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Background: Ledipasvir and sofosbuvir is a well-tolerated regimen with high sustained virological response (SVR) rates in pre-liver transplant patients infected with chronic hepatitis C virus (HCV), but data in liver transplant recipients outside of clinical trials is limited., Aim: To address this knowledge gap and assess SVR rates without the use of ribavirin in liver transplant recipients METHODS: This is a retrospective study examining the treatment of 75 post-liver transplant recipients with ledipasvir and sofosbuvir without ribavirin. Differences between SVR cohorts and predictors of SVR were analysed in an intention-to-treat (ITT) fashion., Results: A total of 408 genotype 1, HCV patients were treated with ledipasvir/sofosbuvir from October 2014 to August 2015 at our centre. Seventy-three patients were post-liver transplant and were treated with a median of 2.9 years from transplant. Ledipasvir/sofosbuvir achieved an SVR12 of 95.9%. African Americans made up 28.8% of the cohort. Sixty-three per cent of patients were treated previously, including 13.7% of patients previously treated with direct-acting antivirals. Only 2.7% had recurrent allograft cirrhosis, and the majority (90.4%) was on calcineurin inhibitor based immunosuppressive therapy. Approximately 82% of patients had chronic kidney disease (CKD) stage 2 or 3. In univariate logistic regression, only detectable week 8 viral load was predictive of failure to achieve SVR., Conclusion: Our data confirm excellent SVR outcomes and favourable safety and tolerability profiles with ledipasvir/sofosbuvir without ribavirin in post-liver transplant recipients infected with HCV, despite treatment guidelines to use ribavirin., (© 2017 John Wiley & Sons Ltd.)

Objectives: Treatment of acute severe colitis (ASC) has been associated with high morbidity and high colectomy rate in children. In the prebiologics era, our centre used short-term high-dose intravenous corticosteroids (IVCS) at 2 to 30 mg · kg · day. We conducted a retrospective review to compare efficacy of different dosing regimes of IVCS., Methods: Thirty-four children treated with IVCS for ASC were included over 8 years. Patients were studied as 2 groups with similar pretreatment patient characteristics. Group 1 (standard dose) received IVCS at 2 mg · kg · day and group 2 (high dose) received IVCS at 10 to 30 mg · kg · day. Safety, efficacy, and follow-up of the entire cohort for >1 year were studied. The median IVCS dose in the standard- and high-dose cohort was 1.5 mg · kg · day (maximum 60 mg · kg · day) and 24.8 mg · kg · day (maximum 1000 mg · kg · day), respectively., Results: Pediatric Ulcerative Colitis Activity Index scores at day 5 were significantly lower in high-dose (15, interquartile range 8.5-20) than in standard-dose IVCS (30, interquartile range 20-30). IVCS side effects were minor and reversible. Overall, medical salvage therapy was required in 5.8% (2 children) before discharge, and in 17% (6 children) at follow-up after 1 year. The colectomy rate of the entire cohort was remarkably low with 0% during admission and 11% (4 children) after 1 year, with a trend of less colectomies in high-dose (4.8%-1 child) than in standard-dose (23%-3 children)., Conclusions: Our data show that in paediatric ASC, the short-term use of high-dose IVCS is safe and effective. Prospective studies are needed to define the role of IVCS within salvage therapy protocols.

Background: Dendritic cells (DC) determine initiation, type and location of immune responses and, in adults, show decreased Toll-like receptors and some increased cytokine levels on ageing. Few studies in children have characterised DC or explored DC-related mechanisms producing age-related immune changes., Results: The pDC marker BDCA2 (but not CD123) was absent in pre-pubertal children and numbers of pDC decreased with age. Blood and colonic DC were more mature and activated in adults. Decrease in pDC numbers correlated with reduced GM-CSF levels with aging, but increasing IL-4 and IL-8 levels correlated with a more activated DC profile in blood. CXCL16 levels decreased with age., Methods: Blood and colonic DC phenotypes were determined in healthy adults and children by flow cytometry and correlated with aging. Blood DC were divided into plasmacytoid (pDC) and myeloid (mDC) while only mDC were identified in colon. Serum cytokine levels were determined by multiplex cytokine assays and correlated with DC properties., Conclusions: In children, lack of BDCA2, a receptor mediating antigen capture and inhibiting interferon induction, may be immunologically beneficial during immune development. Conversely, reduced pDC numbers, probably secondary to decreasing GM-CSF and increasing cytokine-induced maturation of DC are likely to determine deteriorating immunity with ageing.

