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Type 3 von Willebrand's disease (VWD) is a rare bleeding diathesis with complete or near complete deficiency of von Willebrand factor (VWF) and low factor VIII (FVIII) levels. In contrast, only FVIII is decreased in haemophilia A (HA). Both disorders are complicated by arthropathy. The purpose of this study was to further clarify the roles of FVIII and VWF: Antigen (VWF:Ag) in joint range of motion (ROM) loss over time. We compared joint ROM loss and other bleeding manifestations in 100 Type 3 VWD subjects (FVIII<5%) and 1814 moderate HA subjects (FVIII 1-5%) within the U.S. Universal Data Collection (UDC) database. High rates of bleeding were reported at baseline. During follow-up, moderate HA patients reported a joint (46% vs. 34%, P < 0.0001) or muscle bleed (27% vs. 16%, P < 0.0001) in a higher proportion of visits than VWD patients. Other bleeds, including mucosal, were reported in a greater proportion of visits among patients with Type 3 VWD than among those with HA (49% vs. 32%, P < 0.0001). Multivariate analysis revealed no difference in joint ROM loss over time in the Type 3 VWD vs. moderate HA populations. A higher FVIII level was protective in both VWD and HA (P < 0.001). Our findings support the hypothesis of primacy of the FVIII level in determining risk of joint haemorrhage, and may help target therapy in Type 3 VWD and moderate HA to prevent joint disability.

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AIMS: to review our single-center experience of preemptive anticoagulation for the prevention of allograft thrombosis in patients with hypercoagulable states. MATERIAL AND METHODS: this is a retrospective cohort study. Included subjects were first-time kidney allograft recipients transplanted between 2003 and 2007 at a single center, with hypercoagulable states: prior venous thromboembolism, multiple vascular access thromboses, or identifiable thrombophilia. The predictor variable was preemptive anticoagulation and outcome variable was allograft thrombosis. Other risk factors for allograft thrombosis, characteristics of transplantation, and hemorrhagic complications were also examined. RESULTS: among this high-risk cohort (n = 48), 16 received preemptive anticoagulation and 32 did not. The anticoagulated group included significantly more subjects with identifiable thrombophilia (50.0% vs. 0%; p < 0.001). One subject (6.3%) in the anticoagulated group and 6 (18.8%) without anticoagulation developed allograft thrombosis (p = 0.40). A perinephric hematoma was observed in 5 (31.3%) and 2 (6.3%) with and without anticoagulation, respectively (p = 0.03). CONCLUSIONS: preemptive anticoagulation was associated with a non-significant trend towards decreased allograft thrombosis. It may be associated with increased risk of hemorrhage and should be considered cautiously in high-risk patients.

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Type 3 von Willebrand disease (VWD) is a rare bleeding disorder with markedly decreased or absent von Willebrand factor (VWF) protein, accompanied by a parallel decrease in VWF function and factor VIII (FVIII) activity. The goal of this study was to describe the population of patients enrolled in the USA Centers for Disease Control Universal Data Collection (UDC) study with type 3 VWD, defined as a VWF:Ag of <10%, and to correlate bleeding symptoms with VWF and FVIII levels. Data on 150 patients were analysed. Almost all patients experienced bleeding episodes (98%) and required blood and/or factor product treatment (92%). While oral mucosal bleeding (the site of first bleed in 54%) was most common, subsequent muscle and joint bleeds were also seen (28%, 45%, respectively), and intracranial haemorrhage occurred in 8% of individuals. Mean age of first bleed was lower in those with either a FVIII < or =5% or a VWF:Ag <1%. Univariate marginal model analysis showed lower levels of FVIII and VWF:Ag both predicted a higher risk of joint bleeding. Longitudinal multivariate analysis found a lower FVIII level (P = 0.03), increasing age (P < 0.0001), history of joint bleeding (P = 0.001), higher body mass index (BMI) (P < 0.0001), and use of home infusion (P = 0.02) were all negatively associated with joint mobility. Low levels of VWF:Ag (P = 0.003) and male sex (P = 0.007) were also negatively associated with joint function. This study documents the strong bleeding phenotype in severe VWD and provides data to help target therapy, including prophylaxis, for patients most at risk of bleeding complications.

