The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate.

BACKGROUND AND PURPOSE: BAF312 is a next-generation sphingosine 1-phosphate (S1P) receptor modulator, selective for S1P(1) and S1P(5 ) receptors. S1P(1) receptors are essential for lymphocyte egress from lymph nodes and a drug target in immune-mediated diseases. Here, we have characterized the immunomodulatory potential of BAF312 and the S1P receptor-mediated effects on heart rate using preclinical and human data. EXPERIMENTAL APPROACH: BAF312 was tested in a rat experimental autoimmune encephalomyelitis (EAE) model. Electrophysiological recordings of G-protein-coupled inwardly rectifying potassium (GIRK) channels were carried out in human atrial myocytes. A Phase I multiple-dose trial studied the pharmacokinetics, pharmacodynamics and safety of BAF312 in 48 healthy subjects. KEY RESULTS: BAF312 effectively suppressed EAE in rats by internalizing S1P(1) receptors, rendering them insensitive to the egress signal from lymph nodes. In healthy volunteers, BAF312 caused preferential decreases in CD4(+) T cells, T(naïve) , T(central memory) and B cells within 4-6 h. Cell counts returned to normal ranges within a week after stopping treatment, in line with the elimination half-life of BAF312. Despite sparing S1P(3) receptors (associated with bradycardia in mice), BAF312 induced rapid, transient (day 1 only) bradycardia in humans. BAF312-mediated activation of GIRK channels in human atrial myocytes can fully explain the bradycardia. CONCLUSION AND IMPLICATIONS: This study illustrates species-specific differences in S1P receptor specificity for first-dose cardiac effects. Based on its profound but rapidly reversible inhibition of lymphocyte trafficking, BAF312 may have potential as a treatment for immune-mediated diseases.

Immobilisation of the knee and ankle and its impact on drivers' braking times: a driving simulator study.

The purpose of this study was to investigate the effects of right leg restriction at the knee, ankle or both, on a driver's braking times. Previous studies have not investigated the effects of knee restriction on braking performance. A total of 23 healthy drivers performed a series of emergency braking tests in a driving simulator in either an above-knee plaster cast, a below-knee cast, or in a knee brace with an increasing range of restriction. The study showed that total braking reaction time was significantly longer when wearing an above-knee plaster cast, a below-knee plaster cast or a knee brace fixed at 0°, compared with braking normally (p < 0.001). Increases in the time taken to move the foot from the accelerator to the brake accounted for some of the increase in the total braking reaction time. Unexpectedly, thinking time also increased with the level of restriction (p < 0.001). The increase in braking time with an above-knee plaster cast in this study would increase the stopping distance at 30 miles per hour by almost 3 m. These results suggest that all patients wearing any lower-limb plaster cast or knee brace are significantly impaired in their ability to perform an emergency stop. We suggest changes to the legislation to prevent patients from driving with lower-limb plaster casts or knee braces.

Cutaneous Fusarium solani infection in childhood acute lymphoblastic leukaemia.

Cutaneous involvement is often an initial presentation of infection with Fusarium species, which occurs more commonly in immunocompromised hosts and may be either localized or widespread. Skin lesions typically appear as red or grey macules, which may develop central ulceration and black eschar. Secondary dissemination to extracutaneous organs may occur in immunocompromised hosts, especially those with prolonged and severe neutropenia. We describe a case of widespread cutaneous involvement after infection with Fusarium solani in childhood acute lymphoblastic leukaemia that responded successfully to treatment with prolonged liposomal amphotericin B.

A case of haemodialysis-associated pseudoporphyria successfully treated with oral N-acetylcysteine.

We report a 33-year-old woman with haemodialysis-associated pseudoporphyria successfully responding to treatment with oral N-acetylcysteine. We briefly review the current literature on bullous skin disorders in end-stage renal disease, and compare and contrast the pathogenesis of pseudoporphyria and porphyria cutanea tarda in this context. We also discuss the antioxidant properties and clinical applications of N-acetylcysteine, including the treatment of haemodialysis-associated pseudoporphyria.

