TNFalpha polymorphisms and risk of psoriatic arthritis.

BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a cytokine of critical importance in psoriatic arthritis. OBJECTIVES: (1) To examine the association between TNFalpha promoter gene polymorphisms and psoriatic arthritis in two well characterised Canadian populations with the disease; (2) to carry out a meta-analysis of all TNFalpha association studies in white psoriatic arthritis populations. METHODS: DNA samples were genotyped for five TNF variants by time of flight mass spectrometry using the Sequenom platform. All five single nucleotide polymorphisms were in the 5' flanking region of TNFalpha gene at the following positions: -1031 (T-->C), -863 (C-->A), -857 (C-->T), -308 (G-->A), and -238 (G-->A). Primary analyses were based on logistic regression. Summary estimates of disease/genotype relations from several studies were derived from random effects meta-analyses. RESULTS: 237 psoriatic arthritis subjects and 103 controls from Newfoundland and 203 psoriatic arthritis subjects and 101 controls from Toronto were studied. A combined analysis of data from both populations, showed a significant association between disease status and the -238(A) variant (p=0.01). The meta-analysis estimate for the -238(A) TNFalpha variant in eight psoriatic arthritis populations was also significant (odds ratio=2.29 (95% confidence interval, 1.48 to 3.55)). CONCLUSIONS: Analysis of TNFalpha variants in psoriatic arthritis populations shows that the -238 (A) variant is a significant risk factor for this disease.

Association of SEEK1 and psoriatic arthritis in two distinct Canadian populations.

OBJECTIVE: To examine the relationship between SNP +39604 in SEEK1 and psoriatic arthritis (PsA) in two distinct Canadian populations. METHODS: 103 patients with PsA and 105 ethnically matched controls from Newfoundland and 202 patients with PsA and 100 controls from Ontario were studied. Patients and controls were genotyped for SNP +39604 of SEEK1 by time of flight mass spectrometry, using the Sequenom platform. Genomic DNA was amplified by the Dynal RELI SSO HLA-Cw* typing kit for HLA-C typing. RESULTS: The frequency of the minor SEEK1(T) allele in subjects with PsA and controls was 48.5% and 32.4%, respectively (odds ratio (OR) = 2.0; p = 0.017), in the Newfoundland population and 46.5% and 38.0%, respectively (OR = 1.4; p = 0.16), in the Ontario population. Although SEEK1 is associated with PsA, particularly in the Newfoundland population, multivariate analysis showed that SEEK1 does not seem to be a further susceptibility factor if the HLA-Cw*0602 status is already known. No association was noted between SEEK1(T) allele and onset of psoriasis, PsA, or arthritis pattern. CONCLUSION: SEEK1 is associated with PsA in the Newfoundland founder population. This association is probably due to linkage disequilibrium between SEEK1 and HLA-Cw*0602 in this population.

Bardet-Biedl syndrome 1 genotype and obesity in the Newfoundland population.

BACKGROUND AND OBJECTIVES: Obesity is one of the primary clinical features of Bardet-Biedl Syndrome (BBS), a genetically heterogeneous disorder that is usually inherited as an autosomal recessive trait. It has been suggested that heterozygous carriers of BBS are predisposed to obesity. We set out to identify the common mutation in BBS1 families from southwest Newfoundland and to examine the relationship between this mutation and obesity in the general population. METHODS AND SUBJECTS: We genotyped BBS1 families from Newfoundland to determine the nature of the mutation causing BBS in this population. We then screened 200 obese individuals (average body mass index (BMI)=37.9 kg/m2; average waist to hip ratio=0.935; average waist=113.8 cm) and 200 ethnically matched, unrelated, controls (average BMI=25.0 kg/m2; average waist to hip ratio=0.896; average waist=86.9 cm) from the same geographic region for the presence of this mutation. RESULTS: All affected members of the six Newfoundland BBS1 families were homozygous for the most common BBS1 mutation (M390R). This mutation was found in the heterozygous state in three of the 200 obese individuals and also in three of the 200 matched controls. CONCLUSIONS: The high frequency of BBS1 in Newfoundland appears to be the result of a founder event. Our data do not support the hypothesis that the M390R BBS1 mutation plays a significant role in the frequency of obesity in the general public in Newfoundland.

