Incidence of clinically suspected venous thromboembolism in British Indian patients.

Introduction Venous thromboembolism (VTE) remains a major public health issue around the world. Ethnicity is known to alter the incidence of VTE. To our knowledge, there are no reports in the literature investigating the incidence of VTE in British Indians. The aim of this study was to investigate the rates of symptomatic VTE in British Indian patients in the UK. Methods Patients referred to our institution between January 2011 and August 2013 with clinically suspected VTE were eligible for inclusion in the study. Those not of British Indian or Caucasian ethnicity were excluded. A retrospective review of these two cohorts was conducted. Results Overall, 15,529 cases were referred to our institution for suspected VTE. This included 1,498 individuals of British Indian ethnicity. Of these, 182 (12%) had confirmed VTE episodes. A further 13,159 of the patients with suspected VTE were coded as Caucasian, including 2,412 (16%) who had confirmed VTE events. VTE rates were a third lower in British Indians with clinically suspected VTE than in the equivalent Caucasian group. The British Indian cohort presented with VTE at a much earlier age than Caucasians (mean 57.0 vs 68.0 years). Conclusions This study suggests that British Indian patients have a lower incidence of VTE and are more likely to present at an earlier age than Caucasians. There was no significant difference in VTE type (deep vein thrombosis vs pulmonary embolism) among the ethnic groups. Clinicians should be aware of variations within ethnicities but should continue to adhere to existing VTE prevention guidance.

Mental health and well-being in parents of excessively crying infants: Prospective evaluation of a support package.

BACKGROUND: During the first 4 months of age, approximately 20% of infants cry a lot without an apparent reason. Most research has targeted the crying, but the impact of the crying on parents, and subsequent outcomes, need to receive equal attention. This study reports the findings from a prospective evaluation of a package of materials designed to support the well-being and mental health of parents who judge their infant to be crying excessively. The resulting "Surviving Crying" package comprised a website, printed materials, and programme of Cognitive Behaviour Therapy-based support sessions delivered to parents by a qualified practitioner. It was designed to be suitable for United Kingdom (UK) National Health Service (NHS) use. METHODS: Parents were referred to the study by 12 NHS Health Visitor/Community Public Health Nurse teams in one UK East Midlands NHS Trust. Fifty-two of 57 parents of excessively crying babies received the support package and completed the Edinburgh Postnatal Depression Scale and Generalized Anxiety Disorder-7 anxiety questionnaire, as well as other measures, before receiving the support package and afterwards. RESULTS: Significant reductions in depression and anxiety were found, with numbers of parents meeting clinical criteria for depression or anxiety halving between baseline and outcome. These improvements were not explained by reductions in infant crying. Reductions also occurred in the number of parents reporting the crying to be a large or severe problem (from 28 to 3 parents) or feeling very or extremely frustrated by the crying (from 31 to 1 parent). Other findings included increases in parents' confidence, knowledge of infant crying, and improvements in parents' sleep. CONCLUSIONS: The findings suggest that the Surviving Crying package may be effective in supporting the well-being and mental health of parents of excessively crying babies. Further, large-scale controlled trials of the package in NHS settings are warranted.

The incidence, diagnostic clinical manifestations and severity of juvenile systemic lupus erythematosus in New Zealand Maori and Pacific Island children: the Starship experience (2000-2010).

OBJECTIVES: To describe the incidence, diagnostic clinical manifestations and severity of juvenile systemic lupus erythematosus (jSLE) in a cohort of New Zealand Maori and Pacific Island children compared to European children. METHODS: A chart review was conducted of children with jSLE seen by the Starship paediatric rheumatology and/or renal services between January 2000 and November 2010. Diagnostic clinical data and lupus nephritis data at anytime were collated while classic British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were derived retrospectively. RESULTS: Thirty-two children were diagnosed with jSLE with an annual incidence of 0.52 per 100,000 per year. Compared with European children (0.31 per 100,000 per year) the incidence of jSLE was higher among Maori and Pacific (0.67 per 100,000 per year, p=0.06) and significantly higher among Asian children (1.17 per 100,000 per year, p=0.01). Compared with European children, Maori and Pacific children were more frequently diagnosed with lupus nephritis (80% vs 40%, p=0.09) and severe (WHO class 4 or 5) renal lesions (60% vs 40%, p=0.43) at presentation. Similarly, at any time during the study, lupus nephritis (100% vs 40%, p=0.001) and severe (WHO class 4 or 5) renal lesions (73.3% vs 40%, p=0.12) were more frequent among Maori and Pacific compared with European children. Furthermore, retrospective BILAG assessment of diagnostic disease severity demonstrated that Maori and Pacific children experienced the majority of severe "Category A" disease (56.8% vs 22.7%, p=0.17) which was predominantly renal (73.3% vs 40%, p=0.12) in nature. CONCLUSIONS: This is the first description of the incidence and clinical manifestations of jSLE in a cohort of New Zealand children. Although limited by the small numbers involved it confirmed anecdotal suspicions that the incidence of jSLE among Maori, Pacific and Asian children is higher than European children. Lupus nephritis is also more frequent and severe in Maori and Pacific children.