Background: Dry mouth is a common and troublesome symptom in palliative care. Pilocarpine is a cholinergic agent that promotes salivation., Aim: This study aimed to test the feasibility of using n-of-1 trials to test pilocarpine drops compared to placebo, for patients of palliative care units with advanced cancer, who experienced dry mouth., Design: This was an N-of-1 study, in which each participant was offered three cycles of pilocarpine drops 4% (6 mg tds) (3 days) and placebo drops (3 days) in random order., Setting/participants: Participants were patients of specialist palliative care services with advanced cancer assessed as having a dry mouth, defined as having a score of ⩾ 3 on an 11-point self-rated xerostomia numerical rating scale, from any cause. Patients self-completed a diary using validated symptom and quality-of-life scores. The randomisation order was unmasked at the end of each person's trial by a clinician independent of the trial to allow a treatment decisions for individual patients to be made., Results: Nine patients completed at least 1 cycle; 33 cycles of data were completed in total, comprising 438 doses of pilocarpine. Four patients completed the trial: two responded and two did not. Most withdrawals related to deteriorating condition, unacceptable toxicity, non-compliance with study procedures or withdrawal of consent. Many issues contributed to slow recruitment and high withdrawal rate., Conclusion: The formulation of pilocarpine drops proved unacceptable to most participants. More work is required to determine an appropriate formulation, dose and method of delivery and then a retest of pilocarpine drops for this symptom., (© The Author(s) 2015.)

Background & Aims: Most knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103 + DC specialize in generating immune tolerance with the functionality of CD11b +/- subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon., Methods: Paired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing., Results: Colonic DC identified were myeloid (mDC, CD11c + CD123 - ) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103 - SIRPα + DC were the major population and with CD103 + SIRPα + DC were CD1c + ILT3 + CCR2 + (although CCR2 was not expressed on all CD103 + SIRPα + DC). CD103 + SIRPα - DC constituted a minor subset that were CD141 + ILT3 - CCR2 - . Proximal colon samples had higher total DC counts and fewer CD103 + SIRPα + cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4 + CD45RA + T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (β7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c + , but not CD141 + mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments., Conclusions: Proximal colonic DC subsets differ from those in distal colon and are more mature. Targeted immunotherapy using DC in T-cell mediated GI tract inflammation may therefore need to reflect this immune compartmentalization.

Context: Exposure to ozone has acute respiratory effects, but few human clinical studies have evaluated cardiovascular effects., Objective: We hypothesized that ozone exposure alters pulmonary and systemic vascular function, and cardiac function, with more pronounced effects in subjects with impaired antioxidant defense from deletion of the glutathione-S-transferase M1 gene (GSTM1 null)., Methods: Twenty-four young, healthy never-smoker subjects (12 GSTM1 null) inhaled filtered air, 100 ppb ozone and 200 ppb ozone for 3 h, with intermittent exercise, in a double-blind, randomized, crossover fashion. Exposures were separated by at least 2 weeks. Vital signs, spirometry, arterial and venous blood nitrite levels, impedance cardiography, peripheral arterial tonometry, estimation of pulmonary capillary blood volume (Vc), and blood microparticles and platelet activation were measured at baseline and during 4 h after each exposure., Results: Ozone inhalation decreased lung function immediately after exposure (mean ± standard error change in FEV1, air: -0.03 ± 0.04 L; 200 ppb ozone: -0.30 ± 0.07 L; p < 0.001). The immediate post-exposure increase in blood pressure, caused by the final 15-min exercise period, was blunted by 200 ppb ozone exposure (mean ± standard error change for air: 16.7 ± 2.6 mmHg; 100 ppb ozone: 14.5 ± 2.4 mmHg; 200 ppb ozone: 8.5 ± 2.5 mmHg; p = 0.02). We found no consistent effects of ozone on any other measure of cardiac or vascular function. All results were independent of the GSTM1 genotype., Conclusions: We did not find convincing evidence for early acute adverse cardiovascular consequences of ozone exposure in young healthy adults. The ozone-associated blunting of the blood pressure response to exercise is of unclear clinical significance.

