Memantine, an NMDA receptor uncompetitive antagonist, is currently approved by the Food and Drug Administration for the treatment of moderate to severe Alzheimer’s disease. Anecdotal reports have suggested that memantine may improve neurological and cognitive symptoms of individuals with the neurodegenerative disease, fragile X-associated tremor tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial.
A randomized, double-blind, placebo-controlled, one-year trial in individuals with FXTAS ages 34–80 years. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity.
Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants on memantine and 36 on placebo completed the one-year endpoint assessment (n=70). Intention-to-treat analysis showed that there was no improvement with respect to intention tremor severity (memantine vs. placebo: 1.05 ± 0.73 vs. 1.89 ± 2.19, p=0.047) and BDS score (16.12 ± 5.43 vs. 15.72 ± 3.93, p=0.727) at follow-up. Post hoc analyses of participants with early FXTAS (stage ≤ 3), late FXTAS (stage > 3) and different age groups (≤ 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events (AEs) were observed in the placebo group, while more frequent moderate AEs occurred in the memantine group (p=0.007).
This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit with respect to the selected outcome measures compared to placebo.
Incidence of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections decreased substantially among dialysis patients during 2005–2011 based on surveillance data from 9 metropolitan areas. Despite decreases, an estimated 15 169 invasive MRSA infections occurred in US dialysis patients in 2011.
Background. Approximately 15 700 invasive methicillin-resistant Staphylococcus aureus (MRSA) infections occurred in US dialysis patients in 2010. Frequent hospital visits and prolonged bloodstream access, especially via central venous catheters (CVCs), are risk factors among hemodialysis patients. We describe the epidemiology of and recent trends in invasive MRSA infections among dialysis patients.
Methods. We analyzed population-based data from 9 US metropolitan areas from 2005 to 2011. Cases were defined as MRSA isolated from a normally sterile body site in a surveillance area resident who received dialysis, and were classified as hospital-onset (HO; culture collected >3 days after hospital admission) or healthcare-associated community-onset (HACO; all others). Incidence was calculated using denominators from the US Renal Data System. Temporal trends in incidence and national estimates were calculated controlling for age, sex, and race.
Results. From 2005 to 2011, 7489 cases were identified; 85.7% were HACO infections, and 93.2% were bloodstream infections. Incidence of invasive MRSA infections decreased from 6.5 to 4.2 per 100 dialysis patients (annual decrease, 7.3%) with annual decreases of 6.7% for HACO and 10.5% for HO cases. Among cases identified during 2009–2011, 70% of patients were hospitalized in the year prior to infection. Among hemodialysis cases, 60.4% of patients were dialyzed through a CVC. The 2011 national estimated number of MRSA infections was 15 169.
Conclusions. There has been a substantial decrease in invasive MRSA infection incidence among dialysis patients. Most cases had previous hospitalizations, suggesting that efforts to control MRSA in hospitals might have contributed to the declines. Infection prevention measures should include improved vascular access and CVC care.
invasive MRSA; dialysis; methicillin-resistant S. aureus
We propose a new weighted hurdle regression method for modeling count data, with particular interest in modeling cardiovascular events in patients on dialysis. Cardiovascular disease remains one of the leading causes of hospitalization and death in this population. Our aim is to jointly model the relationship/association between covariates and (a) the probability of cardiovascular events, a binary process and (b) the rate of events once the realization is positive - when the ‘hurdle’ is crossed - using a zero-truncated Poisson distribution. When the observation period or follow-up time, from the start of dialysis, varies among individuals the estimated probability of positive cardiovascular events during the study period will be biased. Furthermore, when the model contains covariates, then the estimated relationship between the covariates and the probability of cardiovascular events will also be biased. These challenges are addressed with the proposed weighted hurdle regression method. Estimation for the weighted hurdle regression model is a weighted likelihood approach, where standard maximum likelihood estimation can be utilized. The method is illustrated with data from the United States Renal Data System. Simulation studies show the ability of proposed method to successfully adjust for differential follow-up times and incorporate the effects of covariates in the weighting.
