Cardiovascular and metabolic comorbidities in patients with thyroid nodules: the impact of incidental diagnosis.

PURPOSE: The prevalence of thyroid nodules (TN) in the general population has increased as screening procedures are implemented and an association with metabolic and cardiovascular disorders has been reported. The aim of this study was to investigate the reason leading to the diagnosis of TN and to compare the clinical characteristics of patients diagnosed incidentally with those of patients diagnosed for thyroid-related reasons. METHODS: We designed a retrospective cross-sectional study including consecutive patients with TN from two high-volume hospital-based centers for thyroid diseases (Pavia and Messina) in Italy. Data regarding reason leading to TN diagnosis, age, sex, BMI, presence of cardio-metabolic comorbidities were collected. RESULTS: Among the 623 enrolled subjects, the US diagnosis of TN was prompted by thyroid-related reasons in 421 (67.6%, TD group) and incidental in 202 (32.4%, ID group) with a similar distribution in the two centers (p = 0.960). The ID group patients were more frequently males (38.6% vs 22.1%, p < 0.001) and significantly older (58.9 ± 13.7 vs 50.6 ± 15.5 years, p < 0.001) than the TD group ones, and had a higher rate of cardiovascular comorbidities (73.8% vs 47.5%, p < 0.001), despite having a similar BMI (27.9 ± 5.2 vs 27.8 ± 13.5, p = 0.893). CONCLUSIONS: Stratification of patients with TN according to the diagnostic procedure leading to diagnosis allows a better epidemiological characterization of this inhomogeneous and large population.

Hospital nurses and home care providers' experiences of participation in nutritional care among older persons and their family caregivers: a qualitative study.

BACKGROUND: A person-centred approach to nutritional care has the potential to increase an older person's role in making informed decisions about their own care and possibly improving their quality of life. However, despite the considerable interest shown in person-centred nutritional care in recent years, delivery of such care still appears to lack consideration for older persons' needs and preferences. The present study aimed to explore healthcare professionals' views on how older persons and their family caregivers participate in decisions about their own nutritional care and possible barriers for that participation. METHODS: Semi-structured in-depth interviews with 23 healthcare professionals in acute geriatric care and home care were conducted. Data were analysed thematically. RESULTS: The analysis of the interviews resulted in three main themes: (i) lack of shared decision-making in nutritional care; (ii) conflict between patient's preferences and standard nutritional care procedures; and (iii) the value of family caregivers who are seldom involved in nutritional care. CONCLUSIONS: Healthcare professionals were aware of the importance of actively engaging older persons and their family members in the nutritional care to achieve positive outcomes. However, they encountered individual and structural barriers, including resistance from patients and family caregivers, conflicts between the patients' nutritional wishes and standard nutritional procedures, a wish to shield the family caregivers from the stress of caring for a sick relative, and lack of time and caring structures that facilitate the older persons and their family's active participation.

Arsenic in seafood is associated with increased thyroid-stimulating hormone (TSH) in healthy volunteers - A randomized controlled trial.

BACKGROUND: Exposure to exogenous elements like arsenic (As) may influence thyroid enzymes, thyroid-stimulating hormone (TSH), and the two principal thyroid hormones, free thyroxine (FT4) and free triiodothyronine (FT3), but little is known about how this is related to organic arsenicals, the main form in seafood. AIM: To investigate whether a high intake of dietary arsenic from seafood can impact thyroid function and thyroid hormones by examining possible associations with changes in TSH, FT4, FT3 and the FT4:FT3-ratio in plasma. METHODS: Thirty-eight healthy subjects were randomized into four groups. During a 14-day semi-controlled dietary study, the subjects ingested daily portions of either 150g cod, salmon, blue mussels or potato (control). Plasma concentrations of total As, FT3, FT4, TSH and selenium (Se), and urinary concentrations of iodine were monitored. RESULTS: Plasma concentrations of TSH increased significantly in all seafood groups. The change in plasma As, with different coefficients for each seafood group, was the dominant factor in the optimal multiple regression model for change in TSH (R2=0.47). Plasma Se and iodine were negative and positive factors, respectively. There were also indications of changes in FT4, FT3 and the FT4:FT3 ratio consistent with a net inhibiting effect of As on FT4 to FT3 conversion. CONCLUSION: Ingestion of seafood rich in various organic As species was strongly associated with an increase of the TSH concentrations in plasma. Change in TSH was positively associated with total plasma As, but varied with the type of seafood ingested. These findings indicate that organic dietary As, apparently depending on chemical form, may influence thyroid hormones and function.

