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Purpose: To evaluate the outcomes of a second course of proton beam radiation therapy (PBRT) in patients with recurrent uveal melanoma. Methods and Materials: Thirty-one patients received a second course of PBRT. The mean interval between the first and the second PBRT course was 50.2 months (range, 8–165 months). Most patients (87%) received 70 cobalt Gray equivalent (CGE) for both courses. Visual acuity was 20/200 or better in 30 patients initially and in 22 patients at the second treatment. The mean follow-up time after the second treatment was 50 months (range, 6–164 months). Results: At the time of the last follow-up, 20 patients were classified as having no evidence of disease, defined as tumor regression or an absence of tumor progression. Nine eyes (29%) were enucleated because of local recurrence (n = 5) or intractable pain (n = 4). The 5-year eye retention rate was 55% (95% confidence interval: 25.2–77.4). Six of the 22 patients who retained the eye (27%) had useful vision (20/200 or better). Conclusions A second course of PBRT for recurrent uveal melanoma to total doses between 118 and 140 CGE was associated with a relatively good probability of local control and a low enucleation rate. Although most patients lost vision, the majority were able to retain the reirradiated eye. Further evaluation is needed to assess metastasis-free survival of additional proton irradiation vs. enucleation after local recurrence.

Fragile X syndrome is caused by loss-of-function mutations in the fragile X mental retardation 1 gene. How these mutations affect neuronal development and function remains largely elusive. We generated specific point mutations or small deletions in the Drosophila fragile X-related (Fmr1) gene and examined the roles of Fmr1 in dendritic development of dendritic arborization (DA) neurons in Drosophila larvae. We found that Fmr1 could be detected in the cell bodies and proximal dendrites of DA neurons and that Fmr1loss-of-function mutations increased the number of higher-order dendritic branches. Conversely, overexpression of Fmr1 in DA neurons dramatically decreased dendritic branching. In dissecting the mechanisms underlying Fmr1 function in dendrite development, we found that the mRNA encoding small GTPase Rac1 was present in the Fmr1-messenger ribonucleoprotein complexes in vivo. Mosaic analysis with a repressor cell marker (MARCM) and overexpression studies revealed that Rac1 has a cell-autonomous function in promoting dendritic branching of DA neurons. Furthermore, Fmr1 and Rac1 genetically interact with each other in controlling the formation of fine dendritic branches. These findings demonstrate that Fmr1 affects dendritic development and that Rac1 is partially responsible for mediating this effect.

Background. Body-composition changes are common in individuals infected with human immunodeficiency virus. The purpose of the present study was to measure, as a model of wasting in acquired immunodeficiency syndrome (AIDS), longitudinal body-composition changes in macaques infected with simian immunodeficiency virus (SIV). Methods. Twelve juvenile macaques were inoculated with SlVmac239. Immunologic, virologic, somatometric, and dual-energy x-ray-absorptiometry measurements were performed prospectively every 4 weeks for 72 weeks and were compared to measurements taken from 8 uninfected control macaques. Results. During the first 4 weeks, body-fat percentage decreased in the SIV-infected macaques while lean-tissue percentage increased; during weeks 4-72, these macaques lost a greater percentage of total fat tissue but had more subcutaneous-fat deposition than did the uninfected control macaques. Just prior to death, the SIV-infected macaques that died (n = 7) had a greater loss in body-mass index, abdominal fat, fat tissue, and lean tissue, compared with that in SIV-infected macaques that survived (n = 5). Conclusions. Body-composition changes in SIV-infected juvenile macaques exhibit 3 phases: during acute infection, loss of body weight from fat tissue; a compensation period during which macaques grow, but at a reduced rate; and a terminal phase, during which tissue is lost from all body compartments. The SIV-infected juvenile macaque provides a useful model for the investigation of wasting in AIDS, particularly for pediatric AIDS wasting.

Tumor dimension is an established prognostic factor for metastasis-related death after radiotherapy for uveal melanoma.To compare various methods of modeling the relationship between tumor dimension and metastatic death.The analyses were based on a consecutive series of 1204 patients with primary choroidal melanoma treated with proton beam irradiation (70 cobalt-gray equivalent in 5 fractions) at the Harvard Cyclotron Laboratory, Boston, Mass, between January 1985 and December 1998. Largest basal diameter and largest perpendicular basal diameter were recorded at the time of surgical placement of tantalum rings used for tumor localization during proton treatment. The height of the tumor and the axial diameter of the eye were measured by ultrasonography prior to treatment. Using proportional hazards regression, we compared the prognostic influence of different indices of tumor size with estimated risk ratios and death rates according to tumor basal area and largest basal diameter. All estimates were adjusted for other established prognostic factors.Patients were followed up annually through June 30, 2000. Of the 1204 patients analyzed, 193 died of melanoma metastasis. The median follow-up among survivors was 7.9 years. The 5- and 10-year metastatic death rates were 12.8% and 20.7%, respectively. Among various approaches for modeling tumor dimension, the logarithm of tumor basal area had the highest log-likelihood and performed better than other approaches in 85% of the simulations. Based on this model, the covariate-adjusted rate ratio for any doubling in tumor basal area was 1.92 (95% confidence interval, 1.62-2.28).Tumor basal area is a better prognostic indicator than largest tumor diameter and tumor volume in the prediction of metastatic death after proton beam irradiation for uveal melanoma.

