Overexpression of VEGF-C causes transient lymphatic hyperplasia but not increased lymphangiogenesis in regenerating skin

Vascular endothelial growth factor (VEGF)-C is necessary for lymphangiogenesis and holds potential for lymphangiogenic therapy in diseases lacking adequate lymphatic drainage. However, the ability of VEGF-C to enhance sustainable, functional lymphatic growth in adult tissues remains unclear. To address this, we evaluated VEGF-C overexpression in adult lymphangiogenesis in regenerating skin. We used a model of mouse tail skin regeneration incorporating a suspension of either VEGF-C overexpressing tumor cells, which provide a continuous supplement of excess VEGF-C to the natural regenerating environment for more than 25 days, or otherwise identical control-transfected tumor cells. We found that excess VEGF-C did not enhance the rate of lymphatic endothelial cell (LEC) migration, the density of lymphatic vessels, or the rate of functionality -- even though lymphatic hyperplasia was present early on. Furthermore, the hyperplasia disappeared when VEGF-C levels diminished, which occurred after 25 days, rendering the lymphatics indistinguishable from those in control groups. In vitro, we showed that whereas cell-derived VEGF-C could induce chemoattraction of LECs across a membrane (which involves amoeboid-like transmigration), it did not increase LEC chemoinvasion within a 3-dimensional fibrin matrix (which requires proteolytic migration). These results suggest that whereas excess VEGF-C may enhance early LEC proliferation and cause lymphatic vessel hyperplasia, it does not augment the physiological rate of migration or functionality, and by itself cannot sustain any lasting effects on lymphatic size, density, or organization in regenerating adult skin.     

Publication ethics from the ground up

It is relatively easy to begin policy documents with a general assertion that ethics will be followed. Less obvious is how to ensure that day‐to‐day activities are consonant with ethical standards. We suggest that using day‐to‐day publication activities as the driver for building policies and procedures can promote ethical practices from the ground up. Although basic principles of ethical publication practice may seem straightforward to some, for others this information may require explanation, interpretation and context. Effective policy development includes big‐picture items as well as more day‐to‐day tactical responsibilities such as those discussed below. Research questions, disciplinary practices, applications and team structures may vary. Thus, no single publication plan or policy solution is right for all teams. It is up to team members to review guidelines for best practices and find the optimal implementation for their situations. Experts in publication management, planning and writing can help large teams manage publication activities. These experts have an obligation to maintain and enhance their skills continually. A strong acumen in publication best practices will allow these publication professionals to better address any possible ethical dilemmas in the future.     

Delayed Tooth Eruption in Membrane Type-1 Matrix Metalloproteinase Deficient Mice

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is expressed highly in mineralizing tissues including bones and teeth. Mice deficient in MT1-MMP ( &#109 / &#109 ) display severe defects in skeletal development including dwarfism, osteopenia, and craniofacial abnormalities. Death occurs in these mice by about 3 weeks of age. Since MT1-MMP is expressed by the ameloblasts of the enamel organ and by the odontoblasts of the dental papilla, we asked if the developing teeth were adversely affected in the knockout animals. Molars from MT1-MMP &#109 / &#109 mice and controls were examined by histological, X-ray, and SEM analysis at 4, 18-20, and 25 days of postnatal development. At 4 days of development the molars from the &#109 / &#109 mice appeared histologically normal. At 18-20 days of development, the first molars of the &#109 / &#109 mice had apparently normal tooth crowns with normal dentin and enamel; however, the roots were truncated and the teeth had not yet erupted. In contrast to the &#109 / &#109 mice, the first molars of the 18-20-day control animals had erupted. SEM analysis of a &#109 / &#109 first molar and incisor revealed a normal enamel prism pattern. However, X-ray analysis demonstrated that tooth eruption was delayed by approximately 5 days and that the tooth roots were abnormally short in the knockout animals. Since MT1-MMP-deficient mice have been demonstrated to display a generalized increase in bone resorption, these data suggest that inefficient growth of bone surrounding the tooth root complex causes a delay in tooth eruption.     

Community Mental Health Provider Reluctance to Provide Pharmacotherapy May Be a Barrier to Addressing Perinatal Depression: A Preliminary Study

This is the first study evaluating obstetrics and gynecology (OB/Gyn) provider and staff perceptions of barriers to accessing pharmacotherapy for perinatal depression outside the obstetric setting. Four, 90 min focus groups were conducted with OB/Gyn physicians, advance practice nurses, and support and nursing staff (n = 28). Data were analyzed with a grounded theory approach. Participants perceived that community mental health providers and pharmacists often do not want to participate in pharmacotherapy for perinatal women. Participants believed the solution is training for community mental health providers in the risks and benefits of pharmacotherapy for perinatal depression and improved communication between OB/Gyn’s and community mental health providers. Community mental health provider and pharmacist reluctance to provide pharmacotherapy hinders OB/Gyn’s perceived ability to address perinatal depression. Community mental health provider and pharmacist training are needed to mitigate precipitous discontinuation of treatment and to improve access to pharmacotherapy for perinatal women.     

Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia

Objective

The present study aimed to examine the changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia.

Methods

Sixty-two drug naïve, first-episode schizophrenia (SZ group) and 60 healthy individuals (control group) were enrolled in the study. Serum interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) levels, and body weight were measured at baseline for both groups, and repeated for the SZ group at five different time points during 6-month risperidone treatment.

