Novel application of high-dose rate brachytherapy for severe, recalcitrant palmoplantar pustulosis.

Palmoplantar pustulosis (PPP) is a chronic pustular dermatitis of the palms and soles, which is frequently associated with significant pruritus and pain, often limiting daily activities. We present the case of a 36-year-old man with severe PPP who had treatment failure with multiple medical therapies but showed marked improvement with high-dose rate brachytherapy. Brachytherapy has the advantage of providing a conformal dose distribution over complex curved surfaces, such as the foot and ankle. Our observations suggest that brachytherapy may be a well-tolerated treatment option for patients with severe, refractory PPP.

American Brachytherapy Society consensus guidelines for thoracic brachytherapy for lung cancer.

PURPOSE: To update brachytherapy recommendations for pretreatment evaluation, treatment, and dosimetric issues for thoracic brachytherapy for lung cancer. METHODS AND MATERIALS: Members of the American Brachytherapy Society with expertise in thoracic brachytherapy updated recommendations for thoracic brachytherapy based on literature review and clinical experience. RESULTS: The American Brachytherapy Society consensus guidelines recommend the use of endobronchial brachytherapy for disease palliation in patients with central obstructing lesions, particularly in patients who have previously received external beam radiotherapy. The use of interstitial implants after incomplete resection may improve outcomes and provide enhanced palliation. Early reports support the use of CT-guided intratumoral volume implants within clinical studies. The use of brachytherapy routinely after sublobar resection is not generally recommended, unless within the confines of a clinical trial or a registry. CONCLUSIONS: American Brachytherapy Society recommendations for thoracic brachytherapy are provided. Practitioners are encouraged to follow these guidelines and to develop further clinical trials to examine this treatment modality to increase the evidence base for its use.

Partial breast irradiation: a review of techniques and indications.

The addition of whole-breast external beam radiotherapy (EBRT) to breast-conserving surgery results in a significant reduction in the risk of death due to breast cancer, but this may be offset by an increase in deaths from other causes and toxicity to surrounding organs. Because of this, and with a view to patterns of local recurrence, irradiation of the tumour bed has been explored in selected patients with early breast cancer using a variety of radiotherapeutic modalities. This review article explores the treatment options for partial breast irradiation and examines their role within the field of breast cancer treatment.

Pretreatment frontal EEG and changes in suicidal ideation during SSRI treatment in major depressive disorder.

OBJECTIVE: We investigated frontal quantitative EEG (QEEG) as predictor of changes in suicidal ideation (SI) during SSRI treatment in major depressive disorder (MDD). METHOD: Eighty-two subjects meeting DSM-IV criteria for MDD entered an 8-week, prospective, open-label treatment with flexible dose SSRIs and completed at least 4 weeks of treatment. We assessed MDD severity with the 17-item Hamilton Depression Rating Scale (HAM-D-17); change in SI was measured with HAM-D item no. 3. We recorded four-channel EEGs (F7-Fpz, F8-Fpz, A1-Fpz, A2-Fpz) before treatment. RESULTS: During the first 4 weeks of treatment 9 (11%) subjects experienced worsening SI. Left-right asymmetry of combined theta + alpha power correlated significantly with change in SI from baseline, even when adjusting for changes in depression severity (HAM-D-17) and for the SSRI utilized. CONCLUSION: Frontal QEEG parameters before treatment may predict worsening SI during SSRI treatment in MDD.

Preoperative staging of rectal carcinoma by endorectal ultrasound: is there a learning curve?

BACKGROUND AND AIMS: Endorectal ultrasound (ERUS) is becoming an essential tool in the management of rectal cancer. However, accuracy in the assessment of disease staging may be dependent on operator experience. The aim of this study was to determine if a learning curve exists. MATERIALS AND METHODS: From October 1999 to December 2004, all patients with rectal cancer had a pre-operative ERUS performed by a single radiologist. ERUS staging was compared with post-operative pathology findings using the tumour, node, metastases (TNM) classification. The accuracy of ERUS in tumour (T) and node (N) staging after each additional consecutive ten patients was calculated. RESULTS: One hundred and thirty one patients were investigated by ERUS, of which 36 were excluded, leaving 95 patients in the study (60 men). Overall accuracy for T staging was 71.6%. No improvement with experience was noted (p > 0.05). With regard to T staging, ERUS tended to overstage more frequently than understage (24.2 versus 4.2%). The sensitivity, specificity, positive predictive value and negative predictive value of uT3 staging were 96.6, 33.3, 70.4 and 85.7%, respectively. Overall accuracy of uN staging was 68.8%. ERUS tended to overstage nodal disease more frequently than understage (16.1 versus 15.1%). Sensitivity, specificity, positive predictive value and negative predictive value were calculated for ultrasound-detected nodal disease (73.2, 62.2, 74.5 and 60.5%, respectively). Nodal staging accuracy improved from 50% after assessment of 10 cases to 77% after 30 cases were examined. CONCLUSIONS: ERUS is an accurate method for staging rectal cancer pre-operatively. Accurate assessment of tumour stage can be achieved immediately by an experienced radiologist without specific training in ERUS. Nodal staging accuracy tends to improve with experience but reaches a plateau after 30 cases.

