Potential of Naturally Derived Alkaloids as Multi-Targeted Therapeutic Agents for Neurodegenerative Diseases.

Alkaloids are a class of secondary metabolites that can be derived from plants, fungi and marine sponges. They are widely known as a continuous source of medicine for the management of chronic disease including cancer, diabetes and neurodegenerative diseases. For example, galanthamine and huperzine A are alkaloid derivatives currently being used for the symptomatic management of neurodegenerative disease. The etiology of neurodegenerative diseases is polygenic and multifactorial including but not limited to inflammation, oxidative stress and protein aggregation. Therefore, natural-product-based alkaloids with polypharmacology modulation properties are potentially useful for further drug development or, to a lesser extent, as nutraceuticals to manage neurodegeneration. This review aims to discuss and summarise recent developments in relation to naturally derived alkaloids for neurodegenerative diseases.

Quasi-BIC Resonant Enhancement of Second-Harmonic Generation in WS2 Monolayers.

Atomically thin monolayers of transition metal dichalcogenides (TMDs) have emerged as a promising class of novel materials for optoelectronics and nonlinear optics. However, the intrinsic nonlinearity of TMD monolayers is weak, limiting their functionalities for nonlinear optical processes such as frequency conversion. Here we boost the effective nonlinear susceptibility of a TMD monolayer by integrating it with a resonant dielectric metasurface that supports pronounced optical resonances with high quality factors: bound states in the continuum (BICs). We demonstrate that a WS2 monolayer combined with a silicon metasurface hosting BICs exhibits enhanced second-harmonic intensity by more than 3 orders of magnitude relative to a WS2 monolayer on top of a flat silicon film of the same thickness. Our work suggests a pathway to employ high-index dielectric metasurfaces as hybrid structures for enhancement of TMD nonlinearities with applications in nonlinear microscopy, optoelectronics, and signal processing.

Quantification of Trace Mercury in Water: Solving the Problem of Adsorption, Sample Preservation, and Cross-Contamination.

Adsorption, sample preservation, and cross-contamination are the major impediments to the accurate and sensitive analysis of low-level mercury samples. Common measures to deal with this issue are to use Teflon, quartz, or borosilicate glass bottles for sampling, standard solution and sample preservation with oxidative chemicals, to prepare standard solutions daily and to use dedicated glassware. This paper demonstrates that these measures are neither efficient nor effective. Two common laboratory sample containers (borosilicate volumetric glass flasks and polypropylene tubes) are investigated for the preparation and preservation of water samples and standard solutions of 0.2-1 µg L-1 with 2% HNO3. Mercury adsorption rates of 6-22% are observed within 30 min and after 48 days, the adsorption is greater than 98%. In stark contrast, no adsorption is found during a testing period of 560 days when the solutions are subject to potassium permanganate-persulfate digestion. New glass flasks and polypropylene bottles are free of mercury contamination but reused flasks are a major source of mercury cross-contamination. To minimize adsorption and cross-contamination, standard solutions are treated by potassium permanganate-persulfate or BrCl digestion, and each individual sample and standard solution should be stored and prepared in single-use polypropylene bottle, without transference.

Effects of a combination of non-pharmaceutical psychological interventions on dental anxiety.

BACKGROUND: Dental anxiety is a common problem associated with poorer oral health. Managing anxiety is key to improving oral health of patients with dental anxiety. The present pilot study therefore investigated dental anxiety prevalence among patients visiting a university dental clinic. We further examined the effect of combined psychological interventions on anxiety or concern towards dental treatment procedures before treatment, after treatment, and at follow-up. METHODS: In this prospective pilot study, patients seeking restorative treatment were screened for dental anxiety and dental concern about treatment using the Dental Anxiety Scale-Revised (DAS-R) and Dental Concern Assessment (DCA) questionnaires. Participants with a DAS-R score of 9 or above were randomly assigned to an experimental or control group. The patients in the experimental group received two psycho-logical interventions (psychoeducation and progressive muscular relaxation) prior to dental treatment. Dur-ing treatment, patients received another psychological intervention (music distraction). No psychological interventions were given to control patients. DAS-R and DCA scores were used to assess dental anxiety and concern, respectively, before treatment, after treatment, and at follow-up. Nonparametric tests were used for intergroup and intragroup statistical analyses. RESULTS: Out of 64 patients surveyed, 33 (51.6%) had experienced dental anxiety. Of those, 2 were exclud-ed, and 31 patients with a mean ± SD age of 41.2 ± 15.9 y completed the study. No intergroup differences in dental anxiety were found in terms of pretreatment, posttreatment, and follow-up treatment. The mean rank value of the dental anxiety score was less in the experimental group (13.53) than the control group (18.31), albeit not significant. More specifically, differences (Kruskal-Wallis %2 = 14.82, P = 0.001, effect size = 0.33) were found in the experimental group for pretreatment, posttreatment, and follow-up treatment levels of dental anxiety for extraction (P = 0.01), injection (P = 0.02), and sound/vibration of the drill (P = 0.00). No significant intragroup differences between pretreatment, posttreatment, and follow-up treatment were found in the control group. CONCLUSIONS: The combined brief psychological interventions reduced dental anxiety. RELEVANCE FOR PATIENTS: The psychological interventions of the present study could be applied right before or during dental treatment to reduce the dental anxiety of patients. However, additional research involving larger groups is needed to replicate the results of this pilot study.

