Quantitative Microbial Risk Assessment (QMRA) of Workers Exposure to Bioaerosols at MSW Open Dumpsites.

The bioaerosol exposure data from the study by Akpeimeh, Fletcher, and Evans (2019) was used to compute the risk of infection from the exposure of dumpsite workers to Aspergillus fumigatus and Escherichia coli O157:H7. A stochastic (Markov Chain) model was used to model the transport of the inhaled dose though the human respiratory system and then integrated into the beta-Poisson dose-response model to estimate workers risks of respiratory and gastrointestinal (GI) infection. The infection risk was computed based on workers exposure to E. coli O157:H7 at 10-50% pathogen ingestion rate and pathogen-indicator ratio (P:I) of 1:103 and 1:104 , while exposure to A. fumigatus was based solely on the average initial exposure dose. The results showed that after 11 hours of exposure, workers engaged in scavenging, waste sorting, and site monitoring were at risk of respiratory and GI infection in the magnitude of 10-1 . However, the risk estimates associated with specific areas of the dumpsite showed that, the risk of GI infection at the active area ranged between 3.23 × 10-3 -1.56 × 10-2 and 3.25 × 10-4 -1.62 × 10-3 ; dormant area 2.06 × 10-3 -1.01 × 10-2 and 2.09 × 10-4 -1.04 × 10-3 ; entrance 1.85 × 10-3 -9.09 × 10-3 and 1.87 × 10-4 -9.27 × 10-4 ; boundary 1.82 × 10-3 -8.82 × 10-3 and 2.09 × 10-4 -8.94 × 10-4 for P:I = 1:103 and 1:104 respectively, while the risk of respiratory infection risks were in the magnitude of 10-1 for all four locations. The estimated risk of workers developing respiratory and gastrointestinal infections were high for all activities assessed at the dumpsite.

Fate of faecal pathogen indicators during faecal sludge composting with different bulking agents in tropical climate.

In recent years, composting has increasingly been promoted as a reliable method for sanitizing Faecal Sludge (FS) from onsite sanitation systems, particularly where there are opportunities to use the recovered nutrients in agriculture. However, there remain gaps in our understanding of the fate of infectious faecal pathogens during composting, particularly in tropical climates. This study investigated the influence of different locally available bulking agents on the inactivation efficiency of composting by tracking the fate of four key indicator organisms (E. coli, Salmonella spp., Enterococci spp., and viable helminth eggs). Dewatered FS was mixed with different bulking agents - i.e. Sawdust (SD), Coffee husks (CH) and Brewery waste (BW). Compost piles of FS:SD, FS:CH, and FS:BW in a volumetric ratio of 1:2 were set-up in duplicate (3 m3 each), composted on a pilot scale and monitored weekly for the survival of pathogen indicators for a period of 15 weeks. The study findings suggest that the different bulking agents have a statistically significant (p < 0.05) effect on the temperature evolution and survival of pathogen indicators in compost. CH was the most suitable bulking agent for composting with FS as piles containing CH exhibited higher pathogen inactivation efficiency and shorter inactivation periods of 6 weeks compared to 8 weeks for SD and BW piles. Time-temperature was the most important factor responsible for pathogen inactivation. However, other mechanisms such as indigenous microbial and toxic by-products such as NH4+-N also played an important role in the inactivation of pathogens. The results suggest that co-composting of FS with a sawdust, coffee husk or brewery waste for 8 weeks with thermophilic temperatures of about 48-60 °C sustained in the composting piles for more than 38 days, using 7 days turning frequency, is sufficient to ensure complete sanitization of FS before reuse in agriculture.

Urbanicity, hypothalamic-pituitary-adrenal axis functioning, and behavioral and emotional problems in children: a path analysis.

