bluuebunny/crossref_metadata_2025 huggingface dataset:
CLINICAL QUESTION: What is the best management strategy for patients with severe insulin resistance?
Authors: Semple Robert K. , Williams Rachel M. , Dunger David B.
Published: April 2010

Management of severe insulin resistance (IR) is a major clinical challenge in many patients with obesity or lipodystrophy, and also in rarer patients with proven or suspected genetic defects in the insulin receptor or downstream signalling. The latter group can present at any time between birth and early adult life, with a variable clinical course broadly correlated with the severity of IR. Primary insulin signalling defects are usually associated with poor weight gain rather than obesity. Initially, extreme hyperinsulinaemia produces ovarian enlargement and hyperandrogenism in women, and often fasting or postprandial hypoglycaemia. However, any hypoglycaemia gradually evolves into insulin‐resistant hyperglycaemia when beta cell function declines. Optimal management of these complex disorders depends on early diagnosis and appropriate targeting of both high and low glucose levels. In newborns, continuous nasogastric feeding may reduce harmful glycaemic fluctuations, and in older patients, acarbose may mitigate postprandial hypoglycaemia. Insulin sensitization, initially with metformin but later with trials of additional agents such as thiazolidinediones, is the mainstay of early therapy, but insulin replacement, eventually with very high doses, is required once diabetes has supervened. Preliminary data suggest that rhIGF‐1 can improve survival in infants with the most severe insulin receptor defects and also improve beta cell function in older patients with milder receptoropathies. The utility of newer therapies such as glucagon‐like peptide‐1 agonists and dipeptidyl peptidase‐IV inhibitors remains untested in this condition. Thus, management of these patients remains largely empirical, and there is a pressing need to collate data centrally to optimize treatment algorithms.
ORIGINAL ARTICLE: Pioglitazone improvement of fasting and postprandial hyperglycaemia in Mexican‐American patients with Type 2 diabetes: a double tracer OGTT study
Authors: Glass Leonard C. , Cusi Kenneth , Berria Rachele , Petz Roberta , Cersosimo Eugenio , Defronzo Ralph A. , Gastaldelli Amalia
Published: April 2010

Objectives  By using tracer techniques, we explored the metabolic mechanisms by which pioglitazone treatment for 16 weeks improves oral glucose tolerance in patients with type 2 diabetes when compared to subjects without diabetes.

Methods  In all subjects, before and after treatment, we measured rates of tissue glucose clearance (MCR), oral glucose appearance (RaO) and endogenous glucose production (EGP) during a (4‐h) double tracer oral glucose tolerance test (OGTT) (1‐14C‐glucose orally and 3‐3H‐glucose intravenously). Basal hepatic insulin resistance index (HepIR) was calculated as EGPxFPI. β‐cell function was assessed as the incremental ratio of insulin to glucose (ΔI/ΔG) during the OGTT.

Results  Pioglitazone decreased fasting plasma glucose concentration (10·5 ± 0·7 to 7·8 ± 0·6 mm, P < 0·0003) and HbA1c (9·7 ± 0·7 to 7·5 ± 0·5%, P < 0·003) despite increased body weight and no change in plasma insulin concentrations. This was determined by a decrease both in fasting EGP (20·0 ± 1·1 to 17·3 ± 0·8 μmol/kgffm min, P < 0·005) and HepIR (from 8194 declined by 49% to 3989, P < 0·002). During the OGTT, total glucose Ra during the 0‐ to 120‐min time period following glucose ingestion decreased significantly because of a reduction in EGP. During the 0‐ to 240‐min time period, pioglitazone caused only a modest increase in MCR (P < 0·07) but markedly increased ΔI/ΔG (P = 0·003). The decrease in 2h‐postprandial hyperglycaemia correlated closely with the increase in ΔI/ΔG (r = −0·76, P = 0·004) and tissue clearance (r = −0·74, P = 0·006) and with the decrease in HepIR (r = 0·62, P = 0·006).

Conclusions  In diabetic subjects with poor glycaemic control, pioglitazone improves oral glucose tolerance mainly by enhancing the suppression of EGP and improving β‐cell function.
Effect of cholecalciferol and calcium supplementation on muscle strength and energy metabolism in vitamin D‐deficient Asian Indians: a randomized, controlled trial
Authors: Gupta Rajat , Sharma Uma , Gupta Nandita , Kalaivani M. , Singh U. , Guleria Randeep , Jagannathan N. R. , Goswami Ravinder
Published: April 2010

Context  Vitamin D deficiency is prevalent worldwide. Vitamin D supplementation has shown variable effect on skeletal muscle strength in the elderly with hypovitaminosis D. There is a paucity of similar data in young individuals.

Objective  To study the effect of cholecalciferol and calcium supplementation on muscle strength and energy metabolism in young individuals.

Subjects  Forty healthy volunteers (24M/16F, mean age (SD) 31·5 ± 5·0 year) with hypovitaminosis D were randomized to either oral cholecalciferol (60 000 IU D3/week for 8 weeks followed by 60 000 IU/month for 4 months) with 1 g of elemental calcium daily or dual placebos for 6 months.

Measurements  Handgrip and gastro‐soleus dynamometry, pinch‐grip strength, respiratory pressures, 6‐min walk‐test and muscle energy metabolism on 31P magnetic resonance spectroscopy were assessed at baseline and after 6 months.

