Intravenous low-dose erythromycin administration for infants with feeding intolerance.

BACKGROUND: This study was undertaken to determine the efficacy of low-dose intravenous erythromycin (EM) administration in infants with feeding intolerance. METHODS: The subjects were 26 infants who would not accept enteral feeding within 5 days after birth. Fourteen infants (gestational age: 30.6+/-5.4 weeks and birthweight: 1466+/-825 g) were given EM intravenously at a dose of 1 mg/kg, three times daily (EM group). Doses were increased to 2 mg/kg in five infants who showed a poor response. Twelve infants (gestational age: 30.5+/-5.0 weeks and birthweight: 1317+/-672 g) were observed without EM administration (non-EM group). Blood concentrations of EM at 2 h after administration were measured on 8 (+/-2) days after the start of EM administration in the EM group. RESULTS: Digestive perturbations and intestinal gasless and/or atonic shadows on X-ray findings markedly improved in the EM group soon after the treatment. Comparing the EM group and non-EM group, the postnatal ages at the start of successful enteral feeding were 9.1+/-3.2 days and 14.0+/-4.1 days, respectively (P<0.01). The postnatal ages at feeding of 100 mL/kg per day were 15.2+/-4.0 days and 23.4+/-6.2 days, respectively (P<0.01). The blood EM concentrations of 1 mg/kg and 2 mg/kg were 0.29+/-0.28 microg/mL and 0.57+/-0.20 microg/mL, respectively (P<0.05). No adverse effect on cardiac status or in blood examinations was observed in any infant in the EM group. CONCLUSION: These results suggest that intravenous low-dose EM administration is a useful and safe treatment of feeding intolerance in infants including extremely low-birthweight infants.

Improvement of von Willebrand factor proteolysis after prostacyclin infusion in severe pulmonary arterial hypertension.

BACKGROUND: The presence of dysfunctional von Willebrand factor (vWF) in pulmonary arterial hypertension (PAH) was suggested to be related to increased proteolysis. METHODS AND RESULTS: In 10 patients with severe PAH, we studied the proteolysis of plasma vWF (vWF levels, multimeric distribution, proteolytic pattern, and cleaving protease activity) and hemodynamic variables (mean pulmonary artery pressure, cardiac index, and total pulmonary vascular resistance) at baseline and 30 days after initiation of continuous prostacyclin infusion. At baseline, vWF levels were significantly increased, vWF proteolysis was excessive, and vWF-cleaving protease activity remained normal. These biological abnormalities were reversible and paralleled the improvement of hemodynamics under vasodilator treatment with prostacyclin. CONCLUSIONS: The excessive proteolysis of vWF in PAH is likely to be related to an increased susceptibility of vWF to proteases induced by high shear rates rather than to an enhanced release of enzymes.

Expression of intrapulmonary surfactant apoprotein-A in autopsied lungs: comparative study of cases with or without pulmonary hypoplasia.

To investigate the functional maturity of the lungs of infants with pulmonary hypoplasia, we measured the expression of surfactant apoprotein-A (SP-A) in the autopsied lungs. Autopsied lungs were taken from 16 infants who died at birth or soon after. A lung-to-body weight ratio of less than 1.2% was defined as pulmonary hypoplasia. Eight infants were classified as belonging to the normal group, and eight as belonging to the pulmonary hypoplasia group. Many of the pulmonary hypoplasia group were complicated not only by pulmonary hypoplasia, but also by amniotic fluid volume abnormalities or an anatomical malformation. We measured the expression of SP-A immunologically using murine anti-human SP-A MAb in the autopsied lung tissue, and subjected the tissue to SP-A staining by the direct staining method. The expression of SP-A was assessed as one of four grades: -, +/-, 1+, 2+. The staining intensity of SP-A was high at 1+ or stronger in five infants of the normal group. SP-A expression was significantly reduced, however, in all infants of the pulmonary hypoplasia group except for one infant with normal amniotic fluid volume and relatively mild pulmonary hypoplasia. There was a significant negative correlation between the staining intensity of SP-A and two factors: pulmonary hypoplasia and abnormal amniotic fluid volume (p = 0.039 and p = 0.0063, respectively). In the present study, we demonstrated that SP-A expression was significantly reduced in infants with pulmonary hypoplasia. We speculate that the functional maturity of the lungs of infants with pulmonary hypoplasia is also suppressed.

