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Abstract Background E-health tools are a new mechanism to expand patient care, allowing supplemental resources to usual care, including enhanced patient-provider communication. These applications to smoking cessation have yet to be tested in a hospitalized patient sample. This project aims to evaluate the effectiveness and cost-effectiveness of a tailored web-based and e-message smoking cessation program for current smokers that, upon hospital discharge, transitions the patient to continue a quit attempt when home (Decide2Quit). Design A randomized two-arm follow-up design will test the effectiveness of an evidence- and theoretically-based smoking cessation program designed for post-hospitalization. Methods A total of 1,488 patients aged 19 or older, who smoked cigarettes in the previous 30 days, are being recruited from 27 patient care areas of a large urban university hospital. Study-eligible hospitalized patients receiving usual tobacco cessation usual care are offered study referral. Trained hospital staff assist the 744 patients who are being randomized to the intervention arm with registration and orientation to the intervention website. This e-mail and web-based program offers tailored messages as well as education, self-assessment and planning aids, and social support to promote tobacco use cessation. Condition-blind study staff assess participants for tobacco use history and behaviors, tobacco use cost-related information, co-morbidities and psychosocial factors at 0, 3, 6, and 12 months. The primary outcome is self-reported 30-day tobacco abstinence at 6 months follow-up. Secondary outcomes include 7-day point prevalence quit rates at 3-, 6-, and 12-month follow-up, 30-day point prevalence quit rates at 3 and 12 months, biologically confirmed tobacco abstinence at 6-month follow-up, and multiple point-prevalence quit rates based on self-reported tobacco abstinence rates at each follow-up time period. Healthcare utilization and quality of life are assessed at baseline, and 6- and 12-month follow-up to measure program cost-effectiveness from the hospital, healthcare payer, patient, and societal perspectives. Discussion Given the impact of tobacco use on medical resources, establishing feasible, cost-effective methods for reducing tobacco use is imperative. Given the minimal hospital staff burden and the automated transition to a post-hospitalization tailored intervention, this program could be an easily disseminated approach. Trial registration Current Intervention Trial NCT01277250

Abstract Background New biomarkers that replace or are used in conjunction with the current ovarian cancer diagnostic antigen, CA125, are needed for detection of ovarian cancer in the presurgical setting, as well as for detection of disease recurrence. We previously demonstrated the upregulation of leucine-rich alpha-2-glycoprotein-1 (LRG1) in the sera of ovarian cancer patients compared to healthy women using quantitative mass spectrometry. Methods LRG1 was quantified by ELISA in serum from two relatively large cohorts of women with ovarian cancer and benign gynecological disease. The expression of LRG1 in ovarian cancer tissues and cell lines was examined by gene microarray, reverse-transcriptase polymerase chain reaction (RT-PCR), Western blot, immunocytochemistry and mass spectrometry. Results Mean serum LRG1 was higher in 58 ovarian cancer patients than in 56 healthy women (89.33 ± 77.90 vs. 42.99 ± 9.88 ug/ml; p = 0.0008) and was highest among stage III/IV patients. In a separate set of 193 pre-surgical samples, LRG1 was higher in patients with serous or clear cell ovarian cancer (145.82 ± 65.99 ug/ml) compared to patients with benign gynecological diseases (82.53 ± 76.67 ug/ml, p < 0.0001). CA125 and LRG1 levels were moderately correlated (r = 0.47, p < 0.0001). LRG1 mRNA levels were higher in ovarian cancer tissues and cell lines compared to their normal counterparts when analyzed by gene microarray and RT-PCR. LRG1 protein was detected in ovarian cancer tissue samples and cell lines by immunocytochemistry and Western blotting. Multiple iosforms of LRG1 were observed by Western blot and were shown to represent different glycosylation states by digestion with glycosidase. LRG1 protein was also detected in the conditioned media of ovarian cancer cell culture by ELISA, Western blotting, and mass spectrometry. Conclusions Serum LRG1 was significantly elevated in women with ovarian cancer compared to healthy women and women with benign gynecological disease, and was only moderately correlated with CA125. Ovarian cancer cells secrete LRG1 and may contribute directly to the elevated levels of LRG1 observed in the serum of ovarian cancer patients. Future studies will determine whether LRG1 may serve as a biomarker for presurgical diagnosis, disease recurrence, and/or as a target for therapy.