Results  The mean serum 25(OH)D in the supplemented and placebo groups at baseline, two and 6 months were 25·4 ± 9·9, 94·5 ± 53·8 and 56·0 ± 17·0 nm, and 21·1 ± 9·4, 32·8 ± 14·4 and 29·7 ± 15·0 nm, respectively. The supplemented group gained a handgrip strength of 2·4 kg (95% C.I. = 1·2–3·6); gastro‐soleus strength of 3·0 Nm (95% C.I. = 0·1–5·9) and walking distance of 15·9 m (95% C.I. = 6·3–25·5) over the placebo group after adjustment for age, gender and respective baseline parameters. Muscle energy parameters were comparable at 6 months.

Conclusions  Six months of cholecalciferol and calcium supplementation results in enhanced skeletal muscle strength and physical performance despite no change in muscle energy parameters. Cholecalciferol supplementation of 60 000 IU per month could not maintain 25(OH)D levels in the sufficient range.
ORIGINAL ARTICLE: Characteristics of plasma NOx levels in severe sepsis: high interindividual variability and correlation with illness severity, but lack of correlation with cortisol levels
Authors: Ho J. T. , Chapman M. J. , O’Connor S. , Lam S. , Edwards J. , Ludbrook G. , Lewis J. G. , Torpy D. J.
Published: April 2010

Objectives  Nitric oxide (NO) concentrations are elevated in sepsis and their vasodilatory action may contribute to the development of hyperdynamic circulatory failure. Hydrocortisone infusion has been reported to reduce nitric oxide metabolite (NOx) concentrations and facilitate vasopressor withdrawal in septic shock. Our aim was to determine whether NOx concentrations relate to (i) protocol‐driven vasopressor initiation and withdrawal and (ii) plasma cortisol concentrations, from endogenous and exogenous sources. Demonstration of a relation between NOx, cortisol and vasopressor requirement may provide an impetus towards the study of hydrocortisone‐mediated NOx suppression as a tool in sepsis management.

Design  A prospective study of 62 patients with severe sepsis admitted to the intensive care unit.

Measurements  Plasma NOx, total and free cortisol, and corticosteroid‐binding globulin (CBG) concentrations were measured and related to protocol‐driven vasopressor use for 7 days following admission.

Results  Patients who developed septic shock (n = 35) had higher plasma NOx, total and free cortisol, and lower CBG concentrations than the nonseptic shock group (n = 27). Cortisol, CBG and NOx concentrations correlated with illness severity. Free cortisol, and to a lesser extent total cortisol, but not NOx concentrations, predicted septic shock. NOx concentrations were higher in nonsurvivors, and the concentrations were characteristically stable within individuals but marked interindividual differences were only partly accounted for by illness severity or renal dysfunction. NOx concentrations did not correlate with cortisol, did not relate to vasopressor requirement and did not fall after standard dose hydrocortisone, given for clinical indications.

Conclusions  Nitric oxide production increased with sepsis severity but did not correlate with plasma cortisol or vasopressor requirement. NOx levels were not suppressed reproducibly by hydrocortisone. High interindividual variability of NOx levels suggests that absolute NOx levels may not be a suitable target for individualized hydrocortisone therapy.
ORIGINAL ARTICLE: The association between serum thyrotropin (TSH) levels and bone mineral density in healthy euthyroid men
Authors: Kim Beom‐Jun , Lee Seung H. , Bae Sung J. , Kim Hong K. , Choe Jae W. , Kim Ha Y. , Koh Jung‐Min , Kim Ghi S.
Published: April 2010

Objective  Although osteoporosis is increasingly shown to occur in a considerable proportion of men, data on risk factors for male osteoporosis are limited. In this study, we investigated the association between serum thyrotropin (TSH) concentration and bone mineral density (BMD) in healthy euthyroid men.

Design  A cross‐sectional community (health promotion centre)‐based survey.

Subjects and measurements  For 1478 apparently healthy euthyroid men who participated in a routine health screening examination, we measured BMD at the lumbar spine and femoral neck using dual energy X‐ray absorptiometry and serum TSH concentrations using immunoluminometry.

Results  Lumbar spine BMD linearly increased with TSH level after adjustment for age, weight and height (P for trend = 0·002), and statistical significance persisted after additional adjustment for smoking and drinking habits (P for trend = 0·010). When serum alkaline phosphatase was added as a confounding variable, the relationship was still significant (P for trend = 0·016). Femoral neck BMD also tended to increase in higher TSH concentration after adjustment for age, weight and height (P for trend = 0·042), but this association disappeared after additional adjustment for smoking and drinking habits. The odds of lower BMD (i.e. osteopaenia and osteoporosis combined) were significantly increased in subjects with low‐normal TSH (i.e. 0·4–1·2 mU/l), when compared to high‐normal TSH (i.e. 3·1–5·0 mU/l), after adjustment for confounding factors (odds ratio = 1·45, 95% CI = 1·02–2·10).

