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Background: Tigilanol tiglate (TT) is a protein kinase C (PKC)/C1 domain activator currently being developed as an intralesional agent for the treatment of various (sub)cutaneous malignancies. Previous work has shown that intratumoral (I.T.) injection of TT causes vascular disruption with concomitant tumor ablation in several preclinical models of cancer, in addition to various (sub)cutaneous tumors presenting in the veterinary clinic. TT has completed Phase I dose escalation trials, with some patients showing signs of abscopal effects. However, the exact molecular details underpinning its mechanism of action (MoA), together with its immunotherapeutic potential in oncology remain unclear., Methods: A combination of microscopy, luciferase assays, immunofluorescence, immunoblotting, subcellular fractionation, intracellular ATP assays, phagocytosis assays and mixed lymphocyte reactions were used to probe the MoA of TT in vitro. In vivo studies with TT used MM649 xenograft, CT-26 and immune checkpoint inhibitor refractory B16-F10-OVA tumor bearing mice, the latter with or without anti-programmed cell death 1 (PD-1)/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAb treatment. The effect of TT at injected and non-injected tumors was also assessed., Results: Here, we show that TT induces the death of endothelial and cancer cells at therapeutically relevant concentrations via a caspase/gasdermin E-dependent pyroptopic pathway. At therapeutic doses, our data demonstrate that TT acts as a lipotoxin, binding to and promoting mitochondrial/endoplasmic reticulum (ER) dysfunction (leading to unfolded protein response mt/ER upregulation) with subsequent ATP depletion, organelle swelling, caspase activation, gasdermin E cleavage and induction of terminal necrosis. Consistent with binding to ER membranes, we found that TT treatment promoted activation of the integrated stress response together with the release/externalization of damage-associated molecular patterns (HMGB1, ATP, calreticulin) from cancer cells in vitro and in vivo, characteristics indicative of immunogenic cell death (ICD). Confirmation of ICD in vivo was obtained through vaccination and rechallenge experiments using CT-26 colon carcinoma tumor bearing mice. Furthermore, TT also reduced tumor volume, induced immune cell infiltration, as well as improved survival in B16-F10-OVA tumor bearing mice when combined with immune checkpoint blockade., Conclusions: These data demonstrate that TT is an oncolytic small molecule with multiple targets and confirms that cell death induced by this compound has the potential to augment antitumor responses to immunotherapy., Competing Interests: Competing interests: JKC and GMB were previous recipients of research fellowships co-sponsored by QBiotics Group Ltd. GMB, GA and PGP are recipients of current contract research funding from QBiotics Group Ltd. PWR, SMO, VAG and PGP are employees of QBiotics Group Ltd. JKC became a QBiotics employee during the review process. JKC, P-YY, JJ, GMB, SMO, PWR, VAG and PGP are shareholders in QBiotics Group Ltd. The other authors declare no competing interests. The work described in this study forms the basis of two international patents: PCT/AU2020/050360, PCT/AU2018/050277., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The unusual and sterically constrained amino acid, seco -1-azacubane-2-carboxylic acid, was incorporated into a range of bioactive chemical templates, including enalaprilat, perindoprilat, endomorphin-2 and isoniazid, and subjected to biological testing. The endomorphin-2 derivative displayed increased activity at the δ opioid receptor, but a loss in activity was observed in the other cases, although human normal cell line evaluation suggests limited cytotoxic effects.

Purpose: Procalcitonin (PCT) is an inflammatory marker elevated in bacteremia and bacterial pneumonia. We aimed to assess the real-world diagnostic accuracy of PCT in hospitalized patients with malignancy., Methods: A retrospective cohort of 715 patients with cancer who had PCT measured during 750 admissions was analyzed. Diagnosis of bacteremia was determined using blood culture data. Diagnosis of bacterial pneumonia was based on radiographic infiltrate and/or sputum culture. PCT's performance was assessed using receiver operating characteristic (ROC) curves, sensitivity, and specificity., Results: Patients had bacteremia, bacterial pneumonia, or both during 210 admissions (28%). PCT elevation above 0.5 ng/mL was significantly associated with diagnosed infection in the overall population (p < 0.0001) and in subgroups with solid tumor malignancies (p < 0.0001) and hematologic malignancies (p = 0.008). PCT was associated with infectious status in patients with any metastases, but not those with primary lung cancer, lung metastases, neuroendocrine tumors, febrile neutropenia, or history of bone marrow transplant (BMT). The area under the ROC curve for PCT in the overall population was 0.655. An ideal cutoff of 0.21 ng/mL led to a sensitivity of 60% and specificity of 59%. At cutoffs of 0.5 ng/mL and 0.05 ng/mL, PCT's sensitivity was 39% and 94%, while specificity was 79% and 17%, respectively., Conclusion: In this large cohort of hospitalized oncology patients, PCT elevation was associated with diagnosed bacteremia and/or bacterial pneumonia. However, specificity was limited, and PCT elevation was not associated with diagnosed infection in some subpopulations. While PCT may have some diagnostic utility for hospitalized oncology patients, values must be interpreted cautiously and considering clinical context., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The acquisition of resistance to anoikis, the cell death induced by loss of adhesion to the extracellular matrix, is an absolute requirement for the survival of disseminating and circulating tumour cells (CTCs), and for the seeding of metastatic lesions. In melanoma, a range of intracellular signalling cascades have been identified as potential drivers of anoikis resistance, however a full understanding of the process is yet to be attained. Mechanisms of anoikis resistance pose an attractive target for the therapeutic treatment of disseminating and circulating melanoma cells. This review explores the range of small molecule, peptide and antibody inhibitors targeting molecules involved in anoikis resistance in melanoma, and may be repurposed to prevent metastatic melanoma prior to its initiation, potentially improving the prognosis for patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Neuendorf, Simmons and Boyle.)

Background: αB-Crystallin is a heat shock chaperone protein which binds to misfolded proteins to prevent their aggregation. It is overexpressed in a wide-variety of cancers. Previous studies using human cancer cell lines and human xenograft models have suggested potential tumor promoter (oncogene) roles for αB-Crystallin in a wide-spectrum of cancers., Methods: To determine the causal relationship between CRYAB overexpression and cancer, we generated a Cryab overexpression knock-in mouse model and monitor them for development of spontaneous and carcinogen (DMBA)-induced tumorigenesis. In order to investigate the mechanism of malignancies observed in this model multiple techniques were used such as immunohistochemical characterizations of tumors, bioinformatics analysis of publically available human tumor datasets, and generation of mouse embryonic fibroblasts (MEFs) for in vitro assays (clonogenic survival and migration assays and proteome analysis by mass-spectrometry)., Results: This model revealed that constitutive overexpression of Cryab results in the formation of a variety of lethal spontaneous primary and metastatic tumors in mice. In vivo, the overexpression of Cryab correlated with the upregulation of epithelial-to-mesenchymal (EMT) markers, angiogenesis and some oncogenic proteins including Basigin. In vitro, using E1A/Ras transformed MEFs, we observed that the overexpression of Cryab led to the promotion of cell survival via upregulation of Akt signaling and downregulation of pro-apoptotic pathway mediator JNK, with subsequent attenuation of apoptosis as assessed by cleaved caspase-3 and Annexin V staining., Conclusions: Overall, through the generation and characterization of Cryab overexpression model, we provide evidence supporting the role of αB-Crystallin as an oncogene, where its upregulation is sufficient to induce tumors, promote cell survival and inhibit apoptosis., (© 2023. The Author(s).)

