OBJECTIVE A short interval between the first and second birth was associated with an increased risk of advanced ductal breast cancer among women with 5+ childbirths in our previous study. We now evaluated the significance of this risk factor and its relation to the age at first birth among mothers with 2-4 children. METHODS The cohort of 190,949 Finnish women with 2-4 children comprised 3,834 women with ductal breast cancer diagnosed before 2009. Conditional logistic regression for case-control design nested within the cohort was used to estimate proportional hazard ratios (HR) associated with the birth interval. Controls were matched for age and number of children. Age at the first birth and the interval from the last birth to cancer were co-variables. RESULTS Among women with the first birth <30 years, the HR of advanced ductal breast cancer at 50+ years for a short (<1.5 years) versus long (>3 years) interval between the first and second birth was 0.48 (95% Confidence Interval 0.33-0.70). Among women with the first birth at 30+ years, the HR of this cancer type diagnosed before the age of 50 years for a short versus long interval between the first and second birth was 5.83 (95% CI 2.30-14.8). CONCLUSION The interval between first and second birth strongly influences the risk of ductal breast cancer. Because second pregnancy soon after the first one decreased the risk of ductal breast cancer in young primiparas but increased the risk in older primiparas, it is likely that in such circumstances second pregnancy continues the actions initiated by the first pregnancy/breast-feeding.

Optical tweezers can be used to manipulate small objects and cells. A trap can be used to fix the position of a particle during light scattering measurements. The places of two separately trapped particles can also be changed. In this Letter we present elastic light scattering measurements as a function of scattering angle when two trapped spheres are illuminated with a He-Ne laser. This setup is suitable for trapping noncharged homogeneous spheres. We also demonstrate measurement of light scattering patterns from two separately trapped red blood cells. Two different illumination schemes are used for both samples.

We demonstrate the use of a double-beam optical tweezers system to stabilize red blood cell (RBC) orientation in the optical tweezers during measurements of elastic light scattering from the trapped cells in an angle range of 5-30 degrees. Another laser (He-Ne) was used to illuminate the cell and elastic light scattering distribution from the single cell was measured with a goniometer and a photomultiplier tube. Moreover, CCD camera images of RBCs with and without laser illumination are presented as complementary information. Light scattering from a RBC was measured in different fixed orientations. Light scattering from cells was also measured when the length of the cell was changed in two different orientations. Light scattering measurements from spherical and crenate RBCs are described and the results are compared with other cell orientations. Analysis shows that the measured elastic light scattering distributions reveal changes in the RBC's orientation and shape. The effect of stretching on the changes in scattering is larger in the case of face-on incidence of He-Ne laser light than in rim-on incidence. The scattering patterns from RBCs in different orientations as well as from a spherical RBC were compared with numerical results found in literature. Good correlation was found.

Glycans, i.e. oligosaccharide chains attached to cellular proteins and lipids, are crucial for nearly all aspects of life, including the development of multicellular organisms. They come in multiple forms and much of this diversity between molecules, cells and tissues is generated by Golgi-resident glycosidases and glycosyltransferases. However, their exact mode of functioning in glycan processing is currently unclear. Here we investigate the supramolecular organization of the N-glycosylation pathway in live cells by utilizing the bimolecular fluorescence complementation (BiFC) approach. We show that all four N-glycosylation enzymes tested (GnTI, GnTII, GalT, SiaT) form Golgi-localized homodimers. Intriguingly, the same enzymes also formed two distinct and functionally relevant heterodimers between the medial-Golgi enzymes GnTI and GnTII, and the trans-Golgi enzymes GalT and SiaT. Given their strict Golgi localization and sequential order of function, the two heterodimeric complexes are likely responsible for the processing and maturation of N-glycans in live cells.

Objective: To examine whether a multidisciplinary rehabilitation programme can improve functional recovery and quality of life and reduce the use of rehabilitation services compared with conventional care one year after total knee arthroplasty.Design: Prospective, randomized, non-blinded, controlled trial.Setting: An outpatient centre-based setting.Subjects: Eighty-six patients who were scheduled for primary total knee arthroplasty due to osteoarthritis of the knee.Interventions: A ten-day multidisciplinary rehabilitation programme, which was focused on enhancing functional capacity, was organized 2-4 months after surgery. In both groups, a standard amount of physiotherapy was included in conventional care. MAIN MEASURES: The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the 15D, 15-m walk test, stair test, isometric strength measurement of the knee. Use of rehabilitation services was asked about with a questionnaire. Outcomes were assessed preoperatively and at 2-, 6- and 12-month follow-ups.Results: In both groups, functional capacity and quality of life improved significantly. The mean absolute change in the WOMAC function score was -32.4 mm (SD 26.4) in the rehabilitation group and -32.8 mm (SD 20.1) in the control group (P-time*group = 0.40). No difference was found between groups in any outcome measure or in the use of rehabilitation services during the study period.Conclusions: This study indicates that for knee osteoarthritis patients treated with primary total knee arthroplasty, a 10-day multidisciplinary outpatient rehabilitation programme 2-4 months after surgery does not yield faster attainment of functional recovery or improvement in quality of life than can be achieved with conventional care.

