[Iatrogenic hypospadias a preventable rare complication with two-stage repair with buccal mucosa graft: a case presen- tation].

Urethral catheterization is a common procedure, but it is associated with a number of complications. Iatrogenic hypospadias can rarely occur. There is a limited literature dedicated to this condition. We report a young patient with COVID-19 with iatrogenic hypospadias of grade 3. He was undergone to a two-stage procedure with acceptable outcome. Surgical repair should be offered and performed for young patients to ensure good function with acceptable penile appearance. A surgical treatment will improve psychological, sexual and social outcomes.

[The tale of two stones in an obstructed partial duplex kidney: case presentation].

Duplex renal systems is a common anomalies. Incidence rate of 0.8% in healthy adult population and 2-4% in patients investigated for urinary tract symptoms. Urolithiasis management for patients with anomalies is complex and require proper imaging and planning. We have a patient with a partial duplex collecting system presented with a right renal calculus in a non-functioning lower moiety and multiple distal ureteric calculi. Preoperative planning done and surgery performed with good outcome without any early and late complications.

Gastrointestinal bleeding caused by epitheloid sarcoma: A case report.

Epithelioid sarcoma (ES) of the small bowel is a rare gastrointestinal tumour. We report a case of gastrointestinal bleeding secondary to small bowel ES in a 55-year-old gentleman. After gastroscopy and colonoscopy failed to identify the source of bleeding, we proceeded with computed tomography angiogram of the mesentery, which revealed intraluminal blood clot in the distal jejunum with features of obstruction. This is a rare cause of obscure gastrointestinal bleeding and emphasises the need for additional evaluation in the presence of negative endoscopic findings.

Alendronate, a bisphosphonate, increased upper and lower gastrointestinal bleeding: risk factor analysis from a nationwide population-based study.

UNLABELLED: Patients receiving alendronate for osteoporosis carry a significantly higher risk of developing upper gastrointestinal bleeding (GIB) and lower GIB (hazard ratio 1.32 and 1.84, respectively) after adjusting for potential confounding factors such as age, gender, co-morbidity, and some medications. The risk factors associated with GIB were further analyzed. INTRODUCTION: Patients receiving alendronate, a type of bisphosphonate, for osteoporosis have a higher risk of developing upper gastrointestinal bleeding (UGIB). Whether patients receiving alendronate also have a higher risk of lower gastrointestinal bleeding (LGIB) has not been studied. In this study, we investigated the association between GIB and alendronate use and to identify the possible risk factors of GIB among alendronate users. METHODS: Using the National Health Insurance (NHI) Research Database of Taiwan, 3,000 alendronate users and 12,000 age-, sex-, and enrollment time-matched controls were extracted for analysis from a cohort data set of 1,000,000 randomly sampled subjects. Cox proportional hazard regression models were used to identify the risk factors for UGIB and LGIB in all enrollees and alendronate users after adjustments for age, gender, comorbidity (hypertension, diabetes mellitus, coronary heart disease, heart failure, chronic renal disease, chronic obstructive pulmonary disease, peptic ulcer, and cirrhosis), and medications (nonsteroidal anti-inflammatory drugs [NSAIDs], aspirin, steroids, clopidogrel, ticlopidine, warfarin, and selective serotonin reuptake inhibitors). RESULTS: During a median of 1.30-year follow-up, patients receiving alendronate had significant higher risk of UGIB and LGIB after adjusting for age, gender, and potential confounding factors such as comorbidity and medications. Age, chronic renal disease, NSAID, and clopidogrel use may be independent risk factors for UGIB among alendronate users. Age, male gender, clopidogrel, and ticlopidine use may be independent risk factors for LGIB among alendronate users. CONCLUSION: Patients receiving alendronates seemed to carry a higher risk for UGIB and LGIB, respectively, after adjustment for age, sex, underlying comorbidity, and certain medications.

Effect of systemic urokinase infusion after lower limb percutaneous transluminal angioplasty on limb salvage rate in patients with late-stage critical limb ischemia.

