Death by biscuit--exhumation, post-mortem CT, and revision of the cause of death one year after interment

We describe a case of exhumation, performed to investigate the circumstances and cause of death, one year after burial. Post mortem computed tomography (PMCT) revealed a mass in the pharynx. Imaging directed the subsequent forensic autopsy to careful retrieval of a foreign body. Histological analysis revealed a non-cellular composition. The detection of foreign material in the pharynx and its composition indicated accidental, rather than natural death, secondary to choking on food. This unusual case illustrates how post mortem imaging can significantly contribute to forensic investigation and stresses the importance of interdisciplinary collaboration between forensic pathologists and radiologists.

Meta-analysis and dose-response metaregression: circulating insulin-like growth factor I (IGF-I) and mortality

Context: IGF-I plays a central role in metabolism and growth regulation. High IGF-I levels are associated with increased cancer risk and low IGF-I levels with increased risk for cardiovascular disease. Objective: Our objective was to determine the relationship between circulating IGF-I levels and mortality in the general population using random-effects meta-analysis and dose-response metaregression. Data Sources: We searched PubMed, EMBASE, Web of Science, and Cochrane Library from 1985 to September 2010 to identify relevant studies. Study Selection: Population-based cohort studies and (nested) case-control studies reporting on the relation between circulating IGF-I and mortality were assessed for eligibility. Data Extraction: Data extraction was performed by two investigators independently, using a standardized data extraction sheet. Data Synthesis: Twelve studies, with 14,906 participants, were included. Overall, risk of bias was limited. Mortality in subjects with low or high IGF-I levels was compared with mid-centile reference categories. All-cause mortality was increased in subjects with low as well as high IGF-I, with a hazard ratio (HR) of 1.27 (95% CI = 1.08–1.49) and HR of 1.18 (95% CI = 1.04–1.34), respectively. Dose-response metaregression showed a U-shaped relation of IGF-I and all-cause mortality (P = 0.003). The predicted HR for the increase in mortality comparing the 10th IGF-I with the 50th percentile was 1.56 (95% CI = 1.31–1.86); the predicted HR comparing the 90th with the 50th percentile was 1.29 (95% CI = 1.06–1.58). A U-shaped relationship was present for both cancer mortality and cardiovascular mortality. Conclusions: Both low and high IGF-I concentrations are associated with increased mortality in the general population.

Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis

Objective To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs. Design Network meta-analysis. Data sources Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data. Study selection All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility. Data extraction The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data. Data synthesis 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death. Conclusions Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.

Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease

The occurrence of depression in patients with coronary heart disease (CHD) substantially increases the likelihood of a poorer cardiovascular prognosis. Although antidepressants are generally effective in decreasing depression, their use in patients with CHD is controversial. We carried out a meta-analysis to evaluate the health effects of selective serotonin reuptake inhibitors (SSRIs) versus placebo or no antidepressants in patients with CHD and depression. Observational studies and randomized controlled trials (RCTs) were searched in MEDLINE, EMBASE, PsycINFO, Cochrane Controlled Clinical Trial Register and other trial registries, and references of relevant articles. Primary outcomes were readmission for CHD (including myocardial infarction, unstable angina, and stroke) and all-cause mortality; the secondary outcome was severity of depression symptoms. Seven articles on 6 RCTs involving 2,461 participants were included. One study incorrectly randomized participants, and another was a reanalysis of RCT data. These were considered observational and analyzed separately. When only properly randomized trials were considered (n = 734 patients), patients on SSRIs showed no significant differences in mortality (risk ratio 0.39, 95% confidence interval 0.08 to 2.01) or CHD readmission rates (0.74, 0.44 to 1.23) compared to controls. Conversely, when all studies were included, SSRI use was associated with a significant decrease in CHD readmission (0.63, 0.46 to 0.86) and mortality rates (0.56, 0.35 to 0.88). A significantly greater improvement in depression symptoms was always apparent in patients on SSRIs with all selected indicators. In conclusion, in patients with CHD and depression, SSRI medication decreases depression symptoms and may improve CHD prognosis.

