Fast shut-down protection system for radio frequency breakdown and multipactor testing.

Radio frequency (RF) breakdown such as multipactor or ionization breakdown is a device-limiting phenomenon for on-orbit spacecraft used for communication, navigation, or other RF payloads. Ground testing is therefore part of the qualification process for all high power components used in these space systems. This paper illustrates a shut-down protection system to be incorporated into multipactor/ionization breakdown ground testing for susceptible RF devices. This 8 channel system allows simultaneous use of different diagnostic classes and different noise floors. With initiation of a breakdown event, diagnostic signals increase above a user-specified level, which then opens an RF switch to eliminate RF power from the high power amplifier. Examples of this system in use are shown for a typical setup, illustrating the reproducibility of breakdown threshold voltages and the lack of multipactor conditioning. This system can also be utilized to prevent excessive damage to RF components in tests with sensitive or flight hardware.

Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis.

BACKGROUND: Burkitt's lymphoma (BL) is a highly aggressive B-cell non-Hodgkin's lymphoma (NHL) that may be cured with intensive chemotherapy. The addition of the CD20-directed monoclonal antibody rituximab to CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, alternating with ifosfamide, etoposide, and cytarabine) has not been studied despite efficacy in other aggressive CD20-positive NHLs. PATIENTS AND METHODS: Eighty adult BL patients treated with or without rituximab were identified at our institutions. Response rate, overall survival (OS), and progression-free survival (PFS) are calculated. RESULTS: There were fewer relapses in rituximab-treated patients (3 of 40 versus 13 of 40, P = 0.01). There was a trend for improvement in outcome favoring rituximab-containing therapy, with 3-year PFS (74% versus 61%) and 3-year OS (77% versus 66%), although these did not reach statistical significance. Advanced age and central nervous system involvement were associated with poorer OS on multivariable Cox regression analysis, adjusting for treatment, human immunodeficiency virus (HIV) involvement, and risk group. CONCLUSIONS: CODOX-M/IVAC, with or without rituximab, is a highly effective regimen for the treatment of adult BL. Rituximab decreased the recurrence rate and showed a trend in favor of improvement in PFS and OS. HIV-infected patients achieved outcomes comparable with those of their non-HIV-infected counterparts.

Development and validation of a model predictive of occult nipple involvement in women undergoing mastectomy.

BACKGROUND: This prospective study aimed to build a predictive model using preoperative information to aid selection for nipple-sparing mastectomy. METHODS: Two hundred consecutive skin-sparing mastectomy specimens without overt nipple involvement were evaluated. Demographic, preoperative pathology and imaging information was collected. Nipple specimens (2 x 2 x 2 cm) were sectioned at 3-mm intervals. Haematoxylin and eosin-stained slides were examined by a breast pathologist for involvement by tumour. Logistic regression analyses of 65 therapeutic procedures identified factors associated with occult involvement and created a predictive model. This was tested on specimens from a further 65 therapeutic procedures. RESULTS: Occult nipple involvement was noted in 32 (24.6 per cent) of 130 mastectomy specimens. In the training set, imaging diameter of the lesion and its distance from the nipple predicted nipple involvement on univariable analysis (P = 0.011 and P = 0.014 respectively). The multivariable logistic regression model was validated in the test set. The areas under the receiver-operating characteristic curve were 0.824 and 0.709 for the training and test sets respectively. CONCLUSION: Three-quarters of women undergoing mastectomy did not have occult nipple involvement. A clinical tool including tumour size and distance from the nipple has been developed to improve patient selection for nipple-sparing mastectomy.

Matched pair analyses of stage IV breast cancer with or without resection of primary breast site.

BACKGROUND: Reports demonstrate improved survival of stage IV breast cancer patients with primary cancer resection. This may result from selection for surgery, rather than biological processes. METHODS: We performed matched-pair analysis that minimized potential bias in selecting surgery for primary cancer. Chart review was also performed of 5-year survivors to assess selection bias affecting breast surgery. RESULTS: 19,464 breast cancer patients were identified; 808 (4.2%) were stage IV: 622 were analyzed after eliminating wrong diagnoses or staging, and limiting patients to Massachusetts residents. Matched-pair analysis narrowed or eliminated apparent survival benefit associated with primary site surgery in several comparisons. When the impact of the sequence of systemic and surgical treatments was studied in stage IV patients, 90% 2-year survival occurred in patients receiving chemotherapy first, in contrast to receiving chemotherapy simultaneously with or after surgery, suggesting selection for delayed surgery after excellent response to initial chemotherapy. In bone metastases, the 2-year survival advantage occurred with chemotherapy before surgery; no difference in survival with or without surgery occurred when these treatments were simultaneous. Among 5-year survivors, frequency of primary site surgery after excellent response to systemic therapy, breast surgery in stage III patients incorrectly classified as stage IV, and frequency of oligo metastases all indicated selection bias. CONCLUSIONS: Case selection bias in primary breast cancer resection in state IV patients may explain most, if not all, the apparent survival advantage of such surgery.

