Evaluating the validity of animal models for research into therapies for immune-based disorders

The last few decades of the 20th century have shown an intensified search for safer and more effective medications against chronic diseases that burden ageing societies of the western world. The impressive development of biotechnological production techniques has greatly facilitated the pharmaceutical development of relatively non-toxic biological molecules. However, despite the huge investments, only a few effective therapies for immune-based diseases have reached the clinic. In this article we use examples from monoclonal antibody trials to discuss the validity and predictive strength of the animal models currently used for the development of effective therapies.     

Two further cases of Ohdo syndrome delineate the phenotypic variability of the condition

Ohdo syndrome (MIM 249620) is a multiple malformation syndrome characterized by blepharophimosis, ptosis, dental hypoplasia, hearing impairment and intellectual disability. A wide range of dysmorphic features and congenital abnormalities have been described in cases reported as Ohdo and Ohdo-like syndromes. We report a further two cases of Ohdo syndrome, one with mild features and the other more severely affected, illustrating the phenotypic variability of the condition. A review of the literature highlights the severe phenotype associated with distinctive facial features, as seen in Case 2 in this report All cases with the severe phenotype have been sporadic. Subtelomeric FISH studies of all chromosome arms on the two cases showed no abnormality. We propose clinical criteria for the diagnosis of Ohdo syndrome and delineate features of the severe phenotype.     

Imipenem resistance in Salmonella enterica serovar Wien related to porin loss and CMY-4 beta-lactamase production

Two multidrug-resistant Salmonella enterica serovar Wien strains (SW468 and SW1107) were isolated in 2001 in Tunis. Both strains produced the beta-lactamases TEM-1, SHV-2a, and CMY-4, whereas strain SW1107 also produced the beta-lactamase CTX-M-3. The imipenem-resistant strain (SW468) was totally devoid of the OmpF-immunorelated porin. Imipenem resistance was shown as being related to porin loss and CMY-4 beta-lactamase production.     

Obstetric analgesia and anesthesia with remifentanyl in a patient with von Willebrand disease

A 30-year-old woman with von Willebrand's disease was admitted in labor. As epidural analgesia was ruled out due to risk of spinal hematoma, a pump for patient-controlled analgesia (PCA) was provided with boluses of remifentanil and set for intravenous infusion of 24 micrograms with a lockout time of 5 minutes. The patient reported analgesia to be satisfactory. Later, because of abnormal fetal positioning, an emergency cesarean was performed with the patient under general anesthesia with remifentanil, with propofol and succinylcholine for induction. A healthy girl was born free of respiratory depression. Von Willebrand's disease is a hemorrhagic disorder of autosomal dominant inheritance due to a quantitative or functional factor VIII deficit. Various subtypes and degrees of severity of abnormal bleeding have been described. It is the most common genetic hemostatic disorder affecting obstetric procedures, and although epidural analgesia has been used with strict hematologic monitoring, that technique carries a risk of hematoma. PCA is useful in patients for whom regional techniques are contraindicated. With adequate fetal and maternal monitoring, remifentanil in PCA is safe and more effective than other opiates for labor pain.     

Cross-reactivity between related sequences found in Acinetobacter sp., Pseudomonas aeruginosa, myelin basic protein and myelin oligodendrocyte glycoprotein in multiple sclerosis

To investigate the possible role of molecular mimicry to bacterial components in multiple sclerosis (MS) pathogenesis we examined antibody responses to mimicry peptide sequences of Acinetobacter, Pseudomonas aeruginosa and myelin components. Antibodies to mimicry peptides from Acinetobacter (p<0.001), P. aeruginosa (p<0.001), myelin basic protein (MBP) (p<0.001) and myelin oligodendrocyte glycoprotein (MOG) (p<0.001) were significantly elevated in MS patients compared to controls. Antisera against MBP (residues 110-124) reacted with both Acinetobacter and Pseudomonas peptides from 4- and gamma-carboxymuconolactone decarboxylase, respectively. MOG (residues 43-57) antisera reacted with Acinetobacter peptide from 3-oxo-adipate-CoA-transferase subunit A. The role of these bacteria in MS is unclear but demonstrates that molecular mimicry is not restricted to viruses suggesting bacterial infections could play a role in MS pathogenesis. Further work is required to evaluate the relevance of these cross-reactive antibodies to the neuropathology of MS.     

Effects of D-002 on Lipid Peroxidation in Older Subjects

D-002 is a mixture of higher aliphatic alcohols isolated from beeswax that inhibits rat microsomal lipid peroxidation in vitro and in vivo. This study was undertaken to investigate whether D-002 also inhibits lipid peroxidation in older subjects. The free radical theory of aging suggests that progressive defects in the protection against free radical reactions leads to progressive deleterious effects of free radicals on cells and tissues. This free radical damage has been implicated in several pathophysiological processes associated with the chronic degenerative diseases that occur with aging. Forty-eight older subjects were randomly assigned, in a double-blind fashion, to receive placebo or D-002 tablets (50 mg/day) once daily. At baseline, D-002 and placebo groups were well matched regarding several variables. D-002 significantly reduced the susceptibility of nonfractionated plasma samples to copper-mediated lipid peroxidation. It also significantly increased the length of the lag phase (P <.001) and the total antiioxidant status (P <.05) compared with baseline and placebo. In addition, D-002 significantly decreased malondialdehyde levels (expressed in terms of thiobarbituric acid reactive substances (TBARS, P <.001) compared with baseline, but not with placebo. No significant changes on lipid peroxidation parameters were observed in the placebo group. We conclude that D-002 treatment may be useful to prevent or manage certain pathophysiological conditions in the elderly.     

Antioxidant effects of D002 on the in vitro susceptibility of whole plasma in healthy volunteers

BACKGROUND: It has been recently shown that oral administration of D002, a mixture of higher aliphatic primary alcohols isolated from beeswax, inhibits rat microsomal lipid peroxidation. This justified the present attempt to investigate whether D002 also exerts antioxidant effects in humans. METHODS: The effects of D002 on lipid peroxidation were studied in a double-blind, randomized, placebo-controlled trial conducted in 50 healthy volunteers. Unfractionated plasma samples at baseline and at 12 weeks were subjected to in vitro copper-induced lipid peroxidation and conjugated diene generation was monitored by changes of optical density. RESULTS: The oral treatment with D002 (50 mg/day) not only significantly prolonged (p <0.001) lag time before the onset of conjugated diene formation compared with that of baseline but also increased (p <0.05) lag phase when compared with placebo group. In fact, in the D002 group the lag-phase of oxidation was prolonged 1.5-fold. D002 oral treatment decreased TBARS and increased plasma total antioxidant status (TAS) (p <0.01). CONCLUSIONS: Because prooxidant states have been linked to normal senescence and some age-related diseases, the present data suggest that D002 may find a use in preventing age-related diseases as a dietary natural antioxidant supplement.