In Vitro Antifungal Susceptibility of Neoscytalidium dimidiatum Clinical Isolates from Malaysia.

Neoscytalidium dimidiatum is an opportunistic fungus causing cutaneous infections mostly, which are difficult to treat due to antifungal resistance. In Malaysia, N. dimidiatum is associated with skin and nail infections, especially in the elderly. These infections may be mistaken for dermatophyte infections due to similar clinical appearance. In this study, Neoscytalidium isolates from cutaneous specimens, identified using morphological and molecular methods (28 Neoscytalidium dimidiatum and 1 Neoscytalidium sp.), were evaluated for susceptibility towards antifungal agents using the CLSI broth microdilution (M38-A2) and Etest methods. Amphotericin B, voriconazole, miconazole and clotrimazole showed high in vitro activity against all isolates with MIC ranging from 0.0313 to 1 µg/mL. Susceptibility towards fluconazole and itraconazole was noted in up to 10% of isolates, while ketoconazole was inactive against all isolates. Clinical breakpoints for antifungal drugs are not yet available for most filamentous fungi, including Neoscytalidium species. However, the results indicate that clinical isolates of N. dimidiatum in Malaysia were sensitive towards miconazole, clotrimazole, voriconazole and amphotericin B, in vitro.

Factors associated with the technical quality of root canal fillings performed by undergraduate dental students in a Malaysian dental school

Aim: A retrospective clinical audit was carried out on records of endodontic treatment performed bydental undergraduates. The audit was performed to evaluate the technical quality of root canal fillingsperformed by dental undergraduates and determine the associated factors. Methods: 140 records ofpatients who had received root canal treatment by dental undergraduates were evaluated throughperiapical radiographs by two examiners (ê=0.74). The root canal fillings had their quality evaluatedaccording to extent, condensation and presence of procedural mishap. Possible factors associatedwith technical quality such as tooth type, canal curvature, student level and quality of record keepingwere evaluated. Data were statistically analyzed using chi-square test (p<0.05). Results: Amongthe 140 root-filled teeth, acceptable extent, condensation and no-mishap were observed in 72.1%,66.4% and 77.9% cases respectively. Overall, the technical quality of 68 (48.6%) root-filled teethwas considered acceptable. Overall, non-acceptable root canal fillings were significantly morelikely to be observed in molars (69.2%), moderately and severely curved canals (71.4%) and juniorstudents (61.5%). There was no association between acceptable root canal fillings and quality ofrecord keeping. Conclusions: The technical quality of root canal fillings was acceptable in 48.6%cases and it was associated with tooth type, degree of canal curvature and student seniority.

A first study on the incidence and prevalence of IBD in Malaysia--results from the Kinta Valley IBD Epidemiology Study.

BACKGROUND: Inflammatory bowel disease [IBD] is known to be rare in the Asia Pacific region but epidemiological studies are scarce. METHODS: Kinta Valley [Ipoh] was chosen as the sample population. Malaysia has a multiethnic population consisting of Malays, Chinese, and Indians. New cases over 2 years were prospectively captured as well as all known existing cases. Total numbers of the population as a whole and of each ethnic group were obtained. Incidence, prevalence, and mean incidence over two decades were then calculated. RESULTS: There were 10 new cases of IBD diagnosed from April 2011 to April 2013. The crude incidence rates of IBD, ulcerative colitis [UC], and Crohn's disease[CD], respectively, were 0.68, 0.46, and 0.20 per 100,000 persons. The highest incidence was among the Indians, 1.91 compared with 0.35 and 0.63 per 100,000 persons among the Malays and the Chinese, respectively. The mean incidence of IBD has increased steadily from 0.07 to 0.69 per 100,000 person-years over the past two decades. The UC:CD ratio was 8:1 from 1990 to 2000 and 3.6:1 from 2000 to 2010. The prevalence rates of IBD, UC, and CD, respectively, were 9.24, 6.67, and 2.17 per 100,000 persons. The highest prevalence also was among the Indians: 24.91 compared with 7.00 and 6.90 per 100,000 persons among the Malay and Chinese races, respectively. CONCLUSIONS: The incidence and prevalence rates of IBD are low in Malaysia but the incidence appears to be increasing and marked racial differences exist. As in other Asian countries, the incidence of CD is increasing at a more rapid rate relative to UC.

