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Biomedical subjects

C Merry

Publications and source records attributed to C Merry.

At least 37 records · Page 2Linked to original sources
PubMed1998

Successful use of protease inhibitors in HIV-infected haemophilia patients.

The haemophilias are a group of inherited haemostatic disorders that require regular clotting factor replacement therapy in the severe and moderately severe subgroups. Prior to the introduction of adequate viral inactivation methods in 1985, haemophilia patients were at exceptionally high risk of contracting blood-borne viruses from factor concentrates as each batch was derived from the plasma of thousands of donors. As a result, approximately 60% of these patients were infected with HIV between 1979 and 1985, and HIV infection now contributes significantly to the morbidity and mortality seen in this group. Protease inhibitors (PIs) have been shown to significantly log reduce viral loads and increase CD4 cell counts in HIV-infected individuals. Recently, there has been concern about their use in HIV-infected haemophilia patients following increased bleeding episodes in some patients during PI therapy. We prospectively studied the effect of PI therapy in 20 HIV-infected haemophilia patients at our centre over a 6-month period. The mean increase in CD4 cell count was 70 x 10(6)/l and the mean log decrease in viral load was 1.59 over the study period. Gastrointestinal side-effects (nausea and vomiting in five, diarrhoea in two) were the most frequent and resulted in discontinuation of the medication in two patients. Factor concentrate usage for the group on and off study was similar. One severe FVIII patient reported a single episode of an unusual bleed which responded promptly to FVIII concentrate infusion. The significant clinical and laboratory benefits in terms of HIV disease and the paucity of added bleeding complications suggest that PI therapy should not be withheld from HIV-infected haemophilics. Further prospective studies evaluating the efficacy and possible haemostatic complications related to these promising inhibitors of the HIV protease are needed.

AIDS-Related Opportunistic Infections↗
PubMed1998

Timing of surgery for fulminating pseudomembranous colitis.

BACKGROUND: With increasing antibiotic usage Clostridium difficile colitis is becoming more common. Surgery for fulminating C. difficile colitis, however, is rare because of the effectiveness of specific anticlostridial chemotherapy. Surgical outcome in five patients with fulminating C. difficile colitis involved in a recent outbreak of this disease is reported. METHODS: Five of 138 patients developed fulminating C. difficile colitis unresponsive to medical therapy. All patients had antibiotics in the preceding period. Indications for operation in those who underwent surgery were systemic toxicity with a pyrexia, marked leukocytosis and abdominal signs leading to progressive organ failure, despite appropriate anticlostridial antibiotic therapy. RESULTS: At operation all patients had a markedly oedematous colon with normal serosa but with acute mucosal colitis. All underwent subtotal abdominal colectomy and ileostomy. Progressive organ failure persisted in four, leading to death, giving a mortality rate of four in five in the operated group in comparison with 3.8 per cent (five of 133 patients) in those treated medically. CONCLUSIONS: These results indicate that this increasingly common disease frequently leads to a fatal outcome in patients requiring surgery and implies that earlier surgical consultation may be necessary to improve survival in patients with fulminating C. difficile colitis unresponsive to antibiotic therapy.

Abdomen, Acute↗
PubMed1998

Phosphorylation and the actin cytoskeleton in defective newborn neutrophil chemotaxis.

