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Attention to metabolic hunger and its effects on Helicobacter pylori infection.

A significant decrease in the bacterial count of small intestinal mucosa has been observed in children with recurrent diarrhea or abdominal pain in the time that has elapsed from the previous meal. Humans may be trained to recognize metabolic feelings of hunger that are associated with a steady and slightly lower glycemia than baseline, between 4.7 and 3.9 mmol/L (intervention). An eating habit associated with a decrease in preprandial glycemia prevented diarrhea relapses, and was expected to impair intestinal microflora growth, including Helicobacter pylori in the stomach. The development of Helicobacter pylori infection might be prevented during childhood, and recovery from infection may be expected with intervention. The improvement in attention to metabolic feelings consisted of acquiring a predictive ability of glycemia by distinction between unsolicited hunger feelings (metabolic hunger) and those associated with external cues. Matching intake to the inbetween energy needs served to predict the subsequent emergence of the metabolic hunger. The matching was further compensated for the early or late emergence of metabolic hunger at the subsequent meals. Fruit and vegetables were increased to avoid abrupt glycemia lowering. This intervention was trained in 5-month periods. Subjects (209, 44, and 58) completed their training during 4-year periods between 1982 and 1994, and were enrolled in a prospective, controlled, randomized, interventional, preventive, and cohort study. The "prevention" hypothesis was tested in a subgroup of 86 healthy infants who were recalled in the years 1996 to 1998. A "recovery" study of approximately a 1-year intervention was investigated in 47 healthy subjects between ages 5 and 25, who were positive for anti-H. pylori and had no need for an immediate antibiotic treatment at entry. The following behavioral factors were recorded in a 7-day home diary and calculated: the fraction of meals induced by metabolic hunger out of 21 main mealtimes; average preprandial glycemia (DAP glycemia); daily intakes, activity; and bedtime hours. The decrease in preprandial glycemia was the objective measure of compliance with the recognition of "metabolic" hunger. Anthropometric measures and blood tests were obtained for nutritional and functional verifications. Average preprandial glycemia was 8.5 and 8.6% lower in the intervention groups than the control groups in the "prevention" and "recovery" studies, respectively, at the end of follow-up (p<0.05 and <0.001, respectively). A 4.7% seroprevalence of H. pylori infection was observed in the intervention group, with 30.2% in the control group at a mean age of 10 years after approximately an 8-year follow-up in the "prevention" study (p<0.0005). The seroprevalence decreased to 9 of 24 (37.5%) under intervention as opposed to 20 of 23 controls (87%) in the recovery study (p<0.002). A significant positive correlation was found between DAP glycemia and the anti-H. pylori serum antibody concentration (r = 0.52; p = 0.0002). A decrease in the level of immune stimulation by H. pylori infection was observed due to the intervention, which may have a preventive and therapeutic role on the infection.

Attention↗

Evaluation of frequency and type of errors detected by a computerized record and verify system during radiation treatment.

BACKGROUND: Computerized record and verify systems (RVS) have been introduced to improve the precision of radiation treatment delivery. These systems prevent the delivery of ionizing radiations when the settings of the treatment machine do not match the intended parameters within some maximal authorized deviation. PURPOSE: To assess the potential alteration of the frequency of errors associated with the use of RVS during radiation treatment delivery. MATERIALS AND METHODS: The software of the RVS was altered in order to record the settings actually used for radiation treatment delivery whereas the verification function was suppressed. At the end of the study period, the settings used during daily administration of radiation treatment were compared to the parameters recorded in the RVS using the computer. They were also compared with the planned ones written in the patient treatment chart. RESULTS: Out of the 147,476 parameters examined during the study period, 678 (0.46%) were set erroneously. At least one error occurred in 628 (3.22%) of the 19,512 treated fields. An erroneous parameter was introduced in the RVS memory in 22 (1.17%) of the 1885 fields. CONCLUSIONS: RVS has the potential to improve precision of radiation treatment delivery by detecting a significant number of setting errors. However, excessive confidence in RVS could lead to repeated errors as there is a potential for the entry of erroneous parameters into the RVS memory.

Humans↗

Low settings of the ventricular pacing output in patients dependent on a pacemaker: are they really safe?

