A cochlear prosthesis: further clinical observations; preliminary results of physiological studies

A series of simple psychoacoustic studies were conducted on three deaf patients with indwelling scala tympani electrodes to determine better what they hear as a consequence of electrical stimulation. Physiological experiments on cats implanted with a similar electrode were conducted to determine how the sensation heard by these patients is generated and encoded in the auditory nervous system. Some preliminary results of these animal experiments are described. Additional improvements in the surgical implantation procedure are detailed. Results of these studies suggest the following: 1. long-term intracochlear implantation is technically feasible without unusual complications; 2. mechanical stability of the implant prosthesis has been improved by fixing the implant to the temporal bone with methyl methacrylate cement; 3. with simple periodic electrical stimuli the implanted patients described tonal sensation for frequencies ranging from about 100 Hz to more than 10 kHz; 4. apparent pitch changes rapidly as a function of stimulus frequency at frequencies below about 500 Hz; 5. subjects are able to identify many common environmental sounds and a few words, but conventional speech discrimination is poor; 6. the sound sensation generated by electrical stimulation arises as a consequence of simultaneous excitation of a broad segment of the acoustic nerve; therefore, no “place” coding of the electrical stimuli occurs in the cochlea; 7. if no cochlear place coding occurs then tonal quality ascribed to sounds heard with electrical stimulation at low stimulus frequencies must be encoded by the temporal ordering of discharges in stimulated neurons.     

Effects of combretastatin A-4 prodrug against a panel of malignant human B-lymphoid cell lines

Combretastatin A-4 (CA-4) is one of a family of compounds isolated from the South African willow tree Combretum caffrum. CA-4 was found to be active against murine melanoma and a variety of other human solid tumors. For the first time, we report the effect of CA-4 against a panel of malignant human B-lymphoid cell lines [early pre-B acute lymphoblastic leukemia (Reh), diffuse large cell lymphoma (WSU-DLCL2), chronic lymphocytic leukemia (WSU-CLL) and Waldenstrom's macroglobulinemia (WSU-WM)]. Our results indicate, using the prodrug form of CA-4, a concentration-dependent growth inhibition in all tested cell lines, although WSU-DLCL2 was more sensitive. Exposure to 4 nM CA-4 for 96 h induced 77% growth inhibition in Reh, 86% in WSU-CLL and 92% in WSU-WM. When used against the WSU-DLCL2 cell line, this same concentration of CA-4 was completely toxic. Morphological examination showed CA-4 induced the formation of giant, multinucleated cells, a phenomenon commonly found in mitotic catastrophe. Only minimal numbers of cells showing characteristics of apoptosis were detected. In WSU-DLCL2 cells, CA-4 (3 nM) induced the highest apoptosis (5%) after 48 h, while the percentage of dead cells was approximately 47%. Exposure of Reh, WSU-CLL, WSU-WM and WSU-DLCL2 cells for 24 h to 5 nM CA-4 induced 19, 28, 57 and 75% G2/M arrest, as determined by flow cytometry, respectively. Based on these preliminary studies, we believe that mitotic catastrophe is the predominant mechanism by which CA-4 induces cell death rather than apoptosis. Further studies to elucidate the mechanisms of CA-4 activity in vitro and in vivo are currently under investigation in our laboratory.     

Antineoplastic agents 470. Absolute configuration of the marine sponge bromopyrrole agelastatin A

Two bromopyrrole marine alkaloids were isolated from the Mexican sponge, Agelas sp.: hymenidin (1) and agelastatin A (2). The structures were elucidated by analysis of their spectroscopic data and found to correspond to those in the literature. The absolute configuration of agelastatin A (2) was elucidated by single-crystal X-ray diffraction methods. Agelastatin A (2) exhibited strong activity against a panel of human cancer cell lines as well as human umbilical vein endothelial cells.     

The epidemiology, treatment patterns, and costs of cytomegalovirus retinitis in the post-haart era among a national managed-care population

To examine the epidemiology, treatment patterns, and costs of cytomegalovirus (CMV) retinitis treatment in the post-HAART (highly active antiretroviral therapy) era, a retrospective cohort study was performed using data from US managed-care plans from 1997-2002. Cases with CMV retinitis were defined by requiring diagnosis codes for HIV (or AIDS), CMV, and retinitis and claims for anti-CMV treatment. Costs of oral, intravenous, and intraocular treatment periods were examined. The incidence of enrolled HIV or AIDS cases increased from 7 per million members in 1997 to 150 per million members in 2001. The incidence of CMV retinitis decreased from 23 per 10,000 HIV or AIDS cases in 1997 to 8 per 10,000 HIV or AIDS cases in 2001. The average duration of a CMV episode was 192 days and the average cost was 19,576 US dollars. In a multiple linear regression model adjusting for age, gender, insurance type, geographic region, HAART use, and co-existing AIDS-defining illnesses, intraocular and oral treatment periods saved 7135 and US dollars and 6866 US dollars, respectively, per treatment period compared with intravenous treatment (P < 0.05). The incidence of CMV retinitis decreased in this managed-care population during the post-HAART era. Use of oral or intraocular treatment saves costs compared with intravenous treatment in a managed-care environment.     

Isolation and structure of gustastatin from the Brazilian nut tree Gustavia hexapetala

A bioassay-guided investigation of Gustavia hexapetala led to the isolation of a new cancer cell growth inhibitor designated gustastatin (1) and four previously known cancer cell growth inhibitors that included betulinic acid (2). The structures were assigned on the basis of analyses of HRMS combined with 1D and 2D NMR data. The structure of portentol (5) was confirmed by an X-ray crystal structure determination.     

