It is increasingly clear that inflammation-associated mechanisms can affect breast cancer progression and modulate response to treatment. Estrogen receptor alpha (ER?) is the principal biomarker and therapeutic target for endocrine therapies in breast cancer. Over 70% of patients are ER? positive at diagnosis and are candidates for endocrine therapy. However, ER? positive tumors can become resistant to endocrine therapy. Multiple mechanisms of endocrine resistance have been proposed including ER? suppression. This review discusses the relationship between intratumoral inflammation and endocrine resistance with a particular focus on inflammation-mediated suppression of ER?.
Conventional management of debilitating pediatric scar contractures, including hand therapy and surgery, may often be beset by delayed treatment, suboptimal results, and additional surgical morbidity. Ablative fractional laser resurfacing is an emerging adjunctive procedural option for scar contractures because of its promising efficacy and safety profile. However, its use to improve function has not been studied in the pediatric population. Herein we report 2 pediatric patients with recalcitrant scar contractures, causing persistent functional deficits, treated with an ablative fractional laser protocol. Both patients experienced rapid and cumulative subjective and objective improvements in range of motion and function as measured by an independent occupational therapist without reported complications. We highlight ablative fractional laser resurfacing as a novel and promising tool in the management of function-limiting scar contractures in children and propose that the technique be incorporated into existing scar treatment paradigms, guided by future research.
Human fecal contamination of surface waters and drains is difficult to diagnose. DNA-based and chemical analyses of water samples can be used to specifically quantify human waste contamination, but their expense precludes routine use. We evaluated canine scent tracking, using two dogs trained to respond to the scent of municipal wastewater, as a field approach for surveying human fecal contamination. Fecal indicator bacteria, as well as DNA-based and chemical markers of human waste, were analyzed in waters sampled from canine scent-evaluated sites (urban storm drains and creeks). In the field, the dogs responded positively (70% and 100%) at sites for which sampled waters were then confirmed as contaminated with human waste. When both dogs indicated a negative response, human waste markers were absent. Overall, canine scent tracking appears useful for prioritizing sampling sites for which DNA-based and similarly expensive assays can confirm and quantify human waste contamination.
Elevated levels of fecal indicator bacteria (FIB), including Escherichia coli and enterococci, trigger coastal beach advisories and signal public health risks. Solving FIB pollution in suburban coastal watersheds is challenging, as there are many potential sources. The Arroyo Burro watershed in Santa Barbara, CA is an example, with its popular, but chronically FIB-contaminated beach. To address, a microbial source tracking study was performed. Surface waters were sampled over 2 years, FIB were quantified, and DNA was analyzed for host-associated fecal markers. Surf zone FIB were only elevated when the coastal lagoon was discharging. Among the fecal sources into the lagoon, including upstream human sources and coastal birds, canines were the most important. Canine sources included input via upstream creek water, which decreased after creek-side residences were educated about proper pet waste disposal, and direct inputs to the lagoon and surf zone, where dog waste could have been tidally exchanged with the lagoon. Based on this study, canine waste can be an influential, yet controllable, fecal source to suburban coastal beaches.
This article describes how hand therapy for pediatric patients can be enhanced through the use of play with everyday items. Playful activities integrate purposeful hand skills of pinch, grasp and manipulation, while encouraging the child to fully participate in therapy and home programs. By referring to Takata's developmental hierarchy of play, therapists can design the sessions to include novel, fun and age appropriate activities. The author offers eight sample activities for specific therapy goals utilizing inexpensive, everyday items.
