Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension?

Approximately 10% of patients with hypertension have a high ratio of aldosterone to renin, but the reason for this and the relationships among low-renin essential hypertension, elevation of the ratio, and true primary aldosteronism are unclear. We have previously reported that a polymorphism of the gene (C-to-T conversion at position -344) encoding aldosterone synthase is associated with hypertension, particularly in patients with a high ratio. However, the most consistent association with this variant is a relative impairment of adrenal 11beta-hydroxylation. In this review, we propose that altered conversion of deoxycortisol to cortisol leads to a subtle, chronic increase in adrenocortrophin drive to the adrenal cortex, with eventual development of hyperplasia. In combination with other genetic or environmental factors (such as dietary sodium intake), we suggest that this might be responsible for the long-term development of a resetting of the aldosterone response to angiotensin II, giving rise to the phenotype of hypertension with a raised ratio. In some subjects, this may progress further to true primary aldosteronism with a dominant adrenal nodule. Thus, there may be a genetically influenced continuum from hypertension with a normal ratio, through hypertension with a raised ratio, and primary aldosteronism.     

Right coronary artery-right atrium fistula in primary angiosarcoma of the heart.

We report a case of angiosarcoma of the heart, manifested as a continuous murmur. Right coronary arteriography disclosed a paracardiac mass with fistulas from the coronary vessel to the right atrium. Histologic study revealed this to be an angiosarcoma with sinusoidal pattern. To our knowledge, this is the first case of this kind of cardiac tumor presenting as a fistula from a coronary artery to the right atrium.     

A simple modification in operative technique can reduce the incidence of nonanastomotic biliary strictures after orthotopic liver transplantation

Nonanastomotic strictures after liver transplantations are a source of significant morbidity, often necessitating retransplantation. The purpose of this study was twofold: first to identify features associated with the development of this lesion; second, to make technical modifications that will decrease the incidence of this problem. In the first part of this study, 15 of 131 patients were diagnosed with nonanastomotic biliary stricture. A stepwise logistic-regression analysis associated donor cold ischemic time and dopamine dose with the development of nonanastomotic biliary strictures. All these patients had arterial reconstruction after partial revascularization of the liver with portal venous blood. Because the bile duct receives its blood supply from only the hepatic artery, we hypothesized that the prolonged period of warm ischemia from staged reconstruction of the vascular supply would promote the development of this lesion. In a second part of this study, the stricture rate in 45 patients with simultaneous revascularization using both the hepatic artery and portal vein was compared with that in 83 patients from the first part of this study initially revascularized with portal venous blood. All patients in the second study had grafts preserved using UW solution. Only 1 patient with simultaneous revascularization developed a nonanastomotic biliary stricture. Because we were unable to identify any significant complications related to this method of revascularization, we propose that the hepatic artery and portal vein should be released simultaneously, especially in patients receiving a graft with prolonged storage time.     

Altered pathogenesis in encephalomyocarditis virus (D variant)-infected diabetes-susceptible and resistant strains of mice

Summary The D variant of encephalomyocarditis virus (EMCV-D) induces a diabetes mellitus-like disease in male SJL/J mice. Other inbred strains, while resistant to the diabetogenic effect, exhibit strikingly different responses to this virus. In these studies, infection of diabetes resistant C3H mice with the D variant produces massive acute pancreatitis with little apparent direct islet cell involvement. This exocrine tropism is not altered when C3H mice with an inherent macrophage defect are infected, and appears to be a gender-specific phenomenon, with female C3H mice resistant to this exocrine involvement. Long-term infection of both male and female C3H mice does not change their response to the virus. Castration of male C3H mice, using a protocol that has been reported to block the diabetogenic effect of this virus, does not alter the development of this acinar lesion. The B variant of EMCV does not induce acinar destruction, nor is it diabetogenic. However, preinfection with the B variant 3 days prior to infection with the D variant does protect against the development of the exocrine lesion. Coinfection with equal doses of the two variants also protects against this lesion, as does coinfection with a lower dose of B variant. Therefore, the host response that is generated against the B variant appears to be responsible for this protection from D variant exocrine destruction. Due to the short time frame, it is unlikely that this protection is the result of an antibody response. Rather, this data is more consistent with an interferon response generated against the B variant that would inhibit replication of the D variant.     

Risk of Subsequent Pregnancy in Women With a History of Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a pregnancy-associated myocardial disease with marked left ventricular systolic dysfunction. Although this condition can lead to major complications, including severe heart failure, arrhythmias, thromboembolic events, and death, the majority of women with this condition demonstrate a complete or partial recovery. Many of these women desire to become pregnant again and are concerned regarding the safety of additional pregnancies. The purpose of this paper is to review the available information related to subsequent pregnancies in women with a history of PPCM in an attempt to reach conclusions regarding the risk of such pregnancies in this group of patients.     

