Surgical treatment of rectal prolapse.
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Humans↗
Biomedical subjects
C Cunningham
Publications and source records attributed to C Cunningham.
Preoperative chemoradiotherapy and total mesorectal excision surgery for locally advanced rectal cancer: correlation with rectal cancer regression grade.
PURPOSE: Preoperative long-course chemoradiotherapy is recommended for rectal carcinoma when there is concern that surgery alone may not be curative. Downstaging of the tumor can be measured as rectal cancer regression grade (1-3) and may be of importance when estimating the prognosis. The aim of this study was to look at the long-term results of tumor regression in patients receiving long-course chemotherapy before surgical resection of rectal cancer. METHODS: We reviewed those patients who received preoperative chemoradiotherapy followed by surgical resection for carcinoma of the mid rectum or distal rectum found to be stage T3/4 between January 1995 and November 1999. Patients received 45 to 50 Gy irradiation in 2-Gy fractions and an infusion of 5-fluorouracil. Surgical specimens were assessed for rectal cancer regression grade. Patients were followed up routinely with clinical examination, computed tomography, and colonoscopy. RESULTS: Sixty-five patients with a mean age 65 (range, 32-83) years underwent chemoradiotherapy before surgical resection. Thirty patients (46 percent) were classified as rectal cancer regression Grade 1, with 9 patients (14 percent) having complete sterilization of the tumor. Fifty-three patients (82 percent) underwent a curative resection. Overall survival, with a median follow-up of 39 (range, 24-83) months, was 67 percent and was associated with tumor downstaging. The local recurrence rate was 5.8 percent in those patients who underwent a curative resection and was significantly lower with rectal cancer regression Grade 1 tumors (P = 0.03). Eight of nine patients (89 percent) whose tumor had been sterilized were alive and well with no recurrence of tumor at a median follow-up of 41 (range, 24-70) months. CONCLUSIONS: Preoperative chemoradiotherapy resulted in significant regression of tumor. Overall survival was high and was associated with downstaging of tumor. The local recurrence rate was significantly lower with rectal cancer regression Grade 1 tumors and was not seen in patients with sterilized tumors.
Adenocarcinoma↗
Migration of a UV stabilizer from polyethylene terephthalate (PET) into food simulants.
The migration characteristics of the UV stabilizer Tinuvin 234 (2-(2H-benzotriazol-2-yl)-4,6-bis (1-methyl-1-phenylethyl)phenol) into food simulants has been measured from polyethylene terephthalate (PET) using HPLC with UV detection. Ethanol/ water, isooctane and a fractionated coconut oil simulant (Miglyol) were used as food simulating solvents. The migration characteristics were measured at temperatures in the range of 40-70 degrees C. Diffusion coefficients were determined to be in the range of 1 x 10(-14) cm2 s(-1) to 1 x 10(-18) cm2 s(-1). At 40 degrees C, the amount of migration into 95% ethanol after 10 days was 2 microg dm(-2). Isooctane is determined to be a good fatty food simulant that provides similar results for PET to those of fatty foods.
Chromatography, High Pressure Liquid↗
Neuropil and neuronal changes in hippocampal NADPH-diaphorase histochemistry in the ME7 model of murine prion disease.
Nitric oxide (NO) has been implicated in neurotoxicity and cerebral blood flow changes in chronic neurodegeneration, but its activity in the mammalian prion diseases has not been studied in detail. Nicotine adenine dinucleotide phosphate (NADPH)-diaphorase (NADPH-d) histochemistry is a simple and robust histochemical procedure that allows localization of the tissue distribution of NO synthases. The aim of the present study is to assess whether NADPH-d histochemical activity is altered in the hippocampus in the ME7 model of prion disease in C57BL/6J mice. At early and late stages after the initiation of the disease we assessed features of the NADPH-d positive cells and the neuropil histochemical activity in CA1 and dentate gyrus using densitometric analysis. In C57BL/6J mice 13 weeks postinjection of the prion agent ME7, when behavioural changes first become apparent, neuropil NADPH-d histochemical staining increases, whereas at late stages it decreases dramatically. Both type I and type II NADPH-d positive cells were found to survive throughout the hippocampal formation into the late stages of the disease, but diaphorase activity was reduced in dendritic branches and abnormal varicosities were present in both dendritic and axonal processes of NADPH-d positive type I cells. The pathophysiological implications of the results remain to be investigated but both blood flow alteration and NO neurotoxicity may be features of the disease.