We have investigated the role of actin polymerization in the defective polymorphonuclear neutrophil (PMN) chemotaxis of the human newborn, and its regulation by protein kinase C and by phosphatases 1 and 2A. Isolated PMNs from adult volunteers and healthy term newborns, i.e. umbilical cord blood, were studied. Chemotaxis was measured by a modified micropore filter assay, and actin polymerization was assessed by flow cytometry. Chemotaxis of newborn PMNs (median 18 microm, range 9-21 microm) was significantly reduced compared with adult PMNs (median 23 microm, range 17-34 microm) (p < 0.001). Coincubation with the protein kinase C inhibitor bisindolylmaleimide GF109203X, did not significantly alter chemotaxis, whereas coincubation with the phosphatase inhibitors calyculin A or okadaic acid caused parallel dose-dependent inhibition of chemotaxis in adult and newborn PMNs. Peak actin polymerization was reduced in newborn compared with adult PMNs in response to stimulation with formyl-methionyl-leucyl-phenylalanine and zymosan-activated serum, but was normal in response to phorbol myristate acetate. Prior incubation for 5 min with bisindolylmaleimide GF109203X, calyculin A, or okadaic acid caused no significant alterations in the actin polymerization response to stimulation with formyl-methionyl-leucyl-phenylalanine. We conclude that: 1) newborn PMNs have reduced actin polymerization in response to stimulation with chemotactic agents which act via cell surface receptors, but not with phorbol myristate acetate, which acts directly in the cytoplasm. This suggests that a defect in cell signal transduction may be an underlying factor in defective newborn PMN chemotaxis. 2) Phosphatase inhibitors strongly inhibit chemotaxis but not actin polymerization, therefore phosphatases 1 and 2A may be important regulators of PMN chemotaxis, but this regulation takes place either at a point distal to actin polymerization or via another pathway. 3) Similar results in adult and newborn PMNs suggest that this is not the site of the underlying defect in newborn PMN chemotaxis.

Actins↗
PubMed1998

Splenic cysts--aspiration or partial splenic decapsulation?

We report on 2 children who had partial splenic decapsulation for splenic cysts--a pseudocyst and a congenital epidermoid cyst. Ultrasound-guided percutaneous needle aspiration with drainage was attempted in both patients but resulted in rapid cyst reaccumulation. Used on its own in the management of splenic cysts, percutaneous drainage has limited therapeutic value and delays definitive surgery. Partial splenic decapsulation is a simple and safe procedure.

Child↗
PubMed1997

Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients.

OBJECTIVE: The most important hepatic enzyme involved in the metabolism of protease inhibitors is cytochrome P450 3A4 (CYP3A4). Ritonavir (RIT) is a potent inhibitor of CYP3A4 and inhibits saquinavir (SQV) metabolism in healthy volunteers. In this study we investigated the kinetics of SQV when administered alone and in combination with RIT in HIV-infected patients. DESIGN: SQV pharmacokinetics were determined in seven patients who had advanced HIV disease. Steady-state SQV profiles were obtained on two occasions following treatment with SQV 600 mg three times daily alone and when administered with RIT 300 mg twice daily. METHODS: Blood samples were obtained at times 0, 1, 2, 4, 6 and 8 h post-dosing. Following centrifugation, separated plasma was heated at 58 degrees C for at least 30 min to inactivate HIV and stored at -80 degrees C until analysis using high performance liquid chromatography. RESULTS: For patients treated with SQV alone there was a 12-fold variability in the area under the SQV concentration-time curve (AUC0-8h) ranging from 293 to 3446 ng.h/ml. When combined with RIT there was a marked increase in the maximum plasma concentration of SQV [median (range), 146 (57-702) versus 4795 (1420-15810) ng/ml; approximately 95% confidence interval (CI), 2988-6819; P = 0.0006, Mann-Whitney U test]. The AUC0-8h for SQV was also significantly increased in the presence of RIT [median (range), 470 (29-3446) versus 27,458 (7357-108,001) ng.h/ml; approximately 95% CI, 16,628-35,111; P = 0.0006]. CONCLUSIONS: For some patients, administration of SQV 600 mg three times daily results in very low SQV plasma levels and possibly little antiviral effect. Combination of SQV with RIT results in a significant drug interaction mediated by enzyme inhibition which exposes patients to very high SQV concentrations and potential toxicity. If combination therapy with SQV plus RIT is considered then the dose of SQV should be greatly reduced.

Adult↗
PubMed1997

Effect of major surgery on neutrophil chemotaxis and actin polymerization in neonates and children.

