Musical hallucinations, secondary delusions, and lack of insight: results from a cohort study.

INTRODUCTION: Although musical hallucinations do not tend to be accompanied by delusions, occasionally patients persistently accuse others of being responsible for causing the music they perceive, sometimes with severe social consequences such as frequently calling the police or moving house. In this study we seek to broaden our understanding of this rare type of musical hallucination that comes with secondary delusions and lack of insight, and to explore associations, underlying mechanisms, and treatment possibilities. METHODS: The present study is part of a cohort study on musical hallucinations carried out in the Netherlands from 2010 through 2023. Participants underwent testing with the aid of the MuHa Questionnaire, Launay-Slade Hallucinations Scale (LSHS), Schizotypal Personality Questionnaire (SPQ), Hamilton Depression Rating Scale (HDRS), and Mini Mental State Examination (MMSE). Additionally, they underwent a brain MRI, electroencephalogram, and audiological testing. RESULTS: Five patients out of a group of N = 81 (6%) lacked insight and presented with secondary delusions regarding the perceived music. They were all female, of advanced age, and hearing-impaired, and were diagnosed with cognitive impairment. In three patients (60%), risperidone was started. This had a positive effect on the hallucinations and secondary delusions. CONCLUSION: The pathophysiological process underlying musical hallucinations is multifactorial in nature. We consider cognitive impairment the most likely contributing factor of the secondary delusions and lack of insight encountered in our patients, and antipsychotics the most beneficial treatment. On the basis of these small numbers, no definite conclusions can be drawn, so further research is needed to elucidate the underlying mechanisms and to develop evidence-based treatment methods for people experiencing this rare and debilitating combination of symptoms. Since the black box warning of risperidone cautions against the use of this drug in elderly persons with dementia, a proper comparison with the efficacy and safety of other antipsychotics for this group is paramount

A Recombinant Vaccine Effectively Induces C5a-Specific Neutralizing Antibodies and Prevents Arthritis

OBJECTIVES: To develop and validate a recombinant vaccine to attenuate inflammation in arthritis by sustained neutralization of the anaphylatoxin C5a. METHODS: We constructed and expressed fusion protein of C5a and maltose binding protein. Efficacy of specific C5a neutralization was tested using the fusion protein as vaccine in three different arthritis mouse models: collagen induced arthritis (CIA), chronic relapsing CIA and collagen antibody induced arthritis (CAIA). Levels of anti-C5a antibodies and anti-collagen type II were measured by ELISA. C5a neutralization assay was done using a rat basophilic leukemia cell-line transfected with the human C5aR. Complement activity was determined using a hemolytic assay and joint morphology was assessed by histology. RESULTS: Vaccination of mice with MBP-C5a led to significant reduction of arthritis incidence and severity but not anti-collagen antibody synthesis. Histology of the MBP-C5a and control (MBP or PBS) vaccinated mice paws confirmed the vaccination effect. Sera from the vaccinated mice developed C5a-specific neutralizing antibodies, however C5 activation and formation of the membrane attack complex by C5b were not significantly altered. CONCLUSIONS: Exploitation of host immune response to generate sustained C5a neutralizing antibodies without significantly compromising C5/C5b activity is a useful strategy for developing an effective vaccine for antibody mediated and C5a dependent inflammatory diseases. Further developing of such a therapeutic vaccine would be more optimal and cost effective to attenuate inflammation without affecting host immunity

Age-dependent alteration of TGF-β signalling in osteoarthritis

Osteoarthritis (OA) is a disease of articular cartilage, with aging as the main risk factor. In OA, changes in chondrocytes lead to the autolytic destruction of cartilage. Transforming growth factor-β has recently been demonstrated to signal not only via activin receptor-like kinase 5 (ALK5)-induced Smad2/3 phosphorylation, but also via ALK1-induced Smad1/5/8 phosphorylation in articular cartilage. In aging cartilage and experimental OA, the ratio ALK1/ALK5 has been found to be increased, and the expression of ALK1 is correlated with matrix metalloproteinase-13 expression. The age-dependent shift towards Smad1/5/8 signalling might trigger the differentiation of articular chondrocytes with an autolytic phenotype

