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Efficient cargo uptake is essential for cell-penetrating peptide (CPP) therapeutics, which deliver widely diverse cargoes by exploiting natural cell processes to penetrate the cell's membranes. Yet most current CPP activity assays are hampered by limitations in assessing uptake, including confounding effects of conjugated fluorophores or ligands, indirect read-outs requiring secondary processing, and difficulty in discriminating internalization from endosomally trapped cargo. Split-complementation Endosomal Escape (SEE) provides the first direct assay visualizing true cytoplasmic-delivery of proteins at biologically relevant concentrations. The SEE assay has minimal background, is amenable to high-throughput processes, and adaptable to different transient and stable cell lines. This split-GFP-based platform can be useful to study transduction mechanisms, cellular imaging, and characterizing novel CPPs as pharmaceutical delivery agents in the treatment of disease.

The aims of this study were twofold: to analyze the incidence of patients having synchronous or metachronous bilateral invasive breast cancer (SBBC and MBBC) and to assess the characteristics and outcome compared to those having unilateral breast cancer (UBC). The used data were obtained from our prospective population-based cohort study which had been started in 1983. Bilateral breast cancer (BBC) was categorized as SBBC (≤3 months of the first primary) or MBBC (>3 months after the first primary). The incidence of SBBC was 1% and that of MBBC 7.0 %. Patients with UBC showed more ductal carcinoma compared to patients with BBC. MBBC status was an independent significant predictor of local failure (HR 1.9; 95% CI 1.3-2.7). SBBC status was an independent predictor of distant metastases (HR 2.6; 95% CI 1.4-4.5). Overall survival (OS) was better for MBBC (HR 0.6; 95% CI 0.4-0.8) and worse for SBBC (HR 2.3; 95% CI 1.5-3.6) compared to UBC. We noted: (1) MBBC showed a significant higher local failure compared to UBC, (2) SBBC, compared to MBBC and UBC had a significant higher distant metastases rate, (3) disease-specific survival and OS were significantly worse for SBBC compared to UBC and MBBC, and (4) that the OS for MBBC compared to UBC, was significantly better.

Purpose: The present study was conducted to evaluate whether the bioavailability of pregabalin capsules 150 mg manufactured by PT Dexa Medica was equivalent to the reference formulation., Methods: This was a randomized, open-label, two-period, two-sequence, and crossover study under fasting condition, with a 1-week washout period. Plasma concentrations of pregabalin from 20 subjects were determined by using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) detection method. Pharmacokinetic parameters assessed in this study were: area under the plasma concentration-time curve from time zero to last observed quantifiable concentration (AUC0-t), area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), and terminal half-life (t1/2). The 90% confidence intervals (CIs) for the geometric mean ratios of test formulation/reference formulation were calculated for the AUC and Cmax parameters; while tmax difference was analyzed nonparametrically on the original data using the Wilcoxon matched-pairs test, and t1/2 difference was analyzed using Student's paired t-test., Results: The mean (standard deviation [SD]) AUC0-t, AUC0-∞, Cmax, and t1/2 of pregabalin from the test formulation were 27,845.86 (4,508.27) ng · h/mL, 28,311.70 (4,790.55) ng · h/mL, 3,999.71 (801.52) ng/mL, and 5.66 (1.20) hours, respectively; while the mean (SD) AUC0-t, AUC0-∞,Cmax, and t1/2 of pregabalin from the reference formulation were 27,398.12 (4,266.28) ng · h/mL, 27,904.24 (4,507.31) ng · h/mL, 3,849.50 (814.50) ng/mL, and 5.87 (1.25) hours, respectively. The median (range) tmax of pregabalin from the test formulation and reference formulation was 1.00 (0.67-2.00) hours and 1.00 (0.67-3.00) hours, respectively. The 90% CIs for the geometric mean ratios of test formulation/reference formulation for pregabalin were 101.54% (98.75%-104.41%) for AUC0-t, 101.35% (98.66%-104.11%) for AUC0-∞, and 104.19% (98.75%-109.93%) for Cmax., Conclusion: The study concluded that the two formulations of pregabalin capsules studied were bioequivalent.

Purpose: To investigate four-dimensional flow denoising using the divergence-free wavelet (DFW) transform and compare its performance with existing techniques., Theory and Methods: DFW is a vector-wavelet that provides a sparse representation of flow in a generally divergence-free field and can be used to enforce "soft" divergence-free conditions when discretization and partial voluming result in numerical nondivergence-free components. Efficient denoising is achieved by appropriate shrinkage of divergence-free wavelet and nondivergence-free coefficients. SureShrink and cycle spinning are investigated to further improve denoising performance., Results: DFW denoising was compared with existing methods on simulated and phantom data and was shown to yield better noise reduction overall while being robust to segmentation errors. The processing was applied to in vivo data and was demonstrated to improve visualization while preserving quantifications of flow data., Conclusion: DFW denoising of four-dimensional flow data was shown to reduce noise levels in flow data both quantitatively and visually., (© 2014 Wiley Periodicals, Inc.)