Hyaluronic Acid as an Adjunct After Scaling and Root Planing - A Prospective Randomized Clinical Trial

Aim: The study was designed to determine the effect on clinical variables, subgingival bacteria and local immune response brought about by additional application of hyaluronan-containing gels in early wound healing after scaling and root planing (SRP). Material and Methods: In this randomised clinical study, data from 34 individuals with chronic periodontitis was evaluated after full-mouth SRP. In the test group (n = 17), hyaluronan gels in two molecular weights were additionally applied during the first two weeks after SRP. The control group (n = 17) was treated with SRP only. Probing depth (PD) and attachment level (AL) were recorded at baseline and after 3 and 6 months, and subgingival plaque and sulcus fluid samples were taken for microbiological and biochemical analysis. Results: In both groups, PD and AL were significantly reduced (p < 0.001). The changes in PD and the reduction of the numbers of pockets with PD ≥ 5mm were significantly higher in the test group after 3 (p = 0.014; p = 0.021) and 6 months (p = 0.046; p = 0.045). Six months after SRP, the counts of Treponema denticola were significantly reduced in both groups (both p = 0.043), those of Campylobacter rectus in the test group only (p = 0.028). Prevotella intermedia and Porphyromonas gingivalis increased in the control group. Conclusions: The adjunctive application of hyaluronan may have positive effects on probing depth reduction and may prevent recolonization by periodontopathogens.

Bone dimensions in the posterior mandible: a retrospective radiographic study using cone beam computed tomography. Part 1--analysis of dentate sites

This retrospective radiographic study analyzed the dimensions of the alveolar bone in the posterior dentate mandible based on cone beam computed tomography (CBCT) images. A total of 56 CBCT images met the inclusion criteria, resulting in a sample size of 122 cross sections showing posterior mandibular teeth (premolars and molars). The thickness of the buccal and lingual bone walls was measured at two locations: 4 mm apical to the cementoenamel junction (measurement point 1, MP1) and at the middle of the root (measurement point 2, MP2). Further, alveolar bone width was assessed at the level of the most coronal buccal bone detectable (alveolar bone width 1, BW1) and at the superior border of the mandibular canal (alveolar bone width 2, BW2). The vertical distance between the two as well as the presence of a lingual undercut were also analyzed. There was a steady increase in buccal bone wall thickness from the first premolar to the second molar at both MP1 and MP2. BW1 at the level of the premolars was significantly thinner than that for molars. Alveolar bone height was constant for all teeth examined. For the selection of an appropriate postextraction treatment approach, analysis of the alveolar bone dimensions at the tooth to be extracted by means of CBCT can offer valuable information concerning bone volume and morphology at the future implant site.

Can falls risk prediction tools correctly identify fall-prone elderly rehabilitation inpatients? A systematic review and meta-analysis

Background Falls of elderly people may cause permanent disability or death. Particularly susceptible are elderly patients in rehabilitation hospitals. We systematically reviewed the literature to identify falls prediction tools available for assessing elderly inpatients in rehabilitation hospitals. Methods and Findings We searched six electronic databases using comprehensive search strategies developed for each database. Estimates of sensitivity and specificity were plotted in ROC space graphs and pooled across studies. Our search identified three studies which assessed the prediction properties of falls prediction tools in a total of 754 elderly inpatients in rehabilitation hospitals. Only the STRATIFY tool was assessed in all three studies; the other identified tools (PJC-FRAT and DOWNTON) were assessed by a single study. For a STRATIFY cut-score of two, pooled sensitivity was 73% (95%CI 63 to 81%) and pooled specificity was 42% (95%CI 34 to 51%). An indirect comparison of the tools across studies indicated that the DOWNTON tool has the highest sensitivity (92%), while the PJC-FRAT offers the best balance between sensitivity and specificity (73% and 75%, respectively). All studies presented major methodological limitations. Conclusions We did not identify any tool which had an optimal balance between sensitivity and specificity, or which were clearly better than a simple clinical judgment of risk of falling. The limited number of identified studies with major methodological limitations impairs sound conclusions on the usefulness of falls risk prediction tools in geriatric rehabilitation hospitals.

