Mineralocorticoid receptor activation as an etiological factor in kidney diseases

The mineralocorticoid receptor (MR) is a member of the steroid-responsive nuclear receptor family. Currently, in addition to its classical role in fluid homeostasis, attention has been focused on the pro-proteinuric and pro-inflammatory effects of MR in renal and cardiovascular diseases. Since proteinuria has been shown to be an important factor in the prognosis of patients with chronic kidney disease (CKD) [according to the newest Japanese Society of Nephrology and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for the treatment of CKD], it is worth discussing the role of MR in the progression of proteinuric CKD and the possible association with podocyte injury. Rac1, a Rho-GTPase family protein, is known for its role in the regulation of the cytoskeleton. We discovered the role of active Rac1 in amplifying MR activation in one of our studies and then continued to study how the Rac1?MR pathway contributes to the progression of kidney diseases. We then discovered the harmful effects of the activation of the Rac1?MR pathway in response to salt loading in the kidney for proteinuric kidney diseases of various animal models with salt-sensitive hypertension, such as Dahl salt-sensitive rats, RhoGDIα-knockout mice, angiotensin II-overproducing mice, and aldosterone-infused rats. In this review, we have introduced recent findings that suggest the contribution of MR activation to kidney diseases and the role of the Rac1?MR pathway in kidney injury associated with salt-sensitive hypertension and proteinuria. Thus, the Rac1?MR pathway is a potential therapeutic target in patients with proteinuric CKD.     

The von Hippel-Lindau gene, kidney cancer, and oxygen sensing

Recent studies of a relatively rare hereditary cancer syndrome, von Hippel-Lindau (VHL) disease, have shed new light on the molecular pathogenesis of kidney cancer and, perhaps more important, on how mammalian cells sense and respond to changes in oxygen availability. This knowledge is already translating into new therapeutic targets for kidney cancer as well as for multiple conditions, such as myocardial infarction and stroke, in which ischemia plays a pathogenic role. This review summarizes the current knowledge of the molecular pathogenesis of von Hippel-Lindau disease and the role of the VHL gene product (pVHL) in kidney cancer and the mammalian oxygen sensing pathway.     

Pulmonary pathways and mechanisms regulating transpulmonary shunting into the general circulation: an update

Embolic insults account for a significant number of neurologic sequelae following many routine surgical procedures. Clearly, these post-intervention embolic events are a serious public health issue as they are potentially life altering. However, the pathway these emboli utilize to bypass the pulmonary microcirculatory sieve in patients without an intracardiac shunt such as an atrial septal defect or patent foramen ovale, remains unclear. In the absence of intracardiac routes and large diameter pulmonary arteriovenous malformations, inducible large diameter intrapulmonary arteriovenous anastomoses in otherwise healthy adult humans may prove to be the best explanation. Our group and others have demonstrated that inducible large diameter intrapulmonary arteriovenous anastomoses are closed at rest but can open during hyperdynamic conditions such as exercise in more than 90% of healthy humans. Furthermore, the patency of these intrapulmonary anastomoses can be modulated through the fraction of inspired oxygen and by body positioning. Of particular clinical interest, there appears to be a strong association between arterial hypoxemia and neurologic insults, suggesting a breach in the filtering ability of the pulmonary microvasculature under these conditions. In this review, we present evidence demonstrating the existence of inducible intrapulmonary arteriovenous anastomoses in healthy humans that are modulated by exercise, oxygen tension and body positioning. Additionally, we identify several clinical conditions associated with both arterial hypoxemia and an increased risk for embolic insults. Finally, we suggest some precautionary measures that should be taken during interventions to keep intrapulmonary arteriovenous anastomoses closed in order to prevent or reduce the incidence of paradoxical embolism.     

