Noninvasive Monitoring of Radiation-Induced Salivary Gland Vascular Injury.

Xerostomia is a common side effect of radiation therapy (RT) in patients with head and neck cancer. However, limited information is available on the temporal dynamics of parenchymal and vascular changes in salivary glands following RT. To address this gap in knowledge, we conducted experimental studies in mice employing ultrasound (US) with coregistered photoacoustic imaging (PAI) to noninvasively assess the early and late changes in salivary gland size, structure, vascularity, and oxygenation dynamics following RT. Multiparametric US-PAI of salivary glands was performed in immune-deficient and immune-competent mice before and after RT along with correlative sialometry and ex vivo histologic-immunohistochemical validation. US revealed reduction in gland volume and an early increase in vascular resistance postradiation. This was accompanied by a reduction in glandular oxygen consumption on PAI. Imaging data correlated strongly with salivary secretion and histologic evidence of acinar damage. The magnitude and kinetics of radiation response were impacted by host immune status, with immunodeficient mice showing early and more pronounced vascular injury and DNA damage response compared to immunocompetent animals. Our findings demonstrate the ability of noninvasive US-PAI to monitor dynamic changes in salivary gland hemodynamics following radiation and highlight the impact of the host immune status on salivary gland radiation injury.

Bortezomib and gemcitabine in relapsed or refractory Hodgkin's lymphoma.

BACKGROUND: Given the significant activity and tolerability of gemcitabine in patients with relapsed Hodgkin's lymphoma (HL), the critical role that nuclear factor kappa B (NF-kappaB) appears to play in the pathogenesis of this tumor, the ability of bortezomib to inhibit NF-kappaB activity, and laboratory studies suggesting synergistic antitumor effects of gemcitabine and bortezomib, we hypothesized that this combination would be efficacious in patients with relapsed or refractory HL. PATIENTS AND METHODS: A total of 18 patients participated. Patients received 3-week cycles of bortezomib 1 mg/m(2) on days 1, 4, 8, and 11 plus gemcitabine 800 mg/m(2) on days 1 and 8. RESULTS: The overall response rate for all patients was 22% (95% confidence interval 3% to 42%). Three patients developed grade III transaminase elevation: one was removed from the study and two had doses of gemcitabine held. Almost all patients exhibited inhibition of proteasome activity with treatment. CONCLUSIONS: The combination of gemcitabine and bortezomib is a less active and more toxic regimen in relapsed HL than other currently available treatments. It poses a risk of severe liver toxicity and should be pursued with caution in other types of cancer.

Impact of Age on Disease Progression and Microenvironment in Oral Cancer.

Despite the recognized link between aging and cancer, most preclinical studies in experimental tumor models are conducted with 6- to 8-wk-old rodents. The goal of the present study was to examine the impact of age on tumor incidence, growth, and microenvironmental characteristics in mouse models of head and neck squamous cell carcinoma (HNSCC). Experimental studies were conducted with the 4-nitroquinoline-oxide (4NQO) oral carcinogenesis model and orthotopic FaDu HNSCC xenografts, established in young (7 to 12 wk of age) and old (65 to 70 wk of age) female C57BL/6 mice ( n = 44; 4NQO model) and severe combined immunodeficient mice ( n = 13; HNSCC xenografts). Noninvasive whole body magnetic resonance imaging revealed increased subcutaneous and visceral fat in aging animals of both strains. On histologic examination, a higher incidence ( P < 0.001) of severe dysplasia/invasive squamous cell carcinoma was observed in old mice (92%) as compared with young mice (69%). Old C57BL/6 mice exposed to 4NQO exhibited increased incidence of oral and extraoral (peritoneal masses) neoplasms (42%) versus their young counterparts ( P < 0.05). The incidence of extraoral neoplasms was significantly lower (16%) in the younger cohort. Interestingly, no difference in growth rate and oxygen saturation was observed between orthotopic FaDu xenografts established in old and young severe combined immunodeficient mice. Our observations suggest that host age may have an impact on the growth kinetics and progression of HNSCC in the immunocompetent 4NQO model. Further investigation into the impact of aging on tumor response to preventive and therapeutic intervention is warranted.