Cutaneous malignant melanoma accounts for 5% of cancer diagnoses and is the fifth most common cancer diagnosed in the United States. Risk factors for cutaneous malignant melanoma include ultraviolet radiation from sun exposure, Fitzpatrick skin type I or II, a history of dysplastic nevi, indoor tanning, older age, and a personal or family history of melanoma. The U.S. Preventive Services Task Force recommends counseling with patient education on minimizing early ultraviolet radiation exposure, including the use of protective clothing and sunscreen, especially for patients 6 months to 24 years of age. Tools to aid in the diagnosis of cutaneous malignant melanoma and the decision to biopsy include the ABCDE mnemonic, ugly duckling sign, and dermoscopy. Any suspicious pigmented lesion should be biopsied. Biopsy with a deep scoop shave, saucerization, punch biopsy, or full-thickness excision is preferred to ensure the entire lesion is removed to obtain an accurate measurement of Breslow depth. Breslow depth is important in staging, treatment consideration, and prognosis. Wide local excision by a dermatologist or surgeon with appropriate margins is the primary treatment of choice. Thin lesions with a Breslow depth of less than 0.8 mm usually do not need further treatment after wide local excision and have an excellent prognosis. Lesions with a Breslow depth greater than 0.8 mm may need further diagnostic tests or procedures, including sentinel lymph node biopsy, complete lymph node dissection, gene mutation analysis, and possible treatment with systemic immunotherapy. Use of systemic immunotherapies has improved the prognosis for advanced melanoma (stages III and IV), with 5-year survival rates of 74.8% and 35%, respectively, compared with 62.6% and 16% from 1975 to 2011 before immunotherapy was available.

The liver is a frequent site of benign and malignant, primary and metastatic tumors. Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common primary liver cancers, and colorectal liver metastasis (CRLM) is the most common secondary liver cancer. Although the imaging characteristic of these tumors is central to optimal clinical management, it relies on imaging features that are often non-specific, overlap, and are subject to inter-observer variability. Thus, in this study, we aimed to categorize liver tumors automatically from CT scans using a deep learning approach that objectively extracts discriminating features not visible to the naked eye. Specifically, we used a modified Inception v3 network-based classification model to classify HCC, ICC, CRLM, and benign tumors from pretreatment portal venous phase computed tomography (CT) scans. Using a multi-institutional dataset of 814 patients, this method achieved an overall accuracy rate of 96%, with sensitivity rates of 96%, 94%, 99%, and 86% for HCC, ICC, CRLM, and benign tumors, respectively, using an independent dataset. These results demonstrate the feasibility of the proposed computer-assisted system as a novel non-invasive diagnostic tool to classify the most common liver tumors objectively.

Objectives. To describe differences in maternal admissions to the intensive care unit (ICU) and mortality in rural versus urban areas in the United States. Methods. We performed a nationwide analysis and calculated age-standardized rates and rate ratios (RRs) of maternal ICU admission and mortality per 100 000 live births between 2016 and 2019 in rural versus urban areas. Results. From 2016 to 2019, there was no significant increase in age-standardized rates of maternal ICU admissions in rural (170.6-192.3) or urban (161.7-172.4) areas, with a significantly higher rate, albeit a relatively small difference, in rural versus urban areas (2019 RR = 1.14; 95% confidence interval [CI] = 1.04, 1.20). Maternal mortality increased in both rural (66.9-81.7 deaths per 100 000 live births) and urban (38.1-42.3) areas and was nearly 2 times higher in rural areas (2019 RR = 1.93; 95% CI = 1.71, 2.17). Conclusions. Pregnant individuals in rural areas are at higher risk for ICU admission and mortality than are their urban counterparts. Significant increases in maternal mortality occurred in rural and urban areas. Public Health Implications. Public health efforts need to focus on resource-limited rural areas to mitigate geographic disparities in maternal morbidity and mortality. ( Am J Public Health. 2023;113(2): 224-227.https://doi.org/10.2105/AJPH.2022.307134).