Nitrate-nitrite-nitric oxide pathway: implications for anesthesiology and intensive care

The gaseous radical nitric oxide is involved in numerous physiologic and pathophysiological events important in anesthesiology and intensive care. Nitric oxide is endogenously generated from the amino acid l-arginine and molecular oxygen in reactions catalyzed by complex nitric oxide synthases. Recently, an alternative pathway for nitric oxide generation was discovered, wherein the inorganic anions nitrate (NO3) and nitrite (NO2), most often considered inert end products from nitric oxide generation, can be reduced back to nitric oxide and other bioactive nitrogen oxide species. This nitrate-nitrite-nitric oxide pathway is regulated differently than the classic l-arginine-nitric oxide synthase nitric oxide pathway, and it is greatly enhanced during hypoxia and acidosis. Several lines of research now indicate that the nitrate-nitrite-nitric oxide pathway is involved in regulation of blood flow, cell metabolism, and signaling, as well as in tissue protection during hypoxia. The fact that nitrate is abundant in our diet gives rise to interesting nutritional aspects in health and disease. In this article, we present an overview of this field of research with emphasis on relevance in anesthesiology and intensive care.     

The alveolar-arterial oxygen quotient. standard norms, clinical findings (author's transl)

From the practical standpoint of view the A-aDO2 proved to be a good parameter for evaluation of global gas exchange. The endexspiratory oxygen pressure, recorded by mass spectrometry, is set equal to the alveolar oxygen pressure. Therefore it is possible for clinical use to have an on line monitoring of PETO2--PaO2. It is necessary to specify the pressure difference in dependence of the inspiratory oxygen pressure since the alveolo-arterial oxygen pressure difference increases with increasing inspiratory oxygen pressure concentration. For practical clinical purposes we come out with the relative ratio of the difference adjusted to the alveolar oxygen pressure. The alveolar-arterial oxygen quotient also called "quotient": formula: (see text) has proved to be a clinical suitable figure. For this quotient are no standard norms reported in the literature. This study was set up to evaluate the quotient in 9 healthy volunteers. The standard norms, found in our study, can basically used for practical clinical purposes. This quotient is demonstrated to be practicable in intensive care medicine (obstructive pulmonary disease, acute pulmonary failure, positive pressure ventilation).     

Successful surgical resection of intrapericardial extralobar pulmonary sequestration with congenital pulmonary adenomatoid malformation type II

We report a 7-day-old boy referred to our institution with tachypnea and cardiomegaly who was discovered to have an intrapericardial extra-lobar pulmonary sequestration containing a cystic pulmonary adenomatoid malformation type II. He underwent successful surgical resection of the intrapericardial mass, which we believe represents the first reported case of this rare entity.     

Bidirectional cavopulmonary shunts: clinical applications as staged or definitive palliation

A standard Glenn anastomosis between the superior vena cava and the right pulmonary artery has been the accepted mode of treatment for patients with complex cyanotic congenital heart disease. We report our experience in 18 patients with such disease who underwent a bidirectional cavopulmonary shunt because of increasing cyanosis and growth cessation. All patients were considered less than "ideal" candidates for a Fontan procedure. We divided the patients into two groups: group 1 had azygos continuation and group 2 did not. Fourteen patients required hypothermic cardiopulmonary bypass. Bidirectional pulmonary blood flow was achieved in all patients. Only 1 death occurred (group 2). The improvement in oxygen saturation and overall clinical condition of these patients, together with the low mortality and morbidity, is encouraging. However, long-term follow-up is mandatory for a comprehensive evaluation of this surgical approach as definitive palliation or as a first stage for a Fontan operation.     

The human genome and gene expression profiling.

The mapping and sequencing of the human genome has generated a large resource for answering questions about human disease. This achievement is akin in scientific importance to developing the periodic table of elements. Plastic surgery has always been at the frontier medical research. This resource will help us to improve our understanding on the many unknown physiological and pathogical conditions we deal with daily, such as wound healing keloid scar formation, Dupuytren's disease, rheumatoid arthritis, vascular malformation and carcinogenesis. We are primed in obtaining both disease and normal tissues to use this resource and applying it to clinical use. This review is about the human genome, the basis of gene expression profiling and how it will affect our clinical and research practices in the future and for those embarking on the use of this new technology as a research tool, we provide a brief insight on its limitations and pitfalls.     