Epigenetic regulation of protein phosphatase 2A (PP2A), lymphotactin (XCL1) and estrogen receptor alpha (ER) expression in human breast cancer cells

Absence of the estrogen receptor alpha (ER) in human breast cancer cells is an indicator of poor prognosis, and predictive of lack of response to hormonal therapy. Previous studies in our laboratory and others have shown that epigenetic regulation, including DNA methylation and histone deacetylation, are common mechanisms leading to ER gene silencing. Through the use of pharmacologic inhibitors, 5-aza 2'deoxycytidine (AZA) and Trichostatin A (TSA), we have shown that alterations in both of these mechanisms results in synergistic reexpression of ER mRNA and functional protein. These alterations may play a larger role in stimulation of cell signaling pathways leading to ER expression. We have utilized newly developed genome wide screening microarray techniques to identify gene(s) contributing to the hormone independent phenotype and AZA/TSA mediated ER expression. From this screen, we identified and confirmed expression of 4 candidate genes (PP2A, XCL1, THY1 and NBC4) as potential regulators of the hormone independent phenotype. Expression of two genes, XCL1 and PP2A, appeared to be correlated with ER expression. PP2A expression was not changed with ER degradation using ICI 182,780 whereas XCL1 expression decreased in the presence of AZA/TSA and ICI 182,780. This suggests that PP2A may be a determinant of ER expression while XCL1 appears to be ER responsive and downstream of ER expression. These gene products may be novel targets to be further explored in the development of new therapeutics for ER negative breast cancer.     

A 12-year prospective study of the long-term effects of early child physical maltreatment on psychological,behavioral, and academic problems in adolescence

OBJECTIVE: To determine whether child physical maltreatment early in life has long-term effects on psychological, behavioral, and academic problems independent of other characteristics associated with maltreatment. DESIGN: Prospective longitudinal study with data collected annually from 1987 through 1999. SETTING AND PARTICIPANTS: Randomly selected, community-based samples of 585 children from the ongoing Child Development Project were recruited the summer before children entered kindergarten in 3 geographic sites. Seventy-nine percent continued to participate in grade 11. The initial in-home interviews revealed that 69 children (11.8%) had experienced physical maltreatment prior to kindergarten matriculation. MAIN OUTCOME MEASURES: Adolescent assessment of school grades, standardized test scores, absences, suspensions, aggression, anxiety/depression, other psychological problems, drug use, trouble with police, pregnancy, running away, gang membership, and educational aspirations. RESULTS: Adolescents maltreated early in life were absent from school more than 1.5 as many days, were less likely to anticipate attending college compared with nonmaltreated adolescents, and had levels of aggression, anxiety/depression, dissociation, posttraumatic stress disorder symptoms, social problems, thought problems, and social withdrawal that were on average more than three quarters of an SD higher than those of their nonmaltreated counterparts. The findings held after controlling for family and child characteristics correlated with maltreatment. CONCLUSIONS: Early physical maltreatment predicts adolescent psychological and behavioral problems, beyond the effects of other factors associated with maltreatment. Undetected early physical maltreatment in community populations represents a major problem worthy of prevention.     

Incidence of occult rectal prolapse in patients with clinical rectoceles and defecatory dysfunction

OBJECTIVE: The purpose of this study was to determine the incidence of occult rectal prolapse (rectal intussusception) by defecating proctography in patients with clinical rectoceles and defecatory dysfunction. STUDY DESIGN: Patients who were seen from September 2000 through August 2001 with defecatory dysfunction and clinical rectoceles underwent single contrast defecating proctography. Radiologists who specialized in gastrointestinal fluoroscopy interpreted the results, which were retrieved from a computerized database.Study Design: Sixty patients who met the inclusion criteria were evaluated. Twenty patients (33%) had intussusception; 58 patients (97%) had rectocele; 1 patient (1.7%) had sigmoidocele, and 6 patients (10%) had anismus (paradoxic contraction of the puborectalis). RESULTS: All but 1 case of intussusception was associated with a rectocele radiographically. Anismus was associated with rectoceles radiographically, except in 1 patient for whom it was the sole finding. CONCLUSION: The data suggest a 33% incidence of occult rectal prolapse in patients with clinical rectoceles and defecatory dysfunction. This is highly clinically significant because one third of patients who are examined for defecatory dysfunction and rectocele may require sigmoid resection rectopexy along with other reconstructive procedures to restore pelvic floor function and prevent symptomatic recurrence.     

Evaluation of dendritic cell immunogenicity after activation and chemical fixation: a mixed lymphocyte reaction model

Dendritic cells (DC) are central to the control of adaptive immunity. Their ability to activate antigen-specific T cells depends on their maturation state. Many microbial and inflammatory products have stimulated DC maturation. This in vitro study used assays of phenotype and function to examine the potential of bacillus Calmette-Guerin, muramyl dipeptide, and CpG-rich oligodeoxynucleotides to stimulate DC maturation. A chemical fixation method was developed to reliably assess the functional potential of stimulated DC within a mixed lymphocyte reaction model. Using this method, it was shown that bacillus Calmette-Guerin provides a maturation signal as effective as the prototype DC stimulant interleukin-1beta. Furthermore, weaker stimuli such as muramyl dipeptide and CpG-rich oligodeoxynucleotides also are able to induce functional maturation of DC. Using chemical fixation, it was possible to generate stable DC in an immature or a mature state. These observations have importance for our understanding of the regulation of adaptive immunity and for the design of DC-based immunotherapeutic strategies.