bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of a heated humidifier during continuous positive airway pressure delivered by a helmet
Authors: Chiumello Davide , Chierichetti Monica , Tallarini Federica , Cozzi Paola , Cressoni Massimo , Polli Federico , Colombo Riccardo , Castelli Antonio , Gattinoni Luciano
Published: April 2008

Introduction

The helmet may be an effective interface for the delivery of noninvasive positive pressure ventilation. The high internal gas volume of the helmet can act as a 'mixing chamber', in which the humidity of the patient's expired alveolar gases increases the humidity of the dry medical gases, thus avoiding the need for active humidification. We evaluated the temperature and humidity of respiratory gases inside the helmet, with and without a heated humidifier, during continuous positive airway pressure (CPAP) delivered with a helmet.

Methods

Nine patients with acute respiratory failure (arterial oxygen tension/fractional inspired oxygen ratio 209 ± 52 mmHg) and 10 healthy individuals were subjected to CPAP. The CPAP was delivered either through a mechanical ventilator or by continuous low (40 l/min) or high flow (80 l/min). Humidity was measured inside the helmet using a capacitive hygrometer. The level of patient comfort was evaluated using a continuous scale.

Results

In patients with acute respiratory failure, the heated humidifier significantly increased the absolute humidity from 18.4 ± 5.5 mgH2O/l to 34.1 ± 2.8 mgH2O/l during ventilator CPAP, from 11.4 ± 4.8 mgH2O/l to 33.9 ± 1.9 mgH2O/l during continuous low-flow CPAP, and from 6.4 ± 1.8 mgH2O/l to 24.2 ± 5.4 mgH2O/l during continuous high-flow CPAP. Without the heated humidifier, the absolute humidity was significantly higher with ventilator CPAP than with continuous low-flow and high-flow CPAP. The level of comfort was similar for all the three modes of ventilation and with or without the heated humidifier. The findings in healthy individuals were similar to those in the patients with acute respiratory failure.

Conclusion

The fresh gas flowing through the helmet with continuous flow CPAP systems limited the possibility to increase the humidity. We suggest that a heated humidifier should be employed with continuous flow CPAP systems.
Widespread duplications in the genomes of laboratory stocks of Dictyostelium discoideum
Authors: Bloomfield Gareth , Tanaka Yoshimasa , Skelton Jason , Ivens Alasdair , Kay Robert R
Published: April 2008

Background

Duplications of stretches of the genome are an important source of individual genetic variation, but their unrecognized presence in laboratory organisms would be a confounding variable for genetic analysis.

Results

We report here that duplications of 15 kb or more are common in the genome of the social amoeba Dictyostelium discoideum. Most stocks of the axenic 'workhorse' strains Ax2 and Ax3/4 obtained from different laboratories can be expected to carry different duplications. The auxotrophic strains DH1 and JH10 also bear previously unreported duplications. Strain Ax3/4 is known to carry a large duplication on chromosome 2 and this structure shows evidence of continuing instability; we find a further variable duplication on chromosome 5. These duplications are lacking in Ax2, which has instead a small duplication on chromosome 1. Stocks of the type isolate NC4 are similarly variable, though we have identified some approximating the assumed ancestral genotype. More recent wild-type isolates are almost without large duplications, but we can identify small deletions or regions of high divergence, possibly reflecting responses to local selective pressures. Duplications are scattered through most of the genome, and can be stable enough to reconstruct genealogies spanning decades of the history of the NC4 lineage. The expression level of many duplicated genes is increased with dosage, but for others it appears that some form of dosage compensation occurs.

Conclusion

The genetic variation described here must underlie some of the phenotypic variation observed between strains from different laboratories. We suggest courses of action to alleviate the problem.
Essential roles of the acetylcholine receptor γ-subunit in neuromuscular synaptic patterning
Authors: Liu Yun , Padgett Daniel , Takahashi Masazumi , Li Hongqiao , Sayeed Ayaz , Teichert Russell W. , Olivera Baldomero M. , McArdle Joseph J. , Green William N. , Lin Weichun
Published: April 2008

Formation of the vertebrate neuromuscular junction (NMJ) takes place in a stereotypic pattern in which nerves terminate at select sarcolemmal sites often localized to the central region of the muscle fibers. Several lines of evidence indicate that the muscle fibers may initiate postsynaptic differentiation independent of the ingrowing nerves. For example, nascent acetylcholine receptors (AChRs) are pre-patterned at select regions of the muscle during the initial stage of neuromuscular synaptogenesis. It is not clear how these pre-patterned AChR clusters are assembled, and to what extent they contribute to pre- and post-synaptic differentiation during development. Here, we show that genetic deletion of the AChR γ-subunit gene in mice leads to an absence of pre-patterned AChR clusters during initial stages of neuromuscular synaptogenesis. The absence of pre-patterned AChR clusters was associated with excessive nerve branching, increased motoneuron survival, as well as aberrant distribution of acetylcholinesterase (AChE) and rapsyn. However, clustering of muscle specific kinase (MuSK) proceeded normally in theγ-null muscles. AChR clusters emerged at later stages owing to the expression of the AChR epsilon-subunit, but these delayed AChR clusters were broadly distributed and appeared at lower level compared with the wild-type muscles. Interestingly, despite the abnormal pattern, synaptic vesicle proteins were progressively accumulated at individual nerve terminals, and neuromuscular synapses were ultimately established in γ-null muscles. These results demonstrate that the γ-subunit is required for the formation of pre-patterned AChR clusters, which in turn play an essential role in determining the subsequent pattern of neuromuscular synaptogenesis.
Adaptive active vibration suppression of flexible beam structures
Authors: Xia Y , Ghasempoor A
Published: April 2008

