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P Cox

Publications and source records attributed to P Cox.

At least 55 records · Page 3Linked to original sources
PubMed1998

Orally active indole N-oxide PDE4 inhibitors.

This communication describes the synthesis and in vitro and in vivo evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. Several of the compounds presented possess low nanomolar IC50's for PDE4 inhibition and excellent in vivo activity for inhibition of TNF-alpha levels in LPS challenged mice (mouse endotoxemia model). Emesis studies (dog) and efficacy in a SCW arthritis model for the most potent PDE4 inhibitors are presented.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

Induced massive star formation in the trifid nebula?

The Trifid nebula is a young (10(5) years) galactic HII region where several protostellar sources have been detected with the infrared space observatory. The sources are massive (17 to 60 solar masses) and are associated with molecular gas condensations at the edges or inside the nebula. They appear to be in an early evolutionary stage and may represent the most recent generation of stars in the Trifid. These sources range from dense, apparently still inactive cores to more evolved sources, undergoing violent mass ejection episodes, including a source that powers an optical jet. These observations suggest that the protostellar sources may have evolved by induced star formation in the Trifid nebula.

Journal Article↗
PubMed1998

HindIII liposomes suppress delayed-type hypersensitivity responses in vivo and induce epidermal IL-10 in vitro.

Considerable evidence suggests that ultraviolet-B (UV-B) radiation suppresses certain immune responses through the induction of cyclobutane pyrimidine dimers in DNA. To determine whether induction of other forms of DNA damage in the skin mimicked the immunosuppressive effects of UV-B radiation, we produced double-strand breaks in the DNA of epidermal cells with HindIII restriction endonuclease encapsulated in liposomes. Application of these liposomes, but not liposomes containing inactive HindIII or an irrelevant endonuclease, to the skin of C3H mice suppressed the induction of delayed-type hypersensitivity responses to Candida albicans and alloantigen and induced IL-10 production in the epidermis. Treatment of the Pam212 murine keratinocyte cell line with these liposomes in vitro induced immunosuppressive activity and IL-10 in culture supernatants. Unlike UV-B irradiation, however, HindIII in liposomes failed to induce suppressor T cell activity in vivo or in vitro. We conclude that double-strand breaks in DNA of epidermal cells can induce immunosuppression and up-regulate the production of immunomodulatory cytokines; however, either DNA damage alone does not account for all the immunosuppressive properties of UV-B irradiation, or cyclobutane pyrimidine dimers differ qualitatively from double-strand breaks in their biologic consequences. These studies raise the possibility that drugs causing DNA damage may induce cytokine dysregulation and immune suppression in addition to cytotoxicity.

Animals↗
PubMed1998

The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I.

This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds described contain an indole moiety which replaces the 'rolipram-like' 3-methoxy-4-cyclopentoxy motif. Several of the compounds presented possess low nanomolar IC50's for PDEIV inhibition. In vivo activities determined from measurement of serum TNF-alpha levels in LPS challenged mice (mouse endotoxemia model) are also reported.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

Identification of a non peptidic RANTES antagonist.

A series of phenothiazines demonstrating inhibition of RANTES binding to THP-1 cell membranes has been identified. The lead compound RP23618 (IC50 = 3 microM) was found to inhibit specific binding of 125I-RANTES, but not 125I-MCP-1 to THP-1 cell membranes and furthermore to antagonize RANTES, but not MCP-1-induced chemotaxis of THP-1 cells.

Cell Membrane↗
PubMed1998

Changes in treatment and outcomes of children receiving care in the intensive care unit for severe acute asthma.

OBJECTIVE: Significant changes have occurred in the intensity of treatment of children with severe asthma in the last decade. The objectives of this study are 1) to describe the changes in treatment of asthmatic children needing care in the intensive care unit (ICU) initially treated in our emergency department (ED) in 1983 to 1985 (I) and in 1990 to 1992 (II), and 2) to examine if these changes correspond to changes in clinical outcomes. DESIGN: Retrospective descriptive study. PATIENTS: All asthmatic children less than 18 years old treated in the ED and admitted to the ICU directly or via the ward with a primary diagnosis of asthma. SETTING: Pediatric tertiary care hospital. RESULTS: A total of 89 ICU admissions were required for patients initially treated in our ED, 54 in 1983 to 1985 and 35 in 1990 to 1992. In 1985, 29.7% of asthma patients required hospital admission and 0.5% needed ICU admission, while 30.7 and 0.7% required hospital and ICU admission, respectively, in 1992. Admissions to the ICU directly via the ED were similar in both time periods (I, 27; II, 30), while those admitted to the ICU via the ward decreased significantly (I, 27; II, 5; P < 0.01). Recently, while in the ED, these ICU patients, on average, were treated with < or =q1h albuterol inhalations longer (I, 1.7 hours; II, 3.4 hours; P < 0.001), more frequently (I, 1.8 inhalations/h; II, 3.3 inhalations/h; P < 0.001), and with greater dosages (I, 0.20 mg/kg/h; II, 0.55 mg/kg/h; P < 0.001), than previously. Only 72% of patients in 1983 to 1985 received i.v. steroids in the ED versus 100% in 1990 to 1992. Ward patients in 1990 to 1992 received < or =q1h inhalations for a greater proportion of their ward stay (I, 6.9/14.7 hours = 47%; II, 9.2/9.2 hours = 100%). There was a recent trend toward longer ICU treatment with < or =q1h albuterol inhalations (I, 8.7 hours; II, 12.3 hours; P = 0.24) and with i.v. albuterol (I, 29.4 hours; II, 37.4 hours; P = 0.26). Ventilation rates were low (I, 5/54 = 9.3%; II, 2/35 = 5.7%; P = NS) and the average duration of ICU stay remained unchanged (I, 40.6 hours; II, 42.1 hours; P = NS). CONCLUSIONS: Despite recent dramatic ED and ward treatment changes, ICU admission rates for pediatric asthma remain relatively constant. However, intensive treatment may have contributed to the decrease in ICU admissions via the ED to ward route in slightly less critical cases.

