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.

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.

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.

Costs associated with febrile neutropenia in the US.

BACKGROUND AND OBJECTIVE: Febrile neutropenia (FN) is a potentially life-threatening condition that may develop in cancer patients treated with myelosuppressive chemotherapy and result in considerable costs. This study was designed to estimate US healthcare utilization and costs in those experiencing FN by location of care, tumour type and mortality. METHODS: Cancer patients who received chemotherapy between 2001 and 2006 were identified from the HealthCore Integrated Research Database®, a longitudinal claims database with enrolment, medical, prescription and mortality information covering 12 health plans and more than 20 million US patients. Patients who experienced FN were prospectively matched using propensity score methods within each tumour type of interest (non-Hodgkin's lymphoma, breast, lung, colorectal and ovarian cancer) to those not experiencing FN. Health resource utilization was compared per patient per month for unique prescriptions and visits (inpatient and outpatient) over the length of follow-up. Healthcare total paid costs adjusted to 2009 US dollars per patient per month were examined by FN group (FN vs non-FN, FN died vs FN survived), by source of care (physician office visit, outpatient services, hospitalization and prescriptions) and by tumour type. The number of unique FN-related encounters (inpatient and outpatient) and the number of patients experiencing at least one FN-related encounter were examined. The costs per encounter were tabulated. FN encounters differ from FN episodes in that a single FN episode may include multiple FN encounters (i.e. a patient is seen multiple times [encounters] for treatment of a single FN event [episode]). RESULTS: A total of 5990 patients each were successfully matched between the FN and non-FN (control) groups. Health resource utilization was generally higher in those with FN than in controls. FN patients incurred greater costs (mean ± SD: $US9628 ± 12 517 per patient-month) than non-FN patients ($US8478 ± 12 978). Chemotherapy comprised the majority of costs for both FN (33.5%) and non-FN (40.6%) patients. The largest cost difference by categorical source of care was for hospitalization (p < 0.001). FN patients who died had the highest mean total costs compared with FN surviving patients ($US21 214 ± 25 596 per patient-month vs $US8227 ± 8850, respectively). Follow-up time for those surviving was, on average, 6.6 months longer. Hospitalization accounted for 53.1% of costs in those experiencing mortality with FN, while chemotherapy accounted for the majority of costs (37.1%) in surviving FN patients. A total of 6574 patients with at least one FN encounter experienced a total of 55 726 unique FN-related encounters, 90% of which were outpatient in nature. The majority of FN-related encounters (79%) occurred during the first chemotherapy course. The average costs for FN encounters were highest for inpatient encounters, $US22 086 ± 43 407, compared with $US985 ± 1677 for outpatient encounters. CONCLUSIONS: The occurrence of FN in cancer patients receiving chemotherapy results in greater healthcare resource utilization and costs, with FN patients who die accounting for the greatest healthcare costs. Most FN patients experience at least one outpatient FN encounter, and the total cost of treatment for FN continues to be high.

CT patterns of fungal pulmonary infections of the lung: comparison of standard-dose and simulated low-dose CT.

PURPOSE: To assess the effect of radiation dose reduction on the appearance and visual quantification of specific CT patterns of fungal infection in immuno-compromised patients. MATERIALS AND METHODS: Raw data of thoracic CT scans (64 × 0.75 mm, 120 kVp, 300 reference mAs) from 41 consecutive patients with clinical suspicion of pulmonary fungal infection were collected. In 32 patients fungal infection could be proven (median age of 55.5 years, range 35-83). A total of 267 cuboids showing CT patterns of fungal infection and 27 cubes having no disease were reconstructed at the original and 6 simulated tube currents of 100, 40, 30, 20, 10, and 5 reference mAs. Eight specific fungal CT patterns were analyzed by three radiologists: 76 ground glass opacities, 42 ground glass nodules, 51 mixed, part solid, part ground glass nodules, 36 solid nodules, 5 lobulated nodules, 6 spiculated nodules, 14 cavitary nodules, and 37 foci of air-space disease. The standard of reference was a consensus subjective interpretation by experts whom were not readers in the study. RESULTS: The mean sensitivity and standard deviation for detecting pathological cuboids/disease using standard dose CT was 0.91 ± 0.07. Decreasing dose did not affect sensitivity significantly until the lowest dose level of 5 mAs (0.87 ± 0.10, p=0.012). Nodular pattern discrimination was impaired below the dose level of 30 reference mAs: specificity for fungal 'mixed nodules' decreased significantly at 20, 10 and 5 reference mAs (p<0.05). At lower dose levels, classification drifted from 'solid' to 'mixed nodule', although no lesion was missed. CONCLUSION: Our simulation data suggest that tube current levels can be reduced from 300 to 30 reference mAs without impairing the diagnostic information of specific CT patterns of pulmonary fungal infections.

