Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1.

Neonatal diabetes mellitus can be transient or permanent. The severe form of permanent neonatal diabetes mellitus can be associated with pancreas agenesis. Normal pancreas development is controlled by a cascade of transcription factors, where insulin promoter factor 1 (IPF1) plays a crucial role. Here, we describe two novel mutations in the IPF1 gene leading to pancreas agenesis. Direct sequence analysis of exons 1 and 2 of the IPF1 gene revealed two point mutations within the homeobox in exon 2. Genetic analysis of the parents showed that each mutation was inherited from one parent. Mutations localized in helices 1 and 2, respectively, of the homeodomain, decreased the protein half-life significantly, leading to intracellular IPF1 levels of 36% and 27% of wild-type levels. Both mutant forms of IPF1 were normally translocated to the nucleus, and their DNA binding activity on different known target promoters was similar to that of the wild-type protein. However, transcriptional activity of both mutant IPF1 proteins, alone or in combination with HNF3 beta/Foxa2, Pbx1, or the heterodimer E47-beta 2 was reduced, findings accounted for by decreased IPF1 steady state levels and not by impaired protein-protein interactions. We conclude that the IPF1 level is critical for human pancreas formation.

Human mercury exposure associated with small-scale gold mining in Burkina Faso.

PURPOSE: In Burkina Faso, gold ore is one of the main sources of income for an important part of the active population. Artisan gold miners use mercury in the extraction, a toxic metal whose human health risks are well known. The aim of the present study was to assess mercury exposure as well as to understand the exposure determinants of gold miners in Burkinabe small-scale mines.METHODS: The examined gold miners' population on the different selected gold mining sites was composed by persons who were directly and indirectly related to gold mining activities. But measurement of urinary mercury was performed on workers most susceptible to be exposed to mercury. Thus, occupational exposure to mercury was evaluated among ninety-three workers belonging to eight different gold mining sites spread in six regions of Burkina Faso. Among others, work-related exposure determinants were taken into account for each person during urine sampling as for example amalgamating or heating mercury. All participants were medically examined by a local medical team in order to identify possible symptoms related to the toxic effect of mercury.RESULTS: Mercury levels were high, showing that 69% of the measurements exceeded the ACGIH (American Conference of Industrial Hygienists) biological exposure indice (BEI) of 35 µg per g of creatinine (µg/g-Cr) (prior to shift) while 16% even exceeded 350 µg/g-Cr. Basically, unspecific but also specific symptoms related to mercury toxicity could be underlined among the persons who were directly related to gold mining activities. Only one-third among the studied subpopulation reported about less than three symptoms possibly associated to mercury exposure and nearly half of them suffered from at least five of these symptoms. Ore washers were more involved in the direct handling of mercury while gold dealers in the final gold recovery activities. These differences may explain the overexposure observed in gold dealers and indicate that the refining process is the major source of exposure.CONCLUSIONS: This study attests that mercury exposure still is an issue of concern. North-South collaborations should encourage knowledge exchange between developing and developed countries, for a cleaner artisanal gold mining process and thus for reducing human health and environmental hazards due to mercury use.

Long circulating half-life and high tumor selectivity of the photosensitizer meta-tetrahydroxyphenylchlorin conjugated to polyethylene glycol in nude mice grafted with a human colon carcinoma.

In a mode of nude mice bearing a human colon carcinoma xenograft, the biodistribution and tumor localization of metatetrahydroxyphenylchlorin (m-THPC) coupled to polyethylene glycol (PEG) were compared with those of the free form of this photosensitizer used in photodynamic therapy (PDT). At different times after i.v. injection of both forms of 125I-labeled photosensitizer, m-THPC-PEG gave on average a 2-fold higher tumor uptake than free m-THPC. In addition, at early times after injection, m-THPC-PEG showed a 2-fold longer blood circulating half-life and a 4-fold lower liver uptake than free m-THPC. The tumor to normal tissue ratios of radioactivity concentrations were always higher for m-THPC-PEG than for free m-THPC at any time point studied from 2 to 96 hr post-injection. Significant coefficients of correlation between direct fluorescence measurements and radioactivity counting were obtained within each organ tested. Fluorescence microscopy studies showed that m-THPC-PEG was preferentially localized near the tumor vessels, whereas m-THPC was more diffusely distributed inside the tumor tissue. To verify whether m-THPC-PEG conjugate remained phototoxic in vivo, PDT experiments were performed 72 hr after injection and showed that m-THPC-PEG was as potent as free m-THPC in the induction of tumor regression provided that the irradiation does for m-THPC-PEG conjugate was adapted to a well-tolerated 2-fold higher level. The overall results demonstrate first the possibility of improving the in vivo tumor localization of a hydrophobic dye used for PDT by coupling it to PEG and second that a photosensitizer conjugated to a macromolecule can remain phototoxic in vivo.

A half century retrospective study of homicide-suicide in Geneva--Switzerland: 1956-2005.

