Effect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure

PURPOSE: The development of life-threatening hyperkalemia poses a risk for patients with chronic preterminal renal failure. Various therapeutic options have been suggested for hyperkalemic emergencies in these patients; to date, however, no study has evaluated the relative efficacies of these measures in the presence of renal failure. Our goal was to examine the acute effects of a variety of therapeutic approaches, as well as those of hemodialysis, on plasma potassium levels in a hemodialysis population. PATIENTS AND METHODS: Ten patients with terminal renal failure undergoing maintenance hemodialysis were enrolled in the study. Blood gas parameters and plasma sodium, potassium, glucose, osmolality, renin, aldosterone, epinephrine, norepinephrine, dopamine, and insulin were measured before, during, and after 60-minute infusions of bicarbonate, epinephrine, and insulin in glucose, and before, during, and after performance of regular hemodialysis for one hour. RESULTS: Hypertonic as well as isotonic intravenous bicarbonate (2 to 4 mmol/minute) induced a marked rise in plasma bicarbonate and pH, but failed to lower the plasma potassium level (5.66 versus 5.83 mmol/liter before and after). Epinephrine, 0.05 microgram/kg/minute administered intravenously, decreased plasma potassium only slightly from 5.57 to 5.25 mmol/liter, and five patients showed no decline. On the other hand, insulin in glucose, 5 mU/kg/minute intravenously, effectively lowered plasma potassium levels from 5.62 to 4.70 mmol/liter, and hemodialysis induced the most rapid decline from 5.63 to 4.29 mmol/liter. Plasma aldosterone was elevated before treatment; it correlated with plasma potassium and dropped during intravenous bicarbonate administration or hemodialysis. Pretreatment plasma renin activity, insulin, epinephrine, norepinephrine, and dopamine levels were generally normal. CONCLUSION: We conclude that in patients with terminal renal failure undergoing maintenance hemodialysis, intravenous bicarbonate is ineffective in lowering plasma potassium rapidly, and epinephrine is effective in only half the patients, whereas insulin in glucose is a fast and reliable form of therapy for hyperkalemic emergencies. Plasma aldosterone levels are appropriate in relationship to plasma potassium levels, and levels of other potassium-influencing hormones are generally normal.     

Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis

Background  

Vitamin D insufficiency is common in hospitalized patients. Recent evidence suggests that vitamin D may enhance the innate immune response by induction of cathelicidin (LL-37), an endogenous antimicrobial peptide produced by macrophages and neutrophils. Thus, the relationship between vitamin D status and LL-37 production may be of importance for host immunity, but little data is available on this subject, especially in the setting of human sepsis syndrome and other critical illness.     

Malaria pharmacovigilance in Africa: lessons from a pilot project in Mpumalanga Province, South Africa.

BACKGROUND AND OBJECTIVES: Prior to the introduction of artemisinin-based combination antimalarial therapy in Mpumalanga province, South Africa, a pharmacovigilance strategy was developed to pilot locally relevant surveillance methods for detecting serious adverse drug reactions (ADRs) and signals related to artesunate plus sulfadoxine/pyrimethamine. STUDY DESIGN: From 1 March 2002 to 30 June 2004, five methods for detecting ADRs in patients receiving antimalarials were piloted in the rural communities of Mpumalanga province in South Africa: (i) home follow-up of patients by malaria control staff; (ii) enhanced spontaneous reporting of suspected ADRs by health professionals at clinics and hospitals; (iii) active hospital surveillance for malaria-related admissions and patients recently treated for malaria; (iv) a confidential enquiry into malaria-related deaths; and (v) adverse events monitoring during two therapeutic efficacy studies conducted in 2002 and 2004. RESULTS: During the study period, the malaria control programme was notified of 4778 cases of malaria while sulfadoxine/pyrimethamine monotherapy was the recommended treatment and 7692 cases after the introduction of artesunate plus sulfadoxine/pyrimethamine in January 2003. Of 2393 home follow-up visits of reported cases of malaria, three fatal adverse events were identified where recent use of artesunate plus sulfadoxine/pyrimethamine treatment was reported. Two cases were attributed to poor response to treatment, while one case was considered possibly related to artesunate plus sulfadoxine/pyrimethamine treatment. Clinic and hospital surveillance reported six ADRs in association with sulfadoxine/pyrimethamine treatment, five being treatment failures and one being a non-serious rash. During active hospital surveillance, 38 inpatients exposed to sulfadoxine/pyrimethamine were identified, including one child who experienced pancytopenia following treatment with sulfadoxine/pyrimethamine 11 days before admission; this adverse effect was considered to be possibly due to sulfadoxine/pyrimethamine treatment. The confidential enquiry into malaria-related deaths identified three adverse events, including a death where the contribution of treatment could not be excluded. A therapeutic efficacy study of 95 patients followed over 42 days identified one case of repeated vomiting possibly associated with artesunate plus sulfadoxine/pyrimethamine. CONCLUSION: Multifaceted monitoring throughout the malaria patient journey is necessary in developing countries implementing new treatments to safeguard against missing serious complications associated with malaria treatment.     

