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Biomedical subjects

O P Smith

Publications and source records attributed to O P Smith.

At least 19 recordsLinked to original sources
PubMed2003

Genomic polymorphic profiles in an Irish population with meningococcaemia: is it possible to predict severity and outcome of disease?

Patients with meningococcal disease have increased plasma levels of proinflammatory cytokines IL-6, IL-1beta, and TNF-alpha, with higher levels associated with fatal outcome. This study investigated whether polymorphisms in genes encoding these cytokines, and in those encoding anti-inflammatory IL-10 and IL-1Ra, are associated with the outcome in patients with meningococcal disease. Seven polymorphisms were genotyped in 183 meningococcal disease patients and 389 controls. The IL-6 -174 G/G and IL-10 -1082 A/A genotypes were more frequent in nonsurvivors compared with survivors (P=0.023 IL-6, 0.25 IL-10), and in patients with severe disease compared to those with mild disease (P=0.037 IL-6, 0.0078 IL-10). An association was also found between meningococcal disease and the IL-1RN VNTR polymorphism, but no association was observed with the LTA +252, TNF -308, IL-10 -592, or IL-1B +3953 polymorphisms. We conclude that genetic variability in the IL-6, IL-10, and IL-1RN genes is associated with a poor outcome in meningococcal disease.

Adult↗
PubMed2003

The treatment of flexion contracture of the knee using the Ilizarov technique in a child with haemophilia B.

Severe factor IX deficiency is an X-linked disorder which gives rise to spontaneous and often life-threatening bleeds. The major source of morbidity worldwide is recurrent haemarthroses, giving rise to joint destruction and deformity. However, the incidence of spontaneous haemarthroses has decreased since the advent of prophylactic home-based, on-demand, early replacement therapy. We present the case of a non-ambulant, 13-year-old boy from Chernobyl, who did not have access to this type of treatment, and whose deformity was managed using the Ilizarov external fixator. An external fixator was applied under general anaesthetic in theatre. Haemostasis was achieved by maintaining his FIX levels at 1.0 IU mL(-1) pre- and post-operatively. Three months later, the fixed flexion deformity had been reduced from 50 to 5 degrees. Four months postsurgery, this boy was walking freely without pain. There was no peri- or post-operative bleeding or joint swelling.

Adolescent↗
PubMed2002

Massive pseudotumour resection with recombinant factor VIIa (NovoSeven) cover.

Surgical resection is the only definitive treatment for haemophilic pseudotumour. For patients with high- responding factor (F)VIII inhibitors, the lack of reliable by-passing agents in the past has meant that surgery has been avoided in favour of conservative measures. The development of recombinant factor VIIa (rFVIIa) has revolutionized the management of surgery in these patients. We document the first successful report of the surgical resection of a massive pseudotumour in a patient with high responding FVIII inhibitors using rFVIIa to achieve haemostasis. Serial post-operative measurements indicated that FVII coagulation activity (FVII:C) levels were more sensitive to rFVIIa dose changes than the prothrombin time.

Adult↗
PubMed2002

Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS), described just under 40 years ago, is a rare, autosomal-recessive disorder usually manifest in infancy and characterized by exocrine pancreatic insufficiency, short stature, and bone marrow dysfunction. Additional clinical features include metaphyseal dysostosis, epiphyseal dysplasia, immune dysfunction, liver disease, growth failure, renal tubular defects, insulin-dependent diabetes mellitus, and psychomotor retardation. Hematological manifestations other than neutropenia include anemia, raised fetal hemoglobin (HbF) levels, thrombocytopenia, impaired neutrophil chemotaxis, and aplastic anemia; as with other constitutional bone marrow failure syndromes, there is a predilection to malignant myeloid transformation. No unifying pathogenetic mechanism(s) has yet been shown to be responsible for SDS, although new insights into the molecular, genetic, and cellular basis of this rare disease have recently been described.

Bone Marrow Diseases↗
PubMed2002

von Willebrand's disease: an important cause of dysfunctional uterine bleeding.

