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Ancient Science of Life  1984;4(2):116-122.
In China the antecedent of alchemy is represented by the god of longevity emerging from the peach. The first synthetic drug, Kim-Yeh, red colloidal gold, signified gold-cum -herbal juice. Kim-Yeh=Kimiya (Arabic) =chemeia (Greek). Translated this gave Chrusozomion=Gold Ferment, specifying the drug. Rasayana was translated as Chumeia, herbal juice-incorporate and signified the art alchemy. Chemeia was Chinese and Chumeia, Indian. Originally each signified both, a drug of longevity and the art, alchemy. Finally the art of making red gold was misunderstood as the art of making gold itself
PMCID: PMC3331503  PMID: 22557463
Ancient Science of Life  1988;7(3-4):134-138.
Prime Matter is matter-cum-energy. The first substance identified as such was lead. When gently heated it becomes red and redness means soul or energy so that lead was potentially red or soul-like and as such dual natured. Mercury also becomes red and can return to white metal. It was thus dual natured and was the second substance recognized as Prime Matter. First lead alone and then lead and mercury were considered as the source of all metals.
PMCID: PMC3336634  PMID: 22557603
3.  Residential Mercury Contamination in Adobe Brick Homes in Huancavelica, Peru 
PLoS ONE  2013;8(9):e75179.
This is the first study of adobe brick contamination anywhere in the world. Huancavelica, Peru is the site of historic cinnabar refining and one of the most mercury (Hg) contaminated urban areas in the world. Over 80% of homes in Huancavelica are constructed with adobe bricks made from Hg contaminated soil. In this study we measured total Hg concentrations in adobe brick, dirt floor, surface dust, and air samples from the interior of 60 adobe brick houses located in four neighborhoods. Concentrations of total Hg in adobe bricks, dirt floors, and surface dust ranged from 8.00 to 1070 µg/g, 3.06 to 926 µg/g, and 0.02 to 9.69 µg/wipe, respectively, with statistically significant differences between the four neighborhoods. Concentrations of Hg in adobe brick and dirt floor samples in Huancavelica were orders of magnitude higher than in Ayacucho, a non-mining town in Peru. A strong correlation exists between total Hg concentrations in adobe bricks and dirt floors which confirms that adobe bricks were being made on-site and not purchased from an off-site source. A strong correlation between surface dust and adobe bricks and dirt floors indicates that walls and floors serve as indoor sources of Hg contamination. Elemental Hg vapor concentrations were below detection (<0.5 µg/m3) in most homes; however in homes with detectable levels, concentrations up to 5.1 µg/m3 were observed. No statistically significant differences in Hg vapor measurements were observed between neighborhoods. This study demonstrates that building materials used widely in developing communities, such as adobe bricks, may be a substantial source of residential Hg exposure in silver or gold refining communities where Hg is produced or used for amalgamation in artisanal gold production.
PMCID: PMC3769258  PMID: 24040399
4.  ALCHEMY: a reliable method for automated SNP genotype calling for small batch sizes and highly homozygous populations 
Bioinformatics  2010;26(23):2952-2960.
Motivation: The development of new high-throughput genotyping products requires a significant investment in testing and training samples to evaluate and optimize the product before it can be used reliably on new samples. One reason for this is current methods for automated calling of genotypes are based on clustering approaches which require a large number of samples to be analyzed simultaneously, or an extensive training dataset to seed clusters. In systems where inbred samples are of primary interest, current clustering approaches perform poorly due to the inability to clearly identify a heterozygote cluster.
Results: As part of the development of two custom single nucleotide polymorphism genotyping products for Oryza sativa (domestic rice), we have developed a new genotype calling algorithm called ‘ALCHEMY’ based on statistical modeling of the raw intensity data rather than modelless clustering. A novel feature of the model is the ability to estimate and incorporate inbreeding information on a per sample basis allowing accurate genotyping of both inbred and heterozygous samples even when analyzed simultaneously. Since clustering is not used explicitly, ALCHEMY performs well on small sample sizes with accuracy exceeding 99% with as few as 18 samples.
Availability: ALCHEMY is available for both commercial and academic use free of charge and distributed under the GNU General Public License at
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC2982150  PMID: 20926420
5.  Cinnabar Induces Renal Inflammation and Fibrogenesis in Rats 
BioMed Research International  2015;2015:280958.
The purpose of this study was to investigate whether cinnabar causes renal inflammation and fibrosis in rats. Rats were dosed orally with cinnabar (1 g/kg/day) for 8 weeks or 12 weeks. The control rats were treated with solvent (5% carboxymethylcellulose solution) over the same time periods, respectively. Renal mercury (RHg), urinary mercury (UHg), serum creatinine (SCr), urine kidney injury molecule 1 (KIM-1), renal pathology, and renal mediators were examined. At both 8 weeks and 12 weeks, RHg, UHg, and urine KIM-1 were significantly higher in the cinnabar group than in the control group, although SCr was unchanged. Kidney lesions in the cinnabar-treated rats occurred mainly in the tubules and interstitium, including vacuolization, protein casts, infiltration of inflammatory cells, and slight increase in interstitial collagen. In addition, mild mesangial proliferation was observed in glomeruli. Moreover, the expression of inflammatory and fibrogenic mediators was upregulated in the cinnabar group. In conclusion, cinnabar may cause kidney damage due to the accumulation of mercury, and renal inflammation and slight fibrogenesis may occur in rats. In the clinic, the potential risk of renal injury due to the prolonged consumption of cinnabar should be considered even though the agent is relatively nontoxic.
PMCID: PMC4334861  PMID: 25734058
6.  Cinnabar-Induced Subchronic Renal Injury Is Associated with Increased Apoptosis in Rats 
BioMed Research International  2015;2015:278931.
