Our recent work has shown the feasibility of using a refined immunomagnetic enrichment (IE) assay to detect cytokeratin 20-positive circulating tumour cells (CK20 pCTCs) in colorectal cancer (CRC) patients. We attempted to improve the sensitivity for CRC by detecting another intestinal-type differentiation marker, CDX2 pCTCs, using the same methodology.
CDX2 pCTCs were detected in patients with CRC, colorectal adenoma (CAD), benign colorectal diseases (BCD), other common cancers (OCC) and normal subjects (NS). Statistical analysis was used to correlate CDX2 pCTCs to the clinicohistopathological factors, recurrence, metastasis and survival after follow-up for 42 months in CRC patients.
CDX2 pCTCs were detected in 81% CRC patients (73 out of 90, median number=21.5 CTCs), 7.5% CAD patients (3 out of 40), 0% patients with BCD (0 out of 90), 2.5% patients with OCC (2 out of 80) and 0% NS (0 out of 40). Furthermore, statistical analysis showed that CDX2 pCTC numbers were associated with tumour- node-metastasis stage and lymph node status. Using the median CDX2 pCTC numbers as the cutoff points, stratified groups of CRC patients had significant differences in their recurrence and survival.
This study showed that the refined IE assay can detect CDX2 pCTCs with high sensitivity and that CDX2 pCTCs can generate clinically important information for CRC patients.
clinical significance; CDX2-positive circulating tumour cells; colorectal cancer
Patients with dural arteriovenous fistula (DAVF) are at higher risk of developing neurological deficits when there is retrograde leptomeningeal venous drainage. Our aim is to demonstrate the presence of dilated deep medullary veins in the brain on magnetic resonance imaging (MR) in this group of patients, and to assess their clinical significance. Nine patients with angiographically proven DAVF associated with leptomeningeal venous drainage who had MR before treatment were studied. MR was performed in at least two orthogonal planes before and after gadolinium administration. The dural fistula was located at the cavernous sinus in five patients, at the transverse-sigmoid sinus in three and at the tentorium in one. Dilated deep medullary veins were noted in six patients. Of these, four showed parenchymal abnormalities which included intracerebral haematoma, venous infarction, brain oedema and T2 hyperintensity in brainstem. Venous varix was present in one patient. No neurological complication or parenchymal change was observed in the three patients without dilated deep medullary veins. Therefore, in patients with intracranial DAVF associated with leptomeningeal venous recruitment, the MR finding of dilated deep medullary veins suggests a more severe degree of venous hypertension and congestion in the brain. This subgroup of patients has a much higher chance of neurological complications and warrants urgent intervention.
dural arteriovenous fistula, intracranial, magnetic resonance imaging
By generalizing the concept of spoof surface Plasmons (Science 305, 847), we analytically demonstrate that subwavelength quarter-wave and half-wave plates can be realized in a metal hole array (MHA) sandwiched by two thin-layer materials, whose optical responses can be characterized by their optical conductivities. These abilities of polarization conversion can be attributed to the novel eigenstates induced by the hybridization of the spoof surface plamsons with the current generated in the thin-layer. Due to this mechanism, the robustness of the system is promised. The analytic predictions are verified numerically by modeling the thin-layer material as an experimentally feasible topological-insulator/SiO2 multilayer. Moreover, the possibility of extending the principle to a broad range of materials is dicussed.
Protection against cellular stress from various sources, such as nutritional, physical, pathogenic, or oncogenic, results in the induction of both intrinsic and extrinsic cellular protection mechanisms that collectively limit the damage these insults inflict on the host. The major extrinsic protection mechanism against cellular stress is the immune system. Indeed, it has been well described that cells that are stressed due to association with viral infection or early malignant transformation can be directly sensed by the immune system, particularly natural killer (NK) cells. Although the ability of NK cells to directly recognize and respond to stressed cells is well appreciated, the mechanisms and the breadth of cell-intrinsic responses that are intimately linked with their activation are only beginning to be uncovered. This review will provide a brief introduction to NK cells and the relevant receptors and ligands involved in direct responses to cellular stress. This will be followed by an in-depth discussion surrounding the various intrinsic responses to stress that can naturally engage NK cells, and how therapeutic agents may induce specific activation of NK cells and other innate immune cells by activating cellular responses to stress.
