Clinical presentation, diagnosis, therapy and outcome of alveolar echinococcosis in dogs.

Alveolar echinococcosis (AE), a parasitic disease primarily of the liver caused by the larval stage of Echinococcus multilocularis, is highly endemic in Switzerland. In contrast to well-established management protocols in people, little is known with regard to optimal treatment strategies in dogs. The objective of this study was to describe the clinical signs and diagnostic procedures in dogs with AE and to evaluate outcome following medical treatment alone or surgery and medical treatment. Of 23 putative AE cases between 2004 and 2014, 20 were classified as confirmed (n=18) or probable (n=2) AE, based on abdominal ultrasound, serology, cytology, histology and/or PCR. Most dogs presented with abdominal distension in an advanced stage of disease. Dogs receiving specific treatment (radical or debulking surgery together with medical treatment, or medical treatment alone) survived longer than dogs left untreated, but no difference was found between treatment types. Survival at one year was associated with absence of free abdominal fluid, absence of abdominal distension and treatment of any type. However, dogs treated with debulking surgery all faced relapse. Findings of this study suggest that in AE-affected dogs for which a therapeutic approach is regarded appropriate by owners and veterinarians, radical surgical resection and medical treatment or, if total resection is not possible, medical treatment alone should be considered. However, studies on larger numbers of dogs are necessary before definitive treatment recommendations can be made.

Eye movement problems and differential diagnosis of the parkinsonian syndromes

Differential clinical diagnosis of the parkinsonian syndromes, viz., Parkinson’s disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) can be difficult. Eye movement problems, however, are a chronic complication of many of these disorders and may be a useful aid to diagnosis. Hence, the presence in PSP of vertical supranuclear gaze palsy, fixation instability, lid retraction, blepharospasm, and apraxia of eyelid opening and closing is useful in separating PD from PSP. Moreover, atypical features of PSP include slowing of upward saccades, moderate slowing of downward saccades, the presence of a full range of voluntary vertical eye movements, a curved trajectory of oblique saccades, and absence of square-wave jerks. Downgaze palsy is probably the most useful diagnostic clinical symptom of PSP. By contrast, DLB patients are specifically impaired in both reflexive and saccadic execution and in the performance of more complex saccadic eye movement tasks. Problems in convergence in DLB are also followed by akinesia and rigidity. Abnormal ocular fixation may occur in a significant proportion of MSA patients along with excessive square-wave jerks, a mild supranuclear gaze palsy, a gaze-evoked nystagmus, a positioning down-beat nystagmus, mild-moderate saccadic hypometria, impaired smooth pursuit movements, and reduced vestibulo-ocular reflex (VOR) suppression. There may be considerable overlap between the eye movement problems characteristic of the various parkinsonian disorders, but taken together with other signs and symptoms, can be a useful aid in differential diagnosis, especially in the separation of PD and PSP.

Discovery and validation of serologic biomarkers for the diagnosis and prognosis of invasive candidiasis by computational immunomics

Invasive candidiasis (IC) is an opportunistic systemic mycosis caused by Candida species (commonly Candida albicans) that continues to pose a significant public health problem worldwide. Despite great advances in antifungal therapy and changes in clinical practices, IC remains a major infectious cause of morbidity and mortality in severely immunocompromised or critically ill patients, and further accounts for substantial healthcare costs. Its impact on patient clinical outcome and economic burden could be ameliorated by timely initiation of appropriate antifungal therapy. However, early detection of IC is extremely difficult because of its unspecific clinical signs and symptoms, and the inadequate accuracy and time delay of the currently available diagnostic or risk stratification methods. In consequence, the diagnosis of IC is often attained in advanced stages of infection (leading to delayed therapeutic interventions and ensuing poor clinical outcomes) or, unfortunately, at autopsy. In addition to the difficulties encountered in diagnosing IC at an early stage, the initial therapeutic decision-making process is also hindered by the insufficient accuracy of the currently available tools for predicting clinical outcomes in individual IC patients at presentation. Therefore, it is not surprising that clinicians are generally unable to early detect IC, and identify those IC patients who are most likely to suffer fatal clinical outcomes and may benefit from more personalized therapeutic strategies at presentation. Better diagnostic and prognostic biomarkers for IC are thus needed to improve the clinical management of this life-threatening and costly opportunistic fungal infection...

