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Biomedical subjects

P Cox

Publications and source records attributed to P Cox.

At least 19 recordsLinked to original sources
PubMed1996

DNA double strand breaks in epidermal cells cause immune suppression in vivo and cytokine production in vitro.

UV irradiation of the skin causes immune suppression by a mechanism involving epidermal cytokines. To determine the role of epidermal DNA damage in immune suppression, we used HindIII restriction endonuclease encapsulated in liposomes to cause DNA strand breaks in epidermal cells in vivo and in vitro. Topical application of HindIII in liposomes to murine skin in vivo impaired the induction of contact hypersensitivity responses initiated either locally or at distant sites and impaired the function of APCs. Unlike UV-B radiation, however, treatment of mice with HindIII in liposomes before contact sensitization did not induce tolerance or transferable suppression. The liposome-encapsulated HindIII caused double strand breaks in DNA and induced IL-10 and TNF-alpha production when added to cells of a murine keratinocyte line in vitro. Topical application of liposomal HindIII also induced TNF-alpha in the epidermis of mice. Liposomes containing heat-inactivated HindIII or an endonuclease specific for pyrimidine dimers in DNA did not exhibit these effects. These results support the hypothesis that DNA damage is a trigger for the production of cytokines that modulate immune responses. They also suggest that immune suppression and suppressor cell induction are separate consequences of cutaneous injury that require different stimuli.

Animals↗
PubMed1996

Intensive care management of paediatric organ donors and its effect on post-transplant organ function.

OBJECTIVES: 1. To document the clinical course of paediatric beating heart organ donors. 2. To evaluate the effect of the ICU management of pediatric donors on the immediate function of transplanted organs. 3. To examine the validity of current donor selection criteria. DESIGN: Retrospective chart review and case series study. SETTING: Multidisciplinary ICU of tertiary referral paediatric hospital. PATIENTS: All patients who became solid organ donors between January 1980 and July 1990. OUTCOME MEASURES: 1. Incidence of major physiological abnormalities of the cardiovascular, pulmonary, renal and metabolic systems. 2. Number of organs retrieved and transplanted, reasons for non-transplantation of donated organs. 3. Immediate post-transplant function of transplanted organs. RESULTS: Seventy-seven organ donors were identified from whom 134 kidneys, 31 livers and 12 hearts were transplanted. Sixty (78%) patients developed diabetes insipidus. Sustained hypotension occurred in 41 (53.2%) and was commoner in patients treated with inotropic agents in the presence of a low central venous pressure and in patients with diabetes insipidus who did not receive anti-diuretic hormone replacement. Twenty-seven patients suffered at least one cardiac arrest. The data on post-transplant function were obtained for 129 kidneys (from 70 donors) 30 livers and 9 hearts. Fifty-two kidneys, 10 livers and 2 hearts were transplanted from donors who had suffered at least one cardiac arrest without apparent adverse effect on post-transplant organ function. Thirty-six kidneys from 31 donors suffered either acute tubular necrosis (ATN) or primary non-function. The donors of these organs spent longer in ICU (60.6 +/- 45.7 h versus 41.8 +/- 30.1 h p = 0.045) and had a higher mean maximum serum sodium concentration (163.4 +/- 10.9 versus 158.5 +/- 9.5 mmol/l p = 0.05) than those without these complications. The serum creatinine concentration and degree of inotropic support did not predict post-transplant function. Standard biochemical tests for hepatic function, the dose of inotropic agent received, time in ICU and incidence of hypotension did not predict post-transplant liver function. CONCLUSIONS: Aggressive fluid resuscitation and management of diabetes insipidus may promote stability in paediatric organ donors. Donor cardiac arrest does not alter the ICU course or compromise post-transplant organ function. The current criteria used for donor selection failed to predict post-transplant organ function and their use may increase organ wastage.

Adolescent↗
PubMed1996

Early tracheostomy in trauma patients.

