Implementation of HaemScreen, a workplace-based genetic screening program for hemochromatosis

There is debate as to whether community genetic screening for the mutation(s) causing hereditary hemochromatosis (HH) should be implemented, due to issues including disease penetrance, health economic outcomes, and concerns about community acceptance. Hemochromatosis is a common preventable iron overload disease, due in over 90% of cases to C282Y homozygosity in the HFE gene. We are, therefore, piloting C282Y screening to assess understanding of genetic information and screening acceptability in the workplace setting. In this program, HaemScreen, education was by oral or video presentation in a group setting. C282Y status was assessed by polymerase chain reaction (PCR) and melt-curve analysis on DNA obtained by cheek-brush sampling. Of eligible participants, 5.8% (1.5-15.8%) attended information and screening sessions, of whom 97.7% (5571 individuals) chose to be tested. Twenty-two C282Y (1 : 253) homozygotes were identified and offered clinical follow-up. There were 638 heterozygotes (1 : 8.7). The determinants for participation have been analyzed in terms of the principles outlined in the Health Belief Model. Widespread screening for HH is readily accepted in a workplace setting, and a one-to-many education program is effective. The level of participation varies greatly and the advertizing and session logistics should be adapted to the specific features of each workplace.     

Detection of human perforin by ELISpot and ELISA: ex vivo identification of virus-specific cells

The perforin (PFN) protein is essential for the elimination of target cells by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. The study of cells releasing PFN has been hampered by a lack of sensitive methods. We therefore produced PFN-reactive monoclonal antibodies (mAb) and developed capture enzyme-linked immunosorbent (ELISA) and enzyme-linked immunospot (ELISpot) assays. Three mAbs were generated and shown to react with unique determinants of PFN. All mAbs recognized intracellular PFN in human peripheral blood mononuclear cell (PBMC) as assessed by flow cytometry and immunohistochemistry. Functional PFN capture ELISA and ELISpot assays were developed utilizing two of the mAbs for capture and the third mAb for detection. When examining PFN release by the YT lymphoma cell line, the ELISpot displayed a greater detection sensitivity than the ELISA. Assessment of PFN release by a CTL clone using ELISpot gave results consistent with a parallel (51)Cr-release cytotoxicity assay. Moreover, PFN release by PBMC could be quantified by ELISpot and ELISA after ex vivo stimulation with defined CTL epitopes from common viruses. These novel immunoassays will be valuable for further investigations of the mechanisms underlying granule-mediated apoptosis. In addition, the capture immunoassays could provide tools for studying CTL responses in infectious and tumor diseases as well as for vaccine development.     

Identifying severely atrophic cortical subregions in Alzheimer's disease

The present study analyses the pattern of atrophy in anatomically discrete brain regions in prospectively-studied pathologically-confirmed patients with Alzheimer's disease (AD) and controls. Standard volumetric measurements were made of the entire cortex subdivided into 23 anatomical regions. Analyses determined regions of significant atrophy in AD and differences between the severity and rates of atrophy. Two levels of severity were found. Atrophy concentrated in medial temporal lobe structures as well as in inferior temporal and superior and middle frontal cortices. The degree of atrophy in these regions related to disease duration, consistent with an early and sustained disease process. The rate of atrophy was significantly greater for the fusiform gyrus. The inferior frontal lobes were entirely spared at all AD stages, while atrophy of other cortical regions was less marked and not related to disease duration, suggesting late involvement. Our findings show that the fusiform gyrus is particularly affected by AD, and suggest two levels of atrophy that correspond with published neurofibrillary tangle (most atrophic) and senile plaque (less atrophic) densities.     

Wilms tumor in patients with osteopathia striata with cranial sclerosis

Germline pathogenic variants in AMER1 cause osteopathia striata with cranial sclerosis (OSCS: OMIM 300373), an X-linked sclerosing bone disorder. Female heterozygotes exhibit metaphyseal striations in long bones, macrocephaly, cleft palate, and, occasionally, learning disability. Male hemizygotes typically manifest the condition as fetal or neonatal death. Somatically acquired variants in AMER1 are found in neoplastic tissue in 15–30% of patients with Wilms tumor; however, to date, only one individual with OSCS has been reported with a Wilms tumor. Here we present four cases of Wilms tumor in unrelated individuals with OSCS, including the single previously published case. We also report the first case of bilateral Wilms tumor in a patient with OSCS. Tumor tissue analysis showed no clear pattern of histological subtypes. In Beckwith–Wiedemann syndrome, which has a known predisposition to Wilms tumor development, clinical protocols have been developed for tumor surveillance. In the absence of further evidence, we propose a similar protocol for patients with OSCS to be instituted as an initial precautionary approach to tumor surveillance. Further evidence is needed to refine this protocol and to evaluate the possibility of development of other neoplasms later in life, in patients with OSCS.Subject terms: Genetics, Clinical genetics, Disease genetics     

Stress resistance as a determinate of C. elegans lifespan

It is difficult to exaggerate the progress that has been made in biogerontology over the last 15 years. As with all scientific revolutions, a few experiments in a small number of laboratories have changed the way in which we think about and design experiments. As a result of these experiments, there is much evidence to suggest that a rudimentary understanding of some of the processes that cause aging will be available in the next decade. One particular area of progress is the molecular genetics of lifespan. Although one may draw some distinctions between chronological lifespan and normal aging, extended lifespan remains one of the best indicators that an intervention in an aging process has been made. The isolation of a long-lived variant of a laboratory invertebrate is now essentially a trivial project but the information obtained from this approach is proving invaluable. As with most other biological problems, the most important experimental developments are coming from studying simple organisms in a reductionist fashion.     