Age-dependent effects of TWEAK/Fn14 receptor activation on neural progenitor cells.

TWEAK/Fn14 signaling regulates progenitor cell proliferation, differentiation, and survival in multiple organ systems. This study examined the effects of TWEAK (tumor necrosis factor-like weak inducer of apoptosis) treatment on cultured mouse neural progenitor cells. The receptor for TWEAK is expressed by neural progenitor cells from the early embryonic stages through postnatal development. Although embryonic day 12 (E12) and postnatal day 1 (PN1) neural progenitor cells both express the receptor for TWEAK, TWEAK treatment of cultured E12 and PN1 progenitor cells resulted in age-dependent effects on proliferation and on neurite extension by neuronal progeny. TWEAK treatment did not alter proliferation of E12 neural progenitor cells but shifted PN1 progenitor cells toward cell-cycle phases G0 and G1 and reduced the rate at which they incorporated CldU. Conversely, the effects of TWEAK on axon elongation were more prominent in the earlier developmental stage. TWEAK induced extensive neurite outgrowth by the neuronal progeny of E12 but not PN1 progenitors. Treatment of the E12 progenitor cells with a TWEAK-neutralizing antibody repressed neurite extension, indicating that endogenous activation of this pathway may be required for neurite extension by the embryonic neuronal progeny. These studies indicate that TWEAK/Fn14 receptor activation exerts different effects on neural progenitor cells and their progeny depending on the developmental stage of the cells.

Adolescent butterfly swimmer with bilateral subluxing sternoclavicular joints.

Sternoclavicular joint subluxation/dislocation injuries in the athlete are uncommon. They can be organised by degree (subluxation, dislocation), timing (acute, chronic, recurrent, congenital), direction (anterior, posterior), and cause (traumatic, atraumatic). The unusual case reported is an adolescent butterfly swimmer with recurrent bilateral sternoclavicular subluxation associated with pain and discomfort. The condition was treated and resolved with conservative management. The diagnosis, investigations, and treatment options are discussed.

Spread of human cancer cells occurs with probabilities indicative of a nongenetic mechanism.

There has been much uncertainty as to whether metastasis requires mutation at the time of spread. Here, we use clinical data to calculate the probability of the spread of melanoma and breast cancer cells. These calculations reveal that the probability of the spread of cancer cells is relatively high for small tumours (approximately 1 event of spread for every 500 cells for melanomas of 0.1 mm) and declines as tumours increase in size (approximately 1 event of spread for every 10(8) cells for melanomas of 12 mm). The probability of spread of breast cancer cells from the lymph nodes to the periphery is approximately 1 event of spread for every 10(8) cells in the nodal masses, which have a mean diameter of 5 mm, while the probability of spread of cancer cells from the breast to the periphery when the primary masses are 5 mm is also approximately 1 event of spread for every 10(8) cells. Thus, the occurrence of an event of spread from the breast to the lymph nodes appears not to increase the propensity of the progeny of those cells to spread from the lymph nodes to the periphery. These values indicate that the spread of human breast cancer and melanoma cells is unlikely to occur by a mechanism requiring mutation at the time of spread.

Analysis of benefit:risk ratio and mortality reduction for the UK Breast Screening Programme.

A quantitative analysis has been performed to predict the benefit:risk ratio and associated mortality reduction for the UK National Health Service Breast Screening Programme. The analysis is based on the results of an established biological simulation method coupled with dosimetric information and population statistics applicable to the UK breast screening programme. As well as the general breast screening population, the benefit:risk ratios for specific subgroups of women thought to be at higher risk are estimated. The effects of alterations in screening strategy are also investigated. The results indicate favourable benefit:risk ratios and mortality reductions for all women in the programme, with a breast cancer mortality reduction of approximately 9% over the whole UK female population, equivalent to a breast cancer mortality reduction in the region of 25% for the age range 55-69 years.

beta-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland.

The Wnt signal transduction pathway has been implicated in mammary tumorigenesis in the mouse. beta-catenin, a key downstream effector of this pathway interacts with and thus activates the Tcf/Lef family of transcription factors. Elevated levels of beta-catenin have been found in many human tumors, notably colon carcinomas. Recently, elevated levels of beta-catenin have been associated with poor prognosis in human adenocarcinoma of the breast. In order to assess the possible role of beta-catenin in mammary carcinoma, we have created transgenic mice bearing the MMTV-LTR driving an activated form of beta-catenin. These mice develop mammary gland hyperplasia and mammary adenocarcinoma, a phenotype very similar to that of transgenic mice expressing an MMTV-driven Wnt gene. Indeed, the histopathology of the mammary tumors in Wnt-mediated adenocarcinoma is identical to that observed in our beta-catenin-mediated disease model. Furthermore, putative beta-catenin transcriptional targets, cyclin D1 and c-myc, are elevated in beta-catenin-mediated mammary tumors and cell lines. These observations support the notion that the oncogenic Wnt pathway operates via beta-catenin and its targets in the context of mammary hyperplasia and carcinoma.

