Variation in efficiency of DNA mismatch repair at different sites in the yeast genome

Evolutionary studies have suggested that mutation rates vary significantly at different positions in the eukaryotic genome. The mechanism that is responsible for this context-dependence of mutation rates is not understood. We demonstrate experimentally that frameshift mutation rates in yeast microsatellites depend on the genomic context and that this variation primarily reflects the context-dependence of the efficiency of DNA mismatch repair. We measured the stability of a 16.5-repeat polyGT tract by using a reporter gene (URA3-GT) in which the microsatellite was inserted in-frame into the yeast URA3 gene. We constructed 10 isogenic yeast strains with the reporter gene at different locations in the genome. Rates of frameshift mutations that abolished the correct reading frame of this gene were determined by fluctuation analysis. A 16-fold difference was found among these strains. We made mismatch-repair-deficient (msh2) derivatives of six of the strains. Mutation rates were elevated for all of these strains, but the differences in rates among the strains were substantially reduced. The simplest interpretation of this result is that the efficiency of DNA mismatch repair varies in different regions of the genome, perhaps reflecting some aspect of chromosome structure.     

Autoimmune-Associated Congenital Heart Block: Demographics, Mortality, Morbidity and Recurrence Rates Obtained From a National Neonatal Lupus Registry

Objectives. The present study describes the demographics, mortality, morbidity and recurrence rates of autoimmune-associated congenital heart block (CHB) using information from the Research Registry for Neonatal Lupus.

Background. Isolated CHB detected at or before birth is strongly associated with maternal autoantibodies to 48-kD SSB/La, 52-kD SSA/Ro and 60-kD SSA/Ro ribonucleoproteins and is a permanent manifestation of the neonatal lupus syndromes (NLS). Available data are limited by the rarity of the disease.

Results. The cohort includes 105 mothers whose sera contain anti-SSA/Ro or anti-SSB/La antibodies, or both, and their 113 infants diagnosed with CHB between 1970 and 1997 (56 boys, 57 girls). Of 87 pregnancies in which sufficient medical records were available, bradyarrhythmia confirmed to be CHB was initially detected before 30 weeks of gestation in 71 (82%) (median time 23 weeks). There were no cases in which major congenital cardiac anatomic defects were considered causal for the development of CHB; in 14 there were minor abnormalities. Twenty-two (19%) of the 113 children died, 16 (73%) within 3 months after birth. Cumulative probability of 3-year survival was 79%. Sixty-seven (63%) of 107 live-born children required pacemakers: 35 within 9 days of life, 15 within 1 year, and 17 after 1 year. Forty-nine of the mothers had subsequent pregnancies: 8 (16%) had another infant with CHB and 3 (6%) had a child with an isolated rash consistent with NLS.

Conclusions. Data from this large series substantiate that autoantibody-associated CHB is not coincident with major structural abnormalities, is most often identified in the late second trimester, carries a substantial mortality in the neonatal period and frequently requires pacing. The recurrence rate of CHB is at least two- to three-fold higher than the rate for a mother with anti-SSA/Ro-SSB/La antibodies who never had an affected child, supporting close echocardiographic monitoring in all subsequent pregnancies, with heightened surveillance between 18 and 24 weeks of gestation.     

Steroid-based treatments for patients with total sudden sensorineural hearing loss

Conclusions: In patients with total sudden sensorineural hearing loss (SSNHL), oral prednisone (OP) alone or intratympanic dexamethasone (ITD) alone have comparable results. The addition of salvage ITD following OP does not seem to add over either single modality treatment. Objectives: To study the effect of steroid-based treatments in patients with total SSNHL. Methods: The medical charts of 59 patients with total loss of hearing, defined as pure tone thresholds in the profound range (> 90 dB) with an unobtainable speech reception threshold (SRT) that were treated with OP (n = 20), ITD (n = 13), or OP followed by salvage ITD (n = 26) were analyzed. Response to treatment was evaluated by means of pure tone thresholds, SRT, and speech discrimination score (SDS), immediately after treatment and on a follow-up visit. Results: Forty-nine patients (83%) responded to treatment, with mean significant improvements of 36, 34, 31, and 25 dB at 500, 1000, 2000, and 4000 Hz, respectively. The mean improvement in SRT was 33 dB, and SDS improved by 32%. There were no differences in improvement in pure tone thresholds and SRT among the three treatment groups. The late effect of OP was similar to the effect of salvage ITD.     

Limited use of complementary and alternative medicine in Israeli head and neck cancer patients

HYPOTHESIS/OBJECTIVE: The use of complementary or alternative medicine (CAM) is growing among cancer patients. A Medline search failed to reveal any dedicated report of CAM use specifically in patients with head and neck cancer (HNC). STUDY DESIGN: Use of CAM was evaluated in a cohort of treated HNC patients. METHODS: Patients treated for HNC were asked if they had used CAM since their diagnosis. Demographic data and data pertaining to mode of CAM, duration of treatment and effects were obtained. RESULTS: One hundred forty-three patients (mean age 61 years) were included. Only nine patients (6.3%) reported using disease related CAM. This included acupuncture (4), Reiki (2), naturopathy (2), hypnosis (1), shiatsu (1), chiropractic treatment (1), homeopathy (1), and selenium (1). CONCLUSION: Contrary to the reported use, few of our HNC patients used CAM. Although this could be related to good caregiver-patient relationship, further studies in comparable populations are warranted to evaluate if this is a local or a pervading finding in head and neck cancer patients.     