BACKGROUND: It is generally acknowledged that pacemaker output must be adjusted with a 100% voltage safety margin above the pacing threshold to avoid ineffective pacing, especially in patients dependent on pacemakers. AIMS: The aim of this prospective crossover study was to assess the beat-to-beat safety of low outputs in patients who are dependent on a pacemaker between 2 follow-up examinations. METHODS: The study included 12 patients who had received a DDD pacemaker with an automatic beat-to-beat capture verification function. The ventricular output at 0.4 milliseconds pulse duration was programmed independently of the actual pacing threshold in a crossover randomization to 1.0 V, 1.5 V, and 2.5 V for 6 weeks each. At each follow-up, the diagnostic counters were interrogated and the pacing threshold at 0.4 milliseconds was determined in 0.1-V steps. The diagnostic pacemaker counters depict the frequency of back-up pulses delivered because of a loss of capture. During the randomization to 1.0-V output, we evaluated whether the adjustment of the output under consideration of the >100% voltage safety margin reduced the frequency of back-up pulses. RESULTS: Pacing thresholds at the randomization to 1.0-V, 1.5-V, and 2.5-V output were not significantly different, with 0.7 +/- 0.3 V at 2.5-V output, 0.6 +/- 0.2 V at 1.5-V output, and 0.6 +/- 0.2 V at 1.0-V output. The frequency of back-up pulses was similar at 2.5-V and 1.5-V output, 2.2% +/- 1.9% and 2.0% +/- 2.0%, respectively. The frequency of back-up pulses significantly increased at 1.0-V output to 5.8% +/- 6.4% (P <.05). Back-up pulses >5% of the time between the 2 follow-ups were observed in no patient at 2.5 V, in 1 patient at 1.5 V, and in 5 patients at 1.0 V. At the randomization to the 1.0-V output, 6 patients had pacing thresholds of 0.5 V or less, and 6 patients had pacing thresholds >0.5 V. The frequency of back-up pulses in the 2 groups was not significantly different, 6.4% +/- 8.6% and 5.7% +/- 2.6%. CONCLUSIONS: The frequency of back-up pulses was significantly higher at 1.0-V output than at 1.5-V and 2.5-V output. This also applied to patients with pacing thresholds of < or =0.5 V. Fixed low outputs seem not to be absolutely safe between 2 follow-ups in patients who are dependent on a pacemaker, even when the output has a 100% voltage safety margin above the pacing threshold. When patients with pacemakers programmed to a low ventricular output have symptoms of ineffective pacing, an intermittent increase of the pacing threshold should be carefully ruled out.

Aged↗

COBrA: a bio-ontology editor.

COBrA is a Java-based ontology editor for bio-ontologies that distinguishes itself from other editors by supporting the linking of concepts between two ontologies, and providing sophisticated analysis and verification functions. In addition to the Gene Ontology and Open Biology Ontologies formats, COBrA can import and export ontologies in the Semantic Web formats RDF, RDFS and OWL.

Cell Physiological Phenomena↗

Purinergic regulation of sound transduction and auditory neurotransmission.

In the cochlea, extracellular ATP influences the endocochlear potential, micromechanics, and neurotransmission via P2 receptors. Evidence for this arises from studies demonstrating widespread expression of ATP-gated ion channels (assembled from P2X receptor subunits) and G protein-coupled receptors (P2Y receptors). P2X2 receptor subunits are localized to the luminal membranes of epithelial cells and hair cells lining scala media. These ion channels provide a shunt pathway for K+ ion egress. Thus, when noise exposure elevates ATP levels in this cochlear compartment, the K+ conductance through P2X receptors reduces the endocochlear potential. ATP-mediated K+ efflux from scala media is complemented by a P2Y receptor G protein-coupled pathway that provides coincident reduction of K+ transport into scala media from the stria vascularis when autocrine or paracrine ATP signalling is invoked. This purinergic signalling likely provides a basis for a reactive homoeostatic regulatory mechanism limiting cochlear sensitivity under stressor conditions. Elevation of ATP in the perilymphatic compartment under such conditions is also likely to invoke purinergic receptor-mediated changes in supporting cell micromechanics, mediated by Ca2+ influx and gating of Ca2+ stores. Independent of these humoral actions, ATP can be classified as a putative auditory neurotransmitter based on the localization of P2X receptors at the spiral ganglion neuron-hair cell synapse, and functional verification of ATP-gated currents in spiral ganglion neurons in situ. Expression of P2X receptors by type II spiral ganglion neurons supports a role for ATP as a transmitter encoding the dynamic state of the cochlear amplifier.

Adenosine Triphosphate↗

Acute effects of a class IA antiarrhythmic drug on the ventricular evoked response amplitude in patients with cardiac pacemakers.

