Various therapeutic modalities, which are available for treating plantar wart, have not been successful every time.
To evaluate topical adapalene under occlusion in the treatment of plantar warts and compare it with cryo-therapy.
Materials and Methods:
50 patients with 424 plantar warts were included in this single center, two arm, prospective, randomized, control, open study. Patients were allocated randomly into two groups consisting of 25 patients each. Group A patients having 299 plantar warts were treated using adapalene gel 0.1% under occlusion while Group B patients having 125 warts were treated using cryo-therapy. All the patients were evaluated weekly till the clearance of all the warts and the results compared.
All the warts of 25 patients of Group A that were treated using adapalene gel 0.1% cleared in 36.71 ± 19.24 (55.95-17.47) days except those in one patient. In Group B, warts in all except one treated by cryo-therapy cleared in 52.17 ± 30.06 (82.23-22.11) days. There were no side effects like scar formation, irritation, erythema, or infections with adapalene group while in the cryo group scar was seen in 2 patients, pain in 24, erythema in 10, and infection in 3 patients.
Adapalene gel 0.1% under occlusion is an effective, safe and easy to use treatment for plantar warts and may help clear lesions faster than cryo-therapy.
Adapalene; cryo-therapy; occlusion; plantar wart
Although the exact prevalence of hepatitis C virus (HCV) infection in Canada is unknown, previous studies and anecdotal evidence suggest that the burden of HCV disease, including cirrhosis and hepatocellular carcinoma, is increasing. Recent modelling studies investigating disease burden, however, have reported results that are discordant with actual outcomes. Although likely due to varying methodology, these discrepancies prompted the authors of this study to develop a more refined disease progression model that could describe the future burden of disease and cost of HCV infection. The results may facilitate disease forecasting, resource planning and the development of new management strategies.
Chronic infection with hepatitis C virus (HCV) is a major cause of cirrhosis, hepatocellular carcinoma and liver transplantation.
To estimate the burden of HCV-related disease and costs from a Canadian perspective.
Using a system dynamic framework, the authors quantified the HCV-infected population, disease progression and costs in Canada between 1950 and 2035. Specifically, 36 hypothetical, ageand sex-defined cohorts were tracked to define HCV prevalence, complications and direct medical costs (excluding the cost of antivirals). Model assumptions and costs were extracted from the literature with an emphasis on Canadian data. No incremental increase in antiviral treatment over current levels was assumed, despite the future availability of potent antivirals.
The estimated prevalence of viremic hepatitis C cases peaked in 2003 at 260,000 individuals (uncertainty interval 192,460 to 319,880), reached 251,990 (uncertainty interval 177,890 to 314,800) by 2013 and is expected to decline to 188,190 (uncertainty interval 124,330 to 247,200) in 2035. However, the prevalence of advanced liver disease is increasing. The peak annual number of patients with compensated cirrhosis (n=36,210), decompensated cirrhosis (n=3380), hepatocellular carcinoma (n=2220) and liver-related deaths (n=1880) are expected to occur between 2031 and 2035. During this interval, an estimated 32,460 HCV-infected individuals will die of liver-related causes. Total health care costs associated with HCV (excluding treatment) are expected to increase by 60% from 2013 until the peak in 2032, with the majority attributable to cirrhosis and its complications (81% in 2032 versus 56% in 2013). The lifetime cost for an individual with HCV infection in 2013 was estimated to be $64,694.
Although the prevalence of HCV in Canada is decreasing, cases of advanced liver disease and health care costs continue to rise. These results will facilitate disease forecasting, resource planning and the development of rational management strategies for HCV in Canada.
Cirrhosis; Hepatitis C; Hepatocellular carcinoma; Mortality; Outcomes; Treatment
A 56-year-old male developed an ulcer on his glans penis and mucosae of upper and lower lips 3 days after taking ofloxacin, cephalexin, and ornidazole. Clinically, a provisional diagnosis of fixed drug eruption was made. The causative drug was confirmed by an oral provocation test which triggered a reactivation of all lesions only with ornidazole.