Chloroquine enhances the antimycobacterial activity of isoniazid and pyrazinamide by reversing inflammation-induced macrophage efflux.

Mycobacterium tuberculosis (MTB) is notorious for persisting within host macrophages. Efflux pumps decrease intracellular drug levels, thus fostering persistence of MTB during therapy. Isoniazid (INH) and pyrazinamide (PZA) are substrates of the efflux pump breast cancer resistance protein-1 (BCRP-1), which is inhibited by chloroquine (CQ). In this study, BCRP-1 was found to be expressed on macrophages of human origin and on foamy giant cells at the site of MTB infection. In the current in vitro study, interferon-gamma (IFNγ) increased the expression of BCRP-1 in macrophages derived from the human monocytic leukaemia cell line THP-1. Using a BCRP-1-specific fluorescent dye and radioactively labelled INH, it was demonstrated that efflux from macrophages increased upon activation with IFNγ. CQ was able to inhibit active efflux and augmented the intracellular concentrations both of INH and the dye. In agreement, CQ and specific inhibition of BCRP-1 increased the antimycobacterial activity of INH against intracellular MTB. Although PZA behaved differently, CQ had comparable advantageous effects on the intracellular pharmacokinetics and activity of PZA. The adjunctive effects of CQ on intracellular killing of MTB were measurable at concentrations achievable in humans at approved therapeutic doses. Therefore, CQ, a widely used and worldwide available drug, may potentiate the efficacy of standard MTB therapy against bacteria in the intracellular compartment.

Case management at an outpatient unit for severe and enduring eating disorder patients at Stockholm Centre for Eating Disorders- a study protocol.

BACKGROUND: Patients with severe and enduring eating disorders (SEED) are seriously ill and have a low quality of life. Case management (CM), originally developed for adult patients with severe mental disabilities, has been shown to enhance social functioning and improve quality of life, while reducing the number and length of hospitalizations. In 2014, a special unit based on CM, for patients with SEED (the Eira unit) was started at Stockholm Centre for Eating Disorders, Sweden. METHOD/DESIGN: This study aims to investigate if CM can improve SEED patients' quality of life, and reduce their eating disorder symptoms as well as their health care consumption. Methods for data collection are a semi-structured diagnostic interview, self-report questionnaires, and a qualitative interview. The diagnostic interview and the self-report assessments will be done at start of treatment and at follow-ups after 1, 2, and 3years. The qualitative interview will be conducted 1 year after start of treatment. The study is approved by the ethical review board in Stockholm in compliance with the Helsinki Declaration. DISCUSSION: CM is a possible new contribution to the treatment methods for SEED. It does not aim at remission, but rather to accept life as it is, and to enhance quality of life in the presence of the ED. This study will investigate the potential benefits of this novel intervention in a special unit for SEED patients. TRIAL REGISTRATION: Clinicaltrials.gov Id: NCT02897622.

Lean fish consumption is associated with lower risk of metabolic syndrome: a Norwegian cross sectional study.

