Epidemiology of and risk factors for mortality due to carbapenemase-producing organisms (CPO) in healthcare facilities.

BACKGROUND: Carbapenemase-producing organisms (CPO) have been largely responsible for the extensive spread of carbapenem resistance, and their prevalence is increasing in many parts of the world. AIM: To evaluate clinical and molecular epidemiology and mortality associated with CPO among patients. METHODS: All CPO from clinical and long-term healthcare surveillance cultures across Scotland in 2003-2017 were reviewed retrospectively. Polymerase chain reaction was used to detect genes coding for carbapenemases. A generalized linear mixed model was used to identify risk factors for mortality. FINDINGS: In total, 290 individuals with CPO were identified. The overall incidence increased over time (P<0.001) from 0.02 to 1.38 per 100,000 population between 2003 and 2017. A total of 243 distinct CPO isolates were obtained from 269 isolations in 214 individuals with available metadata. The majority of the isolates were Enterobacterales (206/243, 84.8%), and Klebsiella pneumoniae (65/206, 31.6%) and Enterobacter cloacae (52/206, 25.2%) were the most common species. VIM (75/243, 30.9%) and NDM (56/243, 23.0%) were the most common carbapenemases. The crude 30-day mortality rate was 11.8% (25/211), while the case fatality rate was 5.7% (12/211). Age >60 years [adjusted odds ratio (aOR) 3.36, 95% confidence interval (CI) 1.06-10.63; P=0.033], presence of non-fermenters (aOR 4.88, 95% CI 1.64-14.47; P=0.005), and systemic infection or organ failure (aOR 4.21, 95% CI 1.38-12.81; P=0.032) were independently associated with 30-day mortality. CONCLUSION: The incidence of CPO in Scotland is low but increasing. Awareness is required that inpatients aged >60 years, patients with systemic infection or organ failure, and patients presenting with non-fermenters are at higher risk of death from CPO.

CpG island arrays: an application toward deciphering epigenetic signatures of breast cancer.

CpG island hypermethylation is a frequent epigenetic event in cancer. We have recently developed an array-based method, called differential methylation hybridization (DMH), allowing for a genome-wide screening of CpG island hypermethylation in breast cancer cell lines (T. H-M. Huang et al., Hum. Mol. Genet., 8: 459-470, 1999). In the present study, DMH was applied to screen 28 paired primary breast tumor and normal samples and to determine whether patterns of specific epigenetic alterations correlate with pathological parameters in the patients analyzed. Amplicons, representing a pool of methylated CpG DNA derived from these samples, were used as hybridization probes in an array panel containing 1104 CpG island tags. Close to 9% of these tags exhibited extensive hypermethylation in the majority of breast tumors relative to their normal controls, whereas others had little or no detectable changes. Pattern analysis in a subset of CpG island tags revealed that CpG island hypermethylation is associated with histological grades of breast tumors. Poorly differentiated tumors appeared to exhibit more hypermethylated CpG islands than their moderately or well-differentiated counterparts (P = 0.041). This early finding lays the groundwork for a population-based DMH study and demonstrates the need to develop a database for examining large-scale methylation data and for associating specific epigenetic signatures with clinical parameters in breast cancer.

Hypermethylation of ribosomal DNA in human breast carcinoma.

We examined the methylation status of the transcribed domain of ribosomal DNA (rDNA) in 58 patients with breast cancer. The mean percent of methylation was significantly higher in breast tumours than that of normal control samples (P < 0.0001). This increased rDNA methylation was associated with oestrogen receptor non-expression (P < 0.0273) and with moderately or poorly differentiated tumours as compared to well differentiated tumours (P < 0.0475). Our results suggest that rDNA can be a useful marker for monitoring aberrant methylation during breast tumour progression.

Methylation profiling of CpG islands in human breast cancer cells.