Conclusion  These results suggest that a serum TSH concentration at the lower end of the reference range may be associated with low BMD in men.
Detection of alteration at the Millennium uranium deposit in the Athabasca Basin: a comparison of data from two airborne electromagnetic systems with ground resistivity data
Authors: Smith Richard S. , Wood Garnet R. , Powell Brian
Published: April 2010

The Millennium uranium deposit is located within the Athabasca Basin of northern Saskatchewan. The basement rocks, comprised primarily of paleo‐Proterozoic gneisses, are electrically resistive. However, the deposit is associated with highly conductive graphitic metasediments that are intercalated with the gneisses. An unconformity separates the basement rocks from the overlying, horizontally stratified, Proterozoic sandstones of the Athabasca Group (which are also highly resistive). The strike extents of the graphitic metasedimenary packages are extensive and therefore electromagnetic (EM) survey techniques are successful at identifying these zones but do not identify the specific locations where they are enriched in uranium. Through drilling it has been noted that hydrothermal processes associated with mineralization has altered the rocks in the vicinity of the deposits, which should in theory result in a resistivity low. A significant resistivity low has been mapped coincident with the Millennium deposit using ground resistivity survey techniques.

However, a comparison of the airborne EM and ground resistivity results reveals that the two data sets have imaged different features. The resistive‐limit (on‐time) windows of the MEGATEM data show conductive features corresponding to lakes located to the west and south of the deposit. The late‐time windows show a feature to the east of the deposit, interpreted as being associated with the east‐dipping graphitic basement conductors (similar to that observed in historical ground EM data collected in this area). The early‐time TEMPEST windows (delay times less than 0.2 ms) show a broad resistivity low located at approximately the same location as where the alteration has been identified through drilling. Modelling the data is not easy but a response that decays prior to 0.3 ms is consistent with 500 Ωm material in the sandstone, a resistivity value close to the lower limit with respect to the hydrothermally altered Athabasca group sediments in this area. The MEGATEM system does not see a conductive zone over the alteration as clearly but the high signal‐to‐noise ratio in the late‐time MEGATEM data means that the conductive material at a greater depth is more coherently imaged.
Near‐field seismic effects in a homogeneous medium and their removal in vertical seismic profile attenuation estimates
Authors: Haase Arnim B. , Stewart Robert R.
Published: April 2010

To better understand (and correct for) the factors affecting the estimation of attenuation (Q), we simulate subsurface wave propagation with the Weyl/Sommerfeld integral. The complete spherical wavefield emanating from a P‐wave point source surrounded by a homogeneous, isotropic and attenuative medium is thus computed. In a resulting synthetic vertical seismic profile, we observe near‐field and far‐field responses and a 90° phase rotation between them. Depth dependence of the magnitude spectra in these two depth regions is distinctly different. The logarithm of the magnitude spectra shows a linear dependence on frequency in the far‐field but not in those depth regions where the near‐field becomes significant. Near‐field effects are one possible explanation for large positive and even negative Q‐factors in the shallow section that may be estimated from real vertical seismic profile data when applying the spectral ratio method. We outline a near‐field compensation technique that can reduce errors in the resultant Q estimates.
Rock fracture compliance derived from time delays of elastic waves
Authors: Möllhoff M. , Bean C.J. , Meredith P.G.
Published: April 2010

The purpose of this study is to compare the reliability of various methods of estimating normal rock fracture compliance from elastic wave measurements. We compare ultrasonic through‐transmission laboratory measurements for a smooth fracture in a Westerly granite specimen with numerical simulations and analytical solutions. The focus is on deriving compliance from time delays. The influence of specimen and source transducer width was constrained using numerical wave simulations. We find that measured ultrasonic phase delays are better suited to estimate the fracture compliance than group delays. Using the frequency domain instead of the time domain increases the accuracy of the fracture compliance estimates. We further show that for cases where precise phase delay measurements are unavailable, employing first break times in conjunction with numerical simulations can be considered as an alternative.
Robust reconstruction of aliased data using autoregressive spectral estimates
Authors: Naghizadeh Mostafa , Sacchi Mauricio D.
Published: April 2010

Autoregressive modeling is used to estimate the spectrum of aliased data. A region of spectral support is determined by identifying the location of peaks in the estimated spatial spectrum of the data. This information is used to pose a Fourier reconstruction problem that inverts for a few dominant wavenumbers that are required to model the data. Synthetic and real data examples are used to illustrate the method. In particular, we show that the proposed method can accurately reconstruct aliased data and data with gaps.
Gene therapy for immunological tolerance: using ‘transgenic’ B cells to treat inhibitor formation
Authors: SCOTT D. W.
Published: April 2010

Summary.  B cells have been shown to function as tolerogenic antigen presenting cells (APCs) both in vivo and in vitro. We have taken advantage of this property, as well as the ability of IgG carriers to be potent ‘schleppers’ for tolerogenic entities, to develop a gene therapy approach to induce unresponsiveness in a number of systems, including the elimination of haemophilia inhibitors. Thus, peptide‐IgG constructs have been engineered into retroviral vectors to create ‘transgenic’ B cells for tolerance applications. In this paper, we discuss our gene therapy approach mediated by B cells (as well as bone marrow cells) for tolerance acquisition in various mouse models for autoimmune disease and haemophilia A. The mechanisms that are the underpinning of this effort and role of regulatory T cells are discussed herein. Our results indicate that gene therapy strategies can successfully reduce the incidence and or onset of autoimmune diseases and prevent/reverse inhibitor formation in haemophilia A mice. Based on recent success with a model for tolerance with human T cell clones in vitro, plans for future application in patients are discussed.
Factor VIII‐specific B cell responses in haemophilia A patients with inhibitors
Authors: Van HELDEN P. M. W. , VAN HAREN S. D. , FIJNVANDRAAT K. , MARIJKE van den BERG H. , VOORBERG J.
Published: April 2010

