Effect of cytokine interplay on macrophage polarization during chronic pulmonary infection with Cryptococcus neoformans

The immune response to Cryptococcus neoformans following pulmonary infection of C57BL/6 wild-type (WT) mice results in the development of persistent infection with characteristics of allergic bronchopulmonary mycosis (ABPM). To further clarify the role of Th1/Th2 polarizing cytokines in this model, we performed kinetic analysis of cytokine responses and compared cytokine profiles, pathologies, and macrophage (Mac) polarization status in C. neoformans-infected WT, interleukin-4-deficient (IL-4(-/-)), and gamma interferon-deficient (IFN-γ(-/-)) C57BL/6 mice. Results show that cytokine expression in the infected WT mice is not permanently Th2 biased but changes dynamically over time. Using multiple Mac activation markers, we further demonstrate that IL-4 and IFN-γ regulate the polarization state of Macs in this model. A higher IL-4/IFN-γ ratio leads to the development of alternatively activated Macs (aaMacs), whereas a higher IFN-γ/IL-4 ratio leads to the generation of classically activated Macs (caMacs). WT mice that coexpress IL-4 and IFN-γ during fungal infection concurrently display both types of Mac polarization markers. Concurrent stimulation of Macs with IFN-γ and IL-4 results in an upregulation of both sets of markers within the same cells, i.e., formation of an intermediate aaMac/caMac phenotype. These cells express both inducible nitric oxide synthase (important for clearance) and arginase (associated with chronic/progressive infection). Together, our data demonstrate that the interplay between Th1 and Th2 cytokines supports chronic infection, chronic inflammation, and the development of ABPM pathology in C. neoformans-infected lungs. This cytokine interplay modulates Mac differentiation, including generation of an intermediate caMac/aaMac phenotype, which in turn may support chronic "steady-state" fungal infection and the resultant ABPM pathology.     

Mosaic ACVRL1 and ENG mutations in hereditary haemorrhagic telangiectasia patients

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder caused by mutations in the ACVRL1, ENG, and SMAD4 genes. HHT is commonly characterised by small arteriovenous malformations (AVMs) known as telangiectasias of the skin, oral or gastrointestinal mucosa, as well as larger AVMs of solid organs (lungs, liver, brain). However, the manifestations of HHT are extremely variable. Two patients with no family history of HHT and strikingly different clinical presentations, who are mosaic for mutations in the ACVRL1 or ENG gene, are reported here. These cases represent the first report of mosaicism in patients clinically affected with classical HHT and pulmonary arterial hypertension, and suggest the need for awareness of mosaicism when performing clinical testing for this disorder.     

Tamoxifen enhances therapeutic effects of gemcitabine on cholangiocarcinoma tumorigenesis

Cholangiocarcinoma is a highly malignant tumor with limited therapeutic options. We have previously reported that tamoxifen (TMX) induces apoptosis of cholangiocarcinoma cells and reduces cholangiocarcinoma tumorigenesis in mice. In the present studies, we determined the effect of combination therapy of TMX and gemcitabine (GMT), another chemotherapeutical reagent for many cancers, on cholangiocarcinoma tumorigenesis and investigated the responsible mechanisms. GMT inhibited cell growth and induced apoptosis of cholangiocarcinoma cells in a concentration-dependent manner. TMX enhanced GMT-induced apoptosis of cholangiocarcinoma cells. Consistently, GMT (15?mg/kg) inhibited cholangiocarcinoma tumorigenesis in nude mice by 50%. TMX (15?mg/kg) enhanced the inhibitory effect of GMT on tumorigenesis by 33%. The inhibition of tumor growth correlated with enhanced apoptosis in tumor tissues. To elucidate the mechanisms underlying the additive effects of TMX on GMT-induced apoptosis, we determined the activation of caspases in cholangiocarcinoma cells exposed to GMT, TMX, or both. Activation of caspases 9 and 3, as well as cytochrome c release to the cytosol, was demonstrated in cells exposed to both reagents. In contrast, TMX activated caspase 2, whereas GMT had no effect. Inhibition of caspase 2 activation decreased TMX-, but not GMT-, induced activation of caspase 3 and apoptosis of cholangiocarcinoma cells. Similarly, activation of caspase 2 was found in tumors from TMX-treated mice, but not GMT-treated mice. Therefore, the enhanced effect of TMX on GMT-induced cholangiocarcinoma cell death is partially mediated by activation of caspase 2. TMX and GMT both induce apoptosis and inhibit cholangiocarcinoma tumorigenesis, which may be attributed to the activation of distinct apoptosis signals by TMX and GMT. Our studies provide in vivo evidence and molecular insight to support the use of TMX and GMT in combination as an effective therapy for cholangiocarcinoma.     