cardiovascular outcomes; dialysis; end stage renal disease; hurdle model; infection; Poisson regression; United States Renal Data System
Interleukin-36α (IL-36α), previously designated as IL-1F6, has been found to have a pathogenic role in psoriasis. However, possible functions of IL-36α in cancer remain unclear. In present study, we investigate the possible role of interleukin-36α involved in the pathogenesis of colorectal cancer. IL-36α expression was detected in 345 colorectal cancer tissue samples by immunohistochemical staining, and its relation with clinicopathologic parameters and prognosis of colorectal cancer patients were analyzed. IL-36α was highly expressed in nearly half of all tested colorectal cancer patients. However, low expression level of IL-36α significantly correlated with larger tumor size and advanced TNM stage. Kaplan-Meier survival analysis showed that low expression level of IL-36α resulted in a remarkably poor prognosis of colorectal cancer patients. Multivariate Cox’s analysis revealed that the IL-36α expression level was a significant and independent prognostic factor for overall survival rate of colorectal cancer patients. Thus, our study may provide insight into the application of IL-36α as a novel predictor of prognosis and a potential therapeutic drug for colorectal cancer.
Interleukin-36α; colorectal cancer; prognosis; therapy
To develop a reference of population-based gestational age-specific birth weight percentiles for contemporary Chinese.
Birth weight data was collected by the China National Population-based Birth Defects Surveillance System. A total of 1,105,214 live singleton births aged ≥28 weeks of gestation without birth defects during 2006–2010 were included. The lambda-mu-sigma method was utilized to generate percentiles and curves.
Gestational age-specific birth weight percentiles for male and female infants were constructed separately. Significant differences were observed between the current reference and other references developed for Chinese or non-Chinese infants.
There have been moderate increases in birth weight percentiles for Chinese infants of both sexes and most gestational ages since 1980s, suggesting the importance of utilizing an updated national reference for both clinical and research purposes.
Seizures are a common co-occurring condition in those with fragile X syndrome (FXS), and in those with idiopathic autism spectrum disorder (ASD). Seizures are also associated with ASD in those with FXS. However, little is known about the rate of seizures and how commonly these problems co-occur with ASD in boys with the FMR1 premutation. We, therefore, determined the prevalence of seizures and ASD in boys with the FMR1 permutation compared with their sibling counterparts and population prevalence estimates. Fifty premutation boys who presented as clinical probands (N = 25), or non-probands (identified by cascade testing after the proband was found) (N = 25), and 32 non-carrier controls were enrolled. History of seizures was documented and ASD was diagnosed by standardized measures followed by a team consensus of ASD diagnosis. Seizures (28%) and ASD (68%) were more prevalent in probands compared with non-probands (0 and 28%), controls (0 and 0%), and population estimates (1 and 1.7%). Seizures occurred more frequently in those with the premutation and co-morbid ASD particularly in probands compared with those with the premutation alone (25 vs. 3.85%, p = 0.045). Although cognitive and adaptive functioning in non-probands were similar to controls, non-probands were more likely to meet the diagnosis of ASD than controls (28 vs. 0%, p < 0.0001). In conclusion, seizures were relatively more common in premutation carriers who presented clinically as probands of the family and seizures were commonly associated with ASD in these boys. Therefore, boys with the premutation, particularly if they are probands should be assessed carefully for both ASD and seizures.
The relative risk of immune-mediated disorders (IMDs) among women carrier of premutation alleles is estimated by a survey for IMDs among 344 carrier women (age 19 to 81 years; mean 46.35 and SD 12.60) and 72 controls (age 18 to 87 years; mean 52.40 and SD 15.40). One hundred fifty four (44.77%) women carrier had at least one IMD, as did 20 controls (27.78%). Among women carrier, autoimmune thyroid disorder was the most common (24.4%), then fibromyalgia (10.2%), irritable bowel syndrome (IBS; 9.9%), Raynaud’s phenomenon (7.6%), rheumatoid arthritis (RA; 3.8%), Sjögren syndrome (2.6%), systemic lupus erythematosus (SLE; 2.03%), multiple sclerosis (1.74%). Of 55 carriers age 40 or older with FXTAS, 72.73% had at least one IMD, compared to 46.54% of those without FXTAS (n=159), and 31.58% of controls (n=57). The estimated odds ratio (OR) for IMD is 2.6 (95% CI 1.2–5.6, p = 0.015) for women with FXTAS relative to those without FXTAS; the likelihood of IMD in carriers without or with FXTAS was also significantly higher than for controls (OR 2.1, 95% CI 1.1–4.2, p = 0.034; OR 5.5, 95% CI 2.4–12.5, p < 0.001 respectively). Similarly, the odds of having an IMD among carriers with FXPOI is about 2.4 times higher when compared to carriers without FXPOI (95% CI 1.1–5.0; p = 0.021). The likelihood of IMD in carriers with or without FXPOI is greater (OR 2.4, 95% CI 1.1–5.0; p = 0.021) compared to that of controls.