The role of inflammation in vascular function and pregnancy outcome in the pregnant stroke prone spontaneously hypertensive rat

During pregnancy, the maternal cardiovascular system undergoes major adaptation. One of these changes is a 40-50 % increase in circulating blood volume which requires a systemic remodelling of the vasculature in order to regulate maternal blood pressure and maximise blood supply to the developing placenta and fetus. These changes are broadly conserved between humans and rats making them an appropriate pre-clinical model in which to study the underlying mechanisms of pregnancy-dependent cardiovascular remodelling. Whilst women are normally protected against cardiovascular disease; pregnancy marks a period of time where women are susceptible to cardiovascular complications. Cardiovascular disease is the leading cause of maternal mortality in the United Kingdom; in particular hypertensive conditions are among the most common complications of pregnancy. One of the main underlying pathologies of these pregnancy complications is thought to be a failure of the maternal cardiovascular system to adapt. The remodelling of the uterine arteries, which directly supply the maternal-fetal interface, is paramount to a healthy pregnancy. Failure of the uterine arteries to remodel sufficiently can result in a number of obstetric complications such as preeclampsia, fetal growth restriction and spontaneous pregnancy loss. At present, it is poorly understood whether this deficient vascular response is due to a predisposition from existing maternal cardiovascular risk factors, the physiological changes that occur during pregnancy or a combination of both. Previous work in our group employed the stroke prone spontaneously hypertensive rat (SHRSP) as a model to investigate pregnancy-dependent remodelling of the uterine arteries. The SHRSP develops hypertension from 6 weeks of age and can be contrasted with the control strain, the Wistar Kyoto (WKY) rat. The phenotype of the SHRSP is therefore reflective of the clinical situation of maternal chronic hypertension during pregnancy. We showed that the SHRSP exhibited a deficient uterine artery remodelling response with respect to both structure and function accompanied by a reduction in litter size relative to the WKY at gestational day (GD) 18. A previous intervention study using nifedipine in the SHRSP achieved successful blood pressure reduction from 6 weeks of age and throughout pregnancy; however uterine artery remodelling and litter size at GD18 was not improved. We concluded that the abnormal uterine artery remodelling present in the SHRSP was independent of chronic hypertension. From these findings, we hypothesised that the SHRSP could be a novel model of spontaneously deficient uterine artery remodelling in response to pregnancy which was underpinned by other as yet unidentified cardiovascular risk factors. In Chapter 1 of this thesis, I have characterised the maternal, placental and fetal phenotype in pregnant (GD18) SHRSP and WKY. The pregnant SHRSP exhibit features of left ventricular hypertrophy in response to pregnancy and altered expression of maternal plasma biomarkers which have been previously associated with hypertension in human pregnancy. I developed a protocol for accurate dissection of the rat uteroplacental unit using qPCR probes specific for each layer. This allowed me to make an accurate and specific statement about gene expression in the SHRSP GD18 placenta; where oxidative stress related gene markers were increased in the vascular compartments. The majority of SHRSP placenta presented at GD18 with a blackened ring which encircled the tissue. Further investigation of the placenta using western blot for caspase 3 cleavage determined that this was likely due to increased cell death in the SHRSP placenta. The SHRSP also presented with a loss of one particular placental cell type at GD18: the glycogen cells. These cells could have been the target of cell