The hindbrain and cortico-reticular pathway in adolescent idiopathic scoliosis.

AIM: To characterise the corticoreticular pathway (CRP) in a case-control cohort of adolescent idiopathic scoliosis (AIS) patients using high-resolution slice-accelerated readout-segmented echo-planar diffusion tensor imaging (DTI) to enhance the discrimination of small brainstem nuclei in comparison to automated whole-brain volumetry and tractography and their clinical correlates. MATERIALS AND METHODS: Thirty-four participants (16 AIS patients, 18 healthy controls) underwent clinical and orthopaedic assessments and brain magnetic resonance imaging (MRI) on a 3 T MRI machine. Automated whole-brain volume-based morphometry, tract-based spatial statistics analysis, and manual CRP tractography by two independent raters were performed. Intra-rater and inter-rater agreement of DTI metrics from CRP tractography were assessed by intraclass correlation coefficient. Normalised structural brain volumes and DTI metrics were compared between groups using Student's t-tests. Linear correlation analysis between imaging parameters and clinical scores was also performed. RESULTS: AIS patients demonstrated a significantly larger pons volume compared to controls (p=0.006). Significant inter-side CRP differences in mean (p=0.02) and axial diffusivity (p=0.01) were found in patients only. Asymmetry in CRP fractional anisotropy significantly correlated with the Cobb angle (p=0.03). CONCLUSION: Relative pontine hypertrophy and asymmetry in CRP DTI metrics suggest central supranuclear inter-hemispheric imbalance in AIS, and support the role of the CRP in axial muscle tone. Longitudinal evaluation of CRP DTI metrics in the prediction of AIS progression may be clinically relevant.

Risks and impacts of thromboembolism in patients with pancreatic cancer.

INTRODUCTION: Patients with pancreatic cancer have a high risk of thromboembolism (TE), which may increase mortality. Most relevant studies have been conducted in Western populations. We investigated risk factors for TE in a predominantly Chinese population of patients with pancreatic cancer, along with effects of TE on overall survival. METHODS: This retrospective cohort study included patients diagnosed with exocrine pancreatic cancer in Prince of Wales Hospital in Hong Kong between 2010 and 2015. Data regarding patient demographics, World Health Organization performance status, stage, treatment, TE-related information, and time of death (if applicable) were retrieved from electronic medical records. Univariate and multivariable logistic regression analyses were performed to identify risk factors for TE. Survival analyses were performed using Kaplan-Meier analysis and Cox proportional hazards regression. RESULTS: In total, 365 patients were included in the study. The overall incidence of TE (14.8%) was lower than in Western populations. In univariate logistic regression analysis, stage IV disease and non-head pancreatic cancer were significantly associated with TE (both P=0.01). Multivariable logistic regression analysis showed that stage IV disease was a significant risk factor (odds ratio=1.08, 95% confidence interval [CI]=1.00-1.17; P=0.046). Median overall survival did not significantly differ between patients with and without TE (4.88 months vs 7.80 months, hazard ratio=1.08, 95% CI=0.80-1.49; P=0.58) and between patients with TE who received anticoagulation treatment or not (5.63 months vs 4.77 months, hazard ratio=0.72, 95% CI=0.40-1.29; P=0.27). CONCLUSION: The incidence of TE was low in our Chinese cohort. Stage IV disease increased the risk of TE. Overall survival was not affected by TE or its treatment.

Effects of primary granulocyte-colony stimulating factor prophylaxis on neutropenic toxicity and chemotherapy dose delivery in Chinese patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy: a retrospective cohort study.

INTRODUCTION: This study was performed to examine the effects of primary granulocyte-colony stimulating factor (G-CSF) prophylaxis on neutropenic toxicity, chemotherapy delivery, and hospitalisation among Chinese patients with breast cancer in Hong Kong. METHODS: This retrospective study included patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy from November 2007 to October 2013 at Princess Margaret Hospital. Data were collected regarding the usage of G-CSF prophylaxis; incidences of grade 3 or 4 neutropenia, febrile neutropenia, non-neutropenic fever, and infection; hospital admissions, and chemotherapy dose delivery. Patients who began to receive G-CSF prophylaxis during the first cycle of chemotherapy and continued such prophylaxis in subsequent cycles were regarded as the primary G-CSF prophylaxis group. RESULTS: In total, 231 female Chinese patients with breast cancer were included in the analysis. Overall, 193 (83.5%) patients received primary G-CSF prophylaxis. The demographics and tumour characteristics were comparable between patients with and without primary G-CSF prophylaxis. Primary G-CSF prophylaxis significantly reduced febrile neutropenia incidence from 31.6% to 14.5% (relative risk=0.45, 95% confidence interval=0.25-0.81). Primary G-CSF prophylaxis also significantly reduced the incidence of grade 3 or 4 neutropenia from 57.9% to 24.7% (relative risk=0.43, 95% confidence interval=0.30-0.62) and the incidence of febrile neutropenia-related hospital admission from 31.6% to 12.4% (P=0.025). Finally, it enabled more patients to receive adequate chemotherapy dose delivery. CONCLUSION: Primary G-CSF prophylaxis effectively reduced the incidences of grade 3 or 4 neutropenia and febrile neutropenia, while enabling adequate chemotherapy dose delivery and reducing hospital admissions among Chinese patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy.