Fixed drug eruption; ornidazole; provocation test
Background and Objectives. This is a prospective nested cohort study conducted over a period of 3 years. 2644 women were recruited, out of which final analysis was done for 1884 women. Methods. Cervicovaginal and blood samples were collected for all recruited women. Out of these, 137 women who delivered before 35 weeks were treated as cases and equal number of matched controls were chosen. Analysis of samples for serum G-CSF, AFP, ferritin, and cervicovaginal interleukin-6 and IGFBP-1 was done. Results. Poor orodental hygiene, which can be a social marker, was significantly more common in women who delivered preterm (P = 0.008). Serum alkaline phosphatase and serum ferritin were found to be significantly associated with preterm deliveries. The 90th percentile value of these parameters was considered as cut-off as there is no specific cut-off. Conclusions. Our study did not prove usefulness of any predictive marker. Serum ferritin and alkaline phosphatase were found to have correlation but their values are affected in many conditions and need to be elucidated with caution. Larger studies are needed for predicting preterm labour in asymptomatic women.
Cirrhosis of liver is an important cause of morbidity and mortality and if associated with peripheral neuropathy (PN) it also poses a huge financial, psychological burden for the patients and their families.
The aim of the present study was to study the magnitude of PN among subjects with cirrhosis of liver presenting to tertiary care teaching hospital in central rural India.
Settings and Design:
A cross-sectional study was performed in a tertiary care teaching hospital.
Materials and Methods:
In all patients of cirrhosis of liver irrespective of etiology, aged 15 and above, undergone clinical assessment for peripheral nervous systems damage and confirmed by nerve conduction studies.
Statistical Analysis Used:
We used chi square test to study associations. P value ≤0.05 was considered as significant. Crude odds ratios were computed to assess the strength of association between independent variables and dependent variables along with their 95% confidence intervals.
We included 207 of cirrhosis of liver patients admitted in medicine department from November 2010 through November 2013. Nearly 83% patients were male and 63.2% patients were under the age of 45 years. Common features in these patients were ascites (71%) splenomegaly (63.3%) pedal edema (61.4%) icterus (46.4%) tingling (44.9%) gastrointestinal bleeding(39.1%), ataxia (26.6%), numbness(26.6%), distal motor weakness (21.7%) and paresthesia(20.8%). Among the manifestation of peripheral nerve involvement, loss of ankle reflex was the most common feature in 51.7%, followed by loss of temperature sense 29.5%, loss of vibration sense 20.8%, loss of touch 16.4%, loss of position sense 14.5% and loss of pain in 6.3% of the patients. Peripheral neuropathy was found in 53.6% [95% CI: 46.58- 60.56] study subjects on electrophysiological study.
Analysis of electrophysiological study shows that the PN is very common in study subjects with cirrhosis of liver, especially in male subjects, during the middle age group.
Chronic liver disease; cirrhosis of liver; nerve conduction studies; peripheral neuropathy
The aim of this study was to find whether the visual evoked potential (VEP) latencies and amplitude are altered with different visual angles in healthy adult volunteers or not and to determine the visual angle which is the optimum and most appropriate among a wide range of check sizes for the reliable interpretation of pattern reversal VEPs (PRVEPs).
Materials and Methods:
The present study was conducted on 40 healthy volunteers. The subjects were divided into two groups. One group consisted of 20 individuals (nine males and 11 females) in the age range of 25-57 years and they were exposed to checks subtending a visual angle of 90, 120, and 180 minutes of arc. Another group comprised of 20 individuals (10 males and 10 females) in the age range of 36-60 years and they were subjected to checks subtending a visual angle of 15, 30, and 120 minutes of arc. The stimulus configuration comprised of the transient pattern reversal method in which a black and white checker board is generated (full field) on a VEP Monitor by an Evoked Potential Recorder (RMS EMG. EPMARK II). The statistical analysis was done by One Way Analysis of Variance (ANOVA) using EPI INFO 6.
In Group I, the maximum (max.) P100 latency of 98.8 ± 4.7 and the max. P100 amplitude of 10.05 ± 3.1 μV was obtained with checks of 90 minutes. In Group II, the max. P100 latency of 105.19 ± 4.75 msec as well as the max. P100 amplitude of 8.23 ± 3.30 μV was obtained with 15 minutes. The min. P100 latency in both the groups was obtained with checks of 120 minutes while the min. P100 amplitude was obtained with 180 minutes. A statistically significant difference was derived between means of P100 latency for 15 and 30 minutes with reference to its value for 120 minutes and between the mean value of P100 amplitude for 120 minutes and that of 90 and 180 minutes.
