Immunization against anthrax with aromatic compound-dependent (Aro-) mutants of Bacillus anthracis and with recombinant strains of Bacillus subtilis that produce anthrax protective antigen.

The safety and efficacy of five prototype, live anthrax vaccines were studied in Hartley guinea pigs and CBA/J and A/J mice. Two of the strains, Bacillus anthracis FD111 and FD112, are Aro- mutants derived by Tn916 mutagenesis of B. anthracis UM23-1. Bacillus subtilis PA1 and PA2 contain a recombinant plasmid, pPA101 or pPA102, respectively, that carries the gene from B. anthracis encoding synthesis of protective antigen (PA). The final strain, B. subtilis PA7, was isolated in this study from B. subtilis DB104 transformed with pPA101. All five strains were less virulent in guinea pigs and A/J and CBA/J mice than the toxinogenic, nonencapsulated B. anthracis veterinary vaccine Sterne strain. A/J and CBA/J inbred mice represent strains that are innately susceptible and resistant, respectively, to the Sterne strain. These differences in susceptibility are due to differences in ability to produce complement component 5. In guinea pigs, immunization with PA1 or PA2 vegetative cells or PA7 spores protected greater than or equal to 95% from an intramuscular spore challenge with the virulent, "vaccine-resistant" B. anthracis Ames strain. Strain PA2 vegetative cells and strain PA7 spores were as effective as the Sterne strain in Sterne-resistant CBA/J mice, protecting 70% of the mice from Ames strain spore challenge. Immunization with FD111 or FD112 vegetative cells fully protected guinea pigs from challenge. Immunization with FD111 cells protected up to 100% of CBA/J mice and up to 70% of A/J mice.     

Probe "balloon on a wire" ultra-low-profile coronary catheter: results of PTCA in 107 patients

A new low-profile "balloon-on-a-wire" angioplasty catheter, the Probe (USCI), was used in 107 patients over a 4-month period. Twenty-nine patients had stable angina, 59 had unstable angina, and 19 had had myocardial infarction (MI) 3 to 15 days prior to the procedure; 71 patients had single-vessel and 36 had multi-vessel disease. In this series, 57 lesions were defined as complex. Successful dilatation was defined as a residual stenosis of less than 30%. Of 132 non-total obstructions, 127 (97%) were successfully dilated. Two distal lesions could not be reached, two lesions could not be crossed by the balloon, and a distal lesion dilatation resulted in acute closure in one case. Of 19 total obstructions, 16 (84%) were successfully dilated (mean residual stenosis 23%). The wire tip was unable to cross the lesion in the three unsuccessful procedures. Seven complications occurred in the series, all involving non-total obstructions: closure of a distal vessel and a side branch caused no clinical symptoms or EKG changes; three local dissections were tacked back with repeat dilatation; and two longitudinal dissections caused no apparent reduction in luminal diameter. The Probe's low-profile and exceptional trackability enabled it to cross very tight lesions with minimal trauma to the vessel wall. The high degree of conformability of the PET balloon minimizes vessel straightening or sheer forces and appears to reduce the potential for dissection. The device may therefore extend the indications and ease of PTCA while reducing complications of the procedure.     

The diagnostic use of the second oscillatory potential in clinical electroretinography

Of all the electroretinogram (ERG) components (a-wave, b-wave, and oscillatory potentials) only one oscillatory potential, OP₂, was found to be significantly correlated with the absolute intensity of the flash stimulus (i.e., the intensity of the stimulus irrespective of the state of retinal adaptation). Our finding was further confirmed in single cell recordings of lateral geniculate unit activity in rabbits in which peak time of OP₂ was found to correlate better with the geniculate activity. For these reasons we have identified OP₂ as the intensity coding oscillatory potential of the ERG. In order to investigate if this new feature could have some clinical significance, we examined photopic ERGs recorded from patients affected with various retinopathies. In most instances the peak time of OP₂ paralleled that of the b-wave, that is, in the ERG with delayed b-wave the peak time of OP₂ was also delayed, while in ERGs with normal b-wave peak time the peak time of OP₂ was also normal. However, in some conditions (especially in cone-rod diseases) a delayed OP₂ was found in ERGs with normal b-wave peak times.     

Obstructive jaundice in chronic pancreatitis

Significant obstructive jaundice in chronic pancreatitis is generally considered to be rare. Eleven of 57 consecutive patients with proven chronic pancreatitis have developed significant obstructive jaundice of more than transient duration. Eight presented as jaundice complicating known pancreatitis and three as jaundice of unknown cause. Life table analysis showed a steady rise in the risk of developing jaundice up to the end of 10 years from the onset of chronic pancreatitis. Jaundice was found to occur in the presence of more "destructive" disease, and jaundiced patients had a higher incidence of pancreatic calcification, diabetes and malabsorption at the time of presentation with jaundice. Obstructive jaundice caused by chronic pancreatitis was found to carry a good prognosis for jaundice, for pain and for life. Only one of the 11 patients died in hospital. It is important to distinguish chronic pancreatitis from cancer in these patients. Pre-operative and intra-operative cytology have been helpful. Stent insertion is not an appropriate method of treatment for these patients because of the benign nature of the disease and the possibility of exacerbating the pancreatitis. It is important to be aware of another form of "malignant masquerade" causing obstructive jaundice.     

