Proactive care post-discharge to reduce 30 day readmissions to hospital.

BACKGROUND: Healthwatch England estimated emergency readmissions have risen by 22.8% between 2012-13 and 2016-17. Some emergency readmissions could be avoided by providing patients with urgent out of hospital medical care or support. Sovereign Health Network (SHN) comprises of three GP practices, with a combined population of 38,000. OBJECTIVE: We will decrease the number of SHN patients readmitted within 30 days of discharge from Portsmouth Hospitals Trust following a non-elective admission (excluding Emergency Department attendance) by 40-60% by July 2020. METHODS: Four Plan, Do, Study, Act (PDSA) cycles were used to test the administrative and clinical processes. Our Advanced Nurse Practitioner reviewed all discharge summaries, added alerts to records, and proactively contacted patients either by text, telephone or home visit. RESULTS: 92 patients aged 23 days to 97 years were admitted onto the recent discharge scheme. Half of discharge summaries were received on the day of discharge, whilst 29% of discharge summaries were received more than 24 hours post-discharge, and one was received 11 days post-discharge. Following our interventions, there were 55% less than expected readmissions during the same time period. CONCLUSION: To allow proactive interventions to be instigated in a timely manner, discharge summaries need to be received promptly. The average readmission length of stay following a non-elective admission is seven days. Our proactive interventions saved approximately 102.9 bed days, with potential savings of 1,775 bed days over a year. We feel the results from our model are promising and could be replicated by other Primary Care Networks to result in larger savings in bed days.

Use of naloxone to minimize extubation failure after premedication for INSURE procedure in preterm neonates.

OBJECTIVES: A new guideline for the early respiratory management of preterm infants that included early nCPAP and INSURE was recently introduced in our NICU. This case series describes the clinical courses of a group of preterm infants managed according to this guideline, and reports the rates of successful extubation within 30 minutes of surfactant administration with and without the use of naloxone and adverse events encountered. STUDY DESIGN: Descriptive case series of all preterm babies admitted to our unit who were candidates for INSURE procedure with premedication from August 2012 to August 2013. RESULTS: A total of 31 infants were included with a mean birth weight of 1178 grams and a mean gestational age of 28.4 weeks. Twelve out of thirteen (92%) infants in the naloxone group were extubated within 30 minutes of surfactant administration while only 12/18 (67%) in the non-naloxone group were extubated within the same time frame. No adverse reactions were noted with naloxone usage in this context. CONCLUSION: Naloxone can be effective in reversing the respiratory depressive effect of analgesic premedication and in turn facilitates expeditious extubation in some preterm infants intubated for INSURE procedure.

Utility of neutrophil volume conductivity scatter (VCS) parameter changes as sepsis screen in neonates.

OBJECTIVE: The objective of this study was to determine changes in neutrophil volume conductivity scatter (VCS) parameters and their distribution widths (DW) in neonatal sepsis and to estimate their optimal cutoff levels using receiver operating characteristic (ROC) curves. STUDY DESIGN: In a cohort of neonates evaluated for sepsis, blood counts and blood culture were performed initially, with repeat counts and C-reactive protein (CRP) done after 24 to 48 h. Neutrophil VCS parameters from both the initial and repeat blood counts were analyzed. Babies were classified as having blood culture-positive sepsis, probable sepsis (clinical course consistent with sepsis and CRP-positive, but culture-negative) and no sepsis (clinical course not compatible with sepsis, culture- and CRP-negative). RESULTS: A total of 600 babies were included: 240 (40%) babies in the sepsis group and 360 (60%) babies in the control group. All the neutrophil VCS parameters and their DWs (except for low angle light scatter in the repeat counts) were significantly different between the two groups, with an area under curve in the ROC curve of >0.6 for most parameters. The five most significant VCS parameters (mean neutrophil volume (MNV), median angle light scatter (MALS), lower median angle light scatter (LMALS), MNV-DW and ALL-DW) had around 65 to 75% sensitivity and specificity. A combination of leukopenia, thrombocytopenia, MNV and LMALS had a likelihood ratio (LR)+ of 15.3 and LR- of 0.17. With a pre-test probability of 40%, post-test probability increased to 91% for a positive test and decreased to 10% for a negative test. A prospective validation study was performed recruiting an additional 60 babies, which showed similar results, assuring that the cutoffs were robust. CONCLUSION: Neutrophil VCS parameters cannot be considered as stand-alone tests to diagnose or rule out neonatal sepsis, but can be used in combination with other hematological screening tests to improve the diagnostic accuracy of the neonatal sepsis screen.