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.

Endothelium-dependent and independent vasodilation studies at normoglycaemia in type I diabetes mellitus with and without microalbuminuria.

AIMS/HYPOTHESIS: We examined whether endothelial function is impaired in patients with Type I (insulin-dependent) diabetes mellitus under conditions of near-normoglycaemia compared with age-matched healthy control subjects. Our aim was to determine whether microalbuminuria is associated with endothelial dysfunction in Type I diabetes. METHODS: Endothelial function, measured as post-ischaemic flow-mediated dilatation of the brachial artery using ultrasound, was compared among 17 microalbuminuric and 17 normoalbuminuric diabetic patients, and 17 control subjects. Glyceryl trinitrate-mediated dilatation of the brachial artery was used to measure endothelium-independent function. All diabetic patients were studied at near-normoglycaemia, using insulin and 5 % dextrose infusions to maintain blood glucose between 3.5 and 8.0 mmol/l. RESULTS: Flow-mediated dilatation was significantly lower in microalbuminuric diabetic patients (3.2 +/- 0.3%) compared with normoalbuminuric diabetic patients (5.4 +/- 0.6%) and control subjects (7.9 +/- 0.6%, p < 0.001). Normoalbuminuric diabetic patients also had significantly lower flow-mediated dilatation than control subjects (p = 0.01). Glyceryl trinitrate mediated dilatation was significantly lower in the microalbuminuric patients compared with the control subjects (11.9 +/- 1.1% vs 20.0 +/- 1.2%, p = 0.001). Albumin excretion rate and glycated haemoglobin showed a significant negative independent correlation with flow-mediated dilatation (both p < 0.05). CONCLUSION/INTERPRETATION: Type I diabetic patients show endothelial dysfunction at near-normoglycaemia compared with the control subjects, and this abnormality is more marked in diabetic patients with microalbuminuria. Endothelial dysfunction in Type I diabetes is related to the albumin excretion rate and glycaemic control. The presence of endothelial dysfunction in normoalbuminuric diabetic patients suggests it could precede microalbuminuria as an early risk marker for cardiovascular disease.

Corneal ulcers in patients with Apert syndrome.

Morbidity from corneal ulcers is often severe in patients with Apert syndrome. These patients are at an increased risk of developing corneal ulcers because of the compromised corneal environment secondary to exophthalmos. During the past 6 years, three of five patients treated for Apert syndrome at our hospital have developed corneal ulcers. We present a case series discussing each patient, reasons for the development of ulceration, treatment, and outcomes. Morbidities in our group of patients included decreased visual acuity, opacified corneas, amblyopia, and blindness. Treatment is often difficult and complex. Therefore, an ophthalmologist should be an active team member in treating Apert patients.

Supernumerary orbital muscle in congenital eyelid retraction.

PURPOSE: Although several reports of supernumerary orbital muscles related to the levator palpebrae superioris have been published, no case has been associated with congenital eyelid retraction. This report describes an apparent causal relationship between an accessory levator muscle slip and congenital eyelid retraction. METHODS: Case report and literature review. RESULTS: Release of the anomalous muscle's attachment from the superior tarsal border alone resulted in resolution of the eyelid retraction. CONCLUSIONS: Eyelid muscle anomalies may be a cause of congenital eyelid retraction. Ophthalmologists who treat eyelid disorders should be aware of this possibility when evaluating and operating on patients with congenital eyelid retraction.

Ophthalmic drops causing coma in an infant.

A 1-month-old infant with Peters anomaly had recurrent episodes of unresponsiveness, hypotension, hypotonia, hypothermia, and bradycardia. An extensive medical evaluation determined these episodes to be caused by brimonidine, an anti-glaucoma agent. There is the potential for serious toxic effects from the systemic absorption of topically applied ophthalmic agents in children.

Assessment of ophthalmology residents' contact lens training.