The aim of this study was to explore the role of apoptosis in cinnabar-induced renal injury in rats. To test this role, rats were dosed orally with cinnabar (1 g/kg/day) for 8 weeks or 12 weeks, and the control rats were treated with 5% carboxymethylcellulose solution. Levels of urinary mercury (UHg), renal mercury (RHg), serum creatinine (SCr), and urine kidney injury molecule 1 (KIM-1) were assessed, and renal pathology was analyzed. Apoptotic cells were identified and the apoptotic index was calculated. A rat antibody array was used to analyze expression of cytokines associated with apoptosis. Results from these analyses showed that UHg, RHg, and urine KIM-1, but not SCr, levels were significantly increased in cinnabar-treated rats. Renal pathological changes in cinnabar-treated rats included vacuolization of tubular cells, formation of protein casts, infiltration of inflammatory cells, and increase in the number of apoptotic tubular cells. In comparison to the control group, expression of FasL, Fas, TNF-α, TRAIL, activin A, and adiponectin was upregulated in the cinnabar-treated group. Collectively, our results suggest that prolonged use of cinnabar results in kidney damage due to accumulation of mercury and that the underlying mechanism involves apoptosis of tubular cells via a death receptor-mediated pathway.
PMCID: PMC4300031  PMID: 25629042
7.  Association of cystatin C and estimated GFR with inflammatory biomarkers: the Heart and Soul Study 
Cystatin C is a marker of kidney function that may also be associated with inflammation. In this study, we compared the relative strengths of association of cystatin C and estimated glomerular filtration rate (eGFR) with inflammatory biomarkers.
We measured serum cystatin C and creatinine in 990 outpatients with coronary artery disease enrolled in the Heart and Soul Study. GFR was estimated (eGFR) by the abbreviated Modification of Diet in Renal Disease (MDRD) equation. We compared the associations of serum cystatin C and eGFR with C-reactive protein (CRP) and fibrinogen, after adjustment for 24 h creatinine clearance.
Cystatin C concentrations had moderate correlations with CRP (r=0.15, P<0.001) and fibrinogen (r=0.26, P<0.0001); eGFR had similar correlations with CRP (r=−0.17, P=0.01) and fibrinogen (r=−0.25, P<0.001) among persons with eGFR≤60 ml/min, but had no association with either biomarker among those with eGFR>60 ml/min (r=0.04, P=0.32; r=−0.03, P=0.38). Quartiles of cystatin C were strongly and directly associated with CRP (P=0.02) and fibrinogen (P<0.007) after multivariate adjustment. However, these associations disappeared after adjustment for creatinine clearance (P=0.26 and 0.23, respectively).
Cystatin C concentrations have moderate associations with CRP and fibrinogen that are not independent of creatinine clearance. Although a gold standard of kidney function is lacking, this analysis suggests that cystatin C captures an association of mildly impaired kidney function with increased inflammation.
PMCID: PMC2770338  PMID: 17210589
chronic kidney disease; coronary artery disease; C-reactive protein; creatinine clearance; cystatin-C; inflammation
8.  A Six-Gene Signature Predicts Survival of Patients with Localized Pancreatic Ductal Adenocarcinoma 
PLoS Medicine  2010;7(7):e1000307.
Jen Jen Yeh and colleagues developed and validated a six-gene signature in patients with pancreatic ductal adenocarcinoma that may be used to better stage the disease in these patients and assist in treatment decisions.
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease. For patients with localized PDAC, surgery is the best option, but with a median survival of less than 2 years and a difficult and prolonged postoperative course for most, there is an urgent need to better identify patients who have the most aggressive disease.
Methods and Findings
We analyzed the gene expression profiles of primary tumors from patients with localized compared to metastatic disease and identified a six-gene signature associated with metastatic disease. We evaluated the prognostic potential of this signature in a training set of 34 patients with localized and resected PDAC and selected a cut-point associated with outcome using X-tile. We then applied this cut-point to an independent test set of 67 patients with localized and resected PDAC and found that our signature was independently predictive of survival and superior to established clinical prognostic factors such as grade, tumor size, and nodal status, with a hazard ratio of 4.1 (95% confidence interval [CI] 1.7–10.0). Patients defined to be high-risk patients by the six-gene signature had a 1-year survival rate of 55% compared to 91% in the low-risk group.
Our six-gene signature may be used to better stage PDAC patients and assist in the difficult treatment decisions of surgery and to select patients whose tumor biology may benefit most from neoadjuvant therapy. The use of this six-gene signature should be investigated in prospective patient cohorts, and if confirmed, in future PDAC clinical trials, its potential as a biomarker should be investigated. Genes in this signature, or the pathways that they fall into, may represent new therapeutic targets.
Please see later in the article for the Editors' Summary
Editors' Summary
Pancreatic cancer kills nearly a quarter of a million people every year. It begins when a cell in the pancreas (an organ lying behind the stomach that produces digestive enzymes and hormones such as insulin, which controls blood sugar levels) acquires genetic changes that allow it to grow uncontrollably and to spread around the body (metastasize). Nearly all pancreatic cancers are “pancreatic ductal adenocarcinomas” (PDACs)—tumors that start in the cells that line the tubes in the pancreas that take digestive juices to the gut. Because PDAC rarely causes any symptoms early in its development, it has already metastasized in about half of patients before it is diagnosed. Consequently, the average survival time after a diagnosis of PDAC is only 5–8 months. At present, the only chance for cure is surgical removal (resection) of the tumor, part of the pancreas, and other nearby digestive organs. The operation that is needed for the majority of patients—the Whipple procedure—is only possible in the fifth of patients whose tumor is found when it is small enough to be resectable but even with postoperative chemotherapy, these patients only live for 23 months after surgery on average, possibly because they have micrometastases at the time of their operation.