cellular stress; NK cells; therapy; cancer; immunogenic
Prediabetic NOD mice exhibit hyperglucagonemia, possibly due to an intrinsic α-cell defect. Here, we show that the expression of a potential glucagon inhibitor, the adenosine A1 receptor (Adora1), is gradually diminished in α-cells of NOD mice, autoantibody-positive (AA+) and overtly type 1 diabetic (T1D) patients during the progression of disease. We demonstrated that islet inflammation was associated with loss of Adora1 expression through the alternative splicing of Adora1. Expression of the spliced variant (Adora1-Var) was upregulated in the pancreas of 12-week-old NOD versus age-matched NOD.B10 (non–diabetes-susceptible) control mice and was detected in the pancreas of AA+ patients but not in control subjects or overtly diabetic patients, suggesting that inflammation drives the splicing of Adora1. We subsequently demonstrated that Adora1-Var expression was upregulated in the islets of NOD.B10 mice after exposure to inflammatory cytokines and in the pancreas of NOD.SCID mice after adoptive transfer of activated autologous splenocytes. Adora1-Var encodes a dominant-negative N-terminal truncated isoform of Adora1. The splicing of Adora1 and loss of Adora1 expression on α-cells may explain the hyperglucagonemia observed in prediabetic NOD mice and may contribute to the pathogenesis of human T1D and NOD disease.
To determine the genetic association of an inflammation-related gene, formyl peptide receptor 1 (FPR1), in exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV).
The coding region of FPR1 gene was sequenced in 554 unrelated Chinese individuals: 155 exudative AMD patients, 179 PCV patients, and 220 controls. Interactions and combined effects of FPR1 with complement factor H (CFH), high temperature requirement factor A1 (HTRA1), and smoking were also investigated.
A total of 28 polymorphisms in FPR1 were identified. Single nucleotide polymorphisms (SNP) rs78488639 increased the risk to exudative AMD (P=0.043) and PCV (P=0.016), whereas SNP rs867229 decreased the risk to exudative AMD (P=0.0026), but not PCV. Homozygous G allele of rs1042229 was associated with exudative AMD (P=0.0394, odds ratio (OR)=2.27, 95% confident interval: 1.08–4.74), but not with PCV. Exudative AMD, but not PCV, was associated with the heterozygous genotypes of rs2070746 (P=0.019, OR=0.57) and rs867229 (P=0.0082, OR=0.54). Significantly, interactions were identified among FPR1 rs78488639, CFH rs800292, and HTRA1 rs11200638 in both exudative AMD and PCV. Combined heterozygous risk alleles of CFH rs800292 GA and FPR1 rs78488639 CA were posed to PCV (P=2.22 × 10−4, OR=10.47), but not exudative AMD. Furthermore, FPR1 rs78488639 CA combining with HTRA1 rs11200638 and smoking was also predisposed risks to exudative AMD and PCV.
FPR1 is associated with exudative AMD and PCV in a Hong Kong Chinese cohort. FPR1 rs78488639 interacted with CFH rs800292, HTRA1 rs11200638, and smoking, enhancing risk to exudative AMD and PCV.
Both gemcitabine and bexarotene are established single agents for the treatment of cutaneous T-cell lymphoma (CTCL). We investigated the feasibility and efficacy of combining these drugs in a single-arm phase II study.
Cutaneous T-cell lymphoma patients who had failed standard skin-directed therapy and at least one prior systemic therapy were given four cycles of gemcitabine and concurrent bexarotene for 12 weeks. Responders were continued on bexarotene maintenance until disease progression or unacceptable toxicity.
The median age was 65 years, stage IB (n=5), stage IIA (n=2), stage IIB (n=8), stage III (n=8) and stage IVA (n=12), 17 patients were erythrodermic, 17 patients were B1, and 10 patients were both erythrodermic and B1. Thirty (86%) patients completed four cycles of gemcitabine. In all, 80.0% of patients demonstrated a reduction in modified Severity-Weighted Assessment Tool (mSWAT) score although the objective disease response rate at 12 weeks was 31% (partial response (PR) 31%) and at 24 weeks 14% (PR 14%, stable disease (SD) 23%, progressive disease (PD) 54%, not evaluable 9%). Median progression-free survival was 5.3 months and median overall survival was 21.2 months.
