Genetic and epidemiologic evidence suggests that cellular energy homeostasis is critically associated with Parkinson's disease (PD) pathogenesis. Here we demonstrated that genetic deletion of Poly (ADP-ribose) polymerase 1 completely blocked 6-hydroxydopamine-induced dopaminergic neurodegeneration and related PD-like symptoms. Hyperactivation of PARP-1 depleted ATP pools in dopaminergic (DA) neurons, thereby activating AMP-activated protein kinase (AMPK). Further, blockade of AMPK activation by viral infection with dominant-negative AMPK strongly inhibited DA neuronal atrophy with moderate suppression of nuclear translocation of apoptosis-inhibiting factor (AIF), whereas overactivation of AMPK conversely strengthened the 6-OHDA-induced DA neuronal degeneration. Collectively, these results suggest that manipulation of PARP-1 and AMPK signaling is an effective therapeutic approach to prevent PD-related DA neurodegeneration.
PARP-1; ATP; AMPK; 6-OHDA; Parkinson's disease
The aim of this study was to test the null hypothesis that there is no difference in the alveolar bone thickness, bone loss or incidence of fenestrations between upper and lower incisors in skeletal Class I bidentoalveolar protrusive patients before orthodontic treatment.
Three-dimensional (3D) cone beam CT (CBCT) images were taken of 24 patients from the Republic of Korea (17 females and 7 males). Reformatted CBCT images were used to measure labial and lingual alveolar bone thickness (ABT) of the 4 upper incisors and 4 lower incisors of the 24 patients (total n = 192 incisors) at every 1/10 of root length (Level 0, cementoenamel junction (CEJ) area; Level 10, root apex area) as well as alveolar bone area (ABA) and alveolar bone loss (%BL) rate to dental root length. The numbers of fenestration teeth were also tallied.
All anterior teeth were supported by <1 mm of ABT on the labial surfaces up to root length Level 8. ABA was statistically greater on the lingual aspect than the labial aspect in lower incisors. The %BL was 26.98% in the lower labial region, 19.27% in upper labial aspect and most severe on the lower lingual plate 31.25% compared with the labial plate. There were no significant differences in %BL between subgroups when categorized by sex or age. Fenestrations were 1.37 times more frequent on lower incisors (37) than upper incisors (27).
The null hypothesis was rejected, confirming that incisor periodontal support is poor and alveolar bone loss is severe even prior to the start of orthodontic treatment. Careful diagnosis using 3D CBCT images is needed to avoid iatrogenic degeneration of periodontal support around anterior teeth, particularly in the lower lingual bone plate region.
alveolar bone loss; cone beam computed tomography; fenestration; bidentoalveolar protrusion; extraction
Cytokine and activation of lymphocytes are critical for tumor growth. We investigated whether interleukin (IL)-32β overexpression changes other cytokine levels and activates cytotoxic lymphocyte, and thus modify tumor growth. Herein, IL-32β inhibited B16 melanoma growth in IL-32β-overexpressing transgenic mice (IL-32β mice), and downregulated the expressions of anti-apoptotic proteins (bcl-2, IAP, and XIAP) and cell growth regulatory proteins (Ki-67 antigen (Ki-67) and proliferating cell nuclear antigen (PCNA)), but upregulated the expressions of pro-apoptotic proteins (bax, cleaved caspase-3, and cleaved caspase-9). IL-32β also inhibited colon and prostate tumor growth in athymic nude mice inoculated with IL-32β-transfected SW620 colon or PC3 prostate cancer cells. The forced expression of IL-32β also inhibited cell growth in cultured colon and prostate cancer cells, and these inhibitory effects were abolished by IL-32 small interfering RNA (siRNA). IL-10 levels were elevated, but IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) levels were reduced in the tumor tissues and spleens of IL-32β mice, and athymic nude mice. The number of cytotoxic T (CD8+) and natural killer (NK) cells in tumor tissues, spleen, and blood was significantly elevated in IL-32β mice and athymic nude mice inoculated with IL-32β-transfected cancer cells. Constituted activated NF-κB and STAT3 levels were reduced in the tumor tissues of IL-32β mice and athymic nude mice, as well as in IL-32β-transfected cultured cancer cells. These findings suggest that IL-32β inhibits tumor growth by increasing cytotoxic lymphocyte numbers, and by inactivating the NF-κB and STAT3 pathways through changing of cytokine levels in tumor tissues.