Introduction: Aging population is susceptible to many cutaneous and systemic diseases, simultaneously leading to impairment of quality of life in them., Aim: To know the association of dermatosis and systemic diseases in geriatric age group., Materials and Methods: A retrospective study was carried on patients above 60 years of age who visited the Dermatology OPD at rural tertiary care centre from June 2009 to May 2010. Patients were assessed on a prescribed 30 point proforma., Results: Total 457 geriatric patients with dermatosis were registered under the study, of these 203 patients had one or more systemic diseases. Hypertension (70.9%) was the commonest disease, followed by diabetes (32.5%). Eczema was commonest dermatosis in patients with hypertension and generalized pruritus in diabetes., Conclusion: Skin diseases cause considerable morbidity in elderly, particularly if associated with other comorbid conditions, so health promotion and education can do much to reduce the risk.

Cutaneous angiosarcoma is a rare aggressive tumor of capillary and lymphatic endothelial cell origin. Cutaneous angiosarcoma of the head and neck regions seems to be a distinctive neoplasm with characteristic clinicopathologic features that differ from angiosarcoma in other anatomic locations. Angiosarcoma, regardless of their setting, has a bad prognosis. We presented here a case of 80 years old male, with multiple nontender grouped purple to red hemorrhagic vesicular and bullous lesions over left lower cheek and upper neck area, with bilateral cervical lymph nodes since 1 month. Computed tomography thorax showed nodular opacities in the right upper and midzones. Excisional biopsy showed characterstic "dissection of collagen" with mild nuclear atypia. Immunohistochemistry showed tumor cell positive for CD-31 and Fli-1. Patient died within 1 month of presentation.

Background: Diabetes may confer an increased risk for the cardiovascular health effects of particulate air pollution, but few human clinical studies of air pollution have included people with diabetes. Ultrafine particles (UFP, ≤100 nm in diameter) have been hypothesized to be an important component of particulate air pollution with regard to cardiovascular health effects., Methods: 17 never-smoker subjects 30-60 years of age, with stable type 2 diabetes but otherwise healthy, inhaled either filtered air (0-10 particles/cm3) or elemental carbon UFP (~107 particles/cm3, ~50 ug/m3, count median diameter 32 nm) by mouthpiece, for 2 hours at rest, in a double-blind, randomized, crossover study design. A digital 12-lead electrocardiogram (ECG) was recorded continuously for 48 hours, beginning 1 hour prior to exposure., Results: Analysis of 5-minute segments of the ECG during quiet rest showed reduced high-frequency heart rate variability with UFP relative to air exposure (p = 0.014), paralleled by non-significant reductions in time-domain heart rate variability parameters. In the analysis of longer durations of the ECG, we found that UFP exposure increased the heart rate relative to air exposure. During the 21- to 45-hour interval after exposure, the average heart rate increased approximately 8 beats per minute with UFP, compared to 5 beats per minute with air (p = 0.045). There were no UFP effects on cardiac rhythm or repolarization., Conclusions: Inhalation of elemental carbon ultrafine particles alters heart rate and heart rate variability in people with type 2 diabetes. Our findings suggest that effects may occur and persist hours after a single 2-hour exposure.

Lupus vulgaris is a variant of cutaneous tuberculosis. As the disease has potential to mutilate when left untreated, leaving deforming scars and disfigurement, an early diagnosis is of paramount importance. Though the common type is plaque type, rarely mutilating and vegetative forms also are found. A 28 year old female, labourer presented with progressive annular plaque over right side of cheek extending upto right lower lid and ala of nose. There were two satellite plaques near the right side of giant lesion. On diascopy apple jelly nodule was seen. There was no regional lymhadenopathy. Histopathological examination showed many granulomas in upper dermis extending to deep dermis comprising of epitheloid cells with langhans' type of giant cells, lymphocytic infiltration & focal necrosis suggestive of lupus vulgaris. The consequences of failing to make an early diagnosis can be disastrous for the patients, as the progression of the disease can lead to necrosis, destruction of bones and cartilage leading to permanent deformity. Thus it is vital for clinicians to have a high index of suspicion of such atypical forms and take biopsy samples for histological and bacteriological studies.