Purpose: The aim of this study was to explore the common characteristics of patients diagnosed with upper-extremity venous thromboembolism (UEVTE) during hospitalization., Design: This was a retrospective chart review., Setting: This study was performed at a Midwest multisite hospital of 5 acute-care hospitals and 2051 beds., Sample: The sample was composed of 777 hospitalized adult patients who had a positive upper-extremity venous Doppler from July 2008 to July 2009., Results: Patients were adults with a mean age of 66.6 (SD, 17.0) years and mean hospital stay of 15.7 (SD, 12.4) days. When assessing the arm clots, 398 patients (51.2%) had a right arm clot, 317 patients (40.8%) had a left arm clot, and 62 patients (8.0%) had clots in both arms. Patients were primarily admitted with medical conditions, and more than one-half were overweight or obese (59.2%). Nearly 50% of patients were at the highest venous thromboembolism (VTE) risk upon admission (n = 362), were tobacco users (n = 379), and had surgeries or invasive procedures performed prior to upper-extremity venous Doppler (n = 395). In 58.6% of the patients, chemoprophylaxis through intravenous anticoagulation therapy was administered during the first 3 days of admission. In patients with an intravenous catheter in an arm, UEVTE was likely to occur in the same arm (right and left arm, P < .001)., Implications: Nurses caring for patients with characteristics commonly found in cases of UEVTE should regularly monitor the arms of their patients and communicate findings in shift reports to heighten awareness of UEVTE risk. In addition, patients with medical diagnoses that prevent use of early anticoagulation for VTE prophylaxis such as gastrointestinal bleed, hematologic disorders, trauma, and hemorrhagic strokes should be frequently assessed for UEVTE. Learning the characteristics of patients who had UEVTE during their hospitalization and the role of early and late anticoagulation in the development of UEVTE would advance nurse assessment and lead to novel interventions and future research.

Purpose: To analyze the incidence and prognostic factors of ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) in a large, population-based, single-center study with long-term follow-up., Methods and Materials: We analyzed 3595 cases in which BCT was performed in 3824 women with stage I or II breast cancer. The incidence of IBTR was analyzed over time and was based on IBTR as first event., Results: The 15-year local relapse-free survival was 90.9%. The hazard estimates for IBTR showed a time course with 2 peaks, the first at approximately 5 years and the second, twice as high, at 12 years. Stratifying subjects by age and margin status showed that, for women ≤40 years old with negative margins, adjuvant systemic therapy led to a 5-fold reduced risk of recurrence compared to none, and the presence of lymph vascular space invasion (LVSI) had a 3-fold increased risk compared to its absence. For women >40 years old, the presence of LVSI (hazard ratio [HR] 2.5) and the presence of lobular carcinoma in situ in the lumpectomy specimen (HR 2.3) were the only 2 risk factors., Conclusions: We demonstrated a pattern in risk of IBTR over time, with 2 peaks, first at approximately 5 years and a second, much higher peak at approximately 12 years, especially for women ≤40 years old. For women ≤40 years old with tumor-free resection margins, we noted that the absence of adjuvant systemic therapy and the presence of LVSI were independent prognostic factors of IBTR. For women >40 years old, the presence of LVSI and the presence of lobular carcinoma in situ were independent risk factors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: We investigated the impact of Hodgkin lymphoma (HL) on parenthood, including factors influencing parenthood probability, by comparing long-term HL survivors with matched general population controls., Patients and Methods: A Life Situation Questionnaire was sent to 3,604 survivors treated from 1964 to 2004 in successive clinical trials. Responders were matched with controls (1:3 or 4) for sex, country, education, and year of birth (10-year groups). Controls were given an artificial date of start of treatment equal to that of their matched case. The main end point was presence of biologic children after treatment, which was evaluated by using conditional logistic regression analysis. Logistic regression analysis was used to analyze factors influencing spontaneous post-treatment parenthood., Results: In all, 1,654 French and Dutch survivors were matched with 6,414 controls. Median follow-up was 14 years (range, 5 to 44 years). After treatment, the odds ratio (OR) for having children was 0.77 (95% CI, 0.68 to 0.87; P < .001) for survivors compared with controls. Of 898 survivors who were childless before treatment, 46.7% achieved post-treatment parenthood compared with 49.3% of 3,196 childless controls (OR, 0.87; P = .08). Among 756 survivors with children before treatment, 12.4% became parents after HL treatment compared with 22.2% of 3,218 controls with children before treatment (OR, 0.49; P < .001). Treatment with alkylating agents, second-line therapy, and age older than 35 years at treatment appeared to reduce the chances of spontaneous post-treatment parenthood., Conclusion: Survivors of HL had slightly but significantly fewer children after treatment than matched general population controls. The difference concerned only survivors who had children before treatment and appears to have more personal than biologic reasons. The chance of successful post-treatment parenthood was 76%.

Purpose: The optimal sequence of radiotherapy and chemotherapy in breast-conserving therapy is unknown., Methods and Materials: From 1983 through 2007, a total of 641 patients with 653 instances of breast-conserving therapy (BCT), received both chemotherapy and radiotherapy and are the basis of this analysis. Patients were divided into three groups. Groups A and B comprised patients treated before 2005, Group A radiotherapy first and Group B chemotherapy first. Group C consisted of patients treated from 2005 onward, when we had a fixed sequence of radiotherapy first, followed by chemotherapy., Results: Local control did not show any differences among the three groups. For distant metastasis, no difference was shown between Groups A and B. Group C, when compared with Group A, showed, on univariate and multivariate analyses, a significantly better distant metastasis-free survival. The same was noted for disease-free survival. With respect to disease-specific survival, no differences were shown on multivariate analysis among the three groups., Conclusion: Radiotherapy, as an integral part of the primary treatment of BCT, should be administered first, followed by adjuvant chemotherapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: In this large cohort of Hodgkin's lymphoma survivors with long follow-up, we estimated the impact of treatment regimens on premature ovarian failure (POF) occurrence and motherhood, including safety of nonalkylating chemotherapy and dose-response relationships for alkylating chemotherapy and age at treatment., Patients and Methods: The Life Situation Questionnaire was sent to 1,700 women treated in European Organisation for Research and Treatment of Cancer and Groupe d'Étude des Lymphomes de l'Adulte trials between 1964 and 2004. Women treated between ages 15 and 40 years and currently not using hormonal contraceptives (n = 460) were selected to assess occurrence of POF. Cumulative POF risk was estimated using the life-table method. Predictive factors were assessed by Cox regression analysis., Results: Median follow-up was 16 years (range, 5 to 45 years). Cumulative risk of POF after alkylating chemotherapy was 60% (95% CI, 41% to 79%) and only 3% (95% CI, 1% to 7%) after nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine; epirubicin, bleomycin, vinblastine, and prednisone). Dose relationship between alkylating chemotherapy and POF occurrence was linear. POF risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy at age younger than 32 years and age 32 years or older, cumulative POF risks were 3% (95% CI, 1% to 16%) and 9% (95% CI, 4% to 18%), respectively. If menstruation returned after treatment, cumulative POF risk was independent of age at treatment. Among women who ultimately developed POF, 22% had one or more children after treatment, compared with 41% of women without POF., Conclusion: Nonalkylating chemotherapy carries little to no excess risk of POF. Dose-response relationships for alkylating chemotherapy and age at treatment are both linear. Timely family planning is important for women at risk of POF.