Mobility performance predicts incident depression: A systematic review and meta-analysis.

Impaired mobility often co-occurs with depression. However, there is no systematic review evidence as to whether mobility impairments precede the onset of depression. The objective of this systematic review and meta-analysis was to evaluate whether mobility impairment could predict incident depression. A systematic search of cohort studies were performed in MEDLINE, EMBASE, CINAHL and PsycINFO. The target population was people with no depressive symptoms at baseline and follow-up for depression or depressive symptoms of at least three months. Of 1061 identified abstracts, 13 studies met the review eligibility criteria. The majority of included studies (8 out of 13) were of high methodological quality. Follow-up periods ranged from 12 months to 16 years. Gait speed was the most consistently reported mobility measure. Participants with slow gait speed were at higher risk of developing depressive symptoms (pooled OR = 1.93, 95%CI: 1.54 to 2.42, 11 studies). This review shows that slow gait speed is predictive of the onset of depressive symptoms. Systematic review registration number: CRD42020153791.

Periventricular white matter hyperintensity burden and cognitive impairment in early Parkinson's disease.

BACKGROUND AND PURPOSE: This study quantified the total brain and periventricular white matter hyperintensity (WMH) burdens in patients with early Parkinson's disease (PD) and explored their associations with cardiovascular risk factors and cognitive performance. METHODS: A total of 175 non-demented patients with early PD who had undergone baseline brain magnetic resonance imaging were included. Comprehensive neurocognitive testing was conducted to identify PD with mild cognitive impairment (PD-MCI) and to evaluate performances in individual cognitive domains. Cardiovascular risk was expressed as a modified Framingham 10-year cardiovascular risk score (mFRS). RESULTS: A total of 53.7% of this early PD cohort fulfilled the diagnostic criteria for PD-MCI. An increase in mFRS was significantly associated with increases in the total brain WMH (P = 0.015) and periventricular WMH (P = 0.040) burden, independent of age and gender. The periventricular WMH burden was significantly associated with PD-MCI (P = 0.046) in early PD, independent of cardiovascular risk factors. Patients in the 5th quintile of periventricular WMH burden were 8.6 times more likely to have PD-MCI compared with patients in the 1st quintile of periventricular WMH burden (P = 0.004). However, total brain WMH burden was not associated with PD-MCI (P = 0.158). In individual cognitive domains, heavier periventricular WMH burden was associated with worse executive function and visuospatial function independent of cardiovascular risk factors. CONCLUSION: Periventricular WMHs are a useful imaging biomarker for cognitive impairment in early PD. Cardiovascular risk factors, although associated with periventricular WMHs, were unable to fully explain the association between periventricular WMHs and cognitive impairment in early PD.

Periventricular White Matter Abnormalities on Diffusion Tensor Imaging of Postural Instability Gait Disorder Parkinsonism.

BACKGROUND AND PURPOSE: Postural instability gait disorder is a motor subtype of Parkinson disease associated with predominant gait dysfunction. We investigated the periventricular white matter comprising longitudinal, thalamic, and callosal fibers using diffusion tensor MR Imaging and examined clinical correlates in a cohort of patients with Parkinson disease and postural instability gait disorder and healthy controls. MATERIALS AND METHODS: All subjects underwent the Tinetti Gait and Balance Assessment and brain MR imaging. The DTI indices (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) from ROIs dropped over the superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, anterior thalamic radiation, anterior and posterior limbs of the internal capsule, and the genu and body of corpus callosum were evaluated. RESULTS: Our findings showed that the superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, genu of the corpus callosum, and body of the corpus callosum are more affected in postural instability gait disorder than in those with Parkinson disease or healthy controls, with more group differences among the longitudinal fibers. Only the callosal fibers differentiated the postural instability gait disorder and Parkinson disease groups. DTI measures in the superior longitudinal fasciculus, frontostriatal fibers (anterior thalamic radiation, anterior limb of the internal capsule), and genu of the corpus callosum fibers correlated with clinical gait severity. CONCLUSIONS: Findings from this case-control cohort lend further evidence to the role of extranigral pathology and, specifically, the periventricular fibers in the pathophysiology of postural instability gait disorder.

