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Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, Htt(Q175/+), and from wild-type controls. We used 14- to 15-month-old male mice, a time point at which multiple behavioral, neuroanatomical, and neurophysiological changes are present but at which there is no known cell death. Thousands of differentially expressed genes (DEGs) were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell type-specific transcriptional networks revealed a striking pattern of bidirectional dysregulation for many cell type-specific genes. Typically, these genes were repressed in their primary cell type, yet de-repressed in other striatal cell types. Integration with existing epigenomic and transcriptomic data suggest that partial loss-of-function of the polycomb repressive complex 2 (PRC2) may underlie many of these transcriptional changes, leading to deficits in the maintenance of cell identity across virtually all cell types in the adult striatum. SIGNIFICANCE STATEMENT Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by specific loss of medium spiny neurons (MSNs) in the striatum, accompanied by more subtle changes in many other cell types. It is thought that changes in transcriptional regulation are an important underlying mechanism, but cell type-specific gene expression changes are not well understood, particularly at time points relevant to the onset of disease-related symptoms. Single-nucleus (sn)RNA-seq in a genetically precise mouse model enabled us to identify novel patterns of transcriptional dysregulation because of HD mutations, including bidirectional dysregulation of many cell type identity genes that may be driven by partial loss-of-function of the polycomb repressive complex (PRC). Identifying these regulators of transcriptional dysregulation in HD can be leveraged to design novel disease-modifying therapeutics.

Objectives ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients are still incompletely understood. Methods We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: Results A total of 1338 patients with AAV were included: 66% had disease onset at Conclusion Within 6 months of diagnosis of AAV, patients >65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients.

Working memory forms an important component of the command centre of brain. Incoming information from all sensory modalities lasting from few seconds to several hours requires working memory for immediate storage before those information gets stored as long-term memory. Loading working memory with many information at one time can result in corrupted storage in long term memory. This could lead to less efficient recollection of information. This study aimed to investigate the efficiency of performance while loading the working memory with both primary and secondary task at the same time. Participants performed Backward Wechsler Digit Span test for digits from 3 to 7 as primary task in with-music and no-music condition. Behavioural parameters namely typing duration and accuracy, and electroencephalography (EEG) parameters namely theta, beta and alpha bands was collected for three stages: encode, maintenance and recall. Results revealed decrease in accuracy as size of digit sequence increased in the presence of music. Spectral power of theta band increased during with-music condition in comparison to no-music condition indicating strain on working memory due to music. The study results revealed that listening to favourite music during task, loads the working memory and hinders the task performance.

Pancreatic cancer is one of a lethal form of cancer every four death due to pancreatic cancer. Different therapies are available, that is, surgery and chemotherapy, but chemotherapies produce side effects due to tumor metastasis occurring in the last stage and limited outcomes. PC causes death in patients due to the most common reasons like age, genetic mutation, smoking, obesity, pancreatitis, diabetes, etc. Nanotechnology acts as a magic bullet to formulate anticancer drugs by improving their properties such as solubility, efficacy, release profile, circulation time, etc., as well as being a promising carrier for enhancing site-specific drug delivery, controlled release, and improving diagnosis in the treatment of various cancers, including PC. This chapter describes the delivery of therapeutic agents, the mechanism of nanoparticle uptake, various receptors, and the application of novel drug-delivery systems in PC, including nanoparticles, liposomes, carbon nanotubes, micelles, dendrimers, quantum dots, and patented technology available in the management of PC.

