Diseases and deaths; a statistical survey of 40,130 autopsies at the Los Angeles County General Hospital, 1918 to 1948. II

The 215,468 diagnoses recorded in 40,130 autopsies on patients treated at the Los Angeles County General Hospital during the 30 years between 1918 and 1948 were reviewed and tabulated. The primary causes of death as determined by the pathologists in these cases were recorded and the incidence of death from each disease in relation to the number of cases in which each occurred was computed. The age, sex and race distribution of patients examined postmortem and the incidence and fatality rates from various pathological conditions changed greatly during the period, owing to many factors, among them changes in elements of the population served by the hospital, an increasing incidence of older patients, and medical triumph over some formerly formidable diseases.     

Establishing a cohort at high risk of HIV infection in South Africa: challenges and experiences of the CAPRISA 002 acute infection study

Objectives

To describe the baseline demographic data, clinical characteristics and HIV-incidence rates of a cohort at high risk for HIV infection in South Africa as well as the challenges experienced in establishing and maintaining the cohort.

Methodology/Principle Findings

Between August 2004 and May 2005 a cohort of HIV-uninfected women was established for the CAPRISA 002 Acute Infection Study, a natural history study of HIV-1 subtype C infection. Volunteers were identified through peer-outreach. The cohort was followed monthly to determine HIV infection rates and clinical presentation of early HIV infection. Risk reduction counselling and male and female condoms were provided. After screening 775 individuals, a cohort of 245 uninfected high-risk women was established. HIV-prevalence at screening was 59.6% (95% CI: 55.9% to 62.8%) posing a challenge in accruing HIV-uninfected women. The majority of women (78.8%) were self-identified as sex-workers with a median of 2 clients per day. Most women (95%) reported more than one casual sexual partner in the previous 3 months (excluding clients) and 58.8% reported condom use in their last sexual encounter. Based on laboratory testing, 62.0% had a sexually transmitted infection at baseline. During 390 person-years of follow-up, 28 infections occurred yielding seroincidence rate of 7.2 (95% CI: 4.5 to 9.8) per 100 person-years. Despite the high mobility of this sex worker cohort retention rate after 2 years was 86.1%. High co-morbidity created challenges for ancillary care provision, both in terms of human and financial resources.

Conclusions/Significance

Challenges experienced were high baseline HIV-prevalence, lower than anticipated HIV-incidence and difficulties retaining participants. Despite challenges, we have successfully accrued this cohort of HIV-uninfected women with favourable retention, enabling us to study the natural history of HIV-1 during acute HIV-infection. Our experiences provide lessons for others establishing similar cohorts, which will be key for advancing the vaccine and prevention research agenda in resource-constrained settings.     

Mortality rates in patients with burns; a report of experience at San Francisco City and County Hospital, 1943-1956

A review was made of the cases of 93 patients with burns covering more than 20 per cent of the body surface who were treated at the San Francisco City and County Hospital, University of California Service, between 1943 and 1956. The mortality rate increased from 40 per cent during 1943-1947 to 69 per cent during 1952-1956. A significant change in survival time was noted: During 1943-1947, 69 per cent of the deaths occurred within 48 hours of admission; during 1952-1956, only 19 per cent of the deaths occurred within the first 48 hours. In the period 1943-1947 the majority of deaths resulted from shock in the immediate post-burn period; in the later years of the study the major cause of death was infection. No patient more than 50 years of age who had burns of more than 25 per cent of the body surface survived. Only one patient with burns involving more than 45 per cent survived. No patient who had a blood culture positive for bacteria survived. The use of antibiotics had no effect on the incidence of infection. Elderly patients, children and alcoholics were less able to resist the effects of infection. The lowest mortality rate was in the age group of 15 through 35 years.     

