Studies on the clinical epidemiology and pathophysiology of anaemia and blood transfusion in critically ill and elective orthopaedic patients

Anaemia commonly complicates surgery and critical illness. This thesis comprised four studies ofthis important clinical problem. Thefirst study was a retrospective study based in a major teaching hospital Intensive Care Unit (ICU). Three existing datasets were merged to provide a study dataset that described the demographics and severity of illness for a cohort of critically ill patients (n = 489). The epidemiology of anaemia during ICU admission to death or discharge home from hospital was described. 81.5% of patients were discharged anaemic to the community after surviving critical illness. 35.5% had a haemoglobin concentration <100g/L. 82% of patients had normocytic normochromic blood indices at hospital discharge. The second study was a prospective observational study that further investigated blood transfusion practice in a cohort of patients (n = 185) after ICU discharge. 72.2 % of these patients were discharged home anaemic; 83% had normocytic normochromic blood indices at hospital discharge. These data confirmed the retrospective analysis. Hospital physicians used restrictive transfusion practice after ICU discharge; the median pre-transfusion Hb was 74 g/L (interquartile range: 68-76 g/L). The third study measured red blood cell 2,3- diphosphoglycerate (2,3-DPG) levels and P50, which both reflect the ability of red cells to deliver oxygen to tissues, in a prospective cohort of 111 patients admitted to the ICU. Factors that were associated with 2,3-DPG and P50 were investigated. The data showed that critically ill patients have lower levels of 2,3-DPG compared with normal healthy controls. Red cell 2,3-DPG during critical illness had a strong association with patients' acid base status. Acidemia was strongly associated with low DPG concentrations, which was counterintuitive. 2,3-DPG concentration had the strongest association with P50 raising the possibility that oxygen unloading could be impaired in critically ill patients. The fourth study merged several large existing databases to document the incidence, patterns, and likely aetiology of anaemia and the incidence of red cell transfusion in patients presenting for elective major orthopaedic surgery. The dataset comprised approximately 3500 patients presenting over one year to a single orthopaedic hospital. The relation between pre-operative haemoglobin status, other factors, and peri-operative transfusion was investigated. 17 % of patients with known pre¬ admission Hb levels were anaemic. Most ofthese patients (64%) had normocytic normochromic anaemia. 303 patients received a total of 838 red cell units. Low per-admission Hb levels were common among those who were transfused during hospital admission

New insights into the pathogenesis of adenomyosis: Is the dislocation of the endometrial fragments into the myometrium evident in adenomyosis uteri?

