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Background: Breast conserving surgery (BCS) for central breast tumours with immediate reconstruction of the nipple-areola complex (NAC) is a relatively new addition to the surgical palette of the oncoplastic surgeon. Most oncoplastic techniques presented to date have only been suitable for women with large breasts., Methods: From 2012 to 2013, a series of eligible women with central breast cancers were treated with BCS and NAC reconstruction. According to breast size and shape, three different procedures were performed., Results: 20 women were operated, 13 by breast reduction techniques and 7 by anterior intercostal perforator flaps (AICAP flaps). Overall cosmetic results were good to excellent for breast shape, symmetry and neo-nipple projection., Conclusion: We present a guideline for selecting the best available surgical technique for immediate NAC reconstruction in women with any breast type, size or shape and describe a new replacement technique using a local perforator flap., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Febrile seizures represent a serious adverse event following measles, mumps and rubella (MMR) vaccination. We conducted a series of genome-wide association scans comparing children with MMR-related febrile seizures, children with febrile seizures unrelated to vaccination and controls with no history of febrile seizures. Two loci were distinctly associated with MMR-related febrile seizures, harboring the interferon-stimulated gene IFI44L (rs273259: P = 5.9 × 10(-12) versus controls, P = 1.2 × 10(-9) versus MMR-unrelated febrile seizures) and the measles virus receptor CD46 (rs1318653: P = 9.6 × 10(-11) versus controls, P = 1.6 × 10(-9) versus MMR-unrelated febrile seizures). Furthermore, four loci were associated with febrile seizures in general, implicating the sodium channel genes SCN1A (rs6432860: P = 2.2 × 10(-16)) and SCN2A (rs3769955: P = 3.1 × 10(-10)), a TMEM16 family gene (ANO3; rs114444506: P = 3.7 × 10(-20)) and a region associated with magnesium levels (12q21.33; rs11105468: P = 3.4 × 10(-11)). Finally, we show the functional relevance of ANO3 (TMEM16C) with electrophysiological experiments in wild-type and knockout rats.

Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with P < 5 × 10(-8). Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including HOXA4, IRX5, IRX6 and EYA1). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.

Whether the powerful medications used to treat epilepsy increase the risk of cancer has been debated for decades, but until now no study could disentangle the contributions of anti-epileptic medications and epilepsy itself to cancer risk. Using a cohort comprising all Danish residents ≥ 16 years old at some point during the period 1996-2010 (>56 million person-years of follow-up) and information from national health registers, we examined associations between anti-epileptic medication use and cancer rates in persons with and without epilepsy, and between epilepsy and cancer rates in treated and untreated individuals. Associations were expressed as incidence rate ratios (IRRs) estimated using Poisson regression. Among persons without epilepsy, use of anti-epileptic medication increased the rates of most cancers little or not at all, although we observed moderately increased rates of liver, mouth and throat, and respiratory tract cancers (IRRs 1.40-1.59). In contrast, we observed strong associations between epilepsy and the rates of central nervous system and mouth and throat cancers (IRRs 2.00-3.91), and a modest association between epilepsy and the rate of respiratory tract cancers (IRRs 1.30-1.35), independent of anti-epileptic medication use. Our finding of only modest increases in cancer risk directly attributable to anti-epileptic medication use suggests that these medications may not be as strongly carcinogenic as has been feared, and that it is not primarily anti-epileptic medications that are responsible for the increased cancer risk among epileptics but another aspect of epilepsy diagnosis or treatment or an etiologic factor common to the two conditions., (© 2013 UICC.)

Due to the lack of macromolecular fossils, the enzymatic repertoire of extinct species has remained largely unknown to date. In an attempt to solve this problem, we have characterized a cyclase subunit (HisF) of the imidazole glycerol phosphate synthase (ImGP-S), which was reconstructed from the era of the last universal common ancestor of cellular organisms (LUCA). As observed for contemporary HisF proteins, the crystal structure of LUCA-HisF adopts the (βα)8-barrel architecture, one of the most ancient folds. Moreover, LUCA-HisF (i) resembles extant HisF proteins with regard to internal 2-fold symmetry, active site residues, and a stabilizing salt bridge cluster, (ii) is thermostable and shows a folding mechanism similar to that of contemporary (βα)8-barrel enzymes, (iii) displays high catalytic activity, and (iv) forms a stable and functional complex with the glutaminase subunit (HisH) of an extant ImGP-S. Furthermore, we show that LUCA-HisF binds to a reconstructed LUCA-HisH protein with high affinity. Our findings suggest that the evolution of highly efficient enzymes and enzyme complexes has already been completed in the LUCA era, which means that sophisticated catalytic concepts such as substrate channeling and allosteric communication existed already 3.5 billion years ago.

Cholangiocarcinoma (CCA) is a rare, but devastating disease arising from the epithelium of intrahepatic and extrahepatic bile ducts. There are neither effective systemic therapies nor satisfying treatment options for inoperable CCA. Histopathological and biochemical studies of CCA show frequent dysregulation of the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. Therefore, we investigated the efficacy of the mTOR inhibitor RAD001 and the impact of AKT signaling following mTOR inhibition in the treatment of CCA. RAD001 significantly inhibits proliferation of CCA cell lines, however, a concentration-dependent and isoform specific feedback activation of the three AKT isoforms (AKT1, AKT2 and AKT3) was observed after mTOR inhibition. As activation of AKT might limit the RAD001-mediated anti-tumor effect, the efficacy of combined mTOR and AKT inhibition was investigated using the allosteric AKT inhibitor MK-2206. Our results show that inhibition of AKT potentiates the efficacy of mTOR inhibition both in vitro and in a xenograft mouse model in vivo. Mechanistically, the antiproliferative effect of the pan-AKT inhibitor MK2206 in the CCA cell line TFK-1 was due to inhibition of AKT1 and AKT2, because knockdown of either AKT1 or AKT2, but not AKT3, showed a synergistic reduction of cell proliferation in combination with mTOR treatment. Finally, using an AKT isoform specific in vitro kinase assay, enzymatic activity of each of the three AKT isoforms was detected in all tissue samples from CCA patients, analyzed. In summary, our preclinical data suggest that combined targeting of mTOR and AKT using RAD001 and MK-2206 might be a new, effective strategy for the treatment of CCA., (Copyright © 2013 UICC.)

