Cognitive development in schizophrenia: follow-back from the first episode

Despite consensus that schizophrenia is a neurodevelopmental disorder characterized by cognitive deficits, objective data documenting the course of cognitive development remain sparse. We conducted a follow-back study of patients ascertained at the time of their initial episode of schizophrenia or schizoaffective disorder, and a group of demographically matched healthy volunteers. We obtained school records containing standardized achievement test scores from the 1st through 12th grades, and scholastic aptitude test results from the 11th and 12th grades, and examined the developmental trajectories of cognitive performance with respect to prospective examinations conducted following participants' enrollment in our study. We found significant differences in academic achievement tests as early as the first grade, with scores from participants who would later develop schizophrenia lagging behind their peers by 0.8 to 1.1 grade equivalents. This gap widened resulting in a difference between groups of 1.5 to 1.8 grade equivalents by the 12th grade. In the subset of patients for whom SAT scores were available, we found that WAIS-R Full Scale IQ was 11.5 points lower than predicted from earlier SAT scores, suggesting a substantial decline in cognitive ability accompanying the initial episode of illness. These findings suggest that schizophrenia is marked by substantial cognitive deficits in the first grade, that there may be additional subtle decline preceding the overt onset of psychotic symptoms, and that the initial episode of illness is marked by additional decline. These observations may help advance concepts of premorbid cognitive ability in the schizophrenia syndrome and constrain models of pathophysiology.     

Sulfuric Acid and Streptococci Clearance From Respiratory Tracts of Mice

? The inhalation of 15 mg/cu m (3.2μ count median diameter) of H₂SO₄ aerosol for four hours after exposure to radioactive aerosol resulted in a reduction in the rate of clearance of nonviable streptococci from the lungs and noses of mice. A second exposure to H₂SO₄ lasting 90 minutes (15mg/cu m, 3.2μ count median diameter) for four days prior to the radioactive aerosol resulted in a reduced rate of clearance of nonviable streptococci from the noses but not the lungs. Neither of these exposure regimens caused an alteration in the rate of reduction of viable streptococci from the lungs or noses.

Inhalation of 1.5 mg/cu m of H₂SO₄ (0.6μ count median diameter) for four daily 90-minute exposures prior to, or for four hours after exposure to Streptococcus caused no alteration in the normal rate of clearance of viable or nonviable streptococci from the noses or lungs.     

Disruption of Myc-Max Heterodimerization with Improved Cell-Penetrating Analogs of the Small Molecule 10074-G5

The c-Myc (Myc) oncoprotein is a high-value therapeutic target given that it is deregulated in multiple types of cancer. However, potent small molecule inhibitors of Myc have been difficult to identify, particularly those whose mechanism relies on blocking the association between Myc and its obligate heterodimerization partner, Max. We have recently reported a structure-activity relationship study of one such small molecule, 10074-G5, and generated an analog, JY-3-094, with significantly improved ability to prevent or disrupt the association between recombinant Myc and Max proteins. However, JY-3094 penetrates cells poorly. Here, we show that esterification of a critical para-carboxylic acid function of JY-3-094 by various blocking groups significantly improves cellular uptake although it impairs the ability to disrupt Myc-Max association in vitro. These pro-drugs are highly concentrated within cells where JY-3-094 is then generated by the action of esterases. However, the pro-drugs are also variably susceptible to extracellular esterases, which can deplete extracellular reservoirs. Furthermore, while JY-3-094 is retained by cells for long periods of time, much of it is compartmentalized within the cytoplasm in a form that appears to be less available to interact with Myc. Our results suggest that persistently high extracellular levels of pro-drug, without excessive susceptibility to extracellular esterases, are critical to establishing and maintaining intracellular levels of JY-3-094 that are sufficient to provide for long-term inhibition of Myc-Max association. Analogs of JY-3-094 appear to represent promising small molecule Myc inhibitors that warrant further optimization.     

