The suitability of using domestic pigs (Sus spp.) as human proxies in the geophysical detection of clandestine graves.

Research in many forensic science fields commonly uses domestic pigs (Sus spp.) as proxies for human remains, due to their physiological and anatomical similarities, as well as being more readily available. Unfortunately, previous research, especially that which compares the decompositional process, has shown that pigs are not appropriate proxies for humans. To date, there has not been any published research that specifically addresses whether domestic pigs are adequate human proxies for the geophysical detection of clandestine graves. As such, the aim of this paper was to compare the geophysical responses of pig cadavers and human donor graves, in order to determine if pigs can indeed be used as adequate human proxies. To accomplish this, ground penetrating radar (GPR) and electrical resistivity tomography (ERT) responses on single and multiple pig cadaver graves were compared to single and multiple human donor graves, all of which are in known locations within the same geological environment. The results showed that under field conditions, both GPR and ERT were successful at observing human and pig burials, with no obvious differences between the detected geophysical responses. The results also showed that there were no differences in the geophysical responses of those who were clothed and unclothed. The similarity of the responses may reflect that the geophysical techniques can detect graves despite what their contents are. The study implications suggest that experimental studies in other soil and climate conditions can be easily replicated, benefiting law enforcement with missing persons cases.

A multidisciplinary approach to locating clandestine gravesites in cold cases: Combining geographic profiling, LiDAR, and near surface geophysics.

By nature, clandestine burials are difficult to locate, an issue that can complicate the legal process, and interrupt the natural grief process of the family. The purpose of this paper is to present a three-step process to search for clandestine graves using (1) geographic profiling, (2) light detection and ranging (LiDAR), and (3) near surface geophysics. Each process incrementally decreases the geographic area being searched, while increasing the level of detail provided to investigators. Using two well-known Australian cases and one experimental study, this paper will demonstrate how (1) can highlight potential search areas, (2) can further narrow down the location of potential burial sites within these search areas, and (3) can assist with locating the clandestine grave. Although each technique on its own can successfully locate graves, combining the techniques can provide the most efficient approach to locate those who are missing and buried.

Searching for Gravitational Waves from Cosmological Phase Transitions with the NANOGrav 12.5-Year Dataset.

We search for a first-order phase transition gravitational wave signal in 45 pulsars from the NANOGrav 12.5-year dataset. We find that the data can be modeled in terms of a strong first order phase transition taking place at temperatures below the electroweak scale. However, we do not observe any strong preference for a phase-transition interpretation of the signal over the standard astrophysical interpretation in terms of supermassive black hole mergers; but we expect to gain additional discriminating power with future datasets, improving the signal to noise ratio and extending the sensitivity window to lower frequencies. An interesting open question is how well gravitational wave observatories could separate such signals.

Selective Review of Neuroimaging Findings in Youth at Clinical High Risk for Psychosis: On the Path to Biomarkers for Conversion.

First episode psychosis (FEP), and subsequent diagnosis of schizophrenia or schizoaffective disorder, predominantly occurs during late adolescence, is accompanied by a significant decline in function and represents a traumatic experience for patients and families alike. Prior to first episode psychosis, most patients experience a prodromal period of 1-2 years, during which symptoms first appear and then progress. During that time period, subjects are referred to as being at Clinical High Risk (CHR), as a prodromal period can only be designated in hindsight in those who convert. The clinical high-risk period represents a critical window during which interventions may be targeted to slow or prevent conversion to psychosis. However, only one third of subjects at clinical high risk will convert to psychosis and receive a formal diagnosis of a primary psychotic disorder. Therefore, in order for targeted interventions to be developed and applied, predicting who among this population will convert is of critical importance. To date, a variety of neuroimaging modalities have identified numerous differences between CHR subjects and healthy controls. However, complicating attempts at predicting conversion are increasingly recognized co-morbidities, such as major depressive disorder, in a significant number of CHR subjects. The result of this is that phenotypes discovered between CHR subjects and healthy controls are likely non-specific to psychosis and generalized for major mental illness. In this paper, we selectively review evidence for neuroimaging phenotypes in CHR subjects who later converted to psychosis. We then evaluate the recent landscape of machine learning as it relates to neuroimaging phenotypes in predicting conversion to psychosis.

Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions.