Context Violence-related injuries among children are common, but age-based incidence data are not easily available. Objectives To describe injuries due to violence in a population-based case series of children and to estimate injury incidence. Design Prospective surveillance of children residing in Boston, Mass, who received pediatric emergency department treatment for violence-related injury during a 4-year period beginning April 15, 1995. Setting Pediatric emergency departments in Boston. Patients Children aged 3 through 18 years who came to a hospital emergency department between April 1995 and April 1999. Violence-related injuries were defined as those resulting from a situation of conflict involving 2 or more persons with intent to harm, as assessed by health care personnel caring for the patients. Self-inflicted injuries and injuries caused by child abuse (including any injury resulting from a conflict with a parent or guardian) were excluded. Homicides of Boston children aged 3 through 18 years who were killed during the study period were included based on police data. Main Outcome Measure Population-based violence-related injury rates. Results There were 2035 injury-related visits caused by violence, which reflects a rate of 52.7 (95% confidence interval, 50.5-54.9) per 10 000 person-years. Most injuries were relatively minor; 6.4% of visits resulted in admission. The youth violence-related injury rate in Boston declined at an average rate of 12% annually during the period studied. Conclusion Pediatric emergency department monitoring of violence-related injury in Boston suggests that childhood injuries due to violence declined during the late 1990s.

Background To evaluate the relationship between cyclin D1 overexpression and bladder cancer prognosis. Methods A systematic literature search up to July 27, 2013 was carried out in PubMed and Wanfang databases, and the references of retrieved articles were screened. The hazard ratios (HRs) and their 95% CIs were used to combine the data. Heterogeneity and publication bias were also evaluated. Results A total of 15 studies containing 2,591 cases were included. We found that increased cyclin D1 levels were significantly correlated with progression-free survival with a pooled HR estimate of 0.54 (95% CI: 0.32–0.92). There was a significant degree of heterogeneity (I2 = 93.8%, P

BackgroundDietary guidelines suggest limiting daily sodium intake to MethodsTwo hundred forty participants with metabolic syndrome enrolled in a dietary intervention trial to lose weight and improve dietary quality. Three 24-hour dietary recalls were collected at each visit which provided meal patterns and nutrient data, including sodium intake. A secondary data analysis was conducted to examine sodium consumption patterns at baseline and at one-year study visits. Sodium consumption patterns over time were examined using linear mixed models.ResultsThe percentage of meals reported eaten in the home at both baseline and one-year follow-up was approximately 69%. Follow-up for the one-year dietary intervention revealed that the participants who consumed sodium greater than 2,300 mg/d declined from 75% (at baseline) to 59%, and those that consumed higher than 1,500 mg/d declined from 96% (at baseline) to 85%. Average sodium intake decreased from 2,994 mg at baseline to 2,558 mg at one-year (P P P P ConclusionSodium intake for the majority of participants exceeded the recommended dietary guidelines. Findings support actions that encourage low-sodium food preparation at home and encourage public health policies that decrease sodium in restaurants and prepared foods.

Ciliary body location is an established prognostic factor for metastasis-related death from uveal melanoma. We evaluated alternative approaches for classifying this covariate when constructing predictive models of patient survival.The analyses were based on a consecutive series of 1848 primary choroidal and/or ciliary body melanoma patients treated with proton beam irradiation (70 cobalt gray equivalent in 5 fractions) at the Harvard Cyclotron Laboratory, Boston, Mass, between July 1975 and December 1995. For each patient, the anatomic site of the tumor was classified according to an estimate of the proportion of the tumor base lying anterior to the ora serrata. Using proportional hazards regression, we estimated relative risk ratios and death rates from melanoma metastasis according to the extent of ciliary body involvement. All estimates were adjusted for other established prognostic factors.Patients were followed up through April 30, 1998; none were lost to follow-up. Of 1848 patients analyzed, 378 died of melanoma metastasis. The median follow-up period among survivors was 9.5 years. Ciliary body origin (50% of tumor base anterior to the ora serrata) was positively associated with tumor pigmentation (P.001), tumor height (P.001), and extrascleral extension of the tumor (P.001). Compared with tumors involving only the choroid, melanoma-associated death rates increased with the proportion of the tumor base lying within the ciliary body (P =. 006); the multivariate-adjusted relative risk ratio for greater than 75% involvement was 2.30 (95% confidence interval [CI], 1.26-4.23). The covariate-adjusted 5-year death rates for ciliary body origin and choroidal origin were 15.9% (95% CI, 11.3%-21.2%) and 9.8% (95% CI, 8.3%-11.7%), respectively.Patients with melanomas of presumed ciliary body origin seem to be subject to a higher risk of death resulting from melanoma metastasis. Arch Ophthalmol. 2000;118:1066-1070