Inhibition of cis-diamminedichloroplatinum secretion by the human kidney with probenecid.

The renal handling of cis-diamminedichloroplatinum (CP) was investigated by measuring the renal clearance of creatinine, inulin, and free platinum in ten cancer patients. Free platinum clearances exceeded the glomerular filtration rate in all time periods. For example, at 1 to 2 hr, the mean clearance of free platinum was 224 +/- 32 (S.E.) ml/min compared to a mean creatinine clearance of 94 +/- 15 ml/min or a mean inulin clearance of 94 +/- 17 ml/min (p less than 0.01), indicating secretion of CP or a metabolite. Seven additional cancer patients were treated with probenecid prior to CP. Fractional platinum clearances, calculated as a ratio of free platinum clearance to creatinine clearance, were reduced significantly in the probenecid-treated group (158 +/- 17%) compared to controls (270 +/- 57%) (p less than 0.03). Fractional platinum clearances, calculated as a ratio of free platinum clearance to inulin clearance, were also significantly reduced in the treated group (154 +/- 14%) compared to controls (271 +/- 47%) (p = 0.04). These results suggest that cisplatin is secreted by the human kidney, and this can be inhibited by probenecid. Such maneuvers may be helpful in improving the therapeutic index of this important chemotherapeutic agent.

Atom probe tomography (APT) of carbonate minerals.

Atom probe tomography (APT) combines the highest spatial resolution with chemical data at atomic scale for the analysis of materials. For geological specimens, the process of field evaporation and molecular ion formation and interpretation is not yet entirely understood. The objective of this study is to determine the best conditions for the preparation and analysis by APT of carbonate minerals, of great importance in the interpretation of geological processes, focusing on the bulk chemical composition. Results show that the complexity of the mass spectrum is different for calcite and dolomite and relates to dissimilarities in crystalochemical parameters. In addition, APT bulk chemistry of calcite closely matches the expected stoichiometry but fails to provide accurate atomic percentages for elements in dolomite under the experimental conditions evaluated in this work. For both calcite and dolomite, APT underestimates the amount of oxygen based on their chemical formula, whereas it is able to detect small percentages of elemental substitutions in crystal lattices. Overall, our results demonstrate that APT of carbonate minerals is possible, but further optimization of the experimental parameters are required to improve the use of atom probe tomography for the correct interpretation of mineral geochemistry.

Hypoglycemic coma in anorexia nervosa. Case report and review of the literature.

Clinically significant hypoglycemia is an unusual complication of anorexia nervosa. We describe a 44-year-old woman with a 5-year history of anorexia nervosa who presented with hypoglycemic coma and eventually experienced sudden death. Biochemical studies showed suppressed levels of insulin, C peptide, and proinsulin during hypoglycemia; appropriate elevations of growth hormone and cortisol levels were observed, suggesting that the hypoglycemia was related to severe malnutrition. Nine previously reported cases of severe hypoglycemia in anorexia nervosa are reviewed (six of the patients involved also died). The presence of severe hypoglycemia in anorexia nervosa implies a grave prognosis and mandates aggressive medical and nutritional therapy to improve the chance of survival.

Phosphorus-containing inhibitors of HMG-CoA reductase. 2. Synthesis and biological activities of a series of substituted pyridines containing a hydroxyphosphinyl moiety.

A series of 2,3,4,(5),6-substituted pyridines containing a hydroxyphosphinyl functionally have been prepared and were evaluated for their ability to inhibit the enzyme HMG-CoA reductase. Systematic substitution of both R1-R4 and X-Y led to compounds of type 3-6 with in vitro potency greater than that of mevinolin (Na salt).

Hepatitis C is a poor prognostic indicator in black kidney transplant recipients.

