bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards a taxonomic coherence between average nucleotide identity and 16S rRNA gene sequence similarity for species demarcation of prokaryotes
Authors: Kim Mincheol , Oh Hyun-Seok , Park Sang-Cheol , Chun Jongsik
Published: February 2014

Among available genome relatedness indices, average nucleotide identity (ANI) is one of the most robust measurements of genomic relatedness between strains, and has great potential in the taxonomy of bacteria and archaea as a substitute for the labour-intensive DNA–DNA hybridization (DDH) technique. An ANI threshold range (95–96 %) for species demarcation had previously been suggested based on comparative investigation between DDH and ANI values, albeit with rather limited datasets. Furthermore, its generality was not tested on all lineages of prokaryotes. Here, we investigated the overall distribution of ANI values generated by pairwise comparison of 6787 genomes of prokaryotes belonging to 22 phyla to see whether the suggested range can be applied to all species. There was an apparent distinction in the overall ANI distribution between intra- and interspecies relationships at around 95–96 % ANI. We went on to determine which level of 16S rRNA gene sequence similarity corresponds to the currently accepted ANI threshold for species demarcation using over one million comparisons. A twofold cross-validation statistical test revealed that 98.65 % 16S rRNA gene sequence similarity can be used as the threshold for differentiating two species, which is consistent with previous suggestions (98.2–99.0 %) derived from comparative studies between DDH and 16S rRNA gene sequence similarity. Our findings should be useful in accelerating the use of genomic sequence data in the taxonomy of bacteria and archaea.
Promoting mental health and wellbeing for a young person with a mental illness: Parent occupations
Authors: Honey Anne , Alchin Sarah , Hancock Nicola
Published: February 2014

Background/aims

Parenting is a critical and complex occupational role, requiring different occupations and abilities depending on the developmental stage and specific characteristics of each child. When a young adult child develops a mental illness, assisting and supporting them to overcome or adapt to the mental illness becomes a crucial aspect of this occupational role to which many parents devote a great deal of time and energy. The way parents respond to mental illness can have an important impact on young people. However, to date, research on these parents has focussed almost exclusively on their characteristics and personal coping rather than what they do to try to assist and support young people. The aims of this study were to identify the occupations parents currently engage in to promote mental health and wellbeing for a young person with a mental illness and to explore the perceived helpfulness of these occupations.

Method

Interviews with 26 young people (15–24 years old) and 32 parents were analysed using constant comparative analysis.

Results

Participants reported 78 conceptually distinct mental illness related occupations aimed at promoting: appropriate treatment; positive activities and actions; positive thoughts and feelings; and an ordinary life. Importantly, few participants could evaluate with confidence the helpfulness of individual mental illness related occupations.

Conclusion

This research demonstrates the breadth of the mental illness related occupations parents employ and provides a framework for understanding their complexities. It highlights the need to establish an evidence base for various mental illness related occupations so that parents can have more knowledge and thus confidence in these critical occupations.
Pubic Symphyseal Age Estimation from Three‐Dimensional Reconstructions of Pelvic CT Scans of Live Individuals
Authors: Wink Alexandra E.
Published: February 2014

Skeletal age estimation using the pubic symphysis is a reliable and popular practice among forensic anthropologists. In instances in which accessing the skeleton is impossible, such as in the case of living individuals, three‐dimensional (3D) reconstructions of computed tomography (CT) scans can be created and analyzed for aspects of the biological profile. This study examined 3D reconstructions of pelvic CT scans of a sample of 44 live adults to estimate age using the Suchey–Brooks J Hum Evol 1990;5(3):227‐38 method. Images were created using OsiriX software (Pixmeo, Geneva, Switzerland). Estimated age ranges based on the 3D‐CT images captured the true age of the individual at the time of the CT scan 79.5% of the time with good intra‐observer reliability. The features best visualized on the 3D images included the ossific nodule and the pubic symphyseal rim. This study shows that clinical CT scanning parameters are adequate for creating 3D images to be analyzed for age using the pubic symphysis.
Working Smarter on Cold Cases: Identifying Factors Associated with Successful Cold Case Investigations
Authors: Davis Robert C. , Jensen Carl J. , Burgette Lane , Burnett Kathryn
Published: February 2014

Cold case squads have garnered much attention; however, they have yet to undergo significant empirical scrutiny. In the present study, the authors interviewed investigators and reviewed 189 solved and unsolved cold cases in Washington, D.C., to determine whether there are factors that can predict cold case solvability. In the interviews, new information from witnesses or information from new witnesses was cited as the most prevalent reason for case clearance. The case reviews determined that there were factors in each of the following domains that predicted whether cases would be solved during cold case investigations: Crime Context, Initial Investigation Results, Basis for Opening Cold Case, and Cold Case Investigator Actions. The results suggest that it is possible to prioritize cold case work based on the likelihood of investigations leading to clearances.
A Preliminary Examination of Differential Decomposition Patterns in Mass Graves
Authors: Troutman Lauren , Moffatt Colin , Simmons Tal
Published: February 2014