A retrospective analysis of 118 trauma patients who underwent tracheostomy for airway and pulmonary management was undertaken. Timing of the procedure was defined as early (0-3 days), intermediate (4-7 days), and late (> 7 days). Head injury patients received tracheostomy early (p < 0.00003). Aspiration evaluated by modified bedside aspiration test was a frequent occurrence in all three groups with no difference in incidence (p < 0.34). Pneumonia was less frequent in the early group compared with the intermediate and late groups (p < 0.0034). The incidence of pneumonia in the early group was not different from that observed in early extubated patients (n = 282; p < 0.23). Our study suggests that early tracheostomy may decrease pulmonary septic complications in trauma patients. Although no change in length of stay can be attributed to the early performance of tracheostomy, preventing pneumonia in the intensive care unit setting with its resulting high expense is beneficial.

Adult↗
PubMed1996

[Delayed hypersensitivity to evoked antigens: normal values in Chilean young adults].

Delayed hypersensitivity skin test are widely accepted as in vivo measure of cellular immunity. Since genetic and environmental factors may affect these tests, each population must establish its own normal values. The aim of this work was to study delayed hypersensitivity in Chilean normal young adults. We studied the response to eight antigens using the Multitest CMI (Rhodia Merieux) in 50 students (22 females, 28 males), aged 18 to 25 years old. Skin tests were read at 24, 48 and 72 hours. At 48 Hours, 60% of women responded to 3 and 68% of men to 4 antigens. A mean response to 3.6 antigens was observed. Total score in men and women were 19.5 +/- 7.3 and 12.2 +/- 6.5 mm respectively (p < 0.05). These figures are different from those published abroad and confirm the need for national standards.

Adolescent↗
PubMed1996

A translocation at 12q2 refines the interval containing the Holt-Oram syndrome 1 gene.

A gene for Holt-Oram syndrome (HOS) has been previously mapped to chromosome 12q2 and designated HOS1. We have identified a HOS patient with a de novo chromosomal rearrangement involving 12q. Detailed cytogenetic analysis of this case reveals three breaks on 12q, and two of these are within the HOS1 interval. By using a combination of chromosome painting and FISH with YACs and cosmids, it has been possible to map these breakpoints within the critical HOS1 interval and thus provide a focus for HOS gene-identification efforts.

Arm↗
PubMed1995

Persistent low cerebral blood flow velocity following profound hypothermic circulatory arrest in infants.

Acute neurological morbidity following repair of congenital heart disease (CHD) in infancy is well recognized, particularly with the modalities of hypothermic cardiopulmonary bypass (CPB) and profound hypothermic circulatory arrest (PHCA). Reduced O2 delivery (perfusion defect) during rewarming following PHCA has been shown in the operating room. This reduction in cerebral blood flow coincides with disordered cerebral metabolism and oxygen utilisation after PHCA. The objective of this study was to extend the period of investigation of cerebral blood flow velocity (CBFV) behaviour in infants following PHCA to determine if hypoperfusion persisted in the paediatric intensive care unit (PICU). Ten patients undergoing CHD surgery were divided, based on the pump modality employed, into either mild hypothermic CPB or profound hypothermic CPB with circulatory arrest. Following admission to the PICU, sequential recordings of the mean CBFV in the middle cerebral artery, anterior fontanelle pressure, haemodynamic variables, tympanic membrane temperature, haematocrit and PaCO2 were performed. The PHCA group had a consistently reduced CBFV compared with the control group (P < 0.05). The CBFV values at one, two and four hours were 60 +/- 11, 51.8 +/- 11.4 and 52.6 +/- 11.9 respectively in the mild hypothermic CPB group. The CBFV values at one, two and four hours were 26.6 +/- 6.8, 32.6 +/- 10 and 34 +/- 8 respectively in the PHCA group. There was no difference in cerebral perfusion pressure between both groups. Tympanic temperature, haematocrit and PaCO2 did not vary between groups at any interval. This study demonstrates a sustained reduction in the CBFV pattern following PHCA into the postoperative period despite adequate cerebral perfusion pressures. This abnormality correlates with electroencephalographic aberrations documented after PHCA. It supports the concept of a prolonged unreactive cerebrovascular bed which could potentially contribute to the acute neurological morbidity following PHCA in neonates.

