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Biomedical subjects

D Little

Publications and source records attributed to D Little.

At least 19 recordsLinked to original sources
PubMed2006

Review of deaths related to analgesic- and cough suppressant-opioids; England and Wales 1996-2002.

OBJECTIVE: The data on England and Wales voluntarily supplied by Coroners to the National Programme on Substance Abuse Deaths for the August 1996-December 2002 time frame were analyzed. METHODS: All cases in which at least one analgesic- and cough suppressant-opioid other than heroin/morphine, methadone or buprenorphine was identified were extracted from the database. We hypothesized that: a) populations of addicts and non-addicts presented differences in patterns of drugs involved; and b) within the population of addicts and non-addicts, intentional and non-intentional deaths presented different patterns of substance consumption. RESULTS: A total of 2024 deaths related to selected opioids, either alone or in combination, were included in the analysis. Typically, non-addicts were older than 45 and died as a result of intentional poisoning whilst majority of addicts were young, males and victims of accidental deaths. In about 93% of cases the selected opioids were reported in combination with another substance. Most frequently identified narcotics were propoxyphene, codeine and dihydrocodeine. Co-proxamol, Co-codamol and Co-dydramol were typically prescribed for non-addicts, whilst dihydrocodeine was mostly given to addicts. In non-addicts, alcohol was mostly represented in accidental deaths and antidepressants were typically represented in intentional deaths. Conversely, illicit drugs and hypnotics/sedatives were typically reported in addicts' accidental deaths. CONCLUSIONS: The present report constitutes the largest available collection of analgesic- and cough suppressant-opioid mortality data in the UK. Users should be educated about risks associated with polydrug misuse.

Adult↗
PubMed2006

Mucosal permeability of water-soluble drugs in the equine jejunum: a preliminary investigation.

Ussing chambers have been used to study the mucosal permeability of drugs in humans, rats and other species. This data can then be used to develop in vitro/in vivo correlations (IVIVC) for drugs based on the Biopharmaceutics Classification System (BCS). Due to the poor oral bioavailability of many drugs in the horse, this method may be useful for screening drugs before development to determine if they warrant further study. Cephalexin (CPX), marbofloxacin (MAR), metronidazole (MTZ) and fluconazole (FCZ) were chosen for this study based on the wide range of physicochemical properties and bioavailability in the horse. Permeability was ranked as follows: MTZ > FCZ > MAR > CPX. This correlated with the bioavailability (R(2) = 0.633447), the Log P (R(2) = 0.648517), as well as the molecular weight (R(2) = 0.851208) of the drugs. Metronidazole induced a decrease in the tissue transepithelial resistance, suggestive of the possibility of tissue toxicity, which may have falsely increased its permeability. The low permeability of cephalexin across the tissue may indicate a lack of active transporters that are found in other species. From this study, we can conclude that the Ussing chamber is a promising method for determining mucosal permeability in the horse.

Animals↗
PubMed2005

Pancreas transplantation in Ireland.

BACKGROUND: We report on our experience of pancreatic transplants performed in Beaumont Hospital from 1992 to January 2003. During this period, 63 pancreatic transplants were carried out. Simultaneous pancreas and kidney transplantation is regarded as the treatment of choice for Type 1 diabetics with end stage renal failure (ESRF) by the American Diabetes Association. METHODS: A retrospective review of all the pancreas transplants between 1992 and January 2003 was carried out. All of the patients had insulin-dependent diabetes mellitus (IDDM) and, in addition, 57 of the recipients had concomitant end stage renal failure. For two of the patients, this was a second transplant, one of them having had a previous renal graft which thrombosed. The second patient underwent a simultaneous pancreas and kidney (SPK) transplant in 1998 with loss of the pancreatic graft shortly afterwards. She subsequently received a pancreas only transplant in 2002. RESULTS: The follow-up period ranges from one month to ten years and parameters used to assess graft function include Hb A1c and serum creatnine (SPK only). There have been 22 graft losses (six kidneys, nine pancreases and seven involving both the kidney and pancreas), to date. The one-year graft survival was 80.4% (pancreas) and 92.7% (kidney), with a one-year patient survival of 94.8%, which compares favourably with figures from other centres. At follow-up, the average Hb A1c at six months post-transplant was 5.7% with a serum creatnine of 121micmol/L being recorded at one month. CONCLUSION: Our experience of pancreas transplants at Beaumont Hospital has been very encouraging with graft and patient survival equivalent to other international centres.

