Syphilis and cirrhosis: a lethal combination in a XIX century individual identified from the Medical Schools Collection at the University of Coimbra (Portugal)

Syphilis is a chronic infection that is categorized by a three-stage progression. The tertiary stage may affect bones and produce distinctive skull lesions called caries sicca. This paper aims to present an unusual case of syphilis associated with a diagnosis of cirrhosis, which was recorded as the cause of death in a 28-year-old female in 1899. The appearance and distribution of the lesions were compatible with acquired syphilis, as observed in the skull from the Medical Schools Collection of the University of Coimbra. However, the cause of death was recorded as "hypertrophic cirrhosis of the liver", this is a condition that is compatible with several liver disorders, including a primary liver disorder, such as cirrhosis provoked by alcoholism, infection of the liver by syphilis pathogens or by damage to the liver from the use of mercury compounds, which was the common treatment for syphilis at the time. This paper represents a contribution to the understanding of the natural evolution of syphilis.

Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder

BACKGROUND Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD. METHODS A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women) were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Genotyping of 20 Single Nucleotide Polymorphisms (SNPs), divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype) were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR) with a 95% of confidence interval were calculated. RESULTS Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1) rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002), allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013), allele T of Methylentetrahydrofolate Dehydrogenase (MTHFD) rs2236225 (OR = 3.09; 95%CI 1.27, 7.50; p = 0.016) and allele A of Methionine Synthase Reductase (MTRR) rs1801394 (OR = 2.35; 95CI 1.10, 5.00; p = 0.037). An inflammatory oxidative stress enzyme, Gluthatione S-Tranferase Mu-1(GSTM1), null allele (OR = 2.21; 95%CI 1.24, 4.36; p = 0.030) and a neurotransmission receptor, Dopamine Receptor D4 (DRD4), long allele of 48 bp-repeat (OR = 3.62; 95%CI 0.76, 17.26; p = 0.161). CONCLUSIONS Some genetic polymorphisms related to folates metabolism, inflammatory oxidative stress, and neurotransmission responses to pain, has been significantly associated to TMD syndrome.

Additive effects of LPL, APOA5 and APOE variant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study.

BACKGROUND Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information. METHODS A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the LPL-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the APOA5-S19W (rs3135506) and -1131T/C (rs662799) variants, and the APOE polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG > or = 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption. RESULTS We found a significant lowering effect of the LPL-HindIII and S447X polymorphisms (p < 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the APOE-epsilon4 allele were significantly associated with an independent additive TG-raising effect (p < 0.05, p < 0.01, p < 0.001, p < 0.0001 and p < 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (p < 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; p = 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; p < 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; p < 0.001) were associated with HTG. CONCLUSION Our results showed a significant independent additive effect on TG levels of the LPL polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of APOA5, and the epsilon4 allele of APOE in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia.

Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency.

Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits (ND1 to ND6 and ND4L) in affected tissues. This approach yielded the unexpectedly high rate of 20% mutation identification in our series. Recurrent heteroplasmic mutations included two hitherto unreported (T10158C and T14487C) and three previously reported mutations (T10191C, T12706C and A13514G) in children with Leigh or Leigh-like encephalopathy. The recurrent mutations consistently involved T-->C transitions (p<10(-4)). This study supports the view that an efficient molecular screening should be based on an accurate identification of respiratory chain enzyme deficiency.

Aider les étudiants en médecine à approcher la mort [Helping medical students to approach death].

A project recently launched by the Faculty of biology and medicine of Lausanne introduces the approach of facing death during both the dissection and the course of clinical activities. Existential questions relating to mortality are bound to arise sooner or later during the course of the study. For the sake of humanized clinical practice, these questions must be confronted. In response to a request by a student association, an accompanying curriculum with active student's contribution through encounters with death in anatomy and clinical situations was created in Lausanne. Students will benefit from this new program throughout their curriculum. This program is the first of its kind in Switzerland.

Genetic variations in drug-induced liver injury (DILI): resolving the puzzle.