Cloning, expression and nuclear localization of human NPM3, a member of the nucleophosmin/nucleoplasmin family of nuclear chaperones

BACKGROUND: Studies suggest that the related proteins nucleoplasmin and nucleophosmin (also called B23, NO38 or numatrin) are nuclear chaperones that mediate the assembly of nucleosomes and ribosomes, respectively, and that these activities are accomplished through the binding of basic proteins via their acidic domains. Recently discovered and less well characterized members of this family of acidic phosphoproteins include mouse nucleophosmin/nucleoplasmin 3 (Npm3) and Xenopus NO29. Here we report the cloning and initial characterization of the human ortholog of Npm3. RESULTS: Human genomic and cDNA clones of NPM3 were isolated and sequenced. NPM3 lies 5.5 kb upstream of FGF8 and thus maps to chromosome 10q24-26. In addition to amino acid similarities, NPM3 shares many physical characteristics with the nucleophosmin/nucleoplasmin family, including an acidic domain, multiple potential phosphorylation sites and a putative nuclear localization signal. Comparative analyses of 14 members of this family from various metazoans suggest that Xenopus NO29 is a candidate ortholog of human and mouse NPM3, and they further group both proteins closer with the nucleoplasmins than with the nucleophosmins. Northern blot analysis revealed that NPM3 was strongly expressed in all 16 human tissues examined, with especially robust expression in pancreas and testis; lung displayed the lowest level of expression. An analysis of subcellular fractions of NIH3T3 cells expressing epitope-tagged NPM3 revealed that NPM3 protein was localized solely in the nucleus. CONCLUSIONS: Human NPM3 is an abundant and widely expressed protein with primarily nuclear localization. These biological activities, together with its physical relationship to the chaparones nucleoplasmin and nucleophosmin, are consistent with the proposed function of NPM3 as a molecular chaperone functioning in the nucleus

Vaccination with Plasmodium knowlesi AMA1 Formulated in the Novel Adjuvant Co-Vaccine HT™ Protects against Blood-Stage Challenge in Rhesus Macaques

Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a leading blood stage vaccine candidate. Plasmodium knowlesi AMA1 (PkAMA1) was produced and purified using similar methodology as for clinical grade PfAMA1 yielding a pure, conformational intact protein. Combined with the adjuvant CoVaccine HT™, PkAMA1 was found to be highly immunogenic in rabbits and the efficacy of the PkAMA1 was subsequently tested in a rhesus macaque blood-stage challenge model. Six rhesus monkeys were vaccinated with PkAMA1 and a control group of 6 were vaccinated with PfAMA1. A total of 50 µg AMA1 was administered intramuscularly three times at 4 week intervals. One of six rhesus monkeys vaccinated with PkAMA1 was able to control parasitaemia, upon blood stage challenge with P. knowlesi H-strain. Four out of the remaining five showed a delay in parasite onset that correlated with functional antibody titres. In the PfAMA1 vaccinated control group, five out of six animals had to be treated with antimalarials 8 days after challenge; one animal did not become patent during the challenge period. Following a rest period, animals were boosted and challenged again. Four of the six rhesus monkeys vaccinated with PkAMA1 were able to control the parasitaemia, one had a delayed onset of parasitaemia and one animal was not protected, while all control animals required treatment. To confirm that the control of parasitaemia was AMA1-related, animals were allowed to recover, boosted and re-challenged with P. knowlesi Nuri strain. All control animals had to be treated with antimalarials by day 8, while five out of six PkAMA1 vaccinated animals were able to control parasitaemia. This study shows that: i) Yeast-expressed PkAMA1 can protect against blood stage challenge; ii) Functional antibody levels as measured by GIA correlated inversely with the day of onset and iii) GIA IC50 values correlated with estimated in vivo growth rates