Prostaglandin expression profile in hypoxic osteoblastic cells

Conditions such as fracture and unloading have been shown to be associated with tissue and cellular hypoxia in bone. The effects of hypoxia on bone cell physiology and ultimately its impact on bone tissue repair and remodeling are not well understood. In this study, we investigated the role of hypoxia on prostaglandin release from osteoblastic cells cultured in 2% (hypoxia), 5% (potentially cellular normoxia), and 21% (normoxia for standard cell culture conditions) oxygen for up to 24 h. We quantified the effects of reduced oxygen tension on the release of prostaglandin (PG)E₂, PGF_2α, PGD₂, and PGI₂. The mechanism by which hypoxia increases PG production was investigated by examining the various regulatory components of the PG biosynthetic pathway. Our data show that PGE₂ levels alone are significantly elevated under hypoxic conditions. Also, we show that cyclooxygenase (COX)-1 and COX-2 play an important role in hypoxia-induced PGE₂ production, possibly via a mechanism involving changes in their respective activity levels under low oxygen conditions. The effect of hypoxia on PGE₂ levels was mimicked by dimethyloxaloglycine, a known activator of the HIF pathway. In addition, we confirmed that HIF-1α was stabilized in osteoblastic cells under hypoxia. Taken together these data suggest a role for the HIF pathway in regulation of PGE₂ levels under hypoxic conditions. Previous studies have detected release of prostaglandins from areas of damaged bone, such as a fracture site, and our data may contribute to an understanding of how this release is regulated.     

Monitoring intravascular volumes to direct hypertensive, hypervolemic therapy in a patient with vasospasm

The common therapeutic approach to patients, who develop vasospasm following subarachnoid hemorrhage, is usually composed of hypertension, hypervolemia, and hemodilution (HHH). This therapy often leads to cardiopulmonary complications, including significant heart failure and pulmonary edema. We describe a 40-year-old woman who developed vasospasm 8 days after surgery for clipping an aneurysm, following a large subarachnoid hemorrhage. The patient required HHH therapy with a very high blood pressure to optimize her clinical neurologic status, but she started to develop pulmonary edema resulting from this therapy. This manifested as a need for increasing oxygen to maintain a normal arterial saturation. To avoid further hemodynamic compromise, we used a new monitor of cardiac function to measure intravascular volumes and quantify pulmonary edema to help titrate the fluid management of a patient in severe vasospasm. We conclude that monitoring volumes with the PiCCO cardiac monitor can help make clinical decisions in patients requiring HHH. This enables maintaining a hypertensive and hypervolemic state while avoiding cardiopulmonary complications such as heart failure and pulmonary edema. It may also help prevent the need for mechanical ventilation in these situations.     

Processing,storage and display of physiological measurements

As anaesthetists we rely on the monitoring that we attach to our patients to be accurate, responsive and reliable. The display screen we examine closely daily with its beeps and alarms represents the processing of a large volume of biological signals of disparate types into something easily recognizable that can rapidly alert us to changes in a patient’s physiology. This article uses some common examples of physiological measurements that undergo the pathway of detection, transduction, processing, amplification and filtering before being displayed on a monitoring screen and stored. We explain key components of this pathway such as Fourier analysis, gain and analogue-to-digital conversion; and how confounding factors such as noise, interference and damping are dealt with. We also discuss some newer technologies that are finding their way into common anaesthetic practice such as depth of anaesthesia monitors and electronic anaesthesia records.     

Processing,storage and display of physiological measurements

As anaesthetists we rely on the monitoring that we attach to our patients to be accurate, responsive and reliable. The display screen we examine closely daily with its beeps and alarms represents the processing of a large volume of biological signals of disparate types into something easily recognizable that can rapidly alert us to changes in a patient's physiology. This article uses some common examples of physiological measurements that undergo the pathway of detection, transduction, processing, amplification and filtering before being displayed on a monitoring screen and stored. We explain key components of this pathway such as Fourier analysis, gain and analogue to digital conversion; and how confounding factors such as noise, interference and damping are dealt with. We also discuss some newer technologies that are finding their way into common anaesthetic practice such as depth of anaesthesia monitors and electronic anaesthesia records.     