OBJECTIVE: To evaluate the effect of systemically administered urokinase (UK) after percutaneous transluminal angioplasty with or without stent (PTA ± stent) on the reduction in the rate and level of amputation in patients with critical limb ischemia (CLI) with tissue loss. METHODS: This was an observational, nonrandomized, retrospective study of 183 Taiwanese patients with Rutherford stage 5 or 6, and Fontaine stage 4 lower extremity CLI. Patients received either PTA ± stent or PTA ± stent + UK infusion (250,000 IU, daily for 5 days). PTA of the iliac, femoral, anterior tibial artery, posterior tibial artery, and peroneal arteries was included. Amputation was classified as minor, with direct wound healing, and minor amputation or surgical debridement of toes and major, with below- (BKA) and above-knee amputation (AKA). RESULTS: In groups of patients with comparable baseline characteristics, 85 and 90 patients received PTA ± stent and PTA ± stent + UK, respectively. There were 24 major limb amputations performed. A significant majority (20/24 (83.3%) were performed in patients who did not receive adjuvant urokinase, compared with 4/24 (16.7%) of patients who did receive urokinase (p = 0.000287). There was a significant increase in the limb salvage rate for infrapopliteal lesions in patients treated with PTA + UK (12/72 with UK; 60/72 without UK; p ≤ .0001). Intracranial hemorrhage (n = 1) and bleeding at the inguinal puncture site (n = 2) were reported in the PTA ± stent + UK group. Eight deaths (one in the PTA ± stent + UK group; seven in the PTA ± stent) occurred during the study. CONCLUSION: Systemic administration of UK with the PTA ± stent procedure may reduce the requirement for major amputation in patients with CLI with tissue loss (Rutherford 5 or 6). The difference is more pronounced in patients undergoing infrapopliteal interventions. However, these findings need to be confirmed in a randomized prospective study.

Patients with nonalcoholic fatty liver disease have higher risk of colorectal adenoma after negative baseline colonoscopy.

AIM: The study aimed to determine whether nonalcoholic fatty liver disease (NAFLD) is an independent risk factor of adenoma after negative baseline colonoscopy. METHOD: A retrospective cohort study was conducted on 1522 health-check individuals who underwent two consecutive colonoscopies at Taipei Veterans General Hospital between 2003 and 2010. Those developing an adenoma after an initial negative baseline colonoscopy (adenoma group) were compared with those in whom the second colonoscopy was negative (nonadenoma group). Anthropometric measurements, biochemical tests and the presence of NAFLD were compared between the two groups. RESULTS: The adenoma group had a higher prevalence of NAFLD than the nonadenoma group (55.6% vs 38.8%; P < 0.05). On multivariate logistic regression analysis, NAFLD was an independent risk factor (OR = 1.45, 95% CI: 1.07-1.98) for adenoma formation after a negative baseline colonoscopy. The risk of colorectal adenoma increased when NAFLD patients had other morbidities including metabolic syndrome, hypertension or smoking (OR = 2.85, 4.03 and 4.17). CONCLUSION: NAFLD is an independent risk factor for colorectal adenoma formation after a negative baseline colonoscopy. The risk is higher in individuals with NAFLD and other comorbidities, such as hypertension, smoking or metabolic syndrome.

Scrotal centesis: a broader role beyond the confines of the scrotum.

An elderly man was treated for severe acute scrotum pain with centesis. We report the diagnosis, underlying causes and management, and discuss the procedure. Centesis is performed rarely, but could be undertaken more often given the added benefits.

Distinct association between aberrant methylation of Wnt inhibitors and genetic alterations in acute myeloid leukaemia.

BACKGROUND: Aberrant activation of Wnt signalling through hypermethylation of Wnt inhibitor genes is involved in several human malignancies, including acute myeloid leukaemia (AML). It remains unclear whether hypermethylation of Wnt inhibitors is associated with molecular gene mutations in the development of AML. METHODS: We investigated the association of the promoter hypermethylation of six Wnt inhibitors (Wif-1, SFRP1, SFRR2, SFRP4, SFRP5, and DKK1) with gene aberrations in the leukaemogenesis of 269 AML patients. RESULTS: In total, 166 patients (61.7%) had hypermethylation of at least one Wnt inhibitor. The majority (68.5%) of patients with Wnt inhibitor hypermethylation had concurrent Class II gene mutations that affect transcription factors or cofactors. There was a close association of Wif-1 hypermethylation with t(15;17) (P=0.0005) and CEBPA mutation (P<0.0001), DKK1 hypermethylation with t(8;21) (P<0.0001) and ASXL1 mutation (P=0.0078), SFRP-1 hypermethylation with t(8;21) (P<0.0001), SFRP-2 hypermethylation with AML1/RUNX1 mutation (P=0.0012), and SFRP-5 hypermethylation with MLL/PTD (P=0.0505). On the other side, hypermethylation of Wnt inhibitors was always negatively associated with NPM1 mutation and FLT3/ITD. CONCLUSION: There was distinct association between hypermethylation of individual Wnt inhibitors and specific gene aberrations, especially Class II mutations. The Wnt inhibitor hypermethylation might interact with genetic alterations in the leukaemogenesis.