Disease Activity Score 28-ESR bears a similar relationship to treatment decisions across different rheumatologists, but misclassification is too frequent to replace physician judgement.

OBJECTIVES: To determine whether physician factors are associated with disease activity status in RA, independently of 28-joint disease activity score (DAS28)-ESR and to re-evaluate DAS28-ESR misclassification rates for identifying active disease in usual practice. METHODS: A prospective observational study of outpatients with RA seen by 17 rheumatologists across New Zealand. Active disease was defined by an increase in therapy together with a reason of 'active disease'; very low disease activity was defined by a decrease in therapy together with a reason of 'patient well'. The independent physician effect was assessed using logistic regression. Sensitivity and specificity of current DAS28-ESR thresholds were calculated. RESULTS: In 511 patients, 178 had active disease, 220 had low disease activity, 37 had very low disease activity and 76 had uncertain disease activity status. There was no independent effect of physician upon active disease status (P = 0.16) with DAS28-ESR [(OR) 3.7] explaining around 50% of the variability in active disease status. There was a trend towards an independent effect of physician upon very low disease activity status (P = 0.06) and greater variability in the distribution of DAS28-ESR for patients in very low disease activity. DAS28-ESR thresholds showed a significant risk of misclassification for active disease. CONCLUSIONS: DAS28-ESR discriminates satisfactorily between groups of patients with active and non-active disease, with no evidence of additional physician-specific factors to explain disease activity status. However, DAS28-ESR is not as good for discriminating remission from non-remission status. There are appreciable probabilities of misclassification error, which make DAS28-ESR inappropriate as a sole guide for treatment decisions.

Effects of once-weekly oral alendronate on bone in children on glucocorticoid treatment.

OBJECTIVES: To determine the effects of once-weekly oral alendronate on indices of bone size, density and resorption in children with chronic illness being treated with glucocorticoids. METHODS: Twenty-two children with chronic illness treated with prednisone were randomized to receive 1 year's treatment with either once-weekly oral placebo or alendronate (1-2 mg/kg body weight) in a double-blind study. The main outcome measures were changes in lumbar spine and femoral shaft size and volumetric density (measured by dual energy X-ray absorptiometry) and N-telopeptide excretion (a marker of bone resorption). RESULTS: Once-weekly alendronate was well tolerated, and there were no major adverse events. In both groups bone size and bone mineral content increased through growth. Volumetric bone density of the lumbar spine increased significantly in the alendronate group (P = 0.013), but not in the placebo group. There were no differences between the groups in growth in the cortical width of the femoral shaft, but the cross-sectional moment of inertia per unit length-a derived estimate of mechanical strength-increased significantly in the alendronate group (P = 0.014) but not in the placebo group. Urine N-telopeptide excretion was suppressed significantly in the alendronate group (P = 0.007) but not in the placebo group. Height velocity was positively correlated with changes in both lumbar spine area and the total width of the femoral shaft (P = 0.015, P = 0.026, respectively). CONCLUSION: Once-weekly oral alendronate is well tolerated, suppresses bone resorption and may improve volumetric bone density at the lumbar spine and mechanical strength of the femoral shaft in children with chronic illness taking glucocorticoids. It does not affect bone growth. Larger controlled studies are needed to determine if these changes translate into reduced fracture incidence or greater peak bone mass. This study highlights the importance of differentiating between changes in bone size and changes in volumetric bone density in assessing bone in children, and also having control subjects in intervention studies.