Importance: Infantile hypertrophic pyloric stenosis (IHPS) is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. Infantile hypertrophic pyloric stenosis shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited., Objectives: To search the genome comprehensively for genetic associations with IHPS and validate findings in 3 independent sample sets., Design, Setting, and Participants: During stage 1, we used reference data from the 1000 Genomes Project for imputation into a genome-wide data set of 1001 Danish surgery-confirmed samples (cases diagnosed 1987-2008) and 2371 disease-free controls. In stage 2, the 5 most significantly associated loci were tested in independent case-control sample sets from Denmark (cases diagnosed 1983-2010), Sweden (cases diagnosed 1958-2011), and the United States (cases diagnosed 1998-2005), with a total of 1663 cases and 2315 controls., Main Outcomes and Measures: Association of genetic variation with the presence of infantile hypertrophic pyloric stenosis., Results: We found a new genome-wide significant locus for IHPS at chromosome 11q23.3. The single-nucleotide polymorphism (SNP) with the lowest P value at the locus, rs12721025 (odds ratio [OR], 1.59; 95% CI, 1.38-1.83; P = 1.9 × 10(-10)), is located 301 bases downstream of the apolipoprotein A-I (APOA1) gene and is correlated (r2 between 0.46 and 0.80) with SNPs previously found to be associated with levels of circulating cholesterol. For these SNPs, the cholesterol-lowering allele consistently was associated with increased risk of IHPS., Conclusions and Relevance: This study identified a new genome-wide significant locus for IHPS. Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk, which warrants further investigation.

Objectives: This study investigated whether an individual's risk of developing lone atrial fibrillation (AF) before age 60 years is associated with lone AF in relatives., Background: Genetic factors may play a role in the development of lone AF., Methods: Using Danish national registers, a cohort was established of ~4 million persons born between 1950 and 2008, and those with a family history of lone AF (AF without preceding cardiovascular/endocrine diagnoses) were identified. Individuals were followed up until the first diagnosis of lone AF. Poisson regression was used to estimate incidence rate ratios (IRRs)., Results: In ~92 million person-years of follow-up, 9,507 persons were identified as having lone AF. The IRRs for lone AF given an affected first- or second-degree relative were 3.48 (95% confidence interval [CI]: 3.08 to 3.93) and 1.64 (95% CI: 1.04 to 2.59), respectively. IRRs were higher for men than for women but were not associated with the affected relative's sex. IRR for lone AF was 6.24 (95% CI: 2.59 to 15.0), given at least 2 first-degree relatives affected with lone AF. The IRR for lone AF in persons aged <40 years given a first-degree relative affected at age <40 years was 5.42 (95% CI: 3.80 to 7.72), and 8.53 (95% CI: 3.82 to 19.0) in persons age <30 years given a first-degree relative affected at age <30 years., Conclusions: A family history of lone AF is associated with substantial risk of lone AF, with the strongest risks associated with young age at onset, multiple affected relatives, and in first-degree relatives. These results suggest routine evaluation of the families of at least certain types of patients with lone AF., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to examine the effect of a family history of premature death, cardiovascular death in particular, on the risk of early cardiovascular disease., Background: Studies suggest that fatal cardiovascular events and less severe cardiovascular diseases may co-occur in families. Consequently, a family history of premature death may indicate a familial cardiac frailty that predisposes to early cardiovascular disease., Methods: We ascertained family history of premature death (age <60 years) in all individuals born in Denmark from 1950 to 2008 and followed this cohort for early cardiovascular disease (age <50 years). Using Poisson regression, we estimated incidence rate ratios (IRRs) reflecting the effect of premature death in the family on early cardiovascular disease risk., Results: Among 3,985,301 persons followed up for 89,294,258 person-years, 129,825, 31,172, and 5,214 were diagnosed with any early cardiovascular disease, ischemic heart disease, and ventricular arrhythmia, respectively. IRRs for these conditions given a history of premature cardiovascular death in first-degree relatives were 1.72 (95% confidence interval [CI]: 1.68 to 1.77), 2.21 (95% CI: 2.11 to 2.31), and 1.94 (95% CI: 1.70 to 2.20), respectively. With ≥2 cardiovascular deaths in a family, corresponding IRRs were 3.30 (95% CI: 2.77 to 3.94), 5.00 (95% CI: 3.87 to 6.45), and 6.18 (95% CI: 3.32 to 11.50). The IRR for any early cardiovascular disease given a family history of premature noncardiovascular death was significantly lower, 1.12 (95% CI: 1.10 to 1.14) (p(cardiac vs. noncardiac) < 0.0001)., Conclusions: Family history of premature cardiovascular death was consistently and significantly associated with a risk of early cardiovascular disease, suggesting an inherited cardiac vulnerability. These results should be kept in mind when assessing cardiovascular disease risk in persons with a family history of premature cardiovascular death., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The (βα)(8)-barrel is among the most ancient, frequent, and versatile enzyme structures. It was proposed that modern (βα)(8)-barrel proteins have evolved from an ancestral (βα)(4)-half-barrel by gene duplication and fusion. We explored whether the mechanism of protein folding has remained conserved during this long-lasting evolutionary process. For this purpose, potential primordial (βα)(8)-barrel proteins were constructed by the duplication of a (βα)(4) element of a modern (βα)(8)-barrel protein, imidazole glycerol phosphate synthase (HisF), followed by the optimization of the initial construct. The symmetric variant Sym1 was less stable than HisF and its crystal structure showed disorder in the contact regions between the half-barrels. The next generation variant Sym2 was more stable than HisF, and the contact regions were well resolved. Remarkably, both artificial (βα)(8)-barrels show the same refolding mechanism as HisF and other modern (βα)(8)-barrel proteins. Early in folding, they all equilibrate rapidly with an off-pathway species. On the productive folding path, they form closely related intermediates and reach the folded state with almost identical rates. The high energy barrier that synchronizes folding is thus conserved. The strong differences in stability between these proteins develop only after this barrier and lead to major changes in the unfolding rates. We conclude that the refolding mechanism of (βα)(8)-barrel proteins is robust. It evolved early and, apparently, has remained conserved upon the diversification of sequences and functions that have taken place within this large protein family.