We assessed the prevalence of von Willebrand's disease (VWD) in patients with objectively confirmed dysfunctional uterine bleeding. A case-control study was designed to include 38 patients with objectively confirmed dysfunctional uterine bleeding and 38 age-matched controls with normal menstrual blood loss (MBL). Menorrhagia was defined as a mean MBL of greater than 80 ml on three consecutive menses as measured by the alkali haematin method. von Willebrand factor antigen, von Willebrand factor activity (VWF:Ac) and factor VIII:C were measured on three serial venous blood samples 1 week apart. VWD was diagnosed in five of 38 (13%) patients with menorrhagia and one of 38 (2.6%) patients with normal menstrual blood loss. The mean VWF:Ac value was significantly reduced in patients with menorrhagia (mean +/- standard deviation, 84.5 +/- 26.7 IU/dl versus 103.9 +/- 34.5 IU/dl; P < 0.01) and this effect persisted after exclusion of patients diagnosed with VWD. Failure to investigate patients for VWD will limit the potential benefits of medical therapies such as tranexamic acid or nasal desmopressin [1-desamino-8-D-arginine vasopressin, (DDAVP)] and, in addition, will lead to an increased risk associated with surgical intervention in patients with undiagnosed VWD.

Adult↗
PubMed2001

Bone marrow transplantation corrects osteopetrosis in the carbonic anhydrase II deficiency syndrome.

Carbonic anhydrase II (CAII), found in renal tubules, brain, and osteoclasts, is critical in acid-base homeostasis and bone remodeling. Deficiency of CAII gives rise to a syndrome of osteopetrosis, renal tubular acidosis (RTA), and cerebral calcification with associated developmental delay. It is inherited in an autosomal recessive fashion and found most frequently in the Mediterranean region and the Middle East. We report 2 related Irish families with clinically severe CAII deficiency in whom the gene mutation has been fully elucidated. Two children, one from each family, have undergone allogeneic bone marrow transplantation because of severe progressive visual and hearing loss. The older 2 children had already developed cerebral calcification and marked visual loss at the time of diagnosis and were treated symptomatically. Post-transplantation evaluation at 2 and 3 years demonstrates histologic and radiologic resolution of their osteopetrosis with stabilization of hearing and vision. Both children remain developmentally delayed and continue to have RTA, and the older child has now developed cerebral calcification. Allogeneic bone marrow stem cell replacement cures the osteoclast component of CAII deficiency and retards the development of cerebral calcification, but it appears to have little or no effect on the renal lesions. (Blood. 2001;97:1947-1950)

Acidosis, Renal Tubular↗
PubMed2001

High serum folates and the simplification of red cell folate analysis.

Recent substantial increases in clinical blood folate concentrations are noted. Since red cell folates (RCF) are calculated from whole blood folates (WBF) by subtraction of the endogenous serum folate (SF) component, the reporting of clinical RCF results may be delayed because an ever increasing proportion (15%) of diagnostic SF levels are high (> 20 ng/ml) and need a repeat analysis. We evaluated 'plasma replacement' as a simple preanalytical procedure in which endogenous blood plasma is removed from red cells by washing and substituted with 'low-folate' plasma (serum) as an alternative conjugase (gamma-glutamyl carboxypeptidase) source for folate polyglutamate hydrolysis. Washed and conventional RCF assays compared well after both manual (n = 115, r = 0.98, y = 1x + 1.26) and automated washing of red cells (n = 170, r = 0.96, y = 0.96x - 0.73 ng/ml) and were not significantly different. The interassay reproducibility of folate results from washed blood samples was good (CV = < 6%). This novel 'plasma replacement' step halves the cost of a valid RCF assay by eliminating the need for endogenous SF analysis, and it expedites the reporting of clinical results.

Clinical Laboratory Techniques↗
PubMed2001

Case report: four donors with granulocyte-specific or HLA class I antibodies implicated in a case of transfusion-related acute lung injury (TRALI).