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Exogenous surfactant therapy is not standard in the acute respiratory distress syndrome (ARDS) because of a lack of proven benefit. Nonuniform surfactant distribution after either bolus or aerosol administration may be an important factor limiting response. In a previous study of acute lung injury, we demonstrated that lavage administration of Exosurf (13.5 mg phospholipid/ml) was both effective and distributed uniformly in the lungs. Since the endogenous surfactant pool is much smaller than the typical dose of exogenous surfactant administered, we hypothesized that dilute surfactant preparations (4-4.5 mg phospholipid/ml) administered by lung lavage would be equally effective in reversing pulmonary dysfunction in a piglet model of acute lung injury. We compared three dilute surfactants: Infasurf (n = 5), KL4-Surfactant (n = 6), and Exosurf (n = 5) with controls (n = 6) and undiluted Exosurf (13. 5 mg phospholipid/ml; n = 6). All dilute surfactant preparations were effective in improving oxygenation and other parameters of pulmonary function. Surfactant administered by lavage resulted in uniform lung distribution. We conclude that dilute surfactants administered by lung lavage are effective in reversing pulmonary dysfunction after acute lung injury. We speculate that doses in the range of 20-40 mg phospholipid/kg may be adequate to improve lung function in ARDS when exogenously administered surfactant is uniformly distributed in the lung.

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In a prospective hospital based study, during the period from Jan 95 to Dec 96, 3100 consecutively delivered live newborns were studied for the incidence of low birth weight neonates and to evaluate the associated risk factors. One thousand fourteen newborns were classified as low birth weight babies. The incidence expressed per 1000 live births was 327 (32.7%). Of these, 815 (80.4%) were small for gestational age neonates and 199 (19.6%) were preterm neonates. Five hundred seventy small for gestational age neonates (70%) were weighing between 2001 to 2500 gms. Mothers belonging to the age group of 19-25 years delivered the maximum number of low birth weight babies (618/1014) and of these 82.8% were small for gestational age neonates. There were 48 neonates with low birth weight born to mothers below the age of 18 years. Primiparous mothers were found to contribute higher number of low birth weight neonates (414/1014). Spacing as a factor did not show any major difference. Two hundred sixty two low birth weight neonates were born to mothers with significant obstetrical problems such as pregnancy induced hypertension, bad obstetrical history and premature rupture of membranes. The incidence of 32.7% of low birth weight babies is high enough to ring alarm bells.

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One hundred, non-consecutive, non-randomized, cases of tuberculosis divided in 2 groups i.e. Group A including 50 BCG vaccinated children and Group B including 50 unvaccinated children were studied to determine the pattern of tuberculosis and the role of protein energy malnutrition in the pathogenesis of tuberculosis. Thirty four per cent of Group A and 52 per cent of Group B had severe protein energy malnutrition. Sixty eight per cent in Group A and 76 per cent in Group B had intrathoracic forms of tuberculosis. Twelve (24%) patients in Group A and 11 (22%) in Group B suffered from serious forms of tuberculosis including tubercular meningitis, miliary tuberculosis and disseminated tuberculosis. The difference was not statistically different (p>0.05). However, in severe form of tuberculosis, the morbidity in vaccinated group was less. Sixty six per cent of vaccinated children with disseminated forms of tuberculosis had features of severe protein energy malnutrition. BCG is not effective in preventing tubercular infection in children of preschool age. It is effective to a certain extent in localizing the infection to a particular organ. Severe protein energy malnutrition is a contributing factor in the genesis of tuberculosis in preschool children vaccinated with BCG at or immediately after birth.