Some newer cardiac pacemakers are able to control the efficacy of the ventricular pacing pulse beat by beat and to adjust the ventricular output to the actual pacing threshold. This capture verification is based on the detection of the ventricular evoked response amplitude, which has to be detected immediately after the pacing pulse. The sensitivity of the pacemaker to detect the evoked response amplitude must be adjusted individually to avoid the simultaneous detection of lead polarization. The aim of the present study was to evaluate the acute effects of a class IA antiarrhythmic drug on the evoked response amplitude and polarization in 13 pacemaker patients. The implanted pacemaker was the VVIR pacemaker Regency (St. Jude Medical), which provides the automatic capture verification algorithm Autocapture. The patients received 50 mg of ajmaline intravenously within 1 min. The evoked response amplitude and polarization were measured before and 2, 4, 6 and 8 min after ajmaline injection. The evoked response amplitude significantly decreased from 8.0 +/- 4.0 mV to a minimum value of 6.4 +/- 3.1 mV 2 min after drug administration. The decrease remained significant from the end of the application up to 6 min. The recommended sensitivity setting for the evoked response significantly (p < 0.05) decreased from 4.0 +/- 2.3 mV before to 3.1 +/- 1.3 mV 2 min after administration. No significant changes were observed for polarization. After the ajmaline application in 2 patients, the pacemaker recommended the deactivation of Autocapture for 9 min in 1 patient and 12 min in the other. The reasons were a decrease in the evoked response amplitude from 3.1 to 1.9 mV and from 9.0 to 5.7 mV, respectively, with a polarization ranging to about 3.0 mV. In conclusion, the ajmaline injection decreased the evoked response amplitude for some minutes. These findings indicate that antiarrhythmic drugs can alter the automatic capture verification function.

Aged↗

FOSL1 transcriptionally dictates the Warburg effect and enhances chemoresistance in triple-negative breast cancer.

BACKGROUND: Dysregulated energy metabolism has emerged as a defining hallmark of cancer, particularly evident in triple-negative breast cancer (TNBC). Distinct from other breast cancer subtypes, TNBC exhibits heightened glycolysis and aggressiveness. However, the transcriptional mechanisms of aerobic glycolysis in TNBC remains poorly understood. METHODS: The Cancer Genome Atlas (TCGA) cohort was utilized to identify genes associated with glycolysis. The role of FOSL1 in glycolysis and tumor growth in TNBC cells was confirmed through both loss-of-function and gain-of-function experiments. The subcutaneous xenograft model was established to evaluate the therapeutic potential of targeting FOSL1 in TNBC. Additionally, chromatin immunoprecipitation and luciferase reporter assays were employed to investigate the transcriptional regulation of glycolytic genes mediated by FOSL1. RESULTS: FOSL1 is identified as a pivotal glycolysis-related transcription factor in TNBC. Functional verification shows that FOSL1 enhances the glycolytic metabolism of TNBC cells, as evidenced by glucose uptake, lactate production, and extracellular acidification rates. Notably, FOSL1 promotes tumor growth in TNBC in a glycolysis-dependent manner, as inhibiting glycolysis with 2-Deoxy-D-glucose markedly diminishes the oncogenic effects of FOSL1 in TNBC. Mechanistically, FOSL1 transcriptionally activates the expression of genes such as SLC2A1, ENO1, and LDHA, which further accelerate the glycolytic flux. Moreover, FOSL1 is highly expressed in doxorubicin (DOX)-resistant TNBC cells and clinical samples from cases of progressive disease following neoadjuvant chemotherapy. Targeting FOSL1 proves effective in overcoming chemoresistance in DOX-resistant MDA-MB-231 cells. CONCLUSION: In summary, FOSL1 establishes a robust link between aerobic glycolysis and carcinogenesis, positioning it as a promising therapeutic target, especially in the context of TNBC chemotherapy.

Triple Negative Breast Neoplasms↗

Role of proteomics in translational research in cervical cancer.

Cervical cancer is one of the leading causes of cancer morbidity and mortality in women worldwide. More than 98% of cases are related to a human papillomavirus (HPV) infection. Infection with specific subtypes of HPV has been strongly implicated in cervical carcinogenesis. The identification and functional verification of host proteins associated with HPV E6 and E7 oncoproteins may provide useful information for understanding cervical carcinogenesis and the development of cervical cancer-specific markers. In addition, proteomic profiling of altered proteins by anticancer drugs on cervical cancer cells may contribute to providing the fundamental resources for investigation of disease-specific target proteins, elucidation of the novel mechanisms of action and development of new drugs. The advent of proteomics has provided the hope of discovering novel biological markers for use in the screening, early diagnosis and prediction of response to therapy. This review describes the studies where profiles of protein expression in cervical cancer have been generated.