Granuloma inguinale (GI) is an acquired chronic, slowly progressive, mildly contagious disease of venereal origin, characterized by granulomatous ulceration of the genitalia and neighboring sites, with little or no tendency to spontaneous healing caused by Klebsiella (Calymmatobacterium) granulomatis. A 55-year-old male presented with fissured, foul smelling, fungating growth over prepuce with phimosis mimicking squamous cell carcinoma (SCC) without lymphadenopathy. It started with painless papulonodular showed pseudoepitheliomatous hyperplasia, infiltration in dermis, acanthosis and vacuolated macrophages suggestive of GI and not showing any histopathological features of SCC. Patient was successfully treated by giving cotrimoxazole twice a day for 21 days. Here, we presented a case of GI mimicking SCC of penis, which was diagnosed on basis of histopathology and treated with excision followed by medical therapy with cotrimoxazole.

Garcia-Hafner-Happle syndrome, also known as Fibroblast growth factor receptor 3 epidermal nevus syndrome, is a new neurocutaneous phenotype, which has been identified in 2008 by Garcı'a-Vargas et al. The disorder is caused by a mosaic R248C mutation of the FGFR3 gene, which is characterized by a keratinocytic epidermal nevus, acanthosis nigricans, and neurological abnormalities like seizures, intellectual impairment, cortical atrophy, and underdevelopment of corpus callosum. The epidermal nevus syndromes represent a group of distinct disorders in which an epidermal nevus is associated with abnormalities in other organ systems like central nervous system, cardiovascular system, genitourinary system, eyes, and bone. Recently, nine well-defined different epidermal nevus syndromes (ENSs) have been identified on clinical, histopathologic, and molecular basis. We present here the details of a patient with the clinical features and skin biopsy findings suggestive of Garcia-Hafner-Happle syndrome.

There is no available targeted therapy for triple-negative or its more aggressive subtype, basal-like breast cancer. Multiple therapeutic strategies based on translational knowledge have not improved the treatment options for triple negative patients. As understanding of molecular pathways that drive tumor development is rapidly increasing, it is imperative to adapt our treatment strategies to perturbations in molecular pathways driving the malignant process. Basal-like breast cancers over-express EGFR (without mutations or EGFR gene amplifications) and have p53 mutations. While EGFR drives the malignant behavior in triple negative breast cancer (TNBC), anti-EGFR therapies have fallen short of the expected results in clinical trials. Here we bring evidence that the less than optimal results of the anti-EGFR therapies may be explained in part by the increased potency of the EGFR signaling due to increased endosomal recycling. The functional connection between EGFR and endosomal trafficking in TNBC is mutant p53 found in the most aggressive forms of TNBC. Mutant p53 acquires oncogenic functions and binds p63 protein, a member of p53 family with tumor suppressor activities. In the absence of functional p63 there is an upregulation of endosomal recycling EGFR and integrin to the membrane with increased proinvasive abilities of cancer cells. Blocking endosomal trafficking combined with anti-EGFR treatments may result in better clinical outcomes in TNBC., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: It is estimated that 39,000 Australians die from malignant disease yearly. Of these, 60% to 88% of advanced cancer patients suffer xerostomia, the subjective feeling of mouth dryness. Xerostomia has significant physical, social and psychological consequences which compromise function and quality of life. Pilocarpine is one treatment for xerostomia. Most studies have shown some variation in individual response to pilocarpine, in terms of dose used, and timing and extent of response.We will determine a population estimate of the efficacy of pilocarpine drops (6 mg) three times daily compared to placebo in relieving dry mouth in palliative care (PC) patients. A secondary aim is to assess individual patients' response to pilocarpine and provide reports detailing individual response to patients and their treating clinician., Methods/design: Aggregated n-of-1 trials (3 cycle, double blind, placebo-controlled crossover trials using standardized measures of effect). Individual trials will identify which patients respond to the medication. To produce a population estimate of a treatment effect, the results of all cycles will be aggregated., Discussion: Managing dry mouth with treatment supported by the best possible evidence will improve functional status of patients, and improve quality of life for patients and carers. Using n-of-1 trials will accelerate the rate of accumulation of high-grade evidence to support clinical therapies used in PC., Trial Registration: Australia and New Zealand Clinical Trial Registry Number: 12610000840088.

