A rare partnership: patient community and industry collaboration to shape the impact of real-world evidence on the rare disease ecosystem.

People with rare lysosomal storage diseases face challenges in their care that arise from disease complexity and heterogeneity, compounded by many healthcare professionals being unfamiliar with these diseases. These challenges can result in long diagnostic journeys and inadequate care. Over 30 years ago, the Rare Disease Registries for Gaucher, Fabry, Mucopolysaccharidosis type I and Pompe diseases were established to address knowledge gaps in disease natural history, clinical manifestations of disease and treatment outcomes. Evidence generated from the real-world data collected in these registries supports multiple stakeholders, including patients, healthcare providers, drug developers, researchers and regulators. To maximise the impact of real-world evidence from these registries, engagement and collaboration with the patient communities is essential. To this end, the Rare Disease Registries Patient Council was established in 2019 as a partnership between the Rare Disease Registries and global and local patient advocacy groups to share perspectives on how registry data are used and disseminated. The Patient Council has resulted in a number of patient initiatives including patient representation at Rare Disease Registries advisory boards; development of plain language summaries of registry publications to increase availability of real-world evidence to patient communities; and implementation of digital innovations such as electronic patient-reported outcomes, and patient-facing registry reports and electronic consent (in development), all to enhance patient engagement. The Patient Council is building on the foundations of industry-patient advocacy group collaboration to fully integrate patient communities in decision-making and co-create solutions for the rare disease community.

Association between atopy and variants of the beta subunit of the high-affinity immunoglobulin E receptor.

The beta-subunit of the high-affinity IgE receptor (Fc epsilon RI-beta) on chromosome 11 is maternally linked to atopy, the state of enhanced IgE responsiveness underlying allergic asthma and rhinitis. We have identified a common variant of Fc epsilon RI-beta, lle181Leu within the 4th transmembrane domain. Leu181 shows significant association with positive IgE responses in a random patient sample. Amongst 60 unrelated nuclear families with allergic asthmatic probands, Leu181 is identified in 10 (17%), is maternally inherited in each, and shows a strong association with atopy. Our data indicate that Fc epsilon RI-beta, subject to maternal modification, may be the atopy-causing locus on chromosome 11q.

The inverse association between tuberculin responses and atopic disorder.

Human immune responses are heterogeneous and may involve antagonism between T helper (TH) lymphocyte subsets and their cytokines. Atopy is characterized by immediate immunoglobulin E (IgE)-mediated hypersensitivity to agents such as dust mites and pollen, and it underlies the increasingly prevalent disorder asthma. Among Japanese schoolchildren, there was a strong inverse association between delayed hypersensitivity to Mycobacterium tuberculosis and atopy. Positive tuberculin responses predicted a lower incidence of asthma, lower serum IgE levels, and cytokine profiles biased toward TH1 type. Exposure and response to M. tuberculosis may, by modification of immune profiles, inhibit atopic disorder.

Immune and genetic aspects of asthma, allergy and parasitic worm infections: evolutionary links.

There are important parallels in the immunobiology of allergy and asthma, and of the human host's response to parasitic worms. Th-2 immune actions with 'weep and sweep' mucosal biology are common to both - pathological in the first and protective in the second. Common up-regulating genetic variants of Th-2 immunity, notably in IL13 and STAT6, predict increased risk of asthma and allergy, but diminished intensity of infection by Ascaris and Schistosoma. Endemic exposures of humans to parasitic worms may have been one evolutionary force selecting for genetic variants that promote asthma and allergy.

Mechanisms of enhanced prevalence of asthma and atopy in developed countries.

Atopy--a T helper 2 cell driven hypersensitivity to innocuous antigens (allergens) which causes most cases of asthma-- is of complex genetic and environmental origins. There is compelling epidemiological evidence for a rise in atopic disease in 'westernised' communities. The changing pattern of microbial exposure in early childhood is suggested to be the principal candidate mechanism for this rise.

Laryngeal Desiccation Challenge and Nebulized Isotonic Saline in Healthy Male Singers and Nonsingers: Effects on Acoustic, Aerodynamic, and Self-Perceived Effort and Dryness Measures.

