Widespread occurrence of Mycobacterium tuberculosis DNA from 18th-19th century Hungarians

A large number (265) of burials from 1731-1838 were discovered in sealed crypts of the Dominican Church, Vac, Hungary in 1994. Many bodies were naturally mummified, so that both soft tissues and bones were available. Contemporary archives enabled the determination of age at death, and the identification of family groups. In some cases, symptoms before death were described and, occasionally, occupation. Initial radiological examination of a small number of individuals had indicated calcified lung lesions and demonstrable acid-fast bacteria suggestive of tuberculosis infection. Tuberculosis was endemic in 18th-19th century Europe, so human remains should contain detectable Mycobacterium tuberculosis complex (MTB) DNA, enabling comparisons with modern isolates. Therefore, a comprehensive examination of 168 individuals for the presence of MTB DNA was undertaken. Specific DNA amplification methods for MTB showed that 55% of individuals were positive and that the incidence varied according to age at death and sampling site in the body. Radiographs were obtained from 27 individuals and revealed an association between gross pathology and the presence of MTB DNA. There was an inverse relationship between PCR positivity and MTB target sequence size. In some cases, the preservation of MTB DNA was excellent, and several target gene sequences could be detected from the same sample. This information, combined with MTB DNA sequencing data and molecular typing techniques, will enable us to study the past epidemiology of TB infection, and extends the timeframe for studying changes in molecular fingerprints. Am J Phys Anthropol 120:144-152, 2003. (C) 2003 Wiley-Liss, Inc

Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms

The varying role of the GP in the pathway between colonoscopy and surgery for colorectal cancer: a retrospective cohort study

Extent: 11p.Objectives: To describe general practitioner (GP) involvement in the treatment referral pathway for colorectal cancer (CRC) patients. Design: A retrospective cohort analysis of linked data. Setting: A population-based sample of CRC patients diagnosed from August 2004 to December 2007 in New South Wales, Australia, using the 45 and Up Study, cancer registry diagnosis records, inpatient hospital records and Medicare claims records. Participants: 407 CRC patients who had a colonoscopy followed by surgery. Primary outcome measures: Patterns of GP consultations between colonoscopy and surgery (ie, between diagnosis and treatment). We investigated whether consulting a GP presurgery was associated with time to surgery, postsurgical GP consultations or rectal cancer cases having surgery in a centre with radiotherapy facilities. Results: Of the 407 patients, 43% (n=175) had at least one GP consultation between colonoscopy and surgery. The median time from colonoscopy to surgery was 27 days for those with an intervening GP consultation and 15 days for those without the consultation. 55% (n=223) had a GP consultation up to 30 days postsurgery; it was more common in cases of patients who consulted a GP presurgery than for those who did not (65% and 47%, respectively, adjusted OR 2.71, 95% CI 1.50 to 4.89, p=0.001). Of the 142 rectal cancer cases, 23% (n=33) had their surgery in a centre with radiotherapy facilities, with no difference between those who did and did not consult a GP presurgery (21% and 25% respectively, adjusted OR 0.84, 95% CI 0.27 to 2.63, p=0.76). Conclusions: Consulting a GP between colonoscopy and surgery was associated with a longer interval between diagnosis and treatment, and with further GP consultations postsurgery, but for rectal cancer cases it was not associated with treatment in a centre with radiotherapy facilities. GPs might require a more defined and systematic approach to CRC management.David Goldsbury, Mark Harris, Shane Pascoe, Michael Barton, Ian Olver, Allan Spigelman, Justin Beilby, Craig Veitch, David Weller, Dianne L O'Connel

The intention to hasten death: a survey of attitudes and practices of surgeons in Australia

Objective: To determine attitudes among surgeons in Australia to assisted death, and the proportion of surgeons who have intentionally hastened death with or without an explicit request. Design: Anonymous, cross-sectional, mail-out survey between August and November 1999. Participants: 683 out of 992 eligible general surgeons (68.9% response rate). Main outcome measures: Proportion of respondents answering affirmatively to questions about administering excessive doses of medication with an intention to hasten death. Results: 247 respondents (36.2%; 95% CI, 32.6%-39.9%) reported that, for the purpose of relieving a patient's suffering, they have given drugs in doses that they perceived to be greater than those required to relieve symptoms with the intention of hastening death. More than half of these (139 respondents; 20.4% of all respondents; 95% CI, 17.4%-23.6%) reported that they had never received an unambiguous request for a lethal dose of medication. Of all respondents, only 36 (5.3%; 95% CI, 2.9%-6.1%) reported that they had given a bolus lethal injection, or had provided the means to commit suicide, in response to an unambiguous request. Conclusions: More than a third of surgeons surveyed reported giving drugs with an intention to hasten death, often in the absence of an explicit request. However, in many instances, this may involve the use of an infusion of analgesics or sedatives, and such actions may be difficult to distinguish from accepted palliative care, except on the basis of the doctor's self-reported intention. Legal and moral distinctions based solely on a doctor's intention are problematic

The intention to hasten death: a survey of attitudes and practices of surgeons in Australia