PURPOSE: To characterize the nature and duration of contact lens training in ophthalmology residency training programs and to ascertain the comfort level of residents in fitting various types of contact lenses and in dealing with common contact lens-related complications. METHODS: Surveys were mailed to 126 ophthalmology residency program directors/coordinators and requested to be distributed to 1,381 ophthalmology residents. The questionnaire addressed issues related to contact lens training, hours of clinical and didactic training, comfort with fitting a variety of different types of contact lenses and dealing with common contact lens-related complications, and plans for incorporation of contact lens dispensing into future practice. RESULTS: Two hundred and forty-nine residents (18%) responded from 84 programs (67%). Most programs (87%) have some form of supervised contact lens training, frequently conducted by an optometrist (61% of programs), that consists of 20 hours or less of clinical experience and 20 hours or less of didactic training. A majority of the responding graduating residents (66%) feel comfortable fitting spherical soft contact lenses, while less than half of all residents feel comfortable fitting any other type of contact lens. In addition, most residents (65%) feel comfortable diagnosing and treating common contact lens-related complications. CONCLUSIONS: Most ophthalmology residency programs offer some form of supervised contact lens training which allows a majority of residents to feel comfortable fitting only spherical soft contact lenses, while also dealing comfortably with most contact lens-related problems. A comparison with previous data suggests increasing comfort with fitting most types of contact lenses over the last decade.

Effects of sugars on whey protein isolate gelation.

Whey protein isolate (WPI) gels were prepared from solutions containing ribose or lactose at pH values ranging from 6 to 9. The gels with added lactose had no color development, whereas the gels with added ribose were orange/brown. Lactose stabilized the WPI to denaturation, which increased the time and temperature required for gelation, thus decreasing the fracture modulus of the gel compared to the gels with added ribose and the gels with no sugar added. Ribose, however, favored the Maillard reaction and covalent cross-linking of proteins, which increased gel fracture modulus. The decreased pH caused by the Maillard reaction in the gels containing ribose occurred after protein denaturation and gelation, thus having little if any effect on the gelation process.

Maintenance of safer sexual behaviours: evaluation of a theory-based intervention for HIV seropositive men with haemophilia and their female partners.

A theory-based HIV risk-reduction intervention was developed for HIV-positive men with haemophilia and their HIV-negative female romantic partners. The intervention was based on Prochaska and DiClemente's Transtheoretical Model which describes behaviour change as an incremental, stage-based process. The intervention targeted both communication about safer sex and safer sex behaviours (consistent condom use or abstinence from vaginal intercourse). A total of 255 males and 158 females from six funded haemophilia treatment centres or patient organizations (and 27 associated subsites) participated in the study. Baseline and follow-up (15 months after baseline) measures were administered to assess safer sexual behaviours, communication about safer sex and condom self-efficacy. A quasi-experimental, repeated measures design was utilized to compare two naturally occurring groups; those who received the full intervention package and those who received incomplete or no intervention components. Significant intervention effects for safer sex behaviours, communication about safer sex and condom self-efficacy were identified for the male participants, with those receiving the full intervention package demonstrating better outcomes at follow-up. Women who received the full intervention package were more likely to report the use of a condom by their male partner during the last act of vaginal intercourse.

Photoastigmatic refractive keratectomy in myopes. Nidek US Investigators Group.

PURPOSE: Photoastigmatic refractive keratectomy (PARK) was studied in a multi-center clinical trial. The Nidek EC-5000 excimer laser was evaluated for its effect on refraction, visual acuity, and safety measures as part of a U.S. Food and Drug Administration (FDA) regulated study. METHODS: Eight U.S. centers enrolled adults with eyes having refractive astigmatism up to 4.00 D and a myopic spherical equivalent refraction up to -8.00 D. Results are reported for 749 eyes of 486 patients with at least 6 months follow-up. The rectangular beam scanning Nidek EC-5000 used a 5.5-mm-diameter treatment zone, a 7.0-mm-diameter peripheral blend zone, and a 40 Hz pulse rate for surface treatment of myopic astigmatism. Nomogram corrections to machine settings were required to achieve the desired results. RESULTS: Preoperative average spherical equivalent refraction of -4.90+/-1.74 D was reduced to -0.02+/-0.79 D at 6 months. Refractive stability was established at 3 months. Over 62% of eyes were within +/-0.50 D of desired correction at 6 months, with over 86% within +/-1.00 D. Uncorrected visual acuity improved by an average of 10 Snellen lines; over 64% of eyes saw 20/20 or better uncorrected and over 93% saw 20/40 or better uncorrected at 6 and 12 months. PARK treatment effectively reduced astigmatism with little average axis error or magnitude error. Corneal haze and safety concerns were minimal. CONCLUSIONS: Photoastigmatic refractive keratectomy using the Nidek EC-5000 excimer laser provided significant reduction of myopia and astigmatism, with minimal complications.

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.

Sterile interface keratitis after laser in situ keratomileusis: three episodes in one patient with concomitant contact dermatitis of the eyelids.

