Occupational and Environmental Risk Factors Influencing the Inducement of Erythema among Nigerian Laboratory University Workers with Multiple Chemical Exposures.

: The chemicals from laboratories pose a significant risk forinducing erythema, an abnormal redness of the skin, as a result of poor occupational and environmental factors that promote hypersensitivity to a chemical agent. The aim of this present study was to determine the occupational and environmental risk factors influencing the inducement of erythema in laboratory workers due to exposure to chemicals. This was a cross-sectional study on a population-based sample of Nigerian university laboratory workers. Data were collected using the erythema index meter and an indoor air control meter. The study included 287 laboratory workers. The laboratory workers who properly used personal protective equipment (PPE) were 60% less likely to have induced erythema (adjusted odds ratio (AOR) = 0.40; 95% confidence interval CI: 0.22-0.77; probability value p = 0.011). The chemical mixture exceeding the permissible exposure limit (PEL) was found to have a small effect in inducing the erythema (AOR = 4.22; 95%CI: 2.88-12.11; p = 0.004). Most of the sampled laboratories where the respondents worked had unsuitable temperatures (AOR = 8.21; 95% CI: 4.03-15.01; p = 0.001). Erythema was more frequently found in the respondents who spent 4-5h in the laboratory (AOR = 3.11; 95%CI: 1.77-9.23; p = 0.001). However, high levels of ventilation reduce the likelihood of erythema in a laboratory by 82% (0.18). Multiple logistic regressions revealed that PPE, PEL, exposure time, temperature, and ventilation were the probable predictive factors associated with the inducement of erythema. Providing better educational knowledge and improving the attitude towards hazards and safety in a laboratory would lead to reduced rates of new cases.

Evaluating quality neonatal care, call Centre service, tele-health and community engagement in reducing newborn morbidity and mortality in Bungoma county, Kenya.

BACKGROUND: Neonatal mortality is a major health burden in Bungoma County with the rate estimated at 31 per 1000 live births and is above the national average of 22 per 1000. Nonetheless, out of the nine sub county hospitals, only two are fairly equipped with necessary infrastructure and skilled personnel to manage neonatal complications such as prematurity, neonatal sepsis, neonatal jaundice, birth asphyxia and respiratory distress syndrome. Additionally, with more than 50% of neonates delivered without skilled attendance, in below par hygiene environments such as home and on the roadsides, with non-existent community based referral system, the situation is made worse. The study aims to evaluate the progress made by an intervention "Collaborative Newborn Support Project" geared towards reducing neonatal mortality rate by 30% between October 2015 and December 2018 in Bungoma County, Kenya. METHODS/DESIGN: This intervention will take a quasi-experimental design approach with experimental and control sites. The project will involve pre- and post-intervention data collection with comparison group to assess intervention effects. The primary outcome will be the percentage reduction of neonatal mortality in Bungoma County. Secondary outcomes include; a) Percentage of mothers or care givers able to identify at least three danger signs in neonates in the project area, b) Proportion of neonates with complications referred to specialized neonatal centers, through the call center, c) Percentage of health providers in neonatal care units who adhere to expected neonatal standards of care (rapid and complete application of standard protocols), d) Percentage increase in neonates with severe complications in the specialized neonatal units and e) Percentage of neonates who stay in neonatal care units beyond 5 days. DISCUSSION: We outline implementation details of the ongoing 'Collaborative Newborn Support Project' in Bungoma County, Kenya. This includes strategies in the operations of the telehealth platform, call centre service, community engagement and measuring of the outputs and outcomes. The funding and ethical approvals have been obtained and the study commenced. TRIAL REGISTRATION: PACTR201712002802638 Retrospectively registered on 5th December 2017 at Pan African Clinical Trials Registry.

Skeletal complications of rheumatoid arthritis.

Rheumatoid arthritis (RA) is associated with local and systemic inflammation that induces many changes in the skeletal health. Locally, periarticular bone loss and juxta-articular bone erosions may occur while joint ankylosis, generalized bone loss, osteoporosis, and fractures may develop secondary to inflammation. The aim of this narrative review is to summarize the clinical evidence for abnormal skeletal health in RA, the effects of disease modifying anti-rheumatic drugs (DMARDS) on bone health, and the effects of drugs for the prevention or treatment of osteoporosis in the RA population.

