Method of heart transplantation for treatment of hypoplastic left heart syndrome

Technical details of investigational orthotopic cardiac transplantation for management of hypoplastic left heart syndrome in a neonate are presented. Extracorporeal perfusion technique and need for extensive aortic arch reconstruction are emphasized. Although this experience was with a subhuman primate (baboon) donor, source of donor graft makes little difference with regards to the unique technical aspects of cardiac transplantation in a ductus-dependent newborn infant with a diminutive aortic arch.     

Phenotypic expression of histocompatibility antigens in human primary tumours and metastases

HLA class I and II expression was studied on 244 (177 primary and 67 metastatic) solid human tumours of different origin. Alkaline immunophosphatase (APAAP) and immunoperoxidase were used on cryostatic sections to stain MHC antigens. Monomorphic MoAbs were used against class I heavy chain, 2-microglobulin, DR, DQ and DP molecules.Class I expression was homogeneous on colon, melanoma and epidermoidal primitive tumours. Loss of HLA class I antigens was more frequent on basal cell carcinomas and sarcomas and was related to tumour differentiation on larynx carcinoma. Class I expression was heterogeneous on breast, larynx and stomach primitive neoplasias. Class I negative tumours were more frequent on metastatic than on primitive melanomas. Divergence of class I between primary tumours and autologous metastases was observed on melanomas, larynx and colorectal carcinomas.Class II expression was heterogeneous on all tumours and in a large number of cases was associated with high intensity of leukocytic infiltrate. HLA-DR expression was higher than HLA-DP and HLA-DQ (DR>DP>DQ) and was related to tumour progression. Four human tumour cell lines were modulated with recombinant interferon- for HLA class I and II antigens. Different HLA profiles were obtained: increased class I and II expression, increased class II or a low response.Finally, class I genes from 22 tumours were compared with autologous normal cells by Southern blot analysis: 12 tumours were class I positive and 10 negative. No clear differences in RFLP were observed that could be associated with class I rearrangement. The results are discussed in relation to the role that histocompatibility antigens may play in tumour progression and invasiveness.     

Abnormal calcaemic response to PTH in the uraemic rat without secondary hyperparathyroidism

BACKGROUND: Skeletal resistance to the calcaemic action of parathyroid hormone(PTH) is an important pathogenic factor in the development ofsecondary hyperparathyroidism. Since parathyroidectomy normalizesthe calcaemic response to PTH in uraemic animals, the increasein PTH levels has been advanced as a cause of skeletal resistanceto the calcaemic action of PTH. This study was designed to evaluatein uraemic rats the effect of normal PTH levels on the calcaemicresponse to PTH. METHODS: To maintain normal PTH levels, rats were parathyroidectomized(PTX) and rat 1–34 PTH was infused at a rate of 0.022µg/100 g per hour via a subcutaneously implanted miniosmoticpump; this rate of infusion was considered to be the normalPTH replacement dose since it normalized serum calcium and phosphorusin PTX rats with normal renal function. Two separate studieswere performed. In the first study, rats were maintained ona moderate-phosphorus (0.6%) diet and rats were divided intofour groups: (I) normal; (II) uraemic; (III) PTX with normalPTH replacement; and (IV) uraemic with PTX and normal PTH replacement.In a second study, the groups were the same except that a high-phosphorus(1.2%) diet was given to increase the magnitude of hyperparathyroidismin rats with intact parathyroid glands; an additional group(V) identical to group IV except that rats received daily calcitriolwas included. After 14 days, rats received a 48-h infusion ofhigh-dose rat 1–34 PTH (0.11 µg/100 g per hour)to evaluate the calcaemic response to PTH. RESULTS: The calcaemic response to PTH was similar in normal rats andPTX rats with PTH replacement on both a moderate and high-phosphorusdiet. In uraemic rats, the calcaemic response to PTH was decreasedand the maintenance of normal PTH levels by PTH replacementdid not correct the decreased calcaemic response to PTH; moreover,calcitriol supplementation did not improve the calcaemic responseto PTH. Finally, hypocalcaemia was observed in uraemic ratswith PTH replacement and was more profound than in rats on ahigh-phosphorus diet. CONCLUSIONS: This study demonstrates that the maintenance of a normal PTHlevel in uraemic rats did not correct the impaired calcaemicresponse to PTH, suggesting that factors intrinsic to uraemia,independent of phosphorus, calcitriol, and PTH participate inthe decreased calcaemic response to PTH in uraemia.     

Biodegradable micro- and nanoparticles as long-term delivery vehicles for gentamicin

Micro- and nanoparticles of poly(lactide-co-glycolide) (PLGA) loading gentamicin were prepared by a solvent evaporation method with the aim of obtaining appropriate vectors for systemic administration. Microspheres presented mean diameters below 3 microm and nanoparticles showed homogeneous sizes with a diameter of 320 nm. Drug loading was more efficient in the case of microencapsulation. The more hydrophilic copolymers with carboxyl-end groups yielded higher microparticle loadings, reaching encapsulation efficiencies up to 9.2 microg mg(-1) of polymer (502H, 503H or 75:25H). Nanoparticles made of 502H PLGA also achieved an acceptable level of encapsulation (6.2 microg mg(-1)). Particles prepared by using the solvent evaporation method showed no aggregation after hydration, in contrast to the microparticles prepared by spray-drying which showed fast and high auto-aggregation. In vitro release profiles revealed that 503H microspheres showed the highest burst during the first hour, while the most sustained release was for microparticles of 502H copolymer (40% of gentamicin remained in the formulation after 28 days). In summary, microspheres made of 502H, 503H and 75:25H and nanoparticles of 502H showed the best potential properties for systemic use in the treatment of intra-cellular gentamicin-susceptible pathogens.     

