Core mechanisms in generalized convulsions

A hypothetical model is proposed to account for the generalized convulsions observed in rats. Two versions of the hypothesis are discussed: an earlier, more specific formulation that accounts for kindled convulsions, and a later, general version that applies to generalized convulsions as a whole. Observations leading to the specific formulation of the model included: 1) kindling data that suggested a single downstream center responsible for kindled convulsions; 2) brain-stem stimulation data that indicated that the reticular core of that structure could initiate and maintain generalized convulsive behavior; and 3) spinal hemisection data that indicated that nonspecific systems in the cord could also maintain convulsions, even in the absence of direct input from the brain. The more specific version of the model suggests that kindled convulsions are nonspecific core seizures that occur when self-sustained epileptic activation spreads from forebrain foci to involve descending polysynaptic pathways in the nonspecific core of the brain stem and cord. Observations leading to a more general formulation of the model include the facts that: 1) maximal and submaximal convulsions in a variety of models resemble each other; and 2) they also resemble the maximal and submaximal seizures produced by direct stimulation of the brain stem and cord. The more general formulation of the nonspecific core hypothesis suggests that a wide variety of convulsions in rats may be nonspecific core seizures, differences in tonic-clonic and rostrocaudal configuration being related primarily to differences in the intensity of core activation.     

Electrolyte transport across the basolateral membrane of the parietal cells

The ion-transport properties of the basal lateral membranes of intact isolated parietal cells were studied at the cellular and subcellular level. The presence of an amiloride-sensitive Na+:H+ exchange was demonstrated in cells by proton gradient-driven Na+ uptake and by changes in cell pH as monitored by dimethylcarboxylfluorescein fluorescence both in a fluorimeter and on single isolated cells using a fluorescence microscope and an attached intensified photodiode array spectrophotometer. The presence of the Na+:H+ antiport in vesicles was shown both by intravesicular acidification monitored by acridine orange fluorescent quenching and by proton gradient-dependent Na+ uptake. The presence of Cl-:HCO-3 exchange was determined in intact cells by monitoring changes in cell pH due to Cl- uptake and was shown to be 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid- and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid-sensitive. In vesicles, Cl-:HCO-3 exchange was demonstrated by Cl- flux measurement. The apparent affinities for both Cl- and HCO-3 on either side of the membrane were determined to be Km Cli = 20 mM, Km Clout = 17.5 mM, Km HCO-3in = 2.5 mM, and Km HCO-3out = 7.5 mM. A K+ conductance in cells and vesicles was demonstrated by monitoring K+ gradient-dependent 86Rb uptake. No evidence was found for the presence of a Cl- conductance in either cells or vesicles but a H+ conductance was found to be present in vesicles but not in intact cells. In the latter, by determining the effect of either Na+ or Cl- gradients on cell pH and by flux calculations it was concluded that the Cl-:HCO-3 exchange was the major passive flux mechanism for pH regulation in this cell type.     

Injuries,Death, and Disability Associated with 11 Years of Conflict in Baghdad,Iraq: A Randomized Household Cluster Survey

Background

The objective of this study was to characterize injuries, deaths, and disabilities arising during 11 years of conflict in Baghdad.

Methods

Using satellite imagery and administrative population estimated size for Baghdad, 30 clusters were selected, proportionate to population size estimates. Interviews were conducted during April and May 2014 in 900 households containing 5148 persons. Details about injuries and disabilities occurring from 2003 through May 2014 and resultant disabilities were recorded.

Findings

There were 553 injuries reported by Baghdad residents, 225 of which were intentional, and 328 unintentional. For intentional injuries, the fatality rate was 39.1% and the disability rate 56.0%. Gunshots where the major cause of injury through 2006 when blasts/explosions became the most common cause and remained so through 2014. Among unintentional injuries, the fatality rate was 7.3% and the disability rate 77.1%. The major cause of unintentional injuries was falls (131) which have increased dramatically since 2008, followed by traffic related injuries (81), which have steadily increased. The proportion of injuries ending in disabilities remained fairly constant through the survey period.