Blood Flow Velocity↗
PubMed1995

Renal replacement therapy after repair of congenital heart disease in children. A comparison of hemofiltration and peritoneal dialysis.

The development of renal failure necessitating peritoneal dialysis after cardiac operations is associated with a reported mortality greater than 50%. Improved fluid removal and nutritional support have been reported with the use of continuous arteriovenous hemofiltration and continuous venovenous hemofiltration techniques. We have compared our experience with all three techniques in managing children who required renal replacement therapy after cardiac operations in terms of efficacy (fluid removal, calorie intake, and clearance of urea and creatinine), complications, and outcome. Over a 5-year period renal replacement therapy was initiated in 42 children, and in 34 of them it was successfully established for more than a 24-hour period: 17 were managed with peritoneal dialysis, 8 with continuous arteriovenous hemofiltration, and 9 with continuous venovenous hemofiltration. A net negative fluid balance was achieved in only 6 (35%) patients treated with peritoneal dialysis compared with 50% of those treated with continuous venovenous hemofiltration and 89% of those treated with continuous venovenous hemofiltration. In terms of nutritional support, calorie intake increased by 43% after peritoneal dialysis was started compared with 515% and 409% in the arteriovenous and venovenous hemofiltration groups, respectively, (p < 0.005). The serum urea levels fell by 36% (p = 0.02) and 39% (p = 0.005) compared with pre-therapy levels with arteriovenous and venovenous hemofiltration, respectively, and the creatinine content was reduced by 19% and 33% (p = 0.003). Neither parameter was reduced in the peritoneal dialysis group. We conclude that the use of hemofiltration as a renal replacement therapy after surgical correction of congenital heart disease offers significant advantages over the more traditional approach of peritoneal dialysis. In addition, we suggest that a more aggressive approach to the management of fluid overload and nutritional depletion with hemofiltration may result in a decrease in the very high mortality seen in renal failure after cardiac operations.

Acute Kidney Injury↗
PubMed1995

Sunscreens and T4N5 liposomes differ in their ability to protect against ultraviolet-induced sunburn cell formation, alterations of dendritic epidermal cells, and local suppression of contact hypersensitivity.

Exposure of skin to ultraviolet (UV) radiation can lead to diverse biologic effects, including inflammation, sunburn cell formation, alterations of cutaneous immune cells, and impaired induction of contact hypersensitivity responses. The molecular mechanisms of these UV-induced effects are not completely understood. We investigated the ability of sunscreens and liposomes containing the DNA excision repair enzyme T4 endonuclease V to prevent these effects of UV radiation. The use of T4N5 liposomes, which increase the repair of cyclobutyl pyrimidine dimers, provides an approach for assessing the role of DNA damage in the effects of UV radiation on the skin. Exposing C3H mice to 500 mJ/cm2 UVB radiation from FS40 sunlamps resulted in skin edema, sunburn cell formation, and morphologic alterations and decreased numbers of Langerhans cells and Thy-1+ dendritic epidermal T cells. In addition, the induction of contact hypersensitivity after application of 2,4-dinitrofluorobenzene on UV-irradiated skin was diminished by 80%. Applying sunscreens containing octyl-N-dimethyl-p-aminobenzoate, 2-ethylhexyl-p-methoxycinnamate, or benzophenone-3 before this dose of UV irradiation gave nearly complete protection against all of these effects of UV irradiation. In contrast, topical application of T4N5 liposomes after UV irradiation had no effect on UV-induced skin edema and only partially protected against sunburn cell formation and local suppression of contact hypersensitivity, although its ability to protect against alterations in dendritic immune cells was comparable to that of the sunscreens. These results suggest that DNA damage is involved in only some of the local effects of UV radiation on the skin. In addition, T4N5 liposomes may be a useful adjunct to sunscreens because they can reduce some of the deleterious effects of UV radiation on skin even after a sunburn has been initiated.

