When can we trust structural models derived from pair distribution function measurements?

The pair distribution function (PDF) is an important metric for characterising structure in complex materials, but it is well known that meaningfully different structural models can sometimes give rise to equivalent PDFs. In this paper, we discuss the use of model likelihoods as a general approach for discriminating between such homometric structure solutions. Drawing on two main case studies-one concerning the structure of a small peptide and the other amorphous calcium carbonate-we show how consideration of model likelihood can help drive robust structure solution, even in cases where the PDF is particularly information-poor. The obvious thread of these individual case studies is the potential role for machine-learning approaches to help guide structure determination from the PDF, and our paper finishes with some forward-looking discussion along these lines.

Acute Idiopathic Blind Spot Enlargement and Acute Zonal Occult Outer Retinopathy: Potential Mimics of Neuro-Ophthalmic Disease.

In 1988, William Hoyt, MD, et al described "acute idiopathic blind spot enlargement" (AIBSE) in 7 symptomatic patients who had no apparent abnormalities of the optic disc or surrounding retina. With the use of multifocal electroretinography, they showed that the scotoma was caused by occult retinal dysfunction. In 1992, J. Donald Gass, MD, described "acute zonal occult outer retinopathy" (AZOOR) in 13 patients who had sudden loss of often large zones of visual field without fundus abnormalities. Most patients developed zonal atrophy of retinal pigment epithelium and had no improvement in vision. Gass believed that AZOOR, multiple evanescent white dot syndrome, multifocal choroiditis, and AIBSE were all variants of the same disorder. Despite over 3 decades of numerous reports, the classification of these entities, their pathogenesis, and treatment remain controversial. AIBSE and AZOOR may be mistaken for an acute optic neuropathy, so it behooves the neuro-ophthalmologist to be familiar with these disorders. This review describes the initial recognition of AIBSE and its relationship to AZOOR.

Effect of Increasing Malpractice Insurance Cost and Subsequent Practice of Defensive Medicine on Out-of-Hospital Birth Rates in the United States.

BACKGROUND: Across the United States, the burden of malpractice litigation has influenced obstetricians and obstetric institutions to avoid high-risk patients, favor cesarean delivery, and decrease availability of trial of labor after cesarean. Recently, the United States has experienced an increase in out-of-hospital (OOH) births. OBJECTIVE: The main purpose of this article is to investigate the association between malpractice insurance premium (MIP) and OOH births in the United States from 2000 to 2014. STUDY DESIGN: We analyzed changes in OOH birth rates and MIP from 2000 to 2014 using birth data from the National Vital Statistics System and Medical Liability Monitor's annual survey, respectively. The change in OOH birth rates was then compared with the change in MIP. RESULTS: Between 2000 and 2014, there has been approximately 60% increase in MIP from national average of $40,949 to $65,210 (p < 0.05). OOH births increased 57% from 39,398 births to 59,674 births (p < 0.05). There was a significant positive correlation between increase in MIP and increase in OOH births (p < 0.05, R 2 = 0.14). CONCLUSION: MIP and OOH birth rates have a significantly associated increase from 2000 to 2014. Given that malpractice climate affects other aspects of obstetric practice, we cautiously propose that increasing MIP may be associated with an increase in OOH births.

Multidecadal variability in Atlas cedar growth in Northwest Africa during the last 850 years: Implications for dieback and conservation of an endangered species.