Introduction Adenomyosis (AM) is a prevalent disease among women in the reproductive-age. It is histopathologically defined by the ectopic presence of endometrial tissue deep in the underlying myometrium. Although the disease pathogenesis is so far unclear, a translocation of fragments of the basal endometrium into the myometrium, through micro-dehiscences in the inner myometrium, is the most widely accepted theory. These micro-dehiscences are caused by a uterine hyperperistalsis. The latter induces a tissue micro-trauma at the endometrial myometrial junctional zone (EMJZ) in AM-uteri. In our study, possible microscopic and ultra-microscopic evidence of micro- trauma and corresponding tissue-translocation in the EMJZ was investigated. Materials and methods Uterine wall biopsies were collected from clinically and histopathologically diagnosed AM (n=18) and non-AM (n=14) patients, to study any structural difference in favour of a micro-trauma at EMJZ. The biopsies were examined with Transmission Electron Microscopy (TEM), Van Gieson stain (for extra cellular collagen fibres) and immune-labelled for markers of: myofibroblasts (ASMA, collagen I), mature smooth muscle (desmin), Transforming Growth Factor beta receptor 1 (TGFβR1), TGFβR2, TGFβR3, cell-cell contact (E-cadherin) and hematopoietic cells (CD45, CD68). Results The EMJZ in AM-uteri showed both microscopic as well as ultra-microscopic changes as following: (1) A disarray of the smooth muscle fibres in the inner myometrium of AM-uteri was evident, compared to the parallel arrangement in non-AM uteri. (2) A disruption of the smooth interface between the endometrium and myometrium in AM was clearly seen, but lacked in non-AM. Nevertheless, neither cell disruption nor translocation of fragments of the basal endometrial glands into the stroma in AM-uteri was seen. (3) Interestingly, uterine pale cells were described in the basal endometrial glands in both AM and non-AM-uteri. However, only in the AM group were these cells migrating into the stroma, through ultra-microruptures of the glandular basement membrane at different locations. (4) As a consequence of tissue trauma, both ASMA-immunolabeled stromal cells in the endometrium as well as collagen I immunolabeling in the inner myometrium were significantly higher in AM uteri than in non-AM uteri. Conclusion The different morphological changes at the EMJZ support the theory of occurrence of a micro-trauma in AM-uteri being part of the pathogenesis of the disease. However, there is no evidence of a translocation of the basal endometrium in AM uteri. Moreover, the migrating uterine pale cells in AM-uteri demand an in-depth in-vitro characterization to elucidate if they are involved in the disease pathogenesis.Einleitung Die Adenomyoseis Erkrankung betrifft häufig Frauen im gebärfähigem Alter. Mikroskopisch zeichnet lässt sich die Erkrankung durch das Vorkommen von ektopen endometrialen Drüsen und Stromazellen tief im Myometrium aus. Obwohl die Pathogenese der Adenomyose bis heute nicht geklärt wurde, ist wohl von einer Translokation von Fragmenten des basalen Endometriums durch Mikro-Dehiszenz im inneren Myometrium auszugehen. Als ursächlich wird eine mögliche uterine Hyperperistaltik diskutiert. Die Mikro-Dehiszenzen werden mikroskopisch im Bereich der Übergangzone zwischen dem basalen Endometrium und dem inneren Myometrium verortet. In der vorliegenden Studie wurden betroffene und nicht betroffenen uterine Gewebe, mikroskopisch und ultramikroskopisch, auf Mikro-Traumata und Translokationen des basalen Endometriums hin untersucht und immunhistochemisch charakterisiert. Methodik Zweiunddreißig Patientinnen wurden in die Studie eingeschlossen, davon waren 18 klinisch und histopathologisch von AM betroffen, 14 wiesen klinisch und histopathologisch keine AM auf. Die uterinen Proben wurden mittels Transmissions-Elektronenmikroskopie charakterisiert. Weiterhin wurden folgende Nachweise Immunhistochemisch angefertigt: van Gieson-Färbung (extrazelluläre Kollagenfaserfärbung), Myofibroblasten (ASMA, Kollagen I), glatte Muskulatur (Desmin), Transforming Growth Factor Beta Rezeptor 1, 2 und 3 (TGFβR1, R2 und R3), Zellkontakte (ECadherin) und Immunzellen (CD45, CD68). Ergebnisse Sowohl mikroskopisch als auch ultra-mikroskopisch zeigten sich mehrere Veränderungen in den AM-Uteri: 1. Es zeigte sich eine unkoordinierte Anordnung der glatten Muskelfasern im inneren Myometrium der AM-Kohorte. Die Anordnung der myometrialen glatten Muskelzellen der Kontrollgruppe war hingegen in paralleler Orientierung zu den basalen endometrialen Drüsen. 2. Der Übergang Endometrium/Myometrium in AM-Uteri war äußert unregelmäßig, hingegen glatt in den Kontrollproben. Es ließ sich allerdings keine Dislokation einzelner Zellen darstellen, diese blieben immer im Verband, auch waren die Zell-Zellkontakte nicht gestört. 3. Die sogenannten Pale-Zellen in den basalen endometrialen Drüsen konnte sowohl in AM-Uteri als auch in der Kontrollgruppe nachgewiesen werden. In AM-Uteri stellte sich eine Migration der Pale Zellen ins Stroma dar, die an mehreren Stellen eine Ultra-Mikroruptur der basalen Membran in endometrialen Drüsen verursachten. 4. Als Mikrotraumatisierungsfolge, zeigten sich sowohl die ASMA-Expression im basalen Endometrium als auch die Kollagen-Expression im inneren Myometrium in der AM-Gruppe signifikant gegenüber den Kontrollproben erhöht. Schlussfolgerung Mehrere morphologisch-histologische Veränderungen bestärken die Theorie, dass es in der Endo-Myometrialen Übergangszone zu einer Mikrotraumatisierung kommt, die möglicherweise ursächlich an der Pathogenese der Adenomyosis uteri zu sein scheint. Dabei bleibt aber der Zellverbund intakt. Hingegen scheint der Nachweis von migrierenden Pale Zellen insbesondere in Patientinnen mit Adenomyosis uteri die These zu stärken, dass Gründerzellen mit an der Pathogenese der Adenomyosis beteiligt sein könnten. Um diese Hypothese zu bestätigen bedarf es jedoch weiterer in vivo und vitro Charakterisierung der Pale Zellen

