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The BRAIN Initiative arose from a grand challenge to “accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought.” The BRAIN Initiative is a public-private effort focused on the development and use of powerful tools for acquiring fundamental insights about how information processing occurs in the central nervous system (CNS). As the Initiative enters its fifth year, NIH has supported >500 principal investigators, who have answered the Initiative's challenge via hundreds of publications describing novel tools, methods, and discoveries that address the Initiative's seven scientific priorities. We describe scientific advances produced by individual laboratories, multi-investigator teams, and entire consortia that, over the coming decades, will produce more comprehensive and dynamic maps of the brain, deepen our understanding of how circuit activity can produce a rich tapestry of behaviors, and lay the foundation for understanding how its circuitry is disrupted in brain disorders. Much more work remains to bring this vision to fruition, and the National Institutes of Health continues to look to the diverse scientific community, from mathematics, to physics, chemistry, engineering, neuroethics, and neuroscience, to ensure that the greatest scientific benefit arises from this unique research Initiative.

The “life phenomenology” theme of the 35th International Human Science Research Conference challenged participants to consider pressing questions of life and of living with others of our own and other-than-human kinds. The theme was addressed by keynote speakers Maxine Sheets-Johnstone, Ralph Acampora and David Abram who invoked a motile, affective and linguistic awareness of how we might dwell actively and ethically amongst human communities and with the many life forms we encounter in the wider, wilder world we have in common. Conference participants were provoked to consider the following questions: “How might phenomenology have us recognize a primacy of movement and bring us in touch with the motions and gestures of the multiple lifeworlds of daily living? What worlds from ecology to technology privilege certain animations? What are the affects and effects of an enhanced phenomenological sensitivity? What senses, feelings, emotions and moods of self-affirmation and responsiveness to others sustain us in our daily lives? And to what extent might the descriptive, invocative, provocative language of phenomenology infuse the human sciences and engender a language for speaking directly of life?”

The NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is focused on developing new tools and neurotechnologies to transform our understanding of the brain, and neuroethics is an essential component of this research effort. Coordination with other brain projects around the world will help maximize success.

OBJECTIVES Transmission of drug-resistant HIV-1 has decreased in the UK since the early 2000s. This analysis reports recent trends and characteristics of transmitted drug resistance (TDR) in the UK from 2010 to 2013. METHODS Resistance tests conducted in antiretroviral treatment (ART)-naive individuals between 2010 and 2013 were analysed for the presence of transmitted drug resistance mutations (TDRMs), defined as any mutations from a modified 2009 World Health Organization surveillance list, or a modified 2013 International Antiviral Society-USA list for integrase tests. Logistic regression was used to examine associations between demographics and the prevalence of TDRMs. RESULTS TDRMs were observed in 1223 (7.5%) of 16 425 individuals; prevalence declined from 8.1% in 2010 to 6.6% in 2013 (P = 0.02). The prevalence of TDRMs was higher among men who have sex with men (MSM) compared with heterosexual men and women (8.7% versus 6.4%, respectively) with a trend for decreasing TDRMs among MSM (P = 0.008) driven by a reduction in nucleoside reverse transcriptase inhibitor (NRTI)-related mutations. The most frequently detected TDRMs were K103N (2.2%), T215 revertants (1.6%), M41L (0.9%) and L90M (0.7%). Predicted phenotypic resistance to first-line ART was highest to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) rilpivirine and efavirenz (6.2% and 3.4%, respectively) but minimal to NRTIs, including tenofovir, and protease inhibitors (PIs). No major integrase TDRMs were detected among 101 individuals tested while ART-naive. CONCLUSIONS We observed a decrease in TDRMs in recent years. However, this was confined to the MSM population and rates remained stable in those with heterosexually acquired HIV infection. Resistance to currently recommended first-line ART, including integrase inhibitors, remained reassuringly low.

