Quality and human health risk assessment of uranium and other heavy metals in drinking water from Kwale County, Kenya.

Heavy metal contamination in drinking water is a global health concern. Anthropogenic and geogenic activities exacerbate the concentrations of these metals in surface and groundwater. In this study, we sampled drinking water sourced from surface and groundwater resources at the environs of Mrima Hill and the Kwale heavy minerals sand deposit, Kwale County, Kenya. The concentrations of Cr, Ni, Cu, As, Cd, Pb, and U were measured using the inductively coupled plasma mass spectrometer. The water quality indices were evaluated using the weighted arithmetic index method, while the human health risks due to exposure to these heavy metals through the ingestion pathway were assessed using deterministic and probabilistic techniques. The concentrations of Cr and Cd in samples from both study areas exceeded the national and international maximum contaminant levels in drinking water. The concentration levels of Ni, Cu, As, and U in all samples from both study areas were within the recommended values in drinking water. Therefore, the quality of water from both study areas was unsuitable for human consumption due to Cd and Cr contamination. The non-carcinogenic risk assessment also showed that the hazard indices (HI) evaluated for both children and adults at the study areas were higher than unity. In addition, the estimated carcinogenic risks of both population groups were more than the recommended value of 10-4. This study shows that the residents near Mrima Hill and the Kwale heavy minerals sand deposit remain susceptible to carcinogenic and non-carcinogenic health risks emanating from exposure to these heavy metals in drinking water.

The perils of inhibiting deficient factors.

Essentials Anticoagulation in patients with factor X deficiency is an evidence-poor area. A patient with factor X deficiency was anticoagulated with warfarin followed by rivaroxaban. Warfarin may be a safer anticoagulant option than rivaroxaban in hereditary factor X deficiency. A baseline coagulation screen should be performed prior to commencement of anticoagulation. SUMMARY: We report a case of a previously undiagnosed factor X deficiency in an 83-year-old man who had no previous bleeding history despite multiple hemostatic challenges. He was anticoagulated with warfarin for atrial fibrillation without bleeding complications; however, major hemorrhage occurred soon after a switch to rivaroxaban.

Managing direct oral anticoagulants in patients undergoing dentoalveolar surgery.

Our objective was to describe our experience of managing a cohort of adult patients prescribed direct oral anticoagulants (DOACs) undergoing dentoalveolar procedures between November 2012 and May 2016. Prior to conducting a procedure a formal assessment was made of each patient's anticoagulation treatment. A specific plan was then formulated, balancing the risk of bleeding with the risk of thrombosis. Patients received a telephone consultation one week following treatment to assess any post-operative bleeding. Eighty-two patients underwent 111 oral surgical procedures, the majority of which were dental extractions. In the case of 35 (32%) procedures, advice was given to omit the DOAC, either before or after treatment. There was no bleeding following the majority of procedures. Persistent bleeding followed 15 (13.5%) procedures, of which 7 (6.3%) procedures required specific intervention. The majority of patients prescribed DOACs can undergo dentoalveolar procedures safely. Important considerations when planning treatment are: (i) when the patient usually takes their dose of DOAC, (ii) the time the procedure is performed and, (iii) when the DOAC is taken post-procedure. In our experience, if these factors are considered carefully, omission of DOAC doses is unlikely to be required for most patients.

Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition.

PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 data set. We examined the role of mutated Shp2 in leukemias harboring MLL translocations, which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9-mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. Although the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K, suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small-molecule-mediated Mcl1 inhibition, suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2.

Estimation of annual effective dose and radiation hazards due to natural radionuclides in Mount Homa, southwestern Kenya.

The radiological hazard of naturally occurring radioactive material in Mount Homa in southwestern Kenya was investigated after 210 point measurements and 44 samples were analysed. In situ measured average outdoor absorbed dose rate in air using survey meters was found to vary from 154.8 to 2280.6 nGy h(-1). The mean (range) values of radioactive concentrations measured using an HpGe detection system for (40)K, (226)Ra and (232)Th were 915 ± 3 (64-3017), 195 ± 8 (17-1447) and 409 ± 4 (23-1369) Bq kg(-1), respectively. The calculated range of the annual effective dose for a person living in Homa Mountain area varied from 28.6 to 1681.2, with a mean of 470.4 µSv. All calculated average radiological indices, namely Radium equivalent, Representative level, Gamma activity, External and Internal hazard, were higher than the limits set by various national and international bodies. These results imply that Mount Homa region is a high background radiation area.