Background:The interval between successive births (birth interval) may affect breast cancer risk, whereas interval from last birth to cancer onset may modify its behaviour.Methods:The study cohort consisted of 29 488 Finnish grand multiparous (GM) women, including 628 women with breast cancer. Conditional logistic regression for case-control design nested within the cohort was used to estimate proportional hazards (referred as relative risks, RR). Age at first birth and parity were co-variables.Results:Short interval (<1 year) between first and second birth increased the risk of advanced ductal breast cancer at ages < 50 years (RR=5.29; 95% CI 2.00-14.0) as compared to interval 3+ years. The risk of advanced ductal cancer was also large (RR = 4.00; 95% CI 1.19-13.4) shortly (<3 years) after last birth as compared with the period 15+ years.Conclusions:Short birth interval-associated excess breast cancer risk may be related to stimulatory effects of female steroid hormones produced during two closely connected pregnancies, or defective breast maturation owing to failures in breastfeeding.British Journal of Cancer advance online publication, 8 September 2009; doi:10.1038/sj.bjc.6605300 www.bjcancer.com.

Acidic pH of the Golgi lumen is known to be crucial for correct glycosylation, transport and sorting of proteins and lipids during their transit through the organelle. To better understand why Golgi acidity is important for these processes, we have examined here the most pH sensitive events in N-glycosylation by sequentially raising Golgi luminal pH with chloroquine (CQ), a weak base. We show that only a 0.2 pH unit increase (20 microM CQ) is sufficient to markedly impair terminal alpha(2,3)-sialylation of an N-glycosylated reporter protein (CEA), and to induce selective mislocalization of the corresponding alpha(2,3)-sialyltransferase (ST3) into the endosomal compartments. Much higher pH increase was required to impair alpha(2,6)-sialylation, or the proximal glycosylation steps such as beta(1,4)-galactosylation or acquisition of Endo H resistance, and the steady-state localization of the key enzymes responsible for these modifications (ST6, GalT I, MANII). The overall Golgi morphology also remained unaltered, except when Golgi pH was raised close to neutral. By using transmembrane domain chimeras between the ST6 and ST3, we also show that the luminal domain of the ST6 is mainly responsible for its less pH sensitive localization in the Golgi. Collectively, these results emphasize that moderate Golgi pH alterations such as those detected in cancer cells can impair N-glycosylation by inducing selective mislocalization of only certain Golgi glycosyltransferases.

Objective. To examine the attributes of disability in end-stage knee osteoarthritis (OA) by analyzing the relationships between self-reported disability and objectively measured physical function after controlling pain, personal characteristic factors, and pathophysiological factors. Methods. The present study adopted a cross-sectional design. The subjects (n=88, aged 60-80 years) were scheduled for primary unilateral total knee arthroplasty (TKA) due to knee OA. Self-reported disability and pain were measured with the Western Ontario and McMaster Universities OA Index (WOMAC) and the RAND 36-item Health Survey 1.0 (RAND-36). Physical performance tests included a 15-m walk test and stair performance. Knee isometric muscle strength was measured. A clinical examination included analyses of comorbidity, body mass index (BMI), and a detailed knee examination: The flexion range of motion (ROM) was measured; the presence of varus/valgus malalignments and antero-posterior laxity was assessed. Radiographs were analyzed with the Kellgren-Lawrence grading scale. Results. In the linear regression model the WOMAC pain score, antero-posterior laxity of the knee, age, and BMI accounted for 54.8% of the variance in the WOMAC function score. In the bivariate analyses the WOMAC function score had a positive correlation with the 15-m walk (r(s)=0.32, p=0.003), stairs up (r(s)=0.40, p=0.001), and stairs down (r(s)=0.38, p=0.001) tests, and a negative correlation with RPT extension (r(s)=-0.45, p < 0.001) and RPT flexion (r(s)=-0.39, p=0.001) of the affected side and RPT flexion (r(s)=-0.39, p <0.001) of the contralateral side. The results of the physical performance tests also correlated with the RAND-36 Physical function (PF) score. Comorbid diseases and pain deteriorated the results of the physical performance tests and self-reported disability. Female gender deteriorated the results of the physical performance tests and the RAND-36 PF, but not the WOMAC function score. Malalignments, restriction in the flexion ROM of the knee, and the radiologic severity of knee OA did not affect self-reported disability. Conclusion. Pain, BMI, and antero-posterior laxity of the knee joint were major attributes of self-reported disability. The negative effect of comorbid diseases and female gender on health-related quality of life was significant. The results of objectively measured physical performance tests correlated with self-reported disability.

Carcinoembryonic antigen (CEA, ceacam5) is an important tumor-associated antigen with reported roles, e.g., in immunological defense, cell adhesion, cell survival and metastasis. Its overexpression in cancer cells is known to involve transcriptional activation of the CEA gene, but the underlying molecular details remain unclear. Here, we show that hypoxia and intracellular alkalinization, 2 factors commonly found in solid tumors, increase CEA protein expression in breast (MCF-7) and colorectal (CaCo-2 and HT-29) cancer cells. The increase was comparable (2-3-fold) to that observed in colorectal carcinomas in vivo. CEA promoter analyses further revealed that this upregulation involves a known binding site for HIF-1 transcription factor (5'-ACGTG-3') within one of the CEA promoter's positive regulatory elements (the FP1 site; the E-box). Accordingly, deletion or targeted mutagenesis of this motif rendered the CEA promoter unresponsive to hypoxia. Our chromatin immunoprecipitation data confirmed that endogenous HIF-1alpha binds to the CEA promoter in hypoxic cells but not in normoxic cells. Moreover, overexpression of the hypoxia-inducible factor (HIF-1alpha) was sufficient to increase CEA protein expression in the cells. In contrast, c-Myc, which is known to bind to the overlapping E-box, did not potentiate HIF-1alpha-induced CEA expression. CEA overexpression in vivo was also found to coincide with the expression of carbonic anhydrase IX, a well-known hypoxia marker. Collectively, these results define CEA as a hypoxia-inducible protein and suggest an important role for the tumor microenvironmental factors in CEA overexpression during tumorigenesis.(c) 2007 Wiley-Liss, Inc.