In recent years, natural phytochemicals are gaining much attention for their antimicrobial potential. Garlic and turmeric are most widely used from the natural source, and their constituents directly or indirectly provide various health benefits, especially due to antimicrobial potential. Though the conventional antimicrobial compounds are effective against various pathogens, up till now there is a necessity of effective agents against MDR pathogens. Phytochemicals have been used for their antimicrobial potential from ancient times. These phytochemicals can work by multiple mechanisms, such as by inhibiting target modifying and drug degrading enzymes or as efflux pump inhibitors. The use of natural phytoconstituents (e.g., curcumin from turmeric and allicin from garlic) from these two medicinal plants may be an alternative strategy and can overcome the side effects associated with antibiotics or other allopathic means of treatment. A wide range of indications has revealed the therapeutic efficacy of these compounds on bacterial, viral, and fungal infections. To improve safety and efficacy, these phytoconstituents have been delivered using nanoformulations such as liposomes, hydrogels, and nanoparticles for the treatment against different bacteria, viruses, fungi, and parasites infections. This chapter is attempted to discuss phytochemistry, antimicrobial mechanisms, and application potential of phytoconstituents from turmeric and garlic.

Alzheimer's disease is a chronic neurodegenerative disease. Preparation of transdermal patches is a useful strategy for management of the disease. The transdermal patches bearing Rivastigmine tartarate were prepared using solvent casting method to provide good drug content uniformity. Transdermal patches were characterized for various attributions viz. patch weight, patch thickness, folding endurance, surface morphology study, X-Ray diffraction study, Differential Scanning Calorimetry, tensile strength, surface pH, percent swelling, percent moisture sorption, drug content uniformity, In vitro release study, and ex-vivo study. Results of in vitro drug release studies clearly indicate that the drug release governed polymer interaction. No lag time was observed then reduction in drug release rate was observed. Extended drug release of 75.15 ± 1.43% within 24 h was observed with formulation. The results of the permeation study indicated that the rate of drug permeation was slow and it was found that 61 ± 1.43% of Rivastigmine tartrate could permeate through the skin membrane in 24 h. In the light of the above mentioned considerations, it is clear that the developed transdermal patch bearing Rivastigmine tartrate was retained in skin layer and delivers the therapeutic amount of drug in blood for longer time. This indicates the potential use of transdermal patches in the treatment of Alzheimer disease.

Surgical operating microscope-induced phototoxic maculopathy could occur after a flawless ocular surgery. The microscope light that gets focused on the macula may cause photochemical and thermal damage to it. The risk factors for phototoxicity include the wavelength of light, the duration of surgery, patient’s systemic condition, and consumption of medicines that act as photosensitizers. The patient may present with unexplained visual loss, pericentral scotoma, and metamorphopsia postoperatively. Diagnosis is difficult to establish and can be confirmed by the use of Amsler’s chart, fluorescein angiography, and optical coherence tomography. No specific treatment has been described till now. Prognosis is good with visual recovery seen in majority of cases within a few months’ time. However, patients with foveal involvement have poor visual prognosis, and they may develop choroidal neovascularization. The preventive measures for phototoxic maculopathy include avoidance of coaxial illumination, use of corneal occluder and UV filters, and correction of predisposing systemic diseases.

