometric properties supported its consideration for inclusion in the next edition of DSM as a criterion for cannabis use disorders. Additional work is needed to identify candidate consumption criteria across all drugs that apply to the milder end of the severity continuum while also improving overall model performance and clinical diagnostic utility.

Comparative evaluation of Fecal Calprotectin, Lactoferrin and Occult Blood test in predicting microbiological diagnosis for acute bacterial diarrhea: Prospective Multicenter study

Objective: About 2.2 million deaths occur every year worldwide due to diarrhea. There is lack of accurate diagnostic screening test to triage patients with acute bacterial diarrhea from those having mild and self limiting disease. This poses a formidable challenge to the clinicians in managing these patients appropriately initially at presentation as most of the patients with mild and nonbacterial diarrhea end up being treated with antibiotics. Lactoferrin and Guaiac based fecal occult blood test (FOBT) have been used to predict infective etiology of acute diarrhea but did not prove to be very accurate. In the present prospective, multicenter case-control study, fecal calprotectin has been evaluated for first time as a novel marker in diagnosing acute bacterial diarrhea.

New concepts in cerebral palsy

The incidence of cerebral palsy (CP) in the United States has been increasing, and at least part of this increase is attributable to extremely low birth weight infants. Quality studies of CP have been difficult to perform because of the inconsistency of diagnosis for various subtypes. This inconsistency spills over to practitioners as well, who may have difficulty in assigning meaningful, reproducible diagnoses to their patients. An attempt at standardization is reported in this issue of The Journal. The Extremely Low Gestational Age Newborns (ELGAN) study has developed a classification algorithm, the use of which is aided by a CD-ROM training video which describes a standardized neurologic examination. Using this tool, the group found an incidence of CP of 11% among a group of 2-year-old infants born between 23 and 27 weeks gestation. Not surprisingly, the group of children with quadripesis tended to have the most comorbidities and the greatest functional impairment. The real contribution of this study, however, is the demonstration that a standardized examination and algorithm can be used successfully in a multi-center study of this important and complex disorder. This importance is further stressed in an accompanying editorial by Accardo et al. On the spectrum of CP, children with hemiplegic involvement (HCP) generally fall on the milder end. In particular, they are more likely to complete mainstream school. Another study in this issue, by Russo et al, examined a variety of measures of quality of life in a number of children with HCP. Despite their milder involvement, these children display reductions in quality of life and self concept in comparison to typically developing peers. The impact of CP on the lives of our children and their families occurs throughout the wide range of the disease.

Compound heterozygosity for GDF5 in Du Pan type chondrodysplasia

Du Pan type chondrodysplasia (DPC) represents the milder end of homozygous growth differentiation factor 5 (GDF5) disorders. We report on a 20-month-old child with complex brachydactyly and mild proximal fibular hypoplasia, consistent with DPC, in the absence of other anomalies of long bones and joints. Mutational analysis disclosed two novel GDF5 mutations within the protein's mature domain and in the cleavage site of the prodomain which explains the distinct DPC phenotype found in this patient. The unaffected mother and the father who presented with mild brachybaso/mesophalangy of all digits were both heterozygous carriers.

Search for Subtelomeric Imbalances by Multiplex Ligation-Dependent Probe Amplification in Silver–Russell Syndrome

Chromosomal aberrations are typically associated with primordial growth retardation, psychomotoric constrictions, and dysmorphisms. Since these features may be present in patients with Silver-Russell syndrome (SRS) and chromosomal disturbances are also detected in a subgroup of SRS patients, we screened a cohort of 45 SRS patients for cryptic subtelomeric imbalances. Submicroscopic deletions/duplications in the telomere regions are meanwhile well known to cause a broad spectrum of conspicuous phenotypes, characterized by mental retardation and multiple further congenital anomalies. We hypothesize that SRS might represent at the mild end of the broad phenotypic range of subtelomeric imbalances. Screening of the patients was performed by multiplex ligation-dependent probe amplification (MLPA), a technique that has already been shown to be effective and reliable for measuring copy numbers. We excluded pathogenetically relevant copy number variations in the subtelomeres in our SRS patient cohort, but one patient carried an apathogenic polymorphic Yq deletion. It can therefore be concluded that this type of chromosomal aberration does not belong to the genetic causes of SRS and it is not necessary to include this test in the diagnostic algorithm of the disease.

Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1

We recently identified the X-chromosomal four and a half LIM domain gene FHL1 as the causative gene for reducing body myopathy, a disorder characterized by progressive weakness and intracytoplasmic aggregates in muscle that exert reducing activity on menadione nitro-blue-tetrazolium (NBT). The mutations detected in FHL1 affected highly conserved zinc coordinating residues within the second LIM domain and lead to the formation of aggregates when transfected into cells. Our aim was to define the clinical and morphological phenotype of this myopathy and to assess the mutational spectrum of FHL1 mutations in reducing body myopathy in a larger cohort of patients. Patients were ascertained via the detection of reducing bodies in muscle biopsy sections stained with menadione-NBT followed by clinical, histological, ultrastructural and molecular genetic analysis. A total of 11 patients from nine families were included in this study, including seven sporadic patients with early childhood onset disease and four familial cases with later onset. Weakness in all patients was progressive, sometimes rapidly so. Respiratory failure was common and scoliosis and spinal rigidity were significant in some of the patients. Analysis of muscle biopsies confirmed the presence of aggregates of FHL1 positive material in all biopsies. In two patients in whom sequential biopsies were available the aggregate load in muscle sections appeared to increase over time. Ultrastructural analysis revealed that cytoplasmic bodies were regularly seen in conjunction with the reducing bodies. The mutations detected were exclusive to the second LIM domain of FHL1 and were found in both sporadic as well as familial cases of reducing body myopathy. Six of the nine mutations affected the crucial zinc coordinating residue histidine 123. All mutations in this residue were de novo and were associated with a severe clinical course, in particular in one male patient (H123Q). Mutations in the zinc coordinating residue cysteine 153 were associated with a milder phenotype and were seen in the familial cases in which the boys were still more severely affected compared to their mothers. We expect the mild end of the spectrum to significantly expand in the future. On the severe end of the spectrum we define reducing body myopathy as a progressive disease with early, but not necessarily congenital onset, distinguishing this condition from the classic essentially non-progressive congenital myopathies.

Neuropsychology and clinical neuroscience of persistent post-concussive syndrome

On the mild end of the acquired brain injury spectrum, the terms concussion and mild traumatic brain injury (mTBI) have been used interchangeably, where persistent post-concussive syndrome (PPCS) has been a label given when symptoms persist for more than three months post-concussion. Whereas a brief history of concussion research is overviewed, the focus of this review is on the current status of PPCS as a clinical entity from the perspective of recent advances in the biomechanical modeling of concussion in human and animal studies, particularly directed at a better understanding of the neuropathology associated with concussion. These studies implicate common regions of injury, including the upper brainstem, base of the frontal lobe, hypothalamic-pituitary axis, medial temporal lobe, fornix, and corpus callosum. Limitations of current neuropsychological techniques for the clinical assessment of memory and executive function are explored and recommendations for improved research designs offered, that may enhance the study of long-term neuropsychological sequelae of concussion.

A Japanese patient with a mild Lenz–Majewski syndrome

We report on a sclerosing bone dysplasia, associated with cutis laxa, enamel dysplasia, and mental retardation. The patient was a 17-year-old Japanese boy of normal height and muscular build. Cutis laxa with prominent veins in the scalp and abdominal wall and delayed eruption of permanent teeth attracted the attention of clinicians in infancy and adolescence, respectively. The clinical manifestations included a progeroid facial appearance with prognathism, wrinkled skin, and interdigital webbing. The intelligence quotient was estimated at 60. Enamel dysplasia was histologically confirmed. Skeletal changes included calvarial hyperostosis, sclerosis of the skull base, an enlarged, sclerotic mandible, broad clavicles and ribs, and diaphyseal undermodeling of the tubular bones. Metaepiphyseal sclerosis or longitudinal striation was found in the long bones. Metaphyseal equivalents of the axial skeleton showed dense osteosclerosis. These clinical and radiological manifestations overlapped with those of Lenz-Majewski syndrome. Unlike the classical phenotype of the disorder, however, he did not show brachymesophalangy with proximal symphalangism or growth failure. The present case may be considered to fall in the mildest end in the phenotypic continuum of Lenz-Majewski syndrome, suggesting that the clinical spectrum of the disorder may be broader than currently thought.