OBJECTIVES: This study examined the effects of a laryngeal desiccation challenge and nebulized isotonic saline on voice production in young, healthy male singers and nonsingers. STUDY DESIGN: This is a prospective, double-blind, within-subjects experimental design. METHODS: Participants included 10 male university-trained singers and 10 age-matched nonsingers (mean age, 21.8 years; range, 18-26 years) who underwent a 30-minute oral breathing laryngeal desiccation challenge using medical grade dry air (<1% relative humidity) on two occasions in consecutive weeks. After the challenge, participants received either 3 mL or 9 mL of nebulized isotonic saline (0.9% Na+Cl-); order of administration was counterbalanced. Phonation threshold pressure (PTP), the cepstral spectral index of dysphonia (CSID) for sustained vowels and connected speech, and self-perceived vocal effort, mouth dryness, and throat dryness were measured at each recording (baseline, after challenge, and at 5, 35, and 65 minutes after treatment). RESULTS: Self-perceived effort and dryness measures increased (worsened) after desiccation challenge and decreased (improved) after nebulized treatment (P < 0.05). No consistent changes were observed for PTP or CSID over time. Overall, singers demonstrated significantly lower vocal effort and CSID as compared with nonsingers. CONCLUSIONS: Young, vocally healthy men may not experience physiologic changes in voice production associated with laryngeal desiccation and nebulized saline treatments; however, self-reported increases in vocal effort which are associated with dryness symptoms might improve with nebulized treatments. Future hydration research should consider age and sex variables.

Haloperidol for acute schizophrenic patients. An evaluation of three oral regimens.

The relative efficacy of three oral regimens of haloperidol was compared in a ten-day, double-blind study of 63 acutely ill schizophrenic patients newly admitted to the hospital. One group of patients received 20 mg of haloperidol on day 1, then increasing increments of 20 mg a day, reaching a maximum dosage of 100 mg daily on day 5. Another group received 10 mg of haloperidol on day 1, then increasing increments of 10 mg daily, reaching 100 mg daily on day 10. A third group of patients received a fixed dosage of 10 mg daily for ten days. Haloperidol was well tolerated by the patients; there were no serious adverse reactions. The data indicated that the regimens had similar therapeutic efficacy, suggesting that acutely ill schizophrenic patients respond to a wide range of doses of haloperidol but that onset of response and efficacy are not increased in most patients by providing a high initial loading dosage. Adequate, safe dosage must be determined in each case.

The effects of emotional expression on vibrato.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to investigate the effect of emotional expression on several acoustic measures of vibrato, including its rate, extent, and steadiness. We hypothesized that singing a passage with emotional content would influence these variables. STUDY DESIGN: This study used a within-subjects, repeated-measures design. Singer performance under different conditions was analyzed. METHODS: Ten graduate student singers (eight women, two men) completed a series of tasks including sustained sung vowels at several pitch and loudness levels, an assigned song that was judged to have relatively neutral emotion, and a personal selection that included passages of intense emotion. Vowel tokens were extracted from the recordings and averaged for each task. Dependent measures included the mean fundamental frequency (F0), mean intensity, frequency modulation (FM) rate, FM extent, and measures of FM rate and extent variability. RESULTS: The FM rate and extent were higher and the modulation variability was lower for the more emotional song than for the sustained vowels. Mean F0 and intensity were higher for the emotional song than for the neutral song. CONCLUSIONS: Singing an emotional passage influences acoustic features of vibrato when compared with isolated, sustained vowels. The wider dynamic and pitch ranges for emotional passages only partly explain vibrato differences between emotional and neutral singing.

A genetic map of chromosome 11q, including the atopy locus.

Atopy is a common and genetically heterogeneous syndrome predisposing to allergic asthma and rhinitis. A locus linked to the atopy phenotype has been shown to be present on chromosome 11q12-13. Linkage has only been seen in maternally derived alleles. We have constructed a genetic linkage map of the region, using 15 markers to span approximately 27 cM, and integrate previously published maps. Under a model of maternal inheritance, the atopy locus is placed within a 7-cM interval between D11S480 and D11S451. The interval contains the important candidate gene FCERIB.

Overview: efficacy and safety of the rapid neuroleptization method with injectable haloperidol.