Introduction: Breast cancer, the most common malignancy in women, still holds many secrets. The causes for non-hereditary breast cancer are still unknown. To elucidate any role for circulating naturally secreted proteins, a screen of secreted proteins' influence of MCF10A cell anchorage independent growth was set up., Methods: To systematically screen secreted proteins for their capacity to transform mammalian breast epithelial cells, a soft agar screen of MCF10A cells was performed using a library of ~ 470 secreted proteins. A high concentration of infecting viral particles was used to obtain multiple infections in individual cells to specifically study the combined effect of multiple secreted proteins., Results: Several known breast cancer factors, such as Wnt, FGF and IL were retained, as well as factors that were previously unknown to have a role in breast cancer, such as paraoxonase 1 and fibroblast growth factor binding protein 2. Additionally, a combinatory role of Interleukin 6 with other factors in MCF10A anchorage-independent growth is demonstrated., Conclusion: The transforming effect of combinations of IL6 with other secreted proteins allows studying the transformation of mammary epithelial cells in vitro, and may also have implications in in vivo studies where secreted proteins are upregulated or overexpressed.

Purpose: The aim is to look at the impact of margin status and outcome of invasive lobular carcinoma (ILC) treated with breast-conserving therapy (BCT)., Methods: This manuscript describes an analysis on 330 BCT in 318 patients with ILC., Results: The 12-year local relapse free survival (LRFS) is 89%. In multivariate analysis, positive margin status, age>50 years, contra lateral breast cancer, and adjuvant systemic therapy were significant predictors of local relapse free survival. In a separate analysis limited to a positive margin for invasive carcinoma or carcinoma in situ, only a positive margin for invasive carcinoma was a significant predictor of local relapse free survival. This was limited to women

Objective: To assess the reliability and validity of a new parent report measure of children's dietary patterns, allowing assessment against national guidelines., Methods: The 28-item Children's Dietary Questionnaire (CDQ) was developed based on Australian healthy eating guidelines and knowledge of current dietary intake of Australian children. It assesses intake patterns in either the previous week or 24 hours of foods for which intake is recommended (positive indicators - fruit, vegetables, water, reduced fat products) and foods for which intake is discouraged (negative indicators - high fat/sugar foods [non-core foods], sweetened beverages and full fat dairy products). Four food group subscales are generated: fruit and vegetable, fat from dairy, sweetened beverages and non-core foods. Test-retest reliability, internal consistency, relative validity and the ability to detect change were tested in five separate study samples of children, totalling 706 children aged 4 to 16 years., Results: The fruit and vegetable and non-core foods subscales demonstrated good internal consistency (alpha 0.76 and 0.62, respectively) and item:total correlations greater than 0.2. The fat from dairy and the sweetened beverages subscales consistently performed poorly. All subscales demonstrated satisfactory test-retest reliability (intraclass correlation coefficient 0.51 to 0.90) and ability to detect change in the expected direction following a weight management intervention. Relative validity suggests ability to distinguish positive or negative dietary risk based on CDQ scores at the group but not individual level., Conclusion: The CDQ shows acceptable reliability and relative validity for assessing group level child dietary patterns with key aspects of healthy eating guidelines.

Purpose: To determine the effects of boost volume (BV) in relation to margin status and tumor size on the development of local recurrence with breast-conserving therapy., Methods and Materials: Between 1983 and 1995, 1,073 patients with invasive breast cancer underwent 1,101 breast-conserving therapies. Of these 1,101 BCTs, 967 were eligible for analysis. The BV was categorized into tertiles: <66 cm(3) (n = 330), 66-98 cm(3) (n = 326), and >98 cm(3) (n = 311). The median follow-up was 141 months. Separate analyses were done for women < or =40 years and >40 years., Results: No significant difference in local recurrence was shown between the tertiles and the recurrence site. The 15-year local recurrence-free survival rate was 87.9% for the first tertile, 88.7% for the second, and 89% for the third. For women < or =40 years old, the corresponding 15-year local recurrence-free survival rate was 80%, 74.5%, and 69.2%. For women >40 years old, the corresponding rate was 88.7%, 89.5%, and 90.9%. At 5 years, women >40 years old had significantly more local failures in the first tertile; this difference disappeared with time. A test for trend showed significance at 5 years (p = 0.0105) for positive margins for ductal carcinoma in situ in women >40 years of age., Conclusion: The results of this study have shown that the size of the external BV has no major impact on local control. For women >40 years old, positive margins for ductal carcinoma in situ showed a trend with respect to BV at 5 years. The BV had no influence on local control in the case of positive margins for invasive carcinoma.

A study of the possible difference in outcome for positive margins for invasive carcinoma (IC) versus ductal carcinoma in situ (DCIS), and with regard to different age categories in a large prospective cohort of patients with invasive breast cancer. A total of 2 291 BCT were analyzed. Margins were positive for IC in 8.7% and for DCIS in 4.6%. The median follow-up was 83 months. The 10-year local recurrence-free survival for negative margins vs. positive margins for IC vs. positive for DCIS for women < or = 40 years were 84.4% vs. 34.6% (HR 4.5) vs. 67.5%, and for women >40 years 94.7% vs. 92.6% vs. 82.6% (HR4.2). The 10-year distant disease-free survival for negative margins vs. positive margins for IC vs. positive for DCIS women < or = 40 years were 72.0% vs. 39.7% (HR 3.4) vs. 77.8%. The disease-specific survival showed a significant relation to positive margins for IC in young women. The effect of positive margin for IC seems to be limited to young women only, and is not only restricted to local control, but also to distant metastasis and survival. On the other hand a positive margin for DCIS is a risk factor for local control in women >40 years.

