Age-related Differences in Recall of Information and Handling of Chemotherapy-related Side Effects in Cancer Patients: The ReCap Study.

BACKGROUND: To prevent severe toxicity and hospital admissions, adequate management and recall of information about side effects are crucial and health literacy plays an important role. If age-related factors impact recall of given information and handling of side effects, revised ways to give information are required. PATIENTS AND METHODS: We undertook a questionnaire-based survey among 188 newly diagnosed patients with pancreatic cancer or colorectal cancer and chemo-naive patients with prostate cancer treated with adjuvant or first-line palliative chemotherapy comprising satisfaction with given information, recall of potential side effects, and handling of hypothetical side effect scenarios. We evaluated the association between baseline characteristics, ie, age, frailty (G8 score), comorbidity (Charlson Comorbidity Index), cognitive function (Mini-Cog), satisfaction, recall of information, and handling of side effects. RESULTS: Reduced ability to recall information about several side effects (eg, chest pain) was associated with older age (odds ratio adjusted for cancer [aOR] 0.94 [95% CI, 0.88-0.98]) and poor cognitive screening (aOR 0.56 [95% CI, 0.33-0.91]). Insufficient or dangerous handling of side effects was associated with older age (aOR 0.96 (95% CI, 0.92-0.99)) and cognitive impairment (aOR 0.70 [95% CI, 0.50-0.95]). CONCLUSION: Older age and poor cognitive screening may impact patients' ability to understand and adequately handle chemotherapy-related side effects. Cognitive screening and focus on individual ways to give information including assessment of recall and handling are needed.

Connecting Scrambling and Work Statistics for Short-Range Interactions in the Harmonic Oscillator.

We investigate the relationship between information scrambling and work statistics after a quench for the paradigmatic example of short-range interacting particles in a one-dimensional harmonic trap, considering up to five particles numerically. In particular, we find that scrambling requires finite interactions, in the presence of which the long-time average of the squared commutator for the individual canonical operators is directly proportional to the variance of the work probability distribution. In addition to the numerical results, we outline the mathematical structure of the N-body system which leads to this outcome. We thereby establish a connection between the scrambling properties and the induced work fluctuations, with the latter being an experimental observable that is directly accessible in modern cold-atom experiments.

Regional Differences in Gamma-Aminobutyric Acid and Glutamate Concentrations in the Healthy Newborn Brain.

BACKGROUND AND PURPOSE: Gamma-aminobutyric acid and glutamate system disruptions may underlie neonatal brain injury. However, in vivo investigations are challenged by the need for special 1H-MR spectroscopy sequences for the reliable measurement of the neurotransmitters in this population. We used J-edited 1H-MR spectroscopy (Mescher-Garwood point-resolved spectroscopy) to quantify regional in vivo gamma-aminobutyric acid and glutamate concentrations during the early postnatal period in healthy neonates. MATERIALS AND METHODS: We prospectively enrolled healthy neonates and acquired Mescher-Garwood point-resolved spectroscopy spectra on a 3T MR imaging scanner from voxels located in the cerebellum, the right basal ganglia, and the right frontal lobe. CSF-corrected metabolite concentrations were compared for regional variations and cross-sectional temporal trends with advancing age. RESULTS: Fifty-eight neonates with acceptable spectra acquired at postmenstrual age of 39.1 (SD, 1.3) weeks were included for analysis. Gamma-aminobutyric acid (+ macromolecule) (2.56 [SD, 0.1]) i.u., glutamate (3.80 [SD, 0.2]), Cho, and mIns concentrations were highest in the cerebellum, whereas NAA (6.72 [SD, 0.2]), NAA/Cho, Cr/Cho, and Glx/Cho were highest in the basal ganglia. Frontal gamma-aminobutyric acid (1.63 [SD, 0.1]), Glx (4.33 [SD, 0.3]), Cr (3.64 [SD, 0.2]), and Cho concentrations were the lowest among the ROIs. Glx, NAA, and Cr demonstrated a significant adjusted increase with postmenstrual age (ß = 0.2-0.35), whereas gamma-aminobutyric acid and Cho did not. CONCLUSIONS: We report normative regional variations and temporal trends of in vivo gamma-aminobutyric acid and glutamate concentrations reflecting the functional and maturational status of 3 distinct brain regions of the neonate. These measures will serve as important normative values to allow early detection of subtle neurometabolic alterations in high-risk neonates.

Hospital re-admission after critical care survival: a systematic review and meta-analysis.