Why Was This Study Done?
Despite this poor overall outcome, about a quarter of patients with resectable PDAC survive for more than 5 years after surgery. Might some patients, therefore, have a less aggressive form of PDAC determined by the biology of the primary (original) tumor? If this is the case, it would be useful to be able to stratify patients according to the aggressiveness of their disease so that patients with very aggressive disease could be given chemotherapy before surgery (neoadjuvant therapy) to kill any micrometastases. At present neoadjuvant therapy is given to patients with locally advanced, unresectable tumors. In this study, the researchers compare gene expression patterns in primary tumor samples collected from patients with localized PDAC and from patients with metastatic PDAC between 1999 and 2007 to try to identify molecular markers that distinguish between more and less aggressive PDACs.
What Did the Researchers Do and Find?
The researchers identified a six-gene signature that was associated with metastatic disease using a molecular biology approach called microarray hybridization and a statistical method called significance analysis of microarrays to analyze gene expression patterns in primary tumor samples from 15 patients with localized PDAC and 15 patients with metastatic disease. Next, they used a training set of tumor samples from another 34 patients with localized and resected PDAC, microarray hybridization, and a graphical method called X-tile to select a combination of expression levels of the six genes that discriminated optimally between high-risk (aggressive) and low-risk (less aggressive) tumors on the basis of patient survival (a “cut-point”). When the researchers applied this cut-point to an independent set of 67 tumor samples from patients with localized and resected PDAC, they found that 42 patients had high-risk tumors. These patients had an average survival time of 15 months; 55% of them were alive a year after surgery. The remaining 25 patients, who had low-risk tumors, had an average survival time of 49 months and 91% of them were alive a year after resection.
What Do These Findings Mean?
These and other findings identify a six-gene signature that can predict outcomes in patients with localized, resectable PDAC better than, and independently of, established clinical markers of outcome. If the predictive ability of this signature can be confirmed in additional patients, it could be used to help patients make decisions about their treatment. For example, a patient wondering whether to risk the Whipple procedure (2%–6% of patients die during this operation and more than 50% have serious postoperative complications), the knowledge that their tumor was low risk might help them decide to have the operation. Conversely, a patient in poor health with a high-risk tumor might decide to spare themselves the trauma of major surgery. The six-gene signature might also help clinicians decide which patients would benefit most from neoadjuvant therapy. Finally, the genes in this signature, or the biological pathways in which they participate, might represent new therapeutic targets for the treatment of PDAC.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Cancer Institute provides information for patients and health professionals about all aspects of pancreatic cancer (in English and Spanish), including a booklet for patients
The American Cancer Society also provides detailed information about pancreatic cancer
The UK National Health Service and Cancer Research UK include information for patients on pancreatic cancer on their Web sites
MedlinePlus provides links to further resources on pancreatic cancer (in English and Spanish)
Cure Pancreatic Cancer provides information about scientific and medical research related to the diagnosis, treatment, cure, and prevention of pancreatic cancer
Pancreatic Cancer Action Network is a US organization that supports research, patient support, community outreach, and advocacy for a cure for pancreatic cancer
PMCID: PMC2903589  PMID: 20644708
9.  Mercury in traditional medicines: Is cinnabar toxicologically similar to common mercurials? 
Mercury is a major toxic metal ranking top in the Toxic Substances List. Cinnabar (contains mercury sulfide) has been used in traditional medicines for thousands years as an ingredient in various remedies, and 40 cinnabar-containing traditional medicines are still used today. Little is known about toxicology profiles or toxicokinetics of cinnabar and cinnabar-containing traditional medicines, and the high mercury content in these Chinese medicines raises justifiably escalations of public concern. This minireview searched the available database of cinnabar, compared cinnabar with common mercurials, such as mercury vapor, inorganic mercury, and organic mercury, and discusses differences in their bioavailability, disposition, and toxicity. The analysis showed that cinnabar is insoluble and poorly absorbed from the gastrointestinal tract. Absorbed mercury from cinnabar is mainly accumulated in kidney, resembling the disposition pattern of inorganic mercury. Heating cinnabar results in release of mercury vapor, which in turn can produce toxicity similar to inhalation of these vapors. The doses of cinnabar required to produce neurotoxicity are thousands 1000 times higher than methyl mercury. Following long-term use of cinnabar, renal dysfunction may occur. Dimercaprol and succimer are effective chelation therapies for general mercury intoxication including cinnabar. Pharmacology studies of cinnabar suggest sedative and hypnotic effects, but the therapeutic basis of cinnabar is still not clear. In summary, cinnabar is chemically inert with a relatively low toxic potential when taken orally. In risk assessment, cinnabar is less toxic than many other forms of mercury, but the rationale for its inclusion in traditional Chinese medicines remains to be fully justified.
PMCID: PMC2755212  PMID: 18445765
Cinnabar; Traditional medicines; Elementary mercury; Mercuric chloride; Methylmercury; Bioavailability; Disposition; Toxicology
10.  Fibroblast growth factor-23 and early decrements in kidney function: the Heart and Soul Study 
Background. Fibroblast growth factor-23 (FGF-23) is associated with mortality in dialysis patients, and concentrations are elevated in moderate chronic kidney disease (CKD). The threshold of CKD or albuminuria at which FGF-23 begins to change is unknown.
Methods. In 792 outpatients with stable cardiovascular disease (CVD) and normal kidney function to moderate CKD, we evaluate the associations of estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) with plasma FGF-23 concentrations.