Algorithms↗
Cross-sectional survey of the extent and indicators of hepatitis C virus infection in Houston Department of Health and Human Services' sexually transmitted disease clinics.
To evaluate the prevalence and indicators of hepatitis C virus (HCV) infection in Houston and determine the effectiveness of targeted HCV screening in sexually transmitted disease (STD) clinics. We performed a cross-sectional survey in low-risk and high-risk groups in Houston. This included a blinded survey of HCV conducted in 1010 STD clinic clients having serological syphilis tests, and 1885 multi-speciality group practice patients having metabolic blood work. This was followed with a targeted hepatitis C survey of 822 high-risk clients from STD clinics. The seroprevalence of hepatitis C infection in the blinded survey was 3.9% (95% CI 3.0-4.8) in the multi-speciality group and 5.0% (95% CI 3.7-6.3) in the STD clinics. Prevalence of hepatitis C infection among targeted STD clinic clients was significantly higher at 15.3% (95% CI 12.7-17.7). Risk factors that correlated with HCV infection after logistic regression included: injection drug use (OR = 10, 95% CI = 3.4-30.3), heroin use (OR = 6.6, 95% CI = 2.2-20.5), non-transfusion/ transplantation blood exposure (OR = 3.0, 95% CI = 1.3-6.9), sharing equipment to snort drugs (OR = 2.5, 95% CI 1.2-5.4), and age above 25 years (OR = 51, 95% CI = 9-47). This study demonstrates that targeting clients in STD clinics for known risk behaviours is an effective way to identify cases of HCV infection. STD clinics allow access to clients with both drug use and sexual risk behaviours and are a useful location for targeting hepatitis C screening and prevention efforts.
Adolescent↗
Synaptic changes characterize early behavioural signs in the ME7 model of murine prion disease.
Prion diseases are fatal, chronic neurodegenerative diseases of mammals, characterized by amyloid deposition, astrogliosis, microglial activation, tissue vacuolation and neuronal loss. In the ME7 model of prion disease in the C57BL/6 J mouse, we have shown previously that these animals display behavioural changes that indicate the onset of neuronal dysfunction. The current study examines the neuropathological correlates of these early behavioural changes. After injection of ME7-infected homogenate into the dorsal hippocampus, we found statistically significant impairment of burrowing, nesting and glucose consumption, and increased open field activity at 13 weeks. At this time, microglia activation and PrPSc deposition was visible selectively throughout the limbic system, including the hippocampus, entorhinal cortex, medial and lateral septum, mamillary bodies, dorsal thalamus and, to a lesser degree, in regions of the brainstem. No increase in apoptosis or neuronal cell loss was detectable at this time, while in animals at 19 weeks postinjection there was 40% neuronal loss from CA1. There was a statistically significant reduction in synaptophysin staining in the stratum radiatum of the CA1 at 13 weeks indicating loss of presynaptic terminals. Damage to the dorsal hippocampus is known to disrupt burrowing and nesting behaviour. We have demonstrated a neuropathological correlate of an early behavioural deficit in prion disease and suggest that this should allow insights into the first steps of the neuropathogenesis of prion diseases.
Animals↗
Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer's disease.
Activated microglia, the resident macrophages of the brain, are a feature of Alzheimer's disease. Animal models suggest that when activated microglia are further activated by a subsequent systemic infection this results in significantly raised levels of interleukin 1beta within the CNS, which may in turn potentiate neurodegeneration. This prospective pilot study in Alzheimer's disease subjects showed that cognitive function can be impaired for at least two months after the resolution of a systemic infection and that cognitive impairment is preceded by raised serum levels of interleukin 1beta. These relations were not confounded by the presence of any subsequent systemic infection or by baseline cognitive scores. Further research is needed to determine whether recurrent systemic infections drive cognitive decline in Alzheimer's disease subjects through a cytokine mediated pathway.
Aged↗
Legibility and authorship of clinical notes.
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Authorship↗
Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease.
Peripheral infections in mammals are characterised by local, systemic and CNS effects. The latter give rise to sickness behaviour. Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) are thought to be important mediators of this neuro-immune signalling (Cartmell et al., 1999). There is anecdotal evidence suggesting that peripheral infections in patients with Alzheimer's disease have more severe behavioural consequences than those in otherwise healthy elderly subjects, and it is well known that brain microglia are activated in the elderly and in Alzheimer's disease (McGeer et al., 1987). Using ME7-induced murine prion disease as a model of chronic neurodegeneration that displays chronic microglial activation, and the intra-peritoneal injection of bacterial lipopolysaccharide to mimic a peripheral infection, we have shown that the temperature and activity responses of animals with pre-clinical prion disease were exaggerated compared with controls, and that this was associated with a significant increase in brain levels of IL-1beta. We hypothesise that prior priming of microglia by the degenerative process, followed by further activation through signalling from the periphery, resulted in increased brain IL-1beta synthesis and the consequent acute sickness behavioural responses. These findings demonstrate an interaction between peripheral infection and pre-existing CNS inflammation and suggest that further stimulation of an already primed microglial population by a peripheral infection may drive disease progression in chronic inflammatory conditions such as Alzheimer's disease and prion disease.