Five pairs of mass graves, each containing carcasses of 21 rabbits, were used to examine differential decomposition at four locations within the burial: surface, deep, mid‐outer, and core. Every 100 accumulated degree days (ADD), a pair of graves was exhumed, and total body score (TBS) and internal carcass temperature of each rabbit were recorded. Decomposition did not differ for core‐ and deep‐positioned carcasses (p = 0.13); differences were significant (p < 0.001) for all other location comparisons. Decomposition occurred fastest in shallow carcasses, followed by mid‐outer carcasses; deep and core carcasses decomposed slowest and at rates not significantly different from one another. Adipocere formation was minimal and confined to deep carcasses. Carcass location within the mass grave significantly influenced internal carcass temperature (p < 0.001); a mean internal temperature difference of ca. 1°C existed between deep and shallow carcasses (30 cm apart). Effects of mass compactness and oxygenation require further investigation.
Disopyramide and Mianserin Intoxication: A Unique Fatal Case – Review of the Literature
Authors: Isabelle Le Blanc‐Louvry , Clarot Franck , Vaz Emmanuelle , Jean Pierre Goullé , Proust Bernard
Published: February 2014

Lethal occurrence is exceptional after disopyramide or mianserin poisoning. A case of intentional lethal intoxication with these drugs was reported, as well as a review of the literature. Pre‐ and postmortem blood concentrations of disopyramide or mianserin were assessed in a woman who died from acute cardiac failure after ingestion. The premortem blood concentration of disopyramide alone was considered lethal, and a toxic premortem concentration of mianserin was observed that may have increased cardiovascular failure induced by disopyramide because the metabolism of both drugs is mediated via cytochrome P450. Moreover, it was shown that the postmortem redistribution of disopyramide was limited, as pre‐ and postmortem concentrations were 48 and 65 mg/L, respectively. As regards mianserin, redistribution was observed after death with pre‐ and portmortem concentrations at 0.23 and 0.79 mg/L, respectively. This case illustrates that if postmortem blood concentration of disopyramide is known, the premortem concentration can be deduced.
X‐ray Scattering Evaluation of Ultrastructural Changes in Human Dental Tissues with Thermal Treatment
Authors: Sandholzer Michael A. , Sui Tan , Korsunsky Alexander M. , Damien Walmsley Anthony , Lumley Philip J. , Landini Gabriel
Published: February 2014

Micro‐ and ultrastructural analysis of burned skeletal remains is crucial for obtaining a reliable estimation of cremation temperature. Earlier studies mainly focused on heat‐induced changes in bone tissue, while this study extends this research to human dental tissues using a novel quantitative analytical approach. Twelve tooth sections were burned at 400–900°C (30‐min exposure, increments of 100°C). Subsequent combined small‐ and wide‐angle X‐ray scattering (SAXS/WAXS) experiments were performed at the Diamond Light Source synchrotron facility, where 28 scattering patterns were collected within each tooth section. In comparison with the control sample, an increase in mean crystal thickness was found in burned dentine (2.8‐fold) and enamel (1.4‐fold), however at a smaller rate than reported earlier for bone tissue (5–10.7‐fold). The results provide a structural reference for traditional X‐ray scattering methods and emphasize the need to investigate bone and dental tissues separately to obtain a reliable estimation of cremation temperature.
The Role of Forensic Botany in Crime Scene Investigation: Case Report and Review of Literature
Authors: Aquila Isabella , Ausania Francesco , Di Nunzio Ciro , Serra Arianna , Boca Silvia , Capelli Arnaldo , Magni Paola , Ricci Pietrantonio
Published: February 2014

Management of a crime is the process of ensuring accurate and effective collection and preservation of physical evidence. Forensic botany can provide significant supporting evidences during criminal investigations. The aim of this study is to demonstrate the importance of forensic botany in the crime scene. We reported a case of a woman affected by dementia who had disappeared from nursing care and was found dead near the banks of a river that flowed under a railroad. Two possible ways of access to crime scene were identified and denominated “Path A” and “Path B.” Both types of soil and plants were identified. Botanical survey was performed. Some samples of Xanthium Orientalis subsp. Italicum were identified. The fall of woman resulted in external injuries and vertebral fracture at autopsy. The botanical evidence is important when crime scene and autopsy findings are not sufficient to define the dynamics and the modality of death.
Trigemino‐Cardiac Reflex as Lethal Mechanism in a Suicidal Fire Death Case
Authors: Rossi Riccardo , Lodise Maria , Lancia Massimo , Bacci Mauro , De‐Giorgio Fabio , Cascini Fidelia
Published: February 2014