Apolipoprotein E-ε4 (APOE-ε4) accentuates memory decline, structural volume loss and cerebral amyloid deposition in cognitively healthy adults. We investigated whether APOE-ε4 carriers will show disruptions in the intrinsic cognitive networks, including the default mode (DMN), executive control (ECN) and salience (SN) networks, relative to noncarriers in middle-aged healthy adults; and the extent to which episodic-memory performance is related to the altered functional connectivity (Fc) in these networks. Resting-state functional connectivity MRI (R-fMRI) was used to measure the differences in the DMN, ECN and SN Fc between 20 APOE-ε4 carriers and 26 noncarriers. Multiple linear regression analyses were performed to determine the relationship between episodic-memory performance and Fc differences in the three resting-state networks across all subjects. There were no significant differences in the demographic and neuropsychological characteristics and the gray-matter volumes in the carriers and noncarriers. While mostly diminished DMN and ECN functional connectivities were seen, enhanced connections to the DMN structures were found in the SN in ε4 carriers. Altered DMN and ECN were associated with episodic memory performance. Significant Fc differences in the brain networks implicated in cognition were seen in middle-aged individuals with a genetic risk for AD, in the absence of cognitive decline and gray-matter atrophy. Prospective studies are essential to elucidate the potential of R-fMRI technique as a biomarker for predicting conversion from normal to early AD in healthy APOE-ε4 carriers.

Background Age, sex, Karnofsky (KPS), number of metastatic sites (NMS), primary tumour localization, baseline CEA, CEA response, scan response and k-RAS status are focused on progression free survival (PFS) and overall survival (OS) as predictive factors in chemotherapy metastatic colorectal cancer (mCRC). This study aims to find which might generate impact on PFS and OS for a second line therapy. Patients and methods 138 patients treated with capecitabine and oxaliplatin (CAPOX) in second-line from 2002 to 2010 were analyzed. Cox hazard model was employed to build univariante and multivariate analysis. Results PFS and OS were 3.5 and 7.85 months, respectively. Among all evaluated factors, only KPS ≥70, CEA response and scan response were associated with better PFS and OS on univariate analysis with statistical significance. Age table 1 ) Multivariable analysis showed that scan response (HR = 0.34, p = 0.0003) and KPS ≥70% (HR = 0.96, p = 0.0002) were predictive for better PFS and OS (scan response: HR = 0.36, p = 0.0001 and KPS > 70%: HR = 0.97, p = 0.0007), while PTL (rectum, HR = 1.50, p = 0.032) and NMS (>2 sites, HR = 1.25, p = 0.0043) were predictive for worst PFS and OS, respectively. (See table 2 ) Table 1 . FS and OS univariate analyses N Median P-value PFS KPS 43 2.3 ≥70% 95 4.8 Response Yes 23 6.8 No 115 2.9 CEA response Yes 34 6.9 No 104 2.9 OS KPS 43 4.7 ≥70% 95 11.9 Response Yes 23 23.4 No 115 7.2 CEA response Yes 34 13.6 No 104 7.8 Age 68 11.7 ≥65 70 6.7 NMS ≤ 2 78 9.9 > 2 60 6.8 Table 2 . PFS and OS multivariate analyses P-value HR IC 95% LIC HIC PFS RECIST Response 0.34 0.20 0.56 KPS ≥70 0.96 0.95 0.98 Primary tumor localization Rectum 0.03 1.49 1.03 2.16 OS RECIST Response 0.36 0.21 0.61 KPS ≥70 0.97 0.96 0.98 Metastatic sites >2 0.004 1.25 1.07 1.46 Conclusion These findings suggest that scan response and good KPS may predict better PFS and OS in mCRC while primary tumour localization, CEA response and NMS should be further validated. Disclosure All authors have declared no conflicts of interest.

Background Protective immunity against vaginal challenge in SIVΔnef-vaccinated macaques develops at 20 weeks after vaccination, whereas the magnitude of SIV-specific CD8+ T cell responses peaks at 5 weeks. SIV-specific CD8+ T cells phenotypically mature from week 5 to 20, as characterized by upregulation of CCR7 and CD127, suggesting that the quality of the CD8+ T cell response may correlate with protection.

