What's the signification of nuclear vacuoles in human sperm?

The aim of this study was to determine the extent of DNA fragmentation and the presence of single/denatured or double stranded of DNA in sperm with large nuclear vacuoles (LNV) selected by high-magnification. A total of 30 patients had fresh semen samples prepared by discontinuous concentration gradient. Sperm with normal nucleus (NN) and LNV were selected at 8400x magnification and placed in different slides. DNA fragmentation was determined by TUNEL assay. Denatured and double stranded DNA was identified by acridine orange fluorescence method. The percentage of DNA fragmentation in LNV sperm (29%) was significantly higher (P<0.001) than NN sperm (15.8%). Therefore, cleavage of genomic DNA in low molecular weight DNA fragments (mono and oligonucleosomes), and single strand breaks (nicks) in high molecular weight DNA occur more frequently in LNV. Identically, the percentage denatured stranded DNA in sperm with LNV (67.9%) was significantly higher (P <0.0001) than NN sperm (33%). The high level of denatured DNA in sperm with LNV suggests precocious decondensation and disaggregation of sperm chromatin fibers. Our results support an association between LNV sperm and DNA damage, and the routine selection and injection of morphological motile sperm at high magnification for ICSI. The adverse effect (DNA fragmentation or denaturation) leads to concern particularly about the possibility of iatrogenic transmission of genetic abnormalities. Copyright - SBRA - Sociedade Brasileira de Reprodução Assistida.

Ambulatory care adverse events and preventable adverse events leading to a hospital admission.

BACKGROUND: Most healthcare in the US is delivered in the ambulatory care setting, but the epidemiology of errors and adverse events in ambulatory care is understudied. METHODS: Using the population-based data from the Colorado and Utah Medical Practices Study, we identified adverse events that occurred in an ambulatory care setting and led to hospital admission. Proportions with 95% CIs are reported. RESULTS: We reviewed 14,700-hospital discharge records and found 587 adverse events of which 70 were ambulatory care adverse events (AAEs) and 31 were ambulatory care preventable adverse events (APAEs). When weighted to the general population, there were 2608 AAEs and 1296 (44.3%) APAEs in Colorado and Utah, USA, in 1992. APAEs occurred most commonly in physicians' offices (43.1%, range 46.8-27.8), the emergency department (32.3%, 46.1-18.5) and at home (13.1%, 23.1-3.1). APAEs in day surgery were less common (7.1%, 13.6-0.6) but caused the greatest harm to patients. The types of APAEs were broadly distributed among missed or delayed diagnoses (36%, 50.2-21.8), surgery (24.1%, 36.7-11.5), non-surgical procedures (14.6%, 25.0-4.2), medication (13.1%, 23.1-3.1) and therapeutic events (12.3%, 22.0-2.6). Overall, 10% of the APAEs resulted in serious permanent injury or death. The proportion of APAEs that resulted in death was 31.8% for general internal medicine, 22.5% for family practice and 16.7% for emergency medicine. CONCLUSION: An estimated 75,000 hospitalisations per year are due to preventable adverse events that occur in outpatient settings in the US, resulting in 4839 serious permanent injuries and 2587 deaths.

Influences on general practitioner prescribing with particular reference to community pharmacy

Influences on general practitioner prescribing of drugs continue to be of interest and importance as cost containment becomes central to Government health policy. This thesis employs a plurality of research methods including quantitative and qualitative survey techniques for example, questionnaires, interviews and prescription analyses to investigate some of the factors which may influence GP prescribing such as information sources, hospital consultants and in particular the community pharmacist. When the use and influence of drug information sources by GPs was examined, the community pharmacist was given a relatively low rating as a source but a high rating, similar to that of the consultant, for helpfulness. Influences are needed to improve prescribing and reduce the incidence of iatrogenic disease for the benefit of the patient. The education and expertise of pharmacists and their familiarity with local prescribing habits places them in a unique position to meet the needs of local GPs. As 96.5% of the public always or nearly always take their prescriptions to the same pharmacy, patient medication records, now kept by 77.5% of pharmacies, provide a valuable check on the appropriateness and safety of patients' medication. The barriers to the pharmacist's greater involvement were shown to be suspicion by GPs of pharmacists' motivation, isolation of many community pharmacists, difficulties in leaving the pharmacy for domiciliary visits, residential home care and GP practice meetings. These barriers must be lowered if the pharmacist is to have a greater influence and involvement. It was concluded that changes are necessary in pharmaceutical education, staff training, organisation and remuneration. Some changes in the targeting of remuneration to the pharmaceutical care services provided and registration of patients with pharmacies would contribute greatly to these aims.