Adult↗
PubMed2005

Detection of differentially regulated genes in ischaemic equine intestinal mucosa.

REASONS FOR PERFORMING STUDY: Colic is a serious disease syndrome in horses. Much of the mortality is associated with ischaemic-injured intestine during strangulating obstruction, yet there is limited understanding of the associated molecular events. Identification of differentially expressed genes during ischaemic injury should expand our understanding of colic and may lead to novel targeted therapeutic approaches in the future. OBJECTIVE: To isolate and identify differentially expressed genes in equine jejunum following a 2 h ischaemic event compared to normally perfused jejunum. METHODS: Suppressive subtractive hybridisation was used to clone genes that are differentially expressed in equine jejunum injured by 2 h of complete ischaemia as compared to time-matched control jejunal tissues. Expression of selected clones was further evaluated by northern blot analysis. RESULTS: Of the 384 clones selected, 157 were confirmed to possess cDNAs corresponding differentially expressed genes by dot blot analysis. Two genes, fatty acid binding protein 2 and calcium-activated chloride channel 4 were further confirmed to be differentially expressed by northern blot analysis. CONCLUSIONS: Suppressive subtractive hybridisation can be used to detect changes in expression of a broad array of genes, as confirmed by northern blot analysis of selected genes. POTENTIAL RELEVANCE: These initial results have identified a pool of equine intestinal epithelial genes that are differentially expressed following a 2 h ischaemic event. In particular, genes indicative of deranged metabolic activity and those potentially involved in early repair events were identified and may ultimately provide clues as to the nature of epithelial ischaemic injury in horses.

Animals↗
PubMed2005

Post operative neutrophilic inflammation in equine small intestine after manipulation and ischaemia.

REASONS FOR PERFORMING STUDY: Post operative ileus (POI) remains an important cause of post operative morbidity and mortality in the horse. However, clinical progression of naturally occurring cases of POI in both horse and man does not entirely support the 'neurogenic' hypothesis as the sole mechanism of POI; and the hypothesis that inflammation plays a major role at 12-24 h after surgery requires validation. HYPOTHESIS: An inflammatory infiltrate in the muscularis externa and myenteric plexus of equine jejunum is present 18 h following a period of ischaemia. METHODS: Samples of normal jejunum, jejunum from the proximal resection margins of clinical cases and jejunum obtained 18 h after 1 or 2 h ischaemia or manipulation alone were evaluated for neutrophil infiltration. Samples obtained 18 h after surgery were additionally evaluated for leucocyte activation using calprotectin immunohistochemistry. Results were evaluated by ANOVA and P < 0.05 was considered significant. RESULTS: Significant neutrophilic inflammation was identified in the samples from the proximal resection margins of clinical cases compared to uninjured jejunum. In experimental cases, neutrophilic inflammation appeared to be increased further by 18 h and was identified through all intestinal layers, particularly in the serosa, fascial planes around circular and longitudinal muscle fibres, and myenteric plexus. This elevated level of neutrophilic inflammation was mirrored by an increased number of calprotectin-positive cells in these intestinal layers, indicating leucocyte activation. CONCLUSIONS: Significant neutrophilic inflammation occurs in equine jejunal myenteric layers 18 h after surgery. POTENTIAL RELEVANCE: This neutrophilic inflammation coincides with the clinical time point at which POI is identified and may indicate that inflammatory pathways, rather than solely neurogenic pathways, are responsible for POI in the horse.

Analysis of Variance↗
PubMed2004

Mortality due to constipation and short-segment Hirschsprung's disease.

We report a case of mortality secondary to constipation. A 12-year-old child with a history of constipation from the age of 9 years presented in moribund condition with intestinal obstruction secondary to idiopathic constipation. He underwent laparotomy and died within 24 h of operation. At postmortem there was no evidence of abnormalities of the enteric nervous system. A 2nd case of early neonatal death from Hirschsprung's disease is presented to demonstrate that short-segment aganglionosis can be detected at postmortem. Enterocolitis can rapidly progress and be fatal in short-segment Hirschsprung's disease.