Mood and neural correlates of excessive daytime sleepiness in Parkinson's disease.

For patients with Parkinson's disease (PD), excessive daytime sleepiness (PD-EDS) is a debilitating non-motor symptom and may be affected by mood symptoms, especially depression and anxiety. Few neuroimaging works have attempted to identify the neural features of PD-EDS, but various findings were reported. The purpose of this study was to systematically review the literature on mood and neuroimaging correlates of PD-EDS. A MEDLINE, PubMed, EMBASE, and PsycInfo search for peer-reviewed original research articles on depression, anxiety, and neuroimaging in PD-EDS identified 26 studies on depression, nine on anxiety, and eight on neuroimaging. Half of the studies reported greater depression in PD-EDS-positive patients compared with PD-EDS-negative patients. There was a significantly positive correlation between depression and PD-EDS. Limited studies on anxiety in PD-EDS suggested a weak correlation between anxiety and EDS. For depression and anxiety, the effect sizes were medium when EDS was subjectively measured, but became small when EDS was objective measured. Current neuroimaging studies generally suggested diminished neural structural and functional features (eg, brain volume, white matter integrity as indicated by fractional anisotropy, and cerebral metabolism) in patients with PD-EDS. Future studies should apply objective and subjective measures of mood symptoms and EDS and improve the neuroimaging methodology via using multimodal techniques and whole-brain analysis to provide new clues on the mood and neural correlates of PD-EDS.

Depression, anxiety, and apathy in Parkinson's disease: insights from neuroimaging studies.

Depression, anxiety and apathy are common mood disturbances in Parkinson's disease (PD) but their pathophysiology is unclear. Advanced neuroimaging has been increasingly used to unravel neural substrates linked to these disturbances. A systematic review is provided of neuroimaging findings in depression, anxiety and apathy in PD. A PubMed, MEDLINE and EMBASE search of peer-reviewed original research articles on these mood disturbances in PD identified 38 studies on depression, eight on anxiety and 14 on apathy in PD. Most of the imaging studies used either position emission tomography or single-photon emission computed tomography techniques. These studies generally suggest increased neural activity in the prefrontal regions and decreased functional connectivity between the prefrontal-limbic networks in depressed patients. Functional imaging studies revealed an inverse correlation between dopaminergic density in the caudate and putamen with the severity of anxiety in PD. There was no consistent correlation between dopaminergic density of thalamus and anxiety. Studies demonstrated both positive and inverse correlations between apathy and metabolism or activity in the striatum, amygdalar, prefrontal, temporal and parietal regions. The clinical variability of study subjects and differences in image pre-processing and analytical strategies may contribute to discrepant findings in these studies. Both nigrostriatal and extra-nigrostriatal pathways (in particular the frontal region and its connecting areas) are affected in mood disorders in PD. Identifying the relative contributions of these neural pathways in PD patients with overlapping motor and mood symptoms could provide new pathophysiological clues for the development of better therapeutic targets for affected patients.

Contribution of serine, folate and glycine metabolism to the ATP, NADPH and purine requirements of cancer cells.

Recent observations on cancer cell metabolism indicate increased serine synthesis from glucose as a marker of poor prognosis. We have predicted that a fraction of the synthesized serine is routed to a pathway for ATP production. The pathway is composed by reactions from serine synthesis, one-carbon (folate) metabolism and the glycine cleavage system (SOG pathway). Here we show that the SOG pathway is upregulated at the level of gene expression in a subset of human tumors and that its level of expression correlates with gene signatures of cell proliferation and Myc target activation. We have also estimated the SOG pathway metabolic flux in the NCI60 tumor-derived cell lines, using previously reported exchange fluxes and a personalized model of cell metabolism. We find that the estimated rates of reactions in the SOG pathway are highly correlated with the proliferation rates of these cell lines. We also observe that the SOG pathway contributes significantly to the energy requirements of biosynthesis, to the NADPH requirement for fatty acid synthesis and to the synthesis of purines. Finally, when the PC-3 prostate cancer cell line is treated with the antifolate methotrexate, we observe a decrease in the ATP levels, AMP kinase activation and a decrease in ribonucleotides and fatty acids synthesized from [1,2-(13)C2]-D-glucose as the single tracer. Taken together our results indicate that the SOG pathway activity increases with the rate of cell proliferation and it contributes to the biosynthetic requirements of purines, ATP and NADPH of cancer cells.