Cytochrome c release from mitochondria proceeds by a two-step process

Cytochrome c is often released from mitochondria during the early stages of apoptosis, although the precise mechanisms regulating this event remain unclear. In this study, with isolated liver mitochondria, we demonstrate that cytochrome c release requires a two-step process. Because cytochrome c is present as loosely and tightly bound pools attached to the inner membrane by its association with cardiolipin, this interaction must first be disrupted to generate a soluble pool of this protein. Specifically, solubilization of cytochrome c involves a breaching of the electrostatic and/or hydrophobic affiliations that this protein usually maintains with cardiolipin. Once cytochrome c is solubilized, permeabilization of the outer mitochondrial membrane by Bax is sufficient to allow the extrusion of this protein into the extramitochondrial environment. Neither disrupting the interaction of cytochrome c with cardiolipin, nor permeabilizing the outer membrane with Bax, alone, is sufficient to trigger this protein's release. This mechanism also extends to conditions of mitochondrial permeability transition insofar as cytochrome c release is significantly depressed when the electrostatic interaction between cytochrome c and cardiolipin remains intact. Our results indicate that the release of cytochrome c involves a distinct two-step process that is undermined when either step is compromised.     

Heparin-induced thrombocytopenia and thrombosis syndrome: a case study

Heparin is a commonly used drug in critical care. In this case study we describe a relatively unknown and unforeseen event whereby the administration of heparin to prevent thrombus formation paradoxically resulted in clot formation. Heparin-induced thrombocytopenia and thrombosis syndrome developed in a 36-year-old woman initially admitted to the coronary care unit with complaints of chest pain. We explore the theoretic basis of this syndrome as an immune-mediated response, along with the mechanisms leading to this syndrome as an immune-mediated response, along with the mechanisms leading to the clinical features and the difficulties associated with diagnosis treatment. In view of the frequent use of heparin and nurses' responsibility for recognizing the untoward effects of medications they administer, this case study is useful in gaining insight into a relatively unknown phenomenon.     

Clinical potential of in vitro measured red cell deformability, a myth?

For many years the study of Red Blood Cell (RBC) deformability has been limited to specialised hematological research institutes and this has hampered a widespread clinical testing of this dynamic RBC property. Consequently, the clinical relevance of such in vitro measurements has remained questionable now for a considerable time. The recent availability of the LORCA, a routinely applicable and computer assisted instrument for this purpose, opens now the possibility to evaluate RBC deformability on a large scale in various pathological situations associated with impaired microcirculatory flow. In this communication we present our clinical experience obtained thusfar with this instrument. Besides the effect of physiological aging of normal RBC, the results of a clinical study on malaria tropica, case studies of hereditary elliptocytosis, Smith-Lemli-Opitz syndrome (a cholesterol biosynthesis defect), the treatment of sickle cell crisis with hydroxy-urea as well as the clinical intervention with Cyclosporin, are collected. In conclusion, it can be stated that the limited clinical experience with the LORCA as is reported here, yields sufficient evidence about the clinical potential of this technique.     

Gastroduodenal Crohn's disease presenting as biliary colic.

A 31-year old physician, with a 15-year history of regional enteritis, presented with a gallstone and biliary colic, who on further work-up proved to have Crohn's disease of the stomach and duodenum. Roentgenographic, endoscopic and biopsy material were all consistent with Crohn's disease of the stomach and duodenum. Response to steroid treatment indicated that the symptoms were secondary to Crohn's disease and, as such, this is the first report of this rare problem. Further, to our knowledge this represents only the ninth endoscopy and only the second biopsy via endoscopy to demonstrate a noncaseating granuloma from the stomach in this disease.     

GLUCOCORTICOID DEFICIENCY WITH ACHALASIA OF THE CARDIA AND LACK OF LACRIMATION

Four recent reports describe a multisystem disorder in which ACTH insensitivity is associated with achalasia and alacrima. We report studies on a male patient with this rare triad. The patient had alacrima from birth; isolated glucocorticoid deficiency had been diagnosed at 3.5 years of age and achalasia at age 6. The possibility that this syndrome could be due to a parasympathetic degeneration has already been proposed; the cause of the glucocorticoid deficiency, however, remains unclear. Parasympathetic function in other areas was investigated to determine whether there might be a more generalized abnormality. Specific cardiac tests of parasympathetic function showed that parasympathetic input to the heart was affected in the patient, while the same tests in an Addisonian child were normal. We show, then, a hitherto undetected parasympathetic abnormality in a patient with this syndrome, suggesting a generalized disturbance of this system. On this basis we may hypothesize that the glucocorticoid failure may be a consequence of the loss of parasympathetic input to the adrenal gland, although this remains to be demonstrated experimentally.     