Oxidative damage to DNA and single strand break repair capacity: relationship to other measures of oxidative stress in a population cohort

It is well accepted that oxidative DNA repair capacity, oxidative damage to DNA and oxidative stress play central roles in aging and disease development. However, the correlation between oxidative damage to DNA, markers of oxidant stress and DNA repair capacity is unclear. In addition, there is no universally accepted panel of markers to assess oxidative stress in humans. Our interest is oxidative damage to DNA and its correlation with DNA repair capacity and other markers of oxidative stress. We present preliminary data from a small comet study that attempts to correlate single strand break (SSB) level with single strand break repair capacity (SSB-RC) and markers of oxidant stress and inflammation. In this limited study of four very small age-matched 24-individual groups of male and female whites and African-Americans aged 30-64 years, we found that females have higher single strand break (SSB) levels than males (p=0.013). There was a significant negative correlation between SSB-RC and SSB level (p=0.041). There was a positive correlation between SSBs in African American males with both heme degradation products (p=0.008) and high-sensitivity C-reactive protein (hs-CRP) (p=0.022). We found a significant interaction between hs-CRP and sex in their effect on residual DNA damage (p=0.002). Red blood cell reduced glutathione concentration was positively correlated with the levels of oxidized bases detected by endonuclease III (p=0.047), heme degradation products (p=0.015) and hs-CRP (p=0.020). However, plasma carbonyl levels showed no significant correlation with other markers. The data from the literature and from our very limited study suggest a complex relationship between measures of oxidative stress and frequently used clinical parameters believed to reflect inflammation or oxidative stress.     

AIDS and antibodies to human immunodeficiency virus (HIV) in children and their families: clinical experience at Yale-New Haven Hospital

As of December 1986, we have identified 23 symptomatic children with human immunodeficiency virus (HIV) infection in New Haven. Twelve developed AIDS as manifested by lymphocytic interstitial pneumonitis, Pneumocystis carinii pneumonia (PCP), and/or disseminated mycobacterial infections; seven of them have died. The remainder have milder clinical syndromes, which include failure to thrive, diffuse lymphadenopathy, and parotid swelling. When compared to adults with AIDS, children often have hypergammaglobulinemia and normal numbers of T4 lymphocytes. Intravenous drug abuse by the mother or mother's consort is the risk factor in 87 percent of these children. Two families have now been identified with more than one symptomatic child, but in no family is there evidence of spread from symptomatic children to uninfected siblings. A prospective study was begun to attempt to assess the risk of developing symptomatic HIV infection when a child is born to a mother with antibodies to HIV.     

Mechanistic studies of ionizing radiation and oxidative mutagenesis: genetic effects of a single 8-hydroxyguanine (7-hydro-8-oxoguanine) residue inserted at a unique site in a viral genome

T4 RNA ligase was used to construct a deoxypentanucleotide containing a single 8-hydroxyguanine (7-hydro-8-oxoguanine; G8-OH) residue, which is one of the putatively mutagenic DNA adducts produced by oxidants and ionizing radiation. The pentamer d(GCTAG8-OH)p was prepared by the ligation of a chemically synthesized acceptor molecule, d(GCTA), to an adducted donor, 8-hydroxy-2'-deoxyguanosine 5',3'-bisphosphate. The acceptor was efficiently converted to the reaction product (greater than 95%), and the final product yield was 50%. Following 3'-dephosphorylation, the pentamer was characterized by UV spectroscopy, by high-pressure liquid chromatography, and by gas chromatography-mass spectrometry of the nucleosides released by enzymatic hydrolysis. Both d(GCTAG8-OH) and an unmodified control were 5'-phosphorylated by using [gamma -32P]ATP and incorporated covalently by DNA ligase into a five-base gap at a unique NheI restriction site in the otherwise duplex genome of an M13mp19 derivative. The ligation product contained G8-OH at the 3' residue of an in-frame amber codon (5'-TAG-3') (genome position 6276) of the phage lacZ alpha gene. The adduct was part of a nonsense codon in a unique restriction site in order to facilitate the identification and selection of mutants generated by the replication of the modified genome in Escherichia coli. Both control and adducted pentamers ligated into the genome at 50% of the maximum theoretical efficiency, and nearly all (approximately 90%) of the site-specifically adducted products possessed pentanucleotides that were covalently linked at both 5' and 3' termini. The G8-OH lesion in the NheI site inhibited the cleavage of the site by a 200-fold excess of NheI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biochemical responses and oxidative stress in <Emphasis Type="Italic">Francisella tularensis</Emphasis> infection: a European brown hare model

Background  

The aim of the present study was to investigate biochemical and oxidative stress responses to experimental F. tularensis infection in European brown hares, an important source of human tularemia infections.     