Activity of the growth hormone/insulin-like growth factor-I axis in critically ill children

Critical illness has an important impact on the human endocrine system. Very few studies have been performed to elucidate the alterations of the GH/IGF-I axis in acutely ill children. The aim of this study was to investigate several parameters of this axis in children with trauma (TRA) and sepsis (SEP) requiring admission to the pediatric intensive care unit (PICU). A total of 16 children, ten with TRA and six with SEP (age 1-10 years) as well as 18 healthy children (CS) of similar age and gender were included in the study. Two children, one with TRA and one with SEP, died. Serum IGF-I and -II, IGFBP-1 and -3, and GH levels were measured on days 1, 3 and 7 after admission. GH levels were higher in the patients than in CS (p = 0.04), with no difference between TRA and SEP, and were elevated during PICU stay (p = 0.05). Serum IGF-I, -II and IGFBP-3 were lower in the patients than in CS (p = 0.03, 0.02 and 0.001, respectively) with a tendency to increase up to day 7. Finally, IGFBP-1 levels were similar in the patients and CS. These findings indicate that critically ill children are characterized by low levels of IGF-I and -II as well as IGFBP-3 accompanied by elevated levels of GH, probably reflecting the development of peripheral GH resistance. No significant differences were found between the different catabolic conditions, sepsis and trauma.     

Bacteriology of mastoid subperiosteal abscess in children

OBJECTIVE: Subperiosteal abscess (SA) is the most frequent complication of acute mastoiditis (AM). Of pathogens cultured from the external auditory canal or middle ear during myringotomy, 15% may be different from microorganisms isolated from the SA. We suggest, therefore, that only cultures obtained from the abscess cavity can truly reflect the bacteriology of this complication of AM. The purpose of our study was to analyze the infectious agents which cause SA and mastoid cortex erosion in children. MATERIAL AND METHODS: The medical records of 35 children who underwent mastoidectomy for SA between May 1984 and April 2002 were evaluated. RESULTS: Mastoid cortex erosion was found at surgery in 72.7% of abscesses Purulent discharge was obtained from the SA cavity in 28 cases. The commonest pathogens isolated in these cases, as well as in 18 cases of mastoid cortex erosion, were Staphylococcus aureus and Streptococcus pyogenes, followed by Streptococcus pneumoniae. Hemophilus influenzae, Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. Sterile culture was found in 25% of cases. CONCLUSIONS: Mastoid SA is a unilateral disease that can recur. Early administration of anti-Staphylococcus medications should be considered for patients with SA as a complication of AM.     

Autoantibodies in mothers of children with neonatal liver disease

OBJECTIVES: Neonatal lupus erythematosus (NLE) is associated with maternal anti-Ro/La autoantibodies. It is characterized by heart block and/or cutaneous skin lesions, and occasionally liver disease. This study was performed to determine whether idiopathic neonatal cholestasis (INC) represents NLE without its cardiac or cutaneous findings. METHODS: Sera were obtained for autoantibody analysis from mothers of children with INC (N = 11), biliary atresia (N = 25), other liver disease excluding viral hepatitis (liver disease control subjects, N = 14), and healthy children (normal control subjects [NC], N = 22). RESULTS: The characteristic serologic findings of NLE, high titer antibodies to Ro and/or La, were absent in mothers from all groups. An unexpected finding was the prevalence of autoantibodies in mothers of infants with liver disease of any type. The frequency of maternal antinuclear antibodies at > or = 1:120 dilution was greater than the estimated frequency in the general population (22% vs. 9%, P = 0.044). The frequency of maternal low titer autoantibodies to 52 kD Ro detected by ELISA was significantly greater than in the NC group (31% vs. 5%, P = 0.014). CONCLUSIONS: The majority of cases of INC do not represent NLE. The frequent presence of autoantibodies in mothers of infants in all neonatal liver disease groups raises the possibility that maternal serologic autoimmunity is associated with neonatal liver disease.     

Soiled-bedding sentinel detection of murine norovirus 4.

According to serologic surveys, murine norovirus (MNV) is the most prevalent viral pathogen infecting mice used in biomedical research. However, the use of sentinel mice to detect MNV-infected mouse populations has not been evaluated thoroughly. To this end, an experimental method of soiled bedding transfer was created to mimic a quarterly sentinel monitoring program. Soiled bedding (15 or 30 cm3) from ICR mice experimentally infected with MNV4 was transferred weekly to cages of pair-housed 4-wk-old ICR mice. After 12 wk, both mice in 80% (4 of 5) of cages receiving either 15 or 30 cm3 of soiled bedding were seropositive for MNV and were shedding virus in feces. To evaluate the stability of MNV RNA in mouse feces, fecal pellets from MNV-infected sentinel mice were stored at room temperature for as long as 14 d. After storage, all fecal samples tested positive for MNV by RT-PCR. To determine whether fecal samples could be pooled for MNV detection, 1 MNV-positive fecal pellet was combined with either 9 or 19 MNV-negative fecal pellets. All pooled fecal samples were positive for MNV by RT-PCR at both dilutions. These data indicate that although MNV-infected mouse populations can be detected by exposing sentinel mice to MNV-contaminated bedding, detection failures can occur. In addition, there was high agreement in the MNV infection status of cohoused sentinel mice. These data also demonstrate that MNV is readily detectable in pooled fecal samples and in mouse feces stored at room temperature for 2 wk.