Endogenous bone marrow derived cells express retinal pigment epithelium cell markers and migrate to focal areas of RPE damage

PURPOSE: The aim of the present study was to investigate whether bone marrow-derived cells (BMCs) can be induced to express retinal pigment epithelial (RPE) cell markers in vitro and can home to the site of RPE damage after mobilization and express markers of RPE lineage in vivo. METHODS: Adult RPE cells were cocultured with green fluorescence protein (GFP)-labeled stem cell antigen-1 positive (Sca-1(+)) BMCs for 1, 2, and 3 weeks. Cell morphology and expression of RPE-specific markers and markers for other retinal cell types were studied. Using an animal model of sodium iodate (NaIO(3))-induced RPE degeneration, BMCs were mobilized into the peripheral circulation by granulocyte-colony stimulating factor, flt3 ligand, or both. Immunocytochemistry was used to identify and characterize BMCs in the subretinal space in C57BL/6 wild-type (wt) mice and GFP chimeric mice. RESULTS: In vitro, BMCs changed from round to flattened, polygonal cells and expressed cytokeratin, RPE65, and microphthalmia transcription factor (MITF) when cocultured in direct cell-cell contact with RPE. In vivo, BMCs were identified in the subretinal space as Sca-1(+) or c-kit(+) cells. They were also double labeled for GFP and RPE65 or MITF. These cells formed a monolayer on the Bruch membrane in focal areas of RPE damage. CONCLUSIONS: Thus, it appears that BMCs, when mobilized into the peripheral circulation, can home to focal areas of RPE damage and express cell markers of RPE lineage. The use of endogenous BMCs to replace damaged retinal tissue opens new possibilities for cell replacement therapy in ophthalmology.

Intravascular US-guided direct intrahepatic portocaval shunt with an expanded polytetrafluoroethylene-covered stent-graft

PURPOSE: To retrospectively evaluate the midterm patency rate of the nitinol (Viatorr, W.L. Gore and Associates, Flagstaff, Ariz) stent-graft for direct intrahepatic portacaval shunt (DIPS) creation. MATERIALS AND METHODS: Institutional Review Board approval for this retrospective HIPAA-compliant study was obtained with waiver of informed consent. DIPS was created in 18 men and one woman (median age, 54 years; range, 45-65 years) by using nitinol polytetrafluoroethylene (PTFE)-covered stent-grafts. The primary indications were intractable ascites (n = 14), acute variceal bleeding (n = 3), and hydrothorax (n = 2). Follow-up included Doppler ultrasonography at 1, 6, and 12 months and venography with manometry at 6-month intervals after the procedure. Shunt patency and cumulative survival were evaluated by using the Kaplan-Meier method and survival curves were plotted. Differences in mean portosystemic gradients (PSGs) were evaluated by using the Student t test. Multiple regression analysis for survival and DIPS patency were performed for the following parameters: Child-Pugh class, model of end-stage liver disease score, pre- and post-DIPS PSGs, pre-DIPS liver function tests, and pre-DIPS creatinine levels. RESULTS: DIPS creation was successful in all patients. Effective portal decompression and free antegrade shunt flow was achieved in all patients. Intraperitoneal bleeding occurred in one patient during the procedure and was controlled during the same procedure by placing a second nitinol stent-graft. The primary patency rate was 100% at all times during the follow-up period (range, 2 days to 30 months; mean, 256 days; median, 160 days). Flow restrictors were deployed in two (11%) of 19 patients. The 1-year mortality rate was 37% (seven of 19). CONCLUSION: Patency after DIPS creation with the nitinol PTFE-covered stent-graft was superior to that after TIPS with the nitinol stent-graft.

