International Surveillance of Bloodstream Infections Due to Candida Species: Frequency of Occurrence and Antifungal Susceptibilities of Isolates Collected in 1997 in the United States, Canada, and South America for the SENTRY Program

An international program of surveillance of bloodstream infections (BSIs) in the United States, Canada, and South America between January and December 1997 detected 306 episodes of candidemia in 34 medical centers (22 in the United States, 6 in Canada, and 6 in South America). Eighty percent of the BSIs were nosocomial and 50% occurred in patients hospitalized in an intensive care unit. Overall, 53.3% of the BSIs were due to Candida albicans, 15.7% were due to C. parapsilosis, 15.0% were due to C. glabrata, 7.8% were due to C. tropicalis, 2.0% were due to C. krusei, 0.7% were due to C. guilliermondii, and 5.8% were due to Candida spp. However, the distribution of species varied markedly by country. In the United States, 43.8% of BSIs were due to non-C. albicans species. C. glabrata was the most common non-C. albicans species in the United States. The proportion of non-C. albicans BSIs was slightly higher in Canada (47.5%), where C. parapsilosis, not C. glabrata, was the most common non-C. albicans species. C. albicans accounted for 40.5% of all BSIs in South America, followed by C. parapsilosis (38.1%) and C. tropicalis (11.9%). Only one BSI due to C. glabrata was observed in South American hospitals. Among the different species of Candida, resistance to fluconazole (MIC, ≥64 μg/ml) and itraconazole (MIC, ≥1.0 μg/ml) was observed with C. glabrata and C. krusei and was observed more rarely among other species. Isolates of C. albicans, C. parapsilosis, C. tropicalis, and C. guilliermondii were all highly susceptible to both fluconazole (99.4 to 100% susceptibility) and itraconazole (95.8 to 100% susceptibility). In contrast, 8.7% of C. glabrata isolates (MIC at which 90% of isolates are inhibited [MIC₉₀], 32 μg/ml) and 100% of C. krusei isolates were resistant to fluconazole, and 36.9% of C. glabrata isolates (MIC₉₀, 2.0 μg/ml) and 66.6% of C. krusei isolates were resistant to itraconazole. Within each species there were no geographic differences in susceptibility to fluconazole or itraconazole.     

Conditioning hypoxia causes protection against ischemia in the CA 1-region of hippocampal slices

PURPOSE: At present the mechanisms of ischemic or hypoxic tolerance are not fully understood at the cellular level. METHODS: In order to further characterize the effects of conditioning hypoxia on the synaptic transmission in the hippocampal area CA1, rats were exposed to a moderate normobaric hypoxia for 8 h. Transverse hippocampal slices were prepared 1, 7 or 14 days after this conditioning hypoxia and evoked field potentials were recorded in the CA 1 region upon stimulation of the Schaffer collaterals before, during and up to 4 h after ischemia in vitro (hypoxia and reduced glucose). RESULTS and CONCLUSIONS: The time to disappearance of the evoked potential during ischemia was significantly prolonged after seven, but not after one or 14 days in slices taken from conditioned animals. In addition the input/output (I/O) curves of evoked potentials were not altered 4 h after the ischemia. In contrast, the time to disappearance of the evoked potentials was shorter and the I/O curves were diminished in slices from control animals. Possible mechanisms of the protective effect are discussed.     

A comparison of intramuscular ketamine with high dose intramuscular midazolam with and without intranasal flumazenil in children before suturing

Objectives—(a) To compare the use of high dose intramuscular midazolam with and without intranasal flumazenil in children after suturing. (b) To compare the use of high dose intramuscular midazolam with low dose intramuscular ketamine in children before suturing.

Methods—87 children, aged between 1 and 7 years, presenting with simple wounds needing sedation, were studied. Children considered combative (n=47) were given ketamine (2.5 mg/kg intramuscularly). The remaining 40 children were given midazolam (0.4 mg/kg intramuscularly) with and without flumazenil (25 µg/kg, intranasally).

