Competence, challenges and attitudes of bedside nurses caring for patients with left ventricular assist devices.

OBJECTIVES: We aimed to describe the bedside registered nurses perceived competence, attitudes, and challenges surrounding the management of patients with left ventricular assist devices (LVAD) in the intensive care unit (ICU) and stepdown unit (SDU). RESEARCH METHODOLOGY/DESIGN: An exploratory research was employed using a survey. SETTING: Bedside participants were recruited via an electronic recruitment flyer circulated in online professional and social networking sites. MAIN OUTCOME MEASURES: Items consisted of a numeric rating scale, measuring competence and attitudes related to the management of patients with left ventricular assist devices. The one open-ended question asked the participants to write responses regarding challenges in left ventricular assist device care. Data were analysed using quantitative and qualitative analytics software. RESULTS: A total of 36 intensive care unit and 35 stepdown unit bedside nurse (n = 71) from six regions of the United States responded. Overall mean scores for competency and attitude domains were ≥ 7.0. Intensive care nurses scored higher in competence and attitude when compared to stepdown unit nurses care of short-term left ventricular assist devices. Competence and attitude were positively associated with years of experience. Five themes related to challenges in care were identified. CONCLUSION: Overall, bedside nurses had satisfactory competence and attitudes surrounding the care of hospitalised left ventricular assist device patients.

The influence of hydration on the architectural rearrangement of normal and neoplastic human breast tissues.

In adult women, the water-content represents between 50% and 70% of the mass in normal breast tissues and this percentage is increased within diseased tissues. Water molecules play an essential role in the structural organization of biological tissues such as breast. Then, in this study, we have investigated the influence of the water molecules on the breast tissue organization and their role on the hierarchical tissue rearrangement promoted by tumor growth. SAXS and WAXS techniques were used to analyze healthy, benign and malignant human breast samples in native and lyophilized conditions. The scattering profiles in SAXS and WAXS regime of each tissue type in both conditions were compared in order to identify the structural transformation in these tissues and verify the water influence on the morphological arrangement of normal and pathological human breast tissues. From SAXS, changes at the axial periodicity of collagen fibrils were revealed. Additionally, when the water content has removed a peak at q = 4.17 nm-1 (that was present only in pathological samples) shifted in opposite directions within benign and malignant lesions. From WAXS, water and fatty acids were identified within native samples. However, after freeze-drying, only the fat component was observed in the scattering profiles. Therefore, when the water molecules were removed from the samples, structural changes associated with pathological progression were visible. From this, insights about their influence over the changes promoted by the tumor growth have been proposed. Finally, the findings of this study have the potential to provide valuable information to the development of new target therapy.

Genetic characterisation of molecular targets in carcinoma of unknown primary.

BACKGROUND: Carcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour. Prognosis for patients with CUP is poor because treatment options are generally limited to broad spectrum chemotherapy. A shift towards personalised cancer management based on mutation profiling offers the possibility of new treatment paradigms. This study has explored whether actionable, oncogenic driver mutations are present in CUP that have potential to better inform treatment decisions. METHODS: Carcinoma of unknown primary cases (n = 21) were selected and DNA was isolated from formalin-fixed paraffin embedded sections prior to amplification and sequencing. Two distinct yet complementary targeted gene panels were used to assess variants in up to 76 known cancer-related genes for the identification of biologically relevant and actionable mutations. RESULTS: Variants were detected in 17/21 cases (81%) of which 11 (52%) were potentially actionable with drugs currently approved for use in known primary cancer types or undergoing clinical trials. The most common variants detected were in TP53 (47%), KRAS (12%), MET (12%) and MYC (12%). Differences at the molecular level were seen between common CUP histological subtypes. CUP adenocarcinomas and poorly differentiated carcinomas harboured the highest frequency of variants in genes involved in signal transduction pathways (e.g. MET, EGFR, HRAS, KRAS, and BRAF). In contrast, squamous cell carcinoma exhibited a higher frequency of variants in cell cycle control and DNA repair genes (e.g. TP53, CDKN2A and MLH1). CONCLUSION: Taken together, mutations in biologically relevant genes were detected in the vast majority of CUP tumours, of which half provided a potentially novel treatment option not generally considered in CUP.

