Global health impacts of ambient fine particulate pollution associated with climate variability.

Air pollution is a key global environmental problem raising human health concern. It is essential to comprehensively assess the long-term characteristics of air pollution and the resultant health impacts. We first assessed the global trends of fine particulate matter (PM2.5) during 1980-2020 using a monthly global PM2.5 reanalysis dataset, and evaluated their association with three types of climate variability including El Niño-Southern Oscillation, Indian Ocean Dipole and North Atlantic Oscillation. We then estimated PM2.5-attributable premature deaths using integrated exposure-response functions. Results show a significant increasing trend of ambient PM2.5 during 1980-2020 due to increases in anthropogenic emissions. Ambient PM2.5 caused a total of âˆ¼ 135 million premature deaths globally during the four decades. Occurrence of air pollution episodes was strongly associated with climate variability, which were associated with up to 14 % increase in annual global PM2.5-attributable premature deaths.

Using routine blood parameters to anticipate clinical outcomes in invasive aspergillosis.

OBJECTIVE: In invasive aspergillosis (IA), monitoring response to antifungal treatment is challenging. We aimed to explore if routine blood parameters help to anticipate outcomes following IA. METHODS: Post hoc secondary analysis of two multicenter randomized trials was performed. The Global Comparative Aspergillosis Study (GCA, n = 123) and the Combination Antifungal Study (CAS, n = 251) constituted the discovery and validation cohorts respectively. The outcome measures were response to treatment and survival to 12 weeks. Interval platelet, galactomannan index (GMI) and C-reactive protein (CRP) levels prior and during antifungal treatment were analysed using logistic regression, Kaplan-Meier survival and receiver operating characteristic (ROC) analyses. RESULTS: The 12-week survival was 70.7% and 63.7% for the GCA and CAS cohorts respectively. In the GCA cohort, every 10 × 109/L platelet count increase at week 2 and 4 improved 12-week survival odds by 6-18% (odds ratio (OR) 1.06-1.18, 95% confidence interval (CI) 1.02-1.33). Survival odds also improved 13% with every 10 mg/dL CRP drop at week 1 and 2 (OR 0.87, 95% CI 0.78-0.97). In the CAS cohort, week 2 platelet count was also associated with 12-week survival with 10% improved odds for every 10 × 109/L platelet increase (OR, 1.10, 95% CI 1.04-1.15). A GMI drop of 0.1 unit was additionally found to increase the odds of treatment response by 3% at the baseline of week 0 (OR 0.97, 95% CI 0.95-0.99). Week 2 platelet and CRP levels performed better than GMI on ROC analyses for survival (area under ROC curve 0.76, 0.87 and 0.67 respectively). A baseline platelet count higher than 30 × 109/L clearly identified patients with >75% survival probability. CONCLUSIONS: Higher serial platelets were associated with overall survival while GMI trends were linked to IA treatment response. Routine and simple laboratory indices may aid follow-up of response in IA patients.

The Long-Term Impact of Functional Disability on Hospitalization Spending in Singapore.

Singapore is one of the fastest-aging populations due to increased life expectancy and lowered fertility. Lifestyle changes increase the burden of chronic diseases and disability. These have important implications for social protection systems. The goal of this paper is to model future functional disability and healthcare expenditures based on current trends. To project the health, disability and hospitalization spending of future elders, we adapted the Future Elderly Model (FEM) to Singapore. The FEM is a dynamic Markov microsimulation model developed in the US. Our main source of population data was the Singapore Chinese Health Study (SCHS) consisting of 63,000 respondents followed up over three waves from 1993 to 2010. The FEM model enables us to investigate the effects of disability compounded over the lifecycle and hospitalization spending, while adjusting for competing risk of multi-comorbidities. Results indicate that by 2050, 1 in 6 elders in Singapore will have at least one ADL disability and 1 in 3 elders will have at least one IADL disability, an increase from 1 in 12 elders and 1 in 5 elders respectively in 2014. The highest prevalence of functional disability will be in those aged 85 years and above. Lifetime hospitalization spending of elders aged 55 and above is US$24,400 (30.2%) higher among people with functional disability compared to those without disability. Policies that successfully tackle diabetes and promote healthy living may reduce or delay the onset of disability, leading to potential saving. In addition, further technological improvements may reduce the financial burden of disability.