Importance: De novo hypertensive disorders of pregnancy (HDP) are associated with adverse maternal and offspring outcomes. Heterogeneity among racial and ethnic subgroups may be masked with aggregate reporting of race and ethnicity, such as Asian or Pacific Islander or Hispanic., Objective: To determine patterns in de novo HDP rates among individuals in Asian and Hispanic subgroups with a first live birth in the United States in the period 2011 through 2019., Design, Setting, and Participants: This serial cross-sectional analysis used data from 2011 through 2019 for individuals aged 15 to 44 years with singleton first live births obtained from the US National Center for Health Statistics natality database., Exposures: Stratification by self-report of maternal race and ethnicity: Hispanic/Latina (overall and Hispanic/Latina subgroups [Central/South American, Cuban, Mexican, and Puerto Rican]), non-Hispanic Asian and Pacific Islander (overall and non-Hispanic Asian subgroups [Asian Indian, Chinese, Filipina, Japanese, Korean, and Vietnamese]), non-Hispanic Black, non-Hispanic White., Main Outcomes and Measures: De novo HDP was defined as new-onset hypertension during pregnancy (gestational hypertension or preeclampsia). Age-standardized rates of HDP (per 1000 live births) and respective mean annual percent change in race and ethnicity groups and subgroups were calculated., Results: Among 13 238 918 individuals, the mean (SD) age was 26.3 (5.8) years. Overall, HDP rates increased 7.3% per year (95% CI, 6.5%-8.1%), from 57.2 (95% CI, 56.8-57.6) per 1000 live births in 2011 to 99.7 (95% CI, 99.2-100.2) per 1000 live births in 2019. Rates of HDP significantly increased in all racial and ethnic groups and subgroups over the study period. The highest HDP prevalence among non-Hispanic Asian subgroups in 2019 was in Filipina individuals (92.5 [95% CI, 86.3-98.8] per 1000 live births), and the highest among Hispanic/Latina subgroups in 2019 was in Puerto Rican individuals (98.6 [95% CI, 94.2-102.9] per 1000 live births) with significant heterogeneity observed among subgroups across the study period., Conclusions and Relevance: Rates of HDP among individuals with a singleton first live birth increased in the United States from 2011 to 2019 across all race and ethnicity subgroups, with considerable heterogeneity in HDP rates in non-Hispanic Asian and Hispanic/Latina subgroups.

Purpose: To evaluate the associations between computed tomography (CT) imaging features extracted from the structured American Pancreatic Association (APA)/Society of Abdominal Radiology (SAR) template and overall survival in patients with resected pancreatic ductal adenocarcinoma (PDAC)., Methods: This retrospective analysis included consecutive patients with PDAC who consented to genomic tumor testing and underwent preoperative imaging and curative intent surgical resection from December 2006 to July 2017. Two radiologists assessed preoperative CT imaging using the APA/SAR PDAC-reporting template. Univariable associations between overall survival and imaging variables were evaluated using Cox proportional hazards regression., Results: The study included 168 patients (66 years ± 11; 91 women). 126/168 patients (75%) received upfront surgical resection whereas 42/168 (25%) received neoadjuvant therapy prior to surgical resection. In the entire cohort, features associated with decreased overall survival were tumor arterial contact of any kind (hazard ratio (HR) 1.89, 95% CI 1.13-3.14, p = 0.020), tumor contact with the common hepatic artery (HR 2.33, 95% CI 1.35-4.04, p = 0.009), and portal vein deformity (HR 3.22, 95% CI 1.63-6.37, p = 0.003). In the upfront surgical group, larger tumor size was associated with decreased overall survival (HR 2.30, 95% CI 1.19-4.42, p = 0.013). In the neoadjuvant therapy group, the presence of venous collaterals was the only feature associated with decreased overall survival (HR 2.28, 95% CI 1.04-4.99, p = 0.042)., Conclusion: The application of the APA/SAR pancreatic adenocarcinoma reporting template may identify predictors of survival that can aid in preoperative stratification of patients.

MRI has played a critical role in the evaluation of patients with pancreatic pathologies, from screening of patients at high risk for pancreatic cancer to the evaluation of pancreatic cysts and indeterminate pancreatic lesions. The high mortality associated with pancreatic adenocarcinomas has spurred much interest in developing effective screening tools, with MRI using magnetic resonance cholangiopancreatography (MRCP) playing a central role in the hopes of identifying cancers at earlier stages amenable to curative resection. Ongoing efforts to improve the resolution and robustness of imaging of the pancreas using MRI may thus one day reduce the mortality of this deadly disease. However, the increasing use of cross-sectional imaging has also generated a concomitant clinical conundrum: How to manage incidental pancreatic cystic lesions that are found in over a quarter of patients who undergo MRCP. Efforts to improve the specificity of MRCP for patients with pancreatic cysts and with indeterminate pancreatic masses may be achieved with continued technical advances in MRI, including diffusion-weighted and T 1 -weighted dynamic contrast-enhanced MRI. However, developments in quantitative MRI of the pancreas remain challenging, due to the small size of the pancreas and its upper abdominal location, adjacent to bowel and below the diaphragm. Further research is needed to improve MRI of the pancreas as a clinical tool, to positively affect the lives of patients with pancreatic abnormalities. This review focuses on various MR techniques such as MRCP, quantitative imaging, and dynamic contrast-enhanced imaging and their clinical applicability in the imaging of the pancreas, with an emphasis on pancreatic malignant and premalignant lesions. Level of Evidence 5 Technical Efficacy Stage 3 J. MAGN. RESON. IMAGING 2021;53:347-359., (© 2020 International Society for Magnetic Resonance in Medicine.)