Statins are associated with decreased mortality in abdominal, but not in thoracic aortic aneurysm patients undergoing endovascular repair: propensity score-adjusted analysis

BACKGROUND: Purpose of this study was to compare the correlation of statin use with long-term mortality in patients with abdominal (AAA) and thoracic aortic aneurysm (TAA). PATIENTS AND METHODS: We compared long-term survival of 731 AAA and 59 TAA patients undergoing elective endovascular repair (EVAR). Kaplan-Meier survival curves were compared by the log-rank method. Propensity score-adjusted multivariable logistic regression models were used to determine independent associations of statin use on vital status after EVAR. RESULTS: Statin use was associated with decreased long-term mortality in AAA patients in bivariate and multivariable regression analysis, in which the effect of propensity to receive a statin was considered (adjusted HR: .613, 95%-CI: .379- .993, p = .047) whereas mortality of TAA patients was not associated with use of statins (adjusted HR: 1.795, 95%-CI: .147 -21.942, p = .647). CONCLUSIONS: Use of statins is an independent predictor of decreased mortality after elective EVAR in AAA, but not in TAA patients. These findings indirectly support the concept of a distinct pathogenesis of AAA and TAA.

Good outcome for patients with few lymph node metastases after radical retropubic prostatectomy

BACKGROUND: Conflicting results exist regarding the value of an extended pelvic lymph node dissection (PLND) in node-positive patients undergoing radical retropubic prostatectomy (RRP) for clinically localized prostate cancer. OBJECTIVE: To assess the long-term outcome in node-positive patients who underwent extended PLND followed by RRP. DESIGN, SETTING, AND PARTICIPANTS: A consecutive series of 122 node positive patients with negative preoperative staging examinations, no neoadjuvant hormonal or radiotherapy, and who underwent extended PLND (>/=10 lymph nodes in the surgical specimen) followed by RRP were analyzed. None of the patients received immediate androgen deprivation therapy (ADT). INTERVENTION: All patients underwent extended PLND followed by RRP. MEASUREMENTS: Biochemical recurrence-free survival, cancer-specific, and overall survival were assessed using the Kaplan-Meier technique. RESULTS AND LIMITATIONS: Median prostate-specific antigen (PSA) was 16ng/ml. At pathological examination 76% of the 122 patients had pT3-pT4 tumours, 50% seminal vesicle infiltration. A median of 22 nodes were removed per patient. Median cancer-specific survival at 5 and 10 yr was 84.5% and 60.1%, respectively. In patients with /=3 positive nodes removed, median cancer-specific survival at 10 yr was 78.6% and 33.4%, respectively (p<0.001). After a median period of 33 mo, 61 of the 122 patients (50%) received ADT, particularly those (69%) with >/=3 positive nodes removed. This retrospective study includes a significant percentage of patients with high tumour burden, and therefore may not reflect current patient series. CONCLUSIONS: Patients with /=3 positive nodes, despite extended PLND and despite ADT in 69% of patients.

Motesanib diphosphate in progressive differentiated thyroid cancer

BACKGROUND: The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived growth-factor receptor, and KIT. METHODS: In an open-label, single-group, phase 2 study, we treated 93 patients who had progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end point was an objective response as assessed by an independent radiographic review. Additional end points included the duration of the response, progression-free survival, safety, and changes in serum thyroglobulin concentration. RESULTS: Of the 93 patients, 57 (61%) had papillary thyroid carcinoma. The objective response rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan-Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval [CI] was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%). CONCLUSIONS: Motesanib diphosphate can induce partial responses in patients with advanced or metastatic differentiated thyroid cancer that is progressive. (ClinicalTrials.gov number, NCT00121628.)

Stem cells as tools in regenerative therapy for retinal degeneration

OBJECTIVE: To describe the use of stem cells (SCs) for regeneration of retinal degenerations. Regenerative medicine intends to provide therapies for severe injuries or chronic diseases where endogenous repair does not sufficiently restore the tissue. Pluripotent SCs, with their capacity to give rise to specialized cells, are the most promising candidates for clinical application. Despite encouraging results, a combination with up-to-date tissue engineering might be critical for ultimate success. DESIGN: The focus is on the use of SCs for regeneration of retinal degenerations. Cell populations include embryonic, neural, and bone marrow-derived SCs, and engineered grafts will also be described. RESULTS: Experimental approaches have successfully replaced damaged photoreceptors and retinal pigment epithelium using endogenous and exogenous SCs. CONCLUSIONS: Stem cells have the potential to significantly impact retinal regeneration. A combination with bioengineering may bear even greater promise. However, ethical and scientific issues have yet to be solved.