Widespread forest dieback is a phenomenon of global concern that requires an improved understanding of the relationship between tree growth and climate to support conservation efforts. One priority for conservation is the Atlas cedar (Cedrus atlantica), an endangered species exhibiting dieback throughout its North African range. In this study, we evaluate the long-term context for recent dieback and develop a projection of future C. atlantica growth by exploring the periodic variability of its growth through time. First, we present a new C. atlantica tree-ring chronology (1150-2013 CE) from the Middle Atlas mountains, Morocco. We then compare the new chronology to existing C. atlantica chronologies in Morocco and use principal components analysis (PCA) to isolate the common periodic signal from the seven longest available records (PCA7, 1271-1984 CE) in the Middle and High Atlas portions of the C. atlantica range. PCA7 captures 55.7% of the variance and contains significant multidecadal (˜95 yr, ˜57 yr, ˜21 yr) periodic components, revealed through spectral and wavelet analyses. Parallel analyses of historical climate data (1901-2016 CE) suggests that the multidecadal growth signal originates primarily in growing season (spring and summer) precipitation variability, compounded by slow-changing components of summer and winter temperatures. Finally, we model the long-term growth patterns between 1271-1984 CE using a small number (three to four) of harmonic components, illustrating that suppressed growth since the 1970s - a factor implicated in the dieback of this species - is consistent with recurrent climatically-driven growth declines. Forward projection of this model suggests two climatically-favourable periods for growth in the 21st century that may enhance current conservation actions for the long-term survival of the C. atlantica in the Middle and High Atlas mountains.

Obesity and Weight Loss in Idiopathic Intracranial Hypertension: A Narrative Review.

BACKGROUND: Most patients with idiopathic intracranial hypertension (IIH) are obese. Weight loss is felt to be an important factor in improving IIH. The mechanism by which weight loss leads to a reduction in elevated intracranial pressure is unclear. Evidence from prospective studies evaluating the role of weight loss in IIH is lacking. EVIDENCE ACQUISITION: We performed a detailed review of the published literature regarding the association of IIH and obesity, including proposed pathogenetic mechanisms, and the effect of weight loss and weight-loss interventions in IIH. References were identified by searching PubMed with the terms idiopathic intracranial hypertension and weight loss. Additional citations were found in the identified references. RESULTS: Over 90% of IIH patients are obese or overweight. The risk of IIH increases as a function of body mass index (BMI) and weight gain over the preceding year. The risk of IIH-induced vision loss also increases with increasing BMI, especially with BMI >40 kg/m. Several mechanisms have been proposed linking obesity to the development of IIH but the pathophysiology remains unknown. Published studies and clinical observations strongly support weight loss as an effective treatment, although there are no prospective controlled trials. Weight loss in the range of 6%-10% often leads to IIH remission. Weight loss of ≥5% at 1 year is achieved in roughly 50%-70% of patients if they are enrolled in a high-intensity lifestyle modification program and in 20%-35% of patients if they direct their own weight loss. Weight is typically regained over 1-3 years but about a third of patients maintain ≥5% weight loss over the long term. Patients treated initially with lifestyle modification therapy show a modest persisting benefit over self-directed patients. Selected commercial weight loss programs also may improve long-term maintenance of weight loss. New antiobesity drugs significantly improve the proportion of obese patients who have ≥5% loss of weight at 1 year. CONCLUSIONS: Obesity is an important contributing factor for the development of IIH, although the pathophysiological mechanism linking obesity to IIH is unknown. The risk of developing IIH and associated visual loss increases with increasing BMI. Weight loss is an effective treatment for IIH. Long-term maintenance of initial weight loss is helped modestly by lifestyle modification programs and possibly by selected commercial weight loss programs. New antiobesity drugs may provide further options for IIH therapy in the future.

Mid-term efficacy of the Cartiva synthetic cartilage implant in symptomatic hallux rigidus.