Autoimmune; FXTAS; RNA toxicity; ovarian insufficiency
Previous studies on the mortality rate of omphalocele are limited. The risk of death of non-isolated omphalocele and that of cases of omphalocele that are diagnosed prenatally by ultrasound are unclear. This study aimed to estimate the perinatal mortality of pregnancies with omphalocele. This study also examined the potential risk of death of non-isolated omphalocele and that of cases that are prenatally diagnosed by ultrasound.
Data were retrieved from the national birth defects registry in China, for 1996–2006. Multinomial logistic regression was used to calculate the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) between perinatal mortality and selected maternal and fetal characteristics.
Among 827 cases of omphalocele, 309 (37.4%) cases resulted in termination of pregnancy and stillbirth, and 124 (15.0%) cases resulted in death in the first 7 days after delivery, yielding a perinatal mortality rate of 52.4% (95% CI: 49.0–55.8%). The late fetal death rate (LFDR) of omphalocele that was diagnosed prenatally by ultrasound was 15.91-fold (AOR: 15.91, 95% CI: 10.18–24.87) higher than that of postnatally diagnosed cases. The LFDR of non-isolated omphalocele was 2.64-fold (AOR: 2.64, 95% CI: 1.62–4.29) higher than that of isolated cases. For the early neonatal death rate, neonates with non-isolated omphalocele had a 2.96-fold (AOR: 2.96, 95% CI: 1.82–4.81) higher risk than isolated cases, but the difference between prenatal ultrasound diagnosis and postnatal diagnosis was not significant.
Selected fetal characteristics are significantly associated with the perinatal risk of death from omphalocele. Our findings suggest that improving pregnancy and delivery care, as well as management for omphalocele are important.
Omphalocele; Abdominal wall defects; Mortality; Perinatal outcome; Associated anomalies; Prenatal diagnosis; Ultrasound
The biomechanical performance of the hooks and screws in spinal posterior instrumentation is not well-characterized. Screw-bone interface failure at the uppermost and lowermost vertebrae is not uncommon. Some have advocated for the use of supplement hooks to prevent screw loosening. However, studies describing methods for combined hook and screw systems that fully address the benefits of these systems are lacking. Thus, the choice of which implant to use in a given case is often based solely on a surgeon’s experience instead of on the biomechanical features and advantages of each device.
We conducted a biomechanical comparison of devices instrumented with different combinations of hooks and screws. Thirty-six fresh low thoracic porcine spines were assigned to three groups (12 per group) according to the configuration used for of fixation: (1) pedicle screw; (2) lamina hook and (3) combination of pedicle screw and lamina hook. Axial pullout tests backward on transverse plane in the direction normal to the rods were performed using a material testing machine and a specially designed grip with self-aligned function.
The pullout force for the pedicle screws group was significantly greater than for the hooks and the combination (p < 0.05). However, no significant difference was found between the hooks and the combination (p > 0.05).
Pedicle screws achieve the maximal pullout strength for spinal posterior instrumentation.
Pedicle screw; Lamina hook; Biomechanical study; Porcine model
Schistosomiasis is a chronic debilitating parasitic disease that afflicts more than 200 million individuals worldwide. Long-term administration of chemotherapy with the single available drug, praziquantel, has led to growing concerns about drug resistance. The PSD-95/Dlg/ZO-1 (PDZ) domain is an important module found in many scaffolding proteins, which has been recognized as promising targets for the development of novel drugs. However, the parasite-derived PDZ domains and their associated functions are still largely unknown.