Medication -related adverse events in older people with dementia:causes and possible solutions

This submission for a PhD by previously published work is based upon six publications in peer reviewed journals, reflecting a 9-year research programme. My research has shown, in a coherent and original way, the difficulty in treating people with dementia with safe and effective medication whilst providing research-founded guidance to develop mechanisms to optimise medication choice and minimise iatrogenic events. A wide range of methods, including systematic reviews, meta-analysis, randomised controlled trials (RCTs), quantitative research and mixed methods were used to generate the data, which supported the exploration of three themes. The first theme, to understand the incidence and causes of medication errors in dementia services, identified that people with dementia may be more susceptible to medication-related iatrogenic disease partly due to inherent disease-related characteristics. One particular area of concern is the use of anti-psychotics to treat the Behavioural and Psychological Symptoms of Dementia (BPSD). The second and third themes, respectively, investigated a novel pharmacological and health services intervention to limit anti-psychotic usage. The second phase found that whilst the glutamate receptor blocker memantine showed some promise, further research was clearly required. The third phase found that anti-psychotic usage in dementia may be higher than official figures suggest and that medication review linking primary and secondary care can limit such usage. My work has been widely cited, reflecting a substantial contribution to the field, in terms of our understanding of the causes of, and possible solutions to limit, medication-related adverse events in people with dementia. More importantly, this work has already informed clinical practice, patients, carers and policy makers by its demonstrable impact on health policy. In particular my research has identified key lines of enquiry for future work and for the development of my own personal research programme to reduce the risk associated with medication in this vulnerable population.

Iatrogenic keratoconjunctivitis sicca in a dog

Anormalidades quali-quantitativas em componentes primários da lágrima podem alterar a dinâmica do filme lacrimal, comprometendo sua função. O filme lacrimal é composto por lipídios, uma fração aquosa e por mucoproteínas. A ceratoconjuntivite seca (CCS) é uma enfermidade freqüentemente diagnosticada em cães, caracterizada pela deficiência da fração aquosa do filme lacrimal, resultando em dessecação e inflamação da conjuntiva e córnea, dor, doença corneana progressiva e redução da visão. Devido à contribuição significativa da glândula da terceira pálpebra na produção da porção aquosa do filme lacrimal, a remoção desta glândula, quando prolapsada, constitui-se em importante causa de CCS iatrogênica. Este trabalho relata um caso clínico de ceratoconjuntivite seca iatrogênica, em um cão da raça Boston Terrier de 10 meses de idade, causada pela remoção cirúrgica da glândula lacrimal da terceira pálpebra, quando esta encontrava-se prolapsada.

Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt– Jakob disease: Implications for human health

There is substantial scientific evidence to support the notion that bovine spongiform encephalopathy (BSE) has contaminated human beings, causing variant Creutzfeldt–Jakob disease (vCJD). This disease has raised concerns about the possibility of an iatrogenic secondary transmission to humans, because the biological properties of the primate-adapted BSE agent are unknown. We show that (i) BSE can be transmitted from primate to primate by intravenous route in 25 months, and (ii) an iatrogenic transmission of vCJD to humans could be readily recognized pathologically, whether it occurs by the central or peripheral route. Strain typing in mice demonstrates that the BSE agent adapts to macaques in the same way as it does to humans and confirms that the BSE agent is responsible for vCJD not only in the United Kingdom but also in France. The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate. These data will be key in identifying the origin of human cases of prion disease, including accidental vCJD transmission, and could provide bases for vCJD risk assessment.

Viral particles are required for infection in neurodegenerative Creutzfeldt-Jakob disease.