Persistence of drug-resistant quiescent leukemic stem cells (LSC) and impaired natural killer (NK) cell immune response account for relapse of chronic myelogenous leukemia (CML). Inactivation of protein phosphatase 2A (PP2A) is essential for CML-quiescent LSC survival and NK cell antitumor activity. Here we show that MIR300 has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. MIR300 is upregulated in CML LSCs and NK cells by bone marrow microenvironment (BMM) signals to induce quiescence and impair immune response, respectively. Conversely, BCR-ABL1 downregulates MIR300 in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating TUG1 long noncoding RNA that uncouples and limits MIR300 function to cytostasis. Genetic and pharmacologic MIR300 modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis in vitro and in patient-derived xenografts; hence, the importance of MIR300 and PP2A activity for CML development and therapy.

Ferret brain possesses young interneuron collections equivalent to human postnatal migratory streams.

The human early postnatal brain contains late migratory streams of immature interneurons that are directed to cortex and other focal brain regions. However, such migration is not observed in rodent brain, and whether other small animal models capture this aspect of human brain development is unclear. Here, we investigated whether the gyrencephalic ferret cortex possesses human-equivalent postnatal streams of doublecortin positive (DCX+) young neurons. We mapped DCX+ cells in the brains of ferrets at P20 (analogous to human term gestation), P40, P65, and P90. In addition to the rostral migratory stream, we identified three populations of young neurons with migratory morphology at P20 oriented toward: (a) prefrontal cortex, (b) dorsal posterior sigmoid gyrus, and (c) occipital lobe. These three neuronal collections were all present at P20 and became extinguished by P90 (equivalent to human postnatal age 2 years). DCX+ cells in such collections all expressed GAD67, identifying them as interneurons, and they variously expressed the subtype markers SP8 and secretagogin (SCGN). SCGN+ interneurons appeared in thick sections to be oriented from white matter toward multiple cortical regions, and persistent SCGN-expressing cells were observed in cortex. These findings indicate that ferret is a suitable animal model to study the human-relevant process of late postnatal cortical interneuron integration into multiple regions of cortex.

Emission Measurements from Traditional Biomass Cookstoves in South Asia and Tibet.

Traditional biomass stoves are a major global contributor to emissions that impact climate change and health. This paper reports emission factors of particulate matter (PM2.5), carbon monoxide (CO), organic carbon (OC), black carbon (EC), optical absorption, and scattering from 46 South Asian, 48 Tibetan, and 4 Ugandan stoves. These measurements plus a literature review provide insight into the robustness of emission factors used in emission inventories. Tibetan dung stoves produced high average PM2.5 emission factors (23 and 43 gkg-1 for chimney and open stoves) with low average EC (0.3 and 0.7 gkg-1, respectively). Comparatively, PM2.5 from South Asian stoves (7 gkg-1) was in the range of previous measurements and near values used in inventories. EC emission factors varied between stoves and fuels ( p < 0.001), without corresponding differences in absorption; stoves that produced little EC, produced enough brown carbon to have about the same absorption as stoves with high EC emissions. In Tibetan dung stoves, for example, OC contributed over 20% of the absorption. Overall, EC emission factors were not correlated with PM2.5 and were constrained to low values, relative to PM2.5, over a wide range of combustion conditions. The average measured EC emission factor (1 gkg-1), was near current inventory estimates.

Alternative RNA Processing of Topoisomerase IIα in Etoposide-Resistant Human Leukemia K562 Cells: Intron Retention Results in a Novel C-Terminal Truncated 90-kDa Isoform.

DNA topoisomerase IIα (TOP2α) is a prominent target for anticancer drugs whose clinical efficacy is often limited by chemoresistance. Using antibody specific for the N-terminal of TOP2α, immunoassays indicated the existence of two TOP2α isoforms, 170 and 90 kDa, present in K562 leukemia cells and in an acquired etoposide (VP-16)-resistant clone (K/VP.5). TOP2α/90 expression was dramatically increased in etoposide-resistant K/VP.5 compared with parental K562 cells. We hypothesized that TOP2α/90 was the translation product of novel alternatively processed pre-mRNA, confirmed by 3'-rapid amplification of cDNA ends, polymerase chain reaction, and sequencing. TOP2α/90 mRNA includes retained intron 19, which harbors an in-frame stop codon, and two consensus poly(A) sites. The processed transcript is polyadenylated. TOP2α/90 mRNA encodes a 90,076-Da translation product missing the C-terminal 770 amino acids of TOP2α/170, replaced by 25 unique amino acids through translation of the exon 19/intron 19 read-through. Immunoassays, utilizing antisera raised against these unique amino acids, confirmed that TOP2α/90 is expressed in both cell types, with overexpression in K/VP.5 cells. Immunodetection of complex of enzyme-to-DNA and single-cell gel electrophoresis (Comet) assays demonstrated that K562 cells transfected with a TOP2α/90 expression plasmid exhibited reduced etoposide-mediated TOP2α-DNA covalent complexes and decreased etoposide-induced DNA damage, respectively, compared with similarly treated K562 cells transfected with empty vector. Because TOP2α/90 lacks the active site tyrosine (Tyr805) of full-length TOP2α, these results strongly suggest that TOP2α/90 exhibits dominant-negative properties. Further studies are underway to characterize the mechanism(s) by which TOP2α/90 plays a role in acquired resistance to etoposide and other TOP2α targeting agents.

PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells.

The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase-independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression--but not activity--of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/ß-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase-independent and PP2A-mediated inhibition of JAK2 and ß-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1-positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/ß-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and relieve lifelong patient dependence on TKIs.

Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias.

As tyrosine kinase inhibitors (TKIs) fail to induce long-term response in blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL), novel therapies targeting leukemia-dysregulated pathways are necessary. Exportin-1 (XPO1), also known as chromosome maintenance protein 1, regulates cell growth and differentiation by controlling the nucleocytoplasmic trafficking of proteins and RNAs, some of which are aberrantly modulated in BCR-ABL1(+) leukemias. Using CD34(+) progenitors from CML, B-ALL, and healthy individuals, we found that XPO1 expression was markedly increased, mostly in a TKI-sensitive manner, in CML-BC and Ph(+) B-ALL. Notably, XPO1 was also elevated in Ph(-) B-ALL. Moreover, the clinically relevant XPO1 inhibitor KPT-330 strongly triggered apoptosis and impaired the clonogenic potential of leukemic, but not normal, CD34(+) progenitors, and increased survival of BCR-ABL1(+) mice, 50% of which remained alive and, mostly, became BCR-ABL1 negative. Moreover, KPT-330 compassionate use in a patient with TKI-resistant CML undergoing disease progression significantly reduced white blood cell count, blast cells, splenomegaly, lactate dehydrogenase levels, and bone pain. Mechanistically, KPT-330 altered the subcellular localization of leukemia-regulated factors including RNA-binding heterogeneous nuclear ribonucleoprotein A1 and the oncogene SET, thereby inducing reactivation of protein phosphatase 2A tumor suppressor and inhibition of BCR-ABL1 in CML-BC cells. Because XPO1 is important for leukemic cell survival, KPT-330 may represent an alternative therapy for TKI-refractory Ph(+) leukemias.

Household light makes global heat: high black carbon emissions from kerosene wick lamps.

Kerosene-fueled wick lamps used in millions of developing-country households are a significant but overlooked source of black carbon (BC) emissions. We present new laboratory and field measurements showing that 7-9% of kerosene consumed by widely used simple wick lamps is converted to carbonaceous particulate matter that is nearly pure BC. These high emission factors increase previous BC emission estimates from kerosene by 20-fold, to 270 Gg/year (90% uncertainty bounds: 110, 590 Gg/year). Aerosol climate forcing on atmosphere and snow from this source is estimated at 22 mW/m² (8, 48 mW/m²), or 7% of BC forcing by all other energy-related sources. Kerosene lamps have affordable alternatives that pose few clear adoption barriers and would provide immediate benefit to user welfare. The net effect on climate is definitively positive forcing as coemitted organic carbon is low. No other major BC source has such readily available alternatives, definitive climate forcing effects, and cobenefits. Replacement of kerosene-fueled wick lamps deserves strong consideration for programs that target short-lived climate forcers.

Genetic neuropathology of schizophrenia: new approaches to an old question and new uses for postmortem human brains.