HisF, the cyclase subunit of imidazole glycerol phosphate synthase (ImGPS) from Thermotoga maritima, is an extremely thermostable (βα)(8)-barrel protein. We elucidated the unfolding and refolding mechanism of HisF. Its unfolding transition is reversible and adequately described by the two-state model, but 6 weeks is necessary to reach equilibrium (at 25 °C). During refolding, initially a burst-phase off-pathway intermediate is formed. The subsequent productive folding occurs in two kinetic phases with time constants of ~3 and ~20 s. They reflect a sequential process via an on-pathway intermediate, as revealed by stopped-flow double-mixing experiments. The final step leads to native HisF, which associates with the glutaminase subunit HisH to form the functional ImGPS complex. The conversion of the on-pathway intermediate to the native protein results in a 10(6)-fold increase of the time constant for unfolding from 89 ms to 35 h (at 4.0 M GdmCl) and thus establishes a high energy barrier to denaturation. We conclude that the extra stability of HisF is used for kinetic protection against unfolding. In its refolding mechanism, HisF resembles other (βα)(8)-barrel proteins.

Objective: To report the patellar dislocation recurrence in patients ages 9 to 16 years treated surgically with the Green technique or an arthroscopic approach., Material and Methods: A prospective, longitudinal study was conducted with patients ages 9 to 16 years who presented at the pediatric orthopedics and arthroscopy service at IMSS "Lomas Verdes" UMAE Orthopedics and Traumatology Hospital with a diagnosis of patellar dislocation from January 1st 2003 to December 31st 2006. The patellar dislocation recurrences were recorded., Results: Twenty patients and 24 knees were included; 13 females and 7 males; mean age was 14.3 years +/- 1.75. The dislocations prior to surgical treatment occurred at a mean of 5.5 +/- 2.57 dislocation events, with a range of 2 to 10 events. As regards the side involved, 40% had involvement of the left side, 40% of the right side, with 8 patients each, and 20% were bilateral dislocations. No significant differences were found in the clinical course of the patients treated with the Green technique compared with the arthroscopic surgery group (p = 0.371)., Conclusions: The number of dislocation recurrences after the surgical procedure was not related with the age, gender, number of prior dislocations or surgical technique. No significant difference was found between both groups.

Introduction: The injury of the cruciate ligaments secondary to knee dislocation is caused by high energy trauma; its incidence rate is less than 0.02%; there are multiple treatments, with surgery being the most common one., Objective: To determine the functional characteristics of patients who underwent cruciate ligament plasty and sustained knee dislocation., Material and Methods: An observational, prospective, cross-sectional study was conducted including all adult patients with a diagnosis of cruciate ligament injury resulting from knee dislocation who were surgically treated from January 2006 to December 2007. Two knee functional assessment scales were used., Results: A total of 16 patients were included, 12 males and 4 females; mean age was 32.1 years. The Knee Society Clinical Rating Scale had a positive correlation with the Lysholm Knee Scoring Scale (r = 0.836) with p = 0.001., Discussion: The functional results of patients treated surgically are diverse. This study was not conducted as a controlled clinical trial due to the absence of randomization, which was not possible due to the infrequency of the condition., Conclusions: It will be necessary to confirm the results after a longer follow-up and in a comparative, double-blind study of patients undergoing surgery.

Background: A central question in molecular biology is how transcriptional regulatory elements (TREs) act in combination. Recent high-throughput data provide us with the location of multiple regulatory regions for multiple regulators, and thus with the possibility of analyzing the multivariate distribution of the occurrences of these TREs along the genome., Results: We present a model of TRE occurrences known as the Hawkes process. We illustrate the use of this model by analyzing two different publically available data sets. We are able to model, in detail, how the occurrence of one TRE is affected by the occurrences of others, and we can test a range of natural hypotheses about the dependencies among the TRE occurrences. In contrast to earlier efforts, pre-processing steps such as clustering or binning are not needed, and we thus retain information about the dependencies among the TREs that is otherwise lost. For each of the two data sets we provide two results: first, a qualitative description of the dependencies among the occurrences of the TREs, and second, quantitative results on the favored or avoided distances between the different TREs., Conclusions: The Hawkes process is a novel way of modeling the joint occurrences of multiple TREs along the genome that is capable of providing new insights into dependencies among elements involved in transcriptional regulation. The method is available as an R package from http://www.math.ku.dk/~richard/ppstat/.

The evolution of the prototypical (beta alpha)(8)-barrel protein imidazole glycerol phosphate synthase (HisF) was studied by complementary computational and experimental approaches. The 4-fold symmetry of HisF suggested that its constituting (beta alpha)(2) quarter-barrels have a common evolutionary origin. This conclusion was supported by the computational reconstruction of the HisF sequence of the last common ancestor, which showed that its quarter-barrels were more similar to each other than are those of extant HisF proteins. A comprehensive sequence analysis identified HisF-N1 [corresponding to (beta alpha)(1-2)] as the slowest evolving quarter-barrel. This finding indicated that it is the closest relative of the common (beta alpha)(2) predecessor, which must have been a stable and presumably tetrameric protein. In accordance with this prediction, a recombinantly produced HisF-N1 protein was properly folded and formed a tetramer being stabilised by disulfide bonds. The introduction of a disulfide bond in HisF-C1 [corresponding to (beta alpha)(5-6)] also resulted in the formation of a stable tetramer. The fusion of two identical HisF-N1 quarter-barrels yielded the stable dimeric half-barrel HisF-N1N1. Our findings suggest a two-step evolutionary pathway in which a HisF-N1-like predecessor was duplicated and fused twice to yield HisF. Most likely, the (beta alpha)(2) quarter-barrel and (beta alpha)(4) half-barrel intermediates on this pathway were stabilised by disulfide bonds that became dispensable upon consolidation of the (beta alpha)(8)-barrel., ((c) 2010 Elsevier Ltd. All rights reserved.)