HER2 mRNA transcript quantitation in breast cancer

Purpose. The human epidermal growth factor receptor 2 (HER2) status in breast cancer is important for prognostic prediction and the determination of optimal treatment. Current methods rely on protein expression, as determined by immunohistochemistry (IHC), as well as gene amplification as determined by in situ hybridisation (ISH). We explored whether quantitative droplet digital PCR (ddPCR) can be used for the detection and absolute quantitation of HER2 mRNA. Methods. Digital droplet PCR (ddPCR) was performed for HER2 mRNA on 178 formalin-fixed paraffin-embedded (FFPE) breast cancer specimens. HER2 positive, equivocal and negative cases as defined by standard criteria were included and both core biopsies and tissue sections were assessed. Results. HER2 positive cases contained significantly higher levels of HER2 mRNA (169-1,000,000 copies/µl) by ddPCR compared with equivocal (112-139 copies/µl, p = 0.025) and negative cases (6.2-644 copies/µl. p < 0.001). A continuum of transcript quantity was observed but a cutoff of 490 copies/µl distinguished between HER2 positive and negative cases. Results were consistent between core biopsy and tissue sections. Conclusions. ddPCR can be used to quantify HER2 mRNA transcripts in FFPE breast cancer specimens. Our results highlight the potential of ddPCR on FFPE tissue to be used to accurately quantify HER2 transcripts. Validation in large cohorts will be required to determine a clinically applicable cutoff (AU)

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HER2 mRNA transcript quantitation in breast cancer.

PURPOSE: The human epidermal growth factor receptor 2 (HER2) status in breast cancer is important for prognostic prediction and the determination of optimal treatment. Current methods rely on protein expression, as determined by immunohistochemistry (IHC), as well as gene amplification as determined by in situ hybridisation (ISH). We explored whether quantitative droplet digital PCR (ddPCR) can be used for the detection and absolute quantitation of HER2 mRNA. METHODS: Digital droplet PCR (ddPCR) was performed for HER2 mRNA on 178 formalin-fixed paraffin-embedded (FFPE) breast cancer specimens. HER2 positive, equivocal and negative cases as defined by standard criteria were included and both core biopsies and tissue sections were assessed. RESULTS: HER2 positive cases contained significantly higher levels of HER2 mRNA (169-1,000,000 copies/µl) by ddPCR compared with equivocal (112-139 copies/µl, p = 0.025) and negative cases (6.2-644 copies/µl. p < 0.001). A continuum of transcript quantity was observed but a cutoff of 490 copies/µl distinguished between HER2 positive and negative cases. Results were consistent between core biopsy and tissue sections. CONCLUSIONS: ddPCR can be used to quantify HER2 mRNA transcripts in FFPE breast cancer specimens. Our results highlight the potential of ddPCR on FFPE tissue to be used to accurately quantify HER2 transcripts. Validation in large cohorts will be required to determine a clinically applicable cutoff.

Development of an abbreviated version of the delirium motor subtyping scale (DMSS-4).

BACKGROUND: Delirium is a common neuropsychiatric syndrome with considerable heterogeneity in clinical profile. Identification of clinical subtypes can allow for more targeted clinical and research efforts. We sought to develop a brief method for clinical subtyping in clinical and research settings. METHODS: A multi-site database, including motor symptom assessments conducted in 487 patients from palliative care, adult and old age consultation-liaison psychiatry services was used to document motor activity disturbances as per the Delirium Motor Checklist (DMC). Latent class analysis (LCA) was used to identify the class structure underpinning DMC data and also items for a brief subtyping scale. The concordance of the abbreviated scale was then compared with the original Delirium Motor Subtype Scale (DMSS) in 375 patients having delirium as per the American Psychiatric Association's Diagnostic and Statistical Manual (4th edition) criteria. RESULTS: Latent class analysis identified four classes that corresponded closely with the four recognized motor subtypes of delirium. Further, LCA of items (n = 15) that loaded >60% to the model identified four features that reliably identified the classes/subtypes, and these were combined as a brief motor subtyping scale (DMSS-4). There was good concordance for subtype attribution between the original DMSS and the DMSS-4 (κ = 0.63). CONCLUSIONS: The DMSS-4 allows for rapid assessment of clinical subtypes in delirium and has high concordance with the longer and well-validated DMSS. More consistent clinical subtyping in delirium can facilitate better delirium management and more focused research effort.

Study of fluorescence quenching in aluminum-doped ceria nanoparticles: potential molecular probe for dissolved oxygen.