Bioactivity-guided fractionation was used to isolate two compounds, tomentosenol A ( 1 ) and torellianone A ( 2 ), from a cerumen extract from Tetragonula carbonaria . The anti-fibrotic activity of these compounds was examined using human cultured neonatal foreskin fibroblasts (NFF) and immortalised keratinocytes (HaCaTs). Tomentosenol A ( 1 ), inhibited NFF and HaCaT cell proliferation and prevented NFF and HaCaT scratch wound repopulation at 12.5-25 µM concentrations. These inhibitory effects were associated with reduced cell viability, determined by tetrazolium dye (MTT) and sulforhodamine B (SRB) assays. Compound 1 further inhibited transforming growth factor-β 1 (TGF-β 1 )-stimulated, NFF-myofibroblast differentiation and soluble collagen production; and was an effective scavenger of the model oxidant, 2,2-diphenyl-1-picrylhydrazyl (DPPH·), with an EC 50 value of 44.7 ± 3.1 µM. These findings reveal significant anti-fibrotic potential for cerumen-derived tomentosenol A ( 1 ).

Phenotypic plasticity drives cancer progression, impacts treatment response, and is a major driver of therapeutic resistance. In melanoma, a regulatory axis between the MITF and BRN2 transcription factors has been reported to promote tumor heterogeneity by mediating switching between proliferative and invasive phenotypes, respectively. Despite strong evidence that subpopulations of cells that exhibit a BRN2 high /MITF low expression profile switch to a predominantly invasive phenotype, the mechanisms by which this switch is propagated and promotes invasion remain poorly defined. We have found that a reciprocal relationship between BRN2 and NOTCH1/2 signaling exists in melanoma cells in vitro, within patient datasets, and in in vivo primary and metastatic human tumors that bolsters acquisition of invasiveness. Working through the epigenetic modulator EZH2, the BRN2‒NOTCH1/2 axis is potentially a key mechanism by which the invasive phenotype is maintained. Given the emergence of agents targeting both EZH2 and NOTCH, understanding the mechanism through which BRN2 promotes heterogeneity may provide crucial biomarkers to predict treatment response to prevent metastasis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

There is growing evidence that tumour heterogeneity has an imperative role in cancer development, evolution and resistance to therapy. Continuing advancements in biomedical research enable tumour heterogeneity to be observed and studied more critically. As one of the most heterogeneous human cancers, melanoma displays a high level of biological complexity during disease progression. However, much is still unknown regarding melanoma tumour heterogeneity, as well as the role it plays in disease progression and treatment response. This review aims to provide a concise summary of the importance of tumour heterogeneity in melanoma.

The inverse relationship between transcription factor MITF and receptor tyrosine kinase AXL has received much attention recently. It is thought that melanoma tumors showing AXL high /MITF low levels are resistant to therapy. We show here that a population of cells within melanoma tumors with extremely high expression of AXL are negative/low for both MITF and the transcription factor BRN2. Depletion of both transcription factors from cultured melanoma cell lines produced an increase in AXL expression greater than depletion of MITF alone. Further, re-expression of BRN2 led to decreased AXL expression, indicating a role for BRN2 in regulation of AXL levels unrelated to effects on MITF level. As AXL has been recognized as a marker of therapy resistance, these cells may represent a population of cells responsible for disease relapse and as potential targets for therapeutic treatment., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The long-standing perception of Protein Kinase C (PKC) as a family of oncoproteins has increasingly been challenged by evidence that some PKC isoforms may act as tumor suppressors. To explore the hypothesis that activation, rather than inhibition, of these isoforms is critical for anticancer activity, we isolated and characterized a family of 16 novel phorboids closely-related to tigilanol tiglate (EBC-46), a PKC-activating epoxytigliane showing promising clinical safety and efficacy for intratumoral treatment of cancers. While alkyl branching features of the C12-ester influenced potency, the 6,7-epoxide structural motif and position was critical to PKC activation in vitro. A subset of the 6,7-epoxytiglianes were efficacious against established tumors in mice; which generally correlated with in vitro activation of PKC. Importantly, epoxytiglianes without evidence of PKC activation showed limited antitumor efficacy. Taken together, these findings provide a strong rationale to reassess the role of PKC isoforms in cancer, and suggest in some situations their activation can be a promising strategy for anticancer drug discovery.

Melanoma tumors are highly heterogeneous, comprising of many cell populations that vary in their potential for growth and invasion. Differential transcription factor expression contributes to these phenotypic traits. BRN2, a member of the POU domain family of transcription factors is thought to play important roles in melanoma invasion and metastasis. However, the function of BRN2 during the metastatic process of melanoma remains largely unknown. We therefore investigated the effect of BRN2 expression in melanoma cells with no or low constitutive expression using a doxycycline-inducible system. Induction of BRN2 expression led to reduced proliferation and partial resistance to an inhibitor of mutated BRAF. Whole-genome profiling analysis revealed novel targets and signaling pathway changes related to prevention of cell death induced by detachment from the extracellular matrix, known as anoikis resistance. Further investigation confirmed increased survival of BRN2-expressing cell lines in non-adherent conditions. Functionally, expression of BRN2 promoted induction of c-MET levels as well as increased phosphorylation of STAT3. Treatment with crizotinib, a c-MET inhibitor, decreased cellular viability of BRN2-expressing cells under non-adherent conditions to death by anoikis. Alternative inhibitors of c-MET showed similar results. These results highlight the importance of a largely overlooked transcription factor in the progression and metastasis of melanoma, and may suggest a strategy to target BRN2-expressing cells resistant to therapy and cell death by anoikis.