Longitudinal histopathologic assessment of rejection after bladder-drained canine pancreas allograft transplantation

In preparation for assessment of percutaneous biopsies in our clinical pancreas transplant program, a working knowledge of the histopathologic changes after transplantation was obtained in a longitudinal open biopsy study of 16 dogs receiving bladder-drained whole pancreas allografts. Edema, extravasation of polymorphs, and lymphocytes associated with focal parenchymal injury were early, invariable, and probably nonspecific findings. The initial feature of unmodified rejection was the appearance of capillary and small vein endothelial changes with mainly perivascular inflammatory cell infiltration. Acinar cell loss occurred early and was progressive, whereas islets and ducts were relatively preserved, indicating that acinar tissue may be more vulnerable to lytic necrosis when damaged. Functional rejection, determined by fasting urinary amylase levels, was at a stage of extensive and irreversible necrosis. Functioning grafts in immunosuppressed dogs had minor and transient endothelial changes with absence of class II antigen staining of parenchymal cells.     

Effect of once-daily fluticasone furoate nasal spray on nasal symptoms in adults and adolescents with perennial allergic rhinitis.

BACKGROUND: Intranasal corticosteroids are recommended as first-line therapy for the treatment of allergic rhinitis. Fluticasone furoate is a novel enhanced-affinity glucocorticoid for the treatment of allergic rhinitis. OBJECTIVE: To compare the efficacy and safety of intranasal fluticasone furoate with those of vehicle placebo nasal spray in adult and adolescent patients with perennial allergic rhinitis (PAR). METHODS: After screening (7-14 days), patients 12 years and older with confirmed PAR were randomized to receive fluticasone furoate, 110 microg once daily, or placebo once daily intranasally for 4 weeks in this double-blind, multicenter study. The primary end point was mean change from baseline during the entire treatment period in daily reflective total nasal symptom score (rTNSS), recorded on diary cards by patients, using a 4-point categorical scale. RESULTS: The mean reduction from baseline during the treatment period in daily rTNSS was significantly greater in fluticasone furoate recipients than in placebo recipients (P = .005). This finding was supported by significantly greater mean reductions in morning rTNSS and evening rTNSS (P = .004 and P = .011, respectively). A significantly greater mean reduction in instantaneous morning predose TNSS with fluticasone furoate compared with placebo (P = .006) confirmed the efficacy of once-daily administration. Fluticasone furoate was also significantly more effective than placebo in overall response to therapy (P = .005). CONCLUSIONS: Fluticasone furoate nasal spray, 110 microg once daily, effectively relieved nasal symptoms of PAR in adults and adolescents 12 years and older.     

Low dose exposure to sodium arsenite synergistically interacts with UV radiation to induce mutations and alter DNA repair in human cells

Inorganic arsenic is a known human carcinogen, yet its mechanism of action remains poorly understood. Epidemiological data suggest that arsenic exposure interacts with UV radiation exposure to increase the risk of skin cancer. Studies have suggested that arsenic is able to impair DNA repair enzymes and alter the repair of UV-induced DNA damage. Here we have tested the hypothesis that arsenite [As(III)] and UV interact synergistically to enhance mutagenesis. TK6 human lymphoblastoid cells that are functionally heterozygous at the thymidine kinase (TK) locus were pre-exposed to As(III) alone and in combination with UV. Our data suggest that As(III) is mutagenic only at high doses at the TK locus. As(III) enhanced UV mutagenesis in a more than additive fashion. To investigate the mechanism underlying this synergy we assessed the removal of UV-induced dimers in TK6 cells using the T4 endonuclease-incorporated Comet assay. Pre-treatment with As(III) specifically inhibited the repair of UV-induced pyrimidine dimer-related DNA damage. Taken together, these data suggest that pre-treatment of human cells with arsenic impairs the nucleotide excision repair pathway and leads to enhanced UV mutagenesis.     

Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth

Objective: To investigate the frequency of neonatal and later childhood morbidity in children exposed to antiepileptic drugs in utero.

Design: Retrospective population based study.

Setting: Population of the Grampian region of Scotland.

Participants: Mothers taking antiepileptic drugs in pregnancy between 1976 and 2000 were ascertained from hospital obstetric records and 149 (58% of those eligible) took part. They had 293 children whose health and neurodevelopment were assessed.

Main outcome measures: Frequencies of neonatal withdrawal, congenital malformations, childhood onset medical problems, developmental delay, and behaviour disorders.

Results: Neonatal withdrawal was seen in 20% of those exposed to antiepileptic drugs. Congenital malformations occurred in 14% of exposed pregnancies, compared with 5% of non-exposed sibs, and developmental delay in 24% of exposed children, compared with 11% of non-exposed sibs. After excluding cases with a family history of developmental delay, 19% of exposed children and 3% of non-exposed sibs had developmental delay, 31% of exposed children had either major malformations or developmental delay, 52% of exposed children had facial dysmorphism compared with 25% of those not exposed, 31% of exposed children had childhood medical problems (13% of non-exposed sibs), and 20% had behaviour disorders (5% of non-exposed).

Conclusion: Prenatal antiepileptic drug exposure in the setting of maternal epilepsy is associated with developmental delay and later childhood morbidity in addition to congenital malformation.