The authors review the literature on the rapid neuroleptization (titration) method with I.M. haloperidol. Most of the approximately 650 predominantly schizophrenic and manic patients represented in the studies calmed down rapidly on medication, and some demonstrated an early reduction in core psychotic symptoms. The initial doses varied widely, ranging from 1 to 30 mg, with a maximum total daily dosage of 100 mg. The medication seemed to have been well tolerated in all cases, with no reported major complications. The authors conclude that the method shows definite merit with agitated and belligerent patients. However, they make a number of specific recommendations for further research to clearly establish the effectiveness and safety of this method of neuroleptic administration.

Amplification of mitochondrial ribosomal RNA sequences from Pneumocystis carinii DNA of rat and human origin.

Pneumocystis carinii specific DNA sequences have been cloned from the experimental rat model. The sequence of the gene coding for the large subunit of mitochondrial ribosomal RNA has been used to construct P. carinii specific oligonucleotide primers for the polymerase chain reaction. These oligonucleotides produced amplification of specific sequences from both P. carinii infected rat and human lung samplings, but none from a range of other organisms including potential pulmonary pathogens. Comparison of the sequence of amplified products from the infected rats and humans demonstrated limited but consistent differences between P. carinii from these two hosts and allowed for the construction of a human specific internal oligonucleotide. The application of the specific oligonucleotides for DNA amplification and subsequent Southern hybridisation affords extremely sensitive and specific detection of P. carinii in human samples, which may be applicable to both epidemiological research and clinical studies.

Cardiac abnormalities and skeletal muscle weakness in carriers of Duchenne and Becker muscular dystrophies and controls.

Cardiac abnormalities, cardiomyopathy and skeletal muscle weakness have been described in female carriers of the Xp21 (Duchenne and Becker) muscular dystrophies (J Neurol 1975;209(4):279-285; Br Med J 1969;2:418-420; J AmMed Assoc 1996;275(17):1335-1338; Neurology 1980;30(5):497-501; Neuromusc Disord 1999;9:347-351; Arch Neurol 1989;46:673-675). We have screened volunteers from our Xp21 genetics register and found the prevalence of previously unrecognized, clinically relevant, abnormalities in this group to be less than previously reported. We studied 91 women (56 carriers and 35 controls), aged between 18 and 69 years, from our local population known to the Oxford Regional Genetics Register. Our study included controls, with the investigators being blind to the subject's genetic status. The prevalence of previously unrecognised cardiac abnormalities on echocardiogram and ECG was 18% (10/56). Seven percent (4/56) of carriers had cardiomyopathy, defined by significant LV dilatation and decreased shortening fraction. In most cases, subjects with abnormal cardiac findings were asymptomatic. Echocardiography was more frequently abnormal than electrocardiography, but in many subjects the measurements of left ventricular dimensions were only just outside the normal ranges. The prevalence of skeletal muscle weakness was 12% (7/56). It was usually recognized by the individual, although not previously volunteered, but was mild and did not substantially affect activities of daily living.

Muscle X-inactivation patterns and dystrophin expression in Duchenne muscular dystrophy carriers.

Muscle pathology, dystrophin expression and X-inactivation patterns were studied in the muscle of five asymptomatic females heterozygous for deletions in the dystrophin gene (non-manifesting carriers) and five symptomatic carriers (manifesting carriers). Muscle from the non-manifesting carriers showed an increase in the population of centrally nucleated fibres (9.0 +/- 2.8%; controls, 1.4 +/- 0.3%), frequent fibers with abnormally interrupted dystrophin staining (38 +/- 5%), and, in sections from three individuals, small numbers of dystrophin-negative fibers (1-4%). The amount of dystrophin measured by immunoblotting was reduced to 64 +/- 5% (P < 0.001 n = 5) of normal. The pattern of X-inactivation in muscle DNA was non-biased (50: 50-60: 40) in all cases. In the manifesting carriers both highly biased (90: 10) and non-biased patterns of X-inactivation were found, but no consistent relationship was apparent between the patterns of X-inactivation and the proportions of dystrophin-negative fibers. We conclude from studies of the non-manifesting carriers that the proportion of residual dystrophin is similar to the relative activation in muscle of the X-chromosome carrying the wild-type allele. Extreme bias of X-inactivation can be associated with early clinical symptoms and severe pathology. However, as non-manifesting and some manifesting adult carriers had identical patterns of X-inactivation, abnormalities in the distribution of dystrophin, as well as overall levels of expression, may be important for the development of myopathic pathology.