Human postmortem brain studies are critical for elucidating the pathophysiology and etiology of schizophrenia and other major mental illnesses. The traditional approach compares patients and control subjects but is potentially confounded by a number of artifacts, including medication, substance misuse, and other secondary effects of illness. Genetic advances now make possible a novel approach that focuses on how allelic variation in risk-associated genes affects expression and function of transcripts and proteins. These questions can be addressed in normal brain, overcoming to some extent the confounding effects of studying brains from subjects with schizophrenia; equally, extension of the studies to include cases also has advantages. Conceptually, the approach may be seen as the neuropathologic counterpart of genetic neuroimaging, representing a potentially powerful intermediate phenotype. For several schizophrenia susceptibility genes, the data show that risk-associated polymorphisms do affect gene expression or the function of the encoded protein; in some instances, expression of downstream or interacting partners of the gene are also altered. A further striking finding is that the implicated transcripts often appear to be enriched in, or specific to, human brain. Some also show enhanced expression in fetal brain. These considerations give unique importance to postmortem human brain tissue in elucidating the genetic mechanisms underlying schizophrenia and probably other neurodevelopmental disorders as well. Studies of this kind can provide clues as to the biological mechanisms of genetic association, especially when carried out in conjunction with experimental studies. Moreover, the data, interpreted judiciously, can strengthen the plausibility of the association itself.

Psychiatric brain banking: three perspectives on current trends and future directions.

Postmortem human brain tissue is critical for advancing neurobiological studies of psychiatric illness, particularly for identifying brain-specific transcripts and isoforms. State-of-the-art methods and recommendations for maintaining psychiatric brain banks are discussed in three disparate collections, the National Institute of Mental Health Brain Tissue Collection, the Harvard Brain Tissue Resource Center, and the Mount Sinai School of Medicine Alzheimer's Disease and Schizophrenia Brain Bank. While the National Institute of Mental Health Brain Tissue Collection obtains donations from medical examiners and focuses on clinical diagnosis, toxicology, and building life span control cohorts, the Harvard Brain Tissue Resource Center is designed as a repository to collect large-volume, high-quality brain tissue from community-based donors across a nationwide network, placing emphasis on the accessibility of tissue and related data to research groups worldwide. The Mount Sinai School of Medicine Alzheimer's Disease and Schizophrenia Brain Bank has shown that prospective recruitment is a successful approach to tissue donation, placing particular emphasis on clinical diagnosis through antemortem contact with donors, as well as stereological tissue sampling methods for neuroanatomical studies and frozen tissue sampling approaches that enable multiple assessments (e.g., RNA, DNA, protein, enzyme activity, binding) of the same tissue block. Promising scientific approaches for elucidating the molecular and cellular pathways in brain that may contribute to schizophrenia are briefly discussed. Despite different perspectives from three established brain collections, there is consensus that varied networking strategies, rigorous tissue and clinical characterization, sample and data accessibility, and overall adaptability are integral to the success of psychiatric brain banking.

Development and pilot study of a marketing strategy for primary care/internet-based depression prevention intervention for adolescents (the CATCH-IT intervention).

BACKGROUND: Adolescent depression is both common and burdensome, and while evidence-based strategies have been developed to prevent adolescent depression, participation in such interventions remains extremely low, with less than 3% of at-risk individuals participating. To promote participation in evidence-based preventive strategies, a rigorous marketing strategy is needed to translate research into practice. OBJECTIVE: To develop and pilot a rigorous marketing strategy for engaging at-risk individuals with an Internet-based depression prevention intervention in primary care targeting key attitudes and beliefs. METHOD: A marketing design group was constituted to develop a marketing strategy based on the principles of targeting, positioning/competitor analysis, decision analysis, and promotion/distribution and incorporating contemporary models of behavior change. We evaluated the formative quality of the intervention and observed the fielding experience for prevention using a pilot study (observational) design. RESULTS: The marketing plan focused on "resiliency building" rather than "depression intervention" and was relayed by office staff and the Internet site. Twelve practices successfully implemented the intervention and recruited a diverse sample of adolescents with > 30% of all those with positive screens and > 80% of those eligible after phone assessment enrolling in the study with a cost of $58 per enrollee. Adolescent motivation for depression prevention (1-10 scale) increased from a baseline mean value of 7.45 (SD = 2.05) to 8.07 poststudy (SD = 1.33) (P = .048). CONCLUSIONS: Marketing strategies for preventive interventions for mental disorders can be developed and successfully introduced and marketed in primary care.

From prototype to product: development of a primary care/internet based depression prevention intervention for adolescents (CATCH-IT).

We describe the prototype to product development process of a low cost, socio-culturally relevant, easily implemented Internet-based depression prevention intervention for adolescents in primary care. The intervention named "Project CATCH-IT" (Competent Adulthood Transition with Cognitive-behavioral, Humanistic and Interpersonal Training) includes an initial motivational interview in primary care to engage the adolescent, fourteen Web-based modules based on behavioral activation, cognitive behavioral and interpersonal psychotherapy which target known risk factors, and a follow-up motivational interview in primary care. This was successfully fielded in a pilot study with 25 adolescents. We know of no other similar interventions developed for the prevention of depression in youth that is potentially universally available at low cost and that utilizes existing systems of healthcare providers.

