Successful trimethoprim-sulfamethoxazole therapy in a patient with hyperimmunoglobulin E syndrome

A male patient with hyperimmunoglobulin E syndrome is described. Recurrent lymphadenitis and cutaneous staphylococcal abscesses were resistant to various antibiotics, and chemotaxis and hydrogen peroxide production of polymorphonuclear leukocytes were impaired. Following trimethoprim-sulfamethoxazole therapy, he was free from the above infections, and impaired polymorphonuclear leukocyte functions recovered and serum IgE decreased to approximately one-fifth of its initial level. Subsequent irregular medications, however, resulted in impairment of polymorphonuclear leukocyte functions and an increased serum IgE concentration, which recovered after regular resumption of trimethoprim-sulfamethoxazole treatment. From these results, the beneficial effects of trimethoprim-sulfomethoxazole in hyperimmunoglobulin E syndromgak clinically apparent, but in vitro studies failed to demonstrate the positive effect of trkethoprim-sulfamethoxazole on polymorphonuclear leukocytes and their mechanism still remains to be elucidated.     

Exercise training enhances tumor necrosis factor-alpha-induced expressions of anti-apoptotic genes without alterations in caspase-3 activity in rat epididymal adipocytes

The effect of exercise training on tumor necrosis factor-alpha (TNF-alpha) signaling was investigated in rat epididymal adipocytes. Incubation of isolated adipocytes with TNF-alpha (20 ng/ml) for 5 h enhanced the expression of the inhibitor apoptosis protein 2 (IAP2) gene without any enhancement of caspase-3 activity in both the sedentary control (C) and exercise-trained (TR) groups. However, the ability of TNF-alpha to enhance IAP2 gene expression was significantly greater in TR than in C rats. The basal expression of the IkappaB kinase beta (IKK beta) gene and that of the BCL-x(L) gene were also higher in TR than in C rats. Mn-superoxidedismutase contents in adipocytes were higher in TR than in C rats. Moreover, no apoptotic nucleuses of adipocytes in response to acute exercise were observed in either group at least up to 5 h after exercise. Exercise training also enhanced the inhibitory effect of TNF-alpha on the gene expression of the fatty acid synthase (FAS), a lipogenic enzyme, suggesting that fatty acid synthesis may be reduced. Thus, exercise training enhanced TNF-alpha signaling directed toward the expressions of survival signals and the suppression of FAS gene expression.     

A novel endogenous digitalis, telocinobufagin, exhibits elevated plasma levels in patients with terminal renal failure

BACKGROUND AND OBJECTIVES: There are several potential endogenous digitalis-like factors (EDLF) in mammalian body fluids, and marinobufagenin (MBG) may be the most potent EDLF. Improved assays are needed to confirm the potency of these metabolites. In the present study, we have identified MBG and telocinobufagin (TCB) in human plasma by high-resolution mass spectrometry (MS) and nuclear magnetic resonance (NMR). METHODS AND RESULTS: The high-resolution MS analysis revealed the molecular masses of TCB and MBG to be the same as their respective theoretical values. Using a tandem mass spectrometer, the mass-charge ratio for TCB was determined to be 403.2 for the parent ion and 349.2 for the daughter ion. The mass-charge ratio for MBG was m/z 383.2 and m/z 401.2. The NMR study revealed that the signals for MBG and TCB were the same as those obtained by MS analysis. In human blood, MBG and TCB were also identified by liquid chromatography (LC) as well as MS. In the LC/MS assay, proscillaridin A was used as an internal standard. The plasma was pretreated with Sep-Pak C18, and then 50 microL was applied to the C8 high-performance liquid chromatography (HPLC) column. The mean plasma concentration of MBG in healthy volunteers (0.94 +/- 0.28 ng/mL) was significantly lower than that in patients undergoing regular hemodialysis (3.81 +/- 1.92 ng/mL). The concentration of TCB in the healthy volunteers (1.80 +/- 0.55 ng/mL) was also significantly lower than that in patients with terminal renal failure (6.86 +/- 4.30 ng/mL). CONCLUSION: These results indicate that the major EDLF is TCB because its plasma concentration is the highest among the reported endogenous digitalis candidates.     

Negative-pressure pulmonary edema: a rare complication of upper airway obstruction in children

Negative-pressure pulmonary edema is a rare but life-threatening complication of upper airway obstruction. Because negative-pressure pulmonary edema may occur in a large spectrum of pathologies associated with upper airway obstruction, awareness of this condition is crucial during daily clinical practice. We report a case of negative-pressure pulmonary edema during anesthetic recovery to highlight this condition. CASE: A 2-year-old boy was scheduled for orchidopexy under general anesthesia. Shortly after an uneventful operation, the patient presented airway obstruction. Serious oxygen desaturation and bradycardia ensued, during inefficient attempts at positive-pressure ventilation. After emergency intubation, copious pink secretions emerged from the airway. Pulmonary edema was confirmed by clinical examination, pulse oximetry, and chest radiography. The finding of pulmonary edema was resolved within 24 hours after mechanical ventilation and positive end-expiratory pressure. The child suffered no sequelae. This report highlights the clinical features of negative-pressure pulmonary edema and serves as a reminder to the pediatrician who must be able to recognize and initiate treatment for conditions that are uncommon but life-threatening.     