Women's views on and adherence to low-molecular-weight heparin therapy during pregnancy and the puerperium.

BACKGROUND: Non-adherence to prescribed medication represents a significant factor associated with treatment failure. Pregnant women identified at risk of venous thromboembolism are increasingly being prescribed low-molecular-weight heparin (LMWH) during pregnancy and the puerperium. It is important to understand women's views on and adherence to LMWH during pregnancy and the puerperium, so that women gain maximum benefit from the treatment. OBJECTIVES: To monitor women's adherence to enoxaparin, when prescribed during pregnancy and the puerperium, and explore their beliefs about the enoxaparin therapy prescribed. PATIENTS/METHODS: A prospective cohort study involving 95 nullparous and multiparous women prescribed enoxaparin for recognized antenatal indications. Adherence to enoxaparin was assessed through self-completion of a diary, additionally verified through laboratory tests. An adapted beliefs about medication questionnaire was administered to women during their pregnancy. RESULTS: Women were highly adherent to enoxaparin: antenatally, mean percentage adherence 97.92%; postnatally, mean percentage adherence 93.37% (paired t-test, P = 0.000). In the cohort of women we followed, their perceived necessity for enoxaparin therapy outweighed any concerns they had regarding enoxaparin antenatally, necessity-concerns differential 2.20. In some women, however, this perceived necessity does decrease postnatally. CONCLUSIONS: Our results suggest that most women prescribed enoxaparin are highly adherent to their therapy during the antenatal period and that women's antenatal beliefs about enoxaparin are able to predict a decrease in postnatal adherence. Our results have important clinical implications, particularly when women are initiated on LMWH just during the postnatal period.

Natural radioactivity and external dose in the high background radiation area of Lambwe East,Southwestern Kenya.

Absorbed dose rates around the North and South Ruri hills in Lambwe east, southwestern Kenya were measured using survey meters. The area lies roughly between latitudes 0°30'S and 1°00'S. It is bounded on the east by longitude 34°30'E and on the west by the shores of Lake Victoria and Winnam Gulf. The measured absorbed dose varies from 0.7 to 6.0 µGy h(-1), and the mean is 2.3 µGy h(-1). Assuming an outdoor occupancy factor of 0.4, the corresponding range and mean annual effective doses are 1.7-14.7 and 5.7 mSv, respectively. The average activity concentrations (ACs) of (232)Th, (226)Ra and (40)K in samples of soils and rocks from the area are 1397, 179 and 509 Bq kg(-1), respectively. Values of absorbed dose rates calculated from the ACs are general lower than those obtained from in situ measurements. Possible causes of these discrepancies were discussed in the paper.

Energy dispersive X-ray fluorescence analysis of mine waters from the Migori Gold Mining Belt in Southern Nyanza, Kenya.

Analyses of water samples from Mikei, Osiri, Masara and Macalder (Makalda) gold mines of the Migori gold mining belt of Southwestern Kenya were done to determine the level of heavy metals using the Energy Dispersive X-ray Fluorescence technique. The concentrations of the heavy metals were; copper (29.34 ± 5.01-14,975.59 ± 616.14 µg/L); zinc (33.69 ± 4.29-683.15 ± 32.93 µg/L); arsenic (958.16 ± 60.14-18,047.52 ± 175.00 µg/L) and lead (19.51 ± 5.5-214.53 ± 6.29 µg/L). High levels of arsenic and lead were noted. These heavy metals are not only dangerous to the lives of miners and the local inhabitants; they are also a threat to aquatic life since these waters finally find their way into Lake Victoria.

Multielemental analysis of Migori (Southwest, Kenya) artisanal gold mine ores and sediments by EDX-ray fluorescence technique: implications of occupational exposure and environmental impact.

The results of heavy element profiling of the gold ores and sediments associated with the artisanal gold mining activities of the Migori gold belt of Southwestern Nyanza, Kenya, were reported in this paper. The analysis was made to assess the occupational exposure of the miners as well as to investigate the environmental impact of toxic heavy metals. Gold ores and sediments from the artisanal gold processing were sampled in four artisanal gold mining areas: Osiri A, Osiri B, Mikei and Macalder (Makalda) and analyzed for heavy elemental content using (109)Cd radioisotope excited EDXRF spectrometry technique. Analysis consisted of direct irradiating of sample pellets. The concentrations of major elements detected were: titanium (711.41-10,766.67 mg/kg); cobalt (82.65-1,010.00 mg/kg); zinc (29.90-63,210 mg/kg); arsenic (29.30-8,246.59 mg/kg); gold (14.07-73.48 mg/kg); lead (16.31-14,999.40 mg/kg) and mercury (16.10-149.93 mg/kg). The average concentration of the heavy toxic metals i.e. arsenic, lead, titanium and zinc were found to be above 50 mg/Kg as recommended by World Health Organization.

