Photoacoustic-guided ultrasound therapy with a dual-mode ultrasound array

Photoacoustics has recently been proposed as a potential method to guide and/or monitor therapy based on high-intensity focused ultrasound (HIFU). We experimentally demonstrate the creation of a HIFU lesion at the location of an optical absorber, by use of photoacoustic signals emitted by the absorber detected on a dual mode transducer array. To do so, a dedicated ultrasound array intended to both detect photoacoustic waves and emit HIFU with the same elements was used. Such a dual-mode array provides automatically coregistered reference frames for photoacoustic detection and HIFU emission, a highly desired feature for methods involving guidance or monitoring of HIFU by use of photoacoustics. The prototype is first characterized in terms of both photoacoustic and HIFU performances. The probe is then used to perform an idealized scenario of photoacoustic-guided therapy, where photoacoustic signals generated by an absorbing thread embedded in a piece of chicken breast are used to automatically refocus a HIFU beam with a time-reversal mirror and necrose the tissue at the location of the absorber.     

The long-term effectiveness of generic adult fixed-dose combination antiretroviral therapy for HIV-infected Ugandan children

Background

Access to pediatric antiretroviral formulations is increasing in resource-limited countries, however adult FDCs are still commonly used by antiretroviral therapy (ART) programs.

Objective

To describe long-term effectiveness of using adult FDC of d4T+3TC+NVP (Triomune) in children for HIV treatment.

Methods

Clinical, immunologic, and virologic outcomes of HIV-infected ART-naïve children aged six months to 12 years, were evaluated up to 96 weeks post-ART initiation.

Results

From March 2004 to June 2006, 104 children were followed with a median age of 5.4 years, median CD4 cell percent and HIV-1 RNA were 11.0% (IQR 6.7–13.9) and 348,846copies/mL (IQR 160,941–681,313) respectively at baseline. Using Kaplan-Meir estimates, 75% of children had undetectable viral loads (<400copies/mL) at 96weeks of ART. Children with a baseline CD4 cell percent >15% were 3 times more likely to achieve viral load <400copies/mL than those with baseline CD4 cell percent <5% after adjusting for baseline age {aHR = 3.03 (1.10–8.32), p=0.03}; no difference was found among those with CD4 cell percent >5–14.9% and <5%.

Conclusion

Treatment with generic adult FDC for HIV-infected Ugandan children led to sustained clinical, immunologic and virologic response during 96 weeks of ART. Early initiation of ART is key to achieving virological success.     

Duplication of the STS region in males is a benign copy-number variant

Copy-number variants (CNVs) are a common finding in the human genome, with copy gains occurring at a higher frequency than losses in several databases of genomic variants in normal individuals. Copy gains of the steroid sulfatase (STS) gene have been seen in both males and females. Although deletion of STS in males is known to cause X-linked ichthyosis, the clinical significance of STS copy gains is less clear, with the duplication reported in individuals with abnormal phenotypes and normal relatives. We identified 72 males submitted to our laboratory for microarray-based comparative genomic hybridization with duplications in the STS region (chrX:6,465,812-8,093,195). In 40 (56%) patients, maternal blood was available, and the duplication was found to be inherited from the patient's apparently phenotypically normal mother in each of the 40 patients. We also identified three females who inherited a duplication of the STS region from phenotypically normal fathers, and a phenotypically normal uncle who had the same duplication as his nephews. In the remaining cases the inheritance could not be confirmed owing to lack of parental samples available for testing. Of the 72 subjects, 10 (14%) had an additional CNV elsewhere in the genome known to be clinically significant and likely causative of the patient's presenting symptoms. Based on the frequency with which duplications have been identified in clinically normal and abnormal individuals, we suggest a gain of STS in males is a population variant and unlikely to be clinically significant.     