Results—The median oxygen saturation was 97% in both midazolam groups. Flumazenil significantly reduced the amount of agitation during recovery (p=0.048) and also the time at which children were ready for discharge (median 55 versus 95 minutes, p value <0.001). After discharge both midazolam groups had an unsteady gait (75%) and there was no significant difference in the duration. As expected because of the deliberate selection of combative children into the ketamine group, the pre-sedation behaviour was slightly more disturbed compared with the midazolam group (p=0.10). However, the ketamine group was less agitated during local anaesthetic and suturing p<0.001.

Conclusion—Intramuscular midazolam (0.4 mg/kg) did not effectively sedate the children, in that a significant number still had to be restrained. However, none could remember the suturing. Intranasal flumazenil seems to be effective in shortening the time to discharge. If midazolam is to be used then a dose high enough to produce full amnesia should be used, there seems to be no advantage in increasing the dose further. Low dose intramuscular ketamine remains the drug of choice.

     

Inhibition of NF-κB Signaling Reduces Virus Load and Gammaherpesvirus-Induced Pulmonary Fibrosis

IgA nephropathy (IgAN) and Henoch-Schönlein purpura (HSP) are diseases characterized by IgA deposits in the kidney and/or skin. Both may arise after upper respiratory tract infections, but the pathogenic mechanisms governing these diseases remain unclear. Patients with IgAN (n = 16) and HSP (n = 17) were included in this study aimed at examining whether IgA-binding M proteins of group A streptococci could be involved. As M proteins vary in sequence, the study focused on the IgA-binding-region (IgA-BR) of three different M proteins: M4, M22, and M60. Renal tissue from IgAN and HSP patients and skin from HSP patients were examined for deposits of streptococcal IgA-BR by immunohistochemistry and electron microscopy using specific antibodies, and a skin sample from a HSP patient was examined by mass spectrometry. IgA-BR deposits were detected in 10/16 IgAN kidneys and 7/13 HSP kidneys. Electron microscopy demonstrated deposits of IgA-BRs in the mesangial matrix and glomerular basement membrane, which colocalized with IgA. Skin samples exhibited IgA-BR deposits in 4/5 biopsies, a result confirmed by mass spectrometry in one patient. IgA-BR deposits were not detected in normal kidney and skin samples. Taken together, these results demonstrate IgA-BR from streptococcal M proteins in patient tissues. IgA-BR, would on gaining access to the circulation, encounter circulatory IgA and form a complex with IgA-Fc that could deposit in tissues and contribute to the pathogenesis of IgAN and HSP.Tissue deposits containing IgA characterize IgA nephropathy (IgAN) and Henoch-Schönlein purpura (HSP), two conditions affecting kidney function. IgAN is the most common primary glomerulonephritis worldwide. Its predominant clinical feature is episodic macroscopic hematuria usually coinciding with upper respiratory tract infections. Symptoms may, however, vary from microscopic hematuria to a severe nephritic-nephrotic syndrome. End-stage kidney disease occurs in 30% to 40% of patients within 20 years. Histopathologically IgAN is characterized by mesangial cell proliferation and in progressive cases crescent formation as well as glomerular sclerosis, interstitial fibrosis, and tubular atrophy. Ultramorphologic findings show mesangial deposits of immune complexes containing predominantly IgA.^1,2HSP is the most common form of vasculitis in childhood. It may affect many organs, but usually presents as skin lesions, varying from purpura to bullous intradermal bleedings, arthritis, gastrointestinal involvement with pain and/or bleeding. Renal involvement occurs in up to 50% of cases³ and is known as Henoch-Schönlein nephropathy (HSN). HSN may manifest as microscopic or macroscopic hematuria as well as glomerulonephritis or nephrotic syndrome. Approximately 20% of HSN cases will develop renal failure.⁴ The histopathological lesion termed leukocytoclastic vasculitis is characterized by inflammation of small vessels with perivascular polymorphonuclear leukocyte and mononuclear cell infiltrates. Immune deposits in affected organs contain IgA, and renal pathology resembles that seen in IgAN.^1,3The IgA mesangial deposits in kidneys of patients with IgAN and HSP are primarily composed of galactose-deficient IgA1.^5,6,7 The mechanism by which under-glycosylated IgA1 deposits in the mesangium, possibly in complex with IgG,^8,9 has not been determined. Environmental antigens have been proposed to contribute to the disease but have not been consistently associated with mesangial deposits.⁹ Although the etiology of IgAN and HSP is unclear, these diseases are often preceded by infections, primarily of the upper respiratory tract, and an infectious agent has therefore been suspected. There is circumstantial evidence for involvement of group A streptococcus (GAS, Streptococcus pyogenes),^{10,11,12,13,14,15} but infections with other bacteria^16,17 as well as viruses¹⁸ have been implicated as well.In this study we hypothesized that GAS infection could trigger IgAN and/or HSN, because GAS is a very common cause of upper respiratory tract infection, and because many GAS strains bind IgA-Fc.^19,20,21 The ability of a GAS strain to bind human IgA results from the presence of an IgA-binding region (IgA-BR) in the surface-localized M protein.^22,23 The fibrillar M protein, which is a major virulence factor of GAS, varies in sequence between strains²⁴ allowing classification of GAS isolates into more than 120 M serotypes.²⁵ The exact function of the IgA-BR in an M protein is not known, but there is evidence that it contributes to bacterial phagocytosis resistance.²⁶ The IgA-BR of an M protein represents a distinct domain that can be studied in isolated form, as a peptide that binds IgA.^27,28 Such IgA-binding peptides, designated Sap (streptococcal IgA-binding peptide), were used in the experiments described herein.To analyze whether IgA-binding streptococcal M proteins are present in affected tissues of patients with IgAN and/or HSP, and colocalize with IgA, we used antibodies to the IgA-BR of three different M proteins M4, M22, and M60. Of note, M4 and M22 are among the most common serotypes of clinical GAS isolates.²⁹ As the IgA-BRs of different M proteins vary extensively in sequence,^22,23 the use of antibodies to three different serotypes enhanced our chances to detect tissue deposition of an IgA-BR.     

