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46,XY gonadal dysgenesis (GD) is a Disorder/Difference of Sex Development (DSD) that can present with phenotypes ranging from ambiguous genitalia to complete male‐to‐female sex reversal. Around 50% of 46,XY DSD cases receive a molecular diagnosis. In mice, Fibroblast growth factor 9 (FGF9) is an important component of the male sex‐determining pathway. Two FGF9 variants reported to date disrupt testis development in mice, but not in humans. Here, we describe a female patient with 46,XY GD harbouring the rare FGF9 variant (missense mutation), NM_002010.2:c.583G > A;p.(Asp195Asn) (D195N). By biochemical and cell‐based approaches, the D195N variant disrupts FGF9 protein homodimerisation and FGF9‐heparin‐binding, and reduces both Sertoli cell proliferation and Wnt4 repression. XY Fgf9D195N/D195N foetal mice show a transient disruption of testicular cord development, while XY Fgf9D195N/− foetal mice show partial male‐to‐female gonadal sex reversal. In the general population, the D195N variant occurs at an allele frequency of 2.4 × 10−5, suggesting an oligogenic basis for the patient's DSD. Exome analysis of the patient reveals several known and novel variants in genes expressed in human foetal Sertoli cells at the time of sex determination. Taken together, our results indicate that disruption of FGF9 homodimerization impairs testis determination in mice and, potentially, also in humans in combination with other variants. [ABSTRACT FROM AUTHOR]

Recent reports suggest that combinations of prebiotics and probiotics may be protective against colorectal cancer. We examined in rats the effects of probiotic bacteria, resistant starch (RS), and their interaction on luminal and epithelial events of relevance to the development of colorectal cancer. Lyophilized cultures (1 x [10.sup.10] cfu/g) of Lactobacillus acidophilus and/or Bifidobacterium lactis were added at a concentration of 1% by weight to a semipurified diet containing either low-RS (no supplemented RS) or moderate--RS (10% Hi-maize[R]) and fed to male Sprague-Dawley rats for 4 wk. Experimental end-points included cecal bacterial enumeration, fecal and cecal pH, SCFA levels, cell proliferation, and the acute apoptotic response to a genotoxic carcinogen (AARGC; measured 6 h after a single azoxymethane injection). A significant interaction between dietary RS and supplemental bacteria was observed for the AARGC in the colon and fecal pH (P < 0.01). Rats fed the moderate-RS diet in combination with B. lactis had a significantly greater AARGC in the colon than those fed that diet without B. lactis. Fecal pH was elevated in the moderate-RS fed rats supplemented with bacteria. The moderate-RS diet increased cell proliferation and crypt column height (P < 0.001) compared with the low-RS diet. SCFA levels and numbers of bifidobacteria and lactobacilli species were also increased (P < 0.001) by the moderate-RS diet, whereas pH levels and total coliforms were lowered (P < 0.001). The synbiotic combination of RS and B. lactis significantly facilitated the apoptotic response to a genotoxic carcinogen in the distal colon of rats. It appears likely that ingested RS acts as a metabolic substrate, thus creating the right conditions for B. lactis to exert its proapoptotic action. Because the synbiotic combination of these agents facilitates the apoptotic response to DNA damage by a cancer initiator in the colon of rats, it warrants further study for its capacity to protect against colorectal cancer. KEY WORDS: * apoptosis * prebiotics * probiotics * butyrate * colon cancer

Himalaya 292 (Hordeum vulgare, var. himalaya 292) is a novel, hull-less barley cultivar with a single nucleotide change in the gene encoding starch synthase Ila (EC 2.4.1.21). This leads to loss of enzyme activity, resulting in a grain with less total starch and a higher proportion of amylose. These changes, plus higher total and soluble nonstarch polysaccharides (NSP), could increase its resistant starch (RS) content. Accordingly, rats were fed a diet containing stabilized whole-grain barley flours from Himalaya 292 or two commercial varieties (Namoi or Waxiro) or wheat or oat bran at equivalent NSP concentrations for 14 d. There were favorable significant changes in a number of bowel health-related indices. Fecal output by rats fed Himalaya 292 was higher than by those fed Namoi or oat bran, whereas total large bowel digesta mass was higher than in those fed Waxiro. Cecal starch concentrations and pools were higher in rats fed Himalaya 292 than in all other groups. Fecal and cecal digesta pH was lower in rats fed Himalaya 292 than in all other groups except that fed oat bran. Colonic digesta pH was lower in rats fed Himalaya 292 than in those fed wheat bran or Namoi. Fecal total SCFA excretion was higher in rats fed Himalaya 292 than in those fed Namoi or oat bran. Although cecal total SCFA pools did not differ among groups, colonic SCFA were higher in rats fed Himalaya 292 than in those fed Namoi or Waxiro. These data indicate that changes in Himalaya 292 grain composition result in greater RS with consequent alterations in large bowel SCFA and pH when fed to rats. KEY WORDS: * barley * cereal * dietary fiber * resistant starch * starch

There is a need for better understanding of the roles of dietary fats and fibers in colon cancer risk. We examined the effect of different dietary fiber and fat sources on an azoxymethane (AOM)-induced colon cancer in rats. In a 2 x 3 factorial design, rats were fed a semipurified diet containing soy-derived fiber (Fibrim), [alpha]- cellulose (Solkafloc) or resistant starch (RS; Hi-maize) at 10 g dietary fiber/100 g diet, combined with fish oil (FO) or sunflower seed oil (SSO) at 10 g/100 g diet, and lard added to all diets at 10 g/100 g, to provide a total of 20 g mixed fat/100 g diet. Sprague-Dawley rats (28 d of age) consumed diets for 4 wk and then two doses of AOM (15 mg/kg body) were administered 1 wk apart by subcutaneous injection. Rats were killed after 13 wk of consuming experimental diets. Colons were fixed in formalin and aberrant crypt foci (ACF) were quantified after staining. ACF counts were higher (+66%, P < 0.01) in rats fed SSO and RS, than in those fed [alpha]-cellulose and FO. Rats fed FO had 19% fewer ACF than those fed SSO (P < 0.05). [alpha]-Cellulose was associated with the highest cecal butyrate concentration (P < 0.001), the highest [beta]-glucuronidase specific activity (P < 0.001) and the lowest cecal water cytotoxicity (P < 0.001) relative to soy fiber- and RS-fed rats. There were inverse correlations between the number of ACF and cecal butyrate concentration (r = -0.33, P < 0.05) and between cecal water cytotoxicity and [beta]-glucuronidase activity (r = -0.70, P < 0.001). The greatest protection was associated with a-cellulose as the fiber source and FO as the fat source as measured by colon ACF numbers in rats. KEY WORDS: * fiber * polyunsaturated fatty acids * aberrant crypt foci * cecal water cytotoxicity * rats