A new method of estimating cost effectiveness of cholesterol reduction therapy for prevention of heart disease

The purpose of this study was to demonstrate a new method of estimating the cost effectiveness of interventions that lower blood cholesterol levels in the prevention of coronary heart disease (CHD) at the community level. The participants in the study were 67 651 men aged 35 to 64 years in the Lower Hunter region of New South Wales, Australia. Census data, risk factor profiles and CHD event rates from community surveillance, plus costs in 1988-1989 Australian dollars, were used as inputs to a computer program that used a logistic equation. The output estimated the CHD events avoided and the cost effectiveness of an intervention that identified and treated men with cholesterol levels greater than 6.5 mmol/L with dietary modification and cholestyramine. The cost of implementation of the intervention was $A50.1 million to prevent 104 CHD events. The cost-effectiveness ratio was $A482 224 per CHD event avoided (SD = $A24 761) and the direct medical costs avoided were approximately $A500 000 over a 5-year period ($A4535.07 per CHD event avoided). Drug acquisition costs contributed substantially (88%) to the total costs of interventions that rely on screening to identify individuals with high cholesterol for intensive treatment.     

Intracerebral haemorrhages in surfactant treated neonates with severe respiratory distress syndrome: age at diagnosis,severity and risk factors

Within a randomized European multicentre trial the time of onset, severity and progression of intracerebral haemorrhages (ICH) were investigated prospectively by serial cranial ultrasonography in 343 ventilated infants with severe respiratory distress syndrome (RDS) following instillation of single or multiple doses of a natural porcine surfactant (Curosurf). In 148/343 infants (43%) ICH was diagnosed (grade I or II: 22%, grade III or IV: 21%). In 26 cases (8%) ICH was present on the ultrasound scan prior to surfactant instillation at a median age of 6h. Incidence and severity of ICH was similar after single- or multiple-dose surfactant treatment. Using a logistic regression model the following risk factors predictive of ICH were defined: low birth weight, allocation to certain hospitals, vaginal delivery, Apgar score6, rectal temperature on admission 36°C, primary anaemia, acidosis prior to treatment, RDS grade IV in pre-treatment chest films and poor response to surfactant treatmentOur study provides supportive evidence that multiple doses of Curosurf do not increase the risk for ICH as compared to single-dose administration.A preliminary report of this work was presented at 8th International Workshop on Surfactant Replacement, Oslo, Norway, May 21 1993. The study was supported by grants of the German government (BMFT 93 607 27) and the German Research Council (Deutsche Forschungsgemeinschaft He 2072: 1–2). The surfactant used in the trial was prepared ang tested in Stockholm with the skilful technical assistance of Elin Arvesen, Bim Linderholm. Eva Lundberg, Gunhild Nilsson and Petru Popa (supported by the Swedish Medical Research Council (Project No. 3351) and Oscar II:s Jubileumsfond)Dedicated to the memory of Edgar (Eddi) Laufkötter, one of the most active trial collaborators, who died under tragic circumstances on April 10, 1994.     

Scopolamine Effects on Visual Information Processing, Attention, and Event-Related Potential Map Latencies

We measured performance and event-related brain potential (ERP) map latencies in 12 subjects during four visual discrimination tasks to compare the timing of scopolamine effects on information processing and attention. "Topographic component recognition" found ERP map latencies at times of best fit with a component model map. This "common topography" criterion minimized topographic differences among conditions to facilitate latency interpretations. Scopolamine slowed N1 latency in all tasks, and P3 and reaction time in some tasks. The drug delayed responses to easy targets more than to hard targets. It also induced a disproportionate N1 delay for unilateral high spatial frequency gratings. Both effects reflect a scopolamine-induced impairment when processing targets that usually capture attention. Scopolamine also impaired accuracy for unilateral high spatial frequency gratings, and for gratings presented at probable locations, confirming and extending previous findings. Scopolamine-induced P1 and N1 delays showed that visual processing was affected. Several results were inconsistent with a serial stage model. We suggest that scopolamine both delays selected processes and impairs a processing mode based on automatic capture of attention, inducing more serial processing.     

Scalp potentials following sudden coherence and discoherence of binaural noise and change in the inter-aural time difference: a specific binaural evoked potential or a "mismatch" response?

When uncorrelated random noise signals presented to the two ears suddenly become identical (coherent), a centrally located sound image is abruptly perceived and long latency scalp potentials are evoked. When the same signals are presented monaurally there is no perceived change and no potentials are evoked: hence the response must be purely a function of the binaural interaction. P70, N130 and P220 components were consistently recorded to both coherence and discoherence. N130 was usually largest at Fz and P220 at Cz. No potentials of shorter latency were identified, even after averaging 5000 or more sweeps. When the noise became coherent with an inter-aural time difference (delta T) of +/- 0.5 msec (giving rise to an off-centre sound image), the responses were of slightly longer latency and showed no significant asymmetries between C3 and C4. In binaurally coherent noise, delta T changes of +/- 0.5 or +/- 1.0 msec evoked similar responses which showed no significant asymmetries on the scalp. N130 was of longer latency when delta T was changed from +/- 0.5 msec to zero, as compared with the converse change. In view of the similarity of all these responses it is considered unlikely that they were due to specific populations of binaurally responsive cortical neurones. The N130 and P220 components are thought to be non-specific potentials which are elicited by any perceptible change in steady auditory stimulus conditions, due to a "mismatch" between the stimulus and the contents of a short-term auditory memory.