Surveillance of infectious complications associated with central venous access devices in children with haemophilia.

PURPOSE: To analyse the risk factors for infection associated with central venous access device (CVAD) use in children with haemophilia. METHODS: Risk factors for CVAD infection among patients with congenital haemophilia who had had a CVAD implanted at a single institution were evaluated utilizing the following variables: age at CVAD placement, age at end of study, number of days with a CVAD, percentage of lifetime with a CVAD, and history of inhibitor. RESULTS: Fifty-nine patients had a total of 97,936 (median 1768 days per patient) CVAD days in the study period. The median age at CVAD placement was 2.7 years (range 0-14.0). Twenty-six (44%) patients reported CVAD infections during the study period from January 1993 to October 2000. Twenty-four patients had their CVAD replaced, 17 (71%) of whom reported having infections and seven (29%) of whom had a history of inhibitor. The strongest predictor for having any infections was inhibitor status (P=0.16), although none of the risk factors had statistically significant effects. Among the 26 patients reporting infections, 42% had more than one CVAD-related infection. Seven patients had multiple infections involving the same organism. The mean rate of infection was 0.45 per 1000 catheter days, with a 95% confidence interval of 0.33-0.60. Those with a history of inhibitor had an infection rate of 0.66 compared with 0.38 per 1000 catheter days (P=0.09) for those without a history of inhibitor. Patients who were older (greater than the median age of 2.7) at CVAD placement had a lower rate of infection (0.29 vs. 0.65, P<0.01) compared with those < or =2.7 years. Adjustment for inhibitor status had little impact on these results. For the group as a whole, the median time to first infection was 1977 days from CVAD placement. Patients who were older at CVAD placement or study exit had lower relative hazards of infection (P=0.05 and P=0.09 respectively), while those who had inhibitors had a higher but not statistically significant relative hazard of 1.88 (P=0.13). CONCLUSIONS: These data reveal that while considerable numbers of patients develop CVAD-related infection, the interval between catheter placement and infection can be quite long. In addition, the earlier in life a CVAD is placed, the higher the risk of infectious complications, as evidenced by the tendency towards a higher infection rate. Measures to prevent CVAD-related infection might be focused on very young patients who appear to be at higher risk.

CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis.

A recent genomewide scan in psoriatic arthritis (PsA) revealed a susceptibility locus at 16q. This region overlaps CARD15, a susceptibility gene in Crohn disease. The possibility of a common susceptibility gene between PsA and Crohn disease is further supported by epidemiological studies that note an increased incidence of psoriasis in subjects with Crohn. We screened 187 patients with PsA and 136 healthy controls, all from Newfoundland, for the three common, independent sequence variants of CARD15 (R702W, leu1007fsinsC, and G908R), which were detected by polymerase chain reaction by use of allele-specific primers and visualized through gel electrophoresis. In total, 53/187 (28.3%) probands with PsA had at least one variant of the CARD15 gene, compared with 16/136 (11.8%) controls (odds ratio 2.97; 95% confidence interval 1.61-5.47; P=.0005). Allele frequencies of R702W, leu1007fsinsC, and G908R were 10.43%, 3.21%, and 1.61%, respectively, in patients with PsA, compared with 3.31%, 2.57%, and 0.37%, respectively, in the control patients. CARD15 conferred susceptibility to PsA independent of HLA-Cw*0602. Thus, CARD15 represents a pleiotropic autoimmune gene and is the first non-MHC gene to be associated with PsA.

Primary pulmonary fibrous histiocytoma: report of three cases.

Since 1969, fibrous histiocytoma has been recognized as a distinct entity. It occurs in benign and malignant forms. The authors describe two cases of the malignant pulmonary variety, which is considered very rare, and one case of benign pulmonary fibrous histiocytoma. All patients were treated successfully by local excision; there was no recurrence or metastases after a postoperative follow-up of 1 month, 8 years and 7 years respectively. The diagnosis is confirmed histologically according to criteria set forth by the World Health Organization. Treatment is by early complete surgical excision. Further study is needed to determine the merits of radiotherapy and chemotherapy postoperatively.