CpG island hypermethylation is known to be associated with gene silencing in cancer. This epigenetic event is generally accepted as a stochastic process in tumor cells resulting from aberrant DNA methyltransferase (DNA-MTase) activities. Specific patterns of CpG island methylation could result from clonal selection of cells having growth advantages due to silencing of associated tumor suppressor genes. Alternatively, methylation patterns may be determined by other, as yet unidentified factors. To explore further the underlying mechanisms, we developed a novel array-based method, called differential methylation hybridization (DMH), which allows a genome-wide screening of hypermethylated CpG islands in tumor cells. DMH was used to determine the methylation status of >276 CpG island loci in a group of breast cancer cell lines. Between 5 and 14% of these loci were hypermethylated extensively in these cells relative to a normal control. Pattern analysis of 30 positive loci by Southern hybridization indicated that CpG islands might differ in their susceptibility to hypermethylation. Loci exhibiting pre-existing methylation in normal controls were more susceptible to de novo methylation in these cancer cells than loci without this condition. In addition, these cell lines exhibited different intrinsic abilities to methylate CpG islands not directly associated with methyltransferase activities. Our study provides evidence that, aside from random DNA-MTase action, additional cellular factors exist that govern aberrant methylation in breast cancer cells.

5-HT4 receptor mediated stimulation of gastric emptying in rats.

It is well documented that certain substituted benzamides, such as cisapride, and benzimidazolones, such as BIMU 8, enhance gastric emptying in rats. As these compounds possess 5-HT3 antagonistic and 5-HT4 agonistic properties, the precise mechanisms (5-HT3 or 5-HT4) underlying their gastroprokinetic effects is still unclear. In the present study, we used SC 49518 (a benzamide and selective 5-HT4 receptor agonist) and two selective 5-HT4 receptor antagonists (RS 23597-190 and SB 204070) to elucidate the role of 5-HT4 receptors in gastroprokinesis. SC 49518 (1-316 micrograms/kg; ip) produced significant and dose-dependent stimulation of gastric emptying in rats (ED50 = 2.3 micrograms/kg; ip). SC 49518 also produced dose-dependent inhibition of bradycardia induced by 2-methyl 5-HT (von Bezold-Jarisch reflex) but with a 156 fold lower potency (ID50 = 0.36 mg/kg; ip). The gastroprokinetic effects of SC 49518 (3-316 micrograms/kg; ip) were significantly antagonized by the selective 5-HT4 receptor antagonist RS 23597-190 (0.1 mg/kg/min; iv). SB 204070 (0.003-1 mg/kg; ip), another selective 5-HT4 receptor antagonist, produced dose-dependent inhibition of the gastroprokinetic effects of SC 49518 (10 micrograms/kg; ip), the inhibition attaining statistical significance at the dose of 0.1 mg/kg; ip. RS 23597-190 had no effects on gastric emptying per se whereas SB 204070 significantly increased gastric emptying by itself at 1 mg/kg; ip but not at 0.1 mg/kg; ip. These findings show, for the first time, that SC 49518, a selective 5-HT4 receptor agonist, produces potent stimulation of gastric emptying in rats via a mechanism involving activation of 5-HT4 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for the involvement of 5-hydroxytryptamine 4 receptors in 5-hydroxytryptophan-induced diarrhea in mice.

The objective of this study was to characterize the receptor(s) to 5-HT mediating 5-HTP-induced diarrhea in mice. The severity of diarrhea in mice was assessed using an arbitary scoring scale ranging from 0 (normal stools) to 3 (watery diarrhea). Administration of 5-HTP (1-30 mg/kg i.p.) produced a dose-dependent increase in diarrhea score (ED50, 1.47 mg/kg i.p.). 5-HTP (10 mg/kg i.p.)-induced diarrhea was unaffected by atropine (3 mg/kg i.p.) but was completely abolished by the aromatic L-amino acid decarboxylase inhibitor benserazide (10 mg/kg i.p.). Pretreatment (5 min before 5-HTP) with DAU 6285, a marginally selective 5-HT4 receptor antagonist, significantly inhibited 5-HTP-induced diarrhea (ID50, 0.58 mg/kg i.p.). Pretreatment (5 min before 5-HTP) with GR 113808 or SB 204070, two highly selective 5-HT4 antagonists, significantly inhibited 5-HTP-induced diarrhea with ID50 estimates of 0.31 and 0.003 mg/kg i.p., respectively. The maximal inhibition produced by DAU 6285, GR 113808 and SB 204070 was 63%, 68% and 36%, respectively. Neither GR 113808 (1 and 3 mg/kg i.p.) nor SB 204070 (0.1 and 1 mg/kg i.p.) had any effect on 16,16-dimethyl prostaglandin E2 (30 micrograms/kg i.p.)-induced diarrhea in mice. DAU 6285 significantly inhibited 16,16-dimethyl prostaglandin E2-induced diarrhea at the highest dose (3 mg/kg i.p.). Pretreatment (30 min before 5-HTP) with methysergide (0.1-3 mg/kg i.p.), metergoline (0.01-0.1 mg/kg i.p.), ketanserin (0.01-1 mg/kg i.p.), YM 060 (0.01-0.1 mg/kg i.p.) or ondansetron (0.01-3 mg/kg i.p.) had no significant effects on 5-HTP-induced diarrhea.(ABSTRACT TRUNCATED AT 250 WORDS)