In the vast majority of immediate fire deaths, the mechanism of death is inhalation of toxic gases (especially carbon monoxide), direct thermal injury, or neurogenic shock due to the redistribution of the body's blood volume produced by surface heat on the skin. We present a suicidal case that is unusual because the mechanism of immediate fire death could arguably be explained in terms of a primitive autonomic reflex/the trigemino‐cardiac reflex. Although this reflex is well known to surgeons and anesthetists, with possible lethal consequences in the course of invasive surgical procedures on the head and neck region, it is much less familiar to forensic pathologists.
Atropine Eye Drops: An Unusual Homicidal Poisoning
Authors: Carlier Jérémy , Escard Emmanuel , Péoc'h Michel , Boyer Baptiste , Romeuf Ludovic , Faict Thierry , Guitton Jérôme , Gaillard Yvan
Published: February 2014

In March 2009, the body of a 51‐year‐old man was found in the boot of his car. The body had been frozen before being dismembered at the abdomen. The autopsy failed to determine the cause of death. Systematic toxicological analyses of the victim's peripheral blood and urine showed the presence of atropine, a powerful anticholinergic. Atropine was therefore specifically detected and quantified throughout the victim's biologic samples by HPLC‐MS² in the biologic fluids and UHPLC‐MS² in the hair. The atropine concentrations were 887 ng/mL in the cardiac blood, 489 ng/mL in the peripheral blood, 6693 ng/mL in the gastric contents (1.1 μg), 6753 ng/mL in the urine, and 2290 pg/mg in the hair. The blood concentrations measured in the decedent were consistent with an overdose of atropine, which was determined as the cause of death. The manner of death was a homicide with criminal intent.
Sudden Death in Marfan Syndrome
Authors: Hugar Basappa S. , Praveen Shivaramareddy , Kainoor Sunil K. , Shetty Akshith Raj S.
Published: February 2014

Marfan syndrome is an autosomal dominant genetic disorder of the connective tissue. The most serious complications of this syndrome are defects of the heart valves and aorta. Aneurysms of thoracic aorta are known to develop in Marfan syndrome. Other causes for development of aneurysms of the thoracic aorta are trauma, infections, valve and arch anomalies, genetic disorders, and atherosclerosis. These aneurysms upon rupture may lead to sudden deaths. They are usually detected during routine screening or follow‐up of such persons suffering from Marfan syndrome and upon death will be certified by the treating physician. Thus, an autopsy surgeon rarely comes across such deaths. One such case of sudden death due to cardiac tamponade consequent upon rupture of dissecting aortic aneurysm in a 33‐year‐old male who complained of throbbing pains in the chest, radiating to back, became breathless, cyanotic and died on the way to hospital is being presented here.
Philemon and Baucis Deaths: Case Reports and Postmortem Biochemistry Contribution
Authors: Lardi Christelle , Schmit Gregory , Burkhardt Sandra , Mangin Patrice , Palmiere Cristian
Published: February 2014

The death of a person as a reaction to the death of another is known as Philemon and Baucis death and may represent a difficult challenge for pathologists, especially due to the decompositional changes that often characterized these situations. In this article, we describe two cases of Philemon and Baucis deaths, the first concerning a married couple and the second concerning a father and son. Postmortem investigations including radiology and biochemistry were performed. Based on the results of all investigations, deaths were attributed to natural causes. Third‐party involvement could be excluded in both situations. In one case, biochemical analysis results revealed potentially contributing causes of death. The reported cases emphasize the importance of correlating findings from different postmortem investigations to identify causes of death, precipitating conditions and predisposing disorders, thus allowing the conclusion of natural death to be reached and third‐party involvement to be excluded.
Methadone‐Related Deaths – Epidemiological, Pathohistological, and Toxicological Traits in 10‐year Retrospective Study in Vojvodina, Serbia
Authors: Mijatović Vesna , Samojlik Isidora , Ajduković Nikša , Đurendić‐Brenesel Maja , Petković Stojan
Published: February 2014

The number of methadone‐related deaths (MRDs) during a 10‐year period (2002–2011) in the region of Vojvodina, Serbia, was increased. The cases were evaluated according to epidemiological parameters, pathohistological findings, and toxicological screening. The majority of victims were men, aged from 20 to 38. Pathohistologically, the signs of acute focal myocardial damage were present in the heart of victims with drug abuse history shorter than 2 years, while both signs of recent and chronic focal myocardial damage were developed among victims with longer drug abuse history (2–5 years). In postmortem blood samples of 54.84% of victims, methadone was detected in combination with diazepam, both in therapeutic range. Alcohol was absent in most cases. Other detected drugs were antipsychotics and antidepressants in therapeutic concentrations. These findings raise the attention to the concomitant use of methadone and benzodiazepines with the need for further studies to clarify the mechanism of death in such cases.
Endobronchial/Tracheal Metastasis and Sudden Death
Authors: Byard Roger W.
Published: February 2014