Background: Two plateletpheresis cell separator systems were compared in a paired crossover study with respect to the product quality, the number of platelet (PLT) units per donation, and the donor comfort., Study Design and Methods: Forty-four female and 47 male donors were distributed to three body weight groups. Double PLT units with 6 x 10(11) PLTs were collected from three Fenwal Amicus Crescendo (AC) and three CaridianBCT Trima Accel (TA) machines. Each donor made one donation on each randomly assigned system and answered a questionnaire on the subjective donor comfort. The answers were scored from 5 (best) to 1 (worst)., Results: Based on 182 donations, with 91 donations on AC and TA separators each, 179 runs resulted in double PLT units and three (2xAC, 1xTA) in single units. The white blood cell counts were below 1 x 10(6) in all but eight therapeutic units (8xTA; mean, 1.98 x 10(6)). The mean PLT yield (AC 6.00 x 10(11), TA 5.98 x 10(11)), the collection rate, and the PLT extraction coefficient did not significantly differ between the two devices. Differences of the donor comfort over all groups were only observed for the loudness of the instrument (4.63 AC vs. 4.24 TA, p < 0.001) and the subjective impression of the run time (4.24 AC vs. 4.48 TA, p < 0.05). Male donors greater than 88 kg preferred the TA instruments concerning the impact of the needle, run time, overall experience (p < 0.01 each), and willingness to donate on the same instrument again (p < 0.05)., Conclusions: Only minor differences were observed despite the fact that the AC separators are run with two needles and the TA with one needle.

An oral calcium bolus (Bovikalc, Boehringer Ingelheim Vetmedica) supplying calcium to dairy cows in the form of calcium chloride and calcium sulfate was evaluated to determine the effect on calcium homeostasis immediately after calving. Cows in the treatment group received one bolus immediately after calving and a second bolus 12 hours later. Control cows received no calcium supplementation. Blood was analyzed for ionized calcium, and urine was collected for urinary pH determination. Postpartum supplementation with the Bovikalc bolus significantly increased serum ionized calcium levels and decreased urine pH values.

SlyD, the sensitive-to-lysis protein from Escherichia coli, consists of two domains. They are not arranged successively along the protein chain, but one domain, the "insert-in-flap" (IF) domain, is inserted internally as a guest into a surface loop of the host domain, which is a prolyl isomerase of the FK506 binding protein (FKBP) type. We used SlyD as a model to elucidate how such a domain insertion affects the stability and folding mechanism of the host and the guest domain. For these studies, the two-domain protein was compared with a single-domain variant SlyDDeltaIF, SlyD* without the chaperone domain (residues 1-69 and 130-165) in which the IF domain was removed and replaced by a short loop, as present in human FKBP12. Equilibrium unfolding and folding kinetics followed an apparent two-state mechanism in the absence and in the presence of the IF domain. The inserted domain decreased, however, the stability of the host domain in the transition region and decelerated its refolding reaction by about 10-fold. This originates from the interruption of the chain connectivity by the IF domain and its inherent instability. To monitor folding processes in this domain selectively, a Trp residue was introduced as fluorescent probe. Kinetic double-mixing experiments revealed that, in intact SlyD, the IF domain folds and unfolds about 1000-fold more rapidly than the FKBP domain, and that it is strongly stabilized when linked with the folded FKBP domain. The unfolding limbs of the kinetic chevrons of SlyD show a strong downward curvature. This deviation from linearity is not caused by a transition-state movement, as often assumed, but by the accumulation of a silent unfolding intermediate at high denaturant concentrations. In this kinetic intermediate, the FKBP domain is still folded, whereas the IF domain is already unfolded.

Background: Trends in biologic fertility are elusive. Possible negative trends in male reproductive health are still debated, and their effect on human fertility might be negligible. Time-to-pregnancy (TTP) is a functional measure of couple fecundability., Methods: We analyzed data on TTP among 832,000 primiparous women 20 years of age and older in the nationwide Swedish Medical Birth Registry from 1983 through 2002. This age restriction led to an exclusion of 10% of primiparous pregnancies. Subfertility (TTP > or =1 year) was analyzed as a function of maternal age, calendar time at initiation of attempt, and birth cohort-taking into account the truncation problems that are inherent in birth-based retrospective sampling., Results: Subfertility generally decreased over successive birth cohorts. When studied as a period effect, a transient increase in subfertility was seen in the early 1990s. Subfertility increased with age, except that for women in their late 1930s, an apparent decrease was observed, particularly among the early cohorts., Conclusion: We found decreasing subfertility over time. We speculate that these patterns might be related to a Sweden-specific decrease over time in sexually transmitted diseases, to changes in sexual behavior induced by socioeconomic conditions, or to broader biologic or educational trends.

Approaches for monitoring time trends in couples' fecundity and for studying its sensitivity to environmental factors are needed. Two approaches rely on the inclusion of a cross-sectional sample of couples currently "at risk" of pregnancy either with follow up (prevalent cohort) or without follow up (current-duration design). To illustrate the feasibility of the current-duration design, we contacted a random sample of 1204 French women age 18 to 44 years in 2004 and recruited those who were currently having unprotected sexual intercourse. The current duration since the beginning of unprotected intercourse was defined for 69 women (5.7%). An additional 15 women (1.2%) were planning to start trying to become pregnant within the next 6 months. Parametric methods allowed, based on current duration of unprotected intercourse, estimation of fecundity as if the couples had been followed prospectively. The estimated proportion of couples not pregnant after 12 months of unprotected intercourse was 34% (95% confidence interval [CI] = 15-54%). The accelerated-failure time model allows study of the influence of environmental factors on fecundity. As an illustration, tobacco smoking by the woman was associated with a doubling in the median duration of unprotected intercourse before pregnancy (adjusted time ratio = 2.4; 95% CI = 1.1-5.2). We quantified the influence of time trends in the prevalence of smoking on this estimate. We suggest ways to quantify or avoid other potential bias. In conclusion, it is possible to recruit a sample of couples currently having unprotected intercourse. The current-duration design appears feasible with approximately 5 times as many women eligible for study as for an incident cohort design.

