bluuebunny/crossref_metadata_2025 huggingface dataset:
Generics, chemisimilars and biosimilars: is clinical testing fit for purpose?
Authors: Warren John B.
Published: May 2012

The effectiveness and safety of generic drugs are backed by sound physicochemical control and regulatory bioequivalence acceptance criteria. Statistical testing of bioequivalence, comparing the pharmacokinetic profiles of the test and reference products, was made possible by modern drug assays. When the pharmacokinetic profile correlates with the dose, such comparisons show assay sensitivity and readily detect differences in dose. For large biological molecules, different manufactured batches cannot be validated using pharmacokinetic data alone. For these biosimilars, there is a three‐stage assessment of pharmaceutical quality, laboratory testing and clinical data. This approach has also been applied to certain chemical products, termed ‘chemisimilars’, which have variable or complex synthesis of the active substance, or complex formulation, or a complex delivery device. Although there may be no detectable difference between the test and reference on clinical testing, many of the outcome measures are insensitive to even large differences in dose. For testing to be fit for purpose it should distinguish important dose differences, but many clinical tests of chemisimilars and biosimilars do not. As pharmacokinetic and pharmacodynamic technology advances, the trend of replacing dose‐insensitive clinical trial data with equivalence tests that show assay sensitivity can be expected to continue.
Apple juice greatly reduces systemic exposure to atenolol
Authors: Jeon Hyewon , Jang In‐Jin , Lee SeungHwan , Ohashi Kyoichi , Kotegawa Tsutomu , Ieiri Ichiro , Cho Joo‐Youn , Yoon Seo Hyun , Shin Sang‐Goo , Yu Kyung‐Sang , Lim Kyoung Soo
Published: May 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Atenolol is an antihypertensive drug, of which negligible amounts are metabolized.

• Fruit juices may decrease the oral absorption of drugs by inhibiting intestinal drug transporters, as demonstrated in vitro and in vivo.

WHAT THIS STUDY ADDS

• The pharmacokinetic characteristics of atenolol were determined according to the SLCO2B1 genotype after apple juice administration in healthy Korean volunteers.

• Apple juice ingestion markedly reduced the systemic exposure to atenolol, but genetic variations in SLCO2B1 were unlikely to contribute substantial variability to the pharmacokinetics of atenolol.

AIM Fruit juice reduces the plasma concentrations of several β‐adrenoceptor blockers, likely by inhibiting OATP2B1‐mediated intestinal absorption. The aim of this study was to investigate the effects of apple juice on the pharmacokinetics of atenolol.

METHODS Twelve healthy Korean volunteers with genotypes of SLCO2B1 c.1457C> T (*1/*1 (n= 6) and *3/*3 (n= 6)) were enrolled in this study. In a three‐phase, one‐sequence crossover study, the pharmacokinetics (PK) of atenolol was evaluated after administration of 50 mg atenolol. Subjects received atenolol with either 300 ml water, 1200 ml apple juice or 600 ml apple juice.

RESULTS Apple juice markedly reduced the systemic exposure to atenolol. The geometric mean ratios (95% confidence intervals) of apple juice : water were 0.18 (0.13, 0.25, 1200 ml) and 0.42 (0.30, 0.59, 600 ml) for the AUC(0,tlast). In this study, the PK parameters of atenolol responded in a dose‐dependent manner to apple juice.

CONCLUSIONS Apple juice markedly reduced systemic exposure to atenolol. The genetic variation of SLCO2B1 c.1457C>T had a minimal effect on the pharmacokinetics of atenolol when the drug was administered with water or apple juice.
The risk of adverse outcomes in association with use of testosterone products: a cohort study using the UK‐based general practice research database
Authors: Jick Susan S. , Hagberg Katrina Wilcox
Published: May 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Testosterone products are indicated for primary or secondary hypogonadism and can be delivered through various routes including oral and intramuscular injection.

• While many clinical trials have evaluated the effectiveness of testosterone therapy, there is little information on safety particularly in different formulations.

• Hypertension, polycythemia and prostatic abnormalities (prostatism, benign prostatic hypertrophy or prostate cancer) have been identified as potential adverse effects of testosterone replacement therapy, but data are limited.

WHAT THIS STUDY ADDS

• Risks of prostate cancer and prostatism were similar in users of the oral and injectable testosterone preparations, but risks were higher for hypertension and polycythemia in the injectable compared with the oral testosterone users.

• Risk of benign prostatic hypertrophy was slightly higher in the oral users, but the difference was small and could have been due to bias.

AIMS To study the relative safety of the intramuscular injection formulation of testosterone with oral testosterone undecanoate in relation to the risks for hypertension, polycythemia, prostate cancer, benign prostatic hypertrophy (BPH) and prostatism.

METHODS We conducted a cohort study of men in the UK based General Practice Research Database who were users of the oral undecanoate and injectable forms of testosterone and calculated rates and relative risks of hypertension, polycythemia and prostate conditions (cancer, BPH and prostatism).

RESULTS We identified 5841 men who received at least one study testosterone preparation. There were 202 cases of hypertension (crude incidence rates (IRs) for oral and injectable testosterone respectively 12.3/1000 person‐years (PY) and 14.4/1000 PY). There were 146 cases of polycythemia (IRs 1.2/1000 PY and 10.1/1000 PY), 46 cases of prostate cancer (IRs 2.5/1000 PY and 1.8/1000 PY), 106 cases of BPH (IRs 4.1 /1000 PY and 2.1/1000 PY), and 251 cases of prostatism (IRs 8.4/1000 PY and 6.1/1000 PY respectively). Adjusted relative risks for oral compared with injectable testosterone were 0.8 (95% CI 0.6, 1.2) for hypertension, 0.13 (0.05, 0.35) for polycythemia, 1.1 (0.7, 1.7) for prostate cancer, 1.5 (1.1, 2.2) for BPH and 1.1 (0.8, 1.4) for prostatism.