The overall response rate of the combination did not reach the specified target to proceed further and is lower than that previously reported for gemcitabine as a single agent.
cutaneous T-cell lymphoma; mycosis fungoides; bexarotene; gemcitabine
It is always a challenge to realize extreme and unusual values of refractive index for a broad range of frequencies. We show that when water is covered by a thick, rigid and unmovable plate, it behaves like a medium with zero refractive index for water waves at any frequency. Hence, by covering water with a plate of a concave or rectangular shape, water waves can be focused or collimated in a broad range of frequencies. Experiments were conducted to demonstrate these effects and results are in excellent agreement with numerical simulations.
Mutations in the SNRNP200 gene have been reported to cause autosomal dominant retinitis pigmentosa (adRP). In this study, we evaluate the mutation profile of SNRNP200 in a cohort of southern Chinese RP patients.
Twenty adRP patients from 11 families and 165 index patients with non-syndromic RP with mixed inheritance patterns were screened for mutations in the mutation hotspots of SNRNP200. These included exons 12–16, 22–32, and 38–45, which covered the two helicase ATP-binding domains in DEAD-box and two sec-63 domains. The targeted regions were amplified by polymerase chain reaction and analyzed by direct DNA sequencing, followed by in silico analyses.
Totally 26 variants were identified, 18 of which were novel. Three non-synonymous variants (p.C502R, p.R1779H and p.I698V) were found exclusively in patients. Two of them, p.C502R and p.R1779H, were each identified in one simplex RP patient, whereas p.I698V occurred in one patient with unknown inheritance pattern. All three residues are highly conserved in SNRNP200 orthologs. Nevertheless, only p.C502R and p.R1779H were predicted to affect protein function by in silico analyses, suggesting these two variants are likely to be disease-causing mutations. Notably, all mutations previously identified in other study populations were not detected in this study.
Our results reveal a distinct mutation profile of the SNRNP200 gene in a southern Chinese cohort of RP patients. The identification of two novel candidate mutations in two respective patients affirmed that SNRNP200 contributes to a proportion of overall RP.
retinitis pigmentosa; SNRNP200; mutation
Endogenous c-MYC (MYC) has been reported to be a potential pharmacological target to trigger ubiquitous tumor regression of pancreatic neuroendocrine tumors (PanNETs) and lung tumors. Recently inhibitors of bromodomain and extra-terminal (BET) family proteins have shown antitumor effects through the suppression of MYC in leukemia and lymphoma. In this paper, we investigated the antitumor activity of a BET protein bromodomain inhibitor (BETi) CPI203 as a single agent and in combination with rapamycin in human PanNETs. We found that exposure of human PanNET cell lines to CPI203 led to downregulation of MYC expression, G1 cell cycle arrest and nearly complete inhibition of cell proliferation. In addition, overexpression of MYC suppressed the growth inhibition caused by CPI203 and knockdown of MYC phenocopied the effects of CPI203 treatment. These findings indicate that suppression of MYC contributed to the antiproliferative effects of BETi inhibition in human PanNET cells. Importantly, CPI203 treatment enhanced the antitumor effects of rapamycin in PanNET cells grown in monolayer and in three-dimensional cell cultures, as well as in a human PanNET xenograft model in vivo. Furthermore, the combination treatment attenuated rapamycin-induced AKT activation, a major limitation of rapamycin therapy. Collectively, our data suggest that targeting MYC with a BETi may increase the therapeutic benefits of rapalogs in human PanNET patients. This provides a novel clinical strategy for PanNETs, and possibly for other tumors as well.