Altering the size of stimulus (visual angle) has an effect on the PRVEP parameters. Our study found that the 120 is the appropriate (and optimal) check size that can be used for accurate interpretation of PRVEPs. This will help in better assessment of the optic nerve function and integrity of anterior visual pathways.
Pattern reversal; P100 latency; P100 amplitude; VEP; visual angle
Objective: To Evaluate I, II, III, IV, V wave latencies and I-III, III-V, I-V inter-peak latencies and V/I wave amplitude ratio in Normal subjects in Central India.
Methods: We recorded BAEP from 50 healthy normal subjects from the community of same sex and geographical setup. The absolute, interpeak and wave V/I amplitude ratio were measurement and recording was done using RMS EMG EP MARK II machine manufactured by RMS recorders and Medicare system, Chandigarh.
Result: Absolute, interpeak and wave V/I amplitude ratio were measured in normal subjects and compared with other previous studies.
Conclusion: This study was conducted as exploratory pilot study only on male healthy controls. Since, the study conducted in different regions, there are some differences in the latencies and interpeak latencies and amplitude ratio but they are within range, so reference range of this study can be used for future studies in this Wardha region of Central India.
Conductive deafness; Inter-peak latency; Peak latency; Sensory-neural hearing loss
To survey gastroenterologists in British Columbia and Alberta with regard to awareness of chronic hepatitis C virus (HCV) management and practice patterns among physicians who treat and do not treat HCV-infected patients.
An anonymous two-page mail survey was distributed to actively practicing adult gastroenterologists in British Columbia and Alberta. Among physicians who treated HCV patients, respondents answered assessment of fibrosis pretreatment, measurement of rapid virological response, prescription of protease inhibitors (PIs), barriers to using these agents and referral patterns. For those who did not treat HCV, referral of patients for treatment and to whom was assessed.
Seventy-seven of 166 individuals completed the survey (46% response rate). Most (49%) practiced in academic or large community (42%) settings. Chronic liver disease comprised <25% of individual practice in 71%. Forty-eight (62%) treated HCV and two-thirds prescribed a PI. Barriers to prescription included unfamiliarity (six of 16), lack of allied health (five of 16) and few suitable patients (seven of 16). Pretreatment liver biopsy was performed by 33% (16 of 48) and 69% (33 of 48) used noninvasive measures. Rapid virological response was measured in 83% (40 of 48). Referral patterns changed in 46% (22 of 48) of physicians who treated HCV. All respondents who did not treat HCV referred patients for consideration, with 90% (26 of 29) made to hepatologists.
Chronic liver disease comprised <25% of practice in the majority of surveyed respondents. Among those who treated HCV, one-third have not prescribed a PI. Barriers to prescription and referral pattern changes are noted by those currently treating patients with HCV infection.
Barriers; Guidelines; HCV; Practice; Rapid virological response; Referral; Survey
Validity of Friedewald formula (FF) in patients with serum triglycerides (TGs) <400 mg/dl is unclear.
Materials and Methods:
We compared low-density lipoprotein (LDL)-cholesterol calculated by FF to directly measured LDL in a laboratory database of 14,620 lipid profile samples from south India.
LDL by FF correlated with directly measured LDL with correlation coefficient of 0.89 with the best correlation seen in TG levels 100-150. Higher level of TG (>200) underestimates the LDL calculated by FF particularly at LDL values <70 mg/dl. On the other hand, LDL is overestimated by FF in more than 70% of cases at LDL levels >130 mg/dl.
We suggest repeating the LDL by direct assay techniques particularly in patients with TG >200 and when LDL <70 or >130. This helps in correctly stratifying the coronary artery diseases’ (CADs’) risk and goals of treatment.
Friedewald formula; LDL cholesterol; triglyceride
To validate the pharyngeal findings in sleep nasopharyngoscopy (SNP) of children with snoring - sleep disordered breathing (S-SDB).
Prospective agreement diagnostic study on retrospective data.
We conducted an inter-and intra-rater agreement study on video documentations of SNP performed on children (non-syndromic, complex, or operated upon) who presented with S-SDB. The videos featured various pharyngeal findings (normal, collapse, mixed or obstruction). Three ‘non-expert’ raters at various stages in their otolaryngological careers rated the videos independently, and on two separate occasions following an instructional session. We calculated both weighted and non-weighted linear kappa.
