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Sanfilippo syndrome results from inherited mutations in genes encoding lysosomal enzymes that catabolise heparan sulfate (HS), leading to early childhood‐onset neurodegeneration. This study explores the therapeutic potential of photobiomodulation (PBM), which is neuroprotective and anti‐inflammatory in several neurodegenerative diseases; it is also safe and PBM devices are readily available. We investigated the effects of 10–14 days transcranial PBM at 670 nm (2 or 4 J/cm2/day) or 904 nm (4 J/cm2/day) in young (3 weeks) and older (15 weeks) Sanfilippo or mucopolysaccharidosis type IIIA (MPS IIIA) mice. Although we found no PBM‐induced changes in HS accumulation, astrocyte activation, CD206 (an anti‐inflammatory marker) and BDNF expression in the brains of Sanfilippo mice, there was a near‐normalisation of microglial activation in older MPS IIIA mice by 904 nm PBM, with decreased IBA1 expression and a return of their morphology towards a resting state. Immune cell immunophenotyping of peripheral blood with mass cytometry revealed increased pro‐inflammatory signalling through pSTAT1 and p‐p38 in NK and T cells in young but not older MPS IIIA mice (5 weeks of age), and expansion of NK, B and CD8+ T cells in older affected mice (17 weeks of age), highlighting the importance of innate and adaptive lymphocytes in Sanfilippo syndrome. Notably, 670 and 904 nm PBM both reversed the Sanfilippo‐induced increase in pSTAT1 and p‐p38 expression in multiple leukocyte populations in young mice, while 904 nm reversed the increase in NK cells in older mice. In conclusion, this is the first study to demonstrate the beneficial effects of PBM in Sanfilippo mice. The distinct reduction in microglial activation and NK cell pro‐inflammatory signalling and number suggests PBM may alleviate neuroinflammation and lymphocyte activation, encouraging further investigation of PBM as a standalone, or complementary therapy in Sanfilippo syndrome. [ABSTRACT FROM AUTHOR]

Background: Sanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is an inherited paediatric‐onset neurodegenerative disorder caused by the lysosomal deficiency of sulphamidase with subsequent accumulation of heparan sulphate. The pathological mechanisms responsible for clinical disease are unknown; however, intraneuronal accumulation of aggregation‐prone proteins such as α‐synuclein, phosphorylated tau and amyloid precursor protein suggests inefficient intracellular trafficking and lysosomal degradation. Aim: To investigate the contribution the accumulating α‐synuclein plays in early symptom emergence that is, impaired cognition, reduced anxiety and motor deficits, first detectable between 3–5 months of age. Methods: We have crossed congenic MPS IIIA mice with α‐synuclein‐deficient (Sncatm1Rosl/J) mice and evaluated phenotype and brain disease lesions. Results: In a battery of behavioural tests performed on mice aged 12–22 weeks, we were unable to differentiate α‐synuclein‐deficient MPS IIIA mice from those with one or both copies of the α‐synuclein gene; all three affected genotypes were significantly impaired in test performance when compared to wild‐type littermates. Histological studies revealed that the rate, location and nature of deposition of other proteinaceous lesions, the disruption to endolysosomal protein expression and the inflammatory response seen in the brain of α‐synuclein‐deficient MPS IIIA mice reflected that seen in MPS IIIA mice homo‐ or heterozygous for α‐synuclein. Conclusion: Deletion and/or deficiency of α‐synuclein does not influence clinical and neuropathological disease progression in murine MPS IIIA, demonstrating that in and of itself, this protein does not initiate the cognitive and motor symptoms that occur in the first 5 months of life in MPS IIIA mice. [ABSTRACT FROM AUTHOR]