The experience and effectiveness of the Nova Scotia Rh program, 1964-84.

A program to reduce the incidence of erythroblastosis fetalis was started in Nova Scotia in 1964. Up to the end of 1984, 120 fetuses received 247 intrauterine transfusions. The survival rate was 45.6% in the first 10 years of the program and 66.7% in the next 11 years. For fetuses at or over 26 weeks' gestation the figures were 51.5% and 73.7% respectively. Postpartum prevention was started in 1968, with administration of Rh immune globulin (RhIG) to Rh-negative unimmunized women within 72 hours after the birth of an Rh-positive infant. Antepartum prevention, started in 1979, consisted of administration of RhIG at 28 weeks' gestation to Rh-negative unimmunized women. The effectiveness of the prevention program was evaluated by enumerating the known cases of Rh(D) alloimmunization in the province from 1982 to 1984: 55 cases were identified, a rate of 1.5 per 1000 births instead of the expected rate of about 10 per 1000.

Amniotic fluid phosphatidylglycerol and phosphatidylcholine phosphorus as predictors of fetal lung maturity.

The contents of phosphatidylglycerol and phosphatidylcholine phosphorus in amniotic fluid (10,000 X g pellets) were studied as predictors of fetal lung maturity. The presence of phosphatidylglycerol predicted the absence of neonatal respiratory distress syndrome with 99% probability. When phosphatidylglycerol was absent, phosphatidylcholine phosphorus was a reliable predictor if measured 3 to 7 days before delivery. The probability that respiratory distress syndrome would not occur was 94% when phosphatidylcholine phosphorus was greater than 6. When measurement was performed within 2 days of delivery, the probability that respiratory distress syndrome would not occur fell to 69%. As measured in amniotic fluid, phosphatidylglycerol and phosphatidylcholine phosphorus are reliable antenatal predictors of fetal pulmonary maturity and, therefore, are useful in the management of a number of obstetric conditions.

Perinatal listeriosis: report of an outbreak.

From April to August, 1981, 15 cases of perinatal listeriosis were seen in Halifax, Nova Scotia, Canada. Nine of the 15 mothers presented with 'flu-like' symptoms, 3 had symptoms of an upper respiratory infection and 2 a history of fever alone. During labor 11 mothers had fevers greater than 38 degrees C and 9 had stained amniotic fluid. Twelve delivered prematurely. Among the 15 infants the most common clinical features were perinatal depression, respiratory distress, fever, hematologic abnormalities and rash. There were 7 deaths (case fatality rate of 46.7%). A transplacental route of infection for the fetus was suggested by the signs of systemic illness in most mothers, the lack of positive maternal vaginal cultures and evidence of chorioamnionitis, premature labor, severe fetal disease and intrauterine death prior to membrane rupture. The delivery of healthy infants to two mothers who had received antepartum treatment for listeriosis suggests that earlier recognition and treatment of maternal disease will improve perinatal outcome.

The antenatal management of the Rh sensitized woman.

The antenatal management of the Rh-sensitized woman is aimed at delivery of a living child with an optimum chance of survival. The author describes the improved methods of management that have dramatically reduced associated perinatal wastage and then goes on to describe the continuing search for new, more effective, and less invasive means of treating the Rh-sensitized pregnancy.

Voluntary regionalization and associated trends in perinatal care: the Nova Scotia Reproductive Care Program.

The Nova Scotia Reproductive Care Program is a system of voluntary regionalization that involves the 37 hospitals in the province that provide obstetric care to a population of 850,000. Between 1971 and 1980, the perinatal mortality rate in the central tertiary care unit for nonreferred patients fell progressively from 12.5 per 1,000 total births to 5.16. For all cases, including high-risk referrals, this rate has fallen from 12.7 to 7.2. During the same interval, the perinatal mortality rate for the province's seven regional hospitals fell from 18.7 to 12.2, and that for the 28 community hospitals fell from 18.4 to 7.0. Analysis of these reductions by fitted trend lines demonstrates statistical significance. Further analysis demonstrates that, with regionalization of perinatal services, it is possible to reduce the perinatal mortality rate in small community hospitals to levels that approximate those of a sophisticated tertiary care hospital.