Survivors of critical illness frequently require increased healthcare resources after hospital discharge. We undertook a systematic review and meta-analysis to assess hospital re-admission rates following critical care admission and to explore potential re-admission risk factors. We searched the MEDLINE, Embase and CINAHL databases on 05 March 2020. Our search strategy incorporated controlled vocabulary and text words for hospital re-admission and critical illness, limited to the English language. Two reviewers independently applied eligibility criteria and assessed quality using the Newcastle Ottawa Score checklist and extracted data. The primary outcome was acute hospital re-admission in the year after critical care discharge. Of the 8851 studies screened, 87 met inclusion criteria and 41 were used within the meta-analysis. The analysis incorporated data from 3,897,597 patients and 741,664 re-admission episodes. Pooled estimates for hospital re-admission after critical illness were 16.9% (95%CI: 13.3-21.2%) at 30 days; 31.0% (95%CI: 24.3-38.6%) at 90 days; 29.6% (95%CI: 24.5-35.2%) at six months; and 53.3% (95%CI: 44.4-62.0%) at 12 months. Significant heterogeneity was observed across included studies. Three risk factors were associated with excess acute care rehospitalisation one year after discharge: the presence of comorbidities; events during initial hospitalisation (e.g. the presence of delirium and duration of mechanical ventilation); and subsequent infection after hospital discharge. Hospital re-admission is common in survivors of critical illness. Careful attention to the management of pre-existing comorbidities during transitions of care may help reduce healthcare utilisation after critical care discharge. Future research should determine if targeted interventions for at-risk critical care survivors can reduce the risk of subsequent rehospitalisation.

In Vivo Brain Glutathione is Higher in Older Age and Correlates with Mobility.

Brain markers of oxidative damage increase with advancing age. In response, brain antioxidant levels may also increase with age, although this has not been well investigated. Here, we used edited magnetic resonance spectroscopy to quantify endogenous levels of glutathione (GSH, one of the most abundant brain antioxidants) in 37 young [mean: 21.8 (2.5) years; 19 female] and 23 older adults [mean: 72.8 (8.9) years; 19 female]. Accounting for age-related atrophy, we identified higher frontal and sensorimotor GSH levels for the older compared with the younger adults. For the older adults only, higher sensorimotor (but not frontal) GSH was correlated with poorer balance and gait. This suggests a regionally specific relationship between higher brain oxidative stress levels and motor performance declines with age. We suggest these findings reflect an upregulation of GSH in response to increasing brain oxidative stress with normal aging. Together, these results provide insight into age differences in brain antioxidant levels and implications for motor function.

Effect of Age on GABA+ and Glutathione in a Pediatric Sample.

BACKGROUND AND PURPOSE: Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the human brain and is implicated in several neuropathologies. Glutathione is a major antioxidant in the brain and is considered a marker of oxidative stress. Several studies have reported age-related declines in GABA levels in adulthood, but the trajectory of both GABA and glutathione during childhood has not been well explored. The aim of this study is to establish how GABA and glutathione vary with age during early development. MATERIALS AND METHODS: Twenty-three healthy children (5.6-13.9 years of age) were recruited for this study. MR imaging/MR spectroscopy experiments were conducted on a 3T MR scanner. A 27-mL MR spectroscopy voxel was positioned in the frontal lobe. J-difference edited MR spectroscopy was used to spectrally edit GABA and glutathione. Data were analyzed using the Gannet software, and GABA+ (GABA + macromolecules/homocarnosine) and glutathione were quantified using water (GABA+H2O and GlutathioneH2O) and Cr (GABA+/Cr and glutathione/Cr) as concentration references. Also, the relative gray matter contribution to the voxel volume (GMratio) was estimated from structural images. Pearson correlation coefficients were used to examine the association between age and GABA+H2O (and glutathioneH2O), between age and GABA+/Cr (and glutathione/Cr), and between age and GMratio. RESULTS: Both GABA+H2O (r = 0.63, P = .002) and GABA+/Cr (r = 0.48, P = .026) significantly correlated with age, whereas glutathione measurements and GMratio did not. CONCLUSIONS: We demonstrate increases in GABA and no differences in glutathione with age in a healthy pediatric sample. This study provides insight into neuronal maturation in children and may facilitate better understanding of normative behavioral development and the pathophysiology of developmental disorders.

Task-related measures of short-interval intracortical inhibition and GABA levels in healthy young and older adults: A multimodal TMS-MRS study.