Background Adolescents and young adults (AYA) form one sixth of the world’s population and account for 6% of the world’s global burden of disease. Those with chronic illness are particularly vulnerable. Globally, significant improvements in healthcare related morbidity and mortality have been seen, but not within the 10–24 year old group. Adolescence is a rapidly changing, formative phase of human development; opportunities exist to impact this through restructing care pathways and patient empowerment. Objectives Establish awareness of current national guidance and identify unmet needs in existing rheumatology AYA systems. Methods Interested parties from South East England (South London, Kent, Surrey and Sussex) formed a multi-disciplinary, patient based, co-design initiative (RAYA collaborative) which included representatives from primary/secondary/tertiary care, allied health professionals and a youth worker/patient from the charity sector. Our discussions and an anonymous survey to hospitals in the region, formed the basis of a qualitative and quantitative analysis, which helped gain a holistic insight into the challenges and opportunities in delivering AYA care in our region. Results 15/20 centres, covering an 8 million population, responded; 4 tertiary care hospitals, 11 district general hospitals with 32 responses (19 consultants, 13 senior registrars). 31 (97%) of responders felt that AYA cohort (16–25 years old) required an approach different to that of older adults. 25 (78%) felt there was a need for dedicated AYA services. 23 (72%) and 17 (53%) were aware of UK national guidelinesCQC 2014/NICE NG43 2016 respectively) for transitional/integrated and coordinated care. Barriers to developing dedicated AYA services (% of responders): Not a priority for NHS managers,31 other clinical priorities,31 insufficient patient numbers,22 not cost effective,19 unlikely to be commissioned,19 more research required,13 cohort by diagnosis,13 other ways to deliver care,13 only focus on transitioning patients from paediatrics13 Responders would like assistance in future care delivery through: Clinical toolkit: 63% n=20, Service commissioning toolkit: 43% n=14, Training: 43% n=14, Workshops: 47% n=15. Potential low cost/cost neutral approaches to systems change, cultural change, education and sharing of resource were discussed (see image). Conclusions Improving outcomes for AYA patients through delivering age appropriate care and self advocacy has driven global strategy and guidelines. Our survey identifies that the majority of rheumatologists agree with this, however there is room for improvement regarding awareness and implementation of current guidance. Financial constraints and whole population healthcare delivery has limited change. A systematic, unified approach within regions may help to effect change. There is a demand for the development of clinical and commissioning toolkits and training/workshops to help facilitate this. Reference [1] Global Accelerated Act on for the Health of Adolescents WHO2017. Disclosure of Interest None declared

Purpose: To evaluate the role of fine needle aspiration (FNAC) as a diagnostic tool in cases of orbital and ocular adnexal masses. Cytological findings were correlated with histopathological diagnosis wherever possible. Methods: FNAC was performed in 29 patients of different age groups presenting with orbital and ocular adnexal masses. Patients were evaluated clinically and investigated by non-invasive techniques before fine needle aspiration of the masses. Smears were analyzed by a cytologist in all cases. Further, results of cytology were compared with the histopathological diagnosis. Results: The age of patients ranged from 1 to 68 years (mean: 29.79±19.29). There were 14 males and 15 females with a male to female ratio of 0.93:1. Out of 29 cases, 26 aspirates were cellular. Cellularity was insufficient in three (10.34%) aspirates. Out of 26 cellular aspirates, 11 were non-neoplastic while 15 were neoplastic on cytology. Subsequent histopathologic examination was done in 21/26 cases. Concordance rate of FNAC in orbital and ocular adnexal mass lesions with respect to the precise histologic diagnosis was 90%. Conclusion: When properly used in well-indicated patients (in cases where a diagnosis cannot be made by clinical and imaging findings alone), FNAC of orbital and periorbital lesions is an invaluable and suitable adjunct diagnostic technique that necessitates close cooperation between the ophthalmologist and cytologist. However, nondiagnostic aspirates may sometimes be obtained, and an inconclusive FNAC should not always be ignored.

Background Anti-malarial drug resistance continues to be a leading threat to malaria control efforts and calls for continued monitoring of waning efficacy of artemisinin-based combination therapy (ACT). Artesunate + sulfadoxine/pyrimethamine (AS + SP) is used for the treatment of uncomplicated Plasmodium falciparum malaria in India. However, resistance against AS + SP is emerged in northeastern states. Therefore, artemether–lumefantrine (AL) is the recommended first line treatment for falciparum malaria in north eastern states. This study investigates the therapeutic efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in three malaria-endemic states in India. The data generated through this study will benefit the immediate implementation of second-line ACT as and when required. Methods This was a one-arm prospective evaluation of clinical and parasitological responses for uncomplicated falciparum malaria using WHO protocol. Patients diagnosed with uncomplicated mono P. falciparum infection were administered six-dose regimen of AL over 3 days and subsequent follow-up was carried out up to 28 days. Molecular markers msp-1 and msp-2 were used to differentiate recrudescence and re-infection and K13 propeller gene was amplified and sequenced covering the codon 450–680. Results A total of 402 eligible patients were enrolled in the study from all four sites. Overall, adequate clinical and parasitological response (ACPR) was 98 % without PCR correction and 99 % with PCR correction. At three study sites, ACPR rates were 100 %, while at Bastar, cure rate was 92.5 % on day 28. No early treatment failure was found. The PCR-corrected endpoint finding confirmed that one late clinical failure (LCF) and two late parasitological failures (LPF) were recrudescences. The PCR corrected cure rate was 96.5 %. The mean fever clearance time was 27.2 h ± 8.2 (24–48 h) and the mean parasite clearance time was 30.1 h ± 11.0 (24–72 h). Additionally, no adverse event was recorded. Analysis of total 186 samples revealed a mutation in the k13 gene along with non-synonymous mutation at codon M579T in three (1.6 %) samples. Conclusion AL is an efficacious drug for the treatment of uncomplicated falciparum malaria. However, regular monitoring of AL is required in view of malaria elimination initiatives, which will be largely dependent on therapeutic interventions, regular surveillance and targeted vector control. Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1555-4) contains supplementary material, which is available to authorized users.

