Non-invasive prenatal testing for fetal chromosomal abnormalities by low-coverage whole-genome sequencing of maternal plasma DNA: review of 1982 consecutive cases in a single center.

OBJECTIVE: To review the performance of non-invasive prenatal testing (NIPT) by low-coverage whole-genome sequencing of maternal plasma DNA at a single center. METHODS: The NIPT result and pregnancy outcome of 1982 consecutive cases were reviewed. NIPT was based on low coverage (0.1×) whole-genome sequencing of maternal plasma DNA. All subjects were contacted for pregnancy and fetal outcome. RESULTS: Of the 1982 NIPT tests, a repeat blood sample was required in 23 (1.16%). In one case, a conclusive report could not be issued, probably because of an abnormal vanished twin fetus. NIPT was positive for common trisomies in 29 cases (23 were trisomy 21, four were trisomy 18 and two were trisomy 13); all were confirmed by prenatal karyotyping (specificity=100%). In addition, 11 cases were positive for sex-chromosomal abnormalities (SCA), and nine cases were positive for other aneuploidies or deletion/duplication. Fourteen of these 20 subjects agreed to undergo further investigations, and the abnormality was found to be of fetal origin in seven, confined placental mosaicism (CPM) in four, of maternal origin in two and not confirmed in one. Overall, 85.7% of the NIPT-suspected SCA were of fetal origin, and 66.7% of the other abnormalities were caused by CPM. Two of the six cases suspected or confirmed to have CPM were complicated by early-onset growth restriction requiring delivery before 34 weeks. Fetal outcome of the NIPT-negative cases was ascertained in 1645 (85.15%). Three chromosomal abnormalities were not detected by NIPT, including one case each of a balanced translocation, unbalanced translocation and triploidy. There were no known false negatives involving the common trisomies (sensitivity=100%). CONCLUSIONS: Low-coverage whole-genome sequencing of maternal plasma DNA was highly accurate in detecting common trisomies. It also enabled the detection of other aneuploidies and structural chromosomal abnormalities with high positive predictive value.

Perceptions and experiences of post-irradiation swallowing difficulties in nasopharyngeal cancer survivors.

This study aimed to explore the perceptions and experiences of swallowing difficulties in irradiated survivors of nasopharyngeal carcinoma (NPC). Qualitative semi-structured interviews were conducted with 60 post-irradiation NPC patients after they had answered a set of self-report questions. The interviews were transcribed verbatim for analysis. Results of the self-report data showed that in response to a global question 'Do you have any swallowing difficulties?' eight-five per cent of the respondents reported a certain degree of difficulty. The qualitative interview findings, however, suggested that this figure might have been underestimated. Patient interpretations of swallowing difficulties had excluded part of the symptoms. Some respondents who claimed to have no difficulty swallowing, in fact, were suffering from oral retention of food bolus, regurgitation of food or liquids through the nose, and/or even choking. The risk of aspiration was generally neglected. Informants' concerns focused more on the threat of cancer recurrence, thus paid less attention to the radiation-induced swallowing complication. Respondents did not possess sufficient knowledge to judge their swallowing abilities at a general level. This study suggests ways to enhance patient-provider communication and health education to improve patient knowledge.

Critical roles for the netrin receptor deleted in colorectal cancer in dopaminergic neuronal precursor migration, axon guidance, and axon arborization.

DCC (deleted in colorectal cancer), a receptor for the axon guidance cue netrin-1, is highly expressed by mesencephalic dopaminergic (DA) neurons during development; however, the contribution of DCC to DA development remains largely uncharacterized. DA neurons in ventral mesencephalic nuclei also express UNC5 homologue netrin receptors from late embryogenesis to adulthood, raising the possibility that DA axons could be attracted or repelled by netrins. Examining newborn dcc null mice, we report that loss of DCC function results in profound alterations of DA circuitry, including DA progenitor cell migration defects, reduced numbers of DA cells in midbrain nuclei, an anomalous DA ventral commissure, malformed DA innervation of the ventral striatum, and reduced DA innervation of the cerebral cortex. Caspase-3 activation was detected in inappropriately localized DA cells, consistent with apoptosis contributing to reduced cell numbers. Dcc heterozygous mice express reduced levels of DCC protein. Although less severely disrupted than dcc nulls, newborn and adult dcc heterozygotes also have fewer DA neurons in ventral mesenscephalic nuclei. Despite the reduced numbers of DA neurons, newborn dcc heterozygotes and nulls exhibit similar DA innervation density as wild-type littermates in the nucleus accumbens core, and adult dcc heterozygotes exhibit increased DA innervation in medial prefrontal cortex. A trend towards increased innervation of medial prefrontal cortex was detected in newborn dcc heterozygotes, but did not reach statistical significance, suggesting that the increase in adult heterozygotes results from enhanced DA arborization during postnatal development. Consistent with the hypothesis that DCC regulates DA axonal projections, disrupting DCC function in culture inhibits netrin-1 induced DA axon extension and axon branching. Furthermore, disrupting DCC function in isolated DA neurons grown as micro-island cultures reduces the number of autaptic synapses per cell. We conclude that DCC regulates appropriate precursor cell migration, axon guidance, and terminal arborization by DA neurons.