Light carries angular momentum, and as such it can exert torques on material objects. Applications of these opto-mechanical effects were limited initially due to their smallness in magnitude, but later becomes powerful and versatile after the invention of laser. Novel and practical approaches for harvesting light for particle rotation have since been demonstrated, where the structure is always subjected to a positive optical torque along a certain axis if the incident angular momentum has a positive projection on the same axis. We report here an interesting phenomenon of “negative optical torque”, meaning that incoming photons carrying angular momentum rotate an object in the opposite sense. Surprisingly this can be realized quite straightforwardly in simple planar structures. Field retardation is a necessary condition and discrete rotational symmetry of material object plays an important role. The optimal conditions are explored and explained.
Protein phosphorylation mediated by protein kinases controls numerous cellular processes. A genetically encoded, generalizable split firefly luciferase (FL)-assisted complementation system was developed for noninvasive monitoring phosphorylation events and efficacies of kinase inhibitors in cell culture and in small living subjects by optical bioluminescence imaging.
An Akt sensor (AST) was constructed to monitor Akt phosphorylation and the effect of different PI-3K and Akt inhibitors. Specificity of AST was determined using a non-phosphorylable mutant sensor containing an alanine substitution (ASA).
The PI-3K inhibitor LY294002 and Akt kinase inhibitor perifosine led to temporal- and dose-dependent increases in complemented FL activities in 293T human kidney cancer cells stably expressing AST (293T/AST) but not in 293T/ASA cells. Inhibition of endogenous Akt phosphorylation and kinase activities by perifosine also correlated with increase in complemented FL activities in 293T/AST cells but not in 293T/ASA cells. Treatment of nude mice bearing 293T/AST xenografts with perifosine led to a 2-fold increase in complemented FL activities compared to that of 293T/ASA xenografts. Our system was used to screen a small chemical library for novel modulators of Akt kinase activity.
This generalizable approach for noninvasive monitoring of phosphorylation events will accelerate the discovery and validation of novel kinase inhibitors and modulators of phosphorylation events.
Phosphorylation; Kinases; Noninvasive; Repetitive imaging in living subjects; Optical bioluminescence imaging in living subjects; Drug development; Akt
The first step in attachment of Chlamydia to host cells is thought to involve reversible binding to host heparan sulfate proteoglycans (HSPGs), polymers of variably sulfated repeating disaccharide units coupled to diverse protein backbones. However, the key determinants of HSPG structure that are involved in Chlamydia binding are incompletely defined. A previous genome-wide Drosophila RNAi screen suggested that the level of HSPG 6-O sulfation rather than the identity of the proteoglycan backbone maybe a critical determinant for binding (Elwell et al., 2008). Here, we tested in mammalian cells whether SULF1 or SULF2, human endosulfatases which remove 6-O sulfates from HSPGs, modulate Chlamydia infection. Ectopic expression of SULF1 or SULF2 in HeLa cells, which decreases cell surface HSPG sulfation, diminished C. muridarum binding and decreased vacuole formation. ShRNA depletion of endogenous SULF2 in a cell line that primarily expresses SULF2 augmented binding and increased vacuole formation. C. muridarum infection of diverse cell lines resulted in downregulation of SULF2 mRNA. In a murine model of acute pneumonia, mice genetically deficient in both endosulfatases or in SULF2 alone demonstrated increased susceptibility to C. muridarum lung infection. Collectively, these studies demonstrate that the level of HSPG 6-O sulfation is a critical determinant of C. muridarum infection in vivo and that 6-O endosulfatases are previously unappreciated modulators of microbial pathogenesis.
We developed a forced non-electric-shock running wheel (FNESRW) system that provides
rats with high-intensity exercise training using automatic exercise training patterns
that are controlled by a microcontroller. The proposed system successfully makes a
breakthrough in the traditional motorized running wheel to allow rats to perform
high-intensity training and to enable comparisons with the treadmill at the same
exercise intensity without any electric shock. A polyvinyl chloride runway with a
rough rubber surface was coated on the periphery of the wheel so as to permit
automatic acceleration training, and which allowed the rats to run consistently at
high speeds (30 m/min for 1 h). An animal ischemic stroke model was used to validate
the proposed system. FNESRW, treadmill, control, and sham groups were studied. The
FNESRW and treadmill groups underwent 3 weeks of endurance running training. After 3
weeks, the experiments of middle cerebral artery occlusion, the modified neurological
severity score (mNSS), an inclined plane test, and triphenyltetrazolium chloride were
performed to evaluate the effectiveness of the proposed platform. The proposed
platform showed that enhancement of motor function, mNSS, and infarct volumes was
significantly stronger in the FNESRW group than the control group (P<0.05) and
similar to the treadmill group. The experimental data demonstrated that the proposed
platform can be applied to test the benefit of exercise-preconditioning-induced
neuroprotection using the animal stroke model. Additional advantages of the FNESRW
system include stand-alone capability, independence of subjective human adjustment,
and ease of use.