Adding psychotherapy to antidepressant medication in depression and anxiety disorders: a meta‐analysis

We conducted a meta‐analysis of randomized trials in which the effects of treatment with antidepressant medication were compared to the effects of combined pharmacotherapy and psychotherapy in adults with a diagnosed depressive or anxiety disorder. A total of 52 studies (with 3,623 patients) met inclusion criteria, 32 on depressive disorders and 21 on anxiety disorders (one on both depressive and anxiety disorders). The overall difference between pharmacotherapy and combined treatment was Hedges' g = 0.43 (95% CI: 0.31‐0.56), indicating a moderately large effect and clinically meaningful difference in favor of combined treatment, which corresponds to a number needed to treat (NNT) of 4.20. There was sufficient evidence that combined treatment is superior for major depression, panic disorder, and obsessive‐compulsive disorder (OCD). The effects of combined treatment compared with placebo only were about twice as large as those of pharmacotherapy compared with placebo only, underscoring the clinical advantage of combined treatment. The results also suggest that the effects of pharmacotherapy and those of psychotherapy are largely independent from each other, with both contributing about equally to the effects of combined treatment. We conclude that combined treatment appears to be more effective than treatment with antidepressant medication alone in major depression, panic disorder, and OCD. These effects remain strong and significant up to two years after treatment. Monotherapy with psychotropic medication may not constitute optimal care for common mental disorders.     

Protective role of alpha-tocopherol-succinate (provitamin-E) in cyclophosphamide induced testicular gametogenic and steroidogenic disorders: a correlative approach to oxidative stress

The present study was undertaken to find out the adverse effects of cyclophosphamide on testicular activities along with testicular oxidative stress at its therapeutic dose and the protective effects of alpha-tocopherol succinate on testicular dysfunctions induced by cyclophosphamide in mature albino rats. A significant diminution in the activities of testicular delta 5, 3 beta-hydroxysteroid dehydrogenase (HSD) and 17 beta-hydroxysteroid dehydrogenase (HSD) along with significant reduction in the plasma level of testosterone and number of spermatogonia-A (ASg), preleptotene spermatocytes (pLSc), midpachytene spermatocytes (mPSc) and step 7 spermatids (7Sd) at stage VII of spermatogenic cycle were observed following cyclophosphamide treatment. Oxidative stress was also noted in testis, which was enlightened by significant elevation in the level of malondialdehyde (MDA) and conjugated dienes along with significant reduction in the activities of testicular peroxidase and catalase. Co-administration of alpha-tocopherol succinate in cyclophosphamide-treated rats resulted a significant restoration of all the above-mentioned parameters to the control level. The results of our experiment suggest that cyclophosphamide treatment at its clinical dose is associated with antigonadal activities as well as induction of oxidative stress in gonad that can be ameliorated significantly by alpha-tocopherol succinate co-administration. So, our data have some potential clinical implications.     

Improvement in the oxidative folding of endothelin-1 by a Lys-Arg extension at the amino terminus: Implication of a salt bridge between Arg-1 and Asp8

Summary An amino-terminal extension of endothelin-l by the lys-Arg dipeptide in the prosequence (KR-ET-1) greatly increased the ratio of native-type to non-native-type disulfide isomer (96/4 versus 71/29) during the oxidative folding reaction. This improvement was completely abolished by substituting Asn for Asp at position 8 (D8N-KR-ET-1), whereas most of it was maintained with similar carboxamide analogues replaced at Glu¹⁰ or Asp¹⁸. Structure analyses by circular dichroism spectroscopy revealed that (i) in the carboxylate state, the α-helical content of the native-type isomer of KR-ET-l is higher than that of the native-type isomer of ET-1, while such a variation is not observed in the corresponding non-native-type isomer of KR-ET-l; and (ii) the enhanced α-helicity resulting from the Lys-Arg extension is largely diminished in D8N-KR-ET-l. From these results and our previous findings that the helical structure in KR-ET-l is stabilized by a particular salt bridge between the extended Arg⁻¹ basic moiety and either the Asp⁸ or Glu¹⁰ acidic side chain in Et-1 [Aumelas, A. et al., Biochemistry, 34 (1995) 4546], we conclude that the formation of a specific salt bridge between the side chains of Arg⁻¹ and Asp⁸ in KR-ET-1 is critical for the predominant generation of the native-type disulfide isomer, probably because it stabilizes the helical structure of parental ET-1.     

