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Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a “phenotype first” approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.

Bile acids were estimated in the duodenum of infants with protracted diarrhoea and compared with those in a control group. Significantly lower levels of total bile acids were found in infants with protracted diarrhoea, a finding which may be due to ileal dysfunction. Low concentrations of total bile acids may contribute to the poor nutritional state of these patients by impairing the normal digestion and absorption of dietary fat and fat-soluble vitamins. The absence of deconjugated bile acids in the duodenal juice of most infants with protracted diarrhoea suggests that they do not contribute significantly to the pathophysiology of this disorder.

Duodenal bile acids have been estimated in three age groups in infancy from birth to 7 months, and age-related changes have been shown. The lowest concentrations of duodenal bile acids occurred in the youngest infants, and increasing concentrations were found with increasing age. Taurine conjugated bile acids predominated in early infancy, while in older infants bile acids were mainly conjugated with glycine. The probable presence of taurolithocholic acid in the duodenal bil of 2 newborns before the establishment of a gastrointestinal microflora remains to be confirmed, but could result either from transplacental passage of secondary bile acids or from endogenous synthesis by the fetal liver.

The spiral organism found in the stomach of various carnivora has been investigated by several observers (see the references at the end of this paper). Such studies have been mainly directed to the morphology of the organism, its infectivity and the part it plays in producing a pathological condition. In the present paper I have been concerned rather with the physiological condition of its host as influencing the prevalence and location of the organism in different regions of the stomach. I was anxious further to ascertain if the organism affected the normal processes of digestion in the stomach either to the advantage or the disadvantage of the animal entertaining it.

Lymphedema-distichiasis (LD) is a dominantly inherited syndrome with onset of lymphedema at or just after puberty. Most affected individuals have distichiasis-fine hairs arising inappropriately from the eyelid meibomian glands-which is evident from birth. A study of three families with LD has shown linkage to chromosome 16q24.3, and subsequent analysis of the region for recombinant genes places the locus between D16S422 and D16S3074, a distance of approximately 16 cM. Possible candidate genes in this interval include the N-proteinase for type 3 collagen, PCOLN3; the metalloprotease PRSM1; and the cell matrix-adhesion regulator, CMAR.

Groups of cows received a staphylococcal cell toxoid vaccine either systemically or locally into the udder at drying-off in the hope that this would prime lymphoid cells migrating to the udder during involution. Two weeks before calving, the animals received local infusions of plain vaccine into 2 quarters of the udder. Antitoxic and agglutinating antibodies in serum, colostrum and milk were measured at intervals. All cows had high colostral antibody titres which dropped to background levels by 2 weeks. There was an indication of some local antibody being produced in those quarters of animals which had previously received 2 infusions of plain vaccine, but this was short-lived. There was no evidence for any prolonged local antibody production in the infused glands which might influence the course of a mastitic infection.

It has long been known that the introduction of certain substances into the stomach provoke a secretion of gastric juice. This is regarded as in no sense depending upon mere mechanical stimulation of the mucous membrane, and it has been thought that the nervous mechanism of the gastric glands may be susceptible to certain local chemical stimuli. On the analogy of what has been held to be the mechanism at work in the secretion of pancreatic juice by Bayliss and Starling, it is probable that, in the process of absorption of digested food in the stomach, a substance may be separated from the cells of the mucous membrane which, passing into the blood or lymph, later stimulates the secretory cells of the stomach to functional activity. The following observations support this view:—

The enquiry was directed to answering the following questions:― 1. What is the comparative value of different food substances in evoking the chemical secretion of the stomach? 2. What channels of absorption are available for the different food substances? Experiments in a previous communication to the Society indicated that the mucous membrane of the pyloric end of the stomach contained the gastric hormone, and was therefore probably a channel of absorption. No direct proof was at that time able to be adduced.