CONCLUSIONS Risks of prostate cancer and prostatism were similar in users of the two preparations, but risks were higher for hypertension and polycythemia in the injectable compared with the oral testosterone users. Risk of BPH was slightly higher in the oral users, but the difference was small and could have been due to bias.
Estimation of northern pike population sizes via mark–recapture monitoring
Authors: KUPARINEN A. , ALHO J. S. , OLIN M. , LEHTONEN H.
Published: May 2012

Abstract  Estimates of population size are needed in populations targeted by recreational fisheries, to determine their conservational status and to formulate fishing regulations. Mark–recapture monitoring is a promising tool for this because of the increased popularity of catch‐and‐release angling. Northern pike, Esox lucius L., population sizes were estimated in four lakes based on experimental mark–recapture fishing using a hierarchical Bayesian model that also estimated natural mortality. The approach was compared with output from traditional Petersen’s population size estimates. Despite intensive fishing with multiple gears, the population size estimates suggested that a substantial proportion of individuals remained unobserved by fishing. Petersen’s estimates depended on the assumed rate of natural mortality, and no mortality rate scenario matched with the Bayesian estimates. Consequently, the number of individuals caught by recreational anglers is a poor proxy of population size for which estimations should be carried out using a modelling approach that also estimates natural mortality.
Environmental interactions during host race formation: host fruit environment moderates a seasonal shift in phenology in host races of Rhagoletis pomonella
Authors: Ragland Gregory J. , Sim Sheina B. , Goudarzi Serra , Feder Jeffrey L. , Hahn Daniel A.
Published: May 2012

1. Host race formation is a common form of ecological speciation during which new populations that exploit a novel host (e.g. nutritional resource) experience divergent natural selection, causing adaptive divergence from the ancestral population. Typically, multiple selection pressures drive this divergence, suggesting that interactions among environmental effects may be critical during the speciation process.

2. Host‐race‐forming phytophagous insects often experience divergent natural selection imposed by seasonality and nutritional environment, two factors likely to interact through their effects on growth and life‐history timing. We tested for the presence of such an interaction in the apple maggot fly, Rhagoletis pomonella, asking whether nutritional effects interact with seasonality to determine overwintering success.

3. We find evidence for such an interaction, wherein feeding on a novel host fruit actually mitigates the negative effects of novel seasonality. Feeding on apple (novel) compared to hawthorn (ancestral) fruit conferred greater fly lipid reserves the overwintering, diapause stage. Earlier, seasonal emergence characteristic of the apple host race imposes an overwintering survival cost. But feeding on apples offsets this cost, which confers greater pupal lipid reserves and consequently larger adult body size post‐winter. Seasonality and host fruit interact to determine fly lipid reserves, and host race differences in lipid content are maximized under the most stressful conditions typically experienced by the apple host race. F1 rearing and genetic association tests revealed no evidence for genetically based divergence in lipid content, suggesting that differences in lipid storage among the fly host races are driven primarily by the host fruit environment.

4. Our results suggest that interactions between seasonality and host plant environment shape natural selection and therefore influence adaptive divergence during host race formation.
Long‐term nitrogen additions increase likelihood of climate stress and affect recovery from wildfire in a lowland heath
Authors: Southon Georgina E. , Green Emma R. , Jones Alan G. , Barker Chris G. , Power Sally A.
Published: May 2012

Increases in the emissions and associated atmospheric deposition of nitrogen (N) have the potential to cause significant changes to the structure and function of N‐limited ecosystems. Here, we present the results of a long‐term (13 year) experiment assessing the impacts of N addition (30 kg ha−1 yr−1) on a UK lowland heathland under a wide range of environmental conditions, including the occurrence of prolonged natural drought episodes and a severe summer fire. Our findings indicate that elevated N deposition results in large, persistent effects on Calluna growth, phenology and chemistry, severe suppression of understorey lichen flora and changes in soil biogeochemistry. Growing season rainfall was found to be a strong driver of inter‐annual variation in Calluna growth and, although interactions between N and rainfall for shoot growth were not significant until the later phase of the experiment, N addition exacerbated the extent of drought injury to Calluna shoots following naturally occurring droughts in 2003 and 2009. Following a severe wildfire at the experimental site in 2006, heathland regeneration dynamics were significantly affected by N, with a greater abundance of pioneering moss species and suppression of the lichen flora in plots receiving N additions. Significant interactions between climate and N were also apparent post fire, with the characteristic stimulation in Calluna growth in +N plots suppressed during dry years. Carbon (C) and N budgets demonstrate large increases in both above‐ and below‐ground stocks of these elements in N‐treated plots prior to the fire, despite higher levels of soil microbial activity and organic matter turnover. Although much of the organic material was removed during the fire, pre‐existing treatment differences were still evident following the burn. Post fire accumulation of below‐ground C and N stocks was increased rapidly in N‐treated plots, highlighting the role of N deposition in ecosystem C sequestration.
Drivers and export performance impacts of IT capability in ‘born‐global’ firms: a cross‐national study
Authors: Zhang Man , Sarker Saonee , Sarker Suprateek
Published: May 2012