Each independent observer rated sixty-one videos (2 weeks apart). Intra-observer agreement was 0.64 ± 0.08 (95% CI 0.48-0.81), 0.74 ± 0.07 (95% CI 0.60-0.88), 0.59 ± 0.08 (95% CI 0.43-0.74), for raters 1, two and three. Weighted kappa was 0.6 ± 0.1 (95% CI 0.41-0.79), 0.8 ± 0.06 (95% CI 0.7-0.92), 0.7 ± 0.07 (95% CI 0.57-0.83), respectively. Inter-rater agreements between raters one and two, two and three, three and four were 0.83 ± 0.06 (95% CI 0.71-0.95), 0.52 ± 0.08 (95% CI 0.36-0.70), and 0.53 ± 0.08 (95% CI 0.37-0.69), respectively. Weighted kappa was 0.83 ± 0.073 (95% CI 0.69-0.98), 0.68 ± 0.06 (95% CI 0.56-0.79), and 0.64 ± 0.07 (95% CI 0.49-0.78), respectively.
This is the first validation of pharyngeal findings on SNP in children. It is based on a four types’ classification. Overall reproducibility amongst the three raters and their agreement was moderate to good. Further work should be phase four trials investigating the impact on outcome.
Sleep apnea; Children; Endoscopy; Propofol; Agreement; Diagnosis; Adenotonsillectomy
Deep-sequencing has enabled the identification of large numbers of miRNAs and siRNAs, making the high-throughput target identification a main limiting factor in defining their function. In plants, several tools have been developed to predict targets, majority of them being trained on Arabidopsis datasets. An extensive and systematic evaluation has not been made for their suitability for predicting targets in species other than Arabidopsis. Nor, these have not been evaluated for their suitability for high-throughput target prediction at genome level.
We evaluated the performance of 11 computational tools in identifying genome-wide targets in Arabidopsis and other plants with procedures that optimized score-cutoffs for estimating targets. Targetfinder was most efficient [89% ‘precision’ (accuracy of prediction), 97% ‘recall’ (sensitivity)] in predicting ‘true-positive’ targets in Arabidopsis miRNA-mRNA interactions. In contrast, only 46% of true positive interactions from non-Arabidopsis species were detected, indicating low ‘recall’ values. Score optimizations increased the ‘recall’ to only 70% (corresponding ‘precision’: 65%) for datasets of true miRNA-mRNA interactions in species other than Arabidopsis. Combining the results of Targetfinder and psRNATarget delivers high true positive coverage, whereas the intersection of psRNATarget and Tapirhybrid outputs deliver highly ‘precise’ predictions. The large number of ‘false negative’ predictions delivered from non-Arabidopsis datasets by all the available tools indicate the diversity in miRNAs-mRNA interaction features between Arabidopsis and other species. A subset of miRNA-mRNA interactions differed significantly for features in seed regions as well as the total number of matches/mismatches.
Although, many plant miRNA target prediction tools may be optimized to predict targets with high specificity in Arabidopsis, such optimized thresholds may not be suitable for many targets in non-Arabidopsis species. More importantly, non-conventional features of miRNA-mRNA interaction may exist in plants indicating alternate mode of miRNA target recognition. Incorporation of these divergent features would enable next-generation of algorithms to better identify target interactions.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-348) contains supplementary material, which is available to authorized users.
miRNA; Target prediction; Plants; Deep-sequencing; Non-model plants
Background: Genetic factors cause about 15% of male infertility. Azoospermia factors (AZFa, AZFb, and AZFc) present on Yq are most important for spermatogenesis. We have made an attempt to evaluate the frequencies of microdeletions of AZFa, AZFb, AZFc in idiopathic cases of azoospermia and oligozoospermia from central Indian population.
Materials and Methods: We have analyzed a total of 156 subjects (95 oligozoospermia and 61 azoospermia) & 50 control subjects. DNA samples were analyzed for microdeletions of Y chromosome by PCR-screening of 18 sequences-tagged-site (STS) markers from different region of the AZF on Yq and SRY on Yp.