Objective: To examine how characteristics vary between children with any mental health (MH) diagnosis who have typical spending and the highest spending; to identify independent predictors of highest spending; and to examine drivers of spending groups., Methods: This retrospective analysis utilized 2016 Medicaid claims from 11 states and included 775,945 children ages 3 to 17 years with any MH diagnosis and at least 11 months of continuous coverage. We compared demographic characteristics and Medicaid expenditures based on total health care spending: the top 1% (highest-spending) and remaining 99% (typical-spending). We used chi-squared tests to compare the 2 groups and adjusted logistic regression to identify independent predictors of being in the top 1% highest-spending group., Results: Children with MH conditions accounted for 55% of Medicaid spending among 3- to 17-year olds. Patients in the highest-spending group were more likely to be older, have multiple MH conditions, and have complex chronic physical health conditions (P <.001). The highest-spending group had $164,003 per-member-per-year (PMPY) in total health care spending, compared to $6097 PMPY in the typical-spending group. Ambulatory MH services contributed the largest proportion (40%) of expenditures ($2455 PMPY) in the typical-spending group; general health hospitalizations contributed the largest proportion (36%) of expenditures ($58,363 PMPY) in the highest-spending group., Conclusions: Among children with MH conditions, mental and physical health comorbidities were common and spending for general health care outpaced spending for MH care. Future research and quality initiatives should focus on integrating MH and physical health care services and investigate whether current spending on MH services supports high-quality MH care., (Copyright © 2020 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Skin cancer is a broad term used to describe a number of different malignant indications of the skin. Skin cancers mostly comprise of the keratinocyte cancers [Basal Cell Carcinoma (BCC) and cutaneous Squamous Cell Carcinoma (SCC)], and melanoma. Surgical excision of these malignancies has been the preferred treatment of patients for decades. However, the decision to perform surgery can be affected by various considerations, including co-morbidities of the patient, the anatomical site of the lesion and potential intolerance for repeated excisions. Topical treatment of skin cancer may therefore be more appropriate in certain instances. Topical treatment potentially allows for higher drug levels at the tumor site, and may result in less overall toxicity than systemic agents. This review will specifically address the current agents used in topical treatment of skin cancers, and introduce emerging treatments from the natural product field that may also find utility in these indications., Competing Interests: Declaration of Competing Interest J.M.C. - Declaration of interest: recipient of fellowship co-sponsored by QBiotics Group. J.L.S. – Declaration of interest: none. P.G.P. - Declaration of interest: recipient of contract research funding from QBiotics Group; employee and has ownership interests in QBiotics Group. G.M.B. - Declaration of interest: recipient of fellowship co-sponsored by QBiotics Group; recipient of contract research funding from QBiotics Group., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Spermatogenesis is a dynamic process involving self-renewal and differentiation of spermatogonial stem cells, meiosis, and ultimately, the differentiation of haploid spermatids into sperm. Centrosomal protein 55 kDa (CEP55) is necessary for somatic cell abscission during cytokinesis. It facilitates equal segregation of cytoplasmic contents between daughter cells by recruiting endosomal sorting complex required for transport machinery (ESCRT) at the midbody. In germ cells, CEP55, in partnership with testes expressed-14 (TEX14) protein, has also been shown to be an integral component of intercellular bridge before meiosis. Various in vitro studies have demonstrated a role for CEP55 in multiple cancers and other diseases. However, its oncogenic potential in vivo remains elusive. To investigate, we generated ubiquitously overexpressing Cep55 transgenic ( Cep55 Tg/Tg ) mice aiming to characterize its oncogenic role in cancer. Unexpectedly, we found that Cep55 Tg/Tg male mice were sterile and had severe and progressive defects in spermatogenesis related to spermatogenic arrest and lack of spermatids in the testes. In this study, we characterized this male-specific phenotype and showed that excessively high levels of Cep55 results in hyperactivation of PI3K/protein kinase B (Akt) signaling in testis. In line with this finding, we observed increased phosphorylation of forkhead box protein O1 (FoxO1), and suppression of its nuclear retention, along with the relative enrichment of promyelocytic leukemia zinc finger (PLZF) -positive cells. Independently, we observed that Cep55 amplification favored upregulation of ret ( Ret) proto-oncogene and glial-derived neurotrophic factor family receptor α-1 ( Gfra1). Consistent with these data, we observed selective down-regulation of genes associated with germ cell differentiation in Cep55-overexpressing testes at postnatal day 10, including early growth response-4 ( Egr4) and spermatogenesis and oogenesis specific basic helix-loop-helix-1 ( Sohlh1). Thus, Cep55 amplification leads to a shift toward the initial maintenance of undifferentiated spermatogonia and ultimately results in progressive germ cell loss. Collectively, our findings demonstrate that Cep55 overexpression causes change in germ cell proportions and manifests as a Sertoli cell only tubule phenotype, similar to that seen in many azoospermic men.-Sinha, D., Kalimutho, M., Bowles, J., Chan, A.-L., Merriner, D. J., Bain, A. L., Simmons, J. L., Freire, R., Lopez, J. A., Hobbs, R. M., O'Bryan, M. K., Khanna, K. K. Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling.

We aimed to evaluate whether mindfulness-based cognitive therapy (MBCT) was feasible and acceptable for young people, their parents and the clinicians working with them; whether a parallel course for parents was a useful addition; and whether attendance at MBCT was associated with improved outcomes. The design was a mixed-method service evaluation of an eight-session MBCT programme for young people who were recovering from depression. The course was a manualised eight-session group intervention. Both young people ( n  = 18) and parents ( n  = 21) completed validated measures before and after the course. Semi-structured interviews were completed with some group participants and clinical staff working in the service. Care records were searched for additional contact following the intervention. Qualitative data from young people, parents and clinicians suggested that MBCT was acceptable and feasible and provided strategies to cope. The parent course was reported to provide personal support to parents and helped them cope with their child's depression whilst also impacting the family, promoted shared understanding of depression and strategies to combat it and addressed intergenerational aspects of depression. Eighty-four per cent of participants attended at least 6/8 sessions, and 48% required no further intervention within the following year. Young people had statistically significant improvements across all outcome measures, whilst parents had statistically significant improvements in rumination, self-compassion and decentring., Competing Interests: Compliance with Ethical StandardsThe authors declare that they have no conflict of interest.This project was registered as a service evaluation with Devon Child and Adolescent Mental Health Service Quality Improvement team. All participants were aware that an intervention used with adults was being adapted, and its use with young people and their parents was being evaluated. Information provided ensured that all participants were aware that their pseudonymised data would be analysed for presentation and publication.Written informed consent was obtained from all individual participants included in the study.

Melanoma tumors are highly heterogeneous, comprising of different cell types that vary in their potential for growth and invasion. Heterogeneous expression of the Microphthalmia-associated Transcription Factor (MITF) and the POU domain transcription factor BRN2 (POU3F2) has been found in malignant melanoma. Changing expression of these transcription factors as the disease progresses has been linked to the metastatic mechanism of phenotype switching. We therefore investigated the effects of MITF and BRN2 expression in melanoma growth and metastasis. Depletion of MITF resulted in a cell population that had a slowed cell cycle progression, was less invasive in vitro and had hindered tumor and metastasis forming ability in mouse xenograft studies. BRN2 depletion left a cell population with intact proliferation and invasion in vitro; however metastatic growth was significantly reduced in the mouse xenograft model. These results suggest that the proliferative population within melanoma tumors express MITF, and both MITF and BRN2 are important for metastatic growth in vivo. This finding highlights the importance of BRN2 and MITF expression in development of melanoma metastasis.

