A hypothesis out-of-date. the diet-heart idea

An almost endless number of observations and experiments have effectively falsified the hypothesis that dietary cholesterol and fats, and a high cholesterol level play a role in the causation of atherosclerosis and cardiovascular disease. The hypothesis is maintained because allegedly supportive, but insignificant findings, are inflated, and because most contradictory results are misinterpreted, misquoted or ignored.     

Carcinogen inducibility in vivo and down-regulation of DMBT1 during breast carcinogenesis

Deleted in malignant brain tumors 1 (DMBT1) has been proposed as a candidate tumor suppressor for brain and epithelial cancer. Initial studies suggested loss of expression rather than mutation as the predominant mode of DMBT1 inactivation. However, in situ studies in lung cancer demonstrated highly sophisticated changes of DMBT1 expression and localization, pointing to a chronological order of events. Here we report on the investigation of DMBT1 in breast cancer in order to test whether these principles might also be attributable to other tumor types. Comprehensive mutational analyses did not uncover unambiguous inactivating DMBT1 mutations in breast cancer. Expression analyses in the human and mouse mammary glands pointed to the necessity of DMBT1 induction. While age-dependent and hormonal effects could be ruled out, 9 of 10 mice showed induction of Dmbt1 expression after administration of the carcinogen 7,12-dimethybenz(alpha)anthracene prior to the onset of tumorigenesis or other histopathological changes. DMBT1 displayed significant up-regulation in human tumor-flanking tissues compared to in normal breast tissues (P < 0.05). However, the breast tumor cells displayed a switch from lumenal secretion to secretion to the extracellular matrix and a significant down-regulation compared to that in matched normal flanking tissues (P < 0.01). We concluded that loss of expression also is the predominant mode of DMBT1 inactivation in breast cancer. The dynamic behavior of DMBT1 in lung carcinoma is fully reflected in breast cancer, which suggests that this behavior might be common to tumor types arising from monolayered epithelia.     

Method for quantitative detection and presumptive identification of group B streptococci on primary plating

Maternal prenatal screening for group B streptococci (GBS) followed by offering of intrapartum chemoprophylaxis to carriers is one of the strategies used to reduce the incidence of neonatal early-onset GBS infections. Culturing of vaginal and anorectal swab specimens in selective broth is the screening procedure recommended by the Centers for Disease Control and Prevention. This technique is sensitive; it does not, however, allow either evaluation of the degree of colonization or detection of cocolonization with several GBS clones. We have examined the carriage rate and population dynamics of GBS in a group of Danish women during pregnancy and 1 year after delivery using a new detection method. In the present paper we describe a mixed blood agar medium (MB agar) that identifies GBS in the primary cultures by detection of a double hemolysis pattern consisting of characteristic, large zones of partial hemolysis ("CAMP zones") and of narrow zones of complete hemolysis. The MB agar was at least as sensitive as culturing in selective broth for detection of GBS in vaginal and anorectal swab specimens, and GBS strains could be identified directly on the primary plate due to the CAMP zones without the need for subculturing. The carriage rate of GBS in a group of Danish women was found to be more than 30%, a figure considerably higher than the rate that was reported previously.     

Vaccination for birch pollen allergy. Induction of affinity-matured or blocking IgG antibodies does not account for the reduced binding of IgE to Bet v 1

Specific allergy vaccination (SAV) is associated with increased levels of allergen specific IgG in serum. It is not clear, however, to what extent qualitative changes in allergen binding to IgG may be induced as well. We therefore analyzed the binding of the major allergen in pollen of birch (Betula verrucosa) (Bet v 1), the major allergen in birch pollen, to serum IgG and IgE, separately and in competition. Sera from six birch pollen-allergic patients were obtained before and after 5 years of SAV, and binding was assessed with 125I-Bet v 1. Before SAV, IgG bound more than eight times the amount of Bet v 1 compared with IgE, and together they accounted for more than 85% of the serum binding capacity. While SAV induced minimal changes in IgE binding, the IgG binding capacities increased 6-32 times. In contrast, the binding avidities (K(d) 28-40pM) changed less than 20%, pre- and post-SAV IgG provided similar inhibition of Bet v 1 binding to IgE at equimolar levels, and cross inhibition studies between IgG and IgE showed low inter-individual differences. Following SAV, all sera reduced Bet v 1 binding to CD23(+) cells, correlating with reduced binding of Bet v 1 to IgE (P<0.001). These results show that high avidity IgG of low inter-individual difference in Bet v 1 binding quality is the dominant binding factor of Bet v 1 in sera of birch pollen-allergic patients, and that SAV-induced inhibition of binding of Bet v 1 to IgE can be explained mainly or solely by increased amounts of IgG.     

The blocking activity of birch pollen-specific immunotherapy-induced IgG4 is not qualitatively superior to that of other IgG subclasses

Allergen-specific IgG antibodies induced by specific immunotherapy (SIT) interfere with the allergen-IgE interaction, and act as blocking antibodies in vitro. It has been hypothesised that IgG4, as opposed to other IgG subclasses, is particularly important in this function, which may play a role for the clinical efficacy of SIT. In this study, fractionated serum samples from 14 SIT-treated birch pollen allergic individuals enabled determination of the inhibitory capacity of IgG4 alone versus non-IgG4 IgG. Allergen-binding activities of IgG and the IgG-mediated inhibition of allergen binding to autologous IgE were detected using 125I-labelled rBet v 1.2801, a recombinant variant of the major allergen of Betula verrucosa pollen. Results show that IgG4-depletion resulted in equivalent reductions in binding and blocking activities. In contrast, a significant but less than two-fold higher relative blocking activity was found in the purified IgG4 fraction. There was no significant difference in the binding avidities (1/K(d)) measured in the two IgG fractions. Thus, it appears that SIT-induced specific IgG4 contributes to the IgG blocking of allergen binding to IgE in a simple quantitative manner and not by a particular intrinsic blocking activity.     

