bluuebunny/crossref_metadata_2025_split huggingface dataset:
The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus
Authors: Kasichayanula Sreeneeranj , Liu Xiaoni , Pe Benito Melanie , Yao Ming , Pfister Marc , LaCreta Frank P. , Humphreys William Griffith , Boulton David W. 
Published: December 2012

Aim(s)This study assessed the effect of differences in renal function on the pharmacokinetics and pharmacodynamics of dapagliflozin, a renal sodium glucose co‐transporter‐2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus (T2DM).MethodsA single 50 mg dose of dapagliflozin was used to assess pharmacokinetics and pharmacodynamics in five groups: healthy non‐diabetic subjects; patients with T2DM and normal kidney function and patients with T2DM and mild, moderate or severe renal impairment based on estimated creatinine clearance. Subsequently, 20 mg once daily multiple doses of dapagliflozin were evaluated in the patients with T2DM. Formation rates of dapagliflozin 3‐O‐glucuronide (D3OG), an inactive metabolite, were evaluated using human isolated kidney and liver microsomes.ResultsPlasma concentrations of dapagliflozin and D3OG were incrementally increased with declining kidney function. Steady‐state Cmax for dapagliflozin were 4%, 6% and 9% higher and for D3OG were 20%, 37% and 52% higher in patients with mild, moderate and severe renal impairment, respectively, compared with normal function. AUC(0,τ) was likewise higher. D3OG formation in kidney microsomes was three‐fold higher than in liver microsomes and 109‐fold higher than in intestine microsomes. Compared with patients with normal renal function, pharmacodynamic effects were attenuated with renal impairment. Steady‐state renal glucose clearance was reduced by 42%, 83% and 84% in patients with mild, moderate or severe renal impairment, respectively.ConclusionsThese results indicate that both kidney and liver significantly contribute to dapagliflozin metabolism, resulting in higher systemic exposure with declining kidney function. Dapagliflozin pharmacodynamics in diabetic subjects with moderate to severe renal impairment are consistent with the observation of reduced efficacy in this patient population.
MicroRNAs and lymphomagenesis: a functional review
Authors: Lawrie Charles H. 
Published: December 2012

SummaryThe relatively recent discovery of microRNAs (miRNAs) has exposed an extra layer of gene expression regulation that affects many physiological and pathological processes of biology. Dysregulation of miRNAs is a ubiquitous feature of cancer in general, including lymphomas. The identity of these aberrantly‐expressed miRNAs has been thoroughly investigated in all but a few types of lymphomas, however their functional role in lymphomagenesis much less so. This review focuses on those miRNAs that have an experimentally confirmed functional role in the pathogenesis of the most frequent forms of lymphoma. In particular, the MIR15A/16‐1 cluster, MIR21, MIR155, MIR17HG (MIR17‐92 cluster), MIR34A and MIR125B, which have in vivo animal model evidence for their involvement in lymphomagenesis, are highlighted.
Understanding relationships between autism, intelligence, and epilepsy: a cross‐disorder approach
Authors: van EEGHEN AGNIES M , PULSIFER MARGARET B , MERKER VANESSA L , NEUMEYER ANN M , van EEGHEN ELMER E , THIBERT RONALD L , COLE ANDREW J , LEIGH FAWN A , PLOTKIN SCOTT R , THIELE ELIZABETH A 
Published: December 2012

