Creatine uptake in isolated soleus muscle: kinetics and dependence on sodium,but not on insulin

The increased use of creatine by athletes as a dietary supplement to improve their physical performance assumes that increased serum creatine levels will increase intracellular skeletal muscle creatine. Despite this common assumption, skeletal muscle creatine uptake awaits full characterization. Consequently, we have investigated ¹⁴C-labelled creatine uptake in isolated, incubated rat soleus (type I) muscle preparations at 37 °C. We found that the apparent K_m for creatine uptake was 73 μM and the V_max was 77 nmol h^–1 gww^–1. Creatine uptake was 82% inhibited by 2 m M β-guanidinopropionic acid, the structural analogue of creatine. In addition, a decrease in buffer Na⁺ concentration, from 145 to 25 m M , reduced the rate of ¹⁴C-labelled creatine uptake by 77%, indicating that uptake is largely Na⁺-dependent in soleus muscle. Insulin had no effect on the rate of creatine uptake in vitro. The total creatine content was 34% lower, but the rate of creatine uptake in the presence of 100 μM extracellular creatine was 45% higher, in soleus than in extensor digitorum longus (type II) muscle. However, at 1 m M extracellular creatine, the maximal rate of uptake was not significantly different for the two muscle types, implying that soleus muscle has a lower K_m for creatine uptake. We suggest that intracellular creatine levels may play a role in the regulation of skeletal muscle creatine uptake.     

Diabetes Patients' Experiences With the Implementation of Insulin Therapy and Their Perceptions of Computer-Assisted Self-Management Systems for Insulin Therapy

Background

Computer-assisted decision support is an emerging modality to assist patients with type 2 diabetes mellitus (T2DM) in insulin self-titration (ie, self-adjusting insulin dose according to daily blood glucose levels). Computer-assisted insulin self-titration systems mainly focus on helping patients overcome barriers related to the cognitive components of insulin titration. Yet other (eg, psychological or physical) barriers could still impede effective use of such systems.

Objective

Our primary aim was to identify experiences with and barriers to self-monitoring of blood glucose, insulin injection, and insulin titration among patients with T2DM. Our research team developed a computer-assisted insulin self-titration system, called PANDIT. The secondary aim of this study was to evaluate patients’ perceptions of computer-assisted insulin self-titration. We included patients who used PANDIT in a 4-week pilot study as well as patients who had never used such a system.

Methods

In-depth, semi-structured interviews were conducted individually with patients on insulin therapy who were randomly recruited from a university hospital and surrounding general practices in the Netherlands. The interviews were transcribed verbatim and analyzed qualitatively. To classify the textual remarks, we created a codebook during the analysis, in a bottom-up and iterative fashion. To support examination of the final coded data, we used three theories from the field of health psychology and the integrated model of user satisfaction and technology acceptance by Wixom and Todd.

Results

When starting insulin therapy, some patients feared a lifelong commitment to insulin therapy and disease progression. Also, many barriers arose when implementing insulin therapy (eg, some patients were embarrassed to inject insulin in public). Furthermore, patients had difficulties increasing the insulin dose because they fear hypoglycemia, they associate higher insulin doses with disease progression, and some were ignorant of treatment targets. Patients who never used a computer-assisted insulin self-titration system felt they had enough knowledge to know when their insulin should be adjusted, but still believed that the system advice would be useful to confirm their reasoning. Furthermore, the time and effort saved with automated insulin advice was considered an advantage. Patients who had used PANDIT found the system useful if their glycemic regulation improved. Nevertheless, for some patients, the absence of personal contact with their caregiver was a drawback. While guidelines state that adjustment of basal insulin dose based on fasting plasma glucose values is sufficient, both patients who had and those who had not used PANDIT felt that such a system should take more patient data into consideration, such as lifestyle and diet factors.

Conclusions

Patients encounter multiple obstacles when implementing insulin therapy. Computer-assisted insulin self-titration can increase patient awareness of treatment targets and increase their confidence in self-adjusting the insulin dose. Nevertheless, some barriers may still exist when using computer-assisted titration systems and these systems could also introduce new barriers.     

Genetic Analysis and Attribution of Microbial Forensics Evidence

Because of the availability of pathogenic microorganisms and the relatively low cost of preparing and disseminating bioweapons, there is a continuing threat of biocrime and bioterrorism. Thus, enhanced capabilities are needed that enable the full and robust forensic exploitation and interpretation of microbial evidence from acts of bioterrorism or biocrimes. To respond to the need, greater resources and efforts are being applied to the burgeoning field of microbial forensics. Microbial forensics focuses on the characterization, analysis and interpretation of evidence for attributional purposes from a bioterrorism act, biocrime, hoax or inadvertent agent release. To enhance attribution capabilities, a major component of microbial forensics is the analysis of nucleic acids to associate or eliminate putative samples. The degree that attribution can be addressed depends on the context of the case, the available knowledge of the genetics, phylogeny, and ecology of the target microorganism, and technologies applied. The types of genetic markers and features that can impact statistical inferences of microbial forensic evidence include: single nucleotide polymorphisms, repetitive sequences, insertions and deletions, mobile elements, pathogenicity islands, virulence and resistance genes, house keeping genes, structural genes, whole genome sequences, asexual and sexual reproduction, horizontal gene transfer, conjugation, transduction, lysogeny, gene conversion, recombination, gene duplication, rearrangements, and mutational hotspots. Nucleic acid based typing technologies include: PCR, real-time PCR, MLST, MLVA, whole genome sequencing, and microarrays.     