Aims: The Cartiva synthetic cartilage implant (SCI) entered mainstream use in the management of first metatarsophalangeal joint (MTPJ) arthritis following the positive results of large trials in 2016. Limited information is available on the longer-term outcomes of this implant within the literature, particularly when independent from the originator. This single-centre cohort study investigates the efficacy of the Cartiva SCI at up to five years. Methods: First MTPJ arthritis was radiologically graded according to the Hattrup and Johnson (HJ) classification. Preoperative and sequential postoperative patient-reported outcome measures (PROMs) were evaluated using the Manchester-Oxford Foot Questionnaire (MOXFQ), and the activities of daily living (ADL) sub-section of the Foot and Ankle Ability Measure (FAAM). Results: Patients were followed up for a mean of 66 months (SD 7.1). Of an initial 66 cases, 16 did not return PROM questionnaires. A total of six failures were noted, with survival of 82%. Overall, significant improvement in both objective scores (MOXFQ and FAAM ADL) was maintained versus preoperatively: 18.2 versus 58.0 (p > 0.001) and 86.2 versus 41.1 (p > 0.001), respectively. The improvement was noted to be less pronounced in males. Subjective scores had deteriorated since early follow-up, with an interval decrease in patient satisfaction from 89% to 68%. Furthermore, a subset of cases demonstrated clinically important interval deterioration in objective scores. However, no specific patient factors were found to be associated with outcomes following analysis. Conclusion: This study represents the longest-term independent follow-up in the literature. It shows reassuring mid-term efficacy of the Cartiva SCI with better-than-expected survival. However, deterioration in scores for a subset of patients and lower satisfaction may predict ongoing failure in this group of patients. Additionally, males were noted to have a lower degree of improvement in scores than females. As such, ongoing observation of the SCI to assess durability and survivability, and identify predictive factors, is key to improving patient selection.

Efficient induction of spawning of northern leopard frogs (Lithobates pipiens) during and outside the natural breeding season.

BACKGROUND: Amphibian declines are now recognized globally. It is also well known that many anurans do not reproduce easily in captivity, especially when held over long periods, or if they require hibernation before breeding. A simple method to induce spawning and subsequent development of large numbers of healthy tadpoles is therefore required to meet research and conservation goals. METHODS: The method is based on simultaneous injection of both female and male leopard frogs, Lithobates pipiens (formerly called Rana pipiens) with a cocktail of a gonadotropin-releasing hormone agonist (GnRH-A) and a dopamine antagonist. We call this the AMPHIPLEX method, which is derived from the combination of the words amphibian and amplexus. Following injection, the animals are thereby induced, and perform amplexus and natural fertilization under captive conditions. RESULTS: We tested combinations of a GnRH agonist with 2 different dopamine antagonists in L. pipiens in the breeding season. The combination of des-Gly(10), D-Ala(6), Pro-NHEt(9)-GnRH (0.4 micrograms/g body weight; GnRH-A) with metoclopramide hydrochloride (10 micrograms/g body weight; MET) or domperidone (DOM) were equally effective, producing 89% and 88% successful spawning, respectively. This yielded more than 44,000 eggs for the 16/18 females that ovulated in the GnRH-A+MET group, and more than 39,000 eggs for the 15/17 females that ovulated in the GnRH-A+DOM group. We further tested the GnRH-A+MET in frogs collected in the wild in late autumn and hibernated for a short period under laboratory conditions, and report a low spawning success (43%). However, GnRH-A priming 24 hours prior to injections of the GnRH-A+MET cocktail in animals hibernated for 5-6 weeks produced out-of-season spawning (89%) and fertilization (85%) comparable to those we observed for in-season spawning. Assessment of age and weight at metamorphosis indicated that L. pipiens tadpoles resulting from out-of-season spawning grew normally and metamorphosed successfully. CONCLUSION: We provide evidence for successful captive breeding of the leopard frog, L. pipiens. This simple protocol can be used to obtain large numbers of eggs in a predictable, timed manner.

Ecological impacts of the industrial revolution in a lowland raised peat bog near Manchester, NW England.

