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Government-sanctioned use of nerve agents (NA) has escalated dramatically in recent years. Oxime reactivators of organophosphate (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) serve as antidotes toward poisoning by OPNAs. The oximes used as therapeutics are quaternary compounds that cannot penetrate the blood–brain barrier (BBB). There remains an urgent need for the development of next generation OPNA therapeutics. We have developed two high-throughput screening (HTS) assays using a fluorogenic NA surrogate, O-ethyl methylphosphonyl O-4-methyl-3-cyano-coumarin (EMP-MeCyC). EMP-MeCyC detoxification and EMP-BChE reactivation screening campaigns of ~155,000 small molecules resulted in the identification of 33 nucleophile candidates, including non-quaternary oximes. Four of the oximes were reactivators of both Sarin- and VX-inhibited BChE and directly detoxified Sarin. One oxime also detoxified VX. The novel reactivators included a non-quaternary pyridine amidoxime, benzamidoxime, benzaldoxime and a piperidyl-ketoxime. The VX-inhibited BChE reactivation reaction rates by these novel molecules were similar to those observed with known bis-quaternary reactivators and faster than mono-quaternary pyridinium oximes. Notably, we discovered the first ketoxime reactivator of OP-ChEs and detoxifier of OPNAs. Preliminary toxicological studies demonstrated that the newly discovered non-quaternary oximes were relatively non-toxic in mice. The discovery of unique non-quaternary oximes opens the door to the design of novel therapeutics and decontamination agents following OPNA exposure. Amitai et al. identified 4 potential small molecule antidotes toward nerve agents poisoning by high-throughput-screening of over 150,000 compounds. Unique non-quaternary oximes represent new potential antidotes for future development as they detoxified nerve agents and also reactivated nerve agent-inhibited butyrylcholinesterase. [ABSTRACT FROM AUTHOR]

Background: Asthma and non-asthmatic eosinophilic bronchitis (NAEB) are among the commonest causes of chronic cough in adults. We sought to determine the role of non-invasive measurements of airway inflammation, including induced sputum and fractional exhaled nitric oxide, in the evaluation of cough associated with asthma, and what the best treatment is for cough due to asthma or NAEB.Methods: We undertook three systematic reviews of randomized controlled trials and observational trials of adults and adolescents > 12 years of age with a chronic cough due to asthma or NAEB. Eligible studies were identified in MEDLINE, CENTRAL, and SCOPUS and assessed for relevance and quality. Guidelines were developed and voted upon using CHEST guideline methodology.Results: Of the citations reviewed, 3/1,175, 53/656, and 6/134 were identified as being eligible for inclusion in the three systematic reviews, respectively. In contrast to established guidelines for asthma therapies in general and the inclusion in some guidelines for a role of biomarkers of airway inflammation to guide treatment in severe disease, the evidence of specific benefit related to the use of non-invasive biomarkers in patients with chronic cough due to asthma was weak. The best therapeutic option for cough in asthma or NAEB is inhaled corticosteroids followed by leukotriene receptor antagonism.Conclusions: This guideline offers recommendations on the role of non-invasive measurements of airway inflammation and treatment for cough due to asthma or NAEB based on the available literature, and identifies gaps in knowledge and areas for future research. [ABSTRACT FROM AUTHOR]

