High-resolution mapping of gastric slow-wave recovery profiles: biophysical model, methodology, and demonstration of applications.

Slow waves play a central role in coordinating gastric motor activity. High-resolution mapping of extracellular potentials from the stomach provides spatiotemporal detail on normal and dysrhythmic slow-wave patterns. All mapping studies to date have focused exclusively on tissue activation; however, the recovery phase contains vital information on repolarization heterogeneity, the excitable gap, and refractory tail interactions but has not been investigated. Here, we report a method to identify the recovery phase in slow-wave mapping data. We first developed a mathematical model of unipolar extracellular potentials that result from slow-wave propagation. These simulations showed that tissue repolarization in such a signal is defined by the steepest upstroke beyond the activation phase (activation was defined by accepted convention as the steepest downstroke). Next, we mapped slow-wave propagation in anesthetized pigs by recording unipolar extracellular potentials from a high-resolution array of electrodes on the serosal surface. Following the simulation result, a wavelet transform technique was applied to detect repolarization in each signal by finding the maximum positive slope beyond activation. Activation-recovery (ARi) and recovery-activation (RAi) intervals were then computed. We hypothesized that these measurements of recovery profile would differ for slow waves recorded during normal and spatially dysrhythmic propagation. We found that the ARi of normal activity was greater than dysrhythmic activity (5.1 ± 0.8 vs. 3.8 ± 0.7 s; P < 0.05), whereas RAi was lower (9.7 ± 1.3 vs. 12.2 ± 2.5 s; P < 0.05). During normal propagation, RAi and ARi were linearly related with negative unit slope indicating entrainment of the entire mapped region. This relationship was weakened during dysrhythmia (slope: -0.96 ± 0.2 vs -0.71 ± 0.3; P < 0.05).NEW & NOTEWORTHY The theoretical basis of the extracellular gastric slow-wave recovery phase was defined using mathematical modeling. A novel technique utilizing the wavelet transform was developed and validated to detect the extracellular slow-wave recovery phase. In dysrhythmic wavefronts, the activation-to-recovery interval (ARi) was shorter and recovery-to-activation interval (RAi) was longer compared with normal wavefronts. During normal activation, RAi vs. ARi had a slope of -1, whereas the weakening of the slope indicated a dysrhythmic propagation.

Discovering functional, non-proteinogenic amino acid containing, peptides using genetic code reprogramming.

The protein synthesis machinery of the cell, the ribosome and associated factors, is able to accurately follow the canonical genetic code, that which maps RNA sequence to protein sequence, to assemble functional proteins from the twenty or so proteinogenic amino acids. A number of innovative methods have arisen to take advantage of this accurate, and efficient, machinery to direct the assembly of non-proteinogenic amino acids. We review and compare these routes to 'reprogram the genetic code' including in vitro translation, engineered aminoacyl tRNA synthetases, and RNA 'flexizymes'. These studies show that the ribosome is highly tolerant of unnatural amino acids, with hundreds of unusual substrates of varying structure and chemistries being incorporated into protein chains. We also discuss how these methods have been coupled to selection techniques, such as phage display and mRNA display, opening up an exciting new avenue for the production of proteins and peptides with properties and functions beyond that which is possible using proteins composed entirely of the proteinogenic amino acids.

Police exposure to infectious agents: an audit of protective policies.

BACKGROUND: As first responders, police officers may be exposed to infectious agents such as hepatitis viruses and human immunodeficiency virus. Their risk of infection by these viruses can be reduced with training, monitoring and, with some viruses, vaccination. AIMS: To examine infection prevention policies and practices among police departments and determine provision of vaccination and infection prevention education programmes. METHODS: A questionnaire sent to all police departments in five counties of south-eastern Pennsylvania to capture information about department size, immunization policies and practices, record keeping, infection prevention education and monitoring of exposures. RESULTS: Ninety-six of 168 departments responded (57%). Among these, policies requiring pre-employment physical examinations were almost universal (95%). Vaccination policies were less common with <15% requiring and 50% recommending hepatitis, tetanus or influenza vaccination for officers. Few departments took action to provide (2%) or cover the cost (21%) of vaccination. Fewer than 12% maintained vaccination records. Education about the risk of infectious agents was offered by 60% of the responding departments, but often just once at the start of employment. Fewer than half of the departments had systems to collect exposure information. CONCLUSIONS: Police departments have opportunities to improve policies and practices for infection prevention and control. Accurate documentation of vaccination status is essential to ensure provision of appropriate post-exposure assessment and treatment. Better reporting of exposure will improve understanding of the infection transmission risk, enhancing the ability to offer targeted education and services to officers.