Past research focusing on large firms has argued that information technology (IT) capability enhances firm performance. However, these studies have seldom explored why firms develop IT capability, and have also left a void the understanding of the role of IT capability in Small‐ and medium‐sized enterprises (SMEs). This study attempts to fill that void by examining the effect of relevant environmental and firm‐level factors on IT capability, and the effect of IT capability on the export performance of Chinese and US born‐global firms, a special breed of export‐focused SMEs. Results indicate that environmental factors such as information intensity, and firm‐level factors such as international entrepreneurial orientation, prompt born‐global firms to develop IT capability. Further, our results also strongly emphasise the positive role that IT capability plays on the performance of born‐global firms. Finally, a comparative analysis of the Chinese and US born‐global firms revealed a lack of a cross‐cultural difference in the factors leading these firms to develop IT capability, therefore supporting the ‘convergence’ perspective in cross‐cultural research.
The Neurohypophysis: Fishing for New Insights
Authors: Gutnick Amos , Levkowitz Gil
Published: May 2012

The neurohypophysis is a neurovascular interface through which the brain regulates peripheral organs to maintain homeostasis. The molecular mechanisms underlying its formation are poorly understood, although the emergence of new genetic and imaging tools has begun to yield new insights. In a recent study, researchers discovered that, in embryonic zebrafish, oxytocin secreted from hypophyseal axons serves as a local angiogenic cue that pulls in nearby blood vessels.
Common misconceptions in molecular ecology: echoes of the modern synthesis
Authors: KARL STEPHEN A. , TOONEN R. J. , GRANT W. S. , BOWEN B. W.
Published: May 2012

The field of molecular ecology has burgeoned into a large discipline spurred on by technical innovations that facilitate the rapid acquisition of large amounts of genotypic data, by the continuing development of theory to interpret results, and by the availability of computer programs to analyse data sets. As the discipline grows, however, misconceptions have become enshrined in the literature and are perpetuated by routine citations to other articles in molecular ecology. These misconceptions hamper a better understanding of the processes that influence genetic variation in natural populations and sometimes lead to erroneous conclusions. Here, we consider eight misconceptions commonly appearing in the literature: (i) some molecular markers are inherently better than other markers; (ii) mtDNA produces higher FST values than nDNA; (iii) estimated population coalescences are real; (iv) more data are always better; (v) one needs to do a Bayesian analysis; (vi) selective sweeps influence mtDNA data; (vii) equilibrium conditions are critical for estimating population parameters; and (viii) having better technology makes us smarter than our predecessors. This is clearly not an exhaustive list and many others can be added. It is, however, sufficient to illustrate why we all need to be more critical of our own understanding of molecular ecology and to be suspicious of self‐evident truths.
Phylodynamics of H5N1 avian influenza virus in Indonesia
Authors: LAM TOMMY TSAN‐YUK , HON CHUNG‐CHAU , LEMEY PHILIPPE , PYBUS OLIVER G. , SHI MANG , TUN HEIN MIN , LI JUN , JIANG JINGWEI , HOLMES EDWARD C. , LEUNG FREDERICK CHI‐CHING
Published: May 2012

Understanding how pathogens invade and become established in novel host populations is central to the ecology and evolution of infectious disease. Influenza viruses provide unique opportunities to study these processes in nature because of their rapid evolution, extensive surveillance, large data sets and propensity to jump species boundaries. H5N1 highly pathogenic avian influenza virus (HPAIV) is a major animal pathogen and public health threat. The virus is of particular importance in Indonesia, causing severe outbreaks among poultry and sporadic human infections since 2003. However, little is known about how H5N1 HPAIV emerged and established in Indonesia. To address these questions, we analysed Indonesian H5N1 HPAIV gene sequences isolated during 2003–2007. We find that the virus originated from a single introduction into East Java between November 2002 and October 2003. This invasion was characterized by an initially rapid burst of viral genetic diversity followed by a steady rate of lineage replacement and the maintenance of genetic diversity. Several antigenic sites in the haemagglutinin gene were subject to positive selection during the early phase, suggesting that host‐immune‐driven selection played a role in host adaptation and expansion. Phylogeographic analyses show that after the initial invasion of H5N1, genetic variants moved both eastwards and westwards across Java, possibly involving long‐distance transportation by humans. The phylodynamics we uncover share similarities with other recently studied viral invasions, thereby shedding light on the ecological and evolutionary processes that determine disease emergence in a new geographical region.
DWARF50 (D50), a rice (Oryza sativa L.) gene encoding inositol polyphosphate 5‐phosphatase, is required for proper development of intercalary meristem
Authors: SATO‐IZAWA KANNA , NAKABA SATOSHI , TAMURA KATSUNORI , YAMAGISHI YUSUKE , NAKANO YOSHIMI , NISHIKUBO NOBUYUKI , KAWAI SHINYA , KAJITA SHINYA , ASHIKARI MOTOYUKI , FUNADA RYO , KATAYAMA YOSHIHIRO , KITANO HIDEMI
Published: May 2012

