The Development of Technology for Effective Respiratory-Gated Irradiation Using an Image-Guided Small Animal Irradiator.

The development of image-guided small animal irradiators represents a significant improvement over standard irradiators by enabling preclinical studies to mimic radiotherapy in humans. The ability to deliver tightly collimated targeted beams, in conjunction with gantry or animal couch rotation, has the potential to maximize tumor dose while sparing normal tissues. However, the current commercial platforms do not incorporate respiratory gating, which is required for accurate and precise targeting in organs subject to respiration related motions that may be up to the order of 5 mm in mice. Therefore, a new treatment head assembly for the Xstrahl Small Animal Radiation Research Platform (SARRP) has been designed. This includes a fast X-ray shutter subsystem, a motorized beam hardening filter assembly, an integrated transmission ionization chamber to monitor beam delivery, a kinematically positioned removable beam collimator and a targeting laser exiting the center of the beam collimator. The X-ray shutter not only minimizes timing errors but also allows beam gating during imaging and treatment, with irradiation only taking place during the breathing cycle when tissue movement is minimal. The breathing related movement is monitored by measuring, using a synchronous detector/lock-in amplifier that processes diffuse reflectance light from a modulated light source. After thresholding of the resulting signal, delays are added around the inhalation/exhalation phases, enabling the "no movement" period to be isolated and to open the X-ray shutter. Irradiation can either be performed for a predetermined time of X-ray exposure, or through integration of a current from the transmission monitor ionization chamber (corrected locally for air density variations). The ability to successfully deliver respiratory-gated X-ray irradiations has been demonstrated by comparing movies obtained using planar X-ray imaging with and without respiratory gating, in addition to comparing dose profiles observed from a collimated beam on EBT3 radiochromic film mounted on the animal's chest. Altogether, the development of respiratory-gated irradiation facilitates improved dose delivery during animal movement and constitutes an important new tool for preclinical radiation studies. This approach is particularly well suited for irradiation of orthotopic tumors or other targets within the chest and abdomen where breathing related movement is significant.

The Gray Institute 'open' high-content, fluorescence lifetime microscopes.

We describe a microscopy design methodology and details of microscopes built to this 'open' design approach. These demonstrate the first implementation of time-domain fluorescence microscopy in a flexible automated platform with the ability to ease the transition of this and other advanced microscopy techniques from development to use in routine biology applications. This approach allows easy expansion and modification of the platform capabilities, as it moves away from the use of a commercial, monolithic, microscope body to small, commercial off-the-shelf and custom made modular components. Drawings and diagrams of our microscopes have been made available under an open license for noncommercial use at http://users.ox.ac.uk/~atdgroup. Several automated high-content fluorescence microscope implementations have been constructed with this design framework and optimized for specific applications with multiwell plates and tissue microarrays. In particular, three platforms incorporate time-domain FLIM via time-correlated single photon counting in an automated fashion. We also present data from experiments performed on these platforms highlighting their automated wide-field and laser scanning capabilities designed for high-content microscopy. Devices using these designs also form radiation-beam 'end-stations' at Oxford and Surrey Universities, showing the versatility and extendibility of this approach.

Tolerability of gemcitabine and carboplatin doublet therapy in cats with carcinomas.

