Metformin's Role in Hyperlactatemia and Lactic Acidosis in ICU Patients: A Systematic Review.

INTRODUCTION: Metformin-treated patients may experience severe hyperlactatemia or lactic acidosis (LA). LA often requires intensive-care-unit (ICU) treatment, and mortality rates are high. Here, we investigate the impact of renal dysfunction and renal replacement therapy (RRT) on the outcomes of critically ill patients with metformin-associated LA (MALA). Furthermore, we assessed associations between mortality and metformin dose, metformin plasma/serum concentrations, lactate level, and arterial pH. Finally, we investigated whether the recommended classification in MALA, metformin-unrelated LA, metformin-induced LA, and LA in metformin therapy appears useful in this regard. METHODS: We performed a retrospective analysis based on a systematic PubMed search for publications on hyperlactatemia/LA in metformin-treated ICU patients from January 1995 to February 2020. Case-level data including demographics and clinical conditions were extracted, and logistic regression analyses were performed. RESULTS: A total of 92 ICU patients were reported. Two of these patients had no comorbidities interfering with lactate metabolism. In the overall group, arterial pH, lactate levels, and metformin plasma/serum concentrations were similar in survivors versus non-survivors. Ingested daily metformin doses and plasma/serum creatinine levels were significantly higher in survivors versus non-survivors (p = 0.007 vs. p = 0.024, respectively). Higher plasma/serum creatinine levels, higher lactate levels, and lower arterial pH were all associated with patients receiving RRT (all p < 0.05). Overall mortality was 22% (20 out of 92 patients) and did not differ between the RRT and non-RRT groups. CONCLUSION: Mortality is high in ICU patients with metformin-associated hyperlactatemia/LA. Unexpectedly, higher ingested metformin dose and plasma/serum creatinine were associated with a better outcome. Survival was similar in patients with or without need for RRT.

Early effects of LPS-induced neuroinflammation on the rat hippocampal glycolytic pathway.

Neuroinflammation is a common feature during the development of neurological disorders and neurodegenerative diseases, where glial cells, such as microglia and astrocytes, play key roles in the activation and maintenance of inflammatory responses in the central nervous system. Neuroinflammation is now known to involve a neurometabolic shift, in addition to an increase in energy consumption. We used two approaches (in vivo and ex vivo) to evaluate the effects of lipopolysaccharide (LPS)-induced neuroinflammation on neurometabolic reprogramming, and on the modulation of the glycolytic pathway during the neuroinflammatory response. For this, we investigated inflammatory cytokines and receptors in the rat hippocampus, as well as markers of glial reactivity. Mitochondrial respirometry and the glycolytic pathway were evaluated by multiple parameters, including enzymatic activity, gene expression and regulation by protein kinases. Metabolic (e.g., metformin, 3PO, oxamic acid, fluorocitrate) and inflammatory (e.g., minocycline, MCC950, arundic acid) inhibitors were used in ex vivo hippocampal slices. The induction of early inflammatory changes by LPS (both in vivo and ex vivo) enhanced glycolytic parameters, such as glucose uptake, PFK1 activity and lactate release. This increased glucose consumption was independent of the energy expenditure for glutamate uptake, which was in fact diverted for the maintenance of the immune response. Accordingly, inhibitors of the glycolytic pathway and Krebs cycle reverted neuroinflammation (reducing IL-1ß and S100B) and the changes in glycolytic parameters induced by LPS in acute hippocampal slices. Moreover, the inhibition of S100B, a protein predominantly synthesized and secreted by astrocytes, inhibition of microglia activation and abrogation of NLRP3 inflammasome assembly confirmed the role of neuroinflammation in the upregulation of glycolysis in the hippocampus. Our data indicate a neurometabolic glycolytic shift, induced by inflammatory activation, as well as a central and integrative role of astrocytes, and suggest that interference in the control of neurometabolism may be a promising strategy for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes.

