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The early last glacial termination was characterized by intense North Atlantic cooling and weak overturning circulation. This interval between ~18,000 and 14,600 years ago, known as Heinrich Stadial 1, was accompanied by a disruption of global climate and has been suggested as a key factor for the termination. However, the response of interannual climate variability in the tropical Pacific (El Niño-Southern Oscillation) to Heinrich Stadial 1 is poorly understood. Here we use Sr/Ca in a fossil Tahiti coral to reconstruct tropical South Pacific sea surface temperature around 15,000 years ago at monthly resolution. Unlike today, interannual South Pacific sea surface temperature variability at typical El Niño-Southern Oscillation periods was pronounced at Tahiti. Our results indicate that the El Niño-Southern Oscillation was active during Heinrich Stadial 1, consistent with climate model simulations of enhanced El Niño-Southern Oscillation variability at that time. Furthermore, a greater El Niño-Southern Oscillation influence in the South Pacific during Heinrich Stadial 1 is suggested, resulting from a southward expansion or shift of El Niño-Southern Oscillation sea surface temperature anomalies.

The covariation of carbon dioxide (CO(2)) concentration and temperature in Antarctic ice-core records suggests a close link between CO(2) and climate during the Pleistocene ice ages. The role and relative importance of CO(2) in producing these climate changes remains unclear, however, in part because the ice-core deuterium record reflects local rather than global temperature. Here we construct a record of global surface temperature from 80 proxy records and show that temperature is correlated with and generally lags CO(2) during the last (that is, the most recent) deglaciation. Differences between the respective temperature changes of the Northern Hemisphere and Southern Hemisphere parallel variations in the strength of the Atlantic meridional overturning circulation recorded in marine sediments. These observations, together with transient global climate model simulations, support the conclusion that an antiphased hemispheric temperature response to ocean circulation changes superimposed on globally in-phase warming driven by increasing CO(2) concentrations is an explanation for much of the temperature change at the end of the most recent ice age.

Past sea-level records provide invaluable information about the response of ice sheets to climate forcing. Some such records suggest that the last deglaciation was punctuated by a dramatic period of sea-level rise, of about 20 metres, in less than 500 years. Controversy about the amplitude and timing of this meltwater pulse (MWP-1A) has, however, led to uncertainty about the source of the melt water and its temporal and causal relationships with the abrupt climate changes of the deglaciation. Here we show that MWP-1A started no earlier than 14,650 years ago and ended before 14,310 years ago, making it coeval with the Bølling warming. Our results, based on corals drilled offshore from Tahiti during Integrated Ocean Drilling Project Expedition 310, reveal that the increase in sea level at Tahiti was between 12 and 22 metres, with a most probable value between 14 and 18 metres, establishing a significant meltwater contribution from the Southern Hemisphere. This implies that the rate of eustatic sea-level rise exceeded 40 millimetres per year during MWP-1A.

Child abuse and neglect affects many families each year, but evidence-based parent training programs can be instrumental in reducing maltreatment. Parent-Child Interaction Therapy, a parent training program developed for treatment of disruptive child behavior, has demonstrated effectiveness with families at risk of or exposed to child maltreatment. However, methods for disseminating this evidence-based intervention in community settings are not well understood. This study examined the association between community-based therapists' attitudes toward evidence-based practices (EBPs) and their participation in an implementation research project in which they received two forms of consultation. Results showed that therapists' self-reported unwillingness to diverge from EBPs was positively associated with their use of phone consultation and satisfaction with consultation. The degree to which therapists found EBPs appealing was positively associated with satisfaction as well. Open therapist attitudes toward EBPs were associated with greater attendance for online consultation. The next step in this line of research is to examine how therapists' attitudes toward EBPs can be improved, if changing attitudes affects therapist acquisition of treatment skills, and if such improvements enhance implementation efforts.

Reconstructing sea-level changes during the last deglaciation provides a way of understanding the ice dynamics that can perturb large continental ice sheets. The resolution of the few sea-level records covering the critical time interval between 14,000 and 9,000 calendar years before the present is still insufficient to draw conclusions about sea-level changes associated with the Younger Dryas cold event and the meltwater pulse 1B (MWP-1B). We used the uranium-thorium method to date shallow-living corals from three new cores drilled onshore in the Tahiti barrier reef. No significant discontinuity can be detected in the sea-level rise during the MWP-1B period. The new Tahiti sea-level record shows that the sea-level rise slowed down during the Younger Dryas before accelerating again during the Holocene.