Manganese (Mn) is a common neurotoxicant associated with a clinical syndrome that includes signs and symptoms referable to the basal ganglia. Despite many advances in understanding the pathophysiology of Mn neurotoxicity in humans, with molecular and structural imaging techniques, only a few case reports describe the associated pathological findings, and all are in symptomatic subjects exposed to relatively high-level Mn. We performed an exploratory, neurohistopathological study to investigate the changes in the corpus striatum (caudate nucleus, putamen, and globus pallidus) associated with chronic low-level Mn exposure in South African Mn mine workers. Immunohistochemical techniques were used to quantify cell density of neuronal and glial components of the corpus striatum in eight South African Mn mine workers without clinical evidence of a movement disorder and eight age-race-gender matched, non-Mn mine workers. There was higher mean microglia density in Mn mine workers than non-Mn mine workers in the globus pallidus external and internal segments [GPe: 1.33 and 0.87 cells per HPF, respectively (p=0.064); GPi: 1.37 and 0.99 cells per HPF, respectively (p=0.250)]. The number of years worked in the Mn mines was significantly correlated with microglial density in the GPi (Spearmans rho 0.886; p=0.019). The ratio of astrocytes to microglia in each brain region was lower in the Mn mine workers than the non-Mn mine workers in the caudate (7.80 and 14.68; p=0.025), putamen (7.35 and 11.11; p=0.117), GPe (10.60 and 16.10; p=0.091) and GPi (9.56 and 12.42; p=0.376). Future studies incorporating more detailed occupational exposures in a larger sample of Mn mine workers will be needed to demonstrate an etiologic relationship between Mn exposure and these pathological findings.
Environmentally acquired asbestos-related diseases (ARDs) are of concern globally. In South Africa, there is widespread contamination of the environment due to historical asbestos mining operations that were poorly regulated. Although the law makes provision for the compensation of occupationally acquired ARDs, compensation for environmentally acquired ARDs is only available through the Asbestos Relief Trust (ART) and Kgalagadi Relief Trust, both of which are administered by the ART. This study assessed ARDs and compensation outcomes of environmental claims submitted to the Trusts.
High fecal indicator bacterial (FIB) concentrations signal urban coastal water quality impairments that can threaten public health. However, FIB (total and fecal coliform plus Enterococcus sp.) concentrations are not specific to human waste, and thus, microbial source tracking (MST) is employed to assess public health risks and remediation alternatives. Currently, water quality diagnosis requires several simultaneous MST assays. Relatively unexplored is a community analysis approach for MST where the overall microbial community composition is compared, through multivariate analysis, to link sources and sinks of microbial pollution. In this research, an urban coastal creek and drain sampling transect, previously diagnosed as human-waste-contaminated, were evaluated for bacterial community composition relative to fecal sources; a laboratory spiking study was also performed to assess method sensitivity and specificity. Multivariate statistical analysis of community profiles clearly distinguished different fecal sources, indicated a high sensitivity for sewage spikes, and confirmed creek contamination sources. This work demonstrates that molecular microbial community analysis combined with appropriate multivariate statistical analyses is an effective addition to the MST tool box.
Separating storm drains and sanitary sewers is expected to control sewage pollution, for example, from combined sewer overflows, and to reduce excessive stormwater flow to wastewater treatment plants. However, sewage contamination has been found in such separated storm drain systems in urban areas during dry-weather flow. To determine whether transmission of sewage is occurring from leaking sanitary sewers directly to leaking separated storm drains, field experiments were performed in three watersheds in Santa Barbara, CA. Areas with high and low risks for sewage exfiltration into storm drains were identified, and rhodamine WT (RWT) dye pulses were added to the sanitary sewers. RWT was monitored in nearby storm drain manholes using optical probes set up for unattended continuous monitoring. Above-background RWT peaks were detected in storm drains in high-risk areas, and multiple locations of sewage contamination were found. Sewage contamination during the field studies was confirmed using the human-specific Bacteroidales HF183 and Methanobrevibacter smithii nifH DNA markers. This study is the first to provide direct evidence that leaking sanitary sewers can directly contaminate nearby leaking storm drains with untreated sewage during dry weather and suggests that chronic sanitary sewer leakage contributes to downstream fecal contamination of coastal beaches.