Results. Compared to participants with eGFR ≥90 ml/min/1.73m2, mean FGF-23 concentrations were 7.8 RU/ml higher (4.3–11.5, P = 0.01) in those with eGFR 60–89 ml/min/1.73m2 in models adjusted for age, sex, race, ACR, blood pressure, diabetes and body mass index. More advanced decrements in eGFR were associated with much higher FGF-23 concentrations. In spline analysis, the slope of change in FGF-23 concentration was evident at eGFR <90 ml/min/1.73m2. Compared to participants with ACR <30 mg/g, mean FGF-23 concentrations were 18.4 RU/ml higher (9.3–29.2, P < 0.001) in those with ACR 30–299 mg/g in models adjusted for identical covariates plus eGFR and much higher in individuals with ACR ≥300 mg/g. Spline analysis demonstrated a linear relationship of ACR with FGF-23, independent of eGFR, even among persons with ACR <30 mg/g.
Conclusion. Modest decrements in eGFR or elevations in albuminuria are each independently associated with higher FGF-23 concentrations in outpatients with stable CVD.
PMCID: PMC2902926  PMID: 20037168
albuminuria; chronic; fibroblast growth factor-23; kidney disease; osteodystrophy
11.  “Souls of the ancestor that knock us out” and other tales. A qualitative study to identify demand-side factors influencing malaria case management in Cambodia 
Malaria Journal  2012;11:335.
Appropriate case management of suspected malaria in Cambodia is critical given anti-malarial drug resistance in the region. Improving diagnosis and the use of recommended malarial treatments is a challenge in Cambodia where self-treatment and usage of drug cocktails is widespread, a notable difference from malaria treatment seeking in other countries. This qualitative study adds to the limited evidence base on Cambodian practices, aiming to understand the demand-side factors influencing treatment-seeking behaviour, including the types of home treatments, perceptions of cocktail medicines and reasons for diagnostic testing. The findings may help guide intervention design.
The study used in-depth interviews (IDIs) (N = 16) and focus group discussions (FGDs) (N = 12) with Cambodian adults from malaria-endemic areas who had experienced malaria fever in the previous two weeks. Data were analysed using NVivo software.
Findings suggest that Cambodians initially treat suspected malaria at home with home remedies and traditional medicines. When seeking treatment outside the home, respondents frequently reported receiving a cocktail of medicines from trusted providers. Cocktails are perceived as less expensive and more effective than full-course, pre-packaged medicines. Barriers to diagnostic testing include a belief in the ability to self-diagnose based on symptoms, cost and reliance on providers to recommend a test. Factors that facilitate testing include recommendation by trusted providers and a belief that anti-malarial treatment for illnesses other than malaria can be harmful.
Treatment-seeking behaviour for malaria in Cambodia is complex, driven by cultural norms, practicalities and episode-related factors. Effective malaria treatment programmes will benefit from interventions and communication materials that leverage these demand-side factors, promoting prompt visits to facilities for suspected malaria and challenging patients’ misconceptions about the effectiveness of cocktails. Given the importance of the patient-provider interaction and the pivotal role that providers play in ensuring the delivery of appropriate malaria care, future research and interventions should also focus on the supply side factors influencing provider behaviour.
PMCID: PMC3478967  PMID: 23039260
Treatment-seeking behaviour; Patient perceptions; Patient-provider interactions; Malaria diagnosis; Malaria treatment; Cocktail; ACT; Cambodia; Qualitative research
12.  Understanding Brain, Mind and Soul: Contributions from Neurology and Neurosurgery 
Mens Sana Monographs  2011;9(1):129-149.
Treatment of diseases of the brain by drugs or surgery necessitates an understanding of its structure and functions. The philosophical neurosurgeon soon encounters difficulties when localising the abstract concepts of mind and soul within the tangible 1300-gram organ containing 100 billion neurones. Hippocrates had focused attention on the brain as the seat of the mind. The tabula rasa postulated by Aristotle cannot be localised to a particular part of the brain with the confidence that we can localise spoken speech to Broca’s area or the movement of limbs to the contralateral motor cortex. Galen’s localisation of imagination, reasoning, judgement and memory in the cerebral ventricles collapsed once it was evident that the functional units–neurones–lay in the parenchyma of the brain. Experiences gained from accidental injuries (Phineas Gage) or temporal lobe resection (William Beecher Scoville); studies on how we see and hear and more recent data from functional magnetic resonance studies have made us aware of the extensive network of neurones in the cerebral hemispheres that subserve the functions of the mind. The soul or atman, credited with the ability to enliven the body, was located by ancient anatomists and philosophers in the lungs or heart, in the pineal gland (Descartes), and generally in the brain. When the deeper parts of the brain came within the reach of neurosurgeons, the brainstem proved exceptionally delicate and vulnerable. The concept of brain death after irreversible damage to it has made all of us aware of ‘the cocktail of brain soup and spark’ in the brainstem so necessary for life. If there be a soul in each of us, surely, it is enshrined here.
PMCID: PMC3115284  PMID: 21694966
Brain; Brainstem; Mind; Soul; Neurology; Neurosurgery; Philosophy
13.  The Soul and the Body in the Philosophy of the Rambam 
Among the wide-spectrum contribution of the Rambam – the Maimonides – in philosophy to the word and to Judaism are his ideas on the body and on the soul and on the relations between them. His major approaches in these subjects are the following: 1) The body is the home of the soul, and the soul guides the body. That means the body and the soul are one unit. 2) The soul has five virtual parts. Each part is responsible for another activity in the human being. 3) Except for the treatment of diseases of the body and the soul with drugs, foods, physical exercise, etc., the Rambam believes that maintaining the health – of the body and of the soul – lies first of all, and probably exclusively, in observing the commandments and improving one’s ways, morals and conduct up to their highest levels, toward all of the world’s creatures. 4) The Rambam is of the opinion that one needs to persist in learning the Torah. One should worship God with awe and love and observe good values and virtues. All of these build the frameworks that maintain mental health and strengthen man’s abilities to develop skills for maintaining bodily health. This is so because body and soul are one – which is the basis of the Rambam’s philosophy of health and medicine.