(1) Ombrotrophic peat bogs provide valuable records of environmental change on long timescales but are rarely preserved near the major centers of industrial activity. Holcroft Moss is a rare example of a stratigraphically intact lowland peat bog in NW England, which provides a valuable opportunity to trace industrial impacts on vegetation in a sensitive environmental archive close to the early industrializing cities of Manchester and Liverpool. (2) We reconstructed environmental changes at Holcroft Moss before and after the Industrial Revolution using a decadal-scale record of pollen, non-pollen palynomorphs, microcharcoal, peat composition (organic content and ash-free bulk density) and heavy metal content, constrained by a radiocarbon and SCP (spheroidal carbonaceous particle) chronology. We examine the relationship between abiotic and biotic environmental tracers using principal component analysis and evaluate the role of local and regional climatic and anthropogenic drivers using canonical redundancy analysis and partitioning of variation. (3) Results show significant changes in bog vegetation composition during the last 700 years. Prior to 1750 CE, climate and agro-pastoral activity (grazing and fires) were the main drivers of vegetation change. Subsequently, regional coal-fired industry contributed to major increases in atmospheric pollutants (dust, heavy metals, and acid deposition) that severely impacted vegetation, driving the decline of Sphagnum. Grasses rose to dominance in the 20th century associated especially with bog conversion and cumulative nitrogen deposition. Although atmospheric pollution significantly decreased in the post-industrial era, vegetation has not returned to pre-industrial conditions, reflecting the ongoing impact of global change drivers which pose challenges for conservation and restoration. (4) Synthesis. Paleoecological studies are needed to reveal the long-term history of vegetation degradation and to offer guidelines for restoration and conservation practices. This study reconstructs the last 700 years of a peat bog located between Manchester and Liverpool, revealing the timing and nature of vegetation changes across the trajectory of early industrialization and eventual post-industrial decline. Our study reveals the progressive dominance of regional anthropogenic forcing and highlights that the present-day vegetation does not have past analogs within the last 700 years. Conservation measures favoring the reintroduction of Sphagnum are justified in redressing the major biological legacy of the Industrial Revolution, while steps to increase Calluna should also be considered in light of its resilience to dry and fire-prone conditions.

Atmospheric CO2 forcing on Mediterranean biomes during the past 500 kyrs.

There is growing concern on the survival of Mediterranean forests under the projected near-future droughts as a result of anthropogenic climate change. Here we determine the resilience of Mediterranean forests across the entire range of climatic boundary conditions realized during the past 500 kyrs based on continuous pollen and geochemical records of (sub)centennial-scale resolution from drillcores from Tenaghi Philippon, Greece. Using convergent cross-mapping we provide empirical confirmation that global atmospheric carbon dioxide (CO2) may affect Mediterranean vegetation through forcing on moisture availability. Our analysis documents two stable vegetation regimes across the wide range of CO2 and moisture levels realized during the past four glacial-interglacial cycles, with abrupt shifts from forest to steppe biomes occurring when a threshold in precipitation is crossed. Our approach highlights that a CO2-driven moisture decrease in the near future may bear an impending risk for abrupt vegetation regime shifts prompting forest loss in the Mediterranean region.

Linear and angular control of circular walking in healthy older adults and subjects with cerebellar ataxia.

Linear and angular control of trunk and leg motion during curvilinear navigation was investigated in subjects with cerebellar ataxia and age-matched control subjects. Subjects walked with eyes open around a 1.2-m circle. The relationship of linear to angular motion was quantified by determining the ratios of trunk linear velocity to trunk angular velocity and foot linear position to foot angular position. Errors in walking radius (the ratio of linear to angular motion) also were quantified continuously during the circular walk. Relative variability of linear and angular measures was compared using coefficients of variation (CoV). Patterns of variability were compared using power spectral analysis for the trunk and auto-covariance analysis for the feet. Errors in radius were significantly increased in patients with cerebellar damage as compared to controls. Cerebellar subjects had significantly larger CoV of feet and trunk in angular, but not linear, motion. Control subjects also showed larger CoV in angular compared to linear motion of the feet and trunk. Angular and linear components of stepping differed in that angular, but not linear, foot placement had a negative correlation from one stride to the next. Thus, walking in a circle was associated with more, and a different type of, variability in angular compared to linear motion. Results are consistent with increased difficulty of, and role of the cerebellum in, control of angular trunk and foot motion for curvilinear locomotion.

