The impact of farming on prehistoric culinary practices throughout Northern Europe.

To investigate changes in culinary practices associated with the arrival of farming, we analysed the organic residues of over 1,000 pottery vessels from hunter-gatherer-fisher and early agricultural sites across Northern Europe from the Lower Rhine Basin to the Northeastern Baltic. Here, pottery was widely used by hunter-gatherer-fishers prior to the introduction of domesticated animals and plants. Overall, there was surprising continuity in the way that hunter-gatherer-fishers and farmers used pottery. Both aquatic products and wild plants remained prevalent, a pattern repeated consistently across the study area. We argue that the rapid adaptation of farming communities to exploit coastal and lagoonal resources facilitated their northerly expansion, and in some cases, hunting, gathering, and fishing became the most dominant subsistence strategy. Nevertheless, dairy products frequently appear in pottery associated with the earliest farming groups often mixed with wild plants and fish. Interestingly, we also find compelling evidence of dairy products in hunter-gatherer-fisher Ertebølle pottery, which predates the arrival of domesticated animals. We propose that Ertebølle hunter-gatherer-fishers frequently acquired dairy products through exchange with adjacent farming communities prior to the transition. The continuity observed in pottery use across the transition to farming contrasts with the analysis of human remains which shows substantial demographic change through ancient DNA and, in some cases, a reduction in marine consumption through stable isotope analysis. We postulate that farmers acquired the knowledge and skills they needed to succeed from local hunter-gatherer-fishers but without substantial admixture.

Using metabolic markers to identify insulin resistance in premenopausal women with and without polycystic ovary syndrome.

BACKGROUND: Insulin resistance (IR) is associated with increased risk for type 2 diabetes mellitus and cardiovascular disease. Quantifying IR is invasive and time-consuming, and thus not routinely used in clinical practice. Simple metabolic markers to predict IR exist, but have not been validated in premenopausal women or women with polycystic ovary syndrome (PCOS). OBJECTIVE: To evaluate the ability of metabolic markers to identify premenopausal women with/without PCOS who are insulin resistant. DESIGN/SETTING: Cross-sectional analysis. PARTICIPANTS: One hundred and seventy-one non-diabetic premenopausal overweight/obese women without PCOS and 71 women with PCOS. METHODS: IR was quantified by the steady-state plasma glucose during the modified insulin-suppression test. Metabolic markers (BMI, lipid/lipoprotein concentrations, and fasting glucose) were evaluated for their discriminative ability to identify IR, using area under the receiver-operating-characteristic curve (AUROC) analysis. Optimal cut-points were evaluated for predictive power. RESULTS: In the non-PCOS group, the triglyceride/HDL cholesterol ratio (TG/HDL-C) was the best marker (AUROC 0.73). Optimal diagnostic cut-point was 1.9. In the PCOS group, the TG/HDL-C ratio, cholesterol/HDL-C ratio (TC/HDL-C), and HDL-C performed well (AUROC > 0.80), with optimal cut-points for TG/HDL-C 1.3, TC/HDL-C 3.4, and HDL-C 52 mg/dL: TG/HDL-C was more sensitive, but HDL-C had a higher PPV for IR. CONCLUSION: TG/HDL-C can identify IR in premenopausal women with and/without PCOS; diagnostic cut-points differ from those of men and postmenopausal women. HDL-C is an alternative predictor in women with PCOS. These simple metabolic markers, which are standardized between labs, inexpensive, and routinely measured, can be used to tailor lifestyle and medical interventions to improve health outcomes in insulin-resistant premenopausal women.

Dietary weight loss in insulin-resistant non-obese humans: Metabolic benefits and relationship to adipose cell size.