PMCID: PMC3678934  PMID: 23908798
Maimonides; Rambam; soul; body; soul-body
14.  A home for body and soul: Substance using women in recovery 
We report on an in-depth qualitative study of 28 active and former substance addicted women of low or marginal income on the core components of a harm reduction-based addiction recovery program. These women volunteered to be interviewed about their perceptions of their therapeutic needs in their transition from substance addiction to recovery.
Data were gathered about women’s experiences and essential needs in addiction recovery, what helped and what hindered their past efforts in recovery, and their views of what would constitute an effective woman-centred recovery program. The research was based upon the experience and knowledge of the women in interaction with their communities and with recovery programs. The study was informed by harm reduction practice principles that emphasize the importance of individual experience in knowledge construction, reduction of harm, low threshold access, and the development of a hierarchy of needs in regard to addiction recovery.
Three core needs were identified by study participants: normalization and structure, biopsychosocial-spiritual safety, and social connection. What hindered recovery efforts as identified by participants was an inner urban location, prescriptive recovery, invidious treatment, lack of safety, distress-derived distraction, problem-focused treatment, coercive elements of mutual support groups, and social marginalization. What helped included connection in counselling and therapy, multidisciplinary service provision, spirituality focus, opportunities for learning and work, and a safe and flexible structure. Core components of an effective recovery program identified by women themselves stand in contrast to the views of service providers and policymakers, particularly in regard to the need for a rural location for residential programs, low threshold access, multidisciplinary service provision of conventional and complementary modalities and therapies for integrated healing, long-term multi-phase recovery, and variety and choice of programming.
A key barrier to the addiction recovery of women is the present framework of addiction treatment, as well as current drug laws, policies and service delivery systems. The expectation of women is that harm reduction-based recovery services will facilitate safe, supportive transitioning from the point of the decision to access services, through independent living with community integration.
PMCID: PMC3878194  PMID: 24359089
15.  Lifetime Trauma Exposure and Prospective Cardiovascular Events and All-cause Mortality: Findings from the Heart and Soul Study 
Psychosomatic medicine  2013;75(9):849-855.
Little is known about the effect of cumulative psychological trauma on health outcomes in patients with cardiovascular disease. The objective of this study was to prospectively examine the association between lifetime trauma exposure and recurrent cardiovascular events or all-cause mortality in patients with existing cardiovascular disease.
1,021 men and women with cardiovascular disease were recruited in 2000–2002 and followed annually. Trauma history and psychiatric comorbidities were assessed at baseline using the Computerized Diagnostic Interview Schedule for DSM-IV. Health behaviors were assessed using standardized questionnaires. Outcome data was collected annually, and all medical records were reviewed by two independent, blinded physician adjudicators. We used Cox proportional hazards models to evaluate the association between lifetime trauma exposure and the composite outcome of cardiovascular events and all-cause mortality.
During an average of 7.5 years follow-up, there were 503 cardiovascular events and deaths. Compared with the 251 participants in the lowest trauma exposure quartile, the 256 participants in the highest exposure quartile had a 38% greater risk of adverse outcomes (HR 1.38, 95% CI 1.06–1.81), adjusted for age, sex, race, income, education, depression, posttraumatic stress disorder, generalized anxiety disorder, smoking, physical inactivity, and illicit drug abuse.
Cumulative exposure to psychological trauma was associated with an increased risk of recurrent cardiovascular events and mortality, independent of psychiatric comorbidities and health behaviors. These data add to a growing literature showing enduring effects of repeated trauma exposure on health that are independent of trauma-related psychiatric disorders such as depression and posttraumatic stress disorder.
PMCID: PMC4014357  PMID: 24149074
Cardiovascular disease; psychological trauma; myocardial infarction; depression; post-traumatic stress disorder; cardiovascular mortality
16.  Trauma exposure predicts alcohol, nicotine, and drug problems beyond the contribution of PTSD and depression in patients with cardiovascular disease: Data from the Heart and Soul Study 
Background and Objectives
This study examined the role of lifetime trauma exposure in a longitudinal study of adults with cardiovascular disease to determine the unique contribution of trauma exposure to risk for drug and alcohol problems and smoking.
Data were drawn from the Heart and Soul Study, a prospective cohort study designed to determine the mechanisms of associations between psychological factors and increased risk of cardiovascular events in high-risk patients (n = 1,022).
Lifetime exposure to a higher number of trauma types predicted substance use outcomes beyond risk explained by PTSD and depression. In addition, across trauma types, interpersonal traumas were most strongly associated with substance use problems.
Our results suggest that, though PTSD and depression play a role in the association between trauma exposure and substance use, many other factors also contribute; therefore focusing on these psychological comorbidities alone is not sufficient.
Scientific Significance
The integration of mental health care and/or case management support with primary and specialty medical care may improve detection and treatment for patients with substance use and comorbid mental and physical health problems. Screening for trauma exposure is an important part of good clinical care.
PMCID: PMC3858723  PMID: 24313242
17.  Case of the month: “Bugs are eating my soul” – sternal abscess, osteomyelitis, and mediastinitis complicating a closed sternal fracture 
Emergency Medicine Journal : EMJ  2006;23(9):736-737.
Wound complications of closed sternal fracture are rare, but may have serious consequences if not effectively managed. We report a case of a patient who presented to the emergency department with a sternal abscess, osteomyelitis, and mediastinitis complicating a closed sternal fracture. It is hypothesised that in our patient bacteraemia post intravenous drug use resulted in seeding of the haematoma with Staphylococcus aureus. Early diagnosis and a multidisciplinary team effort were important in ensuring a favourable outcome.