Vibration control strategies strive to reduce the effect of harmful vibrations on machinery and people. In general, these strategies are classified as passive or active. Although passive vibration control techniques are generally less complex, there is a limit to their effectiveness. Active vibration control strategies, on the other hand, can be very effective but require more complex algorithms and are especially susceptible to time delays. The current paper introduces a novel vibration suppression system using non-linear optimization. The proposed methodology eliminates the need for a feedback loop and the sensitivity to time delays. The system has been evaluated experimentally and the results show the validity of the proposed methodology.
Microactuator based on electroplated permanent magnets and flexible polydimethyl siloxane diaphragm
Authors: Su Y , Wang H , Chen W
Published: April 2008

The design, fabrication, and testing of a novel bidirectional magnetic microactuator were presented in the paper. The microactuator is composed of an integrated planar coil and a flexible polydimethyl siloxane (PDMS) diaphragm with embedded CoNiMnP-based permanent magnet arrays. There is a 7 × 7 array of magnets in a unit. The PDMS diaphragm is 2 mm × mm × 40 μm and the magnet post is 50 × 50 × 20 μm. Computer simulation was applied to verify the geometrical parameters. Electroplating under external magnetic field is carried out to improve the magnetic properties of the electroplated magnet, including coercivity, remanence and magnetic energy, and so on. The measured maximum coercivity, remanence and maximum magnetic energy were 2623 Oe (208.73 kA/m), 0.2 T (2000 G), and 10.15 kJ/m3 with the magnetic post, respectively. Moreover, and the deflection of the PDMS membrane is proportional to the exciting current. In a case of 0.35 A current, the maximum deflection of the membrane is 45 μm. Adjusting the electroplating mould results in the variation of the electroplated structure, thus the calibration of the microactuator. Due to the biomedical compatibility and simplicity of the fabrication, the flexible membrane-based microactuator is potential to be used as micropump and optical switch, the microelectromechanical system applications.
Power and efficiency optimization for combined Brayton and two parallel inverse Brayton cycles. Part 2: Performance optimization
Authors: Zhang W , Chen L , Sun F
Published: April 2008

The power and efficiency of the open combined Brayton and two parallel inverse Brayton cycles are analysed and optimized based on the model established using finite-time thermodynamics in Part 1 of the current paper by adjusting the compressor inlet pressure of the two parallel inverse Brayton cycles, the mass flowrate and the distribution of pressure losses along the flow path. It is shown that the power output has a maximum with respect to the compressor inlet pressures of the two parallel inverse Brayton cycles, the air mass flowrate or any of the overall pressure drops, and the maximized power output has an additional maximum with respect to the compressor pressure ratio of the top cycle. The power output and the thermal conversion efficiency have the maximum values when the mass flowrates of the first and the second inverse Brayton cycles are the same. When the optimization is performed with the constraints of a fixed fuel flowrate and the power plant size, the power output and thermal conversion efficiency can be maximized again by properly allocating the fixed overall flow area among the compressor inlet of the top cycle and the turbine outlets of the two parallel inverse Brayton cycles. The numerical examples show the effects of design parameters on the power output and heat conversion efficiency.
Model reduction technique for mechanical behaviour modelling: Efficiency criteria and validity domain assessment
Authors: Ordaz-Hernandez K , Fischer X , Bennis F
Published: April 2008

The current paper presents the study of a neural network-based technique used to create fast, reduced, non-linear behavioural models. The studied approach is the use of artificial neural networks (ANNs) as a model reduction technique to create more efficient models, mostly in terms of computational speed. The test case is the deformation of a cantilever beam under large deflections (geometrical non-linearity). A reduced model is created by means of a multi-layer feed-forward neural network, a type of ANN reported as ‘universal approximator’ in the literature. Then it is compared with two finite-element models: linear (inaccurate for large deflections but fast) and non-linear (accurate but slow). Under large displacements, the reduced model approximates well the non-linear model while having similar speed to the linear model. Unfortunately, the resulting model presents a shortening of its validity domain, as being incapable of approximating the deformed configuration of the cantilever beam under small displacements. In other words, the ANN-based model provides a very good compromise between accuracy and speed within its validity domain, despite the low fidelity presented: accurate for large displacements but inaccurate for small displacements.
Non-linear thermo-mechanical cylindrical bending of functionally graded plates
Authors: Fallah F , Nosier A
Published: April 2008

