Hemorheological, cardiorespiratory, and cerebrovascular effects of pentoxifylline following acclimatization to 3,800 m.

Pentoxifylline is a nonselective phosphodiesterase inhibitor used for the treatment of peripheral artery disease. Pentoxifylline acts through cyclic adenosine monophosphate, thereby enhancing red blood cell deformability, causing vasodilation and decreasing inflammation, and potentially stimulating ventilation. We conducted a double-blind, placebo-controlled, crossover, counter-balanced study to test the hypothesis that pentoxifylline could lower blood viscosity, enhance cerebral blood flow, and decrease pulmonary artery pressure in lowlanders following 11-14 days at 3,800 m. Participants (6 males/10 females; age, 27 ± 4 yr old) received either a placebo or 400 mg of pentoxifylline orally the night before and again 2 h before testing. We assessed arterial blood gases, venous hemorheology (blood viscosity, red blood cell deformability, and aggregation), and inflammation (TNF-α) in room air (end-tidal oxygen partial pressure, ∼52 mmHg). Global cerebral blood flow (gCBF), ventilation, and pulmonary artery systolic pressure (PASP) were measured in room air and again after 8-10 min of isocapnic hypoxia (end-tidal oxygen partial pressure, 40 mmHg). Pentoxifylline did not alter arterial blood gases, TNF-α, or hemorheology compared with placebo. Pentoxifylline did not affect gCBF or ventilation during room air or isocapnic hypoxia compared with placebo. However, in females, PASP was reduced with pentoxifylline during room air (placebo, 19 ± 3; pentoxifylline, 16 ± 3 mmHg; P = 0.021) and isocapnic hypoxia (placebo, 22 ± 5; pentoxifylline, 20 ± 4 mmHg; P = 0.029), but not in males. Acute pentoxifylline administration in lowlanders at 3,800 m had no impact on arterial blood gases, hemorheology, inflammation, gCBF, or ventilation. Unexpectedly, however, pentoxifylline reduced PASP in female participants, indicating a potential effect of sex on the pulmonary vascular responses to pentoxifylline.NEW & NOTEWORTHY We conducted a double-blind, placebo-controlled study on the rheological, cardiorespiratory and cerebrovascular effects of acute pentoxifylline in healthy lowlanders after 11-14 days at 3,800 m. Although red blood cell deformability was reduced and blood viscosity increased compared with low altitude, acute pentoxifylline administration had no impact on arterial blood gases, hemorheology, inflammation, cerebral blood flow, or ventilation. Pentoxifylline decreased pulmonary artery systolic pressure in female, but not male, participants.

Isolated central nervous system familial hemophagocytic lymphohistiocytosis (fHLH) presenting as a mimic of demyelination in children.

Isolated central nervous system (CNS) presentations of haemophagocytic lymphohistiocytosis (HLH), traditionally a systemic inflammatory condition, have been reported in adults and children. We identified nine patients with a diagnosis of isolated CNS familial hemophagocytic lymphohistiocytosis (fHLH) with symptom onset <18 years of age, and one asymptomatic sibling. Children with atypical chronic/recurrent CNS inflammation should be considered for immunological and genetic panel testing for fHLH even in the absence of any systemic inflammatory features. Despite haematopoietic stem cell transplantation (HSCT) being a mainstay of treatment, treatment failure and high morbidity and mortality post-HSCT suggest that alternative immune therapies may be worth considering.

Retinoic acid receptor beta variant-related colonic hypoganglionosis.

Retinoic acid receptor beta (RARB) variants are heavily linked to pathologies of neural crest cell migration. The purpose of this report is to present a 23-month-old male with the previously described R387C RARB gain-of-function variant whose gastrointestinal issues and long-term constipation lead to the discovery of colonic hypoganglionosis. This case further delineates the pattern of malformation associated with RARB variants. The findings are also consistent with the known etiology of aganglionic colon due to failed neural crest cell migration.