Demonstration of ameliorating effect of vardenafil through its anti-inflammatory and neuroprotective properties in autism spectrum disorder induced by propionic acid on rat model.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology. In this study, we aimed to determine the ameliorating effects of vardenafil in the ASD rat model induced by propionic acid (PPA) in terms of neurobehavioral changes and also support these effects with histopathological changes, brain biochemical analysis and magnetic resonance spectroscopy (MRS) findings. MATERIALS AND METHODS: Twenty-one male rats were randomly assigned into three groups. Group 1 (control, 7 rats) did not receive treatment. Rats in groups 2 and 3 were given PPA at the dose of 250 mg/kg/day intraperitoneally for 5 days. After PPA administration, animals in group 2 (PPAS, 7 rats) were given saline and animals in group 3 (PPAV, 7 rats) were given vardenafil. Behavioral tests were performed between the 20th and 24th days of the study. The rats were taken for MRS on the 25th day. At the end of the study, brain levels of interleukin-2 (IL-2), IL-17, tumor necrosis factor-α, nerve growth factor, cGMP and lactate levels were measured. In the cerebellum and the CA1 and CA3 regions of the hippocampus, counts of neurons and Purkinje cells and glial fibrillary acidic protein (associated with gliosis) were evaluated histologically. RESULTS: Three chamber sociability and passive avoiding test, histopathological results, lactate levels derived from MRS, and biochemical biomarkers revealed significant differences among the PPAV and PPAS groups. CONCLUSION: We concluded that vardenafil improves memory and social behaviors and prevent loss of neuronal and Purkinje cell through its anti-inflammatory and neuroprotective effect.

Simultaneous identification of three pseudoallergic components in Danshen injection by using high-expression Mas-related G protein coupled receptor X2 cell membrane chromatography coupled online to HPLC-ESI-MS/MS.

Adverse drug reactions of Danshen injection mainly manifested as pseudoallergic reactions. In the present study, salvianolic acid A and a pair of geometric isomers (isosalvianolic acid C and salvianolic acid C) were identified as pseudoallergic components in Danshen injection by a high-expression Mas-related G protein coupled receptor X2 cell membrane chromatography coupled online with high-performance liquid chromatography with electrospray ionization tandem mass spectrometry. Their pseudoallergic activities were evaluated by in vitro assay, which were consistent with the retention times on the cell membrane chromatography column. Salvianolic acid C, the most outstanding compound, was further found to induce pseudoallergic reaction through Mas-related G protein coupled receptor X2. All the results above indicated that the system developed in this study is an effective method for simultaneously analyzing pseudoallergic components, even those with similar structures and the microcomponents in complex samples (salvianolic acid C in Danshen injection).

Investigations on clonazepam-loaded polymeric micelle-like nanoparticles for safe drug administration during pregnancy.

Medication during pregnancy is often a necessity for women to treat their acute or chronic diseases. The goal of this study is to evaluate the potential of micelle-like nanoparticles (MNP) for providing safe drug usage in pregnancy and protect both foetus and mother from medication side effects. Clonazepam-loaded MNP were prepared from copolymers [polystyrene-poly(acrylic acid) (PS-PAA), poly(ethylene glycol)-b-poly(lactic acid) (PEG-PLA) and distearyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-poly(ethylene glycol) (PEG-DSPE)] with varying monomer ratios and their drug-loading efficiency, drug release ratio, particle size, surface charge and morphology were characterised. The cellular transport and cytotoxicity experiments were conducted on clonazepam and MNP formulations using placenta-choriocarcinoma-BeWo and brain-endothelial-bEnd3 cells. Clonazepam-loaded PEG5000-PLA4500 MNP reduced the drug transport through BeWo cells demonstrating that MNP may lower foetal drug exposure, thus reduce the drug side effects. However, lipofectamine modified MNP improved the transport of clonazepam and found to be promising for brain and in-utero-specific drug treatment.

Variation in aluminium patch test reactivity over time.