Chronic lymphocytic leukaemia skin infiltrates affecting prominent parts of the face and the scalp.

Chronic lymphocytic leukaemia (CLL) infiltrating the skin is uncommon and can present in different forms. We report a case of CLL infiltrating the prominent parts of the face and the scalp. A 63-year-old male with a 10-year history of CLL presented with plum-coloured swelling of the skin of the ears, eyebrows, tip of the nose and the scalp. Histopathology showed dense sheets of lymphoid infiltrate of the dermis which stained positive with B-cell markers CD20 and CD5 in keeping with the infiltrate of CLL.

Coexistence of psoriasis and linear IgA disease in a patient with recent herpes zoster infection.

We report the case of a 29-year-old man with chronic plaque psoriasis who developed linear IgA disease following herpes zoster infection. There has only been one previous report describing the coexistence of psoriasis and linear IgA disease, which was confirmed by immunopathological studies. In our patient, immunoblotting studies identified IgA antibodies binding to BP180 and BP230 antigens, and IgG autoantibodies binding weakly to the BP180 antigen. This is an interesting case that we believe is an example of epitope spreading in the development of autoimmune subepidermal bullous diseases.

Prevalence and patterns of cognitive impairment in sporadic ALS.

OBJECTIVE: To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study. METHODS: Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes. RESULTS: On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance. CONCLUSIONS: These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.

The pathway study: results of a pilot feasibility study in patients suspected of having lung carcinoma investigated in a conventional chest clinic setting compared to a centralised two-stop pathway.

UNLABELLED: The best chance of cure in non-small cell lung cancer (NSCLC) is surgical resection, but UK rates of 8% compare poorly to 25% in the USA and Europe. Delays in diagnosis in the current UK system may be one reason for such discrepancy. To address this problem we set up a rapid diagnostic system and compared it to the conventional method of investigations in a pilot randomised trial. METHODS: Eighty-eight patients were prospectively enrolled from three District General Hospitals and randomised to either investigation locally or to the rapid system at The Royal Marsden Hospital. The pilot end-points were feasibility and audit of radical treatment rates to enable estimates for patient numbers for the full study. RESULTS: Forty-five and 43 patients were in the central and conventional arms, respectively (65% male, median age 69 years). There was a 4-week improvement in time to first treatment in those in the central arm (P=0.0025) with 13/30 (43%) and 9/27 (33%) patients having radical treatment in the central and conventional arms, respectively. Patients in the conventional arm felt the diagnostic process was too slow (P=0.02) while those in the central arm seemed to have a better care experience (P=0.01). There were significantly less visits to the general practitioner (GP) in the central arm (P=0.02). CONCLUSIONS: This pilot study demonstrates that the full study is feasible but would require the commitment and involvement of a large number of patients and physicians. The results show several advantages to investigations and diagnosis in the central arm, particularly in time to treatment initiation, patient satisfaction and rate of radical treatments. The improved rate of radical treatment could lead to an improved survival rate.

Tracheobronchial involvement with Crohn's disease.

We report the case of a young woman with Crohn's disease of the bowel who presented with a purulent tracheobronchitis and life-threatening upper airway obstruction. Fibreoptic bronchoscopy demonstrated severe tracheal and upper bronchial pseudotumours and stenosis. The role of recent discontinuation of corticosteroids, for quiescent inflammatory bowel disease, in the development of endobronchial disease and the dramatic response in airway patency after reintroduction of prednisolone in this rare complication of Crohn's disease are discussed.

The human growth hormone locus control region mediates long-distance transcriptional activation independent of nuclear matrix attachment regions.

