Systematic Review of Binge Eating Rodent Models for Developing Novel or Repurposing Existing Pharmacotherapies.

Recent advances in developing and screening candidate pharmacotherapies for psychiatric disorders have depended on rodent models. Eating disorders are a set of psychiatric disorders that have traditionally relied on behavioral therapies for effective long-term treatment. However, the clinical use of Lisdexamfatamine for binge eating disorder (BED) has furthered the notion of using pharmacotherapies for treating binge eating pathologies. While there are several binge eating rodent models, there is not a consensus on how to define pharmacological effectiveness within these models. Our purpose is to provide an overview of the potential pharmacotherapies or compounds tested in established rodent models of binge eating behavior. These findings will help provide guidance for determining pharmacological effectiveness for potential novel or repurposed pharmacotherapies.

Alcohol Increases Exosome Release from Microglia to Promote Complement C1q-Induced Cellular Death of Proopiomelanocortin Neurons in the Hypothalamus in a Rat Model of Fetal Alcohol Spectrum Disorders.

Microglia, a type of CNS immune cell, have been shown to contribute to ethanol-activated neuronal death of the stress regulatory proopiomelanocortin (POMC) neuron-producing ß-endorphin peptides in the hypothalamus in a postnatal rat model of fetal alcohol spectrum disorders. We determined whether the microglial extracellular vesicle exosome is involved in the ethanol-induced neuronal death of the ß-endorphin neuron. Extracellular vesicles were prepared from hypothalamic tissues collected from postnatal rats (both males and females) fed daily with 2.5 mg/kg ethanol or control milk formula for 5 d or from hypothalamic microglia cells obtained from postnatal rats, grown in cultures for several days, and then challenged with ethanol or vehicle for 24 h. Nanoparticle tracking analysis and transmission electron microscopy indicated that these vesicles had the size range and shape of exosomes. Ethanol treatments increased the number and the ß-endorphin neuronal killing activity of microglial exosomes both in vivo and in vitro Proteomics analyses of exosomes of cultured microglial cells identified a large number of proteins, including various complements, which were elevated following ethanol treatment. Proteomics data involving complements were reconfirmed using quantitative protein assays. Ethanol treatments also increased deposition of the complement protein C1q in ß-endorphin neuronal cells in both in vitro and in vivo systems. Recombinant C1q protein increased while C1q blockers reduced ethanol-induced C3a/b, C4, and membrane attack complex/C5b9 formations; ROS production; and ultimately cellular death of ß-endorphin neurons. These data suggest that the complement system involving C1q-C3-C4-membrane attack complex and ROS regulates exosome-mediated, ethanol-induced ß-endorphin neuronal death.SIGNIFICANCE STATEMENT Neurotoxic action of alcohol during the developmental period is recognized for its involvement in fetal alcohol spectrum disorders, but the lack of clear understanding of the mechanism of alcohol action has delayed the progress in therapeutic intervention of this disease. Proopiomelanocortin neurons known to regulate stress, energy homeostasis, and immune functions are reported to be killed by developmental alcohol exposure because of activation of microglial immune cells in the brain. While microglia are known to use extracellular vesicles to communicate with neurons for maintaining homeostasis, we show here that ethanol exposure during the developmental period hijacks this system to spread apoptotic factors, including complement protein C1q, to induce the membrane attack complex and reactive super-oxygen species for proopiomelanocortin neuronal killing.

Making It Safe to Grow Old: A Financial Simulation Model for Launching MediCaring Communities for Frail Elderly Medicare Beneficiaries.