BACKGROUND: Contact allergy to aluminium has been reported more frequently in recent years. It has been pointed out that positive patch test reactions to aluminium may not be reproducible on retesting. OBJECTIVES: To investigate possible variations in patch test reactivity to aluminium over time. METHODS: Twenty-one adults, who had previously reacted positively to aluminium, were patch tested with equimolar dilution series in pet. of aluminium chloride hexahydrate and aluminium lactate, four times over a period of 8 months. RESULTS: Thirty-six of 84 (43%) serial dilution tests with aluminium chloride hexahydrate and 49 of 84 (58%) serial dilution tests with aluminium lactate gave negative results. The range of reactivity varied between a negative reaction to aluminium chloride hexahydrate at 10% and/or to aluminium lactate at 12%, and a positive reaction to aluminium chloride hexahydrate at 0.1% and/or to aluminium lactate at 0.12%. The highest individual difference in test reactivity noticed was 320-fold when the two most divergent minimal eliciting concentrations were compared. CONCLUSIONS: The patch test reactivity to aluminium varies over time. Aluminium-allergic individuals may have false-negative reactions. Therefore, retesting with aluminium should be considered when there is a strong suspicion of aluminium contact allergy.

Intra-esophageal whitish mass - a challenging diagnosis.

BACKGROUND: Whitish intraluminal esophageal masses might represent the endoscopic feature of a bezoar or a pedunculated tumor, most likely a fibrovascular polyp, without exclusion of other mesenchymal tumors (leiomyoma, lipoma, gastrointestinal stromal tumor, leiomyosarcoma, granular cell tumor). If a process of dystrophic calcification is also encountered the differential diagnosis can be a challenge even after histological analysis, as it is highlighted by our case. CASE PRESENTATION: A 65-year-old female whom took lactate calcium tablets for 5 years presented with progressive dysphagia. A whitish esophageal mass with an appearance of a pharmacobezoar was detected at esophagoscopy. A pedunculated tumor was considered in the differential diagnosis, but the imagistic studies ruled out a pedicle. This intraluminal esophageal mass highly suggestive for a pharmacobezoar was endoscopically removed. The challenge of correct diagnosis was raised by histological examination performed after immersion into trichloracetic acid for decalcification. The identification of hyaline fibrous tissue, with numerous crystalline basophils deposits of minerals, rare fibrocytes and very few vessels brought in discussion a mesenchymal originating mass, most likely a fibrovascular polyp, even the pedicle was not detected. CONCLUSION: Based on our challenging and difficult to diagnose case we proposed an uncommon evolution: auto-amputation and calcification of an esophageal mesenchymal originating tumor (most likely a fibrovascular polyp).

Bicarbonate- versus lactate-buffered solutions for acute continuous haemodiafiltration or haemofiltration.

BACKGROUND: Acute kidney injury (AKI) is a severe loss of kidney function that results in patients' inability to appropriately excrete nitrogenous wastes and creatinine. Continuous haemodiafiltration (HDF) or haemofiltration (HF) are commonly used renal replacement therapies for people with AKI. Buffered dialysates and solutions used in HDF or HF have varying effects on acid-base physiology and several electrolytes. The benefits and harms of bicarbonate- versus lactate-buffered HDF or HF solutions for treating patients with AKI remain unclear. OBJECTIVES: To assess the benefits and harms of bicarbonate- versus lactate-buffered solutions for HDF or HF for treating people with AKI. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 6 January 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. We also searched the Chinese Biomedical Literature Database. SELECTION CRITERIA: All randomised controlled trials (RCT) and quasi-RCTs that reported comparisons of bicarbonate-buffered solutions with lactate-buffered solutions for AKI were selected for inclusion irrespective of publication status or language. DATA COLLECTION AND ANALYSIS: Two authors independently assessed titles and abstracts, and where necessary the full text of studies, to determine which satisfied our inclusion criteria. Data were extracted by two authors who independently assessed studies for eligibility and quality using a standardised data extraction form. Methodological quality was assessed using the Cochrane risk of bias tool. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We identified four studies (171 patients) that met our inclusion criteria. Overall, study quality was suboptimal. There were significant reporting omissions related to methodological issues and potential harms. Outcome measures were not defined or reported adequately. The studies were small and lacked follow-up phases.Serum lactate levels were significantly lower in patients treated with bicarbonate-buffered solutions (4 studies, 171 participants: MD -1.09 mmol/L, 95% CI -1.30 to -0.87; I(2) = 0%). There were no differences in mortality (3 studies, 163 participants: RR 0.76, 95% CI 0.50 to 1.15; I(2) = 0%); serum bicarbonate levels (3 studies, 163 participants: MD 0.27 mmol/L, 95% CI -1.45 to 1.99; I(2) = 78%), serum creatinine (2 studies, 137 participants: MD -22.81 µmol/L, 95% CI -129.61 to 83.99; I(2) = 73%), serum base excess (3 studies, 145 participants: MD 0.80, 95% CI -0.91 to 2.50; I(2) = 38%), serum pH (4 studies, 171 participants: MD 0.01, 95% CI -0.02 to 0.03; I(2) = 70%) or carbon dioxide partial pressure (3 studies, 151 participants: MD -1.04, 95% CI -3.84 to 1.76; I(2) = 83%). A single study reported fewer cardiovascular events (RR 0.39, 95% CI 0.20 to 0.79), higher mean arterial pressure (10.25 mm Hg, 95% CI 6.68 to 13.82) and less hypotensive events (RR 0.44, 95% CI 0.26 to 0.75) in patients receiving bicarbonate-buffered solutions. One study reported no significant difference in central venous pressure (MD 2.00 cm H2O, 95% CI -0.7 to, 4.77). Total length of hospital and ICU stay and relapse were not reported by any of the included studies. AUTHORS' CONCLUSIONS: There were no significant different between bicarbonate- and lactate-buffered solutions for mortality, serum bicarbonate levels, serum creatinine, serum base excess, serum pH, carbon dioxide partial pressure, central venous pressure and serum electrolytes. Patients treated with bicarbonate-buffered solutions may experience fewer cardiovascular events, lower serum lactate levels, higher mean arterial pressure and less hypotensive events. With the exception of mortality, we were not able to assess the main primary outcomes of this review - length of time in ICU, total length of hospital stay and relapse.