The gene encoding the Schistosoma japonicum Scribble protein (SjScrib) was identified by homologous search with the S. mansoni Scrib sequence. By screening an arbitrary peptide library in yeast two-hybrid (Y2H) assays, we identified and confirmed the ligand binding specificity for each of the four PDZ domains of SjScrib. Both SjScrib-PDZ1 and SjScrib-PDZ3 recognize type I C-terminal PDZ-domain binding motifs (PBMs), which can be deduced as consensus sequences of -[Φ][x][E][TS][x][ILF] and -[x][RKx][ETS][T][WΦ][ILV], respectively. SjScrib-PDZ2 prefers stringent type II C-terminal PBMs, which significantly differs from that of its human ortholog. SjScrib-PDZ4 binds to typical II C-terminal PBMs with a consensus sequence -[x][FW][x][LI][x][LIV], in which the aromatic residue Phe is predominantly selected at position -4. The irregular and unconventional internal ligand binding specificities for the PDZ domains of SjScrib were confirmed by point mutations of the key amino acids within the ligand binding motifs. We also compared the differences in ligand specificities between SjScrib-PDZs and hScrib-PDZs, and explored the structural basis for the ligand binding properties of SjScrib-PDZs.
In this study, we characterized and confirmed the ligand binding specificities of all four PDZ domains of SjScrib for the first time. We denoted the differential ligand binding specificities between SjScrib-PDZs and hScrib-PDZs as well as the structural basis for these properties. This work may provide a fundamental basis for the rational design of novel anti-schistosomal drugs.
Schistosomiasis japonica remains a major public health problem in China and Southeast Asia. The long-term of treatments with the only available drug, praziquantel, has raised the concerns about drug resistance. Protein-protein interactions (PPIs), for highly discriminating specificities, are thought to be the innovative targets for a generation of new drugs. The PDZ domain is one of the most important modules for PPIs. A number of compounds screened based on binding specificities of PDZ domains have shown their potential therapeutic power in several disease models with less side effects. Although domain loss events are widespread in S. japonicum, a panel of PDZ domains is conserved in this species. So far, however, little is known about ligand binding specificities and the molecular functions of parasite-derived PDZ domain-containing proteins. In this study, by yeast two-hybrid screening of a random library, we confirmed the ligand binding properties of a multiple PDZ domain-containing protein Scribble of S. japonicum for the first time. Divergent ligand specificities between the homologous PDZ domains of S. japonicum and human Scribble orthologs were revealed. Internal motif recognition and irregular ligand interaction models for the SjScrib-PDZ domains were identified. These results provide an important basis for the rational discovery of anti-schistosomal drugs.
White blood cell (WBC) count has been associated with diabetic risk, but whether the correlation is independent of other risk factors has hardly been studied. Moreover, very few such studies with large sample sizes have been conducted in Chinese. Therefore, we investigated the relationship between WBC count and glucose metabolism in china. We also examined the relevant variables of WBC count. A total of 9,697 subjects (mean age, 58.0 ± 9.1 years) were recruited. The subjects were classified into four groups, including subjects with normal glucose tolerance, isolated impaired fasting glucose, impaired glucose tolerance and type 2 diabetes mellitus (T2DM). We found that WBC count increased as glucose metabolism disorders exacerbated. WBC count was also positively correlated with waist hip ratio, body mass index, smoking, triglycerides, glycosylated haemoglobin A1c (HbA1c) and 2-h postprandial glucose. In addition, high density lipoprotein and the female gender were inversely correlated with WBC levels. In patients with previously diagnosed T2DM, the course of T2DM was not correlated with WBC count. Our findings indicate that elevated WBC count is independently associated with worsening of glucose metabolism in middle-aged and elderly Chinese. In addition, loss of weight, smoking cessation, lipid-modifying therapies, and control of postprandial plasma glucose and HbA1c may ameliorate the chronic low-grade inflammation.
white blood cell; diabetes mellitus, type 2; glucose metabolism disorders; inflammation; glycosylated hemoglobin A1c
Fragile X-associated tremor ataxia syndrome (FXTAS) is a late onset neurodegenerative disease that affects carriers of the fragile X premutation. This study seeks to assess hypertension risk and susceptibility in male premutation carriers with FXTAS. Although many symptoms and diagnostic criteria have been identified, hypertension risk has not been examined in this population. Data from 92 premutation carriers without FXTAS, 100 premutation carriers with FXTAS, and 186 controls was collected via patient medical interview. Age-adjusted logistic regression analysis was used to examine the relative odds of hypertension. We observed a significantly elevated odds ratio (OR) of hypertension relative to controls for premutation carriers with FXTAS (OR = 3.22, 95% CI: 1.72–6.04; P = 0.0003) among participants over 40-year old. The age-adjusted estimated odds of hypertension in premutation carriers without FXTAS in the over 40-year-old age group was higher compared to controls (OR = 1.61, 95% CI: 0.82–3.16), but was not statistically significant (P = 0.164). Chronic hypertension contributes to cardiovascular complications, dementia, and increased risk of stroke. Our results indicate that the risk of hypertension is significantly elevated in male premutation carriers with FXTAS compared with carriers without FXTAS and controls. Thus, evaluation of hypertension in patients diagnosed with FXTAS should be a routine part of the treatment monitoring and intervention for this disease.
hypertension; FMR1 premutation; fragile X-associated tremor/ataxia syndrome; autonomic disease
Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Prior open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial.
Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, ages 3.5-16 years (n=55, mean age 9.2 (SD 3.6 years)). Participants were randomized to minocycline or placebo for three months, then switched to the other treatment.
Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-to-treat analysis demonstrated significantly greater improvements in one primary outcome, Clinical Global Impression Scale-Improvement after minocycline compared to placebo (2.49 ±0.13, 2.97 ±0.13, respectively, p 0.0173) and greater improvement in ad hoc analysis of anxiety and mood-related behaviors on the Visual Analoge Scale (minocycline 5.26 cm ±0.46 cm, placebo 4.05 cm±0.46cm; p 0.0488). Side effects were not significantly different during the minocycline and placebo treatments. No serious adverse events occurred on minocycline. Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding and preliminary efficacy analysis results known to investigators.
Minocycline treatment for three months in children with FXS resulted in greater global improvement than placebo. Treatment for three months appears safe; however, longer trials are indicated to further assess benefits, side effects, and factors associated with a clinical response to minocycline.
Fragile X Syndrome; Intellectual Disability; Minocycline; Matrix Metalloproteinase 9
Protein-protein interactions (PPIs) are essential events to play important roles in a series of biological processes. There are probably more ways of PPIs than we currently realized. Structural and functional investigations of weak PPIs have lagged behind those of strong PPIs due to technical difficulties. Weak PPIs are often short-lived, which may result in more dynamic signals with important biological roles within and/or between cells. For example, the characteristics of PSD-95/Dlg/ZO-1 (PDZ) domain binding to internal sequences, which are primarily weak interactions, have not yet been systematically explored. In the present study, we constructed a nearly random octapeptide yeast two-hybrid library. A total of 24 PDZ domains were used as baits for screening the library. Fourteen of these domains were able to bind internal PDZ-domain binding motifs (PBMs), and PBMs screened for nine PDZ domains exhibited strong preferences. Among 11 PDZ domains that have not been reported their internal PBM binding ability, six were confirmed to bind internal PBMs. The first PDZ domain of LNX2, which has not been reported to bind C-terminal PBMs, was found to bind internal PBMs. These results suggest that the internal PBMs binding ability of PDZ domains may have been underestimated. The data provided diverse internal binding properties for several PDZ domains that may help identify their novel binding partners.
The present study aims to investigate whether the combination treatment of cordycepin (an extracted pure compound from Cordyceps sinensis) and cisplatin (a platinum-based chemotherapy drug) has better apoptotic effect in head and neck squamous cell carcinoma (HNSCC).
The apoptotic influences of cordycepin and/or cisplatin treatments to human OC3, OEC-M1, and FaDu HNSCC cells were investigated by morphological observations, viability assay, flow cytometry assay, and Western blotting methods.
Data showed that the cell death phenomenon increased as the dosage of cordycepin or cisplatin increased, and it appeared more in cordycepin plus cisplatin cotreatment among three cell lines. Cell survival rates significantly decreased as the dosage of cordycepin or cisplatin increased, and the better apoptotic effects were observed in cotreatment. Cell cycle analysis further demonstrated that percentages of subG1 cells in cordycepin or cisplatin treatments significantly increased, suggesting that cells underwent apoptosis, and cordycepin plus cisplatin induced many more subG1 cells. Furthermore, cordycepin or cisplatin induced caspase-8, caspase-9, caspase-3, and poly adenosine diphosphate-ribose polymerase protein cleavages, and stimulated c-Jun NH2-terminal kinase, extracellular signal-regulated kinase, and p38 protein phosphorylations. Moreover, cordycepin plus cisplatin cotreatment significantly activated those proteins with much better effects among three cell lines.
