Mammary mechanobiology - investigating roles for mechanically activated ion channels in lactation and involution.

The ability of a mother to produce a nutritionally complete neonatal food source has provided a powerful evolutionary advantage to mammals. Milk production by mammary epithelial cells is adaptive, its release is exquisitely timed, and its own glandular stagnation with the permanent cessation of suckling triggers the cell death and tissue remodeling that enables female mammals to nurse successive progeny. Chemical and mechanical signals both play a role in this process. However, despite this duality of input, much remains unknown about the nature and function of mechanical forces in this organ. Here, we characterize the force landscape in the functionally mature gland and the capacity of luminal and basal cells to experience and exert force. We explore molecular instruments for force-sensing, in particular channel-mediated mechanotransduction, revealing increased expression of Piezo1 in mammary tissue in lactation and confirming functional expression in luminal cells. We also reveal, however, that lactation and involution proceed normally in mice with luminal-specific Piezo1 deletion. These findings support a multifaceted system of chemical and mechanical sensing in the mammary gland, and a protective redundancy that ensures continued lactational competence and offspring survival.

Evolution of resistance to single and combined floral phytochemicals by a bumble bee parasite.

Repeated exposure to inhibitory compounds can drive the evolution of resistance, which weakens chemical defence against antagonists. Floral phytochemicals in nectar and pollen have antimicrobial properties that can ameliorate infection in pollinators, but evolved resistance among parasites could diminish the medicinal efficacy of phytochemicals. However, multicompound blends, which occur in nectar and pollen, present simultaneous chemical challenges that may slow resistance evolution. We assessed evolution of resistance by the common bumble bee gut parasite Crithidia bombi to two floral phytochemicals, singly and combined, over 6 weeks (~100 generations) of chronic exposure. Resistance of C. bombi increased under single and combined phytochemical exposure, without any associated costs of reduced growth under phytochemical-free conditions. After 6 weeks' exposure, phytochemical concentrations that initially inhibited growth by > 50%, and exceeded concentrations in floral nectar, had minimal effects on evolved parasite lines. Unexpectedly, the phytochemical combination did not impede resistance evolution compared to single compounds. These results demonstrate that repeated phytochemical exposure, which could occur in homogeneous floral landscapes or with therapeutic phytochemical treatment of managed hives, can cause rapid evolution of resistance in pollinator parasites. We discuss possible explanations for submaximal phytochemical resistance in natural populations. Evolved resistance could diminish the antiparasitic value of phytochemical ingestion, weakening an important natural defence against infection.

Conspecific and Heterospecific Aboveground Herbivory Both Reduce Preference by a Belowground Herbivore.

Insect herbivores damage plants both above- and belowground, and interactions in each realm can influence the other via shared hosts. While effects of leaf damage on aboveground interactions have been well-documented, studies examining leaf damage effects on belowground interactions are limited, and mechanisms for these indirect interactions are poorly understood. We examined how leaf herbivory affects preference of root-feeding larvae [Acalymma vittatum F. (Coleoptera: Chrysomelidae)] in cucumber (Cucumis sativus L.). We manipulated leaf herbivory using conspecific adult A. vittatum and heterospecific larval Spodoptera frugiperda Smith (Lepidoptera: Noctuidae) herbivores in the greenhouse and the conspecific only in the field, allowing larvae to choose between roots of damaged and undamaged plants. We also examined whether leaf herbivory induced changes in defensive cucurbitacin C in leaves and roots. We hypothesized that induced changes in roots would deter larvae, and that effects would be stronger for damage by conspecifics than the unrelated caterpillar because the aboveground damage could be a cue to plants indicating future root damage by the same species. In both the greenhouse and field, plants with damaged leaves recruited significantly fewer larvae to their roots than undamaged plants. Effects of conspecific and heterospecific damage did not differ. Leaf damage did not induce changes in leaf or root cucurbitacin C, but did reduce root biomass. While past work has suggested that systemic induction by aboveground herbivory increases resistance in roots, our results suggest that decreased preference by belowground herbivores in this system may be because of reduced root growth.