Purpose: To look at the optimum timing of radiotherapy in breast-conserving therapy (BCT) in relation to outcome in breast cancer., Methods: We analyzed 1473 BCT on 1446 breast cancer patients from our prospective cohort, stage I or II, node-negative, and without adjuvant systemic therapy. Timing was defined as time from lumpectomy till radiotherapy. Patients were categorized into three timing tertiles: 1-36 days, 37-53 days, and 54-112 days., Results: The 10-year local relapse-free survival rates did not show significant differences between the three groups. The 10-year Distant Metastasis-Free Survival (DMFS) was 78.9% for the first tertile, versus 86.1% (HR 0.6; P = 0.009) for the second, and 90.7% (HR 0.3; P < 0.001) for the third. The 10-year Disease-specific Survival (DSS) was 83.8% for the first tertile, versus 90.6% (HR 0.5; P = 0.007) for the second, and 97.2% (HR 02; P < 0.001) for the third. Also in multivariate Cox regression analysis the second (HR 0.6; P = 0.053) and the third tertile (HR 0.3; P = 0.002) had significantly better DSS., Conclusion: Timing of radiotherapy in BCT for breast cancer seems to be highly important in relation to survival. This study shows a 40-70% relative survival benefit with timing after 36 days.

Background: A major outbreak of human enterovirus 71-associated hand, foot and mouth disease in Sarawak in 1997 marked the beginning of a series of outbreaks in the Asia Pacific region. Some of these outbreaks had unusually high numbers of fatalities and this generated much fear and anxiety in the region., Methods: We established a sentinel surveillance programme for hand, foot and mouth disease in Sarawak, Malaysia, in March 1998, and the observations of the first 7 years are described here. Virus isolation, serotyping and genotyping were performed on throat, rectal, vesicle and other swabs., Results: During this period Sarawak had two outbreaks of human enterovirus 71, in 2000 and 2003. The predominant strains circulating in the outbreaks of 1997, 2000 and 2003 were all from genogroup B, but the strains isolated during each outbreak were genetically distinct from each other. Human enterovirus 71 outbreaks occurred in a cyclical pattern every three years and Coxsackievirus A16 co-circulated with human enterovirus 71. Although vesicles were most likely to yield an isolate, this sample was not generally available from most cases and obtaining throat swabs was thus found to be the most efficient way to obtain virological information., Conclusion: Knowledge of the epidemiology of human enterovirus 71 transmission will allow public health personnel to predict when outbreaks might occur and to plan interventions in an effective manner in order to reduce the burden of disease.

From July through December 1997, 11 previously healthy children in Peninsular Malaysia succumbed to an illness clinically characterised by an acute severe refractory left-ventricular failure, following a brief prodromal illness, in the midst of an outbreak of hand, foot and mouth disease (HFMD), similar to the reported experience in Sarawak and Taiwan. Retrospective reviews of the clinical features and results of laboratory, pathological and virological investigations of cases were conducted. The median age of the 11 case-patients was 31 months (range, 13 to 49 months); 6 were males. A brief prodromal illness of 3 days (range, 2 to 5 days) was characterised by fever (axillary temperature > 38 degrees C) (100%), oral ulcers (72%), extremity rashes (45%) and significant vomiting (55%). Upon hospitalisation, 7 of 11 case-patients had features suggestive of cardiogenic shock, while 4 of 11 case-patients developed shock during hospitalisation as evidenced by marked sustained tachycardia (heart rate > or = 180 beats per minute), poor peripheral pulses and peripheral perfusion, mottled extremities, pulmonary oedema (haemorrhagic pulmonary secretions in 8 of 11 cases during tracheal intubation, often precipitated by conservative crystalloid boluses, and radiographic evidence of acute pulmonary oedema in 5 of 7 cases) and markedly impaired left ventricular function on echocardiographic examination (7 of 7 cases). Three of 4 case-patients had aseptic meningitis while one case-patient also had an acute flaccid paraparesis. Despite supportive therapy, death occurred within a median of 13.4 hours following hospitalization. Post-mortem findings (all 8 specimens examined) consistently demonstrated brain-stem encephalitis with foci of neuronal necrosis and micro-abscesses. None of the 11 specimens examined revealed histological evidence of myocarditis. Enterovirus 71 (EV71) was detected in 10 of 11 case-patients, many (7) from various sterile tissue sites (5 from central nervous tissues). No other viruses were isolated or identified. Clinical features and pathological studies closely paralleled the reported experience in Sarawak and Taiwan. The uniform necropsy findings of necrotizing brain-stem encephalitis coupled with essentially normal myocardial histology, in concert with the concurrent and consistent detection of EV71 points to a primary EV71 encephalitis; as yet unclear neurogenic mechanisms may account for the cardiovascular manifestations.

We report the first experimental evidence of nontrivial thermal behavior of the simplest mesoscopic system--a superconducting loop. By measuring the specific heat C of an array of 450,000 noninteracting aluminum loops with very high accuracy of approximately 20 fJ/K, we show that the loops go through a periodic sequence of phase transitions (with a period of an integer number of magnetic flux quanta) as the magnetic flux threading each loop is increased. The transitions are well described by the Ginzburg-Landau theory and are accompanied by discontinuities of C of only several thousands of Boltzmann constants kB.