Purpose: The purpose of this study was to examine provider communication and sociodemographic factors which associate with sperm banking outcomes in at-risk adolescents newly diagnosed with cancer., Methods: A prospective single-group quasi-experimental study design was used to test the contributions of provider factors on sperm banking outcomes. Medical providers (N = 52, 86.5% oncologists) and 99 of their at-risk adolescent patients from eight leading pediatric oncology centers in North America completed questionnaires querying provider factors and patient sperm banking outcomes. Logistic regression with single covariates was used to test each provider factor as a potential correlate of the two binary sperm banking study outcomes (collection attempt/no attempt and successful sperm bank/no bank). Multicovariate logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for specified banking outcomes., Results: Fertility referral (OR, 9.01; 95% CI, 2.54-31.90; p < .001) and provider comfort/skills in negotiating barriers to sperm banking with families (OR, 1.94; 95% CI, 1.03-3.63; p < .04) were associated with collection attempts. Adolescents who were referred for a specialized fertility consultation were also almost five times more likely to successfully bank (OR, 4.96; 95% CI, 1.54-16.00; p < .01) compared to those who were not., Conclusions: Provider training in communicating/managing adolescents and their families about sperm banking, and increasing utilization of fertility preservation referrals, should increase the proportion of at-risk males preserving fertility before treatment initiation., (Copyright © 2016. Published by Elsevier Inc.)

While invasion and metastasis of tumour cells are the principle factor responsible for cancer related deaths, the mechanisms governing the process remain poorly defined. Moreover, phenotypic divergence of sub-populations of tumour cells is known to underpin alternative behaviors linked to tumour progression such as proliferation, survival and invasion. In the context of melanoma, heterogeneity between two transcription factors, BRN2 and MITF, has been associated with phenotypic switching between predominantly invasive and proliferative behaviors respectively. Epigenetic changes, in response to external cues, have been proposed to underpin this process, however the mechanism by which the phenotypic switch occurs is unclear. Here we report the identification of the NFIB transcription factor as a novel downstream effector of BRN2 function in melanoma cells linked to the migratory and invasive characteristics of these cells. Furthermore, the function of NFIB appears to drive an invasive phenotype through an epigenetic mechanism achieved via the upregulation of the polycomb group protein EZH2. A notable target of NFIB mediated up-regulation of EZH2 is decreased MITF expression, which further promotes a less proliferative, more invasive phenotype. Together our data reveal that NFIB has the ability to promote dynamic changes in the chromatin state of melanoma cells to facilitate migration, invasion and metastasis., (Copyright © 2017. Published by Elsevier B.V.)

Squamous cell carcinoma (SCC) is the second most common cancer worldwide and accounts for approximately 30% of all keratinocyte cancers. The vast majority of cutaneous SCCs of the head and neck (cSCCHN) are readily curable with surgery and/or radiotherapy unless high-risk features are present. Perineural invasion (PNI) is recognized as one of these high-risk features. The molecular changes during clinical PNI in cSCCHN have not been previously investigated. In this study, we assessed the global gene expression differences between cSCCHN with or without incidental or clinical PNI. The results of the analysis showed signatures of gene expression representative of activation of p53 in tumors with PNI compared to tumors without, amongst other alterations. Immunohistochemical staining of p53 showed cSCCHN with clinical PNI to be more likely to exhibit a diffuse over-expression pattern, with no tumors showing normal p53 staining. DNA sequencing of cSCCHN samples with clinical PNI showed no difference in mutation number or position with samples without PNI, however a significant difference was observed in regulators of p53 degradation, stability and activity. Our results therefore suggest that cSCCHN with clinical PNI may be more likely to contain alterations in the p53 pathway, compared to cSCCHN without PNI.

Purpose: Human papillomavirus (HPV) is a sexually transmitted infection and the cause of cervical and other cancers. Vaccination is available to protect against genital HPV and is recommended for individuals aged 9-26 years. This study aimed to estimate the prevalence of HPV vaccination among childhood cancer survivors and to identify factors associated with vaccine outcomes., Methods: Young adult females with (n = 114; M age = 21.18 years, SD = 2.48) and without (n = 98; M age = 20.65 years, SD = 2.29) a childhood cancer history completed surveys querying HPV vaccination initiation/completion, as well as sociodemographic, medical, and health belief factors. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for vaccine outcomes., Results: Among survivors, 38.6 % (44/114) and 26.3 % (30/114) initiated or completed vaccination compared to 44.9 % (44/98) and 28.6 % (28/98) among controls, respectively. In the combined survivor/control group, physician recommendation (OR = 11.24, 95 % CI 3.15-40.14) and familial HPV communication (OR = 7.28, 95 % CI 1.89-28.05) associated with vaccine initiation. Perceptions of vaccine benefit associated with vaccine completion (OR = 10.55, 95 % CI 1.59-69.92), whereas perceptions of HPV-related severity associated with non-completion (OR = 0.14, 95 % CI 0.03-0.71)., Conclusion: Despite their increased risk for HPV-related complication, a minority of childhood cancer survivors have initiated or completed HPV vaccination. Modifiable factors associated with vaccine outcomes were identified., Implications for Cancer Survivors: HPV vaccination is a useful tool for cancer prevention in survivorship, and interventions to increase vaccine uptake are warranted.

Most high school adolescents have reported past year gambling, and males gamble more frequently and problematically than females. Ethnic minority adolescents appear to be gambling at a higher rate than Caucasian adolescents. There is evidence indicating that adolescent gambling outcome expectancies are correlated with gambling behavior, but limited evidence that this relation differs by gender. In the present study gender was evaluated as a moderator in the relation between gambling outcome expectancies and gambling behaviors in an African-American high school sample. Males gambled more frequently, gambled more problematically and held more positive gambling outcome expectancies than females. Gender was found to moderate the relations between gambling frequency and the expectations of material gain, affect, self-evaluation and parental approval. Gender also moderated the relations between gambling problems and expectations of affect and self-evaluation. These findings should inform future adolescent gambling prevention and intervention programs.

Introduction: The purpose of this study was to examine the electromyographic (EMG) spectral characteristics of the quadriceps femoris muscles during tendon tap stretch reflexes., Methods: Sixteen healthy subjects (mean ± SD age = 21.2 ± 2.8 years) performed tendon tap reflexes of the leg extensors as surface EMG signals were detected from the vastus lateralis (VL), rectus femoris (RF), and vastus medialis (VM) muscles of the dominant thigh. All EMG signals were processed with a wavelet analysis, and the resulting spectra were decomposed with nonparametric spectral decomposition., Results: The results showed that the spectra for the VL had significantly more high-frequency power than those for the RF and VM, with similar spectral shapes for the RF and VM., Conclusions: These findings could be due to differences in the width of the innervation zone, or the fiber type composition of the muscles, although the latter seems to be more likely., (© 2015 Wiley Periodicals, Inc.)