BACKGROUND AND AIMS: Overweight and obesity increase risk for diabetes and cardiovascular disease, largely through development of insulin resistance. Benefits of dietary weight loss are documented for obese individuals with insulin resistance. Similar benefits have not been shown in overweight individuals. We sought to quantify whether dietary weight loss improves metabolic risk profile in overweight insulin-resistant individuals, and evaluated potential mediators between weight loss and metabolic response. METHODS AND RESULTS: Healthy volunteers with BMI 25-29.9 kg/m2 underwent detailed metabolic phenotyping including insulin-mediated-glucose disposal, fasting/daylong glucose, insulin, triglycerides, FFA, and cholesterol. Subcutaneous fat biopsies were performed for measurement of adipose cell size. After 14 weeks of hypocaloric diet and 2 weeks of weight maintenance, cardiometabolic measures and biopsies were repeated. Changes in weight, % body fat, waist circumference, adipose cell size and FFA were evaluated as predictors of change in insulin resistance. Weight loss (4.3 kg) yielded significant improvements in insulin resistance and all cardiovascular risk markers except glucose, HDL-C, and LDL-C. Improvement in insulin sensitivity was greater among those with <2 vs >2 cardiovascular risk factors at baseline. Decrease in adipose cell size and waist circumference, but not weight or body fat, independently predicted improvement in insulin resistance. CONCLUSIONS: Weight loss yields metabolic health benefits in insulin-resistant overweight adults, even in the absence of classic cardiovascular risk factors. Weight loss-related improvement in insulin sensitivity may be mediated through changes in adipose cell size and/or central distribution of body fat. The insulin-resistant subgroup of overweight individuals should be identified and targeted for dietary weight loss. CLINICAL TRIALS IDENTIFIER: NCT00186459.

Burden of corticosteroid use in patients with systemic lupus erythematosus: results from a Delphi panel.

Corticosteroid-related adverse events (AEs) are commonly reported in systemic lupus erythematosus (SLE), but are often under-represented in claims data. The most common corticosteroid-related AEs are not necessarily the most costly. The present study aimed to examine corticosteroid-related AE rates and identify the associated cost consequences in patients with SLE from the perspective of rheumatologists treating SLE in the United States (US). A modified Delphi process and RAND Appropriateness Method was used to estimate corticosteroid-related AEs and costs based on data from SLE-treating US rheumatologists and estimates from alternative sources. The panel (n=10) participated in two web-based questionnaires, covering disease severity, corticosteroid use, corticosteroid-related AEs, and resource utilization associated with treatment of the AEs. Eight members of the panel then participated in a guided discussion by interactive teleconference, in which the costs associated with specific corticosteroid-related AEs were also discussed. Consensus was achieved in the teleconference when a single response category (consensus values from 1 to 4 [4=strongly agree, 1=strongly disagree]) accounted for ≥80% of responses. Thirteen consensus statements were developed following two Delphi rounds. Costs were estimated for eight corticosteroid-associated AEs from the panel of rheumatologists. In the patients with SLE treated by these physicians, 41.5% were considered to have mild disease, 36.5% moderate disease, and 22.0% severe disease. The number of specialist visits, corticosteroid use, and corticosteroid dose increased with disease severity. The estimated rates of all AEs (except for cataracts) were at least doubled in patients receiving corticosteroid doses>20 mg/day compared with ≤20 mg/day. The highest estimated mean total costs of an event (for the required treatment duration for one patient) were for avascular necrosis ($14,460) and serious infection ($11,660). The costs of more common AEs, such as osteoporosis, obesity, diabetes, and fractures, ranged from $1190 to $8220. Ten rheumatologists concluded that as disease severity increases, corticosteroid doses increased. Greater utilization of resources is needed to manage patients and corticosteroid-related AEs.

Familial clustering of systemic lupus erythematosus in the cayman islands.