Ice cores extracted from the Antarctic ice sheet suggest that glacial conditions, and the relationship between isotopically derived temperatures and atmospheric PCO(2) have been constant over the last 800,000 years of the Late Pleistocene epoch. But independent lines of evidence, such as the extent of Northern Hemisphere ice sheets, sea level and other temperature records, point towards a fluctuating severity of glacial periods, particularly during the more extreme glacial stadials centred around 340,000 and 420,000 years ago (marine isotope stages 10 and 12). Previously unidentified mechanisms therefore appear to have mediated the relationship between insolation, CO(2) and climate. Here we test whether northward migration of the subtropical front (STF) off the southeastern coast of South Africa acts as a gatekeeper for the Agulhas current, which controls the transport of heat and salt from the Indo-Pacific Ocean to the Atlantic Ocean. Using a new 800,000-year record of sea surface temperature and ocean productivity from ocean sediment core MD962077, we demonstrate that during cold stadials (particularly marine isotope stages 10 and 12), productivity peaked and sea surface temperature was up to 6 degrees C cooler than modern temperatures. This suggests that during these cooler stadials, the STF moved northward by up to 7 degrees latitude, nearly shutting off the Agulhas current. Our results, combined with faunal assemblages from the south Atlantic show that variable northwards migration of the Southern Hemisphere STF can modulate the severity of each glacial period by altering the strength of the Agulhas current carrying heat and salt to the Atlantic meridional overturning circulation. We show hence that the degree of northwards migration of the STF can partially decouple global climate from atmospheric partial pressure of carbon dioxide, P CO(2), and help to resolve the long-standing puzzle of differing glacial amplitudes within a consistent range of atmospheric PCO(2).

The timing of sea-level change provides important constraints on the mechanisms driving Earth's climate between glacial and interglacial states. Fossil corals constrain the timing of past sea level by their suitability for dating and their growth position close to sea level. The coral-derived age for the last deglaciation is consistent with climate change forced by Northern Hemisphere summer insolation (NHI), but the timing of the penultimate deglaciation is more controversial. We found, by means of uranium/thorium dating of fossil corals, that sea level during the penultimate deglaciation had risen to ~85 meters below the present sea level by 137,000 years ago, and that it fluctuated on a millennial time scale during deglaciation. This indicates that the penultimate deglaciation occurred earlier with respect to NHI than the last deglacial, beginning when NHI was at a minimum.

The intracellular signaling mechanisms underlying the pathogenesis of cardiac diseases are not fully understood. We report here that selective deletion of Shp2, an SH2-containing cytoplasmic tyrosine phosphatase, in striated muscle results in severe dilated cardiomyopathy in mice, leading to heart failure and premature mortality. Development of cardiomyopathy in this mouse model is coupled with insulin resistance, glucose intolerance, and impaired glucose uptake in striated muscle cells. Shp2 deficiency leads to upregulation of leukemia inhibitory factor-stimulated phosphatidylinositol 3-kinase/Akt, Erk5, and Stat3 pathways in cardiomyocytes. Insulin resistance and impaired glucose uptake in Shp2-deficient mice are at least in part due to impaired protein kinase C-zeta/lambda and AMP-kinase activities in striated muscle. Thus, we have generated a mouse line modeling human patients suffering from cardiomyopathy and insulin resistance. This study reinforces a concept that a compound disease with multiple cardiovascular and metabolic disturbances can be caused by a defect in a single molecule such as Shp2, which modulates multiple signaling pathways initiated by cytokines and hormones.

Objectives: Evaluate if Cockcroft and Gault (CG) estimated glomerular filtration rate (eGFR) might be replaced by abbreviated MDRD eGFR for drug dose adjustment., Design and Methods: eGFR was determined in 140 hospitalized patients (median: 68 years, 65 kg) treated by nephrotoxic and/or renally cleared drugs., Results: CG eGFR was 61 mL/min vs. 78 mL/min/1.73 m(2) for MDRD (p<0.0001). CG-MDRD difference ranged from -93 to +34 mL/min, influenced by patient age, weight, and gender (p<0.001)., Conclusions: CG eGFR cannot be easily replaced by abbreviated MDRD eGFR for drug dose adjustment.