BACKGROUND: This study was performed to determine the toxicity of gemcitabine-carboplatin doublet therapy in cats with carcinomas. HYPOTHESIS: Gemcitabine and carboplatin are safe in tumor-bearing cats. ANIMALS: Twenty cats with spontaneously occurring carcinomas. METHODS: A cohort of 6 cats received gemcitabine (2 mg/kg IV) on days 1, 8, and 15 and carboplatin (10 mg/kg IV) immediately after gemcitabine on day 1 of a 21-day cycle. A 2nd cohort of 14 cats received carboplatin 4 hours after gemcitabine on day 1 and gemcitabine on day 8 but not day 15. The cycles were repeated every 21 days. RESULTS: Cats in the 1st cohort received a median of 3.75 cycles per animal (range, 1-6). Two cats (33.3%) developed grade 3 or 4 neutropenia, 1 (16.7%) grade 4 thrombocytopenia, and 1 (16.7%) grade 3 gastrointestinal toxicity. Gemcitabine dose reductions and treatment delays occurred in 1 and 4 cats, respectively. Cats in the 2nd cohort received a median of 2 cycles per animal (range, 0.5-10). Two cats (14.3%) had grade 3 or 4 neutropenia and 1 (7.1%) had grade 3 and 4 gastrointestinal toxicity. One cat required gemcitabine dose reduction and 6 had treatment delays. In the 2nd cohort, of 11 cats with measurable tumors, there was 1 complete response (pancreatic carcinoma) and 1 partial response (squamous cell carcinoma, receiving concurrent nonsteroidal anti-inflammatory drugs). CONCLUSIONS AND CLINICAL IMPORTANCE: Gemcitabine-carboplatin combination appears moderately well tolerated in tumor-bearing cats. Minimal patient benefit suggests that alternative schedules or combinations of gemcitabine with other agents should be explored.

The cloning and expression of matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase 2 in normal canine lymph nodes and in canine lymphoma.

Matrix metalloproteinase-2 (MMP-2) and its inhibitor, tissue inhibitor of matrix metalloproteinase 2 (TIMP2), are known to be important in cancer. The purposes of this study were to determine the cDNA sequence of canine MMP-2 and to investigate the expression patterns of MMP-2 and TIMP2 in normal canine lymph nodes and spontaneously arising canine lymphomas. We cloned and sequenced a PCR product containing most (1901 base pairs) of the coding sequence of canine MMP-2 that translates into a 623 amino acid protein. The cDNA and deduced amino acid sequences are highly homologous to those of other mammalian species. Canine MMP-2 and TIMP2 mRNAs were detectable in the majority of normal lymph node and lymphomatous samples evaluated. No statistical difference was identified when comparing the expression of either gene with regard to normal versus neoplastic nodes, nodal versus extranodal lymphoma, lymphoma grade, or B versus T cell immunophenotype.

Frequency and perception of cough severity.

OBJECTIVE: The frequency of the common symptom of cough in children is unknown. The aim of this study was to compare cough frequency and perception of cough severity in children with and without recurrent cough. METHODOLOGY: Eighty-four children with (C) and without (NC) recurrent cough were recruited in the same season. Cough frequency (measured with cough-meter) and subjective cough severity (measured on parent-completed and child-completed diary cards on two subjective systems), were compared between the two groups. RESULTS: Cough frequency in C (median 65/day) was significantly higher than in NC (10/day). The correlation between daytime and night-time cough was higher in NC (rs = 0.51, P < 0.00001) than in C (rs = 0.3, P = 0.05). The C group had significantly higher coughs per score than NC, for both subjective methods. CONCLUSIONS: Children with recurrent cough have a higher frequency and different pattern of cough than controls enrolled in the same season. Subjective perception of cough severity is dependent on the population studied.

A novel approach to monitoring adherence to preventive therapy for tuberculosis in adolescence.

OBJECTIVES: To evaluate the usefulness of a microelectronic tablet-dispenser for monitoring adherence to preventive therapy for tuberculosis infection in adolescents. METHODOLOGY: Twenty-one patients with positive Mantoux tests were treated with isoniazid (INH), dispensed in a microelectronic tablet-dispenser that recorded the date, time and duration that the container was opened. Other measures of adherence included attendance at clinic, patient self-report, tablet count, and measurement of urinary INH metabolites. RESULTS: The mean adherence rates were: 83% using attendance at clinic, 91% using tablet counts, 79% using urine assays, and 66% using the electronic tablet-dispenser. Self-reporting appeared to over-estimate adherence. CONCLUSIONS: Adherence to 6 months of INH calculated using different measures is higher in this study than in previous reports. Microelectronic tablet-dispensers are an effective method to objectively measure adherence on a daily basis. Other measures are less helpful.