The salivary microbiota as a diagnostic indicator of oral cancer: a descriptive, non-randomized study of cancer-free and oral squamous cell carcinoma subjects.

BACKGROUND: The purpose of the present investigation was to determine if the salivary counts of 40 common oral bacteria in subjects with an oral squamous cell carcinoma (OSCC) lesion would differ from those found in cancer-free (OSCC-free) controls. METHODS: Unstimulated saliva samples were collected from 229 OSCC-free and 45 OSCC subjects and evaluated for their content of 40 common oral bacteria using checkerboard DNA-DNA hybridization. DNA counts per ml saliva were determined for each species, averaged across subjects in the 2 subject groups, and significance of differences between groups determined using the Mann-Whitney test and adjusted for multiple comparisons. Diagnostic sensitivity and specificity in detection of OSCC by levels of salivary organisms were computed and comparisons made separately between a non-matched group of 45 OSCC subjects and 229 controls and a group of 45 OSCC subjects and 45 controls matched by age, gender and smoking history. RESULTS: Counts of 3 of the 40 species tested, Capnocytophaga gingivalis, Prevotella melaninogenica and Streptococcus mitis, were elevated in the saliva of individuals with OSCC (p < 0.001). When tested as diagnostic markers the 3 species were found to predict 80% of cancer cases (sensitivity) while excluding 83% of controls (specificity) in the non-matched group. Diagnostic sensitivity and specificity in the matched group were 80% and 82% respectively. CONCLUSION: High salivary counts of C. gingivalis, P. melaninogenica and S. mitis may be diagnostic indicators of OSCC.

Telomere lengths and telomerase activity in dog tissues: a potential model system to study human telomere and telomerase biology.

Studies on telomere and telomerase biology are fundamental to the understanding of aging and age-related diseases such as cancer. However, human studies have been hindered by differences in telomere biology between humans and the classical murine animal model system. In this paper, we describe basic studies of telomere length and telomerase activity in canine normal and neoplastic tissues and propose the dog as an alternative model system. Briefly, telomere lengths were measured in normal canine peripheral blood mononuclear cells (PBMCs), a range of normal canine tissues, and in a panel of naturally occurring soft tissue tumours by terminal restriction fragment (TRF) analysis. Further, telomerase activity was measured in canine cell lines and multiple canine tissues using a combined polymerase chain reaction/enzyme-linked immunosorbent assay method. TRF analysis in canine PBMCs and tissues demonstrated mean TRF lengths to range between 12 and 23 kbp with heterogeneity in telomere lengths being observed in a range of normal somatic tissues. In soft tissue sarcomas, two subgroups were identified with mean TRFs of 22.2 and 18.2 kbp. Telomerase activity in canine tissue was present in tumour tissue and testis with little or no activity in normal somatic tissues. These results suggest that the dog telomere biology is similar to that in humans and may represent an alternative model system for studying telomere biology and telomerase-targeted anticancer therapies.

Circadian photoperception.

The circadian clock is intrinsically linked to the daily cycle of day and night. A capacity for entrainment to light-dark cycles has proven to be a universal feature of the clock in all organisms examined. Here we review a wealth of recent advances that reveal more about the light input mechanisms by which the circadian clock is set to the correct time in a range of different systems. Now that we are identifying more of the molecular components of both the light input pathway and the clock mechanism itself, we are becoming increasingly less able to distinguish between the two.

Functional interaction of phytochrome B and cryptochrome 2.

Light is a crucial environmental signal that controls many photomorphogenic and circadian responses in plants. Perception and transduction of light is achieved by at least two principal groups of photoreceptors, phytochromes and cryptochromes. Phytochromes are red/far-red light-absorbing receptors encoded by a gene family of five members (phyA to phyE) in Arabidopsis. Cryptochrome 1 (cry1), cryptochrome 2 (cry2) and phototropin are the blue/ultraviolet-A light receptors that have been characterized in Arabidopsis. Previous studies showed that modulation of many physiological responses in plants is achieved by genetic interactions between different photoreceptors; however, little is known about the nature of these interactions and their roles in the signal transduction pathway. Here we show the genetic interaction that occurs between the Arabidopsis photoreceptors phyB and cry2 in the control of flowering time, hypocotyl elongation and circadian period by the clock. PhyB interacts directly with cry2 as observed in co-immunoprecipitation experiments with transgenic Arabidopsis plants overexpressing cry2. Using fluorescent resonance energy transfer microscopy, we show that phyB and cry2 interact in nuclear speckles that are formed in a light-dependent fashion.