The authors have examined the effect of major surgery in neonates and older children on neutrophil (PMN) chemotaxis and on actin polymerization, an essential early step in PMN movement. Isolated PMNs from the following subjects were studied: healthy adult volunteers (n = 28), healthy newborns (n = 21), newborns undergoing major surgery (n = 7), and older infants and children undergoing major surgery (n = 14). Chemotaxis was measured by a micropore filter assay, and actin polymerization was measured by flow cytometry. Blood samples from surgical patients were obtained preoperatively, hourly during the procedure, immediately postoperatively, and 48 hours after surgery. Mean preoperative newborn PMN chemotaxis was similar to that of healthy newborn PMN, and mean preoperative PMN chemotaxis in children was similar to that of healthy adults. There were no significant alterations in PMN chemotaxis during or after major surgery in neonates or children. Peak PMN actin polymerization, after stimulation with formyl methionyl leucyl phenylalanine (FMLP) (10 nm), was significantly diminished in healthy neonates compared with adults (P < .005). Preoperative surgical neonates had similar peak PMN actin polymerization levels to those of healthy newborns, and older preoperative children had similar levels to adults. PMN actin polymerization did not significantly change during or after major surgery. Despite reductions in PMN chemotaxis and actin polymerization in healthy neonates, there is no further impairment of these PMN functions during or after major surgery. Our data suggest that PMN chemotactic function is resistant to the stress of uncomplicated major surgery in neonates and children.

Actins↗
PubMed1997

Saquinavir pharmacokinetics alone and in combination with nelfinavir in HIV-infected patients.

OBJECTIVE: To investigate the pharmacokinetics of saquinavir (SQV) hard gel when administered alone and in combination with nelfinavir (NLF) to HIV-positive patients. DESIGN: Six patients receiving triple therapy (dual nucleoside plus SQV 600 mg three times daily) were studied. On the first study day blood samples were drawn for assay of SQV. Prior to the second study day, patients received their usual medication plus NLF 750 mg three times daily for 2 days. METHODS: Blood samples were obtained at times 0, 1, 2, 4, 6 and 8 h after dosing on study days 1 and 2. Following centrifugation, separated plasma was heated at 58 degrees C for at least 30 min to inactivate HIV and stored at -80 degrees C until analysis using high performance liquid chromatography. RESULTS: The geometric mean Cmax and AUC0-8 h on the first study day were 253 ng/ml (range, < 25-1200 ng/ml) and 1106 ng/ml.h (range, < 100-3479 ng/ml.h), respectively, and on the second study day were 1204 ng/ml (range, 379-2755 ng/ml) and 5472 ng/ml.h (range, 1434-12,538 ng/ml.h), respectively. The geometric mean ratio for Cmax was 4.75 and for AUC0-8 h was 4.94. CONCLUSIONS: NLF increases the oral bioavailability of SQV (hard gel) approximately fivefold. For some patients the addition of NLF to SQV will increase the drug levels from subtherapeutic to the therapeutic range. In one of our patients the addition of NLF resulted in SQV levels that were much higher than previous work suggests are necessary for maximum antiviral effect. The variability in SQV concentrations both at baseline and following addition of NLF suggest that dosing may best be adjusted by individual therapeutic drug monitoring.

Adult↗
PubMed1997

The vanishing testis: anatomical and histological findings.

OBJECTIVES: To review anatomical and histological findings in 105 vanishing testes. METHODS: Records of 2,509 boys with 3,064 cryptorchid testes treated at our hospital between 1969 and 1995 were reviewed. RESULTS: 691 (23%) testes were clinically impalpable. Exploration in 691 impalpable testes revealed absent testis in 144 (21%). In 39 (27%) of the 144 absent testes, there was complete agenesis of testis along with the epididymis and vas deferens whereas 105 (73%) were associated with blind-ending cord structures-the vanishing testis. The site of blind-ending cord structures in 105 vanishing testes was intra-abdominal in 22 (21%), inguinal canal in 62 (59%), superficial inguinal ring in 19 (18%) and scrotum in 2 (2%). Histological information was available in 47 vanishing testes and revealed vas, epididymis, or both in 32 (68%), fibrous/vascular tissue in 11 (23%) and testicular cords in 4 (9%). Dystrophic calcification and/or haemosiderin were present in 7 (15%). CONCLUSIONS: Our data show that the incidence of vanishing testis in boys with non-palpable testes is over twice the incidence of testicular agenesis. The most common site of blind-ending cord structures is distal to the internal inguinal ring. The finding of viable testicular tissue at the end of the attenuated cord structures in 4 of our patients, and also reported in other series, suggests that inguinal exploration should be carried out in all patients who on laparoscopy are found to have cord structures entering the internal ring.