Analytical and numerical water quality model for a sinusoidally varying pollutant discharge concentration

Analytical solution has been obtained for one-dimensional advection-diffusion equation which includes terms of decay and increasing sources by using Laplace transformation. Also numerical solution has been obtained by using explicit finite difference scheme. In this study the boundary condition applied at x = 0 describes a sinusoidal variation in pollutant concentration. The analytical solution obtained produces results that are exact for any location at any time. Impact of different parameters controlling the pollutant dispersion along the river at any time has been studied separately with figures help. This publication proved mathematically the fact that the high concentration of pollutant can be reduced by releasing fresh water discharges from Delta Barrage in the Nile River. For a real situation, our simple model can give decision support for planning restrictions to be imposed on cultivating and urban practices

The use of cost-benefit analysis for environmental projects

In research, we analysed the way cost-benefit analyses (CBA) were carried out in governmental and selfgovernmental projects which were partly financed by the European Union. The primary aim was to establish how the way these CBAs are carried out can be improved in the case of these institutions. By taking account of the environmental endowments and social factors, it became obvious that the quantity and presence of externalities is usually more significant than in the case of the assessment of economic factors. The presence of quantified benefits in the development documents could make it much easier for the decision makers to decide whether the investment possesses suitable characteristics in an economical, environmental and social sense too, in the case of projects and development concepts, or not. Therefore, its realization will certainly modify the welfare curve in a positive direction. In spite of this it can be stated that the incorrect methodical approach of the economic factors result many extern effects in the evaluation, which place the certain development programmes in the centre of the preferred economic decisions in a way that they cause many social and environmental damages