Right lobe living-donor hepatectomy—the Toronto approach,tips and tricks

Living-donor liver transplantation (LDLT) is a well-established treatment for end-stage liver disease. Nevertheless, it has not been extensively accepted in North America or Europe as it has been in Asia. At the University of Toronto we initiated our LDLT program in 2000 and since then our program has grown each year, representing today the largest LDLT program in North America. Our right-lobe LDLT experience from 2000−2014 includes 474 right lobes. Only 30% of our grafts have included the middle hepatic vein. We present excellent outcomes in terms of graft and patient survival which is not different to that achieved with deceased donor liver transplantation. In the present study we will discuss the evolution, challenges and current practices of our LDLT program. We will discuss what is and has been the program philosophy. We will also discuss how we evaluate our donors and the extensive workup we do before a donor is accepted for live donation. Furthermore we will discuss some tips and tricks of how we perform the right hepatectomy for live donation.     

The hepatopulmonary syndrome: new name, old complexities.

On the basis of previous work, our own experience and findings, and the considerations discussed above, we propose a set of four diagnostic criteria for the hepatopulmonary syndrome: 1. presence of chronic hepatic disease (alcoholic, postnecrotic, or primary biliary cirrhosis or active chronic hepatitis)--severe liver dysfunction may not be mandatory; 2. absence of intrinsic cardiopulmonary disease, with normal chest radiograph or with nodular basal shadowing; 3. pulmonary gas exchange abnormalities--an increased alveolar-arterial oxygen gradient (> or = 2.0 kPa) with or without hypoxaemia; 4. the extrapulmonary appearance of intravenous radiolabelled microspheres or a positive contrast enhanced echocardiogram, suggesting intrapulmonary vascular abnormalities. Although these four criteria appear straightforward, there may be other features that are not always present--namely: 1. low transfer factor (diffusing capacity); 2. shortness of breath, with or without platypnoea and orthodeoxia; 3. increased cardiac output and reduced pulmonary vascular pressures; 4. small (or no) increase in pulmonary vascular resistance when the patient is breathing low oxygen mixtures. From the physiological viewpoint, the hepatopulmonary syndrome provides an excellent model for clinical research in the pathophysiology of pulmonary gas exchange. So far it has been possible to show that arterial hypoxaemia in this condition is (1) partitioned into components resulting from VA/Q mismatching, intrapulmonary shunt, and limitations of oxygen diffusion; (2) modulated by the interplay between the intrapulmonary and the extrapulmonary determinants of PaO2, such as cardiac output and minute ventilation; (3) vulnerable to the influence of inadequate pulmonary vascular tone; and (4) resolved when the injured liver is replaced and hepatic function is restored to within normal limits.     

Gastroesophageal reflux disease and graft failure after lung transplantation

In spite of advances in lung transplantation, the median survival after lung transplant remains less than 5 years, an outcome that is significantly worse than other solid organ transplants. Efforts to understand the unique hurdles faced in lung transplant have revealed gastroesophageal reflux disease (GERD) as a risk factor for ultimate graft failure. The link between GERD and chronic lung rejection parallels the association between GERD and other forms of lung disease such as idiopathic pulmonary fibrosis. Understanding how GERD predisposes to graft failure is an important issue as it may lead to therapies such as surgical correction that aim to lessen the exposure of the pulmonary epithelium to gastric contents. Here, we review the link between GERD and lung disease and discuss the preclinical and clinical studies that are starting to elucidate a mechanism for this association.     

Congenital absence of vas deferens and ectopic kidney

IntroductionCongenital absence of the vas deferens (CUAVD) is a rare clinical entity, usually discovered accidently during surgical procedures of the urogenital zone, CUAVD has the prevalence of 0.5–1.0% in male population and it is associated with various forms of congenital genitourinary malformations like renal agenesis. we present a case of a 21 years old, male, managed in our private hospital for varicoceles and discovered to have CUAVD and ectopic kidney.Presentation of caseA 21 years old male, with no significant medical or surgical history presented to our out-patient clinic complaining of scrotal heaviness and pain. upon physical examination he was discovered to have a bilateral varicocele and was scheduled for a bilateral varicocelectomy, during the procedure he was discovered with left side CUAVD.DiscussionCongenital unilateral absence of the vas deference is a very rare clinical entity in the male population it has an incidence of 0.5–1.0%. it is usually discovered during evaluation for infertility or surgical procedures of the urogenital zone. Unilateral congenital absence of the vas deference is more associated with renal agenesis (73.3%), compared to the bilateral form (11.8%)_. CAVD is responsible of 1–2% of male infertility.ConclusionCongenital absence of the vas deference is a unique clinical entity due to its great association with a large variety of urogenital abnormalities, we present this case to stress the importance of including scrotal examination in the routine physical exam to reduce the late diagnosis of such abnormality and it associated comorbidities.     