Purpose: Our paper contributes to the burgeoning field of surgical data science. Specifically, multimodal integration of relevant patient data is used to determine who should undergo a complex pancreatic resection. Intraductal papillary mucinous neoplasms (IPMNs) represent cystic precursor lesions of pancreatic cancer with varying risk for malignancy. We combine previously defined individual models of radiomic analysis of diagnostic computed tomography (CT) with protein markers extracted from the cyst fluid to create a unified prediction model to identify high-risk IPMNs. Patients with high-risk IPMN would be sent for resection, whereas patients with low-risk cystic lesions would be spared an invasive procedure. Approach: Retrospective analysis of prospectively acquired cyst fluid and CT scans was undertaken for this study. A predictive model combining clinical features with a cyst fluid inflammatory marker (CFIM) was applied to patient data. Quantitative imaging (QI) features describing radiomic patterns predictive of risk were extracted from scans. The CFIM model and QI model were combined into a single predictive model. An additional model was created with tumor-associated neutrophils (TANs) assessed by a pathologist at the time of resection. Results: Thirty-three patients were analyzed (7 high risk and 26 low risk). The CFIM model yielded an area under the curve (AUC) of 0.74. Adding the QI model improved performance with an AUC of 0.88. Combining the CFIM, QI, and TAN models further increased performance to an AUC of 0.98. Conclusions: Quantitative analysis of routinely acquired CT scans combined with CFIMs provides accurate prediction of risk of pancreatic cancer progression. Although a larger cohort is needed for validation, this model represents a promising tool for preoperative assessment of IPMN., (© 2020 Society of Photo-Optical Instrumentation Engineers (SPIE).)

Chondromyxoid fibroma (CMF) is a rare benign bone neoplasm that typically occurs in young adults. Juxtacortical or surface-type CMF are rarer still and we present the case of a surface-type CMF in a 78-year-old woman, with only one other case described in a patient of a similar age previously. This patient was an otherwise healthy woman who presented for evaluation of a palpable lump in the anterior proximal tibia. Initial radiographs obtained demonstrated a focal soft tissue fullness immediately anterior to the anterior cortex of the proximal tibia, which contained faint chondroid-like matrix internally. There was associated scalloping of the anterior tibial cortex. MRI confirmed the presence of a juxtacortical, enhancing lesion. Subsequent excisional biopsy was performed and histopathology demonstrated features, which was consistent with surface-type CMF. At a 6-month follow-up the patient remained free of recurrence. In a patient of this age, paraosteal chondrosarcoma should be excluded. Surface-type CMF, although rare, has been described in older patients and while it is unlikely to feature in a list of differential considerations on initial imaging, awareness of the entity is important.

Purpose: To determine the proportion of women working in academic musculoskeletal (MSK) radiology divisions and how this compares to national benchmarks for women in academic medicine., Materials and Methods: A list of academic radiology departments in the United States was compiled using the U.S. News and World Report listing of Best Hospitals for Orthopedics and Rheumatology to aid in department selection. Faculty information for MSK radiology divisions was obtained using websites pertinent to each department. Figures were obtained from the Association of American Medical Colleges and used as a benchmark for comparison., Results: The 25 top-ranked hospitals with MSK radiology divisions were identified, with a total of 215 MSK trained radiologists. Female radiologists made up 33% of the MSK trained faculty (n = 71). This compares to 38% of fulltime female faculty in academic medicine. 79 assistant professor roles were identified, of which 35% were women (n = 28). 34% of associate professors were women (n = 11). Only 23% of professors were women (n = 10); this compares with 21% of female professors in academic medicine. Six MSK radiologists held either chair or vice-chair roles and three of these were women. Of the 24 chief or director roles identified, 30% of these were held by women., Conclusion: The proportions of women within various roles in academic MSK radiology are similar to and in some instances higher than corresponding national benchmarks. However, there remains a discrepancy between the sexes with an overall male majority. Awareness of this fact is the first step required to help correct this imbalance., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To determine a relationship between increased body mass index (BMI) and fatty involution of the thymus in subjects aged between 20 and 30 years., Methods: CT images of 94 patients aged between 20 and 30 years were reviewed. Quantitative thymic mean attenuation was recorded and qualitative thymic attenuation was assigned to 1 of 4 possible grades. BMI and subcutaneous fat thickness were documented. Correlations between thymic attenuation, and BMI and subcutaneous fat thickness were assessed using linear regression models. Differences in thymic attenuation in overweight vs normal weight patients were assessed using t-test and Pearson Χ 2 analysis., Results: Low mean thymic attenuation values were associated with higher patient BMI (p = 0.024). Normal weight patients had a mean quantitative thymic attenuation of 15.5 Hounsfield unit and overweight patients had a mean quantitative thymic attenuation of -16.4 Hounsfield unit (p = 0.0218). There was a significant association between increasing subcutaneous fat thickness and reduced mean quantitative thymic attenuation (p < 0.0001). There was also a significant difference in subcutaneous fat thickness when comparing qualitatively assessed thymic Grade 0 with grades 2 and 3 (p = 0.027 and 0.001 respectively); and Grade 1 with Grade 3 (p = 0.001)., Conclusion: In patients between 20 and 30 years old, the degree of thymic fatty infiltration is related to BMI. Advances in knowledge: Multidetector CT can assess fatty involution of the thymus gland. This retrospective study demonstrates a relationship between BMI and thymus gland fatty involution. Subjects with increased subcutaneous fat have decreased mean thymus gland attenuation.