IL-32β; lymphocytes; NF-κB; STAT3; tumor growth
Transcriptional profiling results, using our non-invasive induction assay [short exposure intervals (2–5 h) to sub-lethal amounts of insecticides (
Of the cytochrome P450 monooxygenase and ATP binding cassette transporter genes induced by ivermectin, CYP6CJ1, CYP9AG1, CYP9AG2 and PhABCC4 were respectively most significantly over-expressed, had high basal expression levels and were most closely related to genes from other organisms that metabolized insecticides, including ivermectin.
Injection of dsRNAs against either CYP9AG2 or PhABCC4 into non-induced female lice reduced their respective transcript level and resulted in increase sensitivity to ivermectin, indicating that these two genes are involved in the xenobiotic metabolism of ivermectin and in the production of tolerance.
Pediculus humanus humanus; ivermectin; tolerance; transcriptional profiling; RNA interference; P450; ABC transporters
This study was performed in order to verify bifid mandibular canals revealed from panoramic radiographic results.
1000 panoramic radiographs from dental patients and the panorama, cone beam CT (CBCT) and micro-CT from 40 dry mandibles were examined for bifid mandibular canals. The results were confirmed by a stereoscopic and histological examination of the cross-sectioned mandibles.
The prevalence of bifid canals detected from the panoramic radiographs was 0.038. The panoramic radiographs from one dry mandible showed two separate radiolucent mandibular canal-like structures delineated by radio-opaque lines. However, a stereoscopic and histological examination of a cross-section of the mandible showed that only one canal was a true canal containing neurovascular bundles: the other was false, reflecting merely a bony trabecular pattern.
The presence of bifid mandibular canals determined by panoramic radiography should be judged with great caution in relation to dental surgery.
bifid canals; panorama; micro-CT; cone beam computed tomography; inferior alveolar nerve
To obtain quantitative data on the progression of the most common spinocerebellar ataxias (SCAs) and identify factors that influence their progression, we initiated the EUROSCA natural history study, a multicentric longitudinal cohort study of 526 patients with SCA1, SCA2, SCA3, or SCA6. We report the results of the 1- and 2-year follow-up visits.
As the primary outcome measure we used the Scale for the Assessment and Rating of Ataxia (SARA, 0–40), and as a secondary measure the Inventory of Non-Ataxia Symptoms (INAS, 0–16) count.
The annual increase of the SARA score was greatest in SCA1 (2.18 ± 0.17, mean ± SE) followed by SCA3 (1.61 ± 0.12) and SCA2 (1.40 ± 0.11). SARA progression in SCA6 was slowest and nonlinear (first year: 0.35 ± 0.34, second year: 1.44 ± 0.34). Analysis of the INAS count yielded similar results. Larger expanded repeats and earlier age at onset were associated with faster SARA progression in SCA1 and SCA2. In SCA1, repeat length of the expanded allele had a similar effect on INAS progression. In SCA3, SARA progression was influenced by the disease duration at inclusion, and INAS progression was faster in females.
Our study gives a comprehensive quantitative account of disease progression in SCA1, SCA2, SCA3, and SCA6 and identifies factors that specifically affect disease progression.
People come in different shapes and sizes. In particular, calf muscle size in humans varies considerably. One possible cause for the different shapes of calf muscles is the inherent difference in neural signals sent to these muscles during walking. In sedentary adults, the variability in neural control of the calf muscles was examined with muscle size, walking kinematics and limb morphometrics. Half the subjects walked while activating their medial gastrocnemius (MG) muscles more strongly than their lateral gastrocnemius (LG) muscles during most walking speeds (‘MG-biased’). The other subjects walked while activating their MG and LG muscles nearly equally (‘unbiased’). Those who walked with an MG-biased recruitment pattern also had thicker MG muscles and shorter heel lengths, or MG muscle moment arms, than unbiased walkers, but were similar in height, weight, lower limb length, foot length, and exhibited similar walking kinematics. The relatively less plastic skeletal system may drive calf muscle size and motor recruitment patterns of walking in humans.
neural control; walking; heel length; medial gastrocnemius; humans
The purpose of this study was to explore the relation between age at menarche, parity, and oral contraceptive (OC) use, and primary open-angle glaucoma (POAG).