Diagnosis of deep vein thrombosis by plasma-soluble fibrin or D-dimer

The present study was designed to determine the cutoff values of D-dimer and soluble fibrin (SF) for the diagnosis of deep venous thrombosis (DVT) and pulmonary embolism (PE) in Japanese patients. Plasma levels of these molecules were measured in 243 patients suspected of having DVT and 100 healthy volunteers (controls). Out of 243 patients, 20 patients were diagnosed with DVT. In the control group, plasma levels of D-dimer and SF did not show normal distribution, and the 95% confidence intervals (CI) of D-dimer and SF were 2.45 microg/mL and 6.92 microg/mL, respectively. Plasma levels of D-dimer and SF of patients with DVT were significantly higher than of those without DVT. In patients with DVT, the minimum values of D-dimer and SF were 1.71 and 1.44 microg/mL, respectively. When the cutoff value was set at the average+1 SD of those of the control (D-dimer, about 1.8 microg/mL; SF, about 1.4 microg/mL), 1 and 0 patient with DVT was overlooked, respectively. The sensitivity and specificity of D-dimer and SF for DVT were 95% and 100%, and 61.9% and 53.8%, respectively. When the cutoff value was set at 95% CI of the control (D-dimer, 2.5 microg/mL; SF, 6.9 microg/mL), 2 and 9 patients with DVT were overlooked, respectively. The sensitivity and specificity of D-dimer and SF were 90% and 50%, and 77.6% and 88.3%, respectively. When the cutoff values set at 2.5 microg/mL of D-dimer or 6.9 microg/mL of SF, 1 DVT patient was overlooked, with sensitivity and specificity of 95% and 69.5%. Our data suggest that both D-dimer and SF are useful markers for the diagnosis of DVT and that measurement of both D-dimer and SF increases the sensitivity and specificity for the diagnosis of DVT/PE.     

Detection of focal hypoxic-ischemic injury and neuronal stress in a rodent model of unilateral MCA occlusion/reperfusion using radiolabeled annexin V

In this study we wished to determine whether technetium-99m annexin V, an in vivo marker of cellular injury and death, could be used to noninvasively monitor neuronal injury following focal middle cerebral artery (MCA) occlusion/reperfusion injury. Sixteen adult male Sprague-Dawley rats (along with four controls) underwent left (unilateral) MCA intraluminal beaded thread occlusion for 2 h followed by reperfusion. One hour following tail vein injection of 5–10 mCi of ^99mTc-annexin V, animals underwent either single-photon emission computerized tomography (SPECT) or autoradiography followed by immunohistochemical analyses. There was abnormal, bilateral, multifocal uptake of ^99mTc-annexin V in each cerebral hemisphere as seen by both SPECT and autoradiography at 4 h and 1, 3, and 7 days after initiation of occlusion. The average maximal annexin V uptake at 4 h was 310%±85% and 365%±151% above control values (P<0.006) within the right and left hemispheres, respectively, peaking on day 3 with values of 925%±734% and 1,194%±643% (P<0.03) that decreased by day 7 to 489%±233% and 785%±225% (P<0.01). Total lesional volume of the left hemisphere was 226%, 261%, and 451% (P<0.03) larger than the right at 4, 24, and 72 h after injury, respectively. Annexin V localized to the cytoplasm of injured neurons ipsilateral to the site of injury as well as to otherwise normal-appearing neurons of the contralateral hemisphere as confirmed by dual fluorescent microscopy. It is concluded that there is abnormal bilateral, multifocal annexin V uptake, greater on the left than on the right side, within 4 h of unilateral left MCA ischemic injury and that the uptake peaks at 3 days and decreases by 7 days after injury. This pattern suggests that neuronal stress may play a role in the response of the brain to focal injury and be responsible for annexin V uptake outside the region of ischemic insult.Carina Mari and Murat Karabiyikoglu contributed equally to the work presented here.     

Many mechanisms for hsp70 protection from cerebral ischemia

Overexpression of inducible Hsp70 has been shown to provide protection from cerebral ischemia both in animal models of stroke and in cell culture models. New work suggests that there are multiple routes of cell death, including apoptotic and necrotic cell death. Hsp70 is known to protect from both necrotic and apoptotic cell death. In addition to the well-studied role of Hsp70 as a molecular chaperone assisting in correct protein folding, several new mechanisms by which Hsp70 can prevent cell death have been described. Hsp70 is now known to regulate apoptotic cell death both directly by interfering with the function of several proteins that induce apoptotic cell death as well as indirectly by increasing levels of the anti-death protein bcl-2. Despite these new insights into the ways in which Hsp70 functions as an anti-death protein, further surprises are likely as we continue to gain insight into the functioning of this multifaceted protein.     

The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia

Recently, a urate transporter, hURAT1 (human uric acid transporter 1) encoded by SLC22A12, was isolated from the human kidney. hURAT1 is presumed to play the central role in reabsorption of urate from glomerular filtrate. In the present study, we analyzed SLC22A12 in seven unrelated Japanese patients with renal hypouricemia whose serum level of urate was less than 1.0 mg/dl, and their family members. We performed direct DNA sequencing of the exon and exon-intron boundaries of SLC22A12 using genomic DNA. Six of the seven patients (86%) possess mutations in SLC22A12. In five patients, a homozygous G to A transition at nucleotide 774 within exon 4 of SLC22A12, which forms a stop codon (TGA) at codon 258 (TGG), was identified (W258X). In one patient, the C to T transition within exon 3, which changes threonine at codon 217 to methionine (T217 M), and the W258X mutation were found (compound heterozygote). Thus, among 12 mutational alleles in six patients, 11 were the W258X mutation (92%). Family members with the heterozygous W258X mutation (carriers) show relatively low levels of serum urate. The present study demonstrates that homozygous W258X mutation is the predominant genetic cause of idiopathic renal hypouricemia in Japanese patients.