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Abnormalities of pulmonary surfactant function have been described in association with the acute respiratory distress syndrome (ARDS). Because gram-negative sepsis is a common cause of ARDS, we treated neonatal piglets with Escherichia coli endotoxin to create a neonatal ARDS model. We hypothesized that under these conditions administration of exogenous surfactant would improve pulmonary function. Study groups included: control (n-8), Exosurf (5 mL/kg, 13.5 mg phospholipid/mL, n-7), Survanta (4 mL/kg, 25 mg phospholipid/mL, n-6), and saline (5 mL/kg, n = 6). E. coli endotoxin 12 micrograms/kg was infused over 30 min and resulted in significant pulmonary and hemodynamic abnormalities, histopathologic evidence of nonhomogeneous lung injury, and elevated protein levels in bronchoalveolar lavage washings. Neither Exosurf nor Survanta ameliorated the pulmonary effects of endotoxin. Instead, there was a prolonged decrease in arterial oxygen tension (PaO2) and dynamic lung compliance after administration of surfactant and saline. Distribution of a bolus of Exosurf was uneven throughout the lung. We conclude that in this neonatal piglet model of ARDS, bolus surfactant administration had a detrimental effect on oxygenation and pulmonary function.

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Despite evidence of surfactant dysfunction in the acute respiratory distress syndrome (ARDS), treatment with exogenous surfactant remains experimental. Uneven pulmonary distribution is one factor that may limit response. We investigated whether exogenous surfactant administered by lavage, consisting of a 35 ml/kg volume instilled by gravity and followed immediately by passive drainage (LAVAGE), would result in better lung distribution and physiologic response than with surfactant administered as a 5 ml/kg bolus (BOLUS). Exosurf, an artificial surfactant, was administered after acute lung injury induced by saline lung lavage in neonatal piglets. In the LAVAGE group (n= 9), 10.1 +/- 0.4 ml/kg of surfactant was retained, corresponding to a phospholipid dose of 136 +/- 5 mg/kg. In the BOLUS group (n = 9), the dose administered was 203 mg/kg phospholipid. Piglets in the LAVAGE group demonstrated greater improvement in pulmonary function, including PaO2, PaCO2, ventilation efficiency index, functional residual capacity (FRC), and pressure-volume curves than piglets in the BOLUS group. Some differences were found in lung distribution of surfactant. We conclude that Exosurf is more effective when administered by lavage in this lung injury model. We speculate that the lavage method of administration holds promise as an alternative method of surfactant administration in patients with ARDS.

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Evidence for surfactant dysfunction in acute respiratory distress syndrome (ARDS) suggests a role for exogenous surfactant which contains apoprotein for resistance to protein inhibition. We compared the effects of KL-4-Surfactant, an artificial preparation containing a synthetic 21 amino acid peptide with SP-B-like activity, with Exosurf, an artificial protein-free surfactant, and Survanta, a bovine protein-containing surfactant, in a saline lung lavage model of ARDS in neonatal piglets. Two sequential series of lung lavages were performed to lower PaO2 < 100 mm Hg, each followed by administration of surfactant or air and a 90-min observation period. Progressive lung injury was demonstrated by deterioration in pulmonary function, increasing bronchoalveolar lavage protein, and changes in histopathology. All surfactants improved oxygenation, although oxygenation was generally better with Survanta and KL-4-Surfactant. Further, Survanta and KL-4-Surfactant groups showed improvement in ventilation, with decreases in PaCO2 and increases in FRC. Only KL-4-Surfactant demonstrated greater pressure-volume characteristics and lower bronchoalveolar protein than those of Controls. We conclude that the physiologic effects of KL-4-Surfactant are more like Survanta in this model. We speculate that KL-4-Surfactant may improve pulmonary function, reduce alveolar protein leak, and thus be efficacious in the treatment of ARDS.

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