This work investigates a novel usage of aluminum-doped ceria nanoparticles (ADC-NPs), as the molecular probe in optical fluorescence quenching for sensing the dissolved oxygen (DO). Cerium oxide (ceria) nanoparticles can be considered one of the most unique nanomaterials that are being studied today due to the diffusion and reactivity of oxygen vacancies in ceria, which contributes to its high oxygen storage capability. Aluminum can be considered a promising dopant to increase the oxygen ionic conductivity in ceria nanoparticles which can improve the sensitivity of ceria nanoparticles to DO. The fluorescence intensity of ADC-NPs, synthesized via chemical precipitation, is found to have a strong inverse relationship with the DO concentration in aqueous solutions. Stern-Volmer constant of ADC-NPs at room temperature is determined to be 454.6 M(-1), which indicates that ADC-NPs have a promising sensitivity to dissolved oxygen, compared to many presently used fluorophores. In addition, Stern-Volmer constant is found to have a relatively small dependence on temperature between 25 °C to 50 °C, which shows excellent thermal stability of ADC-NPs sensitivity. Our work suggests that ADC-NPs, at 6 nm, are the smallest diameter DO molecular probes between the currently used optical DO sensors composed of different nanostructures. This investigation can improve the performance of fluorescence-quenching DO sensors for industrial and environmental applications.

Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma.

We evaluated the effect of acute and chronic GVHD on relapse and survival after allogeneic hematopoietic SCT (HSCT) for multiple myeloma using non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC). The outcomes of 177 HLA-identical sibling HSCT recipients between 1997 and 2005, following NMA (n=98) or RIC (n=79) were analyzed. In 105 patients, autografting was followed by planned NMA/RIC allogeneic transplantation. The impact of GVHD was assessed as a time-dependent covariate using Cox models. The incidence of acute GVHD (aGVHD; grades I-IV) was 42% (95% confidence interval (CI), 35-49%) and of chronic GVHD (cGVHD) at 5 years was 59% (95% CI, 49-69%), with 70% developing extensive cGVHD. In multivariate analysis, aGVHD (≥ grade I) was associated with an increased risk of TRM (relative risk (RR)=2.42, P=0.016), whereas limited cGVHD significantly decreased the risk of myeloma relapse (RR=0.35, P=0.035) and was associated with superior EFS (RR=0.40, P=0.027). aGVHD had a detrimental effect on survival, especially in those receiving autologous followed by allogeneic HSCT (RR=3.52, P=0.001). The reduction in relapse risk associated with cGVHD is consistent with a beneficial graft-vs-myeloma effect, but this did not translate into a survival advantage.

Analysis of fertility-related soluble mediators in human uterine fluid identifies VEGF as a key regulator of embryo implantation.

Embryo implantation requires synchronized dialogue between the receptive endometrium and activated blastocyst via locally produced soluble mediators. During the midsecretory (MS) phase of the menstrual cycle, increased glandular secretion into the uterine lumen contains important mediators that modulate the endometrium and support the conceptus during implantation. This study aimed first to identify the growth factor and cytokine profile of human uterine fluid from fertile women during the midproliferative (MP; nonreceptive) and MS (receptive) phases of the cycle, and from women with unexplained infertility during the MS phase. The second aim was to determine important functions of endometrial secretions for embryo implantation. Analysis of uterine fluid using quantitative Luminex assays revealed the presence of over 30 cytokines and growth factors, of which eight [platelet-derived growth factor-AA, TNF-B, soluble IL-2 receptor-A, Fms-like tyrosine kinase 3 ligand, soluble CD40 ligand, IL-7, interferon-A2, and chemokine (C-X-C motif) ligand 1-3] were previously unknown in human uterine fluid. Comparison of the fertile MP, MS, and infertile MS cohorts revealed vascular endothelial growth factor (VEGF) levels are significantly reduced in uterine fluid during the MS phase in women with unexplained infertility compared with fertile women. Functional studies demonstrated that culturing mouse embryos with either MS-phase uterine fluid from fertile women or recombinant human VEGF significantly enhanced blastocyst outgrowth. Furthermore, treatment of human endometrial epithelial cells with uterine fluid or recombinant human VEGF-A significantly increased endometrial epithelial cell adhesion. Taken together, our data support the concept that endometrial secretions, including VEGF, play important roles during implantation. Identifying the soluble mediators in human uterine fluid and their actions during implantation provides insight into interactions essential for establishing pregnancy, fertility markers, and infertility treatment options.