Forced non-electric-shock running wheel; Middle cerebral artery occlusion; Inclined plane test; Modified neurological severity score; Triphenyltetrazolium chloride
Knowledge of current epidemiology and spine trauma trends assists in public resource allocation, fine-tuning of primary prevention methods, and benchmarking purposes. Data on all patients with traumatic spine injuries admitted to the Alfred Hospital, Melbourne between May 1, 2009, and January 1, 2011, were collected from the Alfred Trauma Registry, Alfred Health medical database, and Victorian Orthopaedic Trauma Outcomes Registry. Epidemiological trends were analyzed as a general cohort, with comparison cohorts of nonsurvivors versus survivors and elderly versus nonelderly. Linear regression analysis was utilized to demonstrate trends with statistical significance. There were 965 patients with traumatic spine injuries with 2,333 spine trauma levels. The general cohort showed a trimodal age distribution, male-to-female ratio of 2:2, motor vehicle accidents as the primary spine trauma mechanism, 47.7% patients with severe polytrauma as graded using the Injury Severity Score (ISS), 17.3% with traumatic brain injury (TBI), the majority of patients with one spine injury level, 7% neurological deficit rate, 12.8% spine trauma operative rate, and 5.2% mortality rate. Variables with statistical significance trending toward mortality were the elderly, motor vehicle occupants, severe ISS, TBI, C1–2 dissociations, and American Spinal Injury Association (ASIA) A, B, and C neurological grades. Variables with statistical significance trending toward the elderly were females; low falls; one spine injury level; type 2 odontoid fractures; subaxial cervical spine distraction injuries; ASIA A, B, and C neurological grades; and patients without neurological deficits. Of the general cohort, 50.3% of spine trauma survivors were discharged home, and 48.1% were discharged to rehabilitation facilities. This study provides baseline spine trauma epidemiological data. The trimodal age distribution of patients with traumatic spine injuries calls for further studies and intervention targeted toward the 46- to 55-year age group as this group represents the main providers of financial and social security. The study's unique feature of delineating variables with statistical significance trending toward both mortality and the elderly also provides useful data to guide future research studies, benchmarking, public health policy, and efficient resource allocation for the management of spine trauma.
spine trauma; epidemiology; demographics; spinal injury characteristics; neurological status; registry; prevention
A cell is a complex material whose mechanical properties are essential for its normal functions. Heating can have a dramatic effect on these mechanical properties, similar to its impact on the dynamics of artificial polymer networks. We investigated such mechanical changes by the use of a microfluidic optical stretcher, which allowed us to probe cell mechanics when the cells were subjected to different heating conditions at different time scales. We find that HL60/S4 myeloid precursor cells become mechanically more compliant and fluid-like when subjected to either a sudden laser-induced temperature increase or prolonged exposure to higher ambient temperature. Above a critical temperature of 52 ± 1°C, we observed active cell contraction, which was strongly correlated with calcium influx through temperature-sensitive transient receptor potential vanilloid 2 (TRPV2) ion channels, followed by a subsequent expansion in cell volume. The change from passive to active cellular response can be effectively described by a mechanical model incorporating both active stress and viscoelastic components. Our work highlights the role of TRPV2 in regulating the thermomechanical response of cells. It also offers insights into how cortical tension and osmotic pressure govern cell mechanics and regulate cell-shape changes in response to heat and mechanical stress.