Efficacy and safety of deferasirox at low and high iron burdens: results from the EPIC magnetic resonance imaging substudy.

The effect of deferasirox dosing tailored for iron burden and iron loading based on liver iron concentration (LIC) was assessed over 1 year in less versus more heavily iron-overloaded patients in a substudy of the Evaluation of Patients' Iron Chelation with Exjade®. Deferasirox starting dose was 10-30 mg/kg/day, depending on blood transfusion frequency, with recommended dose adjustments every 3 months. Therapeutic goals were LIC maintenance or reduction in patients with baseline LIC <7 or ≥7 mg Fe/g dry weight (dw), respectively. Changes in LIC (R2-magnetic resonance imaging) and serum ferritin after 1 year were assessed. Adverse events (AEs) and laboratory parameters were monitored throughout. Of 374 patients, 71 and 303 had baseline LIC <7 and ≥7 mg Fe/g dw, respectively; mean deferasirox doses were 20.7 and 27.1 mg/kg/day (overall average time to dose increase, 24 weeks). At 1 year, mean LIC and median serum ferritin levels were maintained in the low-iron cohort (-0.02 ± 2.4 mg Fe/g dw, -57 ng/mL; P = not significant) and significantly decreased in the high-iron cohort (-6.1 ± 9.1 mg Fe/g dw, -830 ng/mL; P < 0.0001). Drug-related gastrointestinal AEs, mostly mild to moderate, were more frequently reported in the <7 versus ≥7 mg Fe/g dw cohort (39.4 versus 20.8 %; P = 0.001) and were not confounded by diagnosis, dosing, ethnicity, or hepatitis B and/or C history. Reported serum creatinine increases did not increase in low- versus high-iron cohort patients. Deferasirox doses of 20 mg/kg/day maintained LIC <7 mg Fe/g dw and doses of 30 mg/kg/day were required for net iron reduction in the high-iron cohort, with clinically manageable safety profiles. The higher incidence of gastrointestinal AEs at lower iron burdens requires further investigation.

Ministry of Health clinical practice guidelines: depression.

The Ministry of Health (MOH) have updated the clinical practice guidelines on Depression to provide doctors and patients in Singapore with evidence-based treatment for depression. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on Depression, for the information of readers of the Singapore Medical Journal. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/home/Publications/guidelines/cpg/2012/depression.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Visceral adipose tissue, but not waist circumference is a better measure of metabolic risk in Singaporean Chinese and Indian men.

OBJECTIVES: Visceral adipose tissue (VAT) is an independent risk factor in cardiometabolic diseases and is commonly measured by computed tomography (CT). It is measured clinically by waist circumference (WC). The L4/5 intervertebral space VAT (L4/5 VAT) is traditionally used to represent total VAT volume. We set out to determine (1) the level of intervertebral space on CT that best approximates the total VAT volume; (2) compare the association between WC and VAT in Singaporean Chinese and Indian; and (3) examine the correlation between VAT and cardiometabolic risk factors. SUBJECTS: A total of 60 Chinese and 60 Asian Indian men older than 60 years were recruited. Their medical history was taken and anthropometry was measured. Fasting glucose, insulin, lipids, adipokines and inflammatory markers were measured. Insulin resistance was evaluated by homeostasis model assessment-insulin resistance. VAT was determined by CT. Total VAT volume was calculated in 22 patients from VAT areas at seven intervertebral levels. The optimal VAT area most representative of total VAT volume was determined and used for all patients to approximate total VAT volume. RESULTS: The VAT area at L2/3 intervertebral space (L2/3 VAT) correlated almost perfectly with VAT volume (R(2)=0.974 and 0.946 for Chinese and Indians, respectively). SUBJECTS from the two races had similar height, weight, body mass index (BMI), WC and L2/3 VAT but more Indian men had hypertension, hyperlipidemia and type 2 diabetes mellitus. WC was correlated with the L2/3 VAT area in both Chinese (r=0.484, P<0.001) and Indian subjects (r=0.366, P=0.004) without racial difference (P=0.2 for interaction term). L2/3 VAT also correlated better with cardiometabolic risk factors, adipokines and C-reactive protein than WC, BMI or L4/5 VAT. CONCLUSION: The L2-L3 intervertebral space was the best anatomic level for a single-slice CT cross-sectional area measurement of VAT to approximate total body visceral adipose volume in this population of Chinese and Asian Indian men older than 60 years. L2/3 VAT was better correlated with multiple cardiovascular risk factors, adipokines and inflammatory marker than either L4/5 VAT, WC or BMI.