Diffusion-weighted MRI and intravoxel incoherent motion model for diagnosis of pediatric solid abdominal tumors.

BACKGROUND: Pediatric retroperitoneal tumors in the renal bed are often large and heterogeneous, and their diagnosis based on conventional imaging alone is not possible. More advanced imaging methods, such as diffusion-weighted (DW) MRI and the use of intravoxel incoherent motion (IVIM), have the potential to provide additional biomarkers that could facilitate their noninvasive diagnosis. PURPOSE: To assess the use of an IVIM model for diagnosis of childhood malignant abdominal tumors and discrimination of benign from malignant lesions. STUDY TYPE: Retrospective. POPULATION: Forty-two pediatric patients with abdominal lesions (n = 32 malignant, n = 10 benign), verified by histopathology. FIELD STRENGTH/SEQUENCE: 1.5T MRI system and a DW-MRI sequence with six b-values (0, 50, 100, 150, 600, 1000 s/mm2 ). ASSESSMENT: Parameter maps of apparent diffusion coefficient (ADC), and IVIM maps of slow diffusion coefficient (D), fast diffusion coefficient (D*), and perfusion fraction (f) were computed using a segmented fitting model. Histograms were constructed for whole-tumor regions of each parameter. STATISTICAL TESTS: Comparison of histogram parameters of and their diagnostic performance was determined using Kruskal-Wallis, Mann-Whitney U, and receiver-operating characteristic (ROC) analysis. RESULTS: IVIM parameters D* and f were significantly higher in neuroblastoma compared to Wilms' tumors (P < 0.05). The ROC analysis showed that the best diagnostic performance was achieved with D* 90th percentile (area under the curve [AUC] = 0.935; P = 0.002; cutoff value = 32,376 × 10-6 mm2 /s) and f mean values (AUC = 1.00; P < 0.001; cutoff value = 14.7) in discriminating between neuroblastoma (n = 11) and Wilms' tumors (n = 8). Discrimination between tumor types was not possible with IVIM D or ADC parameters. Malignant tumors revealed significantly lower ADC, D, and higher D* values than in benign lesions (all P < 0.05). DATA CONCLUSION: IVIM perfusion parameters could distinguish between malignant childhood tumor types, providing potential imaging biomarkers for their diagnosis. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1475-1486.

Prospective multicentre evaluation and refinement of an analysis tool for magnetic resonance spectroscopy of childhood cerebellar tumours.

BACKGROUND: A tool for diagnosing childhood cerebellar tumours using magnetic resonance (MR) spectroscopy peak height measurement has been developed based on retrospective analysis of single-centre data. OBJECTIVE: To determine the diagnostic accuracy of the peak height measurement tool in a multicentre prospective study, and optimise it by adding new prospective data to the original dataset. MATERIALS AND METHODS: Magnetic resonance imaging (MRI) and single-voxel MR spectroscopy were performed on children with cerebellar tumours at three centres. Spectra were processed using standard scanner software and peak heights for N-acetyl aspartate, creatine, total choline and myo-inositol were measured. The original diagnostic tool was used to classify 26 new tumours as pilocytic astrocytoma, medulloblastoma or ependymoma. These spectra were subsequently combined with the original dataset to develop an optimised scheme from 53 tumours in total. RESULTS: Of the pilocytic astrocytomas, medulloblastomas and ependymomas, 65.4% were correctly assigned using the original tool. An optimized scheme was produced from the combined dataset correctly assigning 90.6%. Rare tumour types showed distinctive MR spectroscopy features. CONCLUSION: The original diagnostic tool gave modest accuracy when tested prospectively on multicentre data. Increasing the dataset provided a diagnostic tool based on MR spectroscopy peak height measurement with high levels of accuracy for multicentre data.

Expanding the phenotype in argininosuccinic aciduria: need for new therapies.