A 54-year-old female patient with a history of chronic liver disease and portal hypertension was admitted for an elective cholecystectomy. Preoperative evaluation revealed a prolonged prothrombin time of 17.4 seconds (control 12 to 15.5 seconds). Six units of fresh frozen plasma (FFP) were prescribed after failure of correction of the coagulopathy with intravenous vitamin K (10 mgs). During infusion of the fifth unit of FFP, the patient became acutely dyspneic. Arterial blood gas analysis revealed marked hypoxemia (PO(2) 6.58 kPa) and the chest X-ray showed new diffuse bilateral alveolar infiltrates. The patient remained hypoxemic with unstable oxygen saturations over the following 7 days, during which time she required 60 to 100 percent oxygen administered by face mask. Intravenous methylprednisolone (200 mgs) was given for 5 days. Mechanical ventilation was not required. The lung infiltrates gradually cleared over 3 to 4 days and the patient showed clinical improvement after 1 week. Four of the donors of the implicated units of plasma were female and all had a history of pregnancy. Two donors had HLA class I antibodies and two had granulocyte-specific antibodies detectable in their serum. In crossmatch studies, granulocyte-reactive antibodies from two donors bound to granulocytes from the patient, which suggested that these antibodies were clinically relevant. These clinical and serologic findings support a diagnosis of transfusion-related acute lung injury (TRALI).

Journal Article↗
PubMed2000

An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia.

Activated protein C (APC) is a natural anticoagulant that plays a pivotal role in coagulation homeostasis. Severe inherited or acquired deficiency results in a clinical syndrome called purpura fulminans. In addition, APC also appears to have potent cytokine-modifying properties and is protective in animal models of sepsis. The dual functional properties of APC are particularly relevant to severe meningococcemia, where acquired PC deficiency is accompanied by multiorgan failure and purpura fulminans. The authors conducted an open-label prospective study assessing the efficacy of PC replacement therapy in patients with severe meningococcal septicemia, purpura fulminans, and multiorgan failure. The morbidity and mortality were compared with predicted morbidity using the Glasgow Meningococcal Septicemia Prognostic Score. Thirty-six patients with a mean age of 12 years (range 3 months to 72 years) were enrolled in the study. The mean +/- SD for plasma PC was 18 +/- 7 IU/mL. PC was significantly lower than antithrombin or protein S and was also significantly lower than PC levels in a cohort of patients who developed meningococcemia without multiorgan failure and purpura fulminans. A total of 3 of 36 (8%) patients died, which compares favorably with predicted mortality of 18 of 36 (50%). Amputations were required in 4 of 33 (12%) survivors and in 2 of 31 (6.5%) patients who received PC within 24 hours of admission into the hospital, in comparison with the predicted amputation rate of 11 of 33 (30%). In conclusion, PC replacement therapy in severe meningococcal septicemia was associated with a reduction in predicted morbidity and mortality. The beneficial effect of PC replacement may reflect both the anticoagulant and anti-inflammatory properties of the PC pathway. (Blood. 2000;96:3719-3724)

Adolescent↗
PubMed2000

Randomized comparison of unfractionated heparin with corticosteroids in severe active inflammatory bowel disease.

BACKGROUND: Heparin therapy may be effective in steroid resistant inflammatory bowel disease. AIM: A randomized pilot study, to compare unfractionated heparin as a first-line therapy with corticosteroids in colonic inflammatory bowel disease. METHODS: Twenty patients with severe inflammatory bowel disease (ulcerative colitis, n=17; Crohn's colitis, n=3) were randomized to either intravenous heparin for 5 days, followed by subcutaneous heparin for 5 weeks (n=8), or high-dose intravenous hydrocortisone for 5 days followed by oral prednisolone 40 mg daily, reducing by 5 mg per day each week (n=12). After 5 days, non-responders in each treatment group were commenced on combination therapy. Response to therapy was monitored by: clinical disease activity (ulcerative colitis: Truelove and Witt Index; Crohn's colitis: Harvey and Bradshaw Index), stool frequency, serum C-reactive protein and alpha1 acid glycoprotein, endoscopic and histopathological grading. RESULTS: The response rates were similar in both treatment groups: clinical activity index (heparin vs. steroid; 75% vs. 67%; P=0.23), stool frequency (75% vs. 67%; P=0.61), endoscopic (75% vs. 67%; P=0.4) and histopathological grading (63% vs. 50%; P=0.67). Both treatments were well-tolerated with no serious adverse events. CONCLUSION: Heparin as a first line therapy is as effective as corticosteroids in the treatment of colonic inflammatory bowel disease. Large multicentre randomized comparative studies are required to determine the role of heparin in the management of inflammatory bowel disease.