Animals↗
PubMed1994

Localization of liposomes containing a DNA repair enzyme in murine skin.

T4N5 liposomes, which contain the DNA repair enzyme T4 endonuclease V, were applied to mouse skin in vivo and added to cultured murine keratinocytes in vitro. The fate of the liposome membrane was followed using a fluorescent, lipophilic dye, and the fate of the enzyme was traced by immunogold labeling, followed by brightfield, fluorescence, or transmission electron microscopy. In vivo, T4N5 liposomes penetrated the stratum corneum, localized in epidermis and appendages of the skin, and were found inside basal keratinocytes. The enzyme was found inside keratinocytes treated in vitro and in the epidermis, hair follicles, and sebaceous glands of topically treated skin. Ultrastructural studies demonstrated the presence of liposomes in the cytoplasm of cells in the epidermis often concentrated in a perinuclear location. The enzyme was present in both nucleus and cytoplasm of keratinocytes and Langerhans cells. Liposomes were found in cells of the lymph nodes draining the site of contact sensitization, in association with topically applied antigen. The results demonstrate that liposomes can deliver encapsulated proteins into cells of the skin in vivo and provide insight into how liposome-enhanced DNA repair reduces UV-induced skin cancer and systemic immunosuppression in mice.

Animals↗
PubMed1994

A simple method for monitoring the concentration of inhaled nitric oxide.

Nitric oxide is a potent endogenous vasodilator involved in the homeostatic control of systemic blood pressure. It has also recently been demonstrated that when inhaled in low concentrations it acts as a specific pulmonary vasodilator. The concept of inhaled nitric oxide as a form of therapy is almost an anathema to anaesthetists. However, nitric oxide is being used increasingly for the treatment of persistent pulmonary hypertension of the neonate and in the adult respiratory distress syndrome. One major limitation to its frequent and widespread use is the problem of measuring the concentration of nitric oxide delivered. Currently, the gold standard technique used is chemiluminesence. However, the equipment required is costly and can be difficult to use. If the use of inhaled nitric oxide increases and it develops a therapeutic role then its applications may be limited only to centres which can afford such equipment. Others may be prevented from using a potentially valuable therapy due to lack of a controlled delivery system for nitric oxide. An inexpensive, simple alternative technique to chemiluminesence is described, which will allow most intensive care units the freedom to use inhaled nitric oxide if necessary.

Administration, Inhalation↗
PubMed1994

Nucleotide sequence of the equine interferon gamma cDNA.

Interferon gamma, a cytokine produced by T-lymphocytes and natural killer cells, plays a central role in the modulation of the immune response, and its antiviral and antitumourigenic properties have made it a potential candidate for use in immunoprophylactic and therapeutic regimes. We have cloned the equine IFN gamma cDNA to facilitate production of this cytokine for clinical evaluation in the horse. The predicted equine IFN gamma amino acid sequence is 67% identical to that of the human equivalent and 78% to the bovine equivalent.

Amino Acid Sequence↗
PubMed1993

Reproductive axis suppression in acute illness is related to disease severity.

Changes in the adrenal and thyroid axes in critically ill patients are accentuated by increasing disease severity. However, the relationship of gonadal axis suppression to severity of illness is not well defined. We evaluated serial serum levels of LH, FSH, and testosterone (T) in 59 men and 42 postmenopausal women admitted to critical care units with a spectrum of disease severity. Patients were grouped according to severity of illness by the Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores and by survival. Patients with surgery, renal or hepatic failure, alcohol abuse, endocrine disease, or head trauma were excluded to avoid these confounding factors. In men, mean admission serum T levels in all groups were lower than in healthy controls (P < 0.005). In addition, T levels in men with severe illness (APACHE > 15) were lower than in men with relatively mild (APACHE < 10; P < 0.01) or moderate illness (APACHE 10-15; P < 0.05). These differences were accentuated as hospitalization progressed. In postmenopausal women and men, nadir serum FSH but not LH levels during hospitalization were lower in patients with APACHE greater than 15 than in patients with APACHE scores of 10-15 or less than 15 (P < 0.05). Grouping patients by survival yielded similar results. Analysis of drug effects, age, and PRL did not explain these relationships. We conclude that the degree of both central and peripheral suppression of the reproductive axis in acute illness is related to disease severity. This suppression could not be attributed to other factors known to alter the reproductive axis independently from critical illness (e.g. age, drugs, head trauma, hepatic failure, etc.). These findings further document a general endocrine response to acute illness involving several axes which is graded according to disease severity.