BACKGROUND: The significance of hepatitis C in kidney transplant recipients is unclear. The prevalence of antibodies to hepatitis C among candidates for transplantation is up to 50% in some centers. METHODS: We screened 640 frozen serum samples obtained pretransplantation from all kidney recipients at the Medical College of Wisconsin between January 1979 and March 1990 for antibody to hepatitis C using the second generation immunoassay. Charts were reviewed from all hepatitis C antibody-positive (anti-HCV+) patients and 256 randomly chosen hepatitis C antibody negative (anti-HCV-) controls. Actuarial patient and graft survival in these two groups were determined. RESULTS: The prevalence of anti-HCV was 8.3%. Blacks and i.v. drug users were disproportionately represented in the anti-HCV+ group. Of the anti-HCV+ patients, 18.9% developed chronic hepatitis independent of race. Black anti-HCV+ patients had a 5-year graft survival of 28 +/- 11% compared to 67 +/- 7% in black anti-HCV- patients (P = 0.003). Black anti-HCV-, white anti-HCV-, and white anti-HCV+ patients all had similar graft survival. Anti-HCV was not a poor prognostic indicator for overall patient survival or the development of aplastic anemia and malignancies including hepatocellular carcinoma. CONCLUSIONS: Anti-HCV is a significant risk factor for reduced kidney graft survival in blacks apart from i.v. drug abuse. Black anti-HCV- patients had graft survival similar to white transplant recipients, indicating that anti-HCV may be one marker for the poorer graft survival in blacks that has been observed in most transplant programs. Anti-HCV in kidney transplant recipients increases the risk for the development of chronic hepatitis post-transplant.

Decreasing nonurgent emergency department utilization by Medicaid children.

OBJECTIVE: To test interventions to decrease the utilization of hospital emergency departments (EDs) for routine, nonemergent health care among Medicaid recipients. METHODS: Families of a Medicaid-recipient child presenting to a children's hospital ED for nonurgent problems received information from either a health professional or a clerical employee about the importance of a primary care provider and assistance with making an appointment to the provider of their choice. The health professional continued to work with her assigned families in eliminating barriers to appropriate utilization of a primary care provider for up to 3 months after the index ED visit. A third (comparison) group received no intervention. Subsequent health care utilization for each enrollee was tracked via Ohio Medicaid claims data throughout the four subsequent 6-month periods after the index ED visit. RESULTS: Children in the intervention groups had 11.1% and 14.5% fewer nonurgent ED visits in the 6 months after the index ED visit with a concomitant decrease in cost for this type of care when compared with the comparison group during the same time period. No difference in the number of preventive or ill-child primary care visits was seen. There was no difference in health care cost or utilization in the time period 6 to 24 months after the intervention. CONCLUSIONS: Interventions in pediatric EDs aimed at decreasing subsequent ED utilization for nonurgent care can be effective, resulting in modest decreases in the cost of health care for a Medicaid population.

The impact of a brief intervention on maternal smoking behavior.

OBJECTIVE: To determine if mothers receiving a smoking cessation intervention emphasizing health risks of environmental tobacco smoke (ETS) for their children have a higher quit rate than 1) mothers receiving routine smoking cessation advice or 2) a control group. DESIGN: Randomized, controlled trial. SETTING: Primary care center in a large urban children's hospital. INTERVENTION: Four hundred seventy-nine mothers were randomly assigned to a smoking cessation intervention either aimed at their child's health or their own health, or to a control group receiving safety information. OUTCOME MEASURES: Smoking status, stage of change, cigarettes/day, location smoking occurred, and knowledge of ETS effects. RESULTS: Complete data (baseline and both follow-ups) were available for 166 subjects. There was no impact of group assignment on the quit rate, cigarettes/day, or stage of change. The Child Health Group intervention had a sustained effect on location where smoking reportedly occurred (usually outside) and on improved knowledge of ETS effects. CONCLUSIONS: Further research is needed to devise more effective methods of using the pediatric health care setting to influence adult smoking behaviors.

Obesity in black adolescent girls: a controlled clinical trial of treatment by diet, behavior modification, and parental support.

Recent findings indicate that nearly 50% of black American women are obese and that adolescence is a critical period for the development of their obesity. This study investigated the efficacy of a behavioral weight control program in 36 black female adolescents with a mean age of 14.0 years, weight of 95.0 kg, and height of 163.2 cm. All subjects participated in the same 16-week program but had different levels of parent participation: (1) child alone with no parent participation; (2) mother and child treated in the same session; and (3) mother and child treated in separate but concurrent session. At the end of the 16-week program, children in the three conditions lost 1.6, 3.7, and 3.1 kg, respectively. Differences among conditions were not statistically significant; however, a secondary analysis revealed that the greater the number of sessions attended by mothers, the greater their daughters' weight losses. Weight reduction was associated with significant improvements in body composition, serum total cholesterol concentrations, and psychological status. Results are discussed in terms of the need to improve the maintenance of weight loss in adolescents and to explore possible differences between black and white females in their preferred body types.