Slow, reversible, coupled folding and binding of the spectrin tetramerization domain.

Many intrinsically disordered proteins (IDPs) are significantly unstructured under physiological conditions. A number of these IDPs have been shown to undergo coupled folding and binding reactions whereby they can gain structure upon association with an appropriate partner protein. In general, these systems display weaker binding affinities than do systems with association between completely structured domains, with micromolar K(d) values appearing typical. One such system is the association between α- and ß-spectrin, where two partially structured, incomplete domains associate to form a fully structured, three-helix bundle, the spectrin tetramerization domain. Here, we use this model system to demonstrate a method for fitting association and dissociation kinetic traces where, using typical biophysical concentrations, the association reactions are expected to be highly reversible. We elucidate the unusually slow, two-state kinetics of spectrin assembly in solution. The advantages of studying kinetics in this regime include the potential for gaining equilibrium constants as well as rate constants, and for performing experiments with low protein concentrations. We suggest that this approach would be particularly appropriate for high-throughput mutational analysis of two-state reversible binding processes.

Insights into Diagnostic Radiography students' perception of clinical stressors.

INTRODUCTION: Clinical placements are integral components of Diagnostic Radiography (DR) university training programs, providing students with necessary and unique learning experiences. Educators' understanding of the student experience on placement is growing, and it is important for educators to be attentive to students' reactions to their learning environments and to situations identified to reduce wellbeing. This study aimed to explore DR students' perceptions of challenges experienced during clinical placements and their use of coping strategies. METHODS: Final year DR Students at the University of Sydney, were invited to participate in an online focus group. Three focus groups were conducted with a total of 13 participants. Participants were asked to narrate situations experienced while on clinical placement that reduced their emotional wellbeing, and coping strategies considered to support emotional wellbeing. An inductive thematic analysis of focus group transcripts was undertaken to identify the main discussion themes. RESULTS: Three themes were identified regarding situations considered to reduce emotional wellbeing: adapting to the 'reality' of the clinical environment, forming effective relationships, and balancing student role expectations and responsibilities of patient care. Three themes were identified about coping strategies for emotionally challenging situations: support from clinical and academic staff, peer support and personal strategies, and growing knowledge and confidence over time. CONCLUSION: Students' emotional wellbeing during experiential learning experiences is an underappreciated factor in their transformations into competent diagnostic radiographers. Academic training programs are therefore encouraged to be sensitive to the wellbeing of their trainees, and to take deliberate steps to equip students with the skills to navigate emotions and to normalise emotional responses that may be experienced in the clinical setting. IMPLICATIONS FOR PRACTICE: Students' experience of challenges in the clinical environment is largely influenced by students' abilities to deal with negative experiences, hence students' concerns require implementation of focused interventions prior to first clinical placement.

Epicardial wavefronts arise from widely distributed transient sources during ventricular fibrillation in the isolated swine heart.

It has been proposed that VF waves emanate from stable localized sources, often called "mother rotors." However, evidence for the existence of these rotors is conflicting. Using a new panoramic optical mapping system that can image nearly the entire ventricular epicardium, we recently excluded epicardial mother rotors as the drivers of Wiggers' stage II VF in the isolated swine heart. Furthermore, we were unable to find evidence that VF requires sustained intramural sources. The present study was designed to test the following hypotheses: 1. VF is driven by a specific region, and 2. Rotors that are long-lived, though not necessarily permanent, are the primary generators of VF wavefronts. Using panoramic optical mapping, we mapped VF wavefronts from 6 isolated swine hearts. Wavefronts were tracked to characterize their activation pathways and to locate their originating sources. We found that the wavefronts that participate in epicardial reentry were not confined to a compact region; rather they activated the entire epicardial surface. New wavefronts feeding into the epicardial activation pattern were generated over the majority of the epicardium and almost all of them were associated with rotors or repetitive breakthrough patterns that lasted for less than 2 s. These findings indicate that epicardial wavefronts in this model are generated by many transitory epicardial sources distributed over the entire surface of the heart.

Strategies to improve beef tenderness by activating calpain-2 earlier postmortem.