Human chorionic gonadotrophin regulates FGF2 and other cytokines produced by human endometrial epithelial cells, providing a mechanism for enhancing endometrial receptivity.

BACKGROUND: Preimplantation cross-talk between a functional blastocyst and the endometrium is critical for successful blastocyst implantation. This interaction is mediated in part by endometrial cytokines/growth factors secreted by glandular epithelium into the uterine cavity. Recent evidence suggests that blastocyst-derived hCG may influence the endometrial milieu in conception cycles thereby enhancing receptivity and implantation success. This study investigated the effect of hCG on the secretory profile of a select cohort of 44 cytokines/growth factors from primary human endometrial epithelial cells (hEECs). These factors included those with both known and unknown roles during receptivity and implantation. The expression of one previously unknown hCG-regulated factor, fibroblast growth factor 2 (FGF2), in human endometrium and its effects on hEEC function were further examined. METHODS: hEECs isolated from endometrial biopsies collected from fertile cycling women (n = 15) were treated ± recombinant hCG (0.2-20 IU/ml) for 48 h and conditioned media was quantitatively analysed using Luminex™ multiplex technology. FGF2 was further investigated by immunohistochemistry, western blot and cell-adhesion assays. RESULTS: Of 44 cytokines/growth factors examined, 39 were produced by hEECs with a distinct profile. hCG (2 IU/ml) significantly increased the production of six factors, including those with known roles in receptivity and trophoblast function (interleukin-11), blastocyst migration and adhesion (CXCL10), blastocyst development (granulocyte macrophage colony-stimulating factor) and one unknown with respect to receptivity and implantation (FGF2). Up-regulation of known hCG-regulated proteins, vascular endothelial growth factor and leukaemia inhibitory factor, validated this study. Immunoreactive epithelial FGF2 increased across the menstrual cycle, being highest in secretory and first trimester pregnancy endometrium in vivo. FGF2 (100 ng/ml) stimulated phosphorylation of ERK1/2 in hEEC with no effect on ERK1/2 abundance and stimulated hEEC adhesion to fibronectin and collagen IV (components of blastocyst/trophectoderm extracellular matrix). CONCLUSIONS: These findings clearly support roles for hCG and FGF2 in the blastocyst-endometrial cross-talk important for endometrial receptivity and blastocyst implantation.

Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells.

Multiple myeloma causes approximately 10% of all hematologic malignancies. We have previously shown that human T cells expressing chimeric NKG2D receptors (chNKG2D) consisting of NKG2D fused to the CD3ζ cytoplasmic domain secrete proinflammatory cytokines and kill human myeloma cells. In this study, we show chNKG2D T cells are effective in a murine model of multiple myeloma. Mice with established 5T33MM-green fluorescent protein tumors were treated with one or two infusions of chNKG2D T cells. Compared with mice treated with T cells expressing wild type (wt)NKG2D receptors, a single dose of chNKG2D T cells increased survival, with half of the chNKG2D T-cell-treated mice surviving long term. Two infusions of chNKG2D T cells led to tumor-free survival in all mice. ChNKG2D T cells were located at sites of tumor growth, including the bone marrow and spleen after intravenous injection. There was an increase in activated host T cells and NK cells at tumor sites and in serum interferon-γ after chNKG2D T-cell injection. Surviving mice were able to resist a rechallenge with 5T33MM cells but not RMA lymphoma cells, indicating that the mice developed a protective, specific memory response. These data demonstrate that chNKG2D T cells may be an effective adoptive cellular therapy for multiple myeloma.

Optimal pulse durations for the treatment of leg telangiectasias with an alexandrite laser.