Animals↗
JC virus: a biomarker for colorectal cancer?
Chromosomal instability (CIN) is present in most colorectal cancers, though the mechanism for these genetic aberrations is unclear. An explanation may lie in the possible link between JC virus (JCV) Mad-1 strain, found in colorectal cancers, and aneuploid neoplasia. It is proposed here to test the hypothesis that detection of JCV in colorectal cancer patients may serve as a clinically useful biomarker for the presence of colorectal tumors. This may be tested by looking for any correlation that may exist between JCV DNA, viral proteins, and anti-JCV anti-sera detected in samples of stool, blood, and urine obtained from patients with colorectal neoplasm compared with normal age-matched controls.
Biomarkers↗
Transforming growth factor beta1, the dominant cytokine in murine prion disease: influence on inflammatory cytokine synthesis and alteration of vascular extracellular matrix.
Previous studies from our laboratory have shown the ME7 model of murine scrapie to be accompanied by an atypical inflammatory response that is characterized by marked astroglial and microglial activation but also by the lack of significant expression of the pro-inflammatory cytokines interleukin (IL)-1beta and IL-6. The aim of this study was to determine whether, in the absence of IL-1beta and IL-6, tumour necrosis factor (TNF)-alpha may play an equivalent pro-inflammatory role, or if an anti-inflammatory cytokine profile dominates. We have used competitive polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) to determine the levels of TNF-alpha, IL-10 and transforming growth factor (TGF)-beta1 in the ME7 model, using their expression in lipopolysaccharide (LPS)-induced acute inflammation as a positive control. Levels of mRNA were elevated for all three cytokines during acute inflammation, while TGF-beta1 mRNA alone was significantly elevated in ME7-injected brains. Similarly, by ELISA, we detected elevated IL-10, TNF-alpha and TGF-beta1 in LPS-injected animals but only significant elevation of TGF-beta1 in ME7-injected animals. An increase in laminin and collagen IV deposition around blood vessels was also observed and is consistent with up-regulation by active TGF-beta1. These findings suggest that TGF-beta1 may play a central role in maintenance of an atypical microglial phenotype and may also be involved in vascular and extracellular matrix changes.
Animals↗
Neutralisation and binding of VHS virus by monovalent antibody fragments.
We have previously reported the cloning and characterisation of the heavy and light chain variable domain genes encoding three monoclonal antibodies (Mabs) that bind viral haemorrhagic septicaemia virus (VHSV). Two of these antibodies, 3F1H10 and 3F1A2 both neutralised the virus though 3F1A2 appeared to recognise a broader range of virus isolates. The variable domains of these two antibodies differ by only four residues (Lorenzen et al., 2000a. Fish Shellfish Immunol. 10, 129-142). To further study the mechanism of neutralisation, Fab fragments as well as a series of recombinant bacterial single chain antibody (scAb) fragments were generated from the three anti-VHSV Mabs and their variable domain genes, respectively. Fabs and scAbs derived from the neutralising Mabs were both able to neutralise the VHSV type 1 isolate DK-F1. In addition, a series of scAb fragments were produced using the 3F1H10 variable heavy (VH) chain and variable light (Vkappa) chain domains but containing, either alone or in dual combination, each of the four different residues present in 3F1A2. The dissociation constants of Mabs 3F1H10 and 3F1A2 and their respective Fab and scAb fragments were measured by BIAcore analysis and found to correlate with the capacity of each molecule to neutralise DK-F1. These investigations, together with computer assisted molecular analysis of the theoretical influence of each mutation on antigen binding, led to the identification of a single mutation at position 35a in the VH domain as having the most marked impact on viral neutralisation.
Animals↗
Neuropsychological assessment in children with absence epilepsy.
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Bias↗
Human immunodeficiency virus type 1 (HIV-1) gp120-specific antibodies in neonates receiving an HIV-1 recombinant gp120 vaccine.