BACKGROUND: Fish consumption may have a role in reducing the prevalence of metabolic syndrome (MetS). The aim of this study was to identify associations between fish consumption and MetS and its components, especially regarding differences concerning consumption of fatty and lean fish. METHODS: This cross sectional study uses data from the Tromsø 6 survey (2007-08), where a sample of 12 981 adults, aged 30-87 years (47 % men) from the Norwegian general population was included. Fish consumption was assessed using food frequency questionnaires (FFQ). Blood sample assessments, anthropometric and blood pressure measurements were carried out according to standard protocols. MetS was defined using the Joint Interim Societies (JIS) definition. All tests were two-sided. Analyses were performed using IBM SPSS Statistics 22 (Pearson's correlation, Chi-Square tests, analysis of variance (ANOVA), linear and logistic regression models). RESULTS: Mean age was 57.5, and the prevalence of MetS was 22.6 %. Fish consumption once a week or more was associated with lower risk of having MetS among men (OR 0.85, CI 95 % 0.74 to 0.98, P = 0.03). In the adjusted models, lean fish consumption was associated with a decreased risk of having MetS, whereas fatty fish consumption was not associated with a decreased risk of having MetS. Both an increased fatty and lean fish consumption (0-1 times per month, 2-3 times per month, 1-3 times per week, 4-6 times per week, 1-2 times per day) were associated with decreased serum triglyceride (TG), and increased high-density lipoprotein cholesterol (HDL-C). CONCLUSIONS: Fish consumption may be associated with a lower risk of having MetS and consumption of lean fish seems to be driving the association. Further investigation is warranted to establish associations between fish consumption and MetS.

Associations between fish consumption and metabolic syndrome. A large cross-sectional study from the Norwegian Tromsø Study: Tromsø 4.

BACKGROUND: Fish consumption may prevent or improve metabolic health. The aim of this study was to identify associations between fish consumption, both fatty and lean, and metabolic syndrome and its components. METHODS: Associations between fish consumption and metabolic syndrome and its components were studied in a large sample from a Norwegian population (N = 23,907), using cross-sectional data from the Tromsø 4 survey (1994-1995). Metabolic syndrome was defined using the JIS definition, and dietary data was collected using food frequency questionnaires (FFQ). Blood samples were taken for biochemical assessments, and anthropometric and blood pressure measurements were carried out according to standard protocols. RESULTS: In this sample from an adult population (aged 26-70 years, mean age 44 years, SD 11.69, 48 % men), a higher fish consumption (≥1/week) was associated with a healthier lipid profile with increased HDL-C and decreased TG. Participants aged 60-70 years consuming fish once a week or more had significantly lower risk of having MetS, compared to those consuming fish less than once a week (OR 0.64, CI 0.45-0.91). When investigating fatty and lean fish separately, only lean fish consumption was associated with a reduced the risk of having MetS. Participants aged 60-70 years consuming lean fish once a week or more, had lower risk of having MetS compared to those consuming lean fish less than once a week (OR 0.65, CI 0.48-0.87). No association was found for consumption of fatty fish, or for lean fish in the age groups <45 or 45-59 years. CONCLUSIONS: These results indicates that fatty and lean fish consumption influences MetS risk differently, possibly also related to age. However, further investigation is needed to establish how various fish consumption may influence MetS and its components, particularly when stratified by fatty and lean fish.

In vivo parameters influencing 2-Cys Prx oligomerization: The role of enzyme sulfinylation.

2-Cys Prxs are H2O2-specific antioxidants that become inactivated by enzyme hyperoxidation at elevated H2O2 levels. Although hyperoxidation restricts the antioxidant physiological role of these enzymes, it also allows the enzyme to become an efficient chaperone holdase. The critical molecular event allowing the peroxidase to chaperone switch is thought to be the enzyme assembly into high molecular weight (HMW) structures brought about by enzyme hyperoxidation. How hyperoxidation promotes HMW assembly is not well understood and Prx mutants allowing disentangling its peroxidase and chaperone functions are lacking. To begin addressing the link between enzyme hyperoxidation and HMW structures formation, we have evaluated the in vivo 2-Cys Prxs quaternary structure changes induced by H2O2 by size exclusion chromatography (SEC) on crude lysates, using wild type (Wt) untagged and Myc-tagged S. cerevisiae 2-Cys Prx Tsa1 and derivative Tsa1 mutants or genetic conditions known to inactivate peroxidase or chaperone activity or altering the enzyme sensitivity to hyperoxidation. Our data confirm the strict causative link between H2O2-induced hyperoxidation and HMW formation/stabilization, also raising the question of whether CP hyperoxidation triggers the assembly of HMW structures by the stacking of decamers, which is the prevalent view of the literature, or rather, the stabilization of preassembled stacked decamers.