Why are cesarean delivery rates so high in diabetic pregnancies?

AIMS: The purpose of this study was to examine factors relevant to mode of delivery in term pregnancies complicated by gestational and pre-gestational diabetes. METHODS: A retrospective chart review of term (> or = 37 weeks) singleton pregnancies complicated by Class A2 through Class R pregnancies which delivered from 1991-1997 was performed. Exclusion criteria were prior cesarean delivery, non-vertex presentation, fetal structural defects, or any contraindications to vaginal delivery. Maternal and fetal factors relevant to mode of delivery were examined and compared. Stepwise logistic regression analysis was performed to examine factors predictive of delivery mode. RESULTS: A total of 148 patients met study criteria. Induction rates were 60.9% for gestational and 79.8% for pre-gestational diabetics. The overall cesarean delivery rate by Diabetes Class for A2, B, C, D-F pregnancies was 20.3%, 40%, 37%, and 57.1% respectively. In Class A2 pregnancies no factor was associated with cesarean delivery and only nulliparity (p = 0.03) was associated in Class B-F pregnancies. CONCLUSIONS: These results suggest that physician factors may play an important role in the risk for cesarean delivery in our diabetic population.

Vaginal birth after cesarean in the diabetic gravida.

OBJECTIVE: To compare the delivery outcomes in term diabetic patients without a prior cesarean delivery to those attempting vaginal birth after cesarean (VBAC). STUDY DESIGN: A retrospective chart review study was performed of singleton pregnancies complicated by class A-2-R diabetes who delivered at > or = 37 weeks from 1991 to 1997. Exclusion criteria were prior classical or low vertical cesarean, more than one prior cesarean delivery, fetal structural defects or any contraindications to labor. Outcome measures were compared for patients without prior cesarean (group 1) to those with a VBAC attempt (group 2). RESULTS: One hundred fifty-nine patients, 127 patients without a prior cesarean delivery and 32 patients with a VBAC attempt, met all the study criteria. The cesarean delivery rate was 26.3% (34/127) in group 1 and 56.3% (18/32) in group 2 (VBAC success rate, 43.7%). There were no cases of uterine rupture. There were no differences in the frequency of endometritis rates or neonatal intensive care unit admission, whether vaginal or cesarean delivery occurred. CONCLUSION: VBAC success rates appeared to be lower for diabetic gravidas as compared to those for nondiabetic women reported in the literature. Although maternal and neonatal complication rates were low, further studies are necessary to determine the safety of VBAC in this population.

The Daxx enigma.

Several reports describing Daxx and its putative role have emerged without a unifying theme. While Daxx has been implicated in apoptosis, it remains unclear whether Daxx is pro- or anti-apoptotic, and whether its role in apoptosis is direct or indirect. Moreover, whether Daxx plays alternative or additional roles in regulating transcription, centromere binding or any number of other activities within the cell, is uncertain. The ability of Daxx to interact with a wide variety of molecules in yeast-interaction trap systems (Table 1) has allowed for this range of speculation. The fact that Daxx contains no significant homology to other known proteins has rendered its study all the more challenging.

Declining bone mass in men with chronic pulmonary disease: contribution of glucocorticoid treatment, body mass index, and gonadal function.

BACKGROUND: Men with chronic lung disease (CLD) are at risk for osteoporosis, but the relative contributions of their chronic pulmonary disease, glucocorticoid therapy, and other factors toward loss of bone has not been established. Understanding the relative importance of these factors would assist in selecting patients for bone densitometry screening and in policy decisions regarding Medicare reimbursement. OBJECTIVE: To identify patients with CLD who are most likely to benefit from bone densitometry screening based on clinical and biochemical measures. DESIGN: Cross-sectional medical survey. PATIENTS: Patients with CLD who were treated with either oral, inhaled, or no glucocorticoid therapy. A control group without lung disease was recruited from the same clinic population. MEASUREMENTS: Dual-energy X-ray absorptiometry was obtained for each group, and the association between bone mass and clinical variables, glucocorticoid use, gonadal hormones, and biochemical markers of bone metabolism was determined. RESULTS: Osteoporosis (a T score < -2.5 at the hip or spine) was five times as likely in patients with CLD as in control subjects. Although the prevalence of osteoporosis was higher (ninefold) after chronic glucocorticoid therapy, patients with CLD who had never been treated with glucocorticoids had a substantial (fourfold) risk of osteoporosis. Chronic inhaled glucocorticoid therapy offered no protection from bone loss compared to treatment with oral glucocorticoids. Of the clinical and biochemical measures that were obtained, bone mass was weakly correlated with body mass index (BMI), serum estradiol-17beta, and N-telopeptide, but not with testosterone, alkaline phosphatase, bone-specific alkaline phosphatase, or osteocalcin. CONCLUSION: Patients with CLD should be considered for bone densitometry screening regardless of glucocorticoid use. Those patients with a low BMI and/or decreased serum estradiol-17beta comprise a subgroup with increased risk for osteoporosis.

Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development.

The mammalian Daxx gene has been identified in a diverse set of yeast interaction trap experiments. Although a facilitating role for Daxx in Fas-induced apoptosis has been suggested, Daxx's physiologic function remains unknown. To elucidate the in vivo role of Daxx, we have generated Daxx-deficient mice. Surprisingly, rather than a hyperproliferative disorder expected from the loss of a pro-apoptotic gene, mutation of Daxx results in extensive apoptosis and embryonic lethality. These findings argue against a role for Daxx in promoting Fas-induced cell death and suggest that Daxx either directly or indirectly suppresses apoptosis in the early embryo.

Breast cancer: computer simulation method for estimating optimal intervals for screening.

PURPOSE: To develop and evaluate a mathematic method that can be used to determine the optimal screening interval for detection of breast cancer prior to distant metastatic spread. MATERIALS AND METHODS: A computer simulation was developed with the use of biologically based data from the literature on the rates of tumor growth and spread, which can be used to calculate the course of breast cancer growth and metastasis. RESULTS: On the basis of the data available at this time, the results of the simulations suggested that a screening interval of 2 years would result in a 22% reduction in the rate of distant metastatic disease, an interval of 1 year would result in a 51% reduction, and an interval of 6 months would result in an 80% reduction. CONCLUSION: These findings suggest that more frequent screening could dramatically reduce the death rate from breast cancer.

The role of molecular discreteness in normal and cancerous growth.

The physicochemical events that underlie biological processes are inevitably either/or events. Either a growth factor molecule binds to a cell, or it doesn't. Either a site on a cyclin molecule is phosphorylated, or it isn't. Either a regulatory molecule binds to a DNA sequence, or it doesn't. These molecular either/or events lead to cellular either/or events. Either a cell divides, or it doesn't. Either a cell dies, or it doesn't. Either a cell turns on a particular gene, or it doesn't. Either a tumor cell stays where it is, or it forms a distant metastasis. By considering biological processes as the macroscopic aggregate results of these many individual microscopic either/or events, we can gain considerable insight into both normal and cancerous growth. In fact, as will be outlined here, such discrete modeling may allow us to see how the normal cellular populations of the body can grow to predictable sizes, at predictable times, and to predictable shapes. Such modeling can also allow us to gain insight into how normal cellular populations may become cancerous cellular populations. Indeed, such an approach allows us do a sufficiently good job of imitating the growth and spread of tumors as to be able to make estimates the most effective ways to both detect and treat cancer.

Regulation of the replication of the murine immunoglobulin heavy chain gene locus: evaluation of the role of the 3' regulatory region.

DNA replication in mammalian cells is a precisely controlled physical and temporal process, likely involving cis-acting elements that control the region(s) from which replication initiates. In B cells, previous studies showed replication timing to be early throughout the immunoglobulin heavy chain (Igh) locus. The implication from replication timing studies in the B-cell line MPC11 was that early replication of the Igh locus was regulated by sequences downstream of the C alpha gene. A potential candidate for these replication control sequences was the 3' regulatory region of the Igh locus. Our results demonstrate, however, that the Igh locus maintains early replication in a B-cell line in which the 3' regulatory region has been deleted from one allele, thus indicating that replication timing of the locus is independent of this region. In non-B cells (murine erythroleukemia cells [MEL]), previous studies of segments within the mouse Igh locus demonstrated that DNA replication likely initiated downstream of the Igh gene cluster. Here we use recently cloned DNA to demonstrate that segments located sequentially downstream of the Igh 3' regulatory region continue to replicate progressively earlier in S phase in MEL. Furthermore, analysis by two-dimensional gel electrophoresis indicates that replication forks proceed exclusively in the 3'-to-5' direction through the region 3' of the Igh locus. Extrapolation from these data predicts that initiation of DNA replication occurs in MEL at one or more sites within a 90-kb interval located between 40 and 130 kb downstream of the 3' regulatory region.