Facilitating individuals and families affected by fragile X syndrome to participate in medication trials.

BACKGROUND: Recently, there has been an increasing number of trials of medications for fragile X syndrome (FXS). In order to be adequately powered, trials have involved many centres around the world with relatively small numbers of participants recruited at each site. This study aims to understand the barriers to, and how best to facilitate participation in, medication trials in order to improve recruitment and the experience of participants with FXS. METHODS: A mixed methods design was used to collect both quantitative and qualitative data. Participants were invited to participate through the UK Fragile X Society, a local mailing list and through social media. Those who agreed to participate completed a quantitative questionnaire and indicated whether they would be willing to participate in a follow-up focus group. RESULTS: The questionnaire was completed by 328 individuals who either had FXS, or were a parent, carer or family member of an individual with FXS. Over two-thirds of participants reported concern about side effects, while over one-third mentioned swallowing tablets, blood tests, financial aspects and travel as barriers to participation. Focus groups with 12 individuals highlighted themes of trial challenges, strategies to overcome these and motivating factors to participate. CONCLUSIONS: Many of the factors, which potentially negatively influence participation in a clinical trial for FXS, could be mitigated in relatively simple ways. Easily accessible information, particularly about safety issues, the research team and the trial environment should be standard practice. Desensitisation programmes for blood testing, provision of different preparations of medication (e.g. liquid) and use of a combination of local, remote and site visits to reduce travel and time should also be considered.

Universal lower limit on vortex creep in superconductors.

Superconductors are excellent testbeds for studying vortices, topological excitations that also appear in superfluids, liquid crystals and Bose-Einstein condensates. Vortex motion can be disruptive; it can cause phase transitions, glitches in pulsars, and losses in superconducting microwave circuits, and it limits the current-carrying capacity of superconductors. Understanding vortex dynamics is fundamentally and technologically important, and the competition between thermal energy and energy barriers defined by material disorder is not completely understood. Specifically, early measurements of thermally activated vortex motion (creep) in iron-based superconductors unveiled fast rates (S) comparable to measurements of YBa 2Cu3O7-δ (refs ,,,,,). This was puzzling because S is thought to somehow correlate with the Ginzburg number (Gi), and Gi is significantly lower in most iron-based superconductors than in YBa 2Cu3O7-δ. Here, we report very slow creep in BaFe 2(As0.67P0.33)2 films, and propose the existence of a universal minimum realizable S ∼ Gi1/2(T/Tc) (Tc is the superconducting transition temperature) that has been achieved in our films and few other materials, and is violated by none. This limitation provides new clues about designing materials with slow creep and the interplay between material parameters and vortex dynamics.

Quantum Critical Scaling in the Disordered Itinerant Ferromagnet UCo_{1-x}Fe_{x}Ge.

The Belitz-Kirkpatrick-Vojta (BKV) theory shows in excellent agreement with experiment that ferromagnetic quantum phase transitions (QPTs) in clean metals are generally first order due to the coupling of the magnetization to electronic soft modes, in contrast to the classical analogue that is an archetypical second-order phase transition. For disordered metals the BKV theory predicts that the second-order nature of the QPT is restored because the electronic soft modes change their nature from ballistic to diffusive. Our low-temperature magnetization study identifies the ferromagnetic QPT in the disordered metal UCo_{1-x}Fe_{x}Ge as the first clear example that exhibits the associated critical exponents predicted by the BKV theory.

Author Correction: Glassy Dynamics in a heavy ion irradiated NbSe2 crystal.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Glassy Dynamics in a heavy ion irradiated NbSe2 crystal.

Fascination with glassy states has persisted since Fisher introduced the vortex-glass as a new thermodynamic phase that is a true superconductor that lacks conventional long-range order. Though Fisher's original model considered point disorder, it was later predicted that columnar defects (CDs) could also induce glassiness - specifically, a Bose-glass phase. In YBa2Cu3O7-x (YBCO), glassy states can cause distinct behavior in the temperature (T ) dependent rate of thermally activated vortex motion (S). The vortex-glass state produces a plateau in S(T ) whereas a Bose-glass can transition into a state hosting vortex excitations called double-kinks that can expand, creating a large peak in S(T ). Although glass phases have been well-studied in YBCO, few studies exist of other materials containing CDs that could contribute to distinguishing universal behavior. Here, we report on the effectiveness of CDs tilted ~30° from the c-axis in reducing S in a NbSe2 crystal. The magnetization is 5 times higher and S is minimized when the field is parallel to the defects versus aligned with the c-axis. We see signatures of glassiness in both field orientations, but do not observe a peak in S(T ) nor a plateau at values observed in YBCO. Finally, we discuss the possibility that competing disorder induces a field-orientation-driven transition from a Bose-glass to an anisotropic glass involving both point and columnar disorder.