Asbestos is associated with South African diamond mines due to the nature of kimberlite and the location of the diamond mines in relation to asbestos deposits. Very little is known about the health risks in the diamond mining industry. The objective of this study was to explore the possibility of asbestos exposure during the process of diamond mining.
South African miners face an epidemic of occupational lung diseases. Despite a plethora of research on the mining industry, and the gold mining industry in particular, research impact (including disease surveillance) on policy implementation and occupational health systems performance lags. We describe the gold mining environment, and research on silicosis, tuberculosis, HIV and AIDS, and compensation for occupational disease including initiatives to influence policy and thus reduce dust levels and disease. As these have been largely unsuccessful, we identify possible impediments, some common to other low- and middle-income countries, to the translation of research findings and policy initiatives into effective interventions.
Microbiological contamination from runoff is a human health concern in urbanized coastal environments, but the contamination sources are often unknown. This study quantified fecal indicator bacteria and compared the distributions of human-specific genetic markers and bacterial community composition during dry and wet weather in urban creeks draining two neighboring watersheds in Santa Barbara, CA. In a prior study conducted during exclusively dry weather, the creeks were contaminated with human waste as indicated by elevated numbers of the human-specific Bacteroidales marker HF183 (Sercu et al. in Environ Sci Technol 43:293-298, 2009). During the storm, fecal indicator bacterial numbers and loads increased orders of magnitude above dry weather conditions. Moreover, bacterial community composition drastically changed during rainfall and differed from dry weather flow by (1) increased bacterial diversity, (2) reduced spatial heterogeneity within and between watersheds, and (3) clone library sequences more related to terrestrial than freshwater taxa. Finally, the spatial patterns of human-associated genetic markers (HF183 and Methanobrevibacter smithii nifH gene) changed during wet weather, and the contribution of surface soils to M. smithii nifH gene detection was suspected. The increased fecal indicator bacteria numbers during wet weather were likely associated with terrestrial sources, instead of human waste sources that dominated during dry weather flow.
Traditional tuberculosis (TB) treatment outcome measures, such as cure rate, do not provide insight into the underlying reasons for missing clinical targets. We evaluated a TB Process-Based Performance Review (TB-PBPR) tool, developed to identify "missed opportunities" for timely and accurate diagnosis of TB. The tool enables performance assessment at the level of process and quality of care.
Components of promyelocytic leukaemia (PML) nuclear bodies (ND10) are recruited to sites associated with herpes simplex virus type 1 (HSV-1) genomes soon after they enter the nucleus. This cellular response is linked to intrinsic antiviral resistance and is counteracted by viral regulatory protein ICP0. We report that the SUMO interaction motifs of PML, Sp100 and hDaxx are required for recruitment of these repressive proteins to HSV-1 induced foci, which also contain SUMO conjugates and PIAS2?, a SUMO E3 ligase. SUMO modification of PML and elements of its tripartite motif (TRIM) are also required for recruitment in cells lacking endogenous PML. Mutants of PML isoform I and hDaxx that are not recruited to virus induced foci are unable to reproduce the repression of ICP0 null mutant HSV-1 infection mediated by their wild type counterparts. We conclude that recruitment of ND10 components to sites associated with HSV-1 genomes reflects a cellular defence against invading pathogen DNA that is regulated through the SUMO modification pathway.
The mortality rate from unnatural deaths for South Africa is nearly double the world average. Reliable data are limited by inaccurate and incomplete ascertainment of specific causes of unnatural death. This study describes trends in causes of unnatural death between 1992 and 2008 in a cohort of South African miners.