Establishing the associations between magnetic resonance spectroscopy (MRS)-assessed gamma-aminobutyric acid (GABA) levels and transcranial magnetic stimulation (TMS)-derived 'task-related' modulations in GABAA receptor-mediated inhibition and how these associations change with advancing age is a topic of interest in the field of human neuroscience. In this study, we identified the relationship between GABA levels and task-related modulations in GABAA receptor-mediated inhibition in the dominant (left) and non-dominant (right) sensorimotor (SM) cortices. GABA levels were measured using edited MRS and task-related GABAA receptor-mediated inhibition was measured using a short-interval intracortical inhibition (SICI) TMS protocol during the preparation and premotor period of a choice reaction time (CRT) task in 25 young (aged 18-33 years) and 25 older (aged 60-74 years) adults. Our results demonstrated that GABA levels in both SM voxels were lower in older adults as compared to younger adults; and higher SM GABA levels in the dominant as compared to the non-dominant SM voxel pointed to a lateralization effect, irrespective of age group. Furthermore, older adults showed decreased GABAA receptor-mediated inhibition in the preparation phase of the CRT task within the dominant primary motor cortex (M1), as compared to young adults. Finally, results from an exploratory correlation analysis pointed towards positive relationships between MRS-assessed GABA levels and TMS-derived task-related SICI measures. However, after correction for multiple comparisons none of the correlations remained significant.

Comparison of ammonia emissions related to nitrogen use efficiency of livestock production in Europe.

The increasing global demand for food and the environmental effects of reactive nitrogen losses in the food production chain, increase the need for efficient use of nitrogen (N). Of N harvested in agricultural plant products, 80% is used to feed livestock. Because the largest atmospheric loss of reactive nitrogen from livestock production systems is ammonia (NH3), the focus of this paper is on N lost as NH3 during the production of animal protein. The focus of this paper is to understand the key factors explaining differences in Nitrogen Use Efficiency (NUE) of animal production among various European countries. Therefore we developed a conceptual framework to describe the NUE defined as the amount of animal-protein N per N in feed and NH3-N losses in the production of milk, beef, pork, chicken meat and eggs in The Netherlands, Switzerland, United Kingdom, Germany, Austria and Denmark. The framework describes how manure management and animal-related parameters (feed, metabolism) relate to NH3 emissions and NUE. The results showed that the animal product with the lowest NUE had the largest NH3 emissions and vice versa, which agrees with the reciprocal relationship between NUE and NH3 within the conceptual framework. Across animal products for the countries considered, about 20% of the N in feed is lost as NH3. The significant smallest proportion (12%) of NH3-N per unit of Nfeed is from chicken production. The proportions for other products are 17%, 19%, 20% and 22% for milk, pork, eggs and beef respectively. These differences were not significantly different due to the differences among countries. For all countries, NUE was lowest for beef and highest for chicken. The production of 1 kg N in beef required about 5 kg N in feed, of which 1 kg N was lost as NH3-N. For the production of 1 kg N in chicken meat, 2 kg N in feed was required and 0.2 kg was lost as NH3. The production of 1 kg N in milk required 4 kg N in feed with 0.6 kg NH3-N loss, the same as pork and eggs, but those needed 3 and 3.5 kg N in feed per kg N in product respectively. Except for beef, the differences among these European countries were mainly caused by differences in manure management practices and their emission factors, rather than by animal-related factors including feed and digestibility influencing the excreted amount of ammoniacal N (TAN). For beef, both aspects caused important differences. Based on the results, we encourage the expression of N losses as per N in feed or per N in product, in addition to per animal place, when comparing production efficiency and NUE. We consider that disaggregating emission factors into a diet/animal effect and a manure management effect would improve the basis for comparing national NH3 emission inventories.

Habitual coffee consumption and changes in measures of adiposity: a comprehensive study of longitudinal associations.