The SCID/Beige mouse as a model to investigate protection against Yersinia pestis.

In this study, we have shown that severe combined immunodeficient/beige mice reconstituted with hyperimmune Balb/c lymphocytes can be used as a model to demonstrate adoptive and passive protection against plague infection. Reconstitution of severe combined immunodeficient/beige mice was successful in nine out of ten mice as demonstrated by spleen colonisation and sustained circulating immunoglobulin titres. Furthermore, an increase in antibody titre was evident after a booster immunisation of reconstituted mice. Presence of circulating antibody correlated with protection against a systemic plague challenge and indicated that in reconstituted mice adoptive transfer of a functional immune system had occurred. The severe combined immunodeficient/beige mouse was also used to demonstrate passive protection against inhaled and systemic plague infection. The reconstituted severe combined immunodeficient/beige mouse model demonstrating protective immunity against plague will be further developed to identify the immune cell subsets responsible for this protection.

A new improved sub-unit vaccine for plague: the basis of protection.

In this study, we have determined the limit of protection achievable by immunisation with sub-units of Yersinia pestis against the development of plague in an experimental animal model. Co-immunisation with the purified culture-derived F1 and the recombinant V sub-units afforded a greater level of protection than with either sub-unit alone. The protection given by the combined sub-units was several orders of magnitude greater than that afforded by the whole cell killed (Cutter USP) vaccine and was equivalent to that achieved by vaccination with EV76, the live attenuated Y. pestis vaccine strain. However, the combined sub-unit vaccine has clear advantages over the live vaccine in terms of safety of use and absence of side-effects.

'Now and Again It Really Hits Me': The Impact of an HIV-positive Diagnosis upon Psychosocial Well- being.

Quantitative and qualitative data were gathered from a sample of 66 seropositive and 67 seronegative men and women about the impact of an HIV diagnosis upon psychosocial well-being. No significant differences between seropositives and seronegatives were found on any of the psychosocial measures except hopelessness. Nor was there significant variation by disease progression (but this may be due to the restricted size of the sample). The qualitative data are used to illustrate these findings and explore their meaning. It is concluded that, with the exception of a hopeless future orientation, psychosocial disturbance of seropositives tends to be episodic and short-lived and thereby difficult to measure.

Laboratory diagnosis of plague.

In response to an outbreak of a plague-like disease in India, the Public Health Laboratory Service (PHLS) in the UK distributed advice on the isolation and identification of Yersinia pestis. Some of the procedures outlined were evaluated using a number of isolates of Y. pestis, complemented with in-house techniques detecting virulence genes or their products. These laboratory investigations are limited in that they are either only indicative or they take too long (48 hours or more), and thus represent a serious delay to the patient. Successful patient management must be based on a case history, and therapy should be started immediately. Laboratory diagnosis will subsequently rule out most pathogens which cause similar infections, yet will still require confirmation by a reference laboratory.

Characterisation of orbiviruses of the Kemerovo serogroup: comparison of protein and RNA profiles.

Nine viruses of the Kemerovo serogroup (orbivirus genus; family, Reoviridae) isolated from seabird ticks (Ixodes uriae and Ornithodoros maritimus) from eight different geographical locations (four from Scotland, two from Morocco, one from Eire, one from England, one from the Faeroes Islands) were examined. All nine viruses produced unique RNA electropherotypes but showed a 2 : 4 : 3 : 1 grouping of the ten double-stranded RNA segments. The virus-induced proteins were labelled with 35S-methionine in a Vero cell line. Seven of the viruses isolated from Ixodes uriae produced similar profiles of nine major polypeptides. The remaining two viruses, isolated from Ornithodoros maritimus from Morocco, produced profiles in which only five major viral proteins could be readily detected, four of which had similar molecular weights to proteins apparent in the other isolates.