PMCID: PMC2564229  PMID: 16921099
abscess; fracture, closed; mediastinitis; osteomyelitis; sternum
18.  Antinociceptive, muscle relaxant and sedative activities of gold nanoparticles generated by methanolic extract of Euphorbia milii 
Nanotechnology has potential future for enhancing therapeutic efficacy and reducing the unwanted effects of herbal drugs. The biological research on Euphorbia species has been supported by the use of some plants in traditional medicines. Many species of Euphorbia have been reported as having strong sedative and analgesic effects. In the present research work gold nanoparticles of Euphorbia milii methanolic extract (Au-EM) were synthesized, characterized and tested for antinociceptive, muscle relaxant and sedative activities.
Au-EM was prepared by stirring 1 mM warm trihydrated tetrachloroaurate solution with E. milii methanolic extract without using any external reducing agents. The gold nanoparticles were characterized by UV-Visible spectroscopy, infrared spectrophotometery, atomic force microscopy and scanning electron microscopy while their stability was evaluated against varying pH and different volumes of sodium chloride (NaCl). The metal sensing capacity of Au-EM was tested towards cobalt, copper, lead, mercury and nickel. Au-EM was evaluated in BALB/c mice at a dose of 10 and 20 mg/kg for antinociceptive, muscle relaxant and sedative activities in comparison with the crude E. milii methanolic extract.
Au-EM showed remarkable stability in different NaCl and pH solutions. Au-EM produced significant (P < 0.01) antinociceptive effect at doses of 10 and 20 mg/kg as compared to the crude E. milii methanolic extract. In the rotarod test, Au-EM showed significant muscle relaxant effect at 10 mg/kg (P < 0.05) and 20 mg/kg (P < 0.01) after 30, 60 and 90 min. In an open field test significant sedative effect (P < 0.05) of Au-EM was observed at 10 and 20 mg/kg. Moreover significant detection sensitivity was demonstrated towards all the tested heavy metals.
These results concluded that the gold nanoparticles improved the potency of E. milii methanolic extract and exhibited significant analgesic, muscle relaxant and sedative properties. The significant metals sensing ability and enhanced stability in different NaCl and pH solutions may enable us to explore different formulations of E. milii gold nanoparticles for potentially effective and safe nano-herbal therapy.
PMCID: PMC4446853  PMID: 26021441
Gold nanoparticles; Euphorbia milii; Nanotechnology; Herbal drugs; Antinociceptive; Muscle relaxant; Sedative
The Journal of General Physiology  1956;39(5):625-649.
Macrophages isolated from the rabbit peritoneal cavity extract radioactive colloidal gold from solutions in vitro. This reaction (ultraphagocytosis) involves two phases: the reversible adsorption of gold on the cell surface and the subsequent irreversible removal of surface-bound colloid into the cell. The latter process (called ingestion) appears to proceed at a rate which is proportional at any moment to the amount of gold attached to the cell surface; the latter in turn can be related to the concentration in extracellular fluid by a simple adsorption isotherm. In terms of rate, therefore, ingestion is related to the extracellular gold concentration in the same way that many enzyme reactions are related to the substrate concentration. Although enzyme kinetics are useful in describing rates of ultraphagocytosis, there is no evidence that enzymes participate in either adsorption or ingestion or that metabolic energy is required of the macrophage. Exudative leucocytes of the heterophilic series show little or no interaction with these finely dispersed gold sols (mean particle diameter 6 to 9 millimicrons). 37°C. three parameters are sufficient to characterize the reaction between gold and a suspension of macrophages, namely an affinity constant (1/Ks), an adsorption maximum (L), and a rate constant of ingestion (k3). Although numerical values differed markedly among cells of different exudates, all three parameters were estimated in three instances. In these suspensions between 2 and 20 per cent of the surface-bound gold was ingested each minute (37°C., pH 7.4). Under conditions of surface saturation, it was estimated that tens of thousands of gold particles were attached to the surface of an average macrophage; this amount of colloid, however, occupied less than 1 per cent of the geometric area of the cell surface. Although surface saturation imposed an upper limit on the rate of ingestion, no practical limit was noted in the capacity of macrophages to continue the reaction. Optical measurements imply that within the cell agglutination of colloidal gold began promptly after its ingestion. These data are compared with published kinetic studies on the phagocytosis of microscopic particulates and on the parasitism of bacteria by virus.
PMCID: PMC2147563  PMID: 13319653
20.  Design, development and validation of the RedBrick Health Assessment: a questionnaire-based study 
JRSM Short Reports  2011;2(9):71.
Health risk assessment (HRA) questionnaires have become a popular tool to help quantify health issues within populations. Over the last decade HRAs have increasingly been delivered in the online environment. The objective of this study was to create and validate an HRA that is optimized for delivery via the Internet.
After an iterative process of user testing and interface design the RedBrick Health Assessment (RBHA) was validated against known domain specific questionnaires with 464 working Americans, and with medical claims data from over 25,000 employees.
All consumer testing, data capture and analysis occurred at the offices of RedBrick Health Corporation, Minneapolis, USA and via a secure online portal.
Individuals in full-time employment in the USA, who were between 18 and 65 years of age at the time inquiry.
Main outcome measures
Correlation of the included RBHA domains with the output from known gold standard health question sets for each assessed health domain.
The iterative development process employed in creating the RBHA produced a tool that had a high degree of user acceptability. The domains demonstrated good correlations with relevant gold standard questionnaire measures, good internal consistency, and acceptable sensitivity and specificity when compared to gold standard risk stratification and high-risk classification (specificity of domains ranged from 76–94%). A test–retest correlation co-efficient of 0.7, or greater, was achieved 8 weeks after initial completion.
The RBHA is a new breed of HRA that has been specifically developed for capturing health status information in an online environment. At its heart is user centricity and this focus has enabled the creation of a tool that is not only highly engaging but also captures accurate and robust health status information.