We followed 79 440 women in the Nurses' Health Study prospectively from 1980 to 2006 and identified 813 cases of incident POAG. Eligible participants were ≥40 years old, free of POAG at baseline, had information on reproductive history, and reported receiving eye examinations during follow-up. Relevant exposure data and POAG risk factors were updated using biennial questionnaires. We used proportional hazards models to calculate multivariable rate ratios (MVRRs) of POAG and 95% confidence intervals (CI).
In multivariable analysis, there were no significant linear trends between age at menarche (Pfor trend=0.65) or reproductive duration defined as time between age at menarche and menopause (Pfor trend=0.30) and POAG. Although ever using OCs was not associated with POAG risk (MVRR=1.14; 95% CI, 0.98, 1.34), ≥5 years of OC use was associated with a modest 25% increased risk of POAG (MVRR=1.25; 95% CI, 1.02, 1.53; Pfor linear trend=0.04). Furthermore, among past OC users, a shorter time since stopping OC use was also associated with an increased risk of POAG (Pfor linear trend=0.02). Parity was not associated with POAG risk.
The ≥5 years of OC use was associated with a modestly increased risk of POAG. These data add further support for a role of circulating estrogen in the pathogenesis of POAG.
female reproductive factors; age at menarche; parity; oral contraceptives; primary open angle glaucoma
The cAMP-response element-binding protein (CREB) plays an important role in visual cortical plasticity that follows the disruption of sensory activity, as induced by dark rearing (DR). Recent findings indicate that the dorsal lateral geniculate nucleus (dLGN) of thalamus is also sensitive to altered sensory activity. DR disrupts retinogeniculate synaptic strength and pruning in mice, but only when DR starts one week after eye opening (delayed DR, DDR) and not after chronic DR (CDR) from birth. While DR upregulates CREB in visual cortex, whether it also modulates this pathway in dLGN remains unknown. Here we investigate the role of CREB in the dLGN of mice that were CDR or DDR using western blot and immunofluorescence. Similar to findings in visual cortex, CREB is upregulated in dLGN after CDR and DDR. These findings are consistent with the proposal that DR up-regulates the CREB pathway in response to decreased visual drive.
The objective of this article was to illustrate the MRI findings of uncommon non-hepatocyte origin primary liver tumours, correlate them with the pathological features and discuss differential diagnoses. In conclusion, the MRI findings of uncommon benign and malignant non-hepatocyte-origin primary liver tumours vary. Awareness of characteristic MRI features can aid differential diagnosis and prevent unnecessary surgery.
In this study, we investigated whether DHA, a nutritionally important n-3 unsaturated fatty acid, modulated the sensitivity of brain tumor cells to the anticancer drug, etoposide (VP16). Medulloblastoma (MB) cell lines, Daoy and D283, and glioblastoma (GBM) cell lines, U138 and U87, were exposed to DHA or VP16 alone or in combination. The effects on cell proliferation and the induction of apoptosis were determined by using MTS and Hoechest 33342/PI double staining. U87 and U138 cells were found to be insensitive to the addition of DHA and VP16, whereas the two MB cell lines showed high sensitivity. DHA or VP16 alone showed little effect on cell proliferation or death in either the MB or GBM cell lines, but pretreatment with DHA enhanced the responsiveness to VP16 in the MB cell lines. To understand the mechanisms of combined DHA and VP16 on MB cells, pathway specific oligo array analyses were performed to dissect possible signaling pathways involved. The addition of DHA and VP16, in comparison to VP16 added alone, resulted in marked suppression in the expression of several genes involved in DNA damage repair, cell proliferation, survival, invasion, and angiogenesis, including PRKDC, Survivin, PIK3R1, MAPK14, NFκB1, NFκBIA, BCL2, CD44, and MAT1. These results suggest (1) that the effects of DHA and VP16 in brain tumor cells are mediated in part by the down regulation of events involved in DNA repair and the PI3K/MAPK signaling pathways and (2) that brain tumors genotypically mimicked by MB cells may benefit from therapies combining DHA with VP16.