Several models have been proposed for the infectious agents that cause human Creutzfeldt-Jakob disease (CJD) and sheep scrapie. Purified proteins and extracted nucleic acids are not infectious. To further identify the critical molecular components of the CJD agent, 120S infectious material with reduced prion protein (PrP) was treated with guanidine hydrochloride or SDS. Particulate and soluble components were then separated by centrifugation and molecularly characterized. Conditions that optimally solubilized residual PrP and/or nucleic acid-protein complexes were used to produce subfractions that were assayed for infectivity. All controls retained > 90% of the 120S titer (approximately 15% of that in total brain) but lost > 99.5% of their infectivity after heat-SDS treatment (unlike scrapie fractions enriched for PrP). Exposure to 1% SDS at 22 degrees C produced particulate nucleic acid-protein complexes that were almost devoid of host PrP. These sedimenting complexes were as infectious as the controls. In contrast, when such complexes were solubilized with 2.5 M guanidine hydrochloride, the infectious titer was reduced by > 99.5%. Sedimenting PrP aggregates with little nucleic acid and no detectable nucleic acid-binding proteins had negligible infectivity, as did soluble but multimeric forms of PrP. These data strongly implicate a classical viral structure, possibly with no intrinsic PrP, as the CJD infectious agent. CJD-specific protective nucleic acid-binding protein(s) have already been identified in 120S preparations, and preliminary subtraction studies have revealed several CJD-specific nucleic acids. Such viral candidates deserve more attention, as they may be of use in preventing iatrogenic CJD and in solving a fundamental mystery.

Spatial correlations between the vacuolation, prion protein (PrPsc) deposits and the cerebral blood vessels in sporadic Creutzfeldt-Jakob disease

In the variant form of Creutzfeldt-Jakob disease (vCJD), 'florid' deposits of the protease resistant form of prion protein (PrP(sc)) were aggregated around the cerebral blood vessels suggesting the possibility that prions may spread into the brain via the cerebral microcirculation. The objective of the present study was to determine whether the pathology was spatially related to blood vessels in cases of sporadic CJD (sCJD), a disease without an iatrogenic etiology, and therefore, less likely to be caused by hematogenous spread. Hence, the spatial correlations between the vacuolation ('spongiform change'), PrP(sc) deposits, and the blood vessels were studied in immunolabelled sections of the cerebral cortex and cerebellum in eleven cases of the common M/M1 subtype of sCJD. Both the vacuolation and the PrP(sc) deposits were spatially correlated with the blood vessels; the PrP(sc) deposits being more focally distributed around the vessels than the vacuoles. The frequency of positive spatial correlations was similar in the different gyri of the cerebral cortex, in the upper and lower cortical laminae, and in the molecular layer of the cerebellum. It is hypothesized that the spatial correlation is attributable to factors associated with the blood vessels which promote the aggregation of PrP(sc) to form deposits rather than representing the hematogenous spread of the disease. The aggregated form of PrP(sc) then enhances cell death and may encourages the development of vacuolation in the vicinity of the blood vessels.

Weather variability, tides, and Barmah Forest Virus Disease in the Gladstone region, Australia

In this study we examined the impact of weather variability and tides on the transmission of Barmah Forest virus (BFV) disease and developed a weather-based forecasting model for BFV disease in the Gladstone region, Australia. We used seasonal autoregressive integrated moving-average (SARIMA) models to determine the contribution of weather variables to BFV transmission after the time-series data of response and explanatory variables were made stationary through seasonal differencing. We obtained data on the monthly counts of BFV cases, weather variables (e.g., mean minimum and maximum temperature, total rainfall, and mean relative humidity), high and low tides, and the population size in the Gladstone region between January 1992 and December 2001 from the Queensland Department of Health, Australian Bureau of Meteorology, Queensland Department of Transport, and Australian Bureau of Statistics, respectively. The SARIMA model shows that the 5-month moving average of minimum temperature (β = 0.15, p-value < 0.001) was statistically significantly and positively associated with BFV disease, whereas high tide in the current month (β = −1.03, p-value = 0.04) was statistically significantly and inversely associated with it. However, no significant association was found for other variables. These results may be applied to forecast the occurrence of BFV disease and to use public health resources in BFV control and prevention.