Patients with Parkinson’s disease psychosis (PDP) are often treated with an atypical antipsychotic, especially quetiapine or clozapine, but side effects, lack of sufficient efficacy, or both may motivate a switch to pimavanserin, the first medication approved for management of PDP. How best to implement a switch to pimavanserin has not been clear, as there are no controlled trials or case series in the literature to provide guidance. An abrupt switch may interrupt partially effective treatment or potentially trigger rebound effects from antipsychotic withdrawal, whereas cross-taper involves potential drug interactions. A panel of experts drew from published data, their experience treating PDP, lessons from switching antipsychotic drugs in other populations, and the pharmacology of the relevant drugs, to establish consensus recommendations. The panel concluded that patients with PDP can be safely and effectively switched from atypical antipsychotics used off label in PDP to the recently approved pimavanserin by considering each agent’s pharmacokinetics and pharmacodynamics, receptor interactions, and the clinical reason for switching (efficacy or adverse events). Final recommendations are that such a switch should aim to maintain adequate 5-HT2A antagonism during the switch, thus providing a stable transition so that efficacy is maintained. Specifically, the consensus recommendation is to add pimavanserin at the full recommended daily dose (34 mg) for 2–6 weeks in most patients before beginning to taper and discontinue quetiapine or clozapine over several days to weeks. Further details are provided for this recommendation, as well as for special clinical circumstances where switching may need to proceed more rapidly.

Breakthrough Listen is a 10-yr initiative to search for signatures of technologies created by extraterrestrial civilisations at radio and optical wavelengths. Here, we detail the digital data recording system deployed for Breakthrough Listen observations at the 64-m aperture CSIRO Parkes Telescope in New South Wales, Australia. The recording system currently implements two modes: a dual-polarisation, 1.125-GHz bandwidth mode for single-beam observations, and a 26-input, 308-MHz bandwidth mode for the 21-cm multibeam receiver. The system is also designed to support a 3-GHz single-beam mode for the forthcoming Parkes ultra-wideband feed. In this paper, we present details of the system architecture, provide an overview of hardware and software, and present initial performance results.

We undertook observations with the Green Bank Telescope, simultaneously with the 300 m telescope in Arecibo, as a follow-up of a possible flare of radio emission from Ross 128. We report here the non-detections from the GBT observations in C band (4–8 GHz), as well as non-detections in archival data at L band (1.1–1.9 GHz). We suggest that a likely scenario is that the emission comes from one or more satellites passing through the same region of the sky.

Tabby males were irradiated with 500 r and mated to Bn Mobr♀♀. Daughters conceived during the first 3 weeks after irradiation were tested for the presence of sex-linked recessive mutations in their progeny, each daughter representing one irradiated gamete. One visible, but no lethal, was found in the Bn–Mobr segment among 154 tested gametes; one gamete was proved free of lethals or visibles in the Bn–Ta segment, and 21 gametes in the Ta–Mobr segment. Among the whole 176 tested gametes there was no indication of a lethal in the adjoining segments.

1. A mild diabetes insipidus is associated with the oligosyndactyly caused by the dominant gene Os. No recombinants were observed between the diabetes and the oligosyndactyly so the diabetes is probably a pleiotropic effect of the Os gene.

2. There are one or more modifying genes which in combination with Os enhance the manifestation and cause a severe diabetes insipidus. This affects both sexes and becomes progressively worse in older animals, the average water intake reaching 50–60 ml. per 24 hours, or 1·7 times the body weight.

3. The modifying gene or genes, in the absence of the Os gene, themselves produce a mild diabetes insipidus, which becomes severe in some old females.

4. The severe diabetes insipidus associated with Os and the modifying genes together is probably renal in origin.

The sex-linked gene, brindled, in the mouse produces a coat-colour variegation in heterozygous females. There is much individual variation in the relative areas of mutant and wild-type colour, but it was not known if any of this variation was genetic. The main object, when the experiments were started, was to test the simple expectation of the Lyon hypothesis, that if X-inactivation is random the variegation should not be modifiable by selection. On the assumption that the variegation is due to X-chromosome inactivation, modification by selection would show that the inactivation process, or some property of the derived cell populations, is under genetic control. Heterozygous females were accordingly selected for the area of coat showing the mutant colour. Selection based on individual phenotypes was ineffective, but four cycles of reciprocal recurrent selection based on progeny-means produced a ‘High’ line with 64% mutant area and a ‘Low’ line with 30% mutant area, from a base population with 53% mutant area. Autosomal modifiers were not responsible for the response; the difference between the selected lines was entirely due to properties of the X chromosomes carrying the brindled gene. The changed properties of the X chromosomes were not restricted to the locus of brindled, but extended at least as far as the locus of tabby. The chromosomes carrying the wild-type allele of brindled were not altered by the selection, but normal X chromosomes from other strains affected the degree of variegation. It was concluded that the difference between the selected lines was due either to non-random inactivation or to somatic cell selection. It was not possible to distinguish between these two mechanisms. The results obtained in these experiments with a structurally normal X chromosome were in all essentials similar to those obtained by Cattanach with his X-autosome translocation.

The gene ‘sex-linked anaemia’ (sla) appeared first in the progeny of a daughter of a male that had been irradiated with 500 r. of X-rays. The daughter was born one month after the irradiation of her father. Mated to an unrelated wild-type male she produced sixteen sons of which six were anaemic. Her fertility was normal. Experience in subsequent matings showed the anaemia to be rather difficult to classify. In litters examined on the day of birth the anaemic young were usually clearly distinguishable by their pale colour. But in older litters, and even in a few at birth, the classification could not be made with confidence. The haematology of the anaemics is described by Grewal (1962).