BACKGROUND: Urbanization is steadily increasing worldwide. Previous research indicated a higher incidence of mental health problems in more urban areas, however, very little is known regarding potential mechanisms underlying this association. We examined whether urbanicity was associated with mental health problems in children directly, and indirectly via hypothalamic-pituitary-adrenal (HPA)-axis functioning. METHODS: Utilizing data from two independent samples of children we examined the effects of current urbanicity (n = 306, ages seven to 12 years) and early childhood urbanicity (n = 141, followed from birth through age 7 years). Children's mothers reported on their mental health problems and their family's socioeconomic status. Salivary cortisol samples were collected during a psychosocial stress procedure to assess HPA axis reactivity to stress, and at home to assess basal HPA axis functioning. Neighborhood-level urbanicity and socioeconomic conditions were extracted from Statistics Netherlands. Path models were estimated using a bootstrapping procedure to detect indirect effects. RESULTS: We found no evidence for a direct effect of urbanicity on mental health problems, nor were there indirect effects of urbanicity through HPA axis functioning. Furthermore, we did not find evidence for an effect of urbanicity on HPA axis functioning or effects of HPA axis functioning on mental health problems. CONCLUSIONS: Possibly, the effects of urbanicity on HPA axis functioning and mental health do not manifest until adolescence. An alternative explanation is a buffering effect of high family socioeconomic status as the majority of children were from families with an average or high socioeconomic status. Further studies remain necessary to conclude that urbanicity does not affect children's mental health via HPA axis functioning.

Exposure to bioaerosols at open dumpsites: A case study of bioaerosols exposure from activities at Olusosun open dumpsite, Lagos Nigeria.

Activities associated with the open dumping of municipal solid waste has the potential for greater impact on the environment and public health compared to other forms of waste-to-land treatment of such wastes. However, there is a lack of quantitative data on the exposure to bioaerosols from open dumpsites, hence impeding the development of effective interventions that would reduce the risk of respiratory symptoms among scavengers and waste workers at such dumpsites. This study investigated exposure to bioaerosols at Olusosun open dumpsite, Lagos Nigeria using three methodologies; (1) Conducting a cross-sectional survey on the respiratory health of the population on the dumpsite, (2) Measuring bioaerosol concentrations in the ambient air by measuring four bioaerosols indicator groups (total bacteria, gram-negative bacteria, Aspergillus fumigatus and total fungi) using a Anderson six stage impactor sampler, (3) Measuring activity related exposures to bioaerosols using an SKC button personal sampler. After a cross sectional health survey of 149 participants (waste workers, scavengers, middlemen, food vendors and business owners), smokers reported higher symptoms of chronic cough (21%) and chronic phlegm (15%) compared to non-smokers (chronic cough 15%, chronic phlegm 13%). Years of work > 5 years showed no statistically significant association with chronic phlegm (OR 1.2, 95% CI 0.4-3.4; p > 0.05) or asthma (OR 1.8, 95% CI 0.6-5.2; p > 0.05). At the 95th percentile, the concentration of total bacteria was the highest (2189 CFU/m3), then gram negative bacteria (2188 CFU/m3), total fungi (843 CFU/m3) and Aspergillus fumigatus (441 CFU/m3) after ambient air sampling. A comparison of the data showed that the activity-based sampling (undertaken using body worn personal sampler) had higher bioaerosols concentrations (104 -106 CFU/m3), i.e. 2-3 logs higher than those recorded from static ambient air sampling. Bioaerosol exposure was highest during scavenging activities compared to waste sorting and site supervision. Particle size distributions showed that 41%, 46%, 76% and 63% of total bacteria, gram-negative bacteria, Aspergillus fumigatus and total fungi respectively were of respirable sizes and would therefore be capable of penetrating deep into the respiratory system, posing a greater human health risk. This study has shown that exposure to bioaerosols can be associated with activities undertaken at open dumpsites and may contribute to the high prevalence of the chronic respiratory symptoms among the workers in such environments.

Childhood urbanicity and hair steroid hormone levels in ten-year-old children.