[Acid-base status in patients treated with peritoneal dialysis]. / Acidobazni status u bolesnika lijecenih metodom peritonejske dijalize.

When compared to hemodialysis, peritoneal dialysis is very simple yet low cost method of renal replacement therapy. Series of studies have shown its superiority in preserving residual renal function, postponing uremic complications, maintaining the acid-base balance and achieving better post-transplant outcome in patients treated with this method. Despite obvious advantages, its role in the treatment of chronic kidney disease is still not as important as it should be. Metabolic acidosis is an inevitable complication associated with progressive loss of kidney function. Its impact on mineral and muscle metabolism, residual renal function, allograft function and anemia is very complex but can be successfully managed. The aim of our study was to evaluate the efficiency in preserving the acid-base balance in patients undergoing peritoneal dialysis at Zagreb University Hospital Center. Twenty-eight patients were enrolled in the study. The mean time spent on the treatment was 32.39 ± 43.43 months. Only lactate-buffered peritoneal dialysis fluids were used in the treatment. Acid-base balance was completely maintained in 73.07% of patients; 11.54% of patients were found in the state of mild metabolic acidosis, and the same percentage of patients were in the state of mild metabolic alkalosis. In one patient, mixed alkalosis with respiratory and metabolic component was present. The results of this study showed that acid-base balance could be maintained successfully in patients undergoing peritoneal dialysis, even only with lactate-buffered solutions included in the treatment, although they were continuously proclaimed as inferior in comparison with bicarbonate-buffered ones. In well educated and informed patients who carefully use this method, accompanied by the attentive and thorough care of their physicians, this method can provide quality continuous replacement of lost renal function as well as better quality of life.

Modafinil Improves Autism-like Behavior in Rats by Reducing Neuroinflammation.