Therapeutic microbes for infectious disease.

The rapid emergence of multidrug-resistant pathogens has invoked concerns of our current limitations in controlling the spread of infectious disease. To resolve this, we have applied synthetic biology principles to engineer human commensal microbe that can specifically sense and kill an antibiotic-resistant strain of P. aeruginosa. In this chapter, we describe the methods used to assemble, characterize, and evaluate the effectiveness of our engineered microbe in multicellular systems.

Effect of ammonium on liquid- and gas-phase protonation and deprotonation in electrospray ionization mass spectrometry.

The electrospray ionization (ESI) is a complex process and there has been a long debate regarding the gas-phase effect on ion generation in the process. In this paper we investigated the effect of liquid chromatographic mobile phase additives (formic acid, aqueous ammonia and their combination) on the ESI signal intensities for a wide variety of compounds. The addition of a trace amount of aqueous ammonia to the common formic acid-methanol mobile phase significantly enhances the ESI signals of protonated molecules and suppresses the formation of sodium adduct ions. This effect is well observed for the compounds containing the -N-C=O group but not for those without N or O atoms. The ESI signal intensity of deprotonated molecules increases with increase in pH of the mobile phase for neutral compounds, such as substituted urea, whereas this trend is not observed for acidic compounds such as phenoxy acids. The mechanistic analysis regarding liquid- and gas-phase protonation and deprotonation is discussed.

Interaction between a novel intronic IVS3+172 variant and N29I mutation in PRSS1 gene is associated with pancreatitis in a Malaysian Chinese family.

BACKGROUND/AIMS: Hereditary pancreatitis (HP) is a very rare form of early-onset chronic pancreatitis, which usually begins in childhood with a variable spectrum of severity of disease. HP is commonly caused by variants/mutations in the PRSS1 gene as reported in many studies. Therefore, in this study, we aimed to investigate the possible association of PRSS1 gene variants/mutations in a Malaysian Chinese family with HP. METHODS: Genomic DNA of the 6 family members was extracted, amplified using polymerase chain reaction and the entire PRSS1 gene was analyzed via sequencing. RESULTS: PRSS1 gene sequencing results revealed two variants/mutations in this study. The results show that all the subjects (patients) inherited an intronic SNP IVS3+172 variant, together with a p.N29I mutation except for subjects 3 and 4 who are normal. CONCLUSION: We believe that interaction between the novel IVS3+172 intronic variant and p.N29I mutation in the PRSS1 gene is associated with HP in this Malaysian Chinese family.

Engineering microbes to sense and eradicate Pseudomonas aeruginosa, a human pathogen.

Synthetic biology aims to systematically design and construct novel biological systems that address energy, environment, and health issues. Herein, we describe the development of a synthetic genetic system, which comprises quorum sensing, killing, and lysing devices, that enables Escherichia coli to sense and kill a pathogenic Pseudomonas aeruginosa strain through the production and release of pyocin. The sensing, killing, and lysing devices were characterized to elucidate their detection, antimicrobial and pyocin release functionalities, which subsequently aided in the construction of the final system and the verification of its designed behavior. We demonstrated that our engineered E. coli sensed and killed planktonic P. aeruginosa, evidenced by 99% reduction in the viable cells. Moreover, we showed that our engineered E. coli inhibited the formation of P. aeruginosa biofilm by close to 90%, leading to much sparser and thinner biofilm matrices. These results suggest that E. coli carrying our synthetic genetic system may provide a novel synthetic biology-driven antimicrobial strategy that could potentially be applied to fighting P. aeruginosa and other infectious pathogens.

Non-cardiac chest pain: prevalence of reflux disease and response to acid suppression in an Asian population.