Purpose: To identify the importance of positive margins for invasive carcinoma on local control in patients treated with breast-conservative treatment (BCT)., Methods and Materials: A total of 1752 BCT with known margins were analyzed. Fifty-five patients had a second BCT, leaving 1697 patients for analysis. The margins were positive in 193/1752 BCT (11%). The median follow-up was 78 months., Results: The 5- and 10-year local recurrence rates (LRR) were 3.1% and 6.9%, respectively, for negative margins vs. 5.6% and 12.2% for positive margins. A statistical interaction between age category and margin status was noted in relation to disease-free survival (DFS) and local relapse-free survival. The 5-year LRR for women < or =40 years was 8.4% for negative margins and 36.9% for positive margins (p = 0.005). In a multivariate analysis, a positive margin was significant. The 5-year LRR for women >40 years was 2.6% for negative and 2.2% for positive margins. The 5-year DFS for women 40 years was 84.3% for positive and 87.2% for negative margins., Conclusion: Women < or =40 years are a special category of patients in breast cancer. Women < or =40 years must have negative margins for invasive carcinoma when treated with BCT. Minimum surgery for an optimal cosmetic result followed by irradiation, even with microscopic positive margins for invasive carcinoma, yields excellent results with regard to local control in patients older than 40 years.

The purpose of this study was to address the question whether patients with bilateral breast cancer (BBC) have a worse prognosis in terms of recurrence and survival than patients with primarily unilateral breast cancer (UBC) following breast-conserving treatment (BCT). From 1983 to 2000, a total of 1760 BCT were registered in the Radiotherapy Department of the Medisch Spectrum Twente. We defined synchronous a BBC as cancer diagnosed in both breasts at the same time or within a period of 3 months of diagnosis of the first tumor. One thousand seven hundred and sixty BCT were performed on 1705 patients, 26 of whom presented with BBC. Of these 26 patients, 18 had BCT for both breasts. A higher proportion of patients with BBC showed more tubular carcinoma (P=0.029) and medially located tumors (P=0.076) than those with UBC did. The 5- and 10-year local recurrence rates (LRRs) were 4.5% and 9.1%, respectively, in BBC patients, as against 3.3% and 7.6% for UBC after BCT. The 5- and 10-year distant metastasis rates were 26.9% and 50.7%, respectively, for BBC as against 13.4% and 21.1% for UBC after BCT (P=0.065 and P=0.014, respectively). The 5- and 10-year disease-specific survival (DSS) rates for the 1705 patients were 82.1% and 41%, respectively, after BBC, and 91.4% and 84% after UBC (P=0.086 and P=0.0045, respectively). Patients with BBC have a higher rate of distant metastasis and a worse DSS than those with UBC. As the LRR is similar for BBC and UBC, BCT is not contraindicated in BBC. The incidence of BBC is low, at 1.5% which makes it difficult to reach any more definitive conclusions on outcome and treatment.

Background and Purpose: In a recent study on patients with transitional cell cancer of the bladder treated with curative radiotherapy following TUR-T, we demonstrated that a low apoptotic index and p53 positivity were associated with poor local control. The purpose of this study was to assess the prognostic significance of additional markers implicated in regulation of cell cycle and apoptosis., Patients and Methods: Bcl-2, Bax and p21 positivity were detected immunohistochemically on paraffin-embedded pre-treatment biopsies from 83 patients with invasive transitional cell cancer (TCC) of the bladder, treated with radiotherapy. In addition, markers determined in an earlier analysis, i.e.: p53, apoptotic index, cyclin D1, retinoblastoma protein and Ki-67 were included in the multivariate analysis. A stepwise proportional hazard analysis was performed, adjusting for classic prognostic factors (T-stage, grade, multifocality and macroscopic completeness of the TUR). Positivity was defined as >10% of tumor cells staining positive for Bcl-2, Bax and p21, and >20% for p53., Results: Bcl-2 positivity was found in 63%, Bax was positive in 52% and p21 in 55% of cases. In the PH analysis Bcl-2 positivity was found to be related to poor local control (36 vs. 72% at 3 years; P=0.003), as well as to shorter disease-specific survival (74 vs. 94% at 3 years; P=0.017). Evidence for an adverse effect of p53 positivity was also found (local control: 32 vs. 69% at 3 years;P=0.037, disease-specific survival: 76 vs. 92% at 3 years; P=0.043). In an additional PH analysis, we found poor local control rates for bladder cancers with combined Bcl-2 and p53 positivity (17 vs. 65% at 3 years; P=0.0017), and lower disease specific survival (60 vs. 92%; P=0.0024), disease-free survival (7 vs.35%, P=0.0023) and overall survival (39 vs. 80%; P=0.0018)., Conclusion: This study provides evidence for a poor outcome in patients treated with radiotherapy for TCC of the bladder expressing both Bcl-2 and p53. This relationship was found for local control and disease-free, disease-specific and overall survival.