Detection of a secreted form of the murine H-2 class I antigen with an antibody against its predicted carboxyl terminus.

Analysis of H-2 class I-specific cDNA clones has suggested the synthesis by the liver of a class I molecule that is secreted rather than membrane bound. To detect this putative class I-related molecule, we have predicted a unique region of amino acid sequence located toward the carboxyl terminus of the molecule that is not expected to be shared with any of the classical H-2 class I antigens, and we have generated specific antibodies to a synthetic peptide corresponding to this sequence. Indirect immunoprecipitation with this antibody led to the identification of a Mr 40,000 polypeptide in association with beta 2-microglobulin in the serum of mice of five different H-2 haplotypes. This class I molecule is also detected in the liver together with lower molecular weight components, which are presumably underglycosylated precursors. Synthesis of this molecule is not detected in thymus, spleen, kidney, or testis. This class I serum component has no detectable reactivity with either a broad-specificity alloantiserum against H-2b or a xenoantiserum against purified H-2a class I molecules. The availability of a specific antibody against the secreted class I molecule offers a means to purify this protein for structural and functional studies.     

Myocarditis in the pediatric population: A review

Myocarditis has a variable clinical presentation and there is still debate regarding accurate diagnostic criteria. Adding to the controversy surrounding this diagnosis, there is no clear consensus for the treatment or ongoing follow‐up of patients with myocarditis. All of this makes the diagnosis and management of myocarditis a particular challenge in the pediatric population. Furthermore, the literature with respect to this topic is dynamic and ever‐changing. In this review article, we aim to review and summarize the common clinical presentations of myocarditis, along with the latest recommendations for diagnostic criteria, treatment, and follow‐up of patients with myocarditis.     

Bricker-Johnston sigmoid colon graft for repair of postradiation rectovaginal fistula and stricture performed with mechanical sutures

In patients with postradiation rectovaginal fistula who are otherwise healthy and cured of their cancer, repair of the fistula with return to a normal lifestyle is indicated if this repair can be achieved with minimal morbidity, no mortality, and a good prospect for a functionally satisfactory result. The Bricker-Johnston vascular sigmoid colon graft fulfills these conditions by respecting the tissular equilibrium of the radiated rectum and supplying the area with a sound, vascular sigmoid pedicle graft. While this improves tissue vitality locally, it restores rectal function to a near-normal preradiation level and preserves the previously intact sphincter muscles. The concept of this repair is very sound, and its implementation is greatly facilitated technically by the use of mechanical suture instruments. In this presentation, we describe and show the use of stapling instruments in achieving a three-stage repair of a rectovaginal fistula with Bricker and Johnston's technique.     

The association of venous thromboembolism with survival in pediatric cancer patients: a population-based cohort study

Venous thromboembolism (VTE) is a well-recognized complication in pediatric oncology patients. Studies in adult oncology patients have suggested a potential negative association between VTE and survival, but this association has not been examined in pediatric patients yet. The aim of this study was to assess the association of VTE with survival in pediatric oncology patients. Data from all pediatric oncology patients treated at the two tertiary care centers in Atlantic Canada were pooled to create a population-based cohort. The association between VTE and survival was analyzed using a Cox proportional hazards model stratified by diagnosis group (leukemia, lymphoma, and other; sarcoma) and adjusted for age at diagnosis and sex. Out of 939 patients included in this study, 73 had a VTE (8%) and 131 (14%) patients died during the study period. Children in the leukemia/lymphoma/other group with a VTE had significantly poorer survival relative to children in the same group who did not have a VTE. Although children with sarcoma and VTE had poorer survival compared to children with sarcoma with no VTE, this association was not statistically significant. In this population-based study, we found a negative association between VTE and survival in pediatric oncology patients. If future studies confirm this association, this finding may have prognostic implications and potentially offer new avenues for the management of pediatric patients with cancer.     

Rate and pattern of epithelial cell proliferation in ulcerative colitis.

We investigated the pattern of proliferation of epithelial cells in rectal mucosa taken from normal individuals and patients with ulcerative colitis by incubating mucosa with tritiated thymidine in vitro and processing for autoradiography. We found that patients with ulcerative colitis in remission showed a proliferative pattern similar to that seen in both regenerating and "precancerous' mucosa. Patients with a short history were as likely to show this pattern as those with a long history, and this shows that the abnormal pattern does not signify impending malignant change. We also found that mucosa from patients with ulcerative colitis in remission showed an increased proportion of cells synthesising DNA, a proportion surprisingly close to that seen in an active phase; this suggests that the abnormal pattern seen in remission is the pattern of a regenerating mucosa. We feel that this high rate of mucosal turnover, sustained not just during clinically active disease but throughout remission, leads to the increased incidence of carcinoma and to the development of carcinoma in flat mucosa.     