POLICY POINTS: At age 65, the average man and woman can respectively expect 1.5 years and 2.5 years of requiring daily help with "activities of daily living." Available services fail to match frail elders' needs, thereby routinely generating errors, unreliability, unwanted services, unmet needs, and high costs. The number of elderly Medicare beneficiaries likely to be frail will triple between 2000 and 2050. Low retirement savings, rising medical and long-term care costs, and declining family caregiver availability portend gaps in badly needed services. The financial simulation reported here for 4 diverse MediCaring Communities shows lower per capita costs. Program savings are substantial and can improve coverage and function of local supportive services within current overall Medicare spending levels. CONTEXT: The Altarum Institute Center for Elder Care and Advanced Illness has developed a reform model, MediCaring Communities, to improve services for frail elderly Medicare beneficiaries through longitudinal care planning, better-coordinated and more desirable medical and social services, and local monitoring and management of a community's quality and supply of services. This study uses financial simulation to determine whether communities could implement the model within current Medicare and Medicaid spending levels, an important consideration to enable development and broad implementation. METHODS: The financial simulation for MediCaring Communities uses 4 diverse communities chosen for adequate size, varying health care delivery systems, and ability to implement reforms and generate data rapidly: Akron, Ohio; Milwaukie, Oregon; northeastern Queens, New York; and Williamsburg, Virginia. For each community, leaders contributed baseline population and program effect estimates that reflected projections from reported research to build the model. FINDINGS: The simulation projected third-year savings between $269 and $537 per beneficiary per month and cumulative returns on investment between 75% and 165%. CONCLUSIONS: The MediCaring Communities financial simulation demonstrates that better care at lower cost for frail elderly Medicare beneficiaries is possible within current financing levels. Long-term success of the initiative will require reinvestment of Medicare savings to bolster nonmedical supportive services in the community. Successful implementation will necessitate waiving certain regulations and developing new infrastructure in pilot communities. This financial simulation methodology will help leadership in other communities to project fiscal performance. Since the MediCaring Communities model also achieves the Centers for Medicare and Medicaid Services' vision for care for frail elders (better care, healthier people, smarter spending) and since these reforms can proceed with limited waivers from Medicare, willing communities should explore implementation and share best practices about how to achieve fundamental service delivery changes that can meet the challenges of a much older population in the 21st century.

The Frequency of Cytidine Editing of Viral DNA Is Differentially Influenced by Vpx and Nucleosides during HIV-1 or SIVMAC Infection of Dendritic Cells.

Two cellular factors are currently known to modulate lentiviral infection specifically in myeloid cells: SAMHD1 and APOBEC3A (A3A). SAMHD1 is a deoxynucleoside triphosphohydrolase that interferes with viral infection mostly by limiting the intracellular concentrations of dNTPs, while A3A is a cytidine deaminase that has been described to edit incoming vDNA. The restrictive phenotype of myeloid cells can be alleviated through the direct degradation of SAMHD1 by the HIV-2/SIVSM Vpx protein or else, at least in the case of HIV-1, by the exogenous supplementation of nucleosides that artificially overcome the catabolic activity of SAMHD1 on dNTPs. Here, we have used Vpx and dNs to explore the relationship existing between vDNA cytidine deamination and SAMHD1 during HIV-1 or SIVMAC infection of primary dendritic cells. Our results reveal an interesting inverse correlation between conditions that promote efficient infection of DCs and the extent of vDNA editing that may reflect the different susceptibility of vDNA to cytoplasmic effectors during the infection of myeloid cells.

Impact of the MRN Complex on Adeno-Associated Virus Integration and Replication during Coinfection with Herpes Simplex Virus 1.

UNLABELLED: Adeno-associated virus (AAV) is a helper-dependent parvovirus that requires coinfection with adenovirus (AdV) or herpes simplex virus 1 (HSV-1) to replicate. In the absence of the helper virus, AAV can persist in an episomal or integrated form. Previous studies have analyzed the DNA damage response (DDR) induced upon AAV replication to understand how it controls AAV replication. In particular, it was shown that the Mre11-Rad50-Nbs1 (MRN) complex, a major player of the DDR induced by double-stranded DNA breaks and stalled replication forks, could negatively regulate AdV and AAV replication during coinfection. In contrast, MRN favors HSV-1 replication and is recruited to AAV replication compartments that are induced in the presence of HSV-1. In this study, we examined the role of MRN during AAV replication induced by HSV-1. Our results indicated that knockdown of MRN significantly reduced AAV DNA replication after coinfection with wild-type (wt) HSV-1 or HSV-1 with the polymerase deleted. This effect was specific to wt AAV, since it did not occur with recombinant AAV vectors. Positive regulation of AAV replication by MRN was dependent on its DNA tethering activity but did not require its nuclease activities. Importantly, knockdown of MRN also negatively regulated AAV integration within the human AAVS1 site, both in the presence and in the absence of HSV-1. Altogether, this work identifies a new function of MRN during integration of the AAV genome and demonstrates that this DNA repair complex positively regulates AAV replication in the presence of HSV-1. IMPORTANCE: Viral DNA genomes trigger a DNA damage response (DDR), which can be either detrimental or beneficial for virus replication. Adeno-associated virus (AAV) is a defective parvovirus that requires the help of an unrelated virus such as adenovirus (AdV) or herpes simplex virus 1 (HSV-1) for productive replication. Previous studies have demonstrated that the cellular Mre11-Rad50-Nbs1 (MRN) complex, a sensor and regulator of the DDR, negatively regulates AAV replication during coinfection with AdV, which counteracts this effect by inactivating the complex. Here, we demonstrate that MRN positively regulates AAV replication during coinfection with HSV-1. Importantly, our study also indicates that MRN also favors integration of AAV genomes within the human AAVS1 site. Altogether, this work indicates that MRN differentially regulates AAV replication depending on the helper virus which is present and identifies a new function of this DNA repair complex during AAV integration.

