Variable Disposition of Ciprofloxacin in Critically Ill Patients Undergoing Continuous Arteriovenous Hemodiafiltration

Continuous arteriovenous hemodiafiltration (CAVHD) is being used increasingly in critically ill patients with acute renal failure (ARF). We prospectively evaluated extracorporeal and total systemic clearances (Cl_CAVHD and Cl_s) of ciprofloxacin during CAVHD in four patients with severe ARF to assess the adequacy of drug dosing. Ciprofloxacin serum and ultrafiltrate concentrations were measured by high-performance liquid chromatography. The Cl_CAVHD accounted for approximately 5.9% (range 2.8–11.6%) of Cl_s of ciprofloxacin. However, large variability in serum concentrations was observed with the normally recommended dose of 400 mg/day, and doses of up to 800 mg/day were required to maintain concentrations suitable for treatment of serious infections. High daily doses of ciprofloxacin required in these patients are likely related to altered pharmacokinetics in serious illness as well as to the increased extracorporeal clearance during CAVHD. Clinical studies to define appropriate dosing recommendations for ciprofloxacin during CAVHD are necessary to guide clinicians in optimum drug use.     

Physical and Sexual Abuse and their Relation to Psychiatric Disorder and Suicidal Behavior among Adolescents who are Psychiatrically Hospitalized

Adolescents who were psychiatrically hospitalized ( N = 105) were classified as sexually abused, physically abused, both sexually and physically abused, or not abused, and studied to determine the prevalence of suicidal behavior and psychiatric disorders. Self-reports of hopelessness, depression, coping, and self-concept were also examined. No difference in suicidal behavior or psychiatric disorder, based on abuse history, was found, with one exception. Adolescents who were sexually abused, particularly those who experienced the most severe sexual abuse, used negative coping strategies more often than those not sexually abused. Findings suggest that symptomatology of adolescents who are psychiatrically hospitalized does not differ markedly based on history of abuse.     

Relative effect of surgery and radiotherapy on the internal jugular vein following functional neck dissection

We examined the internal jugular veins in three groups of patients who had undergone (1) a functional neck dissection and radiotherapy, (2) a functional neck dissection alone, or (3) radiotherapy alone, using a noninvasive color Doppler ultrasound scan. The internal jugular veins were ultrasonically bilaterally normal in 18% of patients who had undergone a functional neck dissection and radiotherapy, in 88% of patients who had undergone a functional neck dissection alone, and in 57% of patients who had undergone radiotherapy alone. The combination of a functional neck dissection and radiotherapy significantly affected the internal jugular vein when compared with a functional neck dissection alone.     

Detection of Aspergillus fumigatus by polymerase chain reaction.

Aspergillus fumigatus is an opportunistic nosocomial pathogen causing an often fatal pneumonia, invasive aspergillosis (IA), in immunosuppressed patients. Oligonucleotide primers were used to amplify a 401-bp fragment spanning the 26S/intergenic spacer region of the rDNA complex of A. fumigatus by the polymerase chain reaction (PCR). The primers were highly sensitive and specific: as little as 1 pg of A. fumigatus genomic DNA could be detected, and the primers only amplified DNA from A. fumigatus and not any other fungal, bacterial, viral, or human DNA tested. Using the PCR, we were able to detect A. fumigatus DNA in lung homogenates from immunosuppressed mice experimentally infected with A. fumigatus but not from immunosuppressed uninfected controls. There was 93% correlation between the culture results and the PCR results. In a retrospective clinical study, the sensitivity of the PCR for the detection of A. fumigatus in clinical samples was confirmed by positive amplification in three of three culture-positive respiratory samples from confirmed cases of IA. Because isolation of Aspergillus spp. may reflect contamination and colonization without infection, the feasibility of using the PCR was evaluated by analyzing culture-negative samples from both immunosuppressed patients at high risk for IA and immunocompetent patients with other lung infections. Only 2 of 10 patients were culture negative and PCR positive in the high-risk group, and 2 of 7 patients were culture negative and PCR positive in the immunocompetent group. The results indicate that PCR detection might be a valuable adjunct to current laboratory methods to diagnose IA.     

