Skin depigmentation associated with toceranib phosphate in a dog.

BACKGROUND: Drug-induced depigmentation is frequently observed in humans undergoing tyrosine kinase inhibitor therapy, whereas it is not reported in dogs. The skin depigmentation can occur after the first week of treatment and it is reversible within a few weeks after drug discontinuation. OBJECTIVES: To report the clinical and histopathological features of an episode of cutaneous adverse drug reaction associated with short term administration of toceranib phosphate. CASE REPORT: An 11-year-old intact male Bernese mountain dog was presented for investigation of a subcutaneous mast cell tumour (MCT) including treatment options. The major abnormality on physical examination was a 7.5 × 10 cm subcutaneous mass located cranial to the left shoulder joint consistent with a MCT. Toceranib phosphate therapy was initiated. Fourteen days after initiating treatment, the dog presented with skin erosions near the lateral canthus of the left eye. Three weeks later there were multiple skin lesions characterized by alopecia and depigmentation involving left and right eyelids; leukotrichia of the periorbital areas and depigmentation of the nasal planum and all paw pads. Histopathological findings were nonspecific; they were supportive of vitiligo. Resolution of skin lesions was observed after stopping the toceranib phosphate therapy. CONCLUSION AND CLINICAL IMPORTANCE: Based on the gross lesions, histopathological features before and after tyrosine kinase inhibitor therapy, and Naranjo score, this case was considered to be consistent with cutaneous adverse drug effects. To the best of the authors' knowledge, this is the first report describing the clinical and histopathological features of presumed drug-induced skin depigmentation in a dog receiving toceranib phosphate.

Seeds of HOPE: Incorporating Community-Based Strategies to Implement a Weight-Loss and Empowerment Intervention in Eastern North Carolina.

Seeds of HOPE (Health, Opportunities, Partnerships, and Empowerment) was a community-based participatory research project designed to implement an evidence-based weight loss and empowerment intervention aimed at increasing self-efficacy through peer support. HOPE Works, its model, has yielded significant weight loss and increases in participants' ability to set and achieve goals, including in consumption of fruits and vegetables and in physical activity.METHODS The Seeds of HOPE project was implemented through 3 peer leader recruitment approaches using Circle Leaders. Study participants met in hope circles to discuss various topics aimed at developing healthier lifestyles. Changes at 6-month intervals were assessed in health behaviors, weight, and hope. One-way ANOVA was used to test differences in mean change in weight and hope across the 3 recruitment approaches.RESULTS Study participants (N = 146) lost weight (-3.3 pounds, P = 0.003, 95% CI: -5.40 - -1.27). Fruit consumption significantly increased (P = 0.04, 95% CI: 0.01-0.41) while no changes in vegetable consumption or physical activity were observed. No differences based on different leader recruitment approaches were found.LIMITATIONS There were limitations in the power to fully detect differences across Circle Leader recruitment approaches; loss-to-follow up and representativeness of the sample were present. Further research is needed to determine if these approaches would be successful in other rural counties, with different genders, or with individuals in urban and/or higher socioeconomic populations.CONCLUSIONS Participants found modest success in weight loss and fruit consumption. Authors find that community engagement strategies are helpful in finding mutually acceptable adaptations to implement interventions such as Seeds of HOPE in diverse communities.

CEREBELLAR AND MESENCEPHALON NEOPLASIA IN A NILE HIPOPPOTAMUS (HIPPOPOTAMUS AMPHIBIOUS).

A 52-yr-old female Nile hippopotamus ( Hippopotamus amphibious ) was presented for acute onset anorexia, depression, lethargy, instability, and weakness in the pelvic limbs. Clinical signs were rapidly progressive, despite empiric therapy with anti-inflammatory medications, resulting in the death of the animal. Gross necropsy evaluation revealed two tan, firm masses in the cerebellum and mesencephalon and a single mass in the right cranial adrenal gland. All three masses had a similar histologic morphology, and immunohistochemical investigation confirmed the general diagnosis of an adenocarcinoma, but the exact cell of origin remains unclear. In addition, there was evidence of neuroendocrine differentiation in the adrenal gland and not in the brain. These findings suggest either two distinct neoplastic populations or a metastasizing adenocarcinoma with focal endocrine differentiation. In dogs, anal sac and clitoral adenocarcinomas have been reported to undergo focal endocrine differentiation, and both can cause widespread metastasis while the primary lesion can be small. A small neoplasm of these glands may have been missed on gross examination.