Factors Influencing Prevention and Control of Malaria among Pregnant Women Resident in Urban Slums, Southern Ghana.

Throughout Africa and particularly in Ghana, there are concerns about malaria infection during pregnancy. This study aimed to investigate factors that influence malaria prevention and control practices among pregnant women residing in Chorkor and Korle-Gonno in Accra, Ghana. One hundred and twenty pregnant women between ages 18-49 were randomly recruited during antenatal sessions at a maternity facility in Accra, as participants for the study. An interviewer-administered questionnaire was used to collect data, which were analysed using SPSS version16.0. It was found that in Chorkor and Korle-Gonno, 57.4% and 42.6% participants respectively reported having been infected with malaria during their current pregnancy. There was no significant relationship between religious beliefs of participants and their malaria prevention and control practices (X2 = 0.28, P = .53). However, there was a significant relationship between malaria prevention and control practices of participants and their income earning (X2 = 53.94, P = .00) and employment (X2 = 61.76, P = .00) statuses. With the exception of ethnicity (X2 = 35.62, P =.22), other socio-cultural conditions had a significant relationship with malaria prevention and control practices of the participants. The findings suggest the need to consider and integrate factors, such as poverty and poor living conditions in malaria prevention and control strategies.

Large electric-field-induced strain in centrosymmetric crystals of a dipolar ruthenium alkynyl complex.

Dipolar molecular crystals present different physical properties from traditionally strongly correlated ionic solid-state inorganic crystals due to the weak intermolecular bonding. Herein, centrosymmetric dipolar molecular crystals of the organoruthenium complex trans-[Ru(C≡CC6H4-4-NO2)(C≡CPh)(dppe)2] [dppe = 1,2-bis(diphenylphosphino)ethane] display a large electric-field-induced strain behaving differently from conventional piezoelectric materials that must, structurally, be noncentrosymmetric. Further studies of related systematically varied crystalline organoruthenium complexes reveal that the strong electromechanical coupling effect is not from classical ferroelectricity, electrostriction, flexoelectricity or electrochemical strain. It is, instead, attributed to the disorder in the molecular packing, which facilitates reorientation of the molecular dipoles under the action of an applied electric field. This provides a fresh insight into the design and development of new functional materials and a promising source of electromechanical coupling in organometallic, and more generally dipolar molecular, crystals.

Stillbirth rates among Indigenous and non-Indigenous women in Queensland, Australia: is the gap closing?

OBJECTIVE: To determine whether the disparity gap is closing between stillbirth rates for Indigenous and non-Indigenous women and to identify focal areas for future prevention efforts according to gestational age and geographic location. DESIGN: Population-based retrospective cohort study. SETTING: Queensland, Australia. POPULATION: All singleton births of at least 20 weeks of gestation or at least 400 g birthweight. METHODS: Routinely collected data on births were obtained for the period 1995 to 2011. Indigenous and non-Indigenous stillbirth rates and percent reduction in the gap were compared over time and by geographic location and gestational age. MAIN OUTCOME MEASURES: All-cause and cause-specific stillbirth rates (per 1000 ongoing pregnancies). RESULTS: Over the study period there was a 57.3% reduction in the disparity gap. Although marked reductions in the gap were shown for women in regional (57.0%) and remote (56.1%) locations, these women remained at increased risk compared with those in urban regions. There was no reduction for term stillbirths. Major conditions contributing to the disparity were maternal conditions (diabetes) (relative risk [RR] 3.78, 95% confidence intervals [95% CI] 2.59-5.51), perinatal infection (RR 3.70, 95% CI 2.54-5.39), spontaneous preterm birth (RR 3.08, 95% CI 2.51-3.77), hypertension (RR 2.22, 95% CI 1.45-3.39), fetal growth restriction (RR 1.78, 95% CI 1.17-2.71) and antepartum haemorrhage (RR 1.58, 95% CI 1.13-2.22). CONCLUSIONS: The gap in stillbirth rates between Indigenous and non-Indigenous women is closing, but Indigenous women continue to be at increased risk due to a number of potentially preventable conditions. There is little change in the gap at term gestational ages.

Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in-class mirror-image oligonucleotide inhibitor of CXCL12.