cell contraction; calcium; cortical tension; myeloid precursor cell; optical stretcher; cell rheology
Background. Exercise has been suggested to be a viable treatment for depression. This study investigates the effect of supervised aerobic exercise training on depressive symptoms and physical performance among Chinese patients with mild to moderate depression in early in-patient phase. Methods. A randomized repeated measure and assessor-blinded study design was used. Subjects in aerobic exercise group received 30 minutes of aerobic training, five days a week for 3 weeks. Depressive symptoms (MADRS and C-BDI) and domains in physical performance were assessed at baseline and program end. Results. Subjects in aerobic exercise group showed a more significant reduction in depressive scores (MADRS) as compared to control (between-group mean difference = 10.08 ± 9.41; P = 0.026) after 3 weeks training. The exercise group also demonstrated a significant improvement in flexibility (between-group mean difference = 4.4 ± 6.13; P = 0.02). Limitations. There was lack of longitudinal followup to examine the long-term effect of aerobic exercise on patients with depression. Conclusions. Aerobic exercise in addition to pharmacological intervention can have a synergistic effect in reducing depressive symptoms and increasing flexibility among Chinese population with mild to moderate depression. Early introduction of exercise training in in-patient phase can help to bridge the gap of therapeutic latency of antidepressants during its nonresponse period.
Materials with negative permittivity and permeability can overcome the diffraction limit, thereby making the sub-wavelength imaging possible. In this study, we analyze the effects of gradient index on a half-infinite perfect lens. We assume that the sharp interface between the vacuum and the negative-index material is replaced by a smooth transition profile such that the index gradually changing from positive to negative. Interestingly, we find that if the graded index profile is modeled by a tanh function, we can have closed-form analytical solutions for this problem, which is a distinct advantage as numerical solutions are not accurate for evanescent waves with large transverse wave vectors. By analyzing the analytical formulas we confirm that a nonzero total absorption can occur even for a near-zero absorption coefficient in the steady-state limit and the image plane contains multiple sub-wavelength images of an object.
The conventional dose of anti-vascular endothelial growth factor treatment may slowly reduce the subretinal fluid and height of a vascularized pigment epithelial detachment (vPED), but rarely leads to its complete resolution. We report a dramatic outcome involving a high dose (2 mg) of ranibizumab for treating vPED.
This report describes three eyes with vPED that received 2 mg in 0.05 ml of ranibizumab injections on a monthly basis and were followed prospectively. Each patient received a complete ocular examination, including best-corrected standardized ETDRS testing, fundus photography (FP), fluorescein angiography (FA), optical coherent tomography (OCT), and indocyanine-green angiography at baseline. ETDRS and OCT testing were repeated monthly, while FP and FA were performed every 3 months.
Following a single intravitreal injection of 2 mg ranibizumab, there was rapid resolution of the subretinal fluid, haemorrhage, exudates, and flattening of the vPED within 10 days for Case 1, and within 1 month for Case 2 and Case 3.
Rapid and dramatic decrease in the exudative changes and collapse of the vPED may develop after a single injection of high-dose (2 mg) ranibizumab in certain eyes with a vPED. The improvement was maintained with additional monthly injections to 12 months.
age-related macular degeneration; anti-vascular endothelial growth factor therapy; high-dose ranibizumab; 2 mg ranibizumab; retinal pigment epithelial detachment; vascularized pigment epithelial detachment
Background The establishment of a spine trauma registry collecting both spine column and spinal cord data should improve the evidential basis for clinical decisions. This is a report on the pilot of a spine trauma registry including development of a minimum dataset.
Methods A minimum dataset consisting of 56 data items was created using the modified Delphi technique. A pilot study was performed on 104 consecutive spine trauma patients recruited by the Victorian Orthopaedic Trauma Outcomes Registry (VOTOR). Data analysis and collection methodology were reviewed to determine its feasibility.
Results Minimum dataset collection aided by a dataset dictionary was uncomplicated (average of 5 minutes per patient). Data analysis revealed three significant findings: (1) a peak in the 40 to 60 years age group; (2) premorbid functional independence in the majority of patients; and (3) significant proportion being on antiplatelet or anticoagulation medications. Of the 141 traumatic spine fractures, the thoracolumbar segment was the most frequent site of injury. Most were neurologically intact (89%). Our study group had satisfactory 6-month patient-reported outcomes.