The susceptibility of primate lentiviruses to nucleosides and Vpx during infection of dendritic cells is regulated by CA.

The block toward human immunodeficiency virus type 1 (HIV-1) infection of dendritic cells (DCs) can be relieved by Vpx (viral protein X), which degrades sterile alpha motif-hydroxylase domain 1 (SAMHD1) or by exogenously added deoxynucleosides (dNs), lending support to the hypothesis that SAMHD1 acts by limiting deoxynucleoside triphosphates (dNTPs). This notion has, however, been questioned. We show that while dNs and Vpx increase the infectivity of HIV-1, only the latter restores the infectivity of a simian immunodeficiency virus of macaques variant, SIVMACΔVpx virus. This distinct behavior seems to map to CA, suggesting that species-specific CA interactors modulate infection of DCs.

G2/M cell cycle arrest correlates with primate lentiviral Vpr interaction with the SLX4 complex.

UNLABELLED: The accessory gene vpr, common to all primate lentiviruses, induces potent G2/M arrest in cycling cells. A recent study showed that human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) mediates this through activation of the SLX4/MUS81/EME1 exonuclease complex that forms part of the Fanconi anemia DNA repair pathway. To confirm these observations, we have examined the G2/M arrest phenotypes of a panel of simian immunodeficiency virus (SIV) Vpr proteins. We show that SIV Vpr proteins differ in their ability to promote cell cycle arrest in human cells. While this is dependent on the DCAF1/DDB1/CUL4 ubiquitin ligase complex, interaction with human DCAF1 does not predict G2/M arrest activity of SIV Vpr in human cells. In all cases, SIV Vpr-mediated cell cycle arrest in human cells correlated with interaction with human SLX4 (huSLX4) and could be abolished by small interfering RNA (siRNA) depletion of any member of the SLX4 complex. In contrast, all but one of the HIV/SIV Vpr proteins tested, including those that lacked activity in human cells, were competent for G2/M arrest in grivet cells. Correspondingly, here cell cycle arrest correlated with interaction with the grivet orthologues of the SLX4 complex, suggesting a level of host adaptation in these interactions. Phylogenetic analyses strongly suggest that G2/M arrest/SLX4 interactions are ancestral activities of primate lentiviral Vpr proteins and that the ability to dysregulate the Fanconi anemia DNA repair pathway is an essential function of Vpr in vivo. IMPORTANCE: The Vpr protein of HIV-1 and related viruses is essential for the virus in vivo. The ability of Vpr to block the cell cycle at mitotic entry is well known, but the importance of this function for viral replication is unclear. Recent data have shown that HIV-1 Vpr targets the Fanconi anemia DNA repair pathway by interacting with and activating an endonuclease complex, SLX4/MUS81/EME1, that processes interstrand DNA cross-links. Here we show that the ability of a panel of SIV Vpr proteins to mediate cell cycle arrest correlates with species-specific interactions with the SLX4 complex in human and primate cells. The results of these studies suggest that the SLX4 complex is a conserved target of primate lentiviral Vpr proteins and that the ability to dysregulate members of the Fanconi anemia DNA repair pathway is essential for HIV/SIV replication in vivo.

IFITM proteins are incorporated onto HIV-1 virion particles and negatively imprint their infectivity.

BACKGROUND: Interferon induced transmembrane proteins 1, 2 and 3 (IFITMs) belong to a family of highly related antiviral factors that have been shown to interfere with a large spectrum of viruses including Filoviruses, Coronaviruses, Influenza virus, Dengue virus and HIV-1. In all these cases, the reported mechanism of antiviral inhibition indicates that the pool of IFITM proteins present in target cells blocks incoming viral particles in endosomal vesicles where they are subsequently degraded. RESULTS: In this study, we describe an additional mechanism through which IFITMs block HIV-1. In virus-producing cells, IFITMs coalesce with forming virions and are incorporated into viral particles. Expression of IFITMs during virion assembly leads to the production of virion particles of decreased infectivity that are mostly affected during entry in target cells. This mechanism of inhibition is exerted against different retroviruses and does not seem to be dependent on the type of Envelope present on retroviral particles. CONCLUSIONS: The results described here identify a novel mechanism through which IFITMs affect HIV-1 infectivity during the late phases of the viral life cycle. Put in the context of data obtained by other laboratories, these results indicate that IFITMs can target HIV at two distinct moments of its life cycle, in target cells as well as in virus-producing cells. These results raise the possibility that IFITMs could similarly affect distinct steps of the life cycle of a number of other viruses.