death in the SHRSP placenta or were utilised early in pregnancy as a source of energy due to the deficient uterine artery blood supply. Blastocyst implantation was not altered but resorption rate was increased between SHRSP and WKY; indicating that the reduction in litter size in the SHRSP was primarily due to late (>GD14) pregnancy loss. Fetal growth was not restricted in SHRSP which led to the conclusion that SHRSP sacrifice part of their litter to deliver a smaller number of healthier pups. Activation of the immune system is a common pathway that has been implicated in the development of both hypertension and adverse pregnancy outcome. In Chapter 2, I proposed that this may be a mechanism of interest in SHRSP pregnancy and measured the pro-inflammatory cytokine, TNFα, as a marker of inflammation in pregnant SHRSP and WKY and in the placentas from these animals. TNFα was up-regulated in maternal plasma and urine from the GD18 SHRSP. In addition, TNFα release was increased from the GD18 SHRSP placenta as was the expression of the pro-inflammatory TNFα receptor 1 (Tnfr1). In order to investigate whether this excess TNFα was detrimental to SHRSP pregnancy, a vehicle-controlled intervention study using etanercept (a monoclonal antibody which works as a TNFα antagonist) was carried out. Etanercept treatment at GD0, 6, 12 and 18 resulted in an improvement in pregnancy outcome in the SHRSP with an increased litter size and reduced resorption rate. Furthermore, there was an improved uterine artery function in GD18 SHRSP treated with etanercept which was associated with an improved uterine artery blood flow over the course of gestation. In Chapter 3, I sought to identify the source of this detrimental excess of TNFα by designing a panel for maternal leukocytes in the blood and placenta at GD18. A population of CD3- CD161+ cells, which are defined as rat natural killer (NK) cells, were increased in number in the SHRSP. Intracellular flow cytometry also identified this cell type as a source of excess TNFα in blood and placenta from pregnant SHRSP. I then went on to evaluate the effects of etanercept treatment on these CD3- CD161+ cells and showed that etanercept reduced the expression of CD161 and the cytotoxic molecule, granzyme B, in the NK cells. Thus, etanercept limits the cytotoxicity and potential damaging effect of these NK cells in the SHRSP placenta. Analysing the urinary peptidome has clinical potential to identify novel pathways involved with disease and/or to develop biomarker panels to aid and stratify diagnosis. In Chapter 4, I utilised the SHRSP as a pre-clinical model to identify novel urinary peptides associated with hypertensive pregnancy. Firstly, a characterisation study was carried out in the kidney of the WKY and SHRSP. Urine samples from WKY and SHRSP taken at pre-pregnancy, mid-pregnancy (GD12) and late pregnancy (GD18) were used in the peptidomic screen. In order to capture peptides which were markers of hypertensive pregnancy from the urinary peptidomic data, I focussed on those that were only changed in a strain dependent manner at GD12 and 18 and not pre-pregnancy. Peptide fragments from the uromodulin protein were identified from this analysis to be increased in pregnant SHRSP relative to pregnant WKY. This increase in uromodulin was validated at the SHRSP kidney level using qPCR. Uromodulin has previously been identified to be a candidate molecule involved in systemic arterial hypertension but not in hypertensive pregnancy thus is a promising target for further study. In summary, we have characterised the SHRSP as the first model of maternal chronic hypertension during pregnancy and identified that inflammation mediated by TNFα and NK cells plays a key role in the pathology. The evidence presented in this thesis establishes the SHRSP as a pre-clinical model for pregnancy research and can be continued into clinical studies in pregnant women with chronic hypertension which remains an area of unmet research need.