BACKGROUND: A relationship between change in coffee consumption and reduced long-term weight gain has been suggested, but current evidence is inconsistent. OBJECTIVE: To examine longitudinal associations between coffee consumption and changes in body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), body fat percentage (BF %) and waist circumference (WC). DESIGN: The study consisted of 2128 participants from the Danish part of the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) cohort with repeated information on coffee consumption, adiposity measures and covariates during an 11-year period. Linear regression analyses were conducted to assess the associations between baseline coffee consumption and subsequent change in adiposity measures. The same analyses were conducted analyzing associations between change in coffee consumption and concurrent as well as subsequent changes in adiposity measures. RESULTS: We found no consistent evidence of associations between baseline coffee consumption and subsequent 6-year changes in adiposity measures. A statistically significant association between increased coffee consumption over a 6-year period and decreased concurrent gain in BMI, FMI, BF % and WC (-0.05 kg m-2 (95% confidence interval (CI): -0.07, -0.02), -0.04 kg m-2 (95% CI: -0.06, -0.02), -0.08% (95% CI: -0.13, -0.04) and -0.23 cm (95% CI: -0.34, -0.12), respectively, per 1 cup day-1 increase in coffee consumption) was found. No association was seen between change in coffee consumption and concurrent change in FFMI. Moreover, an initial change in coffee consumption during the first 5-year period was not associated with change in adiposity during the subsequent 6-year period. CONCLUSIONS: Increased coffee consumption was associated with a decreased concurrent gain in body weight, fat mass and waist circumference, but the associations were weak. Moreover, a causal relationship could not be established, as we found no evidence of associations between an initial change in coffee consumption and subsequent change in adiposity.

Universal Three-Body Physics in Ultracold KRb Mixtures.

Ultracold atomic gases have recently become a driving force in few-body physics due to the observation of the Efimov effect. While initially observed in equal mass systems, one expects even richer few-body physics in the heteronuclear case. In previous experiments with ultracold mixtures of potassium and rubidium, an unexpected nonuniversal behavior of Efimov resonances was observed. In contrast, we measure the scattering length dependent three-body recombination coefficient in ultracold heteronuclear mixtures of ^{39}K-^{87}Rb and ^{41}K-^{87}Rb and do not observe any signatures of Efimov resonances for accessible scattering lengths in either mixture. Our results show good agreement with our theoretical model for the scattering dependent three-body recombination coefficient and reestablish universality across isotopic mixtures.

Rapid and reliable method for identification of associated endonuclease cleavage and recognition sites.

UNLABELLED: One barrier to cross during genetic engineering is the restriction-modification system found in many bacteria. In this study, we developed a fast and reliable method for mapping the recognition and cleavage site of the restriction endonucleases. Clostridium pasteurianum, a model organism for the study of nitrogen fixation, has been found to harbour at least two restriction-modification systems including the restriction endonucleases CpaPI, which is an isoschizomer of MboI and CpaAI. Dam-methylated DNA was used to isolate the activity of CpaAI. Exposing freshly prepared cell lysate to known nucleotide fragments and directly sequencing the pool of digested nucleotide fragments enabled identification of the cleavage sites in the fragments. By aligning the sequences adjacent to the cleavage site, it was possible to identify the recognition sequence. Using this method, we successfully located all CpaAI recognition and cleavage sites within the template sequence. By modifying DNA with both Dam and CpG methylases (M.SssI) and thereby preventing digestion by CpaPI and CpaAI, no further endonuclease activity was detected. SIGNIFICANCE AND IMPACT OF THE STUDY: Restriction-modification systems are important barriers to successful genetic modification in many bacterial species. In this study, we demonstrate an efficient and general applicable method for identifying endonuclease recognition and cleavage sites. For the study and the trails, the model organism for nitrogen fixation Clostridium pasteurianum was used. The method was proven to be reliable, and by modifying DNA at the identified sites, it is possible to prevent digestion.

Picosecond coherent optical manipulation of a single electron spin in a quantum dot.

Most schemes for quantum information processing require fast single-qubit operations. For spin-based qubits, this involves performing arbitrary coherent rotations of the spin state on time scales much faster than the spin coherence time. By applying off-resonant, picosecond-scale optical pulses, we demonstrated the coherent rotation of a single electron spin through arbitrary angles up to pi radians. We directly observed this spin manipulation using time-resolved Kerr rotation spectroscopy and found that the results are well described by a model that includes the electronnuclear spin interaction. Measurements of the spin rotation as a function of laser detuning and intensity confirmed that the optical Stark effect is the operative mechanism.

Zero-field optical manipulation of magnetic ions in semiconductors.

Controlling and monitoring individual spins is desirable for building spin-based devices, as well as implementing quantum information processing schemes. As with trapped ions in cold gases, magnetic ions trapped on a semiconductor lattice have uniform properties and relatively long spin lifetimes. Furthermore, diluted magnetic moments in semiconductors can be strongly coupled to the surrounding host, permitting optical or electrical spin manipulation. Here we describe the zero-field optical manipulation of a few hundred manganese ions in a single gallium arsenide quantum well. Optically created mobile electron spins dynamically generate an energy splitting of the ion spins and enable magnetic moment orientation solely by changing either photon helicity or energy. These polarized manganese spins precess in a transverse field, enabling measurements of the spin lifetimes. As the magnetic ion concentration is reduced and the manganese spin lifetime increases, coherent optical control and readout of single manganese spins in gallium arsenide should be possible.