Background & Aim: Early studies using functional MRI (fMRI) have demonstrated that volitional swallow is associated with activation of a number of cortical areas (middle cingulate gyrus, ventrolateral prefrontal cortex, ventrolateral sensory/motor cortices andmiddle insula), which collectively represent the “cortical swallowing network” (CSN). Although the activation of these regions has been reported in the literature, the reproducibility of these activations has not been systematically studied. The aim of our study is to investigate the reproducibility of the CSN across different fMRI sessions. Methods: We studied 16 young right-handed healthy volunteers utilizing a standard paradigm driven fMRI protocol and analyzed with an event-related analysis technique. Echo-planar images were obtained during two identical nine minute scans across different sessions while twenty-one dry swallows were performed by visual cues in random intervals. Physiologic circulatory and respiratory-related signal changes were removed retrospectively. Functional images were then aligned, registered (12 degrees of freedom), and mapped stereotaxically to the standard coordinate system. Generalized linear model was then used to remove undesirable signal changes correlated with motion, white matter and cerebrospinal fluid. Finally, the second order group random mixed-effect multilevel analysis was performed to identify active cortical regions. Clusters with p

Lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) is a membrane protein that can support the binding, internalisation, and proteolytic degradation of oxidised low-density lipoprotein. The LOX-1 expression and superoxide generation increases in the neointima after balloon injury. Cilostazol, a well-know phosphodiesterase type 3(PDE3) inhibitor for the treatment of peripheral arterial disease, has vasodilator properties and an anti-proliferative action on the growth of vascular smooth muscle cells. To investigate whether cilostazol suppresses intimal hyperplasia and to elucidate its mechanism, we examined the effects of cilostazol to the expression of LOX-1 mRNA and protein, superoxide generation and neointimal hyperplasia of the rat carotid artery after balloon injury. The injury was performed inserting the balloon catheter through the rat common carotid artery and after 14 days a histopathological analysis revealed a significant restenosis with smooth muscle cell proliferation and neointima formation that was associated with an enhanced expression of LOX-1, superoxide generation, Pretreatment of rats with cilostazol (100 mg/kg/day) reduced neointima formation, superoxide generation, and LOX-1 expression (p

Background: Previous studies have found that, in the US, the incidence rate for colorectal cancer (CRC) is disproportionally high among persons residing in socioeconomic deprived neighborhoods. However, no previous studies have determined if there are disparities in incidence or tumor stage at diagnosis for CRC according to socioeconomic conditions in the neighborhood of residence after adjusting for individual-level CRC risk factors. Methods: Data were obtained from the ongoing NIH-AARP Diet and Health Study, a prospective cohort of 566,402 persons residing in 6 US states and 2 metropolitan areas who were 50-71 years of age at baseline (1995-1996). Detailed individual-level data were obtained on diet, lifestyle and other cancer risk factors using questionnaires. For this analysis, we excluded participants who reported a history of CRC at the time of the baseline questionnaire. CRC incidence was then ascertained from tumor registries through December 31,2003. We used an empirically derived neighborhood socioeconomic deprivation index from linked 2000 US census data based on participants’ home addresses at the time of the baseline questionnaire. The index was categorized into quintiles at the census-tract level. We used proportional hazards models that accounted for clustering of persons within census tracts to separately estimate the hazard ratios for CRC incidence and tumor stage at the time of diagnosis (based on SEER summary staging system). We defined regional, distant or unstaged tumors as non-localized. Results: There were 6,934 incident cases of CRC among the 560,288 eligible participants included in the analyses, of which 59% were non-localized. The age and sex adjusted incidence of CRC among the cohort was 17.5 per 10,000 person-years. The incidence rate was 16.2% among persons residing in census-tracts in the first (least deprived) socioeconomic quintile and 19.8% for the 5th (most deprived) quintile. In proportional hazard models that adjusted for individual-level education and demographic, diet and lifestyle factors, those in the most deprived census-tracts had a higher incidence of CRC, overall (adjusted hazard ratios (HR)=1.16:95% confidence intervals (CI) 1.04-1.29); and non-localized CRC, compared to persons residing in the least socioeconomically deprived (first quintile) census-tracts. Conclusion: Persons residing in socioeconomically deprived neighborhoods were more likely to be diagnosis with non-localized CRC. This may contribute to neighborhood socioeconomic disparities in mortality for CRC. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A106.

Introduction: Total knee replacement is an effective procedure to relieve pain from advanced osteoarthritis of the knee and more than 95% of patients report satisfaction with the outcome. However, a small group of patients is dissatisfied after TKR. The purpose of this study is to examine narcotic use in a national cohort of TKR patients and assess the association of narcotic use with post-TKR satisfaction.