Serum concentrations of oestradiol-17beta, progesterone, relaxin and chorionic gonadotrophin during blastocyst implantation in natural pregnancy cycle and in embryo transfer cycle in the rhesus monkey

The present study was undertaken to assess the temporal association between the profiles of serum concentrations of oestradiol-17beta, progesterone, chorionic gonadotrophin (CG) and relaxin in pregnancies established naturally, and after embryo transfer, as well as in failed pregnancies in rhesus monkeys. In naturally mated cycles (group 1) a conception rate of 75% was obtained. In group 1, the mean day of CG detection in serum was 11.5 +/- 1.9 day post-ovulation, and for relaxin, 9.0 +/- 2.5 day post-ovulation. In group 2, embryo transfer to synchronous, non-mated surrogate recipients was performed; seven embryo transfer cycles yielded three pregnancies which were allowed to continue to term and normal infants were delivered. In embryo transfer cycles the mean day of CG detection was 14.8 +/- 1.8 day post- ovulation, and for relaxin, 11.4 +/- 2.6 day post-ovulation. A delay of about 3 days was observed in the appearance in circulation of CG (P < 0.05) and also of relaxin (P < 0.05) between natural mated and embryo transfer conception cycles. Significant differences (P < 0.05 for progesterone and P < 0.03 for oestradiol) were obtained for the areas under the curves for progesterone and oestradiol between days 12 and 16 in conception cycles compared with failed pregnancies. These data provide the first observation of the normal hormonal signals associated with maternal recognition of transferred embryos during the peri- implantation period, and suggest that the use of such an experimental primate embryo transfer model may help to elucidate components of maternal and embryonic signal-response mechanisms during embryo implantation.      

Predictive value of ventricular arrhythmias in resuscitated out-of-hospital cardiac arrest victims

Twenty-four hour ambulatory electrocardiograms recorded in 103 survivors of out-of-hospital cardiac arrest were analyzed to find those characteristics of the ventricular premature complex (VPC) which provide the best combination of sensitivity, specificity, and predictive accuracy for subsequent mortality. VPC characteristics were grouped as: (1) frequent (greater than or equal to 25 h-1), (2)bigeminal, (3) multiform, (4) early coupled, (5) pairing, (6) repetitive greater than or equal to 2, (7) repetitive greater than or equal to 3, (8) repetitive greater than or equal to 6, (9) the combination of frequent and repetitive, or (10) complex defined as any multiform, early, bigeminal or repetitive VPC. In an average follow-up period of 43 months, 42 deaths occurred, 17 of which were classified as sudden. Each characteristic was a significant predictor for all causes of subsequent death except early coupled VPCs and repetitive VPCs greater than 6. None of the characteristics reached significance as predictors for sudden death. The number of repetitive VPCs when stratified to none, greater than or equal to 2 and greater than or equal to 3 successive VPCs correlated with mortality in an incremental fashion. The combination of frequent VPCs and repetitive VPCs provided the best combination of sensitivity, specificity and predictive accuracy for death from all causes within five years.     

Contributions of subdiaphragmatic activity,attenuation, and diaphragmatic motion to inferior wall artifact in attenuation-corrected Tc-99m myocardial perfusion SPECT

BACKGROUND: Subdiaphragmatic activity and diaphragmatic motion both contribute to inferior wall artifacts in technetium 99m myocardial perfusion single photon emission computed tomography (SPECT). METHODS AND RESULTS: We used an anthropomorphic phantom with ventricular wall activity, liver/spleen inserts containing variable Tc-99m activity, and variable vertical (diaphragmatic) motion amplitude. SPECT and transmission scans were obtained on a GE Optima NX camera. Data were processed by use of filtered backprojection or attenuation correction (AC). Resulting myocardial activity maps were analyzed with standardized inferior-anterior and anterior-lateral wall ratios. At a subdiaphragmatic-myocardial activity ratio of 0.5:1, inferior wall attenuation predominates, producing a cold artifact. AC corrects inferior wall activity to the level of the anterior wall irrespective of diaphragmatic motion. At a subdiaphragmatic-myocardial activity ratio of 1:1, inferior wall counts vary widely depending on the proximity of subdiaphragmatic activity to the ventricle. With increasing diaphragmatic amplitude, the overlap of subdiaphragmatic activity and inferior wall worsens, leading to a complex mixture of cold and hot artifacts, not corrected by AC. CONCLUSIONS: Concentration and proximity of subdiaphragmatic Tc-99m activity relative to myocardium comprise a major factor in the nature and severity of inferior wall artifacts. If the subdiaphragmatic Tc-99m concentration is equivalent to that in the myocardium, complex, potentially uninterpretable hot and cold inferior wall artifacts are produced.     