Nondestructive optical measurements of a single electron spin in a quantum dot.

Kerr rotation measurements on a single electron spin confined in a charge-tunable semiconductor quantum dot demonstrate a means to directly probe the spin off-resonance, thus minimally disturbing the system. Energy-resolved magneto-optical spectra reveal information about the optically oriented spin polarization and the transverse spin lifetime of the electron as a function of the charging of the dot. These results represent progress toward the manipulation and coupling of single spins and photons for quantum information processing.

Spironolactone induces apoptosis in human mononuclear cells. Association between apoptosis and cytokine suppression.

Spironolactone (SPIR) has been described to suppress accumulation of pro-inflammatory cytokines. Here, the suppression of TNF-alpha in lipopolysaccharide (LPS)-stimulated mononuclear cell cultures was confirmed. However, SPIR was also found to induce apoptosis, prompting the investigations of a possible association between the two effects: The apoptosis-inducing and the cytokine-suppressive effects of SPIR correlated with regard to the effective concentration range. Also, pre-incubation experiments demonstrated a temporal separation of the two effects of < or = 4 h, with TNF-alpha suppression preceding apoptosis. An association between the two effects was also seen when testing several SPIR analogues. Contrary to TNF-alpha, the levels of IL-1beta increased in SPIR-treated cultures. However, the amount of IL-1beta in the supernatants depended upon the order of SPIR and LPS addition, as IL-1beta was non-detectable in cultures treated with SPIR prior to LPS, whereas elevated IL-1beta levels were seen when SPIR was added after LPS-stimulation. It is possible that the extracellular accumulation of IL-1beta is due to an increased release of already produced IL-1beta as a result of cell death. In conclusion, suppression of cytokine production by SPIR may be associated with its apoptotic potential, either directly (apoptosis is a consequence of suppressed cytokine production, or vice-versa) or indirectly (suppressed cytokine production and apoptosis are parallel but otherwise unrelated phenomena).

Biosynthesis and metabolic engineering of glucosinolates.

Glucosinolates are amino acid-derived natural plant products found throughout the Capparales order. Glucosinolates and their degradation products have a wide range of biological activities, e.g. in plant defense as deterrents against insect and fungi. The conversion of amino acids to aldoximes is a key step in glucosinolate biosynthesis. This step is catalyzed by cytochromes P450 from the CYP79 family. The post-aldoxime enzymes in the glucosinolate pathway have high substrate-specificity for the functional group and low substrate-specificity for the side chain. Therefore, we have been able to metabolically engineer new glucosinolate profiles into Arabidopsis by altering the levels of endogenous CYP79s and by introducing exogenous CYP79s. The approach has great potential for design of metabolically engineered plants with improved pest resistance and increased nutritional value.

RelE, a global inhibitor of translation, is activated during nutritional stress.

The stringent response is defined as the physiological changes elicited by amino acid starvation. Many of these changes depend on the regulatory nucleotide ppGpp (guanosine tetraphosphate) synthesized by RelA (ppGpp synthetase I), the relA-encoded protein. The second rel locus of Escherichia coli is called relBE and encodes RelE cytotoxin and RelB antitoxin. RelB counteracts the toxic effect of RelE. In addition, RelB is an autorepressor of relBE transcription. Here we reveal a ppGpp-independent mechanism that reduces the level of translation during amino acid starvation. Artificial overexpression of RelE severely inhibited translation. During amino acid starvation, the presence of relBE caused a significant reduction in the poststarvation level of translation. Concomitantly, relBE transcription was rapidly and strongly induced. Induction of transcription occurred independently of relA and spoT (encoding ppGpp synthetase II), but instead depended on Lon protease. Consistently, Lon was required for degradation of RelB. Replacement of the relBE promoter with a LacI-regulated promoter indicated that strong and ongoing transcription of relBE is required to maintain a proper RelB:RelE ratio during starvation. Thus relBE may be regarded as a previously uncharacterized type of stress-response element that reduces the global level of translation during nutritional stress.

A light and electron microscopic study of ectopic tendon and ligament formation induced by bone morphogenetic protein-13 adenoviral gene therapy.