Long-term cellular and regional specificity of the photoreceptor toxin, iodoacetic acid (IAA), in the rabbit retina

This study investigated the anatomical consequences of a photoreceptor toxin, iodoacetic acid (IAA), in the rabbit retina. Retinae were examined 2 weeks, 1, 3, and 6 months after systemic IAA injection. The retinae were processed using standard histological methods to assess the gross morphology and topographical distribution of damage, and by immunohistochemistry to examine specific cell populations in the retina. Degeneration was restricted to the photoreceptors and was most common in the ventral retina and visual streak. In damaged regions, the outer nuclear layer was reduced in thickness or eliminated entirely, with a concomitant loss of immunoreactivity for rhodopsin. However, the magnitude of the effect varied between animals with the same IAA dose and survival time, suggesting individual differences in the bioavailability of the toxin. In all eyes, the inner retina remained intact, as judged by the thickness of the inner nuclear layer, and by the pattern of immunoreactivity for protein kinase C-alpha (rod bipolar cells) and calbindin D-28 (horizontal cells). Müller cell stalks became immunoreactive for glial fibrillary acidic protein (GFAP) even in IAA-treated retinae that had no signs of cell loss, indicating a response of the retina to the toxin. However, no marked hypertrophy or proliferation of Müller cells was observed with either GFAP or vimentin immunohistochemistry. Thus the selective, long lasting damage to the photoreceptors produced by this toxin did not lead to a reorganization of the surviving cells, at least with survival as long as 6 months, in contrast to the remodeling of the inner retina that is observed in inherited retinal degenerations such as retinitis pigmentosa and retinal injuries such as retinal detachment.

Decreased visual function after patchy loss of retinal pigment epithelium induced by low-dose sodium iodate

PURPOSE: To correlate damage to the retinal pigment epithelium (RPE) with decreased visual function after the systemic administration of sodium iodate (NaIO(3)). METHODS: Damage was produced in mice by injection of 15, 25, or 35 mg/kg NaIO(3). Visual function was assessed with the cued water maze (WM) behavioral test and the optokinetic reflex (OKR) measurement at different times after injection. Autofluorescence in whole eye flatmounts was quantified, and hematoxylin and eosin staining of paraffin sections was performed to assess changes in the outer retina. RESULTS: After 15 mg/kg NaIO(3), cued WM test results were normal, whereas OKR measurements were significantly decreased at all times. Focal RPE loss began on day 21, but no significant damage to the outer nuclear layer was observed. After 25 mg/kg NaIO(3), the cued WM test was transitionally reduced and the OKR measurement again decreased at all times. Large areas of RPE loss occurred on day 14 with a reduced outer nuclear layer on the same day. With 35 mg/kg NaIO(3), the cued WM test was reduced beginning on day 14 with complete obliteration of the OKR beginning on day 3, large areas of RPE loss on the same day, and a reduced outer nuclear layer on day 7. CONCLUSIONS: Stable, patchy RPE loss was observed with a low concentration of NaIO(3). The OKR measurement showed changes in visual function earlier than the cued WM test and before histologic findings were observed.

Predicting the evolution of Kaposi sarcoma, in the highly active antiretroviral therapy era

BACKGROUND: The outcome of Kaposi sarcoma varies. While many patients do well on highly active antiretroviral therapy, others have progressive disease and need chemotherapy. In order to predict which patients are at risk of unfavorable evolution, we established a prognostic score. METHOD: The survival analysis (Kaplan-Meier method; Cox proportional hazards models) of 144 patients with Kaposi sarcoma prospectively included in the Swiss HIV Cohort Study, from January 1996 to December 2004, was conducted. OUTCOME ANALYZED: use of chemotherapy or death. VARIABLES ANALYZED: demographics, tumor staging [T0 or T1 (16)], CD4 cell counts and HIV-1 RNA concentration, human herpesvirus 8 (HHV8) DNA in plasma and serological titers to latent and lytic antigens. RESULTS: Of 144 patients, 54 needed chemotherapy or died. In the univariate analysis, tumor stage T1, CD4 cell count below 200 cells/microl, positive HHV8 DNA and absence of antibodies against the HHV8 lytic antigen at the time of diagnosis were significantly associated with a bad outcome.Using multivariate analysis, the following variables were associated with an increased risk of unfavorable outcome: T1 [hazard ratio (HR) 5.22; 95% confidence interval (CI) 2.97-9.18], CD4 cell count below 200 cells/microl (HR 2.33; 95% CI 1.22-4.45) and positive HHV8 DNA (HR 2.14; 95% CI 1.79-2.85).We created a score with these variables ranging from 0 to 4: T1 stage counted for two points, CD4 cell count below 200 cells/microl for one point, and positive HHV8 viral load for one point. Each point increase was associated with a HR of 2.26 (95% CI 1.79-2.85). CONCLUSION: In the multivariate analysis, staging (T1), CD4 cell count (<200 cells/microl), positive HHV8 DNA in plasma, at the time of diagnosis, predict evolution towards death or the need of chemotherapy.