To evaluate the ameliorating effect of Modafinil on neuroinflammation, behavioral, and histopathological alterations in rats induced by propionic acid (PPA). Thirty male Wistar rats were used in the study, divided into 3 groups of ten subjects. One group served as a control, the subjects in the other two were given 250 mg/kg/day of PPA by intraperitoneal injection over the course of 5 days to induce autism. The experimental design was as follows: Group 1: Normal control (orally-fed control, n = 10); Group 2 (PPA + saline, n = 10): PPA and 1 ml/kg/day % 0.9 NaCl saline via oral gavage; Group 3 (PPA + Modafinil, n = 10) PPA and 30 mg/kg/day Modafinil (Modiodal tablets 100 mg, Cephalon) via oral gavage. All of the groups were investigated for behavioral, biochemical, and histological abnormality. Autism-like behaviors were reduced significantly in the rats treated with PPA. TNF-α, Nerve Growth Factor (NGF), IL-17, IL-2, and NF-KB levels as well as MDA levels and lactate were significantly higher in those treated with PPA compared to the control group. Using immunohistochemical methods, the number of neurons and GFAP immunoreactivity was significantly altered in PPA-treated rats compared to the control. Using Magnetic Resonance Spectroscopy (MRS), we found that lactate levels were significantly higher in the PPA-treated rats, while creatinine levels were significantly decreased. In the rats administered with Modafinil, behavior, neuroinflammation, and histopathological changes brought about by PPA were significantly reversed. Our results demonstrate the potential role of Modafinil in ameliorating PPA-induced neuroinflammation in rats.

[Glycogen phosphorylase inhibitor ameliorates pentylenetetrazole-induced acute seizure, neuroinflammation and memory impairment in rats].

OBJECTIVE: In the present study, we determined whether the glycogen phosphorylase(GP)inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) ameliorates pentylenetetrazole (PTZ)-induced acute seizure, neuroinflammation and memory impairment in rats. METHODS: In experiment 1, rats were randomly divided into the Vehicle (n=5) and PTZ (n=5) groups, and received intraperitoneal injection of saline or PTZ (70 mg/kg), respectively. Hippocampal tissues were collected 30 min after drug injection. Western blot was used to examine the levels of GP expression. Colorimetric assay was used to determine the levels of lactate. In experiment 2, rats were randomly divided into the Vehicle+Vehicle (n=18), DAB+Vehicle (n=18), Vehicle+PTZ (n=19) and DAB+PTZ (n=18) groups. Rats received intracerebroventricular injection of PBS or DAB (50 µg/2 µl) 15 min before receiving intraperitoneal injection of saline or PTZ (70 mg/kg). Behavioural assays and the Racine scale were used to evaluate seizure severity. Western blot was used to examine the levels of targeted protein of hippocampal tissues. Novel object recognition test was used to assess memory performance. RESULTS: ① Compared with the Vehicle group, the levels of GP and lactate in the hippocampal tissues of the PTZ group were increased significantly (both P＜0.01). ② Compared with the Vehicle+PTZ group, in the DAB+PTZ group, the levels of myoclonic body jerk latency, forelimb clonus latency and tonic-clonic seizure latency were increased significantly (all P＜0.01), while the duration of seizure and seizure scores were decreased significantly (both P＜0.01). ③ Compared with the Vehicle+Vehicle group, in the Vehicle +PTZ group, the levels of IL-1ß, IL-6, TNF-α, IBA-1 and GFAP in the hippocampal tissues were increased significantly (all P＜0.01), and the discrimination index in the novel object recognition test was decreased significantly (P＜0.01). Compared with the Vehicle+PTZ group, in the DAB+PTZ group, the levels of IL-1ß, TNF-α, IBA-1 and GFAP in the hippocampal tissues were decreased significantly (all, P＜0.01), while the discrimination index in the novel object recognition test was increased significantly (P＜0.01). CONCLUSION: DAB ameliorates PTZ-induced seizure, neuroinflammation and memory impairment in rats, suggesting that DAB may serve as a novel agent for potential clinical treatment of epilepsy.

Recurrent hypoglycemia increases hepatic gluconeogenesis without affecting glycogen metabolism or systemic lipolysis in rat.