Comparison of DNA amplification and immunofluorescence for detecting Pneumocystis carinii in patients receiving immunosuppressive therapy.

Two studies were performed to compare the sensitivity of DNA amplification with immunofluorescence for the detection of Pneumocystis carinii in asymptomatic normal and immunosuppressed subjects receiving no anti-Pneumocystis chemoprophylaxis. In the first study, immunofluorescence and silver stains were used to examine 12 induced sputa and 12 bronchoalveolar lavage specimens from 24 normal control subjects; induced sputa from 20 renal transplant recipients; and induced sputa from 11 patients with fibrosing alveolitis. All specimens were negative for P carinii using both stains, apart from one renal patient in whom 2 P carinii cysts were seen by immunofluorescence alone. In the second study, DNA amplification and immunofluorescence were used to examine induced sputa from 3 groups of 10 control, renal, and heart/lung transplant recipients. All 30 specimens were negative for P carinii by immunofluorescence. However, 3 renal and 2 heart/lung patients were positive for P carinii by DNA amplification alone. One of these patients developed P carinii pneumonia 6 weeks after sputum induction. DNA amplification is a more sensitive technique than immunofluorescence for detecting P carinii. P carinii colonization occurs in asymptomatic organ transplant recipients, but not in normal individuals.

Effect of electrical stimulation and high potassium concentrations on the effux of (14C) glycine from slices of spinal cord.

1. The effects of electrical stimulation and solutions containing a high concentration of potassium on the efflux of [(14)C] glycine from slices of rat spinal cord have been studied.2. Slices of cord were incubated with [(14)C] glycine which rapidly accumulated in the tissue. The slices were then superfused in a small chamber and the radioactivity released from the tissue was measured. After superfusion for 60 min, 98% of the radioactivity remaining in the tissue was present as unchanged glycine.3. The spontaneous efflux of [(14)C] glycine consisted of an initial rapid phase followed by a much slower release of [(14)C] glycine. After superfusion for 60 min, more than 65% of the radioactivity taken up during the incubation period was retained by the tissue.4. When the slices were depolarized by electrical stimulation or by solutions containing a high concentration of potassium (40 mM), a striking increase in the efflux of [(14)C] glycine was produced. This effect was not reduced by the absence of calcium ions in the superfusion medium.5. Electrical stimulation produced similar increases in the efflux of [(3)H] GABA and [(14)C] glutamate from slices of cord but had no significant effects on the efflux of [(3)H] alanine or [(14)C] urea.6. The results are consistent with the suggestion that glycine may be an inhibitory synaptic transmitter substance in the mammalian spinal cord.

Effect of centrally acting drugs on the uptake of gamma-aminobutyric acid (GABA) by slices of rat cerebral cortex.

1. The effects of centrally acting drugs on the uptake of (3)H-gamma-aminobutyric acid (GABA) by slices of rat cerebral cortex have been studied.2. Many centrally acting drugs at concentrations of 0.1-1.0 mM significantly inhibited the uptake of (3)H-GABA by cortical slices, but the only classes of drugs in which all members consistently produced inhibition of uptake were the phenothiazines, tricyclic antidepressants, and butyrophenones.3. The receptor blocking drugs; phentolamine, propranolol, thymoxamine, mepyramine, and diphenhydramine at concentrations of 0.5-1 mM also significantly reduced the uptake of (3)H-GABA. However, atropine, hexamethonium and (+)-tubocurarine had little effect on the uptake of (3)H-GABA by cortical slices.4. Centrally acting drugs, which did not significantly inhibit (3)H-GABA uptake, included barbiturates, local anaesthetics, hallucinogens, monoamine oxidase inhibitors, anticonvulsants, and convulsants (except picrotoxin).5. Chlorpromazine, prochlorperazine, L-2,4,diaminobutyric acid, desmethylimipramine, and iprindole inhibited the uptake of (3)H-GABA by 50% (IC50) at concentrations of 30-100 muM. The most potent inhibitor of (3)H-GABA uptake was p-chloromercuriphenylsulphonate (IC50 = 18 muM).6. With the exception of L-2,4,diaminobutyric acid, an outstanding characteristic of these drugs was their complete lack of specificity. Thus at the IC50 for GABA, p-chloromercuriphenylsulphonate, chlorpromazine, prochlorperazine, iprindole, desmethylimipramine, apomorphine and diphenylhydramine also inhibited the uptake of radioactive glycine, alanine, noradrenaline, and 5-hydroxytryptamine. The uptake of the latter two compounds was often inhibited to a greater extent than GABA, glycine and alanine.7. Kinetic analysis indicated that the inhibition of (3)H-GABA by p-chloromercuriphenylsulphonate, chlorpromazine, and desmethylimipramine was noncompetitive. L-2,4,Diaminobutyric acid reduced the uptake of (3)H-GABA by a ;mixed' type of inhibition.8. The present results do not support the suggestion that some centrally acting drugs may produce their effects by reducing the uptake of GABA in the brain after its release from inhibitory nerve terminals. Conceivably, the design of compounds which interfere effectively with the mechanisms of GABA operated synapses may lead to the introduction of whole new groups of centrally acting drugs.

