Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria.

BACKGROUND: Mutations in the E-cadherin (CDH1) gene are a well documented cause of hereditary diffuse gastric cancer (HDGC). Development of evidence based guidelines for CDH1 screening for HDGC have been complicated by its rarity, variable penetrance, and lack of founder mutations. METHODS: Forty three new gastric cancer (GC) families were ascertained from multiple sources. In 42 of these families at least one gastric cancer was pathologically confirmed to be a diffuse gastric cancer (DGC); the other family had intestinal type gastric cancers. Screening of the entire coding region of the CDH1 gene and all intron/exon boundaries was performed by bi-directional sequencing. RESULTS: Novel mutations were found in 13 of the 42 DGC families (31% overall). Twelve of these mutations occur among the 25 families with multiple cases of gastric cancer and with pathologic confirmation of diffuse gastric cancer phenotype in at least one individual under the age of 50 years. The mutations found include small insertions and deletions, splice site mutations, and three non-conservative amino acid substitutions (A298T, W409R, and R732Q). All three missense mutations conferred loss of E-cadherin function in in vitro assays. Multiple cases of breast cancers including pathologically confirmed lobular breast cancers were observed both in mutation positive and negative families. CONCLUSION: Germline truncating CDH1 mutations are found in 48% of families with multiple cases of gastric cancer and at least one documented case of DGC in an individual under 50 years of age. We recommend that these criteria be used for selecting families for CDH1 mutational analysis.

[Association of plasma ammonia and GABA levels and the degree of hepatic encephalopathy]. / Asociación entre los niveles de amonio y GABA plasmáticos y el grado de encefalopatía hepática.

Several toxic factors have been implicated in the pathogenesis of hepatic encephalopathy (PSE) among which ammonia plays a dominant role. More recently, the gamma-aminobutyric acid (GABA) hypothesis in which an increase in the GABA-ergic tone and the presence of one or more GABA/benzodiazepine receptor ligands which interact with that receptor, has been proposed. We investigated the levels of GABA and ammonia in plasma of patients with acute PSE to test the hypothesis that elevated plasma GABA levels would be found in acute encephalopathy and that GABA levels would correlate with the degree of hepatic encephalopathy. We measured plasma levels of GABA and ammonia during an acute episode of PSE, spontaneous or precipitated by gastrointestinal bleeding or sepsis, and performed assessments of PSE by the PSE index. Patients were evaluated before and two days after standard treatment with lactulose. We also measured plasma GABA levels in the hepatic vein of a selected group of patients undergoing hemodynamic studies. Plasma GABA levels were significantly higher in patients with acute PSE (458 +/- 108 pmol/mL) when compared with normal subjects (110 +/- 23 pmol/mL) (p < 0.01) although no correlation was found between plasma GABA concentration and the degree of PSE. Changes in plasma ammonia, however, correlated with improvements in the PSE index (r = 0.56; p < 0.02) and with abnormalities in the EEG (r = 0.65; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Variations in mean cerebral blood flow under anesthesia at rest and during cortical activation.

More than one cerebral blood flow (CBF) measurement was performed on the same occasion in three groups of patients using the intracarotid 133Xenon technique. In the anesthetized group there was a highly significant reduction in CBF (mean = 24.3%) from the first to the second measurement. In those at rest under local anesthesia there was also a significant fall (mean 9.8%). The third group, who were stimulated during the second estimation, showed no change. A second CBF determination some time after beginning a study is recommended, especially in pharmacological studies, to provide a more reliable resting control, rather than the first value which represents flow in an "activated" brain which has not yet adapted fully to its new environment.

The form and distribution of the surface evoked responses in cerebellar cortex from intercostal nerves in the cat.

1. The form and distribution of the cerebellar evoked responses to electrical stimulation of intercostal and other thoracic segmental nerves were investigated in anaesthetized cats.2. Low intensity stimulation (< 2 x nerve threshold) evoked short latency, low amplitude (< 20 muV), initially surface positive responses which could only be distinguished with certainty from the electrocorticogram with averaging.3. On the basis of experiments involving sectioning of afferent tracts it is concluded that intercostal evoked responses of less than 7.0 msec latency are conducted in dorsal spino-cerebellar, ventral spino-cerebellar and dorsal column (cuneo-cerebellar) pathways.4. The surface positive waves have a highly punctate distribution with a steep potential gradient extending over an area of about 1 mm diameter. It is postulated that these small fields represent activation of single or few mossy fibre inputs.5. Short latency responses to thoracic inputs were found only in the ipsilateral intermediate cortex and lateral margin of the vermis of the anterior lobe (lateral two thirds of Larsell's lobules IV and V of the accessible cortex). The responses were distributed throughout the fore and hind limb areas of the anterior lobe and no rostro-caudal or medio-lateral segmental organization was seen.6. It is suggested that the overlapping distribution of thoracic and fore and hind limb mossy fibre inputs within the cerebellar cortex provides an anatomical basis for the integration of information from the trunk and from the limbs.