Administration, Oral↗
PubMed2000

Liver biopsy in Irish hepatitis C-infected patients with inherited bleeding disorders.

The majority of patients receiving plasma-derived clotting factor concentrates between 1970s and the mid-1980s are now hepatitis C positive. The progression of hepatitis C is extremely variable and there is frequently a poor correlation among liver biochemistry, viral load and the stage of liver disease. Liver biopsy remains the only definitive way of staging fibrosis and grading necroinflammatory activity. Concerns have been expressed about the safety of the procedure; however, with modern regimes for the correction of coagulopathy in patients with inherited bleeding disorders, normal haemostasis may be maintained during the peribiopsy period. We performed 21 liver biopsies between 1984 and 1997 on patients with factor VIII (FVIII) or IX (FIX) deficiency and von Willebrand's Disease (VWD). Four had concomitant human immunodeficiency virus (HIV) infection, five were thrombocytopenic and one had a prolonged prothrombin time (PT). Haemostasis was achieved using an intermittent bolus of factor concentrate or continuous infusion regimens. One patient with VWD received Desmopressin (DDAVP). There were no bleeding episodes associated with biopsy. We suggest that liver biopsy is a safe procedure in patients with inherited bleeding disorders when the coagulopathy is fully corrected. It is the only definitive method of staging the extent of fibrosis associated with hepatitis C infection, and it is this that defines prognosis.

Adult↗
PubMed2000

Desmopressin: therapeutic limitations in children and adults with inherited coagulation disorders.

Desmopressin (DDAVP), a synthetic analogue of vasopressin has been successfully used in the treatment of type I von Willebrand's disease (VWD), mild factor VIII (FVIII) deficiency and intrinsic platelet function defects (PFDs) for almost three decades. However, there is limited published data documenting its efficacy and the reliability of circulating plasma FVIII:C as a surrogate marker of response to therapy in VWD. We report the haemostatic response to DDAVP in 133 consecutive patients (91 type I VWD, 20 mild FVIII deficiency and 22 PFDs). Minimal therapeutic response to DDAVP (0.3 microg/kg) was defined by normalization 30 min post- infusion of bleeding time for PFDs, factor VIII:C (FVIII:C) for mild haemophilia A, and von Willebrand factor antigen (VWF:Ag), von Willebrand factor functional activity (VWF:Ac) and FVIII:C for VWD. Nine out of 91 (10%) VWD patients failed to achieve minimal therapeutic response to DDAVP; plasma FVIII:C levels were an unreliable surrogate marker of DDAVP response as 6 out of 9 (67%) of these patients had normal post-infusion FVIII:C levels. Five out of the 20 (25%) patients with mild FVIII deficiency and 5 out of 22 (23%) patients with PFDs failed to achieve a minimal therapeutic response to DDAVP. DDAVP is an effective therapy in the majority of patients with type I VWD, PFDs and mild FVIII deficiency. The significant failure rate associated with this therapy supports the recent recommendations that response should be assessed in all patients at the time of diagnosis. FVIII:C is an unreliable guide of response to DDAVP in patients with VWD and therefore VWF:Ag and VWF:Ac should also be assessed. Failure to demonstrate the response of VWF:Ag, VWF:Ac and FVIII:C to DDAVP in patients with VWD is likely to increase the risk of haemorrhagic complications in patients with bleeding episodes or who are undergoing surgery.

ABO Blood-Group System↗
PubMed2000

Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line.