Particle-size dependent effects in the Balb/c murine model of inhalational melioidosis.

Deposition of Burkholderia pseudomallei within either the lungs or nasal passages of the Balb/c murine model resulted in different infection kinetics. The infection resulting from the inhalation of B. pseudomallei within a 12 µm particle aerosol was prolonged compared to a 1 µm particle aerosol with a mean time-to-death (MTD) of 174.7 ± 14.9 h and 73.8 ± 11.3 h, respectively. Inhalation of B. pseudomallei within 1 µm or 12 µm particle aerosols resulted in a median lethal dose (MLD) of 4 and 12 cfu, respectively. The 12 µm particle inhalational infection was characterized by a marked involvement of the nasal mucosa and extension of bacterial colonization and inflammatory lesions from the olfactory epithelium through the olfactory nerves (or tracts) to the olfactory bulb (100%), culminating in abscessation of the brain (33%). Initial involvement of the upper respiratory tract lymphoid tissues (nasal-associated lymphoid tissue (NALT) and cervical lymph nodes) was observed in both the 1 and 12 µm particle inhalational infections (80-85%). Necrotising alveolitis and bronchiolitis were evident in both inhalational infections, however, lung pathology was greater after inhalation of the 1 µm particle aerosol with pronounced involvement of the mediastinal lymph node (50%). Terminal disease was characterized by bacteraemia in both inhalational infections with dissemination to the spleen, liver, kidneys, and thymus. Treatment with co-trimoxazole was more effective than treatment with doxycycline irrespective of the size of the particles inhaled. Doxycycline was more effective against the 12 µm particle inhalational infection as evidenced by increased time to death. However, both treatment regimes exhibited significant relapse when therapy was discontinued with massive enlargement and abscessation of the lungs, spleen, and cervical lymph nodes observed.

Kinetics of the immune response to the (F1+V) vaccine in models of bubonic and pneumonic plague.

Protection against aerosol challenge with > 300 MLD of Yersinia pestis was observed 7 days after a single immunisation of mice with the F1+V vaccine. At day 60, mice were protected against injected challenge (10(7)MLD) in a vaccine dose-related manner. Recall responses to rV in splenocytes ex vivo at day 98 correlated significantly (p<0.001) with the immunising dose-level of V antigen; no memory response or anti-V serum IgG was detected in killed whole cell vaccine (KWCV) recipients. This may explain the susceptibility of KWCV recipients to aerosol challenge and the enhanced protection conferred by the F1+V sub-unit vaccine, particularly since the anti-F1 responses induced by either vaccine were similarly IgG1-polarised.

Cell junctions in the developing compound eye of the desert locust Schistocerca gregaria.

Intercellular junctions in the developing retina of the locust Schistocerca gregaria have been examined by electron microscopy. Different types of junction appear in a well defined sequence during development. Five stages of ommatidial development are described. Close junctions and punctate junctions are present throughout development. Gap junctions appear transiently amongst the undifferentiated cells, before clearly defined preommatidia can be distinguished. The subsequent disappearance of gap junctions may be correlated with cell determination. Lanthanum studies confirm these findings. The later sequential appearance of adhesive junction types is described. These include septate desmosomes and two types of desmosomes. In the fully differentiated ommatidium only two types of junction remain, these are: desmosomes and rhabdomeric junctions.

Isolation of an English uukuvirus (family Bunyaviridae).

A virus of the Uukuniemi serogroup was isolated from various organs of a moribund kittiwake (Rissa tridactyla) and from ticks (Ixodes uriae) that were feeding on the bird. The kittiwake was found on Marsden beach, north-east England. This is the first virus in the family Bunyaviridae to have been isolated in England and only the second English arthropod-borne virus after louping ill virus, family Togaviridae (Smith & Varma, 1981). The possibility of infection of humans by uukuviruses is discussed.

Investigation of virus-like particles in Leishmania hertigi.

The promastigote forms of an isolate of Leishmania hertigi contain large numbers of virus-like particles (VLPs) in paracrystalline arrays. The VLPs are not present in the amastigote form and it was not possible to purify them from large amounts of the promastigotes.