Based on the first-order non-linear von Karman theory, cylindrical bending of functionally graded (FG) plates subjected to mechanical, thermal, and combined thermo-mechanical loadings are investigated. Analytical solutions are obtained for an FG plate with various clamped and simply-supported boundary conditions. The closed form solutions obtained are very simple to be used in design purposes. The material properties are assumed to vary continuously through the thickness of the plate according to a power-law distribution of the volume fraction of the constituents. The effects of non-linearity, material property, and boundary conditions on various response quantities are studied and discussed. It is found that linear analysis is inadequate for analysis of simply-supported FG plates even in the small deflection range especially when thermal load is present. Also it is shown that bending—extension coupling can not be seen in response quantities of clamped FG plates. Also an exact solution is developed for the one-dimensional heat conduction equation with variable heat conductivity coefficient.
Microscopic wire guide-based orotracheal mouse intubation: description, evaluation and comparison with transillumination
Authors: Hamacher J , Arras M , Bootz F , Weiss M , Schramm R , Moehrlen U
Published: April 2008

Summary

Airway access is needed for a number of experimental animal models, and the majority of animal research is based on mouse models. Anatomical conditions in mice are small, and the narrow glottic opening allows intubation only with a subtle technique. We therefore developed a microscopic endotracheal intubation method with a wire guide technique in mice anaesthetized with halothane in oxygen. The mouse is hung perpendicularly with its incisors on a thread fixed on a vertical plate. The tongue is placed with a pair of forceps between the left hand's thumb and forefinger and slightly pulled, while the neck and thorax are positioned using the third and fourth fingers. By doing so, the neck can be slightly stretched, which allows optimal visualization of the larynx and the vocal cords. To ensure a safe intubation, a fine wire guide is placed under vision between the vocal cords and advanced about 5 mm into the trachea. An intravenous 22G × 1 in. plastic or Teflon catheter is guided over this wire. In a series of 41 mice, between 21 and 38 g, the success rate for the first intubation attempt was >95%. Certainty of the judgement procedure was 100% and success rate was higher using the described method when compared with a transillumination method in a further series. The technique is safe, less invasive than tracheostomy and suitable for controlled ventilation and pulmonary substance application.
Electroencephalography in the diagnosis of hydrocephalus in golden hamsters (Mesocricetus auratus)
Authors: Bali M S , Gebhardt-Henrich S , Keller P , Steiger A , Gattermann R , Bergamasco L , Kronen P , Doherr M G , Botteron C , Tomek A , Jaggy A
Published: April 2008

Summary

The golden hamster ( Mesocricetus auratus) is a popular laboratory animal and is used in a multitude of behavioural studies. However, it has been shown that it suffers from different forms of hereditary hydrocephalus, which may result in behavioural changes. This prospective study was designed to look into the usefulness of electroencephalography (EEG) measurements in the diagnosis of hydrocephalus in hamsters. The EEGs of the hydrocephalic hamsters were evaluated double-blind and showed a high-voltage slow wave activity, with a fast activity superimposed onto it. This pattern has already been well described in other hydrocephalic species and differed significantly from the EEGs that were obtained from the normal hamsters. It was concluded from our study that a background activity with an amplitude over 50 µV in combination with a frequency of <5 Hz was highly indicative of hydrocephalus in young hamsters. We believe that the EEG could be a very useful diagnostic tool in the screening for hydrocephalus in hamsters.
Effects of buprenorphine on body temperature, locomotor activity and cardiovascular function when assessed by telemetric monitoring in rats
Authors: Ilbäck N-G , Siller M , Stålhandske T
Published: April 2008

Summary

Buprenorphine is a potent analgesic commonly used clinically in humans and rodents experiencing severe pain. However, effects of therapeutic doses on locomotor activity and the cardiovascular system have not been studied in conscious animals. The effects of buprenorphine were therefore evaluated in this study using telemetric monitoring in conscious animals. Telemetry transmitters were implanted in the peritoneal cavity of Wistar rats with a pressure catheter in the aorta and electrodes for electrocardiogram (ECG) recording subcutaneously. After a single subcutaneous administration of saline, each rat was administered single subcutaneous doses of 0.006, 0.03 or 0.15 mg/kg body weight (bw) of buprenorphine. During a 10 h period after administration, buprenorphine induced a varying dose-dependent increase in body temperature, heart rate, d P/d t and systolic–diastolic blood pressure, as well as a corresponding decrease in QT time. At high dose, however, QT time was still decreased 24 h post-administration, but no arrhythmias or visual changes were observed in the ECG complex. Body temperature and heart rate increased at the high dose of buprenorphine, even at 20–24 h after administration. Moreover, the high dose of buprenorphine induced a biphasic response in diastolic blood pressure, with an early and pronounced increase that, at 14 h after administration, reversed to a decrease, failing to normalize within 24 h post-dosage. The results indicate that buprenorphine induces long-lasting effects (such as body temperature and cardiovascular effects) in the rat after a single subcutaneous dose at 0.15 mg/kg bw.
Comparative effects of halothane, isoflurane, sevoflurane and desflurane on the electroencephalogram of the rat
Authors: Murrell J C , Waters D , Johnson C B
Published: April 2008

Summary

Inhalant anaesthetic agents are commonly used in studies investigating the electroencephalographic (EEG) effects of noxious stimuli in animals. Halothane causes less EEG depression than isoflurane, however, the EEG effects of halothane, isoflurane, sevoflurane and desflurane have not been compared in the same model. This study aimed to compare the EEG effects of these inhalational agents in the rat.

