Screening for Inhibition of Vibrio cholerae VipA-VipB Interaction Identifies Small-Molecule Compounds Active against Type VI Secretion

The type VI secretion system (T6SS) is the most prevalent bacterial secretion system and an important virulence mechanism utilized by Gram-negative bacteria, either to target eukaryotic cells or to combat other microbes. The components show much variability, but some appear essential for the function, and two homologues, denoted VipA and VipB in Vibrio cholerae, have been identified in all T6SSs described so far. Secretion is dependent on binding of an α-helical region of VipA to VipB, and in the absence of this binding, both components are degraded within minutes and secretion is ceased. The aim of the study was to investigate if this interaction could be blocked, and we hypothesized that such inhibition would lead to abrogation of T6S. A library of 9,600 small-molecule compounds was screened for their ability to block the binding of VipA-VipB in a bacterial two-hybrid system (B2H). After excluding compounds that showed cytotoxicity toward eukaryotic cells, that inhibited growth of Vibrio, or that inhibited an unrelated B2H interaction, 34 compounds were further investigated for effects on the T6SS-dependent secretion of hemolysin-coregulated protein (Hcp) or of phospholipase A₁ activity. Two compounds, KS100 and KS200, showed intermediate or strong effects in both assays. Analogues were obtained, and compounds with potent inhibitory effects in the assays and desirable physicochemical properties as predicted by in silico analysis were identified. Since the compounds specifically target a virulence mechanism without affecting bacterial replication, they have the potential to mitigate the virulence with minimal risk for development of resistance.     

Fever and neutropenia in children with cancer: diagnostic parameters at presentation

We evaluated 91 episodes of fever in 46 profoundly neutropenic children with cancer, in a search for any symptom, sign or laboratory test that would serve to identify patients with septicemia and differentiate them from those in no immediate need of prompt antimicrobial therapy. Seventeen episodes (19%) were bacteremias, 59 (64%) were suspected septic infections, 9 (10%) were focal bacterial infections and 6 (7%) proved not to be bacterial infections. We were unable to detect any parameter, either on admission or after two days of antimicrobial therapy (except for blood culture findings), that would be helpful in differentiating bacteremia from an episode not of bacterial origin. We focused on serum levels of C reactive protein and found them unreliable on an individual level. Prompt institution of antimicrobial therapy at the occurrence of fever results in low mortality, but does not allow assignment of cases to different categories.     

POSTNATAL DEVELOPMENT OF RENAL FUNCTION IN PRE-TERM AND FULL-TERM INFANTS

ABSTRACT. Aperia, A., Broberger, B., Klinder, G., Herin, P. and Zetterström, R. (Department of Paediatrics, Karolinska Institute, St. Göran's Children's Hospital, Stockholm and Huddinge Hospital, Huddinge, Sweden). Postnatal deveopment of renal function in preterm and full-term infants. Acta Paediatr Scand, 70:183, 1981. –This study has been designed to examine the effect of gestational age (GA) on the postnatal development of renal function and has been performed in pre-term (PT) infants (GA=30–34 weeks) and in full-term (FT) infants (GA=39–41 weeks). Postnatal age has ranged from 1–35 days. From 8 hour urine samples collected after spontaneous voiding and a capillary blood sample, determinations have been made of the clearance of creatinine (C_Cr), the fractional excretion of β₂-microglobulin (FE_β2) and the fractional excretion of sodium (FE_Na). In some infants receiving fluid parenterally, simultaneous determinations were made of the clearance of creatinine and inulin. As judged from this study, C_Cr is a reliable indicator of the glomerular filtration rate (GFR). GFR was almost the same in newborn PT and FT, but from 0.3–1 week of age GFR increased significantly more rapidly in FT than in PT. From 1–5 weeks of age GFR increased at approximately the same rate in PT and FT infants. The absolute value for GFR in 3–5 weeks old infants was lower in PT than in FT. FE_β2 was higher in PT than in FT infants during the entire first month of life and FE_Na was higher in PT than in FT infants during the first week of life, suggesting a glomerular tubular imbalance at least at the level of the proximal tubule in PT infants. It is concluded that different stages of maturation will alter the preconditions for the renal adaptation to extrauterine life during at least the first month of life. Therefore special attention must be paid to the limited renal function in PT during their entire first month of life.     