OBJECTIVES: This UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs. METHODS: Retrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping. RESULTS: Fifty-six patients were defined as early-onset (n = 23) if symptomatic < 28 days of age, late-onset (n = 23) if symptomatic later, or selectively screened perinatally due to a familial proband (n = 10). The median follow-up was 12.4 years (range 0-53). Long-term outcomes in all groups showed a similar neurological phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy-like symptoms (6/52) and abnormal neuroimaging (12/21). Neuroimaging findings included parenchymal infarcts (4/21), focal white matter hyperintensity (4/21), cortical or cerebral atrophy (4/21), nodular heterotopia (2/21) and reduced creatine levels in white matter (4/4). 4/21 adult patients went to mainstream school without the need of additional educational support and 1/21 lives independently. Early-onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early-onset and half of late-onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. ASL was sequenced (n = 19) and 20 mutations were found. Plasma argininosuccinate was higher in early-onset compared to late-onset patients. CONCLUSIONS: Our study further defines the natural history of argininosuccinic aciduria and genotype-phenotype correlations. The neurological phenotype does not correlate with the severity of hyperammonaemia and plasma argininosuccinic acid levels. The disturbance in nitric oxide synthesis may be a contributor to the neurological disease. Clinical trials providing nitric oxide to the brain merit consideration.

Penicillin to prevent recurrent leg cellulitis.

BACKGROUND: Cellulitis of the leg is a common bacterial infection of the skin and underlying tissue. We compared prophylactic low-dose penicillin with placebo for the prevention of recurrent cellulitis. METHODS: We conducted a double-blind, randomized, controlled trial involving patients with two or more episodes of cellulitis of the leg who were recruited in 28 hospitals in the United Kingdom and Ireland. Randomization was performed according to a computer-generated code, and study medications (penicillin [250 mg twice a day] or placebo for 12 months) were dispensed by a central pharmacy. The primary outcome was the time to a first recurrence. Participants were followed for up to 3 years. Because the risk of recurrence was not constant over the 3-year period, the primary hypothesis was tested during prophylaxis only. RESULTS: A total of 274 patients were recruited. Baseline characteristics were similar in the two groups. The median time to a first recurrence of cellulitis was 626 days in the penicillin group and 532 days in the placebo group. During the prophylaxis phase, 30 of 136 participants in the penicillin group (22%) had a recurrence, as compared with 51 of 138 participants in the placebo group (37%) (hazard ratio, 0.55; 95% confidence interval [CI], 0.35 to 0.86; P=0.01), yielding a number needed to treat to prevent one recurrent cellulitis episode of 5 (95% CI, 4 to 9). During the no-intervention follow-up period, there was no difference between groups in the rate of a first recurrence (27% in both groups). Overall, participants in the penicillin group had fewer repeat episodes than those in the placebo group (119 vs. 164, P=0.02 for trend). There was no significant between-group difference in the number of participants with adverse events (37 in the penicillin group and 48 in the placebo group, P=0.50). CONCLUSIONS: In patients with recurrent cellulitis of the leg, penicillin was effective in preventing subsequent attacks during prophylaxis, but the protective effect diminished progressively once drug therapy was stopped. (Funded by Action Medical Research; PATCH I Controlled-Trials.com number, ISRCTN34716921.).

Loss-of-function mutations in RAB18 cause Warburg micro syndrome.