In vivo bubble nucleation probability in sheep brain tissue

Gas nuclei exist naturally in living bodies. Their activation initiates cavitation activity, and is possible using short ultrasonic excitations of high amplitude. However, little is known about the nuclei population in vivo, and therefore about the rarefaction pressure required to form bubbles in tissue. A novel method dedicated to in vivo investigations was used here that combines passive and active cavitation detection with a multi-element linear ultrasound probe (4-7 MHz). Experiments were performed in vivo on the brain of trepanated sheep. Bubble nucleation was induced using a focused single-element transducer (central frequency 660 kHz, f-number = 1) driven by a high power (up to 5 kW) electric burst of two cycles. Successive passive recording and ultrafast active imaging were shown to allow detection of a single nucleation event in brain tissue in vivo. Experiments carried out on eight sheep allowed statistical studies of the bubble nucleation process. The nucleation probability was evaluated as a function of the peak negative pressure. No nucleation event could be detected with a peak negative pressure weaker than -12.7 MPa, i.e. one order of magnitude higher than the recommendations based on the mechanical index. Below this threshold, bubble nucleation in vivo in brain tissues is a random phenomenon.     

Mutation of the BAFF furin cleavage site impairs B-cell homeostasis and antibody responses

B-cell-activating factor of the TNF family (BAFF)/BLyS contributes to B-cell homeostasis and function in the periphery. BAFF is expressed as a membrane-bound protein or released by proteolytic cleavage, but the functional importance of this processing event is poorly understood. Mice expressing BAFF with a mutated furin consensus cleavage site, i.e. furin-mutant BAFF (fmBAFF), were not different from BAFF-deficient mice with regard to their B-cell populations and responses to immunization. It is however noteworthy that an alternative processing event releases some soluble BAFF in fmBAFF mice. Mild overexpression (～ 5-fold) of fmBAFF alone generated intermediate levels of B cells without improving humoral responses to immunization. Processed BAFF was however important for B-cell homeostasis, as peripheral B-cell populations and antibody responses were readily restored by administration of soluble BAFF trimers in BAFF-deficient mice. However, the rescue of CD23 expression in B cells of BAFF-deficient mice required both soluble BAFF trimers and fmBAFF, or a polymeric form of soluble BAFF (BAFF 60-mer). These results point to a predominant role of processed BAFF for B-cell homeostasis and function, and indicate possible accessory roles for membrane-bound BAFF.     

Effect of BH4 on blood phenylalanine and tyrosine variations in patients with phenylketonuria

BackgroundIn patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations.MethodsBlood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV).ResultsBH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 μmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 μmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher.ConclusionBH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis.     

PREDICTORS OF THE PHYSICAL AND PSYCHOLOGICAL INTEGRATION OF HOMELESS ADULTS WITH PROBLEMATIC SUBSTANCE USE

This study examined predictors of physical and psychological integration in homeless adults with problematic substance use. Homeless adults with problematic substance use (n = 115) in Ottawa, Canada, completed questionnaires regarding their demographics (age, gender, Aboriginal ethnicity), health and social functioning (physical health, mental health, alcohol use problems, drug use problems, social skills), environmental factors (satisfaction with personal safety, social support), physical integration, and psychological integration. Participants reported low physical integration (i.e., participation in activities in the community) and did not feel strongly psychologically integrated (i.e., sense of belonging). The final models accounted for 36% and 19% of the variance in physical and psychological integration, respectively. Higher levels of social skills and social support were associated with greater physical integration. Higher levels of mental health functioning and satisfaction with safety were related to greater psychological integration. Implications of the findings for community support services are discussed.     

A mixed methods analysis of housing and neighbourhood impacts on community integration among vulnerably housed and homeless individuals

The current longitudinal study used mixed methods to examine the relationship of housing and neighborhood characteristics and community integration among a population of homeless and vulnerably housed individuals. Participants were recruited at homeless shelters, meal programs, and rooming houses in Ottawa, Canada, and participated in 3 in‐person interviews, each approximately 1 year apart. Participants were placed into either a “high” or a “low” integration group based on their community integration scores at Follow‐up 1 and Follow‐up 2. There were 14 high and 32 low integration participants at Follow‐up 1, and 17 high and 35 low participants at Follow‐up 2. A general inductive approach to analyzing qualitative data was used to code the data. The most salient themes that affected community integration involved substance use in one's housing and neighborhood, neighborhood safety and location, and housing quality. Implications for service provision and policy advancements to better address community integration are discussed.     