Purpose: To determine whether the apoptotic index, the Ki67 index, and the expression of the p53, cyclin D1, and retinoblastoma genes correlate with local control, overall survival, and time to distant metastases in invasive bladder cancer treated with external beam radiation., Methods and Materials: Paraffin-embedded pretreatment biopsies from 83 patients with invasive transitional cell carcinoma of the bladder were scored morphologically for apoptosis and immunohistochemically for Ki67, p53, cyclin D1, and retinoblastoma gene expression. Survival analysis methods were used to assess overall survival, local control, and freedom from distant metastases. A multiple proportional hazard (PH) regression analysis was performed to study the prognostic value of the abovementioned biologic parameters (all divided into two categories, except Ki67) in addition to classical prognostic factors such as T stage, histologic grade, multifocality of the tumor, and completeness of transurethral resection. All patients were treated with external beam radiation as sole treatment. Median follow-up for the 19 patients still living was 7.5 years., Results: Apoptotic index varied from 0% to 3.4% with a mean of 0.8% and a median of 0.6%. Ki67 index varied from 0% to 60% with a mean of 14% and a median of 12%. P53 protein was detectable in 61% of the tumors. Overexpression of cyclin D1 was observed in 39% of the tumors and loss of retinoblastoma protein in 23% of the tumors. High Ki67 index was found to be significantly associated with p53 expression (p = 0.04) and cyclin D1 overexpression (p = 0.023). Cyclin D1 overexpression was found more often in Rb-positive tumors than in Rb-negative tumors (p = 0.006). Other associations between the markers are less clear. Biologic markers were not correlated with T stage or grade. In the PH analysis local control was found to be significantly better for tumors with wild-type p53 (p = 0.028). Also, tumors with an apoptotic index above the median value (0.6%) had a significantly better local control rate (p = 0.035). Ki67 index (p = 0.35), retinoblastoma gene expression (p = 0.30) and cyclin D1 overexpression (p = 0.61) were not found to have an additional predictive value regarding local tumor control. None of the tested biologic parameters were found to be associated with overall survival. Time to distant metastases was significantly shorter for tumors with high Ki67 index (p = 0.01) and tumors with an apoptotic index less than median (p = 0.009)., Conclusions: The results of our study provide evidence for a prognostic value of p53 expression and apoptotic index with respect to the radiation response in bladder cancer in addition to more conventional prognosticators. The value of these parameters as a predictive assay for radiation response warrants confirmation in larger and prospective studies.

A hospital-based case-control study of viral encephalitis was carried out at Port Dickson Hospital, in the state of Negeri Sembilan, Malaysia. Between March and May 1999, 69 clinically diagnosed viral encephalitis cases and 31 controls were interviewed. Job histories on pig farming activities were assessed by a group of epidemiologists and veterinary surgeons. Results show that among clinical cases of viral encephalitis, 52 (75.4%) cases were diagnosed to have Nipah virus infection based on positive serology for antibodies to the cross-reacting Hendra virus antigen. The Nipah virus encephalitis was significantly associated with a history of working in pig farms (p < 0.001, OR = 196.0, 95% CI = 20.4-4741.6), history of contact with animals (p < 0.001, OR = 38.3, 95% CI = 8.2-209.0) and with history of direct contact with pigs (p = 0.002, OR = 34.4, 95% CI = 2.6-1,024.4). The Nipah virus infection was also significantly associated with history of feeding/cleaning pigs (p < 0.001, OR = 102, 95% CI = 11.9-2,271.5). These results provide evidence that involvement in pig farming activities is significantly associated with the risk of getting Nipah virus infection. They are potential risk factors for Nipah virus transmission in the major pig-producing area of Bukit Pelandok, Port Dickson Negeri Sembilan.

An outbreak of encephalitis affecting 265 patients (105 fatally) occurred during 1998-1999 in Malaysia and was linked to a new paramyxovirus, Nipah, that infected pigs, humans, dogs, and cats. Most patients were pig farmers. Clinically undetected Nipah infection was noted in 10 (6%) of 166 community-farm controls (persons from farms without reported encephalitis patients) and 20 (11%) of 178 case-farm controls (persons from farms with encephalitis patients). Case patients (persons with Nipah infection) were more likely than community-farm controls to report increased numbers of sick/dying pigs on the farm (59% vs. 24%, P=.001) and were more likely than case-farm controls to perform activities requiring direct contact with pigs (86% vs. 50%, P=.005). Only 8% of case patients reported no contact with pigs. The outbreak stopped after pigs in the affected areas were slaughtered and buried. Direct, close contact with pigs was the primary source of human Nipah infection, but other sources, such as infected dogs and cats, cannot be excluded.

We determined interleukin-6 (IL-6) levels in the serum of 212 well-defined patients with newly diagnosed paraproteinaemia and evaluated its discriminatory value and prognostic role in multiple myeloma (MM). Results were compared with serum neural cell adhesion molecule and beta-2-microglobulin, both established prognostic MM markers. Paraproteinaemia-related diagnoses were: MM (60), other haematological diseases (46), solid tumours (35), autoimmune diseases (17) and monoclonal gammopathy of unknown significance (MGUS) (54). The range of IL-6 levels in all diagnostic groups overlapped widely and did not serve as a discriminatory marker in newly diagnosed paraproteinaemia even when patients with infection or fever (42) were excluded. In MM high IL-6 levels (>/= 50 pg/ml) were not associated with a shorter survival (P = 0.24). We compared our results with 20 published studies on serum IL-6 in paraproteinaemia and/or MM. IL-6 data have to be related to the assay used (bio- or immunoassay) and to the status of MM (newly diagnosed, during therapy, progressive disease). We conclude that serum IL-6 is not specific for paraproteinaemia-related diseases and will not serve as a reliable discriminatory or prognostic marker in paraproteinaemia and MM.

Diagnoses in patients with paraproteinaemia are diverse; few (mostly single centre based) studies are known that describe incidence, diagnoses and follow-up in patients with paraproteinaemia. In the region of the Comprehensive Cancer Centre West in the Netherlands (population 1.6 million, 1992) a population-based registry was set up in the period 1991-1993. Patients (n = 1464; median age: 72 years; range: 16-102) were entered by clinical chemists, internists, haematologists, and pathologists. Multiple myeloma and plasmacytoma were diagnosed in 261 patients (18%), paraprotein-related haematological diseases in 159 patients (11%) and paraprotein-related internal diseases in 210 patients (14%). After bone marrow examination monoclonal gammopathy of unknown significance (MGUS) was diagnosed in 207 (14%) patients. No further diagnosis could be made in 627 (43%) patients mostly for lack of supplementary bone marrow and (or) X-ray examinations. Consequently, more than two-thirds of all patients with a newly found paraprotein did not show any sign of a haematological malignancy. Using these data a 'myeloma risk score' was developed to predict the presence of a multiple myeloma based on paraprotein type and concentration, aiding the physician in determining which patients should undergo further bone marrow and skeletal examinations.