Urinary excretion of arsenicals following daily intake of various seafoods during a two weeks intervention.

The excretion pattern of arsenic (As) species after seafood intake varies widely depending on species ingested and individual handling. We have previously reported the 72 h urinary excretion of arsenicals following a single dose of seafood. Here, we report the excretion patterns in the same 37 subjects following 15 days daily consumption of either 150 g cod, salmon, blue mussels or potato (control), followed by a 72 h period with a low-As diet. In all seafood groups, total As (tAs) in plasma and urinary excretion of tAs, arsenobetaine (AB) and dimethylarsinate (DMA) increased significantly after the intervention. Confirming the single dose study AB and DMA excreted were apparently endogenously formed from other arsenicals ingested. Total tAs excretion was 1386, 763 and 303 µg in the cod, blue mussel and salmon groups, respectively; about twice the amounts after the single dose study indicating accumulation of arsenicals. In the cod group, rapid excretion after the single dose was associated with lower total As in blood and less accumulation after two weeks with seafood indicating lower accumulation. In the blue mussels group only, inorganic As (iAs) excretion increased significantly, whilst methylarsonate (MA) strongly increased, indicating a possible toxicological concern of repeated mussel consumption.

Major and minor arsenic compounds accounting for the total urinary excretion of arsenic following intake of blue mussels (Mytilus edulis): a controlled human study.

Blue mussels (Mytilus edulis) accumulate and biotransform arsenic (As) to a larger variety of arsenicals than most seafood. Eight volunteers ingested a test meal consisting of 150 g blue mussel (680 µg As), followed by 72 h with an identical, low As controlled diet and full urine sampling. We provide a complete speciation, with individual patterns, of urinary As excretion. Total As (tAs) urinary excretion was 328 ± 47 µg, whereof arsenobetaine (AB) and dimethylarsinate (DMA) accounted for 66% and 21%, respectively. Fifteen minor urinary arsenicals were quantified with inductively coupled plasma mass spectrometry (ICPMS) coupled to reverse-phase, anion and cation-exchange high performance liquid chromatography (HPLC). Thio-arsenicals and non-thio minor arsenicals (including inorganic As (iAs) and methylarsonate (MA)) contributed 10% and 7% of the total sum of species excretion, respectively, but there were large individual differences in the excretion patterns. Apparently, formation of thio-arsenicals was negatively correlated to AB formation and excretion, possibly indicating a metabolic interrelationship. The results may be of toxicological relevance since DMA and MA have been classified as possibly carcinogenic, and six of the excreted As species were thio-arsenicals which recently have been recognized as toxic, while iAs toxicity is well known.

Flow-mediated vasodilation measurements in Cavalier King Charles Spaniels with increasing severity of myxomatous mitral valve disease.

BACKGROUND: Cardiovascular disease is associated with endothelial dysfunction in humans and studies of plasma biomarkers suggest that dogs with myxomatous mitral valve disease (MMVD) might also have endothelial dysfunction. HYPOTHESIS: That progression of mitral regurgitation (MR) is associated with development of endothelial dysfunction. ANIMALS: Forty-three Cavalier King Charles Spaniels (CKCS) with MR of varying severity. METHODS: Privately owned CKCS were prospectively recruited and divided in 4 groups: (1) 12 CKCS with minimal MR; (2) 9 CKCS with mild MR; (3) 11 CKCS with moderate-severe MR; and (4) 11 CKCS with moderate-severe MR and clinical signs compatible with heart failure. Dogs underwent blood sampling, echocardiography, blood pressure (BP) recordings, and flow-mediated vasodilation (FMD) measurements. The effect of progressive MR on FMD was determined by multivariate analyses. RESULTS: Flow-mediated vasodilation decreased with progression of MR. Group 4 (4.79 ± 3.22%) had significantly lower FMD than groups 1 (10.40 ± 4.58%) and 2 (10.14 ± 3.67%) (P < .005) and group 3 (6.79 ± 3.98%) had a significantly lower FMD than group 1 (P = .03). Increasing left ventricular end-diastolic diameter (P = .0004, R(2) = 0.27) and the combination of age (P = .01) and body weight (P = .002) (R(2) = 0.31) were significantly associated with reduced FMD. FMD did not correlate with sex, BP, or plasma markers. CONCLUSIONS AND CLINICAL IMPORTANCE: Reduced FMD indicates that increased disease severity in CKCS with MMVD is associated with development of endothelial dysfunction which might be a future therapeutic and/or diagnostic target.