Intrinsic antiviral resistance mediated by constitutively expressed cellular proteins is one arm of defence against virus infection. Promyelocytic leukaemia nuclear bodies (PML-NBs, also known as ND10) contribute to host restriction of herpes simplex virus type 1 (HSV-1) replication via mechanisms that are counteracted by viral regulatory protein ICP0. ND10 assembly is dependent on PML, which comprises several different isoforms, and depletion of all PML isoforms decreases cellular resistance to ICP0-null mutant HSV-1. We report that individual expression of PML isoforms I and II partially reverses the increase in ICP0-null mutant HSV-1 plaque formation that occurs in PML-depleted cells. This activity of PML isoform I is dependent on SUMO modification, its SUMO interaction motif (SIM), and each element of its TRIM domain. Detailed analysis revealed that the punctate foci formed by individual PML isoforms differ subtly from normal ND10 in terms of composition and/or Sp100 modification. Surprisingly, deletion of the SIM motif from PML isoform I resulted in increased colocalisation with other major ND10 components in cells lacking endogenous PML. Our observations suggest that complete functionality of PML is dependent on isoform-specific C-terminal sequences acting in concert.
Monitoring microbiological water quality is important for protecting water resources and the health of swimmers. Routine monitoring relies on cultivating fecal indicator bacteria (FIB), frequently using defined substrate technology. Defined substrate technology is designed to specifically enrich for FIB, but a complete understanding of the assay microbiology requires culture-independent analysis of the enrichments. This study aimed to identify bacteria in positive wells of Colilert and Enterolert Quanti-Tray/2000 (IDEXX Laboratories) FIB assays in environmental water samples and to quantify the degree of false-positive results for samples from an urban creek by molecular methods. Pooled Escherichia coli- and Enterococcus-positive Quanti-Tray/2000 enrichments, either from urban creek dry weather flow or municipal sewage, harbored diverse bacterial populations based on 16S rRNA gene sequences and terminal restriction fragment length polymorphism analyses. Target taxa (coliforms or enterococci) and nontarget taxa (Vibrio spp., Shewanella spp., Bacteroidetes, and Clostridium spp.) were identified in pooled and individual positive Colilert and Enterolert wells based on terminal restriction fragments that were in common with those generated in silico from clone sequences. False-positive rates of between 4 and 23% occurred for the urban creek samples, based on the absence of target terminal restriction fragments in individual positive wells. This study suggests that increased selective inhibition of nontarget bacteria could improve the accuracy of the Colilert and Enterolert assays.
Nanoparticles are being used in ever increasing numbers in a range of industrial and medical products. Questions surrounding their potential to cause toxic effects in humans have been raised. Although animal experiments predict that nanoparticles are more toxic than their larger counterparts there are few descriptions in the literature of human exposure. A case described in 1994 has been re-examined from a pathology perspective. The subject, a 38-year-old previously healthy male, inhaled nanoparticles of nickel while spraying nickel onto bushes for turbine bearings using a metal arc process. He died 13 days after being exposed and the cause of death at autopsy was adult respiratory distress syndrome (ARDS). Nickel particles <25 nm in diameter were identified in lung macrophages using transmission electron microscopy. High levels of nickel were measured in his urine and his kidneys showed evidence of acute tubular necrosis.
The amphibole asbestos, anthophyllite, is associated with asbestos-related disease in humans, along with mesothelioma in animal models. In humans, however, there are only three cases of histologically proven malignant mesothelioma of the pleura associated with anthophyllite that have been documented in the English-language literature. A fourth case is presented in a man who lived in South Africa and had anthophyllite in his lung. Anthophyllite was never commercially mined in South Africa. Using scanning electron microscopy, his lung fibre burden was calculated to be 358,000 fibres and 31,000 asbestos bodies per gram of dry weight of lung tissue. The mean aspect ratio of the anthophyllite fibres in the lung was 41.2 (SD = 28.8). No other types of asbestos were detected in the lung. His exposure was almost certainly occupational. He worked in the plastic manufacturing industry and was exposed to talc and asbestos blankets that were used to insulate machinery.
In a cohort of 1950 HIV-positive men with known dates of HIV seroconversion, 399 developed tuberculosis. Mortality rates following tuberculosis were greatly increased (hazard ratio, adjusted for age at seroconversion, 4.7, 95% confidence interval 3.7-6.1), and this ratio was similar at different times following seroconversion. Overall mortality was similar to that in western seroconverter cohorts with much lower rates of tuberculosis, suggesting that tuberculosis is more a marker of HIV progression than a cause of it.