Rice internodes are vital for supporting high‐yield panicles, which are controlled by various factors such as cell division, cell elongation and cell wall biosynthesis. Therefore, formation and regulation of the internode cell‐producing intercalary meristem (IM) are important for determining the shape of internodes. To understand the regulation of internode development, we analysed a rice dwarf mutant, dwarf 50 (d50). Previously, we reported that parenchyma cells in the elongated internodes of d50 ectopically deposit cell wall phenolics. In this study, we revealed that D50 encodes putative inositol polyphosphate 5‐phosphatase (5PTase), which may be involved in phosphoinositide signalling required for many essential cellular functions, such as cytoskeleton organization, endocytosis and vesicular trafficking in eukaryotes. Analysis of the rice genome revealed 20 putative 5PTases including D50. The d50 mutation induced abnormally oriented cell division, irregular deposition of cell wall pectins and thick actin bundles in the parenchyma cells of the IM, resulting in abnormally organized cell files of the internode parenchyma and dwarf phenotype. Our results suggest that the putative 5PTase, encoded by D50, is essential for IM formation, including the direction of cell division, deposition of cell wall pectins and control of actin organization.
Cause of death distribution with InterVA and physician coding in a rural area of Burkina Faso
Authors: Ramroth Heribert , Lorenz Eva , Rankin Johanna C. , Fottrell Edward , Yé Maurice , Neuhann Florian , Ssennono Mark , Sié Ali , Byass Peter , Becher Heiko
Published: May 2012

Objectives  To compare the cause of death distribution using the Physician Coded Verbal Autopsy approach versus the Interpreting Verbal Autopsy model, based on information from a French verbal autopsy questionnaire, in rural north‐western Burkina Faso.

Methods  Data from 5649 verbal autopsy questionnaires reviewed by local physicians at the Nouna Health and Demographic Surveillance Site between 1998 and 2007 were considered for analyses. Information from VA interviews was extracted to create a set of standard indicators needed to run the Interpreting Verbal Autopsy model. Cause‐specific mortality fractions were used to compare Physician Coded Verbal Autopsy and Interpreting Verbal Autopsy results.

Results  At the population level, 62.5% of causes of death using the Interpreting Verbal Autopsy model corresponded with those determined by two or three physicians. Although seven of the 10 main causes of death were present in both approaches, the comparison of percentages of single causes of death shows discrepancies, dominated by higher malaria rates found in the Physician Coded Verbal Autopsy approach.

Conclusion  Our results confirm that national mortality statistics, which are partly based on verbal autopsies, must be carefully interpreted. Difficulties in determining malaria as cause of death in holoendemic malaria regions might result in higher discrepancies than those in non‐endemic areas. As neither Physician Coded Verbal Autopsy nor Interpreting Verbal Autopsy results represent a gold standard, uncertainty levels with either procedure are high.
The role of diabetes on the clinical manifestations of pulmonary tuberculosis
Authors: Faurholt‐Jepsen Daniel , Range Nyagosya , PrayGod George , Jeremiah Kidola , Faurholt‐Jepsen Maria , Aabye Martine G. , Changalucha John , Christensen Dirk L. , Krarup Henrik , Witte Daniel R. , Andersen Aase B. , Friis Henrik
Published: May 2012

Objective  Diabetes is associated with pulmonary tuberculosis (TB), possibly due to impaired immunity, and diabetes may exacerbate the clinical manifestations of TB. Our aim was to assess the role of diabetes in the clinical manifestations of TB.

Methods  We studied 1250 patients with pulmonary TB in an urban population in a cross‐sectional study in Tanzania. All participants were tested for diabetes and HIV co‐infection, and TB culture intensity was assessed. Levels of white blood cells, haemoglobin, acute phase reactants, CD4 count and HIV viral load were measured, and a qualitative morbidity questionnaire was used to identify the prevalence of disease‐related symptoms.

Results  Tuberculosis patients with diabetes had a higher neutrophil count (B 0.5 × 109 cells/l, 95% CI 0.2; 0.9, P = 0.001) than non‐diabetic TB patients. Serum C‐reactive protein (B 18.8 mg/l, CI 95% 8.2; 29.4, P = 0.001) and alpha‐1‐acid glycoprotein (B 0.2 g/l, CI 95% 0.03; 0.3, P = 0.02) were similarly higher in patients with diabetes. Diabetes did not affect culture intensity or HIV status, but self‐reported fever was three times higher among participants with diabetes than in those without diabetes (OR 2.9, CI 95% 1.5; 5.7, P = 0.002).

Conclusion  Diabetes is associated with small changes in the manifestations of TB, but may have little clinical significance.
Dust mite species in the households of mite‐sensitive dogs with atopic dermatitis
Authors: Farmaki Rania , Saridomichelakis Manolis N. , Leontides Leonidas , Papazahariadou Margarita G. , Gioulekas Dimitrios , Koutinas Alexander F.
Published: May 2012

Background –  The presence of important house dust and storage mite species in the microenvironment of atopic dogs has not been thoroughly investigated.

Objectives –  To compare the presence and population of five dust mite species (Dermatophagoides farinae, Dermatophagoides pteronyssinus, Acarus siro, Tyrophagus putrescentiae and Lepidoglyphus destructor) among households with mite‐sensitive atopic dogs (Group A), households with clinically healthy dogs (Group B) and households without pets (Group C, n = 25) in Greece.

Animals –  Twenty mite‐sensitive atopic dogs and 20 clinically healthy dogs.

Methods –  Dust samples were collected with a vacuum cleaner from owners’ mattresses (all groups) and from dogs’ sleeping areas (Groups A and B) or living room couch (Group C), once every season of the year. Following dust flotation, mites were counted and identified.