Summary.  Development of inhibitory antibodies to factor VIII (FVIII) provides a major complication of replacement therapy in patients with haemophilia A. The risk of inhibitor formation is influenced by the underlying FVIII gene defect. Moreover, genetic determinants in the promoter region of IL‐10 and TNFα have been linked to an increased risk of inhibitor development. Recent cohort‐studies have provided evidence that the risk of inhibitor formation is linked to intensity of treatment. Eradication of FVIII inhibitors can be achieved by frequent infusion of high dosages of FVIII, so‐called immune tolerance induction (ITI). Until now, the mechanisms involved in downmodulation of the immune response to FVIII during ITI have not been unraveled. Studies performed in an animal model for haemophilia A have suggested that elimination of FVIII‐specific memory B cells by high dosages of FVIII contributes to the decline in FVIII inhibitor levels during ITI. Limited knowledge is available with respect to the development and persistence of FVIII‐specific memory B cells in patients with haemophilia A. Two recent studies suggest that the frequency of peripheral FVIII‐specific memory B cells in haemophilia A patients with inhibitors range from <0.01 to 0.40% of that of total IgG+ B cells. No or very low frequencies of FVIII‐specific memory B cells are observed in haemophilia A patients without inhibitors and in patients treated successfully by ITI. Possible implications of these findings are discussed in the context of currently available information on the role of antigen‐specific memory B cells and long‐living antibody producing plasma cells in humoral immunity.
Surgery in haemophilia patients with inhibitors, with special emphasis on orthopaedics: Madrid experience
Authors: RODRIGUEZ‐MERCHAN E. C. , JIMENEZ‐YUSTE V. , GOMEZ‐CARDERO P. , ALVAREZ‐ROMAN M. , MARTIN‐SALCES M. , RODRIGUEZ DE LA RUA A.
Published: April 2010

Summary.  We report on a series of 92 surgical procedures (90 patients). It includes 35 orthopaedic procedures (33 patients) and 57 non‐orthopaedic procedures (57 patients). The orthopaedic procedures include 27 radiosynovectomies (minor surgery) and eight major orthopaedic procedures. The non‐orthopaedic procedures include 52 minor interventions and five major procedures. The average age of patients was 34 years (range: 8–56), and the average follow‐up time was 3 years (range: 1–6). Of the 92 surgical procedures, 42 were performed with activated prothrombin complex concentrates [factor eight inhibitor bypassing agent (FEIBA)] and 47 with recombinant‐activated factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). Regarding FEIBA treatment in minor surgery, the initial dose was 100 IU kg−1. After 6 h, we continued with 50 IU kg−1 every 12 h for at least 4 days (radiosynovectomies). In minor non‐orthopaedic procedures, the dose was continued until day 14. In patients who underwent surgery with the haemostatic control achieved by means of rFVIIa, the initial dose of rFVIIa in minor procedures (both orthopaedic and non‐orthopaedic) was 90–120 μg kg−1. In postoperative days 1–5, the dose was 2–4 × 90–120 μg kg−1 q3–6 h for 24 h. In major procedures (both orthopaedic and non‐orthopaedic), the dose was 120 μg kg−1 pre‐operatively, 120 μg kg−1 q 3 h day 2/day 3–5, and then 90–120 μg kg−1 q 6 h until day 14. There were 87 good results, four fair results and one poor result. Our study has shown that haemophilic patients with inhibitors requiring surgery can undergo orthopaedic and non‐orthopaedic procedures with a high expectation of success. In other words, surgery (orthopaedic and non‐orthopaedic) is now possible in haemophilia patients with inhibitors, leading to an improved quality of life for these patients.
Role of anti‐idiotypic antibodies in immune tolerance induction
Authors: GILLES J. G.
Published: April 2010

Summary.  Replacement therapy using factor VIII (FVIII) elicits FVIII‐specific antibodies (abs) in about 25% of the patients. A majority of such abs are directed towards specific FVIII regions in which major epitopes have been identified (C‐terminal end of the C2 domain, the N‐terminal end of the A2 domain and C1 domain in cases of mild/moderate haemophilia A). We derived five human monoclonal abs (mabs) that react with high affinity to the FVIII C1, C2 or A2 domains respectively and are representative of most of the specific inhibitors observed in haemophilia A patients. We generated mouse anti‐idiotypic mabs (anti‐Ids) against the paratope of each of the inhibitors. We demonstrated that a combination of these anti‐Ids (anti‐anti‐A2, ‐C1, ‐C2) had the ability to neutralize the inhibitory properties of human polyclonal abs in plasma. In 16 of the 18 plasmas tested, the inhibiting FVIII activity was neutralized up to 100% by the anti‐Ids mixture with restoration of full FVIII activity. These data allow us to conclude that polyclonal high‐affinity FVIII inhibitors could be neutralized with an anti‐Ids mixture and that only a limited number of anti‐Ids were required for inhibitor neutralization in 90% of the patients. We also demonstrated that anti‐Id Abs bound to anti‐FVIII human B cell line produced the corresponding anti‐FVIII Ab and that this binding was followed by surface capping of complexes. Data obtained in vitro at monoclonal and polyclonal level, confirmed by in vivo assays, and the preliminary results obtained at BCR level, indicate that anti‐id mixture made of only a limited number of anti‐Ids could be useful in the restoration of haemostasis in haemophilia patients with inhibitor.
Autoantibodies to coagulation factors
Authors: SAINT‐REMY J.‐M. R.
Published: April 2010