Global quantification of tissue dynamics in the developing mouse kidney.

Although kidneys of equal size can vary 10-fold in nephron number at birth, discovering what regulates such variation has been hampered by a lack of quantitative parameters defining kidney development. Here we report a comprehensive, quantitative, multiscale analysis of mammalian kidney development in which we measure changes in cell number, compartment volumes, and cellular dynamics across the entirety of organogenesis, focusing on two key nephrogenic progenitor populations: the ureteric epithelium and the cap mesenchyme. In doing so, we describe a discontinuous developmental program governed by dynamic changes in interactions between these key cellular populations occurring within a previously unappreciated structurally stereotypic organ architecture. We also illustrate the application of this approach to the detection of a subtle mutant phenotype. This baseline program of kidney morphogenesis provides a framework for assessing genetic and environmental developmental perturbation and will serve as a gold standard for the analysis of other organs.

The effects of temporally secondary co-morbid mental disorders on the associations of DSM-IV ADHD with adverse outcomes in the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A).

BACKGROUND: Although DSM-IV attention deficit hyperactivity disorder (ADHD) is known to be associated with numerous adverse outcomes, uncertainties exist about how much these associations are mediated temporally by secondary co-morbid disorders. METHOD: The US National Comorbidity Survey Replication Adolescent Supplement (NCS-A), a national survey of adolescents aged 13-17 years (n = 6483 adolescent-parent pairs), assessed DSM-IV disorders with the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI). Statistical decomposition was used to compare direct effects of ADHD with indirect effects of ADHD through temporally secondary mental disorders (anxiety, mood, disruptive behavior, substance disorders) in predicting poor educational performance (suspension, repeating a grade, below-average grades), suicidality (ideation, plans, attempts) and parent perceptions of adolescent functioning (physical and mental health, interference with role functioning and distress due to emotional problems). RESULTS: ADHD had significant gross associations with all outcomes. Direct effects of ADHD explained most (51.9-67.6%) of these associations with repeating a grade in school, perceived physical and mental health (only girls), interference with role functioning and distress, and significant components (34.5-44.6%) of the associations with school suspension and perceived mental health (only boys). Indirect effects of ADHD on educational outcomes were predominantly through disruptive behavior disorders (26.9-52.5%) whereas indirect effects on suicidality were predominantly through mood disorders (42.8-59.1%). Indirect effects on most other outcomes were through both mood (19.8-31.2%) and disruptive behavior (20.1-24.5%) disorders, with anxiety and substance disorders less consistently important. Most associations were comparable for girls and boys. CONCLUSIONS: Interventions aimed at reducing the adverse effects of ADHD might profitably target prevention or treatment of temporally secondary co-morbid disorders.

Indirect effects on mutualisms: parasitism of bumble bees and pollination service to plants.

Researchers increasingly recognize the important role of mutualisms in structuring communities and view positive interactions in a community context rather than as simple pairwise interactions. Indirect effects, such as those that predators have on lower trophic levels, are a key process in community ecology. However, such top-down indirect effects have rarely been extended to mutualisms. Antagonists of one mutualist have the potential to negatively affect the second mutualist through negative effects on their partner, and the magnitude of such effects should vary with mutualism strength. Bumble bees are ecologically and economically important pollinators that are an ideal system to determine if such indirect effects play an important role in mutualisms. Bumble bees are attacked by an array of parasites and predators, and they interact with a range of plants that vary in their dependence on bumble bees for reproduction. We tested whether variation in parasitism rates by Nosema bombi, Crithidia bombi, and conopid flies correlated with reproduction of greenhouse-raised plants placed in the field. At multiple sites over two years, we studied four plant species that varied in reliance on bumble bees as pollinators. We found a consistent negative relationship between Nosema parasitism and measures of pollination for Trifolium pratense and Solanum carolinense, plant species with high bumble bee visitation, whereas Rudbeckia hirta and Daucus carota, plant species with generalized pollination, experienced no impacts of Nosema. However, both Crithidia and conopids showed inconsistent relationships with pollination service. Although these patterns are correlational, they provide evidence that parasites of bumble bees may have negative indirect effects on plants, and that mutualism strength can moderate the magnitude of such effects.