Physician organization agreements: reining in physician contractual autonomy--why you should do it now.

The generally accepted meaning of "organization" is a group of individuals with common interests organized to accomplish common goals and objectives. Within the context of physician organizations, however, the actual meaning of "organization" is a group of diverse, independent, solo-practice-minded physicians devoted to individual self-interests and sustained personal autonomy. This article addresses the rarely discussed cause and consequence of physician contractual autonomy and tactics...to rein it in.

Negotiating the best deal with a hospital: if it sounds too good to be true it is.

In the face of mounting uncertainty in the healthcare marketplace, including the strong likelihood of substantial healthcare reform looming on the horizon, one fact remains certain ... the time for physician organizations to correct negotiation deficiencies is now. Factually identifying and correcting negotiating deficiencies is the first step in achieving parity in negotiating with hospitals. This article exposes sensitive, rarely addressed deficiencies; uncovers strengths; and presents a strategy to achieve parity.

The Clinical Integration Movement: is there peril on the horizon?

Clinical Integration provides the means for independent physicians to become the major force in reshaping the health care delivery system, and by default... the means for hospitals and payors to eventually eviscerate what remains of physician independence. This article exposes Clinical Integration reality, high-impact mistakes, opportunities, options, and strategies to reposition independent physicians to take charge of their own future.

Clusters of Behaviors and Beliefs Predicting Adolescent Depression: Implications for Prevention.

OBJECTIVE: Risk factors for various disorders are known to cluster. However, the factor structure for behaviors and beliefs predicting depressive disorder in adolescents is not known. Knowledge of this structure can facilitate prevention planning. METHODS: We used the National Longitudinal Study of Adolescent Health (AddHealth) data set to conduct an exploratory factor analysis to identify clusters of behaviors/experiences predicting the onset of major depressive disorder (MDD) at 1-year follow-up (N=4,791). RESULTS: Four factors were identified: family/interpersonal relations, self-emancipation, avoidant problem solving/low self-worth, and religious activity. Strong family/interpersonal relations were the most significantly protective against depression at one year follow-up. Avoidant problem solving/low self-worth was not predictive of MDD on its own, but significantly amplified the risks associated with delinquency. CONCLUSION: Depression prevention interventions should consider giving family relationships a more central role in their efforts. Programs teaching problem solving skills may be most appropriate for reducing MDD risk in delinquent youth.

Development and process evaluation of a primary care internet-based intervention to prevent depression in emerging adults.

BACKGROUND: Primary care is a potential setting for implementation of depression prevention interventions using cognitive behavioral therapy (CBT) and interpersonal psychotherapy (IPT). The purpose of this study was to develop and conduct a process evaluation of a primary care/ Internet-based intervention that addresses key dissemination barriers in a community setting. METHOD: We used an interdisciplinary team of investigators in a multistep intervention development process among a sample of primary care patients (aged 18 to 24 years). The intervention included an initial primary care motivational interview to engage the participant, 11 Internet-based modules based on CBT (to counter pessimistic thinking) and IPT (to activate social networks and strengthen relationship skills), and a follow-up motivational interview in primary care to enhance behavior change. Each component of the intervention was rated with regard to dissemination barriers of (1) fidelity, (2) motivation, (3) dose, (4) perceived helpfulness (rated on a Likert scale), and (5) potential costs. The study was conducted from April through June of 2004. RESULTS: Fidelity checklist and serial reviews were satisfactory (100% core concepts translated into intervention). Key motivations for participation included (1) risk reduction, (2) intervention effectiveness, (3) "resiliency," and (4) altruism. In terms of dose, 13 of 14 participants engaged the Internet-based components, completing a mean of 7.2 modules (SD = 3.9). The 2 primary care interviews and the self-assessment and resiliency modules received the highest helpfulness ratings. The duration of the 2 motivational interviews was approximately 17-18 minutes, which is similar to a typical primary care visit. CONCLUSIONS: By using multidisciplinary teams and incorporating the opinions of potential users, complex preventive mental health interventions can be translated into primary care settings with adequate fidelity, motivation, dose, and perceived helpfulness, and at a reasonably low cost.