Child↗
PubMed2003

Parental knowledge of school backpack weight and contents.

Parental knowledge of their students' backpack weight and contents was assessed by identifying 188 students who carried backpacks weighing at least 10% of their body weights through a survey of 745 students in three elementary schools. Most parents (96%) had never checked their child's backpack weight; 34% had never checked the backpack contents.

Adult↗
PubMed2003

Management of drug-resistant cyathostominosis on a breeding farm in central North Carolina.

REASONS FOR PERFORMING STUDY: Possible anthelmintic resistance on a breeding farm where a rapid rotation anthelmintic programme had been implemented for 9 years was investigated. Cyathostomins resistant to fenbendazole and pyrantel were documented by faecal worm egg count reduction test (FWECRT). OBJECTIVES: To 1) manage small strongyle transmission in a herd of horses in which resistance to both pyrantel pamoate and fenbendazole was identified and thereby reduce the risk of clinical disease in the individual animal, 2) monitor the change in resistance patterns over time and 3) monitor the efficacy of ivermectin over the study period. METHODS: Targeted ivermectin treatment of horses on the farm was instituted for mature horses with faecal worm egg counts (FWEC) > 200 eggs/g (epg) and for horses < age 2 years with FWEC > 100 epg. RESULTS: Over a 30 month period, targeted ivermectin treatment achieved acceptable control in mares, as judged by FWEC, and improved control of patent cyathostome infection in consecutive foal crops. Egg reappearance time (ERT) after treatment with ivermectin was < 8 weeks in mares and foals more frequently in the second year of the study than in the first year. Numbers of anthelmintic treatments were reduced by 77.6 and 533% in the mare and foal group, respectively. CONCLUSIONS: Targeted ivermectin treatment may be an economically viable method of managing multiple drug resistant cyathostominosis. POTENTIAL RELEVANCE: Use of ivermectin should be monitored closely for development of resistance.

Animals↗
PubMed2002

Recovery of ischaemic injured porcine ileum: evidence for a contributory role of COX-1 and COX-2.

BACKGROUND: We have previously shown that the non-selective cyclooxygenase (COX) inhibitor indomethacin retards recovery of intestinal barrier function in ischaemic injured porcine ileum. However, the relative role of COX-1 and COX-2 elaborated prostaglandins in this process is unclear. AIMS: To assess the role of COX-1 and COX-2 elaborated prostaglandins in the recovery of intestinal barrier function by evaluating the effects of selective COX-1 and COX-2 inhibitors on mucosal recovery and eicosanoid production. METHODS: Porcine ileal mucosa subjected to 45 minutes of ischaemia was mounted in Ussing chambers, and transepithelial electrical resistance was used as an indicator of mucosal recovery. Prostaglandins E1 and E2 (PGE) and 6-keto-PGF1alpha (the stable metabolite of prostaglandin I2 (PGI2)) were measured using ELISA. Thromboxane B2 (TXB2, the stable metabolite of TXA2) was measured as a likely indicator of COX-1 activity. RESULTS: Ischaemic injured tissues recovered to control levels of resistance within three hours whereas tissues treated with indomethacin (5x10(-6) M) failed to fully recover, associated with inhibition of eicosanoid production. Injured tissues treated with the selective COX-1 inhibitor SC-560 (5x10(-6) M) or the COX-2 inhibitor NS-398 (5x10(-6) M) recovered to control levels of resistance within three hours, associated with significant elevations of PGE and 6-keto-PGF1alpha compared with untreated tissues. However, SC-560 significantly inhibited TXB2 production whereas NS-398 had no effect on this eicosanoid, indicating differential actions of these inhibitors related to their COX selectivity. CONCLUSIONS: The results suggest that recovery of resistance is triggered by PGE and PGI2, which may be elaborated by either COX-1 or COX-2.

Animals↗
PubMed2002

Factors associated with development of ileal impaction in horses with surgical colic: 78 cases (1986-2000).