MALT lymphoma in labial salivary gland biopsy from Sjögren syndrome: importance of follow-up in early detection.

Mucosa-associated lymphoid tissue (MALT) lymphomas are known to occur in Sjögren syndrome (SS) patients, but reported cases in labial salivary glands (LSG) are rare. We report a case of 60-year-old female patient with SS who developed MALT lymphoma in the labial salivary glands during a 2-year time interval when she was participating in the Sjögren's International Clinical Collaborative Alliance, an ongoing longitudinal multisite observational study funded by the National Institutes of Health of the United States. At follow-up exam, LSG biopsy showed atypical diffuse infiltration by mononuclear cells of variable size and atypical nuclei affecting the whole specimen with destruction of glandular architecture, leading to a diagnosis of B-cell MALT lymphoma. Computerized tomography and bone marrow biopsy failed to show additional evidence of disease. Clinical, serologic, ocular, histologic and immunohistochemical findings are presented. A "watch and wait" policy was adopted with regular examinations.

LuxS distribution and AI-2 activity of Campylobacter spp.

AIMS: This study investigates the distribution of LuxS within Campylobacter (Camp.) species and Autoinducer (AI)-2 activity of Camp. jejuni NCTC 11168 in food matrices. METHODS AND RESULTS: LuxS (S-ribosylhomocysteinase) sequences of different Campylobacter spp. were compared, and AI-2 activity was measured with an AI-2 reporter assay. Highest LuxS homologies were shared by Camp. jejuni, Camp. coli and Camp. upsaliensis, and their LuxS sequences had more similarities to the analysed Arcobacter and Vibrio harveyi strains than to all other analysed Campylobacter species. Of 15 analysed species only Camp. lari, Camp. peloridis and Camp. insulaenigrae did not produce AI-2 molecules. Cultivation of Camp. jejuni NCTC 11168 in chicken juice reduced AI-2 activity, and this reduction is not because of lower luxS expression or functionality. CONCLUSION: Not all Campylobacter species encode luxS. Food matrices can reduce AI-2 activity in a LuxS-independent manner. SIGNIFICANCE AND IMPACT OF THE STUDY: Besides, Camp. lari, Camp. peloridis and Camp. insulaenigrae do not show AI-2 activity. Further investigations should clarify the function of AI-2 in Campylobacter spp. and how species lacking luxS could overcome this alteration. Furthermore, the impact of food matrices on these functions needs to be determined as we could show that chicken juice reduced AI-2 activity.

Nephron formation adopts a novel spatial topology at cessation of nephrogenesis.

Nephron number in the mammalian kidney is known to vary dramatically, with postnatal renal function directly influenced by nephron complement. What determines final nephron number is poorly understood but nephron formation in the mouse kidney ceases within the first few days after birth, presumably due to the loss of all remaining nephron progenitors via epithelial differentiation. What initiates this event is not known. Indeed, whether nephron formation occurs in the same way at this time as during embryonic development has also not been examined. In this study, we investigate the key cellular compartments involved in nephron formation; the ureteric tip, cap mesenchyme and early nephrons; from postnatal day (P) 0 to 6 in the mouse. High resolution analyses of gene and protein expression indicate that loss of nephron progenitors precedes loss of ureteric tip identity, but show spatial shifts in the expression of cap mesenchyme genes during this time. In addition, cap mesenchymal volume and rate of proliferation decline prior to birth. Section-based 3D modeling and Optical Projection Tomography revealed a burst of ectopic nephron induction, with the formation of multiple (up to 5) nephrons per ureteric tip evident from P2. While the distal-proximal patterning of these nephrons occurred normally, their spatial relationship with the ureteric compartment was altered. We propose that this phase of nephron formation represents an acceleration of differentiation within the cap mesenchyme due to a displacement of signals within the nephrogenic niche.