Sarcoidosis is a multisystem, granulomatous disease of unknown etiology that can affect the pulmonary, reticulo-endothelial, skin, gastrointestinal, cardiac, musculo - skeletal, endocrine or central nervous system. Exclusive cutaneous involvement is very rare in sarcoidosis. Lupus pernio is a variant of cutaneous sarcoidosis presenting with erythematous to violaceous nodules and plaques located symmetrically over the nose, cheeks, ears and digits. We present a case of lupus pernio which showed rapid improvement with topical steroids and has yet not developed any systemic involvement even after 6 years of regular follow up.

Background: It is estimated that 29% of deaths in Australia are caused by malignant disease each year and can be expected to increase with population ageing. In advanced cancer, the prevalence of fatigue is high at 70-90%, and can be related to the disease and/or the treatment. The negative impact of fatigue on function (physical, mental, social and spiritual) and quality of life is substantial for many palliative patients as well as their families/carers., Method/design: This paper describes the design of single patient trials (n-of-1 s or SPTs) of a psychostimulant, methylphenidate hydrochloride (MPH) (5 mg bd), compared to placebo as a treatment for fatigue, with a population estimate of the benefit by the aggregation of multiple SPTs. Forty patients who have advanced cancer will be enrolled through specialist palliative care services in Australia. Patients will complete up to 3 cycles of treatment. Each cycle is 6 days long and has 3 days treatment and 3 days placebo. The order of treatment and placebo is randomly allocated for each cycle. The primary outcome is a reduction in fatigue severity as measured by the Functional Assessment of Cancer Therapy-fatigue subscale (FACIT-F). Secondary outcomes include adverse events, quality of life, additional fatigue assessments, depression and Australian Karnovsky Performance Scale., Discussion: This study will provide high-level evidence using a novel methodological approach about the effectiveness of psychostimulants for cancer-related fatigue. If effective, the findings will guide clinical practice in reducing this prevalent condition to improve function and quality of life., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12609000794202.

Aim: To study the effect of nonclosure of rectourethral (RU) fistula and to do a comparative analysis of the complications with and without nonclosure of RU fistula during posterior sagittal anorectoplasty (PSARP) in anorectal malformation cases (ARM)., Materials and Methods: A total of 68 cases of ARM were included in the study group, of which 34 cases were those in whom RU fistula was not closed (group A) during PSARP. Another 34 successive cases were included in study group B in whom the RU fistula was closed as is conventionally done by using interrupted sutures., Results: Comparatively, group A had none or minimum urological complications as compared to Group B., Conclusion: RU fistula closure is not mandatory during PSARP and nonclosure avoids urological complications. It especially avoids urethral complications, which are 100% preventable.

β1 integrin has been shown to contribute to vascular smooth muscle cell differentiation, adhesion and mechanosensation in vitro. Here we showed that deletion of β1 integrin at the onset of smooth muscle differentiation resulted in interrupted aortic arch, aneurysms and failure to assemble extracellular matrix proteins. These defects result in lethality prior to birth. Our data indicates that β1 integrin is not required for the acquisition, but it is essential for the maintenance of the smooth muscle cell phenotype, as levels of critical smooth muscle proteins are gradually reduced in mutant mice. Furthermore, while deposition of extracellular matrix was not affected, its structure was disrupted. Interestingly, defects in extracellular matrix and vascular wall assembly, were restricted to the aortic arch and its branches, compromising the brachiocephalic and carotid arteries and to the exclusion of the descending aorta. Additional analysis of β1 integrin in the pharyngeal arch smooth muscle progenitors was performed using wnt1Cre. Neural crest cells deleted for β1 integrin were able to migrate to the pharyngeal arches and associate with endothelial lined arteries; but exhibited vascular remodeling defects and early lethality. This work demonstrates that β1 integrin is dispensable for migration and initiation of the smooth muscle differentiation program, however, it is essential for remodeling of the pharyngeal arch arteries and for the assembly of the vessel wall of their derivatives. It further establishes a critical role of β1 integrin in the protection against aneurysms that is particularly confined to the ascending aorta and its branches., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Mycosis Fungoides is a Cutaneous T-cell lymphoma characterized by infiltration of skin with patches, plaques, and nodules composed of T-lymphocytes. It is the most common type of Cutaneous T-Cell Lymphoma and accounts for almost 50% of all primary cutaneous lymphoma. Tumour d' emblee is the term used for the patient presenting with skin tumors not preceded by patches or plaques. We report a rare case of mycosis fungoides d' emblee variant with tumors of only 3 months duration without any preceding skin lesions.