Lipodystrophy and weight changes: data from the Swiss HIV Cohort Study, 2000-2006

BACKGROUND AND OBJECTIVES: Combination antiretroviral therapy (cART) is changing, and this may affect the type and occurrence of side effects. We examined the frequency of lipodystrophy (LD) and weight changes in relation to the use of specific drugs in the Swiss HIV Cohort Study (SHCS). METHODS: In the SHCS, patients are followed twice a year and scored by the treating physician as having 'fat accumulation', 'fat loss', or neither. Treatments, and reasons for change thereof, are recorded. Our study sample included all patients treated with cART between 2003 and 2006 and, in addition, all patients who started cART between 2000 and 2003. RESULTS: From 2003 to 2006, the percentage of patients taking stavudine, didanosine and nelfinavir decreased, the percentage taking lopinavir, nevirapine and efavirenz remained stable, and the percentage taking atazanavir and tenofovir increased by 18.7 and 22.2%, respectively. In life-table Kaplan-Meier analysis, patients starting cART in 2003-2006 were less likely to develop LD than those starting cART from 2000 to 2002 (P<0.02). LD was quoted as the reason for treatment change or discontinuation for 4% of patients on cART in 2003, and for 1% of patients treated in 2006 (P for trend <0.001). In univariate and multivariate regression analysis, patients with a weight gain of >or=5 kg were more likely to take lopinavir or atazanavir than patients without such a weight gain [odds ratio (OR) 2, 95% confidence interval (CI) 1.3-2.9, and OR 1.7, 95% CI 1.3-2.1, respectively]. CONCLUSIONS: LD has become less frequent in the SHCS from 2000 to 2006. A weight gain of more than 5 kg was associated with the use of atazanavir and lopinavir.

Outcomes of the South African National Antiretroviral Treatment Programme for children: the IeDEA Southern Africa collaboration

OBJECTIVES: To assess paediatric antiretroviral treatment (ART) outcomes and their associations from a collaborative cohort representing 20% of the South African national treatment programme. DESIGN AND SETTING: Multi-cohort study of 7 public sector paediatric ART programmes in Gauteng, Western Cape and KwaZulu-Natal provinces. SUBJECTS: ART-naive children (< or = 16 years) who commenced treatment with > or = 3 antiretroviral drugs before March 2008. OUTCOME MEASURES: Time to death or loss to follow-up were assessed using the Kaplan-Meier method. Associations between baseline characteristics and mortality were assessed with Cox proportional hazards models stratified by site. Immune status, virological suppression and growth were described in relation to duration of ART. RESULTS: The median (interquartile range) age of 6 078 children with 9 368 child-years of follow-up was 43 (15 - 83) months, with 29% being < 18 months. Most were severely ill at ART initiation. More than 75% of children were appropriately monitored at 6-monthly intervals with viral load suppression (< 400 copies/ml) being 80% or above throughout 36 months of treatment. Mortality and retention in care at 3 years were 7.7% (95% confidence interval 7.0 - 8.6%) and 81.4% (80.1 - 82.6%), respectively. Together with young age, all markers of disease severity (low weight-for-age z-score, high viral load, severe immune suppression, stage 3/4 disease and anaemia) were independently associated with mortality. CONCLUSIONS: Dramatic clinical benefit for children accessing the national ART programme is demonstrated. Higher mortality in infants and those with advanced disease highlights the need for early diagnosis of HIV infection and commencement of ART.