Background: Among those 9-26 years of age, vaccination can prevent specific types of genital human papillomavirus (HPV), the most common sexually transmitted infection and cause of cervical and other cancers. The objective of this study was to estimate the prevalence of and factors associated with HPV vaccine initiation and completion among females surviving childhood cancer., Procedure: One-hundred fourteen young adults and 230 mothers with daughters surviving childhood cancer completed surveys querying HPV vaccination history along with medical and sociodemographic factors potentially associated with vaccination outcomes. Vaccination rate differences by age necessitated analysis of outcomes by age group: 9-13 years (preadolescents), 14-17 years (adolescents), and 18-26 years (young adults). Multivariable logistic regression was utilized to identify factors associated with HPV vaccination outcomes., Results: Overall, 34.6% (119/344) of survivors initiated and 20.9% (72/344) completed HPV vaccination. Preadolescents were least likely to have initiated vaccination (P < 0.001). Physician recommendation was associated with initiation across age groups (OR = 6.81-11.96, Ps < 0.001-.01), whereas older age at diagnosis (≥12 years of age) was associated with lower vaccination initiation among young adults only (OR = 0.28; 95%CI, 0.10-0.76, P = 0.012). Physician recommendation (OR = 7.54; 95%CI, 1.19-47.69, P = 0.032; adolescent group) and greater treatment intensity (OR = 5.25; 95%CI, 1.00-27.61, P = 0.050; young adult group) were associated with vaccine completion, whereas being non-White was associated with decreased vaccination completion (OR = 0.17; 95%CI, 0.05-0.66, P = 0.010; adolescent group)., Conclusions: A minority of youths surviving childhood cancer have initiated or completed HPV vaccination. Strategies to increase vaccination among survivors are discussed., (© 2015 Wiley Periodicals, Inc.)

Expectancy theory posits that decisions to engage in a given behavior are closely tied to expectations of the outcome of that behavior. Gambling outcome expectancies have predicted adolescent gambling and gambling problems. When high school students' outcome expectancies were measured by Wickwire et al. (Psychol Addict Behav 24(1):75-88 2010), the Adolescent Gambling Expectancy Survey (AGES) revealed five categories of expectancies that were each predictive of gambling frequency and pathology. The present study aimed to explore if the AGES could be successfully replicated with college students. When administered to a diverse college student population, factor analyses identified five factors similar to those found in the high school sample. Several factors of the AGES were also found to predict gambling frequency and gambling problems for college students. Gambling frequency and gambling activity preference were also addressed.

Purpose: Infertility is a frequent consequence of cancer therapy and is often associated with psychological distress. Although adult survivors prioritize fertility and parenthood, this issue remains unexplored among adolescent males. This study examined future fertility as a priority (relative to other life goals) at time of diagnosis for at-risk adolescents and their parents., Methods: Newly diagnosed adolescent males (n = 96; age = 13.0-21.9 years) at increased risk for infertility secondary to cancer treatment prioritized eight life goals: to have school/work success, children, friends, wealth, health, a nice home, faith, and a romantic relationship. Patients' parents (fathers, n = 30; mothers, n = 61) rank-ordered the same priorities for their children., Results: "Having children" was ranked as a "top 3" life goal among 43.8 % of adolescents, 36.7 % of fathers, and 21.3 % of mothers. Fertility ranked third among adolescents, fourth among fathers, and fifth among mothers. Future health was ranked the top priority across groups, distinct from all other goals (ps < 0.001), and fertility ranked higher than home ownership and wealth for all groups (ps < 0.001). For adolescents, low/moderate fertility risk perception was associated with higher fertility rankings than no/high risk perceptions (p = 0.01)., Conclusions: Good health is the most important life goal among adolescents newly diagnosed with cancer and their parents. In this relatively small sample, adolescents prioritized fertility as a top goal, parents also rated fertility as being more important than home ownership and financial wealth. Health care providers should communicate fertility risk and preservation options at diagnosis and facilitate timely discussion among families, who may differ in prioritization of future fertility.

Objective: This study examined whether cochlear implant (CI) recipients with substantial preoperative residual hearing obtained more benefit from a CI than from a hearing aid (HA)., Study Design: Retrospective records review., Setting: Tertiary referral center., Patients: Thirty-seven CI recipients (11 children/teens, 26 adults) were identified that met the following inclusion criteria: preimplant sentence recognition scores greater than 50% correct in the implanted ear or greater than 60% in the best-aided/binaural condition (Group 1, n = 18); audiometric thresholds less than 70 dB HL at 2 or more frequencies (i.e., better than a severe-profound hearing loss; Group 2, n = 13 ears in 12 recipients), or those that met both the audiometric and sentence-recognition criteria (Group 3, n = 7)., Main Outcome Measure: Postimplant speech-perception scores., Results: Postimplant speech perception was substantially better than the preimplant performance for 12 of 18 recipients in Group 1, 10 of 12 recipients (11/13 ears) in Group 2, and 5 of 7 recipients in Group 3 (total, 73.7%). Five recipients (13.1%) showed no change from preimplant performance levels. Results were inconclusive for 2 recipients (5.3%) because preimplant versus postimplant testing was conducted in different conditions. Three recipients (7.9%) exhibited decreased performance postimplant., Conclusion: For most recipients whose hearing was better than that defined by traditional candidacy criteria, performance improved with the CI. These results may help clinicians guide candidates in the decision-making process by providing information on the range of outcomes for recipients with similar preimplant performance levels, identify the need for additional preimplant counseling regarding expectations, and recognize the importance of systematizing preimplant and postimplant testing for longitudinal assessment of performance.

Effective vaccination is now available to prevent human papillomavirus (HPV), the most common sexually transmitted infection and cause of cervical cancer. This study aimed to estimate the prevalence of HPV vaccination among childhood cancer survivors and identify factors associated with HPV vaccine initiation and completion. Mothers of daughters of ages 9 to 17 years with/without a history of childhood cancer (n = 235, Mage = 13.2 years, SD = 2.69; n = 70, Mage = 13.3 years, SD = 2.47, respectively) completed surveys querying HPV vaccination initiation and completion along with sociodemographic, medical, HPV knowledge and communication, and health belief factors, which may relate to vaccination outcomes. Multivariate logistic regression was used to identify factors that associate with HPV vaccination initiation and completion. Among cancer survivors, 32.6% initiated and 17.9% completed the three-dose vaccine series, whereas 34.3% and 20.0% of controls initiated and completed, respectively. Univariate analyses indicated no differences between cancer/no cancer groups on considered risk factors. Among all participants, multivariate logistic regression analyses found vaccine initiation associated with older age of daughter and physician recommendation, whereas increased perceived barriers associated with a decreased likelihood of initiation (all P < 0.05). Among those having initiated, risk factors for noncompletion included being non-White, increased perceived severity of HPV, and increased perceived barriers to vaccination (all P < 0.05). A minority of adolescents surviving childhood cancer has completed vaccination despite their increased risk for HPV-related complication. These results inform the prioritization of strategies to be included in vaccine promotion efforts.