The global and economic success of immunoglobulin-based therapeutics in treating a wide range of diseases has heightened the need to further enhance their efficacy and lifetime while diminishing deleterious side effects. The three most ubiquitous challenges of therapeutic immunoglobulin delivery are their relatively short lifetimes in vivo , the immunologic consequences of soluble antibody-antigen complexes, and the emergence of anti-drug antibodies. We describe the rapid, cell-tolerated chemical engineering of the erythrocyte membrane in order to display any antibody, our model system being the display of anti-Tumor Necrosis Factor (anti-TNFα), on the surface of long-lived red blood cells (RBCs) while masking the antibody's Fc region. We developed four synthetic approaches to generate RBC-Staphylococcal protein A (RBC-SpA) complexes: amino group targeting through N-hydrosuccinidyl ester-functionalized homobifunctional poly(ethylene glycol) (NHS-PEG-NHS), direct thiol group targeting using heterobifunctional NHS-PEG-maleimide (NHS-PEG-MAL), converted thiol targeting using heterobifunctional NHS-PEG-MAL, and click chemistry using heterobifunctional NHS-PEG-azido (NHS-PEG-N 3) and NHS-PEG-alkyne (NHS-PEG-alk). The RBC-PEG-SpA complexes were formed within minutes, followed by the attachment of over 105 antibodies per RBC to the accessible RBC-bound SpA via Fc-Protein A coupling. The RBC-PEG-SpA-antibody arrays were shown to be stable for more than 60 days in PBS and for more than 42 days in serum containing buffer. RBC-PEG-SpA-antibody complexes were shown to remove TNFα from physiological buffer and had similar mechanical properties to unmodified RBCs. Out of the four approaches, the converted thiol method provided the most controlled chemistry and construct stability. We are now ideally positioned to determine the long-term in vivo efficacy of chemically membrane-engineered RBCs to remove antigens, like TNFα, from serum. The global and economic success of immunoglobulin-based therapeutics in treating a wide range of diseases has heightened the need to further enhance their efficacy and lifetime while diminishing deleterious side effects. The three most ubiquitous challenges of therapeutic immunoglobulin delivery are their relatively short lifetimes in vivo , the immunologic consequences of soluble antibody-antigen complexes, and the emergence of anti-drug antibodies. We describe the rapid, cell-tolerated chemical engineering of the erythrocyte membrane to display any antibody, our model system being the display of anti-Tumor Necrosis Factor (anti-TNFα), on the surface of long-lived red blood cells (RBCs) while masking the antibody's Fc region. Conversion of RBCs into therapeutic delivery vehicles, we argue, would enhance the circulation life of immunoglobulin-based therapeutics while simultaneously evading deleterious immune response. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Background: Laboratory-based research with community samples has suggested changes in affective, behavioural and cognitive processes as possible explanations for the effects of serotonergic medications. Examining the effects of serotonergic medications using an ecological momentary measure (such as event-contingent recording) in the daily lives of people with social anxiety disorder would contribute to establishing the effects of these medications on affect, behaviour and one form of cognition: perception of others' behaviour. Methods: The present study assessed changes in affect, interpersonal behaviour and perception of others' behaviour in adults with social anxiety disorder using ecological momentary assessment at baseline and over 4 months of a single-arm, uncontrolled, open-label trial of treatment with the selective serotonin reuptake inhibitor paroxetine. Results: Anxiety and concurrent depressive symptoms decreased. Participants also reported increased positive and decreased negative affect; increased agreeable and decreased quarrelsome behaviour; increased dominant and decreased submissive behaviour; and increased perception that others behaved agreeably toward them. Moreover, participants demonstrated reduced intraindividual variability in affect, interpersonal behaviour and perception of others' behaviour. Limitations: Limitations included the lack of a placebo group, the inability to identify the temporal order of changes and the restricted assessment of extreme behaviour. Conclusion: The results of the present study demonstrate changes during pharmacotherapy in the manifestation of affect, interpersonal behaviour and interpersonal perception in the daily lives of people with social anxiety disorder. Given the importance of interpersonal processes to social anxiety disorder, these results may guide future research seeking to clarify mechanisms of action for serotonergic medications. [ABSTRACT FROM AUTHOR]