The objective of the study was to investigate the effect of offering supplementary creep feed to piglets during the suckling period on the faecal shedding of haemolytic Escherichia coli bacteria and occurrence of spontaneous post-weaning diarrhoea 0-5 days after weaning. Supplementary creep feed was offered to half of the piglets in 12 litters, from 2 weeks of age until weaning at 4 weeks, and the individual feed contact was recorded by direct observations. It was found that diarrhoea occurrence was associated with faecal shedding of haemolytic E. coli bacteria (p=0.003), specifically E. coli O149 (p=0.004). Occurrence of diarrhoea and faecal shedding of haemolytic E. coli was not associated with creep feeding per se. However, the faecal E. coli O149 shedding occurred significantly less often in piglets that were offered creep feed in the suckling period but only showed limited interest in the feed (i.e. contacted the feed less than or equal to the median level of contact) compared to piglets that had frequent creep feed contact or piglets that had not had access to creep feed at all (p=0.015). Correspondingly, the diarrhoea occurrence tended to be lower in these piglets (p=0.081). Piglets with low creep feed contact during the suckling period ate the same total amount of feed during the 5 days after weaning, however, they ate less feed on days 0-2 after weaning compared to the piglets with frequent creep feed contact and non-creep fed piglets. It is suggested that intestinal function associated with a voluntary low creep feed contact during the suckling period leads to decreased feed intake just after weaning, and thus reduces the intestinal proliferation of E. coli O149 in these piglets.

Ex vivo whole blood stimulation with endotoxin has proved to be a useful method for quantitative evaluations of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) response ability in humans. In the present study, a dose- and time-response study was carried out in order to develop an ex vivo whole blood stimulation assay for the quantification of TNF-alpha production in pigs. The TNF-alpha response was enhanced with increasing endotoxin stimulation dose. The maximum TNF-alpha response occurred after 2-8 h of stimulation. Subsequently, the assay was used to evaluate the TNF-alpha response in pigs (n=32) in relation to weaning. The TNF-alpha response was 332 pg ml(-1) (+/-59 pg) plasma 2 days before weaning and 127 pg ml(-1) (+/-23 pg) plasma 2 days after weaning, which was a significant reduction (p<0.001). Total and differential counts of leucocytes were the same before and after weaning. Thus the lower TNF-alpha response may be due to reduced monocyte responsiveness to the endotoxin, rather than caused by a reduction in monocyte numbers. The reduced TNF-alpha response in piglets after weaning may be a factor of importance to the increased disease susceptibility seen in piglets in this period.

Background: This study was carried out to validate the role of virtual reality computer simulation as a method of assessment of psychomotor skills in gastrointestinal endoscopy. We aimed to investigate whether the GI Mentor II computer system (Simbionix Ltd.) was able to differentiate between subjects with different experience with GI endoscopy., Methods: Twenty-eight subjects were included in the study. They were divided into 3 groups according to their experience with GI endoscopy: experienced [group 1, performed > 200 endoscopic procedures, (n = 8)] residents [group 2, performed < 50 endoscopic procedures, (n = 10)] and medical students [group 3, never performed GI endoscopy, (n = 10)]. All participants received identical pretest instruction on the simulator. Assessment of endoscopic skills was performed during a simulated colonoscopy and was based on parameters measured by the computer system: time, percentage of mucosa surface examined, efficiency of screening, time with a clear view, excessive local pressure, pain, time with pain, loop formation, and total time with a loop., Results: Significant differences in performance existed between surgeons in the 3 groups. Experienced surgeons demonstrated best performance parameters, followed by the residents and the medical students. Significant differences in time (Kruskal-Wallis test, P < 0.001), percentage of mucosa surface examined (P = 0.001), efficiency of screening (P = 0.001), time with a clear view (P = 0.001), pain experienced (P = 0.004), time with pain (P = 0.012), loop formation (P < 0.001), time with a loop (P < 0.001), and excessive local pressure (P = 0.001) were demonstrated. Significant differences existed between group 1 and 2 and 1 and 3 (Mann-Whitney test, P < 0.05). Differences between groups 2 and 3 did not reach statistical significance (P > 0.05)., Conclusions: The VR simulator was able to differentiate between subjects with different endoscopic experience. This indicates that the GI Mentor measures skills relevant for gastrointestinal endoscopy and can be used in training programs as an assessment tool.

In nine organic swine herds, faecal excretion and pasture contamination by parasite eggs/larvae were studied in a period from March to October 1999. It was shown that the organic pigs were infected with Ascaris suum (28% of weaners, 33% of fatteners, 4% of sows), Trichuris suis (4% of weaners, 13% of fatteners, <1% of sows) and Oesophagostomum spp. (5% of weaners, 14% of fatteners, 20% of sows) whereas no infections with Hyostrongylus rubidus, Metastrongylus spp. or Strongyloides ransomi were detected. Moreover, no pigs showed clinical signs of infestations with scabies or lice. In the soil samples, very few Trichuris eggs were found throughout the season, whereas Ascaris eggs were found in 14% of the soil samples from sow pastures and in 35% from slaughter pig pastures, with the first infective eggs being recorded in July and the maximum number in August. Infective Oesophagostomum larvae were found in the grass samples in increasing numbers from May to October. Single herd cases of exceptionally high parasite infection levels are described in relation to herd management procedures.

Socioemotional selectivity theory contends that as people become increasingly aware of limitations on future time, they are increasingly motivated to be more selective in their choice of social partners, favoring emotionally meaningful relationships over peripheral ones. The theory hypothesizes that because age is negatively associated with time left in life, the social networks of older people contain fewer peripheral social partners than those of their younger counterparts. This study tested the hypothesis among African Americans and European Americans, two ethnic groups whose social structural resources differ. Findings confirm the hypothesis. Across a wide age range (18 to 94 years old) and among both ethnic groups, older people report as many emotionally close social partners but fewer peripheral social partners in their networks as compared to their younger counterparts. Moreover, a greater percentage of very close social partners in social networks is related to lower levels of happiness among the young age group, but not among the older age groups. Implications of findings for adaptive social functioning across the life span are discussed.