18F‐fluorodeoxyglucose positron emission tomography imaging in brain tumours: The Western Australia positron emission tomography/cyclotron service experience

¹⁸F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) scans in the first 49 patients referred with either possible brain tumour or brain tumour recurrence were reviewed. FDG‐PET imaging was reported with reference to anatomical imaging. Based on the report the FDG study was classified as either positive or negative for the presence of tumour. Thirty‐eight cases were included in the analysis, 21 having pathological data and 17 with diagnostic clinical follow up. Eleven were excluded, as they had inadequate follow‐up data. Of the 21 cases with pathology, 18 were shown to have tumour. In this group there were five false‐negative scans and two false‐positive PET scans. Seventeen cases were assessed by clinical follow up, nine were considered to have been tumour. There were two false negatives with one false positive. The overall sensitivity, specificity and positive and negative predictive values were 74, 73, 87 and 53% respectively. This is similar to figures previously quoted in published work. Despite relatively limited numbers, the utility of FDG PET imaging in our hands is similar to published reports. With a positive predictive value of 87%, a positive FDG study indicates a high likelihood that there is brain tumour present. A negative study does not exclude the presence of tumour.     

Structural basis of RasGRP binding to high-affinity PKC ligands

The Ras guanyl releasing protein RasGRP belongs to the CDC25 class of guanyl nucleotide exchange factors that regulate Ras-related GTPases. These GTPases serve as switches for the propagation and divergence of signaling pathways. One interesting feature of RasGRP is the presence of a C-terminal C1 domain, which has high homology to the PKC C1 domain and binds to diacylglycerol (DAG) and phorbol esters. RasGRP thus represents a novel, non-kinase phorbol ester receptor. In this paper, we investigate the binding of indolactam(V) (ILV), 7-(n-octyl)-ILV, 8-(1-decynyl)benzolactam(V) (benzolactam), and 7-methoxy-8-(1-decynyl)benzolactam(V) (methoxylated benzolactam) to RasGRP through both experimental binding assays and molecular modeling studies. The binding affinities of these lactams to RasGRP are within the nanomolar range. Homology modeling was used to model the structure of the RasGRP C1 domain (C1-RasGRP), which was subsequently used to model the structures of C1-RasGRP in complex with these ligands and phorbol 13-acetate using a computational docking method. The structural model of C1-RasGRP exhibits a folding pattern that is nearly identical to that of C1b-PKCdelta and is comprised of three antiparallel-strand beta-sheets capped against a C-terminal alpha-helix. Two loops A and B comprising residues 8-12 and 21-27 form a binding pocket that has some positive charge character. The ligands phorbol 13-acetate, benzolactam, and ILV are recognized by C1-RasGRP through a number of hydrogen bonds with loops A and B. In the models of C1-RasGRP in complex with phorbol 13-acetate, benzolactam, and ILV, common hydrogen bonds are formed with two residues Thr12 and Leu21, whereas other hydrogen bond interactions are unique for each ligand. Furthermore, our modeling results suggest that the shallower insertion of ligands into the binding pocket of C1-RasGRP compared to C1b-PKCdelta may be due to the presence of Phe rather than Leu at position 20 in C1-RasGRP. Taken together, our experimental and modeling studies provide us with a better understanding of the structural basis of the binding of PKC ligands to the novel phorbol ester receptor RasGRP.