Conclusion The minimum dataset had high completion rates, was practical and feasible to collect. This pilot study is the basis for the development of a spine trauma registry at the Level 1 trauma center.
registry; spine trauma; minimum dataset; Victorian Orthopaedic Trauma Outcomes Registry
The gravity of Earth is responsible for the formation of water waves and usually difficult to change. Although negative effective gravity was recently predicted theoretically in water waves, it has not yet been observed in experiments and remains a mathematical curiosity which is difficult to understand. Here we experimentally demonstrate that close to the resonant frequency of purposely-designed resonating units, negative effective gravity can occur for water waves passing through an array of resonators composing of bottom-mounted split tubes, resulting in the prohibition of water wave propagation. It is found that when negative gravity occurs, the averaged displacement of water surface in a unit cell of the array has a phase difference of π to that along the boundary of the unit cell, consistent with theoretical predictions. Our results provide a mechanism to block water waves and may find applications in wave energy conversion and coastal protection.
Heroin abuse and natural aging exert common influences on immunological cell functioning. This observation led to a recent and untested idea that aging may be accelerated in abusers of heroin. We examined this claim by testing whether heroin use is associated with premature aging at both cellular and brain system levels. A group of abstinent heroin users (n=33) and matched healthy controls (n=30) were recruited and measured on various biological indicators of aging. These measures included peripheral blood telomerase activity, which reflects cellular aging, and both structural and functional measures of brain magnetic resonance imaging. We found that heroin users were characterized by significantly low telomerase activity (0.21 vs 1.78; 88% reduction; t(61)=6.96, P<0.001; 95% confidence interval=1.12–2.02), which interacted with heroin use to affect the structural integrity of gray and white matter of the prefrontal cortex (PFC; AlphaSim corrected P<0.05), a key brain region implicated in aging. Using the PFC location identified from the structural analyses as a ‘seed' region, it was further revealed that telomerase activity interacted with heroin use to impact age-sensitive brain functional networks (AlphaSim corrected P<0.05), which correlated with behavioral performance on executive functioning, memory and attentional control (Pearson correlation, all P<0.05). To our knowledge, this study is the first to attempt a direct integration of peripheral molecular, brain system and behavioral measures in the context of substance abuse. The present finding that heroin abuse is associated with accelerated aging at both cellular and brain system levels is novel and forms a unique contribution to our knowledge in how the biological processes of drug abusers may be disrupted.
addiction; aging; heroin; MRI; prefrontal cortex; resting state; telomerase
The symptoms of Parkinson’s disease (PD) are related to changes in the frequency and pattern of activity in the reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN). In idiopathic and experimental PD the GPe and STN exhibit hypo- and hyper-activity, respectively, and abnormal synchronous rhythmic burst firing. Following lesion of midbrain dopamine neurons abnormal STN activity emerges slowly and intensifies gradually until it stabilizes after 2–3 weeks. Alterations in cellular/network properties may therefore underlie the expression of abnormal firing. Because the GPe powerfully regulates the frequency, pattern and synchronization of STN activity, electrophysiological, molecular and anatomical measures of GPe-STN transmission were compared in the STN of control and 6-hydroxydopamine-lesioned rats and mice. Following dopamine depletion: 1) the frequency (but not the amplitude) of mIPSCs increased by ~70%; 2) the amplitude of evoked IPSCs and isoguvacine-evoked current increased by ~60% and ~70%, respectively; 3) mRNA encoding α1, β2 and γ2 GABAA receptor subunits increased by 15–30%; 4) the density of postsynaptic gephyrin and γ2 subunit co-immunoreactive structures increased by ~40%, whereas the density of vesicular GABA transporter and bassoon co-immunoreactive axon terminals was unchanged; 5) the number of ultrastructurally defined synapses per GPe-STN axon terminal doubled with no alteration in terminal/synapse size or target preference. Thus, loss of dopamine leads, through an increase in the number of synaptic connections per GPe-STN axon terminal, to substantial strengthening of the GPe-STN pathway. This adaptation may oppose hyperactivity but could also contribute to abnormal firing patterns in the parkinsonian STN.