Investigating the secondary care system burden of CRSwNP in sinus surgery patients with clinically relevant comorbidities using the HES database.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic condition that can adversely affect quality of life for patients. There is no cure for CRSwNP, and patients may require intermittent systemic corticosteroids (SCS) and surgery in addition to intranasal treatment throughout their lifetime. This places a significant burden on the NHS which can be compounded by comorbid conditions such as asthma or NSAID-exacerbated respiratory disease (NERD). Patients with comorbidities are likely to experience higher rates of surgery and more secondary care visits. The aim of this study was to evaluate revision rates and the associated burden for patients with CRSwNP undergoing surgery and compare this to sub-cohorts of patients with comorbidities. MATERIALS AND METHODS: This study has utilised the Hospital Episodes Statistics (HES) database across a ten-year time period (April 2010 to March 2020) to investigate the NHS resource use attributable to CRSwNP for all patients with the condition who have undergone sinus surgery, and to examine the burden of clinically relevant sub-groups. RESULTS: Our results showed that 101,054 patients underwent at least one sinus surgery in relation to their nasal polyps, with Kaplan Meier survival analysis estimating that the 10-year probability of revision is between 71-90% for comorbid patients, and 51% for non-comorbid patients. Patients with a relevant comorbid condition in addition to their CRSwNP were up to 4.7 times more likely to undergo at least one revision surgery during the ten-year analytical time window when compared to patients without a comorbidity. Further to this, comorbid patients had a higher tariff associated with their CRSwNP care across the analytical time window and were therefore likely to be more costly to the healthcare system. CONCLUSIONS: In conclusion, this study demonstrates that there is a high burden attached to CRSwNP-related sinus surgery and that comorbidities are a key driver of NHS resource use.

The effect of anesthetic technique on µ-opioid receptor expression and immune cell infiltration in breast cancer.

BACKGROUND: Clinical histological studies demonstrate that the distribution of natural killer (NK) cells, other immune cells and µ-opioid receptors (MOR) within cancer tissue can predict cancer prognosis. No clinical study has evaluated whether anesthetic technique influences immune cell and MOR expression within human breast cancer. METHODS: Excised preoperative biopsies and intraoperative breast cancer specimens from 20 patients randomly chosen from patients previously enrolled in an ongoing, prospective, randomized trial (NCT00418457) investigating the effect of anesthetic technique on long-term breast cancer outcome were immunohistochemically stained and microscopically examined by two independent investigators, masked to randomization, to quantify MOR and immune cell infiltration: CD56, CD57 (NK cells), CD4 (T helper cells), CD8 (cytotoxic T cells) and CD68 (macrophages). Patients had been randomized to receive either a propofol-paravertebral anesthetic with continuing analgesia (PPA, n = 10) or balanced general anesthetic with opioid analgesia (GA, n = 10). RESULTS: There were no differences between the groups in staining intensity in preoperative biopsy specimens. Expression intensity values (median 25-75%) for MOR in intraoperative resected biopsy were higher in GA 8.5 (3-17) versus PPA 1 (0-10), p = 0.04. The numbers of MOR-positive cells were also higher in GA patients. Expression and absolute numbers of CD56, CD57, CD4 and CD68 were similar in resected tumor in both groups. CONCLUSION: General anesthesia with opioid analgesia increased resected tumor MOR expression compared with propofol-paravertebral anesthetic technique, but the anesthetic technique did not significantly influence the expression of immune cell markers.

Investigation of contact acoustic nonlinearities on metal and composite airframe structures via intensity based health monitoring.

Nonlinear structural intensity (NSI) and nonlinear structural surface intensity (NSSI) based damage detection techniques were improved and extended to metal and composite airframe structures. In this study, the measurement of NSI maps at sub-harmonic frequencies was completed to provide enhanced understanding of the energy flow characteristics associated with the damage induced contact acoustic nonlinearity mechanism. Important results include NSI source localization visualization at ultra-subharmonic (nf/2) frequencies, and damage detection results utilizing structural surface intensity in the nonlinear domain. A detection metric relying on modulated wave spectroscopy was developed and implemented using the NSSI feature. The data fusion of the intensity formulation provided a distinct advantage, as both the single interrogation frequency NSSI and its modulated wave extension (NSSI-MW) exhibited considerably higher sensitivities to damage than using single-sensor (strain or acceleration) nonlinear detection metrics. The active intensity based techniques were also extended to composite materials, and results show both NSSI and NSSI-MW can be used to detect damage in the bond line of an integrally stiffened composite plate structure with high sensitivity. Initial damage detection measurements made on an OH-58 tailboom (Penn State Applied Research Laboratory, State College, PA) indicate the techniques can be transitioned to complex airframe structures achieving high detection sensitivities with minimal sensors and actuators.