Results: Out of 156 cases analyzed, 13 (8.33%) subjects (8 azoospermia and 5 oligozoospermia) showed partial deletion of AZF regions, of which deletion in AZFc region was the most common (84.6%) followed by AZFb (15.4%) and AZFa (15.4%). The sites and sizes of deletions varied among patients. Histological study of the testicular tissue of the available subjects, who showed microdeletions of Y chromosome, showed spermatogenic arrest at different stages. The frequency of Y chromosome microdeletion in our subjects was 8.33%.
Conclusion: Some Indian studies reported low frequencies of microdeletions than that of our result. We suggest that the frequency of deletions may be affected by the involvement of different genetic factors, ethnic population and different geographical regions. PCR based Y chromosome screening for microdeletions will be useful and great help to infertility clinics for genetic counselling and assisted reproduction.
Male Infertility; Y microdeletions; AZF factor
To evaluate whether glaucomatous visual field defect particularly the pattern standard deviation (PSD) of Humphrey visual field could be associated with visual evoked potential (VEP) parameters of patients having primary open angle glaucoma (POAG).
Visual field by Humphrey perimetry and simultaneous recordings of pattern reversal visual evoked potential (PRVEP) were assessed in 100 patients with POAG. The stimulus configuration for VEP recordings consisted of the transient pattern reversal method in which a black and white checker board pattern was generated (full field) and displayed on VEP monitor (colour 14″) by an electronic pattern regenerator inbuilt in an evoked potential recorder (RMS EMG EP MARK II).
The results of our study indicate that there is a highly significant (P<0.001) negative correlation of P100 amplitude and a statistically significant (P<0.05) positive correlation of N70 latency, P100 latency and N155 latency with the PSD of Humphrey visual field in the subjects of POAG in various age groups as evaluated by Student's t-test.
Prolongation of VEP latencies were mirrored by a corresponding increase of PSD values. Conversely, as PSD increases the magnitude of VEP excursions were found to be diminished.
pattern reversal; pattern standard deviation; visual field; P100 latency
•Cytokines, and proteases expressed by macrophages play key roles in atherosclerosis.•The proteases ADAMTS-1, -4 and -5 were expressed in human atherosclerotic lesions.•The anti-atherogenic cytokine interleukin-33 (IL-33) inhibited the expression of these ADAMTS proteases in human macrophages.•This action of IL-33 required extracellular signal-regulated kinase, c-Jun N-terminal kinase and phosphoinositide 3-kinase signaling pathways.•These studies reveal novel anti-atherogenic action of IL-33 along with the underlying molecular mechanisms involved.
Atherosclerosis is an inflammatory disorder of the vasculature regulated by cytokines. Amongst the cytokines, IL-33 attenuates the development of atherosclerosis in mouse model systems via several mechanisms, including inhibition of macrophage foam cell formation and promotion of a Th1 to Th2 shift. Proteases produced by macrophages, such as matrix metalloproteinases and members of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, play potential roles in regulating atherosclerotic plaque stability. Despite such importance, the action of IL-33 on the expression of such proteases has not been analyzed. We have therefore investigated the effect of IL-33 on the expression of ADAMTS-1, -4 and -5 in human macrophages. Immunohistochemical analysis showed that these three proteases were expressed in human atherosclerotic lesions, particularly by macrophages and, to a lesser extent, by smooth muscle cells and endothelial cells. The expression of ADAMTS-1, -4 and -5 in human macrophages was specifically inhibited by IL-33. The action of IL-33 on the expression of these ADAMTS members was mediated through its receptor ST2. IL-33 activated ERK1/2, JNK1/2 and c-Jun, but not p38 MAPK or Akt, in human macrophages. RNA interference assays using a combination of adenoviral encoding small hairpin RNA and small interfering RNA showed a requirement of ERK1/2, JNK1/2, c-Jun, PI3Kγ and PI3Kδ, but not p38α, in the IL-33-inhibited expression of these ADAMTS isoforms. These studies provide novel insights into the expression of ADAMTS-1, -4 and -5 in human atherosclerotic lesions and the regulation of their expression in human macrophages by the key anti-atherogenic cytokine IL-33.