INTRODUCTION: Recurrent hypoglycemia (RH) impairs secretion of counterregulatory hormones. Whether and how RH affects responses within metabolically important peripheral organs to counterregulatory hormones are poorly understood. OBJECTIVE: To study the effects of RH on metabolic pathways associated with glucose counterregulation within liver, white adipose tissue and skeletal muscle. METHODS: Using a widely adopted rodent model of 3-day recurrent hypoglycemia, we first checked expression of counterregulatory hormone G-protein coupled receptors (GPCRs), their inhibitory regulators and downstream enzymes catalyzing glycogen metabolism, gluconeogenesis and lipolysis by qPCR and western blot. Then, we examined epinephrine-induced phosphorylation of PKA substrates to validate adrenergic sensitivity in each organ. Next, we measured hepatic and skeletal glycogen content, degree of breakdown by epinephrine and abundance of phosphorylated glycogen phosphorylase under hypoglycemia and that of phosphorylated glycogen synthase during recovery to evaluate glycogen turnover. Further, we performed pyruvate and lactate tolerance tests to assess gluconeogenesis. Additionally, we measured circulating FFA and glycerol to check lipolysis. The abovementioned studies were repeated in streptozotocin-induced diabetic rat model. Finally, we conducted epinephrine tolerance test to investigate systemic glycemic excursions to counterregulatory hormones. Saline-injected rats served as controls. RESULTS: RH increased counterregulatory hormone GPCR signaling in liver and epidydimal white adipose tissue (eWAT), but not in skeletal muscle. For glycogen metabolism, RH did not affect total content or epinephrine-stimulated breakdown in liver and skeletal muscle. Although RH decreased expression of phosphorylated glycogen synthase 2, it did not affect hepatic glycogen biosynthesis during recovery from hypoglycemia or after fasting-refeeding. For gluconeogenesis, RH upregulated fructose 1,6-bisphosphatase 1 and monocarboxylic acid transporter 1 that imports lactate as precursor, resulting in a lower blood lactate profile during hypoglycemia. In agreement, RH elevated fasting blood glucose and caused higher glycemic excursions during pyruvate tolerance test. For lipolysis, RH did not affect circulating levels of FFA and glycerol after overnight fasting or upon epinephrine stimulation. Interestingly, RH upregulated the trophic fatty acid transporter FATP1 and glucose transporter GLUT4 to increase lipogenesis in eWAT. These aforementioned changes of gluconeogenesis, lipolysis and lipogenesis were validated in streptozotocin-diabetic rats. Finally, RH increased insulin sensitivity to accelerate glucose disposal, which was attributable to upregulated visceral adipose GLUT4. CONCLUSIONS: RH caused metabolic adaptations related to counterregulation within peripheral organs. Specifically, adrenergic signaling was enhanced in liver and visceral fat, but not in skeletal muscle. Glycogen metabolism remained unchanged. Hepatic gluconeogenesis was augmented. Systemic lipolysis was unaffected, but visceral lipogenesis was enhanced. Insulin sensitivity was increased. These findings provided insights into mechanisms underlying clinical problems associated with intensive insulin therapy, such as high gluconeogenic flux and body weight gain.

Fish Oil and Primrose Oil Suppress the Progression of Alzheimer's Like Disease Induced by Aluminum in Rats.

The role of fish oil, primrose oil and their mixture in ameliorating the changes in Alzheimer's like model was evaluated in rats. Primrose oil and primrose/fish oil mixture fatty acids composition was assessed by gas chromatography. The rat experiment consisted of 5 groups; the first fed on balanced diet as control normal (CN); the other four groups treated with intraperitoneal aluminum lactate and consumed dyslipidemic diet; one group served as control Alzheimer's like disease (CA) while the other three groups (test groups) received daily oral dose from primrose oil, fish oil and primrose/fish oil mixture separately for 5 weeks. Results showed primrose oil and primrose/ fish oil mixture to contain gamma linolenic acid as 9.15 and 4.3% of total fatty acids, respectively. Eicosapentaenoic and docosahexaenoic were present as 10.9 and 6.5 %, respectively in the oil mixture. Dyslipidemia and increased erythrocyte sedimentation rate (ESR), plasma butyrylcholinesterase (BChE), brain malondialdehyde (MDA) and NO with decrease in plasma magnesium, brain catalase, reduced glutathione, body weight gain and brain weight were demonstrated in CA compared to CN. Brain histopathology and immuno-histochemistry showed neuronal degeneration and neurofibrillary tangles with elevated myeloperoxidase and nuclear factor-kappa B in CA compared to CN. The tested oils demonstrated neuro-protection reflected in the variable significant improvement of biochemical parameters, immuno-histochemistry and brain histopathology. Primrose/fish oil mixture was superior in reducing ESR, brain MDA, plasma activity of BChE and brain histopathological changes along with elevating plasma magnesium. Primrose/fish oil mixture and fish oil were more promising in improving plasma high density lipoprotein cholesterol (HDL-C) than primrose. Fish oil was the most efficient in improving plasma total cholesterol (T-C), low density lipoprotein cholesterol and T-C /HDL-C. Primrose/fish oil mixture and primrose oil were superior in elevating brain catalase compared to fish oil. Other parameters were equally improved by the different oil treatments. Primrose oil, fish oil and their mixture reduced the progression of Alzheimer's disease in rats with superiority to primrose/fish oil mixture.