Curly-whiskers (cw) is a recessive gene which was found in 1958 by Mr C. J. W. Smith of the Chester Beatty Research Institute, London. It arose in a subline of the CBA/Cbi inbred strain. The first mutant animals were one male and one female in a litter of five. The two mutants were mated together and a sib-mated subline was continued from them in which 500 mice were bred, all of which were curly-whiskered. This established the mutant to be fully penetrant. Curly-whiskers resembles the hair-waving genes in causing waving of the vibrissae, but it has no obvious waving effect on the hairs of the coat. The coat texture is, however, slightly abnormal and Mr Smith noted also that on the CBA background there was an appreciable darkening of the coat colour. Homozygotes (cw/cw) are easily classifiable soon after birth by the curled vibrissae. Heterozygotes (+/cw) often have slightly curled vibrissae, and the gene is therefore not fully recessive; but the distinction between +/cw and +/+ could not be relied on, and in the linkage tests cw was treated as a recessive gene.

1. A new semi-dominant gene called shaven (Sha) causes hairlessness in the mouse and it is closely linked to naked. Homozygous shaven mice never grow a first coat and adults grow a few short hairs only. Shaven heterozygotes grow a full coat which is greasy.

2. The percentage recombination between shaven and naked was found to be 0·8%. Three-point tests with naked and caracul showed that the order of the three loci is either N–Sha–Ca or N–Ca–Sha.

3. The failure of homozygous shaven mice to grow a coat is due to abnormal keratinization of the hairs in the follicles. The follicles were found to be deficient in sulphydryl groups.

4. The greasiness of the Sha+ coat is due to the presence of a sudanophilic fluid in the hair medullae.

5. The close linkage between the two genes with similar phenotypic effects is discussed.

Selection for increased and for decreased expression of the sex-linked gene brindled (Mobr) in heterozygous females produced two lines with non-random X chromosome inactivation. In the High line the X chromosome marked by brindled was active in about 60% of cells, while in the Low line it was active in about 25% of cells. The whole of the difference was caused by the chromosomes carrying brindled: neither the unmarked X chromosome nor the autosomes were differentiated. There was a positive correlation between the expression of brindled in daughters and mothers. This was probably not caused by residual genetic variation, but was more probably a maternal effect similar to that described by Cattanach & Papworth (1981). On this assumption the daughters' scores were adjusted to a standard maternal score. Enzyme assays on females doubly heterozygous for brindled and for the sex-linked Pgk-1 locus proved that the percentage of brindled in the coat provided an accurate measure of the X-inactivation proportions in the blood, liver and kidney. The accuracy was improved by adjustment for maternal score. In the selection lines, brindled was always inherited from the mother. When brindled was transmitted by male parents the probability of activation of its chromosome was increased by 8 percentage points in the High line and 18 in the Low line. This effect of the parental source is much greater than has previously been reported. The responses to selection can be interpreted in terms of the Xce locus controlling the activation probability, different alleles on the chromosomes carrying brindled being selected in the two lines. If this interpretation is correct, the alleles on one or both of the chromosomes carrying brindled were different from any of the three known alleles. The different effects of male transmission in the two lines can be described as a difference between the two chromosomes in their reactions to imprinting. This difference might possibly also be due to the Xce locus.

The technologies of nanofabrication as applied to inorganic materials and substrates are advanced and continue to develop. These sophisticated processes enable the formation of complex electronic, optical and mechanical devices with feature sizes down to tens of nanometers. Adaptation of these types of processes to surface chemical patterning and topographical patterning provides a new set of experimental tools for investigating biological systems and realizing sensors and devices that require the interaction of biological systems and fluids with inorganic materials and surfaces.

In this talk we discuss methods of pattering self assembled monolayers, proteins and antibodies on silicon and glass surfaces by lithography and microcontact printing. This is of utility in a variety of experiments in cell-surface interactions and in sensor devices. In certain types of devices the manipulation of fluids and sieving of molecules is a critical function such as in DNA sequencing6 by electrophoretic separation.

The application of nano- and microfabricated devices based on silicon electronics technology is an emerging interdisciplinary area combining engineering and biology. The placement of electrically active probes in damaged or diseased tissues of the central nervous system could have enormous impact on the health and quality of life of large numbers of individuals by restoring lost function, or by treating or controlling disease states. Such probes have been fabricated at a high level of engineering sophistication. Unfortunately, when inserted into the brain a tissue reaction is initiated forming a scar that surrounds and electrically isolates the probe within a few weeks. This reaction is thought to primarily involve glial cells, and is undoubtedly dominated by the bulk surface of the probes which have a silicon oxide layer on top of single crystal silicon.

Model probes (Fig. 1) were microfabricated by photolithography with a 1×1mm tab used for gripping and inserting probes.

The application of nano- and microfabrication to biology is an emerging area linking engineering and biology. We are using microfabrication techniques to make patterns of specific bioactive molecules on glass and silicon surfaces to study central nervous system neurons and glia. Cell adhesion and tissue reaction to implanted silicon based electronic prosthetic devices are being studied, and the methods expanded to interface neurons with integrated circuits to study their electrical properties. The number, type and distribution of cells adhering to particular portions of a substrate can be influenced by patterning amine groups, proteins or polypeptides. We are using microcontact printing as an alternative to lithography for chemical patterning.

Primary cultures of rat cortical astrocytes and hippocampal neurons, and continuous cultures of transformed astrocytes were prepared on microcontact printed patterns produced by an elastomer stamp made from a silicon master. Fig. 1 shows two such patterns prepared by depositing self-assembled monolayers of N1[3-(Trimethoxylsily)propyl] diethylenetriamine (DETA) and octadecyltrichlorosilane (OTS).