Caspofungin activity against clinical isolates of fluconazole-resistant Candida

A total of 7,837 clinical isolates of Candida were tested against fluconazole, and 351 resistant (fluconazole MIC >/=64 micro g/ml) isolates were identified (4% of the total tested). All fluconazole-resistant isolates were inhibited by caspofungin at concentrations that can be exceeded by standard doses (MIC at which 90% of the isolates were inhibited, 1 micro g/ml; 99% of the MICs were 相似文献   

In vitro activities of voriconazole,posaconazole, and four licensed systemic antifungal agents against Candida species infrequently isolated from blood

We determined the in vitro susceptibilities of 314 strains of Candida spp., representing 13 species rarely isolated from blood, to posaconazole and voriconazole as well as four licensed systemic antifungal agents (amphotericin B, flucytosine, fluconazole, and itraconazole). The organisms included 153 isolates of C. krusei, 67 isolates of C. lusitaniae, 48 isolates of C. guilliermondii, 10 isolates of C. famata, 10 isolates of C. kefyr, 6 isolates of C. pelliculosa, 5 isolates of C. rugosa, 4 isolates of C. lipolytica, 3 isolates of C. dubliniensis, 3 isolates of C. inconspicua, 2 isolates of C. sake, and 1 isolate each of C. lambica, C. norvegensis, and C. zeylanoides. MIC determinations were made by the National Committee for Clinical Laboratory Standards reference broth microdilution method and Etest (amphotericin B). Resistance to both amphotericin B and fluconazole was observed in strains of C. krusei, C. lusitaniae, C. guilliermondii, C. inconspicua, and C. sake. Resistance to amphotericin B, but not to fluconazole, was also observed among isolates of C. kefyr and C. rugosa. Posaconazole and voriconazole were active (MIC, < or = 1 micro g/ml) against 94 to 100% of these isolates. In contrast to the more common species of Candida causing bloodstream infection, these rare species appear to be less susceptible to the currently licensed systemic antifungal agents, with the exception of voriconazole. Continued surveillance will be necessary to detect the emergence of these species as more prevalent, resistant pathogens. The new triazoles appear to offer acceptable coverage of uncommon Candida sp. bloodstream infections.     