Warburg Micro syndrome and Martsolf syndrome are heterogenous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Previously, identification of mutations in RAB3GAP1 and RAB3GAP2 in both these syndromes implicated dysregulation of the RAB3 cycle (which controls calcium-mediated exocytosis of neurotransmitters and hormones) in disease pathogenesis. RAB3GAP1 and RAB3GAP2 encode the catalytic and noncatalytic subunits of the hetrodimeric enzyme RAB3GAP (RAB3GTPase-activating protein), a key regulator of the RAB3 cycle. We performed autozygosity mapping in five consanguineous families without RAB3GAP1/2 mutations and identified loss-of-function mutations in RAB18. A c.71T > A (p.Leu24Gln) founder mutation was identified in four Pakistani families, and a homozygous exon 2 deletion (predicted to result in a frameshift) was found in the fifth family. A single family whose members were compound heterozygotes for an anti-termination mutation of the stop codon c.619T > C (p.X207QextX20) and an inframe arginine deletion c.277_279 del (p.Arg93 del) were identified after direct gene sequencing and multiplex ligation-dependent probe amplification (MLPA) of a further 58 families. Nucleotide binding assays for RAB18(Leu24Gln) and RAB18(Arg93del) showed that these mutant proteins were functionally null in that they were unable to bind guanine. The clinical features of Warburg Micro syndrome patients with RAB3GAP1 or RAB3GAP2 mutations and RAB18 mutations are indistinguishable, although the role of RAB18 in trafficking is still emerging, and it has not been linked previously to the RAB3 pathway. Knockdown of rab18 in zebrafish suggests that it might have a conserved developmental role. Our findings imply that RAB18 has a critical role in human brain and eye development and neurodegeneration.

A case of nonischemic cardiomyopathy associated with autoimmune polyglandular syndrome type III.

OBJECTIVE: To report a case of nonischemic dilated cardiomyopathy associated with autoimmune polyglandular syndrome (APS) type III. METHODS: A review of our patient's medical records was undertaken, and her clinical history, investigations, and outcome are described. In addition, a literature review of nonischemic dilated cardiomyopathy occurring in association with autoimmune polyendocrinopathies was performed. RESULTS: APS is diagnosed once a patient has developed at least 2 organ specific autoimmune diseases. APS III involves a combination of autoimmune diabetes and Graves' disease without adrenal insufficiency. Autoimmune cardiomyopathies are not described as a feature of this condition; however, there are a few reported cases of patients with autoimmune polyendocrinopathies developing a nonischemic dilated cardiomyopathy. In this case, a 30-year-old female developed vitiligo, Graves' disease, and latent autoimmune diabetes of the adult (LADA) over a 5-year period before presenting with conscious ventricular tachycardia (VT). This evolved into acute severe biventricular failure within a few weeks, which failed to resolve after adequate treatment of her other autoimmune conditions. CONCLUSION: Although nonischemic cardiomyopathies have been associated with APS in a few published cases, this is the first case to our knowledge in a patient with APS III.

Effects of Naltrexone on Sleep Quality and Periodic Breathing at High Altitude.

Foster, Katharine, James D. Anholm, Gary Foster, Suman Thapamagar, and Prajan Subedi. Effects of naltrexone on sleep quality and periodic breathing at high altitude. High Alt Med Biol. 00:000-000, 2024. Objective: This study examined the effects of naltrexone on breathing and sleep at high altitude. Mu-opioid receptor (MOR) agonists have a depressive effect on respiration. Naltrexone is known to block the MOR. We hypothesized that MOR blockade with naltrexone would result in higher nocturnal oxygen saturations, fewer apneas, and improved sleep at high altitude. Methods: This double-blind, placebo-controlled, crossover study included nine healthy volunteers (four females, five males) aged 27.9 (4.6) (mean [standard deviation]) years. Two overnight trips spaced at least 2 weeks apart took participants from Loma Linda, CA (355 m) to the Barcroft Laboratory, CA (3,810 m) for each arm. Participants ingested either 50 mg naltrexone or matching placebo at bedtime. Sleep metrics were recorded using an ambulatory physiological sleep monitor (APSM). Subjective data were measured with the Groningen Sleep Quality Scale, Stanford Sleepiness Scale, and the 2018 Lake Louise Score (LLS) for acute mountain sickness (AMS). Results: Mean overnight SpO2 was lower after taking naltrexone, 81% (6) versus 83% (4) (mean difference 1.9% [2.1, 95% confidence interval or CI = 0.1-3.6, p = 0.040]). The lowest overnight SpO2 (nadir) was lower on naltrexone 70% (6) versus 74% (4) (dif. 4.6% [4.3], CI = 1.0-8.2, p = 0.020). Total sleep time and total apnea-hypopnea index were unchanged. Subjective sleep quality was significantly worse on naltrexone measured via the Groningen Sleep Quality Scale (p = 0.033) and Stanford Sleepiness Scale (p = 0.038). AMS measured via LLS was significantly worse while taking naltrexone (p = 0.025). Conclusion: Contrary to our hypothesis, this study demonstrated a significant decrease in nocturnal oxygen saturation, worse sleep quality, and AMS scores. Further characterization of the MOR's effects on sleep and AMS is needed to evaluate potential exacerbating mechanisms for AMS and poor sleep quality at altitude.

Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features.

OBJECTIVE: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. METHODS: We conducted a population active surveillance study. All paediatricians, and ophthalmologists (n = 4095) were sent monthly reporting cards (September 2009-September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. RESULTS: Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3-15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years (n = 63) was 1.52:1 (p = 0.045). The incidence of first onset ADS in children aged 1-15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18-11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria. CONCLUSIONS: We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.

Prophylactic antibiotics for the prevention of cellulitis (erysipelas) of the leg: results of the UK Dermatology Clinical Trials Network's PATCH II trial.

BACKGROUND: Cellulitis (erysipelas) of the leg is a common, painful infection of the skin and underlying tissue. Repeat episodes are frequent, cause significant morbidity and result in high health service costs. OBJECTIVES: To assess whether prophylactic antibiotics prescribed after an episode of cellulitis of the leg can prevent further episodes. METHODS: Double-blind, randomized controlled trial including patients recently treated for an episode of leg cellulitis. Recruitment took place in 20 hospitals. Randomization was by computer-generated code, and treatments allocated by post from a central pharmacy. Participants were enrolled for a maximum of 3 years and received their randomized treatment for the first 6 months of this period. RESULTS: Participants (n=123) were randomized (31% of target due to slow recruitment). The majority (79%) had suffered one episode of cellulitis on entry into the study. The primary outcome of time to recurrence of cellulitis included all randomized participants and was blinded to treatment allocation. The hazard ratio (HR) showed that treatment with penicillin reduced the risk of recurrence by 47% [HR 0·53, 95% confidence interval (CI) 0·26-1·07, P=0·08]. In the penicillin V group 12/60 (20%) had a repeat episode compared with 21/63 (33%) in the placebo group. This equates to a number needed to treat (NNT) of eight participants in order to prevent one repeat episode of cellulitis [95% CI NNT(harm) 48 to ∞ to NNT(benefit) 3]. We found no difference between the two groups in the number of participants with oedema, ulceration or related adverse events. CONCLUSIONS: Although this trial was limited by slow recruitment, and the result failed to achieve statistical significance, it provides the best evidence available to date for the prevention of recurrence of this debilitating condition.

Pre-emptive liver transplantation for primary hyperoxaluria (PH-I) arrests long-term renal function deterioration.

BACKGROUND: Primary hyperoxaluria-I (PH-I) is a serious metabolic disease resulting in end-stage renal disease. Pre-emptive liver transplantation (PLT) for PH-I is an option for children with early diagnosis. There is still little information on its effect on long-term renal function in this situation. METHODS: Long-term assessment of renal function was conducted using Schwartz's formula (estimated glomerular filtration rate-eGFR) in four children (Group A) undergoing PLT between 2002 and 2008, and a comparison was done with eight gender- and sex-matched controls (Group B) having liver transplantation for other indications. RESULTS: All patients received a liver graft from a deceased donor. Median follow-up for the two groups was 64 and 94 months, respectively. One child in Group A underwent re-transplantation due to hepatic artery thrombosis, while acute rejection was seen in one. A significant difference was seen in eGFR at transplant (81 vs 148 mL/min/1.73 m(2)) with greater functional impairment seen in the study population. In Group A, renal function reduced by 21 and 11% compared with 37 and 35% in Group B at 12 and 24 months, respectively. At 2 years post-transplantation, there was no significant difference in eGFR between the two groups (72 vs 100 mL/min/1.73 m(2), respectively; P = 0.06). CONCLUSIONS: Renal function remains relatively stable following pre-emptive LTx for PH-I. With early diagnosis of PH-I, isolated liver transplantation may prevent progression to end-stage renal disease and the need for renal transplantation.