A Novel Synthesis of Poly(ester-alt-sulfide)s by the Ring-Opening Alternating Copolymerization of Oxiranes with gamma-Thiobutyrolactone Using Quaternary Onium Salts or Crown Ether Complexes as Catalysts.

Poly(ester-alt-sulfide) (polymer 1) was synthesized by the alternating copolymerization of glycidyl phenyl ether (GPE) with gamma-thiobutyrolactone (TBL) catalyzed by either quaternary onium salts or crown ether complexes. The copolymerization proceeded to produce polymer 1 with good yields in neat or in various organic solvents at 30-120 degreesC, in which quaternary onium salts having Cl- as a counteranion such as tetrabutylammonium chloride (TBAC) had higher activity than quaternary onium salts such as tetrabutylammonium bromide having Br- as a counteranion. It was also found that the alternate copolymer (polymer 1) of GPE with TBL was obtained selectively under different feed ratios of GPE and TBL, although ring-opening homopolymerizations of GPE and TBL did not proceed. Copolymerizations of various oxiranes such as butyl glycidyl ether, styrene oxide, and 1,2-hexene oxide with TBL catalyzed by TBAC also proceeded, and the corresponding poly(ester-alt-sulfide)s (polymers 2, 3, and 4) were obtained under the same conditions as for the synthesis of polymer 1.

Neonatal erythema infectiosum.

A report is presented of a patient with neonatal erythema infectiosum who developed petechiae, transient thrombocytopenia and transient cardiac failure due to transplacental transmission of human parvovirus B19 (HPV B19) infection. It is suggested that the thrombocytopenia was caused by platelet-associated IgG produced by the patient, and that the cardiac failure may have been caused by direct entry of HPV B19 into the cardiac tissue.

Abnormal proteolytic processing of von Willebrand factor Arg611 Cys and Arg611His.

The structural and functional properties of plasma and platelet vWF were studied in 8 patients (5 unrelated families) with vWD demonstrating a mutation at position 611 (R611C or R611H). Following reduction, electrophoresis and immunoblotting with a polyclonal anti-reduced vWF antibody, abnormal proteolysis of vWF was demonstrated in plasma and to a lesser extent in platelets from all patients, leading to the formation of a unique 209 kDa fragment undetectable in control as well as in type 2A, 2B or 2N vWF. Immunoblotting with MoAbs to reduced vWF showed that the C-terminal end of the 209 kDa fragment was located beyond residue 1744 of the subunit and that its N-terminus was between residues 523 and 1114. Multimeric analysis of patients vWF showed an abnormal pattern in both plasma and platelets, with a moderate decrease of the HMW multimers together with a significant increase of the lowest MW forms. The specific sensitivity of vWF R611C and vWF R611H to proteolysis was further evidenced using V-8 protease. In all patient's samples the enzyme produced a unique monomeric 80 kDa fragment, absent in V-8 digested normal vWF, which overlapped the N-terminal part of the subunit. The functional analysis of vWF showed a markedly decreased affinity of mutated plasma vWF for platelet GPIb in the presence of ristocetin. Infusion of DDAVP in two of these patients did not lead to significant platelet count change. It induced a limited increase of the HMW multimers in plasma together with a poor correction of the vWF binding to platelet GPIb. In conclusion, our data demonstrate that in addition to a normal proteolysis, vWF mutated at position 611 undergoes a specific cleavage in plasma and platelets. In contrast to the increased proteolysis observed in type 2A and 2B patients' plasma, this additional cleavage produced a unique 209 kDa species but maintained a HMW multimer-like structure of vWF R611C and R611H.

Characterization of recombinant von Willebrand factors mutated on cysteine 509 or 695.