Antineoplastic Agents↗

Localization of p-glycoprotein mRNA in the tissues of Haemonchus contortus adult worms and its relative abundance in drug-selected and susceptible strains.

Membrane transporter P-glycoproteins (Pgps) are present in a number of nematode species, including Haemonchus contortus. Allelic variation in some Pgp genes has been found to be associated with resistance to the anthelmintic ivermectin (IVM), although functional verification of a role for Pgps in IVM resistance has yet to be demonstrated. By in situ hybridization, the distribution of Pgp mRNA was visualized in transverse cryosections of adult H. contortus, using a digoxigenin-labeled cDNA probe encoding the ATP-binding region of an H. contortus Pgp. The probe sequence targeted a conserved ATP-binding region of Pgp-A (97.9% identity). It also shared 49.7-71.1% identity with 11 other Pgp sequences previously identified in H. contortus and may hybridize these sequences to give an overall measure of the total P-glycoprotein mRNA. Staining was predominately localized along the intestinal tract of the worms, with the most intense staining localized in the pharynx and anterior intestine. In the mid- and posterior intestinal regions, staining was restricted to the luminal side of the intestine. Some staining was also associated with the vas deferens and the lateral hypodermal chords anterior to the nerve ring. Using densitometry, the levels of Pgp mRNA in the pharynges of unselected and IVM- and moxidectin (MOX)-selected strains of male and female H. contortus were compared. No differences were detected between the levels of expression of Pgp in the susceptible strain versus the IVM- or MOX-selected strains. Evidence in the literature suggests that not all Pgp homologues are linked to chemical resistance phenotypes. It is thus possible that expression of I of the H. contortus Pgps is altered in IVM-resistant strains but that this phenomenon was undetectable in our experiments.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Functional studies on sciatic nerve blood flow in respect to its vascular supply and tonic neural activity.

An introduction of laser flow meters for a continuous measurements of a tissue blood flow has opened new avenues for an accurate assessment blood flow in peripheral nerves. The aim of our study was: 1) to carry out a functional verification of anatomical sources of a sciatic nerve blood supply in the rat; 2) develop a measurement technique to facilitate standardisation of results; 3) to determine the role of nerve fibres tonic activity in the maintenance of a resting blood flow in the sciatic nerve. Based on results of the present study the following conclusions have been drawn out: 1) in order to obtain a real values of the blood flow through the sciatic nerve it is necessary to remove its muscular fascia; 2) an uninjured epineurium plays a crucial role in maintaining the resting blood flow; 3) major blood supply of sciatic nerve comes from inferior gluteal and popliteal arteries; 4) the tonic neural activity plays a role in the maintenance of the resting sciatic nerve blood flow in anaesthetised rats.

Anesthetics, Local↗

Uni- and bipolar pacing threshold measurements with capturecontrol, a new automatic pacemaker function for capture verification. Comparison of the automatic and the manual pacing threshold measurement.

It is mandatory in pacemaker patients to determine the pacing threshold at each follow-up visit. To facilitate the pacing threshold measurements, complete automatic pacemaker tests are being developed. A new pacemaker algorithm for automatic capture verification (Capturecontrol) detects the presence of the evoked response signal 70-100 ms after the pacing pulse. The aim of this study was to determine the uni- and bipolar pacing thresholds using this automatic pacemaker function and compare them with the manually determined threshold. The study included 14 patients with the DDD pacemaker Logos (Biotronik) connected to the high-ohmic ventricular pacing lead Synox SX 60-BP (Biotronik). At predischarge and 8, 14, 20 and 26 weeks after implantation the uni- and bipolar pacing thresholds were assessed manually and with the automatic pacemaker function at 0.4 ms duration. Mean pacing thresholds determined with the automatic pacemaker function were not different from the manually measured values. This applied to uni- and bipolar pacing. Seventy percent of all unipolar and 67% of all bipolar measurements had no deviation. A deviation of 0.1 V between manual and automatic threshold measurement was observed in 25% (unipolar) and 28% (bipolar), respectively. A 0.2-volt difference occurred in 3% in the unipolar measurements. Deviations >/=0.3 V were found in 2% of all unipolar and in 5% of all bipolar measurements. In conclusion, automatic pacing threshold measurements using the Capturecontrol algorithm were similar compared to the manually determined thresholds. The excellent agreement between the two methods was observed for bipolar as well as unipolar pacing and on condition that all patients had a high-ohmic ventricular pacing lead. Therefore, fewer requirements are necessary for Capturecontrol than for presently available systems. Such pacemaker functions can help to speed up the measurements during follow-up visits.

Aged↗

Functional in vivo verification in E. coli of promoter activities from the rDNA/tDNA(Val)(GAC) leader region of Zea mays chloroplasts.