New therapeutic strategies against trypanosomiasis and leishmaniasis

Leishmaniasis and African Trypanosomiasis are diseases caused by the Kinetoplastida parasites of Leishmania sp. and Trypanosoma sp. respectively. Control and management of these diseases, which affect a significant number of people in the tropics and subtropical areas of the world, is beset with numerous problems such as drug toxicity, affordability and the emergence and spread of parasites resistance to most of the routinely used drugs. This situation calls for an urgent search for new drugs that would address these concerns. Based on report of excellent antimicrobial activities against other parasites and the possession of other known good values, analogues of choline and curcumin were thoroughly assessed in this study for their potential as antitrypanosomal and antileishmanial drugs. Standard methods such as the Alamar Blue, propidium iodide and direct microscopy methods were used to determine the susceptibility of the parasites to the different analogues. Toxicity tests were performed to determine the effect of these compounds on Human Embryonic Kidney (HEK) cells. The presence of mediated transport of these compounds across the parasite plasma membrane was investigated using the classical uptake technique. In order to investigate the possible mechanism of antiparasitic action of the compounds, this study employed flow cytometry to assess the mitochondrial membrane potential m, as well as parameters such as production of reactive oxygen species (ROS), the permeability of the plasma membrane and any effects of the test copounds on the parasite’s cell cycle. Five out of 7 choline compounds tested in this study had EC50 values of 0.13-1.8 µM against T. brucei, 0.14-6.9 µM against L. major, L. mexicana promastigotes and 1.69-12.9 µM against L. mexicana amastigotes. With regard to the curcuminoid compounds, 35 out of 98 tested were observed to exhibit trypanocidal activity better than the original curcumin with EC50 values between 0.05 and 1 µM. Against Leishmania, most of the compounds displayed higher antiparasitic activity than curcumin but lower than observed against trypanosomes. The activity of choline analogues was very similar against L. mexicana and L. major promastigotes (P>0.05), and much higher than against L. mexicana amastigotes. Interestingly, some of the compounds displayed EC50 values below that of pentamidine, the routinely used drug. Assessment of parasite growth pattern in the presence of choline analogues showed that two of the compounds, T1 and MS1, are fast acting, killing the population of BSF T. b. brucei within 8 h with the onset of cell death at 2-4 hours of treatment. In contrast, the other three choline compounds observed to have antiparasitic activities acted more slowly, completely killing the trypanosome population after more than 30 hours of incubation. However, all the choline compounds appeared to rapidly inhibit trypanosome proliferation. The choline compounds exhibited low toxic effects against HEK cell line T29, with the selectivity index (S.I.) being high for some of the compounds. The curcumin compounds, too, were observed to have generally similar or lower toxicity against the human cells than the parent curcumin compound (AS-HK001), which in itself is not considered toxic and routinely used in food. Investigations on the toxicological and pharmacological effects of the curcumin compounds on the survival and the glutathione and protein content of primary murine hepatocytes showed no significant difference between hepatocyte cells treated with curcuminoid compounds AS-HK001, AS-HK009, and AS-HK014 compared with controls. We also investigated how choline and its analogues enter the trypanmosome. Evidence gathered in this study strongly suggests that unlike in Leishmania species and Plasmodium, choline transporters are not expressed in the bloodstream form of T. b. brucei. It was also conclusively shown that the P2, high affinity pentamidine transporter (HAPT) and low affinity pentamidine transporter (LAPT) do not play any significant role in the uptake of this compound. Lacking radiolabeled forms of the choline analogues, this study could not identify a definitive route of uptake of this class of compounds into the parasite. Analysis of cell cycle progression, by flow cytometry, showed trypanosomes in the G1, S, and G2/M stages. Curcuminoids do not appear to cause any important changes in the proportion of cells in G1, S or G2/M phase of the cell cycle. Cells exposed to various concentrations of some curcumin compounds, such as AS-HK014 and AS-HK096, showed a rapid increase in cell permeability, reaching between 80% and 90% in 4 hours. The permeability was observed to increase with increasing drug concentration and/or the incubation time. Investigations of cell membrane permeability also showed that choline analogues caused plasma membrane defects which could probably lead to cell death. With regard to the effect of the compound on mitochondrial membrane potential m the dicationic choline compounds, including M38, G25, T4 and MS1, were observed to have pronounced effects on m with an onset as early as 8 h of contact and we believe the mitochondria could be the main target of these compounds rather than indicating the induction of apoptosis, as the action of the test compounds was not associated with the production of reactive oxygen species. Indeed, both choline and curcumin analogues reduced the production of reactive oxygen species in T. b. brucei cultures. Furthermore, there were no major defects in choline phospholipid metabolism upon treatment with the choline compounds, suggesting that phospholipid metabolism is not the target of the anti-trypanocidal activity of these compounds. Preliminary results with infected ICR mice infected with T. b. brucei did not reveal significant in vivo activity of the three curcumin compounds on blood parasitemia when they were injected intra-peritoneally with two doses of 50 mg/kg body weight. With reference to evidence obtained in this study, it can firmly be concluded that analogues of choline and curcumin display highly promising antiparasitic activities and are generally non-toxic to human cells. Information provided in this thesis could therefore assist in the further development of these classes of compounds as lead compounds against kinetoplastid diseases. We strongly recommend that further investigation be carried out to understand the full mechanism of action of these compounds in order to facilitate this strategy

Remediation of pollution in a river by releasing clean water using the solution of advection-diffusion equation in two dimensions

Analytical and numerical solutions are obtained for two-dimensional advection-diffusion equation, using Laplace transformation technique and explicit finite difference method for the pollutant concentration in a river or in shallow aquifer with time-dependent dispersion coefficients. We take two cases, first case: concentration of increasing nature (mixed type or third type) is considered at the origin and initially the domain is solute free. Second case: the river’s water is polluted initially (at time t = 0 ) while at the origin, at time t \u3e 0, the source of pollution is removed by releasing fresh water. We have proved mathematically the fact that the high concentration of pollutant can be reduced by releasing adequate discharges from barrage in a river. Both the dispersion coefficients, the velocity components and first order decay term are considered exponentially decreasing function of time. The different effects of the parameters controlling the pollutant dispersion along the river at any time are studied separately with the help of figures. The parameters that have a role in removing or reducing concentration of pollutant along the river have been studied in detail. When comparing the analytical solution with the numerical solution, we found a very good agreement between them. For a real situation, our simple model can provide decision support for planning restrictions to be imposed on farming and urban practices