Results –  Dermatophagoides farinae was the most prevalent (60, 40 and 64% in Groups A, B and C, respectively), followed by D. pteronyssinus (45, 35 and 48%, respectively), whereas the three storage mites were found in fewer households. No major differences could be found between Groups A and B or between households with (Groups A and B) and without dogs (Group C) regarding the presence or numbers of the five dust mite species.

Conclusions and clinical importance –  The presence and population of five common house dust and storage mite species does not differ among Greek households with mite‐sensitive atopic dogs, households with healthy dogs and households without pets.
Are transepidermal water loss and clinical signs correlated in canine atopic dermatitis? A compilation of studies
Authors: Marsella Rosanna
Published: May 2012

Background –  Cutaneous impairment plays a crucial role in atopic dermatitis (AD). Transepidermal water loss (TEWL) measurement is an indirect assessment of skin barrier function and correlates with disease severity in humans. Skin impairment also exists in canine AD; however, concerns exist regarding variability and reliability of TEWL measurements in dogs.

Hypothesis/Objectives –  The purposes of this retrospective study were twofold: first, to investigate the correlation between severity of dermatitis [measured by Canine Atopic Dermatitis Extent and Severity Index (CADESI)] and TEWL; and second, to evaluate whether increased TEWL at a young age correlates with disease severity later in life.

Methods –  Data from atopic beagles and dogs with natural AD were analysed. Transepidermal water loss was measured in atopic beagles (n = 24) with an open chamber and in dogs with naturally occurring AD with a closed chamber device (two studies, with n = 14 and n = 18). Pearson product–moment correlation was used for analyses. Transepidermal water loss of the inguinal region, axilla, antebrachial flexure and pinna was analysed. Correlations were investigated for each study, separately first and then jointly. They included CADESI and TEWL of individual regions, total CADESI and total TEWL of all measured regions, and total CADESI and TEWL of key regions.

Results –  In atopic beagles, TEWL measured at 1 year of age pre‐ and post‐allergen challenge was correlated with CADESI at 1, 3 and 6 years of age. Overall, low correlation coefficients were found; therefore, a biologically relevant connection could not be demonstrated. The main significant positive correlation was found between TEWL in the pinna and total CADESI.

Conclusions and clinical importance –  It is concluded that TEWL does not correlate with disease severity.
Consequences, control and appraisal: cues and barriers to engaging in self‐management among people affected by colorectal cancer – a secondary analysis of qualitative data
Authors: Kidd Lisa A.
Published: May 2012

Background  Little is known about peoples’ self‐management experiences and their desires or expectations to engage in self‐management. As such, there is little understanding about individuals’ perceived cues and barriers to engagement in self‐management, particularly in people affected by cancer.

Objective  To understand cues and barriers to people’s engagement in self‐management during chemotherapy treatment for colorectal cancer.

Design  Secondary analysis of qualitative data from mixed methods, longitudinal study.

Setting and participants  Eleven participants undergoing treatment for colorectal cancer. Semi‐structured interviews were conducted twice with each participant, at the start and end of a 6‐month course of chemotherapy treatment in a Scottish cancer centre.

Results  Cues and barriers to engagement in self‐management appeared to stem from perceptions of the impact and associated severity of side effects experiences as well as the perceptions about the efficacy of chosen self‐management activities and perceptions of control in minimizing the consequences of cancer treatment. Severe, episodic or unexpected side effects coupled with perceptions of uncertainty, lack of control and lack of adequate preparation to engage in self‐management were identified as key barriers to engagement.

Discussion and conclusion  Participants’ reflection on, or appraisal of, their treatment‐related experiences and personal abilities, confidence and preferences to manage the impact of these shaped their subsequent engagement in self‐management. The findings highlight the importance of understanding individual’s self‐management experiences, perceptions, preferences, priorities and needs to help support, prepare and enable them to feel capable and confident to engage actively and effectively in self‐management.
Glycemic management in living donor liver transplantation for patients with glycogen storage disease type 1b
Authors: Karaki Chiaki , Kasahara Mureo , Sakamoto Seisuke , Shigeta Takanobu , Uchida Hajime , Kanazawa Hiroyuki , Kakiuchi Toshihiko , Fukuda Akinari , Nakazawa Atsuko , Horikawa Reiko , Suzuki Yasuyuki
Published: May 2012

Karaki C, Kasahara M, Sakamoto S, Shigeta T, Uchida H, Kanazawa H, Kakiuchi T, Fukuda A, Nakazawa A, Horikawa R, Suzuki Y. Glycemic management in living donor liver transplantation for patients with glycogen storage disease type 1b.

Abstract:  GSD type 1b is an autosomal recessive inborn error of carbohydrate metabolism caused by defects of the G6Pase translocase (G6PT). Patients with GSD1b have severe hypoglycemia with several clinical manifestations of hepatomegaly, obesity, a doll‐like face, and neutropenia. LT has been indicated for severe glucose intolerance. This study retrospectively reviewed glycemic management of eight children with a diagnosis of GSD1b who underwent liver transplantation (LDLT). Between November 2005 and September 2011, 172 children underwent LDLT, of which eight (4.7%) were indicated for GSD1b. Glucose‐rich solution was placed in all children when preoperative fasting started to prevent preoperative hypoglycemia. During the reperfusion of graft, the glucose administration could significantly be reduced to maintain the proper blood glucose level, while the dosage of glucose administration prior to reperfusion of graft was significantly higher in the patients with GSD1b in comparison with patients with BA. The current series also showed significantly high incidence of infectious complications in the patients with GSD1b owing to persistent neutropenia after LDLT. All patients are doing well with an excellent quality of life owing to the stabilization of glucose intolerance. This current study clearly documented drastic change in glycemic management in LDLT. Cautious perioperative management to prevent hypoglycemia and infection is crucial for successful LT.
Transmission of clear cell tumor in a graft liver from cadaveric donor: Case report
Authors: Backes Ariane N. , Tannuri Ana Cristina A. , de Mello Evandro Sobroza , Gibelli Nelson Elias M. , de Castro Andrade Wagner , Tannuri Uenis
Published: May 2012

Backes AN, Tannuri ACA, de Mello ES, Gibelli NEM, de Castro Andrade W, Tannuri U. Transmission of clear cell tumor in a graft liver from cadaveric donor: Case report.