NOX-A12 is a PEGylated mirror-image oligonucleotide (a so-called Spiegelmer) that binds to CXCL12 (stromal cell-derived factor-1, SDF-1) with high affinity thereby inhibiting CXCL12 signaling on both its receptors, CXCR4 and CXCR7. In animals, NOX-A12 mobilized white blood cells (WBCs) and hematopoietic stem and progenitor cells (HSCs) into peripheral blood (PB). In healthy volunteers, single doses of NOX-A12 had a benign safety profile and also dose-dependently mobilized WBCs and HSCs into PB. HSC peak mobilization reached a plateau at five times the baseline level at an i.v. dose of 5.4 mg/kg. In accordance with the plasma half-life of 38 h, the duration of the WBC and HSC mobilization was long lasting and increased dose-dependently to more than 4 days at the highest dose (10.8 mg/kg). In conclusion, NOX-A12 may be appropriate for therapeutic use in and beyond mobilization of HSCs, e.g., in long-lasting mobilization and chemosensitization of hematological cancer cells.

HIV-1 drug resistance emergence among breastfeeding infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention of mother-to-child transmission: a secondary analysis.

BACKGROUND: Nevirapine and lamivudine given to mothers are transmitted to infants via breastfeeding in quantities sufficient to have biologic effects on the virus; this may lead to an increased risk of a breastfed infant's development of resistance to maternal antiretrovirals. The Kisumu Breastfeeding Study (KiBS), a single-arm open-label prevention of mother-to-child HIV transmission (PMTCT) trial, assessed the safety and efficacy of zidovudine, lamivudine, and either nevirapine or nelfinavir given to HIV-infected women from 34 wk gestation through 6 mo of breastfeeding. Here, we present findings from a KiBS trial secondary analysis that evaluated the emergence of maternal ARV-associated resistance among 32 HIV-infected breastfed infants. METHODS AND FINDINGS: All infants in the cohort were tested for HIV infection using DNA PCR at multiple study visits during the 24 mo of the study, and plasma RNA viral load for all HIV-PCR-positive infants was evaluated retrospectively. Specimens from mothers and infants with viral load >1,000 copies/ml were tested for HIV drug resistance mutations. Overall, 32 infants were HIV infected by 24 mo of age, and of this group, 24 (75%) infants were HIV infected by 6 mo of age. Of the 24 infants infected by 6 mo, nine were born to mothers on a nelfinavir-based regimen, whereas the remaining 15 were born to mothers on a nevirapine-based regimen. All infants were also given single-dose nevirapine within 48 hours of birth. We detected genotypic resistance mutations in none of eight infants who were HIV-PCR positive by 2 wk of age (specimens from six infants were not amplifiable), for 30% (6/20) at 6 wk, 63% (14/22) positive at 14 wk, and 67% (16/24) at 6 mo post partum. Among the 16 infants with resistance mutations by 6 mo post partum, the common mutations were M184V and K103N, conferring resistance to lamivudine and nevirapine, respectively. Genotypic resistance was detected among 9/9 (100%) and 7/15 (47%) infected infants whose mothers were on nelfinavir and nevirapine, respectively. No mutations were detected among the eight infants infected after the breastfeeding period (age 6 mo). CONCLUSIONS: Emergence of HIV drug resistance mutations in HIV-infected infants occurred between 2 wk and 6 mo post partum, most likely because of exposure to maternal ARV drugs through breast milk. Our findings may impact the choice of regimen for ARV treatment of HIV-infected breastfeeding mothers and their infected infants.

Meta-analysis and imputation identifies a 109 kb risk haplotype spanning TNFAIP3 associated with lupus nephritis and hematologic manifestations.

TNFAIP3 encodes the ubiquitin-modifying enzyme, A20, a key regulator of inflammatory signaling pathways. We previously reported association between TNFAIP3 variants and systemic lupus erythematosus (SLE). To further localize the risk variant(s), we performed a meta-analysis using genetic data available from two Caucasian case-control datasets (1453 total cases, 3381 total control subjects) and 713 SLE trio families. The best result was found at rs5029939 (P=1.67 x 10(-14), odds ratio=2.09, 95% confidence interval 1.68-2.60). We then imputed single nucleotide polymorphisms (SNPs) from the CEU Phase II HapMap using genotypes from 431 SLE cases and 2155 control subjects. Imputation identified 11 SNPs in addition to three observed SNPs, which together, defined a 109 kb SLE risk segment surrounding TNFAIP3. When evaluating whether the rs5029939 risk allele was associated with SLE clinical manifestations, we observed that heterozygous carriers of the TNFAIP3 risk allele at rs5029939 have a twofold increased risk of developing renal or hematologic manifestations compared to homozygous non-risk subjects. In summary, our study strengthens the genetic evidence that variants in the region of TNFAIP3 influence risk for SLE, particularly in patients with renal and hematologic manifestations, and narrows the risk effect to a 109 kb DNA segment that spans the TNFAIP3 gene.