Activated protein C (APC) protects against sepsis in animal models and inhibits the lipopolysacharide (LPS)-induced elaboration of proinflammatory cytokines from monocytes. The molecular mechanism responsible for this property is unknown. We assessed the effect of APC on LPS-induced tumour necrosis factor alpha (TNF-alpha) production and on the activation of the central proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) in a THP-1 cell line. Cells were preincubated with varying concentrations of APC (200 microg/ml, 100 microg/ml and 20 microg/ml) before addition of LPS (100 ng/ml and 10 microg/ml). APC inhibited LPS-induced production of TNF-alpha both in the presence and absence of fetal calf serum (FCS), although the effect was less marked with 10% FCS. APC also inhibited LPS-induced activation of NF-kappaB, with APC (200 microg/ml) abolishing the effect of LPS (100 ng/ml). The ability of APC to inhibit LPS-induced translocation of NF-kappaB is likely to be a significant event given the critical role of the latter in the host inflammatory response.

Analysis of Variance↗
PubMed2000

Central venous access devices in children with congenital coagulation disorders: complications and long-term outcome.

Reliable venous access is essential to facilitate the administration of prophylactic factor concentrate or blood products in children with congenital coagulation disorders and immune tolerance therapy (ITT) regimens in those who develop high responding inhibitors. Poor venous access is even more problematic in very young children, the vast majority of whom will require the insertion of central venous access devices (CVADs). Previous studies have suggested that infection rates are low and that there are few long-term complications associated with CVAD usage. We have reviewed 86 CVADs that have been inserted, since 1988, in 58 children with congenital bleeding disorders, aged 6 d to 16.5 years, attending Great Ormond Street Hospital, London, and the National Children's Hospital, Dublin. The devices have remained in situ for 2 weeks to 92 months (median 22.5 months). Early (0-2 weeks) complications of CVAD insertion included nine bleeding episodes, one extravasation of factor concentrate, three allergic reactions to factor concentrate and five catheter infections. Overall, CVAD infection was the commonest problem encountered, with 52 devices (60%) becoming infected. Twenty-seven CVADs (31%) required removal. Infection rates in children without inhibitors (29/68) were 1/20 patient-months or 1. 6 infections/1000 patient-days, but infection rates for those with inhibitors were 1/8.5 patient-months or 4.3/1000 patient-days. Staphylococcus epidermidis was the predominant organism (25/52) isolated. Blockage of CVAD (four) and catheter disconnection (four) were the most frequently occurring non-infectious long-term complications. Skin erosion of the port was also seen in three children, in one child at 20 months, in one at 29 months and in one at 34 months after insertion. This study demonstrates a high CVAD infection rate and highlights the long-term complications of CVAD usage.

Adolescent↗
PubMed2000

Prevalence of the factor VR506Q mutation in two Irish control populations: use of a novel nested polymerase chain reaction approach.

The prevalence of factor V (FV) Leiden among normal populations has primarily been determined using blood donors. This control group is carefully selected and therefore may not accurately reflect the true prevalence within the population. We assessed the prevalence of FV Leiden within the Irish population using Guthrie card samples randomly selected from all newborns. We compared this result with the prevalence of FV Leiden within blood donors. A novel nested polymerase chain reaction (PCR) method for FV Leiden was developed for analysis of the Guthrie card samples. There was no significant difference between the allele frequency within the Guthrie card samples and blood donors (2.07% vs. 2.35%, P = 0.66)

Adult↗
PubMed2000

High responding factor VIII inhibitors in mild haemophilia - is there a link with recent changes in clinical practice?

The development of high responding inhibitors is an increasingly recognized complication of mild Haemophilia. Inhibitors tend to develop in adolescence and adulthood and this is frequently preceded by high-intensity factor replacement therapy. We report two patients with mild Haemophilia who developed high responding inhibitors after continuous infusion with recombinant factor VIII (Kogenate) as prophylaxis for surgery. We discuss whether recent changes in clinical practice could be responsible for the apparent increase in high responding inhibitors in mild Haemophilia.

Adult↗