Metastatic breast cancer may emerge from latent tumor cells that remain dormant at disseminated sites for many years. Identifying mechanisms regulating the switch from dormancy to proliferative metastatic growth has been elusive due to the lack of experimental models of tumor cell dormancy. We characterized the in vitro growth characteristics of cells that exhibit either dormant (D2.0R, MCF-7, and K7M2AS1.46) or proliferative (D2A1, MDA-MB-231, and K7M2) metastatic behavior in vivo. Although these cells proliferate readily in two-dimensional culture, we show that when grown in three-dimensional matrix, distinct growth properties of the cells were revealed that correlate to their dormant or proliferative behavior at metastatic sites in vivo. In three-dimensional culture, cells with dormant behavior in vivo remained cell cycle arrested with elevated nuclear expression of p16 and p27. The transition from quiescence to proliferation of D2A1 cells was dependent on fibronectin production and signaling through integrin beta1, leading to cytoskeletal reorganization with filamentous actin (F-actin) stress fiber formation. We show that phosphorylation of myosin light chain (MLC) by MLC kinase (MLCK) through integrin beta1 is required for actin stress fiber formation and proliferative growth. Inhibition of integrin beta1 or MLCK prevents transition from a quiescent to proliferative state in vitro. Inhibition of MLCK significantly reduces metastatic outgrowth in vivo. These studies show that the switch from dormancy to metastatic growth may be regulated, in part, through epigenetic signaling from the microenvironment, leading to changes in the cytoskeletal architecture of dormant cells. Targeting this process may provide therapeutic strategies for inhibition of the dormant-to-proliferative metastatic switch.

Testosterone or its metabolite, estrogen, regulates aggression in males of many mammalian species. Because plasma testosterone levels are typically positively correlated with both aggression and reproduction, aggression is expected to be higher when males are in reproductive condition. However, in some photoperiodic species such as Siberian hamsters (Phodopus sungorus), males are significantly more aggressive in short day lengths when the testes are regressed and circulating testosterone concentrations are reduced. These results led to the formation of the hypothesis that aggression is modulated independently of circulating steroids in Siberian hamsters. Thus, recent studies have been designed to characterize the role of other neuroendocrine factors in modulating aggression. However, aggression may be mediated by testosterone or estrogen despite basal concentrations of these steroids by increasing sensitivity to steroids in specific brain regions. Consistent with this hypothesis, we found that males housed under short days have increased expression of estrogen receptor alpha in the bed nucleus of the stria terminalis, medial amygdala, and central amygdala. Neural activation in response to an aggressive encounter was also examined across photoperiod.

Background & Aims: Whereas severe duodenal ulcer is the hallmark of acid hypersecretion in Zollinger-Ellison syndrome (ZE) and similar states, the esophagus also is at high risk. We quantified the incidence of esophagitis and various risk factors that might contribute to it., Methods: Sixty-eight acid hypersecretors (basal acid output >15 mmol/h), 50 patients with ZE, and 18 patients without ZE with normal gastrin levels were studied by gastric analysis, serum gastrin levels, and endoscopy. In 44 of 68 patients, esophageal manometry was performed after the esophagus had healed., Results: Erosive esophagitis, grade 2 or worse, was found in 65%; an additional 15% had heartburn only, for a total reflux disease incidence of 80%. ZE accounted for 95% of severe esophagitis. Patients with and without esophagitis had the same high overnight fasting gastric residual volume and acidity, as well as basal and peak acid and pepsin outputs. However, patients with esophagitis had a lower median lower esophageal sphincter pressure (LESP) of 15.5 vs. 23 mm Hg in those without symptoms; the critical discriminator threshold was 16 mm Hg. Multivariate analysis further identified frequent vomiting and obesity as positive predictors of esophagitis, whereas Helicobacter pylori was a strong negative predictor (odds ratio, 0.16), possibly related to an elevated LESP in patients infected with H. pylori., Conclusions: Erosive esophagitis is very common in acid hypersecretors. Identified risk factors that could promote abnormal esophageal exposure to the high acid and pepsin levels in our population of hypersecretors were vomiting, LESP < 16 mm Hg, and obesity, whereas H. pylori appeared to protect the esophagus not by reduced acid, but through an elevated LESP.

The test performance of a wideband acoustic transfer function (ATF) test and 226-Hz tympanometry was assessed in predicting the presence of conductive hearing loss, based on an air-bone gap of 20 dB or more. Two ATF tests were designed using an improved calibration method over a frequency range (0.25-8 kHz): an ambient-pressure test and a tympanometric test using an excess static pressure in the ear canal. Wideband responses were objectively classified using moment analyses of energy transmittance, which was a more appropriate test variable than energy reflectance. Subjects included adults and children of age 10 years and up, with 42 normal-functioning ears and 18 ears with a conductive hearing loss. Predictors were based on the magnitudes of the moment deviations from the 10th to 90th percentiles of the normal group. Comparing tests at a fixed specificity of 0.90, the sensitivities were 0.28 for peak-compensated static acoustic admittance at 226 Hz, 0.72 for ambient-pressure ATF, and 0.94 for pressurized ATF. Pressurized ATF was accurate at predicting conductive hearing loss with an area under the receiver operating characteristic curve of 0.95. Ambient-pressure ATF may have sufficient accuracy to use in some hearing-screening applications, whereas pressurized ATF has additional accuracy that may be appropriate for hearing-diagnostic applications.

Renal angiomyolipomas are common in patients with tuberous sclerosis complex (TSC), and the risk of severe haemorrhage from these angiomyolipomas can become substantial. This case illustrates a potentially life-threatening condition due to the development of a large aneurysm within an angiomyolipoma, which was discovered within 14 months of her screening renal ultrasound scan. Renal arterial embolisation and renal sparing surgery resulted in good recovery. Clear guidelines for the screening, surveillance, and treatment of angiomyolipomas in patients with TSC are required. This includes the appropriate frequency of surveillance for patients in different age groups and at different stages of angiomyolipoma development, based on a growing knowledge of the natural history of this condition, since growth of renal angiomyolipomas can be rapid and asymptomatic. Computed tomography or magnetic resonance imaging may be required to demonstrate complications in large lesions, as three ultrasound examinations in this patient failed to detect the large aneurysm which had developed. Angiogenesis inhibitors could potentially play a role in preventing the development of angiomyolipomas, which could improve the prognosis for patients with TSC and therefore warrants investigation through phase II/III clinical trials.

Research has shown that actuarial assessments of violence risk are consistently more accurate than unaided judgments by clinicians, and it has been suggested that the availability of actuarial instruments will improve forensic decision making. This study examined clinical judgments and autonomous review tribunal decisions to detain forensic patients in maximum security. Variables included the availability of an actuarial risk report at the time of decision making, patient characteristics and history, and clinical presentation over the previous year. Detained and transferred patients did not differ in their actuarial risk of violent recidivism. The best predictor of tribunal decision was the senior clinician's testimony. There was also no significant association between the actuarial risk score and clinicians' opinions. Whether the actuarial report was available at the time of decision making did not alter the statistical model of either clinical judgments or tribunal decisions. Implications for the use of actuarial risk assessment in forensic decision making are discussed.