BACKGROUND: Research suggests that it may be more stressful for children to grow up in an urban area than in a rural area. Urbanicity may affect physiological stress system functioning as well as the timing of sexual maturation. The purpose of the current study was to investigate whether moderate urbanicity (current and childhood, ranging from rural areas to small cities) was associated with indices of long-term hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axis functioning (cortisol, cortisone, dehydroepiandrosterone and progesterone levels) and whether sex moderated any associations. METHOD: Children (N = 92) were all 10 years old and from the Dutch general population. Hair samples were collected and single segments (the three cm most proximal to the scalp) were assayed for concentrations of steroid hormones (LCMS/MS method). Neighborhood-level urbanicity and socioeconomic status were measured from birth through age ten years. Analyses were controlled for neighborhood- and family socioeconomic status, body mass index and season of sampling. RESULTS: The results from multivariate analyses of variance showed no associations between current or childhood moderate urbanicity and hair steroid hormone concentrations. Interaction terms between moderate urbanicity and sex were not statistically significant. CONCLUSIONS: Associations between urbanicity and steroid hormone levels may only be detectable in highly urban areas and/or during later stages of adolescence. Alternatively, our findings may have been due to most children being from families with a higher socioeconomic status.

Effect of filter media thickness on the performance of sand drying beds used for faecal sludge management.

The effect of sand filter media thickness on the performance of faecal sludge (FS) drying beds was determined in terms of: dewatering time, contaminant load removal efficiency, solids generation rate, nutrient content and helminth eggs viability in the dried sludge. A mixture of ventilated improved pit latrine sludge and septage in the ratio 1:2 was dewatered using three pilot-scale sludge drying beds with sand media thicknesses of 150, 250 and 350 mm. Five dewatering cycles were conducted and monitored for each drying bed. Although the 150 mm filter had the shortest average dewatering time of 3.65 days followed by 250 mm and 350 mm filters with 3.83 and 4.02 days, respectively, there was no significant difference (p > 0.05) attributable to filter media thickness configurations. However, there was a significant difference for the percolate contaminant loads in the removal and recovery efficiency of suspended solids, total solids, total volatile solids, nitrogen species, total phosphorus, chemical oxygen demand, dissolved chemical oxygen demand and biochemical oxygen demand, with the highest removal efficiency for each parameter achieved by the 350 mm filter. There were also significant differences in the nutrient content (NPK) and helminth eggs viability of the solids generated by the tested filters. Filtering media configurations similar to 350 mm have the greatest potential for optimising nutrient recovery from FS.

Plasma ropivacaine concentrations during bilateral transversus abdominis plane infusions.

BACKGROUND: The transversus abdominis plane (TAP) block is a regional anaesthetic technique that blocks abdominal wall somatic afferent nerves. We conducted a prospective observational study to evaluate the venous plasma concentrations of ropivacaine during a continuous TAP infusion. METHODS: Twenty patients who were planned to undergo intra-abdominal cavity surgery requiring a mid-line laparotomy incision were enrolled. Patients were excluded if they had a history of chronic pain, opioid tolerance, renal or hepatic impairment, or contraindication to study medications. Subjects received a standardized general anaesthetic, and at the completion of surgery, ultrasound-guided subcostal or posterior TAP blocks and catheters. A TAP infusion of 2 mg ml(-1) ropivacaine was administered for 72 h after operation. Data collection during the 72 h included morphine requirements, pain scores, and plasma ropivacaine levels. RESULTS: TAP blocks and catheters were successfully inserted in all recruited subjects. The fourth subject experienced neurological symptoms attributed to local anaesthetic toxicity, but did not have high plasma ropivacaine concentrations. However, the protocol was amended for the subsequent 16 subjects, to a weight-based dosing regimen. The range of total plasma ropivacaine concentrations was 0.98-3.41 mg litre(-1) for posterior infusions and 0.96-3.48 mg litre(-1) for subcostal infusions. Four subjects had total ropivacaine levels >3.4 mg litre(-1). The range of unbound plasma ropivacaine concentrations was 0.022-0.135 mg litre(-1) for posterior infusions and 0.031-0.120 mg litre(-1) for subcostal infusions. CONCLUSION: Given the potential for high plasma concentrations from a bilateral TAP infusion technique, attention should be paid to individualized dosing strategies.