Summary.  Tolerance to autoantigens such as coagulation factors is the result of censoring mechanisms occurring at the level of the thymus and bone marrow for autoreactive T and B cells, respectively. In addition, peripheral mechanisms, both intrinsic and extrinsic further control activation of autoreactive cells that have escaped central deletion. Emergence of autoimmunity can occur from disturbances of these control mechanisms by a number of events, many of which are incompletely understood. Insight into this clinically important field is expected from exploitation of recent animal models.
Diagnosis and treatment of acquired haemophilia
Authors: BAUDO F. , CAIMI T. , De CATALDO F.
Published: April 2010

Summary.  Acquired haemophilia (AH) is an autoimmune syndrome characterized by acute bleeding in patients with negative family and personal history, and factor VIII depletion. Its incidence is 1.6 × 106 population per year. AH is associated with autoimmune diseases, solid tumours, lymphoprolipherative diseases, pregnancy; 50% of the cases idiopathic. Spontaneous or after minor trauma severe bleeding associated with a prolonged activated partial thromboplastin time, not corrected by incubation with normal plasma, with a normal prothrombin time are the diagnostic hallmarks. The goals of management are the control of bleeding and the suppression of inhibitor. First‐line haemostatic treatment includes recombinant factor VIIa and activated prothrombin complex concentrate. Prednisone ± cyclophosphamide and other immunosuppressive agents are the standard intervention for inhibitor eradication.
Plasma and cellular contributions to fibrin network formation, structure and stability
Authors: WOLBERG A. S.
Published: April 2010

Summary.  Growing evidence suggests that fibrin network structure and stability are important determinants of haemostasis and thrombosis, with alterations in fibrin structure implicated as a causative mechanism in various haemostatic and thrombotic disorders. In haemophilia, for example, deficiency of factor VIII or IX reduces the rate and peak of thrombin generation and produces coarse fibrin clots that show increased susceptibility to fibrinolysis. More recently, studies have shown significant effects of cellular activity and integrin composition on fibrin network and stability. Platelets support the formation of a dense, stable fibrin network via interactions between the αIIbβ3 integrin and the fibrin network, whereas tissue factor‐bearing cells regulate fibrin structure and stability predominantly via procoagulant activity. Highly procoagulant extravascular cells (e.g. fibroblasts and smooth muscle cells) support the formation of dense fibrin networks that resist fibrinolysis, whereas unstimulated intravascular cells (e.g. endothelial cells) produce coarser networks that are susceptible to fibrinolysis. Moreover, cellular contributions produce heterogeneous clots in which fibrin network density and stability decrease with increasing distance from the cell surface. Together, these findings suggest that specific plasma and cellular mechanisms link thrombin generation, clot stability and haemostatic or thrombotic outcome. Understanding these mechanisms may provide new therapeutic targets in the management of bleeding and thrombotic disorders.
Prevention of spontaneous bleeding in dogs with haemophilia A and haemophilia B
Authors: NICHOLS T. C. , RAYMER R. A. , FRANCK H. W. G. , MERRICKS E. P. , BELLINGER D. A. , DeFRIESS N. , MARGARITIS P. , ARRUDA V. R. , KAY M. A. , HIGH K. A.
Published: April 2010

Summary. Dogs with haemophilia A or haemophilia B exhibit spontaneous bleeding comparable with the spontaneous bleeding phenotype that occurs in humans with severe haemophilia. The phenotypic and genotypic characteristics of haemophilic dogs have been well‐described, and such dogs are suitable for testing prophylactic protein replacement therapy and gene transfer strategies. In dogs with haemophilia, long‐term effects on spontaneous bleeding frequency (measured over years) can be used as an efficacy endpoint in such studies. Although complete correction of coagulopathy has not been achieved, published data show that prophylactic factor replacement therapy and gene transfer can markedly reduce the frequency of spontaneous bleeding in haemophilic dogs. Further studies are currently ongoing.
Optimizing on‐demand treatment with NovoSeven® room temperature stable
Authors: NEGRIER C.
Published: April 2010

Summary.  Patients with haemophilia can now look forward to greater life expectancy than ever before – a development that can be attributed to improved healthcare strategies and more effective treatments. In the last few decades, the treatment of haemophilia patients with inhibitors has also witnessed dramatic improvements through the development of bypassing agents, including recombinant activated factor VII (rFVIIa, NovoSeven®; Novo Nordisk, Bagsværd, Denmark). Growing evidence suggests that early initiation of treatment with rFVIIa results in greater haemostatic efficacy with fewer doses, leading to improved overall outcome. The new NovoSeven® room temperature stable formulation has been designed to optimize on‐demand treatment by facilitating early initiation of therapy for haemorrhagic episodes, which brings the potential benefits of faster bleed resolution, reduced frequency of re‐bleeding and reduced product consumption. This is particularly important for inhibitor patients, in whom orthopaedic complications are more severe than in non‐inhibitor patients. Early treatment might help improve musculoskeletal status and therefore reduce disability, which improves patient quality of life and aids integration into society. These clinical advantages are also accompanied by both short‐term and long‐term economic benefits. NovoSeven® room temperature stable might also improve patient compliance and treatment convenience, as patients can carry their treatment with them and administer it wherever they are, without being restricted by the need for a refrigerator and without the need to visit a hospital or to return home. The potential benefits of NovoSeven® room temperature stable make this new formulation a valuable addition to our armamentarium in the ongoing effort to improve haemophilia care.
Meeting unmet needs in inhibitor patients
Authors: BLANCHETTE V. S. , MANCO‐JOHNSON M. J.
Published: April 2010