Child, Preschool↗
PubMed1996

Defective neutrophil actin polymerisation and chemotaxis in stressed newborns.

Abnormalities of polymorphonuclear leukocyte (PMN) function contribute to high rates of postoperative infection in the newborn and to the vulnerability of newborns to overwhelming bacterial and fungal sepsis. The authors investigated (1) the effects of major surgery and sepsis on PMN chemotaxis in the newborn and (2) the role of cytoskeletal rearrangements in regulating chemotaxis. The subjects studied included newborns with sepsis (n = 16), newborns who underwent major surgery (n = 7), healthy full-term newborns (n = 21), and healthy adult volunteers (n = 28). Peak actin polymerisation was diminished in all newborns (relative to the adults) after stimulation with formyl methionyl leucyl phenylalanine (FMLP) (10 nmol/L), and with zymosan activated serum (ZAS) (10%). Major surgery and sepsis in newborns caused no further reduction in actin polymerisation. Changes in PMN shape after stimulation with FMLP were reduced in the newborns. PMN chemotaxis was significantly lower in healthy newborns than in adults (17 +/- 4 microns v 24 +/- 5 microns; P < .0001) and was even lower in septic newborns (11 +/- 4 microns; P < .005). Surgery and anaesthesia did not alter chemotaxis.

Actins↗
PubMed1995

Microheterogeneity of erythropoietin carbohydrate structure.

The microheterogeneity of the carbohydrate structures on recombinant human erythropoietin (rHuEPO) expressed in Chinese hamster ovary cells has been evaluated by electrospray ionization (ESI) mass spectrometry (MS) of glycopeptide fragments. The microheterogeneity is largely associated with the presence or absence of terminal N-acetylneuraminic acid (Neu5Ac) residues, varying amounts of O-acetylation of the Neu5Ac residues, and the presence or absence of N-acetyllactosamine extensions. The N-linked carbohydrate structures were structurally diverse; 52 different N-linked oligosaccharide structures were identified. Consistent structural assignments could be made from data obtained using different proteolytic digests, ESI solvent systems (aqueous/methanol systems with acetic or formic acid), and on-line or off-line LC/MS analysis. All glycosylation sites exhibited some level of O-acetylation of Neu5Ac residues. Interestingly, glycosylation site asparagine-83 exhibits mono-O-acetyl and di-O-acetyl Neu5Ac residues, while the other sites, asparagine-24, asparagine-38, and serine-126, exhibit mainly mono-O-acetyl Neu5Ac derivatization. This difference in O-acetylation may be site specific or due to sample handling of labile structures. However, mild base treatment of rHuEPO with NaOH on ice removed the O-acetyl groups associated with a given carbohydrate structure, without adversely affecting the underlying oligosaccharide structure, resulting in a simplified mass spectra. Nuclear magnetic resonance spectroscopy of Neu5Ac residues released by neuraminidase treatment of total rHuEPO indicated that Neu5,9Ac2 residues were present. Additional resonances were also observed that were consistent with other Neu5Ac O-acetyl linkages; these O-acetyl resonances could be removed by mild base hydrolysis of rHuEPO.

Amino Acid Sequence↗
PubMed1990

All day drinking--its impact on an accident and emergency department.

In order to assess the impact of changes in the Licensing Laws in England, a prospective study was undertaken of patients attending the Accident and Emergency Department of the Newcastle General Hospital. Patients were breathalysed in October 1986, before the liberalisation of the Licensing Laws in England and Wales and again in October 1988, after this change. A blood alcohol level of greater than 50 mg/100 ml was detected in 13% of all attenders in 1986 and 14% in 1988. A comparison of the two years revealed no significant change in the number of patients who had ingested alcohol prior to attendance, although there was a trend towards increased frequency of alcohol ingestion in nighttime attenders.

Alcohol Drinking↗