OBJECTIVE: To describe the unusual clustering of systemic lupus erythematosus (SLE) in a family from the Cayman Islands. METHOD: An observational retrospective study of SLE was done following an index case of mixed connective tissue disease in a 51-year old West Indian woman of African descent. Her two daughters of the same father, who is of Cayman Islands origin, were also diagnosed with SLE. A family tree was subsequently drawn up to 1890 to identify other cases in the same family. RESULTS: There were 13 cases identified and all occurred between the 6th and the 8th generation. A family tree linked all cases to a man from the Cayman Islands who died in 1890. The nine cases with full medical records showed eight females and one male (8:1). The mean age at diagnosis was 29 years; polyarthritis occured in all nine patients (100%), kidney involvement in 6/9 (66.6%), skin rash in 6/9 (66.6%), pleuritis and pericarditis in 6/9 (66.6%) and anaemia in 6/9 (66.6%). The autoantibodies were mainly ANA in all patients (100%) and anti-dsDNA in 8/9 (88.8%). CONCLUSION: The unusual extensive familial clustering in this study represents the first to be described in a West Indian population where SLE is most prevalent and may suggest a genetic predisposition.

A collaborative care model to improve access to pediatric mental health services.

To examine if an innovative collaborative care model known as Targeted Child Psychiatric Services designed for primary care pediatricians (PCPs) and child psychiatrists (1) was associated with improved access to child psychiatry services, (2) had the potential to identify optimal care settings for pediatric mental health care and (3) examined if pediatricians appeared as likely to accept children back into their practices at discharge from TCPS depending upon diagnostic category, controlling for severity of illness and function. The diagnostic classes examined were ADHD (39%), depression (31%) and anxiety (13%). This prospective cohort design study collected medical records of 329 children referred to TCPS by 139 PCPs. To detect the likelihood of return to referring pediatricians for follow-up care at discharge from TCPS, we employed logistic regression models. Mean age was 12.3 (SD = 4.0); 43% were female. Ninety-three percent of parents complied with pediatricians' recommendations to have their child assessed by a child psychiatrist. A total of 28.0% of referrals returned to PCPs for follow-up care; the remainder were followed in mental health. Regression findings indicated that children with major depression (OR = 7.5) or anxiety disorders (OR = 5.1) were less likely to return to PCPs compared to ADHD even though severity of psychiatric illness and functional levels did not differ across diagnostic groups. Families widely accepted pediatricians' recommendations for referral to child psychiatrists. Depression and anxiety were strong correlates of retention in mental health settings at discharge from TCPS though children with these disorders appeared to be no more severely ill or functionally limited than peers with ADHD. These children possibly could be managed in a less intensive and expensive primary care treatment setting that could access mental health specialty services as needed in a collaborative model of care. TCPS is contrasted with the well-known collaborative model for adult depression in primary care. TCPS could serve as a feasible model of care that addresses the daunting barriers in accessing pediatric mental health services.

The Associations of Chronotype and Shift Work With Rheumatoid Arthritis.

The circadian clock regulates multiple aspects of human physiology including immunity. People have a circadian preference termed chronotype. Those with an evening preference may be better suited to shift work, but also carry higher risk of adverse health. Shift work leads to misalignment of circadian rhythms and is associated with increased risk of inflammatory disease such as asthma and cancer. Here, we investigate the association between chronotype, shift work, and rheumatoid arthritis (RA). The associations between exposures of shift work and chronotype on risk of RA were studied in up to 444,210 U.K. Biobank participants. Multivariable logistic regression models were adjusted for covariates: age, sex, ethnicity, alcohol intake, smoking history, Townsend Deprivation Index (TDI), sleep duration, length of working week, and body mass index (BMI). After adjusting for covariates, individuals with a morning chronotype had lower odds of having rheumatoid arthritis (RA; odds ratio [OR]: 0.93, 95% confidence interval [CI]: 0.88-0.99) when compared to intermediate chronotypes. The association between morning chronotype and RA persisted with a more stringent RA case definition (covariate-adjusted OR: 0.89, 95% CI: 0.81-0.97). When adjusted for age, sex, ethnicity, and TDI, shift workers had higher odds of RA (OR: 1.22, 95% CI: 1.1-1.36) compared to day workers that attenuated to the null after further covariate adjustment (OR: 1.1, 95% CI: 0.98-1.22). Morning chronotypes working permanent night shifts had significantly higher odds of RA compared to day workers (OR: 1.89, 95% CI: 1.19-2.99). These data point to a role for circadian rhythms in RA pathogenesis. Further studies are required to determine the mechanisms underlying this association and understand the potential impact of shift work on chronic inflammatory disease and its mediating factors.