SPO14 separation-of-function mutations define unique roles for phospholipase D in secretion and cellular differentiation in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, phospholipase D (PLD), encoded by the SPO14 gene, catalyzes the hydrolysis of phosphatidylcholine, producing choline and phosphatidic acid. SPO14 is essential for cellular differentiation during meiosis and is required for Golgi function when the normal secretory apparatus is perturbed (Sec14-independent secretion). We isolated specific alleles of SPO14 that support Sec14-independent secretion but not sporulation. Identification of these separation-of-function alleles indicates that the role of PLD in these two physiological processes is distinct. Analyses of the mutants reveal that the corresponding proteins are stable, phosphorylated, catalytically active in vitro, and can localize properly within the cell during meiosis. Surprisingly, the separation-of-function mutations map to the conserved catalytic region of the PLD protein. Choline and phosphatidic acid molecular species profiles during Sec14-independent secretion and meiosis reveal that while strains harboring one of these alleles, spo14S-11, hydrolyze phosphatidylcholine in Sec14-independent secretion, they fail to do so during sporulation or normal vegetative growth. These results demonstrate that Spo14 PLD catalytic activity and cellular function can be differentially regulated at the level of phosphatidylcholine hydrolysis.

Adsorption and desorption of chemotherapeutic drugs from a magnetically targeted carrier (MTC).

Magnetically targeted carriers (MTCs) are composite microparticles made from metallic iron and activated carbon. Particles, loaded with doxorubicin in the pharmacy (MTC-DOX), are infused intra-arterially through the artery feeding the tumor. With the aid of an externally positioned permanent dipole magnet, they can be localized and retained within a tumor mass. MTC-DOX is currently in use in a Phase I/II clinical study as a delivery vehicle for doxorubicin in primary hepatocellular carcinoma. The adsorption and desorption of doxorubicin, mitomycin C, camptothecin, methotrexate, verapamil and 9AC onto MTCs have been analyzed. Each of these chemotherapeutic agents has a different mechanism of action, suggesting that some benefit may be derived from combined delivery to a tumor using MTCs and magnetic targeting. Each drug displays different behavior with respect to adsorption and desorption. However, this behavior can be described for each drug with a non-linear thermodynamic model. The thermodynamic model predicts a controlled release rate by adjusting a number of parameters, including initial drug loading concentrations. This is confirmed with in vitro extraction experiments using human plasma as the extraction medium.

The influence of bracket type on the force delivery of Ni-Ti archwires.

This study investigated the force delivery of an 0.014 inch nickel-titanium (Ni-Ti) archwire used in combination with a range of commercially available bracket systems, and using a model based on an 'ideal' mandibular archform. The model aimed to replicate the clinical interbracket span. The force delivery was measured at four different sites on an archwire for one batch of 10 nickel titanium archwires from one manufacturer, using one bracket/archwire combination. The four sites represented the lateral incisor, canine, second premolar and first molar positions. Force delivery was also measured for a further four different bracket designs at four different sites on the archwire using five fresh wires of the same archwire type. The wires were loaded with an M5 Nene Universal testing machine. The results demonstrate that the peak and plateau force, both of which are clinically important, are dependent on several factors of the archwire/bracket combination. The results showed that 20 per cent of the batch of 10 wires behaved differently by delivering a higher peak force. There was a statistically significant difference (P < 0.05) between the four bracket/archwire combinations for the peak forces delivered, but there was very little difference between the four bracket/archwire unloading force delivery values. The wires delivered a predictable force on the unloading curves, but self-ligating brackets may not develop sufficient strain within the wire to take full advantage of the superelastic effect of Ni-Ti wires.

Preparation, characterization, and performance of magnetic iron-carbon composite microparticles for chemotherapy.

Magnetic microcarrier particles useful for delivering chemotherapeutic drug molecules are described. The particles are formed by joint deformation of iron and carbon in a ball mill. Physical, chemical, and functional characterization has been carried out on the particles. Physical characteristics include microscopy, particle size analysis (0.5-5 microm), surface area (250 m2/g), water vapor adsorption isotherm (hydrophobic surface), and analysis of the iron-carbon interface by Mössbauer spectroscopy, X-ray diffraction, and differential thermal analysis. Chemical analysis was used to identify elements in the particles other than carbon and iron. Functional characteristics measured included the particles' ability to adsorb and desorb doxorubicin, cytotoxicity, and their magnetic susceptibility.

Factors in the onset of schizophrenia: a comparison between London and Trinidad samples.