Objectives: Determine imaging characteristics specific to epithelioid (eMPM), sarcomatoid (sMPM), and biphasic (bMPM) subtypes of malignant pleural mesothelioma (MPM) on computed tomography., Methods: Preoperative computed tomography scans of patients with MPM were retrospectively assessed for numerous features including primary affected side, volume loss, pleural thickness, pleural calcifications, pleural effusion, and lymphadenopathy., Results: One hundred twenty-five patients with MPM were included. Histologic subdivision was 97 eMPM (77%), 17 bMPM (14%), and 11 sMPM (9%). Nonepithelioid MPM (bMPM and sMPM) was more likely than eMPM to have calcified pleural plaques (P = 0.035). Analyzed separately, bMPM and sMPM each demonstrated calcified plaques more frequently than eMPM, and sMPM more often had internal mammary nodes; however, P values did not reach significance (P = 0.075 and 0.071, respectively)., Conclusions: Calcified plaques are significantly more common in nonepithelioid subtypes compared with eMPM. Given the different prognoses and management of MPM subtypes, accurate noninvasive subtype classification is clinically vital.

Given the repeated failure of amyloid-based approaches in Alzheimer's disease, there is increasing interest in tau-based therapeutics. Although methylthioninium (MT) treatment was found to be beneficial in tau transgenic models, the brain concentrations required to inhibit tau aggregation in vivo are unknown. The comparative efficacy of methylthioninium chloride (MTC) and leucomethylthioninium salts (LMTX; 5-75 mg/kg; oral administration for 3-8 weeks) was assessed in two novel transgenic tau mouse lines. Behavioural (spatial water maze, RotaRod motor performance) and histopathological (tau load per brain region) proxies were applied. Both MTC and LMTX dose-dependently rescued the learning impairment and restored behavioural flexibility in a spatial problem-solving water maze task in Line 1 (minimum effective dose: 35 mg MT/kg for MTC, 9 mg MT/kg for LMTX) and corrected motor learning in Line 66 (effective doses: 4 mg MT/kg). Simultaneously, both drugs reduced the number of tau-reactive neurons, particularly in the hippocampus and entorhinal cortex in Line 1 and in a more widespread manner in Line 66. MT levels in the brain followed a sigmoidal concentration-response relationship over a 10-fold range (0.13-1.38 μmol/l). These data establish that diaminophenothiazine compounds, like MT, can reverse both spatial and motor learning deficits and reduce the underlying tau pathology, and therefore offer the potential for treatment of tauopathies.

A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer's disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296-390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology.

Alzheimer disease (AD) is a degenerative tauopathy characterized by aggregation of Tau protein through the repeat domain to form intraneuronal paired helical filaments (PHFs). We report two cell models in which we control the inherent toxicity of the core Tau fragment. These models demonstrate the properties of prion-like recruitment of full-length Tau into an aggregation pathway in which template-directed, endogenous truncation propagates aggregation through the core Tau binding domain. We use these in combination with dissolution of native PHFs to quantify the activity of Tau aggregation inhibitors (TAIs). We report the synthesis of novel stable crystalline leucomethylthioninium salts (LMTX®), which overcome the pharmacokinetic limitations of methylthioninium chloride. LMTX®, as either a dihydromesylate or a dihydrobromide salt, retains TAI activity in vitro and disrupts PHFs isolated from AD brain tissues at 0.16 μM. The Ki value for intracellular TAI activity, which we have been able to determine for the first time, is 0.12 μM. These values are close to the steady state trough brain concentration of methylthioninium ion (0.18 μM) that is required to arrest progression of AD on clinical and imaging end points and the minimum brain concentration (0.13 μM) required to reverse behavioral deficits and pathology in Tau transgenic mice., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