Reasons for unit non-response in household Surveys in the Arab Gulf Countries

For in-person household surveys, it is fundamental to consider societal customs when choosing appropriate times and interviewer gender. However, even after all these procedures were taken into consideration with an eye to improving or maintaining our Qatari survey response rates, our recorded cases of refusal to participate in polls increased significantly in a relatively short time frame. From early 2011, when the percentage of refusal cases reported at only 3.7% in the Social & Economic Survey Research Institute’s (SESRI) Social Capital survey, to the end of 2012, this proportion jumped to 14.6% in our Health and Expenditure survey. In this paper we will try to assess the drivers of non-response in SESRI’s 2012-2013 surveys, to better understand the reasons for non-response , by focused on refusal causes among survey participants without regard to other disposition statuses in the surveys. Our refusals numbered 1,263 representing 14% of the total number of selected respondents participating in our surveys (9062), and exactly (376) of the refusals (30%) also refused to disclose any reasons for their decision. In all, 887 of our refusal cases agreed to provide a reason for their non-participation.SESRI- Qatar Universit

Evaluation of The Living Escherichia coli-O78 Deleted aroA Vaccine Against Homologous and Heterologous E. coli Challenge in Broiler Chickens

To determine whether the immunization using commercially available living Escherichia coli-O78 aroA deleted vaccine (Poulvac®E. coli) is protective against APEC challenges or not. Ninety chicks were divided into six groups (15 birds/each); two groups were vaccinated at day 1 by spray and drinking routes then challenged intratracheally with homologous E. coli O78 at day 21, the other two groups were similar to the previously mentioned groups but challenged with heterologous E. coli O1 in parallel with the four challenged-vaccinated groups there were two positive control (challenged-not vaccinated) groups; one challenged with O78 and the other one with O1 at day 21 using intratacheal route. The best obtained results were recorded to the vaccinated-challenged group with the homologous strain and vaccinated by spraying method which exhibited decreases in organ lesion scores in comparison to the other groups (non-vaccinated challenged chickens and groups of chickens either homologous challenged-vaccinated through drinking water or heterologous challenged-vaccinated groups). These findings suggest that vaccine is a suitable for minimizing lesion scores against homologous challenge using spraying method that could lead to minimizing the time for treatment and cases of condemnation in processing plants

Implementing ISO 14001 and Environmental Performance Evaluation: A Logistic Regression Model

Due to the growing popularity of environmental management systems and the ongoing debate among practitioners and researchers concerning the influence of environmental management systems on environmental performance, there is a need to assess how the implemented environmental management systems impact the environment. The current study examines the relationship between the guidelines provided by the ISO 14031 and ISO 14001 standards from three aspects, namely, utilizing information and data, planning for environmental performance and reviewing and improving environmental performance. This study will utilize a binary logistic regression to model and analyse the link between ISO 14001 and ISO 14031 using a 7-point Likert scale questionnaire. A total of 590 companies operating within the Saudi Arabia industrial sector were invited to take part in the study. The collection of data using questionnaires lasted from January to March 2019, and the results were analysed and compared with those of related studies. The model included a dependent variable representing whether the company is certified or not for ISO 14001 and 13 independent variables representing the main ISO 14031 guidelines. The research findings revealed that the developed model predicts 92.8% of the values, and the remaining 7.2% of the values are not covered. Thirteen independent variables were positively correlated with the dependent variable, indicating that the company is certified. The results of this study contribute significantly to the determination of the relationship between environmental performance and ISO 14001 certification

The use of cost-benefit analysis for environmental projects

In research, we analysed the way cost-benefit analyses (CBA) were carried out in governmental and selfgovernmental projects which were partly financed by the European Union. The primary aim was to establish how the way these CBAs are carried out can be improved in the case of these institutions. By taking account of the environmental endowments and social factors, it became obvious that the quantity and presence of externalities is usually more significant than in the case of the assessment of economic factors. The presence of quantified benefits in the development documents could make it much easier for the decision makers to decide whether the investment possesses suitable characteristics in an economical, environmental and social sense too, in the case of projects and development concepts, or not. Therefore, its realization will certainly modify the welfare curve in a positive direction. In spite of this it can be stated that the incorrect methodical approach of the economic factors result many extern effects in the evaluation, which place the certain development programmes in the centre of the preferred economic decisions in a way that they cause many social and environmental damages