The transmission of pottery technology among prehistoric European hunter-gatherers.

Human history has been shaped by global dispersals of technologies, although understanding of what enabled these processes is limited. Here, we explore the behavioural mechanisms that led to the emergence of pottery among hunter-gatherer communities in Europe during the mid-Holocene. Through radiocarbon dating, we propose this dispersal occurred at a far faster rate than previously thought. Chemical characterization of organic residues shows that European hunter-gatherer pottery had a function structured around regional culinary practices rather than environmental factors. Analysis of the forms, decoration and technological choices suggests that knowledge of pottery spread through a process of cultural transmission. We demonstrate a correlation between the physical properties of pots and how they were used, reflecting social traditions inherited by successive generations of hunter-gatherers. Taken together the evidence supports kinship-driven, super-regional communication networks that existed long before other major innovations such as agriculture, writing, urbanism or metallurgy.

Variation of health-care resource utilization according to GERD-associated complications.

Complications associated with gastroesophageal reflux disease (GERD) can include esophageal stricture, Barrett's esophagus, gastrointestinal hemorrhage, and extraesophageal symptoms. The impact of GERD-associated complications on health-care utilization deserves further evaluation. We identified commercial enrollees 18-75 years old with claims for GERD (International Classification of Diseases, Ninth Revision, Clinical Modification Codes: 530.81 or 530.11) and subsequent usage of proton pump inhibitors from 01/01/05 to 06/30/09. The initial GERD diagnosis date was designated as the index date, and patients were studied for 6 months preindex and postindex. Eligible patients were subsequently stratified based on medical claims for GERD-associated complications as follows: stage A (GERD diagnosis, no other symptoms), stage B (GERD + extraesophageal symptoms), stage C (GERD + Barrett's esophagus), stage D (GERD + esophageal stricture), and stage E (GERD + iron-deficiency anemia or acute upper gastrointestinal hemorrhage). Patient characteristics, health-care utilization, and costs were compared between stage A and each stage with complicated GERD (B-D). Of the 174,597 patients who were eligible for analysis, 74% were classified as stage A, 20% stage B, 1% stage C, 2% stage D, and 3% stage E. Relative to stage A, patients in stages C, D, and E were significantly more likely to visit a gastroenterologist (13% vs. 68%, 71%, and 38%, respectively) and had higher rates of esophageal ulcers (0.3% vs. 8%, 5%, and 3%, respectively) and Nissen fundoplication (0.05% vs. 0.6%, 0.3%, and 0.2%, respectively). Six-month GERD-related costs ranged from $615/patient (stage A) to $1714/patient (stage D); all-cause costs ranged from $4195/patient (stage A) to $11,340/patient (stage E). Compared with stage A, all other cohorts had significantly higher all-cause and GERD-related costs (P < 0.0001 for all comparisons). While patients with more severe GERD represented a relatively small portion of the GERD cohort, they demonstrated significantly greater health-care costs and overall utilization than patients with uncomplicated GERD.

Ancient Maltese genomes and the genetic geography of Neolithic Europe.