BACKGROUND AND OBJECTIVES: Determine optimal settings using a long pulse 755 nm alexandrite laser in the treatment of superficial leg veins. STUDY DESIGN\ MATERIALS AND METHODS: Fifteen patients with Fitzpatrick skin types I-III with telangiectasia ranging from 0.2 to 1.0 mm were enrolled. Spot size varied from 3 to 6 mm. Pulse durations ranged from 3 to 100 milliseconds. For each pulse duration, test sites were performed to determine threshold radiant exposures using persistent bluing and/or immediate stenosis (closure) as the clinical endpoint. Test sites were re-evaluated 21 days later. Optimal settings, those that resulted in the greatest clearance with minimal side effects (pain, purpura, epidermal damage, pigment changes), were used to treat a larger area of like-sized vessels. Follow-up evaluations were conducted 12 weeks after a single treatment using the optimal setting. Polarized digital photographs were obtained at each visit. Improvement was determined by blinded evaluation of pre/post-treatment photographs. RESULTS: Fourteen patients completed the study. Radiant exposure thresholds for immediate vessel changes depended on vessel diameter, with larger radiant exposures required for smaller spot sizes and smaller vessels. The average threshold radiant exposure for closure was 89 J/cm(2). The optimal pulse duration was 60 milliseconds for most of the patients. With this pulse width, clearance approached 65% 12 weeks after a single treatment. Transient hyperpigmentation occurred in four patients. Increasing the pulse duration improved epidermal tolerance and decreased the likelihood of purpura. CONCLUSIONS: By lengthening the pulsewidth beyond 3 milliseconds, a long pulse alexandrite laser achieves satisfactory clearance with an improved side effect profile.

Development of a clinical model for ex vivo expansion of multiple populations of effector cells for adoptive cellular therapy.

BACKGROUND: We have previously demonstrated a laboratory model for expanding autologous mononuclear cells into populations of effector killer cells. The goal of the current experiments was to develop a good manufacturing practice (GMP) method for expanding clinical-grade activated effector cells that mediate tumor cell killing through various mechanisms that could be infused into patients following high-dose chemotherapy and autologous stem cell transplant. METHODS: Mobilized mononuclear cells (MNC) from myeloma patients were placed in culture with serum-free AIM V media, interleukin-2 (1000 IU/mL) and OKT-3 (500 ng/mL) at 37 degrees C and 5% CO2. After 7 days of expansion, the cells were analyzed for cell concentration, viability, phenotype and cytotoxicity directed against human myeloma cell lines. Expansion was compared using culture bags and flasks. Cryopreserved expanded cells were also analyzed. RESULTS: This clinical model of ex vivo expansion yielded polyclonal populations of cytotoxic lymphocytes, including CD3+ CD4+ T cells, CD3+ CD8+ T cells, CD8+ CD56+ T cells and CD56+ natural killer cells. Compared with flasks, culture bags provided a 2-3-fold effector cell expansion with minimal risk of contamination. The optimal cell concentration at the time of expansion was 2.5-3.5 x 10(6) peripheral blood MNC/mL. Viability and cytotoxicity were maintained if the expanded cells were cryopreserved and then thawed for use. DISCUSSION: The results demonstrate a reproducible and reliable GMP procedure that is currently being employed in a clinical trial. These expanded cells, and their various pathways of tumor cell killing, may circumvent tumor escape mechanisms and improve outcomes.

Early recovery of aggressive cytotoxic cells and improved immune resurgence with post-transplant immunotherapy for multiple myeloma.

A phase I/II trial evaluated early administration and dose escalation of interleukin (IL)-2 with granulocyte macrophage colony stimulating factor (GM-CSF) post-transplant. Following melphalan (200 mg/m(2)) and an autologous transplant, IL-2 was initiated (day 0) and continued for 4 weeks. GM-CSF (250 mcg/m(2)/day) began on day 5. Fifteen of 19 patients completed therapy. No treatment-related deaths occurred. IL-2 (1 x 10(6) IU/m(2)/day) was not tolerated in two of six patients due to > or =grade 3 fatigue/diarrhea (n=1) or supraventricular tachycardia (n=1). The maximum tolerated dose of IL-2 was 6 x 10(5) IU/m(2)/day; this dose was well tolerated by 11 of 13 patients. Neutrophil and platelet engraftment occurred on day 13 (median; range 10-17 days) and day 13 (median; range 0-74 days), respectively. When compared to control patients, there was a marked increase in the number of CD3+ T cells (P=0.005), CD4+ T cells (P=0.01), CD8+ T cells (P=0.001) and CD4+CD25+Treg cells (P=0.015) post-transplant. Cytotoxicity directed against myeloma cells was markedly increased when compared to control patients (P=0.017). This unique trial design using early administration of IL-2 with GM-CSF during the period of lymphodepletion, demonstrated a marked increase in the number and function of early cytotoxic effector T cells, without suppression of engraftment.

Ex vivo expansion of non-MHC-restricted cytotoxic effector cells as adoptive immunotherapy for myeloma.