Comparison of perimeter trap crop varieties: effects on herbivory, pollination, and yield in butternut squash.

Perimeter trap cropping (PTC) is a method of integrated pest management (IPM) in which the main crop is surrounded with a perimeter trap crop that is more attractive to pests. Blue Hubbard (Cucurbita maxima Duch.) is a highly effective trap crop for butternut squash (C. moschata Duch. ex Poir) attacked by striped cucumber beetles (Acalymma vittatum Fabricius), but its limited marketability may reduce adoption of PTC by growers. Research comparing border crop varieties is necessary to provide options for growers. Furthermore, pollinators are critical for cucurbit yield, and the effect of PTC on pollination to main crops is unknown. We examined the effect of five border treatments on herbivory, pollination, and yield in butternut squash and manipulated herbivory and pollination to compare their importance for main crop yield. Blue Hubbard, buttercup squash (C. maxima Duch.), and zucchini (C. pepo L.) were equally attractive to cucumber beetles. Border treatments did not affect butternut leaf damage, but butternut flowers had the fewest beetles when surrounded by Blue Hubbard or buttercup squash. Yield was highest in the Blue Hubbard and buttercup treatments, but this effect was not statistically significant. Native bees accounted for 87% of pollinator visits, and pollination did not limit yield. There was no evidence that border crops competed with the main crop for pollinators. Our results suggest that both buttercup squash and zucchini may be viable alternatives to Blue Hubbard as borders for the main crop of butternut squash. Thus, growers may have multiple border options that reduce pesticide use, effectively manage pests, and do not disturb mutualist interactions with pollinators.

Using trap crops for control of Acalymma vittatum (Coleoptera: Chrysomelidae) reduces insecticide use in butternut squash.

Striped cucumber beetle, Acalymma vittatum F., is the primary insect pest of cucurbit crops in the northeastern United States. Adult beetles colonize squash crops from field borders, causing feeding damage at the seedling stage and transmitting bacterial wilt Erwinia tracheiphila Hauben et al. 1999. Conventional control methods rely on insecticide applications to the entire field, but surrounding main crops with a more attractive perimeter could reduce reliance on insecticides. A. cittatum shows a marked preference for Blue Hubbard squash (Cucurbita maxima Duchesne) over butternut squash (C. moschata Poir). Given this preference, Blue Hubbard squash has the potential to be an effective perimeter trap crop. We evaluated this system in commercial butternut fields in 2003 and 2004, comparing fields using perimeter trap cropping with Blue Hubbard to conventionally managed fields. In 2003, we used a foliar insecticide to control beetles in the trap crop borders, and in 2004, we compared systemic and foliar insecticide treatments for the trap crop borders. We found that using a trap crop system reduced or eliminated the need to spray the main crop area, reducing insecticide use by up to 94% compared with conventional control methods, with no increase in herbivory or beetle numbers. We surveyed the growers who participated in these experiments and found a high level of satisfaction with the effectiveness and simplicity of the system. These results suggest that this method of pest control is both effective and simple enough in its implementation to have high potential for adoption among growers.

[Stability of the "amok runner syndrome"]. / Zur Stabilität des "Amokläufer"-Syndroms.