Endobronchial and endotracheal metastases are rare lesions that may cause acute occlusion of major airways. A case is reported of a 62‐year‐old man with history of renal cell carcinoma and hemoptysis who died after having suddenly become short of breath with cyanosis. At autopsy, recurrent renal cell carcinoma was identified with metastases to the lungs, pulmonary hilar lymph nodes, and brain. In addition, a solitary papillomatous metastasis arising from the mucosa of the carina was obstructing both the main bronchi and distal trachea. Death was due to acute airway obstruction by a metastatic deposit at the bifurcation of the trachea in a case of disseminated renal cell carcinoma. This case demonstrates an extremely rare cause of sudden death that may complicate disseminated malignancy.
Development of Latent Fingermarks from Rocks and Stones
Authors: Hefetz Ido , Cohen Amit , Cohen Yaron , Chaikovsky Alan
Published: February 2014

Since the beginning of recorded history, stones have been used in the commission of crimes due to their widespread availability. Stones can be used as a lethal weapon that sometimes might be the only evidence in a serious case. The common perception, even in professional fingermark circles, is that stones do not yield identifiable latent fingermarks. The authors of this research paper examined the feasibility of developing fingermarks from seven types of stones using three latent fingermark techniques: magnetic powder, cyanoacrylate fuming, and ninhydrin. The paper will demonstrate that by classifying stones and rocks according to their natural properties (porosity, permeability, and the nature of surface area), even application of the simplest development techniques can produce good results. In conclusion, chert and limestone yielded the most qualitative and quantitative results using magnetic powder. The time factor is also important in recovering latent fingermarks on stones and rocks.
The Average Direct Current Offset Values for Small Digital Audio Recorders in an Acoustically Consistent Environment
Authors: Koenig Bruce E. , Lacey Douglas S.
Published: February 2014

In this research project, nine small digital audio recorders were tested using five sets of 30‐min recordings at all available recording modes, with consistent audio material, identical source and microphone locations, and identical acoustic environments. The averaged direct current (DC) offset values and standard deviations were measured for 30‐sec and 1‐, 2‐, 3‐, 6‐, 10‐, 15‐, and 30‐min segments. The research found an inverse association between segment lengths and the standard deviation values and that lengths beyond 30 min may not meaningfully reduce the standard deviation values. This research supports previous studies indicating that measured averaged DC offsets should only be used for exclusionary purposes in authenticity analyses and exhibit consistent values when the general acoustic environment and microphone/recorder configurations were held constant. Measured average DC offset values from exemplar recorders may not be directly comparable to those of submitted digital audio recordings without exactly duplicating the acoustic environment and microphone/recorder configurations.
Producing Authenticity in Global Capitalism: Language, Materiality, and Value
Authors: Cavanaugh Jillian R. , Shankar Shalini
Published: February 2014

In this article, we bring together two distinct ethnographic cases of capitalist production—food producers in northern Italy and Asian American advertising executives in New York City—to illustrate how these producers use language and materiality to produce value in global capitalism. Taken together, the cases illustrate how contemporary capitalist producers utilize particular notions of ethnolinguistic heritage in ways that reflect group‐specific values and enable economic profitability in globalizing economies. We consider the work that producers do to construct authenticity by identifying the links they create among and across linguistic and material elements. Whether the product in question is a locally crafted salami or a car commercial aimed at Chinese Americans, constructing authenticity is a complex process that is not assured of success but that is driven by various possibilities of reward. Noting the ways in which authenticity construction seldom goes unchallenged, we consider producers’ linguistic and material work to create authentic goods against those who question and contest their efforts. In so doing, we examine broader implications of this capitalist production and contribute to literature on global capitalism, commodity creation, brand, and relationships between language and materiality.
Progranulin gene variability influences the risk for bipolar I disorder, but not bipolar II disorder
Authors: Galimberti Daniela , Prunas Cecilia , Paoli Riccardo A , Dell'Osso Bernardo , Fenoglio Chiara , Villa Chiara , Palazzo Carlotta , Cigliobianco Michela , Camuri Giulia , Serpente Maria , Scarpini Elio , Altamura A Carlo
Published: February 2014

Objective

Recent data have shown that genetic variability in the progranulin (GRN) gene may contribute to the susceptibility to developing bipolar disorder (BD). However, in regard to patients with BD, no information is available on the role of genetic variability and plasma progranulin levels in different types of this disorder.

Methods

In this study, we performed an association analysis of GRN in an Italian population consisting of 134 patients with BD and 232 controls to evaluate progranulin plasma levels.

Results

The presence of the polymorphic variant of the rs5848 single nucleotide polymorphism is protective for the development of bipolar I disorder (BD‐I) (odds ratio = 0.55, 95% confidence interval: 0.33–0.93; p = 0.024) but not bipolar II disorder (BD‐II) (p > 0.05). In addition, plasma progranulin levels are significantly decreased in BD [mean ± standard deviation (SD) 112 ± 35 versus 183 ± 93 ng/mL in controls; p < 0.001].