Background: Sexually transmitted infections (STIs) promote Human immunodeficiency virus (HIV) transmission by augmenting HIV infectiousness and susceptibility. In our society, especially in rural areas, males are common visitors to STI clinic than females who are generally traced as a contact. This difference may be due to the asymptomatic nature of infections in females, lower awareness among women of need for availing medical facilities, or their frequent consultation in gynecological clinics instead of STI clinics., Aim: To determine the prevalence, clinical profile, and the pattern of STIs in males and the prevalence of HIV infection in them at a rural-based tertiary care center., Materials and Methods: A retrospective study of male cases attending STI clinic between January 2008 and December 2009 was carried out. Diseases were diagnosed on the basis of clinical morphology of the lesion, and HIV and Venereal disease research laboratory (VDRL) testing was done in all cases., Results: Of 23 433 male patients presenting at the Skin/VD department, 201 were diagnosed to have STI. Most common age group affected was 25 to 44 years (59.7%). Incidence of STI was high among married individuals (77.2%). Herpes genitalis was most common STI in 49 (24.37%) cases. Viral infections (herpes genitalis, genital warts, and molluscum contagiosum) accounted for 62.2% of cases. Prevalence of HIV in STI was 2.48%., Conclusions: The persistent and recurrent nature of viral infections is responsible for their increasing trend in the current STI scenario. HIV and STIs are perfect examples of epidemiologic synergy as they are core transmitters of each other. STI being higher in married individuals further underlines the importance of contact tracing, counseling, and prompt management of the partners.

Background: This systematic review examines whether radioguided localization surgery (RGL) (radioguided occult lesion localization - ROLL and radioguided seed localization - RSL) for non-palpable breast cancer lesions produces lower positive margin rates than standard wire-guided localization surgery., Methods: We performed a comprehensive literature review to identify clinical studies using either ROLL or RSL. Included studies examined invasive or in situ BC and reported pathologically assessed margin status or specimen volume/weight. Two reviewers independently assessed study eligibility and quality and abstracted relevant data on patient and surgical outcomes. Quantitative data analyses were performed., Results: Fifty-two clinical studies on ROLL (n = 46) and RSL (n = 6) were identified. Twenty-seven met our inclusion criteria: 12 studies compared RGL to WGL and 15 studies were single cohorts using RGL. Ten studies were included in the quantitative analyses. Data for margin status and re-operation rates from 4 randomized controlled trials (RCT; n = 238) and 6 cohort studies were combined giving a combined odds ratio (OR) of 0.367 and 95% confidence interval (CI): 0.277 to 0.487 (p < 0.001) for margins status and OR 0.347, 95% CI: 0.250 to 0.481 (p < 0.001) for re-operation rates., Conclusions: The results of this systematic review of RGL versus WGL demonstrate that RGL technique produces lower positive margins rates and fewer re-operations. While this review is limited by the small size and quality of RCTs, the odds ratios suggest that RGL may be a superior technique to guide surgical resection of non-palpable breast cancers. These results should be confirmed by larger, multi-centered RCTs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cre/loxP recombination enables cellular specificity and, in the case of inducible systems, temporal control of genomic deletions. Here we used a SM22α tamoxifen-inducible Cre line to inactivate β1 integrin in adult smooth muscle. Interestingly, analysis of two distinct β1 loxP transgenic mice revealed vastly different outcomes after β1 integrin deletion. Lethality occurred 4 weeks postinduction in one Cre/loxP line, while no apparent phenotype was seen in the other line. Genetic analysis revealed appropriate DNA excision in both cases; however, differences were found in the degree of protein loss with absolutely no change in protein levels in the model that lacked a phenotype. Seeking to understand protein persistence despite appropriate recombination, we first validated the flox allele using a constitutive Cre line and demonstrated its ability to mediate effective protein inactivation. We then examined the possibility of heterozygous cell selection, protein turnover, and deletion efficiency with no success for explaining the phenotype. Finally, we documented the presence of the Cre-recombination episomal product, which persisted in tissue samples with no protein loss. The product was only noted in cells with low proliferative capacity. These findings highlight the potential for protein expression from the products of Cre-recombinase excised genes, particularly when deletion occurs in low turnover populations.