Association Between Parity, Pre-pregnancy Body Mass Index And Gestational Weight Gain.

To analyze the relationship between parity, pre-pregnancy body mass index (BMI), and gestational weight gain (GWG). This observational controlled study was conducted from November 2013 to April 2014, with postpartum women who started antenatal care up to 14 weeks and had full-term births. Data were collected from medical records and antenatal cards. Descriptive and bivariate analyses were performed. The significance level was 5%. Data were collected from 130 primiparous and 160 multiparous women. At the beginning of prenatal care, 54.62% of the primiparous were eutrophic, while the majority of multiparous were overweight or obese (62.51%). Multiparas are two times more likely to be obese at the beginning of their pregnancies, when compared to primiparas. The average pre-pregnancy weight and final pregnancy weight was significantly higher in multiparous, however, the mean GWG was higher among primiparous. We found an inverse correlation between parity and the total GWG, but initial BMI was significantly higher in multiparas. Nevertheless, monitoring of the GWG through actions that promote a healthier lifestyle is needed, regardless of parity and nutritional status, in order to prevent excessive GWG and postpartum weight retention and consequently inadequate pre-pregnancy nutritional status in future pregnancies.

Contribution Of Antepartum And Intrapartum Hemorrhage To The Burden Of Maternal Near Miss And Death In A National Surveillance Study

Objective To evaluate the occurrence of severe obstetric complications associated with antepartum and intrapartum hemorrhage among women from the Brazilian Network for Surveillance of Severe Maternal Morbidity.Design Multicenter cross-sectional study.Setting Twenty-seven obstetric referral units in Brazil between July 2009 and June 2010.Population A total of 9555 women categorized as having obstetric complications.Methods The occurrence of potentially life-threatening conditions, maternal near miss and maternal deaths associated with antepartum and intrapartum hemorrhage was evaluated. Sociodemographic and obstetric characteristics and the use of criteria for management of severe bleeding were also assessed in these women.Main outcome measures The prevalence ratios with their respective 95% confidence intervals adjusted for the cluster effect of the design, and multiple logistic regression analysis were performed to identify factors independently associated with the occurrence of severe maternal outcome.Results Antepartum and intrapartum hemorrhage occurred in only 8% (767) of women experiencing any type of obstetric complication. However, it was responsible for 18.2% (140) of maternal near miss and 10% (14) of maternal death cases. On multivariate analysis, maternal age and previous cesarean section were shown to be independently associated with an increased risk of severe maternal outcome (near miss or death).Conclusion Severe maternal outcome due to antepartum and intrapartum hemorrhage was highly prevalent among Brazilian women. Certain risk factors, maternal age and previous cesarean delivery in particular, were associated with the occurrence of bleeding.

Analysis of the PTPN11 gene in idiopathic short stature children and Noonan syndrome patients

Background Mutations in the PTPN11 gene are the main cause of Noonan syndrome (NS). The presence of some NS features is a frequent finding in children with idiopathic short stature (ISS). These children can represent the milder end of the NS clinical spectrum and PTPN11 is a good candidate for involvement in the pathogenesis of ISS. Objective To evaluate the presence of mutations in PTPN11 in ISS children who presented NS-related signs and in well-characterized NS patients. Patients and methods We studied 50 ISS children who presented at least two NS-associated signs but did not fulfil the criteria for NS diagnosis. Forty-nine NS patients diagnosed by the criteria of van der Burgt et al. were used to assess the adequacy of these criteria to select patients for PTPN11 mutation screening. The coding region of PTPN11 was amplified by polymerase chain reaction (PCR), followed by direct sequencing. Results No mutations or polymorphisms were found in the coding region of the PTPN11 gene in ISS children. Nineteen of the 49 NS patients (39%) presented mutations in PTPN11. No single characteristic enabled us to distinguish between NS patients with or without PTPN11 mutations. Conclusion Considering that no mutations were found in the present cohort with NS-related signs, it is unlikely that mutations would be found in unselected ISS children. The van der Burgt et al. criteria are adequate in attaining NS diagnosis and selecting patients for molecular studies. Mutations in the PTPN11 gene are commonly involved in the pathogenesis of NS but are not a common cause of ISS.

Early Identification of Infectious Complications in Bariatric Surgery by the Determination of Peritoneal and Systemic Cytokines

Obesity has become a global epidemic and bariatric surgery is one of the therapeutic tools to deal with it. Postoperative complications can occur, such as staple line dehiscence and anastomotic leaks, leading to increased patient mortality. The diagnosis of these complications is frequently difficult. The objective of the present study was to determine whether peritoneal and systemic cytokines could early detect those complications. All patients who underwent open Roux-en-Y gastric bypass from February 2007 to August 2008 were prospectively evaluated. Blood and peritoneal effluent from the drain were collected for the determination of cytokine levels. We also evaluated the clinical signs and the leukograms of the patients. A total of 107 obese patients were studied. Ninety patients had no complications; 17 had at least one infectious complication which include five cases of staple line dehiscence. Until the third postoperative day, the vital signs and the leukogram did not predict the onset of infectious complications, but the cytokines (interleukin-1 beta and interleukin-6) were early markers of these complications. Cytokines are good predictors of poor postoperative evolution in bariatric surgery since peritoneal cytokines diagnose better these infectious complications even before changes in blood count and before the occurrence of clinical manifestations.