The predator-prey interactions in the offshore food web of Lake Superior have been well documented, but the sensory systems mediating these interactions remain unknown. The deepwater sculpin, (Myoxocephalus thompsoni), siscowet (Salvelinus namaycush siscowet), and kiyi (Coregonus kiyi) inhabit low light level environments. To investigate the potential role of vision in predator-prey interactions, electroretinography was used to determine visual sensitivity for each species. Spectral sensitivity curves revealed peak sensitivity at 525 nm for each species which closely corresponds to the prevalent downwelling light spectrum at depth. To determine if sufficient light was available to mediate predator-prey interactions, visual sensitivity was correlated with the intensity of downwelling light in Lake Superior to construct visual depth profiles for each species. Sufficient daytime irradiance exists for visual interactions to approximately 325 m for siscowet and kiyi and 355 m for the deepwater sculpin during summer months. Under full moon conditions, sufficient irradiance exists to elicit ERG response to light available at approximately 30 m for the siscowet and kiyi and 45 m for the deepwater sculpin. Visual interactions are therefore possible at the depths and times when these organisms overlap in the water column indicating that vision may play a far greater role at depth in deep freshwater lakes than had been previously documented.

Introduction: The chemokines Stromal Cell-Derived Factor-1alpha (SDF-1alpha/CXCL12) and Monocyte Chemotactic Protein-1 (MCP-1/CCL2) have been implicated in breast cancer progression. We recently reported elevated systemic MCP-1 in breast cancer patients. This study investigated circulating levels of SDF-1alpha in breast cancer patients, and addressed potential hormonal regulation of these two potent chemokines., Methods: SDF-1alpha levels were determined by ELISA in 114 breast cancer patients and 85 controls, and correlated with clinical data. Blood samples were collected from 36 healthy premenopausal volunteers weekly for four weeks to measure Luteinising Hormone (LH), Follicular Stimulating Hormone (FSH), Oestradiol and Progesterone using a Bayer ADVIA Centaur Immunoassay system, in parallel with SDF-1alpha and MCP-1. CXCL12 expression was determined using RQ-PCR in primary tumour stromal cells (n = 16) harvested at surgery., Results: Plasma SDF-1alpha was significantly higher in breast cancer patients than age-matched controls and had a significant correlation with tumour grade and epithelial subtype. Investigation of menstrual variations of these chemokines revealed lower SDF-1alpha levels in the mid-luteal phase of the menstrual cycle and a significant positive correlation with circulating Oestradiol. MCP-1 levels showed no correlation with menstrual hormones. There was a trend towards increased CXCL12 expression in tumour compared to normal stromal cells., Conclusions: The elevated level of SDF-1alpha detected in breast cancer patients, and it's correlation with prognostic indicators, highlights the importance of this chemokine in disease progression. Elucidation of factors influencing chemokine secretion supports clarification of their role in tumourigenesis.

Purpose: Major barriers to effective adenovirus-based gene therapy include induction of an immune response and tumor-specific targeting of vectors. The use of mesenchymal stem cells (MSC) as systemic delivery vehicles for therapeutic genes has been proposed as a result of their combined ability to home in on the tumor site and evade the host immune response. This study is aimed at investigating factors mediating homing of human MSCs to breast cancer primary cultures and cell lines in vitro and in vivo., Experimental Design: Fluorescently labeled MSCs were given to mice bearing breast cancer xenografts, and tumor tissue was harvested to detect MSC engraftment. MSC migration in response to primary breast tumors in vitro was quantified, and chemokines secreted by tumor cells were identified. The role of monocyte chemotactic protein-1 (MCP-1) in cell migration was investigated using antibodies and standards of the chemokine. Serum MCP-1 was measured in 125 breast cancer patients and 86 healthy controls., Results: Engrafted MSCs were detected in metastatic breast tumors in mice after systemic administration. There was a significant increase in MSC migration in response to primary breast tumor cells in vitro (6-fold to 11-fold increase). Tumor explants secreted a variety of chemokines including GROalpha, MCP-1, and stromal cell-derived factor-1alpha. An MCP-1 antibody caused a significant decrease (37-42%) in MSC migration to tumors. Serum MCP-1 levels were significantly higher in postmenopausal breast cancer patients than age-matched controls (P < 0.05)., Conclusions: These results highlight a role for tumor-secreted MCP-1 in stimulating MSC migration and support the potential of these cells as tumor-targeted delivery vehicles for therapeutic agents.