OBJECTIVE: Sociodemographic factors play an important role in the genesis of mental disorders. High rates of unemployment and other social factors have been reported previously among African-Caribbeans with schizophrenia in London. The aim of the present study was to compare these factors in Trinidad with London African-Caribbeans. METHOD: Using internationally defined criteria, patients with first-onset schizophrenia were recruited in both countries, and information on the onset of symptoms, help-seeking, pathways into care, premorbid personality and educational and employment status were collected. These two samples are compared on a number of these factors. A total of 56 cases of first onset of psychosis coming into contact with psychiatric services in Trinidad were studied. Of these, 46 cases were diagnosed as having schizophrenia using the CATEGO program. Over a period of 2 years, 38 African-Caribbean patients with schizophrenia were recruited in London. RESULTS: African-Caribbean patients with schizophrenia in London were more likely to be admitted for perceived threat to others and to have shown loss of interest and serious neglect and to have assaulted others. A lower proportion were admitted via a psychiatrist and a higher proportion by the police. The unemployment rate among the London sample of African-Caribbeans was much higher than that in the general population, whereas this was not the case for the Trinidad patients. CONCLUSION: These findings are discussed in the context of culture and aetiology of schizophrenia, and suggestions with regard to future research are made.

Factors in the onset of schizophrenia: a comparison between London and Trinidad samples

Objective: Sociodemographic factors play an important role in the genesis of mental disorders. High rates of unemployment and other social factors have been reported previously among African-Caribbeans with schizophrenia in London. The aim of the present study was to compare these factors in Trinidad with London African-Caribbeans. METHOD: Using internationally-defined criteria, patients with first-onset schizophrenia were recruited in both countries, and information on the onset of symptoms, help-seeking, pathways into care, premorbid personality and educational and employment status were collected. These two samples are compared on a number of these factors. A total of 56 cases of first-onset of psychosis coming into contact with psychiatric services in Trinidad were studied. Of these, 46 cases were diagnosed as having schizophrenia using the CATEGO program. Over a period of 2 years, 38 African-Caribbean patients with schizophrenia were recruited in London. RESULTS: African-Caribbean patients with schizophrenia in London were more likely to be admitted for perceived threat to others and to have shown loss of interest and serious neglect and to have assaulted others. A lower proportion were admitted via a psychiatrist and a higher proportion by the police. The unemployment rate among the London sample of African-Caribbeans was much higher than in the general population, whereas this was not the case for the Trinidad patients. CONCLUSION: These findings are discussed in the context of culture and aetiology of schizophrenia, and suggestions with regard to future research are made. (AU)

Identification of a phosphoinositide binding motif that mediates activation of mammalian and yeast phospholipase D isoenzymes.

Phosphoinositides are both substrates for second messenger-generating enzymes and spatially localized membrane signals that mediate vital steps in signal transduction, cytoskeletal regulation and membrane trafficking. Phosphatidylcholine-specific phospholipase D (PLD) activity is stimulated by phosphoinositides, but the mechanism and physiological requirement for such stimulation to promote PLD-dependent cellular processes is not known. To address these issues, we have identified a site at which phosphoinositides interact with PLD and have assessed the role of this region in PLD function. This interacting motif contains critical basic amino acid residues that are required for stimulation of PLD activity by phosphoinositides. Although PLD alleles mutated at this site fail to bind to phosphoinositides in vitro, they are membrane-associated and properly localized within the cell but are inactive against cellular lipid substrates. Analogous mutations of this site in yeast PLD, Spo14p, result in enzymes that localize normally, but with catalytic activity that has dramatically reduced responsiveness to phosphoinositides. The level of responsiveness to phosphoinositides in vitro correlated with the ability of PLD to function in vivo. Taken together, these results provide the first evidence that phosphoinositide regulation of PLD activity observed in vitro is physiologically important in cellular processes in vivo including membrane trafficking and secretion.

Social factors and first onset schizophrenia among Asians and whites.

Previous studies from the Indian subcontinent had suggested that the onset and outcome of schizophrenia is linked with social factors. We set out to study the inception rates and social factors in whites and Asians who were presenting for the first time ever to various catchment facilities in Ealing catchment area. A total of 62 cases (38 white and 24 Asians) were diagnosed as having schizophrenia. Using well established and previously validated standardised instruments we collected information on various social factors and inception rates of schizophrenia. The inception rates and social factors were largely similar in these two groups. By and large the social factors in the two groups were broadly similar except that Asians were significantly more likely to show increased religious activity compared with their white counterparts. Contrary to previous findings Asians were more likely to have had longer duration of symptoms prior to seeking help. These findings are discussed in relation to Asian support systems and suggestions made for future research.

Regulation and function of PLDs in yeast.

While yeast contain multiple phospholipase D activities, only one, encoded by SPO14, appears to be a member of the phosphatidylcholine-specific phospholipase D gene family. Genetic analyses have revealed a role for this enzyme in regulated membrane trafficking events.

Early manifestations, personality traits and pathways into care for Asian and white first-onset cases of schizophrenia.