Aim  As relationships between autistic traits, epilepsy, and cognitive functioning remain poorly understood, these associations were explored in the biologically related disorders tuberous sclerosis complex (TSC), neurofibromatosis type 1 (NF1), and epilepsy.Method  The Social Responsiveness Scale (SRS), a quantitative measure of autistic traits, was distributed to caregivers or companions of patients with TSC, NF1, and childhood‐onset epilepsy of unknown cause (EUC), and these results were compared with SRS data from individuals with idiopathic autism spectrum disorders (ASDs) and their unaffected siblings. Scores and trait profiles of autistic features were compared with cognitive outcomes, epilepsy variables, and genotype.Results  A total of 180 SRS questionnaires were completed in the TSC, NF1, and EUC outpatient clinics at the Massachusetts General Hospital (90 females, 90 males; mean age 21y, range 4–63y), and SRS data from 210 patients with ASD recruited from an autism research collaboration (167 males, 43 females; mean age 9y, range 4–22y) and 130 unaffected siblings were available. Regression models showed a significant association between SRS scores and intelligence outcomes (p<0.001) and various seizure variables (p<0.02), but not with a specific underlying disorder or genotype. The level of autistic features was strongly associated with intelligence outcomes in patients with TSC and epilepsy (p<0.01); in patients with NF1 these relationships were weaker (p=0.25). For all study groups, autistic trait subdomains covaried with neurocognitive comorbidity, with endophenotypes similar to that of idiopathic autism.Interpretation  Our data show that in TSC and childhood‐onset epilepsy, the severity and phenotype of autistic features are inextricably linked with intelligence and epilepsy outcomes. Such relationships were weaker for individuals with NF1. Findings suggest that ASDs are not specific in these conditions.
Topography of brain damage in metabolic hypoglycaemia is determined by age at which hypoglycaemia occurred
Authors: GATAULLINA SVETLANA , LONLAY PASCALE DE , DELLATOLAS GEORGES , VALAYANNAPOULOS VASSILI , NAPURI SILVIA , DAMAJ LÉNA , TOUATI GUY , ALTUZARRA CECILA , DULAC OLIVIER , BODDAERT NATHALIE 
Published: December 2012

Aim  Having previously shown that comorbidity is a major determinant of neurological sequelae in hypoglycaemia, our aim was to describe the neuroimaging patterns of brain damage in different hypoglycaemic situations and to elucidate the factors that determine lesion topography.Method  We reviewed 50 patients (31 females, 19 males) with symptomatic hypoglycaemia (<2.8mmol/L) occurring between 1 day and 5 years of age (median 4d) who had undergone magnetic resonance imaging (MRI; at least axial T2‐weighted, sagittal T1‐weighted, and coronal fluid‐attenuated inversion recovery [FLAIR]‐weighted imaging). MRI was performed during the follow‐up examination at least 1 month after the occurrence of symptomatic hypoglycaemia, i.e. between 1 month and 5 years of age (median 3mo). Hypoglycaemia resulted from three inborn errors of metabolism: congenital hyperinsulinism (33 patients), fatty acid β‐oxidation disorders (13 patients), or glycogen storage disease type I (four patients). We selected the patients with clear MRI abnormalities and analysed their topography according to aetiology and age at occurrence of the lesion.Results  The topography of the brain lesions depended on age: from the neonatal period to 6 months of age, lesions predominantly involved the posterior white matter; between 6 and 22 months the basal ganglia, and after 22 months the parietotemporal cortex (p=0.04).Interpretation  The relationship between brain lesions and age could reflect the maturation sequence of the brain.
Mate‐finding allee effect in spruce budworm population dynamics
Authors: Régnière Jacques , Delisle Johanne , Pureswaran Deepa S. , Trudel Richard 
Published: December 2012

AbstractAllee effects can cause populations to decline due to decreasing population growth rates with decreasing density and play a major role in population dynamics. Mate‐finding failure, a common mechanism contributing to demographic Allee effects, is usually difficult to demonstrate because of the arduous nature of sampling individuals at very low densities. In a rising outbreak of the eastern spruce budworm, Choristoneura fumiferana (Clemens) (Lepidoptera: Tortricidae), we used caged and tethered virgin females in traps to measure mating success over population densities ranging from deep endemic to outbreak conditions. We found that mating success increased with increasing population density, and that at endemic population densities, females experienced difficulties attracting males and mating, demonstrating for the first time a mate‐finding Allee effect in the spruce budworm. The relationship between population density and mating success is nonlinear. As population density increased, the proportion of mated females eventually reached a plateau and mating success was not 100% even at the highest moth densities, probably due to female reluctance to mate and perhaps interference competition by males for access to females. Both laboratory‐reared and wild females were equally effective in synthesizing pheromone, attracting males, and mating. Our results strongly suggest that a mate‐finding Allee effect is involved in maintaining low‐density spruce budworm populations below an Allee threshold where they fail to grow. Factors such as changes in predation pressure and immigration could help populations overcome this Allee threshold.
Normalization of free light chain kappa/lambda ratio is a robust prognostic indicator of favorable outcome in patients with multiple myeloma
Authors: Iwama Kan‐ichi , Chihara Dai , Tsuda Kenji , Ugai Tomotaka , Sugihara Hiroyuki , Nishida Yuhki , Yamakura Masayuki , Takeuchi Masami , Matsue Kosei 
Published: December 2012