Objective Ventricular hypertrophy (VH) has been observed in children with congenital hyperinsulinism (CHI), a condition of hypoglycaemia characterised by dysregulated insulin secretion, but the prevalence is not known. Patients and methods Cardiac assessment was performed in children (n=49) with CHI at diagnosis and follow-up. Two dimensional and Doppler echocardiography studies were used to assess cardiac structures, while M-mode study was used to measure left ventricular (LV) dimensions, subsequently converted to Z scores. Where possible, LV hypertrophy was confirmed by LV mass index (g/m2.7) >95th centile. Results Cardiac structural lesions were found in 14 (28%) children. At initial echocardiography, VH was present in 31 (65%) children with median (range) LV posterior wall dimension in diastole Z scores of +1.6 (−2.4 to +5.8) and interventricular septal wall dimension in end diastole Z scores of +1.9 (−1.7 to +17.2). At follow-up echocardiography, performed after an interval of 178 (45–390) days, VH persisted in 16 (33%) children. In regression analysis, the presence of VH (odds ratio (95% confidence intervals) 1.1 (1.0–1.2), P=0.04) at initial echocardiography was correlated with maximum glucose requirement at diagnosis, indicating that severity of CHI at presentation may play a role in the pathogenesis of VH. Conclusions A significant proportion of children with CHI have cardiac structural lesions. A majority also have VH, which may be associated with the severity of CHI at diagnosis. VH may persist in some children, which requires careful long-term cardiac review.

Auto-titrating positive airway pressure (APAP) devices are an effective treatment alternative for certain patients with obstructive sleep apnea (OSA). In patients with positional sleep apnea and sleep stage dependent OSA, APAP devices may be more preferable than continuous positive airway pressure (CPAP). The myriad of APAP machines currently available employ increasingly sophisticated mathematical algorithms to identify and ameliorate respiratory disturbances. The cardiovascular benefits accrued from consistent CPAP usage still remain to be proven with APAP use. Although a reasonable alternative to CPAP, APAP titration or treatment should not be used in patients in whom OSA coexists with risk factors for central sleep apnea and hypoventilation syndromes.