Cryptochromes are required for phytochrome signaling to the circadian clock but not for rhythmicity.

The circadian clock is entrained to the daily cycle of day and night by light signals at dawn and dusk. Plants make use of both the phytochrome (phy) and cryptochrome (cry) families of photoreceptors in gathering information about the light environment for setting the clock. We demonstrate that the phytochromes phyA, phyB, phyD, and phyE act as photoreceptors in red light input to the clock and that phyA and the cryptochromes cry1 and cry2 act as photoreceptors in blue light input. phyA and phyB act additively in red light input to the clock, whereas cry1 and cry2 act redundantly in blue light input. In addition to the action of cry1 as a photoreceptor that mediates blue light input into the clock, we demonstrate a requirement of cry1 for phyA signaling to the clock in both red and blue light. Importantly, Arabidopsis cry1 cry2 double mutants still show robust rhythmicity, indicating that cryptochromes do not form a part of the central circadian oscillator in plants as they do in mammals.

Parasitic nematodes, proteinases and transgenic plants.

Parasite proteinases have important functions in host-parasite interactions. Consequently, they have been investigated as targets for the control of both plant and animal parasites. Plant parasitic nematodes cause estimated annual losses to world agriculture of US$100 billion and, currently, their control often relies on highly toxic nematicides, with associated environmental risks. The potential of disrupting digestive proteinases for plant parasitic nematode control, via expression of proteinase inhibitors in transgenic plants, is summarized here by Catherine Lilley, Pauline Devlin, Peter Urwin and Howard Atkinson. They then consider whether the approach of expressing antinematode proteins in plants can be adapted for control of certain animal parasitic nematodes.

Cryptochromes--bringing the blues to circadian rhythms.

Cryptochromes are blue/UV-A-absorbing photoreceptor proteins discovered originally in plants and so named because their nature proved elusive in over a century of research. Now we know that the photoreceptor essential for proper seedling establishment in blue light has homologues in the animal kingdom - in insects, in mice and in humans. In recent months, evidence has emerged pointing to a common role for cryptochromes in all of these organisms in entraining the circadian clock, a biochemical timing mechanism running within cells, synchronizing metabolism to the daily light-dark cycle and having consequences on a much larger scale in the regulation of behaviour such as the sleep-wake cycle.

Phytochrome D acts in the shade-avoidance syndrome in Arabidopsis by controlling elongation growth and flowering time.

Shade avoidance in higher plants is regulated by the action of multiple phytochrome (phy) species that detect changes in the red/far-red ratio (R/FR) of incident light and initiate a redirection of growth and an acceleration of flowering. The phyB mutant of Arabidopsis is constitutively elongated and early flowering and displays attenuated responses to both reduced R/FR and end-of-day far-red light, conditions that induce strong shade-avoidance reactions in wild-type plants. This indicates that phyB plays an important role in the control of shade avoidance. In Arabidopsis phyB and phyD are the products of a recently duplicated gene and share approximately 80% identity. We investigated the role played by phyD in shade avoidance by analyzing the responses of phyD-deficient mutants. Compared with the monogenic phyB mutant, the phyB-phyD double mutant flowers early and has a smaller leaf area, phenotypes that are characteristic of shade avoidance. Furthermore, compared with the monogenic phyB mutant, the phyB-phyD double mutant shows a more attenuated response to a reduced R/FR for these responses. Compared with the phyA-phyB double mutant, the phyA-phyB-phyD triple mutant has elongated petioles and displays an enhanced elongation of internodes in response to end-of-day far-red light. These characteristics indicate that phyD acts in the shade-avoidance syndrome by controlling flowering time and leaf area and that phyC and/or phyE also play a role.

Phytochromes and photomorphogenesis in Arabidopsis.