Apoptosis; docosahexaenoic acid; etoposide; glioblastoma; medulloblastoma
We investigated the effect of a non-mammalian omega-3 desaturase in a mouse hepatocarcinogenesis model. Mice containing double mutations (DM) in c-myc and TGF-α (transforming growth factor-α), leading to liver neoplasia, were crossed with mice containing omega-3 desaturase. MRI analysis of triple mutant (TM) mice showed the absence of neoplasia at all time points for 92% of mice in the study. Pathological changes of TM (TGFα/c-myc/fat-1) mouse liver tissue was similar to control mouse liver tissue. Magnetic resonance spectroscopy (MRS) measurements of unsaturated fatty acids found a significant difference (p<0.005) between DM and TM transgenic (Tg) mice at 34 and 40 weeks of age. HPLC analysis of mouse liver tissue revealed markedly decreased levels of omega-6 fatty acids in TM mice when compared to DM (TGFα/c-myc) and control (CD1) mice. Mass spectrometry (MS) analysis indicated significantly decreased 16:0/20:4 and 18:1/20:4 and elevated 16:0/22:6 fatty acyl groups in both GPCho and GPEtn, and elevated 16:0/20:5, 18:0/18:2, 18:0/18:1 and 18:0/22:6 in GPCho, within TM mice compared to DM mice. Total fatty acid analysis indicated a significant decrease in 18:1n9 in TM mice compared to DM mice. Western blot analysis of liver tissue showed a significant (p<0.05) decrease in NF-κB (nuclear factor- κB) levels at 40 weeks of age in TM mice compared to DM mice. Microarray analysis of TM versus DM mice livers at 40 weeks revealed alterations in genes involved in cell cycle regulation, cell-to-cell signaling, p53 signaling, and arachidonic acid (20:4) metabolism. Endogenous omega-3 fatty acids were found to prevent HCC development in mice.
Omega-3 fatty acids; liver cancer; HCC; Fat-1; TGF-α/c-myc; transgenic mouse model
An enteric-coated levonorgestrel emergency contraceptive pill (E-LNG-ECP) is an improved formulation, in terms of side effects, which both dissolves and is absorbed in the intestine. Our aim was to evaluate the efficacy and safety of E-LNG-ECP as an over-the-counter (OTC) drug for emergency contraception (EC) in Chinese women.
A Phase IV clinical trial was conducted in five family planning clinics in China. Women seeking EC within 72 h after unprotected sexual intercourse or contraceptive failure who met the inclusion criteria were recruited. The efficacy of contraception (primary end-point was pregnancy rate), side effects (i.e. safety) and the value of E-LNG-ECP for EC were investigated.
Of 2445 women (aged 15–48 years) who took E-LNG-ECP with follow-up to determine pregnancy, only five pregnancies (0.2%) occurred. The efficacy of contraception was 95.3%. In total, 6.5% of women reported at least one adverse event after taking E-LNG-ECP, and no serious adverse events were reported. Only four subjects (0.16%) reported vomiting. The incidence of menstrual cycle disturbance was 20.1% after taking E-LNG-ECP. Subjects who had previously taken ECPs (54.4% of these women) rated the acceptability of E-LNG-ECP at 9.36 (on a 10-point scale) higher (P<0.05) than the rating of other LNG-EC pills taken previously.
The study found that E-LNG-ECP was effective, safe and well tolerated as an OTC drug. However, an randomized controlled trial should be performed to compare standard LNG tablets with E-LNG-ECP.
emergency contraception; levonorgestrel enteric-coated tablet; over-the-counter drug; clinical trial
We have investigated the usage of gold-plated bare fiber probes for in situ imaging of retinal layers and surrounding ocular tissues using time-domain common-path optical coherence tomography. The fabricated intra-vitreous gold-plated micro-fiber probe can be fully integrated with surgical tools working in close proximity to the tissue to provide subsurface images having a self-contained reference plane independent to the Fresnel reflection between the distal end of the probe and the following medium for achieving reference in typical common-path optical coherence tomography. We have fully characterized the probe in an aqueous medium equivalent to the vitreous humor in the eye and were able to differentiate various functional retinal tissue layers whose thickness is larger than the system’s resolution.