AbstractPurposeTo clarify the impact of serum free light chain (sFLC) ratio normalization in patients with multiple myeloma (MM) treated with novel agents.Patients and methodsTreatment response in 126 consecutive patients over 7 yr was assessed by IMWG criteria and sFLC assay.ResultsThirty‐four patients (27%) showed complete response (CR), 37 (29%) very good partial response (VGPR), 39 (31%) partial response (PR), and 16 (13%) stable disease (SD) or less at a median follow‐up of 28 months. Fifty‐two patients (41%) with sFLC ratio normalization showed superior progression‐free survival (PFS) and overall survival (OS) compared to those who did not (3‐yr OS, 94% vs. 48%; P < 0.001). This favorable effect of sFLC ratio normalization occurred irrespective of high (>1000 mg/dL) or low (<100 mg/dL) baseline sFLC. Rates of normal sFLC ratio were as follows: CR, 69%; VGPR, 64%; PR, 16%; and SD or less, 0%. OS was significantly superior in patients with than without normal sFCL ratio in respective response groups. Although various factors (advanced age >70, high LDH, ISS stage 3) showed negative prognostic impacts on PFS and OS on univariate analysis, normal sFLC ratio and achievement of CR emerged as the strongest prognostic predictors for longer OS in MM patients on multivariate analysis.ConclusionsThis study demonstrated the significance of obtaining normal sFLC ratio independent of other clinical variables. Analysis of sFLC ratio could identify the favorable group of patients as well as immunofixation test and support the inclusion of sFLC ratio as part of the response criteria for MM.
Malaria infection increases bird attractiveness to uninfected mosquitoes
Authors: Cornet Stéphane , Nicot Antoine , Rivero Ana , Gandon Sylvain 
Published: December 2012

AbstractThe epidemiology of vector‐borne pathogens is largely determined by the host‐choice behaviour of their vectors. Here, we investigate whether a Plasmodium infection renders the host more attractive to host‐seeking mosquitoes. For this purpose, we work on a novel experimental system: the avian malaria parasite Plasmodium relictum, and its natural vector, the mosquito Culex pipiens. We provide uninfected mosquitoes with a choice between an uninfected bird and a bird undergoing either an acute or a chronic Plasmodium infection. Mosquito choice is assessed by microsatellite typing of the ingested blood. We show that chronically infected birds attract significantly more vectors than either uninfected or acutely infected birds. Our results suggest that malaria parasites manipulate the behaviour of uninfected vectors to increase their transmission. We discuss the underlying mechanisms driving this behavioural manipulation, as well as the broader implications of these effects for the epidemiology of malaria.
Roles of circadian clock genes in insect photoperiodism
Authors: Goto Shin G. 
Published: December 2012

AbstractFunctional involvement of a circadian clock in photoperiodism for measuring the length of day or night had been proposed more than 70 years ago, and various physiological experiments have supported the idea. However, the molecular basis of a circadian clock has remained veiled in insects. Nevertheless, our knowledge of the functional elements of a circadian clock governing circadian rhythmicity has advanced rapidly. Since both circadian rhythms and photoperiodism depend on the daily cycles of environmental changes, it is easy to assume that the same clock elements are involved in both processes. Recently, the RNA interference (RNAi) technique clarified that the molecular machinery of a circadian clock governing photoperiodism is identical to that governing circadian rhythmicity. Here, I review the theoretical background of photoperiodic responses incorporating a circadian clock(s) and recent progress on the molecular clockwork involved in photoperiodism in the bean bug Riptortus pedestris and other insect species. I have focused on the intense controversy regarding the involvement of a circadian clock in insect photoperiodism.
Comparison between hepatic resection and radiofrequency ablation as first‐line treatment for solitary small‐sized hepatocellular carcinoma of 3 cm or less
Authors: Imai Kastunori , Beppu Toru , Chikamoto Akira , Doi Koichi , Okabe Hirohisa , Hayashi Hiromitsu , Nitta Hidetoshi , Ishiko Takatoshi , Takamori Hiroshi , Baba Hideo 
Published: December 2012