BACKGROUND: PBMC can be expanded ex vivo into aggressive cytotoxic effector cells (CEC) comprising T, NK and NKT cells. We identified the phenotype, cytotoxicity and mechanisms of killing of these CEC. METHODS: CY- and G-CSF-mobilized PBMC from myeloma patients were placed in Aim-V serum-free medium, IL-2 (50 IU/mL) and OKT-3 (50 ng/mL). Cytotoxicity was evaluated by selectively blocking the TCR, MHC class I or NKG2D receptor. RESULTS: The CEC expanded three-fold by day 7 and aggressively lysed myeloma cells (41.9%) compared with day 0 (4%; P=0.012). CD8+ CD56+ NKT cells performed the majority of lysis. The CD8+ cells greatly increased NKG2D expression during culture (P=0.005). Cytotoxicity correlated with target NKG2D ligand expression (P=0.0002). Blocking the TCR or MHC class I did not affect cytotoxicity (P>0.22). CD8+ cell-mediated lysis dropped 48% when the NKG2D receptor was blocked. Day 7 CEC aggressively lysed myeloma cells in an MHC- and non-MHC-restricted fashion, through the NKG2D receptor. DISCUSSION: Because MHC expression is often down-regulated on tumor cells and the NKG2D ligands are generally specific to malignant cells, the adoptive transfer of CEC that kill through different pathways may circumvent tumor-resistant mechanisms and improve outcomes.

One-pass CO2 versus multiple-pass Er:YAG laser resurfacing in the treatment of rhytides: a comparison side-by-side study of pulsed CO2 and Er:YAG lasers.

BACKGROUND: The CO2 laser is normally described as an aggressive resurfacing tool, whereas the erbium:YAG laser has enjoyed a reputation as the ideal tool for superficial resurfacing. The implication from many studies is that the CO2 laser is incapable of "minimally invasive" resurfacing. OBJECTIVE: To compare a short-pulsed CO2 laser with an Er:YAG laser over a range of parameters intended to produce equivalent microscopic and clinical injuries. METHODS: A prospective, randomized, comparative interventional trial was conducted in a tertiary care teaching hospital. Thirteen patients with facial wrinkles were enrolled in the study. A side-by-side comparison was performed using periorbital and perioral regions as treatment sites. One side was treated with a pulsed CO2 laser and the other with an Er:YAG laser. Postauricular skin was treated in an identical fashion to the study sites and biopsied for microscopic analysis. The biopsies were obtained before treatment, immediately after treatment, and either 3 or 6 months after treatment to evaluate the acute level of injury and subsequent degree of fibroplasia. Photographs were taken at baseline, immediately after treatment, 1, 2, and 6 weeks, and 3 and 6 months after treatment. Nine physicians evaluated the photographs for erythema, pigmentation, and wrinkle improvement. RESULTS: Investigator assessment showed no statistically significant differences between the lasers with respect to hyperpigmentation and wrinkle reduction. There was less erythema at the CO2 laser-treated sites 2 weeks after treatment; the differences had resolved by 6 weeks after treatment. Histologic examination demonstrated equivalent dermal thermal injury on immediate postoperative biopsies and equivalent fibroplasia on subsequent biopsies. Both CO2 and Er:YAG laser-treated sites showed overall modest wrinkle improvement compared to the pretreatment photographs. CONCLUSION: When CO2 and Er:YAG lasers are used in a manner such that there are equivalent immediate postoperative histologic results, equivalent healing and cosmetic improvement occurs. One can use CO2 laser with one pass to mimic a moderately aggressive Er:YAG laser treatment.

The clinical challenge of onychomycosis.

Onychomycosis continues to be a difficult diagnosis to establish and treat. Better testing modalities need to be developed. Although new antimycotic agents [table: see text] are far more promising than previous treatments, relapse rates remain high. Patient education must be a mainstay of therapy. Establishing realistic expectations, providing a detailed treatment plan with follow-up, and reviewing preventive measures will enhance patient satisfaction and improve cure rates.

A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania.