Anaphylaxis to oral iron salts. desensitization protocol for tolerance induction.

Allergies to iron salts are seldom reported. We studied a patient with iron-deficiency anemia who had suffered anaphylactic reactions caused by oral iron salts. An allergy study was performed using single-blind, placebo-controlled oral challenge and skin tests with various iron salts as well as excipients in commercial formulations. Oral challenges were positive for 2 of the commercial formulations of iron salts. Intradermal tests with ferrous sulphate and ferrous lactate also showed positive results. All of the cutaneous tests using the excipients were negative. A desensitization protocol was designed which enabled us to readminister ferrous sulphate, although antihistamines were necessary to guarantee good tolerance to iron salts. We report a patient with allergy to iron salts, positive skin tests, and positive controlled challenge. We highlight the desensitization protocol designed to complete the therapeutic management of the anemia.

Penile calciphylaxis in a patient on combined peritoneal dialysis and hemodialysis.

Calciphylaxis presents with painful purpura and intractable skin ulcers on the trunk and particularly the distal extremities, and it mainly occurs in patients on chronic dialysis. A 66-year-old man with renal failure due to diabetic nephropathy was on peritoneal dialysis alone for 1 year, followed by peritoneal dialysis combined with hemodialysis for 3 years. He developed calciphylaxis of the penis, which was diagnosed from the skin biopsy findings and clinical observation. To treat this condition, PD was stopped and HD was performed three times a week. In addition, warfarin therapy was discontinued and infusion of sodium thiosulfate was performed. The penile ulcers decreased in size and pain was markedly improved, so the patient was discharged from hospital. Following discharge, PD was resumed after changing the peritoneal dialysis fluid to bicarbonate-buffered dialysate. The penile ulcers eventually resolved completely. There have been very few reports about calciphylaxis in patients on combined dialysis modalities. In our patient, penile calciphylaxis progressed when lactate-buffered peritoneal dialysis fluid was used and resolved after switching to bicarbonate-buffered fluid together with cessation of warfarin therapy and infusion of sodium thiosulfate.

Pseudomelanoma after Solcoderm treatment.

We describe a case of pseudomelanoma after Solcoderm treatment. Pseudomelanoma is a pathological entity describing the histological findings in cases of recurrences of a partially excised melanocytic nevus, resembling melanoma. Solcoderm is an aqueous solution containing organic and inorganic acids that destroys a lesion by tissue mummification. It has been used for the treatment of benign skin lesions. Appearance of pseudomelanoma after Solcoderm treatment stressed the controversy of the use of Solcoderm in pigmentary lesions, and that surgical removal is preferred in cases of pigmented nevi.

Acid-base profile and predictors of metabolic acidosis in patients undergoing peritoneal dialysis with lactate- and bicarbonate-buffered peritoneal dialysis solutions.