Auditory neuropathy (AN) has been described in the literature as presenting with a combination of audiometric findings that include elevated behavioral audiometric thresholds, auditory brainstem response findings that are not consistent with audiometric findings, poor speech recognition, and present otoacoustic emissions (OAEs) and/or cochlear microphonics. Since the availability of clinical OAE testing, AN has come to be identified with increasing frequency; however, incidence and prevalence figures are unavailable. There is a great deal of discussion about the accurate diagnosis of AN, its characteristics, and its treatment. Some of this discussion is occurring on the Internet and over the telephones. The need to continue to provide information in accessible peer-reviewed journals is paramount. Following a review of the literature, a case study is presented of a boy who was diagnosed with AN as a newborn. He experienced hyperbilirubinemia and other neonatal health complications. His educational intervention was managed elsewhere until recently. Information is presented about the progression of the case over a 5-year period that includes audiologic data and communication development results.

This study developed and tested the idea that social categorization processes help to explain framing effects in social dilemmas. Using self-categorization theory, we predicted that members of a collective would cooperate more when they faced homogeneous rather than heterogeneous resource frames. We manipulated the starting point of resources for the members of each of two subgroups making up a larger collective in a nested social dilemma. The resources of the subject's own subgroup started at the individual, subgroup, or collective level, and the resources of the opposing subgroup also started at the individual, subgroup, or collective level. The condition in which both subgroups' resources began at the collective level was similar to a traditional commons dilemma, while the condition in which both subgroups' resources began at the individual level was similar to a traditional public goods problem. The other conditions were new to this research domain. We found higher allocations to the collective account when the initial resource location was the same for both subgroups (versus different for each subgroup), even when this initial location was the subgroup or individual level. Whereas previous explanations for framing effects cannot account for these results, social categorization processes provide a parsimonious explanation for the observed pattern of allocations. Copyright 1999 Academic Press.

Behavior therapy has been shown to improve the functioning of institutionalized clients, but front-line staff often have difficulty implementing behavior therapy techniques. In the case described in this report, staff with inadequate training in behavior therapy inconsistently used negative and positive reinforcement in the attempt to reduce the aggressive behavior of an inpatient diagnosed as having schizophrenia, and the interventions were associated with an increase in assaults and related behavior. The case illustrates the effects of poor behavior management and the importance of data collection in evaluating clinical interventions.

This study evaluated the accuracy of acoustic response tests in predicting conductive hearing loss in 161 ears of subjects from the age of 2 to 10 yr, using as a "gold standard" the air-bone gap to classify ears as normal or impaired. The acoustic tests included tympanometric peak-compensated static admittance magnitude (SA) and tympanometric gradient at 226 Hz, and admittance-reflectance (YR) measurements from 0.5 to 8 kHz. The performance of individual, frequency-specific, YR test variables as predictors was assessed. By applying logistic regression (LR) and discriminant analysis (DA) techniques to the multivariate YR response, two univariate functions were calculated as the linear combinations of YR variables across frequency that best separated normal and impaired ears. The tympanometric and YR tests were also combined in a multivariate manner to test whether predictive efficacy improved when 226-Hz tympanometry was added to the predictor set. Conductive hearing loss was predicted based on air-bone gap thresholds at 0.5 and 2 kHz, and on a maximum air-bone gap at any octave frequency from 0.5 to 4 kHz. Each air-bone gap threshold ranged from 5 to 30 dB in 5-dB steps. Areas under the relative operating characteristic curve for DA and LR were larger than for reflectance at 2 kHz, SA and Gr. For constant hit rates of 80% and 90%, both DA and LR scores had lower false-alarm rates than tympanometric tests-LR achieved a false-alarm rate of 6% for a sensitivity of 90%. In general, LR outperformed DA as the multivariate technique of choice. In predicting an impairment at 0.5 kHz, the reflectance scores at 0.5 kHz were less accurate predictors than reflectance at 2 and 4 kHz. This supports the hypothesis that the 2-4-kHz range is a particularly sensitive indicator of middle-ear status, in agreement with the spectral composition of the output predictor from the multivariate analyses. When tympanometric and YR tests were combined, the resulting predictor performed slightly better or the same as the predictor calculated from the use of the YR test alone. The main conclusion is that these multivariate acoustic tests of the middle ear, which are analyzed using a clinical decision theory, are effective predictors of conductive hearing loss.

Hydrofluoroalkane-134a (HFA-134a) is a new chlorofluorocarbon (CFC)-free propellant for use in metered dose inhalers. It provides a more environmentally friendly alternative to CFC propellants because it does not contain chlorine which is responsible for ozone depletion by CFCs. Beclomethasone dipropionate (BDP) is widely used for inhalation asthma therapy and is most commonly delivered by a CFC propellant system. The present study evaluated the acute safety of BDP formulated with the new propellant (HFA-134a BDP) compared with BDP in a CFC-11/12 formulation by measuring the acute bronchial response in asthmatic patients. The study was conducted as a randomized, single-blind, placebo-controlled, four-period cross-over trial. Asthmatic patients received eight inhalations of four treatment regimens (HFA-134a BDP, 1600 mg total dose; CFC-11/12 BDP, 2000 mg total dose; HFA-134a placebo and CFC-11/12 placebo) in random order over four study days. Forced expired volume in 1 s (FEV1) was measured before and 2, 10, 20, 40 and 60 min after inhalation of the study treatments. The number of coughs was counted from the start of the first inhalation to 60 s after the last inhalation. There were no statistically significant differences between the treatment groups for changes in FEV1, for the number of coughs or for the occurrence or severity of bronchoconstriction. In asthmatic patients withholding bronchodilators, the new HFA-134a BDP propellant system proved as safe and was as well tolerated as the current CFC-11/12 BDP system. The two propellant systems without active drug were also equally well tolerated.

The utility of ultrastructural evaluation of eosinophilic renal cell neoplasms is illustrated by two case studies. The differential diagnosis between granular renal cell carcinoma and renal cell oncocytoma may be difficult. Ultrastructural demonstration of the presence of abundant mitochondria is useful in the definitive diagnosis of fine-needle aspiration specimens, those neoplasms with nuclear pleomorphism, or in patients requiring renal parenchymal sparing surgery.

A 28-day double-blind parallel group study has been conducted to compare the safety and tolerability of HFA-134a, a chlorofluorocarbon-free propellant in a pressurized metered-dose inhaler (MDI A), with a chlorofluorocarbon propellant (MDI C). Sixteen subjects were randomly assigned to receive one of the two MDIs, either four inhalations four times per day for 14 days or eight inhalations four times a day for 14 days, and were then crossed over to the alternative exposure regime with the same propellant for the next 14-day period. No clinically significant changes occurred in blood pressure, heart rate, electrocardiograms, pulmonary function (FEV1, FVC, FEF25-75%), haematology or serum chemistry. One subject in the MDI A group had elevated eosinophil counts throughout the study; there were no other remarkable clinical laboratory data. Fifty six adverse events were related to the study propellants; 34 of these occurred in the MDI C group and 22 in the MDI A group. For each adverse event no statistically significant differences were detected between propellant systems or between exposure levels. The most frequent adverse event was headache, which was reported by four subjects with each propellant system. Blood samples for HFA-134a in the MDI A group were collected on day 28 to measure systemic absorption. Blood levels of HFA-134a were detected in all subjects given this propellant within 1 min post-exposure, and these levels decreased to one-tenth of the original value by 18 min after the start of exposure. The safety and tolerability of an HFA-134a chlorofluorocarbon-free system was demonstrated over 28 days of exposure in healthy subjects. These negative results are clinically important because they indicate it will be safe to proceed with the study of this chlorofluorocarbon-free system in asthmatic patients.

