Defining trajectories of response in patients with psoriasis treated with biologic therapies.

BACKGROUND: The effectiveness and cost-effectiveness of biologic therapies for psoriasis are significantly compromised by variable treatment responses. Thus, more precise management of psoriasis is needed. OBJECTIVES: To identify subgroups of patients with psoriasis treated with biologic therapies, based on changes in their disease activity over time, that may better inform patient management. METHODS: We applied latent class mixed modelling to identify trajectory-based patient subgroups from longitudinal, routine clinical data on disease severity, as measured by the Psoriasis Area and Severity Index (PASI), from 3546 patients in the British Association of Dermatologists Biologics and Immunomodulators Register, as well as in an independent cohort of 2889 patients pooled across four clinical trials. RESULTS: We discovered four discrete classes of global response trajectories, each characterized in terms of time to response, size of effect and relapse. Each class was associated with differing clinical characteristics, e.g. body mass index, baseline PASI and prevalence of different manifestations. The results were verified in a second cohort of clinical trial participants, where similar trajectories following the initiation of biologic therapy were identified. Further, we found differential associations of the genetic marker HLA-C*06:02 between our registry-identified trajectories. CONCLUSIONS: These subgroups, defined by change in disease over time, may be indicative of distinct endotypes driven by different biological mechanisms and may help inform the management of patients with psoriasis. Future work will aim to further delineate these mechanisms by extensively characterizing the subgroups with additional molecular and pharmacological data.

Genome-wide association analysis of copy number variation in recurrent depressive disorder.

Large, rare copy number variants (CNVs) have been implicated in a variety of psychiatric disorders, but the role of CNVs in recurrent depression is unclear. We performed a genome-wide analysis of large, rare CNVs in 3106 cases of recurrent depression, 459 controls screened for lifetime-absence of psychiatric disorder and 5619 unscreened controls from phase 2 of the Wellcome Trust Case Control Consortium (WTCCC2). We compared the frequency of cases with CNVs against the frequency observed in each control group, analysing CNVs over the whole genome, genic, intergenic, intronic and exonic regions. We found that deletion CNVs were associated with recurrent depression, whereas duplications were not. The effect was significant when comparing cases with WTCCC2 controls (P=7.7 × 10(-6), odds ratio (OR) =1.25 (95% confidence interval (CI) 1.13-1.37)) and to screened controls (P=5.6 × 10(-4), OR=1.52 (95% CI 1.20-1.93). Further analysis showed that CNVs deleting protein coding regions were largely responsible for the association. Within an analysis of regions previously implicated in schizophrenia, we found an overall enrichment of CNVs in our cases when compared with screened controls (P=0.019). We observe an ordered increase of samples with deletion CNVs, with the lowest proportion seen in screened controls, the next highest in unscreened controls and the highest in cases. This may suggest that the absence of deletion CNVs, especially in genes, is associated with resilience to recurrent depression.

Failure to confirm NOTCH4 association with schizophrenia in a large population-based sample from Scotland.

The NOTCH4 gene was recently reported to be associated with schizophrenia based on TDT analysis of 80 British trios. The strongest evidence for association derived from two microsatellites. We genotyped both loci in a large sample of unrelated Scottish schizophrenics and controls, but failed to replicate the reported association, finding instead that each putative schizophrenia-associated allele had a somewhat lower frequency in schizophrenics than in controls.

Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function.

Schizophrenia is a severe psychiatric disorder with a world-wide prevalence of 1%. The pathophysiology of the illness is not understood, but is thought to have a strong genetic component with some environmental influences on aetiology. To gain further insight into disease mechanism, we used microarray technology to determine the expression of over 30 000 mRNA transcripts in post-mortem tissue from a brain region associated with the pathophysiology of the disease (Brodmann area 10: anterior prefrontal cortex) in 28 schizophrenic and 23 control patients. We then compared our study (Charing Cross Hospital prospective collection) with that of an independent prefrontal cortex dataset from the Harvard Brain Bank. We report the first direct comparison between two independent studies. A total of 51 gene expression changes have been identified that are common between the schizophrenia cohorts, and 49 show the same direction of disease-associated regulation. In particular, changes were observed in gene sets associated with synaptic vesicle recycling, transmitter release and cytoskeletal dynamics. This strongly suggests multiple, small but synergistic changes in gene expression that affect nerve terminal function.

Polymorphisms in the endothelin-1 (EDN1) are associated with asthma in two populations.

Endothelin-1 (EDN1) has been reported to be implicated in the pathophysiology of asthma. Literature results on the genetic association of EDN1 in asthma are inconsistent. Eleven single nucleotide polymorphisms in EDN1 were genotyped in 342 and 100 families from UK and Norway, respectively. Asthma, bronchial hyperreactivity (BHR) and atopic asthma phenotypes were analyzed for the family-based association. Five single nucleotide polymorphisms (SNPs) were associated with asthma (0.0017

Identification of a novel mutation R42P in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis.