FOXM1 and polo-like kinase 1 are co-ordinately overexpressed in patients with gastric adenocarcinomas.

BACKGROUND: Gastric cancers present late in life with advanced disease and carry a poor prognosis. Polo-like Kinase 1 (PLK1) is a mitotic kinase with regulatory functions during G2/M and mitosis in the cell cycle. In mammalian cells, there is an intricate co-regulatory relationship between PLK1 and the forkhead transcription factor FOXM1. It has been demonstrated that individually either PLK1 or FOXM1 expression predicts poorer survival. However, the co-expression of both of these markers in gastric adenocarcinomas has not been reported previously. METHODS: We aimed to assess the expression of PLK1 and FOXM1 in Gastric adenocarcinomas in a Western Population, to examine whether there is a relationship of PLK1 to FOXM1 in cancer samples. We assess both the protein and mRNA expression in this patient population by Tissue Microarray immunohistochemistry and RT-PCR. RESULTS: Immunohistochemistry was performed on biopsy samples from 79 patients with gastric cancer. Paired normal controls were available in 47 patients. FOXM1 expression was significantly associated with gastric adenocarcinoma (p = 0.001). PLK1 and FOXM1 co-expression was demonstrated in 6/8 (75 %) tumours when analysed by RT-PCR. FOXM1 is overexpressed in a large proportion of gastric carcinomas at the protein level and FOXM1 and PLK1 are concomitantly overexpressed at the mRNA level in this cancer type. CONCLUSIONS: This study has demonstrated that FOXM1 and its target gene PLK1 are coordinately overexpressed in a proportion of gastric adenocarcinomas. This suggests that chemotherapeutic treatments that target this pathway may be of clinical utility.

The FOXM1-PLK1 axis is commonly upregulated in oesophageal adenocarcinoma.

BACKGROUND: The transcription factor FOXM1 is an important regulator of the cell cycle through controlling periodic gene expression during the G2 and M phases. One key target for FOXM1 is the gene encoding the protein kinase PLK1 and PLK1 itself acts in a positive feedback loop to phosphorylate and activate FOXM1. Both FOXM1 and PLK1 have been shown to be overexpressed in a variety of different tumour types. METHODS: We have used a combination of RT-PCR, western blotting, tissue microarrays and metadata analysis of microarray data to study whether the FOXM1-PLK1 regulatory axis is upregulated and operational in oesophageal adenocarcinoma. RESULTS: FOXM1 and PLK1 are expressed in oesophageal adenocarcinoma-derived cell lines and demonstrate cross-regulatory interactions. Importantly, we also demonstrate the concomitant overexpression of FOXM1 and PLK1 in a large proportion of oesophageal adenocarcinoma samples. This co-association was extended to the additional FOXM1 target genes CCNB1, AURKB and CKS1. In a cohort of patients who subsequently underwent surgery, the expression of several FOXM1 target genes was prognostic for overall survival. CONCLUSIONS: FOXM1 and its target gene PLK1 are commonly overexpressed in oesophageal adenocarcinomas and this association can be extended to other FOXM1 target genes, providing potentially important biomarkers for predicting post-surgery disease survival.

Optimization studies on acid hydrolysis of oil palm empty fruit bunch fiber for production of xylose.

Oil palm empty fruit bunch fiber is a lignocellulosic waste from palm oil mills. It is a potential source of xylose which can be used as a raw material for production of xylitol, a high value product. The increasing interest on use of lignocellulosic waste for bioconversion to fuels and chemicals is justifiable as these materials are low cost, renewable and widespread sources of sugars. The objective of the present study was to determine the effect of H(2)SO(4) concentration, reaction temperature and reaction time for production of xylose. Batch reactions were carried out under various reaction temperature, reaction time and acid concentrations and Response Surface Methodology (RSM) was followed to optimize the hydrolysis process in order to obtain high xylose yield. The optimum reaction temperature, reaction time and acid concentration found were 119 degrees C, 60 min and 2%, respectively. Under these conditions xylose yield and selectivity were found to be 91.27% and 17.97 g/g, respectively.