Should aortic arch replacement be performed during initial surgery for aortic root aneurysm in patients with Marfan syndrome?

OBJECTIVES: The aim of this study was to investigate whether total arch replacement (TAR) during initial surgery for root aneurysm should be routinely performed in patients with Marfan syndrome (MFS). METHODS: Retrospective analysis of 94 consecutive MFS patients fulfilling Ghent criteria who underwent 148 aortic surgeries and were followed at this institution during the past 16 years. RESULTS: The mean follow-up interval was 8.8 ± 7 years. Initial presentation was acute aortic dissection (AAD) in 35% of patients (76% Type A and 24% Type B) and aneurismal disease in 65%. TAR was performed in 8% of patients during initial surgery for AAD (otherwise a hemi-arch replacement was performed) and 1.6% in elective root repair. Secondary TAR had to be performed in only 3% of patients without, but in 33% following AAD (33% Type A and 33% Type B; P = 0.0001). Thirty-day, 6-month, 1-year and overall mortalities were 3.2, 5.3, 6.4 and 11.7%, respectively. Operative and 30-day mortalities in secondary aortic arch replacement were zero. Secondary TAR after AAD did not increase the need for the replacement of the entire thoracoabdominal aorta during follow-up compared with patients without secondary TAR (37 vs 40%, P = 1.0). CONCLUSIONS: MFS patients undergoing elective root repair have small risk of reinterventions on the aortic arch, and primary prophylactic replacement does not seem to be justified. In patients with AAD, the need for reinterventions is precipitated by the dissection itself and not by limiting the procedure to the hemi-arch replacement in the emergency setting. Limiting surgery to the aortic root, ascending aorta and proximal aortic arch is associated with low mortality in MFS patients presenting with AAD.

A proteome signature for intrauterine growth restriction derived from multifactorial analysis of mass spectrometry-based cord blood serum profiling

Intrauterine growth restriction (IUGR) is defined as a condition in which the fetus does not reach its genetically given growth potential, resulting in low birth weight. IUGR is an important cause of perinatal morbidity and mortality, thus contributing substantially to medically indicated preterm birth in order to prevent fetal death. We subjected umbilical cord blood serum samples either belonging to the IUGR group (n = 15) or to the control group (n = 15) to fractionation by affinity chromatography using a bead system with hydrophobic interaction capabilities. So prepared protein mixtures were analyzed by MALDI-TOF mass spectrometric profiling. The six best differentiating ion signals at m/z 8205, m/z 8766, m/z 13 945, m/z 15 129, m/z 15 308, and m/z 16 001 were collectively assigned as IUGR proteome signature. Separation confidence of our IUGR proteome signature reached a sensitivity of 0.87 and a specificity of 0.93. Assignment of ion signals in the mass spectra to specific proteins was substantiated by SDS-PAGE in conjunction with peptide mass fingerprint analysis of cord blood serum proteins. One constituent of this proteome signature, apolipoprotein C-III(0) , a derivative lacking glycosylation, has been found more abundant in the IUGR cord blood serum samples, irrespective of gestational age. Hence, we suggest apolipoprotein C-III(0) as potential key-marker of the here proposed IUGR proteome signature, as it is a very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) member and as such involved in triglyceride metabolism that itself is discussed as being of importance in IUGR pathogenesis. Our results indicate that subtle alterations in protein glycosylation need to be considered for improving our understanding of the pathomechanisms in IUGR.