Interpretation

Intentional injuries added substantially to the burden of unintentional injuries for the population. For Baghdad, the phases of the Iraqi conflict are reflected in the patterns of injuries and consequent deaths reported. The scale of injuries during conflict is most certainly under-reported. Difficulties recalling injuries in a survey covering 11 years is a limitation, but it is likely that minor injuries were under-reported more than severe injuries. The in- and out-migration of Baghdad populations likely had effects on the events reported which we could not measure or estimate. Damage to the health infrastructure and the flight of health workers may have contributed to mortality and morbidity. Civilian injuries as well as mortality should be measured during conflicts, though not currently done.     

A goodness-of-fit test for capture-recapture model Mt under closure

A new, fully efficient goodness-of-fit test for the time-specific closed-population capture-recapture model Mt is presented. This test is based on the residual distribution of the capture history data given the maximum likelihood parameter estimates under model Mt, is partitioned into informative components, and is based on chi-square statistics. Comparison of this test with Leslie's test (Leslie, 1958, Journal of Animal Ecology 27, 84-86) for model Mt, using Monte Carlo simulations, shows the new test generally outperforms Leslie's test. The new test is frequently computable when Leslie's test is not, has Type I error rates that are closer to nominal error rates than Leslie's test, and is sensitive to behavioral variation and heterogeneity in capture probabilities. Leslie's test is not sensitive to behavioral variation in capture probabilities but, when computable, has greater power to detect heterogeneity than the new test.     

Human male pair bonding and testosterone

Previous research in North America has supported the view that male involvement in committed, romantic relationships is associated with lower testosterone (T) levels. Here, we test the prediction that undergraduate men involved in committed, romantic relationships (paired) will have lower T levels than men not involved in such relationships (unpaired). Further, we also test whether these differences are more apparent in samples collected later, rather than earlier, in the day. For this study, 107 undergraduate men filled out a questionnaire and collected one saliva sample (from which a subject’s T level was measured) at various times across the day. As in previous studies, men involved in committed, romantic relationships had lower salivary T levels, though only during later times of the day. Furthermore, additional analysis of the variation among unpaired subjects indicated that men without prior relationship experience had lower T levels than experienced men. Finally, while paired men as a group had lower T levels than unpaired men, those men at the earliest stage (less than six months) of a current relationship had higher T levels than unpaired men as well as men in longer-term relationships. These results suggest that variation in male testosterone levels may reflect differential behavioral allocation to mating effort. Peter Gray recently completed his Ph.D. in biological anthropology at Harvard with a dissertation entitled, "Human Male Reproductive Strategies: Cross-Cultural and Endocrine Aspects." He is now a postdoctoral fellow at Charles Drew University of Medicine and Science, working with Dr. Shalender Bhasin on human androgen research. Judith Flynn Chapman and Matthew McIntyre are Ph.D. candidates inbiological anthropology at Harvard University. Judith Flynn Chapman focuses on variation in human ovarian function. Matthew McIntyre studies the role of testosterone in psychological development. Terry Burnham is an economist at the Harvard Business School. He studies economic behavior in a framework based in evolution by natural selection. Susan Lipson is a Lecturer in Anthropology and director of the Reproductive Ecology Laboratory at Harvard University. Her research includes work on the effects of age and energy balance on female reproductive function, and on hormonal correlates of conception and cancer risk. Peter Ellison is John Cowles Professor of Anthropology and Dean of the Graduate School of Arts and Sciences at Harvard University. He studies hormones, behavior, and the reproductive ecology of humans and nonhuman primates.     