Nonpeptide oxytocin antagonists: analogs of L-371,257 with improved potency.

Structure-activity studies on the oxytocin antagonist 1 (L-371,257; Ki = 9.3 nM) have led to the identification of a related series of compounds containing an ortho-trifluoroethoxyphenylacetyl core which are orally bioavailable and have significantly improved potency in vitro and in vivo, e.g., compound 8 (L-374,943; Ki = 1.4 nM).

A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents.

The slowly activating delayed rectifier K+ current, IKs, is an important modulator of cardiac action potential repolarization. Here, we describe a novel benzodiazepine, [L-364,373 [(3-R)-1, 3-dihydro-5-(2-fluorophenyl)-3-(1H-indol-3-ylmethyl)-1-methyl-2H- 1,4-benzodiazepin-2-one] (R-L3), that activates IKs and shortens action potentials in guinea pig cardiac myocytes. These effects were additive to isoproterenol, indicating that channel activation by R-L3 was independent of beta-adrenergic receptor stimulation. The increase of IKs by R-L3 was stereospecific; the S-enantiomer, S-L3, blocked IKs at all concentrations examined. The increase in IKs by R-L3 was greatest at voltages near the threshold for normal channel activation, caused by a shift in the voltage dependence of IKs activation. R-L3 slowed the rate of IKs deactivation and shifted the half-point of the isochronal (7.5 sec) activation curve for IKs by -16 mV at 0.1 microM and -24 mV at 1 microM. R-L3 had similar effects on cloned KvLQT1 channels expressed in Xenopus laevis oocytes but did not affect channels formed by coassembly of KvLQT1 and hminK subunits. These findings indicate that the association of minK with KvLQT1 interferes with the binding of R-L3 or prevents its action once bound to KvLQT1 subunits.

Progress in the development of oxytocin antagonists for use in preterm labor.

There is currently a need for new therapeutic agents for treating preterm labor which could offer improved safety and efficacy beyond what has been achieved with the widely employed beta-mimetics. In this regard, the longstanding hypothesis of oxytocin receptor blockade as representing a potentially more selective method of tocolysis has continued to gain support from results obtained in clinical studies with the peptide oxytocin antagonist, atosiban. Our laboratory has focussed on the identification of non-peptide oxytocin antagonists with properties suitable for both oral and intravenous administration. We have previously described the development of potent, camphor-based oxytocin antagonists, including L-368,899 which entered phase I human studies. More recently we have pursued a new structural class of oxytocin antagonists based on the 1-(N-benzoylpiperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one template. L-372,662 is a new member of this structural class and in our preclinical assays possesses an attractive overall profile from the standpoint of human oxytocin receptor affinity (Ki = 4.9 nM), human oxytocin vs. vasopressin receptor selectivity (> 500-fold), potency as an antagonist of oxytocin-induced uterine contractions in late gestation pregnant rhesus monkeys (AD50 = 36 micrograms/kg), oral bioavailability (F = 90% in dogs), and aqueous solubility (10 mg/mL).

Progress in the development of oxytocin antagonists for use in preterm labor.