Our objectives were to determine the effect of post rigor calcium chloride injection or freezing on 1) sarcoplasmic calcium concentration and calpain-2 activity of beef longissimus lumborum (LL) and semimembranosus (SM) steaks aged 1, 4, and 14days post-treatment and on 2) Warner-Bratzler shear force, water holding capacity, and consumer acceptability of LL and SM steaks aged 4 and 14days post-treatment. Free calcium levels in the calcium, frozen, and control steaks averaged 1256, 127, and 121µM for the LL and 1520, 120, and 111µM for the SM, respectively. Measurable LL native calpain-2 activity was lower in calcium and frozen steaks than control steaks (P<0.01), while SM native calpain-2 activity was lowest in calcium steaks and intermediate in frozen steaks (P<0.01). LL calcium steaks were more tender (P=0.04) than control steaks. In conclusion, calcium chloride injection and freezing activate calpain-2 earlier postmortem in both muscles and calcium injection improves LL tenderness.

Search for the missing lncs: gene regulatory networks in neural crest development and long non-coding RNA biomarkers of Hirschsprung's disease.

Hirschsprung's disease (HSCR), a birth defect characterized by variable aganglionosis of the gut, affects about 1 in 5000 births and is a consequence of abnormal development of neural crest cells, from which enteric ganglia derive. In the companion article in this issue (Shen et al., Neurogasterenterol Motil 28: 266-73), the authors search for long non-coding RNAs (lncRNAs) differentially expressed in bowel tissues of infants with HSCR. Microarray analysis of over 37 000 lncRNAs and 34 000 mRNAs was done. The key result was identification of a set of 5 lncRNAs that is a potential diagnostic biomarker of HSCR. In this minireview, I provide an overview of neural crest development and the gene regulatory networks involved in specification, epithelial-mesenchymal transition, and migration of neural crest cells. Genes involved in later development, proliferation, and differentiation of neural crest cells as they migrate into the gut are also reviewed. Many of these genes are associated with HSCR, including RET, GDNF, GFRα, EDN3, and EDNRB. LncRNAs and their roles in development and disease and their use as biomarkers are discussed. The authors of the companion article previously used a multipronged approach to elucidate the etiology of HSCR by examining the effects of specific miRNAs or lncRNAs and target genes on cell migration, proliferation, cell cycle, and apoptosis in vitro. These studies are discussed in terms of their elegance and limitations. The companion article identifies many new lncRNAs that, in addition to providing potential biomarkers of HSCR, may be a treasure trove for future investigations.

Influence of postshock epicardial activation patterns on initiation of ventricular fibrillation by upper limit of vulnerability shocks.

BACKGROUND: Shocks of identical strength and timing sometimes induce ventricular fibrillation (VFI) and other times do not (NoVFI). To investigate this probabilistic behavior, a shock strength near the upper limit of vulnerability, ULV(50), was delivered to yield equal numbers of VFI and NoVFI episodes. METHODS AND RESULTS: In 6 pigs, a 504-electrode sock was pulled over the ventricles. ULV(50) was determined by scanning the T wave. S(1) pacing was from the right ventricular apex. Ten S(2) shocks of approximate ULV(50) strength were delivered at the same S(1)-S(2) coupling interval. Intercycle interval (ICI) and wave front conduction time (WCT) were determined for the first 5 postshock cycles. ICI and the WCT of cycle 1 were not different for VFI versus NoVFI episodes (P=0.3). Beginning at cycle 2, ICI was shorter and WCT was longer for VFI than NoVFI episodes (P<0.05). CONCLUSIONS: The first cycle after shocks of the same strength (ULV(50)) delivered at the same time has the same activation pattern regardless of shock outcome. During successive cycles, however, a progressive decrease in ICI and increase in WCT occur during VFI but not NoVFI episodes. These findings suggest shock outcome is (1) deterministic but exquisitely sensitive to differences in electrophysiological state at the time of the shock that are too small to detect or (2) probabilistic and not determined until after the first postshock cycle.

Improvement of defibrillation efficacy and quantification of activation patterns during ventricular fibrillation in a canine heart failure model.