The coronavirus disease clavicle study: a predictor of future trauma trends.

Background: Clavicle fractures are a common presentation to the emergency department after falls and sporting injuries. During 2020, the coronavirus disease 2019 (COVID-19) pandemic brought with it a long period of social isolation, resulting in a change of behavior patterns and, in return, the presentation of fractures to our local hospitals. The effects of this global pandemic on the presentation and management of clavicles were noted with particular interest to the change in mechanism and its future implications. Methods: We performed a longitudinal observational study in 10 hospitals in the North West of England, reviewing all patients presenting with a clavicle fracture during 6 weeks in the first peak of COVID-19 pandemic and compared these with the same period in 2019. Collection points included the patient demographics, fracture characteristics, mechanism of injury, and management. Results: A total of 427 clavicle fractures were assessed with lower numbers of patients presenting with a clavicle fracture during the COVID-2020 period (n = 177) compared with 2019 (n = 250). Cycling-related clavicle fractures increased 3-fold during the pandemic compared with the 2019 control group. We also noted an overall increase in clavicle fractures resulting from higher energy trauma as opposed to low energy or fragility fracture. We also found a faster time to surgery in the COVID cohort by 2.7 days on average when compared with 2019. Conclusions: Government restrictions and the encouragement of social distancing led to behavioral changes with a vast increase in cyclists on the road. This created a significant rise in clavicle fractures related to this activity. This is likely to be further driven by the government pledge to double cyclists on the road by 2025 in the United Kingdom. We forecast that this increase in cyclists, a behavior change accelerated by the pandemic, is a reliable predictor for future trauma trends.

The effect of insertions, deletions, and alignment errors on the branch-site test of positive selection.

The detection of positive Darwinian selection affecting protein-coding genes remains a topic of great interest and importance. The "branch-site" test is designed to detect localized episodic bouts of positive selection that affect only a few amino acid residues on particular lineages and has been shown to have reasonable power and low false-positive rates for a wide range of selection schemes. Previous simulations examining the performance of the test, however, were conducted under idealized conditions without insertions, deletions, or alignment errors. As the test is sometimes used to analyze divergent sequences, the impact of indels and alignment errors is a major concern. Here, we used a recently developed indel-simulation program to examine the false-positive rate and power of the branch-site test. We find that insertions and deletions do not cause excessive false positives if the alignment is correct, but alignment errors can lead to unacceptably high false positives. Of the alignment methods evaluated, PRANK consistently outperformed MUSCLE, MAFFT, and ClustalW, mostly because the latter programs tend to place nonhomologous codons (or amino acids) into the same column, producing shorter and less accurate alignments and giving the false impression that many amino acid substitutions have occurred at those sites. Our examination of two previous studies suggests that alignment errors may impact the analysis of mammalian and vertebrate genes by the branch-site test, and it is important to use reliable alignment methods.

INDELible: a flexible simulator of biological sequence evolution.

Many methods exist for reconstructing phylogenies from molecular sequence data, but few phylogenies are known and can be used to check their efficacy. Simulation remains the most important approach to testing the accuracy and robustness of phylogenetic inference methods. However, current simulation programs are limited, especially concerning realistic models for simulating insertions and deletions. We implement a portable and flexible application, named INDELible, for generating nucleotide, amino acid and codon sequence data by simulating insertions and deletions (indels) as well as substitutions. Indels are simulated under several models of indel-length distribution. The program implements a rich repertoire of substitution models, including the general unrestricted model and nonstationary nonhomogeneous models of nucleotide substitution, mixture, and partition models that account for heterogeneity among sites, and codon models that allow the nonsynonymous/synonymous substitution rate ratio to vary among sites and branches. With its many unique features, INDELible should be useful for evaluating the performance of many inference methods, including those for multiple sequence alignment, phylogenetic tree inference, and ancestral sequence, or genome reconstruction.