Results

At baseline, serum IL-1β, IL-6, and TNF-α levels in the SZ group (53.28?±?12.62, 33.98?±?14.13, 50.08?±?12.86 pg/mL, respectively) were significantly higher than those in the control group (23.49?±?15.27, 15.53?±?7.16, 32.12?±?15.23 pg/mL, respectively) (p's?<?0.001). Within the SZ group, serum IL-1β levels decreased significantly at 2 weeks (48.02?±?16.00 pg/mL, p?<?0.01) and 1 month (44.70?±?16.63 pg/mL, p?<?0.001), but then gradually increased at 2 months (48.49?±?18.87 pg/mL), 3 months (50.59?±?18.48 pg/mL) and 6 months (53.64?±?16.22 pg/mL) to the levels comparable to baseline; serum IL-6 levels changed significantly over the course of treatment (p?=?0.001), but reached the levels comparable to baseline at 6 months (37.13?±?13.23 pg/mL); serum levels of TNF-α increased significantly at 3 months (55.02?±?16.69 pg/mL, p?<?0.01) and 6 months (58.69?±?13.57 pg/mL, p?<?0.001); steady and significant weight gain was observed at each follow-up time point (p's?<?0.001), from 56.71?±?9.25 kg at baseline to 62.72?±?9.53 kg at 6 months.

Conclusions

Risperidone treatment is associated with changes in serum pro-inflammatory cytokines levels and weight. There is an initial anti-inflammatory effect that reduces with treatment, potentially due to its weight gain side effect.     

An analysis of cue reactivity among persons with and without schizophrenia who are addicted to cocaine

OBJECTIVE: Persons with schizophrenia who are addicted to cocaine experience more psychiatric and substance abuse relapses and worse long-term outcomes than persons with only one of these conditions. This study examined whether individuals with cocaine dependence and schizophrenia experience more cue-elicited craving than those without schizophrenia. METHODS: Ninety-one cocaine-dependent participants who had been abstinent from cocaine for at least 72 hours were recruited from substance abuse treatment programs in the Veterans Affairs New Jersey Health Care System. The study used a cue-exposure paradigm to stimulate cocaine craving. A self-report instrument was used to measure changes from baseline in four areas: craving intensity, happy or depressed mood, increased or decreased energy, and physical health or sickness. RESULTS: The participants with schizophrenia (N=35) reported significantly more cocaine craving than those without schizophrenia (N=56). When data for participants who were cue reactive were analyzed without regard to diagnosis, 97 percent of the cocaine-dependent participants with schizophrenia were cue reactive, compared with 43 percent of those without schizophrenia. CONCLUSIONS: Future research on cocaine dependence should focus on craving, particularly among patients with coexisting psychiatric disorders.     

A case series of nicotine nasal spray in the treatment of tobacco dependence among patients with schizophrenia

A retrospective case series of 12 smokers with schizophrenia or schizoaffective disorder who had not successfully quit smoking with previous treatments for tobacco dependence were treated with nicotine nasal spray. All but one patient (92 percent) tolerated the nasal spray well, and nine (75 percent) used it at maximal doses for prolonged periods. After treatment five patients (42 percent) were abstinent from smoking for more than 90 days, and four patients (33 percent) substantially reduced the amount that they smoked. Ten patients (83 percent) used the spray in combination with other medications, and all received psychosocial support. Nicotine nasal spray was found to be well tolerated.     

Cognitive disparity in schizophrenics with and without cocaine dependency

Although cognition has been investigated in individuals with schizophrenia and in non-schizophrenic cocaine abusers, few studies have focused on cocaine-abusing schizophrenics. Previous studies have shown contradictory results despite the fact that individuals with schizophrenia and cocaine dependence have worse long-term outcomes, and that each disorder separately is associated with neuropsychological impairment. The present study intended to clarify these inconsistencies with a comprehensive neuropsychological battery. Twenty-four cocaine-dependent schizophrenics and 23 non-drug abusing schizophrenics were recruited from the VA. Participants were administered tests focusing on motor skills, processing speed, attention, concentration, and executive functioning. While individuals with schizophrenia and cocaine dependence performed worse on the Grooved Peg Board and the Stroop A, the non-drug abusing schizophrenics performed worse on Trails Part A and B. However, a MANOVA failed to show group differences in overall neuropsychological performance. These findings are similar to the existing literature and suggest that cocaine may compromise motor functioning.     

Stroma formation and angiogenesis by overexpression of growth factors,cytokines, and proteolytic enzymes in human skin grafted to SCID mice

Reorganization of skin during wound healing, inflammatory disorders, or cancer growth is the result of expression changes of multiple genes associated with tissue morphogenesis. We wanted to identify proteins involved in skin remodeling and select those that may be targeted for agonistic or antagonist therapeutic approaches in various disease processes. Full-thickness human skin was grafted to severe combined immunodeficient mice and injected intradermally with 38 different adenoviral vectors inserted with 37 different genes coding for growth factors, cytokines, proteolytic enzymes and their inhibitors, adhesion receptors, oncogenes, and tumor suppressor genes. Responses were characterized for infiltration of inflammatory cells, vascular density, matrix formation, fibroblast-like cell proliferation, and epidermal hyperplasia. Of the 17 growth factor vectors, 16 induced histological changes in human skin. Members of the VEGF and angiopoietin families induced neovascularization. PDGFs and TGF-betas stimulated connective tissue formation, and the chemokines IL-8 and MCP-1 attracted inflammatory neutrophils and monocytes, respectively. The serine protease uPA induced a vascular response similar to that of VEGF. Vectors with adhesion receptors, oncogenes and tumor suppressor genes had, with few exceptions, little effects on skin architecture. The overall results suggest that adenoviral vectors can effectively remodel the architecture of human skin for studies in morphogenesis, inflammatory skin disorders, wound healing, and cancer development.