There are no rapid-acting intramuscular formulations of atypical antipsychotics available for quickly calming an agitated patient with bipolar disorder. In this study, 201 agitated patients with bipolar mania were randomly assigned to receive one to three injections of the atypical antipsychotic olanzapine (10 mg, first two injections; 5 mg, third injection), the benzodiazepine lorazepam (2 mg, first two injections; 1 mg, third injection), or placebo (placebo, first two injections; olanzapine, 10 mg, third injection) within a 24-hour period. Agitation was measured at baseline, every 30 minutes for the first 2 hours, and at 24 hours after the first injection using the Positive and Negative Syndrome Scale-Excited Component subscale and two additional agitation scales. At 2 hours after the first injection, patients treated with olanzapine showed a significantly greater reduction in scores on all agitation scales compared with patients treated with either placebo or lorazepam. At 24 hours after the first injection, olanzapine remained statistically superior to placebo in reducing agitation in patients with acute mania, whereas patients treated with lorazepam were not significantly different from those treated with placebo or olanzapine. Furthermore, no significant differences among the three treatment groups were observed in safety measures, including treatment-emergent extrapyramidal symptoms, the incidence of acute dystonia, or QTc interval changes. These findings suggest that intramuscular olanzapine is a safe and effective treatment for reducing acute agitation in patients with bipolar mania.

Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia.

OBJECTIVE: The authors evaluated the comparative efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular placebo for the treatment of acute agitation in schizophrenia. METHOD: Hospitalized patients with schizophrenia received one to three injections of intramuscular olanzapine, 10 mg, intramuscular haloperidol, 7.5 mg, or intramuscular placebo over a 24-hour period. Agitation was measured with the excited component of the Positive and Negative Syndrome Scale and two additional scales. RESULTS: According to scores on the excited component of the Positive and Negative Syndrome Scale, both intramuscular olanzapine and intramuscular haloperidol reduced agitation significantly more than intramuscular placebo 2 and 24 hours following the first injection. Intramuscular olanzapine reduced agitation significantly more than intramuscular haloperidol 15, 30, and 45 minutes following the first injection. No patients treated with intramuscular olanzapine experienced acute dystonia, compared with 7% of those who were treated with intramuscular haloperidol. No significant QT(c) interval changes were observed in any patients. CONCLUSIONS: Intramuscular olanzapine represents a rapid, effective, and safe treatment for acute agitation in schizophrenia.

Ex vivo cytokine activation of peripheral blood stem cells: a potential role for adoptive cellular immunotherapy.

Ex vivo activation of peripheral blood stem cells (PBSC) using interleukin-2 (IL-2) results in cytotoxic effector cells that may possess beneficial in vivo effects. We proposed to evaluate ex vivo stimulation of PBSC using various cytokines alone or in combination to optimize their function. Cytokine-activated PBSC were analyzed for tumor-directed cytotoxicity and their ability to remove tumor cells from long-term clonogenic assays. Mononuclear cells were obtained from the apheresis products of normal donors and cultured with IL-2 (1000 U/ml), interferon-alpha (IFN-alpha) (1000 U/ml), or IL-12 (50 U/ml) either alone or in combinations at 37 degrees C and 5% CO(2) for 24 h. Colony-forming unit-tumor (CFUT) assays were initiated using cytokine-activated PBSC with varying concentrations of MCF-7 or SKBR-3 human breast cancer cells. Standard 4-h (51)Cr-release assays were performed with cytokine-activated PBSC using MCF-7 or SKBR-3 cells as targets. Activation of PBSC with IL-2, IFN-alpha, or IL-12 resulted in enhanced cytotoxicity against the two breast cancer cell lines when compared to controls. PBSC activated with IL-2 and IFN-alpha or IL-2 and IL-12 were more cytotoxic than PBSC activated with single cytokines (p = 0.0004 for MCF-7 cells and p < 0.001 for SKBR-3 cells). Using clonogenic assays, IL-2-activated PBSC reduced the number of CFU-T to a greater extent than did IL-12 or IFN-alpha-activated PBSC (p = 0.0006). However, PBSC activated with a combination of IL-2 and IFN-alpha or IL-2 and IL-12 demonstrated 95% and 90% reductions, respectively, compared to 79% reduction using IL-2-activated PBSC (p < 0.0001). The greatest reduction in cytotoxicity occurred in the cell populations depleted of CD56(+) cells (p = 0.016) and CD8(+) CD56(+) cells (p = 0.002), suggesting that the effector cell population includes a combination of cytotoxic CD8(+) T cells and CD56(+) natural killer cells. These results demonstrate that the ex vivo activation of PBSC with cytokines, either alone or in combination, enhances cytotoxicity against, and removal of two human breast cancer cells. The combinations of IL-2 with IFN-alpha or IL-12 are most beneficial in cytotoxicity and purging assays. These results could play an important role in designing adoptive cellular immunotherapy clinical trials in the autologous hematopoietic stem cell transplant setting.