Purpose: In advanced cancer, the prevalence of fatigue is high and can be related to treatment or disease. Methylphenidate hydrochloride (MPH) is a central nervous system stimulant that has been used to palliate fatigue. There is no standard dose for MPH when used for this indication; recommended doses range from 5–20 + mg/d., Method: To identify a dose to test formally in a subsequent n-of-1 trial of fatigue, we recruited patients with advanced cancer and a fatigue score of 4 or more on a 10-point scale. Following a 3-day baseline assessment, each patient titrated MPH at doses ranging from 5 mg/d to 15 mg twice daily at 3-day intervals. In a daily diary, patients recorded measures of fatigue, depression, toxicity, and symptom control., Results: Ten patients provided consent, 9 completed 8 days and 5 received maximum dose at day 15. Three patients were unwilling to increase the dose to maximum levels as they were satisfied with the response at a lower dose. Across all patients, there was a pattern of rapidly improving fatigue and depression scores to day 9 (5 mg twice daily), with minimal improvement thereafter., Conclusion: The results indicate a dose of 5 mg twice daily for the definitive study. There was little correlation between performance status and maximum tolerated dose. No patient withdrew because of toxicity.

We describe a neonate in whom a right congenital diaphragmatic hernia and an anorectal malformation coexisted. Their coexistence in the same patient is rare., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective., Patients and Methods: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP)., Results: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient., Conclusions: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.

The aim of this project was to develop clinical practice guidelines for the use and administration of pharmacological agents for symptom control via syringe drivers within Australia. By developing evidence-based clinical practice guidelines for the use of this common device, this project aimed to improve patient outcomes, reduce practice variation, minimize errors and encourage more efficient use of resources. A literature review identified current literature regarding syringe driver management and an expert panel was assembled to assist in the development of the guidelines. The development of these practice guidelines provides an example of how palliative care practitioners can use a framework of contemporary evidence to enhance clinical practice.

A yolk sac tumor, also known as an endodermal sinus tumor, was diagnosed in a 15-month-old infant who presented with rapidly progressive right eye proptosis. Imaging of the orbits and brain revealed a mass in the right orbit, middle cranial fossa, and pterygopalatine fossa. A lateral orbitotomy was performed to take a biopsy specimen and to partially debulk the tumor secondary to signs of optic nerve compromise. The biopsy specimen revealed a yolk sac tumor, and the patient underwent systemic chemotherapeutic treatment. Because orbital endodermal sinus tumors have been infrequently reported, there are no firm prognostic or treatment guidelines. Our case demonstrates that early recognition, limited orbital debulking, and chemotherapy can have an excellent short-term outcome.

Newly arrived refugees and asylum seekers are faced with many difficulties in accessing effective health care when settling in Australia. Cultural, language and financial constraints, lack of awareness of available services, and lack of health provider understanding of the complex health concerns of refugees can all contribute to limiting access to health care. Understanding the complexities of a new health care system under these circumstances and finding a regular health provider may be difficult. In some cases there may be a fundamental distrust of government services. The different levels of health entitlements by visa category and (for some) detention on arrival in Australia may further complicate the provision and use of health services for providers and patients. Children are particularly at risk of suboptimal health care due to the impact of these factors combined with the effect of resettlement stresses on parents' ability to care for their children. Unaccompanied and separated children, and those in detention experience additional challenges in accessing care. This article aims to increase awareness among health professionals caring for refugee children of the challenges faced by this group in accessing and receiving effective health care in Australia. Particular consideration is given to the issues of equity, rights of asylum seekers, communication and cultural sensitivities in health care provision, and addressing barriers to health care. The aim of the paper is to alert practitioners to the complex issues surrounding the delivery of health care to refugee children and provide realistic recommendations to guide practice.

Infantile tremor syndrome is characterized by coarse tremors, mental and physical retardation, light colored brown hair, skin pigmentation and anemia. Amongst the theories proposed for the etilogy of the disorder, the nutritional theory is most accepted. In this case report, we have presented a fourteen-month-old male child with ITS and documented zinc deficiency. Though most of the previous workers have proposed vitamin-B12 deficiency as the etimology for ITS, our report suggests that zinc deficiency could also have a causative role.