Metabolic acidosis correction is one of the goals of renal replacement therapy. Correction of acidosis in peritoneal dialysis (PD) may be affected by PD modalities such as automated PD (APD) or by new solutions containing a combination of bicarbonate and lactate as a buffer [bicarbonate continuous ambulatory PD (CAPD)]. The aim of the present study was to examine the acid-base status of our PD population and to compare the effects of APD, lactate CAPD, and bicarbonate CAPD on serum bicarbonate levels. We studied 35 stable patients undergoing APD (n = 15), lactate-buffered (35 mEq/L) CAPD (n = 14), and bicarbonate/lactate-buffered CAPD (n = 6) for 48.5 +/- 38.1 months. Most of our patients had serum bicarbonate levels in the normal range. In 3 patients (8%), HCO3 was below 22 mEq/L, and in 8 patients (22%; APD = 2, lactate CAPD = 2, bicarbonate CAPD = 4), HCO3 was above 28 mEq/L. We found no statistically significant correlations between HCO3 serum levels and PD prescription, peritoneal membrane characteristics, or intake of calcium carbonate and sevelamer hydrochloride. Patients on bicarbonate CAPD had higher HCO3 serum levels, but this difference disappeared when corrections for duration of dialysis, residual urine volume, and PD adequacy indices were applied. In the studied PD population, adequate correction of metabolic acidosis was achieved, as reflected in serum bicarbonate levels. We observed no difference in serum bicarbonate levels between APD and lactate CAPD patients. The new bicarbonate-buffered PD solutions are more biocompatible and can result in higher serum bicarbonate levels. However, a significant number of PD patients on bicarbonate-buffered solutions may become alkalotic. The clinical significance of these results needs further examination in prospective studies.

Iron Supplements and Magnesium Peroxide: An Example of a Hazardous Combination in Self-Medication.

The use of self-medication, which includes dietary supplements and over-the-counter drugs, is still on the rise, while safety issues are not well addressed yet. This especially holds for combinations. For example, iron supplements and magnesium peroxide both produce adverse effects via the formation of reactive oxygen species (ROS). This prompted us to investigate the effect of the combination of three different iron supplements with magnesium peroxide on ROS formation. Hydroxyl radical formation by the three iron supplements either combined with magnesium peroxide or alone was determined by performing a deoxyribose assay. Free iron content of iron supplements was determined using ferrozine assay. To determine hydrogen peroxide formation by magnesium peroxide, a ferrous thiocyanate assay was performed. Finally, electron spin resonance spectroscopy (ESR) was performed to confirm the formation of hydroxyl radicals. Our results show that magnesium peroxide induces the formation of hydrogen peroxide. All three iron supplements induced the formation of the extremely reactive hydroxyl radical, although the amount of radicals formed by the different supplements differed. It was shown that combining iron supplements with magnesium peroxide increases radical formation. The formation of hydroxyl radicals after the combination was confirmed with ESR. All three iron supplements contained labile iron and induced the formation of hydroxyl radicals. Additionally, magnesium peroxide in water yields hydrogen peroxide, which is converted into hydroxyl radicals by iron. Hence, iron supplements and magnesium peroxide is a hazardous combination and exemplifies that more attention should be given to combinations of products used in self-medication.

Supplement nephropathy due to long-term, high-dose ingestion of ascorbic acid, calcium lactate, vitamin D and laxatives.

A 48-year-old Japanese woman previously in good health was found to have severe proximal tubular dysfunction with a high serum level of ascorbic acid (57.3 microg/ml, reference range: 1.9 - 15.0 microg/ml). Renal biopsy specimen showed marked tubulointerstitial damage, i.e. tubular atrophy, dilatation of tubular lumen with flattened tubular epithelial cells, vacuolization of proximal and distal tubular epithelial cells, and severe interstitial fibrosis with mild infiltration of mononuclear cells. Calcified lesions, which caused tubular obstruction or stenosis, were also seen in interstitial area adjacent to degenerated proximal tubuli. Hypokalemic nephropathy, probably due to long-term use of laxatives, was clearly shown. However, calcified lesions seemed to be caused by inappropriate excessive daily ingestion of ascorbic acid (6 000 mg/day), calcium lactate, and vitamin D because of the patient's misunderstanding that these supplements could keep her in a good health. This condition may be clinically called "supplement nephropathy".

Disruption of neuronal calcium homeostasis after chronic aluminium toxicity in rats.

The present study was designed to investigate the possible effects of chronic aluminium exposure on the various aspects of calcium homeostasis in rat brain. Chronic aluminium administration caused significant rise in the intrasynaptosomal calcium levels. The activity of major calcium-expelling enzyme, i.e. Ca2+ ATPase was found to be lowered. Also, the calcium uptake via voltage-operated calcium channels increased significantly. Similar to the increase in intrasynaptosomal calcium, calpain activity was found to be increased. The results presented here, indicate that the toxic effects of aluminium could be mediated through modifications in the intracellular calcium homeostasis, which may lead to impaired neuronal function.