Ability of bacteria associated with chronic inflammatory disease to stimulate E-selectin expression and promote neutrophil adhesion.

Porphyromonas gingivalis, Pseudomonas aeruginosa, and Helicobacter pylori have been shown to be associated with adult periodontal disease, chronic lung infections, and peptic ulcers, respectively. The ability of these bacteria to stimulate E-selectin expression and promote neutrophil adhesion, two components necessary for the recruitment of leukocytes in response to infection, was investigated. Little or no stimulation of E-selectin expression was observed with either P. gingivalis or H. pylori when whole cells, lipopolysaccharide (LPS), or cell wall preparations added to human umbilical cord vein endothelial cells were examined. P. aeruginosa was able to induce E-selectin to near-maximal levels; however, it required approximately 100 to 1,000 times more whole cells or LPS than that required by E. coli. Neutrophil-binding assays revealed that LPS and cell wall preparations obtained from these bacteria did not promote endothelial cell adhesiveness by E-selectin-independent mechanisms. In addition, P. gingivalis LPS blocked E-selectin expression by LPS obtained from other bacteria. We propose that lack of E-selectin stimulation and the inability to promote endothelial cell adhesiveness are two additional indications of low biologically reactive LPS. We suggest that this property of LPS may contribute to host tissue colonization. In addition, the ability of P. gingivalis to inhibit E-selectin expression may represent a new virulence factor for this organism.     

Evaluation of a Standard Protocol for Retentive Encopresis: A Replication

Replicated the efficacy of a short-term, combined medical andbehavioral intervention protocol for retentive encopresis. Fifty-ninechildren who had failed standard medical management for retentiveencopresis and their parents participated in six 1-hour grouptreatment sessions. Treatment protocol combined the medicalmanagement strategies of enema clean out, increasing dietaryfiber, and daily toilet sitting with the child behavior managementstrategies of differential attention, contingency management,and contracting. For the overall sample, the number of soilingincidents decreased 85%, the weekly frequency of independentbowel movements increased 15%, the weekly frequency of parent-promptedbowel movements increased 9%, and daily dietary fiber intakeincreased 121% pre-to posttreatment. The majority of the sample(86%) stopped soiling by the end of treatment and did not requirefurther treatment. Results are discussed in terms of the comparabilitywith previous findings and the utility of combined medical andpsychological treatments for children with encopresis who havefailed standard medical approaches     

Multiple antigenic peptides facilitate generation of anti-prion antibodies

Recent reports have demonstrated the ability of anti-prion antibodies to inhibit PrPSc propagation. Due to the relatively poor immunogenic properties of both PrPC and PrPSc, the generation of anti-prion antibodies still causes a significant problem in the development of immunotherapeutic strategies. This study examines the potential of multiple antigenic peptides (MAPs) to raise an antibody response to prion derived sequences in mice. The MAP was constructed of a four spiked ring. Two spikes containing human or mouse derived prion amino acid sequences and two spikes containing the universally promiscuous tetanus toxoid sequence (aa 830-844) which was used to assist T-cell-dependent B-cell antibody production. Following vaccinations with the MAP or MAP plus adjuvant, sera were taken and antibody titres assessed. The MAP containing only the mouse sequence failed to elicit a significant antibody response. MAPs containing human prion sequences elicited antibody production to the corresponding prion sequence. Further analysis also demonstrated that these peptides were able to generate antibody responses that recognize conserved human and mouse sequences. These homologous sequences contain the heralded PrPSc specific sequence 'Tyr-Tyr-Arg' and therefore these MAPs may have some therapeutic potential.     

PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.

PURPOSE: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. MATERIALS AND METHODS: We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. RESULTS: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. CONCLUSION: Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.