Forty male Sprague-Dawley rats were assigned to four groups and anaesthetized with halothane, isoflurane, sevoflurane or desflurane. EEG was recorded from the left and right somatosensory cortices for 5 min at three different multiples of minimal alveolar concentration (MAC) (1.25, 1.5 and 1.75). Median, 95% spectral edge frequency and total power were derived and a single mean value for each was calculated for the first 60 s of each recording period. When the raw EEG contained burst suppression (BS), the BS ratio (BSR) over 60 s was calculated. No BS was found in EEG recorded from the halothane group at any concentration. BS was present at all concentrations with the other anaesthetic agents. BS was almost complete at all concentrations of isoflurane, whereas BSR increased significantly with increasing concentrations of sevoflurane and desflurane. No significant differences were found between the BSR due to the 1.75 MAC multiple of isoflurane, sevoflurane or desflurane. Halothane causes significantly less depression of cortical activity than the newer inhalant agents at equivalent multiples of MAC. These data support the hypothesis that halothane has a fundamentally different mechanism of action than the other inhalant agents.
Compensating Nondedicated Cross-Functional Teams
Authors: Wang Sijun , He Yuanjie
Published: April 2008

In today's ever-changing, competitive business environment, nondedicated cross-functional teams have become an important organizational work unit. This paper studies how the firm should optimally compensate such teams. Most previous studies on team compensation deal with dedicated work groups, where team members essentially allocate all their time and effort to team work. Little research has addressed issues related to compensating nondedicated teams, where team members perform tasks assigned by their home departments while also completing team work. In this paper, we provide analytical models to describe the unique decision-making processes engaged both by the firm and by such nondedicated team members. Our game-theoretic approach incorporates interdependency among team members into cross-functional team yield functions and takes into account the social benefits generated from team interactions for both firms and individual employees. The models also consider the technical and social skill differences among team members. Our results not only generate managerial insights on how firms should compensate nondedicated team members, but also build the foundation for future empirical studies.
Childhood rituals and executive functions
Authors: Tregay Jenifer , Gilmour Jane , Charman Tony
Published: April 2008

Repetitive and ritualistic behaviours (RRBs) are a feature of both typical and atypical development. While the cognitive correlates of these behaviours have been investigated in some neurodevelopmental conditions these links remain largely unexplored in typical development. The current study examined the relationship between RRBs and executive functions (EF) in a sample of typically developing children aged between 37 and 107 months. Results showed that cognitive flexibility, and not response inhibition or generativity, was most strongly associated with the frequency of RRBs in this sample. In younger children (<67.5 months) cognitive flexibility was significantly associated with ‘Repetitive Behaviours’ but in older children (>67.5 months) cognitive flexibility was associated with both ‘Just Right’ and ‘Repetitive Behaviour’, suggesting that the association between EF and RRBs may become stronger with age in typically developing children.
Direct mixed and open questions in child interviewing: An analog study
Authors: Horowitz Steven W.
Published: April 2008

Purpose. This study evaluated the relative value of direct questions, open‐ended questions, and mixed questions (including cued invitations) in eliciting accurate statements from young children about a known episode.

Methods. Children, 25 aged 5–7 years, and 25 aged 10–12 years, were interviewed concerning a standardized experience the previous week. Direct, mixed, and open‐ended question sequences were counterbalanced between participants. Transcribed videos were assessed for quantity and quality of statements.

Results. Mixed questions tended to fall in the middle, between direct and open questions on length of statement, and number of errors. For the younger children, direct questions, but not mixed questions, increased the number of errors of commission in subsequent open question sequences. Cued invitations, where the direct portion of the mixed question pair reiterated information previously elicited from the child, produced fewer errors of omission than mixed questions without adding errors of commission.

Conclusions. Mixed questions, especially cued invitations, were found to be a useful alternative for obtaining specific content when open questions alone were not sufficient. Support for conducting the interview in an ‘inverted pyramid’ or ‘funnel’ fashion was found in an analog study where ground truth was firmly established.
Delusions and hallucinations in students compared to the general population
Authors: Lincoln Tania M. , Keller Eva.
Published: April 2008

The Peters Delusions Inventory and the Launay–Slade Hallucination Scale were used to assess psychotic experiences in the population (N=359) and in students (N=78). Students revealed more delusional beliefs and more distress and preoccupation associated with beliefs than persons from the general population. The differences disappeared when samples were matched for age.
Applying principles of intercultural communication to personality disorder therapy
Authors: Leising Daniel.
Published: April 2008

Psychotherapy with patients who were diagnosed with a personality disorder bears a strong resemblance to intercultural communication. I suggest conceptualizing the situation of a patient with a personality disorder as being similar to that of an overseas traveller. Like the traveller, the patient faces the task of getting along in a social environment that does not share many of his or her ingrained values regarding ‘appropriate’ interpersonal behaviour. In order to reduce the potential for misunderstandings and interpersonal problems, the patient would benefit from (a) learning about the culturally accepted rules of interacting and (b) partly adopting those rules. Borrowing from training manuals for intercultural communication, I suggest a number of therapeutic principles that specifically address the discrepancies between the patient's habits and internalized values, and the cultural conventions that govern the social environment in which the patient lives.
Proving Negligence
Authors: Robertson Bernard
Published: April 2008