Insulin resistance in NASH.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease observed in the clinical practice of hepatology. The coexistence of metabolic syndrome in this cohort of patients has made insulin resistance central to the pathogenesis of these disorders. The metabolic consequence of insulin resistance is impaired hepatic glucose output and abnormal lipid handling. In the face of continued metabolic insults the normal hepatic regulatory mechanism gets overwhelmed and fat accumulates in the hepatocytes. The subsequent fate of steatotic hepatocytes depends on the capacity of additional factors such as adipocytokines and toxicity induced by the free fatty acids themselves to induce inflammatory response. This latter process is responsible for the producing the phenotype of non-alcoholic steatohepatitis (NASH). Irrespective of the process by which these phenotypic response occurs, it is now universally accepted that in the absence of insulin resistance the spectrum of changes one associates with NAFLD does not develop. In this review we will discuss the various processes that are involved in the pathogenesis of NAFLD.

Sudden death: a clinicopathological study.

OBJECTIVE: To ascertain the causes of sudden death (SD) by autopsy examination. METHODS: All cases of sudden death were subjected to a postmortem examination. In addition previous postmortem reports of sudden death over a two years were also included. Postmortem findings were correlated to clinical state and the cause of death was ascertained. The information was analyzed to find out the cause of sudden death in our patients. RESULTS: Out of a total of 130 autopsies there were 13 cases of SD. All were males (age 23 to 50 years). Death was within one your of onset of symptoms in five (38.5%) cases and within 24 hours in eight (61.5%) cases. Death was due to coronary artery disease (CAD) in 10 (76.93%) cases, aortoarteritis, cardiomyopathy and cerebrovascular accident (CVA) in (7.69%) case each. Amongst CAD patients triple vessel disease (TVD) was seen in eight cases (which included one case of cardiomyopathy), two vessel disease (DVD) in two and single vessel disease (SVD) in one. No specific preponderance of right or left coronary artery was seen. One patient of 21 year who died following exertion showed anomalous origin of coronary arteries. His right and left coronary artery originated from aortic arch 1.5 cm above the aortic valve. Right coronary artery was ill developed and had atheromatous plaque. The case of cardiomyopathy also had TVD. In the case of aortoarteritis all vessels were affected (carotids, renal and coronary). In one case of CVA bleeding was from an arterio-venous malformation in right temporal lobe. Nine out of 11 cases of CAD had atheromatous plaque without coronary thrombosis. CONCLUSIONS: Coronary artery disease (Triple vessel disease) contributed to maximum number of cases of SD. Aortoarteritis, cardiomyopathy and cerebrovascular accident (CVA) was the cause of death in one case each. Postmortem identified the cause of death in all cases.

CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells.

Fas-mediated mechanisms of apoptosis are thought to be involved in the bile duct loss that characterizes diseases such as primary biliary cirrhosis (PBC). We have previously shown that activation of CD40 on hepatocytes can amplify Fas-mediated apoptosis; in the present study, we investigated interactions between CD40 and Fas in biliary epithelial cells (BEC). We report that the bile ducts in PBC liver tissue frequently express increased levels of Fas, Fas ligand (FasL), and CD40 associated with apoptotic BEC. The portal mononuclear infiltrate contains CD40L+ve T cells and macrophages, thereby demonstrating a potential mechanism for CD40 engagement in vivo. Primary cultures of human BEC also expressed Fas, FasL, and CD40 but not CD40L protein or mRNA. Activation of CD40 on BEC using recombinant CD40L increased transcriptional expression of FasL and induced apoptosis, which was inhibited by neutralizing antibodies to either Fas or FasL. Thus, CD40-induced apoptosis of BEC is mediated through Fas/FasL. We then investigated the intracellular signals and transcription factors activated in BEC and found that NF-kappaB and AP-1 were both activated after CD40 ligation. Increased functional NF-kappaB was seen early after CD40 ligation, but returned to baseline levels after 4 h. In contrast, the rapid up-regulation of AP-1 was sustained over 24 h. This study provides further functional evidence of the ability of CD40 to induce Fas/FasL-dependent apoptosis of liver epithelial cells supporting the importance of cross-talk between tumor necrosis factor (TNF) receptor family members as an amplification step in apoptosis induction. Sustained activation of AP-1 in the absence of NF-kappaB signaling may be a critical factor in determining the outcome of CD40 engagement.