A simple and inexpensive home sperm test could be of considerable value to couples attempting to conceive and to men curious about their fertility potential. A two-strip lateral flow immunochromatographic diagnostic device that allows men to evaluate their sperm count at low cost in the privacy of their own homes is described.
The ability of SpermCheck Fertility to predict sperm counts obtained using a hemacytometer procedure based on standard World Health Organization methodology was assessed. Test results obtained by lay users were also compared with those obtained by trained laboratory professionals, and the ease of use of the device was evaluated in consumer studies.
A total of 225 semen samples were analyzed in the method comparison, and the performance of SpermCheck Fertility was excellent with over 96% of all samples correctly classified as normozoospermic (≥2 × 107 sperm/ml), oligozoospermic (5 × 106–2 × 107 sperm/ml) or severely oligozoospermic (<5 × 106 sperm/ml). Consumer studies with 164 lay users demonstrated that SpermCheck Fertility was easy to use. Lay users and laboratory professionals agreed 95% of the time when reading the same test independently. Overall, the correct response rate on a 20-question survey about the test was over 97%.
SpermCheck Fertility is a simple and reliable immunodiagnostic test that can quickly inform men as to whether their sperm count is normal, low or very low. This home test can assist couples in deciding whether to seek comprehensive clinical evaluation of the fertility status of the male partner.
cytology; home test; instrumentation; male fertility; sperm count
A simple common path optical coherence tomography using a fibre optic bundle as a probe is demonstrated experimentally. The mechanical lateral scans are accomplished outside the specimen, proximal entrance of the fibre bundle, which eliminated the need for moving parts in the distal end of the probe. This feature allows the probe to be made submillimetre in size and easily integrated into surgical tools for intraoperative imaging. The axial and lateral resolutions of the system, and preliminary images of phantom samples, are reported.
FOXP3 expressing regulatory T cells are vital for maintaining peripheral T cell tolerance and homeostasis. The mechanisms by which FOXP3 target genes orchestrate context-dependent Treg cell function are largely unknown. Here we show that in mouse peripheral lymphocytes, the Drosophila Disabled-2 (Dab2) homolog, a gene that is involved in enhancing TGFβ responses, is exclusively expressed in FOXP3+ regulatory T cells. Dab2 is a direct target of FOXP3 and regulatory T cells lacking DAB2 are functionally impaired in vitro and in vivo. However, not all aspects of Treg cell function are perturbed and DAB2 appears dispensable for Treg cell function in maintaining naïve T cell homeostasis.
To examine the strength of the associations of fibrinogen with subclinical atherosclerosis in healthy persons.
A population-based, prospective, observational study of black and white men and women (Coronary Artery Risk Development in Young Adults [CARDIA]). Fibrinogen levels were measured at year 7 (ages 25–37, n = 2969), and again at year 20 (ages 38–50, n = 2832). Measures of subclinical atherosclerosis (coronary artery calcification [CAC] and carotid intimal-medial thickness [CIMT]) were recorded at year 20.
Over the 13-year study interval (1992–1993 to 2005–2006), fibrinogen rose from a mean of 3.32 to 4.05 g L−1. After adjusting for age, gender and race, fibrinogen was positively associated with greater incidence of CAC and increased CIMT cross-sectionally as well as after 13 years of follow-up (all P-trend < 0.001). After further adjustment for field center, BMI, smoking, education, systolic blood pressure, diabetes, antihypertensive medication use, total and HDL cholesterol, and CRP, significant positive relationships between fibrinogen and incidence of CAC remained for the total cohort longitudinally (P-trend = 0.037), but not cross-sectionally (P-trend = 0.147).
This 13-year study demonstrates that higher levels of fibrinogen during young adulthood are positively associated with incidence of CAC and increased CIMT in middle-age, but the strength of the association declines with increasing age.
atherosclerosis; carotid thickening; coronary calcification; fibrinogen