Patients with monoclonal gammopathies comprise a heterogenous group. The few studies on incidence and follow-up are single-centre-based and may reflect referral bias. To avoid this, all patients (n=1275) in midwestern Netherlands with a newly discovered paraproteinaemia in 1991, 1992 and 1993 were included in a population-based registry and divided into four major diagnostic groups: multiple myeloma and plasmacytoma (n=230, 18%), other haematological diseases (n=141, 11%), paraprotein-related internal diseases (n=191, 15%) and monoclonal gammopathy of undetermined significance (MGUS, n=713, 56%). To avoid a possibly erroneous diagnosis, patients who were classified as having MGUS but who did not undergo confirmatory bone marrow examination were included in a separate group 'provisional MGUS' (n=524, 41%), whereas patients who did were classified as having 'definite MGUS' (n=189, 15%). The 'provisional MGUS' patients were relatively older and had more often a poor performance status, but differences between this and the 'definite MGUS' group were otherwise small. Patients complaining of general malaise more often had a full work-up of their paraproteinaemia. Bone pain, hypercalcaemia, high total protein, and high ESR occurred predominantly in the myeloma group, whereas fever or infection was less often seen in these patients. This registry of patients with paraproteinaemias provided valuable data related to all different diseases associated with paraproteinaemia.

Diagnostic systems for monoclonal gammopathies use bone marrow and X-ray examinations to exclude multiple myeloma (MM). Data from a population-based registry of unselected patients with paraproteinemia indicate that these tests are often done only when MM is suspected. We used 441 randomly selected patients to develop a simple four point "Myeloma Risk Score" based on two readily available laboratory tests. One point was given for paraprotein concentration > or = 10 g/l, one point for IgG and IgA, and two points for IgD and light chains only. A score of 0 or 1 indicated a low risk for MM, with scores of 2 and 3 signifying high risks. Sensitivity, specificity, positive and negative predictive value (PV) for the Myeloma Risk Score in the training sample were 92%, 88%, 79%, and 96% respectively. Extrapolating these results to a larger cohort showed that 90% of patients with a monoclonal gammopathy could be classified correctly as having MM or a non-myeloma condition. The Myeloma Risk Score can identify patients with a paraproteinemia at risk for MM, and who are therefore candidates for bone marrow and X-ray examination.

The development of a population-based registry on paraproteinemia and multiple myeloma is described. A unique feature of this registry is the multidisciplinary approach to obtain and collect new cases. Clinical chemists, internists, hematologists, and pathologists could all enter patients. All patients newly diagnosed in the mid-western part of The Netherlands (1.7 million inhabitants in 1992) with a paraproteinemia or multiple myeloma in 1991, 1992, and 1993 were included. The project was composed of a registry of clinical and laboratory data extracted from the patient's records, storage of 1 ml serum at diagnosis, and a yearly follow-up. A total of 1832 entries was received, of which 83% met the inclusion criteria. Comparison of this database with the Regional Cancer Registry showed that the paraprotein registry was successful as far as registration of myeloma patients was concerned. We conclude that the multidisciplinary approach used in this paraprotein registry is feasible and has resulted in a unique collection of patients for studying potential pre-malignant conditions such as paraproteinemia.

Serum neural cell adhesion molecule (NCAM) has been described as a prognostic marker in multiple myeloma (MM). Both C-reactive protein (CRP) and beta 2-microglobulin (beta 2M) are established prognostic markers in MM. We tested the diagnostic value of these markers in 212 serum samples of patients with paraproteinemia registered prospectively in a population-based registry. Sixty patients had MM and 152 had other monoclonal gammopathies (hematologic diseases [48], paraneoplastic disease [35], autoimmune disease [15], and monoclonal gammopathy of undetermined significance [56]). CRP and beta 2M had wide and overlapping ranges in all diagnostic categories. However, serum neural cell adhesion molecule (NCAM) was low (< 20 U/mL) in all but 4 of 152 nonmyeloma cases and high (> or = 20 U/mL) in 31 (52%) of the 60 MM cases. Two patients with non-Hodgkin's lymphoma, 1 with chronic lymphatic leukemia, and 1 with autoimmune disease had serum NCAM values between 20 and 30 U/mL. In a discriminant analysis in which serum NCAM, CRP, beta 2M, paraprotein type and concentration, hemoglobin, leukocyte and thrombocyte counts, creatinine, corrected calcium, lactate dehydrogenase, and alkaline phosphatase were included, paraprotein type and concentration and serum NCAM turned out to be the best combination of parameters predicting whether a patient had MM, with 89% of cases being correctly classified. Even without bone marrow and x-ray examinations, serum NCAM, in combination with paraprotein type and concentration, can differentiate between MM and nonmyeloma patients.

An International Prognostic Index (IPI) for patients with aggressive non-Hodgkin's lymphoma (NHL) has recently been published. The IPI is based on pretreatment clinical characteristics and developed on clinical trial patients, classified as intermediate grade according to the Working Formulation (WF). We applied this IPI in a population-based registry of NHL patients. This registry does not have the restrictions that usually hold for patients in clinical trials, eg, with respect to age and performance status. Moreover, it covers all the three WF classes (low, intermediate, and high). The IPI turned out to be of prognostic value for response rate and survival in our unselected cohort of 744 patients, as well. In each of the three WF classes separately, the four IPI classes showed going from low to high substantially decreasing response rates and survival percentages. For our cohort of WF intermediate grade patients 5-year survival levels were lower in all four IPI classes (59%, 34%, 14%, and 10%, respectively), probably reflecting the selection of clinical trial patients in the original study (73%, 51%, 43%, and 26%).