BACKGROUND: Previous studies have shown that manifestations of symptoms and premorbid personality of patients with schizophrenia differ across cultures. However, these have only been demonstrated in cultural settings apart from each other. METHOD: We set out to compare these across different ethnic groups from a catchment area in west London. The Asian and the white group had similar inception rates of schizophrenia and we therefore decided to compare these two groups to ascertain similarities in social, demographic and personality factors and pathways into care. First-onset cases of schizophrenia were studied on a number of parameters using previously validated instruments. RESULTS: There were more similarities than differences between the two groups. When compared with the findings of a previous multicentre study in India, London Asians, like their counterparts in India, were more likely than the London white sample to present with loss of appetite, become more religious and behave as if hearing voices. However, compared to their Indian counterparts, the onset of symptoms was more likely to be insidious and alternative sources of healing were less likely to be approached. CONCLUSIONS: These findings are discussed in relation to the findings for white patients and recommendations made for future research.

ADP-Ribosylation factors do not activate yeast phospholipase Ds but are required for sporulation.

ADP-ribosylation factor (ARF) proteins in Saccharomyces cerevisiae are encoded by two genes, ARF1 and ARF2. The addition of the c-myc epitope at the C terminus of Arf1 resulted in a mutant (arf1-myc arf2) that supported vegetative growth and rescued cells from supersensitivity to fluoride, but homozygous diploids failed to sporulate. arf1-myc arf2 mutants completed both meiotic divisions but were unable to form spores. The SPO14 gene encodes a phospholipase D (PLD), whose activity is essential for mediating the formation of the prospore membrane, a prerequisite event for spore formation. Spo14 localized normally to the developing prospore membrane in arf1-myc arf2 mutants; however, the synthesis of the membrane was attenuated. This was not a consequence of reduced PLD catalytic activity, because the enzymatic activity of Spo14 was unaffected in meiotic arf1-myc arf2 mutants. Although potent activators of mammalian PLD1, Arf1 proteins did not influence the catalytic activities of either Spo14 or ScPld2, a second yeast PLD. These results demonstrate that ARF1 is required for sporulation, and the mitotic and meiotic functions of Arf proteins are not mediated by the activation of any known yeast PLD activities. The implications of these results are discussed with respect to current models of Arf signaling.

A clinical study of space closure with nickel-titanium closed coil springs and an elastic module.

A previous study has shown that a 150-gram nickel-titanium closed coil spring (Sentalloy, GAC International Inc.) closed spaces more quickly and more consistently than an elastic module (Alastik, Unitec/3M). This study used the same friction sensitive sliding mechanics of pitting the six anterior teeth against the second bicuspid and first molars, to examine the rate of space closure of 100-gram and 200-gram nickel-titanium closed coil springs. The results for the three springs and elastic module were compared. The nickel-titanium closed coil springs produced a more consistent space closure than the elastic module. The 150- and 200-gram springs produced a faster rate of space closure than the elastic module or the 100-gram spring. No significant difference was noted between the rates of closure for the 150- and the 200-gram springs.

Relocalization of phospholipase D activity mediates membrane formation during meiosis.

Phospholipase D (PLD) enzymes catalyze the hydrolysis of phosphatidylcholine and are involved in membrane trafficking and cytoskeletal reorganization. The Saccharomyces cerevisiae SPO14 gene encodes a PLD that is essential for meiosis. We have analyzed the role of PLD in meiosis by examining two mutant proteins, one with a point mutation in a conserved residue (Spo14pK--> H) and one with an amino-terminal deletion (Spo14pDeltaN), neither of which can restore meiosis in a spo14 deletion strain. Spo14pK--> H is enzymatically inactive, indicating that PLD activity is required, whereas Spo14pDeltaN retains PLD catalytic activity in vitro, indicating that PLD activity is not sufficient for meiosis. To explore other aspects of Spo14 function, we followed the localization of the enzyme during meiosis. Spo14p is initially distributed throughout the cell, becomes concentrated at the spindle pole bodies after the meiosis I division, and at meiosis II localizes to the new spore membrane as it surrounds the nuclei and then expands to encapsulate the associated cytoplasm during the formation of spores. The catalytically inactive protein also undergoes relocalization during meiosis; however, in the absence of PLD activity, no membrane is formed. In contrast, Spo14pDeltaN does not relocalize properly, indicating that the failure of this protein to complement a spo14 mutant is due to its inability to localize its PLD activity. Furthermore, we find that Spo14p movement is correlated with phosphorylation of the protein. These experiments indicate that PLD participates in regulated membrane formation during meiosis, and that both its catalytic activity and subcellular redistribution are essential for this function.