Comparison of high-resolution structures of the diphtheria toxin repressor in complex with cobalt and zinc at the cation-anion binding site

The diphtheria toxin repressor (DtxR) from Corynebacterium diphtheriae is a divalent-metal activated repressor of chromosomal genes responsible for siderophore-mediated iron-uptake and of a gene on several corynebacteriophages that encodes diphtheria toxin. Even though DtxR is the best characterized iron-dependent repressor to date, numerous key properties of the protein still remain to be explained. One is the role of the cation-anion pair discovered in its first metal-binding site. A second is the reason why zinc exhibits its activating effect only at a concentration 100-fold higher than other divalent cations. In the presently reported 1.85 A resolution Co-DtxR structure at 100K, the sulfate anion in the cation-anion-binding site interacts with three side chains that are all conserved in the entire DtxR family, which points to a possible physiological role of the anion. A comparison of the 1.85 A Cobalt-DtxR structure at 100K and the 2.4 A Zinc-DtxR structure at room temperature revealed no significant differences. Hence, the difference in efficiency of Co2+ and Zn2+ to activate DtxR remains a mystery and might be hidden in the properties of the intriguing second metal-binding site. Our studies do, however, provide a high resolution view of the cationanion-binding site that has most likely evolved to interact not only with a cation but also with the anion in a very precise manner.     

Ca(2+)-ATPases in the cochlear duct

Differing levels of the Ca(2+)-ATPase enzymes that reside on the plasma membrane (PM) and on the endoplasmic reticulum (ER) were identified in individual rat cochlear tissues by the use of a semi-quantitative enzyme-linked immunosorbent assay (ELISA). Unlike other studies, a specific antibody to PM Ca(2+)-ATPase was used to detect significantly greater levels (about 2x) of PM Ca(2+)-ATPase in the stria vascularis (SV) than that in the spiral ligament (SL) and organ of Corti (OC) tissues. Similarly, levels of ER Ca(2+)-ATPase were also significantly higher in the SV than in the SL and OC tissues. The presence of ER Ca(2+)-ATPase in the tissues of the SV has not been demonstrated previously. Given the importance of Ca2+ homeostasis in the inner ear, the statistically significantly higher densities of both PM and ER Ca(2+)-ATPase measured in the SV relative to the SL and OC regions would indicate tissue-specific responses to fluctuations in systemic and local Ca2+ concentrations.     

Eucalyptus oil poisoning among young children: mechanisms of access and the potential for prevention

Among 267 patients with central nervous system infections, 43 patients (16.1%) suffered from purulent bacterial meningitis. An etiological agent was established in 15 cases (34.9%): Str. pneumoniae--9 cases, N. meningitidis--4 cases and Staph. aureus--2 cases. Most patients had severe course of the disease; lethality was 18.6%, the recovery with subsequent sequelae was noted in 11.6% cases, and 69.8% cases fully recovered. In two patients brain abscess and intracranial empyema, and persistent cerebral ischaemia were found, one of these patients died. Frequent use of antibiotics before hospitalization reduces the possibility of establishing the etiological agent. Bacterial infections of the central nervous system are still danger diseases producing high lethality and subsequent neurological sequelae.     

Thoracoscopic-assisted pulmonary resection in lung cancer

BACKGROUND: Thoracoscopic-assisted pulmonary resection for lung cancer is controversial. The appropriateness of this approach has to be compared with the golden standard of an open resection. METHODS: This study consists of 66 patients with a clinical stage 1 disease. A thoracoscopic exploration was executed in 41 patients. Only in 16 cases was a thoracoscopic resection finally possible. The clinical and pathological TNM classification, the histological types and the surgical procedure are reported. The reasons for conversion are documented. RESULTS: To investigate the appropriateness of the thoracoscopic approach we evaluated only the pathologically proven stage 1 disease in both groups. Postoperative complications, hospital stay and survival are compared. CONCLUSION: Until now we can conclude that there is no adverse effect on survival because of the thoracoscopic approach.     

6-Hydroxycatecholine, a choline-mimicking analogue of the selective neurotoxin, 6-hydroxydopamine

The purpose of this prospective study was to verify whether the percentage area of lung occupied by lowest attenuation values on high-resolution computed tomography (HRCT) scans reflects microscopic emphysema and to compare this quantification with the information yielded by the most widely used pulmonary function tests (PFT). Preoperative HRCT scans were obtained with 1-cm intervals in 38 subjects. With a semiautomatic evaluation procedure, the percentage areas occupied by attenuation values inferior to thresholds ranging from -900 Hounsfield units (HU) to -970 HU were calculated for the lobe or lung to be resected. Emphysema was microscopically quantified by using a computer-based method, measuring the perimeters and interwall distances of alveoli and alveolar ducts. The strongest correlation was found for -950 HU. As a second step, we evaluated possible correlations between PFT and microscopic measurements. Finally, considering the microscopic measurements as a standard, we tried to investigate their relationships with each of the PFT and with the relative area occupied by attenuation values lower than -950 HU for both lungs. This revealed that the diffusing capacity for carbon monoxide associated with HRCT quantification is sufficient to predict microscopic measurements. We concluded that the percentage area of lung occupied by attenuation values lower than -950 HU is a valid index of pulmonary emphysema.     

Liver cell necrosis during administration of clozapine

A 38-year-old woman was treated for mutism with clozapine. After a week liver function disturbances developed, which disappeared when the treatment was discontinued. Histopathological investigation of a liver biopsy specimen revealed extensive liver cell necrosis. So far two patients have been described with cholestatic jaundice induced by clozapine, and one patient with toxic hepatitis due to clozapine.     

Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-alpha: role of the p38 and p42/44 mitogen-activated protein kinases

IL-10 is an anti-inflammatory cytokine with potent immunomodulatory effects, including inhibition of cytokine production. However, regulation of monocyte IL-10 production is poorly understood. In this report we have investigated the mechanisms of LPS-induced IL-10 production by human peripheral blood monocytes and demonstrate that IL-10 synthesis is uniquely dependent on the endogenous proinflammatory cytokines IL-1 and/or TNF-alpha. LPS signal transduction in monocytes has been shown to involve activation of the p38 and p42 mitogen-activated protein kinase (MAPK) cascades. The results in this paper indicate that inhibition of p38 MAPK potently inhibited the production of IL-10, IL-1beta, and TNF-alpha, whereas blockade of the p42/44 MAPK pathway, while partially inhibiting TNF-alpha and IL-1beta production, had no effect on monocyte secretion of IL-10. Furthermore, neither the inhibition of monocyte TNF-alpha induced by IL-10 nor the stimulation of soluble TNF receptor production was affected by inhibition of the p42/44 MAPK pathway, suggesting that this signaling event is not involved in either monocyte production of or anti-inflammatory responses to IL-10. These data raise the interesting possibility that proinflammatory TNF-alpha-mediated effects may be selectively blocked without modulating the induction or the response to IL-10, whereas the signaling events associated with the anti-inflammatory events induced by IL-10 remain to be elucidated.