Humans seem to produce arsenobetaine and dimethylarsinate after a bolus dose of seafood.

Seafood is the predominant food source of several organoarsenic compounds. Some seafood species, like crustaceans and seaweed, also contain inorganic arsenic (iAs), a well-known toxicant. It is unclear whether human biotransformation of ingested organoarsenicals from seafood result in formation of arsenicals of health concern. The present controlled dietary study examined the urinary excretion of arsenic compounds (total arsenic (tAs), iAs, AB (arsenobetaine), dimethylarsinate (DMA) and methylarsonate (MA)) following ingestion of a single test meal of seafood (cod, 780 µg tAs, farmed salmon, 290 µg tAs or blue mussel, 690 µg tAs or potato (control, 110 µg tAs)) in 38 volunteers. The amount of ingested tAs excreted via the urine within 0-72 h varied significantly among the groups: Cod, 74% (52-92%), salmon 56% (46-82%), blue mussel 49% (37-78%), control 45% (30-60%). The estimated total urinary excretion of AB was higher than the amount of ingested AB in the blue mussel group (112%) and also ingestion of cod seemed to result in more AB, indicating possible endogenous formation of AB from other organoarsenicals. Excretion of iAs was lower than ingested (13-22% of the ingested iAs was excreted in the different groups). Although the ingested amount of iAs+DMA+MA was low for all seafood groups (1.2-4.5% of tAs ingested), the urinary DMA excretion was high in the blue mussel and salmon groups, counting for 25% and 11% of the excreted tAs respectively. In conclusion our data indicate a possible formation of AB as a result of biotransformation of other organic arsenicals. The considerable amount of DMA excreted is probably not only due to methylation of ingested iAs, but due to biotransformation of organoarsenicals making it an inappropriate biomarker of iAs exposure in populations with a high seafood intake.

Effects of an eight-month weight-control program on body composition and lipid oxidation rate during exercise in obese children.

OBJECTIVE: To investigate the effects of an 8-month multidisciplinary weight-control program, including 2 h/week of moderate physical activity, nutritional education lessons and psychological follow-up, on body composition and lipid oxidation rate during exercise in obese children. DESIGN: Nineteen (7 boys and 12 girls) obese children, aged 8-12 yr [mean body mass index (BMI) z-score: 2.3 and fat mass: 35.8%] participated in this study. Before and at the end of the weight-control period body composition was assessed by bioelectrical impedance, lipid oxidation rate by indirect calorimetry during a graded exercise test, and time devoted to various activities and energy intake in free-living conditions by questionnaire. RESULTS: All children completed the study, at the end of which BMI decreased significantly by mean 0.6+/-0.5 and 0.5+/-0.8 kg/m2, in boys and girls, respectively (p<0.05), and fat mass (FM) decreased by 1.7+/-2.8 and 1.4+/-1.3 kg in boys and girls, respectively (p<0.05). In addition, lipid oxidation rate during exercise increased significantly throughout the graded exercise test up to 21% at maximal lipid oxidation rate which happened at 48+/-5% of maximal oxygen uptake (VO2max), corresponding to 64+/-5% of maximal heart rate. Time spent at sedentary and very light physical activities decreased (p<0.001) to the benefit of recreational activities at home. CONCLUSIONS: Multidisciplinary weight-control program, with moderate-intensity physical activities, induced decreases in FM without decreases in free FM, increases in VO2max, lipid oxidation rate during exercise, and time devoted to recreational activities in free-living conditions.