High-Dose Famotidine in the Maintenance Treatment of Refractory Esophagitis: Results of a "Medium-Term" Open Study

Forty-four patients with esophagitis refractory to standard H2-blocker therapy, who had healed after a 4- to 16-wk course with either 20-40 mg omeprazole or ranitidine at doses of 300-600 mg daily in a randomized double-blind study, commenced a 3-month maintenance course of therapy with 40 mg bid famotidine. The aims of this investigation were to assess the effectiveness of this regimen in preventing recurrence of esophagitis lesions and symptoms in this subgroup of patients with therapy-resistant disease and to verify whether patients previously healed with omeprazole have a higher recurrence rate than those healed with ranitidine. The results of the study show that, despite the high dose of famotidine, 48% of patients relapsed within 3 months, a third of whom were asymptomatic. Moreover, previous omeprazole treatment is associated with a significantly higher risk of recurrence.     

Mastitis due to Mycobacterium abscessus after body piercing.

We describe a patient with granulomatous mastitis due to Mycobacterium abscessus that presented as a mass lesion and was associated with a pierced nipple. To our knowledge, this is the first reported case of mastitis due to M. abscessus and the first association of this organism with body piercing.     

Lipoprotein abnormalities in South Asians and its association with cardiovascular disease: Current state and future directions

South Asians have a high prevalence of coronary heart disease (CHD) and suffer from early-onset CHD compared to other ethnic groups. Conventional risk factors may not fully explain this increased CHD risk in this population. Indeed, South Asians have a unique lipid profile which may predispose them to premature CHD. Dyslipidemia in this patient population seems to be an important contributor to the high incidence of coronary atherosclerosis. The dyslipidemia in South Asians is characterized by elevated levels of triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, elevated lipoprotein(a) levels, and a higher atherogenic particle burden despite comparable low-density lipoprotein cholesterol levels compared with other ethnic subgroups. HDL particles also appear to be smaller, dysfunctional, and proatherogenic in South Asians. Despite the rapid expansion of the current literature with better understanding of the specific lipid abnormalities in this patient population, studies with adequate sample sizes are needed to assess the significance and contribution of a given lipid parameter on overall cardiovascular risk in this population. Specific management goals and treatment thresholds do not exist for South Asians because of paucity of data. Current treatment recommendations are mostly extrapolated from Western guidelines. Lastly, large, prospective studies with outcomes data are needed to assess cardiovascular benefit associated with various lipid-lowering therapies (including combination therapy) in this patient population.     

Palliative care for people with COPD: we need to meet the challenge

The need to extend the palliative care approach to people dying with a wide range of chronic diseases is increasingly recognised. Whilst of relevance internationally, this topic is particularly timely in the UK as the General Medical Services contract will reward practices that create a register of patients "in need of palliative/supportive care". Difficulty predicting prognosis can lead to uncertainty about which patients with COPD to include in a register, potentially reducing the impact of this initiative. In this Discussion paper we highlight this challenge, and offer some practical strategies to help clinicians recognise these patients.     

Severe paroxysmal hypertension (pseudopheochromocytoma): understanding the cause and treatment

Severe, symptomatic paroxysmal hypertension always generates suspicion of a pheochromocytoma, a catecholamine-secreting tumor. However, most patients with this disorder do not have this tumor and their condition remains undiagnosed and ineffectively treated. This case series, summarizing the course of 21 such patients, suggests a cause and an effective treatment approach. All 21 patients insisted that the paroxysms were not related to stress or emotional distress, initially discouraging consideration of a link to emotions. Nevertheless, with careful psychosocial interviewing, the disorder could be attributed to emotions patients were not aware of, and, therefore, unable to report. Such emotions were related either to previous severe emotional trauma or to a general tendency to keep distressful emotions out of awareness. With treatment based on this understanding, further paroxysms were eliminated in 13 (62%) of 21 patients. Alpha- plus beta-blockade was used, combined, when necessary, with an antidepressant agent, with or without an anxiolytic agent. In 3 cases, the disorder was cured with psychotherapy alone. Because the presenting symptoms are physical rather than emotional, patients present to internists and primary care physicians rather than to psychotherapists. For this reason, more awareness of this disorder in the medical community is needed.