From a targeted screening effort and medicinal chemistry program, L-368,899 was selected as the first orally-active oxytocin (OT) antagonist to enter clinical trials. In animal studies, L-368,899 was shown to be a potent and selective OT antagonist and was orally bioavailable in rats, dogs and chimpanzees. L-368,899 was further shown to be a potent OT antagonist in pregnant rhesus and to inhibit spontaneous nocturnal uterine contractions. In Phase I human studies, L-368,899 was generally well-tolerated given intravenously and showed significant plasma levels after oral administration. In addition, L-368,899 blocked OT-stimulated uterine activity in postpartum women with a potency similar to that in the pregnant rhesus monkey. More recently, another structural series has been pursued, represented by L-371,257 [1-(1-(4-(N-acetyl-4-piperidinyloxy)-2-methoxybenzoyl)pip eridin-4-yl)- 1,2-dihydro-4(H)-3,1-benzoxazin-2-one]. L-371,257 exhibits high affinity (Ki, 4.6 nM) for human uterine OT receptors with high selectivity vs. human vasopressin receptors. In rat tissues in vitro, L-371,257 is a potent and competitive OT antagonist (pA2, 8.4) and, in vivo, blocks OT-stimulated uterine activity given both i.v. and intraduodenally. L-371,257 highlights the promise of this novel structural class.

1-((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo [2.2.1]-heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperaz ine (L-368,899): an orally bioavailable, non-peptide oxytocin antagonist with potential utility for managing preterm labor.

Modifications to the previously reported spiroindenylpiperidine camphor-sulfonamide oxytocin (OT) antagonist L-366,509 have produced a new series of o-tolylpiperazine (TP) camphor-sulfonamides. A number of analogues in the TP series that incorporate a modified or unmodified L-methionine sulfone amide at the C2 endo position on the camphor ring exhibit high affinity for OT receptors (IC50 = 1.3-15 nM) and good selectivity for binding to OT versus arginine vasopressin V1a and V2 receptors. Several of these analogues were additionally characterized as potent antagonists of OT-stimulated contractions of the isolated and/or in situ rat uterus. Compound 7 (L-368,899) exhibited the best overall profile of OT receptor affinity (IC50 = 8.9 nM, rat uterus; 26 nM, human uterus), potency for inhibition of OT-stimulated contractions of the isolated rat uterus (pA2 = 8.9) and in situ rat uterus (AD50 = 0.35 mg/kg after intravenous (i.v.) administration and 7.0 mg/kg after intraduodenal administration), aqueous solubility (3.7 mg/mL at pH 5.0), and oral bioavailability in several species (35% (rat), 25% (dog), and 21% (chimpanzee) as estimated from radioreceptor determination of drug levels in plasma after oral and i.v. dosing). On the basis of these favorable properties, 7 has begun clinical testing for use as an oral and i.v. tocolytic agent. Molecular modeling alignment studies have provided support for the hypothesis that the TP camphor-sulfonamide portion of the non-peptide structures may serve as a mimetic of the important D-AA2-Ile3 dipeptide (AA = aromatic amino acid) found in many potent OT antagonists from the cyclic hexapeptide and OT analogue structural classes.

Nanomolar-affinity, non-peptide oxytocin receptor antagonists.

Non-peptide antagonists of the peptide hormone oxytocin (OT) with nanomolar OT receptor affinities are described. These compounds incorporate novel amido- and amidoalkylcamphor variations to the lead structure L-366,509 (1) to achieve receptor affinity enhancements of 2-3 orders of magnitude over that compound. The new OT antagonist L-367,773 (35) is shown to be an orally bioavailable agent with good duration in vivo and to inhibit OT-stimulated uterine contractions effectively in several in vitro and in vivo models.

Development of 1,4-benzodiazepine cholecystokinin type B antagonists.

A series of 3-(arylureido)-5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by reasoned modification of the CCK-A selective 3-carboxamido-1,4-benzodiazepine, MK-329, this paper chronicles the development of potent, orally effective compounds in which selectivity for the CCK-B receptor subtype was achieved. The principal lead structure that emerged from these studied is L-365,260, a compound which has been submitted for clinical evaluation. Details of the ability to modulate the receptor interactions of these benzodiazepines by appropriate structure modifications are discussed which imply the possibility of further refining the CCK-B receptor affinity and selectivity of this class of compounds.

Identification of an orally active, nonpeptidyl oxytocin antagonist.