The spatial location of the mandibular canal in Chinese: a CT study.

The inferior alveolar nerve (IAN) is vulnerable to injury from mandible fractures and surgical procedures so anatomical variations of IAN are important. Postoperative sensory alteration of the lip and chin region is high after mandibular orthognathic surgery. The incidence of IAN paresthesia following sagittal split ramus osteotomy (SSRO) ranges from 54% to 86% at 4-8 days, 41 to 75% at 1 month, 33 to 66% at 3 months, 17 to 58% at 6 months and 15 to 33% at 1 year postoperatively. This study determined the anatomical position of the mandibular canal in relation to cortical bone and molar teeth in Chinese using archived CT records. The mandibular canal was the farthest from the buccal cortex at the second molar region (mean 6.79mm; minimum distance 4.80mm). The anatomical location of the mandibular canal in local Chinese compares with studies on Asian cadavers. The mandible body was thickest in the region of the second molar (11.9mm). The vertical buccal cut for SSRO should be in the region of the mandibular second molar where the bone is thickest and the mandibular canal is furthest from the buccal cortex. The safe depth for the vertical buccal cut is 4.8mm (minimum horizontal distance).

Ministry of Health clinical practice guidelines: schizophrenia.

The Ministry of Health (MOH) has updated the clinical practice guidelines on Schizophrenia to provide doctors and patients in Singapore with evidence-based treatment for schizophrenia. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on Schizophrenia, for the information of readers of the Singapore Medical Journal. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov. sg/mohcorp/publications.aspx?id=26138. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Auditory hallucinations and migraine of possible brainstem origin.

BACKGROUND: Concurrence of migraine and hallucinations is extremely rare and the underlying mechanism is poorly understood. METHODS: We report a 22-year-old man with migraine associated with auditory hallucinations. Concurrent psychotic illness has been excluded. RESULTS: Brain MR scans showed a stable, patchy FLAIR hyperintensity over the posterolateral aspect of the left cerebral peduncle, just below the level of the red nucleus. This was felt to represent an area of gliosis based on the interval stability over 19 months. There was absence of features for aggressive neoplasms, such as lesional high cellular turnover (choline/NAA ratio >1.0) or high cerebral blood volume on advanced MR imaging with MR spectroscopy and dynamic perfusion MR. EEG and brainstem auditory evoked potentials were unremarkable. CONCLUSIONS: To our knowledge, there are no reports to date on similar auditory hallucinations in adult migraine patients, as well as with associated MRI brainstem lesions. The peduncular lesion could represent a previous migrainous infarct, and a possible analogy can be drawn from the descriptions of peduncular hallucinosis. Brainstem lesions, particularly in the midbrain and pons, have rarely been associated with this condition. It has been postulated that the damage to ascending reticular systems or thalamocortical circuitry may contribute to its pathogenesis.

Maternal nutrient restriction during late gestation and early postnatal growth in sheep differentially reset the control of energy metabolism in the gastric mucosa.

Fetal growth restriction followed by accelerated postnatal growth contributes to impaired metabolic function in adulthood. The extent to which these outcomes may be mediated centrally within the hypothalamus, as opposed to in the periphery within the digestive tract, remains unknown. In a sheep model, we achieved intrauterine growth restriction experimentally by maternal nutrient restriction (R) that involved a 40% reduction in food intake through late gestation. R offspring were then either reared singly to accelerate postnatal growth (RA) or as twins and compared with controls also reared singly. From weaning, all offspring were maintained indoors until adulthood. A reduced litter size accelerated postnatal growth for only the first month of lactation. Independently from postnatal weight gain and later fat mass, R animals developed insulin resistance as adults. However, restricted accelerated offspring compared with both the control accelerated and restricted restricted offspring ate less and had higher fasting plasma leptin as adults, an adaptation which was accompanied by changes in energy sensing and cell proliferation within the abomasum. Additionally, although fetal restriction down-regulated gene expression of mammalian target of rapamycin and carnitine palmitoyltransferase 1-dependent pathways in the abomasum, RA offspring compensated for this by exhibiting greater activity of AMP-activated kinase-dependent pathways. This study demonstrates a role for perinatal nutrition in the peripheral control of food intake and in energy sensing in the gastric mucosal and emphasizes the importance of diet in early life in regulating energy metabolism during adulthood.