BACKGROUND: Little is known about the effects of heart failure (HF) on the defibrillation threshold (DFT) and the characteristics of activation during ventricular fibrillation (VF). METHODS AND RESULTS: HF was induced by rapid right ventricular (RV) pacing for at least 3 weeks in 6 dogs. Another 6 dogs served as controls. Catheter defibrillation electrodes were placed in the RV apex, the superior vena cava, and the great cardiac vein (CV). An active can coupled to the superior vena cava electrode served as the return for the RV and CV electrodes. DFTs were determined before and during HF for a shock through the RV electrode with and without a smaller auxiliary shock through the CV electrode. VF activation patterns were recorded in HF and control animals from 21x24 unipolar electrodes spaced 2 mm apart on the ventricular epicardium. Using these recordings, we computed a number of quantitative VF descriptors. DFT was unchanged in the control dogs. DFT energy was increased 79% and 180% (with and without auxiliary shock, respectively) in HF compared with control dogs. During but not before HF, DFT energy was significantly lowered (21%) by addition of the auxiliary shock. The VF descriptors revealed marked VF differences between HF and control dogs. The differences suggest decreased excitability and an increased refractory period during HF. Most, but not all, descriptors indicate that VF was less complex during HF, suggesting that VF complexity is multifactorial and cannot be expressed by a scalar quantity. CONCLUSIONS: HF increases the DFT. This is partially reversed by an auxiliary shock. HF markedly changes VF activation patterns.

Controlled postcardioplegia reperfusion: mechanism for attenuation of reperfusion injury.

OBJECTIVE: Controlled reperfusion and secondary cardioplegia are used to minimize reperfusion injury. The mechanisms for their benefit are incompletely defined and may include attenuation of myocyte sodium uptake. METHODS: Pigs had 1 hour of cardioplegic arrest followed by reperfusion with blood (control) or warm cardioplegic solution followed by blood (test). Reperfusion injury in the control and test groups was quantified by measuring changes of intramyocyte ion content with atomic absorption spectrometry and by analyzing electrophysiologic recovery from recordings of reperfusion arrhythmias. RESULTS: Control animals had an increase in intramyocyte sodium content at 5 minutes after initiating reperfusion (+20.2 micromol/g dry weight, P <.04), whereas the test group had an insignificant decrease (-14.0 micromol/g dry weight, P =.33). The first rhythm after initiating reperfusion was more often ventricular fibrillation in the control group (100% vs 50%, P <.02), and the control group required more defibrillations to establish a nonfibrillating rhythm (4.5 +/- 1.2 vs 1.1 +/- 0.3, P <.03). CONCLUSIONS: Controlled reperfusion eliminated the increase in intramyocyte sodium that was observed in the control group at 5 minutes after cardioplegic arrest. This improvement in myocyte ion homeostasis during postcardioplegia reperfusion was associated with fewer reperfusion arrhythmias. These data support the hypothesis that attenuation of myocyte sodium gain during postischemic reperfusion is a mechanism by which controlled reperfusion and secondary cardioplegia are beneficial.

Equivalent efficacy and reduced occurrence of diarrhea from a new formulation of amoxicillin/clavulanate potassium (Augmentin) for treatment of acute otitis media in children.

OBJECTIVE: To compare the safety and efficacy, in treating acute otitis media (AOM) in children, of a new formulation of amoxicillin/clavulanate potassium (Augmentin) oral suspension providing 45/6.4 mg/kg/day and administered twice daily (bid) for 5 and 10 days, respectively, with the safety and efficacy of the original formulation providing 40/10 mg/kg/day and administered three times daily (tid) for 10 days. STUDY DESIGN: Eight hundred sixty-eight children ages 2 months to 12 years with AOM were randomly assigned to one of the three treatment groups. Stringent criteria were used for the diagnosis of AOM and for determinations of "cure" and "improvement." Subjects were reexamined on Days 12 to 14 and 32 to 38. RESULTS: Among subjects whose treatment and follow-up conformed fully to protocol, the proportion of treatment successes (clinically cured or improved) on Days 12 to 14 was 78.8% (149 of 189) in the tid 10-day group, 86.5% (154 of 178) in the bid 10-day group and 71.1% (140 of 197) in the bid 5-day group. Corresponding values on Days 32 to 38 were 64.2% (95 of 148) in the tid 10-day group, 63.1% (94 of 149) in the bid 10-day group and 57.8% (93 of 161) in the bid 5-day group. None of the differences between the tid 10-day regimen and either of the 2 bid regimens were statistically significant, but the bid 10-day regimen was significantly more effective than the bid 5-day regimen in younger subjects. In the study population as a whole, results were similar to those in per protocol subjects. Overall the incidence of protocol-defined diarrhea was 26.7% (74 of 277) in the tid 10-day group, compared with 9.6% (27 of 280) in the bid 10-day group (P < 0.0001) and 8.7% (25 of 286) in the bid 5-day group (P < 0.0001). CONCLUSIONS: In comparison with the original formulation of Augmentin administered tid for 10 days in the treatment of AOM in children, the new formulation administered bid for 10 days provides at least equivalent efficacy and causes substantially less diarrhea. Administration for 5 days appears not to provide equivalent efficacy, but the difference appears limited to younger children and the margin of difference is small.