A Toxoplasma gondii lipoxygenase-like enzyme is necessary for virulence and changes localization associated with the host immune response.

IMPORTANCE: Lipoxygenases (LOXs) are enzymes that catalyze the deoxygenation of polyunsaturated fatty acids such as linoleic and arachidonic acid. These modifications create signaling molecules that are best characterized for modulating the immune response. Deletion of the first lipoxygenase-like enzyme characterized for Toxoplasma gondii (TgLOXL1) generated a less virulent strain, and infected mice showed a decreased immune response. This virulence defect was dependent on the mouse cytokine interferon gamma IFNγ. TgLOXL1 changes location from inside the parasite in tissue culture conditions to vesicular structures within the host immune cells during mouse infection. These results suggest that TgLOXL1 plays a role in the modification of the host immune response in mice.

Examining the Baby Café Model and Mothers' Breastfeeding Duration, Meeting of Goals, and Exclusivity.

Objective: Accessible community lactation support impacts a woman's breastfeeding success by offering timely intervention and solutions, thereby allowing mothers to achieve breastfeeding goals and improve overall breastfeeding rates. Although the impact of breastfeeding support has been well established, there is a lack of consistency in the development and evaluation of support models. This report examines two differing populations of Baby Café attendees. The study evaluated the mother's achievement of personal and nationally recommended breastfeeding goals, the frequency of attending a Baby Café, and their ratings of the program as helpful in solving breastfeeding problems. Methods: A total of 559 mothers attending two Baby Cafés, one in Massachusetts and the other in southern Texas, were surveyed when their babies were 6 months old and again over age 12 months. Actual breastfeeding duration was compared with the mothers' initially stated goals and American Academy of Pediatrics (AAP) recommended goals, and then evaluated against the number of Café attendances. The mother's rating of the Café for helpfulness was measured using a 1-5 effectiveness scale. Results: Results show that mothers attending either of the surveyed Baby Cafés that served distinctly different populations reported higher breastfeeding exclusivity rates and higher rates of 12-month breastfeeding duration than national rates reported by the Centers for Disease Control and Prevention (CDC). More than 70% of all mothers surveyed rated the Café as most effective. Conclusions: The Baby Café model was shown to be effective at helping mothers reach breastfeeding goals regardless of the Café's different geographical settings and the socioeconomic characteristics of the populations served.

Covalent reactions of wortmannin under physiological conditions.

Wortmannin (Wm), a steroid-like molecule of 428.4 Da, appears to be unstable in biological fluids (apparent chemical instability), yet it exhibits an antiproliferative activity in assays employing a 48 hr incubation period (prolonged bioactivity), a situation we refer to as the "wortmannin paradox." Under physiological conditions, Wm covalently reacts with nucleophiles such as the side chains of cysteine, N-methyl hexanoic acid, lysine, or proline at the C20 position on the furan ring. Like Wm, WmC20 amino acid derivatives had significant antiproliferative activities. Three Wm derivatives, WmC20-proline, WmC20-cysteine, and a WmC20-N-methyl hexanoic acid, generated Wm that then reacted with lysine in an exchange-type reaction. This unusual, reversible, covalent reaction of Wm with nucleophiles under physiological conditions provides an explanation for the wortmannin paradox.

Dataset of the livability performance of the city of Birmingham, UK, as measured by its citizen wellbeing, resource security, resource efficiency and carbon emissions.