Women at work. Interview by Jill L. Sherer.

System redesign can work--just ask the staff at Sentara Norfolk (VA) General Hospital's Women's Health Pavilion. In 1991, Sentara implemented a new patient-focused care delivery system and has garnered some very impressive results all around. After almost two years, baseline comparisons show per-case cost decreases for obstetrical services ranging from 0.2 percent to 26.3 percent. Reimbursement per case has increased 14 percent, and decreases in lengths of stay ranged from 1.1 percent to 8.4 percent. But cost savings weren't the only benefits measured. After only one year, employee satisfaction went up; so did patient satisfaction (which in some instances increased by as much as 11 percent). Laboratory turnaround times decreased on the average by about 30 minutes--some by as much as 64 minutes. So how did the folks at Sentara do it? H&HN staff editor Jill L. Sherer posed that question to Megan R. Perry, who, at the time of the patient-focused care redesign (officially completed in 1992), was director of the women's pavilion. Today, Perry is vice president at Sentara Norfolk General Hospital.

Plasma levels of peptide YY correlate with cisplatin-induced emesis in dogs.

The effect of cisplatin on plasma peptide YY (PYY) and 5-hydroxytryptamine (5-HT) concentrations was determined in conscious dogs (n = 6 per group) pretreated with either saline, or the 5-HT3-receptor antagonists ondansetron or granisetron. Cisplatin (3.0 mg kg-1, i.v.) caused emesis (18.8 +/- 2.9 episodes; 75-284 min) and significantly increased the mean area under the curve (AUC) over a 6-h period of plasma PYY concentrations (7.4 +/- 1.8 to 11.5 +/- 3.7 ng) in all saline-pretreated dogs, whereas the mean AUC of plasma 5-HT concentrations did not significantly increase (34.7 +/- 7.4 vs 35.6 +/- 12.3 pM h). The concentrations of PYY correlated closely with the incidence of emesis (r = 0.99). In animals pretreated (36 min) with ondansetron (0.316 mg kg-1, i.v.) or granisetron (0.316 mg kg-1, i.v.), the number of cisplatin-induced emetic episodes was significantly (P < 0.005) decreased compared with control. In animals receiving cisplatin and pretreated with ondansetron, PYY concentrations were not significantly altered, whereas the mean AUC of plasma concentrations of 5-HT over 6 h increased (35.6 +/- 12.3 to 82.3 +/- 34.6 pM h; P < 0.05). In animals receiving cisplatin and pretreated with granisetron, plasma concentrations of 5-HT were not significantly altered, whereas the mean AUC of plasma PYY concentrations were significantly reduced compared with control (6.2 +/- 1.7 vs 11.5 +/- 3.7 ng h).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the natural and unnatural isomers and degradation products of enprostil on gastric acid secretion and gastrointestinal motility in the rat.

The gastric antisecretory and gastrointestinal (GI) motility activity of the natural and unnatural allenic isomers and degradation products of enprostil (methyl(+/-)-7-[(1R*,2R*,3R*)-3-hydroxy-2-[(E)-(3R*)-3-hydroxy-4-phenoxy - 1-butenyl]-5-oxocyclopentyl]-4,5-heptadienoate, RS-84135-004) were studied in the rat. The natural R-allenic isomer of enprostil was the most potent antisecretory compound. The 8-iso-enprostil, enprostil free acid, and the 5-acetylene isomer had somewhat less activity while the other compounds were relatively inactive. The natural and unnatural allenic isomers increased intestinal dye transit with the same rank potency as the gastric antisecretory activity. Enprostil, 8-iso-enprostil, prostaglandin A-enprostil and enprostil free acid, all increased intestinal dye transit.