Anti-endotoxin therapy in primate bacteremia with HA-1A and BPI.

OBJECTIVE: The in vivo neutralizing activities of an anti-lipopolysaccharide (LPS) antibody HA-1A (Centoxin [Centocor, Malvern, PA]), a human immunoglobulin M monoclonal antibody, and of bactericidal/permeability-increasing protein (BPI), an endogenously produced human LPS-neutralizing protein, were studied in a primate model of lethal Escherichia coli bacteremia. SUMMARY BACKGROUND DATA: HA-1A has been used with variable success against LPS activity in some animal models and in a recently reported clinical trial. However, no data assessing the efficacy of this agent in subhuman primates is available. Bactericidal/permeability-increasing protein is a product of polymorphomononuclear cells (PMNs) that is stored in azurophilic granules and exhibits LPS-neutralizing activity in vitro and in some in vivo models. METHODS: Immediately after E. coli infusion and in a blinded fashion, three baboons were treated with BPI (5 mg/kg bolus infusion and 95 micrograms/kg/min infusion over 4 hr). Three animals received 3 mg/kg BW of HA-1A, whereas another three baboons received a placebo treatment. RESULTS: The BPI-treated animals demonstrated significantly (p < 0.03) lower circulating LPS-limulus amoebocyte lysate (LAL) activity compared with the control animals, but this reduction in LPS-LAL activity was not associated with improved survival. HA-1A treatment did not reduce LPS-LAL activity. However, both BPI and HA-1A treatment did attenuate the pro-inflammatory cytokine response. CONCLUSION: The current data suggests that incomplete neutralization of endotoxin activity does not alter mortality from severe bacteremia. Given the diversity of mediator production under such circumstances, a strategy of combination therapy in the form of anti-lipopolysaccharide and anticytokine treatment may be necessary to achieve optimal survival.     

Gastro-oesophageal reflux disease: Medical or surgical treatment? Report of an interactive workshop

Gastroesophageal reflux disease (GERD) is the most common disease of the upper gastrointestinal tract. With the introduction of proton pump inhibitors medical treatment of GERD has been significantly improved. However, the development of laparoscopic antireflux surgery resulted in an increasing interest of surgeons in this disease. An interactive meeting was organized in order to develop an agreement between gastoenterologists and surgeons regarding therapeutic decisions and this is the main topic of this paper.     

The frequency, prognosis and significance of nerve injuries in total hip arthroplasty

Summary. Although the incidence of post-operative nerve palsy after total hip replacement is rare, it is an important complication for the patient. In a retrospective study the results of 2713 hip arthroplasties were reviewed. Sixty-one cases (2.24%) of post-operative neuropathy were identified, 13 of the sciatic nerve, 33 of the peroneal nerve and 15 of the femoral nerve. The risk is significantly higher in revisions (3.06%), especially when exchanging the acetabular component (8.5%) rather than in primary arthroplasties (2.13%). After an average period of 107 months (11 – 240) from operation, 41 patients with nerve lesions were questioned about their subjective functional capacity: 17% had recovered completely, 39% had noticed an improvement, and in 44% there was no change; 56.1% complained of weakness and had a complete paralysis. In all cases there was dysfunction of sensibility. Another 17.1% had a sensibility defect without weakness. There was pain in 51.2%, paraesthesia in 34.1% and areas of complete anaesthesia in 19.5%. Altogether 61% of the 41 patients had either gait problems or were dependent on orthotic devices. In summary, only about a third of the patients studied achieved a satisfactory degree of functional recovery.

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Résumé. Bien que les lésions nerveuses soient assez rares après l’implantation de prothèses totales de la hanche, il s’agit d’une complication grave pour le patient. Dans une étude rétrospective, on a analysé les résultats de 2723 endoprothèses totales: il y avait 61 cas de neuropathie postopératoires, 13 cas concernaient le nerf sciatique, 33 cas le nerf sciatique poplité externe et 15 cas le nerf crural. Le risque augmente d’une manière plus significative en cas de révision (3,06%) – surtout en cas de changements isolés du cotyle (8,5%) – qu’en cas d’implantation de prothèses primaires. Après une durée moyenne de 107 mois (11 – 240), 41 patients ont été interrogés sur leurs pertes fonctionnelles actuelles: 17% parlaient d’une récupération complète, 39% d’une récupération partielle, et 44% d’une absence de récupération.

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Accepted: 29 April 1996     

Beta-defensin genomic copy number is not a modifier locus for cystic fibrosis

Human beta-defensin 2 (DEFB4, also known as DEFB2 or hBD-2) is a salt-sensitive antimicrobial protein that is expressed in lung epithelia. Previous work has shown that it is encoded in a cluster of beta-defensin genes at 8p23.1, which varies in copy number between 2 and 12 in different individuals. We determined the copy number of this locus in 355 patients with cystic fibrosis (CF), and tested for correlation between beta-defensin cluster genomic copy number and lung disease associated with CF. No significant association was found.     

Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1)

Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. In the most common subtype (TD1), femurs are curved, while in TD2, straight femurs are associated with cloverleaf skull. Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene were identified in both subtypes. While TD2 was accounted for by a single recurrent mutation in the tyrosine kinase 2 domain, TD1 resulted from either stop codon mutations or missense mutations in the extracellular domain of the gene. Here, we report the identification of FGFR3 mutations in 25/26 TD cases. Two novel missense mutations (Y373C and G370C) were detected in 8/26 and 1/26 TD1 cases respectively. Both mutations created cysteine residues in the juxta extramembrane domain of the receptor. Sixteen cases carried the previously reported R248C (9/26 cases), S249C (2/26 cases) or stop codon FGFR3 mutations (5/26 cases). Our results suggest that TD1 is a genetically homogeneous condition and give additional support to the view that newly created cysteine residues in the extracellular domain of the protein play a key role in the severity of the disease.      

Morphological analysis of degeneration and regeneration of syncytiotrophoblast in first trimester placental villi during organ culture

We have recently shown using dansyl-L-lysine exclusion studies that the release of human chorionic gonadotrophin (HCG) in conjunction with L- lactate dehydrogenase (LDH) from first trimester villi during organ culture is symptomatic of syncytiotrophoblast degeneration. The purpose of this study was to examine chorionic villi at the ultrastructural level in order to determine events occurring during organ culture. The tissue was sampled after 0, 24, 48 and 120 h in culture and processed for electron microscopy. In addition to confirming the previously recorded syncytial degeneration, the electron micrographs showed clearly the generation of a new syncytiotrophoblast layer. The new layer, derived from differentiating cytotrophoblast cells, was largely formed by 48 h and was maintained for at least 120 h in culture. This study demonstrates a model which provides an opportunity to study the differentiation of cytotrophoblast cells whilst they retain their anatomical relationships within the villous structure.