Acute chagasic myocardiopathy after orthotopic liver transplantation with donor and recipient serologically negative for Trypanosoma cruzi: A case report

Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi. Chagas disease following solid-organ transplantation has occurred in Latin America. This report presents the occurrence of Chagas disease despite negative serological tests in both the donor and the recipient, as well as the effectiveness of treatment. A 21-year-old woman from the state of Sao Paulo (Brazil) underwent cadaveric donor liver transplantation in November 2005, due to cirrhosis of autoimmune etiology. Ten months after liver transplantation, she developed signs and symptoms of congestive heart failure (New York Heart Association functional class IV). The echocardiogram, which was normal preoperatively, showed dilated cardiac chambers, depressed left ventricular systolic function (ejection fraction = 35%) and moderate pulmonary hypertension. Clinical investigation discarded ischemic heart disease and autoimmune and other causes for heart failure. Immuno fluorescence (immunoglobulin M and immunoglobulin G) and hemagglutination tests for T cruzi were positive, and abundant T cruzi amastigotes were readily identified in myocardial biopsy specimens. Treatment with benznidazole for 2 months yielded an excellent clinical response. At the moment of submission, the patient remains in functional class I. This case highlighted that more appropriate screening for T cruzi infection is mandatory in potential donors and recipients of solid-organ transplants in regions where Chagas disease is prevalent. Moreover, it stressed that this diagnosis should always be considered in recipients who develop cardiac complications, since negative serological tests do not completely discard the possibility of disease transmission and since good results can be achieved with prompt trypanocidal therapy.

Evaluation of Adult Chronic Chagas` Heart Disease Diagnosis by Molecular and Serological Methods

Chagas` disease caused by Trypanosoma cruzi is endemic in Latin America. T. cruzi presents heterogeneous populations and comprises two main genetic lineages, named T. cruzi I and T. cruzi II. Diagnosis in the chronic phase is based on conventional serological tests, including indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA), and diagnosis in the acute phase based on parasitological methods, including hemoculture. The objective of this study was to evaluate the diagnostic procedures of Chagas` disease in adult patients in the chronic phase by using a PCR assay and conventional serological tests, including TESA-blot as the gold standard. Samples were obtained from 240 clinical chronic chagasic patients. The sensitivities, compared to that of TESA-blot, were 70% for PCR using the kinetoplast region, 75% for PCR using the nuclear repetitive region, 99% for IIF, and 95% for ELISA. According to the serological tests results, we recommend that researchers assess the reliability and sensitivity of the commercial kit Chagatest ELISA recombinant, version 3.0 (Chagatest Rec v3.0; Wiener Lab, Rosario, Argentina), due to the lack of sensitivity. Based on our analysis, we concluded that PCR cannot be validated as a conventional diagnostic technique for Chagas` disease. These data have been corroborated by low levels of concordance with serology test results. It is recommended that PCR be used only for alternative diagnostic support. Using the nuclear repetitive region of T. cruzi, PCR could also be applicable for monitoring patients receiving etiologic treatment.

Otologic symptoms of temporomandibular disorder and effect of orofacial myofunctional therapy

The aim of this study was to investigate the frequency of otologic symptoms and their relationship to orofacial signs and symptoms of temporomandibular disorder (TMD), and the effect of orofacial myofunctional therapy. The study was conducted on eight asymptomatic subjects (Group C) and 20 subjects with articular TMD, randomly distributed over two groups: one treated using orofacial myofunctional therapy (OMT Group) and a control group with TMD (Group CTMD). Patient selection was based upon the Research Diagnostic Criteria for TMD (RDC/TMD). All subjects submitted to a clinical examination with self-reporting of symptom severity, and to orofacial myofunctional and electromyographic evaluation at diagnosis and again, at the end of the study. Correlations were calculated using the Pearson test and inter- and intragroup comparisons were made (p<0.05). In the diagnosis phase, subjects with TMD reported earache (65%), tinnitus (60%), ear fullness (90%), and 25% of the asymptomatic subjects reported tinnitus. The otologic symptoms were correlated with tenderness to palpation of the temporomandibular muscles and joints and with orofacial symptoms. Only the OMT group showed a reduction of otologic and orofacial symptoms, of tenderness to palpation and of the asymmetric index between muscles. OMT may help with muscle coordination and a remission of TMD symptoms.