Bond strength of luting materials to ceramic crowns after different surface treatments.

The aim of present study was to evaluate the effect of different pre-treatments of alumina and zirconia copings on the bond strength of different luting materials. Pull out tests was performed on 60 alumina and 80 zirconia copings. Randomly selected, copings were divided in groups of i) un-treated alumina and zirconia copings, (n=20) ii) alumina and zirconia copings sandblasted with 50 or 110 microm alumina particles respectively (n=20), iii) zirconia copings treated with monolayer of glass pearls fused to the inner surface (n=20), iv) zirconia copings treated with silanized glass pearls (n=10). Zinc phosphate, Panavia 21 and VarioLink II were used for cementation. Pull out tests were done in an Instron universal testing machine with a speed of 0.5 mm/min and fracture loads was measured in N. Untreated zirconia copings cemented with zinc phosphate showed significantly higher bond strength values compared to those with sandblasted surfaces. No difference was seen between untreated alumina copings and those with sandblasted surfaces. Sandblasting decreased bond strength of zirconia and alumina copings. Glass pearls increased bond strength of zirconia copings, which was even better after silanization. Variolink II in combination with alumina gave significantly lower bond strength.

Implants and/or teeth: consensus statements and recommendations.

In August 23-25, 2007, the Scandinavian Society for Prosthetic Dentistry in collaboration with the Danish Society of Oral Implantology arranged a consensus conference on the topic 'Implants and/or teeth'. It was preceded by a workshop in which eight focused questions were raised and answered in eight review articles using a systematic approach. Twenty-eight academicians and clinicians discussed the eight review papers with the purpose to reach consensus on questions relevant for the topic. At the conference the consensus statements were presented as well as lectures based on the review articles. In this article the methods used at the consensus workshop are briefly described followed by the statements with comments.

Surface roughness of five different dental ceramic core materials after grinding and polishing.

In clinical practice, core materials can be exposed after adjustments are made to previously-luted all-ceramic restorations. The purpose of this study was to evaluate the surface roughness of five different dental ceramic core materials after grinding and polishing. Five different ceramic core materials, Vita In-Ceram Alumina, Vita In-Ceram Zirconia, IPS Empress 2, Procera AllCeram, and Denzir were evaluated. Vita Mark II was used as a reference material. The surface roughness, Ra value (mum), was registered using a profilometer. The measurements were made before and after grinding with diamond rotary cutting instruments and after polishing with the Sof-Lex system. The surface of representative specimens was evaluated qualitatively using scanning electron microscopy (SEM). Results were statistically analysed using analysis of variance (anova) supplemented with Scheffè's and Bonferroni multiple-comparison tests. Before grinding, Procera AllCeram and Denzir had the smoothest surfaces, while IPS Empress 2 had the coarsest. After grinding, all materials except IPS Empress 2 became coarser. Polishing with Sof-Lex provided no significant (P > 0.05) differences between Denzir, Vita Mark II and IPS Empress 2 or between Procera AllCeram and In-Ceram Zirconia. There were no significant differences (P > 0.05) either between the ground and the polished Procera AllCeram or In-Ceram Alumina specimens. Polishing of Denzir, IPS Empress 2 and In-Ceram Zirconia made the surfaces smoother compared with the state after grinding, whereas the polishing effect on Procera AllCeram and In-Ceram Alumina was ineffective. The findings of the SEM evaluation were consistent with the profilometer readings.

Adenovirus vector designed for expression of toxic proteins.