Pulmonary infiltrates in immunocompromised patients: diagnosis by cytological examination of bronchoalveolar lavage fluid.

Thirty pulmonary infiltrates in 26 patients were investigated by bronchoalveolar lavage. Sixteen of the patients were on therapeutic immunosuppression for renal disease or transplant and 10 had leukaemia, lymphoma, or allied conditions. A rapid specific diagnosis was made in 21 (70%) episodes by cytological examination of the fluid and in 28 (93%) by a combination of cytology and microbiology. No complications from haemorrhage or pneumothorax ensued. Pneumonia due to Pneumocystis carinii was the most common diagnosis (27%), but opportunistic infections from cytomegalovirus, candida, aspergillus, zygomycetes, and acid fast bacilli were also identified by cytology. Two episodes were caused by occult pulmonary haemorrhage and five patients had malignant infiltration of the lung from leukaemia, myeloma, Hodgkin's disease, and lymphoplasmacytoid lymphoma. In two of these there was also evidence of infection. In seven cases with non-diagnostic cytology infections due to Staphylococcus aureus, Pseudomonas aeruginosa, pneumococcus, micrococcus, and Aspergillus fumigatus were identified on culture. In two patients (7%) no specific diagnosis was established by lavage: one had serological evidence of legionella infection and the second had P aeruginosa septicaemia. Twelve (75%) of the renal patients and six (60%) of those with leukaemia, lymphoma, and allied conditions recovered.

Granulomatous Pneumocystis carinii pneumonia: DNA amplification studies on bronchoscopic alveolar lavage samples.

Three HIV positive subjects presented with symptoms and radiographic changes suggestive of Pneumocystis carinii pneumonia. Methenamine silver staining of bronchoscopic alveolar lavage (BAL) fluid was negative (from one sample in one patient and two samples in the other two patients). Open lung biopsy was performed because of uncertain clinical progress and diagnosis; all three patients were found to have multiple pulmonary granulomata encasing numerous P carinii organisms. DNA amplification, using P carinii specific oligonucleotides, was performed on stored bronchoscopic BAL samples. P carinii specific amplification product was detected by ethidium bromide staining after electrophoretic separation on agarose gel in one case, and by the more sensitive technique of oligohybridisation in all three cases. In granulomatous P carinii pneumonia organisms are rarely identified in bronchoscopic alveolar lavage samples using histochemical staining, but are detectable by DNA amplification, although not at levels which can be readily distinguished from low, subclinical infection.

Acute herpes hepatitis in pregnancy.

A 36 year old primigravid woman presented with a "flu-like" illness and premature labour, followed by severe pneumonitis and hepatitis in the late second trimester of pregnancy. Progressive deterioration obliged an elective delivery of twins, stillborn at 25 weeks of gestation. Herpes virus isolated from one placenta, but not from any fetal tissue, was the only indication of a systemic herpes simplex infection in which there were no mucocutaneous lesions seen before or during the illness. There was no history of herpes simplex infection and antibody studies were not helpful initially for a diagnosis that was confirmed in retrospect. Double staining for viral DNA and antigen showed that the virus was present in host monocytes.