This article comments on the chapter ‘Proof and uncertainty’ in Allan Beever's Rediscovering the law of negligence, from the stand***point of an evidence scholar interested in ‘The New Evidence Scholarship’. The article discusses the nature of uncertainty and probability and their application in contested negligence cases. While the author agrees with Beever's main thrust, this article provides a gloss on Beever's writing, ironing out some ambiguities, expanding some points and correcting some errors.
Pixel Cowboys and Silicon Gold Mines: Videogames of the American West
Authors: Wills John
Published: April 2008

This article explores representations of the American West in computer and videogames from the late 1970s through 2006. The article reveals how several titles, including the early Boot Hill (1977), invoked classic nineteenth-century western motifs, employing the six-shooter, wagon train, and iron horse to sell late twentieth-century entertainment technology to a global audience. Such games allowed players, typically adolescent males, to recreate a version of history and to participate actively in the more violent aspects of the “Wild West.” The arcade Western emerged as a subgenre within computer entertainment, offering a distinctive, interactive amalgam of popular frontier-based fictions, including the nineteenth-century dime novel, Buffalo Bill Cody’s Wild West show, and the modern Hollywood western. Computer technology thus served established myths surrounding the “Wild West,” even as New Western History was challenging their authenticity.
Sialochemical and oxidative analyses in radioactive I131-treated patients with thyroid carcinoma
Authors: Ish-Shalom Sophia , Durleshter Lena , Segal Elena , Nagler Rafael M
Published: April 2008

Background

I131 in relatively high doses has been shown in the past to cause damaging salivary effects and oral discomfort in patients. Although lower dosage is now widely accepted, I131 may still be the source of salivary damage over the long-term and subsequent harmful effects on both the oral cavity and the gastrointestinal tract, into which the saliva is swallowed. This study examined the effects of radioactive I131 on salivary gland activity, saliva composition and oxidative profile, and related oral discomfort complaints following thyroidectomy due to carcinoma of thyroid gland.

Methods

Out of 40 consenting female post-thyroidectomy patients, 23 (mean age 50±4 years old) were treated with I131 while 17 (mean age 46±4) were not. Whole saliva from all subjects was analyzed for antioxidant and biochemical composition and flow rate.

Results

The salivary flow rates of both groups were similar but their composition differed considerably. Salivary superoxide dismutase enzyme (SOD), total protein, and albumin concentrations were significantly reduced in the treated patients by 40, 25, and 18% respectively (P<0.05), as were all other salivary antioxidants. Oral discomfort complaints were far more prevalent in the I131-treated patients.

Conclusions

I131-dependent damage to the salivary glands was evidenced by a broad spectrum of compositional alterations and oral complaints. Reduction in salivary antioxidant status, SOD enzyme, and the uric acid molecule leaves the oral cavity less protected against oxidative stress. This is the first report of radioactive I131 treatment being harmful to salivary glands due to compromised salivary compositional and oxidative profile and oral discomfort complaints.
Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism
Authors: Loves Sandra , Ruinemans-Koerts Janneke , de Boer Hans
Published: April 2008

Objective

Isolated hypogonadotropic hypogonadism (IHH) is frequently observed in severely obese men, probably as a result of increased estradiol (E2) production and E2-mediated negative feedback on pituitary LH secretion. Aromatase inhibitors can reverse this process. This study evaluates whether letrozole once a week can normalize serum testosterone in severely obese men and maintain its long term effect.

Design

Open, uncontrolled 6-month pilot study in 12 severely obese men (body mass index>35.0 kg/m2) with obesity-related IHH and free testosterone levels <225 pmol/l, treated with 2.5 mg letrozole once a week for 6 months.

Results

Six weeks of treatment reduced total E2 from 123±11 to 58±7 pmol/l (P<0.001, mean±s.e.m.), and increased serum LH from 4.4±0.6 to 11.1±1.5 U/l (P<0.001). Total testosterone rose from 5.9±0.5 to 19.6±1.4 nmol/l (P<0.001), and free testosterone from 163±13 to 604±50 pmol/l (P<0.001). Total testosterone rose to within the normal range in all subjects, whereas free testosterone rose to supraphysiological levels in 7 out of 12 men. The testosterone and E2 levels were stable throughout the week and during the 6-month treatment period.

Conclusion

Letrozole 2.5 mg once a week produced a sustained normalization of serum total testosterone in obese men with IHH. However, free testosterone frequently rose to supraphysiological levels. Therefore, a starting dose <2.5 mg once a week is recommended.
Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction
Authors: De Feyter H M , van den Broek N M A , Praet S F E , Nicolay K , van Loon L J C , Prompers J J
Published: April 2008

Objective

Several lines of evidence support a potential role of skeletal muscle mitochondrial dysfunction in the pathogenesis of insulin resistance and/or type 2 diabetes. However, it remains to be established whether mitochondrial dysfunction represents either cause or consequence of the disease. We examined in vivo skeletal muscle mitochondrial function in early and advanced stages of type 2 diabetes, with the aim to gain insight in the proposed role of mitochondrial dysfunction in the aetiology of insulin resistance and/or type 2 diabetes.