Archaeological consideration of maritime connectivity has ranged from a biogeographical perspective that considers the sea as a barrier to a view of seaways as ancient highways that facilitate exchange. Our results illustrate the former. We report three Late Neolithic human genomes from the Mediterranean island of Malta that are markedly enriched for runs of homozygosity, indicating inbreeding in their ancestry and an effective population size of only hundreds, a striking illustration of maritime isolation in this agricultural society. In the Late Neolithic, communities across mainland Europe experienced a resurgence of hunter-gatherer ancestry, pointing toward the persistence of different ancestral strands that subsequently admixed. This is absent in the Maltese genomes, giving a further indication of their genomic insularity. Imputation of genome-wide genotypes in our new and 258 published ancient individuals allowed shared identity-by-descent segment analysis, giving a fine-grained genetic geography of Neolithic Europe. This highlights the differentiating effects of seafaring Mediterranean expansion and also island colonization, including that of Ireland, Britain, and Orkney. These maritime effects contrast profoundly with a lack of migratory barriers in the establishment of Central European farming populations from Anatolia and the Balkans.

Late Glacial and Early Holocene human demographic responses to climatic and environmental change in Atlantic Iberia.

Successive generations of hunter-gatherers of the Late Glacial and Early Holocene in Iberia had to contend with rapidly changing environments and climatic conditions. This constrained their economic resources and capacity for demographic growth. The Atlantic façade of Iberia was occupied throughout these times and witnessed very significant environmental transformations. Archaeology offers a perspective on how past human population ecologies changed in response to this scenario. Archaeological radiocarbon data are used here to reconstruct demographics of the region over the long term. We introduce various quantitative methods that allow us to develop palaeodemographic and spatio-temporal models of population growth and density, and compare our results to independent records of palaeoenvironmental and palaeodietary change, and growth rates derived from skeletal data. Our results demonstrate that late glacial population growth was stifled by the Younger Dryas stadial, but populations grew in size and density during the Early to Middle Holocene transition. This growth was fuelled in part by an increased dependence on marine and estuarine food sources, demonstrating how the environment was linked to demographic change via the resource base, and ultimately the carrying capacity of the environment. This article is part of the theme issue 'Cross-disciplinary approaches to prehistoric demography'.

Seroprevalence of SARS-CoV-2 antibodies, associated epidemiological factors and antibody kinetics among healthcare workers in Connecticut.

BACKGROUND: Healthcare workers (HCWs) are at the front line of the ongoing coronavirus 2019 (COVID-19) pandemic. Comprehensive evaluation of the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) among HCWs in a large healthcare system could help to identify the impact of epidemiological factors and the presence of symptoms on the immune response to the infection over time. AIM: To determine the seroprevalence of SARS-CoV-2-specific antibodies among HCWs, identify associated epidemiological factors and study antibody kinetics. METHODS: A longitudinal evaluation of the seroprevalence and epidemiology of SARS-CoV-2-specific antibodies was undertaken in approximately 30,000 HCWs in the largest healthcare system in Connecticut, USA. FINDINGS: At baseline, the prevalence of SARS-CoV-2 antibody among 6863 HCWs was 6.3% [95% confidence interval (CI) 5.7-6.9%], and was highest among patient care support (16.7%), medical assistants (9.1%) and nurses (8.2%), and lower for physicians (3.8%) and advanced practice providers (4.5%). Seroprevalence was significantly higher among African Americans [odds ratio (OR) 3.26 compared with Caucasians, 95% CI 1.77-5.99], in participants with at least one symptom of COVID-19 (OR 3.00, 95% CI 1.92-4.68), and in those reporting prior quarantine (OR 3.83, 95% CI 2.57-5.70). No symptoms were reported in 24% of seropositive participants. Among the 47% of participants who returned for a follow-up serological test, the seroreversion rate was 39.5% and the seroconversion rate was 2.2%. The incidence of re-infection in the seropositive group was zero. CONCLUSION: Although there is a decline in the immunoglobulin G antibody signal over time, 60.5% of seropositive HCWs had maintained their seroconversion status after a median of 5.5 months.

Inflammation in subcutaneous adipose tissue: relationship to adipose cell size.