Objectives To characterize a single centre retrospective case series of patients with infra-orbital inflammatory masses with autoimmune disease including granulomatosis with polyangiitis (GPA) (formerly Wegener9s granulomatosis), eGPA (eosinophillic granulomatosis with polyangiitis) or Immunoglobulin G4 (IgG4) related disease (IgG4-RD). Methods We identified 30 patients with infra-orbital inflammation on MRI imaging. Clinical and laboratory data was collected from electronic clinical records. Comprehensive Diagnostic Criteria were used for IgG4-RD and Chapel Hill criteria for GPA and eGPA. Statistical analysis was performed by GraphPad software; continuous variables were compared between IgG4-RD and GPA groups using non-parametric Mann-Whitney test and categorical variables were compared by Fisher9s exact test. Results The study included 21 Caucasian, 6 Asian and 3 patients of African descent. There were 19 female and 11 male patients. The median age of the patients was 44 years (range 29–76). 13 patients were diagnosed with GPA, 1 with eosinophillic granulomatosis with polyangitis 9eGPA), 11 patients had IgG-RD, 1 patient with lymphoma, 2 other vasculitis, 1 IgA dacryoadenitis, 1 non-specific granuloma. 7/12 patients with IgG4-RD had isolated infra-orbital masses whereas all 14 GPA patients suffered extra-ocular manifestations (p=0.01), usually sino-nasal or pulmonary. 11/14 GPA patients had positive ANCA vs 2/12 patients with Ig4-RD (p=0.04). IgG4 level was elevated pre-treatment in IgG4 RD patients (median 2.46 g/l (range 1.2–23.7)) and dropped to 1.25 g/l (range 0.37–10.4) after therapy; immunoglobulin subclasses were not checked routinely in GPA. All 12 patients with IgG4-RD underwent diagnostic orbital biopsy vs 3/14 GPA (p=0.0001). All 30 patients were treated with corticosteroids (used alone in 3/12 IgG4-RD patients). The median number of DMARDs ever used to treat GPA was 3 vs 1 DMARD for IgG4-RD (p=0.001). Rituximab was effectively administered to 10/14 GPA patients vs 3/12 IgG4-RD (p=0.04), is planned for 2 further IgG4-RD patients and approval was refused for 1 case. Surgical debulking was undertaken in 6/12 IgG4-RD vs 1/14 GPA (p=0.03). All 40 patients had subsequent MRI to assess response to therapy. Conclusions IgG4-RD is an important differential diagnosis of infra-orbital inflammation, especially if ANCA is negative. Unlike GPA that was associated with extra-ocular manifestations in all patients, IgG4-RD was more likely to present with isolated orbital inflammation and to require biopsy or surgical debulking as the diagnosis was initially uncertain. Treatment with corticosteroids +/− DMARDs was effective. Rituximab can specifically deplete the pool of autoreactive B lymphocytes producing IgG4 and future systematic studies are required to establish the optimum therapeutic strategy. Disclosure of Interest None declared

SummaryTo determine the long-term results in patients with critical aortic stenosis who survive initial intervention, and to identify factors which predict prognosis, we studied patients who underwent intervention between 1979 and 1992 for critical aortic stenosis treated within the first three months of life. Patients with a hypoplastic left ventricle or mitral stenosis who were not considered for a biventricular repair were excluded. Follow-up examination included cross-sectional and Doppler echocardiography. All initial and subsequent patient data were reviewed. Of the 64 patients with critical aortic stenosis, 41 (64%) survived more than one month after initial intervention (surgical valvotomy in 39, balloon valvoplasty in two). These survivors constitute the study group. Mild or moderate residual aortic stenosis or regurgitation without further intervention was found in 28 patients at a median duration of 3.1 years (range 0.2–15.0 years). A poor result with re-intervention (n=6) or death (n=7) occurred in 13 patients. The diameter of the aortic valve at presentation was smaller (p

A 3-year-old boy with Down’s syndrome with no underlying cardiac anomalies presented with hypoglycaemia due to congenital hyperinsulinism (CHI). He received treatment with oral diazoxide (Proglycem) (10 mg/kg/day), along with the diuretic chlorothiazide, which ensured glycaemic stability. However, a large pericardial effusion (figure 1A) requiring drainage was noted within a month. Diazoxide was discontinued and second line treatment with octreotide was …