Methods

Ten long-standing, insulin-treated type 2 diabetes patients, 11 subjects with impaired fasting glucose, impaired glucose tolerance and/or recently diagnosed type 2 diabetes, and 12 healthy, normoglycaemic controls, matched for age and body composition and with low habitual physical activity levels were studied. In vivo mitochondrial function of the vastus lateralis muscle was evaluated from post-exercise phosphocreatine (PCr) recovery kinetics using 31P magnetic resonance spectroscopy (MRS). Intramyocellular lipid (IMCL) content was assessed in the same muscle using single-voxel 1H MRS.

Results

IMCL content tended to be higher in the type 2 diabetes patients when compared with normoglycaemic controls (P=0.06). The31P MRS parameters for mitochondrial function, i.e. PCr and ADP recovery time constants and maximum aerobic capacity, did not differ between groups.

Conclusions

The finding that in vivo skeletal muscle oxidative capacity does not differ between long-standing, insulin-treated type 2 diabetes patients, subjects with early stage type 2 diabetes and sedentary, normoglycaemic controls suggests that mitochondrial dysfunction does not necessarily represent either cause or consequence of insulin resistance and/or type 2 diabetes.
Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias
Authors: Beleza-Meireles Ana , Töhönen Virpi , Söderhäll Cilla , Schwentner Christian , Radmayr Christian , Kockum Ingrid , Nordenskjöld Agneta
Published: April 2008

Introduction

Hypospadias is a common inborn error of the genital development, whose complex etiology remains elusive. Defects of the androgen metabolism and activity have been found in a subset of boys with hypospadias. Moreover, the balance between androgens and estrogens seems to be important to the proper male genital development. Activating transcription factor 3 (ATF3), an estrogen responsive gene, has been reported to be expressed during sexual development and up-regulated in hypospadic genital skin. We investigated ATF3 as a candidate gene for hypospadias.

Material and methods

Genotyping of eight-tagged single nucleotide polymorphisms (SNP)s was performed in 330 boys with hypospadias and in 380 healthy controls. Screening for mutations in ATF3 was conducted in a subset of boys with hypospadias. ATF3 expression was evaluated in the foreskin of boys with hypospadias and in healthy controls and in the human fetal genitalia by immunohistochemistry.

Results

Three common SNPs, spanning a region of about 16 kb in intron 1 of ATF3, are associated with hypospadias. These SNPs are not linked and their effects are independent. The combination of the three risk SNPs yields the highest significance. Mutation screening identified the gene variant c536A>G in one patient and c817C>T in the 3′-UTR in two other patients. ATF3 expression was evidenced in the developing male urethra.

Conclusions

ATF3 gene variants influence the risk of hypospadias. Its hormonal responsiveness may underlie this risk effect. But also other ATF3-dependent biological aspects, such as cell survival and death, response to stress stimuli, or the control of epithelial–mesenchymal interactions, may be of importance.
Impact of musculoskeletal disease on quality of life in long-standing acromegaly
Authors: Miller Anne , Doll Helen , David Joel , Wass John
Published: April 2008

Objective

To provide rheumatological assessment of patients with long-standing acromegaly and investigate the impact of musculoskeletal disease on quality of life.

Design

Cross-sectional observational study.

Methods

Fifty-eight patients diagnosed with acromegaly at least 5 years previously were interviewed and examined by a rheumatologist. Each patient completed the short form-36 (SF-36), arthritis impact measurement scales 2 (AIMS2) and acromegaly quality of life questionnaires (AcroQol).

Results

Fifty-two out of 58 (90%) reported musculoskeletal pain, with 29 (50%) reporting neck pain. Hip osteoarthritis was present in 49 (84%) and knee osteoarthritis in 20 (34%). Half the patients (52%) reported sleep disturbance, but only 2 (3.5%) had fibromyalgia. Ten (17.2%) had previously undergone carpal tunnel decompression. Fifty-one (88%) patients had consulted their general practioner and 31 (54%) complementary therapists. SF-36, AIMS2 and AcroQol scores were lower in patients with musculoskeletal pain.

Conclusions

This study of musculoskeletal problems in patients with acromegaly reports systematic rheumatological examination, use of medical services and quality of life scores. Musculoskeletal problems should be routinely addressed in acromegaly by both endocrinologist and rheumatologist and a multidisciplinary approach taken to management.
Characterization of a novel complex BRAF mutation in a follicular variant papillary thyroid carcinoma.
Authors: Barzon Luisa , Masi Giulia , Boschin Isabella Merante , Lavezzo Enrico , Pacenti Monia , Casal Ide Eric , Toniato Antonio , Toppo Stefano , Palù Giorgio , Pelizzo Maria Rosa
Published: April 2008

Introduction

Activating mutations of the BRAF oncogene are frequently detected in papillary thyroid carcinoma (PTC) and have been associated with a worse prognosis. The amino acid substitution V600E accounts for 90% of all oncogenic BRAF mutations and is typically detected in classic PTCs, whereas other less frequent BRAF mutations seem to be associated with other PTC histotypes.