Trichuris trichiura is a human parasitic whipworm infecting around 500 million people globally, damaging the physical growth and educational performance of those infected. Current drug treatment options are limited and lack efficacy against the worm, preventing an eradication programme. It is therefore important to develop new treatments for trichuriasis. Using Trichuris muris, an established model for T. trichiura, we screened a library of 480 novel drug-like small molecules for compounds causing paralysis of the ex vivo adult parasite. We identified a class of dihydrobenz[e][1,4]oxazepin-2(3H)-one compounds with anthelmintic activity against T. muris. Further screening of structurally related compounds and resynthesis of the most potent molecules led to the identification of 20 active dihydrobenzoxazepinones, a class of molecule not previously implicated in nematode control. The most active immobilise adult T. muris with EC50 values around 25–50μM, comparable to the existing anthelmintic levamisole. The best compounds from this chemotype show low cytotoxicity against murine gut epithelial cells, demonstrating selectivity for the parasite. Developing a novel oral pharmaceutical treatment for a neglected disease and deploying it via mass drug administration is challenging. Interestingly, the dihydrobenzoxazepinone OX02983 reduces the ability of embryonated T. muris eggs to establish infection in the mouse host in vivo. Complementing the potential development of dihydrobenzoxazepinones as an oral anthelmintic, this supports an alternative strategy of developing a therapeutic that acts in the environment, perhaps via a spray, to interrupt the parasite lifecycle. Together these results show that the dihydrobenzoxazepinones are a new class of anthelmintic, active against both egg and adult stages of Trichuris parasites. They demonstrate encouraging selectivity for the parasite, and importantly show considerable scope for further optimisation to improve potency and pharmacokinetic properties with the aim of developing a clinical agent. [ABSTRACT FROM AUTHOR]

Cognitive behavioral therapy (CBT) is efficacious for many Axis I disorders, though its effectiveness in the real world, for patients with Axis II comorbidity is less well known. This study examines the effectiveness of CBT for Axis I disorders in three groups of patients: those with personality disorders, those with personality disorder traits and those with no Axis II pathology. Consecutive referrals of patients with non-psychotic Axis I disorders were assessed for short-term CBT in a University Teaching Unit. While the acceptance rate was lower for individuals with personality disorders, there were no group differences in dropout rates. Of those who completed therapy (mean number of sessions=17.8, SD =11.2), those in the Personality Disorders group ( n =45) had 4 sessions more on average than the Personality Disorder Traits group ( n =42) or the No Axis II Group ( n =266). All 3 groups were equally successful, whether the outcome was therapist opinion of success, the clinical global impression, or the reliable change index based on patient-reported symptom change. Intent to treat analysis results paralleled those of the completer analysis. Our findings indicate that the presence of a personality disorder does not negatively impact therapy adherence or success in short-term CBT for an Axis I disorder. [ABSTRACT FROM AUTHOR]

Objectives We examined core features of patient suitability for cognitive-behavioral therapy (CBT) and their ability to predict CBT outcomes. Method A sample of 256 outpatients diagnosed with depression and anxiety disorders were assessed using the Suitability for Short-Term Cognitive Therapy (SSCT) scale. Therapists rated patients' symptom severity using the Clinical Global Impression scale before and after therapy. Results A factor analysis of the SSCT scale yielded 2 factors: (a) Capacity for Participation in CBT Process and (b) Attitudes Relevant to the CBT Process. A multiple regression analysis revealed that only Capacity for Participation in CBT Process uniquely predicted improvement at termination. Conclusions These findings highlight the importance of assessing the suitability of CBT for individual patients. Specifically, patients with greater capacity to identify and articulate thoughts and feelings and to share them in a nondefensive, focused way benefit most from CBT. [ABSTRACT FROM AUTHOR]