Deal impaction is prevalent in the south-eastern USA, where feeding of Coastal Bermuda hay has been implicated as a risk factor. Alternatively, infection with the tapeworm Anoplocephala perfoliata has been identified as a risk factor for ileal impaction in the UK. We hypothesised that feeding Coastal Bermuda hay and failure to administer routinely an anthelmintic with efficacy against tapeworms would place horses at risk of developing ileal impaction in the USA. Seventy-eight horses, with surgically confirmed ileal impaction and 100 horses admitted for colic that did not have an ileal impaction, were selected retrospectively for logistic regression analysis. Using odds ratios (OR) as an index of risk, feeding Coastal Bermuda hay (OR = 2.9) and failure to administer a pyrantel salt within 3 months of admission (OR = 3.1) placed horses at risk of development of ileal impaction. This study confirms the belief that feeding Coastal Bermuda hay places horses at risk of ileal impaction, although the quality of the hay may also play a role. Periodic administration of anthelmintics with efficacy against tapeworms should be considered to reduce risk of ileal impaction.

Animal Feed↗
PubMed2001

Hepatitis and death following vaccination with 17D-204 yellow fever vaccine.

We describe a man vaccinated with the 17D204 strain of yellow fever virus, who subsequently died of yellow fever. Sequencing of the NS5-39 untranslated region showed that the virus isolated from the patient was identical to the vaccine strain of the same batch, and different from wild-type virus. Both viruses contained a mutation, although the association of this mutation with virulence is unknown. Severe, rapidly progressive, and ultimately fatal disease can follow use of the 17D204 vaccine strain. There is need for renewed discussion as to the safety of the vaccine and the indications for its use.

Adverse Drug Reaction Reporting Systems↗
PubMed2001

Evaluation of a four-channel multiplexed electrospray triple quadrupole mass spectrometer for the simultaneous validation of LC/MS/MS methods in four different preclinical matrixes.

A four-channel multiplexed electrospray interface on a triple quadrupole mass spectrometer was evaluated for the simultaneous validation of LC/MS/MS methods for the quantitation of loratadine and its metabolite, descarboethoxyloratadine, in four different biological matrixes. The assays were performed in rat, rabbit, mouse, and dog plasma from 1 to 1000 ng/mL using 96-well solid-phase extraction for sample preparation. The limit of quantitation of 1 ng/mL corresponded to 5.56 pg of each analyte injected on-column. For the drug, quality control samples (n = 6 at four concentrations) had precision ranging from 0.967 to 16.0% and accuracy ranging from -8.44 to 10.5% across all four species. For the metabolite, the precision ranged from 0.684 to 11.0% and the accuracy was between 6.36 and -9.06%. Intersprayer cross talk for the multiplexed electrospray ion source was evaluated as a function of analyte concentration and was less than 0.08% at concentrations as high as 1000 ng/mL. These results demonstrate the feasibility of using parallel analysis to reduce the time required for method validation and to increase sample throughput in drug development studies.

Animals↗
PubMed2001

Risk factors for reduced postoperative fecal output in horses: 37 cases (1997-1998).

OBJECTIVE: To determine prevalence and risk factors for development of ileus of the large intestine after surgery in horses, identified by reduced postoperative fecal output (RPFO). DESIGN: Retrospective study. ANIMALS: 37 horses that developed RPFO after undergoing general anesthesia for reasons unrelated to the gastrointestinal tract. PROCEDURE: Fecal output was obtained from medical records as number of defecations per 24-hour period after surgery; RPFO was defined as < or = 3 defecations per 24-hour period after surgery. The reference population included 48 horses that defecated > or = 4 times during the same period. Demographic, clinical, and surgical variables were evaluated for their association with development of RPFO by use of logistic regression analysis. RESULTS: Ten (12%) horses, all of which had RPFO, developed signs of colic after surgery. Horses > or = 5 years old that underwent orthopedic procedures of > 60 minutes' duration and that did not receive phenylbutazone after surgery were at significant risk for developing RPFO. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that after surgery unrelated to the gastrointestinal tract in horses, there is an intermediate clinical phase characterized by reduced fecal output preceding overt signs of colic. Recognition of RPFO may reduce morbidity and mortality of such horses.

Anesthesia↗
PubMed2001

Immunohistochemical analysis of cellular infiltrate and gamma interferon, interleukin-12, and inducible nitric oxide synthase expression in leprosy type 1 (reversal) reactions before and during prednisolone treatment.