PMCID: PMC3184010  PMID: 21969882
21.  Plasmodium vivax Invasion of Human Erythrocytes Inhibited by Antibodies Directed against the Duffy Binding Protein 
PLoS Medicine  2007;4(12):e337.
Plasmodium vivax invasion requires interaction between the human Duffy antigen on the surface of erythrocytes and the P. vivax Duffy binding protein (PvDBP) expressed by the parasite. Given that Duffy-negative individuals are resistant and that Duffy-negative heterozygotes show reduced susceptibility to blood-stage infection, we hypothesized that antibodies directed against region two of P. vivax Duffy binding protein (PvDBPII) would inhibit P. vivax invasion of human erythrocytes.
Methods and Findings
Using a recombinant region two of the P. vivax Duffy binding protein (rPvDBPII), polyclonal antibodies were generated from immunized rabbits and affinity purified from the pooled sera of 14 P. vivax–exposed Papua New Guineans. It was determined by ELISA and by flow cytometry, respectively, that both rabbit and human antibodies inhibited binding of rPvDBPII to the Duffy antigen N-terminal region and to Duffy-positive human erythrocytes. Additionally, using immunofluorescent microscopy, the antibodies were shown to attach to native PvDBP on the apical end of the P. vivax merozoite. In vitro invasion assays, using blood isolates from individuals in the Mae Sot district of Thailand, showed that addition of rabbit anti-PvDBPII Ab or serum (antibodies against, or serum containing antibodies against, region two of the Plasmodium vivax Duffy binding protein) (1:100) reduced the number of parasite invasions by up to 64%, while pooled PvDBPII antisera from P. vivax–exposed people reduced P. vivax invasion by up to 54%.
These results show, for what we believe to be the first time, that both rabbit and human antibodies directed against PvDBPII reduce invasion efficiency of wild P. vivax isolated from infected patients, and suggest that a PvDBP-based vaccine may reduce human blood-stage P. vivax infection.
Christopher King and colleagues found that both rabbit and human antibodies inhibited binding of rPvDBPII to the Duffy antigen N-terminal region and to Duffy-positive human erythrocytes, suggesting that a PvDBP-based vaccine may reduce blood stage Plasmodium vivax infection.
Editors' Summary
Malaria is a parasitic infection transmitted to people through the bite of an infected mosquito. Four different parasites cause malaria—the commonest and most widely distributed of these is Plasmodium vivax. Infections with P. vivax are rarely fatal, but they cause debilitating chills and fevers that recur every other day if untreated. Like other malaria parasites, P. vivax has a complex life cycle. Infected mosquitoes inject a form of the parasite known as sporozoites into people. The sporozoites replicate inside liver cells without causing any symptoms. Then, 8–9 d later, merozoites (another form of the parasite) are released from the liver cells and invade young red blood cells. Here, they replicate rapidly before bursting out and infecting more red blood cells. The characteristic symptoms of malaria are caused by this cyclical increase in the parasite burden. P. vivax infections are usually treated with chloroquine, but patients must also take a second drug called primaquine. This drug kills hypnozoites, a form of the parasite that hibernates in the liver and that can cause a relapse many months after the initial bout of malaria.
Why Was This Study Done?
P. vivax is becoming resistant to chloroquine and, although other antimalarial drugs still kill it, a vaccine that would limit the severity of P. vivax infections by blocking its ability to invade red blood cells is urgently needed. The invasion of red blood cells by P. vivax depends on an interaction between the Duffy antigen (a protein on the surface of human red blood cells) and the Duffy binding protein (PvDBP), which is expressed by merozoites. People who lack the Duffy antigen are resistant to blood-stage infections of P. vivax. Similarly, people who express half the normal amount of Duffy antigen on their red blood cells have reduced susceptibility to these infections. In this study, the researchers investigated whether antibodies (proteins made by the immune system that recognize foreign proteins) directed against PvDBP inhibit the invasion of human red blood cells by P. vivax.
What Did the Researchers Do and Find?
The researchers injected a fragment of PvDBP called PvDBPII into rabbits and purified the part of the blood that contains antibodies from the animals. They also isolated antibodies to PvDBPII from the blood of several Papua New Guineans who had been exposed to P. vivax. Both types of antibodies bound to PvDBPII in test tubes and to PvDBP expressed on P. vivax merozoites. Then, the researchers showed that both types of antibody inhibited the binding of PvDBPII to Duffy antigen when the antigen was in solution and when it was present on human red blood cells. Finally, to test the ability of the antibodies to inhibit red blood cell invasion by P. vivax, the researchers established short-term cultures of the parasite from blood taken from infected adults living in Thailand. Addition of the rabbit or human antibodies to these cultures inhibited parasite invasion of red blood cells by more than 50%.
What Do These Findings Mean?
These findings show, for what is believed to be the first time, that antibodies recognizing a fragment of PvDBP can partly inhibit the invasion of red blood cells by P. vivax merozoites. The results with the human antibodies are particularly important as they strongly suggest that a PvDBP-based vaccine might provide protection against blood-stage P. vivax infections. Whether the level of inhibition of invasion seen in this study will be sufficient to reduce the clinical severity of these infections will only become clear, however, when a vaccine is tested in people. The findings also indicate that short-term P. vivax cultures can be used to test whether antibodies that recognize other merozoite proteins also inhibit invasion. Unlike P. falciparum (the other major malarial parasite), P. vivax cannot be grown continuously in the laboratory. These short-term cultures will at last provide vaccine developers with a way to evaluate antigens as candidates for inclusion in P. vivax vaccines.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia page on malaria (in English and Spanish)
Information from the US Centers for Disease Control and Prevention on malaria (in English and Spanish)
Vivaxmalaria, information for the malaria research community on topics related to Plasmodium vivax
Information from the Malaria Vaccine Initiative about malaria and malaria vaccines, including a fact sheet on Plasmodium vivax malaria
PMCID: PMC2140086  PMID: 18092885
22.  Standardization of ‘Lingha Chendooram’ – Number 1, A Siddha Drug 
Ancient Science of Life  1999;19(1-2):49-51.