The herpes simplex virus type 1 (HSV-1) UL25 gene encodes a minor capsid protein, pUL25, that is essential for packaging the full-length viral genome. Six regions which contain disordered residues have been identified in the high-resolution structure of pUL25. To investigate the significance of these flexible regions, a panel of plasmids was generated encoding mutant proteins, with each member lacking the disordered residues in one of the six regions. In addition, UL25 constructs were produced, which specified proteins that contained missense mutations individually affecting two of the four regions on the surface of pUL25 predicted from evolutionary trace analysis to be important in protein-protein interactions. The impacts of these mutations on viral DNA packaging, virus assembly, and growth were examined. Of the nine mutant proteins analyzed, five failed to complement the growth of a UL25 deletion mutant in Vero cells. These noncomplementing proteins fell into three classes. Proteins in one class did not alter the DNA packaging phenotype of an HSV-1 UL25 deletion mutant, whereas proteins from the other two classes allowed the UL25 null mutant to package full-length viral DNA. Subsequent analysis of the latter classes of mutant proteins demonstrated that one class enabled the null virus to release enveloped virus particles from U2OS cells, whereas the other class prevented egress of mature HSV-1 capsids from the nucleus. These findings reveal a new role for pUL25 in virion assembly, consistent with its flexible structure and location on the capsid.
S100A7 (psoriasin) is a calcium- and zinc-binding protein implicated in breast cancer. We have shown previously that S100A7 enhances survival mechanisms in breast cells through an interaction with c-jun activation domain binding protein 1 (Jab1), and an engineered S100A7 triple mutant (Asp(56)Gly, Leu(78)Met, and Gln(88)Lys-S100A7(3)) ablates Jab1 binding. We extend these results to include defined breast cancer cell lines and demonstrate a disrupted S100A7(3)/Jab1 phenotype is maintained. To establish the basis for the abrogated Jab1 binding, we have recombinantly produced S100A7(3), demonstrated that it retains the ability to form an exceptionally thermostable dimer, and solved the three dimensional crystal structure to 1.6 A. Despite being positioned at the dimer interface, the Leu(78)Met mutation is easily accommodated and contributes to a methionine-rich pocket formed by Met(12), Met(15), and Met(34). In addition to altering the surface charge, the Gln(88)Lys mutation results in a nearby rotameric shift in Tyr(85), leading to a substantially reorganized surface cavity and may influence zinc binding. The final mutation of Asp(56) to Gly results in the largest structural perturbation shortening helix IV by one full turn. It is noteworthy that position 56 lies in one of two divergent clusters between S100A7 and the functionally distinct yet highly homologous S100A15. The structure of S100A7(3) provides a unique perspective from which to characterize the S100A7-Jab1 interaction and better understand the distinct functions between S100A7, and it is closely related paralog S100A15.