Vascular endothelial growth factors, angiogenesis, and survival in human ileal enterochromaffin cell carcinoids

BACKGROUND AND AIMS: Well-differentiated neuro-endocrine ileal carcinoids are composed of serotonin-producing enterochromaffin (EC) cells. Life expectancy is determined by metastatic spread to the liver because medical treatment options are still very limited. Selective inhibition of angiogenesis or lymphangiogenesis might prevent tumour growth and metastatic spread. We examined the role of the vascular endothelial growth factors (VEGFs) A, B, C, D, and their receptors (VEGFRs) 1, 2, 3 in angiogenesis and lymphangiogenesis of ileal EC cell carcinoids with and without liver metastases. METHODS: The expression of various VEGFs and VEGFRs was determined by quantitative real-time RT-PCR in healthy mucosa, primary tumour, lymph node metastases and liver metastases of 25 patients with ileal EC cell carcinoids. Microvessel density (MVD) was determined by CD-31 staining in primary tumours and lymphatic vessel density (LVD) by LYVE-1 staining. VEGF expression levels, MVD, LVD, and patients' survival time were correlated using logistic regression and Kaplan-Meier survival analysis. RESULTS: VEGF-A was highly expressed with no difference between normal mucosa and tumours. VEGF-B and -D as well as VEGFR-1 and -2 expression levels were significantly increased in the tumours when compared to normal mucosa. Patients with liver metastasis, however, had a significantly lower expression of the factors A, B, and C and the receptors 2 and 3. MVD in primary tumours positively correlated with the expression of VEGF ligands and their receptors, except for VEGF-D. LVD did not correlate with any VEGF ligand or receptor. Interestingly, low expression levels of VEGF-B were associated with poor survival. CONCLUSION: Patients with more aggressive metastatic spreading had relatively decreased expression levels of VEGF ligands and receptors. Thus, anti-angiogenic therapy may not be a suitable target in metastatic ileal EC cell carcinoids.

Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m

Bloch, Konrad E., Alexander J. Turk, Marco Maggiorini, Thomas Hess, Tobias Merz, Martina M. Bosch, Daniel Barthelmes, Urs Hefti, Jacqueline Pichler, Oliver Senn, and Otto D. Schoch. Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m. High Alt. Med. Biol. 10:25-32, 2009.-Data on acclimatization during expedition-style climbing to > 5000 m are scant. We evaluated the hypothesis that minor differences in ascent protocol influence acute mountain sickness (AMS) symptoms and mountaineering success in climbers to Muztagh Ata (7546 m), Western China. We performed a randomized, controlled trial during a high altitude medical research expedition to Muztagh Ata. Thirty-four healthy mountaineers (mean age 45 yr, 7 women) were randomized to follow one of two protocols, ascending within 15 or 19 days to the summit of Muztagh Ata at 7546 m, respectively. The main outcome measures, AMS symptom scores and the number of proceeding climbers, were assessed daily. Mean +/- SD AMS-C scores of 16 climbers randomized to slow ascent were 0.06 +/- 0.18, 0.26 +/- 0.08, 0.41 +/- 0.45, 0.53 +/- 0.77 at camps I (5533 m), II (6265 m), III (6865 m), and the summit (7546 m), respectively. Corresponding values in 18 climbers randomized to fast ascent were significantly higher: 0.17 +/- 0.23, 0.43 +/- 0.75, 0.49 +/- 0.36, and 0.69 +/- 0.54 (p < 0.008, vs. slow ascent in regression analysis accounting for weather-related protocol deviation). Climbers randomized to slow ascent were able to ascend according to the protocol without AMS for significantly more days than climbers randomized to fast ascent (p = 0.04, Kaplan-Meier analysis). More climbers randomized to slow ascent were successful in reaching the highest camp at 6865 m without AMS (odds ratio 9.5; 95% confidence interval 1.02 to 89). In climbers ascending to very high altitudes, differences of a few days in acclimatization have a significant impact on symptom severity, the prevalence of AMS, and mountaineering success. ClinicalTrials.gov Identifier NCT00603122.