Summary.  For patients with haemophilia, the development of inhibitors complicates treatment, and inhibitor patients may thus have a range of unmet needs. Although successful inhibitor eradication will render patients responsive to factor replacement therapy, with potentially beneficial effects on long‐term outcomes, this may not always be possible. Physicians treating inhibitor patients should aim to achieve reliable control of bleeding episodes, and the prevention of joint disease should also be a priority. Patients with high‐titre inhibitors require therapy with bypassing agents – recombinant activated factor VII (rFVIIa) or a plasma‐derived activated prothrombin complex concentrate (pd‐APCC) – for the treatment of bleeding. When treating joint haemorrhage in inhibitor patients, both aggressive treatment of intercurrent joint bleeds and prophylaxis should be considered, although evidence is needed as to whether prophylaxis with bypassing agents can significantly delay/prevent the development of osteochondral changes in patients with inhibitors. Despite physicians’ best efforts, joint disease may ultimately occur in inhibitor patients, and in such instances optimizing treatment, of both early and late stages, is important. There is no single therapeutic modality for dealing with the various treatment challenges posed by inhibitor patients, but overall goals should be to improve quality of life, with the provision of cost‐effective care that aims to maintain physical function.
Cardiovascular disease in haemophilia patients: a contemporary issue
Authors: MANNUCCI P. M. , MAUSER‐BUNSCHOTEN E. P.
Published: April 2010

Summary.  Improvements in treatment options and healthcare provision mean that haemophilia patients now have a life expectancy approaching that of the normal male population. An increased life expectancy, however, also brings an increased risk of developing age‐related disorders, the foremost of which is cardiovascular disease. The epitome of age‐related morbidity, cardiovascular disease is also a leading cause of mortality in elderly individuals, and presents a particular challenge when it occurs in persons with haemophilia. While the exact incidence of cardiovascular disease in haemophilia is unknown, incidence rates from conditions such as ischaemic heart disease (IHD) have steadily risen over the last 20–30 years, suggesting that cardiac problems are increasingly relevant for these patients. Management of cardiovascular disease in haemophilia warrants close cooperation between cardiologists and haematologists, and evidence‐based guidelines are not available. In the absence of such guidelines, antithrombotic treatment is currently based on local clinical experience and adaptation of the general guidelines used in the non‐haemophilic population. In this article, we outline the local guidelines used by our two centres in the antithrombotic treatment of IHD, coronary bypass and valve surgery, and atrial fibrillation in patients with haemophilia. Strategies for the management of haemostasis and thrombosis during cardiovascular surgery in haemophilia patients are also briefly reviewed. Finally, we present the cases of three elderly haemophilia patients with cardiovascular and other age‐related health problems in whom such treatment strategies were applied.
A comparative study of dental pulp response to several pulpotomy agents
Authors: Tabarsi B. , Parirokh M. , Eghbal M. J. , Haghdoost A. A. , Torabzadeh H. , Asgary S.
Published: April 2010

Tabarsi B, Parirokh M, Eghbal MJ, Haghdoost AA, Torabzadeh H, Asgary S. A comparative study of dental pulp response to several pulpotomy agents. International Endodontic Journal 43, 565–571, 2010.

Aim  To examine the in vivo response of dental pulps in dogs to three pulp‐capping agents: calcium hydroxide (CH), mineral trioxide aggregate (MTA) and a new endodontic calcium enriched mixture (CEM) cement.

Methodology  Thirty‐six second and third premolar teeth in six beagle dogs were randomly assigned to three experimental groups; CH, MTA or CEM cement. Following isolation and exposure, pulp tissues were removed with a fissure bur and haemostasis achieved. The pulps were dressed with appropriate materials, and the access cavity restored with amalgam. Histological analysis was performed 8 weeks after treatment; the samples were assessed by an independent observer for calcified bridge formation, pulp vitality and pulp inflammation. The data were analysed by Kruskal–Wallis, Mann–Whitney and one‐way anova tests.

Results  The number of root canals that showed calcified bridge formation, pulp vitality and lack of inflammation was significantly higher for teeth capped with either MTA or CEM cement in comparison with CH (P < 0.05). No significant difference was found between the CEM cement and MTA in terms of calcified bridge formation, pulp vitality and lack of inflammation (P > 0.05).

Conclusions  Mineral trioxide aggregate and CEM cement were associated with a similar favourable biological response to pulpotomy treatment and demonstrated a more effective induction of dentinal bridge formation compared to CH.
Antibacterial effects of MDPB against anaerobes associated with endodontic infections
Authors: Izutani N. , Imazato S. , Noiri Y. , Ebisu S.
Published: April 2010

Izutani N, Imazato S, Noiri Y, Ebisu S. Antibacterial effects of MDPB against anaerobes associated with endodontic infections. International Endodontic Journal.

Aim  To investigate the antibacterial effects of 12‐methacryloyloxydodecylpyridinium bromide (MDPB), an antibacterial monomer synthesized by combining quaternary ammonium with a methacryloyl group, against three anaerobes associated with endodontic infections using planktonic and biofilm cells.

Methodology  The antibacterial activity of unpolymerized MDPB against Enterococcus faecalis, Fusobacterium nucleatum and Prevotella nigrescens was examined by agar‐disc diffusion tests and determination of the minimum inhibitory/bactericidal concentrations (MIC/MBC). Rapid killing effects of MDPB against three bacteria in planktonic form were examined by a cell number counting method, and those against biofilm cells were assessed by a viability staining method.