Monoclonal antibodies directed against B cell antigens have shown clinical benefits to hematologic malignancies. CD40 is a member of the TNFR superfamily and is a target for potential treatment of B cell lineage hematological malignancies as well as certain carcinomas. To date, majority of the therapeutic monoclonal antibodies are of murine origin. To evaluate the therapeutic potential of rabbit monoclonal antibodies (RabMAb®), we generated functional RabMAbs against CD40 using Epitomics' RabMAb® platform. Here we report the characterization of EPI0050, a novel humanized anti-CD40 rabbit monoclonal antibody. EPI0050 specifically recognizes the CD40 ligand binding domain and selectively blocks the ligand binding to CD40. EPI0050 itself exhibits modest agonist effects as shown in the up-regulation of CD80, CD83 and CD86 in differentiated dendritic cells and direct inhibition of CD40 positive malignant B cells. EPI0050 bound CD40 strongly without much internalization, which conferred to a potent ADCC effect in vitro. In an established preclinical Ramos lymphoma model, EPI0050 significantly inhibited tumor growth with a long-term stabilization of the tumor post dosing as compared with Rituximab and another anti-CD40 antibody. EPI0050 was also able to regress established rebound tumors post Rituximab treatment. More animal models and MOA are being explored for EPI0050. Both in vitro and in vivo results support the preclinical and clinical development of EPI0050 as a bio-better tumor therapy. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2451.

BACKGROUND Dietary quality may impact heart failure outcomes. However, the current status of the dietary quality of persons with heart failure has not been previously reported.

Background: Persons from lower socioeconomic backgrounds have higher exposure to risk factors for, and higher mortality rate from, colorectal cancer (CRC), but there is a paucity of published population-based studies on the relationship between neighborhood socioeconomic context and CRC incidence. In this study, we used national prospective data to determine: 1) whether CRC incidence varied according to area-level socioeconomic context; and 2) if area-level differences in incidence are explained by clustering of CRC risk factors. Methods: We used data from the NIH-AARP Diet and Health Study, a prospective cohort of 566,402 persons residing in 6 US states and 2 metropolitan areas who were 50–71 years of age at baseline (1995–1996). Detailed data on diet, lifestyle and medical history were collected using questionnaires. Cancer incidence was ascertained from tumor registries through December 31, 2003. Participants were linked to the 2000 US Census data at the tract level. We used principal component factor analyses to derive an index of neighborhood socioeconomic deprivation from 10 census variables about education, poverty, employment and occupation. We restricted the analyses to 319,057 men and 214,298 women who did not have history of CRC at baseline and had complete data including valid geocoded information. Results: In single predictor Cox models with frailty, compared to persons residing in the lowest quintile of the deprivation index, those in the most deprived census tracts had a higher incidence of CRC (HR=1.27; 95% confidence interval [CI]: 1.16–1.40 for men and HR=1.32, CI: 1.15–1.52 for women). This increased risk was robust to adjustments for age, race-ethnicity and family history of colon cancer, body mass index, physical activity and dietary variables including calcium intake, smoking and a history of diabetes (HR: 1.13, CI: 1.03–1.24) for men and HR: 1.17, CI: 1.01–1.34 for women) and to further adjustment for use of non-steroidal inflammatory agents (HR=1.18; CI 1.05–1.34) for men; and HR= 1.19, CI: 0.99–1.42 for women). Significant heterogeneity was observed for the incidence of CRC among census tracts for both men and women (likelihood ratio test p-value Conclusion: Our study found significant variation in the incidence of CRC by neighborhood of residence and neighborhood socioeconomic conditions after adjusting for recognized individual risk factors. Further studies are needed to explore other factors that may be associated with area-level differences in CRC incidence such as the use of screening. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B128.

Background The current food pyramid guidelines have been criticized because of their complexity and the knowledge required for users to understand the recommendations. Simplification of a dietary message to focus on a single key aspect of dietary quality, e.g., fiber intake, may make the message much easier to comprehend and adhere, such that respondents can achieve greater weight loss, better dietary quality and overall metabolic health. Methods and design This is a randomized controlled clinical trial with two equal sized arms. In total, 240 obese adults who meet diagnostic criteria for the metabolic syndrome will be randomized to one of the two conditions: 1) a high fiber diet and 2) the American Heart Association (AHA) diet. In the high fiber diet condition, patients will be given instruction only on achieving daily dietary fiber intake of 30 g or more. In the AHA diet condition, patients will be instructed to make the several dietary changes recommended by the AHA 2006 guidelines. The trial examines participant weight loss and dietary quality as well as changes in components of the metabolic syndrome, inflammatory biomarkers, low-density lipoprotein cholesterol levels, insulin levels, and glycosolated hemoglobin. Potential mediators, i.e., diet adherence and perceived ease of the diet, and the intervention effect on weight change will also be examined. Discussions The purpose of this paper is to outline the study design and methods for testing the simple message of increasing dietary fiber. If the simple dietary approach is found efficacious for weight loss; and, improves dietary quality, metabolic health, and adherence, it might then be used to develop a simple public health message. Trial registration NCT00911885