Biochemical analysis of mutations in P450 oxidoreductase

All microsomal P450s require POR (cytochrome P450 reductase) for catalytic activity. Most of the clinically used drugs are metabolized by a small number of P450s and polymorphisms in the cytochrome P450s are known to cause changes in drug metabolism. We have recently found a number of POR missense mutations in the patients with disordered steroidogenesis. Our initial report described five missense mutations (A284P, R454H, V489E, C566Y and V605F) identified in four patients. We built bacterial expression vectors for each POR variant, purified the membranes expressing normal or variant POR and characterized their activities with cytochrome c and P450c17 assays. We have recently completed an extensive study of the range of POR mutations and characterized the mutants/polymorphisms A112V, T139A, M260V, Y456H, A500V, G536R, L562P, R613X, V628I and F643del from sequencing of patient DNA. We also studied POR variants Y179D, P225L, R313W, G410S and G501R that were available in databases or the published literature. We analysed the mutations with a three-dimensional model of human POR that was based on an essentially similar rat POR with known crystal structure. The missense mutations found in patients with disordered steroidogenesis mapped to functionally important domains of POR and the apparent polymorphisms mapped to less crucial regions. Since a variation in POR can alter the activity of all microsomal P450s, it can also affect the drug metabolism even with a normal P450. Understanding the genetic and biochemical basis of POR-mediated drug metabolism will provide valuable information about possible differences in P450-mediated reactions among the individuals carrying a variant or polymorphic form of POR.

Rates of disease progression according to initial highly active antiretroviral therapy regimen: a collaborative analysis of 12 prospective cohort studies

BACKGROUND: No large clinical end-point trials have been conducted comparing regimens among human immunodeficiency virus type 1-positive persons starting antiretroviral therapy. We examined clinical progression according to initial regimen in the Antiretroviral Therapy Cohort Collaboration, which is based on 12 European and North American cohort studies. METHODS: We analyzed progression to death from any cause and to AIDS or death (AIDS/death), comparing efavirenz (EFV), nevirapine (NVP), nelfinavir, idinavir, ritonavir (RTV), RTV-boosted protease inhibitors (PIs), saquinavir, and abacavir. We also compared nucleoside reverse-transcriptase inhibitor pairs: zidovudine/lamivudine (AZT/3TC), stavudine (D4T)/3TC, D4T/didanosine (DDI), and others. RESULTS: A total of 17,666 treatment-naive patients, 55,622 person-years at risk, 1,617 new AIDS events, and 895 deaths were analyzed. Compared with EFV, the adjusted hazard ratio (HR) for AIDS/death was 1.28 (95% confidence interval [CI], 1.03-1.60) for NVP, 1.31 (95% CI, 1.01-1.71) for RTV, and 1.45 (95% CI, 1.15-1.81) for RTV-boosted PIs. For death, the adjusted HR for NVP was 1.65 (95% CI, 1.16-2.36). The adjusted HR for death for D4T/3TC was 1.35 (95% CI, 1.14-1.59), compared with AZT/3TC. CONCLUSIONS: Outcomes may vary across initial regimens. Results are observational and may have been affected by bias due to unmeasured or residual confounding. There is a need for large, randomized, clinical end-point trials.

Mutations in Uroplakin IIIA are a rare cause of renal hypodysplasia in humans

BACKGROUND: Renal hypodysplasia, characterized by a decrease in nephron number, small overall kidney size, and maldeveloped renal tissue, is a leading cause of chronic renal failure in young children. Familial clustering and renal hypodysplasia phenotypes observed in transgenic animal models suggest a genetic contribution. Uroplakin IIIa (encoded by UPIIIA) is an integral membrane protein present in urothelial plaques, and the murine UPIIIa knockout is associated with urothelial anomalies and vesicoureteral reflux. De novo UPIIIA mutations recently were identified in 4 of 17 patients with severe bilateral renal adysplasia. METHODS: To evaluate the overall role of UPIIIA in human renal hypodysplasia pathogenesis, we performed UPIIIA mutation analysis in a cohort of 170 pediatric patients affected by severe unilateral or bilateral renal hypodysplasia. Eighty-one patients were affected by bilateral nonobstructive renal hypodysplasia; of these, 61 were without vesicoureteral reflux. Eighty-four patients presented with unilateral nonobstructive renal hypodysplasia, including 24 patients with unilateral multicystic dysplastic kidneys. Family history was positive in 11%. RESULTS: Mutation analysis showed 2 heterozygous mutations not observed in 200 race-matched control chromosomes. In only 1 family was distribution of the UPIIIA mutation consistent with a disease-causing effect. This de novo missense mutation (Gly202Asp) was identified in a patient with unilateral multicystic dysplastic kidneys. The second (intronically located) mutation appeared unlikely to be disease causing because it did not segregate with an obvious disease phenotype in the affected family. CONCLUSION: Our results indicate that de novo mutations in UPIIIA can be involved in defective early kidney development, but probably constitute only a rare cause of human renal hypodysplasia in a minor subset of individuals.

Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study

BACKGROUND: The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo. METHODS: Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations. RESULTS: The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone. CONCLUSION: Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.

Analysis of gene order data supports vertical inheritance of the leukotoxin operon and genome rearrangements in the 5' flanking region in genus Mannheimia

BACKGROUND: The Mannheimia subclades belong to the same bacterial genus, but have taken divergent paths toward their distinct lifestyles. For example, M. haemolytica + M. glucosida are potential pathogens of the respiratory tract in the mammalian suborder Ruminantia, whereas M. ruminalis, the supposed sister group, lives as a commensal in the ovine rumen. We have tested the hypothesis that vertical inheritance of the leukotoxin (lktCABD) operon has occurred from the last common ancestor of genus Mannheimia to any ancestor of the diverging subclades by exploring gene order data. RESULTS: We examined the gene order in the 5' flanking region of the leukotoxin operon and found that the 5' flanking gene strings, hslVU-lapB-artJ-lktC and xylAB-lktC, are peculiar to M. haemolytica + M. glucosida and M. granulomatis, respectively, whereas the gene string hslVU-lapB-lktC is present in M. ruminalis, the supposed sister group of M. haemolytica + M. glucosida, and in the most ancient subclade M. varigena. In M. granulomatis, we found remnants of the gene string hslVU-lapB-lktC in the xylB-lktC intergenic region. CONCLUSION: These observations indicate that the gene string hslVU-lapB-lktC is more ancient than the hslVU-lapB-artJ-lktC and xylAB-lktC gene strings. The presence of (remnants of) the ancient gene string hslVU-lapB-lktC among any subclades within genus Mannheimia supports that it has been vertically inherited from the last common ancestor of genus Mannheimia to any ancestor of the diverging subclades, thus reaffirming the hypothesis of vertical inheritance of the leukotoxin operon. The presence of individual 5' flanking regions in M. haemolytica + M. glucosida and M. granulomatis reflects later genome rearrangements within each subclade. The evolution of the novel 5' flanking region in M. haemolytica + M. glucosida resulted in transcriptional coupling between the divergently arranged artJ and lkt promoters. We propose that the chimeric promoter have led to high level expression of the leukotoxin operon which could explain the increased potential of certain M. haemolytica + M. glucosida strains to cause a particular type of infection.

Analysis and mapping of CACNB4, CHRNA1, KCNJ3, SCN2A and SPG4, physiological candidate genes for porcine congenital progressive ataxia and spastic paresis

The cause of porcine congenital progressive ataxia and spastic paresis (CPA) is unknown. This severe neuropathy manifests shortly after birth and is lethal. The disease is inherited as a single autosomal recessive allele, designated cpa. In a previous study, we demonstrated close linkage of cpa to microsatellite SW902 on porcine chromosome 3 (SSC3), which corresponds syntenically to human chromosome 2. This latter chromosome contains ion channel genes (Ca(2+), K(+) and Na(+)), a cholinergic receptor gene and the spastin (SPG4) gene, which cause human epilepsy and ataxia when mutated. We mapped porcine CACNB4, KCNJ3, SCN2A and CHRNA1 to SSC15 and SPG4 to SSC3 with the INRA-Minnesota porcine radiation hybrid panel (IMpRH) and we sequenced the entire open reading frames of CACNB4 and SPG4 without finding any differences between healthy and affected piglets. An anti-epileptic drug treatment with ethosuximide did not change the severity of the disease, and pigs with CPA did not exhibit the corticospinal tract axonal degeneration found in humans suffering from hereditary spastic paraplegia, which is associated with mutations in SPG4. For all these reasons, the hypothesis that CACNB4, CHRNA1, KCNJ3, SCN2A or SPG4 are identical with the CPA gene was rejected.