Restriction fragments containing upstream sequences of the rRNA operon from Zea mays chloroplasts were tested for promoter activity in vivo by insertion into an E. coli promoter-probe vector. The expression of this vector's reporter gene, which codes for alkaline phosphatase, was stimulated more than 1,500-fold upon linkage with the chloroplast rRNA promoter. Site specific mutagenesis of the invariant T of the -10 sequence of this promoter reduced the expression of the reporter gene to 2% of the wild type. This indicates that the chloroplast rRNA promoter, which directs transcriptional initiation 117 bp upstream of the 16S rRNA gene, is also active in the bacterial system. A restriction fragment further upstream containing the gene for tRNA(Val) (GAC) also showed strong promoter activity (29% as compared with the rRNA promoter). This promoter activity probably reflects the chloroplast promoter directing the synthesis of the tRNA(Val) (GAC) primary transcript. Surprisingly, this restriction fragment also displayed promoter activity (13% compared with the rRNA promoter) in reverse orientation.

Base Sequence↗

The feeling of a presence and verbal meaningfulness in context of temporal lobe function: factor analytic verification of the muses?

We hypothesized that the feeling of a presence, particularly during periods of profound verbal creativity (reading or writing prose or poetry), is an endemic cognitive phenomenon. Factor analyses of 12 clusters of phenomenological experiences from 348 men and 520 women supported the hypothesis. We conclude that periods of intense meaningfulness (a likely correlate of enhanced burst-firing in the left hippocampal-amygdaloid complex and temporal lobe) allow access to nonverbal representations that are the right hemispheric equivalents of the sense of self; they are perceived as "a presence." The relevance of our results to the theories of Jaynes, Bear, Edelman, and MacLean is discussed.

Adolescent↗

[Lung hyperinflation and verification of its functional parameters].

A functional testing of lung hyperinflation parameters have been performed by two methods: body-plethysmography and helium single-breath method. The results obtained have been thereafter compared. In a group of 15 healthy patients no significant differences have been established except for the residual volume (RV). However, in a group of patients with C.O.P.D. significant differences among parameters have been established most of them for RV. The body-plethysmography method has no equal, however with the help of helium method it is also possible to measure out the closed noncommunicative airspaces in the lungs.

Adult↗

Effects of inositol hexasulfate on the oxygen affinity of hemoglobin: verification of the integral function theory of thermodynamic linkage.

A detailed series of experimental measurements have been carried out to investigate the effects of inositol hexasulfate (IHS) on the oxygen binding curves of human hemoglobin. The data provide a critical test of the integral function theory for the mutual interaction of two ligands binding to a nondissociating macromolecule [Ackers, G. K. (1979) Biochemistry 18, 3372-3380]. This theory, which is required for cases where the fractions of bound and unbound ligands are of comparable magnitude, was found to predict quantitatively the observed effects. The experimentally determined variation of the median oxygen concentration with IHS concentration was analyzed by least-squares methods to determine the IHS binding constants for unliganded and fully oxygenated hemoglobin. The derived constants are in good agreement with independent estimates of their values, providing further verification of the theoretical treatment. General aspects of the integral function approach to thermodynamic linkage are briefly outlined. The importance of this approach for treating physiological situations is discussed.

Allosteric Regulation↗

Enzyme genomics: Application of general enzymatic screens to discover new enzymes.

In all sequenced genomes, a large fraction of predicted genes encodes proteins of unknown biochemical function and up to 15% of the genes with "known" function are mis-annotated. Several global approaches are routinely employed to predict function, including sophisticated sequence analysis, gene expression, protein interaction, and protein structure. In the first coupling of genomics and enzymology, Phizicky and colleagues undertook a screen for specific enzymes using large pools of partially purified proteins and specific enzymatic assays. Here we present an overview of the further developments of this approach, which involve the use of general enzymatic assays to screen individually purified proteins for enzymatic activity. The assays have relaxed substrate specificity and are designed to identify the subclass or sub-subclasses of enzymes (phosphatase, phosphodiesterase/nuclease, protease, esterase, dehydrogenase, and oxidase) to which the unknown protein belongs. Further biochemical characterization of proteins can be facilitated by the application of secondary screens with natural substrates (substrate profiling). We demonstrate here the feasibility and merits of this approach for hydrolases and oxidoreductases, two very broad and important classes of enzymes. Application of general enzymatic screens and substrate profiling can greatly speed up the identification of biochemical function of unknown proteins and the experimental verification of functional predictions produced by other functional genomics approaches.

Enzymes↗