The oncoprotein bcl-2 can be expressed in malignant plasma cells and might play a role in the prevention of corticosteroid-mediated apoptosis, thereby prolonging survival of the myeloma cells. We retrospectively investigated whether bcl-2 expression in bone marrow plasma cells measured by two-color fluorescence for immunoglobulin light chains would be related to survival duration in patients suffering from multiple myeloma. In all patients the large majority of plasma cells expressed bcl-2 (median 91%, range 74-100%). Contrary to our expectations, a tendency was observed toward higher percentages bcl-2+ plasma cells in patients with a long survival (more than 5 years, n = 9) vs patients who died from refractory myeloma within a year of diagnosis (n = 7). This tendency was found even when analysis was extended to include four patients in the short diagnosis group (n = 11) who had received chemotherapy prior to bone marrow examination.

We studied the medical histories of 127 patients diagnosed with multiple myeloma included in a population-based registry of 945 patients with a para-protein or multiple myeloma in the region of the Comprehensive Cancer Center West (CCCW). We defined patients "not immediately diagnosed" or "delayed diagnosis" as those patients in whom myeloma was not included in the initial differential diagnosis. We found that 37% belonged to this category. These patients more often had symptoms not associated with multiple myeloma. Since a surprising 51% of patients with delayed diagnosis turned out to have stage-III myeloma, the physician should be alert to the presence of this disease, despite the fact that co-morbidity may mask its presence.

There are a number of systems for diagnosing multiple myeloma, myeloma variants and monoclonal gammopathy of undetermined significance. We compared three systems, those according to Durie and Salmon, to Kyle and Greipp, and to the British Columbia Cancer Agency, using material from a population-based registry of 847 patients with a paraproteinemia or multiple myeloma. Of these, 157 underwent both bone marrow and X-ray examinations and were subsequently included in our analysis. The differences between the systems were small, even though in only 64% of the cases the diagnosis according to all three systems was identical. The system used by the British Columbia Cancer Agency turned out to be the shortest and easiest system reviewed here. We propose a more frequent application of this system instead of the more commonly used Durie and Salmon and Kyle and Greipp criteria.

Objectives: To assess the practicality, acceptability to patients and salary costs of the antenatal care of low risk obstetric patients by midwives., Design: A randomised controlled trial., Setting: The antenatal clinic at Westmead Hospital, a teaching hospital of the University of Sydney in western Sydney., Patients: From January 1989 until November 1990, 89 women booking for full antenatal care at Westmead Hospital and classified as low risk were randomly allocated to one of two groups. Group 1 (43 patients) had their antenatal care provided by registered midwives. Group 2 (46 patients) had their antenatal care provided by an obstetrician (either Visiting Medical Officer or Staff Specialist) in a routine hospital antenatal clinic., Interventions: Patients in the midwives' clinic were seen by an obstetrician at their first visit to the antenatal clinic and again at 30 weeks and at 40 weeks., Main Outcome Measures: These were the salary costs of each clinic and the patients' levels of satisfaction. Maternal and neonatal indicators, delivery details and analgesic requirements were also considered. These indicators were planned before data collection commenced., Results: The major differences found were a 28% to 68% salary cost saving and that patients cared for by midwives showed appreciation of the continuity of care and information given at the midwives' clinic., Conclusions: The care of low risk obstetric patients by midwives in a midwives' clinic showed salary cost savings and high patient acceptance.

The nutritional status of 641 children between the ages of 0 to 4 years old, from 835 households in 41 randomly selected rural villages with water supply in Sarawak were determined. Based on Waterlow's classification and the National Center for Health Statistics (NCHS) standards, 61% of the children were stunted and 44.1% were wasted. Based on Gomez's classification and the NCHS standards 81.9% of the children were malnourished. There was no sex difference in nutritional status. The percentage of malnourished children increased continuously with age while the percentage of children who were wasted increased from 6 to 36 months and then it leveled off. The percentage of stunted children also increased with age but the increase was sharpest in children who were 12 to 23 months old. It is noted that the Gomez classification overestimates the prevalence of undernutrition.

The role of angiotensin II (ANG II) in Na-depletion-induced Na appetite of mice was investigated. Intraperitoneal injection of the angiotensin-converting enzyme inhibitor captopril at 1.7 mg/mouse (high dose) decreased the Na intake of the Na-depleted (furosemide-treated) mice by 80-85%. The decrease in Na intake was restored to the initial level by concurrent subcutaneous infusion of ANG II. High dose of captopril also decreased the Na intake of fluid-deprived, Na-depleted mice. High dose of captopril did not alter water intake in any of the four conditions examined, i.e., in fluid-replete, Na-depleted, water-deprived, or fluid-deprived, Na-depleted mice. Low dose of captopril (1.7 microgram/mouse) tended to or significantly enhanced Na intake of Na-depleted mice. Low dose of captopril, however, did not enhance water intake in any of the conditions examined. Both high- and low-dose captopril treatment decreased food intake in water-deprived mice, whether or not the mice were Na depleted as well. The addition of captopril (0.1 or 1.0 mg/ml) to the drinking water did not influence Na or food intake. Water intake was enhanced during treatment with the low but not with the high dose of captopril. The results are consistent with the proposition that ANG II is involved in the Na appetite of Na-depleted mice. ANG II does not appear to have a role in water intake of Na-depleted or water-deprived mice, but neural mechanisms in which angiotensin has a role may influence food intake of water-deprived mice.

BALB/c mice exhibited a small hedonic intake of 0.3 M NaCl, which was not influenced by change from high to low salt diet or by withholding access to NaCl solution for 1 day. Sodium deficiency produced by furosemide injection consistently caused a highly significant increase in sodium intake. Sodium deficiency was corrected rapidly over 10 min. The appetite was specific for sodium in a cafeteria experiment and was exhibited by naive animals on the first experience of sodium deficiency and subsequent access to salt. The appetite was significantly related to the extent of body deficit, but overdrinking proportionate to initial deficit was characteristic. No increase in sodium intake occurred with repeated experience of sodium deficit. Water deprivation caused a subsequent increase of sodium intake. Total deprivation of food for 48 h caused a large sustained increase of sodium intake, but reduction of food intake by 40% did not influence sodium appetite.