Abstract:  Neoplasms in children after organ transplantation are related to the type and intensity of immunosuppression and the donor–recipient serostatus, especially in relation to the Epstein–Barr virus. The patient was a two‐yr‐old female child with biliary atresia who underwent a liver transplantation from a female cadaver donor. Two adults received kidney transplants from the same donor. Nine months after transplantation, one of the adult recipients developed an urothelial tumor in the kidney graft. Imaging tests were repeated monthly in the liver‐transplanted child and revealed no abnormalities. However, one yr and two months after the transplantation, the patient developed episodes of fever. At that time, imaging and liver biopsy showed a clear cell tumor of urothelial origin in the graft and the disease was limited to the liver. The patient underwent liver retransplantation, and she is currently free of tumor recurrence. Although rare, the occurrence of tumors in the post‐transplant period from cadaver donors, without previously diagnosed tumors, is one of the many problems encountered in the complex world of organ transplantation.
Graft loss due to recurrent disease in pediatric kidney transplant recipients on a rapid prednisone discontinuation protocol
Authors: Chavers Blanche M. , Rheault Michelle N. , Gillingham Kristen J. , Matas Arthur J.
Published: May 2012

Chavers BM, Rheault MN, Gillingham KJ, Matas AJ. Graft loss due to recurrent disease in pediatric kidney transplant recipients on a rapid prednisone discontinuation protocol.

Abstract:  Recurrent disease is the fourth most common cause of graft loss (GL) in pediatric KTx recipients. We studied the incidence of recurrent disease and GL due to recurrent disease in pediatric KTx recipients on a RDP protocol. Between 2002 and 2010, we performed 74 KTxs in patients aged 5–18 yr using an RDP protocol, 25 (34%) were at risk of recurrence of primary disease. Outcomes were compared to 69 historical controls (18 [26%] at risk of recurrence), KTx between 1996 and 2000. Follow‐up period was 39 ± 25 months in RDP and 124 ± 38 months in controls. The incidence of recurrent disease at three yr post‐KTx was 16% in RDP and 28% in controls (p = NS). Mean time to recurrent disease was 22 ± 26 months in RDP and 46 ± 48 months in controls (p = 0.54). Nine (12%) grafts were lost in the RDP group (1‐recurrence) and 32 (46%) in the control group (4‐recurrence). Time to GL was 85 months in the RDP recipient and 46 ± 21 months in controls. An RDP protocol in pediatric KTx recipients may not be associated with increased risk of graft loss due to recurrent disease.
Corticosterone, Avoidance of Novelty, Risk‐Taking and Aggression in a Wild Bird: No Evidence for Pleiotropic Effects
Authors: Garamszegi László Zsolt , Rosivall Balázs , Rettenbacher Sophie , Markó Gábor , Zsebők Sándor , Szöllősi Eszter , Eens Marcel , Potti Jaime , Török János
Published: May 2012

Certain inherent characteristics of individuals can determine both physiological and behavioural responses to environmental challenges, which could drive a correlation between levels of corticosterone (CORT), the most important stress hormone and behavioural profiles. Therefore, CORT level may mediate consistent behaviours along the shy/bold continuum, and thus, it could serve as a pleiotropic basis for behavioural syndromes. Moreover, behavioural responses to environmental challenges may have consequences for CORT concentrations, which would also result in a correlation between physiology and behaviours even without requiring pleiotropic mechanisms. Accordingly, we investigated the relationship between CORT and behaviour in free‐living male collared flycatchers, Ficedula albicollis, using recently developed field assays. More specifically, we characterised novel object avoidance, intraspecific aggression and risk‐taking in males and related these correlated behaviours to the concentration of CORT metabolites in droppings measured by enzyme immunoassay. Individuals with higher levels of excreted CORT metabolites had no consistently higher or lower behavioural scores along the shy/bold spectrum, as avoidance of novelty, aggression and risk‐taking were not systematically related to CORT metabolite concentrations in the same direction. Moreover, environmental challenges owing to the presence of a novel object, territorial intruder and a potential predator caused no elevation in the level of CORT metabolites. Therefore, we did not find correlative evidence for CORT driving correlated behaviours through pleiotropic effects or for particular behaviours during courtship causing elevation in CORT levels.
Practical considerations on current guidelines for the management of non‐neutropenic adult patients with candidaemia
Authors: Glöckner A. , Cornely O. A.
Published: May 2012