A case series of emphysematous pyelonephritis.

Introduction. Emphysematous pyelonephritis (EPN) is an uncommon infection characterized by gas in the renal parenchyma and surrounding tissues. It is rapidly progressive, requiring appropriate therapy to salvage the infected kidney. Case Description. The case series presents 5 patients with a clinical and radiologic diagnosis of EPN. Each patient had a unique predisposing factor for developing EPN. Early goal directed therapy with intravenous fluids and antibiotics was given. This was followed by less invasive urologic interventions in an attempt to avoid nephrectomy and thereby salvage the infected kidney. All five patients were discharged in clinically stable conditions. Discussion and Conclusion. This case series provides added practice based support to available literature for managing EPN. Early goal directed medical therapy for sepsis coupled with interventional urologic procedures is a valuable alternative to circumvent an upfront emergent nephrectomy, except in cases where a fulminant infection may be present at the time of admission or develop later on in the course of the patients illness despite conservative line of therapy. It also highlights the importance of considering a diagnosis of EPN in patients with urinary infections, who have certain common predisposing factors listed in our case series.

A Case of Septic Arthritis of the Wrist due to Finegoldia magna.

Finegoldia magna (F. magna) has been described as one of the most frequent pathogens in the etiology of postoperative and prosthetic implant associated septic arthritis. In this report, we document our first experience with septic arthritis of the wrist caused by F. magna occurring in a joint with primary disease from prior trauma.

SIVSM/HIV-2 Vpx proteins: function and uses in the infection of primary myeloid cells.

Vpx is coded almost exclusively by members of the SIVSM/HIV-2 lineage of primate lentiviruses, it is incorporated into virion particles and is thus present during the early phases of infection of target cells. While Vpx exerts no detectable function during the infection of most cell types, it potently counteracts a cellular restriction that targets incoming lentiviruses specifically in myeloid cells. As a consequence of this function, Vpx improves the efficiency of lentiviral infection of dendritic cells (DCs), macrophages, and monocytes. Here, we describe how the positive function exerted by Vpx during the early phases of infection of myeloid cells can be used to augment the efficiency of lentiviral vector-mediated gene transfer in these cells.

Characterization of Fusarium Head Blight Resistance and Deoxynivalenol Accumulation in Hulled and Hulless Winter Barley.

Fusarium head blight (FHB), caused by Fusarium graminearum, is one of the most serious diseases impacting the U.S. barley (Hordeum vulgare) industry. The mycotoxin deoxynivalenol (DON), produced by the pathogen, renders grain unmarketable if concentrations exceed threshold values set for end-use markets. Development of cultivars with improved FHB resistance and reduced DON accumulation is necessary to ensure minimal losses. Elite hulled and hulless genotypes developed by the Virginia Tech winter barley breeding program were screened in inoculated, mist-irrigated FHB nurseries over 2 years at two locations in Virginia to validate resistance levels over years and locations. Results demonstrated that barley genotypes varied significantly for resistance to FHB and DON accumulation. The hulled 'Nomini', hulless 'Eve', and hulless line VA06H-48 were consistently resistant across locations to both FHB and DON accumulation. Screening the genotypes with molecular markers on chromosomes 2H and 6H for FHB and DON revealed quantitative trait loci regions which may confer resistance in the Virginia Tech germplasm. Ongoing and future work with mapping populations seeks to identify novel regions for resistance to FHB and DON accumulation unique to the Virginia Tech breeding program.

Marker-trait associations in Virginia Tech winter barley identified using genome-wide mapping.