This study provides a retrospective review from the forensic files of the University Centre of Legal Medicine in Western Switzerland in Geneva, from January 1956 to December 2005. The studied homicide-suicide cases cover a period of half a century (50 years). As a rule, all police-ordered forensic examinations of violent death cases in the Canton of Geneva are conducted by the University Centre of Legal Medicine. All of the data necessary for an exhaustive retrospective study are thus readily available. During the period covered in this work, 228 homicides were perpetrated in Geneva. In 23 cases, the homicide was followed by the suicide of the aggressor. The 34 victims of these homicides (18 women, 1 man and 15 children) had either an intimate or filial relationship with the perpetrator. Most of the suicidal perpetrators were men that killed their spouses or intimate partners, with children as additional victims in some cases. Shooting was the most common means to kill, followed by stabbing. The majority of the victims and perpetrators were Swiss nationals. This retrospective study shows that in the last 50 years, homicide-suicide cases in the Canton of Geneva have been a rare and an episodic phenomena with a very variable frequency from 1 year to another.

Single-metal deposition: optimization of this fingermark enhancement technique

Following the introduction of single-metal deposition (SMD), a simplified fingermark detection technique based on multimetal deposition, optimization studies were conducted. The different parameters of the original formula were tested and the results were evaluated based on the contrast and overall aspect of the enhanced fingermarks. The new formula for SMD was found based on the most optimized parameters. Interestingly, it was found that important variations from the base parameters did not significantly affect the outcome of the enhancement, thus demonstrating that SMD is a very robust technique. Finally, a comparison of the optimized SMD with multi-metal deposition (MMD) was carried out on different surfaces. It was demonstrated that SMD produces comparable results to MMD, thus validating the technique.

Reconstruction of metal pollution and recent sedimentation processes in Havana Bay (Cuba): A tool for coastal ecosystem management.

Since 1998 the highly polluted Havana Bay ecosystem has been the subject of a mitigation program. In order to determine whether pollution-reduction strategies were effective, we have evaluated the historical trends of pollution recorded in sediments of the Bay. A sediment core was dated radiometrically using natural and artificial fallout radionuclides. An irregularity in the (210)Pb record was caused by an episode of accelerated sedimentation. This episode was dated to occur in 1982, a year coincident with the heaviest rains reported in Havana over the XX century. Peaks of mass accumulation rates (MAR) were associated with hurricanes and intensive rains. In the past 60 years, these maxima are related to strong El Niño periods, which are known to increase rainfall in the north Caribbean region. We observed a steady increase of pollution (mainly Pb, Zn, Sn, and Hg) since the beginning of the century to the mid 90s, with enrichment factors as high as 6. MAR and pollution decreased rapidly after the mid 90s, although some trace metal levels remain high. This reduction was due to the integrated coastal zone management program introduced in the late 90s, which dismissed catchment erosion and pollution.

Retention half times in the skeleton of plutonium and 90Sr from above-ground nuclear tests: a retrospective study of the Swiss population.

Plutonium and (90)Sr are considered to be among the most radiotoxic nuclides produced by the nuclear fission process. In spite of numerous studies on mammals and humans there is still no general agreement on the retention half time of both radionuclides in the skeleton in the general population. Here we determined plutonium and (90)Sr in human vertebrae in individuals deceased between 1960 and 2004 in Switzerland. Plutonium was measured by sensitive SF-ICP-MS techniques and (90)Sr by radiometric methods. We compared our results to the ones obtained for other environmental compartments to reveal the retention half time of NBT fallout (239)Pu and (90)Sr in trabecular bones of the Swiss population. Results show that plutonium has a retention half time of 40+/-14 years. In contrast (90)Sr has a shorter retention half time of 13.5+/-1.0 years. Moreover (90)Sr retention half time in vertebrae is shown to be linked to the retention half time in food and other environmental compartments. These findings demonstrate that the renewal of the vertebrae through calcium homeostatic control is faster for (90)Sr excretion than for plutonium excretion. The precise determination of the retention half time of plutonium in the skeleton will improve the biokinetic model of plutonium metabolism in humans.

Uranium-enrichment in soils and plants in the vicinity of a pitchblende vein at La Creusaz-Les Marecottes (W of Martigny, Valais, Switzerland)

In the NE part of the Aiguilles Rouges Massif near Martigny, at the eastern contact of the Variscan Vallorcine granite to adjacent gneisses, a series of pitchblende (UO2)-veins occur. This paper determines the level of enrichment and mobility of uranium in soils situated in the vicinity of such a UO2-vein 7 km west of Martigny. Within an area of 50 x 100 m, situated on a relatively steep slope and characterized by a strong gramma-ray anomaly, six soil profiles including their plant cover and a reference soil profile outside the influence of the UO2-vein have been examined. The soil shows pH-values between 4 and 5 and is colluvial. The applied analytical methods for the metal contents include extraction methods, common for soil studies, and bulk analysis performed with X-ray fluorescence and ICP-MS. Uranium contents found in the uppermost 20 cm of the soil profiles vary from 2,500 ppm close to the vein to 15 ppm at the lowermost point of the study area. The reference soil has around 3 ppm uranium. At greater depth (20 to 40 cm) the U-content decreases to about half of the surface values, indicating a vertical transport of uranium within the soil profile. No systematic dependance of uranium-contents to grain size (amount of clay) nor to the amount of organic matter has been found. However, the good correlation between uranium and free iron oxide concentration suggests adsorption of uranium on iron oxy-hydroxides. The ashes of grass and mosses contain up to 90 ppm U, the blueberry and redwood only up to 3 ppm. Our observations suggest that at the surface the uranium is transported by downhill creep (solifluxion) of uranium-rich rock fragments. Liberated by oxidation of the uppermost fragments in a given soil column, the uranium migrates vertically until the conditions are favourable to adsorption onto Fe-oxy-hydroxides. However, as high U-contents of local surface water show, this adsorption does not lead to a significant retention of the uranium.