Recent guideline recommendations on the management of candidaemia provide valuable treatment guidance for routine clinical practice, but need to be interpreted in the light of the actual situation of the patient and the local epidemiology of fungal infections. Echinocandins emerge as the generally preferred primary treatment. Treatment should be initiated immediately after notification of a Candida‐positive blood culture in all patients. Ambiguous issues include the definition of optimum duration of treatment, the indication and time point to step down to oral azoles, catheter management, and the appropriate approach in critically ill patients at high risk for candidaemia in the absence of definitive proof of infection. Patients with clinical suspicion of antifungal treatment failure need prompt workup for adequacy of treatment, focal sources of sustained infection and potential superinfection.
Predicting mortality among older adults hospitalized for community‐acquired pneumonia: An enhanced Confusion, Urea, Respiratory rate and Blood pressure score compared with Pneumonia Severity Index
Authors: ABISHEGANADEN JOHN , DING YEW YOONG , CHONG WAI‐FUNG , HENG BEE‐HOON , LIM TOW KEANG
Published: May 2012

Background and objective:  Pneumonia Severity Index (PSI) predicts mortality better than Confusion, Urea >7 mmol/L, Respiratory rate >30/min, low Blood pressure: diastolic blood pressure <60 mm Hg or systolic blood pressure <90 mm Hg, and age >65 years (CURB‐65) for community‐acquired pneumonia (CAP) but is more cumbersome. The objective was to determine whether CURB enhanced with a small number of additional variables can predict mortality with at least the same accuracy as PSI.

Methods:  Retrospective review of medical records and administrative data of adults aged 55 years or older hospitalized for CAP over 1 year from three hospitals.

Results:  For 1052 hospital admissions of unique patients, 30‐day mortality was 17.2%. PSI class and CURB‐65 predicted 30‐day mortality with area under curve (AUC) of 0.77 (95% confidence interval (CI): 0.73–0.80) and 0.70 (95% CI: 0.66–0.74) respectively. When age and three co‐morbid conditions (metastatic cancer, solid tumours without metastases and stroke) were added to CURB, the AUC improved to 0.80 (95% CI: 0.77–0.83). Bootstrap validation obtained an AUC estimate of 0.78, indicating negligible overfitting of the model. Based on this model, a clinical score (enhanced CURB score) was developed that had possible values from 5 to 25. Its AUC was 0.79 (95% CI: 0.76–0.83) and remained similar to that of PSI class.

Conclusions:  An enhanced CURB score predicted 30‐day mortality with at least the same accuracy as PSI class did among older adults hospitalized for CAP. External validation of this score in other populations is the next step to determine whether it can be used more widely.
SU6668, a multiple tyrosine kinase inhibitor, inhibits progression of human malignant pleural mesothelioma in an orthotopic model
Authors: VAN TRUNG THE , HANIBUCHI MASAKI , GOTO HISATSUGU , KURAMOTO TAKUYA , YUKISHIGE SAWAKA , KAKIUCHI SOJI , SATO SEIDAI , SAKAGUCHI SATOSHI , DAT LE TAN , NISHIOKA YASUHIKO , AKIYAMA SHIN‐ICHI , SONE SABURO
Published: May 2012

Background and objective:  Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the mesothelium with high chemotherapeutic resistance. In this study, the preclinical therapeutic activity of the multiple tyrosine kinase inhibitor, SU6668, against MPM was examined.

Methods:  Two human MPM cell lines with different pro‐angiogenic cytokine expression, Y‐MESO‐14 cells that express high levels of vascular endothelial growth factor (VEGF) and MSTO‐211H cells that express high levels of basic fibroblast growth factor (bFGF), were orthotopically inoculated into the thoracic cavities of mice with severe combined immunodeficiency. The mice with MPM were treated or not treated with SU6668 (200 mg/kg/day).

Results:  SU6668 abrogated the proliferation of endothelial cells stimulated by VEGF or bFGF, but did not directly affect the growth of human MPM cells in vitro. In this orthotopic implantation model, treatment with SU6668 effectively reduced tumour weight and pleural effusion volumes, in association with inhibition of the growth of tumour vasculature. More importantly, treatment with SU6668 significantly prolonged survival time in mice with MPM.

Conclusions:  These findings suggest that SU6668 has a promising therapeutic effect on the progression of MPM in vivo through its anti‐angiogenic effects.
Evisceration occurred 1 year after vaginal vault repair for relapsed pelvic organ prolapse
Authors: Muraoka Mitsue , Nagano Hiroaki , Takagi Koichiro
Published: May 2012

This report describes the case of an 81‐year‐old woman with sudden evisceration of the small intestine through the vagina. It occurred one year after repair of a vaginal vault prolapse, which was initially treated by vaginal hysterectomy and colporrhaphy three years prior to the repair. On examination, we found a 70–80‐cm loop of bowel prolapsing through a 3‐cm oval defect in the vaginal vault. The patient underwent emergency exploratory laparotomy under general anesthesia. After careful reduction of the eviscerated small intestine, the hernia hiatus was closed and the widened cul‐de‐sac was obliterated by performing a Moschcowitz culdoplasty. Rapid intervention by abdominovaginal surgery may enable smooth repositioning of the eviscerated intestine, thus preventing subsequent morbidity.
Current status of robot‐assisted partial nephrectomy
Authors: Gohil Rishma , Ahmed Kamran , Kooiman Gordon , Khan Mohammed Shamim , Dasgupta Prokar , Challacombe Ben
Published: May 2012

What's known on the subject? and What does the study add?

The use of robotic assistance for the partial nephrectomy procedure has emerged as an alternative that may help some of the technical challenges of laparoscopic partial nephrectomy. The main concerns in laparoscopic partial nephrectomy relates to a steeper ‘learning curve’, prolonged warm ischaemia times and the potential for postoperative haemorrhage.