Conclusions

Regarding the influence of GRN variability on BD susceptibility, the predisposing genetic background differs between BD‐I and BD‐II, possibly implying that pathogenic mechanisms differ between the two subtypes of BD.
Parental age and the risk of bipolar disorders
Authors: Chudal Roshan , Gissler Mika , Sucksdorff Dan , Lehti Venla , Suominen Auli , Hinkka‐Yli‐Salomäki Susanna , Brown Alan S , Sourander Andre
Published: February 2014

Objectives

Studies on the association between parental age and bipolar disorder (BPD) are scarce and with inconsistent findings. The aim of this study was to examine the association of parental age and age difference between parents with risk of BPD in offspring.

Methods

This nested case–control study identified 1,861 cases of individuals with BPD born in Finland during 1983–1998 and diagnosed by the end of 2008, and 3,643 sex‐ and date of birth‐matched controls from nationwide population‐based registers. Conditional logistic regression was used to examine the association adjusting for potential confounding due to age of the other parent, parental psychiatric history, educational level, and place of birth.

Results

A U‐shaped association of unadjusted odds ratios (ORs) for BPD risk was seen in different paternal age categories, with the odds increasing at both ends of the age spectrum. In the adjusted analyses, offspring of fathers aged ≥50 years had a 2.8‐fold increased odds [OR = 2.84, 95% confidence interval (CI): 1.32–6.12] of BPD as compared to those with fathers aged 30–34 years. The odds were increased 1.3‐fold (OR = 1.35, CI: 1.06–1.72) in fathers aged 20–24 years. No significant association was found between maternal age and BPD in the adjusted analyses. Age difference between parents was not associated with BPD.

Conclusions

The increased risk of BPD in offspring of the youngest and oldest fathers in the study suggests the involvement of different biological and psychosocial factors at the two ends of the paternal age spectrum. These findings may be significant in the context of advancing parental age in recent times.
Fisher in Adelaide
Authors: Mayo Oliver
Published: February 2014

R. A. Fisher spent much of his final 3 years of life in Adelaide. It was a congenial place to live and work, and he was much in demand as a speaker, in Australia and overseas. It was, however, a difficult time for him because of the sustained criticism of fiducial inference from the early 1950s onwards. The article discusses some of Fisher's work on inference from an Adelaide perspective. It also considers some of the successes arising from this time, in the statistics of field experimentation and in evolutionary genetics. A few personal recollections of Fisher as houseguest are provided. This article is the text of a article presented on August 31, 2012 at the 26th International Biometric Conference, Kobe, Japan.
ON THE SUSTAINABILITY OF COLLUSION IN A DIFFERENTIATED OLIGOPOLY WITH A CARTEL AND A FRINGE
Authors: Escrihuela‐Villar Marc , Guillén Jorge
Published: February 2014

We discuss the effects of the existence of non‐colluding (fringe) firms on cartel sustainability. We obtain, using trigger strategies, that with product differentiation collusion is always more easily sustained when firms compete in prices than when firms compete in quantities. This is true basically because (i) price competition is more intense than quantity competition, and (ii) fringe firms exacerbate the fact that cartel firms have more incentives to deviate from the agreement under quantity competition. This result reverses previous findings where, in the absence of fringe firms, product differentiation plays a crucial role in determining the effectiveness of price or quantity competition in sustaining collusion.
Differences in Survival and Growth Among Tropical Rain Forest Pioneer Tree Seedlings in Relation to Canopy Openness and Herbivory
Authors: Goodale Uromi M. , Berlyn Graeme P. , Gregoire Timothy G. , Tennakoon Kushan U. , Ashton Mark S.
Published: February 2014

Although differences in canopy openness, herbivory and their interaction may promote species coexistence, how these factors affect pioneer tree species and potentially limit growth, and survival has been poorly studied, particularly in tropical South Asia. We monitored the effect of canopy openness and herbivore damage on seedling survival and growth of 960 individuals of six pioneer tree species: Dillenia triquetra, Macaranga indica, Macaranga peltata, Schumacheria castaneifolia, Trema orientalis, and Wendlandia bicuspidata. Seedlings were placed in four gap‐understory positions—center, outer gap edge, inner forest edge, and understory—in four large, natural gaps within the Sinharaja World Heritage Reserve, Sri Lanka. Canopy openness positively affected survival probability beyond the 550‐d experiment, while herbivory decreased survival and was highest in understory conditions. The relative order of species survival stayed fairly consistent between gap‐understory positions and followed their known shade tolerance rankings. When averaged across all experimental conditions, T. orientalis had the lowest survival probability estimate beyond the 550‐d experiment (0.05), but the greatest capacity for growth where it successfully established, while the species with highest averaged survival probability (0.79), D. triquetra, showed the lowest growth. One species, W. bicuspidata, responded positively to herbivory by re‐sprouting. Coexistence of D. triquetra, T. orientalis, and W. bicuspidata can be explained by a trade‐off among species in survival, growth, and response to herbivory. In addition to variation in canopy light environment, herbivory may be important in determining pioneer species distribution through fine‐scale niche partitioning and should be carefully considered in reforestation efforts.
A study of 133 Chinese children with mitochondrial respiratory chain complex I deficiency
Authors: Ma Y.‐Y. , Wu T.‐F. , Liu Y.‐P. , Wang Q. , Li X.‐Y. , Ding Y. , Song J.‐Q. , Yang Y.‐L. , Zou L.‐P.
Published: February 2014