S100A7 (psoriasin) is a member of the S100 family of signaling proteins. It is implicated in and considered a therapeutic target for inflammation and cancer, yet no small molecule ligands for S100A7 have been identified. To begin the development of specific small molecule inhibitors of S100A7 function, we have used a series of surface binding fluorescent dyes to probe the surface hydrophobic sites. Two naphthalene-based dyes (2,6-ANS and 1,8-ANS) were found to bind S100A7 in a distinct cleft. We characterized the binding interaction by determining both the structure of S100A7 bound to 2,6-ANS and the structure of S100A7 bound to 1,8-ANS to 1.6 A. In both cases, two molecules of dye were docked such that the naphthalene groups were positioned in two symmetry-related grooves that are formed by the N-terminal helices of each monomer. We observed that Met12 acts as a gatekeeper to the binding cleft, adopting an "open" conformation for the more elongated 2,6-ANS while remaining in a "closed" conformation for the more compact 1,8-ANS. Steady-state fluorescence experiments revealed that S100A7 binds two copies of 2,6-ANS, each with a K(d) of 125 muM. Time-resolved fluorescence lifetime measurements indicated that the two molecules of 2,6-ANS bind in two independent binding sites with different fluorescence lifetimes, suggesting that the S100A7 homodimer is not perfectly symmetric in solution. Isothermal titration calorimetry studies demonstrate that S100A7 has a higher affinity for 2,6-ANS than 1,8-ANS. Yeast two-hybrid studies were also used to probe contributions of individual residues of an S100A7 triple mutant with respect to Jab1 binding. Mutation of Leu78, which forms part of the Met12 cleft occupied by 2,6-ANS, reduced the level of Jab1 binding, suggesting a potentially important role for the Met12 hydrophobic pocket in defining a Jab1 interface. Additional Y2H studies also delineate contributions of Gln88 and in particular Asp56 that shows the most significant abrogated binding to Jab1. Collectively, these data suggest a complex interaction between S100A7 and the much larger Jab1. These studies form the basis for the development of small molecule reporters and modifiers of S100A7 form and function.
The association of paraneoplastic hypoglycemia [Doege-Potter syndrome] and finger clubbing [Pierre-Marie-Bamberg syndrome] with pleural solitary fibrous tumour is rare. We present a previously unpublished but typical example of this rare occurrence together with a detailed updated literature review of previously published cases of pleural SFT discussing the histopathology of SFT; pathophysiology of the hypoglycemia and finger clubbing; treatment and outcome of pleural SFT. The patient, a 57-year-old African male was admitted at our hospital with recurrent episodes of hypoglycemia. He was found to have digital clubbing and decreased breath sounds in the right lower chest but no other significant clinical findings. His insulin level measured during an episode of hypoglycemia was undetectable. Chest radiograph and CT-scan revealed a lobulated mass in the right chest which was diagnosed to be SFT on histology. Surgical excision of the mass resulted in cure of the hypoglycemic episodes and rapid regression of the clubbing. Less than 65 cases of pleural SFT manifesting with hypoglycemia with or without finger-clubbing have been published in the English literature. The mean diameter of these tumours manifesting with hypoglycemia is 20 cm, 54% being benign while 42% were malignant. They predominantly present in the 6th-8th decade, average age of 64 years and a slight male preponderance at 58%. Complete surgical resection remains the most important predictor of clinical outcome in terms of recurrence and metastases, while providing instant cure for the hypoglycemia and rapid resolution of the finger clubbing.
Coastal urbanized areas in Southern California experience frequent beach water quality warnings in summer due to high concentrations of fecal indicator bacteria (FIB). Remediation can be difficult, as sources are often unknown. During two summers, we sampled three urbanized watersheds in Santa Barbara, CA at sites with historically high FIB concentrations to determine if human fecal matter was influencing water quality. By quantification of a human-specific Bacteroides marker (HBM), human waste was evidenced throughout both transects, and concentrations were highest in the discharges of several flowing storm drains. The HBM concentrations in storm drain discharges varied by up to 5 orders of magnitude on the same day. While the exact points of entry into the storm drain systems were not definitively determined, further inspection of the drain infrastructure suggested exfiltrating sanitary sewers as possible sources. The HBM and FIB concentrations were not consistently correlated, although the exclusive occurrence of high HBM concentrations with high FIB concentrations warrants the use of FIB analyses for a first tier of sampling. The association of human fecal pollution with dry weather drainage could be a window into a larger problem for other urbanized coastal areas with Mediterranean-type climates.