Rapid advances in our ability to localize and quantify macromolecular changes in health and disease are being brought about by the availability of genetically altered animals (mutants), purified reagents such as monoclonal antibodies, and new molecular methods. Targeted gene deletion (knockouts) and gene insertions (transgenics) in animals can allow identification of the importance and function of macromolecules. Monoclonal antibodies and fluorescent labels coupled with advances in microscopy provide exacting and multi-dimensional information about localization and cellular changes in proteins, carbohydrates, and lipids using immunohistochemistry, fluorescent activated cell sorting, and immunoprecipitation. Similarly, new applications of molecular methods can be used to identify and localize nucleic acids in tissues via in situ hybridization, polymerase chain reaction (PCR), reverse transcription (RT) PCR, differential display RT-PCR, RNase protection assays, and microchip arrays. The ligand for CD40 (CD40L), an important immunoregulatory molecule, is an example of the successful application of mutants, monoclonal antibodies, and molecular methods to cloning and biological characterization of new molecules. CD40L knockout mice, monoclonal antibodies, and several molecular methods were used to identify mutations in CD40L as the genetic basis for hyper-IgM syndrome in humans, to provide new insights into the pathobiology of Pneumocystis carinii infection, and to evaluate CD40L for immunotherapy of tumors and opportunistic infections.

The cellular expression of DAT mRNA and VMAT2 mRNA was investigated in sections of the human post-mortem substantia nigra in control and Parkinson's disease tissue using in situ hybridisation techniques. Short synthetic oligodeoxynucleotides were used to detect these gene transcripts at the cellular level. In the control human nigra, high levels of expression were seen in all sub-divisions of the substantia nigra, especially within medial regions. By contrast, the level of expression of both DAT mRNA and VMAT2 mRNA was markedly reduced in Parkinson's disease; these reductions in hybridisation signal were associated with (i) a marked loss of dopamine-containing cells in the substantia nigra, and (ii) a reduction in both DAT and VMAT2 signal per cell in the remaining pigmented neurones. These disease-related decreases in the cellular abundance of both DAT and VMAT2 gene transcripts in the surviving cells of the parkinsonian nigra may reflect compensatory changes in catecholamine signalling or may be a consequence of neuronal dysfunction.

Genes for five high affinity somatostatin receptors, named sst1-5, have been cloned recently. In this study we describe the tissue distribution and cellular localisation of mRNA encoding sst1, sst3 and sst4 receptors in the human cerebellum, frontal cortex (Brodmann's area 11) and hippocampus. RT-PCR and in situ hybridisation studies indicated a distinct, but partially overlapping pattern of expression of the receptor mRNAs. In situ hybridisation studies using co-expression techniques with probes for sst1, sst3 and sst4 receptor mRNA on paraffin sections revealed the presence of neurones expressing more than one somatostatin receptor mRNA type in both the hippocampus and pyramidal cells of layer V of the frontal cortex.

The cellular expression of the mRNAs encoding the dopamine D1 receptor, dopamine D2 receptor and the neuropeptides enkephalin and substance P was determined in fresh frozen sections of human post-mortem caudate nucleus from control and schizophrenic brains using the technique of radioactive in situ hybridisation coupled with computer-assisted image analysis. Measurements of silver grain densities and mean cross-sectional somatic areas revealed no significant differences in the expression of any of these four gene transcripts. Further, cell count estimates revealed that each of these four mRNAs was expressed by approximately 20% of caudate cells (neurones and glia) in both control and schizophrenic tissue. These data demonstrate that the cellular expression of the dopamine D1 and D2 receptors and the neuropeptides enkephalin and substance P mRNAs are stable post mortem and that the relative cellular abundance of these mRNAs is not altered in the caudate nucleus of schizophrenic brains when compared to controls. These findings draw into focus the possible sites of action of clinically prescribed neuroleptics and suggest that chronic neuroleptic treatment of patients displaying negative schizophrenic symptoms may 're-set' an underlying neurochemical imbalance within the caudate nucleus.

The distribution and cellular localisation of somatostatin receptor subtype 4 (SSTR4) was investigated in the adult rat brain using the technique of in situ hybridisation with subtype specific oligonucleotide probes. Somatostatin receptor subtype 4 was found mainly in the hippocampus CA1 > CA2 > CA3 pyramidal cells and in the pyramidal cells in layers (IV-VI) of the cerebral cortex. Reverse transcription-PCR with SSTR4 specific primers confirmed the tissue distribution revealed by in situ hybridisation.

A synaptic vesicle amine transporter cDNA, termed hSVAT, has been isolated by the reverse transcription and polymerase chain reaction (PCR) technique from human substantia nigra and subsequent screening of a human substantia nigra library. The hSVAT sequence obtained is highly homologous to the rat SVAT sequence (92% homology) and is essentially identical to the human sequence identified recently by Surratt and colleagues [33]. This labelled hSVAT cDNA detected a single band (approximately 5.0 kb) when used as a probe for Northern analysis of human nigral RNA extract. In situ hybridization studies using hSVAT specific antisense oligonucleotides showed a strong hybridization signal concentrated over the cells of the substantia nigra pars compacta. This cDNA sequence when expressed in chinese hamster ovary (CHO) cells conferred resistance to MPP+ the toxic metabolite of MPTP and cells containing it accumulated dopamine.