Ixabepilone, a novel microtubule-targeting agent for breast cancer, is a substrate for P-glycoprotein (P-gp/MDR1/ABCB1) but not breast cancer resistance protein (BCRP/ABCG2).

Ixabepilone is the first epothilone to be approved for clinical use. Current data suggest the epothilones have a role in treating taxane-resistant cancers and ixabepilone is unaffected by at least some of the mechanisms underlying chemoresistance. Here, we report a series of cytotoxicity and transport studies to assess the potential role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in ixabepilone resistance. A significant decrease in ixabepilone-mediated cytotoxicity was observed in Madin-Darby canine kidney cells transfected with human multidrug resistance 1 (MDR1) comparative with the parental cells (IC(50) > 2000 nM versus 90 nM). Overexpression of P-gp also resulted in significantly decreased cell susceptibility to docetaxel, paclitaxel, and vinblastine. Bidirectional transport of ixabepilone across monolayers of porcine kidney-derived cells expressing human MDR1 showed a significantly increased efflux ratio relative to the parental cells. A BCRP-overexpressing cell line was developed by transfecting human embryonic kidney (HEK)-293 cells with BCRP cDNA and confirmed by immunoblotting and bodipy prazosin and mitoxantrone uptake. Neither P-gp nor multidrug resistance protein 2 was detected in the cells by corresponding polyclonal antibodies. This HEK-BCRP cell line demonstrated resistance to docetaxel, paclitaxel, vinblastine, and mitoxantrone, in comparison with the parental cell line (7.3, 4.3, 2.9, and 11.9 resistance factor, respectively). Transport inhibition by BCRP inhibitor fumitremorgin C and broad efflux inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) restored drug sensitivity. In contrast, ixabepilone was far less susceptible to BCRP-mediated resistance, resulting in a resistance factor of only 1.2-fold. In summary, these results suggest that P-gp could cause resistance to ixabepilone in tumors and affect the disposition of the drug, but it is unlikely that BCRP mediates any drug resistance to ixabepilone.

Loss of normal p53 function confers sensitization to Taxol by increasing G2/M arrest and apoptosis.

The anticancer agent paclitaxel (Taxol) stabilizes tubulin polymerization resulting in arrest in mitosis and apoptotic cell death. Normal human fibroblasts depleted of functional p53 by SV40 T antigen or HPV-16 E6, and primary embryo fibroblasts from p53 null mice showed seven- to ninefold increased cytotoxicity by paclitaxel. Reduced levels of p53 correlated with increased G2/M phase arrest, micronucleation, and p53-independent paclitaxel-induced apoptosis. Surviving cells with intact p53 progressed through mitosis and transiently accumulated in the subsequent G1 phase, coincident with increased p53 and p21cip1,waf1 protein levels. These results are in contrast to studies linking p53 loss with resistance to DNA damaging anticancer agents.

Association of the G-protein and α2-adrenergic receptor gene and plasma norepinephrine level with clonidine improvement of the effects of diuretics in patients with cirrhosis with refractory ascites: a randomised clinical trial.