AIMS/HYPOTHESIS: Inflammation is associated with increased body mass and purportedly with increased size of adipose cells. We sought to determine whether increased size of adipose cells is associated with localised inflammation in weight-stable, moderately obese humans. METHODS: We recruited 49 healthy, moderately obese individuals for quantification of insulin resistance (modified insulin suppression test) and subcutaneous abdominal adipose tissue biopsy. Cell size distribution was analysed with a multisizer device and inflammatory gene expression with real-time PCR. Correlations between inflammatory gene expression and cell size variables, with adjustment for sex and insulin resistance, were calculated. RESULTS: Adipose cells were bimodally distributed, with 47% in a 'large' cell population and the remainder in a 'small' cell population. The median diameter of the large adipose cells was not associated with expression of inflammatory genes. Rather, the fraction of small adipose cells was consistently associated with inflammatory gene expression, independently of sex, insulin resistance and BMI. This association was more pronounced in insulin-resistant than insulin-sensitive individuals. Insulin resistance also independently predicted expression of inflammatory genes. CONCLUSIONS/INTERPRETATION: This study demonstrates that among moderately obese, weight-stable individuals an increased proportion of small adipose cells is associated with inflammation in subcutaneous adipose tissue, whereas size of mature adipose cells is not. The observed association between small adipose cells and inflammation may reflect impaired adipogenesis and/or terminal differentiation. However, it is unclear whether this is a cause or consequence of inflammation. This question and whether small vs large adipose cells contribute differently to inflammation in adipose tissue are topics for future research. TRIAL REGISTRATION: ClinicalTrials.gov NCT00285844.

Isolation and characterization of cDNAs encoding human brain ankyrins reveal a family of alternatively spliced genes.

Ankyrins are a family of membrane-associated proteins that can be divided into two immunologically distinct groups: (a) erythrocyte-related isoforms (ankyrinR) that have polarized distributions in particular cell types; and (b) brain-related isoforms (ankyrinB) that display a broader distribution. In this paper, we report the isolation and sequences of cDNAs related to two ankyrinB isoforms, human brain ankyrin 1 and 2, and show that these isoforms are produced from alternatively spliced mRNAs of a single gene. Human brain ankyrin 1 and 2 share a common NH2-terminus that is similar to human erythrocyte ankyrins, with the most striking conservation occurring between areas composed of a repeated 33-amino acid motif and between areas corresponding to the central portion of the spectrin-binding domain. In contrast, COOH-terminal sequences of brain ankyrin 1 and 2 are distinct from one another and from human erythrocyte ankyrins, and thus are candidates to mediate protein interactions that distinguish these isoforms. The brain ankyrin 2 cDNA sequence includes a stop codon and encodes a polypeptide with a predicted molecular mass of 202 kD, which is similar to the Mr of the major form of ankyrin in adult bovine brain membranes. Moreover, an antibody raised against the conserved NH2-terminal domain of brain ankyrin cross-reacts with a single Mr = 220 kD polypeptide in adult human brain. These results strongly suggest that the amino acid sequence of brain ankyrin 2 determined in this report represents the complete coding sequence of the major form of ankyrin in adult human brain. In contrast, the brain ankyrin 1 cDNAs encode only part of a larger isoform. An immunoreactive polypeptide of Mr = 440 kD, which is evident in brain tissue of young rats, is a candidate to be encoded by brain ankyrin 1 mRNA. The COOH-terminal portion of brain ankyrin 1 includes 15 contiguous copies of a novel 12-amino acid repeat. Analysis of DNA from a panel of human/rodent cell hybrids linked this human brain ankyrin gene to chromosome 4. This result, coupled with previous reports assigning the human erythrocyte ankyrin gene to chromosome 8, demonstrates that human brain and erythrocyte ankyrins are encoded by distinct members of a multigene family.

Ankyrin-binding proteins related to nervous system cell adhesion molecules: candidates to provide transmembrane and intercellular connections in adult brain.