The effects of prednisolone treatment on the cellularity and cytokine (gamma interferon, interleukin-12, and inducible nitric oxide synthase) profiles of leprosy skin type 1 (reversal) reactions were studied using immunohistochemistry. Skin biopsies were taken from 15 patients with leprosy type 1 (reversal) reactions at days 0, 7, 28, and 180 after the start of steroid treatment. Prednisolone treatment had little effect at day 7, but by day 28 significant decreases were found in cytokine levels. Some patients maintained cytokine production at days 28 and 180. These results illustrate the strong Th1 profile of type 1 reactional lesions, the slow response to steroid therapy, and continuing activity at 180 days.

Humans↗
PubMed2000

Parallel ultra-high flow rate liquid chromatography with mass spectrometric detection using a multiplex electrospray source for direct, sensitive determination of pharmaceuticals in plasma at extremely high throughput.

Recent years have seen increasing usage of large particle size stationary phases and ultra-high flow rate liquid chromatography/mass spectrometry (LC/MS) for rapid determination of pharmaceuticals in plasma without prior sample preparation. This lack of sample preparation prior to analysis, together with the extremely high throughput of the chromatography, makes the technique extremely attractive to the bioanalyst. Further, the introduction of multiple sprayer interfaces to mass spectrometers provides the potential for even higher throughput. In this paper, we present parallel ultra-high flow rate liquid chromatography using four columns in parallel and a four-way multiple sprayer interface to the mass spectrometer. We have applied this on both the narrow-bore and capillary scale. This technique enables the quantification of drugs from four plasma samples simultaneously, at nanogram per millilitre concentrations, from small aliquots of plasma without sample preparation and with throughputs of up to 120 samples per hour.

Calibration↗
PubMed1999

Accurate mass determinations for the confirmation and identification of organic microcontaminants in surface water using on-line solid-phase extraction liquid chromatography electrospray orthogonal-acceleration time-of-flight mass spectrometry.

The identification of polar microcontaminants in surface water is an important issue in environmental analysis. Liquid chromatography/mass spectrometry (LC/MS) is frequently applied for this purpose. However, even in combination with tandem mass spectrometry (MS/MS), unambiguous identification of the compounds detected is often difficult. The potential of an alternative strategy, based on the ability of an orthogonal-acceleration time-of-flight mass spectrometer to routinely perform accurate mass determination at 10 ppm in on-line LC/MS, is explored. On-line solid-phase extraction LC electrospray orthogonal-acceleration time-of-flight mass spectrometry is shown to enable the determination of pesticides from various compound classes in surface water in the concentration range of 0.1 to 10 micrograms/L. In addition, the ability to discriminate and unambiguously identify pesticides in mixtures of isobaric and/or isomeric compounds is investigated.

Chromatography, High Pressure Liquid↗
PubMed1999

Interferon-gamma and interleukin-2 release by lymphocytes derived from the blood, mesenteric lymph nodes and intestines of normal sheep and those affected with paratuberculosis (Johne's disease).

This study sought to determine if T-cell cytokine responses to mycobacterial infections in sheep were similar to those in other species and if such responses correlated with prevailing gut pathology. Lymphocytes were isolated from the blood (PBL), mesenteric lymph nodes (MLN) and ileal lamina propria (LPL) of control sheep and of sheep with clinical Johne's disease due to infection with Mycobacterium avium ssp. paratuberculosis (M.a. paratuberculosis). These animals had previously been categorised into two groups exhibiting either the 'tuberculoid' (paucibacillary) form of lesion or the 'lepromatous' (multibacillary) form. Lymphocytes were examined for their capacity, following stimulation with johnin-PPD, to release interferon-gamma (IFN-gamma) and interleukin 2 (IL-2) characteristic of the Th1 subset of MHC Class II-restricted CD4+ (helper) T-cells in other species. The expression of the two cytokines appeared related to the type of histological lesion observed. Antigen-stimulated lymphocytes from the tuberculoid group exhibited greater release of IFN-gamma and IL-2 than lymphocytes from the lepromatous group suggesting a Th1-type of response in the former in which expression of IFN-gamma by PBL showed a significant positive correlation with that expressed by MLN and LPL. Lymphocytes from animals with lepromatous lesions released lesser mycobacterium-induced IFN-gamma and IL-2 indicating a diminished role for a Th1 subset in this group of sheep. Differences in cytokine expression were much more apparent with lymphocytes which were derived from MLN.

Animals↗