Results  MDPB demonstrated inhibition against all of the bacteria tested by agar‐disc diffusion tests. The MIC/MBC values of MDPB for the three anaerobes were much smaller than those of other resin monomers, although greater compared with those of cetylpyridinium chloride or chlorhexidine diacetate for E. faecalis and F. nucleatum. Significant reduction in viable planktonic cells was obtained by contact with 250 μg mL−1 of MDPB for 20 s (P < 0.05, Fisher’s PLSD tests), and 40 s contact with 500 μg mL−1 or 20 s contact with 1000 μg mL−1 of MDPB resulted in more than 90% killing. Biofilm cells of all species were completely killed by application of 1000 μg mL−1 of MDPB for 60 s.

Conclusion  MDPB was found to have strong antibacterial effects against E. faecalis, F. nucleatum and P. nigrescens, and such effects were rapidly exhibited even against biofilm cells, suggesting the usefulness of application of MDPB to resin‐based materials for root canal filling.
Bird community response to fruit energy
Authors: Peters Valerie E. , Mordecai Rua , Ronald Carroll C. , Cooper Robert J. , Greenberg Russell
Published: April 2010

1. The abundance and predictability of food resources have been posited as explanations for the increase of animal species richness in tropical habitats. However, the heterogeneity of natural ecosystems makes it difficult to quantify a response of animal species richness to these qualities of food resources.

2. Fruit‐frugivore studies are especially conducive for testing such ecological theories because fruit is conspicuous and easily counted. Fruit‐frugivore research in some locations has demonstrated a relationship between animal abundance and fruit resource abundance, both spatially and temporally. These studies, which typically use fruit counts as the variable of fruit abundance, have never documented a response of species richness at the community level. Furthermore, these studies have not taken into account factors influencing the detection of an individual within surveys.

3. Using a combination of nonstandard approaches to fruit‐frugivore research, we show a response of bird species richness to fruit resources. First, we use uniform and structurally similar, one‐ha shade‐grown coffee plots as replicated experimental units to reduce the influence of confounding variables. Secondly, we use multi‐season occupancy modelling of a resident omnivorous bird assemblage in order to account for detection probability in our analysis of site occupancy, local immigration and local emigration. Thirdly, we expand our variable of fruit abundance, Fruit Energy Availability (FEA), to include not only fruit counts but also fruit size and fruit quality.

4. We found that a site’s average monthly FEA was highly correlated (0·90) with a site’s average bird species richness. In our multi‐season occupancy model 92% of the weight of evidence supported a single model that included effects of FEA on initial occupancy, immigration, emigration and detection.

5. These results demonstrate that fruit calories can broadly influence the richness of a neotropical bird community, and that fluctuations of FEA explains much of the site occupancy patterns of component species. This study shows that in depauperate, managed landscapes fruit resource abundance supports more species and fruit constancy allows for higher levels of avian persistence, an important practical concept for conservation planning.
‘Take‐away’ foraging spatially uncouples predator and prey‐attack distributions
Authors: Smallegange Isabel M. , Van Der Meer Jaap , Sabelis Maurice W.
Published: April 2010

1. Ideal‐free distribution theory assumes that in a patchy environment foragers maximize fitness and hence their feeding rate by balancing gains from more food against losses from more competition. Ultimately, individuals cannot increase their feeding rate by moving to another patch and they distribute themselves over patches in proportion to prey density per patch.

2. In our experiments with shore crabs Carcinus maenas foraging on two adjacent patches with mussels Mytilus edulis, the implicit assumption of ideal‐free distribution theory that catch should match time spent in a prey patch is not met, however. Despite aggregating their attack where it is most profitable shore crabs distributed themselves homogeneously across mussel patches: they ‘take away’ the prey caught and consume it elsewhere to reduce interference.

3. Thus, predator distributions can be quite different from prey‐attack distributions. This is important because the latter is shown to be decisive for persistence of predator and prey populations in ecological models.
Phenological changes in six Australian subalpine plants in response to experimental warming and year‐to‐year variation
Authors: Hoffmann Ary A. , Camac James S. , Williams Richard J. , Papst Warwick , Jarrad Frith C. , Wahren Carl‐Henrik
Published: April 2010

1. The likely phenological responses of plants to climate warming can be measured through experimental manipulation of field sites, but results are rarely validated against year‐to‐year changes in climate. Here, we describe the response of 1–5 years of experimental warming on phenology (budding, flowering and seed maturation) of six common subalpine plant species in the Australian Alps using the International Tundra Experiment (ITEX) protocol.

2. Phenological changes in some species (particularly the forbCraspedia jamesii) were detected in experimental plots within a year of warming, whereas changes in most other species (the forbErigeron bellidioides, the shrubAsterolasia trymalioidesand the graminoidsCarex breviculmisandPoa hiemata) did not develop until after 2–4 years; thus, there appears to be a cumulative effect of warming for some species across multiple years.

3. There was evidence of changes in the length of the period between flowering and seed maturity in one species (P. hiemata) that led to a similar timing of seed maturation, suggesting compensation.

4. Year‐to‐year variation in phenology was greater than variation between warmed and control plots and could be related to differences in thawing degree days (particularly, forE. bellidioides) due to earlier timing of budding and other events under warmer conditions. However, inCarex breviculmis, there was no association between phenology and temperature changes across years.