Positive traits versus previous trauma: racially different correlates with PTSD symptoms among hurricane katrina‐rita volunteers

This study compared risks and protective factors for acquiring symptoms of posttraumatic stress disorder (PTSD) between African‐American (n=299) and European‐American (n=206) student volunteers 3 months after Hurricanes Katrina and Rita (H‐KR). Respondents retrospectively provided information on peritraumatic emotional reactions and previous trauma that were recalled by H‐KR and H‐KR stressors. African‐American respondents reported higher levels of symptoms and higher rates of recollection of prior traumas during H‐KR than their European‐American counterparts. Hierarchical regression analyses found that previous trauma recollections predicted symptoms among European Americans but not among African Americans. Disaster‐related stressors, however, affected African Americans more than European Americans. Though negative emotions had negative outcomes for both groups, positive emotions and hope served as protective factors for African Americans. © 2011 Wiley Periodicals, Inc.     

Early fracture callus displays smooth muscle‐like viscoelastic properties ex vivo: Implications for fracture healing

Cells of early, fibrous callus in bone fractures possess much alpha smooth muscle actin. This callus contracts and relaxes; however, active and passive components of its force production have yet to be defined. We aimed to establish whether passive viscoelastic properties of early soft fracture callus are smooth muscle‐like in nature. Under anesthesia one rib was fractured in rats and calluses removed 7 days later for analysis. Urinary bladder detrusor muscle and Achilles tendon were also resected and analyzed. Force production in these tissues was measured using a force transducer when preparations were immersed in calcium‐free Krebs‐Henseleit solution (pH 7.4, 22°C). Viscoelastic responses were measured in each preparation in response to 50 µN increases and decreases in force after achieving basal tissue tension by preconditioning. Callus, bladder, and tendon all displayed varying, reproducible degrees of stress relaxation (SR) and reverse stress relaxation (RSR) (n = 7 for all groups). Hysteresis was observed in callus, with the first SR response significantly larger than that produced in subsequent stretches (p < 0.05). Callus SR responses were greater than tendon (p < 0.001) but less than bladder (p < 0.001). Callus RSR responses were greater than tendon (p < 0.001), but no significant difference was seen between RSR of callus and bladder. We concluded that early, soft callus displayed significant SR and RSR phenomena similar to smooth muscle tissue, and SR and RSR may be important in maintenance of static tension in early callus by promoting osteogenesis and fracture healing. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:1508–1513, 2009     

The validity and diagnostic efficiency of the Davidson Trauma Scale in military veterans who have served since September 11th, 2001

The present study examined the psychometric properties and diagnostic efficiency of the Davidson Trauma Scale (DTS), a self-report measure of posttraumatic stress disorder (PTSD) symptoms. Participants included 158 U.S. military veterans who have served since September 11, 2001 (post-9/11). Results support the DTS as a valid self-report measure of PTSD symptoms. The DTS demonstrated good internal consistency, concurrent validity, and convergent and divergent validity. Diagnostic efficiency was excellent when discriminating between veterans with PTSD and veterans with no Axis I diagnosis. However, although satisfactory by conventional standards, efficiency was substantially attenuated when discriminating between PTSD and other Axis I diagnoses. Thus, results illustrate that potency of the DTS as a diagnostic aid was highly dependent on the comparison group used for analyses. Results are discussed in terms of applications to clinical practice and research.     

Chemo-radiotherapy: an alternative to surgery for squamous cell carcinoma of the rectum – report of six patients and literature review

Purpose  Since 1943 [ 1 ], only 45 patients of squamous cancer of the rectum have been reported in the published reports and the largest series to date consists of 12 patients. Reports suggest that the primary treatment is surgical resection but, in the light of nonsurgical advances in the treatment of anal squamous cell carcinoma (SCC), we present a review of the literature and report six patients treated by chemoradiation therapy (CRT).
Method  A literature search was undertaken using the keywords squamous cell, epidermoid, basaloid and cloacagenic and cancer of rectum and colon to provide evidence for this discussion from studies of surgery, radiation therapy and CRT in rectal SCC. A prospective database of the Mount Vernon Cancer Centre, UK was searched from 1995 to 2005 for patients diagnosed with pure SCC of the rectum.
Results  Six patients with histologically confirmed primary SCC of the rectum were treated with primary combination chemo-radiotherapy according to protocols used for SCC of the anal canal over a 15-year period. Surgery was avoided in four, and they remain disease-free on follow-up.
Conclusions  Primary CRT, as currently utilized in anal cancer, can be extended to primary SCC of the rectum.     