Fetal and maternal responses to yoga in the third trimester.

Objective: The primary purpose of this study was to examine maternal and fetal responses to a typical, moderate-intensity yoga session in healthy pregnant women during the third trimester using continuous monitoring.Methods: This prospective observational study in low-risk, pregnant women used the Monica AN24 Abdominal ECG wireless maternal-fetal monitor to measure fetal heart rate, maternal heart rate, and uterine activity during a prenatal yoga session. Sessions included 4 time periods: (1) 20-minute rest, (2) 50 minutes standard prenatal yoga, (3) 10-minute meditation, (4) 20-minute recovery. Data were continuously recorded throughout the entire session, stored at 0.25-second intervals, and then averaged over 5-minute intervals. To evaluate changes over time, overall means for the four time periods (rest, yoga, meditation, recovery) were compared using one-way ANOVA with repeated measures. Post-hoc pairwise comparisons (Tukey's) were used to probe significant differences between the four time points. Statistical significance was reached at p < .05.Results: Twenty participants were enrolled; 19 completed the yoga session. Mean gestational age was 35 weeks and 6 days (range of 32-0/7 to 38-6/7) with an average participant age of 32 ± 2.7 years. Maternal heart rates significantly increased during the yoga period (102 ± 11 bpm) compared to rest (90 ± 10), meditation (85 ± 12), and recovery (88 ± 10) (p < .01). The maximum maternal heart rate reached during the yoga session was 125 ± 13 bpm. While fetal heart rates fluctuated slightly over the course of the yoga session, there were no significant fetal heart rate decelerations to suggest deleterious fetal effects. There were no statistically significant differences among resting (138 ± 14 bpm), yoga (137 ± 11 bpm), meditation (139 ± 7 bpm), or recovery (135 ± 22 bpm) fetal heart rates (p = .814). Uterine activity was significantly greater during the yoga period compared with the other time points (p < .001).Conclusion: Yoga can be recommended for low-risk women during pregnancy as no adverse fetal or maternal heart rate changes were observed during a typical prenatal yoga session.

Medical, psychological, cognitive and educational late-effects in pediatric low-grade glioma survivors treated with surgery only.

BACKGROUND: Surgical resection is often the only treatment necessary for pediatric low-grade gliomas (LGGs) and is thought to define a population with an excellent long-term prognosis. The goal of this study was to describe the multidimensional late-effects of pediatric LGG survivors treated exclusively with surgery. METHODS: A retrospective chart review of "surgery-only" LGG survivors followed at Dana-Farber/Children's Hospital Cancer Care was undertaken. Patients had to be diagnosed with an LGG before the age of 22 years, treated with "surgery-only" and be at least 2 years from diagnosis. RESULTS: Sixty survivors were eligible with a median age at the time of review of 16.3 years and the median time since diagnosis of 8.4 years. Tumor locations were predominantly posterior fossa (47%) or cortical (33%). Eighty-five percent of patients had at least one ongoing late-effect, and 28% had three or more. The most common late-effects consisted of motor dysfunction (43%), visual problems (32%), anxiety (19%), social difficulties (19%), seizure disorders (17%), depression (15%), poor coordination/ataxia (14%), behavioral problems (13%), and endocrinopathies (10%). Nine patients had a history of suicidal ideation; two with suicide attempts. The mean full-scale IQ was normal, however, the number of survivors scoring one standard deviation below the mean was twice the expected number. Special education services were utilized by more than half of the survivors. CONCLUSIONS: "Surgery-only" LGG survivors may be more affected by their tumor and its resection than previously appreciated. A prospective study is needed to address this survivor population.

Holocene forest dynamics in central and western Mediterranean: periodicity, spatio-temporal patterns and climate influence.