5. These findings indicate that, although phenological changes occurred earlier in response to warming in all six species, some species showed buffered rather than immediate responses.

6. Synthesis. Warming in ITEX open‐top chambers in the Australian Alps produced earlier budding, flowering and seed set in several alpine species. Species also altered the timing of these events, particularly budding, in response to year‐to‐year temperature variation. Some species responded immediately, whereas in others the cumulative effects of warming across several years were required before a response was detected.
Effects of clonal integration and light availability on the growth and physiology of two invasive herbs
Authors: Xu Cheng‐Yuan , Schooler Shon S. , Van Klinken Rieks D.
Published: April 2010

1. Clonal plants benefit from the ability to translocate resources among interconnected ramets to colonize heterogeneous habitats. Clonal integration affects the resource level and morphological traits of ramets, and thus may influence their physiology and general performance. Although leaf gas exchange and its associated physiological adjustments are key traits to assess plant fitness, the effect of clonal integration on these functional traits is insufficiently understood.

2. In a glasshouse experiment, we addressed how clonal integration affects gas exchange properties, leaf characters and growth of ramets in two invasive plants, Alternanthera philoxeroides and Phyla canescens, under full sun and 85% shade. We also used stable‐isotope labelling to assess the maternal subsidy to daughter ramets.

3. Similar effects of connection were observed in both species for most gas exchange parameters and leaf characters. Clonal integration did not affect photosynthetic capacity and respiratory rates of ramets. When grown in shade, ramets connected with an unshaded mother plant displayed higher area‐based leaf nitrogen and chlorophyll content than severed ramets, but the additional nitrogen and chlorophyll was not translated to increased photosynthetic capability. Overall, severed ramets displayed significant light response for leaf nitrogen (area‐based), photosynthetic nitrogen use efficiency, chlorophyll to nitrogen ratio, and nitrogen stable‐isotope signature, but the light response was eliminated by clonal integration in connected ramets.

4. Both species displayed substantial maternal carbohydrate subsidy that benefited the growth of daughter ramets, but species‐specific patterns were observed in the growth of daughter ramets and the amount of subsidy. The amount of subsidy was independent of ramet growth light levels for P. canescens, but shaded, connected ramets of A. philoxeroides received more subsidy than unshaded controls, facilitating a larger growth improvement relative to severed counterparts than P. canescens.

5. Synthesis. We observed increased leaf nitrogen and chlorophyll in shaded, connected ramets of two clonal invasive plants. Clonal integration may facilitate nitrogen assimilation and allow pre‐acclimation to high‐light conditions for shaded, connected ramets, thus promoting the opportunistic expansion of these invaders on site scale. The species‐specific maternal subsidy pattern demonstrated that clonal plants possess different strategies to subsidize ramets under light‐limited conditions.
Cell Life and Death in the Anterior Pituitary Gland: Role of Oestrogens
Authors: Seilicovich A.
Published: April 2010

Apoptotic processes play an important role in the maintenance of cell numbers in the anterior pituitary gland during physiological endocrine events. In this review, we summarise the regulation of apoptosis of anterior pituitary cells, particularly lactotrophs, somatotrophs and gonadotrophs, and analyse the possible mechanisms involved in oestrogen‐induced apoptosis in anterior pituitary cells. Oestrogens exert apoptotic actions in several cell types and act as modulators of pituitary cell renewal, sensitising cells to both mitogenic and apoptotic signals. Local synthesis of growth factors and cytokines induced by oestradiol as well as changes in phenotypic features that enhance the responsiveness of anterior pituitary cells to pro‐apoptotic factors may account for cyclical apoptotic activity in anterior pituitary cells during the oestrous cycle. Considering that tissue homeostasis results from a balance between cell proliferation and death and that mechanisms involved in apoptosis are tightly regulated, defects in cell death processes could have a considerable physiopathological impact.
AFLP genome scan in the black rat (Rattus rattus) from Madagascar: detecting genetic markers undergoing plague‐mediated selection
Authors: TOLLENAERE C. , DUPLANTIER J.‐M. , RAHALISON L. , RANJALAHY M. , BROUAT C.
Published: April 2010

The black rat (Rattus rattus) is the main reservoir of plague (Yersinia pestis infection) in Madagascar’s rural zones. Black rats are highly resistant to plague within the plague focus (central highland), whereas they are susceptible where the disease is absent (low altitude zone). To better understand plague wildlife circulation and host evolution in response to a highly virulent pathogen, we attempted to determine genetic markers associated with plague resistance in this species. To this purpose, we combined a population genomics approach and an association study, both performed on 249 AFLP markers, in Malagasy R. rattus. Simulated distributions of genetic differentiation were compared to observed data in four independent pairs, each consisting of one population from the plague focus and one from the plague‐free zone. We found 22 loci (9% of 249) with higher differentiation in at least two independent population pairs or with combining P‐values over the four pairs significant. Among the 22 outlier loci, 16 presented significant association with plague zone (plague focus vs. plague‐free zone). Population genetic structure inferred from outlier loci was structured by plague zone, whereas the neutral loci dataset revealed structure by geography (eastern vs. western populations). A phenotype association study revealed that two of the 22 loci were significantly associated with differentiation between dying and surviving rats following experimental plague challenge. The 22 outlier loci identified in this study may undergo plague selective pressure either directly or more probably indirectly due to hitchhiking with selected loci.