MULTIPLE ENZYME CHANGES IN THE PLASMA OF NORMAL AND TUMOR-BEARING MICE FOLLOWING INFECTION WITH THE LACTIC DEHYDROGENASE AGENT

Within 72 hours after injection of the LDH agent into normal mice, five (LDH, ICDH, MDH, PHI, and GOT) out of the seven plasma enzymes studied were elevated. This elevation persisted for the duration of the experiment. Alkaline phosphatase and aldolase were not elevated. Plasma from mice bearing tumor SS-70429 and infected with the LDH agent showed 7 times more LDH, 8 times more ICDH, and 4 times more MDH activity than the plasma from mice with the same tumor but uninfected. The plasma aldolase activity from the infected tumor-bearing animal was approximately the same as that from the uninfected tumor-bearing animal. Somewhat similar results, but lower in magnitude, were found with mice bearing mammary carcinoma C₃HBA. The early rise in plasma enzyme activity (LDH, MDH, ICDH) prior to the actual appearance of the tumor was shown to be due not to the tumor, but to the LDH agent. Uninfected tumor-bearing mice showed a late increase in plasma enzyme activity which appeared to be related to tumor growth. The findings reported above suggest that contamination with the LDH agent may have been responsible for much of the increased plasma enzyme activity previously attributed to the tumor.     

STUDIES ON THE TRANSMISSION AND THE EXCRETION OF THE LACTIC DEHYDROGENASE AGENT

The lactic dehydrogenase agent (LDH agent) was found in the urine, feces, and saliva of mice within 24 hours after inoculation. The titer of virus in these materials appears to be directly related to the titer in the plasma. Infection by the oral route occurred only when a high concentration of virus was used. Animals infected prior to mating rarely transmitted the LDH agent to their progeny. However, 91.2 per cent of the progeny of mothers infected during gestation and 51.5 per cent of the progeny of mothers infected within 48 hours after giving birth became infected with the LDH agent. Evidence is discussed which suggests that the transmission of the LDH agent from the infected mother to her offspring is related to the titer of the LDH agent in the maternal circulation.     

Correlation of hearing screening with developmental outcomes in infants over a 2-year period

CONCLUSION: Evoked otoacoustic emission (OAE) and auditory brainstem response (ABR) results for hearing screening among infants have good concordance. However, good correlation with the Griffiths Developmental Scales remains to be desired. OBJECTIVE: To correlate hearing screening outcomes of a cohort of infants with developmental outcomes at 6 and 12 months. SUBJECTS AND METHODS: A cohort of pregnant women was identified in several communities in a rural area (Bulacan province) from April 2002 to February 2003 as part of a population-based study determining maternal exposure to pollutants and infant outcomes, with a total follow-up of 2 years. Pregnant mothers were identified and followed up until delivery at a secondary, provincial hospital. Hearing screening was performed with OAEs and ABR. Mental development of infants was assessed at 6 and 12 months using Griffiths Mental Developmental Scales - locomotor, personal-social, hearing and speech, hand and eye coordination, performance tests. RESULTS: Among the 1086 babies recruited, there were 724 with hearing assessment. Of these 724 babies, 565 had both OAE testing and ABR. Overall in 1130 ears, OAE and ABR testing showed an observed agreement of 99%, agreement due to chance of 96%, and kappa agreement of 79% (p=0.00) in diagnosing bilateral hearing losses. OAEs had a sensitivity of 86.4% (95% CI 64-96.4%) and a specificity of 99.4% (95% CI 98.6-99.7%). At the end of the study, there were 708/724 (97.8%) infants with normal hearing, 7/724 (1.0%) with unilateral hearing loss, 8/724 (1.1%) with bilateral mild hearing loss, and 1/724 (0.1%) with bilateral profound hearing loss, who demonstrated consistent mental delay throughout. Follow-up rates for developmental examinations at 6 and 12 months were 98% and 81.25%, respectively. In these groups, there were 8 (1%) infants at 6 months and 18 (2.4%) at 12 months with developmental delay (Griffiths Mental Developmental Scales).     