Case

Screening for activating BRAF mutations in a series of 83 PTCs identified the most common V600E mutation in 39 cases (histologically, 38 classic PTCs and 1 sclerosing variant PTC) and a complex in-frame mutation involving amino acids V600–S605 in a stage III multicentric follicular variant PTC, occurring in a 50-year-old female patient, who was affected by hypothyroidism in autoimmune thyroiditis and had a family history of PTC and autoimmune thyroiditis. Since the identified BRAF mutation was novel in the literature, bioinformatic modeling was performed to predict its impact on BRAF activity. Although the mutation resulted in loss of a phosphorylation site in the activation loop of BRAF, it was predicted to increase BRAF kinase activity by mimicking an activating phosphorylation.

Conclusions

This study, which reports a new BRAF mutation, highlights the usefulness of bioinformatic modeling in the prediction of functional effects of new mutations and indicates that mutation-specific screening tests might miss some rare BRAF mutations. These facts should be taken into consideration in the molecular diagnosis of thyroid cancer and in the design of therapeutic protocols based on inhibitors of the BRAF pathway.
Semidominant Mutations in Reduced Epidermal Fluorescence 4 Reduce Phenylpropanoid Content in Arabidopsis
Authors: Stout Jake , Romero-Severson Ethan , Ruegger Max O , Chapple Clint
Published: April 2008

Plants synthesize an array of natural products that play diverse roles in growth, development, and defense. The plant-specific phenylpropanoid metabolic pathway produces as some of its major products flavonoids, monolignols, and hydroxycinnamic- acid conjugates. The reduced epidermal fluorescence 4 (ref4) mutant is partially dwarfed and accumulates reduced quantities of all phenylpropanoid-pathway end products. Further, plants heterozygous for ref4 exhibit intermediate growth and phenylpropanoid-related phenotypes, suggesting that these mutations are semidominant. The REF4 locus (At2g48110) was cloned by a combined map- and sequencing-based approach and was found to encode a large integral membrane protein that is unique to plants. The mutations in all ref4 alleles cause substitutions in conserved amino acids that are located adjacent to predicted transmembrane regions. Expression of the ref4-3 allele in wild-type and null REF4 plants caused reductions in sinapoylmalate content, lignin content, and growth, demonstrating that the mutant alleles are truly semidominant. Further, a suppressor mutant was isolated that abolishes a WW protein–protein interaction domain that may be important for REF4 function.
Interactions Between Stressful Environment and Gene Deletions Alleviate the Expected Average Loss of Fitness in Yeast
Authors: Jasnos Lukasz , Tomala Katarzyna , Paczesniak Dorota , Korona Ryszard
Published: April 2008

The conjecture that the deleterious effects of mutations are amplified by stress or interaction with one another remains unsatisfactorily tested. It is now possible to reapproach this problem systematically by using genomic collections of mutants and applying stress-inducing conditions with a well-recognized impact on metabolism. We measured the maximum growth rate of single- and double-gene deletion strains of yeast in several stress-inducing treatments, including poor nutrients, elevated temperature, high salinity, and the addition of caffeine. The negative impact of deletions on the maximum growth rate was relatively smaller in stressful than in favorable conditions. In both benign and harsh environments, double-deletion strains grew on average slightly faster than expected from a multiplicative model of interaction between single growth effects, indicating positive epistasis for the rate of growth. This translates to even higher positive epistasis for fitness defined as the number of progeny. We conclude that the negative impact of metabolic disturbances, regardless of whether they are of environmental or genetic origin, is absolutely and relatively highest when growth is fastest. The effect of further damages tends to be weaker. This results in an average alleviating effect of interactions between stressful environment and gene deletions and among gene deletions.
The Protease Activity of Yeast Separase (Esp1) Is Required for Anaphase Spindle Elongation Independently of Its Role In Cleavage of Cohesin
Authors: Baskerville Chris , Segal Marisa , Reed Steven I
Published: April 2008

Separase is a caspase-family protease required for the metaphase–anaphase transition in eukaryotes. In budding yeast, the separase ortholog, Esp1, has been shown to cleave a subunit of cohesin, Mcd1 (Scc1), thereby releasing sister chromatids from cohesion and allowing anaphase. However, whether Esp1 has other substrates required for anaphase has been controversial. Whereas it has been reported that cleavage of Mcd1 is sufficient to trigger anaphase in the absence of Esp1 activation, another study using a temperature-sensitive esp1 mutant concluded that depletion of Mcd1 was not sufficient for anaphase in the absence of Esp1 function. Here we revisit the issue and demonstrate that neither depletion of Mcd1 nor ectopic cleavage of Mcd1 by Tev1 protease is sufficient to support anaphase in an esp1 temperature-sensitive mutant. Furthermore, we demonstrate that the catalytic activity of the Esp1 protease is required for this Mcd1-independent anaphase function. These data suggest that another protein, possibly a spindle-associated protein, is cleaved by Esp1 to allow anaphase. Such a function is consistent with the previous observation that Esp1 localizes to the mitotic spindle during anaphase.
Visual Mutations Reveal Opposing Effects of Illumination on Arousal in Drosophila
Authors: Cheng Yuzhong , Nash Howard A
Published: April 2008

The effect of illumination on alertness can be assessed by comparing the efficacy of an anesthetic under light vs. dark conditions. Results from such tests on wild-type flies and visual mutants demonstrate that, surprisingly, light has both positive and negative influences on arousal. These dual effects may explain aspects of the fly's daily activity and have potential clinical implications.
TheCaenorhabditis elegans rsd-2andrsd-6Genes Are Required for Chromosome Functions During Exposure to Unfavorable Environments
Authors: Han Wang , Sundaram Prema , Kenjale Himanshu , Grantham James , Timmons Lisa
Published: April 2008