Toward a biologically based dose-response model for developmental toxicity of 5-fluorouracil in the rat: a mathematical construct.

Biologically based dose-response (BBDR) models comprise one way to incorporate mechanistic information into a dose-response assessment to be used for risk assessments. The chemotherapeutic drug 5-fluorouracil (5-FU) has been used as a prototypic compound for the construction of a BBDR model for developmental toxicity. Previous work has provided data and a general mechanistic framework for the developmental toxicity of 5-FU when it was administered to pregnant rats subcutaneously on gestation day 14. In this paper, a mathematical model relating maternally administered treatment with 5-FU to embryonal thymidylate synthetase inhibition and thymidylate synthetase inhibition to various measures of deoxyribonucleotide triphosphate (dNTP) pool perturbation is developed, and parameters are estimated using the data collected. The strategy used was to develop semi-empirical submodels for each of the intervening steps, and to estimate model parameters from previously described data. The models developed predict that there is no practical threshold for dNTP pool perturbation; that is, even minimal doses of 5-FU should result in some perturbation of dNTP pools. In particular, the relationship between dNTP pool perturbation and fetal weight deficit suggests that if there is a biological threshold for the effect of 5-FU on fetal weight, the responsible repair or compensation mechanism must be downstream of dNTP pool perturbation, and saturable at 5-FU doses lower than 10 mg/kg (the lowest dose examined for developmental effects in these studies).

Toward a biologically based dose-response model for developmental toxicity of 5-fluorouracil in the rat: acquisition of experimental data.

Biologically based dose-response (BBDR) models represent an emerging approach to improving the current practice of human health-risk assessment. The concept of BBDR modeling is to incorporate mechanistic information about a chemical that is relevant to the expression of its toxicity into descriptive mathematical terms, thereby providing a quantitative model that will enhance the ability for low-dose and cross-species extrapolation. Construction of a BBDR model for developmental toxicity is particularly complicated by the multitude of possible mechanisms. Thus, a few model assumptions were made. The current study illustrates the processes involved in selecting the relevant information for BBDR modeling, using an established developmental toxicant, 5-fluorouracil (5-FU), as a prototypic example. The primary BBDR model for 5-FU is based on inhibition of thymidylate synthetase (TS) and resultant changes in nucleotide pools, DNA synthesis, cell-cycle progression, and somatic growth. A single subcutaneous injection of 5-FU at doses ranging from 1 to 40 mg/kg was given to pregnant Sprague-Dawley rats at gestational day 14; controls received saline. 5-FU was absorbed rapidly into the maternal circulation, and AUC estimates were linear with administered doses. We found metabolites of 5-FU directly incorporated into embryonic nucleic acids, although the levels of incorporation were low and lacked correlation with administered doses. On the other hand, 5-FU produced dose-dependent inhibition of thymidylate synthetase in the whole embryo, and recovery from enzyme inhibition was also related to the administered dose. As a consequence of TS inhibition, embryonic dTTP and dGTP were markedly reduced, while dCTP was profoundly elevated, perhaps due to feedback regulation of intracellular nucleotide pools. The total contents of embryonic macromolecules (DNA and protein) were also reduced, most notably at the high doses. Correspondingly, dose-related reductions of fetal weight were seen as early as GD 15, and these deficits persisted for the remainder of gestation. These detailed dose-response parameters involved in the expression of 5-FU developmental toxicity were incorporated into mathematical terms for BBDR modeling. Such quantitative models should be instrumental to the improvement of high-to-low dose and cross-species extrapolation in health-risk assessment.

Comparison of firing patterns and sensory responsiveness between supraoptic and other hypothalamic neurons in the unanesthetized sheep.