Oxygen treatment with special reference to treatment of complications incident to goiter

We believe that the therapeutic administration of oxygen by means of the chamber or tent is most helpful in a restricted group of cases, such as postoperative pulmonary edema, bronchopneumonia, and respiratory obstruction. The patients who show most marked benefit are those with evidence of anoxemia, or of impending anoxemia. Treatment should be begun as early as is possible, as in many instances the progress of pulmonary edema to pneumonia probably can be averted. Treatment should be continuous, or as nearly continuous as possible, until the pathologic process is well controlled. Binger and others have called attention to the deleterious effects of oxygen concentrations of 70 per cent or more. We have not raised the oxygen above 60 per cent for more than a few hours at a time. From these concentrations we have not seen harmful effect. Treatment with oxygen can be carried out more efficiently in oxygen chambers than in oxygen tents, although excellent results can be obtained in tents properly manipulated. We do not know that the life of any individual patient has been saved by oxygen treatment; however, we believe that at least an occasional patient is saved when marked lowering of the temperature and increased comfort can be secured in such a large series of patients who are seriously ill. Our results not only warrant the continuation of this method of treatment but indicate the advisability of more general adoption of efficient methods of the administration of oxygen in those diseases known to be benefited by its use. The patients who obtain the greatest benefit are those with postoperative pulmonary edema, bronchopneumonia, or respiratory obstruction accompanied by cyanosis or impending cyanosis.     

Klinischer Behandlungspfad „Knieendoprothetik“

Total knee arthroplasty is a standardized intervention in orthopedic departments. Due to the standard character of the procedure it is predestinated to be performed in a clinical pathway. We developed a clinical pathway for total knee arthroplasty and aim to show the details of it and discuss it together with the current literature. Total knee arthroplasty is a standardized procedure and is therefore predestinated to be included in a clinical pathway. The team consists of different groups which are combined in this path to work together in a very structured and standardized manner. We describe and discuss our clinical pathway for total knee arthroplasty and the initial experiences which are very promising.     

Pulmonary Renal Syndrome Due to Anti-GBM and IgM C-ANCA Disease Requiring the Use of Novel Therapeutic Agents

There are several known causes for the clinical syndrome of pulmonary hemorrhage and acute renal failure. Here, we report a unique case of a 50-year-old man presenting in this manner. The initial diagnosis was one of antiglomerular basement membrane (anti-GBM) disease that responded well to steroids, cyclophosphamide, and plasma exchange (PE). The pulmonary hemorrhage resolved, but he remained dialysis dependent. However, despite falling anti-GBM titers, the symptoms relapsed and standard therapy was reinitiated with limited success. The anti-GBM antibody titer fell to zero despite clinical deterioration, prompting a search for an alternative diagnosis. He was found to be IgM anti-proteinase-3 antineutrophil cytoplasmic antibody (C-ANCA) positive. The pulmonary hemorrhage responded successfully to the use of intravenous immunoglobulin and the antilymphocyte monoclonal antibody CD52. To our knowledge, this is the first known case of IgM C-ANCA in association with anti-GBM disease. As such, it highlights the predominance of pulmonary hemorrhage in this condition, as well as the need to consider alternative therapies in refractory cases.     

Accuracy of pulse oximetry in patients with low systemic vascular resistance

In order to assess the accuracy of pulse oximeters in patients with septic shock, we compared 80 paired readings of oxygen saturations taken from pulse oximeters and oxygen saturations obtained from co-oximetry in patients receiving intensive therapy with indwelling pulmonary artery flotation catheters. Comparison between groups with low or normal systemic vascular resistance indices showed a small (1.4%) but significant (p < 0.001) underreading of the saturation from the pulse oximeter in the presence of a low systemic vascular resistance. With normal or high systemic vascular resistance pulse oximeter readings correlated well with co-oximetry. We hypothesise that the main cause of this underreading is because the pulse oximeter is sensing pulsatile venous flow due to the opening of arteriovenous channels in the skin in septic states.