R. D. Jolly, N. R. Marshall, M. R. Perrott, K. E. Dittmer, K. M. Hemsley and H. Beard (2011) Neuropathology and Applied Neurobiology 414-422 ? The research concerns enzyme replacement therapy in lysosomal storage diseases with central nervous system involvement. The principle aim was to understand the routes of entry of enzyme into the brain when delivered directly into the cerebrospinal fluid (CSF) via the cerebellomedullary cistern. Pathways for absorption of replacement enzyme were investigated in dogs with mucopolysaccharidosis IIIA (MPSIIIA) following intracisternal injections of human recombinant N?sulphoglucosamine sulphohydrolase (rhSGSH, EC3.10.1.1) by light and confocal microscopy using chromogenic and fluorescent immune probes. Enzyme entered the brain superficially by penetration of the pia/glia limitans interface, but the main route was perivascular along large veins, arteries and arterioles extending onto capillaries. It further dispersed into surrounding neuropil to be taken up by neurones, macrophages, astrocytes and oligodendroglia. Enzyme also entered the lateral ventricles adjacent to the choroid plexus, probably also by the tela choroidea and medullary velum, with further spread throughout the ventricular system and spinal canal. There was secondary spread back across the ependyma into nervous tissue of brain and spinal cord. Enzyme mainly enters the brain by a perivascular route involving both arteries and veins with subsequent spread within the neuropil from where it is taken up by a proportion of neurones and other cells. Penetration of enzyme through the pia/glia limitans is minor and superficial. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type IIIA (MPS IIIA) is an inherited neurodegenerative lysosomal storage disorder characterized by progressive loss of learned skills, sleep disturbance and behavioural problems. Reduced activity of sulphamidase (N-sulphoglucosamine sulphohydrolase; SGSH; EC 3.10.1.1) results in intracellular accumulation of heparan sulphate (HS), with the brain as the primary site of pathology. We have used a naturally occurring MPS IIIA mouse model to determine the effectiveness of SGSH replacement through the cerebrospinal fluid (CSF) to decrease neuropathology. This is a potential therapeutic option for patients with this disorder. Mice received intra-CSF injections of recombinant human SGSH (30, 50 or 70 μg) fortnightly from 6 to 18 weeks of age, and the cumulative effect on neuropathology was examined and quantified. Anti-SGSH antibodies detected in plasma at euthanasia did not appear to impact upon the health of the mice or the experimental outcome, with significant but region-dependent and dose-dependent reductions in an HS-derived oligosaccharide observed in the brain and spinal cord using tandem mass spectrometry. SGSH infusion reduced the number of storage inclusions observed in the brain when visualized using electron microscopy, and this correlated with a significant decrease in the immunohistochemical staining of a lysosomal membrane marker. Reduced numbers of activated isolectin B4-positive microglia and glial fibrillary acidic protein-positive astrocytes were seen in many, but not all, brain regions. Significant reductions in the number of ubiquitin-positive intracellular inclusions were also observed. These outcomes show the effectiveness of this method of enzyme delivery in reducing the spectrum of neuropathological changes in murine MPS IIIA brain. [ABSTRACT FROM AUTHOR]

Bone quality consists of a number of factors including the amount of bone, bone architecture and the degree of bone mineralization. Quantitative backscattered electron imaging is a technique that allows the degree of mineralization of trabeculae to be assessed and in this study is applied to inter-trochanteric bone biopsies of the proximal femur. Biopsy cores from 22 controls, nine individuals with acute and chronic medical conditions and 22 fragility fracture individuals undergoing total hip replacement were processed into methyl methacrylate, polished and analysed in a Philips XL20 scanning electron microscope. A mean and distribution of weight percent calcium were determined for each individual, and for the control, medically ill and fragility fracture groups. All individuals and groups of individuals showed normal distributions of percent calcium with both the ill and fragility fracture groups being under mineralized relative to the control group. The shape and position of the mineralization distributions suggest that the fragility group resulted from increased bone turnover with a slow progression to under mineralization. In contrast, the ill group appears to have had a more rapid change in the mineralization dynamic. Clear distinctions between the control, fragility fracture and medically ill groups could be seen when the mineralization data were plotted as a scatter graph against age. Graphing the data in this way showed an age-related increase in the degree of mineralization in control individuals with the under-mineralized, fragility fracture group scattered below this normal trend. The medically ill group was similarly less mineralized which highlighted the degree to which medical conditions and treatments can alter bone matrix mineralization. [ABSTRACT FROM AUTHOR]

Relocation stress is a phenomenon in which physical and psychological disturbances are experienced following transfer from one environment to another [Carpenito LJ. (2000). Nursing Diagnosis. Application to Clinical Practice, 8th edn]. The purpose of this review was to identify whether a period of intermediate care minimizes the problems associated with relocation stress after discharge from the intensive care unit (ICU) and before transfer to the ward. Methods of retrieving the literature involved identifying key terms, utilizing a range of databases and applying specific criteria in order to delineate the boundaries of the search. Using electronic and manual search methods, 11 studies were selected, both primary and secondary research. Following tabulation and critiquing of the studies, the findings of the review suggest that the factors which contribute towards relocation stress are the loss of one-to-one nursing, a reduction of visible monitoring equipment, lack of continuity of care and inadequate preparation of the patient for the transfer. The evidence also indicates that in order to minimize these factors, early planning and preparation of the patient for transfer are required, incorporating strategies of gradual reduction in nursing attention and monitoring equipment and the provision of information. Although the benefits of intermediate care are established as being advanced monitoring, appropriate nurse-to-patient ratio, heightened demonstration of expert knowledge and skill, there is no sufficient evidence to indicate a period of intermediate care that can ease the transition from the ICU to the ward. [ABSTRACT FROM AUTHOR]