Mucopolysaccharidosis type IH (MPSIH) is a lysosomal storage disorder whose untreated course involves progressive multisystem deterioration and death within the first decade of life. Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment modality that improves functional outcome and long-term survival. Optimal outcome requires transplantation early in life and with myeloablative conditioning. Severe cardiomyopathy can be present at diagnosis and may seemingly preclude this approach. We performed a retrospective review of those cases transplanted in Manchester since 2000 that initially presented with established cardiomyopathy, with a view to identifying general management principles. Of 44 MPSIH children transplanted in this period, 6 had displayed moderate or severe cardiomyopathy at presentation; symptomatic cardiac failure was the predominant presenting feature in five of these. Echocardiographic and clinical improvement in cardiac function was observed with extended enzyme replacement therapy (ERT) in all cases, with recovery of fractional shortening to ≥25 % achieved in all patients before coming to transplant (after median 19 weeks ERT). All were transplanted successfully, with good functional and cardiologic outcomes. However, cyclophosphamide conditioning was implicated in acute post-transplant cardiac decompensation in several cases. Our experiences highlight three important messages: (1) A diagnosis of MPSIH should be considered in any infant presenting with unexplained severe cardiac failure; (2) ERT pre-transplant can improve cardiac function sufficiently to permit safe HSCT using myeloablative conditioning; and (3) High dose cyclophosphamide should be avoided in conditioning these patients.

OBJECTIVE--To determine the incidence of the various types of obstruction of the left ventricular outflow tract in patients born in the five health districts of Liverpool and to compare their prognosis into early adult life. DESIGN--Notes of all patients with obstruction of the left ventricular outflow tract born in the study area between 1960 and 1991 were reviewed. Patients with hypoplastic left ventricle, mitral valve atresia, and those with discordant atrioventricular or ventriculoarterial connections were excluded. Survivors were traced and assessed clinically; eight were lost to follow up. RESULTS--Obstruction of the left ventricular outflow tract occurred in 313 patients (67% male), giving an incidence of 6.1/10,000 live births. The median (range) age at presentation was 13.9 months (0-20 yr). Aortic valve stenosis occurred in 71.2%: subvalve in 13.7%, supravalve in 7.7%, and multilevel in 7.4%. The median (range) duration of follow up was 10.0 (1-29) yr. Aortic regurgitation at presentation occurred more often (p < 0.001) in patients with subvalve stenosis than in those with other types of obstruction, but there was an increased incidence (p < 0.001) at follow up in patients with valve stenosis. Ninety eight patients (31.3%) underwent operation. The reoperation rate was 27% for valve stenosis and 9% for subvalve obstruction. No patients with supravalve stenosis underwent reoperation. The median duration from first operation to aortic valve replacement (17 patients) was 12.3 years. Hazard analysis confirmed that the risk of death was higher in patients presenting at a younger age, with more severe stenosis, and those with subaortic, multilevel obstruction or a syndrome. Hazard analysis also showed that the risk of a clinical event (surgery, balloon dilatation, or endocarditis) was greater in patients who presented at a younger age, with more severe stenosis or aortic regurgitation, and in those with subvalve or multilevel obstruction. CONCLUSIONS--Aortic valve stenosis was the most common type of obstruction. Hazard analysis indicates that the age and severity of obstruction at presentation have a significant effect on survival and freedom from a clinical event. The risk of premature death in patients presenting with moderately severe valve stenosis is reasonably small, but increases considerably in those with subvalve, supravalve, and multilevel obstruction. Patients who present with mild valve stenosis have a good prognosis. The risk of sudden death is less than previous predictions. Patients with subvalve and multilevel obstruction, even when mild at presentation, are more likely to undergo intervention or develop endocarditis than those with valve or supravalve stenosis. Follow up into adult life is essential.

Prediction of vulnerability discovery rates can be used to assess security risks and to determine the resources needed to develop patches quickly to handle vulnerabilities discovered. An examination of the vulnerability data suggests a seasonal behavior that has not been modeled by the recently proposed vulnerability discovery models. This seasonality has not been identified or examined so far. This study examines whether vulnerability discovery rates for Windows NT, IIS Server and the Internet Explorer exhibit a significant annual seasonal pattern. Actual data has been analyzed using seasonal index and auto correlation function approaches to identify seasonality and to evaluate its statistical significance. The results for the three software systems show that there is indeed a significant annual seasonal pattern.