Apoptosome-dependent caspase activation proteins as prognostic markers in Stage II and III colorectal cancer.

BACKGROUND: Critical to successful execution of mitochondrial-mediated apoptosis is apoptosome formation and subsequent activation of caspases. Defects in this pathway have an important role in colorectal carcinogenesis and chemoresistance; therefore, the expression of apoptosome-associated proteins may be associated with clinical outcome and response to chemotherapy. METHODS: Here we performed a systematic analysis of the immunohistochemical expression of the key proteins involved in apoptosome-dependent caspase activation (APAF1, Pro-caspases 9 and 3, SMAC, and XIAP) in a cohort of Stage II and III colorectal cancer patients from a Phase III trial of adjuvant 5-fluorouracil-based chemotherapy vs postoperative observation alone. RESULTS: Survival analysis indicated that of the apoptosome-associated proteins examined here, Pro-caspase 3 and APAF1 have potential clinical utility as predictive markers in Stage II and III colorectal cancer, respectively. Interestingly, we identified APAF1 staining to be associated with better recurrence-free and overall survival in patients receiving chemotherapy. CONCLUSION: These studies reveal the importance of the apoptosome-dependent caspase activation pathway, specifically Pro-caspase 3 and APAF1 proteins, for predicting both prognosis and response to therapy.

The expression and prognostic impact of CXC-chemokines in stage II and III colorectal cancer epithelial and stromal tissue.

BACKGROUND: The CXC-chemokine expression is linked with colorectal cancer (CRC) progression but their significance in resected CRC is unclear. We explored the prognostic impact of such expression in stage II and III CRC. METHODS: Tissue microarrays were constructed from stage II and III CRC biopsies (n=254), and the expression of CXCL1 and CXCL8, and their receptors CXCR1 and CXCR2, in malignant and adjacent normal tissue was graded by immunohistochemistry and was correlated with prognostic factors. RESULTS: Expression of CXCL1, CXCR1 and CXCR2 was elevated in tumour epithelium relative to normal adjacent tissue (P<0.001). CXCL8 expression was detectable in the peritumoural inflammatory infiltrate. There was no overall association between CXCL1, CXCR1 or CXCR2 expression and prognostic endpoints; however, univariate subgroup survival analysis demonstrated an inverse association between CXCL1 and recurrence-free survival (RFS) in stage III patients (P=0.041). The CXCL8 positivity in the tumour infiltrate, however, correlated with earlier disease stage (P<0.001) and improved relapse-free survival across the cohort (P<0.001). Disease stage (P<0.001) and tumour infiltrate CXCL8 positivity (P=0.007) were associated with enhanced RFS in multivariate Cox regression analysis. CONCLUSION: Autocrine CXC-chemokine signalling may have adverse prognostic effects in early CRC. Conversely, CXCL8 positivity within the immune infiltrate may have good prognostic significance.

Collagenous colitis as a possible cause of toxic megacolon.

Collagenous colitis is a microscopic colitis characterized by normal appearing colonic mucosa on endoscopy. It is regarded as a clinically benign disease which rarely results in serious complications. We report a case of toxic megacolon occurring in a patient with collagenous colitis. This is the first reported case of toxic megacolon occurring in this subset of patients.

Predicting the vibroacoustic response of satellite equipment panels.

Modern satellites are constructed of large, lightweight equipment panels that are strongly excited by acoustic pressures during launch. During design, performing vibroacoustic analyses to evaluate and ensure the integrity of the complex electronics mounted on the panels is critical. In this study the attached equipment is explicitly addressed and how its properties affect the panel responses is characterized. FEA and BEA methods are used to derive realistic parameters to input to a SEA hybrid model of a panel with multiple attachments. Specifically, conductance/modal density and radiation efficiency for nonhomogeneous panel structures with and without mass loading are computed. The validity of using the spatially averaged conductance of panels with irregular features for deriving the structure modal density is demonstrated. Maidanik's proposed method of modifying the traditional SEA input power is implemented, illustrating the importance of accounting for system internal couplings when calculating the external input power. The predictions using the SEA hybrid model agree with the measured data trends, and are found to be most sensitive to the assumed dynamic mass ratio (attachments/structure) and the attachment internal loss factor. Additional experimental and analytical investigations are recommended to better characterize dynamic masses, modal densities and loss factors.

Regulation of citrulline recycling in nitric oxide-dependent neurotransmission in the murine proximal colon.