Screening for otitis media with effusion to measure its prevalence in Chinese children in Hong Kong.

In an attempt to gain a better understanding of the prevalence of otitis media with effusion (OME) in the Hong Kong community, and to compare the characteristics of the disease here with OME as it is described in the Western literature, we screened more than 6,000 6- and 7-year-old children with both clinical and audiologic examinations. The initial positive screening rate was 5.3%. Upon further evaluation, we determined that the overall prevalence of persistent OME was 2.2%. We found that the disease pattern and natural history of persistent OME in Hong Kong children are similar to those reported in the Western literature.

Dietary choline requirements of juvenile hybrid tilapia, Oreochromis niloticus x O. aureus.

An 8-wk feeding trial was conducted to determine the dietary choline requirement for juvenile hybrid tilapia, Oreochromis niloticus x O. aureus. Purified basal diets were formulated using vitamin-free casein (contained 370 mg choline/kg) as the protein source. Graded levels (0, 100, 200, 400, 600, 800, 1,000 and 2,000 mg choline/kg diet) of choline chloride were added to the basal diet, resulting in eight dietary treatments in the experiment. Each diet was fed to three replicate groups of tilapia initially averaging 0.62 +/- 0.01 g/fish in a closed, recirculating rearing system. Feed efficiency, survival and blood triglyceride, cholesterol and phospholipid concentrations were generally high in fish fed choline-supplemented diets compared to fish fed the control diet. Analysis by broken-line regression of weight gain and body choline concentration and by polynomial regression of liver lipid concentration of the fish indicated that the dietary choline concentration for tilapia is about 900 mg/kg. Taking into account the choline concentration of the unsupplemented basal diet, the optimal dietary choline requirement for growing tilapia is about 1,000 mg/kg.

Effect of combined metronidazole and DMSO on tumour control and skin tolerance in the rat.

A combination of the radiosensitizer, metronidazole, and the radioprotector, dimethyl sulfoxide (DMSO), was tested for its effects on the radiation tolerance of rat skin and on the radiosensitivity of the BA1112 rhabdomyosarcoma. The simplest interpretation of the effects of the combined treatment is that: metronidazole radiosensitizes BA1112 in one-fraction but not in five-fraction treatments; metronidazole slightly increases the radiosensitivity of skin in one-fraction treatments; metronidazole radiosensitization is independent of the radioprotection produced by DMSO.

Effect of actinomycin D and neoarsphenamine on tumor control and skin tolerance in the rat.

Actinomycin D and neoarsphenamine were tested for their ability to produce therapeutically favorable radiosensitization in the WAG/Rij rat. Acute and late skin reactions and control of the BA1112 rhabdomyosarcoma were examined in drug-treated and untreated animals irradiated in single- and five-fraction schedules. Actinomycin D was found to protect skin and tumors when added 15 minutes before irradiation. Actinomycin D added 2 hours before irradiation in a five-fraction trial produced slight tumor sensitization accompanied by slight skin protection. Neoarsphenamine produced significant tumor sensitization without skin sensitization in one of the single-fraction trials, but had no effect in the five-fraction trials.

Effect of the radioprotective drugs MEA, DMSO, and WR-2721 on tumor control and skin tolerance in the rat.

Mercaptoethylamine (MEA), dimethylsulfoxide (DMSO), and S-2-(3-aminopropylamino)ethylphosphorothioate (WR-2721) were tested for their protective effects against single and fractionated doses of 250 kv X-rays. Acute and late skin reactions and control of the BA-1112 rhabdomyosarcoma were examined in protected and unprotected WAG/Rij rats. All drugs protected skin in both single and fractionated treatment regimens, with MEA giving the most protection and DMSO the least. DMSO and WR-2721 protected tumors against single doses of radiation, and all three drugs tested protected tumors against fractionated irradiation. As a result, only single-fraction treatments of MEA-protected animals showed therapeutically favorable differential protection.

Norepinephrine pools in rat brain: differences in turnover rates and pathways of metabolism.

The rate of disappearance of intracisternally administered [(3)H]norepinephrine from rat brain gradually declines as a multiphasic exponential function of time. Conversion to [(3)H]normetanephrine accounts for a larger fraction of the [(3)H]norepinephrine released in the brain shortly after its intracisternal injection than that released at later times. Pools of norepinephrine in the brain thus appear to differ in their turnover rates and pathways of metabolism. The pool of norepinephrine with a rapid rate of turnover and an appreciable conversion to normetanephrine, identified by the techniques reported here, may correspond to a pool of newly synthesized norepinephrine in the brain.