Cell lineage and cell determination in the developing compound eye of the cockroach, Periplaneta americana.

By grafting between eye colour mutants of the cockroach Periplaneta americana we have investigated (i) the hypothesis that cells within an ommatidium of the fused rhabdom type are clonally derived from a single mother cell and (ii) we have tested the suggestion that cells from non-prospective eye epidermis can form ommatidia when grafted next to eye tissue. Mosaic eyes containing cells of the two genotypes contain ommatidia with unpredictable combinations of the two sorts of cells at the host/graft border. This finding is inconsistent with the first hypothesis. Using grafts of prothoracic epidermis and head epidermis from non-prospective eye regions we have shown that only cells from the prospective eye region can form ommatidia. Possible ways that eye cells could be determined are discussed in the light of these findings.

Has psychological distress among UK South Asians been under-estimated? A comparison of three measures in the west of Scotland population.

OBJECTIVES: Previous work has shown low levels of psychological distress among UK South Asians, but some argue that the distress is under-reported. The present paper assesses distress on one clinically validated measure (the 12-item General Health Questionnaire), a psychosomatic measure and a self-report measure. METHODS: Interviews of 159 South Asians in Glasgow aged 30-40 years, mean age 35 years and 319 from the general population, all aged 35 years. RESULTS: The three distress measures were moderately correlated and at the thresholds chosen there was no hierarchy of severity between them. Distress on the GHQ12 was at similar levels for all the social groups assessed, but distress on the psychosomatic measure and self-assessment was higher for women, Muslims and limited English speakers. CONCLUSIONS: Clinical measures may have under-estimated distress in several South Asian groups. The results may be due to a preference for a particular language of emotion in the affected groups or to a higher frequency of stressful situations which provoke distinctive reactions.

The proteins expressed in vivo and in vitro by an orbivirus of the Kemerovo serogroup isolated from Ixodes uriae ticks from St. Abb's Head, Scotland.

The genome of FT363 virus, a member of the Kemerovo serogroup of orbiviruses, was shown to consist of 10 segments of dsRNA. Examination of the intracellular proteins expressed by this virus in Vero cells showed the presence of 9 major and several minor products. Similar results were obtained by translation of the virus dsRNA in a rabbit reticulocyte lysate. Comparison of in vivo and in vitro products by immunoprecipitation using polyclonal FT363 ascitic fluid showed a difference in the numbers of polypeptides precipitated. The significance of these results is discussed.

A reovirus from the bedbug, Cimex lectularius.

Large numbers of virus particles were identified by electron microscopy in the epithelial cells of the ventriculus of the bedbug, Cimex lectularius. The morphology of the virus particles and the presence of a segmented double-stranded RNA genome imply that this isolate should be included in the Reoviridae.

The efficacy of ciprofloxacin and doxycycline against experimental tularaemia.

The efficacy of doxycycline and ciprofloxacin against an experimental tularaemia infection was assessed by comparing the median lethal dose (MLD) of Francisella tularensis Schu4 biotype A strain given intraperitoneally to antibiotic-treated and untreated mice. In untreated Porton outbred mice this was <1 cfu. Ciprofloxacin and doxycycline given at 40 mg/kg bd, initiated 48 h before infection and continued for 5 days after infection, afforded protection against intraperitoneal challenges of 3.7 x 10(6) cfu and 6.0 x 10(6) cfu, respectively. Protection was reduced when both antibiotics were given over a similar period at a lower dose regimen (20 mg/kg bd) to 8.8 x 10(5) cfu and 3.5 x 10(2) cfu, respectively. The greater reduction in protection offered by doxycycline was a reflection of the higher in-vitro MIC. Protection also decreased when the antibiotics were initiated 24 h after challenge. The MLD was 3.2 x 10(5) cfu and 1.6 x 10(6) cfu for ciprofloxacin and doxycycline respectively given at 40 mg/kg bd and was reduced further using the lower dose regimen. Overall, 90% of the deaths occurred following the withdrawal of antibiotic, irrespective of the antibiotic dose or type. It was possible to prevent this relapse by extending the antibiotic administration to 10 days after challenge. Ciprofloxacin and doxycycline may be useful for treating tularaemia, although the possibility of relapse should be considered.