DHCR7 mutation carrier rates and prevalence of the RSH/Smith‐Lemli‐Opitz syndrome: Where are the patients?

RSH/Smith-Lemli-Opitz (SLOS) is an inborn error of metabolism with protean manifestations. Its exact incidence and prevalence are not known; however, the carrier rate for the most frequently occurring mutation, the null mutation IVS8-1G > C, is approximately 1 in 100 for the Caucasian population in North America (1%) and possibly as high as 1 in 50 to 1 in 30 in Central European populations (2-3.3%). Based on the allele frequencies and the proportion of this mutation observed in various patient populations, the expected incidence of RSH/SLOS in those populations was calculated and reported to be between 1 in 1,590 and 1 in 17,000. However, around the world the observed prevalence and incidence are much lower than those calculated from the individual mutation carrier rates observed in any given population. The discrepancy between the expected incidence and prevalence can be explained only in part by the neonatal and infancy deaths of the most severely affected children with RSH/SLOS and the under ascertainment of mild and atypical cases at the mild end of the spectrum. RSH/SLOS may be responsible for a high number of miscarriages. Recent observations estimate the prevalence of SLOS at 16 weeks of gestation as similar to that observed at birth (approximately 1 in 60,000) suggesting that either reduced fertility of carrier couples or losses of affected embryos or fetuses in the first trimester play a significant role in reducing the second trimester prevalence of RSH/SLOS. It is possible that the estimates of carrier rates based on population screening for the most commonly occurring mutations may not reflect the true carrier rates in the population. In order to reconcile the above-mentioned paradoxes, we propose a model based on a higher than observed carrier frequency of the most common mutation and on very high fetal loss of homozygotes for that mutation.

The nomenclature, definition and classification of hypoplastic left heart syndrome

The hypoplastic left heart syndrome encompasses a spectrum of cardiac malformations that are characterized by significant underdevelopment of the components of the left heart and the aorta, including the left ventricular cavity and mass. At the severe end of the spectrum is found the combination of aortic and mitral atresia, when the left ventricle can be close to non-existent. At the mild end are the patients with hypoplasia of the aortic and mitral valves, but without intrinsic valvar stenosis or atresia, and milder degrees of left ventricular hypoplasia. Although the majority of the patients are suitable only for functionally univentricular repair, a small minority may be candidates for biventricular repair. The nature of the syndrome was a topic for discussion at the second meeting of the International Working Group for Mapping and Coding of Nomenclatures for Paediatric and Congenital Heart Disease, the Nomenclature Working Group, held in Montreal, Canada, over the period January 17 through 19, 2003. Subsequent to these discussions, the Nomenclature Working Group was able to create a bidirectional crossmap between the nomenclature initially produced jointly on behalf of the European Association for Cardio-Thoracic Surgery and the Society of Thoracic Surgeons, and the alternative nomenclature developed on behalf of the Association for European Paediatric Cardiology. This process is a part of the overall efforts of the Nomenclature Working Group to create a comprehensive and all-inclusive international system of nomenclature for paediatric and congenital cardiac disease, the International Paediatric and Congenital Cardiac Code. In this review, we discuss the evolution of nomenclature and surgical treatment for the spectrum of lesions making up the hypoplastic left heart syndrome and its related malformations. We also present the crossmap of the associated terms for diagnoses and procedures, as recently completed by the Nomenclature Working Group.

The Impact of Late Presentation of Posterior Urethral Valves on Bladder and Renal Function