BACKGROUND: Running amok is considered a rare but dangerous act of violence which has been investigated predominantly on a case by case basis. German-wide data on amok cases covering the decades 1980 - 1989 and 1991 - 2000 were used to perform the first epidemiological study world-wide on the stability of socio-demographic, criminological and psychiatric variables of amok behaviour. METHODS: A content analysis study on nation-wide press reports of amok cases included a total of 104 subjects who were identified by combined homicidal-suicidal acts of violence and fulfilled structured criteria originally defined according to former Malayan amok events. RESULTS: Amok cases in both decades were comparable except for the significant increase of weapon use, especially of firearms. Total prevalence showed a tendency to decline from 1 : 5.5 million to 1 : 8.5 million men per year, females were involved in rare single cases only. The male offenders showed a bimodal age distribution with a mean of 35 years. They were professionally well qualified, but had a 5 - 7fold higher risk of unemployment than the normal population. Motives and reasons for running amok were serious but not unusual, they varied widely and addressed all areas of daily life. Most offenders were characterized by abnormal personality patterns such as passive, aggressive, impulsive and paranoid and were in possession of firearms and previously convicted. Psychiatric diseases such as psychosis, paranoia, depression or personality disorders were present in more than 50 % of cases; further 20 % were intoxicated. The presence of psychiatric disorders influenced patterns of violent behaviour in individual subjects. Victims were predominantly unknown to the offenders. Close to one third of the amok runners committed suicide or were killed by legal authorities. CONCLUSION: Amok represents a temporarily stable syndrome of extreme violent behaviour even in modern industrialized societies. Subjects exhibit a complex combination of serious causative motives, social burden and psychiatric diseases which do not explain common causes of amok rather than the origin of amok behaviour in individual cases. Amok joins the wide spectrum of human homicidal-suicidal acts which show similarities in many aspects.

Characterization of allelic variants at chromosome 15q14 in schizophrenia.

Evidence of genetic linkage for schizophrenia at chromosome 15q14 has been reported in nine independent studies, but the molecular variants responsible for transmission of genetic risk are unknown. National Institute of Mental Health Schizophrenia Genetics Initiative families were genotyped for single nucleotide polymorphisms (SNPs) and dinucleotide repeat markers in the 15q14 linkage region and analyzed based on the presence of particular alleles of the dinucleotide repeat marker D15S165 in the 15q14 region. Two alleles showed both familial transmission disequilibrium and population-wide association with schizophrenia. The two groups identified by these two D15S165 alleles differ in age of onset, number of hospitalizations and intensity of nicotine abuse, as well as in predominant ethnicity. Variations in the frequency of SNPs in CHRNA7, the alpha-7-nicotinic acetylcholine receptor subunit gene at 15q14, were found in each group. Further sequencing in these two groups may yield more definitive identification of the molecular pathology.

Association between body weight of newborn rats and density of serotonin transporters in the frontal cortex at adulthood.

Persisting alterations in monoaminergic innervation patterns have been observed following various environmental manipulations and neuro-psychopharmacological treatments during fetal or early postnatal life. The present study investigates the question how differences in initial growth conditions at birth might interfere with subsequent development of both serotonergic and noradrenergic innervation in the rat frontal cortex (FC) and brain stem. For this purpose, newborn rat littermates were divided into two groups, a low and a high birth weight group, and the densities of both serotonin (5-HT) and norepinephrine (NE) transporters in the FC and brain stem were analyzed at adulthood. 5-HT transporter density in the FC was significantly higher in the high birth weight group as compared with the low birth weight group. No significant differences were observed between both groups in the density of 5-HT transporters in the brain stem and in the densities of NE transporters in FC and brain stem. It is discussed that differences in birth weight may affect the postnatal development of 5-HT projections to the frontal cortex.

Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma.