Subjective scoring of cough in children: parent-completed vs child-completed diary cards vs an objective method.

Cough is often used as an outcome measure, although the reporting of cough is unreliable. Using a 24 h ambulatory cough meter to measure cough frequency, the aim of this study was to compare: 1) the correlation of child-completed diary cards to the objective measurement, with that of parent-completed diary cards; and 2) the visual analogue scale (VAS) to the verbal category descriptive (VCD) score. The cough meter consisted of a previously validated Holter monitor and a cough processor. Eighty four children (39 with recurrent cough and 45 controls, aged 6-17 yrs) used a cough meter at least once. Thirty three subjects used the cough meter twice. Parents and children completed separate diary cards using the VAS and VCD scores. The strength of the relationship between the subjective scores and the objective recordings was analysed by spearman's rank correlation coefficient. For daytime cough, child-completed diary cards and the VCD correlated better to the objective measurement than parent-completed diary cards and the VAS, respectively. In subjects that used the cough meter twice, the difference between the cough frequency correlated to the difference in the subjective scores. The confidence intervals for the correlation coefficients were wide. The agreement between the objective and subjective presence of daytime cough was good but that for night-time cough was poor. We conclude that the severity of cough defined on diary cards may not represent cough frequency. Objective readings are first choice but currently not yet practical. The verbal category descriptive diary card completed by children and assisted by parents has the highest correlation to cough frequency measured objectively.

A new use for an old Holter monitor: an ambulatory cough meter.

Cough is commonly used as an outcome measure in clinical studies, although the subjective reporting of cough is unreliable when compared to objective measures. We describe an inexpensive new ambulatory cough meter that is based on a disused Holter monitor. The cough meter consists of a Holter monitor and a cough processor, designed on a computer to select the most appropriate filters. The cough meter was then validated against the overnight tape recorder on 21 occasions in 18 children (aged 6-15 yrs). The agreement between the cough meter and the tape recorder was good (mean difference of -0.3 coughs x h(-1); limits of agreement -2.2 to 1.7 coughs x h(-1)). We conclude that our newly described ambulatory cough meter provides a valid and inexpensive method of objectively monitoring cough for up to 24 h.

Medical knowledge overload: a disturbing trend for physicians.

The article examines responses of more than 500 physicians questioned about the time available for reading professional journals over the past 5 years as well as their utilization of information retrieval systems. It also examines physicians' perceptions of professional medical sales personnel as medical information sources.

Regulating controversial programs for unpopular people: methadone maintenance and syringe exchange programs.

One third of all cases of the acquired immunodeficiency syndrome (AIDS) in the United States are associated with the injection of illicit drugs. There is mounting evidence for the effectiveness of syringe exchange programs in reducing human immunodeficiency virus (HIV) risk behavior and HIV transmission among injection drug users. Expansion of syringe exchange would require increased public funding and undoubtedly would include government regulation of syringe exchanges. An analogy is drawn with the present system of regulation of methadone maintenance treatment programs and possible regulation of syringe exchange programs. Specific recommendations are offered to reduce the likelihood of repeating the regulatory problems of methadone maintenance treatment in future regulation of syringe exchange programs.

Another wall that crumbled--methadone maintenance treatment in Germany.

During the past quarter-century there have been innumerable reports throughout the world documenting the effectiveness of methadone maintenance treatment. None have been as consistently positive as those from Germany, where just a few years ago methadone was effectively banned. The German accomplishments in the past 6 years in treating addicts with methadone confirm the experience elsewhere: Methadone treatment is a highly desired alternative to many who wish to escape the life of the street addict; it is very effective in benefiting the individual patient as well as the general community; and it can be expanded rapidly and on a large scale. What is needed today is not further discussion but a firm commitment to make treatment available on request to every addict willing to accept it. With methadone maintenance--one treatment approach among many--this goal is achievable. There is no justification for settling for less.