OBJECTIVE: Clonidine is an α(2)-adrenoceptor agonist which, by coupling with G-protein, has been proposed as an alternative treatment for refractory ascites of patients with cirrhosis for several years. Genetic polymorphisms of ß-adrenoceptor and angiotensin II type 1 receptor blockers have been reported to affect drug response in patients with cirrhosis. This study evaluated the clonidine-diuretic response rate, favourable predictors and genetic components of the clonidine-diuretic response in patients with cirrhosis with refractory ascites. METHODS: 270 patients with cirrhosis with refractory ascites were randomised equally into two treatment groups to receive diuretics alone or the clonidine-diuretics association. The primary end point was clonidine-diuretic response rate. Secondary end points were mean daily dose of diuretics, times of paracentesis, ascites-related readmission and 1-year survival rate. RESULTS: Good clonidine responders had better natriuresis and diuresis as well as a significant decrease in abdominal circumference, plasma renin, aldosterone and norepinephrine levels. The overall clonidine-diuretics response rate was 55-60%. In patients with cirrhosis, the prevalence of ARDA(2)C WD/DD and GNB3 CT/TT genotypes was 71% and 77%, respectively. Among the responders, 71% of patients with cirrhosis had the ARDA(2)C WD/DD genotype and 67% has the GNB3 CT/TT genotype. Besides higher baseline norepinephrine levels, the presence of both ARDA(2)C WD/DD and GNB3 CT/TT genotypes showed a positive predictive value of 82% and a negative predictive value of 79% for good clonidine response. CONCLUSIONS: These results suggest that neurohormonal and genetic testing may be used as predictive factors for the additive effects of clonidine on the diuresis and natriuresis effects of diuretics in patients with cirrhosis with refractory ascites.

Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells.

BACKGROUND: Src family kinases control multiple cancer cell properties including cell cycle progression, survival, and metastasis. Recent studies suggest that the Src inhibitor dasatinib blocks these critical cancer cell functions. METHODS: Because the molecular mechanism of action of dasatinib in breast cancers has not been investigated, we evaluated the effects of dasatinib as a single agent and in combination with the commonly used chemotherapeutic doxorubicin, on the proliferation, viability, and invasive capacity of breast cancer cells lines earlier categorised as dasatinib-sensitive (MDA-MB-231) and moderately resistant (MCF7 and T47D). We also tested the effects of these drugs on the actin cytoskeleton and associated signalling pathways. RESULTS: The cell lines tested varied widely in sensitivity to growth inhibition (IC(50)=0.16-12.3 microM), despite comparable Src kinase inhibition by dasatinib (IC(50)=17-37 nM). In the most sensitive cell line, MDA-MB-231, dasatinib treatment induced significant G(1) accumulation with little apoptosis, disrupted cellular morphology, blocked migration, inhibited invasion through Matrigel (P<0.01), and blocked the formation of invadopodia (P<0.001). Importantly, combination treatment with doxorubicin resulted in synergistic growth inhibition in all cell lines and blocked the migration and invasion of the highly metastatic, triple-negative MDA-MB-231 cell line. CONCLUSION: The observed synergy between dasatinib and doxorubicin warrants the re-evaluation of dasatinib as an effective agent in multi-drug regimens for the treatment of invasive breast cancers.

YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-kappaB signaling to HIF-1alpha accumulation during hypoxia.

Hypoxia-inducible factor 1 (HIF-1), a transcription factor that is critical for tumor adaptation to microenvironmental stimuli, represents an attractive chemotherapeutic target. YC-1 is a novel antitumor agent that inhibits HIF-1 through previously unexplained mechanisms. In the present study, YC-1 was found to prevent HIF-1alpha and HIF-1beta accumulation in response to hypoxia or mitogen treatment in PC-3 prostate cancer cells. Neither HIF-1alpha protein half-life nor mRNA level was affected by YC-1. However, YC-1 was found to suppress the PI3K/Akt/mTOR/4E-BP pathway, which serves to regulate HIF-1alpha expression at the translational step. We demonstrated that YC-1 also inhibited hypoxia-induced activation of nuclear factor (NF)-kappaB, a downstream target of Akt. Two modulators of the Akt/NF-kappaB pathway, caffeic acid phenethyl ester and evodiamine, were observed to decrease HIF-1alpha expression. Additionally, overexpression of NF-kappaB partly reversed the ability of wortmannin to inhibit HIF-1alpha-dependent transcriptional activity, suggesting that NF-kappaB contributes to Akt-mediated HIF-1alpha accumulation during hypoxia. Overall, we identify a potential molecular mechanism whereby YC-1 serves to reduce HIF-1 expression.

Emphysema in young adult survivors of moderate-to-severe bronchopulmonary dysplasia.