Human methyltransferase (hAT) catalyzes the transfer of an alkyl group from the 6-position of guanine to an active site Cys residue. The physiological role of hAT is the repair of alkylated guanine residues in DNA. However, the repair of methylated or chloroethylated guanine bases negates the effects of certain chemotherapeutic agents. A model of how hAT binds DNA might be useful in the design of compounds that could inactivate hAT. We have used computer modeling studies to generate such a model. The model utilizes a helix-loop-wing DNA binding motif found in Mu transposase. The model incorporates a flipped out guanine base in order to bring the methylated oxygen atom close to the active site Cys residue. The model is consistent with a variety of chemical and biochemical data.

Apoptosis, or programmed cell death, is a process where developmental or environmental stimuli activate a genetic program to implement a series of events that culminate in cell death. To study the nature of genes that are induced during the apoptotic death of myeloid precursor cells, we utilized the 32Dcl3 cell line, which is derived from normal mouse bone marrow, is non-tumorigenic and diploid. These cells are strictly dependent on IL-3 for growth and apoptose when deprived of IL-3. However, when these cells are transferred to medium containing G-CSF, the cell number increases 4-5-fold and after 12 days the entire population is differentiated into granulocytes followed by apoptotic death. In our search for genes that are induced during apoptosis and/or terminal differentiation of 32Dcl3 cells, we identified a novel gene termed AATYK (Apoptosis Associated Tyrosine Kinase), whose expression is dramatically upregulated during IL-3 deprivation as well as G-CSF-induced terminal differentiation. In this report, we describe the sequence of the cDNA clone, derived from the mRNA transcript of this gene. These studies show that this gene encodes a protein with a tyrosine kinase domain at the N-terminal end and a proline-rich domain at the C-terminal end. We also report that the expression of this gene is blocked in v-abl or bcr-abl transformed myeloid cells which are unable to apoptose when grown in the absence of IL-3. However, AATYK expression is induced in 32D cells transformed by the v-abl gene when these cells are incubated in the presence of DMSO, which induces growth arrest and apoptotic death of the cells. On the other hand, DMSO fails to induce apoptosis or AATYK expression in 32D cells transformed by the bcr-abl oncogene, suggesting that AATYK expression may be a necessary pre-requisite for the induction of growth arrest and/or apoptosis of myeloid precursor cells.

Bovine vWF cDNA has been cloned from a bovine endothelial cell library. A fragment of this cDNA, corresponding to amino acid sequence Leu 469-Ser 723, called primary adhesion domain (PAD-1), and containing the binding sites for platelet glycoprotein Ib (GPIb), heparin and collagen, has been expressed in E. coli. The reduced and alkylated form of fragment PAD-1 inhibited native vWF binding to GPIb. Fragment PAD-1 bound to heparin and botrocetin in a specific and dose dependent manner as did the native vWF. In a solid-phase assay, fragment PAD-1 bound to calf skin collagen in contrast to a human vWF recombinant fragment (Ser 445-Val 733) which was inactive in the same assay. The studies presented in this paper demonstrated that the A1 domain of bovine vWF contained the GPIb, heparin, botrocetin as well as collagen binding sites and that integrity of the disulfide bond (Cys 509-Cys 695), did not seem to be essential for binding of bovine vWF fragment to GPIb.

This paper describes a procedure for performing ligand binding assays with recombinant proteins or protein fragments that can bind to an affinity matrix in the presence or absence of a denaturing agent but which require the presence of the denaturing agent to remain in solution. The method involves coupling of a known amount of the protein in a denaturing medium to a known amount of the affinity matrix, replacing the denaturing agent with a physiological buffer, and finally using the suspension of this protein-coupled matrix as the source of the recombinant protein to be studied for its functional properties. A constant volume of this suspension is incubated with different concentrations of a radiolabeled ligand. Radioactivity bound to the protein-coupled affinity matrix is determined after centrifugation and washing of the pellet. Nonspecific binding is determined either by using the uncoupled affinity matrix or by the standard technique of measuring the binding in the presence of excess unlabeled ligand.