Age differences in emotional experience over the adult life span were explored, focusing on the frequency, intensity, complexity, and consistency of emotional experience in everyday life. One hundred eighty-four people, age 18 to 94 years, participated in an experience-sampling procedure in which emotions were recorded across a 1-week period. Age was unrelated to frequency of positive emotional experience. A curvilinear relationship best characterized negative emotional experience. Negative emotions declined in frequency until approximately age 60, at which point the decline ceased. Individual factor analyses computed for each participant revealed that age was associated with more differentiated emotional experience. In addition, periods of highly positive emotional experience were more likely to endure among older people and periods of highly negative emotional experience were less stable. Findings are interpreted within the theoretical framework of socioemotional selectivity theory.

Socioemotional selectivity theory claims that the perception of time plays a fundamental role in the selection and pursuit of social goals. According to the theory, social motives fall into 1 of 2 general categories--those related to the acquisition of knowledge and those related to the regulation of emotion. When time is perceived as open-ended, knowledge-related goals are prioritized. In contrast, when time is perceived as limited, emotional goals assume primacy. The inextricable association between time left in life and chronological age ensures age-related differences in social goals. Nonetheless, the authors show that the perception of time is malleable, and social goals change in both younger and older people when time constraints are imposed. The authors argue that time perception is integral to human motivation and suggest potential implications for multiple subdisciplines and research interests in social, developmental, cultural, cognitive, and clinical psychology.

In 2 studies the postulate that the perception of time left in life influences the ways that people conceptualize social relationships was explored. It was hypothesized that when time is limited, emotional aspects of relationships are highly salient. In Study 1, a card-sort paradigm involving similarity judgments demonstrated, for a sample of persons 18 to 88 years old, that the prominence of affect in the mental representations of prospective social partners is positively associated with age. In Study 2, the same experimental approach was applied to a sample of young gay men similar to one another in age, but notably different in their health status (that is, HIV negative; HIV positive, asymptomatic; and HIV positive, symptomatic). It was found that, with age held constant, increasing closeness to the end of life is also associated with an increasing prominence of affect in the mental representations of social partners. The results suggest that the perception of limited time, rather than chronological age, is the critical variable influencing mental representations of social partners.

In exploring the emotional climate of long-term marriages, this study used an observational coding system to identify specific emotional behaviors expressed by middle-aged and older spouses during discussions of a marital problem. One hundred and fifty-six couples differing in age and marital satisfaction were studied. Emotional behaviors expressed by couples differed as a function of age, gender, and marital satisfaction. In older couples, the resolution of conflict was less emotionally negative and more affectionate than in middle-aged marriages. Differences between husbands and wives and between happy and unhappy marriages were also found. Wives were more affectively negative than husbands, whereas husbands were more defensive than wives, and unhappy marriages involved greater exchange of negative affect than happy marriages.

Self-reported affect and autonomic and somatic physiology were studied during three 15-min conversations (events of the day, problem area, pleasant topic) in a sample of 151 couples in long-term marriages. Couples differed in age (40-50 or 60-70) and marital satisfaction (satisfied or dissatisfied). Marital interaction in older couples was associated with more affective positivity and lower physiological arousal (even when controlling for affective differences) than in middle-age couples. As has previously been found with younger couples, marital dissatisfaction was associated with less positive affect, greater negative affect, and greater negative affect reciprocity. In terms of the relation between physiological arousal and affective experience, husbands reported feeling more negative the more they were physiologically aroused; for wives, affect and arousal were not correlated. These findings are related to theories of socioemotional change with age and of gender differences in marital behavior and health.

Recent research on emotion has rendered equivocal traditional views of diminished emotionality in late life. This study focused on the salience of emotion in 83 Ss age 20 to 83 years. Using an incidental memory paradigm, Ss read a narrative containing equivalent amounts of emotional and neutral information. Salience was measured by the proportion of emotional versus neutral phrases recalled at the end of a 1-hr experimental session. Contrary to models of diminished emotionality, results suggest that the relative salience of emotion increases linearly with age and cohort. Results are discussed within the framework of cognitive theories of adult development and socioemotional selectivity theory.

The idea that age-related reductions in network size are proactively managed by older people is explored by examining the interrelationships among chronological age, network composition, social support, and feelings of social embeddedness (FSE) in a representative sample of 156 community-dwelling and institutionalized adults ages 70-104 years. Comparisons between people with and without nuclear families are made to explore the influence of opportunity structures on network size. Social networks of very old people are nearly half as large as those of old people, but the number of very close relationships does not differentiate age groups. Among Ss without living nuclear family members, the number of emotionally close social partners predicted FSE better than among Ss with nuclear family members. Findings provide evidence for proactive selection, compensation, and optimization toward the goal of emotional enhancement and social functioning in old age.

Long-term marriages (N = 156) varying in spouses' age (40-50 years or 60-70 years) and relative marital satisfaction (satisfied and dissatisfied) were studied. Spouses independently completed demographic, marital, and health questionnaires and then participated in a laboratory-based procedure focused on areas of conflict and sources of pleasure. Findings supported a positive view of older marriages. Compared with middle-aged marriages, older couples evidenced (a) reduced potential for conflict and greater potential for pleasure in several areas (including children), (b) equivalent levels of overall mental and physical health, and (c) lesser gender differences in sources of pleasure. The relation between marital satisfaction and health was stronger for women than for men. In satisfied marriages, wives' and husbands' health was equivalent; in dissatisfied marriages, wives reported more mental and physical health problems than did their husbands.

This investigation explored 2 hypotheses derived from socioemotional selectivity theory: (a) Selective reductions in social interaction begin in early adulthood and (b) emotional closeness to significant others increases rather than decreases in adulthood even when rate reductions occur. Transcribed interviews with 28 women and 22 men from the Child Guidance Study, conducted over 34 years, were reviewed and rated for frequency of interaction, satisfaction with the relationship, and degree of emotional closeness in 6 types of relationships. Interaction frequency with acquaintances and close friends declined from early adulthood on. Interaction frequency with spouses and siblings increased across the same time period and emotional closeness increased throughout adulthood in relationships with relatives and close friends. Findings suggest that individuals begin narrowing their range of social partners long before old age.