Acute Disease↗
PubMed1998

Colour Doppler energy insonation of placental vasculature in monochorionic twins: absent arterio-arterial anastomoses in association with twin-to-twin transfusion syndrome.

OBJECTIVE: To determine in vivo whether monochorionic pregnancies complicated by twin-to-twin transfusion syndrome are associated with absence of haemodynamically-compensatory arterio-arterial anastomoses. DESIGN: Forty monochorionic pregnancies were prospectively recruited for an ultrasonographic survey of the chorionic plate using colour Doppler energy. Arterio-arterial anastomoses were identified by their characteristic bidirectional interference pattern on spectral Doppler. Angioarchitecture was confirmed by postnatal injection study. SETTING: Fetal medicine tertiary referral centre in London. MAIN OUTCOME MEASURES: Presence of arterio-arterial anastomoses, development of twin-to-twin transfusion syndrome, survival. RESULTS: Arterio-arterial anastomoses were detected by colour Doppler energy in 21 pregnancies (53%), and there were no false positives. An arterio-arterial anastomosis was more commonly found in unaffected (n=28) compared to pregnancies affected by twin-to-twin transfusion syndrome (n=12), both by colour Doppler energy [20/28 (71%) is 1/12 (8%); delta=63%, 95% CI 40%-86%] and by postnatal injection study [25/28 (89%) vs 3/12 (25%); delta=64%, 95% CI 37%-91%]. In pregnancies in which no arterio-arterial anastomoses were detected, a diagnosis of twin-to-twin transfusion syndrome was made in 58%, and the perinatal loss rate was 40%, compared with one case of twin-to-twin transfusion syndrome (5%) (P < 0.001) and a loss rate of 12% (P=0.005) in pregnancies in which an arterio-arterial anastomosis was detected. CONCLUSION Twin-to-twin transfusion syndrome is associated with an absence of functional arterio-arterial anastomoses in vivo in monochorionic twin pregnancies. This contributes to our understanding of the pathophysiology of twin-to-twin transfusion syndrome and confirms ex vivo studies demonstrating that twin-to-twin transfusion syndrome is associated with a paucity of superficial anastomoses. Prospective studies are indicated to determine the utility of colour Doppler energy for arterio-arterial anastomoses in predicting risk in monochorionic pregnancies.

Arterio-Arterial Fistula↗
PubMed1997

Sunlight and skin cancer: inhibition of p53 mutations in UV-irradiated mouse skin by sunscreens.

UV-induced mutations in the p53 tumor suppressor gene play an essential role in skin cancer development. We report here that such mutations can be detected in UV-irradiated mouse skin months before the gross appearance of skin tumors. Application of SPF-15 sunscreens to mouse skin before each UV irradiation nearly abolished the frequency of p53 mutations. These results indicate that p53 mutation is an early event in UV skin carcinogenesis and that inhibition of this event may serve as an early end point for assessing protective measures against skin cancer development.

Animals↗
PubMed1997

Nosocomial acquisition of pertussis diagnosed by polymerase chain reaction.

Awareness is growing of the role of pertussis infection among adolescents and adults, and of the possibility of nosocomial transmission. However, pertussis remains difficult to diagnose. We report a case of nosocomially acquired pertussis in a healthcare worker, diagnosed by polymerase chain reaction. The high sensitivity and rapid turnaround time for this test is useful to confirm the diagnosis when advising a healthcare worker to refrain from working.

Adult↗
PubMed1997

Apoptosis in the brains of infants suffering intrauterine cerebral injury.

This study addressed the hypothesis that in human infants severe in utero insults induce a significant proportion of brain cells to undergo apoptosis. Morphologic criteria were used to quantify apoptosis and necrosis in the cingulate gyrus of two groups of infants: six infants who died after severe birth asphyxia with hypoxic-ischemic encephalopathy, and six others who suffered unexpected and apparently sudden intrauterine death at or close to term. The fraction of apoptotic cells was much higher than basal levels determined in animal experiments, and within both groups increased in proportion to the severity of injury as determined by total cell death (p < 0.05). The mean fraction of apoptotic cells was similar in asphyxiated infants, 8.3% (95% confidence interval for the population, 3.7-12%), and in stillbirths, 6.7% (0.2-13.6%). In the asphyxiated group, 20.8% (11-30.6%) of cells were necrotic, but significantly less necrosis, 3% (0.4-5.6%), was seen in stillborn infants (p < 0.05). Cell death was apoptotic after birth asphyxia in 26% (1-51%) and 78% (41-100%) in stillborn infants. In situ end labeling studies confirmed the presence of DNA fragmentation in apoptotic cells. These results demonstrate that infants who die after intrauterine insults, both those with evidence of delayed cerebral injury after hypoxia-ischemia and those without, have a significant number of cells in the brain with the morphologic characteristics of apoptosis. They confirm that apoptosis contributes significantly to cerebral damage in the perinatal period.

Apoptosis↗
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↗