Comparison between medium-chain acyl-CoA dehydrogenase mutant proteins overexpressed in bacterial and mammalian cells

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a potentially lethal inherited defect in the β-oxidation of fatty acids. By comparing the behaviour of five missense MCAD mutant proteins expressed in COS cells and in Escherichia coli, we can define some of these as “pure folding mutants.” Upon expression in E. coli, these mutant proteins produce activity levels in the range of the wild-typeenzyme only if the chaperonins GroESL are co-overproduced. When Over expressed in COS cells, the pure folding mutants display enzyme activities comparable to the wild-type enzyme. The results suggest that the MCAD mutations can be modulated by chaperones, a phenomenon that may influence the manifestation of the MCAD disease. © 1995 Wiley-Liss, Inc.     

Evaluation of the walking pattern in two types of patients with anterior cruciate ligament deficiency: copers and non-copers

The purpose of the present study was to investigate whether different walking patterns in healthy subjects and in coper and non-coper subjects with deficient anterior cruciate ligaments could be quantified. An inverse dynamics approach was used to calculate joint kinematics and kinetics for flexion and extension. EMG signals of the hamstrings and quadriceps muscles were recorded. The results showed that the peak knee flexion angle was greater in the copers than in the controls. There was a positive correlation between the peak knee extensor moment and peak knee flexion angle. Furthermore, at a given peak knee flexion angle, the peak knee extensor moment was significantly larger in the controls than in the non-copers. The hip extensor moment in the copers was significantly larger than that of the non-copers and the controls. In conclusion, the three groups walked according to different patterns. It is suggested that the copers stabilized their knee joint by co-contraction of the hamstrings and quadriceps muscles, while the non-copers lacked this ability. Instead, the non-copers reduced the knee extensor moment in order to decrease anterior displacement of the tibia. The walking pattern differences observed between the copers and non-copers may explain their different post-injury activity levels. Electronic Publication     

Less improvement following meniscal repair compared with arthroscopic partial meniscectomy: a prospective cohort study of patient-reported outcomes in 150 young adults at 1- and 5-years’ follow-up

Background and purpose — Meniscal repair may reduce long-term risk of knee osteoarthritis compared with arthroscopic partial meniscectomy (APM), whereas patient-reported outcomes may be poorer at short term than for APM. We compared patient-reported outcomes in young adults undergoing meniscal repair or APM up to ∼5 years after surgery.Patients and methods — We included 150 patients aged 18–40 years from the Knee Arthroscopy Cohort Southern Denmark (KACS) undergoing meniscal repair or APM. Between-group differences in change in a composite of 4 of 5 Knee injury and Osteoarthritis Outcome Score (KOOS) subscales (pain, symptoms, sport and recreation, and quality of life—KOOS₄) from baseline, 12, and 52 weeks, and a median of 5 years (range 4–6 years) were analyzed using adjusted mixed linear models, with 52 weeks being the primary endpoint.Results — 32 patients had meniscal repair (mean age 26 [SD 6]), and 118 patients underwent APM (mean age 32 [SD 7]). The repair and APM groups improved in KOOS₄ from before to 52 weeks after surgery (least square means 7 and 19, respectively; adjusted mean difference –12, [95% CI –19 to –4] in favor of APM). Both groups improved further from 52 weeks to 5 years after surgery with the difference in KOOS₄ scores between the groups remaining similar.Interpretation — Patients having meniscal repair experienced less improvements in patient-reported outcomes from baseline to 52 weeks and 5 years post-surgery. The findings highlight the need for randomized trials comparing these interventions in terms of patient-reported outcomes and knee OA development.

Recent studies have reported that arthroscopic partial meniscectomy (APM) is associated with increased risk of osteoarthritis (OA) development and knee replacement surgery as compared with knees with meniscal tears left in situ (Roemer et al. 2017, Rongen et al. 2017). Consequently, meniscal repair, which aims to preserve the meniscal tissue and thereby reduce knee OA risk, has been strongly advocated in recent years, especially for younger individuals with traumatic meniscal tears (Kopf et al. 2020). However, meniscal repair often requires longer rehabilitation time, and has a higher reoperation rate compared with APM, suggesting a trade-off between the 2 procedures (Paxton et al. 2011, Cavanaugh and Killian 2012).Currently, the evidence of the protective ability of meniscal repair against OA compared with APM is limited to retrospective observational data (Stein et al. 2010, Lutz et al. 2015, Persson et al. 2018). Similarly, reliable information on differences in patient-reported outcomes between meniscal repair and APM is scarce, and results from the few retrospective studies are conflicting and lack assessment of change over time (Stein et al. 2010, Paxton et al. 2011, Lutz et al. 2015).The number of meniscal repairs is increasing in accordance with current guidelines (Kopf et al. 2020). While awaiting a randomized trial evaluating knee OA development and patient-reported outcomes following meniscal repair compared with APM, we used a prospective study design with pre-specified outcomes to compare change in patient-reported outcomes in patients aged 18–40 years undergoing meniscal repair or APM at multiple time points up to between 4 and 6 years after surgery.