Effects of growth factors on corneal wound healing.

Rabbits received nonpenetrating central corneal knife wounds. Immediately after wounding, a single 2.5 or 5.0 micron dose of mesodermal growth factor (MGF) was applied topically to the wound. Controls were treated with saline. Electron microscopic studies compared the healing responses of the control and treated animals over a 7-day period. MGF was a potent nitrogen for keratocytes in rabbit corneas. The single dose enhanced fibroblast proliferation and metabolic activity. Control wounds were not healed after 7 days, whereas those of treated animals showed complete healing.

Stereo-discrimination between diplopic images in clinically normal observers.

When retinal disparity exceeds the limits for fusion, the resulting images are perceived as diplopic. In a stereo test that allowed comparison of crossed and uncrossed disparity sensitivities, 74% of the subjects perceived convergent disparities more readily than divergent disparities. This asymmetric sensitivity to disparity did not appear to be related to measurements of phoria, vergence amplitudes, or clinical measurements of stereo acuity.

Detection of mRNA for the cytokines, interleukin-1 alpha and interleukin-8, in corneas from patients with pseudophakic bullous keratopathy.

PURPOSE: Cytokines have been implicated in corneal inflammatory diseases. The authors sought to determine if corneal diseases with different patterns of inflammation are accompanied by characteristic patterns of cytokine expression. METHODS: The authors used reverse transcription-polymerase chain reaction to detect mRNA for 12 specific cytokines from patients with Fuch's dystrophy (n = 7), pseudophakic bullous keratopathy (n = 12), or normal corneas (n = 4). RESULTS: Using Wilcoxon rank sum analysis, mRNA for interleukin (IL)-1 alpha or IL-8 was significantly more abundant in corneas from patients with pseudophakic bullous keratopathy relative to either comparison group. mRNA for the T-cell marker, CD4, and for T-cell derived cytokines, IL-2, IL-4, and interferon gamma, could not be detected in any corneal sample. Message for IL-1 receptor antagonist and transforming growth factor-beta 1 or -beta 2 was readily detectable in most corneas regardless of diagnosis. CONCLUSION: The findings indicate that the pattern of cytokine mRNA expression reflects differences in the pathogenesis of these corneal diseases.

Keratocyte survival in keratophakia lenticules.

Keratocyte survival in corneal lenticules preparing by cryolathing was evaluated using the vital stain, nitroblue tetrazolium. A comparison was made between lenticules inserted in the recipient cornea immediately after grinding and those inserted after one week of storage in either glycerin or liquid nitrogen. In all three groups, no viable keratocytes stained in the donor lenticule at one or three days after surgery. Ten days after insertion, however, all three groups showed a few staining cells within the body of the lenticule, suggesting beginning repopulation of the donor collagenous framework with viable cells from the host. Since the donor keratocytes are dead, healing of keratophakia lenticules is not influenced adversely by storing the donor material. Thus, keratophakia lenticules could be prepared in advance of surgery and stored in glycerin or liquid nitrogen until needed.

Stimulation of corneal wound healing with mesodermal growth factor.

Mesodermal growth factor (MGF) from mouse submaxillary glands was tested in vivo for stimulating effects on corneal wounds in rabbits. Intrastromal injection of 5 microgram of MGF induced widespread fibroblast activity and stromal cell division, and markedly stimulated stromal healing. At high doses (greater than 25 microgram), corneal destruction was indicated by extensive necrosis and perforation. When low doses (1 to 5 microgram) of MGF were applied to the lip of nonperforating knife wounds of the cornea, three major differences were noted between control and experimental wounds. In wounds treated with MGF, the depth of stromal healing was greater, as was the intensity of the fibroblast activity, and the width and depth of the epithelial plug were significantly decreased. These results establish that MGF is an effective growth-stimulating agent in vivo and that the initial stages of corneal wound healing may be accelerated in vivo.