Objective: To determine attitudes among surgeons in Australia to assisted death, and the proportion of surgeons who have intentionally hastened death with or without an explicit request. Design: Anonymous, cross-sectional, mail-out survey between August and November 1999. Participants: 683 out of 992 eligible general surgeons (68.9% response rate). Main outcome measures: Proportion of respondents answering affirmatively to questions about administering excessive doses of medication with an intention to hasten death. Results: 247 respondents (36.2%; 95% CI, 32.6%-39.9%) reported that, for the purpose of relieving a patient's suffering, they have given drugs in doses that they perceived to be greater than those required to relieve symptoms with the intention of hastening death. More than half of these (139 respondents; 20.4% of all respondents; 95% CI, 17.4%-23.6%) reported that they had never received an unambiguous request for a lethal dose of medication. Of all respondents, only 36 (5.3%; 95% CI, 2.9%-6.1%) reported that they had given a bolus lethal injection, or had provided the means to commit suicide, in response to an unambiguous request. Conclusions: More than a third of surgeons surveyed reported giving drugs with an intention to hasten death, often in the absence of an explicit request. However, in many instances, this may involve the use of an infusion of analgesics or sedatives, and such actions may be difficult to distinguish from accepted palliative care, except on the basis of the doctor's self-reported intention. Legal and moral distinctions based solely on a doctor's intention are problematic

Germline Missense Changes in the APC Gene and Their Relationship to Disease

Familial adenomatous polyposis (FAP) is characterized by the presence of hundreds to thousands of adenomas that carpet the entire colon and rectum. Nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene account for the majority of mutations identified to date and predispose primarily to the typical disease phenotype. Some APC mutations are associated with a milder form of the disease known as attenuated FAP. Virtually all mutations that have been described in the APC gene result in the formation of a premature stop codon and very little is known about missense mutations apart from a common Ashkenazi Jewish mutation (1307 K) and a British E1317Q missense change. The incidence of missense mutations in the APC gene has been underreported since the APC gene lends itself to analysis using an artificial transcription and translation assay known as the Protein Truncation Test (PTT) or the In Vitro Synthetic Protein assay (IVSP)

Tuberculosis in Dr Granville's mummy: a molecular re-examination of the earliest known Egyptian mummy to be scientifically examined and given a medical diagnosis

‘Dr Granville's mummy’ was described to the Royal Society of London in 1825 and was the first ancient Egyptian mummy to be subjected to a scientific autopsy. The remains are those of a woman, Irtyersenu, aged about 50, from the necropolis of Thebes and dated to about 600 BC. Augustus Bozzi Granville (1783–1872), an eminent physician and obstetrician, described many organs still in situ and attributed the cause of death to a tumour of the ovary. However, subsequent histological investigations indicate that the tumour is a benign cystadenoma. Histology of the lungs demonstrated a potentially fatal pulmonary exudate and earlier studies attempted to associate this with particular disease conditions. Palaeopathology and ancient DNA analyses show that tuberculosis was widespread in ancient Egypt, so a systematic search for tuberculosis was made, using specific DNA and lipid biomarker analyses. Clear evidence for Mycobacterium tuberculosis complex DNA was obtained in lung tissue and gall bladder samples, based on nested PCR of the IS6110 locus. Lung and femurs were positive for specific M. tuberculosis complex cell-wall mycolic acids, demonstrated by high-performance liquid chromatography of pyrenebutyric acid–pentafluorobenzyl mycolates. Therefore, tuberculosis is likely to have been the major cause of death of Irtyersenu

Gene expression signatures affected by alcohol-induced DNA methylomic deregulation in human embryonic stem cells

AbstractStem cells, especially human embryonic stem cells (hESCs), are useful models to study molecular mechanisms of human disorders that originate during gestation. Alcohol (ethanol, EtOH) consumption during pregnancy causes a variety of prenatal and postnatal disorders collectively referred to as fetal alcohol spectrum disorders (FASDs). To better understand the molecular events leading to FASDs, we performed a genome-wide analysis of EtOH's effects on the maintenance and differentiation of hESCs in culture. Gene Co-expression Network Analysis showed significant alterations in gene profiles of EtOH-treated differentiated or undifferentiated hESCs, particularly those associated with molecular pathways for metabolic processes, oxidative stress, and neuronal properties of stem cells. A genome-wide DNA methylome analysis revealed widespread EtOH-induced alterations with significant hypermethylation of many regions of chromosomes. Undifferentiated hESCs were more vulnerable to EtOH's effect than their differentiated counterparts, with methylation on the promoter regions of chromosomes 2, 16 and 18 in undifferentiated hESCs most affected by EtOH exposure. Combined transcriptomic and DNA methylomic analysis produced a list of differentiation-related genes dysregulated by EtOH-induced DNA methylation changes, which likely play a role in EtOH-induced decreases in hESC pluripotency. DNA sequence motif analysis of genes epigenetically altered by EtOH identified major motifs representing potential binding sites for transcription factors. These findings should help in deciphering the precise mechanisms of alcohol-induced teratogenesis

Treatment of Highly Drug-Resistant Pulmonary Tuberculosis

BACKGROUND Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs — bedaquiline, pretomanid, and linezolid — that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799. opens in new tab.