Moisture transport from the Atlantic to the Pacific ocean across Central America leads to relatively high salinities in the North Atlantic Ocean and contributes to the formation of North Atlantic Deep Water. This deep water formation varied strongly between Dansgaard/Oeschger interstadials and Heinrich events-millennial-scale abrupt warm and cold events, respectively, during the last glacial period. Increases in the moisture transport across Central America have been proposed to coincide with northerly shifts of the Intertropical Convergence Zone and with Dansgaard/Oeschger interstadials, with opposite changes for Heinrich events. Here we reconstruct sea surface salinities in the eastern equatorial Pacific Ocean over the past 90,000 years by comparing palaeotemperature estimates from alkenones and Mg/Ca ratios with foraminiferal oxygen isotope ratios that vary with both temperature and salinity. We detect millennial-scale fluctuations of sea surface salinities in the eastern equatorial Pacific Ocean of up to two to four practical salinity units. High salinities are associated with the southward migration of the tropical Atlantic Intertropical Convergence Zone, coinciding with Heinrich events and with Greenland stadials. The amplitudes of these salinity variations are significantly larger on the Pacific side of the Panama isthmus, as inferred from a comparison of our data with a palaeoclimate record from the Caribbean basin. We conclude that millennial-scale fluctuations of moisture transport constitute an important feedback mechanism for abrupt climate changes, modulating the North Atlantic freshwater budget and hence North Atlantic Deep Water formation.

During the Last Glacial Maximum, the sea-level lowstand combined with the large extent of the Fennoscandian and British ice sheets led to the funneling of European continental runoff, resulting in the largest river system that ever drained the European continent. Here, we show an abrupt and early reactivation of the European hydrological cycle at the onset of the last deglaciation, leading to intense discharge of the Channel River into the Bay of Biscay. This freshwater influx, probably combined with inputs from proglacial or ice-dammed lakes, dramatically affected the hydrology of the region, both on land and in the ocean.

Objective: To undertake a preliminary study to assess the feasibility of clinical implementation and evaluate the effectiveness of a novel adventure- and recreation-based group intervention in the rehabilitation of individuals with schizophrenia., Methods: In a 2-year, prospective, case-control study, 23 consecutively referred, clinically stabilized schizophrenia patients received the new intervention over an 8-month period; 31 patients on the wait list, considered the control group, received standard clinical care that included some recreational activities. Symptom severity, self-esteem, self-appraised cognitive abilities, and functioning were documented for both groups with standardized rating scales administered at baseline, on completion of treatment, and at 12 months posttreatment., Results: Treatment adherence was 97%, and there were no dropouts. Patients in the study group showed marginal improvement in perceived cognitive abilities and on domain-specific functioning measures but experienced a significant improvement in their self-esteem and global functioning (P < 0.05), as well as a weight loss of over 12 lb. Improvement was sustained over 1 year with further occupational and social gains., Conclusion: In the context of overcoming barriers to providing early intervention for youth and preventing metabolic problems among older adults with schizophrenia, adventure- and recreation-based interventions could play a useful complementary role.

Although amoxicillin/clavulanic acid (AMC) is the most frequently administered antibiotic in France, its in vivo effects on immunity in healthy adults have never, to our knowledge, been described. Eighteen healthy adult male volunteers, 25+/-6 years old, were treated for 5 days with oral amoxicillin (1 g) /clavulanate potassium (125 mg), two times daily. Systemic and local intestinal immunity parameters were sequentially explored before, during and after the antibiotic treatment. No significant differences were obtained for transudation markers (albumin and alpha1-antitrypsin) in sera, feces and saliva, showing that AMC did not induce inflammatory reaction. Phagocytosis, peripheral blood cell subsets, intracellular interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production by natural killer (NK) cells and cytotoxic T lymphocytes, intracellular TNF-alpha production by monocytes showed no significant differences throughout the trial. In fecal outputs, no significant differences were found in secretory immunoglobulin A (S-IgA), lactoferrin (Lf), lysozyme (Lz) and transforming growth factor (TGF)-beta1. In sera, concentrations of total IgA (T-IgA), S-IgA, IgM, Lf and Lz did not show any significant variations throughout the study, whereas concentrations of IgG were slightly but significantly reduced 15 days after AMC treatment. In saliva, concentrations of T-IgA were slightly but significantly higher, whereas S-IgA concentrations were unchanged. Our results showed that oral AMC intake did not induce any significant adverse effects on immunity in adult humans.