Background on the National Institutes of Health BRAIN Initiative and neuroethics The National Institutes of Health (NIH) works tirelessly to support the best science and ensure that its funded research adheres to the highest ethical standards. From its inception, the NIH Brain Research through

AIM: To perform a blind study to assess the capability of the Ion Personal Genome Machine® (PGM™) system to sequence forensically relevant genetic marker panels and to characterize unknown individuals for ancestry and possible relatedness. METHODS: Twelve genomic samples were provided by a third party for blinded genetic analysis. For these 12 samples, the mitochondrial genome and three PGM™ panels containing human identity single nucleotide polymorphisms (SNPs), ancestry informative SNPs, and short tandem repeats (STRs) were sequenced on the PGM™ system and analyzed. RESULTS: All four genetic systems were run and analyzed on the PGM™ system in a reasonably quick time frame. Completeness of genetic profiles, depth of coverage, strand balance, and allele balance were informative metrics that illustrated the quality and reliability of the data produced. SNP genotypes allowed for identification of sex, paternal lineage, and population ancestry. STR genotypes were shown to be in complete concordance with genotypes generated by standard capillary electrophoresis-based technologies. Variants in the mitochondrial genome data provided information on population background and maternal relationships. CONCLUSION: All results from analysis of the 12 genomic samples were consistent with sample information provided by the sample providers at the end of the blinded study. The relatively easy identification of intra-STR allele SNPs offered the potential for increased discrimination power. The promising nature of these results warrants full validation studies of this massively parallel sequencing technology and its further development for forensic data analysis.

Exome sequencing in families affected by rare genetic disorders has the potential to rapidly identify new disease genes (genes in which mutations cause disease), but the identification of a single causal mutation among thousands of variants remains a significant challenge. We developed a scoring algorithm to prioritize potential causal variants within a family according to segregation with the phenotype, population frequency, predicted effect, and gene expression in the tissue(s) of interest. To narrow the search space in families with multiple affected individuals, we also developed two complementary approaches to exome-based mapping of autosomal-dominant disorders. One approach identifies segments of maximum identity by descent among affected individuals; the other nominates regions on the basis of shared rare variants and the absence of homozygous differences between affected individuals. We showcase our methods by using exome sequence data from families affected by autosomal-dominant retinitis pigmentosa (adRP), a rare disorder characterized by night blindness and progressive vision loss. We performed exome capture and sequencing on 91 samples representing 24 families affected by probable adRP but lacking common disease-causing mutations. Eight of 24 families (33%) were revealed to harbor high-scoring, most likely pathogenic (by clinical assessment) mutations affecting known RP genes. Analysis of the remaining 17 families identified candidate variants in a number of interesting genes, some of which have withstood further segregation testing in extended pedigrees. To empower the search for Mendelian-disease genes in family-based sequencing studies, we implemented them in a cross-platform-compatible software package, MendelScan, which is freely available to the research community.

Phenomenology has remained a sheltering place for those who would seek to understand not only their own "first person" experiences but also the first person experiences of others. Recent publications by renowned scholars within the field have clarified and extended our possibilities of access to "first person" experience by means of perception (Lingis, 2007) and reflection (Zahavi, 2005). Teaching phenomenology remains a challenge, however, because one must find ways of communicating to the student how to embody it as a process rather than simply to learn about it as a content area. Another challenge issues from the fact that most writings on applied phenomenology emphasize individual subjectivity as the central focus, while offering only indirect access to the subjectivity of others (for example, by way of analyzing written descriptions provided by the individual under study). While one finds in the literature of psychotherapy plentiful elucidations of the "we-experience" within which therapists form impressions of their clients' experience, there is still need for a more thoughtful clarification of our rather special personal modes of access to the experience of others in everyday life. This paper will present "second person perspectivity" as a mode of resonating with the expressions of others and will describe class activities that can bring students closer to a lived understanding of what it means to be doing phenomenology in the face of the other.

MIV-210 is a prodrug of 3′-fluoro-2′,3′-dideoxyguanosine with high oral bioavailability in humans and potent activity against hepatitis B virus (HBV). Woodchucks infected with woodchuck hepatitis virus (WHV) represent an accurate model of HBV infection that is utilized for evaluation of the efficacy and safety of novel anti-HBV agents. Oral administration of MIV-210 at 20 or 60 mg/kg of body weight/day induced a rapid virological response in chronically infected woodchucks, reducing serum WHV DNA levels by 4.75 log10and 5.72 log10, respectively, in 2 weeks. A progressive decline in WHV viremia occurred throughout the 10-week therapy, giving final reductions of 7.23 log10and 7.68 log10in the 20- and 60-mg/kg/day groups, respectively. Further, a daily dose of 10 mg/kg decreased the serum WHV load 400-fold after 4 weeks of treatment, and a dose of 5 mg/kg/day was sufficient to maintain this antiviral effect during the following 6-week period. MIV-210 at 20 or 60 mg/kg/day reduced the liver WHV DNA load 200- to 2,500-fold from pretreatment levels and, importantly, led to a 2.0 log10drop in the hepatic content of WHV covalently closed circular DNA. The treatment with 60 mg/kg/day was well tolerated. Liver biopsy specimens obtained after the 10-week treatment with 20 or 60 mg/kg/day and after the 10-week follow-up showed hepatocyte and mitochondrial ultrastructures comparable to those in the placebo-treated group. It was concluded that MIV-210 is highly effective against chronic WHV infection. These findings, together with the previously demonstrated inhibitory activity of MIV-210 against lamivudine-, adefovir-, and entecavir-resistant HBV variants, make MIV-210 a highly valuable candidate for further testing as an agent against chronic hepatitis B.