10-year follow-up of a prospective randomized trial comparing bare-metal stenting with internal mammary artery grafting for proximal, isolated de novo left anterior coronary artery stenosis the SIMA (Stenting versus Internal Mammary Artery grafting) trial

OBJECTIVES: This study was designed to compare the long-term clinical outcome of coronary artery bypass grafting (CABG) with intracoronary stenting of patients with isolated proximal left anterior descending coronary artery. BACKGROUND: Although numerous trials have compared coronary angioplasty with bypass surgery, none assessed the clinical evaluation in the long term. METHODS: We evaluated the 10-year clinical outcome in the SIMA (Stent versus Internal Mammary Artery grafting) trial. Patients were randomly assigned to stent implantation versus CABG. RESULTS: Of 123 randomized patients, 59 underwent CABG and 62 received a stent (2 patients were excluded). Follow-up after 10 years was obtained for 98% of the randomized patients. Twenty-six patients (42%) in the percutaneous coronary intervention group and 10 patients (17%) in the CABG group reached an end point (p < 0.001). This difference was due to a higher need for additional revascularization. The incidences of death and myocardial infarction were identical at 10%. Progression of the disease requiring additional revascularization was rare (5%) and was similar for the 2 groups. Stent thrombosis occurred in 2 patients (3%). Angina functional class showed no significant differences between the 2 groups. CONCLUSIONS: Both stent implantation and CABG are safe and highly effective in relieving symptoms in patients with isolated, proximal left anterior descending coronary artery stenosis. Stenting with bare-metal stents is associated with a higher need for repeat interventions. The long-term prognosis for these patients is excellent with either mode of revascularization.

Concentration-dependent half-lives of polychlorinated biphenyl in sera from an occupational cohort.

Polychlorinated biphenyls (PCBs) are carcinogenic. Estimating PCB half-life in the body based on levels in sera from exposed workers is complicated by the fact that occupational exposure to PCBs was to commercial PCB products (such as Aroclors 1242 and 1254) comprised of varying mixtures of PCB congeners. Half-lives were estimated using sera donated by 191 capacitor manufacturing plant workers in 1976 during PCB use (1946-1977), and post-exposure (1979, 1983, and 1988). Our aims were to: (1) determine the role of covariates such as gender on the half-life estimates, and (2) compare our results with other published half-life estimates based on exposed workers. All serum PCB levels were adjusted for PCB background levels. A linear spline model with a single knot was used to estimate two separate linear equations for the first two serum draws (Equation A) and the latter two (Equation B). Equation A gave half-life estimates of 1.74 years and 6.01 years for Aroclor 1242 and Aroclor 1254, respectively. Estimates were 21.83 years for Aroclor 1242 and 133.33 years for Aroclor 1254 using Equation B. High initial body burden was associated with rapid PCB elimination in workers at or shortly after the time they were occupationally exposed and slowed down considerably when the dose reached background PCB levels. These concentration-dependent half-life estimates had a transition point of 138.57 and 34.78 ppb for Aroclor 1242 and 1254, respectively. This result will help in understanding the toxicological and epidemiological impact of exposure to PCBs in humans.

The metal ion binding protein Cnnm4 is mutated in rod-cone dystrophy/amelogenesis imperfecta syndrome

Purpose:To identify the gene causing rod-cone dystrophy/amelogenesis imperfecta Methods:Homozygosity mapping was performed using the Affymetrix 50K XbaI array in one family and candidate genes in the linked interval were sequenced with ABI Dye Terminator, vers. 1 in the index patient of 3 families. The identified mutations were screened in normal control individuals. Expression analyses were performed on RNA extracted from the brain, various parts of the eye and teeth; immunostaining was done on mouse eyes and jaw and knock-down experiments were carried out in zebrafish embroys. Results:Sequencing the coding regions of ancient conserved domain protein 4 (CNNM4), a metal ions transporter, revealed a 1-base pair duplication (p.L438fs) in family A, a p.R236Q mutation in family B and a p.L324P in family C. All these mutations were homozygous and involved very conserved amino acids in paralogs and orthologs. Immunostaining and RT-PCR confirmed that CNNM4 was strongly expressed in various parts of the eye and in the teeth. Morpholino experiments in zebrafish showed a loss of ganglion cells at 5 days post fertilization. Conclusions:The rod-cone dystrophy/amelogenesis imperfecta syndrome is caused by mutation in CNNM4 and is due to aberrant metal ion homeostasis.