A major class of ankyrin-binding glycoproteins have been identified in adult rat brain of 186, 155, and 140 kD that are alternatively spliced products of the same pre-mRNA. Characterization of cDNAs demonstrated that ankyrin-binding glycoproteins (ABGPs) share 72% amino acid sequence identity with chicken neurofascin, a membrane-spanning neural cell adhesion molecule in the Ig super-family expressed in embryonic brain. ABGP polypeptides have the following features consistent with a role as ankyrin-binding proteins in vitro and in vivo: (a) ABGPs and ankyrin associate as pure proteins in a 1:1 molar stoichiometry; (b) the ankyrin-binding site is located in the COOH-terminal 21 kD of ABGP186 which contains the predicted cytoplasmic domain; (c) ABGP186 is expressed at approximately the same levels as ankyrin (15 pmoles/milligram of membrane protein); and (d) ABGP polypeptides are co-expressed with the adult form of ankyrinB late in postnatal development and are colocalized with ankyrinB by immunofluorescence. Similarity in amino acid sequence and conservation of sites of alternative splicing indicate that genes encoding ABGPs and neurofascin share a common ancestor. However, the major differences in developmental expression reported for neurofascin in embryos versus the late postnatal expression of ABGPs suggest that ABGPs and neurofascin represent products of gene duplication events that have subsequently evolved in parallel with distinct roles. The predicted cytoplasmic domains of rat ABGPs and chicken neurofascin are nearly identical to each other and closely related to a group of nervous system cell adhesion molecules with variable extracellular domains, which includes L1, Nr-CAM, and Ng-CAM of vertebrates, and neuroglian of Drosophila. The ankyrin-binding site of rat ABGPs is localized to the C-terminal 200 residues which encompass the cytoplasmic domain, suggesting the hypothesis that ability to associate with ankyrin may be a shared feature of neurofascin and related nervous system cell adhesion molecules.

Primary structure and domain organization of human alpha and beta adducin.

Adducin is a membrane-skeletal protein which is a candidate to promote assembly of a spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. The complete sequence of both subunits of human adducin, alpha (737 amino acids), and beta (726 amino acids) has been deduced by analysis of the cDNAs. The two subunits have strikingly conserved amino acid sequences with 49% identity and 66% similarity, suggesting evolution by gene duplication. Each adducin subunit has three distinct domains: a 39-kD NH2-terminal globular protease-resistant domain, connected by a 9-kD domain to a 33-kD COOH-terminal protease-sensitive tail comprised almost entirely of hydrophilic amino acids. The tail is responsible for the high frictional ratio of adducin noted previously, and was visualized by EM. The head domains of both adducin subunits exhibit a limited sequence similarity with the NH2-terminal actin-binding motif present in members of the spectrin superfamily and actin gelation proteins. The COOH-termini of both subunits contain an identical, highly basic stretch of 22 amino acids with sequence similarity to the MARCKS protein. Predicted sites of phosphorylation by protein kinase C include the COOH-terminus and sites at the junction of the head and tail. Northern blot analysis of mRNA from rat tissues, K562 erythroleukemia cells and reticulocytes has shown that alpha adducin is expressed in all the tissues tested as a single message size of 4 kb. In contrast, beta adducin shows tissue specific variability in size of mRNA and level of expression. A striking divergence between alpha and beta mRNAs was noted in reticulocytes, where alpha adducin mRNA is present in at least 20-fold higher levels than that of beta adducin. The beta subunit thus is a candidate to perform a limiting role in assembly of functional adducin molecules.

Photoinduced nucleation of water vapor.

Strong photoinduced nucleation of pure water vapor was found to occur in a wavelength range where no ultraviolet absorption of water vapor has been reported. Systematic studies were made of the dependence of the nucleation rate and the delay time for the initiation of nucleation on light intensity. The results obtained were accurately fitted by a phenomenological mechanism whereby the nucleation is initiated by clusters accumulating an appropriate number of photoexcited water molecules.