AimIt is a matter of debate whether hepatic resection (HR) or radiofrequency ablation (RFA) should be preferred for the treatment of patients with hepatocellular carcinoma (HCC). The aim of this study is to compare the long‐term outcome between HR and RFA in patients with solitary small‐sized HCC.MethodsOne hundred and eighty‐three patients with solitary HCC of 3 cm or less who underwent either HR (n = 101) or RFA (n = 82) as a first‐line treatment were enrolled in this study. Their cumulative disease‐free and overall survival and prognostic factors were compared.ResultsThe disease‐free and overall survival in the HR group were significantly better than those in the RFA group for HCC of 3 cm or less; the 5‐year disease‐free and overall survival rates were 46.8% versus 23.9% and 87.5% versus 59.4% (P = 0.0008, =0.0002), respectively. In the subgroup analysis, the disease‐free and overall survival in the HR group were significantly better than those in the RFA group for HCC of more than 2 cm (P < 0.0001, <0.0001, respectively), whereas there were no significant differences between the two groups for HCC of 2 cm or less. In patients treated with RFA, a tumor size of more than 2 cm was the only independent prognostic factor for disease‐free survival (risk ratio = 1.832, P = 0.039).ConclusionHR is proposed as the first‐line treatment for patients with solitary small‐sized HCC rather than RFA, especially for those with tumors in the range 2–3 cm.
The Prusso‐German Idea of War: The Values of a virtual Rogue State†
Authors: Moses John 
Published: December 2012

AbstractThe point of departure for this paper is the apparent unwillingness or inability of some Australian historians to comprehend the character of Wilhelmine Germany and her extensive war‐aims, 1914–18. Part of the explanation for this is the tendency to assess imperial Germany as just another 19th century imperialist power essentially indistinguishable from all others. As recent research shows Imperial Germany evinced many of the characteristics of a so‐called rogue state. Apart from a handful of Australian aficionados (who are identified) there are very few historians who can make a nuanced judgment of Bismarckian‐Wilhelmine German policy. Consequently, one often hears and reads very garbled and tendentious accounts of why Britain’s Pacific dominions were involved in the ‘Great War’. This paper explains the Bismarckian philosophy of both domestic and foreign policy and argues, along with many notable German historians that a great European conflict was already embedded in both the structures set in place by the famous Reich Chancellor and his style of conducting diplomacy based on the so‐called ‘bluff theory’ (Kurt Riezler). Thereby an explanation is provided as to how the understanding of the traditions andmentalitésof one Great Power in the ‘Age of Imperialism’ impacted on the history of remote outposts of a rival political culture, namely the British Pacific dominions.This paper is based on a reading of the most recent as well as standard sources in both German and English.
Phylogeographic pointers to conservation needs: South Africa's flagship dung beetle, Circellium bacchus
Authors: Sole Catherine L. , Scholtz Clarke H. 
Published: December 2012

Abstract

Circellium bacchus is South Africa's largest ball‐rolling dung beetle and a habitat specialist of dense bush. It is also wingless, a rare phenomenon amongst large dung beetles and, unusual for the group, only females construct and bury brood balls. She cares for the single brood for 4–5 months, and lives for 3–5 years.

The beetles currently occur in two separate populations in South Africa, one in the south‐east and one consisting of at least eight fragmented sub‐populations in the south‐west. Here, we use both mitochondrial and nuclear DNA sequences to infer the evolutionary history of this species.

The Eastern and Western populations are genetically separated by 14% mitochondrial sequence divergence, sharing only a single nuclear haplotype. Mitochondrial and nuclear data indicate that C. bacchus belongs to an ancient (Eocene) relict lineage and that the Eastern and Western populations appear to have been separated by Pliocene continental uplift and a relictual Pleistocene block of temperate forest. Subsequent Plio‐Pleistocene climatic change caused further fragmentation of the Western population, now exacerbated by human‐induced land transformation.