Calmodulin regulates the disassembly of cortical F-actin in mast cells but is not required for secretion

Secretion is dependent on a rise in cytosolic Ca(2+)concentration and is associated with dramatic changes in actin organization. The actin cortex may act as a barrier between secretory vesicles and plasma membrane. Thus, disassembly of this cortex should precede late steps of exocytosis. Here we investigate regulation of both the actin cytoskeleton and secretion by calmodulin. Ca(2+), together with ATP, induces cortical F-actin disassembly in permeabilized rat peritoneal mast cells. This effect is strongly inhibited by removing endogenous calmodulin (using calmodulin inhibitory peptides), and increased by exogenous calmodulin. Neither treatment, however, affects secretion. Low concentrations ( approximately 1 microM) of a specific inhibitor of myosin light chain kinase, ML-7, prevent F-actin disassembly, but not secretion. In contrast, a myosin inhibitor affecting both conventional and unconventional myosins, BDM, decreases cortical disassembly as well as secretion. Observations of fluorescein-calmodulin, introduced into permeabilized cells, confirmed a strong (Ca(2+)-independent) association of calmodulin with the actin cortex. In addition, fluorescein-calmodulin enters the nuclei in a Ca(2+)-dependent manner. In conclusion, calmodulin promotes myosin II-based contraction of the membrane cytoskeleton, which is a prerequisite for its disassembly. The late steps of exocytosis, however, require neither calmodulin nor cortical F-actin disassembly, but may be modulated by unconventional myosin(s).     

Ion pathways in renal brush border membranes

The absorbance change of the weak base dye probe, Acridine orange, was used to monitor alterations of pH gradients across renal brush border membrane vesicles. The presence of Na⁺/H⁺ or Li⁺/H⁺ exchange was demonstrated by diluting Na₂SO₄ or Li₂SO₄ loaded vesicles into Na⁺- or Li⁺-free solutions, which caused dye uptake. About 20% of the uptake was abolished by lipid permeable cations such as valinomycin-K⁺ or tetraphenylphosphonium, indicating perhaps the presence of a finite Na⁺ conductance smaller than electroneutral Na⁺/H⁺ exchange. The protonophore tetrachlorosalicylanilide raised the rate of dye uptake under these conditions, hence the presence of an Na⁺ conductance greater than the H⁺ conductance was suggested. K⁺ gradients also induced changes of pH, at about 10% of the Na⁺ or Li⁺ rate. Partial inhibition (21%) was seen with 0.1 mM amiloride indicating that K⁺ was a low affinity substrate for the Na⁺/H⁺ exchange. Acceleration both by tetrachlorosalicylanilide (2-fold) and valinomycin (4-fold) suggested the presence of 2 classes of vesicles, those with high and those with low K⁺ conductance. The larger magnitude of the valinomycin dependent signal suggested that 75% of the vesicles had a low K⁺ conductance. Inward Cl^? gradients also induced acidification, partially inhibited by the presence of tetraphenylphosphonium, and accelerated by tetrachlorosalicylanilide. Thus both a Cl^? conductance greater than the H⁺ conductance and a Cl^?/OH^? exchange were present. The rate of Na⁺/H⁺ exchange was amiloride sensitive with a pH optimum of 6.5 and an apparent K_m for Na⁺ or Li⁺ of about 10 mM and an E_A of 14.3 kcal per mol. A 61-fold Na₂SO₄ gradient resulted in a pH gradient of 1.64 units which increased to 1.8 with gramicidin. An equivalent NaCl gradient gave a much lower ΔpH even in the presence of gramicidin showing that the H⁺ and Cl^? pathways could alter the effects of the Na⁺/H⁺ exchange.     

Men in committed, romantic relationships have lower testosterone

Variation in human male testosterone levels may reflect, and effect, differential behavioral allocation to mating and parenting effort. This proposition leads to the hypothesis that, among North American men, those involved in committed, romantic relationships will have lower testosterone levels than men not involved in such relationships. Our study is the first to examine whether being in such a relationship (rather than being married) is the meaningful predictor of male testosterone levels. To test this hypothesis, 122 male Harvard Business School students filled out a questionnaire and collected one saliva sample (from which testosterone level was measured). Results revealed that men in committed, romantic relationships had 21% lower testosterone levels than men not involved in such relationships. Furthermore, the testosterone levels of married men and unmarried men who were involved in committed, romantic relationships did not differ, suggesting that, at least for this sample, male pair bonding status is the more significant predictor of testosterone levels than is marital status.     