Improved survival following extreme preterm birth complicated by bronchopulmonary dysplasia (BPD) is resulting in an increasing number of affected infants surviving to adulthood. The aim of the present pilot study was to describe the functional and structural pulmonary sequelae of moderate and severe BPD in a population of adult survivors. All babies were cared for at one institution (King Edward Memorial Hospital, Subiaco, Australia). Subjects born between 1980 and 1987 with birthweight <1,500 g and requiring supplementary oxygen at 36 weeks post-menstrual age were identified from a complete neonatal database and recruited prospectively. Local physicians were concurrently asked to refer suitable patients. Demographics, respiratory symptoms and examination results, pulmonary function tests and computed tomography images were acquired. In total, 21 subjects were studied. Of these, 12 were female, the median (range) age was 19 (17-33) yrs and 15 (71%) had persistent respiratory symptoms. The median (range) forced expiratory volume in one second (FEV(1)) z-score was -0.77 (-8.20-1.37), the forced expiratory flow at 25-75% of forced vital capacity was -1.81 (-6.00-0.75) and the diffusing capacity of the lung for carbon monoxide was -5.04 (-13.17- -1.24). Computed tomography was carried out on 19 subjects and all had abnormal findings, with emphysema being the most common, present in 84% of subjects. The extent of radiological emphysema was inversely related to the FEV(1) z-score. Young adult survivors of moderate and severe bronchopulmonary dysplasia may be left with residual functional and characteristic structural pulmonary abnormalities, most notably emphysema.

YC-1 induces apoptosis of human renal carcinoma A498 cells in vitro and in vivo through activation of the JNK pathway.

BACKGROUND AND PURPOSE: The aim of this study was to elucidate the mechanism of YC-1{3-(5'-hydroxy methyl-2'-furyl)-1-benzylindazole}-induced human renal carcinoma cells apoptosis and to evaluate the potency of YC-1 in models of tumour growth in mice. EXPERIMENTAL APPROACH: YC-1-mediated apoptosis was assessed by analysis of MTT, SRB, DAPI staining and flow cytometry analysis. Knockdown of JNK protein was achieved by transient transfection using siRNA. The mechanisms of action of YC-1 on different signalling pathways involved were studied using western blot. Fas clustering was analysed by confocal microscopy and in vivo efficacy was examined in a A498 xenograft model. KEY RESULTS: YC-1 displayed cytotoxicity in renal carcinoma cells at 10(-7)-10(-8) M. Increased condensation of chromatin was observed and an increase in the cell population in subG1 phase. Moreover, YC-1 triggered mitochondria-mediated and caspase-dependent pathways. YC-1 significantly induced Fas ligand expression, but did not modify either the protein levels of death receptors or ligands. In addition, Fas clustering in cells responsive to YC-1 was observed, suggesting involvement of a Fas-mediated pathway. Furthermore, YC-1 markedly induced phosphorylation of JNK and a JNK inhibitor, SP600125, and siRNA JNK1/2 significantly reversed YC-1-induced cytotoxicity and protein expression. We suggest that YC-1 induced JNK phosphorylation, the upregulation of FasL and Fas receptor clustering to promote the activation of caspases 8 and 3, resulting in apoptosis. Finally, we demonstrated the antitumour effect of YC-1 in vivo. CONCLUSIONS AND IMPLICATIONS: These data suggest that YC-1 is a good candidate for development as an anticancer drug.

Dose-Response Relationship Between Diltiazem and Tacrolimus and Its Safety in Renal Transplant Recipients.