Despite stringent requirements for drug development imposed by regulatory agencies, drug-induced liver injury (DILI) is an increasing health problem and a significant cause for failure to approve drugs, market withdrawal of commercialized medications, and adoption of regulatory measures. The pathogenesis is yet undefined, though the rare occurrence of idiosyncratic DILI (1/100,000–1/10,000) and the fact that hepatotoxicity often recurs after re-exposure to the culprit drug under different environmental conditions strongly points toward a major role for genetic variations in the underlying mechanism and susceptibility. Pharmacogenetic studies in DILI have to a large extent focused on genes involved in drug metabolism, as polymorphisms in these genes may generate increased plasma drug concentrations as well as lower clearance rates when treated with standard medication doses. A range of studies have identified a number of genetic variants in drug metabolism Phase I, II, and III genes, including cytochrome P450 (CYP) 2E1, N-acetyltransferase 2, UDP-glucuronosyltransferase 2B7, glutathione S-transferase M1/T1, ABCB11, and ABCC2, that enhance DILI susceptibility (Andrade et al., 2009; Agundez et al., 2011). Several metabolic gene variants, such as CYP2E1c1 and NAT2 slow, have been associated with DILI induced by specific drugs based on individual drug metabolism information. Others, such as GSTM1 and T1 null alleles have been associated with enhanced risk of DILI development induced by a large range of drugs. Hence, these variants appear to have a more general role in DILI susceptibility due to their role in reducing the cell's antioxidative capacity (Lucena et al., 2008). Mitochondrial superoxide dismutase (SOD2) and glutathione peroxidase 1 (GPX1) are two additional enzymes involved in combating oxidative stress, with specific genetic variants shown to enhance the risk of developing DILI

Prenatal detection of rare chromosomal autosomal abnormalities in Europe.

The aim of the present study was to evaluate the prenatal detection of rare chromosomal autosomal abnormalities by ultrasound (US) examination. Data were obtained from 19 congenital malformation registries from 11 European countries, between 01/07/96 and 31/12/98. A total of 664,340 births were covered and 7,758 cases with congenital malformations were recorded. Rare autosomal abnormalities were diagnosed in 114 cases (6.6%) from a total of 1,738 chromosome abnormalities. There were a wide variety of autosomal abnormalities: the most common were deletions (33 cases), duplications (32 cases), trisomies of chromosomes 8, 9, 10, 14, 15, and 16 (23 cases), and unbalanced rearrangements (19 cases). Out of these cases, 45.6% were detected prenatally by US examination due to the presence of congenital anomaly. As for the types of chromosomal anomaly, unbalanced rearrangements and deletions were the most frequently detected by US. A high percentage of cases with balanced rearrangements were associated with severe congenital anomalies. The most frequent congenital anomalies detected by US were cystic hygroma (20.6%), central nervous system defects (17.6%), cardiac defects (13.2%), and diaphragm defects (10.3%). This large series offers useful information about prenatal diagnosis by US of congenital defects associated with rare autosomal abnormalities and it provides a valuable knowledge about outcome. Fetal anomalies detected by US that were associated with rare autosomal abnormalities were significantly more frequent than those associated with common chromosomal abnormalities (45.6 vs. 34.7%). This study indicates the need to increase the detection of congenital anomalies by US.

Organisation des secours extrahospitaliers lors du sommet 2003 du G8: nouveau concept de poste médical mobile (PMM) [Prehospital medical care organization during the 2003 G8 summit: a new concept of Mobile Medical Squadrons (MMS)].

OBJECTIVE: The occurrence of the 2003 G8 summit in Evian and the threat of major civil riots or even terrorist attacks in the Swiss neighbourhood forced us to imagine a new system of rescue and medical care in case of numerous victims. Previous occurrences of the G8 in Europe or America have demonstrated the need of flexible and mobile structures, able to respond quickly to crowd movements, unlike the usual static structure of rescue systems designed for major accidents. METHODS: We developed a new concept of Mobile Medical Squadrons (MMS) consisting of several vehicles and medical care and rescue human resources. In our concept, each MMS consisted of 3 emergency doctors, 5 paramedics and 9 first-aid workers. They were designed to handle 15 patients, with a large autonomy in terms of rescue, medical care, evacuation and medical authority. The equipment included medical, resuscitation, simple decontamination, evacuation and communication materials. RESULTS: The MMS were dispatched four times during the G8 summit following civil riots. They took care of 12 injured patients. CONCLUSION: The concept of MMS as a reinforcement of the existing rescue and health care resources appears as a new flexible, a modular and useful concept for the medical management of collective prehospital emergency situations. Its use is suggested instead of the traditional static concept of rescue systems designed for major accidents.

Basic life support teaching in the second year pregraduate medical curriculum: quality of acquisition after 6 months