Radiological survey and assessment of associated activity concentration of the naturally occurring radioactive materials (NORM) in the Migori artisanal gold mining belt of southern Nyanza, Kenya.

A radiological survey and assessment was carried out at selected sites (Osiri, Mikei, Masara and Macalder) in the Migori gold mines of southern Nyanza, Kenya to determine the levels of exposure of the artisanal miners to the naturally occurring radioactive materials (NORM) and dust. The activity concentrations of (40)K and the decay products of (232)Th and (226)Ra were obtained using an innovative method in single channel NaI(Tl) gamma-ray spectrometry. The counts for both the sample and the reference material in a specific window for a particular radionuclide were compared to arrive at the activity concentration of the radionuclide in the sample. Measurement of dust loading at various crushing sites was carried out by trapping the dust particles on a 0.45 µm cellulose acetate filter paper (47 mm diameter) using a vacuum pump. The activity concentration levels range widely 80-413, 12-145 and 21-258 Bq/kg for (40)K, (232)Th and (226)Ra, respectively. The calculated absorbed dose in air range from 16 to 178 nGy/h (with a mean of 42 nGy/h). Dust loading was found to range from 1.3 to 3.7 mg/m(3). Although the activity concentration of the radionuclides and the calculated annual absorbed dose is below the world's average, the dust level at the mines was relatively high. The results obtained show that the artisanal miners are exposed to various levels of radionuclides and dust and necessary precautions need to be taken.

Where do we go now with low molecular weight heparin use in obstetric care?

The use of low molecular weight heparins (LMWH) in obstetric care has grown considerably since their introduction into clinical practice in the early 1990s. However, because of the physiological changes of pregnancy, the predictable pharmacokinetic profile of LMWH is lost and some uncertainty exists around the optimal dosing regimen for LMWH in obstetric care. Two recent United Kingdom prospective surveys of the management of acute venous thromboembolism (VTE) suggest that despite recommendations from the Royal College of Obstetricians and Gynaecologists (RCOG) for a twice daily LMWH regimen, a once daily regimen is acceptable for the treatment of venous thromboembolism; and that accepted thromboprophylactic doses licensed for non-pregnant individuals may not be applicable during the second and third trimester for VTE thromboprophylaxis. Accepting that randomized clinical studies are difficult in obstetric care, future advances could be made through population-based multi-center studies, coupled with pharmacokinetic modeling studies, which have the potential to determine the optimal dosing regimen for the various obstetric indications.

An investigation of the repeatability of calibration factors in gamma-ray spectrometry of geological materials.

A NaI(Tl)-based gamma spectrometer for the analysis of geological materials was calibrated using the IAEA reference materials RGU-1, RGTH-1 and RGK-1. To simulate typical geological samples, two additional standards were prepared from aliquots of the three reference materials. The reproducibility of the instrument calibration factors (CFs) was tested by repeated measurements of the pure IAEA reference materials and the mixed samples in a reproducible counting geometry. The results were analysed using a two-way classification analysis of variance; it was found that the variance in the CFs is significantly higher between standards than it is between measurements. Allowance should be made for this when estimating uncertainties in measurements with the NaI(Tl) spectrometers.

Beneficial effects of combined thromboxane and leukotriene receptor antagonism in hemorrhagic shock.