Cordycepin plus cisplatin have better apoptotic effect by activating caspase activation with possible MAPK pathway involvement in HNSCC cells.
cordycepin; cisplatin; apoptosis; caspase; MAPK; HNSCC
Liver resections for hepatocellular carcinoma (HCC) in cirrhotic livers are associated with early recurrence and poor survival. Somatostatin analogues (SSAs) have been reported to inhibit cell proliferation by interacting with specific somatostatin receptors (SSTRs) 2 and 5. The present study investigated whether SSTR expression in HCC was associated with the clinical outcome following octreotide long-acting release (LAR) treatment. Paired tumor and cirrhotic liver samples were obtained following a liver resection from 99 patients with stage I–II HCC and HBV-related cirrhosis. The expression of SSTR2 and 5 was assessed using quantitative (q)PCR and immunohistochemistry. The patients were classified into two groups, the high expression (n=47) and low expression (n=52) groups, based on the gene expression levels. The clinicopathological data and survival results of the two groups were compared. When compared with the surrounding cirrhotic tissue, the SSTR2 and 5 mRNA levels were significantly decreased in the HCC tissue. There were no significant differences between the groups with respect to the baseline characteristics. The tumor recurrence rate was significantly lower in the high expression group compared with that of the low expression group (63.83% vs. 82.69%; P=0.033). The 1-, 3- and 5-year disease-free and overall survival rates of the high expression group were 97, 89 and 71% and 98, 89 and 74%, respectively. The survival time of the members of the high expression group was longer compared with that of the low expression group. The multivariate analysis revealed that the TNM-7 stage and SSTR2 expression were independent prognostic factors for survival. In conclusion, SSTR mRNA expression correlated with survival in patients with early-stage hepatitis B virus (HBV)-related HCC who were treated with octreotide LAR following surgery. The inhibitory effects of SSAs on tumor growth may be mediated by SSTR expression.
hepatocellular carcinoma; somatostatin receptor; survival; octreotide long-acting release; quantitative polymerase chain reaction
Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and autism. The protein (FMRP) encoded by the fragile X mental retardation gene (FMR1), is an RNA-binding protein linked to translational control. Recently, in the Fmr1 knockout mouse model of FXS, dysregulated translation initiation signaling was observed. To investigate whether an altered signaling was also a feature of subjects with FXS compared to typical developing controls, we isolated total RNA and translational control proteins from lymphocytes of subjects from both groups (38 FXS and 14 TD). Although we did not observe any difference in the expression level of mRNAs for translational initiation control proteins isolated from participant with FXS, we found increased phosphorylation of the mammalian target of rapamycin (mTOR) substrate, p70 ribosomal subunit 6 kinase1 (S6K1) and of the mTOR regulator, the serine/threonine protein kinase (Akt), in their protein lysates. In addition, we observed increased phosphorylation of the cap binding protein eukaryotic initiation factor 4E (eIF4E) suggesting that protein synthesis is upregulated in FXS. Similarly to the findings in lymphocytes, we observed increased phosphorylation of S6K1 in brain tissue from patients with FXS (n=6) compared to normal age matched controls (n=4). Finally, we detected increased expression of the cytoplasmic FMR1-interacting protein 2 (CYFIP2), a known FMRP interactor. This data verify and extend previous findings using lymphocytes for studies of neuropsychiatric disorders and provide evidence that misregulation of mTOR signaling observed in a FXS mouse model also occurs in human FXS and may provide useful biomarkers for designing target treatments in FXS.
Fragile X; CYFIP1; CYFIP2; mTOR; phosphorylation
Schistosomiasis is a serious global health problem that afflicts more than 230 million people in 77 countries. Long-term mass treatments with the only available drug, praziquantel, have caused growing concerns about drug resistance. PSD-95/Dlg/ZO-1 (PDZ) domain-containing proteins are recognized as potential targets for the next generation of drug development. However, the PDZ domain-containing protein family in parasites has largely been unexplored.
We present the molecular characteristics of a PDZ domain-containing protein, GIPC3, from Schistosoma japonicum (SjGIPC3) according to bioinformatics analysis and experimental approaches. The ligand binding specificity of the PDZ domain of SjGIPC3 was confirmed by screening an arbitrary peptide library in yeast two-hybrid (Y2H) assays. The native ligand candidates were predicted by Tailfit software based on the C-terminal binding specificity, and further validated by Y2H assays.