Background: Rickettsia conorii, the causative agent of the Mediterranean spotted fever, is transmitted to humans by the bite of infected ticks Rhipicephalus sanguineus. The skin thus constitutes an important barrier for the entry and propagation of R. conorii. Given this, analysis of the survival strategies used by the bacterium within infected skin is critical for our understanding of rickettsiosis. Methodology/Principal Findings: Here, we report the first genome-wide analysis of R. conorii gene expression from infected human skin biopsies. Our data showed that R. conorii exhibited a striking transcript signature that is remarkably conserved across patients, regardless of genotype. The expression profiles obtained using custom Agilent microarrays were validated by quantitative RT-PCR. Within eschars, the amount of detected R. conorii transcripts was of 55%, this value being of 74% for bacteria grown in Vero cells. In such infected host tissues, approximately 15% (n = 211) of the total predicted R. conorii ORFs appeared differentially expressed compared to bacteria grown in standard laboratory conditions. These genes are mostly down-regulated and encode proteins essential for bacterial replication. Some of the strategies displayed by rickettsiae to overcome the host defense barriers, thus avoiding killing, were also pointed out. The observed up-regulation of rickettsial genes associated with DNA repair is likely to correspond to a DNA-damaging agent enriched environment generated by the host cells to eradicate the pathogens. Survival of R. conorii within eschars also involves adaptation to osmotic stress, changes in cell surface proteins and up-regulation of some virulence factors. Interestingly, in contrast to down-regulated transcripts, we noticed that up-regulated ones rather exhibit a small nucleotide size, most of them being exclusive for the spotted fever group rickettsiae. Conclusion/Significance: Because eschar is a site for rickettsial introduction, the pattern of rickettsial gene expression observed here may define how rickettsiae counteract the host defense.

Background Leptospirosis is an emerging zoonosis that is often under-recognized in children and commonly confused with dengue in tropical settings. An enhanced ability to distinguish leptospirosis from dengue in children would guide clinicians and public health personnel in the appropriate use of limited healthcare resources. Methodology/Principal Findings We conducted a prospective, hospital-based, study of children with acute febrile illnesses and dengue in Thailand. Among the children without dengue, we identified those with leptospirosis using anti-leptospira IgM and microscopic agglutination titers in paired acute and convalescent blood samples. We then performed a case-control comparison of symptoms, signs, and clinical laboratory values between children with leptospirosis and dengue. In a semi-rural region of Thailand, leptospirosis accounted for 19% of the non-dengue acute febrile illnesses among children presenting during the rainy season. None of the children with leptospirosis were correctly diagnosed at the time of hospital discharge, and one third (33%) were erroneously diagnosed as dengue or scrub typhus. A predictive model to distinguish pediatric leptospirosis from dengue was generated using three variables: the absolute neutrophil count, plasma albumin, and aspartate aminotransferase levels in the first 72 hours of illness. Conclusions/Significance Unrecognized leptospirosis can be a significant cause of “dengue-like” febrile illness in children. Increased awareness of pediatric leptospirosis, and an enhanced ability to discriminate between leptospirosis and dengue early in illness, will help guide the appropriate use of healthcare resources in often resource-limited settings., Author Summary Two of the most common causes of acute febrile illnesses among children in the tropics are leptospirosis and dengue. Early in illness, these two conditions are often indistinguishable and rapid laboratory confirmation of the infecting pathogen is generally not available. An enhanced ability to distinguish leptospirosis from dengue in children would guide clinicians and public health personnel in the appropriate use of limited healthcare resources. In a prospective, hospital-based, study of children with acute febrile illnesses conducted in Thailand, we compared clinical and laboratory characteristics between children with leptospirosis and dengue. Unrecognized leptospirosis was a significant cause of “dengue-like” febrile illness among children presenting to a semi-rural hospital during the rainy season. The presenting symptoms and physical examination findings were poor at discriminating between children with leptospirosis and dengue. A predictive model to distinguish pediatric leptospirosis from dengue was generated using three laboratory values on hospital admission. Our results provide important information on the characteristics of pediatric leptospirosis in Southeast Asia and its distinguishing features from dengue in a region where both pathogens circulate.