This data article presents the UK City LIFE1 data set for the city of Birmingham, UK. UK City LIFE1 is a new, comprehensive and holistic method for measuring the livable sustainability performance of UK cities. The Birmingham data set comprises 346 indicators structured simultaneously (1) within a four-tier, outcome-based framework in order to aid in their interpretation (e.g., promote healthy living and healthy long lives, minimize energy use, uncouple economic vitality from CO2 emissions) and (2) thematically in order to complement government and disciplinary siloes (e.g., health, energy, economy, climate change). Birmingham data for the indicators are presented within an Excel spreadsheet with their type, units, geographic area, year, source, link to secondary data files, data collection method, data availability and any relevant calculations and notes. This paper provides a detailed description of UK city LIFE1 in order to enable comparable data sets to be produced for other UK cities. The Birmingham data set is made publically available at http://epapers.bham.ac.uk/3040/ to facilitate this and to enable further analyses. The UK City LIFE1 Birmingham data set has been used to understand what is known and what is not known about the livable sustainability performance of the city and to inform how Birmingham City Council can take action now to improve its understanding and its performance into the future (see "Improving city-scale measures of livable sustainability: A study of urban measurement and assessment through application to the city of Birmingham, UK" Leach et al. [2]).

Herpes simplex encephalitis in a captive black howler monkey (Alouatta caraya).

An 18-month-old captive black howler monkey (Alouatta caraya) died after a 3-day history of neurologic signs. Gross findings at autopsy were limited to bloody, yellow, and foul-smelling intestinal contents. Histologically, there was extensive necrotizing meningoencephalitis predominantly in both cerebral hemispheres, and lymphohistiocytic, neutrophilic infiltrate expanded the subarachnoid and Virchow-Robbin space. In the most severely affected regions, neurons contained eosinophilic intranuclear inclusion bodies surrounded by a clear halo and margination of the chromatin. Electron microscopy of the affected cells revealed numerous intranuclear viral particles characteristic of herpesvirus. Immunohistochemically, neurons and glial cells in the affected regions were labeled with a monoclonal antibody against Human herpesvirus 1, and was confirmed by polymerase chain reaction.

Synthesis, characterization, and cytotoxicity of a series of estrogen-tethered platinum(IV) complexes.

Several estrogen-tethered platinum(IV) complexes were prepared and characterized by ESI-MS and (1)H NMR spectroscopy. Their design was inspired by the observation that estrogen receptor-positive cells exposed to the hormone are sensitized to cisplatin. Intracellular reduction of bis-estrogen-cis-diamminedichloroplatinum(IV), BEP(n) (where n = 1-5 methylene groups between Pt and estrogen), occurs to afford cisplatin and two equivalents of the linker-modified estrogen. The ability of BEP(n) to induce overexpression of HMGB1 was established by immunofluorescence microscopy. The cytotoxicity of the compounds was evaluated in ER(+) MCF-7 and ER(-) HCC-1937 human breast cancer cell lines. BEP3 selectively induces overexpression of HMGB1 in MCF-7 cells, compared to HCC-1937 cells, and enhances their sensitivity (IC(50) = 2.1 +/- 0.4 microM versus 3.7 +/- 0.9 microM, respectively) to the compound. The difference in compound activities and the potential of compounds of this class for treating breast and ovarian cancer are discussed.

Membrane-permeable and -impermeable sensors of the Zinpyr family and their application to imaging of hippocampal zinc in vivo.

Esterification of fluorescent biosensors is a common strategy used to trap probes within the cell. Zinpyr-1 (ZP1) is a fluorescein-based bright fluorescent sensor for divalent zinc that is cell permeable without prior modification. We describe here the synthesis and characterization of ZP1 sensors containing a carboxylic acid or ethyl ester functionality at the 5 or 6 position of the fluorescein. The presence of an electronegative carboxylate decreases the proton-induced background fluorescence of the probe by lowering the pKa of the benzylic amines responsible for fluorescence quenching. The charged species ZP1(6-CO2-) is membrane-impermeant, whereas the permeability of the neutral ZP1(5/6-CO2Et) is similar to that of the parent sensor. Intracranial microinfusion of ZP1(6-CO2Et) into rat hippocampus produces reduced staining of vesicular zinc in neuropil and very clear delineation of zinc-positive injured neuronal somata and dendrites as compared with ZP1.