We retrospectively reviewed the records of patients with late presentation of PUVs, and compared bladder and renal function to that in patients with an early diagnosis of PUVs. We retrospectively reviewed the charts of 36 males (mean age at diagnosis 8.8 years, range 5 to 14) with late presentation of PUVs who were treated at our institution between 1986 and 2004. Of these patients 20 had undergone urodynamic evaluation during followup (mean age 10.65 years, range 5 to 23). We chose as controls 19 age matched children with PUVs who were diagnosed and treated before age 5 years and underwent urodynamic evaluation during followup (mean age at urodynamic evaluation 8.52 years, range 6 to 15). Urodynamic parameters were compared between the 2 patient groups. Renal function in the late presenting cases was also compared to controls. The most common symptoms at presentation were diurnal enuresis (17 patients, 47.2%) poor stream (7, 19.4%) and urinary retention (5, 13.9%). Overall, urodynamic bladder abnormalities were detected in 17 of 20 patients (85%), detrusor overactivity in 3 (15%), significant post-void residual in 9 (45%) and bladder capacity greater than expected for age in 9 (45%). No significant difference in bladder capacity, compliance or post-void residual was demonstrated between the late presenting and control groups. Only detrusor overactivity was significantly lower in the late presenting group (p = 0.013). After a mean followup of 67.03 months age specific creatinine levels were increased in 13 of 27 patients (48.1%), including 7 (25.9%) with ESRD. Renal function was significantly impaired in the late presenting group compared to controls (48.1% vs 13.7%, p = 0.001). We found a significantly lower rate of detrusor overactivity (15%) in patients with late presenting PUVs. Comparison of urodynamic parameters between the early and late presenting groups did not reveal any significant difference. This similar pattern of bladder dysfunction, independent of age at relief of obstruction, may indicate a common pathophysiological etiology for bladder dysfunction in all patients with PUVs. Also, renal function was significantly impaired in the late presenting group in this series.

Growing up and moving on in rheumatology: Parents as proxies of adolescents with juvenile idiopathic arthritis

To examine agreement about physical health, functional ability, and health-related quality of life (HRQOL) between adolescents with juvenile idiopathic arthritis (JIA) and their parents. The study group comprised 303 adolescent-parent dyads who completed individual questionnaires, including the Childhood Health Assessment Questionnaire with visual analog scales for pain and general well-being, and the Juvenile Arthritis Quality of Life Questionnaire. Agreement was determined using the Bland and Altman method. Approximately half of the adolescent-parent dyads showed clinically acceptable agreement for pain, general well-being, functional disability, and HRQOL. Where discrepancies occurred, there were similar numbers of parental overestimation and underestimation, with the exception that parents rated functional ability worse than did adolescents. Parents were also consistent with respect to overestimation or underestimation, irrespective of the health domain in question. Agreement was associated with better disease-related outcome variables, but was not significantly influenced by demographic factors. Agreement between adolescents and parents was dependent on the level of disease outcome and the health domain under scrutiny, and was less for moderate disease outcomes (as compared with mild or severe) and less visible phenomena (e.g., pain, global well-being). There is a wide variation in agreement between adolescents with JIA and their parents that is dependent on which health-related variable is under scrutiny. Proxy report is likely to be valid for adolescents with JIA at either the mild or severe end of the spectrum and/or for the visible manifestations of the disease. Consideration of both adolescent and parent-proxy reports is therefore important in future research.

Supernumerary marker chromosome 7 and maternal uniparental disomy 7 in a boy with growth retardation and triangular face

We report on a 12-month-old boy with pre and post-natal growth retardation, triangular face and mild psychomotor retardation. Karyotyping revealed a supernumerary marker chromosome (SMC) in 36% of cells. Using fluorescence in situ hybridization and BAC clones, the supernumerary marker chromosome was found to be a highly deleted chromosome 7 with breakpoints within the pericentric euchromatin (partial trisomy 7). Microsatellite typing indicated maternal uniparental disomy of chromosome 7 (matUPD7). The patient showed only few signs of the Silver-Russell syndrome. He therefore reflects the mild end of the phenotypic spectrum in patients with matUPD7. The case supports the argument that karyotyping is warranted in patients with short stature and only few additional features, and that UPD studies are required in patients with a SMC(7). Considering that the SMC(7) contributed very little, if any, to the phenotype of this boy, we propose that UPD7 studies should be carried out in children with pre- and postnatal growth retardation of unknown cause even in the absence of a SMC.

Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD

To use fMRI to investigate whether hippocampal and entorhinal activation during learning is altered in the earliest phase of mild cognitive impairment (MCI). Three groups of older individuals were studied: 10 cognitively intact controls, 9 individuals at the mild end of the spectrum of MCI, and 10 patients with probable Alzheimer disease (AD). Subjects performed a face-name associative encoding task during fMRI scanning, and were tested for recognition of stimuli afterward. Data were analyzed using a functional-anatomic method in which medial temporal lobe (MTL) regions of interest were identified from each individual's structural MRI, and fMRI activation was quantified within each region. Significantly greater hippocampal activation was present in the MCI group compared to controls; there were no differences between these two groups in hippocampal or entorhinal volumes. In contrast, the AD group showed hippocampal and entorhinal hypoactivation and atrophy in comparison to controls. The subjects with MCI performed similarly to controls on the fMRI recognition memory task; patients with AD exhibited poorer performance. Across all 29 subjects, greater mean entorhinal activation was found in the subgroup of 13 carriers of the APOE epsilon4 allele than in the 16 noncarriers. The authors hypothesize that there is a phase of increased medial temporal lobe activation early in the course of prodromal Alzheimer disease followed by a subsequent decrease as the disease progresses.

OP5. GCA AND PMR: A GENERAL PRACTITIONER'S PERSPECTIVE

PMR can be a challenging condition within primary care. Diagnosis can be difficult as it largely depends on having a high index of suspicion supported by history, examination and raised levels of inflammatory markers which of course are not specifically diagnostic for PMR. The incidence of PMR has variously been reported as between 13 and 68 per 100,000 of the population aged over 50 with a peak incidence around age 70. As most general medical practitioners in the UK look after a patient population of around 2000 patients it follows that a new case of PMR does not occur frequently in most GPs clinical practice. General practitioners whose patient population is skewed towards a younger age group may only rarely see a case of PMR and may develop little experience of dealing with the condition. When PMR presents with classical clinical features of a sudden onset of stiffness and pain in shoulder and pelvic girdles, with tenderness of shoulder muscles and some systemic features of debility, weight loss, tiredness and low-grade fever together with a raised ESR the diagnosis can be fairly straightforward. If the symptoms are not rapidly relieved within a few days with steroid therapy (15 mg/day prednisolone) the diagnosis should be re-considered and various laboratory tests should be undertaken to exclude conditions such as multiple myeloma, other malignancy, connective tissue disease, inflammatory arthritis, myopathy, and myositis. One of the most difficult differential diagnoses is that of rheumatoid arthritis. A polymyalgic presentation of RA may occur especially in elderly patients and in the very early stages before there are overt joint signs such as synovitis, may very closely resemble PMR. Generally these patients do not have a rapid response to steroid therapy. It is important to remember the overlap between PMR and GCA. These two conditions may in fact represent opposite ends of the spectrum of the same disease with PMR at the milder end. All patients suspected of having PMR should be asked about symptoms of headache, jaw claudication and scalp tenderness and if present the patient should be referred immediately for a temporal artery biopsy and treatment with higher dose steroids. If immediate referral is not possible patients should be treated with high dose steroids in primary care to avoid possible blindness. PMR is a challenging condition in primary care but can be very satisfying to treat as patients often have a very dramatic response to therapy and are most grateful for the relief of their symptoms.

The role of sequence variations within the genes encoding collagen II, IX and XI in non-syndromic, early-onset osteoarthritis

We sought to determine whether sequence variations in cartilage collagen genes are associated with primary, early-onset osteoarthritis (OA). The cartilage collagen genes, COL2A1, COL9A1, COL9A2, COL9A3, COL11A1 and COL11A2, were screened for sequence variations in 72 Finnish probands and one US family with primary early-onset hip and/or knee OA. In addition, allelic association studies were performed using six to 12 common polymorphisms from each gene by genotyping 72 OA patients and 103 controls. Altogether 239 sequence variations were found, of which 16 were not present in the controls. Seven of the unique variations, four in COL11A1, two in COL11A2 and one in COL2A1, were studied further, because they resulted in the substitution of conserved amino acids or were predicted to affect mRNA splicing. Co-segregation of a sequence variation and the phenotype was found in all four families available for study. Association analysis failed to identify any common predisposing alleles. Early-onset OA demonstrates locus and allelic heterogeneity since the identified variations were in three different collagen genes and each of the six probands had a different mutation. It is also possible that some OA cases represent the mild end of the chondrodysplasia phenotypic spectrum. The major susceptibility alleles in this form of OA, however, remain to be identified.