Infants born to human immunodeficiency virus type 1 (HIV-1)-infected mothers were immunized at birth and at ages 4, 12, and 20 weeks with low-, medium-, or high-dose recombinant gp120 vaccine with MF59 adjuvant (HIV-1(SF-2); n=52) or with MF59 alone as a placebo (n=9). An accelerated schedule (birth and ages 2, 8, and 20 weeks) was used for an additional 10 infants receiving the defined optimal dose and for 3 infants receiving placebo. At 24 weeks, anti-gp120 ELISA titers were greater for vaccine-immunized than for placebo-immunized infants on both schedules, and 87% of vaccinees had a vaccine-induced antibody response. At 12 weeks, antibody titers of infants on the accelerated vaccine schedule exceeded those of infants receiving placebo (4949 vs. 551; P=.01), and 63% of the vaccinees met the response criteria. Thus, an accelerated schedule of gp120 vaccinations generated an antibody response to HIV-1 envelope distinct from transplacental maternal antibody by age 12 weeks. These results provide support for further studies of vaccine strategies to prevent mother-to-infant HIV-1 transmission.
AIDS Vaccines↗
The production and bioactivity of rainbow trout (Oncorhynchus mykiss) recombinant IL-1 beta.
The predicted rainbow trout mature interleukin-1 beta (IL-1 beta) peptide has been produced as a recombinant protein in E. coli. The bioactivity of this molecule has been studied using trout head kidney cell preparations and a trout macrophage cell line (RTS11). Trout rIL-1 beta was shown to increase the expression level of IL-1 beta, cyclooxygenase (COX2) and MHC class II beta chain transcription, as determined by Northern blot analysis. Stimulatory doses of rIL-1 beta were typically > or =10 ng/ml. Induction of IL-1 beta expression occurred within 1h post-stimulation with trout rIL-1 beta and was maximal 3-6h post-stimulation. Trout rIL-1 beta was also able to increase murine D10.G4.1 cell proliferation and trout head kidney leukocyte phagocytic activity, in a dose-dependent manner. However, equivalent D10.G4.1 cell proliferation was induced with approximately 1000-fold lower doses of human rIL-1 beta. That LPS contamination did not contribute to the effects seen was confirmed by determining its concentration in the trout rIL-1 beta preparation, and demonstrating that the rIL-1 beta activity was inhibited by heating or pre-incubation with a polyclonal anti-trout rIL-1 beta antibody.
Animals↗
A phase I trial of genetically modified Salmonella typhimurium expressing cytosine deaminase (TAPET-CD, VNP20029) administered by intratumoral injection in combination with 5-fluorocytosine for patients with advanced or metastatic cancer. Protocol no: CL-017. Version: April 9, 2001.
An attenuated strain of Salmonella typhimurium, designated VNP20009, was generated by deletion of the msbB and purl genes. When VNP20009 was administered intravenously (IV) to mice bearing spontaneous, syngeneic, or human xenograft tumors, the bacteria accumulated preferentially within the extracellular components of tumors, forming tumor-to-normal tissue ratios exceeding 300-1000 to 1. NVP20009 was administered safely at doses up to 2.5 x 10(9) cfu/kg in monkey toxicology studies. Based on the preclinical data, VNP20009 entered Phase I human clinical trials in November 1999, and has now been administered to >45 patients by IV or direct intratumoral injection. By the intratumoral route, a maximum tolerated dose has not been reached, and dose escalation continues past the current dose level of 4 x 10(7)/m2. Furthermore, VNP20009 persisted in injected tumors for at least 2 weeks in 8/11 patients treated to date. By 30-min IV administration, a maximum tolerated dose (MTD) of 3 X 10(8) cfu/m2 has been established. In all patients treated to date, VNP20009 was not shed in urine or stool. VNP20009 has been further modified by chromosomal insertion of an E. coli cytosine deaminase (CD) gene at the deltamsbB locus which, when expressed, converts 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU). The CD containing VNP20009 was designated TAPET-CD or VNP20029. TAPET-CD had similar efficacy and safety in murine tumor models and similar safety profiles in animal toxicology studies, compared to its parent VNP20009. Specifically, TAPET-CD had a reduced virulence of >10,000 fold, when compared to the wild-type Salmonella strain. It was well-tolerated at doses up to 2 x 10(6) cfu/mouse and 1 X 10(10) cfu/monkey. After an IV or direct tumor injection to tumor-bearing mice, TAPET-CD reached tumor levels as high as 10(8)-10(9) cfu/gm. When compared to the accumulation in liver or spleen, the normal tissues with the greatest colonization of TAPET-CD, tumor-to-normal tissue