Plants have evolved exquisite sensory systems for monitoring their light environment. The intensity, quality, direction and duration of light are continuously monitored by the plant and the information gained is used to modulate all aspects of plant development. Several classes of distinct photoreceptors, sensitive to different regions of the light spectrum, mediate the developmental responses of plants to light signals. The red-far-red light-absorbing, reversibly photochromic phytochromes are perhaps the best characterized of these. Higher plants possess a family of phytochromes, the apoproteins of which are encoded by a small, divergent gene family. Arabidopsis has five apophytochrome-encoding genes, PHYA-PHYE. Different phytochromes have discrete biochemical and physiological properties, are differentially expressed and are involved in the perception of different light signals. Photoreceptor and signal transduction mutants of Arabidopsis are proving to be valuable tools in the molecular dissection of photomorphogenesis. Mutants deficient in four of the five phytochromes have now been isolated. Their analysis indicates considerable overlap in the physiological functions of different phytochromes. In addition, mutants defining components acting downstream of the phytochromes have provided evidence that different members of the family use different signalling pathways.

Phytochromes and cryptochromes in the entrainment of the Arabidopsis circadian clock.

Circadian clocks are synchronized by environmental cues such as light. Photoreceptor-deficient Arabidopsis thaliana mutants were used to measure the effect of light fluence rate on circadian period in plants. Phytochrome B is the primary high-intensity red light photoreceptor for circadian control, and phytochrome A acts under low-intensity red light. Cryptochrome 1 and phytochrome A both act to transmit low-fluence blue light to the clock. Cryptochrome 1 mediates high-intensity blue light signals for period length control. The presence of cryptochromes in both plants and animals suggests that circadian input pathways have been conserved throughout evolution.

Phytochrome E influences internode elongation and flowering time in Arabidopsis.

From a screen of M2 seedlings derived from gamma-mutagenesis of seeds doubly null for phytochromes phyA and phyB, we isolated a mutant lacking phyE. The PHYE gene of the selected mutant, phyE-1, was found to contain a 1-bp deletion at a position equivalent to codon 726, which is predicted to result in a premature stop at codon 739. Immunoblot analysis showed that the phyE protein was undetectable in the phyE-1 mutant. In the phyA- and phyB-deficient background, phyE deficiency led to early flowering, elongation of internodes between adjacent rosette leaves, and reduced petiole elongation. This is a phenocopy of the response of phyA phyB seedlings to end-of-day far-red light treatments. Furthermore, a phyE deficiency attenuated the responses of phyA phyB seedlings to end-of-day far-red light treatments. Monogenic phyE mutants were indistinguishable from wild-type seedlings. However, phyB phyE double mutants flowered earlier and had longer petioles than did phyB mutants. The elongation and flowering responses conferred by phyE deficiency are typical of shade avoidance responses to the low red/far-red ratio. We conclude that in conjunction with phyB and to a lesser extent with phyD, phyE functions in the regulation of the shade avoidance syndrome.

Fluorescence spectroscopy and photochemistry of phytochromes A and B in wild-type, mutant and transgenic strains of Arabidopsis thaliana.

Phytochrome (P) was characterized in etiolated seedlings of wild-type, mutant and transgenic strains of Arabidopsis with the use of low-temperature (85 K) fluorescence spectroscopy and photochemistry. The position (lambda max) of the Pr emission spectrum, its intensity (F0) proportional to [P tot] and the extent of the Pr-->lumi-R phototransformation at 85 K (gamma 1) were shown to vary depending on the plant strains and tissues used, while the extent of the Pr-->Pfr transformation at 273 K (gamma 2) remained relatively constant. Depletion of phyA (fre1-1 in Nagatani et al., Plant Physiol. 102 (1993) 269-277, and fhy2-2 in Whitelam et al., Plant Cell 5 (1993) 757-768) resulted in a steep decrease of F0 to approximately equal to 10%. The phyB mutant (hy3-B064 in Reed et al., Plant Cell 5 (1993) 147-157) revealed a slight reduction (by approximately equal to 20%) of F0 while lambda max and gamma 1 remained practically unaffected. In phyAphyB mutuant no P emmission was observed. Overexpression of oat phyA (13k7 and 21k15 in Boylan and Quail, Proc. Natl. Acad. Sci. USA 88 (1991) 10806-10810) brought about an increase of F0 by two or three times, a shift of lambda max to 685 nm and an increase of gamma 1 to 0.3-0.4. On the contrary, an increase of F0 (up to 40%) in Arabidopsis and rice phyB overexpressors (ABO and RBO in Wagner et al., Plant Cell 3 (1991) 1275-1288) was followed by a decrease of gamma 1 values to 0.13-0.14. These data together with the results on phyB (lh) mutant of cucumber prove the existence of the two phyA populations with high (phyA') and low (phyA") photochemical activity at low temperatures. PhyB emits maximally in the same region as phyA in Arabidopsis (approximately equal to 683 nm) and at shorter wavelength (< 680 nm) in rice. It is characterized by low photochemical activity at 85 K (gamma 1 < or = 0.05) and can be attributed in this respect to the same pigment type as phyA".