Nucleation on photoexcited molecules.

On irradiation with light of suitable wavelength and intensity, certain organic compounds, even at very low concentrations, cause very efficient nucleation of supersaturated vapors. A mechanism is suggested to account for this phenomenon. Nuclei containing only a few photoexcited molecules are responsible for the nucleation.

Bridging from clinical endpoints to estimates of treatment value for external decision makers.

AIM: While clinical endpoints provide important information on the efficacy of treatment in controlled conditions, they often are not relevant to decision makers trying to gauge the potential economic impact or value of new treatments. Therefore, it is often necessary to translate changes in cognition, function or behavior into changes in cost or other measures, which can be problematic if not conducted in a transparent manner. The Dependence Scale (DS), which measures the level of assistance a patient requires due to AD-related deficits, may provide a useful measure of the impact of AD progression in a way that is relevant to patients, providers and payers, by linking clinical endpoints to estimates of cost effectiveness or value. The aim of this analysis was to test the association of the DS to clinical endpoints and AD-related costs. METHOD: The relationship between DS score and other endpoints was explored using the Predictors Study, a large, multi-center cohort of patients with probable AD followed annually for four years. Enrollment required a modified Mini-Mental State Examination (mMMS) score >or= 30, equivalent to a score of approximately >or= 16 on the MMSE. DS summated scores (range: 0- 15) were compared to measures of cognition (MMSE), function (Blessed Dementia Rating Scale, BDRS, 0-17), behavior, extrapyramidal symptoms (EPS), and psychotic symptoms (illusions, delusions or hallucinations). Also, estimates for total cost (sum of direct medical cost, direct non-medical cost, and cost of informal caregivers' time) were compared to DS scores. RESULTS: For the 172 patients in the analysis, mean baseline scores were: DS: 5.2 (SD: 2.0), MMSE: 23.0 (SD: 3.5), BDRS: 2.9 (SD: 1.3), EPS: 10.8%, behavior: 28.9% psychotic symptoms: 21.1%. After 4 years, mean scores were: DS: 8.9 (SD: 2.9), MMSE: 17.2 (SD: 4.7), BDRS: 5.2 (SD: 1.4), EPS: 37.5%, behavior: 60.0%, psychotic symptoms: 46.7%. At baseline, DS scores were significantly correlated with MMSE (r=-0.299, p < 0.01), BDRS (r=0.610, p < 0.01), behavior (r=.2633, p=0.0005), EPS (r=0.1910, p=0.0137) and psychotic symptoms (r=0.253, p < 0.01); and at 4-year follow-up, DS scores were significantly correlated with MMSE (r=-0.3705, p=0.017), BDRS (r=0.6982, p < 0.001). Correlations between DS and behavior (-0.0085, p=0.96), EPS (r=0.3824, p=0.0794), psychotic symptoms (r=0.130, ns) were not statistically significant at follow-up. DS scores were also significantly correlated with total costs at baseline (r=0.2615, p=0.0003) and follow-up (r=0.3359, p=0.0318). DISCUSSION: AD is associated with deficits in cognition, function and behavior, thus it is imperative that these constructs are assessed in trials of AD treatment. However, assessing multiple endpoints can lead to confusion for decision makers if treatments do not impact all endpoints similarly, especially if the measures are not used typically in practice. One potential method for translating these deficits into a more meaningful outcome would be to identify a separate construct, one that takes a broader view of the overall impact of the disease. Patient dependence, as measured by the DS, would appear to be a reasonable choice - it is associated with the three clinical endpoints, as well as measures of cost (medical and informal), thereby providing a bridge between measures of clinical efficacy and value in a single, transparent measure.

Understanding the Scientific Basis of Post-traumatic Stress Disorder (PTSD): Precision Behavioral Management Overrides Stigmatization.

Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype-phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation "Precision Behavioral Management" (PBM™) based on GARS test values and other pro-dopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.