BACKGROUND: Roflumilast is an oral, once-daily phosphodiesterase 4 inhibitor with anti-inflammatory activity in development for the treatment of asthma. Roflumilast was compared with inhaled beclomethasone dipropionate (BDP) in patients with asthma. METHODS: In a double blind, double-dummy, randomized, noninferiority study, 499 patients (forced expiratory volume in 1 s [FEV1] = 50-85% predicted) received roflumilast 500 microg once daily or BDP 200 microg twice daily (400 microg/day) for 12 weeks. Lung function and adverse events were monitored. RESULTS: Roflumilast and BDP significantly improved FEV1 by 12% (270 +/- 30 ml) and 14% (320 +/- 30 ml), respectively (P < 0.0001 vs baseline). Roflumilast and BDP also significantly improved forced vital capacity (FVC) (P < 0.0001 vs baseline). There were no significant differences between roflumilast and BDP with regard to improvement in FEV1 and FVC. Roflumilast and BDP showed small improvements in median asthma symptom scores (-0.82 and -1.00, respectively) and reduced rescue medication use (-1.00 and -1.15 median puffs/day, respectively; P < 0.0001 vs baseline). These small differences between roflumilast and BDP were not considered clinically relevant. Both agents were well tolerated. CONCLUSIONS: Once daily, oral roflumilast 500 microg was comparable with inhaled twice-daily BDP (400 microg/day) in improving pulmonary function and asthma symptoms, and reducing rescue medication use in patients with asthma.

The YIG1 (YPL201c) encoded protein is involved in regulating anaerobic glycerol metabolism in Saccharomyces cerevisiae.

Under anaerobic conditions S. cerevisiae produces glycerol to regenerate NAD(+) from the excess NADH produced in cell metabolism. We here report on the role of an uncharacterized protein, Yig1p (Ypl201cp), in anaerobic glycerol production. Yig1p was previously shown to interact in two-hybrid tests with the GPP1 and GPP2 encoded glycerol 3-phosphatase (Gpp), and we here demonstrate that strains overexpressing YIG1 show strongly decreased Gpp activity and content of the major phosphatase, Gpp1p. However, cells overexpressing YIG1 exhibited only slightly decreased GPP1 transcript levels, suggesting that Yig1p modulates expression on both transcriptional and post-transcriptional levels. In agreement with such a role, a GFP-tagged derivate of Yig1p was localized to both the cytosol and the nucleus. Deletion or overexpression of YIG1 did not, however, significantly affect growth yield or glycerol yield in anaerobic batch cultures, which is consistent with the previously proposed low flux control exerted at the Gpp level.

Gender differences in plasma levels of lipoprotein (a) in patients with angiographically proven coronary artery disease.

The objective of the study was to assess the association between plasma levels of lipoprotein(a) [Lp(a)] and the presence of angiographically defined coronary artery disease (aCAD). Patients (346 men and 184 women) undergoing selective coronary angiography (SCA) were classified into groups with positive [aCAD(+)] and negative [aCAD(-)] findings and their age, body mass index (BMI), waist circumference, blood pressure, smoking, plasma total, LDL-, HDL-cholesterol (TC, LDL-C, HDL-C), triglycerides (TG), apolipoprotein B (apoB), Log(TG/HDL-C) and TC/HDL-C were determined. Concentration of plasma Lp(a) was estimated using the commercial solid phase two-side immunoradiometric assay of apolipoprotein apo(a). The plasma Lp(a) was significantly higher in both women and men with aCAD(+) compared to those with aCAD(-). While there was no significant difference in the Lp(a) level between men and women with aCAD(-) (median 138 vs. 145 units/l), the women with aCAD(+) had almost twice as high Lp(a) levels as men (median 442 vs. 274 units/l, p<0.001). Women with aCAD(+) had also significantly lower HDL cholesterol levels (1.09 vs. 1.20 mmol/l, p<0.05), higher triglycerides (1.82 vs. 1.46 mmol/l, p<0.05) and Log(TG/HDL-C) than women with aCAD(-). The differences in Lp(a) between positive and negative findings remained highly significant (p<0.001 in women, p<0.05 in men) after the adjustment for age, plasma HDL- and LDL-cholesterol and triglycerides in logistic regression analyses. In logistic regression model the Lp(a) and Log(TG/HDL-C) and smoking in women but smoking and age in men were the most powerful predictors of positive aCAD findings. Our findings suggest that Lp(a) is more strongly associated with aCAD+ in women than in men.

Modulated angle beam ultrasonic spectroscopy for evaluation of imperfect interfaces and adhesive bonds.