We collected 3D ultrasound images of the medial gastrocnemius muscle belly (MG) in 16 children with spastic hemiplegic cerebral palsy (SHCP) (mean age: 7.8 years; range: 4-12) and 15 typically-developing (TD) children (mean age: 9.5 years; range: 4-13). All children with SHCP had limited passive dorsiflexion range on the affected side with the knee extended (mean+/-1SD: -9.3 degrees +/-11.8). Scans were taken of both legs with the ankle joint at its resting angle (RA) and at maximum passive dorsiflexion (MD), with the knee extended. RA and MD were more plantar flexed (p0.05) in children with SHCP than in TD children. We measured the volumes and lengths of the MG bellies. We also measured the length of muscle fascicles in the mid-portion of the muscle belly and the angle that the fascicles made with the deep aponeurosis of the muscle. Volumes were normalised to the subject's body mass; muscle lengths and fascicle lengths were normalised to the length of the fibula. Normalised MG belly lengths in the paretic limb were shorter than the non-paretic side at MD (p=0.0001) and RA (p=0.0236). Normalised muscle lengths of the paretic limb were shorter than those in TD children at both angles (p=0.0004; p=0.0003). However, normalised fascicle lengths in the non-paretic and paretic limbs were similar to those measured in TD children (p0.05). When compared to the non-paretic limb, muscle volume was reduced in the paretic limb (p0.0001), by an average of 28%, and normalised muscle volume in the paretic limb was smaller than in the TD group (p0.0001). The MG is short and small in the paretic limb of children with SHCP. The altered morphology is not due to a decrease in fascicle length. We suggest that MG deformity in SHCP is caused by lack of cross-sectional growth.

Background The role of Fluoro-Deoxy-Glucose PET for the diagnosis of large vessel vasculitis (LVV) remains uncertain. Temporal artery biopsy (TAB) is the gold standard investigation for suspected Giant Cell Arteritis. Biopsy is invasive, may be negative due to skip lesions and does not provide information about the extent of vascular territories involved. Objectives We aimed to determine the value of PET in the diagnosis of LVV and if any patient or clinical characteristics could help predict positive scans. Methods We retrospectively reviewed all PET scans requested for the clinical indication of LVV, over the previous 12 months. Data collected were patient demographics, clinical characteristics at presentation, initial working diagnosis (categorised as low, moderate or high probability of LVV), ESR & CRP (at presentation, TAB and at PET), cumulative steroid dose in the 28 days prior to PET, temporal artery biopsy (TAB), reason for PET request, PET results including aortic maximum standard uptake value (SUV max). Results 20 patients were identified who underwent PET scanning to look for the presence of underlying LVV. The female:male ratio was 3:1. Mean age 67 years (range 44-88 years). The initial working clinical diagnoses prior to PET scanning was GCA/LVV in 15 patients (clinical probability low =7, moderate=4, high =4 based on physician judgement) or PMR with LVV in the remaining 5 patients. Based on the PET findings a final diagnosis of LVV was made in 10/20 (50%) patients (including one borderline positive scan for LVV). The remaining scans 10/20 (50%) were negative for LVV with 5 of these being investigated for incidental findings (thyroid nodule, lung nodule, cutaneous uptake, adrenal nodule and sigmoid colon uptake). Of the 10 positive PET scans 5/10 had a prior negative TAB. In the remaining 5, TAB was not performed as there were no clinical features of GCA. 7/10 PET negative scans had a prior negative TAB and the remaining 3 had no TAB performed. Prednisolone use in the 28 days prior to PET varied. Median daily dose was 6 mg per day (range 0-40mg) and mean cumulative dose 192 mg (range 0-1120mg). Median aortic SUVmax was 3.3 (range Conclusions PET scanning can be useful in selected patients with suspected LVV. In our cohort of such patients PET was positive in 50% of TAB negative patients and changed their management plan. We also found it useful in identifying whether there was active LVV as opposed to conditions such as malignancy irrespective of TAB findings. There was an inverse relationship between cumulative steroid dose and isotope uptake suggesting that if indicated PET scanning should be done early in the course of the patients9 symptoms. Disclosure of Interest None declared