The article delineates the dynamics of patient preparation, the surgical team, surgical technique & post‐operative care to conclude that robotic‐assisted partial nephrectomy is a viable alternative to both open and laparoscopic techniques.

Partial nephrectomy has shown both improved overall patient survival and more effective preservation of renal function, when compared with radical nephrectomy. Robot‐assisted partial nephrectomy has several potential advantages over the laparoscopic approach. Robotic assistance allows urologists to perform this complex reconstructive procedure more quickly, with improved precision and dexterity, tremor elimination and improved visualization. The present article aims to delineate the dynamics of patient preparation and surgical team, surgical technique and postoperative care. The oncological outcomes and disease‐free survival of partial nephrectomy have been found to be equivalent to open partial nephrectomy [1–4].
Impact of tumour location and surgical approach on recurrence‐free and cancer‐specific survival analysis in patients with ureteric tumours
Authors: Bin Xu , Roy Ornob P. , Ghiraldi Eric , Manglik Niti , Liang Tang , Vira Manish , Kavoussi Louis R.
Published: May 2012

Study Type – Therapy (case series)

Level of Evidence 4

What's known on the subject? and What does the study add?

Pathological stage, lymph node metastasis and tumour grade have been established as prognostic factors for upper‐tract urothelial carcinoma, but there are few studies to date assessing location within the ureter as a prognostic factor. There are also few studies comparing surgical approaches to radical nephroureterectomy (NU), partial ureterectomy and endoscopic resection (ENDO) with regard to oncological outcomes.

This study did not find any prognostic significance for tumour location or surgical approach with regard to outcomes in patients with ureteric tumours. Although NU is the standard treatment for invasive ureteric tumours, partial ureterectomy and ENDO can safely be performed in selected patients. Despite the risk of a shorter time to recurrence, ENDO can be recommended in low grade, non‐invasive ureteric tumours but only with close, thorough surveillance practices.

OBJECTIVE

To assess the impact of tumour location within the ureter and the impact of surgical approach on recurrence‐free survival (RFS) and cancer‐specific survival (CSS) with regard to ureteric tumours.

PATIENTS AND METHODS

Data were retrospectively reviewed from 60 patients with isolated primary ureteric tumours, treated at a single tertiary referral centre.

Patients were treated with radical nephroureterectomy (NU, n= 33), partial ureterectomy (n= 17) or endoscopic resection (ENDO, n= 10).

Kaplan–Meier curves were used for the analysis of RFS and CSS after surgery, stratified by tumour location and surgical approach.

RESULTS

With a median follow‐up of 29 months, tumour location was not associated with disease recurrence (P= 0.423).

The ENDO group had shorter time to disease recurrence.

There were no significant differences in the probability of CSS with regard to either tumour location or surgical approach (P= 0.523 and P= 0.904, respectively).

CONCLUSIONS

Tumour location or surgical approach were not significant predictors of oncological outcomes in patients with ureteric tumours.

Although NU is standard treatment for invasive ureteric tumours, partial ureterectomy and ENDO can safely be performed in selected patients. Despite the risk of a shorter time to recurrence, ENDO can be recommended in low grade, non‐invasive ureteric tumours.

All urothelium‐preserving approaches require thorough surveillance.
How to reduce the risk of failing to reach recruitment targets: lessons learnt from a pump pilot trial
Authors: Barnard K. D. , Campbell M. J. , Emery C. , Young A. J. , Heller S.
Published: May 2012

Diabet. Med. 29, 1600–1601 (2012)
Factor XIII Val34Leu polymorphism is associated with increased factor XIII activation and decreased transcutaneous oxygen readings in patients with diabetic foot ulcers
Authors: Küper M. A. , Schüle R. , Mayer P. , Königsrainer A. , Beckert S.
Published: May 2012

Diabet. Med. 29, 1596–1599 (2012)

Aim  To investigate the relationship between the factor XIII Val34Leu polymorphism, plasma factor XIII activation and transcutaneous oxygen readings in patients with diabetic foot ulcers.

Methods  Ninety‐two consecutive patients with Type 2 diabetes and active foot ulcers were investigated. Plasma factor XIII activation was assessed by ELISA. Genetic polymorphism was detected using the ABI PRISM® SNaPshotTM Multiplex Kit. Results are expressed as median (minimum–maximum). Differences between groups were calculated by Mann–Whitney U‐test or χ2‐test where appropriate. A P‐value < 0.05 was considered significant.

Results  The Val34Leu polymorphism was found in 50 subjects (54%) with 42 being heterozygous (Val/Leu) and eight being homozygous (Leu/Leu). The rate of plasma factor XIII activation was increased in patients with Val/Leu or Leu/Leu [Val/Leu or Leu/Leu 152 (55–283) % vs. Val/Val 103 (33–282) %; P < 0.0001]. Transcutaneous oxygen readings were lower in the Val/Leu or Leu/Leu group [Val/Leu or Leu/Leu 16 (0–58) mmHg vs. Val/Val 35 (1–65) mmHg; P = 0.008]. Similarly, plasma factor XIII activation negatively correlated with transcutaneous oxygen readings (r2 = −0.314; P = 0.014).

Conclusions  Val34Leu polymorphism is associated with increased plasma factor XIII activation and seems to be linked with impaired cutaneous microcirculation in patients with diabetic foot ulcers.