We report a missense mutation in the gap junction protein beta-3 (encoding Connexin 31), which was detected in only the affected members of a family in which the autosomal dominant skin disease erythrokeratoderma variabilis was segregating. The nucleotide change results in an arginine to proline substitution in codon 42. This residue is positioned on the first transmembrane/first extracellular domain of the gap junction protein with the mutation replacing a negatively charged residue with a nonpolar residue. This change may disrupt the conformation of the protein and voltage gating polarity leading to impaired channel function.

Regulation of histamine H1 receptor-mediated phosphoinositide hydrolysis by histamine and phorbol esters in DDT1 MF-2 cells.

The regulation of histamine-stimulated phosphoinositide turnover by histamine and phorbol esters was examined in intact DDT1 MF-2 cells grown in suspension culture. Histamine increased the incorporation of 32P into phosphatidylinositol (PI) in these cells, and this stimulation was inhibited by the H1 antagonist diphenhydramine but not by the H2 antagonist cimetidine. Pretreatment of cells with histamine or with phorbol 12-myristate 13-acetate (PMA) or other activators of protein kinase C induced a marked decrease in the subsequent stimulation by histamine. PMA, but not histamine, also decreased the ability of epinephrine to stimulate PI labelling through alpha 1-adrenoceptors. Thus, histamine appears to induce homologous desensitization of histamine H1 receptor-mediated PI turnover, whereas direct activation of protein kinase C in the absence of receptor occupancy by agonist induces nonspecific heterologous desensitization of both histamine H1- and alpha 1-adrenoceptor-mediated responses.

A review of cervical-spine radiographs in casualty patients.

This study reviews the radiographs and clinical case notes of 897 patients who attended the Accident and Emergency (A & E) Department of Leicester Royal Infirmary, over an 8-month period, for whom radiographs of the cervical spine were requested. The radiological interpretations by the casualty officers and junior radiologists in training were compared with those by a consultant radiologist and large discrepancies were observed. There was a predominance of fractures and subluxations at the levels of C1 and C2, and at C7 and T1. A study of the adequacy of the radiographs has shown that 90% of the lateral radiographs included C7 but only 57% included T1. Through-the-mouth views were adequate for interpretation in 67% of cases. The practice of the A & E and radiology departments at the Leicester Royal Infirmary is briefly described. The poor performance of the casualty officers and junior radiologists is discussed and suggestions made which might improve the accuracy of the radiological diagnosis of cervical-spine injuries in the A & E department.

Job satisfaction-dissatisfaction. A comparison of private practitioners and organizational physical therapists.

Job factors which results in feelings of satisfaction or dissatisfaction were studied in a sample of 25 physical therapists engaged in private practice and 25 physical therapists employed as chiefs of departments. Our purpose was to determine the meaningfulness of work for physical therapists and to compare private practitioners with therapists who work within an organization. Ten factors of the sixteen studied were found to be significantly satisfying or dissatisfying for all therapists. In addition, organizational therapists were satisfied with the work itself and valued recognition for their efforts, whereas private practitioners were more concerned with personal responsibility. Organizational therapists experienced periods of unhappiness with some aspects of interpersonal relationships and with some policies of the organization, and private practitioners were unhappy with long working hours. There was no significant difference in salaries, achievement, possibilities for growth, status, or security.

Exercise pain in the lower leg. Chronic compartment syndrome and medial tibial syndrome.

The aetiology of pain in the lower leg during exercise has been studied in 110 athletes by monitoring intracompartmental pressure during exercise and by technetium bone scans. Patients were assigned to three diagnostic groups: chronic compartment syndrome, medial tibial syndrome and those with non-specific findings. Our results indicate that subcutaneous fasciotomy of the affected compartment(s) is the treatment of choice for chronic compartment syndrome. The treatment of patients with medial tibial syndrome, either by operation or conservatively, has been unsuccessful; non-specific symptoms have been treated conservatively with success.

Femoral head blood flow in femoral neck fractures. An analysis using intra-osseous pressure measurement.

We studied 50 patients with fractures of the femoral neck, 33 intracapsular and 17 extracapsular. Intraosseous pressure was measured by a transducer within the bone to quantify blood flow, and intracapsular pressure by a needle introduced into the joint space. The mean intracapsular pressure was lower in the extracapsular fractures. In these, the mean intraosseous pressure in the femoral head was unchanged by aspiration of the joint. However in the intracapsular fractures aspiration produced a significant decrease in intra-osseous pressure and an increase in pulse pressure within the femoral head. The results suggest that aspiration of intracapsular haematoma produced an increase in femoral head blood flow by relieving tamponade.

The value of 99Tcm-MDP bone scans in young patients with exercise-induced lower leg pain.

This study compares the bone scan appearances in 32 patients with medial tibial syndrome (MTS) with the appearance in 28 patients with confirmed chronic compartment syndrome (CCS). A distinctive pattern of uptake was seen in 30 patients, 24 of whom had MTS and 6 of whom had CCS. Of the patients with normal scans, only 4 had MTS, the remaining 15 had CCS. Both of these findings are statistically significant and confirm that bone scans are a useful diagnostic tool in the differential diagnosis of exercise-induced lower leg pain.

