Salmonella meningitis in an immunocompetent adult.

Non-enteric salmonella infections in immunocompetent adults are exceedingly rare in the United States, and meningitis is one of the least common extra-intestinal sites. In addition, it is very unusual for a patient with bacterial meningitis to present with classic meningitis signs and symptoms of > 72 h duration. The objective of this work is to describe a rare case of salmonella meningitis in an immunocompetent adult and, in the context of previously published case reports, describe the frequently atypical clinical course of salmonella meningitis along with the potential pitfalls encountered during its evaluation and treatment. An otherwise healthy 45-year-old man presented to our Emergency Department with frontal headache, fever, and stiff neck of 7 days duration. He was alert and oriented in triage, where he was noted to be afebrile, mildly tachycardic, with a normal blood pressure and respiratory rate; shortly after triage he developed a high fever, severe tachycardia, hypotension, and a change in mental status. He was resuscitated according to our severe sepsis protocol and treated empirically for bacterial meningitis. Blood and cerebrospinal fluid cultures grew group D Salmonella berta. An evaluation for underlying immunodeficiency was unrevealing. The patient was discharged home on hospital day 7 in good condition. Salmonella meningitis can present with an indolent course and can mimic, in many misleading ways, the less serious diagnosis of aseptic meningitis. This case highlights the need for an unbiased clinical assessment, aggressive management of critical illness, and point-for-point correspondence between clinical data and assigned diagnosis.

A dinucleotide deletion in the ankyrin promoter alters gene expression, transcription initiation and TFIID complex formation in hereditary spherocytosis.

Ankyrin defects are the most common cause of hereditary spherocytosis (HS). In some HS patients, mutations in the ankyrin promoter have been hypothesized to lead to decreased ankyrin mRNA synthesis. The ankyrin erythroid promoter is a member of the most common class of mammalian promoters which lack conserved TATA, initiator or other promoter cis elements and have high G+C content, functional Sp1 binding sites and multiple transcription initiation sites. We identified a novel ankyrin gene promoter mutation, a TG deletion adjacent to a transcription initiation site, in a patient with ankyrin-linked HS and analyzed its effects on ankyrin expression. In vitro, the mutant promoter directed decreased levels of gene expression, altered transcription initiation site utilization and exhibited defective binding of TATA-binding protein (TBP) and TFIID complex formation. In a transgenic mouse model, the mutant ankyrin promoter led to abnormalities in gene expression, including decreased expression of a reporter gene and altered transcription initiation site utilization. These data indicate that the mutation alters ankyrin gene transcription and contributes to the HS phenotype by decreasing ankyrin gene synthesis via disruption of TFIID complex interactions with the ankyrin core promoter. These studies support the model that in promoters that lack conserved cis elements, the TFIID complex directs preinitiation complex formation at specific sites in core promoter DNA and provide the first evidence that disruption of TBP binding and TFIID complex formation in this type of promoter leads to alterations in start site utilization, decreased gene expression and a disease phenotype in vivo.

Variegated expression from the murine band 3 (AE1) promoter in transgenic mice is associated with mRNA transcript initiation at upstream start sites and can be suppressed by the addition of the chicken beta-globin 5' HS4 insulator element.

The anion exchanger protein 1 (AE1; band 3) is an abundant erythrocyte transmembrane protein that regulates chloride-bicarbonate exchange and provides an attachment site for the erythrocyte membrane skeleton on the cytoplasmic domain. We analyzed the function of the erythroid AE1 gene promoter by using run-on transcription, RNase protection, transient transfection, and transgenic mouse assays. AE1 mRNA was transcribed at a higher level and maintained at a higher steady-state level than either ankyrin or beta-spectrin in mouse fetal liver cells. When linked to a human gamma-globin gene, two different AE1 promoters directed erythroid-specific expression of gamma-globin mRNA in 18 of 18 lines of transgenic mice. However, variegated expression of gamma-globin was observed in 14 of 18 lines. While there was a significant correlation between transgene copy number and the amount of gamma-globin mRNA in all 18 lines, the transgene mRNAs initiated upstream of the start site of the endogenous AE1 mRNA. Addition of the insulator element from 5'HS4 of the chicken beta-globin cluster to the AE1/gamma-globin transgene allowed position-independent, copy-number-dependent expression at levels similar to the AE1 transcription rate in six of six lines of transgenic mice. The mRNA from the insulated AE1/gamma-globin transgene mapped to the start site of the endogenous AE1 mRNA, and gamma-globin protein was expressed in 100% of erythrocytes in all lines. We conclude that the chicken beta-globin 5'HS4 element is necessary for full function of the AE1 promoter and that position effect variegation is associated with RNA transcription from the upstream start sites.