Older people engage in social interaction less frequently than their younger counterparts. As I mentioned at the start, the change has been interpreted in largely negative terms. Yet when asked about their social relationships, older people describe them as satisfying, supportive, and fulfilling. Marriages are less negative and more positive. Close relationships with siblings are renewed, and relationships with children are better than ever before. Even though older people interact with others less frequently than younger people do, old age is not a time of misery, rigidity, or melancholy. Rather than present a paradox, I argue here that decreasing rates of contact reflect a reorganization of the goal hierarchies that underlie motivation for social contact and lead to greater selectivity in social partners. This reorganization does not occur haphazardly. Self-definition, information seeking, and emotion regulation are ranked differently depending not only on past experiences, but on place in the life cycle and concomitant expectations about the future. I contend that the emphasis on emotion in old age results from a recognition of the finality of life. In most people's lives this does not appear suddenly in old age but occurs gradually across adulthood. At times, however, life events conspire to bring about endings more quickly. Whether as benign as a geographical relocation or as sinister as a fatal disease, endings heighten the salience of surrounding emotions. When each interaction with a grandchild or good-bye kiss to a spouse may be the last, a sense of poignancy may permeate even the most casual everyday experiences. When the regulation of emotion assumes greatest priority among social motives, social partners are carefully chosen. The most likely choices will be long-term friends and loved ones, because they are most likely to provide positive emotional experiences and affirm the self. Information seeking will motivate some social behavior, but for reasons discussed previously, this will also require judicious choices of social partners. Narrowing the range of social partners allows people to conserve physical and cognitive resources, freeing time and energy for selected social relationships. As such, SST is highly consistent with the selective optimization with compensation model of successful aging formulated by P. Baltes and M. Baltes (1990) described above. SST is meant to describe and explain the underlying mechanisms for age-related changes in social behavior. It is not intended to be prescriptive.(ABSTRACT TRUNCATED AT 400 WORDS)

Emotion-specific autonomic nervous system (ANS) activity was studied in 20 elderly people (age 71-83 years, M = 77) who followed muscle-by-muscle instructions for constructing facial prototypes of emotional expressions and relived past emotional experiences. Results indicated that (a) patterns of emotion-specific ANS activity produced by these tasks closely resembled those found in other studies with younger Ss, (b) the magnitude of change in ANS measures was smaller in older than in younger Ss, (c) patterns of emotion-specific ANS activity showed generality across the 2 modes of elicitation, (d) emotion self-reports and spontaneous production of emotional facial expressions that occurred during relived emotional memories were comparable with those found in younger Ss, (e) elderly men and women did not differ in emotional physiology or facial expression, and (f) elderly women reported experiencing more intense emotions when reliving emotional memories than did elderly men.

Carstensen's selectivity theory, which explains age-related change in social behavior in terms of emotion conservation and increasing discrimination among social partners, was investigated in 2 studies. In Study 1, 80 people aged 14 to 95 classified descriptions of people according to their similarities as social partners in terms of affect anticipated in the interaction and that this dimension was most important to older people. Study 2 showed how anticipated social endings influence partner selection: 380 people aged 11 to 92 chose familiar or novel partners under unspecified and ending conditions. Overall, older people chose familiar partners most frequently; yet when social endings were salient, younger people patterned the preferences of the elderly. These results suggest that social partner selectivity functions to conserve emotion resources in the face of limited future opportunities.

The treatment histories and current social, financial, and clinical status of 111 chronically mentally ill (CMI) persons over the age of 60 were examined. Information was obtained from Ss, family, mental health records, and mental health professionals familiar with Ss. Psychiatric symptoms were observed in 74% of Ss. Many Ss experienced long periods without acute episodes of illness. Recurring episodes eventually appeared in most Ss, however, and ongoing deficits in daily functioning and social contacts were prototypical. Two thirds of the Ss were living in the community, relying heavily on family contacts; the rest lived primarily in nursing homes (23.4%) or psychiatric hospitals (7.2%). Social support was the best predictor of level of functioning. Findings suggest that failure of CMI elderly to use mental health services is not due to lack of need. Mental health services currently do not appear to be meeting the needs of this population.

The present study represents a long-term follow-up of elderly persons who completed a behavioral treatment program for alcohol problems. Subjects over the age of 60 at the time they obtained treatment for alcohol abuse were contacted two to four years after discharge. Interviews with the alcohol abuser and a significant other were conducted in an effort to identify the percentage of persons for whom treatment had sustained beneficial effects, differences in outcome for early-versus late-onset alcohol abusers, and demographic and daily activity variables that distinguish abstinent from nonabstinent individuals. Results suggest that beneficial effects of the program maintained for 50% of the patients two or more years following completion of the program. An additional 12% reported significant modification of their drinking. Directions for future research are suggested.

We examined the relation between 38 nationally televised news or feature stories about suicide from 1973 to 1979 and the fluctuation of the rate of suicide among American teenagers before and after these stories. The observed number of suicides by teenagers from zero to seven days after these broadcasts (1666) was significantly greater than the number expected (1555; P = 0.008). The more networks that carried a story about suicide, the greater was the increase in suicides thereafter (P = 0.0004). These findings persisted after correction for the effects of the day of the week, the month, holidays, and yearly trends. Teenage suicides increased more than adult suicides after stories about suicide (6.87 vs. 0.45 percent). Suicides increased as much after general-information or feature stories about suicide as after news stories about a particular suicide. Six alternative explanations of these findings were assessed, including the possibility that the results were due to misclassification or were statistical artifacts. We conclude that the best available explanation is that television stories about suicide trigger additional suicides, perhaps because of imitation.