In Caenorhabditis elegans, exogenous dsRNA can elicit systemic RNAi, a process that requires the function of many genes. Considering that the activities of many of these genes are also required for normal development, it is surprising that exposure to high concentrations of dsRNA does not elicit adverse consequences to animals. Here, we report inducible phenotypes in attenuated C. elegans strains reared in environments that include nonspecific dsRNA and elevated temperature. Under these conditions, chromosome integrity is compromised in RNAi-defective strains harboring mutations in rsd-2 or rsd-6. Specifically, rsd-2 mutants display defects in transposon silencing, while meiotic chromosome disjunction is affected in rsd-6 mutants. RSD-2 proteins localize to multiple cellular compartments, including the nucleolus and cytoplasmic compartments that, in part, are congruent with calreticulin and HAF-6. We considered that the RNAi defects in rsd-2 mutants might have relevance to membrane-associated functions; however, endomembrane compartmentalization and endocytosis/exocytosis markers in rsd-2 and rsd-6 mutants appear normal. The mutants also possess environmentally sensitive defects in cell-autonomous RNAi elicited from transgene-delivered dsRNAs. Thus, the ultimate functions of rsd-2 and rsd-6 in systemic RNAi are remarkably complex and environmentally responsive.
Functional Conservation of the Yeast and Arabidopsis RAD54-Like Genes
Authors: Klutstein Michael , Shaked Hezi , Sherman Amir , Avivi-Ragolsky Naomi , Shema Efrat , Zenvirth Drora , Levy Avraham A , Simchen Giora
Published: April 2008

The Saccharomyces cerevisiae RAD54 gene has critical roles in DNA double-strand break repair, homologous recombination, and gene targeting. Previous results show that the yeast gene enhances gene targeting when expressed in Arabidopsis thaliana. In this work we address the trans-species compatibility of Rad54 functions. We show that overexpression of yeast RAD54 in Arabidopsis enhances DNA damage resistance severalfold. Thus, the yeast gene is active in the Arabidopsis homologous-recombination repair system. Moreover, we have identified an A. thaliana ortholog of yeast RAD54, named AtRAD54. This gene, with close sequence similarity to RAD54, complements methylmethane sulfonate (MMS) sensitivity but not UV sensitivity or gene targeting defects of rad54Δ mutant yeast cells. Overexpression of AtRAD54 in Arabidopsis leads to enhanced resistance to DNA damage. This gene's assignment as a RAD54 ortholog is further supported by the interaction of AtRad54 with AtRad51 and the interactions between alien proteins (i.e., yeast Rad54 with AtRAD51 and yeast Rad51 with AtRad54) in a yeast two-hybrid experiment. These interactions hint at the molecular nature of this interkingdom complementation, although the stronger effect of the yeast Rad54 in plants than AtRad54 in yeast might be explained by an ability of the Rad54 protein to act alone, independently of its interaction with Rad51.
Heterogeneidade do diabetes melito tipo 1
Authors: Dib Sergio Atala
Published: April 2008

O diabetes melito tipo 1 (DM1) caracteriza-se pela deficiência de insulina por causa da destruição das células-beta pancreáticas. O DM1 atualmente é classificado em dois subtipos: um auto-imune (DM1A) e outro não auto-imune (DM1B). O DM1A poligênico (isolado ou associado a outras doenças auto-imunes) é a forma mais prevalente. O DM1A pode fazer parte de síndromes raras em virtude de alterações monogênicas [gene regulador da auto-imunidade (AIRE)] e mutações no gene FOX-p3. O DM1B corresponde de 4% a 7% do DM1 e pode incluir formas não clássicas, como o diabetes fulminante e o DATC. Jovens com DM1A e sinais de resistência à insulina associados têm sido denominados de diabetes duplo (DD), tipo 1 e tipo 2. Nessa revisão são discutidas as patofisiologias e as características clínicas das formas raras de DM1A, o DM1B, as formas atípicas de DM1 não auto-imune e as inter-relações entre a inflamação subclínica da obesidade e o processo auto-imune do DM1A no DD. Em resumo, apresentamos o conceito de heterogeneidade do DM1.
Abordagem do diabetes melito na primeira infância
Authors: Calliari Luis Eduardo P. , Monte Osmar
Published: April 2008

A ocorrência de diabetes melito tipo 1 em crianças abaixo de 5 anos é rara, mas vem apresentando um aumento em sua incidência em vários países do mundo. O diagnóstico é comumente postergado e a criança em geral encontra-se em estado avançado de descompensação. Um dos desafios do acompanhamento desses casos é estimular o total envolvimento da família, já que a criança é dependente de seus cuidados. A atenção com os pequenos pacientes deve ser intensa, já que dificilmente há queixas que possam sugerir a hipoglicemia. A aceitação alimentar e as atividades físicas são irregulares e imprevisíveis e a sensibilidade insulínica é maior. A terapêutica com insulina necessita ser individualizada, e a monitorização glicêmica domiciliar é fundamental para que o melhor controle seja obtido.