Purpose of the study: Basic life support (BLS) and automated externaldefibrillation (AED) represent important skills to be acquired duringpregraduate medical training. Since 3 years, our medical school hasintroduced a BLS-AED course (with certification) for all second yearmedical students. Few reports about quality and persistence over timeof BLS-AED learning are available to date in the medical literature.Comprehensive evaluation of students' acquired skills was performedat the end of the 2008 academic year, 6 month after certification.Materials and methods: The students (N = 142) were evaluated duringa 9 minutes «objective structured clinical examination» (OSCE) station.Out of a standardized scenario, they had to recognize a cardiac arrestsituation and start a resuscitation process. Their performance wererecorded on a PC using an Ambuman(TM) mannequin and the AmbuCPR software kit(TM) during a minimum of 8 cycles (30 compressions:2 ventilations each). BLS parameters were systematically checked. Nostudent-rater interactions were allowed during the whole evaluation.Results: Response of the victim was checked by 99% of the students(N = 140), 96% (N = 136) called for an ambulance and/or an AED. Openthe airway and check breathing were done by 96% (N = 137), 92% (N =132) gave 2 rescue breaths. Pulse was checked by 95% (N=135), 100%(N = 142) begun chest compression, 96% (N = 136) within 1 minute.Chest compression rate was 101 ± 18 per minute (mean ± SD), depthcompression 43 ± 8 mm, 97% (N = 138) respected a compressionventilationratio of 30:2.Conclusions: Quality of BLS skills acquisition is maintained during a6-month period after a BLS-AED certification. Main targets of 2005 AHAguidelines were well respected. This analysis represents one of thelargest evaluations of specific BLS teaching efficiency reported. Furtherfollow-up is needed to control the persistence of these skills during alonger time period and noteworthy at the end of the pregraduatemedical curriculum.

Incongruence between test statistics and P values in medical papers

Given an observed test statistic and its degrees of freedom, one may compute the observed P value with most statistical packages. It is unknown to what extent test statistics and P values are congruent in published medical papers. Methods:We checked the congruence of statistical results reported in all the papers of volumes 409–412 of Nature (2001) and a random sample of 63 results from volumes 322–323 of BMJ (2001). We also tested whether the frequencies of the last digit of a sample of 610 test statistics deviated from a uniform distribution (i.e., equally probable digits).Results: 11.6% (21 of 181) and 11.1% (7 of 63) of the statistical results published in Nature and BMJ respectively during 2001 were incongruent, probably mostly due to rounding, transcription, or type-setting errors. At least one such error appeared in 38% and 25% of the papers of Nature and BMJ, respectively. In 12% of the cases, the significance level might change one or more orders of magnitude. The frequencies of the last digit of statistics deviated from the uniform distribution and suggested digit preference in rounding and reporting.Conclusions: this incongruence of test statistics and P values is another example that statistical practice is generally poor, even in the most renowned scientific journals, and that quality of papers should be more controlled and valued

Human genetic selection on the MTHFR 677C>T polymorphism.

BACKGROUND The prevalence of genotypes of the 677C>T polymorphism for the MTHFR gene varies among humans. In previous studies, we found changes in the genotypic frequencies of this polymorphism in populations of different ages, suggesting that this could be caused by an increase in the intake of folate and multivitamins by women during the periconceptional period. The aim was to analyze changes in the allelic frequencies of this polymorphism in a Spanish population, including samples from spontaneous abortions (SA). METHODS A total of 1305 subjects born in the 20th century were genotyped for the 677C>T polymorphism using allele specific real-time PCR with Taqman probes. A section of our population (n = 276) born in 1980-1989 was compared with fetal samples (n = 344) from SA of unknown etiology from the same period. RESULTS An increase in the frequency of the T allele (0.38 vs 0.47; p < 0.001) and of the TT genotype (0.14 vs 0.24; p < 0.001) in subjects born in the last quarter of the century was observed. In the 1980-1989 period, the results show that the frequency of the wild type genotype (CC) is about tenfold lower in the SA samples than in the controls (0.03 vs 0.33; p < 0.001) and that the frequency of the TT genotype increases in the controls (0.19 to 0.27) and in the SA samples (0.20 to 0.33 (p < 0.01)); r = 0.98. CONCLUSION Selection in favor of the T allele has been detected. This selection could be due to the increased fetal viability in early stages of embryonic development, as is deduced by the increase of mutants in both living and SA populations.

Genetics of leprosy reactions: an overview

Type-1 (T1R) and Type-2 (T2R) leprosy reactions (LR), which affect up to 50% of leprosy patients, are aggressive inflammatory episodes of sudden onset and highly variable incidence across populations. LR are often diagnosed concurrently with leprosy, but more frequently occur several months after treatment onset. It is not uncommon for leprosy patients to develop recurring reactional episodes; however, they rarely undergo both types of LR. Today, LR are the main cause of permanent disabilities associated with leprosy and represent a major challenge in the clinical management of leprosy patients. Although progress has been made in understanding the immunopathology of LR, the factors that cause a leprosy patient to suffer from LR are largely unknown. Given the impact that ethnic background has on the risk of developing LR, host genetic factors have long been suspected of contributing to LR. Indeed, polymorphisms in seven genes [Toll-like receptors (TLR)1, TLR2, nucleotide-binding oligomerisation domain containing 2, vitamin D receptor, natural resistance-associated macrophage protein 1, C4B and interleukin-6] have been found to be associated with one or more LR outcomes. The identification of host genetic markers with predictive value for LR would have a major impact on nerve damage control in leprosy. In this review, we present the recent advances achieved through genetic studies of LR.