OBJECTIVE--To compare the incidence and prognosis of subaortic stenosis associated with a ventricular septal defect and to define the morphological basis of subaortic stenosis. DESIGN--Presentation and follow up data on 202 patients with subaortic stenosis seen at the Royal Liverpool Children's Hospital between 1 January 1960 and 31 December 1991 were reviewed. Survivors were traced to assess their current clinical state. Necropsy specimens of 291 patients with lesions associated with subaortic stenosis were also examined. RESULTS--In the clinical study; 65 (32.1%) of the 202 patients with subaortic stenosis had a ventricular septal defect (excluding an atrioventricular septal defect). 32 of these patients had a short segment (fibromuscular) subaortic stenosis. 33 had subaortic stenosis produced by deviation of muscular components of the outflow tracts. In 17 patients (51.5%) this was caused by posterior deviation or extension of structures into the left ventricular outflow tract, resulting in obstruction above the ventricular septal defect. In the other 16 patients (48.5%) there was over-riding of the aorta with concordant ventriculoarterial connections, (without compromise to right ventricular outflow) producing subaortic stenosis below the ventricular septal defect. Additional fibrous obstruction occurred in 39% of the patients with deviated structures. The age at presentation was lower (P < 0.01) in patients with deviated structures (median (range) 0.4 (0 to 9.2) months) than in those with short segment obstruction (median (range) 4.2 (0 to 84.9) months). The incidence of aortic arch obstruction was higher (P < 0.002) in patients with deviated structures than in those with short segment obstruction (38%). In the morphological study 35 pathological specimens showed obstructive muscular structures in the left ventricular outflow tract either above or below the ventricular septal defect. 16 had either posterior deviation of the outlet septum or extension of the right ventriculoinfundibular fold, or both of these together into the left ventricle. 19 had anterior deviation of the outlet septum into the right ventricle with overriding of the aorta (without compromise to right ventricular outflow). The earliest age at which additional fibrous obstruction was seen was 9 months. The aortic valve circumference was small in 18% of specimens. FOLLOW UP--The median (range) duration of follow up in survivors from the clinical study was 6.6 (1 to 25.7) years. 16 patients with deviated musculature (49%) and 16 with short segment fibromuscular stenosis (50%) underwent operation for subaortic stenosis. Patients with deviated structures were younger at operation than those with short segment stenosis (P < 0.005). Patients with posterior deviation or extension of structures into the left ventricular outflow tract underwent operation for subaortic stenosis more frequently (P < 0.05) than those with anterior deviation of the outlet septum and aortic override. The ventricular septal defect required surgical closure more frequently (P < 0.005) in patients with deviation (93.9%) than in those with short segment obstruction (21.9%). There was no significant difference in the mortality between patients with deviation (27%) and those with short segment obstruction (12%). CONCLUSIONS--32% of patients in the clinical study with subaortic stenosis had a ventricular septal defect. Only 51% of these had obstructive and deviated muscular structures in the left ventricular outflow tract. These patients had a significantly higher incidence of aortic arch obstruction and required surgery for subaortic stenosis at a younger age than those with short segment obstruction. The ventricular septal defect also required surgical closure more frequently in those patients with deviation. The morphological study defined the two sites of obstruction. The presence or absence and type of deviation should be clearly defined in all patients with a ventricular septal defect

The in vivo magnet responsiveness and kinetics of distribution of indomethacin entrapped in a magnetic and plain carrier were characterized by rat tail model and periodic monitoring of drug concentration in various visceral organs after intraarterial and intravenous administration respectively. Up to 60 min post injection time 60-fold higher concentrations could be achieved in tail target segment which resulted in considerably reduced drug concentration in other organs as evinced by data from control rats. Following normal administration (no magnetic field applied) the drug concentration was higher in the liver and spleen where endocytosis and phagocytosis occur. The magnetic nanoparticle of indomethacin holds promise for selective targeting under magnetic field of 8000 Oe strength.