Formulation, stability and thermal analysis of lyophilised wound healing wafers containing an insoluble MMP-3 inhibitor and a non-ionic surfactant.

Lyophilised wafers are being developed as topical drug delivery systems for the treatment of chronic wounds. This study describes the formulation of xanthan wafers containing a selective, insoluble MMP-3 inhibitor (UK-370,106) and a non-ionic surfactant, designed to release accurate doses of UK-370,106 directly to a suppurating wound bed. Stability of UK-370,106 in the wafer compared to a non-lyophilised gel suspension was investigated using a combination of light scattering, thermal and microscopic techniques. Particle size distributions in UK-370,106-loaded wafers were constant throughout an accelerated stability study (12 weeks, 40 degrees C) while the mean particle size in a non-lyophilised suspension increased by 15 microm in the same period. Thermal analysis of UK-370,106-loaded wafers highlighted an unexpected interaction between the drug and the surfactant that was further investigated using simple mixtures of each component. It was concluded that an in situ solvate of UK-370,106 and the non-ionic surfactant can form and that this may have implications towards the stability of UK-370,106 during the formulation process. Further concerns regarding high water contents (14%) in the wafer and its effect on product stability were unfounded and it was concluded that these novel delivery systems provided a viable alternative to gel suspensions.

Investigation of regional mechanisms responsible for poor oral absorption in humans of a modified release preparation of the alpha-adrenoreceptor antagonist, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003): the rational use of ex vivo intestine to predict in vivo absorption.

Modified release (MR) formulations are used to enhance the safety and compliance of existing drugs by improving their pharmacokinetics. Predicting the likely success of MR formulations is often difficult before clinical studies. A systematic in vitro approach using mouse and human tissues was adopted to rationalize the in vivo pharmacokinetics of 9- and 15-h MR formulations of an alpha-adrenoreceptor antagonist, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003). Immediate release UK-338,003 was well absorbed in humans consistent with moderate Caco-2 cell monolayer permeability. In contrast, 9- and 15-h modified release formulations showed marked reductions in C(max) (47.1 and 68.9%) and AUC(0-72) (32.6 and 54.0%). Colonic intubation resulted in 81.3 and 73.8% reductions in C(max) and AUC(0-72). Mechanistic studies in isolated mouse tissues showed that colonic UK-338,003 permeability (P(app) < 0.5 x 10(-6) cm/s) was at least 40 times lower than that for ileum with marked asymmetry. UK-338,003 was found to be a substrate for P-glycoprotein (PGP) with a weaker interaction for multidrug resistance-associated protein-type transporters in mouse intestine. PGP inhibition dramatically increased colonic UK-338,003 permeability to the levels observed in ileum. Low UK-338,003 apical to basolateral permeability was also observed in ex vivo human distal intestine, but both the asymmetry and increase in permeability after PGP inhibition were significantly lower. In conclusion, the poor absorption of MR UK-338,003 in humans can be explained by a combination of PGP-dependent efflux and low intrinsic permeability in the lower bowel. Regional permeability studies in ex vivo tissues used during drug development can highlight absorption problems in the distal bowel and assess the feasibility of developing successful MR formulations.

Gamma-irradiation of lyophilised wound healing wafers.