Summary The number of patients who present with advanced human immunodeficiency virus (HIV) disease [defined as a helper lymphocyte (CD4) count

The peptide content of individual mammalian cells is profiled using matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry. Both enzymatic and non-enzymatic procedures, including a glycerol cell stabilization method, are reported for the isolation of individual mammalian cells in a manner compatible with MALDI MS measurements. Guided microdeposition of MALDI matrix allows samples to be created with suitable analyte-to-matrix ratios. More than fifteen peptides are observed in individual rat intermediate pituitary cells. The combination of accurate mass data, expected cleavages by proteolytic enzymes, and post-source decay sequencing allows identification of fourteen of these peptides as pro-opiomelanocortin prohormone-derived molecules. These protocols permit the classification of individual mammalian cells by peptide profile, the elucidation of cell-specific prohormone processing, and the discovery of new signaling peptides on a cell-to-cell basis in a wide variety of mammalian cell types.

All zoology assumes from our side a methodical Einfuehlung into animal behaviour, with the participation of the animal in our perceptive life and the participation of our perceptive life in animality. (Merleau-Ponty, 1970, pp. 97-98) Looking into his eyes, I could not bring myself to pretend to talk to him the way I would to a dog or a horse: He would probably have looked at me sceptically and swaggered away. Nor could I embarrass myself by speaking English as though he could understand me. Silence, and gesture, were suddenly of paramount importance. Our eyes met, and I think that I experienced that chiasm, that criss-crossing of intentions and gestures, of which Merleau-Ponty speaks.

Aim To perform a blind study to assess the capability of the Ion Personal Genome Machine® (PGM™) system to sequence forensically relevant genetic marker panels and to characterize unknown individuals for ancestry and possible relatedness. Methods Twelve genomic samples were provided by a third party for blinded genetic analysis. For these 12 samples, the mitochondrial genome and three PGM™ panels containing human identity single nucleotide polymorphisms (SNPs), ancestry informative SNPs, and short tandem repeats (STRs) were sequenced on the PGM™ system and analyzed. Results All four genetic systems were run and analyzed on the PGM™ system in a reasonably quick time frame. Completeness of genetic profiles, depth of coverage, strand balance, and allele balance were informative metrics that illustrated the quality and reliability of the data produced. SNP genotypes allowed for identification of sex, paternal lineage, and population ancestry. STR genotypes were shown to be in complete concordance with genotypes generated by standard capillary electrophoresis-based technologies. Variants in the mitochondrial genome data provided information on population background and maternal relationships. Conclusion All results from analysis of the 12 genomic samples were consistent with sample information provided by the sample providers at the end of the blinded study. The relatively easy identification of intra-STR allele SNPs offered the potential for increased discrimination power. The promising nature of these results warrants full validation studies of this massively parallel sequencing technology and its further development for forensic data analysis.

Hepatitis B virus (HBV) and the closely related woodchuck hepatitis virus (WHV) are potent carcinogens that trigger development of primary hepatocellular carcinoma (HCC). The initial sites of hepadnavirus–host genome integration, their diversity and kinetics of formation can be central to virus persistence and the initiation and progression of HCC. To recognize the nature of the very early virus–host interactions, we explored de novo infection of human hepatocyte-like HepaRG cells with authentic HBV and naive woodchucks with WHV. HepaRG were analyzed from several minutes post exposure to HBV onwards, whereas woodchuck liver biopsies at 1 or 3 h and 6 weeks post infection with WHV. Inverse PCR and clonal sequencing of the amplicons were applied to identify virus–host genomic junctions. HBV and WHV DNA and their replication intermediates became detectable in one hour after virus exposure. Concomitantly, HBV DNA integration into various host genes was detected. Notably, junctions of HBV X gene with retrotransposon sequences, such as LINE1 and LINE2, became prominent shortly after infection. In woodchucks, insertion of WHV X and preS sequences into host genome was evident at 1 and 3 h post infection (h.p.i.), confirming that hepadnavirus under natural conditions integrates into hepatocyte DNA soon after invasion. The HBV and WHV X gene enhancer II/core promotor sequence most often formed initial junctions with host DNA. Moreover, multiple virus–virus DNA fusions appeared from 1 h.p.i. onwards in both infected hepatocytes and woodchuck livers. In summary, HBV DNA integrates almost immediately after infection with a variety of host’s sequences, among which tandemly repeating non-coding DNAs are common. This study revealed that HBV can engage mobile genetic elements from the beginning of infection to induce pro-oncogenic perturbations throughout the host genome. Such swift virus insertion was also evident in natural hepadnaviral infection in woodchucks.