Adult Southdown ewes were surgically prepared with pituitary stimulating electrodes, carotid and jugular cannulae, and a cranial platform-cylinder arrangement for chronic single unit recording. Isolated neurons (n = 112) in the region of the supraoptic nucleus (SON) were identified by pituitary stalk stimulastion as AD + (antidromically invaded) SON neuroendocrine cells (n = 75) or AD--(not antidromically invaded) SON neurons (n = 37). Spontaneous firing pattern distribution and sensory evoked behavior of these SON region neurons were compared with activity recorded from 112 randomly located non-identified neurons of extra-SON areas of the hypothalamus. Spontaneous discharge activity was categorized into six distinct firing pattern types: continuously active slow (CAS), continuously active fast (CAF), continuously active bursting (CAB), continuously active regular (CAR), low frequency bursting (LFB), and high frequency bursting (HFB). These 6 firing pattern types were characterized by computer analysis and their mean order independent statistical parameters compared. Bursting discharge patterns (LFB, HFB, and CAB) were compared with respect to mean burst duration, burst mean firing rate, and interburst interavls. Ninety-three per cent of all neurons maintained a stable discharge pattern in the absence of apparent stimuli. Occasionally CAS and CAF neurons spontaneously generated spike clusters sufficient to give the transient appearance of a bursting discharge pattern and LFB neurons lapsed spontaneously into CAS acitivity. All 6 firing pattern types recorded from non-identified extra-SON neurons were also recorded in the SON region. However, spontaneously discharging AD+ SON neurons exhibited only continuously active slow (CAS), continuously active fast (CAF), and low frequency bursting (LFB) activity. The total absence of high frequency bursting (HFB), continuously active regular (CAR), and continuously active bursting (CAB) patterns of discharge from AD+ SON neurons suggests that AD- SON neurons exhibiting these firing patterns may function as interneurons, pacemaker neurons, or receptor neurons. A significant number of LFB discharging neurons were recorded in widespread extra-SON regions of the hypothalamus, indicating this discharge pattern may not be unique to magnocellular neuroendocrine cells. AD+ SON LFB neurons sampled in this study demonstrated a significantly longer mean interburst interval (20.86 sec) compared to extra-SON LFB neurons (12.43 sec). No AD+ SON neuron tested was significantly sensitive to non-specific sensory arousal or sleep-waking state changes. In extra-SON areas of the hypothalamus, 11 of 75 neurons tested to sensory arousal and 6 of 19 neurons tested to sleep-waking changes responded with significant changes in mean firing rate (MFR); no significant difference between firing pattern types was demonstrated in arousal or sleep-waking sensitivity...

MR in temporal lobe epilepsy: analysis with pathologic confirmation.

PURPOSE: We evaluated the MR findings in patients with temporal lobe epilepsy to determine the predictive value of MR imaging in assessing patient outcome. METHODS: MR studies from 186 of 274 consecutive patients who underwent temporal lobectomy for intractable epilepsy were reviewed retrospectively. Images were interpreted by an experienced neuroradiologist, who was blinded to the side of seizure activity and to pathologic findings. RESULTS: MR imaging exhibited 93% sensitivity and 83% specificity in detecting hippocampal/amygdalar abnormalities (n = 121), and 97% sensitivity and 97% specificity in detecting abnormalities in the rest of the temporal lobe (n = 60). Abnormal high signal of the hippocampus on T2-weighted images had a sensitivity of 93% and specificity of 74% in predicting mesial temporal sclerosis (n = 115). The presence of hippocampal atrophy on MR correlated with the duration of seizures. Sensitivity and specificity of MR imaging in detecting temporal lobe tumors (n = 42) were 83% and 97%, respectively, based on abnormal signal and mass effect. After surgery, 63% of patients were seizure free and 28% had a significant reduction of seizure frequency at an average of 24 months (range, 12 to 78 months) after surgery. Patients with a single lesion in the anterior temporal lobe or hippocampus/amygdala had a better outcome than patients with multiple lesions (n = 22). Interrater agreement varied from 0.4 to 0.93, with best agreement for tumors or abnormal hippocampal signal on T2-weighted images. CONCLUSION: MR imaging is highly sensitive in detecting and locating abnormalities in the temporal lobe and the hippocampus/amygdala in patients with temporal lobe epilepsy. Hippocampal atrophy appears to correspond to the duration of seizure disorder.

Specific competitive inhibitor of secreted phospholipase A2 from berries of Schinus terebinthifolius.