Lyophilised wafers are being developed as drug delivery systems that can be applied directly to the surface of suppurating wounds. They are produced by the freeze-drying of polymer solutions and gels. This study investigates the possibility of sterilising these glassy, solid dosage forms with gamma-irradiation and determining the rheological properties of rehydrated wafers post-irradiation. One series of wafers was formulated using sodium alginate (SA) modified with increasing amounts of methylcellulose (MC), the other being composed of xanthan gum (XG) and MC. Batches were divided into three lots, two of which were exposed to 25 and 40 kGrays (kGy) of Cobalt-60 gamma-irradiation, respectively, the third being retained as a non-irradiated control. Apparent viscosities of solutions/gels resulting from the volumetric addition of distilled water to individual wafers were determined using continuous shear, flow-rheometry. Flow behaviour on proprietary suppurating surfaces was also determined. Large reductions in viscosity were apparent for irradiated SA samples while those of XG appeared to be largely unaffected. In addition, an increase in the yield stress of xanthan formulations was observed. Xanthan wafers appeared to withstand large doses of irradiation with no detrimental effect on the rheology of reconstituted gels. This offers the possibility of manufacturing sterilisable delivery systems for wounds.

Lyophilised wafers as a drug delivery system for wound healing containing methylcellulose as a viscosity modifier.

Lyophilised wafers have potential as drug delivery systems for suppurating wounds. A dual series of wafers made from low molecular weight sodium alginate (SA) and xanthan gum (XG) respectively, modified with high molecular weight methylcellulose (MC) were produced. The swelling and flow properties of these wafers on model suppurating surfaces were both qualitatively and quantitatively investigated. The wafers instantaneously adhered to the surfaces, absorbing water and transforming from glassy, porous solids to highly viscous gels. The rate at which this occurred varied for the series studied with clear distinctions between the behaviour of SA and XG systems. For SA wafers there was a distinct relationship between the flow-rate and MC content. Increased amounts of MC decreased the rate at which the SA wafers flowed across a model gelatine surface. Flow rheometry was used to quantify the effect of increased MC content on both series of wafers and for the SA series, highlighted a substantial increase in apparent viscosity as a function of incremental increases in MC content. These results reflected those from the gelatine model. Observations of the reluctance of a swollen, unmodified XG wafer to flow compared with the relative ease of unmodified, low molecular weight SA was attributed to the yield stress characteristic of xanthan gels. XG is known to exhibit complex, loosely bound network structures in solution via the association of helical backbone structures. The inclusion of sodium fluorescein as a visible model for a soluble drug highlighted the potential of lyophilised wafers as useful drug delivery systems for suppurating wounds.

Nucleotide and predicted amino acid sequence-based analysis of the avian metapneumovirus type C cell attachment glycoprotein gene: phylogenetic analysis and molecular epidemiology of U.S. pneumoviruses.

A serologically distinct avian metapneumovirus (aMPV) was isolated in the United States after an outbreak of turkey rhinotracheitis (TRT) in February 1997. The newly recognized U.S. virus was subsequently demonstrated to be genetically distinct from European subtypes and was designated aMPV serotype C (aMPV/C). We have determined the nucleotide sequence of the gene encoding the cell attachment glycoprotein (G) of aMPV/C (Colorado strain and three Minnesota isolates) and predicted amino acid sequence by sequencing cloned cDNAs synthesized from intracellular RNA of aMPV/C-infected cells. The nucleotide sequence comprised 1,321 nucleotides with only one predicted open reading frame encoding a protein of 435 amino acids, with a predicted M(r) of 48,840. The structural characteristics of the predicted G protein of aMPV/C were similar to those of the human respiratory syncytial virus (hRSV) attachment G protein, including two mucin-like regions (heparin-binding domains) flanking both sides of a CX3C chemokine motif present in a conserved hydrophobic pocket. Comparison of the deduced G-protein amino acid sequence of aMPV/C with those of aMPV serotypes A, B, and D, as well as hRSV revealed overall predicted amino acid sequence identities ranging from 4 to 16.5%, suggesting a distant relationship. However, G-protein sequence identities ranged from 72 to 97% when aMPV/C was compared to other members within the aMPV/C subtype or 21% for the recently identified human MPV (hMPV) G protein. Ratios of nonsynonymous to synonymous nucleotide changes were greater than one in the G gene when comparing the more recent Minnesota isolates to the original Colorado isolate. Epidemiologically, this indicates positive selection among U.S. isolates since the first outbreak of TRT in the United States.

Metapneumoviruses in birds and humans.