L-366,509, a member of a novel class of nonpeptidyl compounds, has been characterized as an orally active oxytocin (OT) antagonist. L-366,509 exhibits a moderate binding affinity (K(i) values, 370-780 nM) for the rat, rhesus and human uterine OT receptor. L-366,509 also binds to vasopressin receptor subtypes (arginine vasopressin-V1 and V2) with measurable affinity in rat (K(i) values, 25-30 microM) and primate (K(i) values, 2-6 microM) tissues. In rat uterine slices, L-366,509 inhibits (IC50 = 1.6 microM) the stimulation of phosphatidylinositol turnover induced by OT but not bradykinin. In the rat isolated uterus, L-366,509 is a competitive and reversible OT antagonist (pA2 = 7.32). In vivo, L-366,509 given i.v. (10 mg/kg) or intraduodenally (10-50 mg/kg) to rats causes a marked and long-lasting inhibition of OT-stimulated uterine activity. OT antagonist activity in a pregnant rhesus macaque (approximately day 135 gestation) is also observed with L-366,509 after i.v. or p.o. dosing. L-366,509 represents a prototype for a new chemical class of OT antagonists with significant p.o. bioavailability.

Orally active, nonpeptide oxytocin antagonists.

The first nonpeptide antagonists of the neurohypophyseal hormone, oxytocin (OT) are described. Derivatives of the spiroindenepiperidine ring system, these compounds include L-366,509, an orally bioavailable OT antagonist with good in vivo duration. The potential use of these agents for treatment of preterm labor and their significance as new nonpeptide ligands for peptide receptors are discussed.

Vulvar vestibulitis syndrome: a clinico-pathological study.

Twenty four patients with the vulvar vestibulitis syndrome formed the basis of this clinicopathological study. Entry dyspareunia was the constant presenting complaint and vestibular erythema with acute superficial tenderness the invariable clinical finding. In our series there was a marked predominance of Caucasians, patients were most often of social classes I and II and most frequently in the third decade. The results of laboratory investigation revealed that this syndrome has a diverse range of potential aetiologies including vulval infections, dysplasia and in one instance acute vasculitis.

Molecular design of potent specific antagonists for the gastrin and cholecystokinin receptors.

Widespread distribution of receptors for the peptide hormones cholecystokinin (CCK) and gastrin in the gut and in the CNS suggests therapeutic potential for selective antagonists of these hormones. Discovery of the natural product Asperlicin provided a new class of non-peptidal CCK antagonists, but oral bioavailability in this class remained elusive. With Asperlicin as a guide, the new, selective, orally bioavailable, high affinity CCK-A antagonist, MK-329 (L-364,718; Devazepide) and CCK-B/gastrin antagonist, L-365,260 have been developed. Biological profiles of these compounds are presented and results of early clinical evaluation of MK-329 are described. The significance of these agents as models for development of non-peptidal ligands for other receptors are briefly summarized.

Cholecystokinin-A receptor ligands based on the kappa-opioid agonist tifluadom.

Tifluadom, a kappa-opioid agonist and cholecystokinin-A (CCK-A) receptor antagonist, was utilized as a model to prepare a series of 2-(aminomethyl)- and 3-(aminomethyl)-1,4-benzodiazepines. These compounds were tested in vitro as inhibitors of the binding of [125I]CCK to rat pancreas and guinea pig brain receptors. All compounds with IC50's less than 100 microM proved to have greater affinity for the CCK-A receptor, with the most potent analogue, 6e, having an IC50 of 0.16 microM. The benzodiazepines described in this study are simultaneously CCK-A and opioid receptor ligands. The ramification of this dichotomy on current concepts of peptide hormone action are discussed. These results further demonstrate the versatility of the benzodiazepine core structure for designing nonpeptide ligands for peptide receptors and the ability to fine-tune the receptor interactions of these benzodiazepines by appropriate structure modifications.