1. We investigated the contribution of nitric oxide (NO) to inhibitory neuromuscular transmission in murine proximal colon and the possibility that citrulline is recycled to arginine to maintain the supply of substrate for NO synthesis. 2. Intracellular microelectrode recordings were made from circular smooth muscle cells in the presence of nifedipine and atropine (both 1 microM). Electrical field stimulation (EFS, 0.3-20 Hz) produced inhibitory junction potentials (i.j.ps) composed of an initial transient hyperpolarization (fast component) followed by a slow recovery to resting potential (slow component). 3. L-Nitro-arginine-methyl ester (L-NAME, 100 microM) selectively abolished the slow component of i.j.ps. The effects of L-NAME were reversed by L-arginine (0.2-2 mM) but not by D-arginine (2 mM). Sodium nitroprusside (an NO donor, 1 microM) reversibly hyperpolarized muscle cells. This suggests that NO mediates the slow component of i.j.ps. 4. L-Citrulline (0.2 mM) also reversed the effects of L-NAME, and this action was maintained during sustained exposures to L-citrulline (0.2 mM). This may reflect intraneuronal recycling of L-citrulline to L-arginine. 5. Higher concentrations of L-citrulline (e.g. 2 mM) had time-dependent effects. Brief exposure (15 min) reversed the effects of L-NAME, but during longer exposures (30 min) the effects of L-NAME gradually returned. In the continued presence of L-citrulline, L-arginine (2 mM) readily restored nitrergic transmission, suggesting that during long exposures to high concentrations of L-citrulline, the ability to generate arginine from citrulline was reduced. 6. Aspartate (2 mM) had no effect on i.j.ps, the effects of L-NAME, or the actions of L-citrulline in the presence of L-NAME, L-Citrulline (0.2-2 mM) alone had no effect on i.j.ps under control conditions. 7. S-methyl-L-thiocitrulline (10 microM), a novel NOS inhibitor, blocked the slow component of i.j.ps. The effects of this inhibitor were reversed by L-arginine (2 mM), but not by L-citrulline (2 mM). 8. These results suggest that i.j.ps in the murine colon result from release of multiple inhibitory neurotransmitters. NO mediates a slow component of enteric inhibitory neurotransmission. Recycling of L-citrulline to L-arginine may sustain substrate concentrations in support of NO synthesis and this pathway may be inhibited when concentrations of L-citrulline are elevated.

The Yarrowia lipolytica LEU2 gene.

A 2810 bp DNA fragment containing the beta-isopropylmalate dehydrogenase gene of the dimorphic yeast Yarrowia lipolytica has been sequenced. The sequence contains an open reading frame of 405 codons, predicting a protein of 43,366 molecular weight. Protein sequence homology with the polypeptide encoded by the LEU2 gene of Saccharomyces cerevisiae is 64%, whereas DNA sequence homology is 61%. The 5'- and 3'-flanking regions of the Y. lipolytica LEU2 gene share only some general structural features common to genes of S. cerevisiae such as the presence and location of TATA boxes, CAAT boxes, CACACA repeats, the lack of G residues in the 5'-untranslated region and 3'-transcription terminators. Transcription of a 1.4 kb mRNA begins at a small cluster of sites approximately 40 base pairs before the initial ATG.

Initiation of genetic recombination: homologous pairing between duplex DNA molecules promoted by recA protein.

recA protein has been shown to promote hydrogen bonding between single-stranded DNA fragments and duplex DNA molecules homologous to them. However, genetic and biochemical evidence indicates that genetic exchanges generally take place between duplex molecules. We therefore chose to study the interactions promoted by recA protein between intact duplex DNA molecules and molecules containing gaps that are believed to increase the frequency of genetic exchanges. In the present paper, we show that incubation of intact and gap-containing plasmid DNA in the presence of recA protein leads to homologous pairing between duplex molecules which can be detected by centrifugation analysis and electron microscopy. The reaction is completely dependent on an active recA gene product, on genetic homology between the DNA species involved, and on the presence of ATP; under certain conditions, its efficiency can be increased considerably by the presence of the single-stranded DNA binding protein of Escherichia coli.

Initiation of DNA synthesis in mammary epithelium and mammary tumors by lithium ions.

The growth promoting effects of lithium and insulin on cultures of mammary gland epithelium and CZF mouse mammary tumor cells were investigated. Lithium chloride exerts a 450-fold increase in the rate of DNA synthesis in mammary epithelium from mid-pregnant mice in organ culture or monolayer culture. There is an increase in both the percentage of cells initiating DNA synthesis and the net accumulation of DNA. The most effective lithium concentration is 10 mM, and the maximally effective rate of stimulation is reached 48 hours after addition. The magnitude of response to lithium varies with the physiological state of the mammary epithelial cell donor: epithelium from non-pregnant or lactating mice is less responsive than that from mid-pregnant mice. In combination, insulin and lithium produce either a synergistic or an additive effect on the growth of epithelium dependent upon the physiological state of the donor animal. Lithium also promotes the growth of mammary tumor cells in the absence or serum or other mitogens. The action of lithium on DNA synthesis appears to be a direct effect on the epithelial cells.