Paediatric UK demyelinating disease longitudinal study (PUDDLS).

BACKGROUND: There is evidence that at least 5% of Multiple sclerosis (MS) cases manifest in childhood. Children with MS present with a demyelinating episode involving single or multiple symptoms prior to developing a second event (usually within two years) to then meet criteria for diagnosis. There is evidence from adult cohorts that the incidence and sex ratios of MS are changing and that children of immigrants have a higher risk for developing MS. A paediatric population should reflect the vanguard of such changes and may reflect trends yet to be observed in adult cohorts. Studying a paediatric population from the first demyelinating event will allow us to test these hypotheses, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS. METHODS/DESIGN: The Paediatric UK Demyelinating Disease Longitudinal Study (PUDDLS) is a prospective longitudinal observational study which aims to determine the natural history, predictors and outcomes of childhood CNS inflammatory demyelinating diseases. PUDDLS will involve centres in the UK, and will establish a cohort of children affected with a first CNS inflammatory demyelinating event for long-term follow up by recruiting for approximately 5 years. PUDDLS will also establish a biological sample archive (CSF, serum, and DNA), allowing future hypothesis driven research. For example, the future discovery of a biomarker will allow validation within this dataset for the evaluation of novel biomarkers. Patients will also be requested to consent to be contacted in the future. A secondary aim is to collaborate internationally with the International Paediatric Multiple Sclerosis Study Group when future collaborative studies are proposed, whilst sharing a minimal anonymised dataset. PUDDLS is the second of two jointly funded studies. The first (UCID-SS) is an epidemiological surveillance study that already received ethical approvals, and started on the 1st September 2009. There is no direct patient involvement, and UCID-SS aims to determine the UK and Ireland incidence of CNS inflammatory demyelinating disorders in children under 16 years. DISCUSSION: A paediatric population should reflect the vanguard of MS epidemiological changes and may reflect trends yet to be observed in adult MS cohorts. The restricted window between clinical expression of disease and exposure to environmental factors in children offers a unique research opportunity. Studying a paediatric population from the first demyelinating event will allow us to investigate the changing epidemiology of MS, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS.

Multiplex ligation-dependent probe amplification (MLPA) analysis is an effective tool for the detection of novel intragenic PLA2G6 mutations: implications for molecular diagnosis.

Phospholipase associated neurodegeneration (PLAN) comprises a heterogeneous group of autosomal recessive neurological disorders caused by mutations in the PLA2G6 gene. Direct gene sequencing detects approximately 85% mutations in infantile neuroaxonal dystrophy. We report the novel use of multiplex ligation-dependent probe amplification (MLPA) analysis to detect novel PLA2G6 duplications and deletions. The identification of such copy number variants (CNVs) expands the PLAN mutation spectrum and may account for up to 12.5% of PLA2G6 mutations. MLPA should thus be employed to detect CNVs of PLA2G6 in patients who show clinical features of PLAN but in whom both disease-causing mutations cannot be identified on routine sequencing.

Childhood autoimmune liver disease: indications and outcome of liver transplantation.