To construct recombinant adenoviruses expressing biologically active proteins may be impossible, or result in a significant reduction in virus yield, if the protein expressed has an inhibitory effect on virus replication or cellular growth. To overcome this problem, we previously designed adenovirus vectors expressing foreign proteins from inducible promoters. However, during our work with a replication-deficient virus expressing the ASF/SF2 splicing factor from a progesterone antagonist-inducible gene cassette, we discovered that ASF/SF2 was expressed at a significant level in the 293 producer cell line, even in the absence of inducer. 293 cells code for adenovirus E1A and E1B proteins and thus support the growth of E1-deficient adenoviruses. Here we show that this background ASF/SF2 expression results from a low level of E1A-mediated transactivation of the basal promoter driving transgene expression. To overcome the problem of leaky expression, we reconstructed a novel gene cassette that combines an inducible promoter and a Lac repressor protein-based block to reduce transcriptional elongation. We show that this novel vector system dramatically reduced background transgene expression and therefore should be useful for the rescue and propagation of high-titer stocks of recombinant adenoviruses expressing toxic proteins.

Cisplatin induces the proapoptotic conformation of Bak in a deltaMEKK1-dependent manner.

In a panel of four human melanoma cell lines, equitoxic doses of cisplatin induced the proapoptotic conformation of the Bcl-2 family protein Bak prior to the execution phase of apoptosis. Because cisplatin-induced modulation of the related Bax protein was seen in only one cell line, a degree of specificity in the signal to Bak is indicated. Little is known about upstream regulation of Bak activity. In this study, we examined whether the apoptosis-specific pathway mediated by a kinase fragment of MEKK1 (DeltaMEKK1) is involved in the observed Bak modulation. We report that expression of a kinase-inactive fragment of MEKK1 (dominant negative MEKK [dnMEKK]) efficiently blocked cisplatin-induced modulation of Bak and cytochrome c release and consequently also reduced DEVDase activation and nuclear fragmentation. Accordingly, expression of a kinase-active MEKK1 fragment (dominant positive MEKK) was sufficient to induce modulation of Bak in three cell lines and to induce apoptosis in two of these. dnMEKK did not block cisplatin-induced c-Jun N-terminal kinase (JNK) activation, in agreement with a specifically proapoptotic role for the DeltaMEKK1 pathway. Finally, we show that reduction of Bak expression by antisense Bak reduced cisplatin-induced loss of mitochondrial integrity and caspase cleavage activity in breast cancer cell lines. In summary, we have identified Bak as a cisplatin-regulated component downstream in a proapoptotic, JNK-independent DeltaMEKK1 pathway.

Multicenter trial of sentinel node biopsy for breast cancer using both technetium sulfur colloid and isosulfan blue dye.

OBJECTIVE: To determine the factors associated with false-negative results on sentinel node biopsy and sentinel node localization (identification rate) in patients with breast cancer enrolled in a multicenter trial using a combination technique of isosulfan blue with technetium sulfur colloid (Tc99). SUMMARY BACKGROUND DATA: Sentinel node biopsy is a diagnostic test used to detect breast cancer metastases. To test the reliability of this method, a complete lymph node dissection must be performed to determine the false-negative rate. Single-institution series have reported excellent results, although one multicenter trial reported a false-negative rate as high as 29% using radioisotope alone. A multicenter trial was initiated to test combined use of Tc99 and isosulfan blue. METHODS: Investigators (both private-practice and academic surgeons) were recruited after attending a course on the technique of sentinel node biopsy. No investigator participated in a learning trial before entering patients. Tc99 and isosulfan blue were injected into the peritumoral region. RESULTS: Five hundred twenty-nine patients underwent 535 sentinel node biopsy procedures for an overall identification rate in finding a sentinel node of 87% and a false-negative rate of 13%. The identification rate increased and the false-negative rate decreased to 90% and 4.3%, respectively, after investigators had performed more than 30 cases. Univariate analysis of tumor showed the poorest success rate with older patients and inexperienced surgeons. Multivariate analysis identified both age and experience as independent predictors of failure. However, with older patients, inexperienced surgeons, and patients with five or more metastatic axillary nodes, the false-negative rate was consistently greater. CONCLUSIONS: This multicenter trial, from both private practice and academic institutions, is an excellent indicator of the general utility of sentinel node biopsy. It establishes the factors that play an important role (patient age, surgical experience, tumor location) and those that are irrelevant (prior surgery, tumor size, Tc99 timing). This widens the applicability of the technique and identifies factors that require further investigation.