An experimental method incorporating high frequency pulsed angle beam ultrasonic measurements modulated by low frequency vibrations of a bonded structure is described. This method uses parametric/nonlinear mixing between high and low frequencies to characterize adhesive degradation. It is demonstrated that good quality (undamaged) bonds exhibit little dependence of ultrasonic signature on the overlay of low frequency vibration loads; however, environmentally degraded or imperfect bonds exhibit strong modulation of the resonance frequency of the ultrasonic signal reflected from the bond. The results are interpreted using a model for normal and oblique wave interaction with two nonlinear interfaces separated by an adhesive layer under quasi-static stress modulation.

Attention-deficit/hyperactivity disorder in adult patients with posttraumatic stress disorder (PTSD): is ADHD a vulnerability factor?

OBJECTIVE: There is limited evidence suggesting a link between posttraumatic stress disorder (PTSD) and Attention-Deficit/ Hyperactivity Disorder (ADHD). This study examined the association between PTSD and ADHD using retrospective and current clinical evaluations. METHOD: Twenty-five male veterans with PTSD and 22 male veterans with panic disorder were evaluated for ADHD. The data was analyzed using chi-square and student's t-tests. RESULTS: Thirty-six percent of participants with PTSD and 9% of participants with panic disorder met criteria for childhood ADHD. Twenty-eight percent of participants with PTSD and 5% of participants with panic disorder met criteria for current ADHD. CONCLUSIONS: There appears to be a significant association of PTSD with ADHD. ADHD or common predisposing factors may increase the vulnerability for developing PTSD.

Interpreting abnormality: an EEG and MEG study of P50 and the auditory paired-stimulus paradigm.

Interpretation of neurophysiological differences between control and patient groups on the basis of scalp-recorded event-related brain potentials (ERPs), although common and promising, is often complicated in the absence of information on the distinct neural generators contributing to the ERP, particularly information regarding individual differences in the generators. For example, while sensory gating differences frequently observed in patients with schizophrenia in the P50 paired-click gating paradigm are typically interpreted as reflecting group differences in generator source strength, differences in the latency and/or orientation of P50 generators may also account for observed group differences. The present study examined how variability in source strength, amplitude, or orientation affects the P50 component of the scalp-recorded ERP. In Experiment 1, simulations examined the effect of changes in source strength, orientation, or latency in superior temporal gyrus (STG) dipoles on P50 recorded at Cz. In Experiment 2, within- and between-subject variability in left and right M50 STG dipole source strength, latency, and orientation was examined in 19 subjects. Given the frequently reported differences in left and right STG anatomy and function, substantial inter-subject and inter-hemispheric variability in these parameters were expected, with important consequences for how P50 at Cz reflects brain activity from relevant generators. In Experiment 1, simulated P50 responses were computed from hypothetical left- and right-hemisphere STG generators, with latency, amplitude, and orientation of the generators varied systematically. In Experiment 2, electroencephalographic (EEG) and magnetoencephalographic (MEG) data were collected from 19 subjects. Generators were modeled from the MEG data to assess and illustrate the generator variability evaluated parametrically in Experiment 1. In Experiment 1, realistic amounts of variability in generator latency, amplitude, and orientation produced ERPs in which P50 scoring was compromised and interpretation complicated. In Experiment 2, significant within and between subject variability was observed in the left and right hemisphere STG M50 sources. Given the variability in M50 source strength, orientation, and amplitude observed here in nonpatient subjects, future studies should examine whether group differences in P50 gating ratios typically observed for patient vs. control groups are specific to a particular hemisphere, as well as whether the group differences are due to differences in dipole source strength, latency, orientation, or a combination of these parameters. Present analyses focused on P50/M50 merely as an example of the broader need to evaluate scalp phenomena in light of underlying generators. The development and widespread use of EEG/MEG source localization methods will greatly enhance the interpretation and value of EEG/MEG data.