‘Lingha chendooram’ number 1 is a single drug useful in Siddha system of medicine. This is prepared from Cinnabar, the chief ore of mercury. The standardization is carried out with respect to the presence of Mercury and Sulphur in the drug.
PMCID: PMC3336452  PMID: 22556919
‘Lingha chendooram’; Cinnabar; Siddha drug; Standardisation
23.  Application of DNA Aptamers and Quantum Dots to Lateral Flow Test Strips for Detection of Foodborne Pathogens with Improved Sensitivity versus Colloidal Gold 
Pathogens  2014;3(2):341-355.
Preliminary studies aimed at improving the sensitivity of foodborne pathogen detection via lateral flow (LF) test strips by use of high affinity DNA aptamers for capture and reporter functions when coupled to red-emitting quantum dots (Qdot 655) are reported. A variety of DNA aptamers developed against Escherichia coli, Listeria monocytogenes, and Salmonella enterica were paired in capture and reporter combinations to determine which yielded the strongest detection of their cognate bacteria using a colloidal gold screening system. Several promising sandwich combinations were identified for each of the three bacterial LF strip systems. The best E. coli aptamer-LF system was further studied and yielded a visible limit of detection (LOD) of ~3,000 E. coli 8739 and ~6,000 E. coli O157:H7 in buffer. These LODs were reduced to ~300–600 bacterial cells per test respectively by switching to a Qdot 655 aptamer-LF system. Novel aspects of these assays such as the use of high levels of detergents to avoid quantum dot agglutination and enhance migration in analytical membranes, identification of optimal analytical membrane types, UV-immobilization of capture aptamers, and novel dual biotin/digoxigenin-end labeled aptamer streptavidin-colloidal gold or -Qdot 655 conjugates plus anti-digoxigenin antibody control lines are also discussed. In general, this work provides proof-of-principle for highly sensitive aptamer-Qdot LF strip assays for rapid foodborne pathogen detection.
PMCID: PMC4243449  PMID: 25437803
aptamer; colloidal gold; detergent; digoxigenin; E. coli; lateral flow test strip; Listeria; quantum dot; Salmonella; SELEX
24.  Introduction of customized inserts for streamlined assembly and optimization of BioBrick synthetic genetic circuits 
BioBrick standard biological parts are designed to make biological systems easier to engineer (e.g. assemble, manipulate, and modify). There are over 5,000 parts available in the Registry of Standard Biological Parts that can be easily assembled into genetic circuits using a standard assembly technique. The standardization of the assembly technique has allowed for wide distribution to a large number of users -- the parts are reusable and interchangeable during the assembly process. The standard assembly process, however, has some limitations. In particular it does not allow for modification of already assembled biological circuits, addition of protein tags to pre-existing BioBrick parts, or addition of non-BioBrick parts to assemblies.
In this paper we describe a simple technique for rapid generation of synthetic biological circuits using introduction of customized inserts. We demonstrate its use in Escherichia coli (E. coli) to express green fluorescent protein (GFP) at pre-calculated relative levels and to add an N-terminal tag to GFP. The technique uses a new BioBrick part (called a BioScaffold) that can be inserted into cloning vectors and excised from them to leave a gap into which other DNA elements can be placed. The removal of the BioScaffold is performed by a Type IIB restriction enzyme (REase) that recognizes the BioScaffold but cuts into the surrounding sequences; therefore, the placement and removal of the BioScaffold allows the creation of seamless connections between arbitrary DNA sequences in cloning vectors. The BioScaffold contains a built-in red fluorescent protein (RFP) reporter; successful insertion of the BioScaffold is, thus, accompanied by gain of red fluorescence and its removal is manifested by disappearance of the red fluorescence.
The ability to perform targeted modifications of existing BioBrick circuits with BioScaffolds (1) simplifies and speeds up the iterative design-build-test process through direct reuse of existing circuits, (2) allows incorporation of sequences incompatible with BioBrick assembly into BioBrick circuits (3) removes scar sequences between standard biological parts, and (4) provides a route to adapt synthetic biology innovations to BioBrick assembly through the creation of new parts rather than new assembly standards or parts collections.
PMCID: PMC3022552  PMID: 21172029
25.  A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR 
Yin Zhi Huang, a decoction of Yin Chin (Artemisia capillaris) and three other herbs, is widely used in Asia to prevent and treat neonatal jaundice. We recently identified the constitutive androstane receptor (CAR, NR1I3) as a key regulator of bilirubin clearance in the liver. Here we show that treatment of WT and humanized CAR transgenic mice with Yin Zhi Huang for 3 days accelerates the clearance of intravenously infused bilirubin. This effect is absent in CAR knockout animals. Expression of bilirubin glucuronyl transferase and other components of the bilirubin metabolism pathway is induced by Yin Zhi Huang treatment of WT mice or mice expressing only human CAR, but not CAR knockout animals. 6,7-Dimethylesculetin, a compound present in Yin Chin, activates CAR in primary hepatocytes from both WT and humanized CAR mice and accelerates bilirubin clearance in vivo. We conclude that CAR mediates the effects of Yin Zhi Huang on bilirubin clearance and that 6,7-dimethylesculetin is an active component of this herbal medicine. CAR is a potential target for the development of new drugs to treat neonatal, genetic, or acquired forms of jaundice.
PMCID: PMC300765  PMID: 14702117

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