The presence of widespread hemorrhage from the microvasculature of the lung into the alveolar spaces defines what is called the "alveolar hemorrhage syndrome", which can occur in association with a wide variety of clinical disorders. The cardinal manifestations of this syndrome include: hemoptysis, unexplained anemia and diffuse alveolar infiltrates on chest roentgenograms. Since the pulmonary features are similar, the diagnosis usually depends on the clinical, laboratory and pathologic evaluations. Early diagnosis and treatment is crucial since the occurrence of pulmonary hemorrhage in this syndrome may represent a catastrophic event with fatal consequences. Idiopathic pulmonary hemosiderosis (IPH) has been identified as a cause of alveolar hemorrhage in a small number of cases, mainly by exclusion criteria. We report a case of a 70-year old man who presented with a 40-year history of intermittent hemoptysis and bilateral upper lobes alveolar infiltrates proved to be secondary to idiopathic pulmonary hemosiderosis. Although the lung apices are frequently spared in IPH, they were the site of the infiltrates in our case. To our knowledge, our patient had the longest survival time ever reported in the literature in adult IPH. A brief review of some of the disorders commonly associated with alveolar hemorrhage is also presented.

The objective of this study was to determine the long-term effect of different dietary macronutrients on renal hemodynamics in obese Zucker rats. Female obese (fa/fa) Zucker rats were allowed to eat control chow (ObCL) or diets high in unsaturated fat (ObHF), protein (ObHP) or sucrose (ObHS) for a period of 24 weeks. Lean chow fed (LnCL) Zucker rats served as lean controls. After 24 weeks of dietary treatments, glomerular filtration rate (GFR, ml/mg/g, mean +/- SE) of ObHP and ObHS (0.38 +/- 0.06 and 0.27 +/- 0.05) rats were significantly (p < 0.005) lower than ObCL (0.74 +/- 0.05) and ObHF (0.88 +/- 0.1) rats. In a similar manner, the effective renal plasma flow (ERPF, ml/min/g) was significantly (p < 0.005) lower in ObHP and ObHS (1.28 +/- 0.16 and 1.04 +/- 0.2) than ObCL (2.46 +/- 0.31) or ObHF (2.85 +/- 0.25) rats. The ObHF rats appeared "protected" since they had similr GFR and ERPF but less proteinuria and glucosuria than ObCL rats. Histological examination of renal tissue from ObHP and ObHS fed rats revealed significant (p < 0.005) increase in sclerosis relative to ObCL rats. The sclerosis of renal tissue in ObHF was minimized and was found to be similar to ObCL rats. The mean arterial pressure and heart rates were similar in all dietary treated obese Zucker rats. When comparing obese and lean controls, ObCL rats had significantly (p < 0.03) lower GFR (0.74 +/- 0.05 vs 0.92 +/- 0.05) but similar ERPF (2.46 +/- 0.3 vs 2.82 +/- 0.12) than LnCL rats.(ABSTRACT TRUNCATED AT 250 WORDS)

This study documents the neurodevelopmental outcome at 3 years of 52 of 55 extremely low birthweight (ELBW) survivors (survival rate 49%) born in a tertiary maternity centre from July 1985 through December 1988, and examines more closely the developmental profile of the neurologically normal survivors. At 3 years, 6 (12%) children had severe neurodevelopmental impairment (severe cerebral palsy, blindness, deafness or a General Quotient (GQ) < 70 on the Griffiths Scales), 11 (21%) had mild to moderate impairment and 35 (67%) had no neurosensory impairment and normal development (GQ > or = 85). Significant risk factors for severe impairment were stage 3 or 4 retinopathy of prematurity (odds ratio [OR] 21.5), treatment with postnatal steroids (OR 21), grade III or IV intraventricular haemorrhage (OR 11) and supplemental oxygen at 'term' (OR 6.4). The developmental profile of the 35 neurologically normal children revealed a significant weakness in eye and hand coordination skills and a relative strength in hearing and speech skills. Early recognition of this developmental profile may allow implementation of more appropriate preschool programmes for ELBW children.

Twenty-five patients with reversible airways obstruction inhaled salbutamol (200 micrograms) from the standard press and breathe-metered dose inhaler or a new breath-actuated metered dose inhaler (Aerolin in the Autohaler inhalation device; 3M Health Care Ltd.) in a single dose, double-blind, double-dummy, 2-period, cross-over study. Forced expiratory volume in 1 s, forced vital capacity and peak expiratory flow rate were measured in the 4-hour period after inhalation. The equivalence of the two inhaler devices was determined by analysis of the peak change and time to peak, with reference to the initial recorded baselines of the measured parameters. The efficacy of the two devices was very similar. The breath-actuated device is likely to benefit inhaler users who suffer from poor co-ordination of actuation and inhalation with a standard inhaler.

Computed tomography and angiography were performed in two patients with ileal carcinoid tumor and in one with retractile mesenteritis. In each instance, a low density right lower quadrant mass with small bowel displacement and thickened mesenteric neurovascular bundles was identified at CT. Superior mesenteric artery (SMA) angiography revealed contraction, kinking and irregularity of mesenteric branches in all cases, but specific histologic diagnosis was not established by angiography alone. Our preliminary experience suggests that SMA angiography may not always be necessary in the diagnosis of either carcinoid tumor or retractile mesenteritis.

For ten years, a 25-year-old immune-competent man experienced a progressive disseminated infection with the saprophytic soil fungus, Curvularia lunata, following presumptive cutaneous inoculation while playing football. Deep, soft tissue abscesses, pulmonary suppuration, paravertebral abscess, and cerebral abscess all followed leg ulcers from neglected abrasions. The patient's delay in obtaining treatment was partially responsible for the paravertebral-mediastinal-pleural-cutaneous fistula that resulted. The importance of prompt and aggressive surgical drainage procedures is clear. Infection was arrested only by surgery. The fungus was inhibited by miconazole nitrate and amphotericin B but it developed resistance to flucytosine. Miconazole appeared to cause resolution of the cerebral abscess. Amphotericin B (1 mg/kg/day) clearly was beneficial but only after effective drainage procedures were done. The patient refused to continue amphotericin B after 5.4 g had been given in two treatments. He became bedridden one year later from back pain that was caused by recurrent disease.