Avian pneumovirus (APV, Turkey rhinotracheitis virus) and Human metapneumovirus (hMPV) are pathogens of birds and humans, respectively, that are associated with upper respiratory tract infections. Based on their different genomic organization and low level of nucleotide (nt) and amino acid (aa) identity with paramyxoviruses in the genus Pneumovirus, APV and hMPV have been classified into a new genus referred to as Metapneumovirus. First isolated in 1970s, APV strains have since been isolated in Europe, Africa, middle east, and United States (US) and classified in four subgroups, APV/A, APV/B, APV/C, and APV/D based on nt and predicted aa sequence identity. Although it was first isolated in 2001, serological evidence indicates that hMPV may have been present in human population from as early as the 1950s. There is only one subgroup of hMPV so far, whose nt and aa sequence identity indicates that it is more closely related to APV/C than to APV/A, APV/B, or APV/D.

Region-dependent modulation of intestinal permeability by drug efflux transporters: in vitro studies in mdr1a(-/-) mouse intestine.

Information on the extent to which xenobiotics interact with P-glycoprotein (PGP) during transit through the intestine is crucial in determining the influence of PGP on oral drug absorption. We have recently described a novel use of isolated ileum from PGP-deficient mdr1a(-/-) mice to resolve PGP- and non-PGP-dependent drug efflux and provide a definitive measure of intrinsic drug permeability without recourse to inhibitors. The present study uses this approach to investigate the impact of PGP on intestinal permeability of paclitaxel and digoxin in different regions of the mouse intestine (jejunum, ileum, and proximal and distal colon). Absorption of paclitaxel and digoxin in tissues from wild-type mice was low and showed little regional variation. In contrast, absorption of both drugs was markedly higher in mdr1a(-/-) intestine, although the increase was highly region-dependent, with the ileum and distal colon showing the greatest effect and much smaller changes in the jejunum and proximal colon. These effects were accompanied by the abolition of paclitaxel and digoxin secretion in mdr1a(-/-) mice, suggesting that regional variations in intestinal permeability are masked by differential PGP expression, confirmed by immunoblotting studies. Propranolol permeability, which is not influenced by PGP, showed similar regional variation in both wild-type and mdr1a(-/-) tissues, suggesting that differences are at the level of transcellular permeability. These data suggest that the ileum and the distal colon are regions of relatively high transcellular permeability for xenobiotics that are compensated by enhanced expression of PGP.

Resolution of P-glycoprotein and non-P-glycoprotein effects on drug permeability using intestinal tissues from mdr1a (-/-) mice.

1. Intestinal xenobiotic transporters are a significant barrier to the absorption of many orally administered drugs. P-glycoprotein (PGP) is the best known, but several others, including members of the multidrug resistance-associated protein (MRP) family, are also expressed. Definitive information on their precise effect on intestinal drug permeability is scarce due to a lack of specific inhibitors and the difficulty of studying non-PGP activity in the presence of high PGP expression. 2. We have investigated the in vitro use of intestinal tissues from PGP knockout (mdr1a (-/-)) mice as a tool for dissecting the mechanisms of intestinal drug efflux. The permeability characteristics of digoxin (DIG), paclitaxel (TAX) and etoposide (ETOP) were measured in ileum from mdr1a (-/-) and wild-type (FVB) mice mounted in Ussing chambers. 3. DIG and TAX exhibited marked efflux across FVB tissues (B-A : A-B apparent permeability (P(app)) ratio 10 and 17 respectively) which was absent in mdr1a (-/-) tissues, confirming that PGP is the sole route of intestinal efflux for these compounds. The A-B P(app) of both compounds was 3 - 5 fold higher in mdr1a (-/-) than in FVB. 4. Polarized transport of ETOP in FVB tissues was reduced but not abolished in mdr1a (-/-) tissues. Residual ETOP efflux in mdr1a (-/-) tissues was abolished by the MRP inhibitor MK571, indicating involvement of both PGP and MRP. 5. MK571 abolished calcein efflux in mdr1a (-/-) tissues, while quinidine had no parallel effect in FVB tissues, suggesting involvement of MRP but not PGP. 6. Tissues from mdr1a (-/-) mice provide a novel approach for investigating the influence of PGP ablation on intestinal permeability and for resolving PGP and non-PGP mechanisms that modulate drug permeability.

Anaphylactoid reactions associated with menstruation affecting two sisters.

Cyclical anaphylactoid reactions associated with menstruation are exceedingly rare. We report two sisters who were both affected, one severely and one mildly. Treatment involved suppression of menstruation and use of a cyclooxygenase-2 (COX-2) inhibitor. An abnormal reaction to prostaglandins, perhaps produced by COX-2 enzyme activity in the endometrium, is a possible mechanism.