Hepadnavirus invasion in woodchucks has been identified as a potent inducer of autoantibodies against asialoglycoprotein receptor (anti-ASGPR), a molecule essentially unique to hepatocytes that mediate clearance of desialylated serum proteins. We evaluated the possible pathogenetic importance of anti-ASGPR triggered by woodchuck hepatitis virus (WHV), using anti-ASGPR-reactive serum immunoglobulins (Igs) from five animals with different stages of WHV hepatitis or self-limited WHV infection and isolated woodchuck hepatocytes or HepG2 cells as targets. The results revealed that WHV-induced anti-ASGPR can specifically inhibit asialoglycoprotein recognition by both homologous and heterologous liver cells, as tested in an asialofetuin (ASFN)-binding radioassay. However, the extent of the interference significantly varied (from 85% inhibition to none) for anti-ASGPR with similar titer from different animals, indicating a high degree of heterogeneity in the ASGPR epitope specificity and in the potential biological effects of these autoantibodies. The WHV-triggered anti-ASGPR also induced complement-mediated hepatocytolysis in a microculture tetrazolium (MTT) assay, which ranged from 8.9% +/- 0.3% to 33.6% +/- 3.6% (mean +/- SD) for different animals and target cell numbers. This cytopathic effect was strictly ASGPR-specific, complement-dependent, and was not related to the anti-ASGPR ability to inhibit ligand-hepatocyte binding. Our findings indicate that among pathways by which anti-ASGPR autoimmunity could cause liver damage, hepadnavirus-induced anti-ASGPR might impair hepatocytes by both disrupting clearance of desialylated proteins and activation of the complement-mediated cytolysis. These cytopathic effects might contribute to the pathogenesis, aggravate severity, and prolong recovery from liver injury in viral hepatitis.

A site capable of strictly host- and cell type-specific recognition was identified in the preS1 domain of woodchuck hepatitis virus (WHV) through the use of antipeptide antisera generated against the extreme N-terminal fragment of the large virus envelope protein. The crucial determinant of this binding site was mapped to amino acids 10-13. Although a synthetic analogue of the site was highly immunogenic, natural WHV envelope did not display the site activity unless it was modified by proteolysis or acidic pH treatment, indicating an internal location of the determinant in viral envelope. Synthetic peptides encompassing the sequence of this site bound woodchuck lymphoid cells and hepatocytes in a species-restricted manner which followed characteristics of a specific ligand-receptor interaction, although their ability to interact with lymphoid cells was considerably greater than that for hepatocytes. In WHV-infected animals, a natural antibody to the identified cryptic cell-binding site arose independently of that directed against epitopes of unmodified virus envelope and its appearance constituted the earliest immunovirological indicator of virus invasion. Our results demonstrated that the preS1 domain of the large WHV envelope protein is endowed with the species- and cell type-specific recognition site which is protected against antibody surveillance by the natural tertiary structure of the protein and we suggest that proteolytic cleavage is required to induce the binding activity.

An unexpected run-up of the ocean along Daytona Beach, Florida, on 3–4 July 1992 was associated with at least one large ocean wave. The wave, which reached a height of about 3 m above normal tide, injured 75 people and damaged property along Daytona Beach. Analyses of meteorological and oceanographic observations are consistent with the hypothesis that a squall line generated a long water wave. The critical evidence is that the propagation speed of the squall line matched the shallow-water wave speed that prevailed along the direction of motion of the squall line. The squall line exerted force on the ocean for at least 3 h. The issues of recurrence and public safety are discussed.