Background: The aim of this study is to verify the effects of fenofibrate monotherapy and fenofibrate combined with exercise for improving metabolic syndrome and hepatic steatosis. Methods: Thirty-four weeks old OLETF rats (Otsuka Long-Evans Tokushima Fatty Rats, n = 20) were divided four groups: the regular diet group (n = 5, DD group), the exercise group (n = 5, DE group), the fenofibrate (100 mg/kg) treated group (n = 5, DF group) and the combination treatment group {fenofibrate and exercise (n = 5, EF group)}. After 5 weeks of treatment, blood was drawn for measuring the blood glucose, insulin, lipid and leptin levels. All the subjects were sacrificed for assessment of their body adiposity and hepatic steatosis. Results: The total amount of food intake, body weight and total body weight of the rat were significantly decreased in the EF and DF groups compared to the DD group. The plasma triglyceride and glucose levels were significantly decreased in the EF and DF groups compared to the DD group. The HOMA-IR of EF, DF and DE groups were significantly decreased compared with that of the DD group. The plasma leptin levels of the EF and DF groups were significantly decreased compared with those of the DD and DE groups. The hepatic steatosis index was significantly decreased in the EF and DF groups compared to the DD and DE groups. Conclusion: Fenofibrate monotherapy was effective to control three major components (obesity, hypertriglyceridemia and hyperglycemia) of metabolic syndrome and hepatic steatosis in OLETF rats. Exercise combined with fenofibrate treatment showed an additional effect compared to that of fenofibrate monotherapy.

Background Melanoma of the eye is the only potentially fatal ocular malignancy in adults. Until radiation therapy gained wide acceptance in the 1980s, enucleation was the standard treatment for the tumor. Long-term results after proton beam irradiation are now available. Methods We developed risk score equations to estimate probabilities of the 4 principal treatment outcomes—local tumor recurrence, death from metastasis, retention of the treated eye, and vision loss—based on an analysis of 2069 patients treated with proton beam radiation for intraocular melanoma between July 10, 1975, and December 31, 1997. Median follow-up in surviving patients was 9.4 years. Results Tumor regrowth occurred in 60 patients, and 95% of tumors (95% confidence interval, 93%-96%) were controlled locally at 15 years. Risk scores were developed for the other 3 outcomes studied. Overall, the treated eye was retained by 84% of patients (95% confidence interval, 80%-87%) at 15 years. The probabilities for vision loss (visual acuity worse than 20/200) ranged from 100% to 20% at 10 years and for death from tumor metastases from 95% to 35% at 15 years, depending on the risk group. Conclusions High-dose radiation treatment was highly effective in achieving local control of intraocular melanomas. In most cases, the eye was salvaged, and functional vision was retained in many patients. The mortality rate was high in an identifiable subset of patients who may benefit from adjuvant therapies directed at microscopic liver metastases.

To determine if a reduction in proton radiation dose from the standard dose of 70 cobalt gray equivalents (CGE) to 50 CGE would decrease radiation-induced complications, thereby improving visual prognosis, without compromising local tumor control for patients with uveal melanoma at high risk of these complications.Randomized, double-masked clinical trial.A total of 188 patients with small or medium-sized choroidal melanomas (15 mm in diameter and5 mm in height) near the optic disc or macula (within 4 disc diameters of either structure).Patients were treated with proton beam therapy at doses of either 50 CGE or 70 CGE between October 1989 and July 1994, and followed up biannually through April 1998. Outcomes included visual acuity, radiation complications, melanoma recurrence, and metastasis.Proportions of patients retaining visual acuity of at least 20/200 were similar in the 2 dose groups at 5 years after radiation (approximately 55%). Similar numbers of patients in each group experienced tumor regrowth (2 patients at 50 CGE vs 3 patients at 70 CGE; P.99) and metastasis (7 patients at 50 CGE vs 8 patients at 70 CGE;P=.79). Five-year rates of radiation maculopathy also were similar (for both groups, approximately 75% for tumors within 1 disc diameter and 40% for tumors1 disc diameter from the macula). Rates of radiation papillopathy were nonsignificantly decreased in the 50-CGE treatment group when tumors were located 1 disc diameter or less from the optic disc (P=.20). Patients treated with the lower dose also experienced significantly less visual field loss.This level of dose reduction did not result in a lesser degree of visual acuity loss. The lower-dose group did experience significantly less visual field loss. Local tumor recurrence and metastatic death rates were similar in both dose groups. Arch Ophthalmol. 2000;118:773-778