Pregnancy and Maternal Outcomes Among Kidney Transplant Recipients

Fertility rates, pregnancy, and maternal outcomes are not well described among women with a functioning kidney transplant. Using data from the Australian and New Zealand Dialysis and Transplant Registry, we analyzed 40 yr of pregnancy-related outcomes for transplant recipients. This analysis included 444 live births reported from 577 pregnancies; the absolute but not relative fertility rate fell during these four decades. Of pregnancies achieved, 97% were beyond the first year after transplantation. The mean age at the time of pregnancy was 29 ± 5 yr. Compared with previous decades, the mean age during the last decade increased significantly to 32 yr (P < 0.001). The proportion of live births doubled during the last decade, whereas surgical terminations declined (P < 0.001). The fertility rate (or live-birth rate) for this cohort of women was 0.19 (95% confidence interval 0.17 to 0.21) relative to the Australian background population. We also matched 120 parous with 120 nulliparous women by year of transplantation, duration of transplant, age at transplantation ±5 yr, and predelivery creatinine for parous women or serum creatinine for nulliparous women; a first live birth was not associated with a poorer 20-yr graft or patient survival. Maternal complications included preeclampsia in 27% and gestational diabetes in 1%. Taken together, these data confirm that a live birth in women with a functioning graft does not have an adverse impact on graft and patient survival.One of the many perceived benefits of kidney transplantation has been restoration of pituitary-ovarian function and fertility in women of reproductive age. Prenatal advice for women with a functioning kidney transplant has been primarily based on data derived from observational research,^1–13 and the reported live-birth rates achieved in such women range from 43.2¹⁴ to 82%.¹⁵Although an increased pregnancy event number has been reported for women with a functioning kidney transplant,¹⁶ little is actually known about “pregnancy rate changes” during the past 40 yr. More importantly, long-term graft and maternal survival analyses, referred to when advising women who have undergone transplantation and are considering a pregnancy, have been mostly performed without adequate matching,¹² or, alternatively, matching has been used but outcomes followed up for only brief intervals^14,17,18 and in small cohorts.^19–22 Published graft matching studies to date suggest no adverse impact 10 yr after a live birth.¹⁴In most instances, pregnancies in women with a kidney graft have been encouraged. Historically, renal function,^8,15,17,18 baseline proteinuria,²³ intercurrent hypertension,^1,24 and time from transplantation^{1,3,5,8,14,15,18,24,25} have been used to predict adverse event risks to the mother, kidney, and offspring. To this are added the often unquantifiable inherent risks for genetically transmitted diseases or the problems associated with prematurity.^26,27 More recently, epidemiologic evidence suggests low birth weight may be associated with the development of hypertension,²⁸ cardiovascular disease,²⁹ insulin resistance,³⁰ and end-stage renal failure.³¹ Moreover, low birth weight is associated with an increased risk for hypertension, independent of genetic and shared environmental factors.³²Series published to date have not captured all pregnancy events or their outcomes. Limitations of some of the published studies include short duration of follow-up and studies with no adequate or long-term matching for decade and renal function.We examined fertility rates, pregnancy rates, and pregnancy outcomes over 40 yr in an at-risk population, defined as women who were aged between 15 and 49 and had a functioning kidney transplant, using ANZDATA registry data. In addition, maternal and graft outcomes were analyzed, and, uniquely, a matched cohort analysis of 120 nulliparous and 120 parous women who had undergone transplantation enabled analysis of outcomes at 20 yr.     

Relationship between Dialysis Modality and Mortality

Mortality differences between peritoneal dialysis (PD) and hemodialysis (HD) are widely debated. In this study, mortality was compared between patients treated with PD and HD (including home HD) using data from 27,015 patients in the Australia and New Zealand Dialysis and Transplant Registry, 25,287 of whom were still receiving PD or HD 90 d after entry into the registry. Overall mortality rates were significantly lower during the 90- to 365-d period among those being treated with PD at day 90 (adjusted hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.81 to 0.99]; P < 0.001). This effect, however, varied in direction and size with the presence of comorbidities: Younger patients without comorbidities had a mortality advantage with PD treatment, but other groups did not. After 12 mo, the use of PD at day 90 was associated with significantly increased mortality (adjusted HR 1.33; 95% CI 1.24 to 1.42; P < 0.001). In a supplementary as-treated analysis, PD treatment was associated with lower mortality during the first 90 d (adjusted HR 0.67; 95% CI 0.56 to 0.81; P < 0.001). These data suggest that the effect of dialysis modality on survival for an individual depends on time, age, and presence of comorbidities. Treatment with PD may be advantageous initially but may be associated with higher mortality after 12 mo.The merits of peritoneal dialysis (PD) compared with hemodialysis (HD) therapy have been extensively debated.¹ A key factor is the relative mortality between modalities. The ideal vehicle for comparison is a randomized, controlled trial. Previous attempts at such trials were complicated by lack of statistical power² and poor recruitment.³In the absence of trial evidence, large observational studies are of value, although they do not directly offer evidence of causality. Several registry-based or multicenter studies have been performed but with conflicting results^4–17; however, these studies were performed in the United States or Europe, where rates of PD are generally lower than those in Australia and New Zealand.¹⁸Across Australia and New Zealand, PD is used to treat between 20 and 40% of prevalent dialysis patients. Both modalities are available in all major treatment centers. Thus, selection bias toward PD either at a patient or a unit level is less likely than in countries with lower PD usage.