The segmented insect integument, composed of an epidermal monolayer and its cuticular secretion, is a paradigm for the study of pattern formation during development (Lawrence, 1992). Epidermal activity during development may be coordinated by the transfer of cytoplasmic molecules through cell–cell gap-junctional channels (reviewed in Caveney, 1985). Gap junctions within intact epidermal segments exhibit dynamic changes in their permeability properties during the moult cycle in vivo (Caveney, 1978) and with exposure to the developmental hormone 20-hydroxyecdysone in vitro (Caveney and Blennerhassett, 1980). In addition, the row of epidermal cells at segment borders has distinct permeability properties creating developmental and communication compartments (Warner and Lawrence, 1982; Blennerhassett and Caveney, 1984). This paper documents a method for isolating epidermal cells that are suitable for dual whole-cell voltage-clamp studies of gap-junctional currents. We have identified a large-conductance gap-junctional channel in cell pairs with octanol-reduced junctional currents. This cell model may be useful for examining mechanisms of gap-junctional channel gating during development.

Opioid receptor signaling via EGF receptor (EGFR) transactivation and ERK/MAPK phosphorylation initiates diverse cellular responses that are cell type-dependent. In astrocytes, multiple μ opioid receptor-mediated mechanisms of ERK activation exist that are temporally distinctive and feature different outcomes. Upon discovering that chronic opiate treatment of rats down-regulates thrombospondin 1 (TSP1) expression in the nucleus accumbens and cortex, we investigated the mechanism of action of this modulation in astrocytes. TSP1 is synthesized in astrocytes and is released into the extracellular matrix where it is known to play a role in synapse formation and neurite outgrowth. Acute morphine (hours) reduced TSP1 levels in astrocytes. Chronic (days) opioids repressed TSP1 gene expression and reduced its protein levels by μ opioid receptor and ERK-dependent mechanisms in astrocytes. Morphine also depleted TSP1 levels stimulated by TGFβ1 and abolished ERK activation induced by this factor. Chronic morphine treatment of astrocyte-neuron co-cultures reduced neurite outgrowth and synapse formation. Therefore, inhibitory actions of morphine were detected after both acute and chronic treatments. An acute mechanism of morphine signaling to ERK that entails depletion of TSP1 levels was suggested by inhibition of morphine activation of ERK by a function-blocking TSP1 antibody. This raises the novel possibility that acute morphine uses TSP1 as a source of EGF-like ligands to activate EGFR. Chronic morphine inhibition of TSP1 is reminiscent of the negative effect of μ opioids on EGFR-induced astrocyte proliferation via a phospho-ERK feedback inhibition mechanism. Both of these variations of classical EGFR transactivation may enable opiates to diminish neurite outgrowth and synapse formation.

Background: The transcription factor TCF21 is involved in mesenchymal-to-epithelial differentiation and was shown to be aberrantly hypermethylated in lung and head and neck cancers. Because of its reported high frequency of hypermethylation in lung cancer, further characterization of the stages and types of nonsmall cell lung cancer (NSCLC) that are hypermethylated and the frequency of hypermethylation and associated "second hits" were assessed. Methods: TCF21 promoter hypermethylation in 105 NSCLC including various stages and histologies in smokers and nonsmokers was determined. In addition, TCF21 loss of heterozygosity and mutational status were examined. Twenty-two cancer cell lines from varied tissue origins were also assayed. The NSCLC results were validated and expanded by examining TCF21 immunohistochemical expression on a tissue microarray containing 300 NSCLC cases. Results: Overall, 81% of NSCLC samples showed TCF21 promoter hypermethylation, and 84% showed decreased TCF21 protein expression. Multivariate analysis showed that TCF21 expression, although below normal in both histologies, was lower in adenocarcinoma than in squamous cell carcinoma and was not independently correlated with sex, smoking, and EGFR mutation status or with clinical outcome. Cell lines from other cancer types also showed frequent TCF21 promoter hypermethylation. Conclusions: Hypermethylation and decreased expression of TCF21 were tumor specific and very frequent in all NSCLCs, even early-stage disease, thus making TCF21 a potential candidate methylation biomarker for early-stage NSCLC screening. TCF21 hypermethylation in a variety of tumor cell lines suggests it may also be a valuable methylation biomarker in other tumor types. © 2010 American Cancer Society., link_to_subscribed_fulltext

A twi-dimensional kinematic model has been used to diagnose the thermodynamic, water vapor, and hydrometeor fields of the stratiform clouds associated with a mesoscale tropical cloud cluster. The model incorporates ice- and water-cloud microphysics, visible and infrared radiation, and convective adjustment. It is intended to determine the relative contributions of radiation, mycrophysics, and turbulence to diabatic heating, and the effects that radiation has on the water budget of the cluster in the absence of dynamical interactions. The model has been initialized with thermodynamic fields and wind velocities diagnosed from a GATE tropical squall line. It is found that radiation does not directly affect the water budget of the stratiform region, and any radiative effect on hydrometeors must involve interaction with dynamics.