ratios of TAPET-CD were 300-1000 to 1. TAPET-CD also caused tumor growth inhibition of >90% in several murine tumor models. When 5-FC was administered by intraperitoneal (IP) injection once or 3 times daily to tumor-bearing mice that had been pre-treated with TAPET-CD, high levels of 5-FU (reaching 20-40 microM/g) were detected in the tumor, with low or undetectable 5-FU levels in normal tissues (e.g., spleen, liver, etc.). Furthermore, co-administration of 5-FC and TAPET-CD in 4 different murine tumor models enhanced anti-tumor activity compared to the significant anti-tumor activity of TAPET-CD alone, further confirming the benefit of the inserted CD gene. On the basis of the preclinical data, a Phase I clinical protocol is proposed in which advanced cancer patients will receive TAPET-CD by direct intratumoral injection and 5-FC. TAPET-CD will be administered on day 1. 5-FC will be given orally q8h daily beginning day 4 or when all toxicities of TAPET-CD have resolved to < or = grade 1, and continued for 14 days. Tumor tissues will be sampled to verify TAPET-CD colonization and to measure intratumoral 5-FC and 5-FU concentrations on day 8. A second sample of tumor tissue will be obtained between day 15-17 in selected patients to confirm the persistence of high levels of bacteria in tumor and to obtain a second measurement of 5-FC and 5-FU intra-tumoral concentrations. The TAPET-CD/5-FC treatment cycle will be repeated in appropriate patients on day 29.
Acyltransferases↗
Prevalence of HTLV-I-associated T-cell lymphoma.
In order to assess the prevalence rate of HTLV-1-associated T-cell lymphomas and human retrovirus infection in general, approximately 21,000 individuals representing various patient populations, retroviral risk groups, and blood donors were examined for HTLV-I, HTLV-II, HIV-1, or HIV-2 infection using serologic and PCR assays. The prevalence rates among volunteer blood donors were 0.02% and 0% for HTLV and HIV, respectively. Significantly increased HTLV prevalence rates were observed among paid blood donors, African American health care clinic patients, Amerindians, recipients of HTLV-positive cellular blood products, intravenous drug users, sexual contacts and family members of HTLV-positive people, and patients with primary thrombocytosis and other-than-low-grade non-Hodgkin's lymphoma (NHL). Among some of these groups there were significant differences in the prevalence of HTLV-I versus HTLV-II. The eight HTLV-positive NHL patients all had mature, high-grade, CD4+ T-cell lymphomas with clonally integrated HTLV-I, for a prevalence of 4% among other-than-low-grade NHL patients. Seven of the eight died from their disease within 2 years despite treatment. Interestingly, two groups at risk for HTLV infection, namely needle stick victims and recipients of HTLV-infected and/or pooled plasma products, showed no evidence for infection. Significantly increased HIV-1 prevalence was observed among paid blood donors, African Americans, homosexuals, female prostitutes, hemophiliacs, and other-than-low-grade NHL patients. Only one patient was infected with HIV-2. Of the nine HIV-positive, other-than-low-grade NHL patients, seven HIV-1 positives had B-cell lymphomas, one HIV-1 positive had an HTLV-I-positive CD4+ T-cell lymphoma, and one infected with HIV-2 had a CD4+ T-cell lymphoma that was HTLV negative. The data indicate that HTLV-I lymphoma, while uncommon, is not necessarily rare among other-than-low-grade NHL cases in the United States and, given its poor prognosis, should probably be studied separately in clinical trials.
Black or African American↗
Verbal aggression in Alzheimer's disease. Clinical, functional and neuropsychological correlates.
OBJECTIVES: To determine the clinical, functional and neuropsychological correlates of verbal aggression in Alzheimer's disease in a group of consecutive first attendees to a memory clinic. METHODS: 150 people were evaluated and diagnosed as suffering with probable Alzheimer's disease. These people were tested using the Behave-AD for the presence of verbal aggression, delusions, depression and agitation. They were also assessed with cognitive, functional and neuropsychological scales. RESULTS: Twenty-eight per cent of this group of Alzheimer patients had exhibited some verbal aggression in the preceding month. Male gender (p = 0.022), the presence of paranoid and delusional ideation (p = 0.003) and agitation (p = 0.042) were significantly associated with verbal aggression in a stepwise backward logistic regression analysis. CONCLUSION: The presence of verbal aggression should prompt the clinician to search for delusional ideation, which may respond to pharmacotherapy.
Aged↗