SjGIPC3 is a single PDZ domain-containing protein comprised of 328 amino acid residues. Structural prediction revealed that a conserved PDZ domain was presented in the middle region of the protein. Phylogenetic analysis revealed that SjGIPC3 and other trematode orthologues clustered into a well-defined cluster but were distinguishable from those of other phyla. Transcriptional analysis by quantitative RT-PCR revealed that the SjGIPC3 gene was relatively highly expressed in the stages within the host, especially in male adult worms. By using Y2H assays to screen an arbitrary peptide library, we confirmed the C-terminal binding specificity of the SjGIPC3-PDZ domain, which could be deduced as a consensus sequence, -[SDEC]-[STIL]-[HSNQDE]-[VIL]*. Furthermore, six proteins were predicted to be native ligand candidates of SjGIPC3 based on the C-terminal binding properties and other biological information; four of these were confirmed to be potential ligands using the Y2H system.
In this study, we first characterized a PDZ domain-containing protein GIPC3 in S. japonicum. The SjGIPC3-PDZ domain is able to bind both type I and II ligand C-terminal motifs. The identification of native ligand will help reveal the potential biological function of SjGIPC3. These data will facilitate the identification of novel drug targets against S. japonicum infections.
Schistosoma japonicum; GIPC3, PDZ domain-containing protein; Ligand binding specificity
Low-toxicity magnetic nanocarriers (MNCs) composed of a shell of poly [aniline-co-N-(1-one-butyric acid) aniline] over a Fe3O4 magnetic nanoparticle core were developed to carry recombinant tissue plasminogen activator (rtPA) in MNC-rtPA for targeted thrombolysis. With an average diameter of 14.8 nm, the MNCs exerted superparamagnetic properties. Up to 276 μg of active rtPA was immobilized per mg of MNCs, and the stability of the immobilized rtPA was greatly improved during storage at 4°C and 25°C. In vitro thrombolysis testing with a tubing system demonstrated that magnet-guided MNC-rtPA showed significantly improved thrombolysis compared with free rtPA and reduced the clot lysis time from 39.2 ± 3.2 minutes to 10.8 ± 4.2 minutes. In addition, magnet-guided MNC-rtPA at 20% of the regular rtPA dose restored blood flow within 15–25 minutes of treatment in a rat embolism model without triggering hematological toxicity. In conclusion, this improved system is based on magnetic targeting accelerated thrombolysis and is potentially amenable to therapeutic applications in thromboembolic diseases.
thrombolysis; recombinant tissue plasminogen activator; magnetic nanocarriers; magnetic targeting; targeting therapy
Nanoparticles (NPs) play an important role in the molecular diagnosis, treatment, and monitoring of therapeutic outcomes in various diseases. Their nanoscale size, large surface area, unique capabilities, and negligible side effects make NPs highly effective for biomedical applications such as cancer therapy, thrombolysis, and molecular imaging. In particular, nontoxic superparamagnetic magnetic NPs (MNPs) with functionalized surface coatings can conjugate chemotherapeutic drugs or be used to target ligands/proteins, making them useful for drug delivery, targeted therapy, magnetic resonance imaging, transfection, and cell/protein/DNA separation. To optimize the therapeutic efficacy of MNPs for a specific application, three issues must be addressed. First, the efficacy of magnetic targeting/guidance is dependent on particle magnetization, which can be controlled by adjusting the reaction conditions during synthesis. Second, the tendency of MNPs to aggregate limits their therapeutic use in vivo; surface modifications to produce high positive or negative charges can reduce this tendency. Finally, the surface of MNPs can be coated with drugs which can be rapidly released after injection, resulting in targeting of low doses of the drug. Drugs therefore need to be conjugated to MNPs such that their release is delayed and their thermal stability enhanced. This chapter describes the creation of nanocarriers with a high drug-loading capacity comprised of a high-magnetization MNP core and a shell of aqueous, stable, conducting polyaniline derivatives and their applications in cancer therapy. It further summarizes some newly developed methods to synthesize and modify the surfaces of MNPs and their biomedical applications.
magnetic nanoparticles; drug delivery; biomedical applications; cancer therapy
Young children with fragile X syndrome (FXS) often experience anxiety, irritability, and hyperactivity related to sensory hyperarousal. However, there are no medication recommendations with documented efficacy for children under 5 years old of age with FXS. We examined data through a chart review for 45 children with FXS, 12–50 months old, using the Mullen Scales of Early Learning (MSEL) for baseline and longitudinal assessments. All children had clinical level of anxiety, language delays based on MSEL scores, and similar early learning composite (ELC) scores at their first visit to our clinic. Incidence of autism spectrum disorder (ASD) was similar in both groups. There were 11 children who were treated with sertraline, and these patients were retrospectively compared to 34 children who were not treated with sertraline by chart review. The baseline assessments were done at ages ranging from 18 to 44 months (mean 26.9, SD 7.99) and from 12 to 50 months (mean 29.94, SD 8.64) for treated and not treated groups, respectively. Mean rate of improvement in both expressive and receptive language development was significantly higher in the group who was treated with sertraline (P < 0.0001 and P = 0.0071, resp.). This data supports the need for a controlled trial of sertraline treatment in young children with FXS.