Weakness of foot dorsiflexion and changes in compartment pressures after tibial osteotomy.

Weakness of dorsiflexion of the foot is a common complication of proximal tibial osteotomy and it has been suggested that this may be caused by an anterior tibial compartment syndrome. A prospective study of 20 patients undergoing tibial osteotomy was undertaken, in which compartment pressures were recorded and related to clinical signs. In 10 of the patients, the operation site was drained, and in 10 no drainage was employed. The undrained group showed significant elevation (greater than 45 mmHg) of the anterior compartment pressure in seven patients, and five of these had transient clinical signs. Only one patient had any permanent deficit, a minor asymptomatic weakness of extensor hallucis longus. In the drained group the pressures remained below 30 mmHg in all except two patients, who both had only a minor pressure rise and no significant early clinical signs. However, two patients from this group later developed weakness of dorsiflexion, probably due to common peroneal nerve injury, the cause of which is not clear.

Cement pressurisation during hip replacement.

The newer techniques of cementing aim to improve interlock between cement and bone around a femoral stem by combining high pressure and reduced viscosity. This may produce increased embolisation of fat and marrow leading to hypotension, impaired pulmonary gas exchange and death. For this reason the use of high pressures has been questioned. We compared finger-packing with the use of a cement gun by measuring intramedullary pressures during the cementing of 31 total hip replacements and measuring physiological changes in 19 patients. We also measured pressure in more detail in a laboratory model. In the clinical series the higher pressures were produced by using a gun, but this caused less physiological disturbance than finger-packing. The laboratory studies showed more consistent results with the gun technique, but for both methods of cementing the highest pressures were generated during the insertion of the stem of the prosthesis.

Intracompartmental pressure monitoring of leg injuries. An aid to management.

Acute compartment syndromes often develop insidiously and are often recognised too late to prevent permanent disability. Management is difficult as the compartment involved is seldom clinically apparent. By continuously monitoring the intracompartmental pressure these problems can be avoided: transient compartment syndromes can be differentiated from established ones and the correct compartment can be surgically decompressed. Pressure monitoring techniques were used in 28 patients; three developed a compartment syndrome requiring surgical intervention, seven had a temporary increase of pressure and in 18 the pressure remained unaltered. Of the three with compartment syndromes, one was unusual in that it affected the thigh and another, unique in our experience, affected both the thigh and the calf. Intracompartmental pressure monitoring significantly altered the management of two cases giving successful results with minimal intervention.

Compartment pressures after closed tibial shaft fracture. Their relation to functional outcome.

We measured pressures in the anterior and deep posterior compartments continuously for up to 72 hours in 20 patients with closed fractures of the tibial shaft treated primarily in plaster casts. All were examined independently after periods of three to 14 months. Pressures above 40 mmHg occurred in seven (35%) and above 30 mmHg in 14 (70%). No patient had the symptoms of compartment syndrome during monitoring. Abnormalities at review did not correlate with the maximum consecutive time periods during which the compartment pressures were raised. Thus, in the absence of symptoms the monitored pressures did not relate to outcome. Routine monitoring in this type of patient is therefore of doubtful benefit.

Chronic compartment syndrome of the flexor muscles in the forearm: a case report.

A case is reported of a professional racing motor-cyclist who developed a chronic compartment syndrome of the flexor muscles in the forearm, confirmed by pressure measurements after exercise. Open fasciotomy of both the superficial and deep compartments cured the condition.

Deaths following trauma: an audit of performance.

The TRISS methodology was applied to identify preventable trauma deaths in a retrospective audit of 267 (M = 0.908) patients admitted to a teaching hospital through the resuscitation room of its accident and emergency department during a 1-year period. No unexpected survivors were identified; of the 44 deaths (Z = 5.35), 25 (56.8%) were judged preventable by the TRISS method. Those deaths deemed preventable were subjected to peer review by a panel of six consultants. The findings are discussed in respect of recommendations made for UK trauma centre provision by the Working Party Report of the Royal College of Surgeons of England on the management of patients with major injuries.

Does oedema following lower limb revascularisation cause compartment syndromes?

Oedema of the leg, particularly the calf, is a well-recognised complication following lower limb reconstructive vascular surgery, but its effect on the limb is unknown. In this study, anterior compartment pressures and calf circumference were measured in both the operated and non-operated limbs following femoropopliteal bypass in 15 patients. All the patients developed lower limb swelling, which was significantly greater than the non-operated limb, P less than 0.05 paired t test (day 2-5). There was a significant difference in the mean anterior compartment pressures between the operated and non-operated limbs on the third and fourth postoperative days for the overall and below knee group, P less than 0.05 (paired t test). However, none of the patients developed signs, symptoms or pressures indicative of a compartment syndrome. These results suggest that the oedema following reconstructive vascular surgery is subcutaneous rather than compartmental in origin and that compartment pressure measurements should only be undertaken if a fasciotomy is being contemplated.