Resting state alpha-band functional connectivity and recovery after stroke

After cerebral ischemia, disruption and subsequent reorganization of functional connections occur both locally and remote to the lesion. However, the unpredictable timing and extent of sensorimotor recovery reflects a gap in understanding of these underlying neural mechanisms. We aimed to identify the plasticity of alpha-band functional neural connections within the perilesional area and the predictive value of functional connectivity with respect to motor recovery of the upper extremity after stroke. Our results show improvements in upper extremity motor recovery in relation to distributed changes in MEG-based alpha band functional connectivity, both in the perilesional area and contralesional cortex. Motor recovery was found to be predicted by increased connectivity at baseline in the ipsilesional somatosensory area, supplementary motor area, and cerebellum, contrasted with reduced connectivity of contralesional motor regions, after controlling for age, stroke onset-time and lesion size. These findings support plasticity within a widely distributed neural network and define brain regions in which the extent of network participation predicts post-stroke recovery potential.     

Recently published papers: Acute kidney injury – diagnosis and treatment

When faced with the management of the patient on intensive care with acute kidney injury, the clinician has various choices to consider. The conventional therapy, where appropriate, is renal replacement therapy. This technique used to be relatively straightforward but now a relative feast of alternatives is available, not least in choice of buffer and anticoagulant. Two recent studies add to the growing body of literature concerning alternative anticoagulant regimes, and one in particular should lead to a change in practice for many of us. We also review some new studies on biomarkers in the diagnosis of acute kidney injury as well as add yet another nail in the coffin for loop diuretics in the therapy of acute kidney injury.     

Neuroimaging Characteristics of Patients with Focal Hand Dystonia

Narrative ReviewAdvances in structural and functional imaging have provided both scientists and clinicians with information about the neural mechanisms underlying focal hand dystonia (FHd), a motor disorder associated with aberrant posturing and patterns of muscle contraction specific to movements of the hand. Consistent with the hypothesis that FHd is the result of reorganization in cortical fields, studies in neuroimaging have confirmed alterations in the topography and response properties of somatosensory and motor areas of the brain. Noninvasive stimulation of these regions also demonstrates that FHd may be due to reductions in inhibition between competing sensory and motor representations. Compromises in neuroanatomical structure, such as white matter density and gray matter volume, have also been identified through neuroimaging methods. These advances in neuroimaging have provided clinicians with an expanded understanding of the changes in the brain that contribute to FHd. These findings should provide a foundation for the development of retraining paradigms focused on reversing overlapping sensory representations and interactions between brain regions in patients with FHd. Continued collaborations between health professionals who treat FHd and research scientists who examine the brain using neuroimaging tools are imperative for answering difficult questions about patients with specific movement disorders.     

Ixabepilone in combination with capecitabine and as monotherapy for treatment of advanced breast cancer refractory to previous chemotherapies

PURPOSE: To describe the considerations leading to marketing approval of ixabepilone in combination with capecitabine and as monotherapy for the treatment of advanced breast cancer that is refractory to other chemotherapies. EXPERIMENTAL DESIGN: Data from one randomized multicenter trial comparing combination therapy with ixabepilone and capecitabine to capecitabine alone were analyzed for support of the combination therapy indication. For monotherapy, a single-arm trial of ixabepilone was analyzed. Supporting data came from an additional single-arm combination therapy study and two single-arm monotherapy studies. RESULTS: In patients with metastatic or locally advanced breast cancer who had disease progression on or following an anthracycline and a taxane, ixabepilone plus capecitabine showed an improvement in progression-free survival compared with capecitabine alone {median progression-free survival, 5.7 [95% confidence interval (95% CI), 4.8-6.7] versus 4.1 (95% CI, 3.1-4.3) months, stratified log-rank P < 0.0001; hazard ratio, 0.69 (95% CI, 0.58-0.83)}. As monotherapy for patients who had disease progression on or following an anthracycline, a taxane, and capecitabine, ixabepilone as monotherapy showed a 12% objective response rate by independent blinded review and 18% by investigator assessment. The major toxicities from ixabepilone therapy were peripheral neuropathy and myelosuppression, particularly neutropenia. CONCLUSIONS: On October 16, 2007, the Food and Drug Administration approved ixabepilone for injection in combination with capecitabine or as monotherapy for the treatment of patients with advanced breast cancer who have experienced disease progression on previous chemotherapies.