Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes.

Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.

Rodent models have been used to study the anticarcinogenic properties of the soy isoflavones, particularly genistein, but there is little information regarding the pharmacokinetics of the absorption and excretion of genistein. In this study, rats were given a single oral dose of genistein (20 mg/kg body weight) or an equivalent dose of its glycone forms, as an isoflavone-rich soy extract. Concentrations of genistein were measured in plasma, urine and feces at intervals up to 48 h after dosing. Plasma genistein concentration at 2 h after dosing was 11.0 +/- 2.3 mumol/L in genistein-treated rats compared with 4.93 +/- 0.22 mumol/L (P = 0.025) in soy extract-treated rats, but there were no significant differences at 8 h and later times. The mean urinary excretion rate during the first 2 h after dosing was more than 10 times higher in the genistein group compared with the soy extract group (0.27 +/- 0.08 mumol/h and 0.020 +/- 0.011 mumol/h, respectively, P = 0.017) but the percentage of dose recovered in urine over 48 h was not different between groups (19.9 +/- 2.4% genistein treated; 17.5 +/- 1.1% soy extract treated). There were no significant differences between groups in the recovery of genistein in feces (21.9 +/- 2.8% and 21.1 +/- 2.5% of dose, respectively). Only 6.1 +/- 0.9% of the daidzein from the soy extract was recovered in the feces. The results suggest that the extent of absorption of genistein is similar for the glycone and aglycone forms. Although higher initial plasma concentrations may be achieved with the aglycone, similar long-term concentrations exist for both forms of isoflavone.

A lipid-rich extract, preparared by supercritical fluid extraction of fresh stabilized mussel powder (Lyprinol), showed significant anti-inflammatory (AI) activity given therapeutically and prophylactically po to Wistar and Dark Agouti rats developing either (a) adjuvant-induced polyarthritis or (b) collagen(II)-induced autoallergic arthritis, with ED(50)/=25 mg/kg or various therapeutic oils (flaxseed, evening primrose, fish)>/=1800 mg/kg given orally. Lyprinol showed little or no activity in acute irritation assays (carrageenan, kaolin, histamine) indicating it is not mimicking rapid-acting NSAIDs.Incorporating Lyprinol into arthritigenic adjuvants composed of heat-killed Mycobacterium. tuberculosis suspended in olive oil or squalane, effectively prevented arthritis development at a dose of 5 mg/rat. By contrast, 'dummy adjuvants' prepared with Mycobacterium tuberculosis and flaxseed, evening primrose or fish oils were still arthritigenic in Dark Agouti rats (doses of oil=90 mg/rat).Lyprinol subfractions inhibited leukotriene-B(4) biosynthesis by stimulated human polymorphonuclear leukocytes in vitro, and prostaglandin-E(2) production by activated human macrophages in vitro. Much of this AI activity was associated with polyunsaturated fatty acids and natural antoxidants (carotenoids, etc.).In contrast to NSAIDs, Lyprinol is non-gastrotoxic in disease-stressed rats at 300 mg/kg po and does not seem to affect platelet aggregation (human, rat). These data show Lyprinol to be a reproducible, relatively stable, source of bioactive lipids with much greater potency than plant/marine oils currently used as nutritional supplements to ameliorate signs of inflammation.

II.

Consumption of soy products has been linked to a reduced mortality and morbidity from a number of cancers. Genistein, one of the principal soy isoflavones, has been shown to inhibit the growth of a number of tumour cell lines in vitro; however, a role of genistein in retarding tumour growth in vivo is less well documented. In this study, in addition to examining the effects of genistein on the growth of murine B16 melanoma cells in vitro, we have examined the effects of feeding a genistein‐rich diet on s.c. growth of these tumour cells in mice. In vitro, the melanoma cells showed an increase in sensitivity to genistein with increasing time of exposure, culminating in a 50% growth inhibition (IC50) at 12.5 μM after 7 days. Genistein at 25 μM induced micronucleus formation after 24 hr and at concentrations as low as 2.5 μM induced morphological changes indicative of differentiation. Growth of solid tumours implanted into female C57BL/6J mice was inhibited by 50% when mice were fed genistein for 1 week before and for 1 week after inoculation with B16 melanoma cells. Plasma genistein concentrations at the time of tumour removal were 1.1 μM, which is similar to levels reported in humans consuming diets high in soybeans or soybean products, while control animals had no detectable genistein in plasma. Our results provide additional in vivo evidence suggesting that genistein retards the growth of implanted tumours, adding further to studies suggesting that this isoflavonoid is a biologically active component of soy foods. Int. J. Cancer 72:860–864, 1997. © 1997 Wiley‐Liss, Inc.

There has been a continuing decline in both the overall prevalence and length of use of conventional HT from 2003, probably in association with negative media about HT. Of medical concern is that about one-quarter of women using HT around menopause now chooses unregistered hormonal mixtures that are untested for long-term safety and efficacy.

Background: Despite recommendations for women to take folic acid supplements, there has been little reduction in the number of neural tube defect cases occurring each year.