To investigate the clinical, enzymological and mitochondrial gene profiles of complex I deficiency in Chinese, clinical and laboratory data of the patients (79 boys, 54 girls) were retrospectively assessed. Activities of mitochondrial respiratory chain complexes in peripheral leucocytes were spectrophotometrically measured. The entire mitochondrial DNA (mtDNA) sequence was analyzed in 62 patients. Restriction fragment length polymorphism and gene sequencing analyses were performed in 15 families. Ninety‐one patients had isolated complex I deficiency; 42 had combined deficiencies of complex I and other complexes. The main clinical presentations were neuromuscular disorders (107 patients) and non‐neurological dysfunction (hepatopathy, renal damage and cardiomyopathy; 26 patients). In 32 of 62 patients who underwent mtDNA sequencing, 24 mutations were identified in 15 mitochondrial genes. The 12338T>C, 4833A>G and 14502T>C mutations were found in 12.9%, 11.3% and 4.8% patients, respectively. Seven patients had multiple mutations. Three novel mutations were identified. Chinese patients with complex I deficiency presented heterogeneous phenotypes and genotypes. Twenty‐four mutations were identified in 15 mitochondrial genes in 51.6% patients. mtDNA mutations were more common in isolated complex I deficiency than in combined complex deficiencies. The 12338T>C, 4833A>G and 14502T>C mutations were common.
A systematic review on the innervation of peri‐implant tissues with special emphasis on the influence of implant placement and loading protocols
Authors: Huang Yan , Jacobs Reinhilde , Van Dessel Jeroen , Bornstein Michael M. , Lambrichts Ivo , Politis Constantinus
Published: February 2014

Objectives

To systematically review the available literature on the influence of dental implant placement and loading protocols on peri‐implant innervation.

Material and methods

The database MEDLINE, Cochrane, EMBASE, Web of Science, LILACS, OpenGrey and hand searching were used to identify the studies published up to July 2013, with a populations, exposures and outcomes (PEO) search strategy using MeSH keywords, focusing on the question: Is there, and if so, what is the effect of time between tooth extraction and implant placement or implant loading on neural fibre content in the peri‐implant hard and soft tissues?

Results

Of 683 titles retrieved based on the standardized search strategy, only 10 articles fulfilled the inclusion criteria, five evaluating the innervation of peri‐implant epithelium, five elucidating the sensory function in peri‐implant bone. Three included studies were considered having a methodology of medium quality and the rest were at low quality. All those papers reported a sensory innervation around osseointegrated implants, either in the bone–implant interface or peri‐implant epithelium, which expressed a particular innervation pattern. Compared to unloaded implants or extraction sites without implantation, a significant higher density of nerve fibres around loaded dental implants was confirmed.

Conclusions

To date, the published literature describes peri‐implant innervation with a distinct pattern in hard and soft tissues. Implant loading seems to increase the density of nerve fibres in peri‐implant tissues, with insufficient evidence to distinguish between the innervation patterns following immediate and delayed implant placement and loading protocols. Variability in study design and loading protocols across the literature and a high risk of bias in the studies included may contribute to this inconsistency, revealing the need for more uniformity in reporting, randomized controlled trials, longer observation periods and standardization of protocols.
Biological width formation to immediate implants placed at different level in relation to the crestal bone: an experimental study in dogs
Authors: Negri Bruno , López Marí Marta , Maté Sánchez de Val José Eduardo , Iezzi Giovanna , Bravo González Luis Alberto , Calvo Guirado José Luis
Published: February 2014

Purpose/Aim

Evaluate differences in bone remodeling, soft tissue reactions and biological width formation around immediate implants placed at different level in relation to the crestal bone in beagle dogs.

Material and methods

The mandibular second, third and fourth premolars of six beagle dogs were extracted, and three implants were placed in the right side of each dog. Healing abutments were adjusted (n = 18). After 4 weeks, the procedure was repeated on the left side of the mandible (n = 18). Randomly, three implants were placed at crestal level (control group), and three implants were placed 2 mm subcrestally (test group) in relation to the crestal bone in each animal. The dogs were sacrificed after 8 weeks from the first surgical procedure, and biopsies were obtained. Samples were processed for ground sectioning. Histometric analysis was carried out to compare buccal and lingual bone resorption, soft tissue behavior and biological width formation in both groups.