Activities of micafungin against 315 invasive clinical isolates of fluconazole-resistant Candida spp

Micafungin is a new echinocandin exhibiting broad-spectrum activity against Candida spp. The activity of the echinocandins against Candida species known to express intrinsic or acquired resistance to fluconazole is of interest. We determined the MICs of micafungin and caspofungin against 315 invasive clinical (bloodstream and other sterile-site) isolates of fluconazole-resistant Candida species obtained from geographically diverse medical centers between 2001 and 2004. MICs were determined using broth microdilution according to the CLSI reference method M27-A2. RPMI 1640 was used as the test medium, and we used the MIC endpoint of prominent growth reduction at 24 h. Among the 315 fluconazole-resistant Candida isolates, 146 (46%) were C. krusei, 110 (35%) were C. glabrata, 41 (13%) were C. albicans, and 18 (6%) were less frequently isolated species. Micafungin had good in vitro activity against all fluconazole-resistant Candida spp. tested; the MICs at which 50% (MIC(50)) and 90% (MIC(90)) of isolates were inhibited were 0.03 microg/ml and 0.06 microg/ml, respectively. All the fluconazole-resistant Candida spp. were inhibited at a micafungin MIC that was 相似文献   

Bidirectional fusion of the heart-forming fields in the developing chick embryo.

It is generally thought that the early pre-tubular chick heart is formed by fusion of the anterior or cephalic limits of the paired cardiogenic fields. However, this study shows that the heart fields initially fuse at their midpoint to form a transitory "butterfly"-shaped, cardiogenic structure. Fusion then progresses bi-directionally along the longitudinal axis in both cranial and caudal directions. Using in vivo labeling, we demonstrate that cells along the ventral fusion line are highly motile, crossing future primitive segments. We found that mesoderm cells migrated cephalically from the unfused tips of the anterior/cephalic wings into the head mesenchyme in the region that has been called the secondary heart field. Perturbing the anterior/cranial fusion results in formation of a bi-conal heart. A theoretical role of the ventral fusion line acting as a "heart organizer" and its role in cardia bifida is discussed.     

In vitro susceptibilities of Candida spp. to caspofungin: four years of global surveillance

Caspofungin is being used increasingly as therapy for invasive candidiasis. Prospective sentinel surveillance for emergence of in vitro resistance to caspofungin among invasive Candida spp. isolates is indicated. We determined the in vitro activity of caspofungin against 8,197 invasive (bloodstream or sterile-site) unique patient isolates of Candida collected from 91 medical centers worldwide from 1 January 2001 to 31 December 2004. We performed antifungal susceptibility testing according to the Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) M27-A2 method and used a 24-h prominent inhibition endpoint for determination of the MIC. Of 8,197 invasive Candida spp. isolates, species distribution was as follows: 54% Candida albicans, 14% C. glabrata, 14% C. parapsilosis, 11% C. tropicalis, 3% C. krusei, and 4% other Candida spp. Overall, caspofungin was very active against Candida (MIC50/MIC90, 0.03/0.25 microg/ml; 98.2% were inhibited at a MIC of < or = 0.5 microg/ml and 99.7% were inhibited at a MIC of < or = 1 microg/ml). Results by species (expressed as MIC50/MIC90 and the percentage inhibited at < or = 1 microg/ml) were as follows: C. albicans, 0.03/0.06, 99.9; C. glabrata, 0.03/0.06, 99.9; C. parapsilosis, 0.5/0.5, 99.0; C. tropicalis, 0.03/0.06, 99.7; C. krusei, 0.12/0.5, 99.0; and C. guilliermondii, 0.5/1, 94.4. Of the 25 isolates with caspofungin MICs of >1 microg/ml, 12 isolates were C. parapsilosis, 6 isolates were C. guilliermondii, 2 isolates were C. rugosa, and 1 isolate each was C. albicans, C. glabrata, C. krusei, C. lusitaniae, and C. tropicalis. There was no significant change in caspofungin activity over the 4-year study period. Likewise, there was no difference in activity by geographic region. Caspofungin has excellent in vitro activity against invasive clinical isolates of Candida from centers worldwide. Our prospective sentinel surveillance reveals no evidence of emerging caspofungin resistance among invasive clinical isolates of Candida.