Expression of the human growth hormone (hGH-N) transgene in the mouse pituitary is dependent on a multicomponent locus control region (LCR). The primary determinant of hGH LCR function maps to the pituitary-specific DNase I hypersensitive sites (HS) HSI,II, located 15 kb 5' to the hGH-N gene. The mechanism by which HSI,II mediates long-distance activation of the hGH locus remains undefined. Matrix attachment regions (MARs) comprise a set of AT-rich DNA elements postulated to interact with the nuclear scaffold and to mediate long-distance interactions between LCR elements and their target promoters. Consistent with this model, sequence analysis strongly predicted a MAR determinant in close proximity to HSI,II. Surprisingly, cell-based analysis of nuclear scaffolds failed to confirm a MAR at this site, and extensive mapping demonstrated that the entire 87 kb region encompassing the hGH LCR and contiguous hGH gene cluster was devoid of MAR activity. Homology searches revealed that the predicted MAR reflected the recent insertion of a LINE 3'-UTR segment adjacent to HSI,II. These data point out discordance between sequence-based MAR predictions and in vivo MAR function and predict a novel MAR-independent mechanism for long-distance activation of hGH-N gene expression.

Patterns of histone acetylation suggest dual pathways for gene activation by a bifunctional locus control region.

The five genes of the human growth hormone (hGH) cluster are expressed in either the pituitary or placenta. Activation of the cluster is dependent on a locus control region (LCR) comprising pituitary- specific (HSI,II, -15 kb), placenta-specific (HSIV, -30 kb) and shared (HSIII, -28 kb; HSV, -32 kb) DNase I hypersensitive sites. Gene activation in the pituitary is paralleled by acetylation of a 32 kb chromatin domain 5' to the cluster centered at HSI,II. In the present study we observed that acetylation of this region in placental chromatin was discretely limited to shared HSIII and HSV. Transgenic studies revealed placenta-specific activation of linked genes by a determinant (P-element) located 2 kb 5' to each of the four placentally expressed genes. A localized peak of histone acetylation was observed at these P-elements in placenta but not pituitary. These data support a model for bifunctional action of the hGH LCR in which separate positive determinants, HSI,II and the P-elements, activate their respective target genes by tissue-specific recruitment of distinctly regulated histone acetyl transferase activities.

HIV seroprevalence by anonymous testing in patients with Mycobacterium tuberculosis and in tuberculosis contacts.

Having witnessed a large increase in Mycobacterium tuberculosis notifications in south London, we wanted to ascertain the prevalence of HIV and tuberculosis co-infection in our patients. All patients with tuberculosis and their contacts were anonymously tested for HIV in blood and saliva, respectively. 11.4% of patients (from various demographic groups) with tuberculosis who attend chest clinics in south London are HIV positive. In addition, 5% of individuals seen in the tuberculosis contact screening clinics and 4% new entrants are HIV positive. All patients with Mycobacterium tuberculosis, irrespective of background, should be urged to have an HIV test.

The multifunctional properties and characteristics of vitamin D-binding protein.

In recent years, our understanding of the many physiological, biochemical, and molecular functions and attributes of vitamin D-binding protein (DBP) has seen exciting and significant advances. Since its identification in 1959, many important functions of this abundant serum protein have been discovered. These range from the transport of vitamin D metabolites to possible roles in the immune system and host defense. With these discoveries, many questions regarding the biology of DBP have been raised and many remain to be answered. Our current understanding of the classic and less-recognized activities of DBP is discussed here.

Measuring team knowledge.

Multioperator tasks often require complex cognitive processing at the team level. Many team cognitive processes, such as situation assessment and coordination, are thought to rely on team knowledge. Team knowledge is multifaceted and comprises relatively generic knowledge in the form of team mental models and more specific team situation models. In this methodological review paper, we review recent efforts to measure team knowledge in the context of mapping specific methods onto features of targeted team knowledge. Team knowledge features include type, homogeneity versus heterogeneity, and rate of knowledge change. Measurement features include knowledge elicitation method, team metric, and aggregation method. When available, we highlight analytical conclusions or empirical data that support a connection between team knowledge and measurement method. In addition, we present empirical results concerning the relation between team knowledge and performance for each measurement method and identify research and methodological needs. Addressing issues surrounding the measurement of team knowledge is a prerequisite to understanding team cognition and its relation to team performance and to designing training programs or devices to facilitate team cognition.