The aim of this study was to explore lysozyme and lactoferrin concentrations in human immunodeficiency virus (HIV)-infected patients with oropharyngeal candidiasis (OPC). These proteins were measured by time-resolved immunofluorometric assay, validated in Part I of this study, in paired serum and salivary secretions of 30 patients. Eleven HIV-positive patients without OPC, eight HIV-positive patients with OPC and eleven HIV-negative healthy subjects were included in the study. The relative coefficient of excretion of salivary albumin was used to establish protein origin. In serum, the low lactoferrin concentrations in HIV-infected patients with and without OPC (0.610 mg/l (p < 0.05) and 0.896 mg/l (p < 0.01) vs. 1.439 mg/l in healthy subjects) were probably due to a decrease in nonspecific immunity, particularly the polymorphonuclear cells. In HIV-infected patients with OPC, the high salivary lysozyme and lactoferrin concentrations (170.94 mg/l and 66.48 mg/l vs. 23.35 mg/l and 10.20 mg/l in healthy subjects, respectively) and their mean relative coefficient of excretion of above 1 indicated a high local production of lysozyme and lactoferrin in saliva. The development of OPC in HIV-infected patients could be a consequence of inefficient lysozyme and lactoferrin concentrations and of decreased cooperation between innate and adaptative immune systems.

Mucous peristalsis, mucus and immunity proteins, such as lysozyme and lactoferrin, are part of humoral innate immunity. The aim of this study was to develop a quantitative method, a time-resolved-immunofluorometric assay, to measure lysozyme and lactoferrin in sera, saliva, stools and cervico-vaginal secretions. This method was validated in 51 healthy subjects. Linearity for lysozyme was between 1.02 and 25 microg/l and for lactoferrin between 1.02 and 100 microg/l. The detection limit was 0.5 microg/l for lysozyme and 1 microg/l for lactoferrin. Albumin and alpha1-antitrypsin were measured by immuno-nephelometry to calculate salivary, intestinal and cervico-vaginal coefficients of excretion. Lysozyme and lactoferrin were present in all types of mucosal surfaces. Very high concentrations of lysozyme and lactoferrin were found in cervico-vaginal fluid (166.2 and 72.7 mg/l, respectively), compared to the concentrations found in the other mucosal fluids. Lysozyme in stools was produced at the rate of 0.42 mg/d compared to 0.02 mg/d lactoferrin production. Lysozyme and lactoferrin greatly exceeded the values expected from the molecular weight-affected seepage from plasma, suggesting primarily local synthesis in healthy subjects. Quantitative measurement of lysozyme and lactoferrin can aid in the assessment of the activity of mucus-associated lymphoid tissues in innate immunity, and can help in further understanding of the role of these proteins in mucosal diseases.

Reconstructing the impact of Heinrich events outside the main belt of ice rafting is crucial to understanding the underlying causes of these abrupt climatic events. A high-resolution study of a marine sediment core from the Iberian margin demonstrates that this midlatitude area was strongly affected both by cooling and advection of low-salinity arctic water masses during the last three Heinrich events. These paleoclimatic time series reveal the internal complexity of each of the last three Heinrich events and illustrate the value of parallel studies of the organic and inorganic fractions of the sediments.

To characterize the cellular basis of IgE responses in HIV-positive (HIV+) children, we obtained central (bone marrow [BM], thymus) and peripheral (Peyer's patches [PP], mesenteric [MLN], and other lymph nodes [OLN], spleen), lymphoid organs from two children with AIDS (females, 2 and 8 years old), and from a non-HIV-infected trauma victim (female, 5 years old) at autopsy. PP were obtained from one of the HIV+ children (2 yr old) and from the non-infected child, but no PP were detected in small intestine of the 8-yr-old HIV+ child. Numbers of lymphocytes bearing surface IgE, CD19, CD3, CD4, and CD8 in lymphoid organs were determined (flow cytometry) and evaluated for expression of epsilon-specific (E) mRNA (RT-PCR). Thymus and MLN of the HIV+ child without PP contained high numbers of IgE+ (34% and 41%, respectively) and CD19+ (32% and 28%, respectively) cells; IgE+ cells were not found in any other organ. In contrast, in the HIV+ child with PP, IgE+ cells were detected in all organs, except BM. The thymus of this child contained fewer CD19+ cells (7%). However, in both HIV+ children, all lymphoid organs, including thymus, contained E mRNA. Because numbers of IgE+ cells often far exceeded numbers of CD19+ B cells, and because CD8+ T cells predominated in all organs, some of the IgE+ cells were probably CD8+ T cells with cytophilic IgE and may include IgE-specific regulatory and/or memory T cells. IgE responses were not detected in the healthy trauma victim nor were B cells found in thymus. The data suggest that during HIV infection, IgE+ B cells may be found in thymus and that synthesis of IgE may occur in all lymphoid organs except BM.