Use of cone-beam volumetric tomography in the diagnosis of root fractures

Objectives. The diagnosis of root fractures by conventional radiographs is still difficult because of limitations of 2D images. Cone-beam volumetric tomography improves the diagnosis capacity in dentistry, such as increased radiation dose to the patient and presence of artifacts on the image. Study design. This study compared the images obtained on conventional periapical radiographs and 3D scans (Accuitomo 3DX) for the diagnosis of root fractures. Twenty patients with suspected root fractures were submitted to examination by periapical radiography and CBCT. Two professionals, unaware of the symptomatology, examined these radiographs and CBCT images according to pre-established scores, which were later checked against the signs and symptoms. Results. The results revealed statistical difference for cone-beam volumetric tomography compared with conventional radiographs in the diagnosis of root fractures. Conclusion. It could be concluded that cone-beam volumetric tomography was better than conventional radiography in the diagnosis of root fractures, thereby constituting an excellent alternative for diagnosis in general practice. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009; 108: 270-277)

Back, chest and abdominal pain: How good are spinal signs at identifying musculoskeletal causes of back, chest or abdominal pain?

Background: Spinal signs found in association with atypical chest and abdominal pain may suggest the pain is referred from the thoracic spine. However, the prevalence of such signs in these conditions has rarely been compared with that in those without pain. In this study, the prevalence of spinal signs and dysfunction in patients with back, chest and abdominal pain is compared with that in pain free controls. The aim of the study is to determine the significance of spinal findings in patients with such pain. Methods: A general practitioner blinded to the patients' histories performed a cervical and thoracic spinal examination on general practice patients with back, chest and/or abdominal pain and on controls without pain. Thoracic intervertebral dysfunction was diagnosed on the basis of movement and palpation findings. Results: Seventy three study patients plus 24 controls, were examined. For cervical spinal signs, pain in the back, chest and/or abdomen was associated with pain with active movements and overpressure at end range and with loss of movement range. For thoracic spinal signs, this association held for pain with active movements and overpressure, but not with loss of movement range. The prevalence of thoracic intervertebral dysfunction was 25.0% in controls, 65.5% with chest/abdominal pain, 72.0% with back pain and 79.0% with back pain with chest/abdominal pain. This prevalence was higher with chest pain than with abdominal pain. Conclusions: The results show an association, but not a causal link between thoracic intervertebral dysfunction and atypical chest/abdominal pain. A spinal examination should be performed routinely assessing these conditions. The minimum examination for the detection of intervertebral dysfunction is testing for pain with spinal movements and palpation for tenderness. The interpretation of positive signs requires knowledge of their prevalence in pain free controls and in patients with visceral disease

Crohn's disease with oral presenting signs masquerading as chronic osteomyelitis

Background: A case of Crohn's disease (CD) was diagnosed following recognition of oral and systemic signs and symptoms in a 19-year-old male patient. Methods: Clinical investigation utilized included blood tests (full blood count, electrolytes, urea, creatinine, liver function tests), computed tomogrphy scans, magnetic resonance imaging scans, oral biopsies, colonoscopy and biopsies of the terminal ileum and colon. Results: A diagnosis of CD was made which then allowed appropriate medical treatment to be initiated. Conclusion: The importance of a thorough medical history and full physical examination with appropriate investigations as dictated by clinical findings is demonstrated.

Training control centers' operators in incident diagnosis and power restoration using intelligent tutoring systems

The activity of Control Center operators is important to guarantee the effective performance of Power Systems. Operators’ actions are crucial to deal with incidents, especially severe faults like blackouts. In this paper, we present an Intelligent Tutoring approach for training Portuguese Control Center operators in tasks like incident analysis and diagnosis, and service restoration of Power Systems. Intelligent Tutoring System (ITS) approach is used in the training of the operators, having into account context awareness and the unobtrusive integration in the working environment. Several Artificial Intelligence techniques were criteriously used and combined together to obtain an effective Intelligent Tutoring environment, namely Multiagent Systems, Neural Networks, Constraint-based Modeling, Intelligent Planning, Knowledge Representation, Expert Systems, User Modeling, and Intelligent User Interfaces.