It is well-known that the Holocene exhibits a millennial-scale climate variability. However, its periodicity, spatio-temporal patterns and underlying processes are not fully deciphered yet. Here we focus on the central and western Mediterranean. We show that recurrent forest declines from the Gulf of Gaeta (central Tyrrhenian Sea) reveal a 1860-yr periodicity, consistent with a ca. 1800-yr climate fluctuation induced by large-scale changes in climate modes, linked to solar activity and/or AMOC intensity. We show that recurrent forest declines and dry events are also recorded in several pollen and palaeohydrological proxy-records in the south-central Mediterranean. We found coeval events also in several palaeohydrological records from the south-western Mediterranean, which however show generally wet climate conditions, indicating a spatio-temporal hydrological pattern opposite to the south-central Mediterranean and suggesting that different expressions of climate modes occurred in the two regions at the same time. We propose that these opposite hydroclimate regimes point to a complex interplay of the prevailing or predominant phases of NAO-like circulation, East Atlantic pattern, and extension and location of the North African anticyclone. At a larger geographical scale, displacements of the ITCZ, modulated by solar activity and/or AMOC intensity, may have also indirectly influenced the observed pattern.

Pollen from the Deep-Sea: A Breakthrough in the Mystery of the Ice Ages.

Pollen from deep-sea sedimentary sequences provides an integrated regional reconstruction of vegetation and climate (temperature, precipitation, and seasonality) on the adjacent continent. More importantly, the direct correlation of pollen, marine and ice indicators allows comparison of the atmospheric climatic changes that have affected the continent with the response of the Earth's other reservoirs, i.e., the oceans and cryosphere, without any chronological uncertainty. The study of long continuous pollen records from the European margin has revealed a changing and complex interplay between European climate, North Atlantic sea surface temperatures (SSTs), ice growth and decay, and high- and low-latitude forcing at orbital and millennial timescales. These records have shown that the amplitude of the last five terrestrial interglacials was similar above 40°N, while below 40°N their magnitude differed due to precession-modulated changes in seasonality and, particularly, winter precipitation. These records also showed that vegetation response was in dynamic equilibrium with rapid climate changes such as the Dangaard-Oeschger (D-O) cycles and Heinrich events, similar in magnitude and velocity to the ongoing global warming. However, the magnitude of the millennial-scale warming events of the last glacial period was regionally-specific. Precession seems to have imprinted regions below 40°N while obliquity, which controls average annual temperature, probably mediated the impact of D-O warming events above 40°N. A decoupling between high- and low-latitude climate was also observed within last glacial warm (Greenland interstadials) and cold phases (Greenland stadials). The synchronous response of western European vegetation/climate and eastern North Atlantic SSTs to D-O cycles was not a pervasive feature throughout the Quaternary. During periods of ice growth such as MIS 5a/4, MIS 11c/b and MIS 19c/b, repeated millennial-scale cold-air/warm-sea decoupling events occurred on the European margin superimposed to a long-term air-sea decoupling trend. Strong air-sea thermal contrasts promoted the production of water vapor that was then transported northward by the westerlies and fed ice sheets. This interaction between long-term and shorter time-scale climatic variability may have amplified insolation decreases and thus explain the Ice Ages. This hypothesis should be tested by the integration of stochastic processes in Earth models of intermediate complexity.

Risk factors for poor visual outcome in patients with idiopathic intracranial hypertension.