Kinesin-2 and photoreceptor cell death: requirement of motor subunits

Kinesin-2 function is essential for photoreceptor cell viability. The removal of one of the kinesin-2 motor proteins, KIF3A, by photoreceptor-specific conditional mutagenesis, has been shown to cause rapid photoreceptor cell degeneration. We have explored the possibility that the genes encoding the kinesin-2 motor proteins (KIF3A, KIF3B, and KIF3C)are linked to retinal disease, by examining retinas of knockout mice. We conclude that the reduced KIF3A and KIF3B in heterozygous animals, or the complete absence of KIF3C in homozygous animals does not affect photoreceptor cell survival. Photoreceptor cell death seems to be limited to conditions that, if systemic, are embryonic lethal, indicating that reduced function of the kinesin-2 motor genes is unlikely to underlie inherited retinal degeneration.     

Vasoconstrictors in spinal anesthesia with tetracaine--a comparison of epinephrine and phenylephrine

A randomized double-blind study was conducted in 50 orthopedic patients to determine the effect of epinephrine and phenylephrine on the anesthetic properties of intrathecally administered tetracaine. Two doses of each vasoconstrictor agent were studied: 0.2 mg of epinephrine, 0.3 mg of epinephrine, 1 mg of phenylephrine, and 2 mg of phenylephrine. The results show that both vasoconstrictor agents in the doses used significantly prolong duration of sensory anesthesia and motor blockade produced by the subarachnoid administration of tetracaine. At equipotent doses no differences existed between the ability of epinephrine and phenylephrine to prolong the duration of spinal anesthesia produced by tetracaine.     

Human antibody to the group-specific polysaccharide of group B Streptococcus

IgG antibody to purified group polysaccharide of group B Streptococcus was detected with a specific, reproducible enzyme-linked immunosorbent assay in sera of 178 human subjects: 106 parturient patients, 67 of their healthy infants, and 5 adults with invasive infection. Antibody concentrations in 44 parturient carriers of group B streptococci were significantly greater than in 44 noncarriers (geometric mean level, 3.5 and 1.2 micrograms/ml, respectively). Cord serum levels agreed closely with maternal serum levels. The sera of 18 mothers of infants with early-onset streptococcal infection contained levels (geometric mean level, 5.5 micrograms/ml) similar to those of carriers and significantly higher than noncarriers. Of five adults with invasive group B streptococcal infection, three demonstrated significant increases in antibody titer in consecutive sera, and four had antibody concentrations greater than most (93%) noncarriers. These findings suggest that group B polysaccharide is immunogenic in humans and that levels of specific IgG antibody increase with colonization or infection of adults with group B streptococci.     

Does consumption of two portions of salmon per week enhance the antioxidant defense system in pregnant women?

Salmon is a rich source of marine n-3 fatty acids, which may increase oxidative stress and, in turn, could affect the antioxidant defense system in blood plasma and erythrocytes of pregnant women. The Salmon in Pregnancy Study provided two meals of salmon per week to pregnant women from week 20 of gestation; the control group maintained their habitual diet low in oily fish. Higher selenium and retinol plasma concentrations were observed after dietary salmon supplementation. Besides, a concomitant increase in selenium and glutathione concentration as well as glutathione peroxidase and reductase activities were detected as pregnancy progressed. However, tocopherols, retinol, β-carotene, and coenzyme Q(10) decreased in late pregnancy. Collectively, our findings lead to the hypothesis that increased farmed salmon intake may increase antioxidant defenses during pregnancy. Clinical trials identifier NCT00801502.     

Full-genome dissection of an epidemic of severe invasive disease caused by a hypervirulent, recently emerged clone of group A Streptococcus

Group A Streptococcus (GAS) causes an exceptionally broad range of infections in humans, from relatively mild pharyngitis and skin infections to life-threatening necrotizing fasciitis and toxic shock syndrome. An epidemic of severe invasive human infections caused by type emm59 GAS, heretofore an exceedingly rare cause of disease, spread west to east across Canada over a 3-year period (2006 to 2008). By sequencing the genomes of 601 epidemic, historic, and other emm59 organisms, we discovered that a recently emerged, genetically distinct emm59 clone is responsible for the Canadian epidemic. Using near-real-time genome sequencing, we were able to show spread of the Canadian epidemic clone into the United States. The extensive genome data permitted us to identify patterns of geographic dissemination as well as links between emm59 subclonal lineages that cause infections. Mouse and nonhuman primate models of infection demonstrated that the emerged clone is unusually virulent. Transmission of epidemic emm59 strains may have occurred primarily by skin contact, as suggested by an experimental model of skin transmission. In addition, the emm59 strains had a significantly impaired ability to persist in human saliva and to colonize the oropharynx of mice, and seldom caused human pharyngitis. Our study contributes new information to the rapidly emerging field of molecular pathogenomics of bacterial epidemics and illustrates how full-genome data can be used to precisely illuminate the landscape of strain dissemination during a bacterial epidemic.