Two structurally related triterpenoids 1 and 2 from pink peppercorn (berries of Schinus terebinthifolius) are identified and characterized as active site-directed specific competitive inhibitors of the three classes of secreted 14 kDa phospholipase A2. The inhibitors not only protect the active site histidine from alkylation but also inhibit the action of secreted phospholipase A2 from pig pancreas, human synovial fluid, and bee venom. Detailed X-ray crystallographic results on the structures of the inhibitors are provided. By physical methods and X-ray crystallography the triterpenoids were identified as masticadienoic acid and masticadienolic acid (schinol). Several other triterpenoids were ineffective as inhibitors of phospholipase A2; however certain ganoderic acid derivatives showed noticeable inhibition. Results show that the side chain of these acidic tetracyclic terpenoids can access the catalytic-site region of phospholipase A2, whereas the acyclic nucleus is at the interfacial recognition region. The selectivity of the assay protocol used here is demonstrated by the fact that the original screen of ethyl acetate extracts of 60 commercially available spices and herbs was carried out with phospholipase A2 from pig pancreas, and only one extract showed inhibitory action on the hydrolytic activity in the scooting mode. Under such assay conditions the enzyme remains tightly bound to the surface of the substrate vesicles. In this way, nonspecific effects of additives that promote desorption of the enzyme from the substrate vesicle surface, under conditions in which the binding of the enzyme to the vesicle is weak, are avoided. The assay protocol is useful for the kinetic characterization of the inhibitors of phospholipase A2, and it does not give false positive results with amphiphilic and hydrophobic compounds, as is the case with virtually all assay systems in use.

An analysis of factors associated with interval as opposed to screen-detected breast cancers, including hormone therapy and mammographic density.

A comparison of 270 interval breast cancers in South Australian women aged 50 years and over with 628 age-matched screen-detected cases indicated that the former had more advanced stages (P<0.001), higher grades (P<0.001), and more frequently a history of past breast problems (P<0.027). After adjusting for these factors, and presence of a self-reported breast lump at the last screen, using conditional logistic regression, hormone replacement therapy (HRT) exposure in the 6 months prior to this screen had a raised relative odds (95% CL) of an interval cancer of 1.48 (1.02, 2.14). For 479 women where breast density was measured, high density showed an elevated relative odds of an interval cancer of 2.62 (1.71, 4.02). The relative odds of a high density was raised to 2.02 (1.33, 3.06) when the HRT history was positive. Screeners should be aware when there is a history of HRT or past breast problems, or a high breast density, that there is an increased probability of a subsequent interval cancer.

An overview of maternal toxicity and prenatal development: considerations for developmental toxicity hazard assessments.

The objective of testing xenobiotics for potential developmental toxicity is to extrapolate laboratory animal information to the human species, thereby deriving biologically rational regulatory policies. One of the problems that significantly contributes to the difficulty of this task is the possibility that general effects on the maternal organism could affect the developing conceptus. Published data have indicated that factors intrinsic to the maternal organism affect developmental outcome. This overview examines factors which may bear directly or indirectly upon developmental outcome, with emphasis on those of greatest relevance to the hazard assessment process. Standard teratology testing protocols often call for dose levels that induce overt maternal toxicity, and the developmental effects of this toxicity (both alone, and with concurrent embryo/fetal insult) continue to present regulators with considerable interpretive difficulties. In response to these problems there have been both research and literature review efforts dealing with the relationship of maternal and developmental toxicity. Relevant studies are reviewed here, and suggestions for avenues of future research are offered including the identification of any syndromes of developmental effects occurring at maternally toxic levels irrespective of the causative agent, and experimental approaches for the characterization of maternal toxicity.

A review of the literature on potential reproductive and developmental toxicity of electric and magnetic fields.

The potential of electric and magnetic fields to adversely affect the health of the human population is an issue which continues to receive a great deal of attention in both public and scientific forums. One of the critical issues is the possibility that such fields may adversely affect the reproductive process. Numerous studies investigating the potential of electric and/or magnetic fields to alter reproduction in vertebrates have been conducted. These studies have, in many instances, yielded seemingly contradictory results. A number of epidemiological studies have been conducted as well. This review of the literature examines relevant studies and attempts to draw biologically rational conclusions from them. The studies are ordered in broad categories based upon both classification of the species studied (i.e. submammalian, mammalian exclusive of man and human) and the agent used (i.e. extremely low frequency electric, very low frequency electric, and magnetic fields). From our review we conclude that laboratory experimental and epidemiological results to date have not yielded conclusive data to support the contention that such fields induce adverse reproductive effects under the test or environmental conditions studied. Additional studies may, however, be warranted to clarify some of the experimental results obtained.