Human NK cells constitutively express membrane TNF-alpha (mTNFalpha) and present mTNFalpha-dependent cytotoxic activity

We have evaluated the expression and the involvement of membrane-associated TNF-alpha (mTNF-alpha) in human NK cell-mediated cytotoxicity. Results from FCM analysis show that peripheral blood NK cells constitutively express mTNF-alpha. In contrast, mTNF-alpha expression is undetectable on resting T cells, B cells and monocytes. Western blotting analysis confirmed that freshly purified NK cells express the 17-kDa soluble form (sTNF-alpha) and the 26-kDa transmembrane form of TNF-alpha. Stimulation with IL-2, IL-15 and IL-18 up-regulates TNF-alpha mRNA, sTNF-alpha and mTNF-alpha expression in NK cells. The role of mTNF-alpha in the cytotoxic activity of resting NK cells has been evaluated in in vitro cytotoxic assays using freshly purified NK cells fixed with paraformaldehyde as effector cells (in order to avoid the participation of cytotoxic soluble mediators such as perforin, granzymes or sTNF-alpha) and the TNF-alpha-sensitive Fas ligand- and TRAIL-resistant cell line KYM-1-D4 as target cell. Results show that fixed NK cells kill the KYM-1-D4 cells and that neutralizing anti-TNF-alpha antibodies partly prevent this effect. In contrast to the other types of peripheral blood mononuclear cells NK cells from adult blood constitutively express functional mTNF-alpha in the absence of prior contact with target cells or activation. These data demonstrate a novel mechanism of cell-mediated cytotoxicity by non-acitvated human peripheral blood NK cells.     

Patient dose considerations for routine megavoltage cone-beam CT imaging

Megavoltage cone-beam CT (MVCBCT), the recent addition to the family of in-room CT imaging systems for image-guided radiation therapy (IGRT), uses a conventional treatment unit equipped with a flat panel detector to obtain a three-dimensional representation of the patient in treatment position. MVCBCT has been used for more than two years in our clinic for anatomy verification and to improve patient alignment prior to dose delivery. The objective of this research is to evaluate the image acquisition dose delivered to patients for MVCBCT and to develop a simple method to reduce the additional dose resulting from routine MVCBCT imaging. Conventional CT scans of phantoms and patients were imported into a commercial treatment planning system (TPS: Phillips, Pinnacle) and an arc treatment mimicking the MVCBCT acquisition process was generated to compute the delivered acquisition dose. To validate the dose obtained from the TPS, a simple water-equivalent cylindrical phantom with spaces for MOSFETs and an ion chamber was used to measure the MVCBCT image acquisition dose. Absolute dose distributions were obtained by simulating MVCBCTs of 9 and 5 monitor units (MU) on pelvis and head and neck patients, respectively. A compensation factor was introduced to generate composite plans of treatment and MVCBCT imaging dose. The article provides a simple equation to compute the compensation factor. The developed imaging compensation method was tested on routinely used clinical plans for prostate and head and neck patients. The quantitative comparison between the calculated dose by the TPS and measurement points on the cylindrical phantom were all within 3%. The dose percentage difference for the ion chamber placed in the center of the phantom was only 0.2%. For a typical MVCBCT, the dose delivered to patients forms a small anterior-posterior gradient ranging from 0.6 to 1.2 cGy per MVCBCT MU. MVCBCT acquisitions in the pelvis and head and neck areas deliver slightly more dose than current portal imaging but render soft tissue information for positioning. Overall, the additional dose from daily 9 MU MVCBCTs of prostate patients is small compared to the treatment dose (<4%). Dose-volume histograms of compensated plans for pelvis and head and neck patients imaged daily with MVCBCT showed no additional dose to the target and small increases at low doses. The results indicate that the dose delivered for MVCBCT imaging can be precisely calculated in the TPS and therefore included in the treatment plan. This allows simple plan compensations, such as slightly reducing the treatment dose, to minimize the total dose received by critical structures from daily positioning with MVCBCT. The proposed compensation factor reduces the number of MU per treatment beam per fraction. Both the number of fractions and the beam arrangement are kept unchanged. Reducing the imaging volume in the cranio-caudal direction can further reduce the dose delivered for MVCBCT. This is a useful feature to eliminate the imaging dose to the eyes or to focus on a specific region of interest for alignment.