Previous research suggests that elderly people utilize fewer coping strategies than younger people. Some researchers suggest that these quantitative changes reflect decreases in the use of maladaptive strategies; others contend that they reflect decreases in the use of adaptive strategies by older adults. The present article reports the findings of three studies of coping in older people, two addressing coping with health problems, and the other addressing coping with moving. In all three studies, the number of self-reported coping strategies decreases with age. Results do not support the idea that decreases in the number of strategies imply decrements in the quality of coping, however: in two studies, age was unrelated to the effectiveness of strategies, in the third, effectiveness ratings were higher for older subjects. The need for evaluation of specific outcomes of coping strategies is discussed, along with the need for task-specific measurement of coping. It is proposed that decreases in the number of coping strategies reflect improved coping efficiency, rather than a deterioration of adaptational skills.

We determined the circulating dopamine levels in 17 patients with insulin-dependent diabetes mellitus (IDDM), of whom eight had amenorrhoea (DM-AM) and nine were normally menstruating (DM). Seven non-diabetic women with normoprolactinaemic, normogonadotrophic secondary amenorrhoea (AM) and nine normally menstruating women (controls) were studied. In all subjects basal blood concentrations of free dopamine (f-DA), conjugated dopamine (c-DA), epinephrine (E), norepinephrine (NE), prolactin (PRL), luteinizing hormone (LH), thyroid-stimulating hormone (TSH) and oestradiol-17 beta were determined and all subjects, except for three AM patients, had a Metoclopramide test performed for measurements of f-DA, c-DA, PRL, LH and TSH. Plasma c-DA was significantly (p less than 0.05) increased in patients with amenorrhoea compared to the respective control groups. In diabetic patients c-DA levels were significantly (p less than 0.05) lower compared to controls. The ratio between basal f-DA and c-DA concentrations was significantly (p less than 0.01) higher in diabetic patients compared with non-diabetic patients. After Metoclopramide stimulation DM-AM patients showed a significant (p less than 0.05) rise in c-DA, whereas this was not seen in other groups. DM-AM patients had significantly (p less than 0.05) lower basal PRL and LH levels than DM patients and controls. In addition DM-AM patients had a significantly (p less than 0.05) lower PRL response to Metoclopramide compared with DM patients. There were no significant correlations between catecholamines and basal as well as Metoclopramide stimulated pituitary hormones. This study suggests that the abnormal pituitary hormone secretion in patients with amenorrhoea may in part be caused by an increased dopaminergic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Gonadotropin responses to GnRH and PRL responses to TRH and metoclopramide (MTC) were investigated in nine consecutive women with amenorrhea and insulin-treated diabetes mellitus. Nine normal menstruating diabetic women, 12 normal women in the early follicular phase, and nine consecutive nondiabetic women with functional amenorrhea served as controls. No significant differences were found in relation to diabetes regulation within the two diabetic groups. Amenorrheic patients with diabetes mellitus had significantly lower basal PRL levels than normal women and estradiol levels compared to the other groups. Basal plasma LH concentrations were significantly lower in women with amenorrhea and diabetes mellitus than in nondiabetics with amenorrhea, whereas plasma FSH levels were similar in all groups. The LH response to GnRH was significantly lower in amenorrheic patients with diabetes mellitus than in normal women, and a significant correlation (r = 0.81, P less than 0.01) was found between the LH response to GnRH and the basal estradiol level in these women. The FSH response to GnRH and the PRL response to TRH were similar in all groups. Amenorrheic diabetics had significantly lower PRL responses to MTC compared to other groups, and nondiabetics with amenorrhea had significantly lower PRL response than normal women. It is concluded that diabetic patients with functional amenorrhea have low basal and MTC-stimulated PRL levels, low basal LH levels, and decreased LH response to GnRH despite low estrogen levels. These hormonal changes may in part be caused by a raised central dopaminergic activity leading to a depression of pituitary ovulatory mechanisms.

Clinical characteristics and basal hormonal parameters related to ovulatory function were investigated in 22 diabetic patients with anovulation (group 1) and in nine normally menstruating diabetic patients (group 2) and 45 nondiabetic patients with anovulation (group 3). No significant differences according to control of the diabetes were demonstrated within the two diabetic groups. Groups 1 and 3 did not differ according to classification of anovulation. Group 1 had significantly (P less than 0.01) lower levels of prolactin (PRL), 17 beta-estradiol (E2), thyrotropin (TSH), 3,3',5-triiodothyronine (T3), and thyroxine (T4) than those of group 3, and significantly (P less than 0.01) lower levels of E2 and TSH than those of group 2. The urinary excretion of cortisol was significantly higher in group 1 than in group 2 (P less than 0.05) and group 3 (P less than 0.01). These data suggest a derangement in pituitary-gonadal feedback mechanisms or a depression of pituitary function in anovulatory diabetic patients, and we hypothesize that an increased central/peripheral dopamine and/or cortisol activity in these patients may to some extent influence the hypothalamic-pituitary axis.

In order to assess whether a possible altered dopamine activity in normal-menstruating diabetic patients may influence the pituitary hormone secretion we have measured the basal serum concentrations of Prl, LH and FSH in 28 patients with insulin dependent diabetes mellitus (IDDM) and in 55 normal-menstruating women at day 3 to 6 of the menstrual cycle. In addition basal levels of oestradiol-17 beta, TSH, thyroxine (T4), triiodothyronine (T3) and resin-T3 uptake (RT3U) were determined in 17 patients with IDDM and in 17 controls. The responses of FSH, LH, Prl, GH and TSH to metoclopramide (MTC) administration (10 mg iv) were studied in 17 patients and 17 controls. In 10 patients with IDDM and 8 controls the short-term variations in pituitary hormones and blood glucose concentration were evaluated. Patients with IDDM had significantly lower basal levels of Prl (P less than 0.01) and TSH (P less than 0.05) and significantly (P less than 0.05) higher basal levels of GH than normal women. No significant (P greater than 0.05) differences were found regarding basal serum concentrations of FSH, LH, oestradiol, T4, T3 and RT3U. During the 3 h period the mean coefficient of variation of Prl, FSH, LH and GH was not significantly (P greater than 0.05) different between diabetic patients and controls. Both groups responded significantly (P less than 0.01) in Prl and TSH to MTC but the TSH response was significantly (P less than 0.05) lower in patients with IDDM. The Prl response to MTC was not significantly (P greater than 0.05) different within the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)