Master's programs in advanced nursing practice: new strategies to enhance course design for subspecialty training in neonatology and pediatrics.

The advanced nurse practitioner (ANP) role first developed in the USA in the 1960s in primary care. Since then, it has evolved in many different countries and subspecialties, creating a variety of challenges for those designing and implementing master's programs for this valuable professional group. We focus on ANPs in the neonatal and pediatric intensive care setting to illustrate the complexity of issues faced by both faculty and students in such a program. We review the impact of limited resources, faculty recruitment/accreditation, and the relationship with the medical profession in establishing a curriculum. We explore the evidence for the importance of ANP role definition, supervision, and identity among other health professionals to secure a successful role transition. We describe how recent advances in technology can be used to innovate with new styles of teaching and learning to overcome some of the difficulties in running master's programs for small subspecialties. We illustrate, through our own experience, how a thorough assessment of the available literature can be used to innovate and develop strategies to create an individual MSc programs that are designed to meet the needs of highly specialized advanced neonatal and pediatric nursing practice.

Fate of a bioactive fluorescent wortmannin derivative in cells.

Here, we report on NBD-Wm, a fluorescent wortmannin (Wm) probe that maintains the bioactivity of Wm as an inhibitor of PI3 kinase and as an antiproliferative agent. The attachment of the NBD fluorochrome permits NBD-Wm in cells to be monitored by NBD fluorescence-based methods such as FACS or fluorescence microscopy or with an anti-NBD antibody. The fluorescence of NBD-Wm treated cells reached a peak at 1.5 h and then decreased because of the extrusion of a fluorescent compound into the culture media. Cells accumulated NBD-Wm to levels about 30-fold higher than those in the media. NBD-Wm modified five major proteins, with the modification of the catalytic subunit of PI3 kinase being a minor band. The bioactivity of NBD-Wm, coupled with a variety of techniques available for determining its disposition, suggest that NBD-Wm can be a useful tool in understanding the mechanism of action of viridins.

Conjugated platinum(IV)-peptide complexes for targeting angiogenic tumor vasculature.

The integrins alpha vbeta3 and alpha vbeta5 and the membrane-spanning surface protein aminopeptidase N (APN) are highly expressed in tumor-induced angiogenesis, making them attractive targets for therapeutic intervention. Both integrins and APN recognize a broad range of peptides containing RGD (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) motifs, respectively. Here, we describe the design, synthesis, and characterization of a series of mono- and difunctionalized platinum(IV) complexes in which a conjugated peptide motif, containing RGD, (CRGDC)c, (RGDfK)c, or NGR, is appended as a "tumor-homing device" to target tumor endothelial cells selectively over healthy cells. Platinum(IV)-peptide complexes with nonspecific amino acids or peptide moieties were prepared as controls. Concentration-response curves of these compounds were evaluated against primary proliferating endothelial cells and tumor cell lines and compared to those of cisplatin, a well-described platinum-based chemotherapeutic agent. The Pt(IV)-RGD conjugates were highly and specifically cytotoxic to cell lines containing alpha vbeta3 and alpha vbeta5, approaching the activity of cisplatin. The Pt(IV)-NGR complexes were less active than Pt(IV)-RGD-containing compounds but more active than nonspecific Pt-peptide controls. Integrin alpha vbeta3 mediated, at least in part, the anti-proliferative effect of a Pt(IV)-RGD conjugate, as demonstrated by a decreased inhibitory response when endothelial cells were either (1) incubated with an excess of alpha vbeta3/alpha vbeta5-specific RGD pentapeptides or (2) transfected with RNAi for beta 3, but not beta 1, integrins. These results suggest a rational approach to improved chemotherapy with Pt(IV)-peptide conjugates by selective drug delivery to the tumor compartment.