Speech addressed to children is supposed to be helpfully redundant, but redundant or predictable words addressed to adults tend to lose intelligibility. Word tokens extracted from the spontaneous speech of the parents of 12 children aged 1; 10 to 3; 0 and presented in isolation to adult listeners showed loss of intelligibility when the words were redundant because they had occurred in repetitions of an utterance (Experiment 1) or referred to an entity which was physically present when named (Experiment 2). Though children (N = 64; mean age 3; 5, S.D. 6.1 months) recognized fewer excerpted object names than adults (N = 40), less intelligible tokens appeared to induce child listeners to rely on the word's extra-linguistic context during the recognition process (Experiment 3), much as such tokens normally induce adults to rely on discourse context. It is proposed that interpreting parental utterances with reference to non-verbal context furthers linguistic development.

This chapter focuses on protein sorting in the secretory pathway. From primary and secondary biosynthetic sites in the cytosol and mitochondrial matrix, respectively, proteins and lipids are distributed to more than 30 final destinations in membranes or membrane-bound spaces, where they carry out their programmed function. Molecular sorting is defined, in its most general sense, as the sum of the mechanisms that determine the distribution of a given molecule from its site of synthesis to its site of function in the cell. The final site of residence of a protein in a eukaryotic cell is determined by a combination of various factors, acting in concert: (1) site of synthesis, (2) sorting signals or zip codes, (3) signal recognition or decoding mechanisms, (4) cotranslational or posttranslational mechanisms for translocation across membranes, (5) specific fusion-fission interactions between intracellular vesicular compartments, and (6) restrictions to the lateral mobility in the plane of the bilayer. Improvements in cell fractionation, protein separation, and immune precipitation procedures in the past decade have made them possible. Very little is known about the mechanisms that mediate the localization and concentration of specific proteins and lipids within organelles. Various experimental model systems have become available for their study. The advent of recombinant DNA technology has shortened the time needed for obtaining the primary structure of proteins to a few months., (© 1985 Academic Press Inc.)

To study the biogenetic pathway of influenza hemagglutinin (HA), a model apical glycoprotein, in polarized epithelial MDCK cells, anti-HA antibodies were added to the basolateral surface during influenza infection. In monolayers grown on collagen gels influenza and VSV plaque development was blocked only when the antibodies were added to the respective budding surface. Addition of anti-HA antibodies to the basal medium of monolayers grown on nitrocellulose filter chambers neither resulted in HA-coupled transport of antibody nor inhibited HA migration to the apical surface. These results indicate that the bulk of HA is vectorially inserted into the apical surface of MDCK cells by polarized exocytosis. Other apical proteins in epithelia may use a similar mechanism during biogenesis.

Comparison of the regulation of RNA metabolism following stimulation of mammalian fibroblasts in culture and of lymphocytes reveals that in both systems it is the processing and transport of gene transcripts which are the initial targets of the activation process rather than the gene transcription itself. In the case of the human lymphocyte, the time required for appearance of labeled RNA in cytoplasm after addition of labeled uridine diminishes progressively with duration of incubation with mitogen. Using adenine as a marker diminishes the latent period between addition of label and its appearance in cytoplasmic RNA. This may be due to polyadenylation of preexisting transcripts which are turned over at a high rate in the nucleus of resting cells but stabilized, processed and exported to the cytoplasm after stimulation.

Leishmania is a trypanosomatid protozoa with a digenetic life cycle. Sandflies inject promastigotes, the free living form present in their salivary glands, into mammals where the parasite colonizes macrophages, transforming into intracellular amastigotes. The cycle is completed when during a blood meal the insect ingests infected macrophages, the amastigotes are released in the gut where they transform back into promastigotes. Leishmania has to adapt to the changing life conditions, from free-living forms in the poikilothermic insect vector to obligatory intracellular parasite in the homeothermic mammalian host. It also has to adapt to the acidic pH of the macrophage's phagolysosome where amastigotes multiply. The adaptative response of Leishmania includes morphological, physiological, and biochemical changes. Promastigotes can be grown in culture medium. Studies of changes taking place during adaptation have been facilitated by the establishment of in vitro conditions that allow the transformation of amastigotes into promastigotes and vice versa. The system is well suited for studying regulation of gene expression during adaptative differentiation. Some mechanisms of mRNA processing are unique to these protozoa: trans-splicing and RNA editing. Several genes that are differentially expressed in the two stages have been studied. No obvious cis regulatory motifs have been found in the DNA.