The importance of effective immune responses in recovery from acute hepadnaviral hepatitis has been demonstrated. However, there is no conclusive delineation of virological and immunological events occurring in the liver immediately after hepadnavirus invasion and during the preacute phase of infection. These very early events might be of primary importance in determining the recovery or progression to chronic hepatitis and the intrinsic hepadnaviral propensity to persist. In this study, applying the woodchuck model of acute hepatitis B, the hepatic kinetics of hepadnavirus replication and activation of genes encoding cytokines, cytotoxicity effectors, and immune cell markers were quantified in sequential liver biopsies collected from 1 h postinoculation onward by sensitive real-time cDNA amplification assays. The results revealed that hepadnavirus replication is established in the liver as early as 1 hour after infection. In 3 to 6 h, significantly augmented intrahepatic transcription of gamma interferon and interleukin-12 were evident, suggesting activation of antigen-presenting cells. In 48 to 72 h, NK and NKT cells were activated and virus replication was transiently but significantly reduced, implying that this early innate response is at least partially successful in limiting virus propagation. Nonetheless, T cells were activated 4 to 5 weeks later when hepatitis became histologically evident. Collectively, our data demonstrate that virus replication is initiated and the innate response activated in the liver soon after exposure to a liver-pathogenic dose of hepadnavirus. Nevertheless, this response is unable to prompt a timely adaptive T-cell response, in contrast to infections caused by other viral pathogens.

Previously, we identified separate genetic influences on ventral versus dorsal hippocampal volume in BXD recombinant inbred mice [Martin MV, Dong HX, Vallera D, Lu L, Williams RW, Rosen GD, et al. Independent quantitative trait loci influence ventral and dorsal hippocampal volume in recombinant inbred strains of mice. Genes Brain Behav 2006;5:614-23]. Based on genotype at genetic markers associated with ventral hippocampal volume, we evaluated BXD mouse strains with relatively small versus large ventral hippocampal volumes using numerous behavioral paradigms known to rely upon hippocampal function and several other tasks that tap into behaviors analogous to those often impaired in schizophrenia. We observed a relationship between genotype at markers known to influence ventral hippocampal volume and working memory at an intermediate memory load. There was no association between genotype at markers known to influence ventral hippocampal volume and spatial reference memory, prepulse inhibition, or elevated plus maze performance. The relevance of these findings for understanding the pathophysiology of schizophrenia are discussed, including the possibility that genetic predisposition toward anterior hippocampal volume reductions and working memory deficits in schizophrenia may be related through a shared genetic locus.

Thrombolytic therapy for patients with acute myocardial infarction (AMI) has produced the need for an accurate early diagnostic marker. We previously developed and assessed an assay for the creatine kinase (CK)-MB subforms; assay time is 25 minutes. Plasma MB2 (tissue subform) activity, MB1 (plasma-modified subform) activity, and MB2/MB1 ratio in 56 healthy individuals were 0.61 +/- 0.33 units/l, 0.63 +/- 0.33 units/l, and 0.94 +/- 0.39, respectively. Only one individual had both an MB2 activity greater than 1.0 units/l and an MB2/MB1 ratio of more than 1.5. Similar results were obtained in 50 hospitalized patients without cardiac disease; two of these patients had both an MB2 activity and an MB2/MB1 ratio greater than the cutoff values. Among 49 patients with AMI, MB2 activity and the MB2/MB1 ratio began to increase 2 hours after AMI; the ratio reached a plateau of 3.1 by 4-6 hours. The first available plasma sample was abnormal by the subform assay in 67% of patients and by a conventional MB assay in 27% of patients. Assay sensitivities in samples collected at 2-4, 4-6, and 6-8 hours after AMI were 59%, 92%, and 100% for the subform assay and 23%, 50%, and 71% for the conventional assay (p less than 0.03 versus subform assay at each time interval). False-negative results were obtained by the subform and conventional assays in 15 and 45 samples at a mean of 2.3 and 5.8 hours, respectively. Subform assay provides rapid and reliable diagnosis of AMI within 4-6 hours after the onset of symptoms, which is 6 hours before conventional CK-MB assays are accurate.