The protein kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperzine (H-7) prevents and reverses Ca(2+)-mediated injury in isolated rat hepatocyte couplets.

We have recently shown that protein kinase C (PKC) activation induces similar morphological and functional alterations in couplets to that caused by increments of intracellular Ca(2+). Since certain PKC isoforms are activated by Ca(2+), we tested whether the PKC inhibitor H-7 can counteract the alterations induced by this ion in couplets. The Ca(2+) ionophore A23187, which can mobilize Ca(2+) from extracellular and intracellular sources, decreased, in a dose-dependent manner, the percentage of couplets accumulating the fluorescent bile acid analogue cholyl-lysyl-fluorescein (CLF) in their canalicular vacuoles, i.e., in the canalicular vacuolar accumulation test (cVA of CLF), a measure of the overall capability of the couplets to secrete and retain CLF. To a similar extent, A23187 also decreased the percentage of couplets retaining CLF once secreted, i.e., in the canalicular vacuole retention test (cVR of CLF), a measure of tight junctional integrity. ATP (50 microM), another Ca(2+)-elevating compound, altered canalicular function in a similar extent to A23187. All these functional changes were prevented by H-7 in a dose-dependent manner. Canalicular dysfunction was accompanied by bleb formation and extensive redistribution of F-actin from the pericanalicular area to the cell body, which was also fully prevented by H-7; the intracellular Ca(2+) chelator, 1, 2-bis(o-aminophenoxy)-ethene-N,N,N',N'-tetraacetate tetrakis-(acetomethylester), (BAPTA/AM) (20 microM) had virtually the same preventive effects as H-7. Both H-7 and BAPTA/AM not only prevented but also reversed the decrease in cVA of CLF and blebbing induced by A23187. Thus, H-7 can both prevent and reverse Ca(2+)-mediated hepatocellular injury.

ANIT-induced disruption of biliary function in rat hepatocyte couplets.

alpha-Naphthylisothiocyanate (ANIT) induces intrahepatic cholestasis in rats, involving damage to biliary epithelial cells; our study aims to investigate whether disruption of biliary function in hepatocytes can contribute to early stages of ANIT-induced intrahepatic cholestasis. Isolated rat hepatocyte couplets were used to investigate biliary function in vitro by canalicular vacuolar accumulation (cVA) of a fluorescent bile acid analogue, cholyl-lysyl-fluorescein (CLF), within the canalicular vacuole between the two cells. After a 2-h exposure to ANIT, there was a concentration-dependent inhibition of cVA (cVA-IC50; 25 microM), but no cytotoxicity (LDH leakage or [ATP] decline) within this ANIT concentration range. There was no loss of cellular [GSH] at low ANIT concentrations, but, at 50 microM ANIT, a small but significant loss of [GSH] had occurred. Diethylmaleate (DEM) partially depleted cellular [GSH], but addition of 10 microM ANIT had no further effect on GSH depletion. Reduction in cVA was seen in DEM-treated cells; addition of ANIT to these cells reduced cVA further, but the magnitude of this further reduction was no greater than that caused by ANIT alone, indicating that glutathione depletion does not enhance the effect of ANIT. F-actin distribution (by phalloidin-FITC staining) showed an increased frequency of morphological change in the canalicular vacuoles but only a small, non-significant (0.05 < p < 0.1) increase in proportion of the F-actin in the region of the pericanalicular web. The results are in accord with a disruption of hepatocyte canalicular secretion within two h in vitro, at low, non-cytotoxic concentrations of ANIT, and the possible involvement of a thiocabamoyl-GSH conjugate of ANIT (GS-ANIT) in this effect.

Tauroursodeoxycholate and S-adenosyl-L-methionine exert an additive ameliorating effect on taurolithocholate-induced cholestasis: a study in isolated rat hepatocyte couplets.