Diurnal variation in vision after radial keratotomy.

We tested eight patients who had undergone radial keratotomy with regard to refraction, keratometry, corneal thickness, and intraocular pressure one to two weeks after surgery. Patients were examined immediately after eye-lid opening at 7:30 A.M. and again at 4:00 P.M. The contralateral eye was used as a control. The treated eye was 1.48 +/- 0.24 diopters (mean +/- S.E.M.) more hyperopic at the morning examination compared to the afternoon visit, whereas the control eye had an insignificant shift (0.16 +/- 0.06 diopters). The treated eye was significantly flatter (1.37 +/- 0.19 diopters) in the morning than in the afternoon when compared to the control eyes, which were only 0.11 +/- 0.09 diopter flatter. The intraocular pressure changed insignificantly in both the treated and control eyes (-0.5 +/- 0.53 mm Hg and -0.5 +/- 0.84 mm Hg, respectively). The mean morning corneal thickness was significantly greater (5.7%) than the afternoon thickness when compared to the controls (1.7% morning increase in thickness). These data suggest that diurnal variation in corneal thickness after radial keratotomy plays a role in diurnal variation of vision in the early postoperative period.

The effects of hard and soft contact lenses on the corneal endothelium.

We examined the morphologic characteristics of the corneal endothelium in three groups of contact lens wearers: those who had used daily-wear soft contact lenses for an average of 6.3 years, long-term (greater than 20 years) users of hard contact lenses, and former users of hard contact lenses who had worn them for an average of 9.6 years but who had discontinued them for an average of 4.3 years. When compared to age-matched controls, all groups had similar endothelial cell densities but demonstrated significant increases in variation of cellular size (polymegethism) and shape (pleomorphism). We found that daily-wear soft contact lenses can cause endothelial polymegethism and pleomorphism similar to those caused by hard contact lenses and that the endothelial changes induced by hard contact lenses are more profound with greater duration of wear and are apparently not completely reversible.

The effect of radial keratotomy on the corneal endothelium.

Morphometric analysis of the corneal endothelium was performed on 11 eyes of patients who underwent anterior radial keratotomy with the contralateral eye serving as the controls. We analyzed cell density, variation in cell size (polymegethism), and cell shape (pleomorphism) by computer analysis of central and midperipheral specular micrograms one year after surgery. The central endothelial density decreased from 2,503 to 2,419 cells/mm2 (3.3% decrease). The coefficient of variation in cell size (polymegethism) was 0.290 preoperatively and 0.309 postoperatively centrally. Central hexagonality was reduced centrally from 61.4% preoperatively to 56.8% in the operated on eye. These differences were not statistically significant (P greater than .05). In a separate subgroup of six patients, midperipheral specular microscopy under and between incisions disclosed a similar pattern of mild cell density decrease and morphometric remodeling one year after surgery. No morphometric characteristic was significantly different from the central control values (P greater than .05), suggesting that the corneal endothelial monolayer had stabilized one year after radial keratotomy.

Long-term effects of radial keratotomy on the corneal endothelium.

BACKGROUND: The long-term effects of radial keratotomy on the corneal endothelium are not well understood. We evaluated the effects of radial keratotomy on the corneal endothelium on the central and midperipheral corneal endothelium. METHODS: Anterior radial keratotomy in 25 eyes was performed and patients were followed for a duration of 4 to 10 years after surgery. Eleven non- contact lens wearing control eyes did not have surgery and were followed for the same period. Morphometric analysis of specular microscopic images was performed with regard to cell density, percent hexagonality, and coefficient of variation. RESULTS: Mean corneal endothelial cell loss rates were 0.4% per year in the radial keratotomy group and 0.9% in the untreated control group over the study duration (mean 7 yr). Morphometric analysis of the cells failed to show a significant change in hexagonality and coefficient of variation. Evaluation of the midperipheral corneal cell counts demonstrated a 1% per year cell loss rate. The cell loss rates in radial keratotomy patients followed over this period were consistent with that noted for normal aging (0.5 to 2.5% per year). CONCLUSION: Radial keratotomy does not cause accelerated endothelial cell loss over 4 to 10 years.