BACKGROUND: Gastroesophageal reflux disease is thought to be the commonest cause of 'non-cardiac chest pain'. The use of proton-pump inhibitors resulting in improvement in the chest pain symptom would support this causal association. OBJECTIVES: To determine the prevalence of gastroesophageal reflux disease in non-cardiac chest pain and the response of chest pain to proton-pump inhibitor therapy. METHODS: Patients with recurrent angina-like chest pain and normal coronary angiogram were recruited. The frequency and severity of chest pain were recorded. All patients underwent esophagogastroduodenoscopy and 48-h Bravo ambulatory pH monitoring before receiving rabeprazole 20 mg bd for 2 weeks. RESULTS: The prevalence of gastroesophageal reflux disease was 66.7% (18/27). The improvement in chest pain score was significantly higher in reflux compared to non-reflux patients (P = 0.006). The proportion of patients with complete or marked/moderate improvement in chest pain symptoms were significantly higher in patients with reflux (15/18, 83.3%) compared to those without (1/9, 11.1%) (P < 0.001). CONCLUSION: The prevalence of gastroesophageal reflux disease in patients with 'non-cardiac chest pain' was high. The response to treatment with proton-pump inhibitors in patients with reflux disease, but not in those without, underlined the critical role of acid reflux in a subset of patients with 'non-cardiac chest pain'.

Transnasal endoscopic placement of nasoenteric feeding tubes: outcomes and limitations in non-critically ill patients.

Transnasal endoscopic placement of nasoenteric tubes (NETs) has been demonstrated to be useful in the critical care setting, with limited data on its role in non-critically ill patients. The authors collected data on consecutive patients from a non-critical care setting undergoing transnasal endoscopic NET placement. All NETs were endoscopically placed using a standard over-the-guidewire technique, and positions were confirmed with fluoroscopy. Patients were monitored until the removal of NETs or death. Twenty-two patients (median age = 62.5 years, 36.4% female) were referred for postpyloric feeding, with main indications of persistent gastrocutaneous fistula (n = 6), gastroparesis or gastric outlet obstruction (n = 5), duodenal stenosis (n = 6), acute pancreatitis (n = 4), and gastroesophageal reflux after surgery (n = 1). Postpyloric placement of NET was achieved in 19 of 22 (86.3%) patients, with 36.8% tube positions in the jejunum, 47.4% in the distal duodenum, and 15.8% in the second part of the duodenum. NET placement was least successful in cases with duodenal stenosis. NETs remained in situ for a median of 24 days (range, 2-94), with tube dislodgement (n = 3) and clogging (n = 5) as the main complications. NET feeding resulted in complete healing of gastrocutaneous fistulae in 5 of 6 patients and provision of total enteral nutrition in 3 of 4 cases of acute pancreatitis and 9 of 11 cases of gastroparesis or proximal duodenal obstruction. Transnasal endoscopy has a role in the placement of NET in non-critically ill patients requiring postpyloric feeding. However, there are some limitations, particularly in cases with altered duodenal anatomy.

The role of proton-pump inhibitor therapy in patients with gastroesophageal reflux disease and difficult-to-control asthma.

Difficult-to-control asthma is a frustratingly difficult condition to treat. Many factors contribute to this condition, including gastroesophageal reflux disease. Response to potent acid suppressive therapy with proton-pump inhibitors is less than universal or complete, and underlines the multifactorial nature of the disease. However, the authors of this paper feel strongly that, whereas gastroesophageal reflux disease can be reliably identified, patients with difficult-to-control asthma will experience an improvement in symptoms when treated with acid-suppressive therapy, while bearing in mind that other contributory factors may have to be eliminated at the same time.

Gastroesophageal Reflux Disease: An Emerging Disease in Asia.

Gastroesophageal reflux disease (GERD) has been reported to be uncommon among Asians. Although prevalence rates of reflux esophagitis and symptoms of GERD in Asian patients vary, most of the recently published studies have shown an increasing trend, likely due to better awareness and diagnosis as well as to a true increase in the prevalence of the disease. The exact reasons for this increase in prevalence are unclear but must be linked in some way to the dramatic socioeconomic development taking place in the region. Changes in dietary patterns and body mass index have been suggested as underlying reasons. On the other hand the high prevalence of Helicobacter pylori infection in Asia and its association with decreased acid secretion and a low prevalence of GERD have also been noted. Another interesting observation is differing rates of GERD among different Asian ethnic groups, indicating a possible genetic susceptibility to GERD. Diagnosis of GERD is usually based on symptoms; many Asian patients, however, do not understand the term "heartburn," as there is no equivalent term in the major Asian languages. Patients therefore describe their symptoms variously, such as chest discomfort or wind and soreness in the chest. Nonerosive reflux disease appears to be common among Asians. Atypical manifestations of GERD, including noncardiac chest pain, asthma, and laryngitis, appear to be common among Asian patients as well.