Conflict-related intentional injuries in Baghdad,Iraq, 2003–2014: A modeling study and proposed method for calculating burden of injury in conflict

BackgroundPrevious research has focused on the mortality associated with armed conflict as the primary measure of the population health effects of war. However, mortality only demonstrates part of the burden placed on a population by conflict. Injuries and resultant disabilities also have long-term effects on a population and are not accounted for in estimates that focus solely on mortality. Our aim was to demonstrate a new method to describe the effects of both lives lost, and years of disability generated by a given conflict, with data from the US-led 2003 invasion and subsequent occupation of Iraq.Methods and findingsOur data come from interviews conducted in 2014 in 900 Baghdad households containing 5,148 persons. The average household size was 5.72 persons. The majority of the population (55.8%) were between the ages of 19 and 60. Household composition was evenly divided between males and females. Household sample collection was based on methodology previously designed for surveying households in war zones. Survey questions were answered by the head of household or senior adult present. The questions included year the injury occurred, the mechanism of injury, the body parts injured, whether injury resulted in disability and, if so, the length of disability.We present this modeling study to offer an innovative methodology for measuring “years lived with disability” (YLDs) and “years of life lost” (YLLs) attributable to conflict-related intentional injuries, using the Global Burden of Disease (GBD) approach. YLDs were calculated with disability weights, and YLLs were calculated by comparing the age at death to the GBD standard life table to calculate remaining life expectancy. Calculations were also performed using Iraq-specific life expectancy for comparison.We calculated a burden of injury of 5.6 million disability-adjusted life years (DALYs) lost due to conflict-related injuries in Baghdad from 2003 to 2014. The majority of DALYs lost were attributable to YLLs, rather than YLDs, 4.99 million YLLs lost (95% uncertainty interval (UI) 3.87 million to 6.13 million) versus 616,000 YLDs lost (95% UI 399,000 to 894,000). Cause-based analysis demonstrated that more DALYs were lost to due to gunshot wounds (57%) than any other cause.Our study has several limitations. Recall bias regarding the reporting and attribution of injuries is possible. Second, we have no data past the time of the interview, so we assumed individuals with ongoing disability at the end of data collection would not recover, possibly counting more disability for injuries occurring later. Additionally, incomplete data could have led to misclassification of deaths, resulting in an underestimation of the total burden of injury.ConclusionsIn this study, we propose a methodology to perform burden of disease calculations for conflict-related injuries (expressed in DALYs) in Baghdad from 2003 to 2014. We go beyond previous reports of simple mortality to assess long-term population health effects of conflict-related intentional injuries. Ongoing disability is, in cross section, a relatively small 10% of the total burden. Yet, this small proportion creates years of demands on the health system, persistent limitations in earning capacity, and continuing burdens of care provision on family members.

In a modelling study, Guy Jensen and colleagues propose a method for calculating burden of injury in conflict using data on conflict-related intentional injuries in Baghdad, Iraq 2003-2014.     

Spectra, membrane binding, and potentiometric responses of new charge shift probes

The properties of a series of new potentiometric membrane probes have been explored. The probes all contain an (aminostyryl)pyridinium chromophore or a more highly conjugated analogue. The spectral properties of the dyes are discussed in terms of the excitation-induced charge shift from the pyridine to the aniline; this charge shift also provides the basis for the voltage dependence of the spectra according to an electrochromic mechanism. The spectral responses to a membrane potential on a hemispherical bilayer have been obtained and, grossly, are quite similar for all probes tested. The more subtle variations from dye to dye can be partially rationalized by consideration of binding parameters, the depth within the membrane, and structural factors. The most potential sensitive dye in this collection has been designated di-4-ANEPPS and has a 6-amino-2-naphthyl group in place of the p-anilino on the parent chromophore. Both the relative fluorescence emission and excitation responses have maxima of 8% per 100 mV, and these two spectra display a striking symmetry.