Fire in the operating theatre. Evacuation pre–planning may save lives

An operating theatre fire and the steps taken to deal with it are described; the difficulties encountered in evacuating anaesthetised patients are highlighted. Measures which might be taken to prevent recurrence of these problems, and recommendations on the institution of fire drills for the safety of patients and staff are given.     

A phase II study of sulofenur,a novel sulfonylurea,in recurrent epithelial ovarian cancer

Summary A total of 16 patients with recurrent epithelial ovarian cancer were treated with sulofenur (LY 186641), a novel oral sulfonylurea. All subjects had received previous chemotherapy. Anaemia occurred in all 16 patients, 14 of whom required a blood transfusion, and 2/16 patients received methylene blue for breathlessness due to methaemaglobinaemia. Treatment was discontinued in 2/16 cases due to rising liver enzyme values, which reverted to normal on cessation of the drug. There was no nausea or alopecia. Only two minor responses were seen. Plasma drug levels were insufficient to result in antitumour activity as extrapolated from animal data. Further studies that attempt to increase the bioavailability and improve the therapeutic index are warranted.     

Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.      

Interaction of capsulate Haemophilus influenzae with human airway mucosa in vitro.

Two pairs of isogenic capsulate and noncapsulate and one pair of capsulate fimbriate and nonfimbriate strains of Haemophilus influenzae type b were studied in an organ culture of human respiratory mucosa. Over 24 h, the numbers of recovered bacteria increased from the original inoculum size of 10(5) to 10(8) CFU/ml. Transmission electron microscopy and scanning electron microscopy showed that noncapsulate organisms caused significant epithelial damage, whereas capsulate strains did not. Association of noncapsulate bacteria with damaged epithelial cells was observed by 14 h of incubation. In contrast, capsulate organisms were associated with a dense, thick, gel-like matrix which was observed above the epithelial surface. These capsulate organisms were not seen to associate with the epithelial surface (by transmission electron microscopy), though they were occasionally seen adhering to cells by scanning electron microscopy. Fimbriate capsulate H. influenzae showed increased adherence to buccal cells compared with nonfimbriate capsulate organisms. There was also association of fimbriate capsulate bacteria with damaged organ culture epithelium in one of four experiments. It is concluded that both capsule and fimbriae affect the interaction of H. influenzae with human airway mucosa in vitro by influencing adherence to and damage of the epithelium.     

Examination of Haemophilus pleuropneumoniae for immunoglobulin A protease activity.

Haemophilus pleuropneumoniae, the etiological agent of porcine contagious pneumonia, was examined for the ability to produce an immunoglobulin A (IgA) protease specific for porcine IgA. No IgA protease activity against either porcine or human IgA was detected. Furthermore, no sequence homology was found between H. pleuropneumoniae chromosomal DNA and the gene which specifies IgA protease in Haemophilus influenzae.     

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.      

Haemophilus influenzae b infection in rats: effect of splenectomy on bloodstream and meningeal invasion after intravenous and intranasal inoculations.

We investigated the effect of splenectomy on the susceptibility of rats to intravenous or intranasal inoculation of Haemophilus influenzae, type b. The 50% lethal dose for asplenic rats inoculated either by intravenous (i.v.) (10(4.7)) or intranasal (i.n.) (10(4.6)) injection was similar, but significantly lower than the 50% lethal dose value in sham-operated rats (10(8.6) i.v. and 10(9.0) i.n.). Mean survival time was significantly longer for asplenic rats inoculated i.n. (49.3 h) compared to asplenic rats inoculated i.v. (24.4h). Similarly, sham-operated rats inoculated i.n. survived significantly longer after i.n. challenge (mean survival time, 171.4 h) than after i.v. challenge (34.7 h). Bacteremia was detected in 100% of asplenic rats and in 80% of sham-operated rats. The geometric mean number of bacteria in the blood of asplenic rats (10(4.90) per ml) was significantly greater than in sham-operated rats (10(3.29) per ml). Meningitis was detected in 7 of 15 randomly sacrificed asplenic rats, whereas none of 15 sham-operated rats had evidence of meningeal invasion. Thus, the asplenic rat was more susceptible to experimentally induced H. influenzae bacteremia, meningitis, and fatal sepsis and offers a biologically relevant experimental model for investigating the role of the spleen in defense against infection with encapsulated bacteria.     

Clonal population structure of encapsulated Haemophilus influenzae.

Chromosomal genotypes of 2,209 isolates of the six polysaccharide capsule types of Haemophilus influenzae recovered from human hosts worldwide were characterized by an analysis of electrophoretically demonstrable allelic profiles at 17 metabolic enzyme loci. For 222 representative isolates, restriction fragment length polymorphism patterns produced by digestion of cap region DNA were also determined. With few exceptions, isolates belonging to individual phylogenetic lines or groups of allied lineages identified by multilocus enzyme electrophoresis had characteristic cap region restriction fragment length polymorphism patterns and characteristic combinations of cap region patterns and outer membrane protein types. The occurrence of strong associations of characters and the recovery of isolates with identical genetic properties in widely separated geographic regions and over a 40-year period indicated that the population structure of encapsulated H. influenzae is clonal. Recombination of chromosomal genes, including those mediating capsule synthesis, apparently is not a major factor in the short-term evolution of these pathogenic organisms and, therefore, may be of minor clinical significance.     

Pathogenesis of bloodstream invasion with Haemophilus influenzae type b

Possible route(s) by which encapsulated bacteria invade the blood from the nasopharynx include (i) the direct invasion of submucosal blood vessels and (ii) clearance via lymphatics to regional nodes followed by bloodstream invasion. These possibilities were investigated in rats after intranasal inoculation with 10(5) Haemophilus influenzae type b. Within 24 h of inoculation, 10 of 42 rats with sterile blood cultures had similar numbers of H. influenzae b recovered from both cervical (local) and periiliac (distant) lymph nodes, which suggested early bacteremic spread. When virtually continuous blood cultures were obtained for 30 min after inoculation with 10(8) H. influenzae b, early transient bacteremia was documented in four of eight rats. Also, we found no significant difference in bacteremia among rats whose cervical lymph nodes had been removed surgically compared with sham-operated rats. These findings favor the hypothesis of a rapid, perhaps direct invasion of pharyngeal blood vessels as an initial determinant of the systemic spread of H. influenzae b.