Study of the electronic structure of the interfaces between 2-TNATA and MoOx.

In order to understand the characteristics of ohmic hole-contacts for the inverted/conventional organic light emitting devices, a hole-only device with all ohmic contacts, which is composed of glass/ITO/MoOx/4,4,4-tris[2-naphthyl-phenyl-amino]triphenylamine (2-TNATA)/MoOx/Al, the elements of the electronic structures of MoOx-on-2-TNATA interface and 2-TNATA-on-MoOx interface were investigated by photoemission spectroscopy, with regards to interface energetics, formative mechanism, and a potential charge carrier injection. The electronic structures revealed that the behavior of the interface between MoOx and 2-TNATA was different whether MoOx was deposited on (2-TNATA) or vice versa. The bottom interfaces of 2-TNATA-on-MoOx in this hole-only devices showed no hole-injecting barrier height (Phi(h)B) when the thickness of 2-TNATA was deposited in the range of 0.1 to 5.0 nm on the 10.0 nm-thick MoOx thin films. This has been explained to be attributed to both metal-induced gap states and a chemical reaction at the interfaces. The top interfaces of MoOx-on-2-TNATA in this hole-only device structure also showed no Phi(h)B when a hole was injected from the MoOx-on-2-TNATA interfaces to cathode. The hole-ohmic property in the top interfaces depends on interface dipole by the formation of charge transfer complexes as well as interdiffusion of MoOx into the 2-TNATA film in these interfaces.

Oral steroids enhance epithelial repair in nasal polyposis via upregulation of the AP-1 gene network.

BACKGROUND: Chronic mucosal inflammation, epithelial damage and aberrant tissue remodelling are common features in nasal polyposis (NP). A study was undertaken to characterise the gene expression profile in NP tissues and to explore the molecular mechanisms underlying the ameliorative effects of glucocorticosteroids (GCs) in NP. METHODS: Two sets of NP biopsies (before and after GC treatment) were taken from 10 patients with untreated (GC-naïve) bilateral NP. Biopsy specimens of inferior turbinate from 6 patients who underwent surgery for nasal septal deviation served as nasal mucosal controls. DNA microarrays containing 38 500 genes were used to characterise the global gene expression profile. Functional network analysis was applied to identify the key molecular pathways and genes in response to GC treatment (GC-treated). Selected genes were retested by quantitative RT-PCR and immunohistochemistry in the same polyps and control samples. RESULTS: 64 genes were differentially expressed in GC-treated vs GC-naïve NP tissues. The highest scoring network was assembled around activation protein 1 (AP-1), a heterodimer of c-Fos and c-Jun oncoprotein, and five AP-1-related genes (COX-2, IL-6, AREG, HBEGF and EGR1) with tissue repair function. Quantitative PCR confirmed that AP-1 and its related genes were markedly repressed in GC-naïve polyps and were upregulated after GC treatment. Immunohistochemical staining indicated that epithelial restitution in GC-treated polyps was associated with increased expression of c-Jun protein. CONCLUSIONS: Oral steroids promote epithelial repair in NP via upregulation of the AP-1 (especially c-Jun) network and its related genes.

The effect of preoperative symptom severity on functional outcome of total knee replacement--patients with the lowest preoperative scores achieve the lowest marks.