ADAMTS; Cytokine action; Cardiovascular disease; Macrophages; Signal transduction; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; apoE, apolipoprotein E; BMDM, bone marrow-derived macrophages; DAB, 3,3′-diaminobenzidine; ECM, extracellular matrix; HMDM, human monocyte-derived macrophages; IHC, immunohistochemistry; MMP, matrix metalloproteinase; RT-qPCR, real-time quantitative PCR; shRNA, small hairpin RNA; siRNA, small interfering RNA
To assess the impact of being born preterm or small for gestational age (SGA) on several adult outcomes.
We analyzed data for 4518 adult participants in 5 birth cohorts from Brazil, Guatemala, India, the Philippines, and South Africa.
In the study population, 12.8% of males and 11.9% of females were born preterm, and 26.8% of males and 22.4% of females were born term but SGA. Adults born preterm were 1.11 cm shorter (95% CI, 0.57-1.65 cm), and those born term but SGA were 2.35 cm shorter (95% CI, 1.93-2.77 cm) compared with those born at term and appropriate size for gestational age. Blood pressure and blood glucose level did not differ by birth category. Compared with those born term and at appropriate size for gestational age, schooling attainment was 0.44 years lower (95% CI, 0.17-0.71 years) in those born preterm and 0.41 years lower (95% CI, 0.20-0.62 years) in those born term but SGA.
Being born preterm or term but SGA is associated with persistent deficits in adult height and schooling, but is not related to blood pressure or blood glucose level in low- and middle-income settings. Increased postnatal growth is associated with gains in height and schooling regardless of birth status, but not with increases in blood pressure or blood glucose level.
AGA, Appropriate for gestational age; BMI, Body mass index; GA, Gestational age; IFG, Impaired fasting glucose; LGA, Large for gestational age; LMP, Last menstrual period; SGA, Small for gestational age
Signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) are transcription factors involved in cell survival, inflammation and metastasis. Constitutively activated STAT3 is found in many cancers, including melanoma. To study the crosstalk between STAT3 and NFκB signaling and its role in regulation of cancer cell survival, we used RNA interference (RNAi) to down-regulate STAT3 expression in human melanoma cells. RNAi strategies including double-stranded RNA, small interfering RNA (siRNA), short hairpin RNA (shRNA) and microRNA are widely used to knock down disease-causing genes in a targeted fashion. We found that shRNAs up-regulate non-specific NFκB activity, while siRNA directed against STAT3 specifically increase NFκB activity. The basal survival of melanoma cells is unaffected by STAT3 knockdown—likely due to activation of pro-survival NFκB signaling. Whereas, owing to off-target effects, plasmid-transcribed shRNA affects melanoma survival. Our data show that shRNA-mediated gene silencing induces non-specific or off-target effects that may influence cell functions.
Electronic supplementary material
The online version of this article (doi:10.1007/s11033-013-2817-7) contains supplementary material, which is available to authorized users.
Transcription factor STAT3; STAT3-NFκB crosstalk; Cancer cell survival; RNAi
We report a 50-year-old female patient with a stage 2 idiopathic macular hole that closed spontaneously.
The case is presented on the basis of an observational case report.
The stage 2 idiopathic macular hole closed spontaneously in 6 weeks with a lamellar defect in the outer retina due to the formation of the bridging retinal tissue, but without any evidence of the common mechanisms of spontaneous closure such as posterior vitreous detachment or epiretinal membrane formation.
Macular holes; Posterior vitreous detachment; Retina; Optical coherence tomography
Currently there is no treatment for juvenile Batten disease, a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3Δex1-6) mouse model recapitulates several features of the human disorder. Cln3Δex1-6 mice, similarly to juvenile Batten disease patients, have a motor coordination deficit detectable as early as postnatal day 14. Previous studies demonstrated that acute attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity by the non-competitive AMPA antagonist, EGIS-8332, in both 1- and 6–7-month-old Cln3Δex1-6 mice results in improvement in motor coordination. Here we show that acute inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptors by memantine (1 and 5 mg/kg i.p.) had no effect on the impaired motor coordination of one-month-old Cln3Δex1-6 mice. At a later stage of the disease, in 6–7-month-old Cln3Δex1-6 mice, memantine induced a delayed but extended (8 days) improvement of motor skills similarly to that observed previously with EGIS-8332 treatment. An age-dependent therapeutic effect of memantine implies that the pathomechanism in juvenile Batten disease changes during disease progression. In contrast to acute treatment, repeated administration of memantine or EGIS-8332 (1 mg/kg, once a week for 4 weeks) to 6-month-old Cln3Δex1-6 mice had no beneficial effect on motor coordination. Moreover, repeated treatments did not impact microglial activation or the survival of vulnerable neuron populations. Memantine did not affect astrocytosis in the cortex. EGIS-8332, however, decreased astrocytic activation in the somatosensory barrelfield cortex.