Genome-wide association studies (GWAS) provide an opportunity to examine the genetic architecture of quantitatively inherited traits in breeding populations. The objectives of this study were to use GWAS to identify chromosome regions governing traits of importance in six-rowed winter barley (Hordeum vulgare L.) germplasm and to identify single-nucleotide polymorphisms (SNPs) markers that can be implemented in a marker-assisted breeding program. Advanced hulled and hulless lines (329 total) were screened using 3,072 SNPs as a part of the US. Barley Coordinated Agricultural Project (CAP). Phenotypic data collected over 4 years for agronomic and food quality traits and resistance to leaf rust (caused by Puccinia hordei G. Otth), powdery mildew [caused by Blumeria graminis (DC.) E.O. Speer f. sp. hordei Em. Marchal], net blotch (caused by Pyrenophora teres), and spot blotch [caused by Cochliobolus sativus (Ito and Kuribayashi) Drechsler ex Dastur] were analyzed with SNP genotypic data in a GWAS to determine marker-trait associations. Significant SNPs associated with previously described quantitative trait loci (QTL) or genes were identified for heading date on chromosome 3H, test weight on 2H, yield on 7H, grain protein on 5H, polyphenol oxidase activity on 2H and resistance to leaf rust on 2H and 3H, powdery mildew on 1H, 2H and 4H, net blotch on 5H, and spot blotch on 7H. Novel QTL also were identified for agronomic, quality, and disease resistance traits. These SNP-trait associations provide the opportunity to directly select for QTL contributing to multiple traits in breeding programs.

Evidence for a different susceptibility of primate lentiviruses to type I interferons.

Type I interferons induce a complex transcriptional program that leads to a generalized antiviral response against a large panel of viruses, including human immunodeficiency virus type 1 (HIV-1). However, despite the fact that interferons negatively regulate HIV-1 ex vivo, a chronic interferon state is linked to the progression of AIDS and to robust viral replication, rather than protection, in vivo. To explain this apparent contradiction, we hypothesized that HIV-1 may have evolved a partial resistance to interferon, and to test this hypothesis, we analyzed the effects of alpha interferon (IFN-α) on the infectivity of HIV-1, human immunodeficiency virus type 2 (HIV-2), and rhesus monkey simian immunodeficiency virus (SIVmac). The results we obtained indicate that HIV-1 is more resistant to an IFN-α-induced response than are HIV-2 and SIVmac. Our data indicate that the accumulation of viral DNA is more compromised following the infection of IFN-α-treated cells with HIV-2 and SIVmac than with HIV-1. This defect correlates with a faster destabilization of HIV-2 viral nucleoprotein complexes (VNCs), suggesting a link between VNC destabilization and impaired viral DNA (vDNA) accumulation. The differential susceptibilities to IFN-α of the primate lentiviruses tested here do not map to the capsid protein (CA), excluding de facto a role for human tripartite motif protein isoform 5 alpha (Trim5α) in this restriction; this also suggests that an additional restriction mechanism differentially affects primate lentivirus infection. The different behaviors of HIV-1 and HIV-2 with respect to IFN-α responses may account at least in part for the differences in pathogenesis observed between these two virus types.

Functional analysis of the relationship between Vpx and the restriction factor SAMHD1.

SAMHD1 is a newly identified restriction factor that targets lentiviruses in myeloid cells and is countered by the SIV(SM)/HIV-2 Vpx protein. By analyzing a large panel of Vpx mutants, we identify several residues throughout the 3-helix bundle predicted for Vpx that impair both its functionality and its ability to degrade SAMHD1. We determine that SAMHD1 is a strictly non-shuttling nuclear protein and that as expected WT Vpx localizes with it in the nucleus. However, we also identify a functional Vpx mutant with predominant cytoplasmic distribution that colocalizes with SAMHD1 in this location, suggesting that Vpx may also retain SAMHD1 in the cell cytoplasm, prior to its entry into the nucleus. Several mutations in Vpx were shown to affect the stability of Vpx, as well as Vpx:Vpx interactions. However, no strict correlation was observed between these parameters and the functionality of Vpx, implying that neither properties is absolutely required for this function and indicating that even unstable Vpx mutants may be very efficient in inducing SAMHD1 degradation. Overall, our analysis identifies several Vpx residues required for SAMHD1 degradation and points to a very efficient and plastic mechanism through which Vpx depletes this restriction factor.

APOBEC3A is a specific inhibitor of the early phases of HIV-1 infection in myeloid cells.