To determine if the functional outcome of total knee replacement (TKR) was affected by the level of preoperative symptom severity, the association between preoperative Oxford Knee Scores (OKS), and 2 year OKS, American Knee Society clinical and function scores (AKSS) was assessed. Data were prospectively collected on 45 cases who had single joint osteoarthritis and no other comorbidities. We have specifically focused on patients with single knee involvement to remove the effect of multiple joint involvement and comorbidities on the OKS. The mean preoperative OKS was 21.4, postoperative OKS 40.0 and postoperative ROM 117 degrees. The postoperative mean AKSS was 86.7 and mean function score was 85.0. The 'usual pain' and 'limp' components of the OKS had the greatest rises and the 'kneel' component had the least improvement. Rather than all patients achieving uniform results post-TKR, patients with more severe symptoms achieved poorer absolute outcomes. The Spearman correlation coefficient between pre- and postoperative OKS was r = 0.4 (p = 0.006). Although the results suggest that waiting too long before intervention compromises the final outcome, a correlation of 0.4 is not strong enough to necessitate change in current practice.

Malignant melanoma seen in a tertiary dermatological centre, Singapore.

INTRODUCTION: Primary malignant melanoma is an uncommon skin tumour in Singapore compared with the Western countries. The clinical characteristics of melanoma have been rarely reported in Asians. OBJECTIVES: Our purpose was to study the incidence, clinical characteristics and risk factors of biopsy proven malignant melanoma seen in a tertiary referral skin hospital. METHODS: Case records of patients with histology proven malignant melanoma from January 1989 to December 1998 were retrieved. Patients were interviewed and a complete skin and systemic examination was performed. Data on demographics, histological types, clinical characteristics and risk factors were collated. RESULTS: Between 1989 and 1998, 27 patients were diagnosed with histology proven malignant melanoma. There was a predominance of Chinese with a female to male ratio of 1.3:1. There was a mean lag period of 1.6 years to diagnosing melanoma and there is a general lack of knowledge among the local patients. Most of the lesions (89%) occurred on the extremities. Acral lentiginous melanoma (41%) and nodular melanoma (41%) were the two commonest histologic types. Of the nodular melanomas, 64% were observed in patients below 50 years (64%) while majority of the acral lentiginous melanomas occurred in those above 50 years (91%). In terms of risk factors, we reported a high prevalence of diabetes mellitus with acral lentiginous melanoma. CONCLUSIONS: This study highlighted interesting aspects in terms of clinical characteristics and risk factors in our local patients. It also served as a remainder of the need to raise awareness among the public and medical community of skin cancers or melanomas as they are potentially treatable if detected early.

Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice.

Inhibition of neocortical beta-amyloid (Abeta) accumulation may be essential in an effective therapeutic intervention for Alzheimer's disease (AD). Cu and Zn are enriched in Abeta deposits in AD, which are solubilized by Cu/Zn-selective chelators in vitro. Here we report a 49% decrease in brain Abeta deposition (-375 microg/g wet weight, p = 0.0001) in a blinded study of APP2576 transgenic mice treated orally for 9 weeks with clioquinol, an antibiotic and bioavailable Cu/Zn chelator. This was accompanied by a modest increase in soluble Abeta (1.45% of total cerebral Abeta); APP, synaptophysin, and GFAP levels were unaffected. General health and body weight parameters were significantly more stable in the treated animals. These results support targeting the interactions of Cu and Zn with Abeta as a novel therapy for the prevention and treatment of AD.

Neoadjuvant hormone therapy and external beam radiation for localized prostate cancer: Vancouver Island Cancer Centre experience.

OBJECTIVES: To evaluate the effects of neo-adjuvant hormone therapy (NAHT) given prior to radiation in patients with clinically localized adenocarcinoma of the prostate. METHODS: Six hundred nine patients were treated between 1992 and 1997 with NAHT prior to radiation therapy. Clinical stage, presenting PSA and Gleason score were examined for influence on outcome. Time to post radiotherapy failure was defined from the first assessed PSA value over 4 microg/L at follow-up. Radiation therapy was confined to the prostate and seminal vesicles. Median follow-up was 2.6 years. RESULTS: PSA disease free survival (PDFS) decreased with increasing cancer risk factors (p <.0.0001). The overall duration of NAHT was significant with patients receiving >8 months having a lower failure rate than those on therapy for <3 months (p <0.0001). The PSA prior to starting radiation correlated with outcome, a PSA <=0.1 microg\L having a better PDFS than those with a PSA >=4 microg\L (P <0.0001). NAHT for >8 months gave improved PDFS in intermediate grade Gleason score 5-7, (n = 256, p <0.0001), high grade Gleason score 8-10 (n = 80, p =0.005), but not in low grade, Gleason score <=4. CONCLUSION: Neo-adjuvant hormone therapy for >8 months offers prolonged PSA disease free survival in patients with less well differentiated tumors, Gleason score >4. Clinical trials are required to confirm this.

