Oxazolidinones, a new class of synthetic antituberculosis agent. In vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis.

DL-S-n-(3-(4-acetyl)-2-oxo-5-oxazolidynyl methyl) acetamide (DuP-721) is an orally active representative of the oxazolidinone series of antimicrobials. At concentrations ranging from 1.5 to 4 micrograms/ml, DuP-721 inhibited equally the strains of Mycobacterium tuberculosis susceptible and resistant to conventional antituberculosis drugs. DuP-721 inhibited M. gordonae and M. fortuitum at 3.9 micrograms/ml, M. kansasii at 1.95, and M. scrofulaceum at 15.6 micrograms/ml. It was not active against M. avium and M. intracellulare at concentrations of 250 micrograms/ml. The inhibition of the metabolism of M. tuberculosis as indicated by the liquid scintillation radiometric method was 56% at fourfold the minimum inhibitory concentration (MIC) of DuP-721 that compared well to that of the fourfold MIC concentrations of rifampicin and isoniazid. The in vitro activity of DuP-721 was not affected by reducing the pH from 6.8 to 5.5. In mice infected with M. tuberculosis, the 50% effective dose (ED50) for DuP-721 was 13.2 mg/kg when administered daily beginning 4 hr postinfection for 17 days. The ED50 was 71.8 mg/kg when DuP-721 was administered only on days 11 and 12 postinfection. A 100% survival rate was obtained at 50 and 160 mg/kg when DuP-721 was administered daily for 17 days, and only on days 11 and 12 after the infection, respectively. The increase in the survival time by DuP-721 at 100 mg/kg (eightfold the ED50 dose) when administered daily for 17 days beginning 4 hr after infection was inferior to that by eightfold the ED50 dose of rifampicin and isoniazid administered on days 11 and 12 postinfection.(ABSTRACT TRUNCATED AT 250 WORDS)     

A randomised controlled trial of delayed cord clamping in very low birth weight preterm infants

This study was carried out to assess the feasibility of late cord clamping of 45 s in preterm infants delivered mainly by caesarean section and the effects on post-partal adaptation and anaemia of prematurity. Prior to delivery, 40 infants of <33 gestational weeks were randomised to either 20 s or 45 s of late cord clamping. After the first shoulder was delivered, oxytocin was given intravenously to the mother in order to enhance placento-fetal transfusion while the infant was held below the level of the placenta. The 20 infants in group 1 (20 s) had a mean birth weight of 1070 g and a mean gestational age of 29 + 4/7 weeks versus 1190 g and 30 weeks in group 2 (45 s). On day 42 of life there were ten infants without transfusions in group 2 versus three in group 1 (P < 0.05). Out of the 20 infants in group 1, 19 and 15/19 in group 2 were delivered by caesarean section. There were no significant differences in Apgar scores, temperature on admission, heart rate, blood pressure and requirements for artificial ventilation. Conclusion Delayed cord clamping of 45 s is feasible and safe in preterm infants below 33 weeks of gestation. It is possible to perform the procedure at caesarean section deliveries and it should be performed whenever possible. It reduces the need for packed red cell transfusions during the first 6 weeks of life. Received: 10 February 2000 / Accepted: 12 April 2000     

Granular cell tumor of the penis: clinicopathologic evaluation of 9 cases

The occurrence of granular cell tumor (GCT) in penile tissue is very rare, with only 9 examples reported to date in the English-language literature. Herein, we describe the clinicopathologic and immunohistochemical findings in 9 additional cases. The patients ranged in age from 20 to 60 years (mean, 42 years; median, 40 years) at time of diagnosis. All penile tumors were solitary and arose in the dermis of the penile shaft (n=4), prepuce (n=3), and corona (n=2). A patient had a history of multiple cutaneous GCTs. Duration of symptoms before surgery ranged from 5 days to 2 years with the presence of an asymptomatic nodule representing the most common tumor-related complaint (n=8). The lesions ranged in size from 0.6 to 2.5 cm (mean, 1.5 cm; median, 1.5 cm). Microscopically, the tumors were moderate to highly cellular and were composed of oval to polygonal-shaped cells with abundant coarsely granular eosinophilic cytoplasm. Tumor cells grew in infiltrating nests, cords, and trabeculae and showed neural (n=2) and vessel wall (n=1) invasion or formed a relatively well-marginated solid nodule. Bland cytological features with only rare cells showing nucleomegaly (n=7) or spindling (n=3) were exhibited by 8 tumors. A tumor demonstrated diffuse nuclear atypia and was classified as "atypical." Mitotic activity ranged from 0 to 8 mitoses (mean, 1.4 mitoses) per 50 high-powered fields with no atypical division figures identified. All tumors tested showed moderate to strong immunohistochemical expression of S100 protein (n=6) and low-affinity nerve growth factor receptor (n=5), which was useful for detecting small deposits of tumor and helpful in evaluating surgical margins. Focal tumor cell immunoreactivity was observed for calretinin (4/6 cases) and glial fibrillary acidic protein (1/6 cases). All patients underwent simple (local) excision of their tumor. Complete follow-up data (mean, 21 years; interval range, 0.5-28 years) were available for 6 patients. No patient experienced recurrence or metastatic spread of tumor although surgical margins were microscopically involved by tumor in 5 cases. Benign GCT involving superficial soft tissue of the penis can be adequately managed by a simple excision. Patients with microscopically involved surgical margins can be clinically followed without immediate additional surgery.     