OBJECT: Bone morphogenetic proteins (BMPs) are involved in the growth and development of many tissues, but it is their role in skeletal development and their unique ability to induce ectopic and orthotopic osteogenesis that have attracted the greatest interest. Expression of the BMP-13 gene is predominantly localized to hypertrophic chondrocytes in regions of endochondral bone formation during development, as well as in mature articular cartilage in the adult. In addition, the application of BMP-13 on a collagen carrier induces neotendon/neoligament formation when delivered subcutaneously or intramuscularly in rodents. The aim of the present study was to determine the histological and ultrastructural changes that occur after the intramuscular injection of a first-generation BMP-13 adenoviral vector. METHODS: Athymic nude rats were injected with 3.75 x 10(10) plaque-forming units of adenovirus (Ad)-BMP-13 or Ad-beta-galactosidase in the thigh musculature, and the region was examined using light and electron microscopy at various time points between 2 days and 100 days postinjection. As early as 2 days after injection of Ad-BMP-13, progenitor cells were observed infiltrating between the transduced muscle fibers. These cells subsequently proliferated, differentiated, and secreted large amounts of collagenous extracellular matrix. By 100 days postinjection, the treated tissue displayed the histological and ultrastructural appearance of neotendon/neoligament, which was clearly demarcated from the surrounding muscle. Small foci of bone and fibrocartilage were also seen within the treated tissue. A short-term bromodeoxyuridine study also demonstrated rapid mesenchymal cell proliferation at the Ad-BMP-13 injection site as early as 48 hours postinjection. At all time points, the control AD-beta-gal injection sites were found to contain only normal muscle, without evidence of inflammation or mesenchymal cell proliferation. CONCLUSIONS: The results of this study indicate that in the future the use of the BMP-13 gene may have therapeutic utility for the healing of tendon and ligament tears and avulsion injuries.

Investigation of a cluster of children with Down's syndrome born to mothers who had attended a school in Dundalk, Ireland.

OBJECTIVES: To investigate a reported cluster of Down's syndrome in offspring of former pupils of a girls' school in Ireland, to establish the prevalence of Down's syndrome among live births in the area around the school, and to review the literature on the possible causes of reported clusters of Down's syndrome. METHODS: Questionnaire survey of obstetric and personal histories of women who had attended the girls' school at Dundalk, County Louth, Republic of Ireland, at some time during 1956-7, and also of women who had attended another, nearby, girls' school during the same period. Comparison of observed numbers of cases of Down's syndrome identified by these surveys with maternal age adjusted expected numbers for the reported live births. Laboratory tests were conducted to verify and characterise the cases of Down's syndrome constituting the cluster. Retrospective collection and collation of data on Down's syndrome occurring among live births, and the compilation of maternal age specific incidences, in County Louth and in Newry and Mourne District in neighbouring Northern Ireland, during 1961-80. These rates were compared with reference rates and rates for other areas of Ireland. RESULTS: Six children with Down's syndrome were confirmed among 387 reported live births to women who had been pupils at the girls' school in Dundalk during 1956-7, compared with 0.69 expected (nominal p<10(-4)). Five of the affected births were to mothers under 30 years of age, against 0.15 expected (nominal p<10(-6)), although only four of these mothers were attending the school at any one time. The origin of the non-disjunction was found to be maternal first meiotic in four children, mitotic after fertilisation in another (with the youngest mother), and in the remaining one could not be determined. The marked excess of Down's syndrome in births to young mothers did not extend to offspring of former pupils of the other Dundalk girls' school surveyed, or to live births in County Louth generally or in adjacent Newry and Mourne District. CONCLUSION: A striking, highly localised, excess of Down's syndrome in births to young mothers who had attended a girls' school in Dundalk during 1956-57 has been confirmed. However, not all of the mothers of the affected children attended the school concurrently and the origin of non-disjunction in one child was an error occurring after conception. Some exposure essentially confined to girls attending the school at this time is a possible, although unlikely, explanation, but a review of potential risk factors does not suggest what this could be. Previous suggestions that an influenza epidemic or contamination from the Windscale nuclear reactor fire might be implicated, both of which occurred in October 1957, can be effectively dismissed because three of the women with affected offspring had left the school by then and had moved away from Dundalk, and Down's syndrome in the child of another mother originated in an error after fertilisation. Owing to the retrospective nature of the investigation and the characteristics of the cases, chance is the most likely explanation for the cluster.