3-Hydroxykynurenine and 3-hydroxyanthranilic acid generate hydrogen peroxide and promote alpha-crystallin cross-linking by metal ion reduction.

The kynurenine pathway catabolite 3-hydroxykynurenine (3HK) and redox-active metals such as copper and iron are implicated in cataractogenesis. Here we investigate the reaction of kynurenine pathway catabolites with copper and iron, as well as interactions with the major lenticular structural proteins, the alpha-crystallins. The o-aminophenol kynurenine catabolites 3HK and 3-hydroxyanthranilic acid (3HAA) reduced Cu(II)>Fe(III) to Cu(I) and Fe(II), respectively, whereas quinolinic acid and the nonphenolic kynurenine catabolites kynurenine and anthranilic acid did not reduce either metal. Both 3HK and 3HAA generated superoxide and hydrogen peroxide in a copper-dependent manner. In addition, 3HK and 3HAA fostered copper-dependent alpha-crystallin cross-linking. 3HK- or 3HAA-modifed alpha-crystallin showed enhanced redox activity in comparison to unmodified alpha-crystallin or ascorbate-modified alpha-crystallin. These data support the possibility that 3HK and 3HAA may be cofactors in the oxidative damage of proteins, such as alpha-crystallin, through interactions with redox-active metals and especially copper. These findings may have relevance for understanding cataractogenesis and other degenerative conditions in which the kynurenine pathway is activated.

Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc.

Abeta binds Zn(2+), Cu(2+), and Fe(3+) in vitro, and these metals are markedly elevated in the neocortex and especially enriched in amyloid plaque deposits of individuals with Alzheimer's disease (AD). Zn(2+) precipitates Abeta in vitro, and Cu(2+) interaction with Abeta promotes its neurotoxicity, correlating with metal reduction and the cell-free generation of H(2)O(2) (Abeta1-42 > Abeta1-40 > ratAbeta1-40). Because Zn(2+) is redox-inert, we studied the possibility that it may play an inhibitory role in H(2)O(2)-mediated Abeta toxicity. In competition to the cytotoxic potentiation caused by coincubation with Cu(2+), Zn(2+) rescued primary cortical and human embryonic kidney 293 cells that were exposed to Abeta1-42, correlating with the effect of Zn(2+) in suppressing Cu(2+)-dependent H(2)O(2) formation from Abeta1-42. Since plaques contain exceptionally high concentrations of Zn(2+), we examined the relationship between oxidation (8-OH guanosine) levels in AD-affected tissue and histological amyloid burden and found a significant negative correlation. These data suggest a protective role for Zn(2+) in AD, where plaques form as the result of a more robust Zn(2+) antioxidant response to the underlying oxidative attack.

Separation of related opiate compounds using capillary electrochromatography.

Capillary electrophoretic separations have been investigated for six controlled narcotic analgesic compounds having related structures. Owing to the similar charge-to-mass ratios of these compounds, capillary zone electrophoresis failed to provide a satisfactory separation, whereas a baseline-resolved separation was achieved in 10 min using micellar electrokinetic chromatography. Column efficiencies of 40,000-150,000 plates/m were obtained with a 50 cm long, 50 microm inner diameter (ID) capillary using 50 mM sodium dodecyl sulfate (SDS) in a 50 mM borate solution containing 12% isopropanol. In contrast, separation of this mixture by capillary electrochromatography proved to be significantly superior. The capillary was 15 cm long, with an ID of 75 microm, and was packed with 1.5 microm nonporous octadecyl silica (ODS) particles. The mobile phase consisted of 80% 10 mM tris(hydroxymethyl)aminomethane (Tris) and 20% acetonitrile, and contained 5 mM SDS. A complete separation was obtained in 2.5 min with an efficiency of 250,000-500,000 plates/m.