Acute inhibition of NMDA receptors can induce a prolonged therapeutic effect, identifying NMDA receptors as a new therapeutic target for juvenile Batten disease.
juvenile Batten disease; neuronal ceroid lipofuscinoses; Cln3; NMDA receptor; AMPA receptor; rotarod
•Macrophages can internalise LDL through scavenger receptor-independent mechanisms.•Macropinocytosis has been shown to contribute significantly to foam cell formation.•Cytokines such as TGF-β, IL-33, IFN-γ and IL-17A can modulate macropinocytosis.•TGF-β mediated inhibition of macropinocytosis is a Smad-2/-3-independent process.•Macropinocytosis is a promising target for therapeutic intervention of atherosclerosis.
A key event during the formation of lipid-rich foam cells during the progression of atherosclerosis is the uptake of modified low-density lipoproteins (LDL) by macrophages in response to atherogenic mediators in the arterial intima. In addition to scavenger receptor-dependent uptake of LDL, macropinocytosis is known to facilitate the uptake of LDL through the constitutive and passive internalization of large quantities of extracellular solute. In this study we confirm the ability of macropinocytosis to facilitate the uptake of modified LDL by human macrophages and show its modulation by TGF-β, IFN-γ, IL-17A and IL-33. Furthermore we show that the TGF-β-mediated inhibition of macropinocytosis is a Smad-2/-3-independent process.
AcLDL, acetylated LDL; Apo, apolipoprotein; BMDM, bone marrow-derived macrophage; CD-36, cluster of differentiation 36; DiI, 1,1-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyane perchlorate; THP-1, human acute monocytic leukemia cells; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HMDM, human monocyte-derived macrophages; IL, interleukin; IFN-γ, interferon-γ; LDL, low-density lipoproteins; LY, lucifer yellow; OxLDL, oxidized LDL; SR-A, scavenger receptor A; shRNA, short hairpin RNA; TGF-β, transforming growth factor-β; Macropinocytosis; Cytokine; Foam cell; Atherosclerosis; Low density lipoprotein
•Atherosclerosis is an inflammatory disorder regulated by cytokines.•ADAMTS proteases have been suggested to play an important role in this disease.•The action of key cytokines on the expression of ADAMTS proteases in macrophages is poorly understood.•The effect of IFN-γ, TGF-β, TL1A and IL-17A on the expression of ADAMTS-1, -4 and -5 was studied.•Novel differential actions and synergistic interactions were identified.
Atherosclerosis is an inflammatory disease of the vasculature regulated by cytokines. Macrophages play a crucial role at all stages of this disease, including regulation of foam cell formation, the inflammatory response and stability of atherosclerotic plaques. For example, matrix metalloproteinases produced by macrophages play an important role in modulating plaque stability. More recently, the ADAMTS proteases, which are known to play a key role in the control of cartilage degradation during arthritis, have been found to be expressed in atherosclerotic lesions and suggested to have potentially important functions in the control of plaque stability. Unfortunately, the action of cytokines on the expression of ADAMTS family in macrophages is poorly understood. We have investigated the effect of classical cytokines (IFN-γ and TGF-β) and those that have been recently identified (TL1A and IL-17) on the expression of ADAMTS-1, -4 and -5 in human macrophages. The expression of all three ADAMTS members was induced during differentiation of monocytes into macrophages. TGF-β had a differential action with induction of ADAMTS-1 and -5 expression and attenuation in the levels of ADAMTS-4. In contrast, IFN-γ suppressed the expression of ADAMTS-1 without having an effect on ADAMTS-4 and -5. Although TL-1A or IL-17A alone had little effect on the expression of all the members, they induced their expression synergistically when present together. These studies provide new insight into the regulation of key ADAMTS family members in human macrophages by major cytokines in relation to atherosclerosis.
ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; ApoB, apolipoprotein B; ApoE, apolipoprotein E; DR3, death receptor 3; ECM, extracellular matrix; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HMDM, human monocyte-derived macrophages; IFN-γ, interferon-γ; IL, interleukin; LDL, low-density lipoprotein; LDLR, LDL receptor; LPL, lipoprotein lipase; MMP, matrix metalloproteinase; PMA, phorbol 12-myristate 13-acetate; RT-qPCR, real-time quantitative polymerase chain reaction; TGF-β, transforming growth factor-β; TL1A, tumour necrosis factor-like protein 1A; TNF-α, tumour necrosis factor-α; VSMC, vascular smooth muscle cells; ADAMTS proteases; Atherosclerosis; Cytokines; Macrophages; Gene expression
A case of multidrug resistance central nervous system tuberculosis is described. During the initial 6 months of therapy, intracranial embolic spread of tuberculomas from exudates around the proximal left middle cerebral artery was seen. This phenomenon was reported earlier. Further management, therapeutic considerations, particularly with secondary and tertiary line of antitubercular medication and neuroimaging are discussed.
Carotid intima-media thickness (CIMT) and carotid plaques represent preclinical markers of atherosclerosis. We sought to describe predictors of CIMT and carotid plaques, including early life growth, in a young urban Indian cohort free of clinical cardiovascular disease (CVD).
In 2006-2009, we performed B-mode carotid ultrasound on 600 participants (mean [SD] age 36 [1.1] years; 45% women) from the New Delhi Birth Cohort to evaluate CIMT and carotid plaques (> 1mm). Height and weight were recorded at birth, 2 and 11 years of age. Data on CVD risk factors, anthropometry, medical history, socio-economic position, and lifestyle habits were collected in 1998-2002.
Mean (SD) CIMT for men and women was 0.91 (0.12) and 0.86 (0.13) mm, respectively. Carotid plaque was present in 33% of men and 26% of women. Waist circumference in 1998-2002 was positively associated with CIMT (β coefficient 0.26 mm [0.17, 0.36] per SD) and carotid plaque (OR 1.27 [1.06,1.52] per SD) in 2006-2009. Higher triglycerides, PAI-1, insulin resistance, and diastolic blood pressure, metabolic syndrome, and lower HDL-cholesterol and physical activity predicted higher CIMT and/or plaque (p<0.05). Longer length at 2 years was associated with higher CIMT (p<0.05). These associations were attenuated after adjusting for adult waist circumference.
These are the first prospective data from India showing that early life growth, adult socio-demographics, and CVD risk factors predict future CIMT and /or carotid plaque. These relationships appear primarily mediated through central adiposity, highlighting the importance of maintaining a healthy weight in early adulthood to prevent CVD.
carotid intima media thickness; carotid plaque; India; cohort; birth weight; infant and childhood growth
Supracondylar fractures are the commonest elbow injury in children. Most displaced Supracondylar fractures are manipulated and held with a medial/lateral entry or two lateral Kirschner wires. It was the purpose of this study to investigate the treatment of this injury in this unique patient population.
Materials and Methods:
This study was conducted in the Department of Orthopaedic surgery in M. M. Medical College from July 2005 to July 2010. One hundred seventy patients were recruited from Emergency and outpatient department having closed displaced Supracondylar fractures of humerus in children. They were treated either with medial-lateral pin fixation (n = 85) or with 2-lateral pin fixation (n = 85). All patients were operated under general anaesthesia. All patients were followed for 6 months. Results were analysed using Flynn's criteria.
Statistical Analysis Used:
Chi Square Test. Chi Square calculator was used as a software.
All children achieved union in a mean time of 4 weeks (range: 3-6 weeks). Post-operatively, eight patients (4.70%) got ulnar nerve injury and six (3.52%) patients got pin tract infection. Comparison between two groups such as cross K-wire group (85) and lateral K-wire group (n = 85) by using the Chi Square Test showed that in case of 8 weeks with (P-values = 0.89), in 16 weeks (P = 0.91) and 24 weeks (P = 0.85) with respective excellent, good, fair and poor categories were not found statistically significant.
The lateral percutaneous pinning technique of displaced Supracondylar fractures of the humerus offers a viable alternative to the crossed pinning group as it offers the same stability without the incipient risk of iatrogenic ulnar nerve injury.
Close reduction; chi square test; humerus; percutaneous pinning; supracondylar fracture