Myeloid cells play numerous roles in HIV-1 pathogenesis serving as a vehicle for viral spread and as a viral reservoir. Yet, cells of this lineage generally resist HIV-1 infection when compared to cells of other lineages, a phenomenon particularly acute during the early phases of infection. Here, we explore the role of APOBEC3A on these steps. APOBEC3A is a member of the APOBEC3 family that is highly expressed in myeloid cells, but so far lacks a known antiviral effect against retroviruses. Using ectopic expression of APOBEC3A in established cell lines and specific silencing in primary macrophages and dendritic cells, we demonstrate that the pool of APOBEC3A in target cells inhibits the early phases of HIV-1 infection and the spread of replication-competent R5-tropic HIV-1, specifically in cells of myeloid origins. In these cells, APOBEC3A affects the amount of vDNA synthesized over the course of infection. The susceptibility to the antiviral effect of APOBEC3A is conserved among primate lentiviruses, although the viral protein Vpx coded by members of the SIV(SM)/HIV-2 lineage provides partial protection from APOBEC3A during infection. Our results indicate that APOBEC3A is a previously unrecognized antiviral factor that targets primate lentiviruses specifically in myeloid cells and that acts during the early phases of infection directly in target cells. The findings presented here open up new venues on the role of APOBEC3A during HIV infection and pathogenesis, on the role of the cellular context in the regulation of the antiviral activities of members of the APOBEC3 family and more generally on the natural functions of APOBEC3A.

A simple, versatile and efficient method to genetically modify human monocyte-derived dendritic cells with HIV-1-derived lentiviral vectors.

Lentiviral vectors derived from the human immunodeficiency type 1 virus (HIV-1 LV) are among the finest tools available today for the genetic modification of human monocyte-derived dendritic cells (MDDCs). However, this process is largely inefficient because MDDCs show a strong resistance to HIV-1 transduction. Here we describe a step-by-step protocol from the production of LVs to cell transduction that allows the efficient genetic modification of MDDCs. This protocol can be completed in 23 d from the initial phase of LV production to the final analysis of the results of MDDC transduction. The method relies on the simultaneous addition of HIV-1 LVs along with noninfectious virion-like particles carrying Vpx, a nonstructural protein encoded by the simian immunodeficiency virus (Vpx-VLPs). When thus provided in target cells, Vpx exerts a strong positive effect on incoming LVs by counteracting the restriction present in MDDCs; accordingly, 100% of cells can be transduced with low viral inputs. Vpx-VLPs will improve the efficiency of LV-mediated transduction of MDDCs with vectors for both ectopic gene expression and depletion studies.

How a new 'public plan' could affect hospitals' finances and private insurance premiums.

Two key health reform bills in the House of Representatives and Senate include the option of a "public plan" as an additional source of health coverage. At least initially, the plan would primarily be structured to cover many of the uninsured and those who now have individual coverage. Because it is possible, and perhaps even likely, that this new public payer would pay less than private payers for the same services, such a plan could negatively affect hospital margins. Hospitals may attempt to recoup losses by shifting costs to private payers. We outline the financial pressures that hospitals and private payers could experience under various assumptions. High uninsured enrollment in a public plan would bolster hospital margins; however, this effect is reversed if the privately insured enter a public plan in large proportions, potentially stressing the hospital industry and increasing private insurance premiums.

Characterization of the behavior of functional viral genomes during the early steps of human immunodeficiency virus type 1 infection.

Infectious viral DNA constitutes only a small fraction of the total viral DNA produced during retroviral infection, and as such its exact behavior is largely unknown. In the present study, we characterized in detail functional viral DNA produced during the early steps of human immunodeficiency virus type 1 infection by analyzing systematically their kinetics of synthesis and integration in different target cells. In addition, we have compared the functional stability of viral nucleoprotein complexes arrested at their pre-reverse transcription state, and we have attempted to measure the kinetics of loss of capsid proteins from viral complexes through the susceptibility of the early phases of infection to cyclosporine, a known inhibitor of the interaction between viral capsid and cyclophilin A. Overall, our data suggest a model in which loss of capsid proteins from viral complexes and reverse transcription occur concomitantly and in which the susceptibility of target cells to infection results from a competition between the ability of the cellular environment to quickly destabilize viral nucleoprotein complexes and the capability of the virus to escape such targeting by engaging the reverse transcription reaction.

Obesity and managed care.

Over the past 20 years, obesity has become a national and worldwide epidemic-one with well-established medical and financial consequences. Nonetheless, the health care industry lacks effective and affordable therapies for its treatment. Managed care knows this all too well; yet it has still demonstrated a reluctance to pay for expensive surgeries and drug therapies. Managed care organizations, however, may have the ability to provide leadership in other ways.