A randomized controlled Alzheimer’s disease prevention trial’s evolution into an exposure trial: The preadvise trial

Objectives

To summarize the ongoing Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) trial as an ancillary study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study.

Design

PREADViSE was designed as a double blind randomized controlled trial (RCT).

Setting

SELECT terminated after median of 5.5 years of exposure to supplements due to a futility analysis. Both trials then converted into an exposure study.

Participants

In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22.0% reporting a family history of dementia.

Intervention

In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and 200 µg of selenium or placebo using a 2×2 factorial structure.

Measurements

In the RCT, participants completed the Memory Impairment Screen (MIS), and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the telephone version of the memory impairment screen (MIS-T) screen. If they fail the MIS-T, a Modified Telephone Interview of Cognitive Status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in-depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes.

Results

While this ancillary trial was open to all 427 SELECT clinical sites, only 130 (30.0%) of the sites chose to participate in PREADViSE. Staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered. In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84.0% failed and were asked to contact their physicians for a more detailed memory assessment, and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD.

Conclusion

Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (Southwest Oncology Group or SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.     

IN VITRO EVALUATION OF GRISEOFULVIN, KETOCONAZOLE, AND ITRACONAZOLE AGAINST VARIOUS DERMATOPHYTES IN SINGAPORE

Background. Superficial cutaneous fungal infection, principally dermatophytosis, is an extremely common skin disease. Various in vitro test systems have been developed in recent years to determine the antifungal activity of various drugs. The minimum inhibitory concentration (mic ) obtained may give an indication of the in vivo potency of the drugs. Methods. One hundred patients (69 men and 31 women) with a clinical diagnosis of dermatophytosis were entered into the study. Direct microscopy and culture were done on all patients. The Mies were determined using the broth dilution method. Results. The age range was 1–76 years. The most common diagnosis was tinea corporis (36%), followed by tinea cruris (22%), and tinea pedis (19%). The most common fungus isolated was T. rubrum (58%), followed by E. floccosum (14%), and T. mentagrophytes (10%). The majority of the isolates was sensitive to the three drugs tested (griseofulvin, ketoconazole, and itraconazole). Of the isolates, 82% were sensitive to griseofulvin, 78% to ketoconazole, and 81% to itraconazole, all at a concentration of < 0.25 μg/mL. For T. rubrum, there were four isolates that had an mic of 64 μg/mL to griseofulvin, seven isolates and nine isolates with an mic > 64 g/mL to ketoconazole and itraconazole, respectively. T. interdigitale was relatively resistant to the three drugs in vitro with four of seven isolates having an mic 4 μg/mL with griseofulvin, one of seven isolate with an mic 64 μg/mL with ketoconazole, and three of seven isolates with an mic 32 μg/mL with itraconazole. Conclusions. The in vitro antifungal activity of griseofulvin, ketoconazole, and itraconazole are similar against dermatophytes in Singapore. Griseofulvin may be given as the first-line drug for treating such infections in Singapore.     

Prediction of preclinical Alzheimer's disease: longitudinal rates of change in cognition

Preclinical Alzheimer's disease (pAD) reflects neuropathological findings of AD in cognitively normal subjects. The present study represents an effort to determine if differences could be identified in the longitudinal patterns of cognitive performance in persons classified as pAD compared to those who did not meet criteria for AD at autopsy. We included 121 subjects who were cognitively normal from baseline through their last assessment before death and who underwent autopsy. Participants were classified into two groups: pathologically normal (PN; NIA-Reagan low or no-likelihood of AD, n = 89) and preclinical AD (pAD; NIA-Reagan criteria of intermediate or high-likelihood of AD in the absence of clinical dementia symptoms, n = 32) followed for a mean 7.5 years prior to death. Longitudinal rates and patterns of change in scores on a standard cognitive battery were compared between these two groups. While cognitive results at baseline and last evaluations revealed no clear cross sectional group differences after adjustment for age, ApoE status, education, and gender, statistically significant differences between the pAD and PN groups in slope of decline were seen on a composite score of cognitive function. Further analyses showed three components of this score reached significance: constructional praxis, delayed recall of a word list, and category verbal fluency. Despite being clinically viewed as normal at enrollment and at the final exam, there are significant differences in rates of cognitive decline in participants classified as pAD compared to those without this pathology. Longitudinal changes in slope of decline in specific cognitive test measures can serve as non-invasive methods for the detection of pAD.     