Results

Crestal bone resorption was higher in the test group when considering the difference of 2 mms (IS‐B = 2.05 ± 0.36 mm, control; 1.75 (+2)  ± 0.38 mm, test). However, the dimensions of the biological width were similar for both groups (PM‐C = 3.34 ± 0.53 mm, control; 3.13 ± 0.55 mm, test).

Conclusions

The alterations that occurred in the peri‐implant soft tissues may be related to the hard tissue remodeling, showing similar quantitative findings in the biological width formation in both groups. Even though the subcrestal placement might reduce the distance from the implant shoulder to the first bone‐to‐implant contact and reestablish the biological width dimension in a most coronal position, it might not have any effect on minimizing the marginal bone loss.
Randomised clinical trial: study of escalating doses of NRL001 given in rectal suppositories of different weights
Authors: Bell D. , Pediconi C. , Jacobs A.
Published: February 2014

Aims

The application of α‐adrenoceptor agonists can improve faecal incontinence symptoms. The aim of this study was to investigate the pharmacokinetic and systemic effects of NRL001 administered as different strengths in 1 or 2 g suppositories.

Methods

This randomised, double‐blind, placebo controlled study included 48 healthy subjects. Group 1 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 5, 7.5 or 10 mg NRL001, or matching placebo. Group 2 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 10, 12.5 or 15 mg NRL001, or matching placebo. Doses were given in an escalating manner with placebo at a random position within the sequence.

Results

Tmax was at ~4.5 h post‐dose for all NRL001 doses. Median AUC0–tz, AUC0–∞ and Cmax increased with increasing dose for both suppository sizes. The estimate of ratios of geometric means comparing 2 g with 1 g suppository, and regression analysis for dose proportionality, was close to 1 for the variables AUC0–tz, AUC0–∞ and Cmax (P > 0.05). For both suppository sizes, 20‐min mean pulse rate was significantly decreased compared with placebo with all doses (P < 0.05). Blood pressure decreased overall. There were 144 adverse events (AEs) and no serious AEs reported during the study. All AEs were mild in severity.

Conclusions

The regression analysis concluded that the doses were dose proportional.
A randomised, controlled, crossover study to investigate the pharmacodynamics, pharmacokinetics and safety of 1R,2S‐methoxamine hydrochloride (NRL001) in healthy elderly subjects
Authors: Bell D. , Duffin A. , Gruss H. J. , Pediconi C. , Jacobs A.
Published: February 2014

Aims

This study aimed to assess the effects of a single dose of 10 mg NRL001 (the 1R,2S stereoisomer of methoxamine hydrochloride) in a 2 g suppository on pharmacodynamic and pharmacokinetic (PK) variables, and safety, in a healthy elderly population.

Methods

This was a Phase I, single‐centre, randomised, double‐blind, placebo‐controlled crossover study during which subjects received a single 2 g suppository of 10 mg NRL001 and a matching placebo in two separate treatment periods. The main outcome measures were Holter‐, vital signs‐ and electrocardiogram‐derived cardiovascular variables; plasma PK analysis; and safety assessments.

Results

Twenty‐six subjects were dosed with study medication. Statistically significant reductions in Holter‐derived heart rate (HR), vital signs‐derived HR and diastolic blood pressure (BP) were observed comparing NRL001 with placebo treatment, and also with increasing NRL001 plasma concentration. No statistically significant relationships were observed between NRL001 concentration and systolic BP, mean arterial pressure or QTC interval (both Bazett's and Fridericia's correction). Thirty‐nine adverse events were reported in 20 (76.9%) subjects, mostly after dosing with NRL001.

Conclusion

Administration of NRL001 suppositories led to decreases in HR when compared with placebo data. NRL001 was well tolerated with a good safety profile during the study. Healthy elderly subjects did not show significantly different biological responses to NRL001 suppositories compared with younger healthy volunteers in previous studies.
A double‐blind, placebo‐controlled, randomised, parallel‐group, dose‐escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days
Authors: Bell D. , Duffin A. , Jacobs A. , Pediconi C. , Gruss H. J.
Published: February 2014

Aims

The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1‐adrenoceptor agonist being developed for the local treatment of non‐structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg).

Methods

Healthy volunteers aged 18–45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs.

Results

Forty‐eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection.

Conclusions

Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α‐adrenergic effect.
Meta‐analysis for cardiovascular effects of NRL001 after rectal application in healthy volunteers
Authors: Gruss H. J. , Pediconi C. , Jacobs A.
Published: February 2014

Aims

NRL001 is a highly specific α1–adrenoceptor agonist currently under evaluation for the treatment of faecal incontinence caused by a weak internal anal sphincter. The aim of this meta‐analysis was to quantify the effect of NRL001 on cardiovascular parameters including heart rate, blood pressure and QT interval.

Methods

Data from the four Phase I healthy volunteer studies SUM (NCT00857467), SURD (NCT01099670), SUSD (NCT00850590) and SAGE (NCT01099683) were pooled and analyses were performed on individual subject data. Mixed effects regression analysis was used to determine the effect of NRL001 on heart rate, blood pressure and QT intervals. A multivariate statistical model was used to determine the effect of covariates on heart rate.