BACKGROUND: Inhibition of calcineurin inhibitor (CNI) metabolism with diltiazem reduces the dose of tacrolimus required to achieve its therapeutic blood concentration in kidney transplant recipients (KTRs). This cost-savings maneuver is practiced in several countries, including Malaysia, but the actual impacts of diltiazem on tacrolimus blood concentration, dose-response relationship, cost-savings, and safety aspects are unknown. METHODS: This retrospective study was performed on all KTRs ≥18 years of age at our center from January 1, 2006 to December 31, 2015, who were prescribed diltiazem as tacrolimus-sparing agent. Blood tacrolimus trough level (TacC0) and other relevant clinical data for 70 eligible KTRs were reviewed. RESULTS: The dose of 1 mg tacrolimus resulted in a median TacC0 of 0.83 ± 0.52 ng/mL. With the introduction of a 90-mg/d dose diltiazem, there was a significant TacC0 increase to 1.39 ± 1.31 ng/mL/mg tacrolimus (P < .01). A further 90-mg increase in diltiazem to 180 mg/d resulted in a further increase of TacC0 to 1.66 ± 2.58 ng/mL/mg tacrolimus (P = .01). After this, despite a progressive increment of every 90-mg/d dose diltiazem to 270 mg/d and 360 mg/d, there was no further increment in TacC0 (1.44 ± 1.15 ng/mL/mg tacrolimus and 1.24 ± 0.94 ng/mL/mg tacrolimus, respectively [P < .01]). Addition of 180 mg/d diltiazem reduced the required tacrolimus dose to 4 mg/d, resulting in a cost-savings of USD 2045.92 per year (per patient) at our center. Adverse effects reported within 3 months of diltiazem introduction were bradycardia (1.4%) and postural hypotension (1.4%), which resolved after diltiazem dose reduction. CONCLUSION: Coadministration of tacrolimus and diltiazem in KTRs appeared to be safe and resulted in a TacC0 increment until reaching a 180-mg/d total diltiazem dose, at which point it began to decrease. This approach will result in a marked savings in immunosuppression costs among KTRs in Malaysia.

YC-1 attenuates LPS-induced proinflammatory responses and activation of nuclear factor-kappaB in microglia.

BACKGROUND AND PURPOSE: An inflammatory response in the central nervous system mediated by the activation of microglia is a key event in the early stages of the development of neurodegenerative diseases. LPS has been reported to cause marked microglia activation. It is very important to develop drugs that can inhibit microglia activation and neuroinflammation. Here, we investigated the inhibitory effect of YC-1, a known activator of soluble guanylyl cyclase, against LPS-induced inflammatory responses in microglia. EXPERIMENTAL APPROACH: To understand the inhibitory effects of YC-1 on LPS-induced neuroinflammation, primary cultures of rat microglia and the microglia cell line BV-2 were used. To examine the mechanism of action of YC-1, LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production, iNOS, COX-2 and cytokine expression were analyzed by Griess reaction, ELISA, Western blotting and RT-PCR, respectively. The effect of YC-1 on LPS-induced activation of nuclear factor kappa B (NF-kappaB) was studied by NF-kappaB reporter assay and immunofluorocytochemistry. KEY RESULTS: YC-1 inhibited LPS-induced production of NO and PGE2 in a concentration-dependent manner. The protein and mRNA expression of iNOS and COX-2 in response to LPS application were also decreased by YC-1. In addition, YC-1 effectively reduced LPS-induced expression of the mRNA for the proinflammatory cytokines, TNF-alpha and IL-1beta. Furthermore, YC-1 inhibited LPS-induced NF-kappaB activation in microglia. CONCLUSIONS AND IMPLICATIONS: YC-1 was able to inhibit LPS-induced iNOS and COX-2 expression and NF-kappaB activation, indicating that YC-1 may be developed as an anti-inflammatory neuroprotective agent.

BLOC-1 deficiency causes alterations in amino acid profile and in phospholipid and adenosine metabolism in the postnatal mouse hippocampus.

Biogenesis of lysosome-related organelles complex-1 (BLOC-1) is a protein complex involved in the formation of endosomal tubular structures that mediates the sorting of protein cargoes to specialised compartments. In this study, we present insights into the metabolic consequences caused by BLOC-1 deficiency in pallid mice, which carry a null mutation in the Bloc1s6 gene encoding an essential component of this complex. The metabolome of the hippocampus of pallid mice was analysed using an untargeted, liquid chromatography-coupled mass spectrometric approach. After data pre-treatment, statistical analysis and pathway enrichment, we have identified 28 metabolites that showed statistically significant changes between pallid and wild-type control. These metabolites included amino acids, nucleobase-containing compounds and lysophospholipids. Interestingly, pallid mice displayed increased hippocampal levels of the neurotransmitters glutamate and N-acetyl-aspartyl-glutamic acid (NAAG) and their precursor glutamine. Expression of the sodium-coupled neutral amino acid transporter 1 (SNAT1), which transports glutamine into neurons, was also upregulated. Conversely, levels of the neurotransmitter precursors phenylalanine and tryptophan were decreased. Interestingly, many of these changes could be mapped to overlapping metabolic pathways. The observed metabolic alterations are likely to affect neurotransmission and neuronal homeostasis and in turn could mediate the memory and behavioural impairments observed in BLOC-1-deficient mice.