OBJECTIVES: Determine potential risk factors for progressive visual field loss in the Idiopathic Intracranial Hypertension Treatment Trial, a randomized placebo-controlled trial of acetazolamide in patients with idiopathic intracranial hypertension and mild visual loss concurrently receiving a low sodium, weight reduction diet. METHODS: Logistic regression and classification tree analyses were used to evaluate potential risk factors for protocol-defined treatment failure (>2 dB perimetric mean deviation [PMD] change in patients with baseline PMD -2 to -3.5 dB or >3 dB PMD change with baseline PMD -3.5 to -7 dB). RESULTS: Seven participants (6 on diet plus placebo) met criteria for treatment failure. The odds ratio for patients with grades III to V papilledema vs those with grades I and II was 8.66 (95% confidence interval [CI] 1.65-∞, p = 0.025). A 1-unit decrease in the number of letters correct on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart at baseline was associated with an increase in the odds of treatment failure by a factor of 1.16 (95% CI 1.04-1.30, p = 0.005). Compared with female participants, the odds ratio for male participants was 26.21 (95% CI 1.61-433.00, p = 0.02). The odds of treatment failure were 10.59 times higher (95% CI 1.63-116.83, p = 0.010) for patients with >30 transient visual obscurations per month vs those with ≤30 per month. CONCLUSIONS: Male patients, those with high-grade papilledema, and those with decreased visual acuity at baseline were more likely to experience treatment failure. All but one of these patients were treated with diet alone. These patients should be monitored closely and be considered for aggressive treatment of their idiopathic intracranial hypertension.

The highly conserved Gln49 and Ser50 of mammalian connexin43 are present in chick connexin43 and essential for functional gap junction channels.

In an attempt to compare the regulation of chick connexin43 channels to those of mammalian connexin43, we found that the nucleotide sequence reported for chick connexin43 differs from that of the chick connexin gene by two codons that had been entered as histidine49 (H49) and valine50 (V50) (accession no. M29003), but are in fact glutamine49 (Q49) and serine50 (S50). Neuro2A cells were transfected with corrected wild-type (Q49/S50) chick connexin43 (accession no. AF233738), the double-replacement Q49H/S50V connexin43, or the single replacement of Q49H or S50V. All clones had gap junctions in membrane based on immunocytochemistry and immunoblots of the triton-resistant membrane fraction. Wild-type transfectants had three conductance states with a predominant channel conductance of 85 +/- 5 pS. Cells producing the Q49H-Cx43 or the double-replacement Q49H/S50V-Cx43 protein had no detectable connexin43 channels. In contrast, cells expressing S50V-Cx43 gap junctions had channels with reduced conductances (75 +/- 8 pS) compared to wild-type controls. Low or high pH of the bathing solution had no effect on the Q49H-Cx43 channels. We conclude that glutamine49 is important for channel function, and replacement of this residue with histidine most likely distorts secondary structure of the first extracellular loop, possibly by changing the orientation of conserved cysteines, and this inhibits channel function. The S50V substitution may also cause similar but less severe structural changes.

Dehydroepiandrosterone sulfate causes proliferation of estrogen receptor-positive breast cancer cells despite treatment with fulvestrant.

HYPOTHESIS: Dehydroepiandrosterone sulfate (DHEA-S) causes a proliferation of estrogen receptor (ER)-positive breast cancer cells, even with tamoxifen citrate blockade. The ER antagonist ICI 182780 (fulvestrant) will more effectively stop the proliferative effect of DHEA-S on breast cancer cells. DESIGN: Examination of in vitro breast cancer cell growth in the presence of fulvestrant and DHEA-S. SETTING: Surgical oncology research laboratory. INTERVENTIONS: The ER-positive and ER-negative breast cancer cells were pretreated with fulvestrant and stimulated with 900 microg/dL (22.8 micromol/L) of DHEA-S. MAIN OUTCOME MEASURES: Assays using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, thiazolyl blue, were performed on the third, fifth, and seventh days poststimulation and permitted the calculation of growth percent change. RESULTS: The ER-positive and progesterone receptor-positive cells demonstrated universal proliferation of 107% by day 7 when treated with fulvestrant, regardless of the dose. The ER-negative and progesterone receptor-negative cells demonstrated growth inhibition. CONCLUSIONS: The DHEA-S circumvented fulvestrant inhibition and caused ER-positive breast cancer cell growth.