Acute Disease↗
PubMed1992

Both hyper- and hypogonadotropic hypogonadism occur transiently in acute illness: bio- and immunoactive gonadotropins.

Previous reports of hypogonadotropic hypogonadism in critically ill men may not reflect the complexity of changes in the hypothalamic-pituitary-gonadal (HPG) axis during acute illness. We sampled blood throughout hospitalization in 55 men admitted to acute care units to delineate the spectrum of changes in circulating gonadotropin and sex steroid levels at the onset and during recovery from acute illness. Bioactive LH and FSH were measured in a subset of patients. Percent free testosterone was measured to assess changes in binding to sex hormone binding globulin. Medications and serum estrogen and prolactin levels were monitored as potential causes of hypogonadotropism. Sustained suppression of serum testosterone levels below the normal range occurred in 62% of men with varying diagnoses and disease severity. Percent free testosterone remained constant. Hypogonadotropism was observed in most men (60%) and occurred independently from head injury, surgery, medications, or hyperprolactinemia. In a subset of men (n = 16), LH and/or FSH rose transiently above the normal range. Bioactivity of both LH and FSH remained constant while serum testosterone levels decreased. In contrast to serum testosterone levels, mean serum levels of E1, E2 and androstenedione were not less than control values. We conclude that both primary and secondary hypogonadism occur transiently in acutely ill men and cannot be explained solely by medications, hyperprolactinemia, or hyperestrogenemia. Neither biopotency of gonadotropins nor binding of testosterone to SHBG change across the course of acute illness. The hypogonadism, often severe and prolonged, may contribute to the persistent catabolic state observed in many critically ill patients.

Acute Disease↗
PubMed1991

Differential expression of GABAA receptor alpha-subunits in rat brain during development.

Unique cytoplasmic loop regions of the alpha 1, alpha 2, alpha 3, and alpha 5 subunits of the GABAA receptor have been expressed in E. coli and used to generate polyclonal antisera specific for these subunits. The antibodies identify proteins by SDS-polyacrylamide gel electrophoresis and western blotting of molecular size 51 kDa, 53 kDa, 59 kDa and 55 kDa, respectively, which show differential patterns of expression during development. Whereas the alpha 2 and alpha 3 subunits are present at early stages, the expression of alpha 1 and alpha 3 subunits is low at birth and increases with age. This differential expression could be correlated with previous studies examining the developmental expression of BZ1 and BZ2 benzodiazepine binding sites.

Animals↗
PubMed1991

Prevention of IUD-related pelvic infection: the efficacy of prophylactic doxycycline at IUD insertion.

It is believed that much of the small increased risk for developing pelvic inflammatory disease (PID) associated with the use of an intrauterine device (IUD) appears to be caused by bacterial contamination of the endometrial cavity at the time of insertion. Previous research suggests that use of prophylactic antibiotics immediately prior to IUD insertion may reduce the risk of developing PID. This paper presents results from a randomized clinical trial of 1485 women in Ibadan, Nigeria evaluating the effectiveness of 200 mg of doxycycline (versus placebo) given orally at the time of IUD insertion in reducing the incidence of PID during the first three months of IUD use. Rate of PID infection in the doxycycline-treated group was not significantly lower than that in the placebo-treated group. The rate of unscheduled IUD-related visits to the clinic also was not significantly lower among the doxycycline-treated group. However, the incidence of PID was low (21 cases) for both study groups. Aseptic conditions during IUD insertion, follow-up visits with short intervals to monitor health, and treatment of opportunistic infections may have reduced the potential of PID within this population.

Administration, Oral↗