Pre-ART nutritional status and its association with mortality in adult patients enrolled on ART at Fiche Hospital in North Shoa,Oromia region,Ethiopia: a retrospective cohort study

Background

Human immunodeficiency virus (HIV) compromises the nutritional status of infected individuals and in turn, malnutrition worsens the effects of the infection itself by weakening the immune system consequently accelerating disease progression and death. However, few studies have examined the association between nutritional status at antiretroviral therapy (ART) initiation and early mortality. Therefore, this study assesses pre-ART nutritional status and other baseline characteristics and mortality among adult patients on ART at Fiche Hospital, Ethiopia.

Methods

A retrospective cohort study was conducted among 489 ART enrolled adult patients between August 01, 2006 and September 30, 2013 in Fiche Hospital. Study participants were selected by using systematic random sampling method. Actuarial table was used to estimate survival of patients after ART initiation and log rank test was used to compare the survival curves. Cox proportional-hazard regression was used to determine independent predictors of time to death.

Results

Most of the study subjects were females 254 (51.9%). A total of 489 patients were included in the analysis, of whom 87 died during a median study follow-up of 22 months. The estimated mortality among malnourished was 21, 28, 33, and 38% at 5, 10, 15, and 25 months respectively with mortality incidence density of 5.63 deaths per 100 person years. The independent predictors of mortality were: BMI <18.5 kg/m² (AHR = 5.4 95% CI 3.03–9.58), baseline ambulatory functional status (AHR = 3.84; 95% CI 2.19–6.74), bedridden functional status (AHR = 4.78; 95% CI 2.14–10.65), WHO clinical stage III (AHR 2.21; 95% CI 1.16–4.21), WHO clinical stage IV (AHR 4.05; 95% CI 1.50–10.97) and CD4 count less than 200 cells/μl (AHR = 2.95; 95% CI 1.48–5.88), two and more opportunistic infections (AHR 2.30; 95% CI 1.11–4.75).

Conclusions

Undernutrition at the time of ART initiation was associated with increased risk of death, particularly during the first 3 months after ART initiation. Interventions to promote earlier HIV diagnosis and treatment and integrating nutrition counseling at all stages of ART implementation may improve ART outcomes in this vulnerable population.

     

New multiple labelling method for improved satellite cell identification in human muscle: application to a cohort of power-lifters and sedentary men

Presently applied methods to identify and quantify human satellite cells (SCs) give discrepant results. We introduce a new immunofluorescence method that simultaneously monitors two SC markers (NCAM and Pax7), the basal lamina and nuclei. Biopsies from power-lifters, power-lifters using anabolic substances and untrained subjects were re-examined. Significantly different results from those with staining for NCAM and nuclei were observed. There were three subtypes of SCs; NCAM⁺/Pax7⁺ (94%), NCAM⁺/Pax7⁻ (4%) and NCAM⁻/Pax7⁺ (1%) but large individual variability existed. The proportion of SCs per nuclei within the basal lamina of myofibres (SC/N) was similar for all groups reflecting a balance between the number of SCs and myonuclei to maintain homeostasis. We emphasise that it is important to quantify both SC/N and the number of SCs per fibre. Our multiple marker method is more reliable for SC identification and quantification and can be used to evaluate other markers of muscle progenitor cells.     