The many dimensions of the field of reproduction (clinical, scientific, social, ethical, legal) must be addressed by those with editorial responsibility for the major journals in the field. As the editorial team of the leading reproductive journal Human Reproduction, we have evolved processes that attempt to ensure a transparent but robust approach to complexities whose impact varies across international boundaries. [ABSTRACT FROM AUTHOR]

Background: Sanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is a childhood dementia caused by inherited mutations in the sulfamidase gene. At present, there is no treatment and children with classical disease generally die in their late teens. Intravenous or intra-cerebrospinal fluid (CSF) injection of AAV9-gene replacement is being examined in human clinical trials; evaluation of the impact on brain disease is an intense focus; however, MPS IIIA patients also experience profound, progressive photoreceptor loss, leading to night blindness., Aim: To compare the relative efficacy of the two therapeutic approaches on retinal degeneration in MPS IIIA mice., Methods: Neonatal mice received i.v. or intra-CSF AAV9-sulfamidase or vehicle and after 20 weeks, biochemical and histological evaluation of neuroretina integrity was carried out., Results: Both treatments improved central retinal thickness; however, in peripheral retina, outer nuclear layer thickness and photoreceptor cell length were only significantly improved by i.v. gene replacement. Further, normalization of endo-lysosomal compartment size and microglial morphology was only observed following intravenous gene delivery., Conclusions: Confirmatory studies are needed in adult mice; however, these data indicate that i.v. AAV9-sulfamidase infusion leads to superior outcomes in neuroretina, and cerebrospinal fluid-delivered AAV9 may need to be supplemented with another therapeutic approach for optimal patient quality of life., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Lysosomal storage disorders are a large group of inherited metabolic conditions resulting from the deficiency of proteins involved in lysosomal catabolism, with resulting accumulation of substrates inside the cell. Two-thirds of these disorders are associated with a neurodegenerative phenotype and, although few therapeutic options are available to patients at present, clinical trials of several treatments including lysosomal enzyme replacement are underway. Although animal studies indicate the efficacy of presymptomatic treatment, it is largely unknown whether symptomatic disease-related pathology and functional deficits are reversible. To begin to address this, we used a naturally-occurring mouse model with Sanfilippo syndrome (mucopolysaccharidosis type IIIA) to examine the effectiveness of intracisternal cerebrospinal fluid enzyme replacement in early, mid- and symptomatic disease stage mice. We observed a disease-stage-dependent treatment effect, with the most significant reductions in primary and secondary substrate accumulation, astrogliosis and protein aggregate accumulation seen in mucopolysaccharidosis type IIIA mice treated very early in the disease course. Affected mice treated at a symptomatic age exhibited little change in these neuropathological markers in the time-frame of the study. Microgliosis was refractory to treatment regardless of the age at which treatment was instigated. Although longer-term studies are warranted, these findings indicate the importance of early intervention in this condition.

Mucopolysaccharidosis type IIIA is a neurodegenerative lysosomal storage disorder characterized by progressive loss of learned skills, sleep disturbance and behavioural problems. Absent or greatly reduced activity of sulphamidase, a lysosomal protein, results in intracellular accumulation of heparan sulphate. Subsequent neuroinflammation and neurodegeneration typify this and many other lysosomal storage disorders. We propose that intra-cerebrospinal fluid protein delivery represents a potential therapeutic avenue for treatment of this and other neurodegenerative conditions; however, technical restraints restrict examination of its use prior to adulthood in mice. We have used a naturally-occurring Mucopolysaccharidosis type IIIA mouse model to determine the effectiveness of combining intravenous protein replacement (1 mg/kg) from birth to 6 weeks of age with intra-cerebrospinal fluid sulphamidase delivery (100 microg, fortnightly from 6 weeks) on behaviour, the level of heparan sulphate-oligosaccharide storage and other neuropathology. Mice receiving combination treatment exhibited similar clinical improvement and reduction in heparan sulphate storage to those only receiving intra-cerebrospinal fluid enzyme. Reductions in micro- and astrogliosis and delayed development of ubiquitin-positive lesions were seen in both groups. A third group of intravenous-only treated mice did not exhibit clinical or neuropathological improvements. Intra-cerebrospinal fluid injection of sulphamidase effectively, but dose-dependently, treats neurological pathology in Mucopolysaccharidosis type IIIA, even when treatment begins in mice with established disease.