Prostatic evaluation by transrectal sonography with histopathologic correlation: the echopenic appearance of early carcinoma

Fifty-two patients with clinical stage A and B carcinomas of the prostate were imaged by ultrasound (US) transrectally with a 5-MHz linear array transducer and transabdominally with a 3-MHz sector scanner prior to radical prostatectomy. The fresh specimens of 44 prostate glands were scanned in a water bath with a 5-MHz linear array transducer in multiple planes. In all cases, histopathologic correlation was obtained. Prostatic carcinoma presented as an echopenic lesion in 54% of the specimens, as a slightly hypoechoic area in 22%, and could not be identified in 24% because of its isoechoic characteristics. In contrast to many previous reports, no instance of echogenic cancer was observed.     

Self-report as a selection instrument in screening for cardiovascular disease risk

INTRODUCTION: Cardiovascular disease (CVD) risk screening may rely partly on self-report information. The accuracy of self-reporting in relation to the actual risk factor status is insufficiently known. DESIGN: Self-report (yes, no, don't know) of presence of hypertension, hyperlipidemia, and overweight was compared to the corresponding risk factor data obtained by physical examination and blood analysis. The examinations carried out in a primary health care setting in Sweden were on a randomized population of 122 men and 127 women aged 20 to 60 years. RESULTS: Unawareness of hyperlipidemia was 71% in women and 56% in men, as compared to 29% or lower for the other risk factors. The sensitivity of self-report was 69% or higher for the other risk factors, with the exception of hypertension in women, where it was 29%. Specificity was generally high, except for hyperlipidemia. CONCLUSION: On a population level, self-reports of hypertension, hyperlipidemia, and overweight provide a feasible selection instrument by which a subpopulation with high risk factor frequency can be identified. However, the rate of misclassification is considerable. For hyperlipidemia, the benefit of self-reporting is presently limited, due to the high unawareness of this risk factor. Individual awareness and accurate knowledge about the presence or absence of risk factors needs to improve before self-reporting can be used as a reliable instrument in risk factor screening.     

Bronchoscopic features and bronchoscopic intervention for endobronchial hamartoma

Background and objective: Bronchoscopic resection of endobronchial hamartomas has been reported to have a favourable outcome. This study describes the bronchoscopic features of endobronchial hamartoma and reports the clinical outcome of bronchoscopic intervention. Methods: A retrospective analysis was conducted of patients with histologically proven endobronchial hamartomas, diagnosed in the 10‐year period 1999–2009 to elucidate the clinical, radiological and bronchoscopic features of hamartoma and to describe the clinical outcomes. Results: Seventeen of the 135 patients with pulmonary hamartomas were diagnosed as having endobronchial hamartomas. CXR was abnormal in 11 of the 17 patients. On chest CT (n = 16), the median diameter of the lesion was 15.6 mm. Calcification and areas of focal fat in the lesion, the diagnostic CT findings of pulmonary hamartoma, were found in two of 16 (12.5%) patients. At bronchoscopy (n = 16), all tumours had a mass appearance and most were smooth surfaced round masses (50.0%) with 18.8% having a ‘stalk’. Bronchoscopic forceps biopsies were performed in 13 patients, which resulted in five patients (38.5%) being diagnosed with endobronchial hamartoma. Fifteen patients were treated with rigid or flexible bronchoscopic resection, one had lobectomy, and one had no intervention. No procedure‐related mortalities or late complications developed. Conclusions: Bronchoscopic intervention appears to be a safe and effective method to resect endobronchial hamartomas.