Summary The global diversity of HIV-1 represents a critical challenge facing HIV-1 vaccine development. HIV-1 mosaic antigens are bioinformatically optimized immunogens designed for improved coverage of HIV-1 diversity. However, the protective efficacy of such global HIV-1 vaccine antigens has not previously been evaluated. Here, we demonstrate the capacity of bivalent HIV-1 mosaic antigens to protect rhesus monkeys against acquisition of infection following heterologous challenges with the difficult-to-neutralize simian-human immunodeficiency virus SHIV-SF162P3. Adenovirus/poxvirus and adenovirus/adenovirus vector-based vaccines expressing HIV-1 mosaic Env, Gag, and Pol afforded a significant reduction in the per-exposure acquisition risk following repetitive, intrarectal SHIV-SF162P3 challenges. Protection against acquisition of infection correlated with vaccine-elicited binding, neutralizing, and functional nonneutralizing antibodies, suggesting that the coordinated activity of multiple antibody functions may contribute to protection against difficult-to-neutralize viruses. These data demonstrate the protective efficacy of HIV-1 mosaic antigens and suggest a potential strategy for the development of a global HIV-1 vaccine. PaperClip

Summary Objective To examine potential risk factors for hallux valgus in community-dwelling elders. Method Data from 600 MOBILIZE Boston Study participants (386 women and 214 men) were analyzed. Hallux valgus was defined as >15° angular deviation of the hallux with respect to the first metatarsal bone toward the lesser toes. Associations of hallux valgus with age, body mass index (BMI), race, education, pes planus, foot pain, and in women, history of high heel shoe use, were assessed using sex-specific Poisson regression with robust variance estimation for risk ratios (RR) and 95% confidence intervals (CI). Results Hallux valgus was present in 58% of women and 25% of men. Higher BMI was inversely associated with presence of hallux valgus in women ( P trend=0.001), with the strongest inverse association observed in those with BMI of 30.0 or more compared to those with normal BMI (RR=0.7, 95% CI: 0.5, 0.9). Women, who usually wore high-heeled shoes during ages 20–64 years compared to those who did not, had increased likelihood of hallux valgus (RR=1.2, 95% CI: 1.0, 1.5). Among men, those with BMI between 25.0 and 29.9 had increased likelihood of hallux valgus compared to those with normal BMI (RR=1.9, 95% CI: 1.0, 3.5). Men with pes planus were more likely to have hallux valgus (RR=2.1, 95% CI: 1.3, 3.3) compared to men without pes planus. Conclusion In women, hallux valgus was associated with lower BMI and high heel use during ages 20–64, while in men, associations were observed with higher BMI and pes planus. Our results suggest that the etiologic mechanisms for hallux valgus may differ between men and women.

How dendrites of different neuronal subtypes exhibit distinct branching patterns during development remains largely unknown. Here we report the mapping and identification of loss-of-function mutations in the abrupt (ab) gene that increased the number of dendritic branches of multiple dendritic (MD) sensory neurons in Drosophila embryos. Ab encodes an evolutionarily conserved transcription factor that contains a BTB/POZ domain and C2H2 zinc finger motifs. We show that ab has a cell-autonomous function in postmitotic neurons to limit dendritic branching. Ab and the homeodomain protein Cut are expressed in distinct but complementary subsets of MD neurons, and Ab functions in a transcriptional program that does not require Cut. Deleting one copy of ab or overexpressing ab had opposite effects on the formation of higher-order dendritic branches, suggesting that the Ab level in a specific neuron directly regulates dendritic complexity. These results demonstrate that dendritic branching can be suppressed by neuronal subtype-specific transcription factors in a cell-autonomous and dosage-dependent manner.

Objectives Orthotopic left lung transplantation in the mouse, as recently developed by our laboratory, represents a physiologic model for studies in transplantation biology. However, because of the limited overall respiratory contribution of the murine left lung, left lung transplant recipients remain healthy despite immune-mediated graft necrosis. We sought to develop a lung transplantation model in which animal survival depends on graft function. Methods Orthotopic vascularized right lung transplantations using cuff techniques were performed in syngeneic and allogeneic strain combinations. Grafts were assessed histologically or functionally by measuring arterial blood gases from 7 to 28 days after transplantation. In a parallel set of experiments, syngeneic and immunosuppressed allogeneic hosts underwent a left pneumonectomy 2 weeks after right lung transplantation, with assessment of graft function 1 week later. Results We performed 40 right lung transplantations, with a survival rate of 87.5%. Syngeneic grafts remain free of inflammation as far as 28 days after transplantation. On day 7, arterial oxygen levels in syngeneic recipients (481 ± 90 mm Hg) are equivalent to those in naive mice (503 ± 59 mm Hg) after left hilar occlusion. Alternatively, allogeneic grafts develop histologic evidence of acute rejection, and arterial oxygen levels are significantly decreased after left hilar clamping (53.3 ± 10.3 mm Hg). Both syngeneic and immunosuppressed allogeneic right lung recipients tolerate a left pneumonectomy. Conclusions Right lung transplantation followed by left pneumonectomy represents the first survival model of vascularized lung transplantation in the mouse and will therefore allow for the design of novel studies in experimental lung transplantation.