HIV-1 Matrix Dependent Membrane Targeting Is Regulated by Gag mRNA Trafficking

Retroviral Gag polyproteins are necessary and sufficient for virus budding. Productive HIV-1 Gag assembly takes place at the plasma membrane. However, little is known about the mechanisms by which thousands of Gag molecules are targeted to the plasma membrane. Using a bimolecular fluorescence complementation (BiFC) assay, we recently reported that the cellular sites and efficiency of HIV-1 Gag assembly depend on the precise pathway of Gag mRNA export from the nucleus, known to be mediated by Rev. Here we describe an assembly deficiency in human cells for HIV Gag whose expression depends on hepatitis B virus (HBV) post-transcriptional regulatory element (PRE) mediated-mRNA nuclear export. PRE-dependent HIV Gag expressed well in human cells, but assembled with slower kinetics, accumulated intracellularly, and failed to associate with a lipid raft compartment where the wild-type Rev-dependent HIV-1 Gag efficiently assembles. Surprisingly, assembly and budding of PRE-dependent HIV Gag in human cells could be rescued in trans by co-expression of Rev-dependent Gag that provides correct membrane targeting signals, or in cis by replacing HIV matrix (MA) with other membrane targeting domains. Taken together, our results demonstrate deficient membrane targeting of PRE-dependent HIV-1 Gag and suggest that HIV MA function is regulated by the trafficking pathway of the encoding mRNA

Treatment of osteochondral lesions of the talus: a systematic review

The aim of this study was to summarize all eligible studies to compare the effectiveness of treatment strategies for osteochondral defects (OCD) of the talus. Electronic databases from January 1966 to December 2006 were systematically screened. The proportion of the patient population treated successfully was noted, and percentages were calculated. For each treatment strategy, study size weighted success rates were calculated. Fifty-two studies described the results of 65 treatment groups of treatment strategies for OCD of the talus. One randomized clinical trial was identified. Seven studies described the results of non-operative treatment, 4 of excision, 13 of excision and curettage, 18 of excision, curettage and bone marrow stimulation (BMS), 4 of an autogenous bone graft, 2 of transmalleolar drilling (TMD), 9 of osteochondral transplantation (OATS), 4 of autologous chondrocyte implantation (ACI), 3 of retrograde drilling and 1 of fixation. OATS, BMS and ACI scored success rates of 87, 85 and 76%, respectively. Retrograde drilling and fixation scored 88 and 89%, respectively. Together with the newer techniques OATS and ACI, BMS was identified as an effective treatment strategy for OCD of the talus. Because of the relatively high cost of ACI and the knee morbidity seen in OATS, we conclude that BMS is the treatment of choice for primary osteochondral talar lesions. However, due to great diversity in the articles and variability in treatment results, no definitive conclusions can be drawn. Further sufficiently powered, randomized clinical trials with uniform methodology and validated outcome measures should be initiated to compare the outcome of surgical strategies for OCD of the talus

A Dutch guideline for the treatment of scoliosis in neuromuscular disorders

<p>Abstract</p> <p>Background</p> <p>Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.</p> <p>Methods</p> <p>The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.</p> <p>Results</p> <p>For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.</p> <p>Conclusion</p> <p>In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders.</p

Scabies Mite Peritrophins Are Potential Targets of Human Host Innate Immunity

The gut of most invertebrates is lined by a protective layer of chitin and glycoproteins, often designated as a peritrophic matrix. Previous research suggests that it forms a barrier that may protect the midgut epithelium from abrasive food particles and pathogens. Parasitic invertebrates ingesting vertebrate plasma have evolved additional strategies to protect themselves from hazardous host molecules consumed during feeding. An important part of the immediate defense in vertebrate plasma is complement-mediated killing. The Complement system is a complex network of more than 35 proteins present in human plasma that results in killing of foreign cells including the gut epithelial cells of a feeding parasite. Recently we found that scabies mites, who feed on skin containing plasma, produce several proteins that inhibit human complement within the mite gut. The mites excrete these molecules into the upper epidermis where they presumably also inhibit complement activity. Mite gut antigens that initially trigger the complement cascade have not been identified previously. Obvious possible targets of complement attack within the mite gut could be peritrophins. Our study describes the first peritrophin identified in scabies mites and indicates a possible role in complement activation