The monohydroxy bile acid, taurolithocholate (TLC), causes cholestasis in vivo and in isolated perfused livers. It is also cholestatic in vitro and, in this study using isolated rat hepatocyte couplets, causes a reduction of the accumulation of (fluorescent) bile acid in the canalicular vacuoles (cVA) of this polarized cell preparation. The hepatoprotective bile acid, tauroursodeoxycholate (TUDCA), partially protects against the action of TLC when added at the same time. It also partially reverses the cholestatic effect if added after the cells have been exposed to TLC. A second hepatoprotective compound, S-adenosyl-L-methionine (SAMe) also not only partially protects against the action of TLC when added at the same time, but it too is able to partially reverse the cholestatic effect. Neither hepatoprotective agent is fully effective alone, but their effects are additive. In combination, a full restoration of cVA is observed in moderate cholestasis, but not in severe cholestasis. We discuss briefly some possible mechanisms involved in the additive mode of action of both hepatoprotective compounds. In summary, we show for the first time that SAMe and TUDCA can exert an additive effect in the amelioration of TLC-induced cholestasis in isolated rat hepatocyte couplets. This finding may be of possible clinical relevance.

Hepatobiliary effects of tertiary-butylhydroperoxide (tBOOH) in isolated rat hepatocyte couplets.

The organic hydroperoxide, tertiary-butylhydroperoxide (tBOOH), causes oxidative damage in a number of cell types. It is used here in an isolated rat hepatocyte couplet preparation to study adverse hepatobiliary effects of peroxidative damage in vitro. At subcytotoxic concentrations (as determined by lactate dehydrogenase release and maintenance of cytoplasmic ATP concentrations) tBOOH caused decreased accumulation of a fluorescent bile acid analogue, cholyl-lysyl-fluorescein (CLF), in the canalicular vacuole of couplets (a hepatobiliary effect; cholestasis). This was dose dependent in the range 100-200 microM. At the same concentrations it brought about release of preaccumulated CLF, suggesting that its effect was more likely to be on sealing properties of the vacuole than processes of uptake, transcytosis, and secretion. Pretreatment of tBOOH-treated couplets with the antioxidants deferoxamine mesylate (iron chelator) and dimethyl sulfoxide (free radical scavenger) resulted in the prevention of both canalicular vacuolar accumulation (cVA, which assesses canalicular function) and canalicular vacuolar retention (cVR, which assesses the retaining ability of couplets) depression at 100 microM tBOOH but not at higher concentrations. This indicates that the cholestatic effect of tBOOH has a preventable and nonpreventable phase and that free radicals are involved in these processes. By selectively generating the two types of tBOOH radical, peroxyl (tBOO.) and alkoxyl (tBO.), using suitable catalysts, we were able to determine that the peroxyl radical was most probably involved in tBOOH-induced cholestasis. This was further supported by experiments employing specific peroxyl and alkoxyl radical scavengers; only the peroxyl scavenger reduced the effect of tBOOH upon canalicular function under the conditions studied.

Urinary levels of neopterin and biopterin in autism.

The pterins, neopterin and biopterin, occur naturally in body fluids including urine. It is well established that increased neopterin levels are associated with activation of the cellular immune system and that reduced biopterins are essential for neurotransmitter synthesis. It has been suggested that some autistic children may be suffering from an autoimmune disorder. To investigate this further we performed high performance liquid chromatography analyses of urinary pterins in a group of pre-school autistic children, their siblings and age-matched control children. Both urinary neopterin and biopterin were raised in the autistic children compared to controls and the siblings showed intermediate values. This supports the possible involvement of cell-mediated immunity in the aetiology of autism.

CT-GUIDED FNAC AND BIOPSY : OUR EXPERIENCE.

Twenty five patients with mass lesions in the chest, abdomen, pelvis, and paraspinal region underwent contrast enhanced computed tomographic scan (CT Scan) followed by CT guided FNAC or Tru-cut biopsy. CT was found to be extremely valuable in ensuring needle placement within the lesion. It also helped in avoiding the necrotic areas and obtaining tissue from an area most likely to yield an adequate sample. A post-procedure scan helped in ruling out post-procedure complications.

Marriage conception interval.

The relationship between length of menstrual cycle and first birth interval is explored using data for 400 urban and 190 rural women in Lodha, India. The women were divided into three groups: urban women married before menarche, urban women married after menarche, and rural women married before menarche. The results indicate that "marriage-conception is delayed with longer menstrual cycles. Thus the females with longer menstrual cycle lengths appear to have a lesser chance of reproductive performances during the span of their reproductive life than those who are with shorter cycle lengths."