Synthesis, structure, and optical-limiting properties of heterobimetallic [M(3)CuS(4)] cuboidal clusters (M = Mo or W) with terminal phosphine ligands.

Cubane-type clusters of formula [Mo(3)CuS(4)Cl(4)(dmpe)(3)](PF(6)) (4), [Mo(3)CuS(4)Br(4)(dmpe)(3)](PF(6)) (5), and [W(3)CuS(4)Br(4)(dmpe)(3)](PF(6)) (6) have been prepared by reacting the incomplete cuboidal trimers [Mo(3)S(4)Cl(3)(dmpe)(3)](PF(6)) (1), [Mo(3)S(4)Br(3)(dmpe)(3)](PF(6)) (2), and [W(3)S(4)Br(3)(dmpe)(3)](PF(6)) (3), respectively, with CuX (X = Cl or Br) or the mononuclear copper complex [Cu(CH(3)CN)(4)](+) in THF. The reaction takes place without global changes in the metal oxidation states, and compounds 4-6 with a [M(3)CuS(4)](5+) core possess 16 e(-) for metal-metal bonding. X-ray structural analysis of 4-6 revealed an effective C(3v) symmetry for the M(3)Cu unit with the M-M distances being statistically the same for M = Mo or W. However, the M-Cu distance is 0.04 and 0.1 A longer than the M-M bond length for Mo and W, respectively. There is no significant structural rearrangement of the ligand-metal bonding in proceeding from [M(3)S(4)X(3)(dmpe)(3)](+) to [M(3)CuS(4)X(4)(dmpe)(3)](+). The cyclic voltammograms of the [Mo(3)CuS(4)] cubane clusters show one quasi-reversible reduction process at E(1/2) = -0.31 V for 4 and at E(1/2) = -0.23 V for 5 and one irreversible reduction at -0.69 and -0.58 V for 4 and 5, respectively. The tungsten cluster 6 shows a unique quasi-reversible reduction wave at E(1/2) = -0.71 V. The incorporation of copper into the incomplete [M(3)S(4)] cuboidal complexes produces a decrease of the reduction potential for both molybdenum and tungsten. Absorption spectra of 1-6 are broadly similar; replacing Mo by W in proceeding from 2 to 3 or from 5 to 6 and replacing Br by Cl in proceeding from 2 to 1 or from 5 to 4 results in a blue shift of the three UV-visible absorption bands. All six clusters exhibit optical limiting, as measured by the Z-scan technique at 523 nm using 40 ns pulses. The power-limiting mechanism remains obscure, but under the conditions employed, threshold-limiting fluence decreases on replacing W by Mo on proceeding from 3 to 2 or 6 to 5 and on proceeding from tetranuclear cluster (4-6) to trinuclear precursor (1-3, respectively). For all six clusters, values of the excited-state cross section sigma(eff) are larger than those of the corresponding ground-state cross section sigma(0); i.e., all clusters are efficient optical limiters.

Evaluation of the Intelisite capsule to deliver theophylline and frusemide tablets to the small intestine and colon.

The objective of the research was to establish the capability of the Intelisite capsule to deliver the probe drugs, theophylline and frusemide, in the form of split immediate release (IR) tablets, to the small intestine and colon. The two probe drugs were administered together in an open, random, three-way crossover study in eight healthy volunteers, comparing absorption following Intelisite delivery in the small bowel and colon to conventional IR dosing. Gamma scintigraphy was employed to monitor the gastrointestinal transit and activation of the Intelisite capsule. Standard pharmacokinetic parameters, and the percentage remaining in the capsules post defecation were determined. The Intelisite capsule was well tolerated in human volunteers and successfully activated on 15/16 occasions. Pharmacoscintigraphy showed internal marker release from the Intelisite capsule to be approximately 10-fold faster in the small intestine than in the colon. Theophylline and frusemide were both well absorbed following Intelisite activation in the small intestine, whereas complete colonic absorption was only observed in 1/7 subjects for theophylline, and 0/7 subjects for frusemide. The probe drugs were successfully delivered in particulate form from the Intelisite capsule in the small intestine and produced expected pharmacokinetic profiles. However drug release in the colon was incomplete and variable possibly due to: low water content, poor mixing, and a high loading dose.