The Eastern and Western populations are identifiable as two distinctly separate entities of possible species status, but with definite need for recognition as evolutionary significant units. The Western sub‐populations are genetically significantly different enough to be defined and recognised as management units. The Eastern population is largely distributed in the Addo Elephant National Park where its persistence is currently secure, but the sub‐populations of the Western lineage occur as fragments of various sizes in a matrix of agriculturally transformed landscape.
Major dermatological malignancies encountered in the University of Calabar Teaching Hospital, Calabar, southern Nigeria
Authors: Asuquo Maurice E. , Ebughe Godwin 
Published: December 2012

AbstractBackground  Dermatologic malignancies are among the most common forms of cancer. Sun exposure is the major risk factor in white people, while non‐solar factors appear to be the leading risk factor in the darkly pigmented.Methods  We examined 162 patients with histologic diagnosis of dermatological malignancy who consulted at the University of Calabar Teaching Hospital, Calabar from January 2000 to December 2009.Results  The 162 patient cases observed during the study represent 12% of all cancers diagnosed within the same period. Squamous cell carcinoma (SCC) was the most common (n = 62; 38.3% followed by Kaposi sarcoma (KS) (n = 33; 30.9%). Others were malignant melanoma (MM) (n = 16; 9.9%), dermatofibrosarcoma protuberans (DFSP) (n = 11; 6.8%), and basal cell carcinoma (BCC) (n = 8; 4.9%). The lower limb was the most commonly afflicted site (n = 82; 48.8%) while the head and neck ranked second (n = 32; 22.0%); 146 patients (90%) were darkly pigmented and 16 (10%) were people with albinism. Some patients with SCC and MM consulted late for curative surgery. Surgery resulted in healing in patients with BCC, while the recurrent rate for DFSP was high. The endemic KS responded to cytotoxic chemotherapy but the result was poor for KS associated with human immunodeficiency virus.Conclusion  The pattern of dermatologic malignancy revealed in this study is different from that of European skin cancer. Health education, early implementation of preventive measures, early consultation, and treatment will improve outcome in our region.
Prevalence of linea nigra in patients with benign prostatic hyperplasia and prostate carcinoma
Authors: Okeke Linus Ikechukwu , George Adekunle Olufemi , Ogunbiyi Adebola Olufunmilayo , Wachtel Mitchelle 
Published: December 2012

AbstractBackground  Linea nigra (LN) is linear hyperpigmentation occurring from the umbilicus to the pubic symphysis. Although commonly associated with pregnancy (when it is known as linea gravidarum), it has been found in normal male and female individuals, particularly in the younger age group where estrogen or lack of sensitivity of androgen receptors has been suggested as a possible factor. From a previous study the incidence of LN varied in different genders, age groups, and certain clinical status such as pregnancy and, in men, benign prostate hyperplasia (BPH)/prostate carcinoma (PC).Objective  The need to get a clinical feature that can aid diagnosis of PC, the commonest male neoplasm in Nigeria, at an affordable cost prompted us to look at the incidence of LN in three male populations (i.e., one with BPH, one with PC, and a control population unaffected by these two conditions). Gynecomastia and female hair distribution, two features considered hormone related were looked for additionally in the study population. The study was carried out in a teaching hospital in Ibadan, southwestern Nigeria.Results  LN was found in 48% of PC, 26% of BPH, and 8% of controls. Female pubic hair was found in 48% of PC, 26% of BPH, and 12% of controls. Gynecomastia was found in 36% of PC, 12% of BPH, and 0% of controls. Differences between patients with BPH, PC, and controls regarding incidence of LN and female pubic hair were deemed explicable by chance (P = 0.17, Fisher exact test). Differences between PC and BPH patients with respect to gynecomastia were deemed inexplicable by chance (P = 0.008, Fisher exact test).Conclusion  LN alone cannot be used to differentiate PC and BPH. Further studies will be needed to characterize the role of LN in these conditions in men before and after treatment.