The interacting domain of vWF with platelet GPIb has been shown to overlap the large A1 loop formed by the intra-chain disulfide bond linking Cys 509 to Cys 695. In order to further investigate the role of the conformation of this region, we have expressed in COS-7 cells three mutated full-length recombinant vWFs (rvWFs) in which the substitutions Cys509Gly, Cys509Arg or Cys695Gly have been introduced by site-directed mutagenesis. SDS-agarose gel electrophoresis demonstrated an impaired multimerization of the mutants with undetectable high molecular weight multimers and a decrease of the relative amounts of the intermediate sized multimers. Binding analysis showed that rvWFC509G and rvWFC509R did not interact with botrocetin but spontaneously interacted with GPIb; the latter binding remained unchanged in the presence of ristocetin. This indicates that the substitution of Cys509 by Gly or Arg creates a conformation of vWF that increases its binding to GPIb. In contrast, rvWFC695G which did not react with botrocetin was also unable to interact with GPIb even in the presence of ristocetin, indicating that sequences interacting with GPIb are masked and/or disrupted. In conclusion, the substitution of each of the Cys509 and 695 results in mutant proteins which may be "locked" into active or inactive conformations in regard to the binding to platelet GPIb receptor.

Investigation of type IIC von Willebrand disease.

Type II von Willebrand disease (vWD) is characterized by qualitative abnormality of von Willebrand factor (vWF). It is characterized by the absence of the largest, or the largest and intermediate-size plasma vWF multimers. Type IIC vWD is a very rare variant subtype. We report the tenth case of type IIC vWD who is a 32-year-old Japanese with a history of lifelong mild bleeding problems. The multimeric analysis of vWF of the patient's plasma revealed that the multimers were composed of the increased smallest multimer and progressively decreased larger multimers, with each multimer replaced by a single band instead of a normal triplet structure. The family study highly suggested that the propositus is the first case of homozygote for type IIC vWD gene, although previous studies have suggested that type IIC vWD is due to double heterozygosity of two different mutant genes. The patient's von Willebrand factor antigen showed a slight response to 1-deamino-8-D-arginine vasopressin (DDAVP), whereas his ristocetin cofactor showed no response. The patient responded very well to an intermediate-purity factor VIII concentrate, and then underwent cholecystectomy without bleeding problems.

Renal impairment in very low birthweight infants following antenatal indomethacin administration.

Three cases of neonatal renal insufficiency in very low birthweight (VLBW) infants following repeated antenatal administration of indomethacin to prevent premature labor are reported. Three pregnant women received indomethacin (total doses of 150-850 mg) for 3-14 days from admission until delivery. The gestational ages and birthweights of the infants ranged from 24 to 28 weeks and 612 to 1432 g, respectively. Oliguria, early onset of hyperkalemia and prolonged renal dysfunction occurred after birth. Renal failure did not improve in one infant. Despite the efficacy of indomethacin for tocolysis in premature labor, VLBW infants born after repeated maternal administration near the time of delivery may have developed impairment of the premature kidney.

Hemostatic effect of a heat-treated factor VIII concentrate (Haemate P) in von Willebrand's disease.

A heat-treated factor VIII (F VIII) concentrate (Haemate P) has been administered to patients with various types of von Willebrand's disease (vWD). The 4 activities of F VIII/vWF as well as change in the multimeric structure of vWF were then studied. In 4 patients with type I vWF who were given a Ristocetin cofactor (Rcof) dose of 42-78 U/kg, there was a clear reduction of the bleeding time and an increase of F VIII: C, F VIII: Ag, Rcof and vWF: Ag for several hours. The recovery of Rcof. after 1 h was 50-75%. Although the multimeric composition of vWF in these patients was similar to that of normal plasma, the density of each multimer band was very low. After infusion, however, the density of all multimer bands increased for several hours, to decrease again after 24 h. In 4 patients with type II A vWD who received a dose of Rcof of 55-76 U/kg, the 4 activities of F VIII/vWF increased similarly as was the case in type I. All patients had only 3-4 smaller multimer bands. New larger and intermediate multimers appeared for several hours after infusion of the preparation. Two patients with type III vWD who received doses of Rcof of 52 and 65 U/kg showed also a similar increase in the 4 activities of F VIII/vWF after infusion. All the multimers lacking in these patients appeared for several hours after infusion.