Primary chemo-radiotherapy and selective oesophagectomy for oesophageal cancer: goal of cure with organ preservation.

PURPOSE: The role of definitive chemo-radiotherapy in squamous cell oesophageal carcinoma has been established by the Radiation Therapy Oncology Group (RTOG). We have studied a modification of the RTOG chemo-radiotherapy protocol in patients with any histologic type of oesophageal carcinoma. We planned oesophagectomy for patients with post-treatment positive endoscopic biopsy or <75% regression on CAT scan, or with resectable local recurrence. Study end-points were histologic response, toxicity, oesophagectomy and survival rates after primary chemo-radiotherapy. METHODS: Consecutive patients with any T or N status, M0, disease encompassable in radical radiotherapy ports, no prior surgical excision, and fit for chemo-radiotherapy, were eligible. Treatment plan was three cycles of cisplatin/5-fluorouracil chemotherapy and radical external radiation therapy (50 Gy in 25 fractions) starting with cycle 2. Selective oesophagectomy was performed in patients with post-treatment positive biopsy or <75% regression on CT scan, or with localized recurrence. RESULTS: From 1993-1996, 32 patients were treated. Post-treatment complete histologic response rate was 77% (95% confidence limits 58-90%). Grade 3 or 4 toxicities occurred in 31 and 3 patients, respectively. Minimum follow-up time was 12 months. Median disease-specific survival time was 16.1 months for all patients, and was not significantly different according to histologic type (17 squamous, 12 adenocarcinoma). Oesophagectomy was performed in six of 15 surviving and five of 17 deceased patients. CONCLUSION: It is possible to cure oesophageal cancer with chemo-radiotherapy and selective oesophagectomy, and achieve organ preservation in the majority of long term survivors.

Retrospective study of Behcet's disease seen at the National Skin Centre, Singapore.

This retrospective study characterises the clinical manifestations and outcome of 34 patients diagnosed with Behcet's disease seen at the National Skin Centre from 1990 to 1997. The 2 diagnostic criteria used were the International Study Group and the O'Duffy criteria. Seventy-six per cent satisfied both criteria and the remaining 24% satisfied only the incomplete form of the O'Duffy criteria. We found that the male to female ratio was 1:1.8. The mean age of presentation was 33 years (range 21 to 63 years). The majority were Chinese (73%). In our series, patients had prominent mucocutaneous involvement. These findings may be attributed to patient selection to a tertiary dermatology clinic. Oral (100%) and genital (99%) ulceration were the 2 commonest symptoms. The other cutaneous features included papulo-pustular or acneiform eruption (26%), erythema nodosum (14.7%) and positive pathergy test. Five patients (15%) had arthritis, 1 patient had recurrent thrombophlebitis and 2 patients had eye complications. The outcome of our patients was generally good with minimal functional impairment and no mortality detected. Our patients were primarily outpatient referrals and this may explain why systemic complications were rare in our series.

The therapeutic efficacy of mometasone furoate cream 0.1% applied once daily vs clobetasol propionate cream 0.05% applied twice daily in chronic eczema.