BACKGROUND: Graft rejection and disease recurrence are well-recognized complications of liver transplantation (LT) for autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC). We describe indications and outcome of LT for childhood AIH and AISC. PATIENTS AND METHODS: Twenty-year retrospective review of a cohort of children (n = 101) with AIH, AISC, or AIH/sclerosing cholangitis overlap syndrome from a single center. RESULTS: AIH type 1 (AIH1, n = 67) was more common than AIH type 2 (AIH2, n = 18), AISC (n = 8), or overlap syndrome (n = 8). Overall, 18 patients (18%) required LT, the indications being failure of medical therapy (n = 16) and fulminant liver failure (n = 2). Patients with AIH who required LT had a more prolonged prothrombin time at presentation compared with those who did not undergo transplantation (P = 0.01). Patients with AIH1 who received LT had a lower aspartate transaminase (P = 0.009) and alanine transaminase (P = 0.02) levels at initial diagnosis compared with those with AIH1 who did not undergo transplantation. Post-LT, 11 patients (61%) had 18 episodes of rejection, most were steroid sensitive. Disease recurrence was observed in 7 patients (39%, median duration post-LT 33 months), more common in AIH2 (80% recurrence rate), and those taking cyclosporine (71%, 5/7 patients) compared with those taking tacrolimus (18%, 2/11 patients; P < 0.05) and in 3 of 3 children who did not have maintenance steroids post-LT. The overall 5- and 7-year post-LT survival rate was 94% and 88%, respectively. CONCLUSIONS: LT is a good therapeutic option for progressive AIH and AISC, although recurrence of the primary autoimmune process limits the outcome.

Mesencephalic enlarged Virchow-Robin spaces in a 6-year-old boy: a case-based update.

BACKGROUND: Perivascular spaces or Virchow-Robin spaces are normal anatomical structures within the brain, typically less than 5 mm in diameter. Rarely, they can reach much larger sizes and adopt bizarre single or multi-cystic configurations, as was the case in the patient that we report on. When there is such markedly gross dilatation, the phenomenon is known as Giant or tumefactive perivascular space enlargement. CASE REPORT: We report a 6-year-old boy with a multi-cystic mesencephalic lesions presenting with obstructive hydrocephalus secondary to obstruction of the aqueduct of Sylvius due to tumefactive dilatation of Virchow-Robin spaces. The patient underwent an endoscopic fenestration and biopsy of the cystic portion abutting into the ventricular system. CONCLUSION: In this paper, we discuss the phenomenon of perivascular (Virchow-Robin) spaces and their treatment options and review the relevant literature. To our knowledge, this is the first pediatric case of tumefactive dilatation of the Virchow-Robin spaces causing obstructive hydrocephalus that were directly fenestrated using neuroendoscopy.

Hepatic venous outflow obstruction in paediatric liver transplantation.

INTRODUCTION: Vascular complications after orthotopic split liver transplantation in children result in significant post-operative complications. MATERIALS AND METHODS: A review of children undergoing liver transplantation from 2004 to 2006 was undertaken. The data was obtained based on a proforma-based analysis. RESULTS: Seven of 106 transplants were identified to have hepatic venous outflow obstruction (HVOO) of whom five were males and two were females. Median age at transplant was 8 years (range 3 years 4 months-15 years). The median donor-to-recipient weight ratio was 2.78 (range 0.97-6.15). ANASTOMOTIC TECHNIQUE: Hepatic vein-IVC in four, Hepatic vein-hepatic vein (HV-IVC) confluence in two and cavo hepatic in one. Ascites was the commonest post op manifestation of HVOO. Although Doppler USG was useful in identifying the venous outflow obstruction, venography confirmed the exact site of obstruction aiding in therapeutic dilatation. Three of seven cases had early onset (<1 month) while 4/7 had late onset (>1 month). 5/7 underwent venography and dilatation, of whom three are well and one is awaiting a repeat venography and dilatation. 2/7 died without intervention and 1/7 died in the waiting list for retransplantation. CONCLUSION: The diagnosis of HVOO requires a high index of suspicion, prompting early venography to manage HVOO successfully. Technical steps to avoid HVOO are to keep the hepatic vein-caval anastomosis short and wide with triangulation and to avoid graft rotation at the hepato caval junction.