Association of preceding psychosis risk states and non‐psychotic mental disorders with incidence of clinical psychosis in the general population: a prospective study in the NEMESIS‐2 cohort

The validity and clinical utility of the concept of “clinical high risk” (CHR) for psychosis have so far been investigated only in risk‐enriched samples in clinical settings. In this population‐based prospective study, we aimed – for the first time – to assess the incidence rate of clinical psychosis and es­timate the population attributable fraction (PAF) of that incidence for preceding psychosis risk states and DSM‐IV diagnoses of non‐psychotic mental disorders (mood disorders, anxiety disorders, alcohol use disorders, and drug use disorders). All analyses were adjusted for age, gender and education. The incidence rate of clinical psychosis was 63.0 per 100,000 person‐years. The mutually‐adjusted Cox proportional hazards model indicated that preceding diagnoses of mood disorders (hazard ratio, HR=10.67, 95% CI: 3.12‐36.49), psychosis high‐risk state (HR=7.86, 95% CI: 2.76‐22.42) and drug use disorders (HR=5.33, 95% CI: 1.61‐17.64) were associated with an increased risk for clinical psychosis incidence. Of the clinical psychosis incidence in the population, 85.5% (95% CI: 64.6‐94.1) was attributable to prior psychopathology, with mood disorders (PAF=66.2, 95% CI: 33.4‐82.9), psychosis high‐risk state (PAF=36.9, 95% CI: 11.3‐55.1), and drug use disorders (PAF=18.7, 95% CI: –0.9 to 34.6) as the most important factors. Although the psychosis high‐risk state displayed a high relative risk for clinical psychosis outcome even after adjusting for other psychopathology, the PAF was comparatively low, given the low prevalence of psychosis high‐risk states in the population. These findings provide empirical evidence for the “prevention paradox” of targeted CHR early intervention. A comprehensive prevention strategy with a focus on broader psychopathology may be more effective than the current psychosis‐focused approach for achieving population‐based improvements in prevention of psychotic disorders.     

Relation of family physician or specialist care to obstetric interventions and outcomes in patients at low risk: a western Canadian cohort study.

To determine the relation of family physician or specialist care to intrapartum interventions and outcomes, we carried out a historical cohort study of 1456 obstetric patients at low risk admitted between Nov. 15, 1984, and Mar. 15, 1986, to a western Canadian teaching hospital. The patients were classified as being at low risk on admission by means of chart review. Family physicians and specialists were found to have similar rates for most of the interventions measured, although the interventions for which significantly different rates were found suggest a less interventionist style of intrapartum care by family physicians. There were no significant differences in maternal or neonatal outcomes except for a higher proportion of infants weighing less than 2500 g among primigravid women cared for by family physicians compared with those under the care of specialists. Self-selection of physician specialty by patients resulted in differences in the demographic characteristics of the two patient populations. The findings support the continued involvement of family physicians in the provision of obstetric care.     

<Emphasis Type="Italic">TP53</Emphasis> gene polymorphism: Importance to cancer,ethnicity and birth weight in a Brazilian cohort

Arg72Pro SNP of p53 has been associated with many types of cancer as well as with survival and longevity. We evaluated the Arg72Pro SNP frequencies of a Brazilian birth cohort and their association with current, demographic and birth epidemiological parameters available. In 1982, all hospital births of Pelotas, southern Brazil, were identified and studied prospectively. In 2004–5, blood samples were collected and DNA extracted. PCR-RFLP was used to genotype the Arg72Pro SNP in 3794 individual samples of the Brazil birth cohort and DNA sequencing was performed to confirm the genotypes. The genotype distribution, which was in Hardy–Weinberg equilibrium, showed a predominance of the arginine amino acid with a frequency of 46.9% Arg/Arg, 42.2% Arg/Pro and 10.9% Pro/Pro. The allele frequency was 0.68 of Arginine and 0.32 of Proline. The Arg72Pro SNP genotype and allelic frequency were related to skin colour where proline amino acid was observed more among black subjects, while arginine amino acid was observed more among white subjects. The individuals without family history of cancer and those with low birth weight were associated with arginine amino acid. The Arg72Pro SNP was strongly associated with important epidemiological variables confirming that genetic profiles on cohort studies can improve our understanding of the susceptibility of diseases and its risk factors.