Assessment of fetal lung maturity: relationship of gestational age and pregnancy complications to phosphatidylglycerol levels.

Phosphatidylglycerol (PG) was measured in the pellet fraction of 863 amniotic fluid samples, and charts were reviewed for maternal disease, duration of gestation at collection, and outcome of pregnancy. PG was present at 32 to 34 weeks' gestation in 24.1% of samples; at 35 to 36 weeks, in 52.3%; and at 37 weeks, in 85.4%. Pre-eclamptic toxemia/hypertension, diabetes, premature rupture of membranes, and preterm labor all had earlier appearance of PG than a comparison group. There was no delay in lung maturity in gestational diabetics or Rh isoimmunization. Infants of patients with overt diabetes with PG greater than or equal to 0.5% did not develop respiratory distress syndrome. This value appeared in 30% of diabetic patients by 35 to 36 weeks and in 76.9% by 37 weeks' gestation.

Phosphatidylglycerol determination on amniotic fluid 10,000 x g pellet in the prediction of fetal lung maturity.

Phosphatidylglycerol and the lecithin/sphingomyelin (L/S) ratio were determined, and the shake test was performed, as indicators of fetal lung maturity, in more than 600 patients. A clinical review of the outcome was made in all patients who underwent delivery within 2 days after collection of amniotic fluid. Correlation was made phosphatidylglycerol, shake test, and L/S ratio results. L/S ratio had a false positive rate of 5%, and a false negative rate of 58.1%. The shake test had a false positive rate of 1.1%, and a false negative rate of 63.5%. Phosphatidylglycerol determination had a false positive rate of 1.8%, and a false negative rate of 26.9%. Phosphatidylglycerol determination is an accurate predictor of fetal lung maturity, and predicts lung immaturity more correctly than do the L/S ratio and shake test.

Fetal scalp blood pH sampling: its value in an active obstetric unit.

Two hundred thirty-two patients had fetal scalp blood pH sampling performed from January 1, 1978, to September 30, 1978. Ninety-eight percent of samples were obtained for fetal heart rate (FHR) changes: 62% for variable decelerations, 10% for late and 3% for early decelerations, 10% for decreased baseline variability, and 12% for baseline rate abnormalities. Fourteen fetuses were mildly acidotic, and six were severely acidotic. All were delivered within 1 hour of the last fetal blood sample. Acidosis was significantly more frequent with late decelerations (p less than 0.05). Neonatal depression was significantly more frequent (50% incidence) only with severe fetal acidosis (p less than 0.05). Complications of fetal blood sampling occurred in 15 infants (6%), and all were minor. Based on independent review of the FHR tracings by three members of the perinatal department, it was estimated that 20 to 30 cesarean sections were avoided by determining fetal blood pH (approximately 10%).

A simplified antepartum high-risk pregnancy scoring form: statistical analysis of 5459 cases.

An antenatal high-risk assessment form has facilitated the identification of the fetus at risk, Although such a form in general has potential limitations its simplicity and demonstrated ability to assist in high-risk selection makes it worth including in an antenatal high-risk program.

Fetal monitoring during maternal cardiac surgery with cardiopulmonary bypass.

Fetal cardiac activity was monitored with an external ultrasound transducer in two patients with clinical class III heart disease due to severe mitral stenosis complicated by pulmonary hypertension, undergoing open heart surgery with cardiopulmonary bypass in the 2nd trimester of pregnancy. Fetal distress was detected in one patient, who had mitral valvuloplasty, and was corrected by increasing the rate of blood flow, and the other patient had a mitral valve replacement but no fetal distress was noted. The postoperative course of both mothers and fetuses was uneventful.