Results

Subjects given NRL001 experienced a dose related decrease in heart rate of up to 9.48 bpm compared with subjects in the placebo arms. No statistically significant evidence for a threshold effect was found. There was no clear evidence of dose effect of NRL001 on blood pressure. QT interval increased in all NRL001 subject as expected; QTCF also showed a statistically significant increase. However, QTCB was shortened with no significant treatment effect.

Conclusions

NRL001 was found to have a dose‐dependent effect on heart rate; however clinically–relevant bradycardia was not reported, indicating the decrease in heart rate was not of clinical significance. Furthermore, no clinically‐significant drug effect on blood pressure or mean arterial pressure was observed. QT intervals were affected by changes in heart rate. However, trends were dependant on the correction factor used. No consistent QT effect was observed, but a thorough QTC study will be required to confirm the effects of rectally applied NRL001.
Outcomes and treatments of patients with immunoglobulin light chain amyloidosis who progress or relapse postautologous stem cell transplant
Authors: Warsame Rahma , Bang Soo Mee , Kumar Shaji K. , Gertz Morie A. , Lacy Martha Q. , Buadi Francis , Dingli David , Hayman Suzanne R. , Kapoor Prashant , Kyle Robert A. , Leung Nelson , Lust John A. , Russell Stephen J. , Witzig Thomas E. , Zeldenrust Steven R. , Rajkumar S. Vincent , Dispenzieri Angela
Published: February 2014

Immunoglobulin light chain (AL) Amyloidosis is a condition whereby misfolded proteins generated by plasma cells deposit in tissues causing organ dysfunction. Chemotherapy and autologous stem cell transplant when eligible are standard treatment options. Several studies report long‐term outcomes of patients post‐transplant. However, there is a paucity of literature describing outcomes of relapsed patients post‐transplant. We performed a retrospective study to assess outcomes and therapies employed upon relapse after transplant. Between 1996 and 2009, 410 patients received transplant at the Mayo Clinic as first‐line therapy. Of those patients, 42 (10%) died within 3 months of transplant, 64 (16%) died without documented relapse, 158 (38%) were alive without documented progression, and 146 (36%) had documented progression. Those 146 patients are the subject of our study, and their median time to hematologic relapse/progression was 23.6 months (95%CI 18.3, 26.3 months). Their median overall survival and 5‐yrs overall survival from post‐transplant relapse/progression was 51.7 months (95%CI 34.1–62.3) and 39%, respectively. The most common first regimen for treatment after relapse was lenalidomide or thalidomide. In conclusion, our study indicates that patients with AL amyloidosis fare well post‐transplant relapse/progression. Additionally, it provides a yardstick to design clinical trials to determine best treatment options.
Emergency management of febrile status epilepticus: Results of the FEBSTAT study
Authors: Seinfeld Syndi , Shinnar Shlomo , Sun Shumei , Hesdorffer Dale C. , Deng Xiaoyan , Shinnar Ruth C. , O'Hara Kathryn , Nordli Douglas R. , Frank L. Matthew , Gallentine William , Moshé Solomon L. , Pellock John M. ,   FEBSTAT study team
Published: February 2014

Objective

Treatment of seizures varies by region, with no standard emergency treatment protocol. Febrile status epilepticus (FSE) is often a child's first seizure; therefore, families are rarely educated about emergency treatment.

Methods

From 2002 to 2010, 199 subjects, age 1 month to 6 years, were recruited as part of a prospective, multicenter study of consequences of FSE, which was defined as a febrile seizure or series of seizures lasting >30 min. The patients' charts were reviewed. No standardized treatment protocol was implemented for this observational study.

Results

One hundred seventy‐nine children received at least one antiepileptic drug (AED) to terminate FSE, and more than one AED was required in 140 patients (70%). Median time from the seizure onset to first AED by emergency medical services (EMS) or emergency department (ED) was 30 min. Mean seizure duration was 81 min for subjects given medication prior to ED and 95 min for those who did not (p = 0.1). Median time from the first dose of AED to end of seizure was 38 min. Initial dose of lorazepam or diazepam was suboptimal in 32 (19%) of 166 patients. Ninety‐five subjects (48%) received respiratory support by EMS or ED. Median seizure duration for the respiratory support group was 83 min; for the nonrespiratory support group the duration was 58 min (p‐value < 0.001). Reducing the time from seizure onset to AED initiation was significantly related to shorter seizure duration.

Significance

FSE rarely stops spontaneously, is fairly resistant to medications, and even with treatment persists for a significant period of time. The total seizure duration is composed of two separate factors, the time from seizure onset to AED initiation and the time from first AED to seizure termination. Earlier onset of treatment results in shorter total seizure duration. A standard prehospital treatment protocol should be used nationwide and education of EMS responders is necessary.