Analyses of phenotypic and functional characteristics of CX3CR1-expressing natural killer cells

We previously demonstrated a correlation between the frequency of CX3CR1-expressing human natural killer (NK) cells and disease activity in multiple sclerosis and showed that CX3CR1(high) NK cells were more cytotoxic than their CX3CR1(neg/low) counterparts. Here we aimed to determine whether human NK cell fractions defined by CX3CR1 represent distinct subtypes. Phenotypic and functional NK cell analyses revealed that, distinct from CX3CR1(high), CX3CR1(neg/low) NK cells expressed high amounts of type 2 cytokines, proliferated robustly in response to interleukin-2 and promoted a strong up-regulation of the key co-stimulatory molecule CD40 on monocytes. Co-expression analyses of CX3CR1 and CD56 demonstrated the existence of different NK cell fractions based on the surface expression of these two surface markers, the CX3CR1(neg) CD56(bright), CX3CR1(neg) CD56(dim) and CX3CR1(high) CD56(dim) fractions. Additional investigations on the expression of NK cell receptors (KIR, NKG2A, NKp30 and NKp46) and the maturation markers CD27, CD62L and CD57 indicated that CX3CR1 expression of CD56(dim) discriminated between an intermediary CX3CR1(neg) CD56(dim) and fully mature CX3CR1(high) CD56(dim) NK cell fractions. Hence, CX3CR1 emerges as an additional differentiation marker that may link NK cell maturation with the ability to migrate to different organs including the central nervous system.     

High trait emotional intelligence in men: Beneficial for perceived stress levels but disadvantageous for the physiological response to acute stressors?

This study examined the relationship between trait emotional intelligence (EI) and stress in 110 male employees. Particularly, the association between trait EI and perceived chronic stress, occupational stress, and the physiological stress response was examined. Trait EI, perceived chronic stress, and occupational stress levels were assessed via questionnaires. The physiological stress response was measured by means of salivary free cortisol and heart rate variability (HRV) in response to the Trier Social Stress Test for Groups. Consistent with previous findings, men with high trait EI showed significantly lower perceived chronic and occupational stress levels than men with low trait EI. However, men with high trait EI also showed significantly higher cortisol reactivity than their low trait EI counterparts. Similarly, HRV in men with high trait EI appeared to be lower than in men with low trait EI but HRV differences between groups were not significant. Our findings suggest that trait EI might play a critical role in the stress regulation process but due to the cross‐sectional design of the study no causal conclusions can be drawn. Experimental studies need to explore further whether and how trait EI affects psychological and physiological stress responses.     

Concurrent interaction of DCs with CD4+ and CD8+ T cells improves secondary CTL expansion: It takes three to tango

T‐cell help is essential for CTL‐memory formation. Nevertheless, it is unclear whether the continuous presence of CD4⁺ T‐helper (Th) cells is required during dendritic cell (DC)/CD8⁺ T‐cell encounters, or whether a DC will remember the helper signal after the Th cell has departed. This question is relevant for the design of therapeutic cancer vaccines. Therefore, we investigated how human DCs need to interact with CD4⁺ T cells to mediate efficient repetitive CTL expansion in vitro. We established an autologous antigen‐specific in vitro system with monocyte‐derived DCs, as these are primarily used for cancer vaccination. Contrary to common belief, a sequential interaction of licensed DCs with CD8⁺ T cells barely improved CTL expansion. In sharp contrast, simultaneous encounter of Th cells and CTLs with the same DC during the first in vitro encounter is a prerequisite for optimal subsequent CTL expansion in our in vitro system. These data suggest that, in contrast to DC maturation, the activation of DCs by Th cells, which is necessary for optimal CTL stimulation, is transient. This knowledge has significant implications for the design of new and more effective DC‐based vaccination strategies. Furthermore, our in vitro system could be a valuable tool for preclinical immunotherapeutical studies.