The effect of timing of surgery for velopharyngeal dysfunction on speech

The timing of surgery for velopharyngeal dysfunction has been based on assumptions about the relation between age, speech development, and velopharyngeal dysfunction. Cleft palate teams often counsel parents to have an intervention for velopharyngeal dysfunction performed earlier rather than later, believing that earlier interventions result in more rapid or better normalization of speech. The objective of this retrospective chart review study is to determine whether the age at surgical intervention for velopharyngeal dysfunction has an effect on the subsequent length of speech therapy. Of 174 patients included in the study database, 36 had velopharyngeal dysfunction for which further velopharyngeal management was required. Of the 36 patients who received surgical velopharyngeal dysfunction management, 27 had verifiable speech therapy records. These 27 patients represent the study population. The outcome measure was the total length of subsequent speech therapy until speech normalization. The data suggest that there is no relation between the age at velopharyngeal dysfunction surgical management and the amount of speech therapy needed to achieve normalization of the speech impairments secondary to velopharyngeal dysfunction after that management. In conclusion, 1) the age at surgical velopharyngeal dysfunction management (pharyngeal flap or sphincter pharyngoplasty) does not have an effect on subsequent normalization of speech as measured by the duration of speech therapy necessary to achieve normalization of the speech impairments secondary to velopharyngeal dysfunction after that management, and 2) the age at surgical velopharyngeal dysfunction management does not affect the likelihood of subsequent surgical velopharyngeal dysfunction management procedures.     

TNF-R1 as a first trimester marker for prediction of pre-eclampsia

Objective: To examine whether the maternal serum concentration of the soluble receptor-1 of tumor necrosis factor-α (TNF-R1) at 11–13?+?6 weeks of gestation is a predictor of development of pre-eclampsia (PE).

Methods: This is a nested case–control study in which the concentration of TNF-R1 at 11?+?0 to 13?+?6 weeks was measured in 426 pregnant women in the first trimester. TNF-R1 values were expressed as multiples of the median (MoM) adjusted for maternal factors. The distributions of log TNF-R1 MoM in the control group and hypertensive disorders (early-PE [ePE], late-PE [lPE] and gestational hypertension [GH]) groups were compared. Logistic regression analysis was used to determine whether maternal factors, TNF-R1 or their combination make a significant contribution to the prediction of PE. Screening performance was determined by analysis of receiver–operating characteristics curves.

Results: Median concentration of TNF-R1 (ng/ml) was higher in ePE (2.62?±?0.67), lPE (2.12?±?0.56) and GH (2.19?±?0.45) compared to controls (2.04?±?0.42), p?=?0.001. Logistic regression analysis demonstrated that the addition of TNFR-1 to maternal factors did not make a significant contribution to the prediction of PE.

Conclusions: The maternal serum TNF-R1 concentration at 11–13?+?6 weeks of gestation was increased in pregnancies which developed hypertensive disorders, however, the addition of TNFR-1 did not improve the detection rate of these conditions compared with maternal factors alone.     

Health related quality of life patterns in patients treated with interstitial prostate brachytherapy for localized prostate cancer--data from CaPSURE

PURPOSE: We measured the impact brachytherapy monotherapy (BMT) has on general and disease specific health related quality of life (HRQOL) compared to patients treated with radical prostatectomy (RP). MATERIALS AND METHODS: We studied 419 men with newly diagnosed prostate cancer who enrolled in CaPSURE (Cancer of the Prostate Strategic Urological Research Endeavor) data base whose primary treatment was brachytherapy monotherapy (92) or radical prostatectomy (327). The validated RAND 36-Item Health Survey and the UCLA Prostate Cancer Index were used to measure HRQOL before treatment and at 6-month intervals during the first 2 years after treatment. RESULTS: Patients treated with BMT or RP did not differ greatly in general HRQOL after treatment. Both treatment groups showed early functional impairment in most general domains with scores returning to or approaching baseline in most domains 18 to 24 months after treatment. Patients treated with BMT had significantly higher urinary function scores at 0 to 6 months after treatment (84.5, SD 18.7) than patients treated with RP (63.3, SD 26.6). Urinary bother scores at 0 to 6 months after treatment were not significantly different between patients treated with BMT (67.7, SD 31.2) and those treated with RP (67.4, SD 29.1). Both treatment groups had decreases in sexual function that did not return to pretreatment levels. CONCLUSIONS: Overall BMT and RP are well tolerated procedures that cause mild changes in general HRQOL. Disease specific HRQOL patterns are different in patients treated with BMT or RP. Baseline and serial HRQOL measurements after treatment can provide valuable information regarding expected quality of life outcome after treatment for localized prostate cancer.