Mice were infected intravenously with two antibiotic resistance tagged variants of the same S. typhimurium strain given in close succession, or simultaneously with strains of different virulence. The first manifestation of acquired resistance--suppression of exponential bacterial growth in liver and spleen--occurred independently for the different strains in the same individuals, implying that it is due to localized rather than systemic events. This early suppression of bacterial growth was ablated by whole body X-irradiation (800R), whereas the immediately preceding phase of exponential growth (Ity controlled innate resistance) was not affected. Transfer of spleen cell suspensions from infected mice into syngeneic recipients conferred protection by suppressing the growth of an intravenous challenge. Pre-treatment of the suspensions to deplete them of macrophages abolished their protective capacity, while depletion of T-cells did not. Mice deficient in T-cells by adult thymectomy and anti-T-cell monoclonal antibody treatment were able to suppress the growth of an intravenous challenge. Taken collectively, the present data show that the very early phase of acquired resistance to salmonellae, essential for survival, is not the result of systemically developing resistance but a localized event at the site of infection.

Determinations of 50% lethal dose (LD50) values in H-2 congenic B10 lines showed that late-emerging resistance (postimmune response phase) to salmonellae of intermediate virulence was less in H-2b and H-2d than in H-2a, H-2k, and H-2f mice. Association of resistance to H-2 was confirmed by backcross analysis, and LD50 determinations on H-2 recombinant haplotype strains showed that resistance maps to the I-E subregion. Bacterial growth curves in liver and spleen showed that susceptible mice carried bacteria for longer in the reticuloendothelial system than did resistant mice and that susceptible mice showed greater splenomegaly. Association of resistance and susceptibility to H-2 was not different when sister transductant salmonellae expressing somatic antigens O4 and O9 were used. Thus a gene(s) within the major histocompatibility complex controls natural resistance to salmonellae in mice by influencing the ability to clear bacteria from the reticuloendothelial system in the later phase of the infection, and the immunodominant O antigen cannot be solely involved.

Twenty-nine patients having myocardial infarction (MI) of recent origin (6 weeks or less) were evaluated and treated using a program in which assessment and progression were based not on generalized data but on the individual responses of each patient. Fourteen patients had complications including left ventricular impairment, continuing ischemia or rhythm disturbances, and 15 did not. Cardiac tolerance for the common self-care activities, walking and light exercise, was objectively defined by 3 levels of functional monitoring. The physician, occupational therapist and physical therapist evaluated the patient's responses to mild exertion, utilizing a 12-lead electrocardiogram (ecg), physical examination, 24-hour monitoring with a portable ecg, self-care evaluation and a modified treadmill screening test. Patient performance was assessed at each stage of testing and individualized activity levels were determined in accordance with cardiac responses. Thus patients progressed at their optimum rate with safety and without loss of time, ie, artificially induced invalidism. Following the 1st self-care evaluation, 3 patients were ordered to bedrest for further medical treatment while 26 were cleared for ward activity. When their conditions improved the 3 patients were reevaluated and began the program. The 15 patients without complications had appropriate responses to activity and proceeded to a mild exercise program with minimal observation. Of the 14 with complications, 5 experienced a temporary program interruption and 2 were dropped from the program secondary to severity of complications. The remaining 7 were progressed in the same manner as those without complication.

Early innate resistance to salmonellae in mice is controlled by the chromosome 1 gene Ity which regulates the in vivo net growth rate of bacteria in the RES by an unknown mechanism. It similarly controls innate resistance to Leishmania donovani, BCG and Mycobacterium lepraemurium. Murine Kupffer cell cultures were infected with virulent Salmonella typhimurium and followed for 12 h. Multiresistant organisms were used so that the antibiotics in the medium could not interfere with the results; extracellular bacteria were removed by repeated washes. Monolayers from resistant Ityr (C3H/He, CBA, A/J) and Ityr/s (B10 x A/J)F1 mice resisted infection with S. typhimurium C5 better than those from susceptible Itys (DBA/1, BALB/c, B10.M) mice, which were progressively lost from the culture plates at a faster rate than resistant monolayers. Organisms were clearly visible inside large vacuoles in the macrophages. The results confirm and amplify results of others on salmonella-infected peritoneal and splenic macrophages, and support the view that the Ity gene is expressed as a function of macrophages.