Malignant glioma is a common and severe primary brain tumor with a high recurrence rate and an extremely high mortality rate within 2 years of diagnosis, even when surgical, radiological, and chemotherapeutic interventions are applied. Intravenously administered drugs have limited use because of their adverse systemic effects and poor blood–brain barrier penetration. Here, we combine 2 methods to increase drug delivery to brain tumors. Focused ultrasound transiently permeabilizes the blood–brain barrier, increasing passive diffusion. Subsequent application of an external magnetic field then actively enhances localization of a chemotherapeutic agent immobilized on a novel magnetic nanoparticle. Combining these techniques significantly improved the delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea to rodent gliomas. Furthermore, the physicochemical properties of the nanoparticles allowed their delivery to be monitored by magnetic resonance imaging (MRI). The resulting suppression of tumor progression without damaging the normal regions of the brain was verified by MRI and histological examination. This noninvasive, reversible technique promises to provide a more effective and tolerable means of tumor treatment, with lower therapeutic doses and concurrent clinical monitoring.
BCNU; glioma; magnetic nanoparticle; MRI; ultrasound
1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranose (PGG) is an active ingredient in plants that are commonly used in Chinese medicine to treat inflammation. We demonstrate here that PGG, at 6.25 μM, does not inhibit the growth of Staphylococcus aureus, and yet it prevents biofilm formation on polystyrene and polycarbonate surfaces. At the same concentration, PGG is not toxic to human epithelial and fibroblast cells. PGG has an IB50 value, i.e., the PGG concentration that inhibits 50% biofilm formation, of 3.6 μM. The value is substantially lower than that of N-acetylcysteine, iodoacetamide, and N-phenyl maleimide, which are known to inhibit biofilm formation by S. aureus. Biochemical and scanning electron microscopy results also reveal that PGG inhibits initial attachment of the bacteria to solid surface and the synthesis of polysaccharide intercellular adhesin, explaining how PGG inhibits biofilm formation. The results of this study demonstrate that coating PGG on polystyrene and silicon rubber surfaces with polyaniline prevents biofilm formation, indicating that PGG is highly promising for clinical use in preventing biofilm formation by S. aureus.
The asymmetric unit of the title compound, C14H10O4, contains one half molecule, the complete molecule being generated by a twofold axis. The two benzene rings form a dihedral angle of 43.11 (5)°. Intermolecular O—H⋯O hydrogen bonds link the molecules into one-dimensional zigzag chains. These chains are further connected into two-dimensional supramolecular layers by weak π–π stacking interactions between neighbouring benzene rings, with centroid–centroid distances of 3.7648 (8) Å.
A series of dopant-type polyaniline-polyacrylic acid composite (PAn-PAA) films with porous structures were prepared and developed for an enzyme-free hydrogen peroxide (H2O2) sensor. The composite films were highly electroactive in a neutral environment as compared to polyaniline (PAn). In addition, the carboxyl group of the PAA was found to react with H2O2 to form peroxy acid groups, and the peroxy acid could further oxidize the imine structure of PAn to form N-oxides. The N-oxides reverted to their original form via electrochemical reduction and increased the reduction current. Based on this result, PAn-PAA was used to modify a gold electrode (PAn-PAA/Au) as a working electrode for the non-enzymatic detection of H2O2. The characteristics of the proposed sensors could be tuned by the PAA/PAn molar ratio. Blending PAA with PAn enhanced the surface area, electrocatalytic activity, and conductivity of these sensors. Under optimal conditions, the linear concentration range of the H2O2 sensor was 0.04 to 12 mM with a sensitivity of 417.5 μA/mM-cm2. This enzyme-free H2O2 sensor also exhibited a rapid response time, excellent stability, and high selectivity.
polyaniline; polyacrylic acid; enzyme-free; hydrogen peroxide sensor