Prospective trial of gasless laparoscopic Burch colposuspension using conventional surgical instruments

STUDY OBJECTIVE: To prospectively evaluate the use of gasless laparoscopy techniques in the performance of a traditional Burch colposuspension in women with urodynamically-demonstrated genuine stress incontinence and urethral hypermobility. DESIGN: Multicenter, prospective, single-intervention series (Canadian Task Force Classification II-2). SETTING: Three urogynecologic referral centers. PATIENTS: Fifty-eight women. INTERVENTION: Traditional Burch colposuspension performed utilizing gasless laparoscopic access and conventional surgical instruments. MEASUREMENTS AND MAIN RESULTS: Follow-up was 12 to 38 months. On pad testing, urine loss was significantly reduced, from 6.0 g (CI: 0.55-11.45) to 0.3 g (CI: 0-1.53). Average daily incontinence episodes based on 7-day voiding diaries decreased from 4.7 (CI: 0.87-8.53) to 0.3 (CI: 0-1.58). Q-tip angles were normalized: 49.8 degrees (CI: 40.86-58.74) to 10 degrees (CI: 1.49-18.51). Ninety-five percent of subjects reported resolution of stress incontinence. Three subjects (5%) reported recurrent/persistent genuine stress incontinence: one was operated on during the postpartum period while breastfeeding, and two developed intrinsic sphincteric deficiency postoperatively. Fifty-five percent of subjects underwent other pelvic reconstructive surgery including posterior wall repairs. Average operative time was 60.8 minutes (range, 40-92). The ideal candidate has an unscarred abdominal wall. CONCLUSION: Gasless laparoscopic access was used to effectively perform traditional Burch colposuspension using conventional open surgical instruments. Bladder neck hypermobility was normalized in all subjects, and 95% of subjects reported no further stress incontinence.     

Infectious mononucleosis mimicking lymphoma: distinguishing morphological and immunophenotypic features

The diagnosis of infectious mononucleosis (acute Epstein-Barr virus (EBV) infection) is usually made on the basis of clinical and laboratory findings. However, an atypical clinical presentation occasionally results in a lymph node or tonsillar biopsy. The morphological features of EBV-infected lymphoid tissue can easily mimic lymphoma. Furthermore, the immunophenotype of the immunoblasts has not been well characterized. To assess the morphological spectrum of acute EBV infection and the utility of immunohistochemistry in diagnosing difficult cases that resemble lymphoma, we reviewed 18 cases of acute EBV infection submitted in consultation to our institution with an initial diagnosis of/or suspicion for lymphoma. Patients included nine male and nine female individuals with a median age of 18 years (range 9-69). Biopsies were obtained from lymph nodes (3/18) or Waldeyer's ring (15/18). Infectious mononucleosis was confirmed by monospot or serological assays in 72% of cases (13/18). All cases featured architectural distortion by a polymorphous infiltrate with an immunoblastic proliferation, sometimes forming sheets. Reed-Sternberg-like cells were present in 8/18 (44%) of the cases. Infiltrates were often accompanied by necrosis (10/18) and mucosal ulceration (6/15). The majority of immunoblasts in all cases were CD20+ B cells with a post-germinal center immunophenotype (strongly positive for MUM1/IRF4 (18/18), CD10- (18/18 negative) and BCL-6- (16/18 negative; 2/18 faint BCL-6 expression in <10% of immunoblasts)). Immunoblasts showed variable weak expression of BCL-2 and polyclonal expression of κ and λ immunoglobulin light chains in 81% cases. Reed-Sternberg-like cells in 8/8 cases were CD30+, CD15-, BOB.1+ and OCT-2+. In conclusion, an atypical lymphoid infiltrate with numerous MUM1+, CD10-, BCL-6- immunoblasts should raise the suspicion of a reactive process, such as infectious mononucleosis, and warrants additional consideration before a diagnosis of lymphoma is made.