PURPOSE: To illustrate a case in which sterile interface keratitis after laser in situ keratomileusis (LASIK) occurred concomitantly with an allergic contact dermatitis of the eyelids. METHODS: Retrospective case review. RESULTS: Resolution of the interface keratitis and dermatitis occurred following an intense course of topical corticosteroids and brief course of oral corticosteroids. Despite an attempt to eliminate potential causes, the same patient developed interface keratitis in the fellow eye following both the initial LASIK and an enhancement, in which no microkeratome was used. Intense treatment with both topical and oral corticosteroids led to a final uncorrected visual acuity of 20/20 in the right eye and 20/25+2 in the left eye. CONCLUSION: The etiology and mechanism of sterile interface keratitis after LASIK are unknown, but are probably multifactorial. The concomitant contact dermatitis reaction may indicate a common immune mechanism.

Sterile interface keratitis associated with micropannus hemorrhage after laser in situ keratomileusis.

Numerous etiologies have been suspected to lead to sterile interface keratitis after laser in situ keratomileusis. This tan interface haze with a rippled appearance has been called Sands of the Sahara. We present 2 cases in which red blood cells entered the interface after a small hemorrhage from peripheral corneal vascularization during the microkeratome pass. Although this bleeding was controlled and all visible blood cells were removed at surgery, both patients developed the appearance of a focal interface keratitis on the first postoperative day.

Managed care of children with special health care needs: the ABC Program.

Families of children voluntarily enrolled in a managed care program for children with special health care needs receiving SSI and Medicaid benefits and their case managers were surveyed regarding care satisfaction, quality, and access. Claims data were used to compare the cost and utilization of health care before and during program enrollment. Families rated health care quality improved in 43%, unchanged as "excellent" in 50% of cases. The care received was seen as more nearly complete and of higher quality when the provider was based in the hospital or the hospital's community clinics as compared with "private" community pediatricians. Hospitalization decreased, but no decrease in cost was demonstrated. A carefully planned and implemented managed care program can improve patient perception of quality among chronically ill children.

Evaluation of prior photorefractive keratectomy in donor tissue.

PURPOSE: To describe a case in which an eye donor had prior bilateral photorefractive keratectomies and to elucidate possible methods of evaluation and screening of donor tissue. METHODS: Case report. A 62-year-old eye donor was reported to have received radial keratotomy before his death. Further investigation by the eye bank showed a history of photorefractive keratectomy (PRK), not radial keratotomy. The corneas were therefore not used for transplantation, and the eyes were evaluated by slit-lamp examination, photography, corneal topography, and histology. RESULTS: Slit-lamp and photographic examination did not indicate the presence of PRK ablations. Corneal topography mapping with the TMS-1 was relatively ambiguous for identifying PRK flattening, while multiple data formatting of the cornea with the Orbscan resulted in the strongest suggestion of prior PRK. Histologic analysis showed central corneal thinning and loss of Bowman's membrane consistent with PRK. CONCLUSIONS: In the absence of a positive donor history for PRK, current methods of screening donor tissue for prior PRK often are insufficient to exclude these corneas from use in transplantation. More refined placido imagery corneal topography or newer technologies such as the Orbscan may allow more sensitive and specific methods of donor tissue screening.

Expanding the scope of lamellar keratoplasty.

PURPOSE: To investigate whether applications of current technology, such as cryolathe and excimer laser, might improve outcomes and increase use of lamellar keratoplasty. METHODS: Six studies were performed, beginning with animals and progressing to human subjects. The first study compared cryolathed with hand-dissected rabbit corneas to ascertain which created a smoother donor interface. The second animal pilot study was done to determine whether thickness of donor cornea resection could be accurately predicted with the cryolathe. A prospective animal trial was then undertaken to compare lamellar keratoplasty outcomes using cryolathed versus hand-dissected tissue. The fourth work extrapolated previous animal findings to lamellar keratoplasty in human disease. Finally, two ongoing studies are described. The first explores the possibility of sutureless lamellar keratoplasty. The second utilizes the excimer laser to dissect the recipient stromal bed. RESULTS: The initial animal pilot study demonstrated a clearer stromal surface in cryolathed versus hand-dissected corneal tissue. The second pilot showed that plano-powered donor tissue could be generated to predetermined thickness. The prospective animal trial revealed that clear grafts of intended thickness could be obtained with cryolathing. Human studies suggested that lamellar keratoplasty using cryolathe-prepared donor tissue may offer superior results to free-hand dissection. Finally, one ongoing study indicates that sutureless lamellar keratoplasty is untenable, and the other shows that clear grafts can be obtained by combining cryolathed donor tissue with recipient photoablation. CONCLUSION: This body of work demonstrates that use of new lamellar keratoplasty technology may offer expanded scope and better outcomes than traditional lamellar keratoplasty techniques.