BACKGROUND: Mometasone furoate [9a, 21-dichloro-llb, 17dihydroxy-16a-methyl-pregna-14-dione-3, 20-dione-17-(2furoate)] is a synthetic, 17-heterocyclic corticosteroid which has been shown to be highly effective as an anti-inflammatory agent which is approximately half as potent is suppressing hypothalamic-pituitary-adrenal (HPA) axis function as betamethasone valerate. METHOD: The present open, randomised, third party blinded, left-right sided study was designed to compare the therapeutic efficacy of mometasone furoate cream 0.1% with clobetasol propionate cream 0.05% applied twice daily in chronic eczema following a 3-week course of therapy. PATIENTS/RESULTS: Sixty consecutive patients with moderate to severe bilateral chronic eczema on the limbs were recruited into the study. The mean scores of various signs/symptoms including erythema, induration, crusting, scaling, excoriation and pruritus before and after 3 weeks treatment with mometasone furoate (MF) and clobetasol propionate (CP) cream, were compared. The baseline scores for MF and CP treated sites were almost identical. There was significant decrease in the mean scores of all signs/symptoms after 3 weeks treatment with MF and CP. There was also a significant difference in the mean scores between MF and CP treated sites after 3 weeks of treatment. The mean scores were significantly lower for CP treated sites than MF treated sites. More CP treated sites achieved "cleared" or "marked improvement" response than MF treated sites. There were more "excellent" or "good" grades on CP treated sites than MF treated sites at the end of 3 weeks of treatment. None of the patients showed any side-effects after 4 weeks of treatment. CONCLUSION: Overall, 53% of patients considered the MF treated sites to be good or excellent vs 88% for CP treated sites.

Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines.

We examined the activity of two metabolites of sulindac (a nonsteroidal anti-inflammatory drug), sulindac sulfide and sulindac sulfone (exisulind, Prevatec), and a novel highly potent analog of exisulind (CP248) on a series of human prostate epithelial cell lines. Marked growth inhibition was seen with the BPH-1, LNCaP, and PC3 cell lines with IC50 values of about 66 microM, 137 microM, and 64 nM for sulindac sulfide, exisulind, and CP248, respectively. DNA flow cytometry and 4',6'-diamido-2-phenylindole (DAPI) staining indicated that these three compounds also induced apoptosis in all of these cell lines. Similar growth inhibition also was seen with the PrEC normal human prostate epithelial cell line, but these cells were resistant to induction of apoptosis at concentrations up to 300 microM, 1 mM, and 750 nM of sulindac sulfide, exisulind, and CP248, respectively. Derivatives of LNCaP cells that stably overexpress bcl-2 remained sensitive to growth inhibition and induction of apoptosis by these compounds. In vitro enzyme assays indicated that despite its high potency in inhibiting growth and inducing apoptosis, CP248, like exisulind, lacked cyclooxygenase (COX-1 and COX-2) inhibitory activity even at concentrations up to 10 mM. Moreover, despite variations of COX-1 and COX-2 expression, the three benign and malignant prostate cell lines showed similar sensitivity to growth inhibition and induction of apoptosis by these three compounds. Therefore, sulindac derivatives can cause growth inhibition and induce apoptosis in human prostate cancer cells by a COX-1 and -2 independent mechanism, and this occurs irrespective of androgen sensitivity or increased expression of bcl-2. These compounds may be useful in the prevention and treatment of human prostate cancer.

Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid.

BACKGROUND: Melasma is difficult to clear. Many agents have been used, such as hydroquinone, and glycolic acid and glycolic acid peels, kojic acid, a tyrosinase inhibitor in the fungus Aspergilline oryzae. OBJECTIVE: To see if the addition of 2% kojic acid in a gel containing 10% glycolic acid and 2% hydroquinone will improve melasma further. METHODS: Forty Chinese women with epidermal melasma were treated with 2% kojic acid in a gel containing 10% glycolic acid and 2% hydroquinone on one half of the face. The other half was treated with the same application but without kojic acid. The side receiving the kojic acid was randomized. Determination of efficacy was based on clinical evaluation, photographs and self-assessment questionnaires at 4 weekly intervals until the end of the study at 12 weeks. The non-parametric Wilcoxon's rank sum test was used for statistical analysis. RESULTS: All patients showed improvement in melasma on both sides of the face. The side receiving the kojic acid did better. More than half of the melasma cleared in 24/40 (60%) patients receiving kojic acid compared to 19/40 (47.5%) patients receiving the gel without kojic acid. In 2 patients, there was complete clearance of melasma, and this was on the side where kojic acid was used. Side effects include redness, stinging, and exfoliation. These were seen on both sides of the face, and they settled by the third week. CONCLUSION: The addition of kojic acid to a gel containing 10% glycolic acid and 2% hydroquinone further improves melasma.