In earwigs, the male reproductive system is complex, comprising accessory glands and long dual intromittent organs for transfer of materials to the female and for removal of rival sperm. We investigated potential factors altering contractions of the male reproductive tracts in vitro. Tracts from 0-day (newly emerged) males displayed relatively little motility in vitro; however, those from 5-day (intermediate stage of sexual maturity) and 8-day (fully mature) males pulsed vigorously. Both 1 and 100 nM proctolin (RYLPT-OH) stimulated the rate of contraction of reproductive tracts from both 5-day and 8-day males. In contrast, 1 nM and 100 nM FGLa AST (cockroach allatostatin) did not affect pulsations. However, 10 microM FGLa AST decreased activity of reproductive tracts. Mating decreased motility of tracts from 5-day old males, but did not alter motility of tracts from 8-day old males. Castration of larvae significantly suppressed reproductive tract motility in subsequent 8-day old adults compared with those of intact or sham-operated adults. Castration also suppressed seminal vesicle size. Lastly, we assessed the presence and distribution of proctolin-like and allatostatin-like immunoreactivity in tissues. Immunoreactivity to FGLa AST and proctolin was widespread, occurring in the brain and ventral ganglia. Surprisingly, we did not detect immunoreactivity to either FGLa AST or proctolin within the reproductive system; however, proctolin immunoreactivity was evident in nerves extending from the terminal ganglion of 8-day, but not 0-day, males. Collectively, these experiments demonstrate that the male earwig reproductive system is an appropriate model for use in addressing sexual maturation and activities in male insects.
HIV and tuberculosis (TB) are the most common causes of death in South Africa. Antiretroviral therapy (ART) programmes should have had an impact on mortality rates. This study describes the impact of HIV, a Wellness (HIV/ART) programme and TB on population-wide trends in mortality and causes of death among South African platinum miners, from before the HIV epidemic into the ART era.
S100 proteins are a family of small, EF-hand containing calcium-binding signaling proteins that are implicated in many cancers. While the majority of human S100 proteins share 25-65% sequence similarity, S100A7 and its recently identified paralog, S100A15, display 93% sequence identity. Intriguingly, however, S100A7 and S100A15 serve distinct roles in inflammatory skin disease; S100A7 signals through the receptor for advanced glycation products (RAGE) in a zinc-dependent manner, while S100A15 signals through a yet unidentified G-protein coupled receptor in a zinc-independent manner. Of the seven divergent residues that differentiate S100A7 and S100A15, four cluster in a zinc-binding region and the remaining three localize to a predicted receptor-binding surface.
Manganese (Mn) is a common occupational exposure worldwide. Recent studies indicate clinical and imaging evidence of neurotoxicity in chronically exposed workers. The pathologic significance of these findings is unclear. South Africa produces over 80% of the worlds Mn from mines from a desert region in the Northern Cape Province. An autopsy program at the National Institute for Occupational Health (NIOH) in South Africa has provided compensation to families for mining-related lung diseases for almost 100 years. Building on this, we implemented a brain autopsy program to investigate the feasibility of obtaining brains from South African Mn miners and non-exposed reference miners to investigate neuropathologic consequences of chronic Mn exposure. Employing an experienced occupational health nurse, we identified deceased miners within 100 square km of the Mn mines. The nurse was notified of any Mn (case) or other (reference) miner or ex-miner death by local medical practitioners, occupational health and mine physicians, and community members, and families were approached for consent to remove the brains in addition to the cardio-respiratory organs. Families of deceased miners who had an autopsy at the NIOH in Johannesburg were also approached. To confirm exposure in Mn miners, mean pallidal indices were compared between Mn miners and non-exposed reference miners. Sixty-eight potential brain donors were identified; we obtained consent from the families to remove 51 (75%). The mean autopsy interval was seven days. With optimized fixation methods, the tissue quality of the brains for gross and regular microscopic examination was excellent. Ex vivo MRI demonstrated increased pallidal index in Mn miners compared to reference miners. We conclude that obtaining brain tissue from deceased miners in South Africa is highly successful with only a modest investment in local infrastructure. Tissue quality was excellent and should be ideal to investigate the neuropathologic consequences of chronic occupational Mn exposure.
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