The horizontal precipitation structure of cloud clusters observed over the South China Sea during the Winter Monsoon Experiment (WMONEX) is analyzed using a convective-stratiform technique (CST) developed by Adler and Negri (1988). The technique was modified by altering the method for identifying convective cells in the satellite data, accounting for the extremely cold cloud tops characteristic of the WMONEX region, and modifying the threshold infrared temperature for the boundary of the stratiform rain area. The precipitation analysis was extended to the entire history of the cloud cluster by applying the modified CST to IR imagery from geosynchronous-satellite observations. The ship and aircraft data from the later period of the cluster's lifetime make it possible to check the locations of convective and stratiform precipitation identified by the CST using in situ observations. The extended CST is considered to be effective for determining the climatology of the convective-stratiform structure of tropical cloud clusters.

The number of patients who present with advanced human immunodeficiency virus (HIV) disease [defined as a helper lymphocyte (CD4) count50 cells/mm3 or the presence of an acquired immunodeficiency syndrome (AIDS)-defining illness] is increasing. In the USA during 1994-1999, a relatively stable proportion of 43% of people diagnosed with HIV infection were tested late in the infection (had AIDS diagnosed within 1 year of diagnosis). A recent review of newly diagnosed infections in 2003 found that 301/977 (31%) of patients in the UK and Ireland presented late (200 CD4 cells/mm3). Before a diagnosis is made, patients with advanced disease do not benefit from antiretroviral therapy and may continue to transmit the infection to others. Furthermore, when antiretroviral therapy is initiated in patients with CD4 counts of 201-350 cells/mm(3), the risk of death is lower than when treatment is started at lower CD4 cell counts. With the increasing prevalence of HIV in women and African immigrants, some doctors are concerned that different management approaches need to be used in these groups. This article reviews the evidence and some clinical scenarios for patients with advanced disease without complications and women and Africans who may present with advanced HIV disease. The aim is to offer practical advice on therapeutic options for treatment-naïve patients who present with advanced HIV disease on the basis of available clinical evidence.

Pediatric urolithiasis is commonly associated with structural renal tract anomalies and metabolic disorders. Antenatal diagnosis of renal calculi is extremely rare, with only one report in the literature. We present a case of renal stone formation diagnosed at 34 weeks' gestation on ultrasound examination.

Traces of hepatitis B virus (HBV) genome can persist for years following recovery from hepatitis B. To determine overall duration, molecular characteristics, and pathological implications of this serologically undetectable form of hepadnaviral carriage, we have analyzed the expression of transcriptionally active virus genomes, their infectivity, and examined liver alterations during the natural lifespan of woodchucks convalescent from acute infection with HBV- related woodchuck hepatitis virus (WHV). In this study, we document lifelong persistence of scanty amounts of replicating virus both in the liver and lymphatic system after spontaneous resolution of an episode of experimental hepadnaviral hepatitis. Antibodies to virus nucleocapsid (core) were found to be the most reliable immunovirological marker coexisting with occult infection. In the majority of convalescent woodchucks, serial liver biopsies showed protracted minimal to mild necroinflammation with periods of normal morphology; however, hepatocellular carcinoma (HCC) ultimately developed in 2 of 9 animals studied. Inocula derived from lymphoid cells of convalescent animals induced classical acute hepatitis in virus-naive woodchucks that progressed to chronic hepatitis and HCC in 1 of the animals, demonstrating infectivity and pathogenic competence of the carried virus. Our results reveal that low levels of infectious WHV and residual hepatic inflammation usually continue for life after resolution of hepatitis and that this recovery does not avert HCC development. They also demonstrate that, in addition to the liver, the lymphatic system is the site of the occult lifelong maintenance of replicating hepadnavirus.

This is an introduction to the Gut tutorial “Chronic pancreatitis: diagnosis and management of complications” hosted on BMJ Learning—the best available learning website for medical professionals, from the BMJ Group. Chronic pancreatitis is a progressive inflammatory condition that leads to irreversible loss of pancreatic structure and function. Eighty percent of cases are due to alcohol misuse. Chronic pancreatitis usually presents with abdominal pain, followed at a variable interval …