OBJECTIVE: Both thromboxane A2 and peptide leukotrienes D4/E4 have been implicated in the pathophysiology of circulatory shock. In the present study, we evaluated the effect of thromboxane A2 and leukotriene D4/E4 receptor antagonism in circulatory shock. DESIGN: Prospective, randomized, controlled trial. SETTING: Research laboratory. SUBJECTS: Male Sprague-Dawley rats (325 to 375 g). INTERVENTIONS: The effect of selective receptor antagonists of thromboxane A2 (i.e., SQ-29,548) and leukotrienes D4/E4 (i.e., LY-171883) was investigated, either alone or in combination, in a model of hemorrhagic circulatory shock. Animals were randomly assigned to one of eight experimental groups: a) sham plus vehicle; b) sham plus LY-171883 (4 mg/kg); c) sham plus SQ-29,548 (2 mg/kg); d) sham plus SQ-29,548 (2 mg/kg) plus LY-171883 (4 mg/kg); e) hemorrhage plus vehicle; f) hemorrhage plus LY-171883 (4 mg/kg); g) hemorrhage plus SQ-29,548 (2 mg/kg); and h) hemorrhage plus SQ-29,548 (2 mg/kg) plus LY-171883 (4 mg/kg). Circulatory shock was induced by acute hemorrhage to a mean arterial pressure (MAP) of 45 mm Hg. We investigated the effect of SQ-29,548 and LY-171883 on the progression of circulatory shock. MEASUREMENTS AND MAIN RESULTS: Neither pharmacologic agent, alone or in combination, had any significant effect on MAP or heart rate in nonhemorrhaged rats. Both thromboxane receptor antagonism (p < .01) and combined thromboxane/leukotriene receptor antagonism (p < .001) significantly improved survival time after hemorrhage. However, leukotriene receptor antagonism alone did not significantly improve survival time after hemorrhage. After acute blood loss and 20% decompensation, the shed blood was returned to the animal; maximal postreinfusion blood pressures were not significantly different between experimental groups. The postreinfusion MAP was maintained at higher values in hemorrhaged rats given the thromboxane receptor antagonist or the combination of thromboxane and leukotriene receptor antagonists. Only the combined therapy significantly altered all of the measured indices of cardiovascular compensation (i.e., maximum bleed-out volume, time to maximum blood loss, and 20% decompensation time). Furthermore, only combined receptor antagonism resulted in a significant (p < .02) attenuation of plasma cathepsin D activity. CONCLUSIONS: The present findings support a role for thromboxane A2 and peptide leukotrienes D4/E4 as important mediators in circulatory shock and suggest that combined thromboxane/leukotriene receptor antagonism may have superior therapeutic efficacy to leukotriene receptor antagonism.

Chemical pathways of peptide degradation. VII. Solid state chemical instability of an aspartyl residue in a model hexapeptide.

The chemical stability of an Asp-hexapeptide (Val-Tyr-Pro-Asp-Gly-Ala) in lyophilized formulations was evaluated as a function of multiple formulation variables--specifically pH of the bulk solution, temperature, moisture content, and type of bulking agent (amorphous vs. crystalline). The disappearance of the starting Asp-hexapeptide in the solid state conformed to pseudo-first-order reversible kinetics. This type of degradation profile was accounted for by the product distribution. The factorial experimental design of this study allowed statistical analysis of the effects of individual formulation variable (main effects) as well as those of two-factor interactions on the degradation of the Asp-hexapeptide. Analysis of Variance (ANOVA) calculations of the main effects indicated that while the influence of pH of the starting solution was not statistically significant, residual moisture level, temperature, and, especially, type of bulking agent had a significant impact on the solid state chemical reactivity of the hexapeptide. Furthermore, depending on which type of excipient was used in the lyophilized formulations, residual moisture level and temperature could be important stability variables. These types of factorial experiments have proven to be useful in the rapid identification of significant formulation variables in a given system and, consequently, in optimization of formulations.

Evaluation of pain and irritation following local administration of parenteral formulations using the rat paw lick model.

Water miscible cosolvents in parenteral products generally increase pain and/or local irritation post injection. The goal of this study was to validate the usefulness of the rat paw lick model (Cleozzi et al., J. Pharmacol. Meth., 4, 1980, 285-289) in screening pain and local irritation with parenteral formulations. Paw licks were counted in 3 min. intervals, over a total period of 15 min., following subplantar injection of test formulations in the hind paw of rats. A dose-response relationship following the injection of solutions containing increasing concentrations of a known painful compound was used to validate the model. The results obtained from additional experiments were found to correlate closely to those obtained using other tests (e.g. in vitro hemoglobin release test, and in vivo creatine kinase release test in rabbits). It was found that: (a) the model is responsive to changes in the sensation of pain and/or irritation due to drug or non-active components; (b) the increase in propylene glycol or ethanol concentrations results in increased pain and/or local irritation, (c) the increase in the apparent pH of cosolvent-based formulations from 7.2 to > or = 10 may increase pain and/or local irritation, and (d) there is generally a "thresh-hold limit" between the concentration of painful component and the paw licks, which should be established for the component under evaluation. The data overall suggest that the rat paw lick model is a rapid and simple method for rapid screening of formulations for pain/irritation following local administration.