Background The balance of benefit versus burden of ongoing treatments for comorbid disease in palliative populations as death approaches needs careful consideration given their particular susceptibility to adverse drug effects. Aim To provide descriptive data regarding the medications being prescribed to patients who have a life-limiting illness at the time of referral to a palliative care service in regional Australia, with particular focus on lipid-lowering medications. Methods A prospective case note review of 203 patients reporting the number of medications prescribed and, for lipid-lowering medications, the indication and level of prevention sought (primary, secondary, tertiary). Rates were compared by performance status, disease phase and comorbidity burden. Results Mean number of regular medications prescribed was 7.2, with higher rates observed in those patients with a non-malignant primary diagnosis (rate ratio 1.28, confidence interval ( CI) 1.11-1.50) or poorer performance status (rate ratio 1.37, CI 1.11-1.69) and lower rates for those in the terminal phase of disease (rate ratio 0.48, CI 0.30-0.76). Over one fifth of patients were prescribed a lipid-lowering medication, and two fifths of these prescriptions were for primary prevention of cardiovascular disease. Patients in the highest quartile of Charlson Comorbidity Index score were 4.6 ( CI 2.06-10.09) times more likely to be prescribed a lipid-lowering medication than those in the lowest quartile. Conclusions Polypharmacy is prevalent for this group of patients, placing them at high risk of drug-drug and drug-host interactions. Prescribing may be driven by risk factors and disease guidelines rather than a rational, patient-centred approach. [ABSTRACT FROM AUTHOR]

Purpose: To describe the effect of radiation therapy on intraocular pressure in patients who have had orbital radiation for Graves' orbitopathy, and to provide a descriptive analysis of these patients. Design: Retrospective case series. Participants: 24 consecutive patients referred for orbital radiation therapy for Graves' orbitopathy from December 1st, 2001 through July 31st, 2009. Intervention: Patients received a total of 2000 cGy fractionated over 10 days. Main Outcome Measures: Medical records were reviewed for: demographics, tobacco history, ocular history, history related to Graves' disease, medications, visual field tests, retinopathy, and physical exam findings. The two-tailed Student's t-test was used to determine statistically significant differences in intraocular pressure before radiation therapy and 0-3 (T1), 4-6 (T2), 7-12 (T3), and 13-18 (T4) months following radiation therapy. Results: 34 eyes were available for analysis. There was no correlation between intraocular pressure and SPECS scores. Mean intraocular pressure prior to radiation therapy was 18.15 ± 3.83 mm Hg. Patients who had orbital decompression, eye muscle surgery, or glaucoma were excluded from the final analysis. There were 7, 11, 14, and 11 eyes with data at times T1, T2, T3, and T4 following radiation therapy, respectively. There was a significant decrease in mean intraocular pressure at T2, T3 and T4 of 26.00% ± 9.25%, 11.75% ± 27.58%, and 16.72% ± 13.94%, respectively. Conclusions: There was a significant drop in mean intraocular pressure between 4 and 18 months after radiation therapy in our patient population. The mechanism by which this decrease in intraocular pressure occurs is not understood. [ABSTRACT FROM AUTHOR]

Purpose: To describe the effect of radiation therapy on intraocular pressure in patients who have had orbital radiation for Graves' orbitopathy, and to provide a descriptive analysis of these patients. Design: Retrospective case series. Participants: 24 consecutive patients referred for orbital radiation therapy for Graves' orbitopathy from December 1st, 2001 through July 31st, 2009. Intervention: Patients received a total of 2000 cGy fractionated over 10 days. Main Outcome Measures: Medical records were reviewed for: demographics, tobacco history, ocular history, history related to Graves' disease, medications, visual field tests, retinopathy, and physical exam findings. The two-tailed Student's t-test was used to determine statistically significant differences in intraocular pressure before radiation therapy and 0-3 (T1), 4-6 (T2), 7-12 (T3), and 13-18 (T4) months following radiation therapy. Results: 34 eyes were available for analysis. There was no correlation between intraocular pressure and SPECS scores. Mean intraocular pressure prior to radiation therapy was 18.15 ± 3.83 mm Hg. Patients who had orbital decompression, eye muscle surgery, or glaucoma were excluded from the final analysis. There were 7, 11, 14, and 11 eyes with data at times T1, T2, T3, and T4 following radiation therapy, respectively. There was a significant decrease in mean intraocular pressure at T2, T3 and T4 of 26.00% ± 9.25%, 11.75% ± 27.58%, and 16.72% ± 13.94%, respectively. Conclusions: There was a significant drop in mean intraocular pressure between 4 and 18 months after radiation therapy in our patient population. The mechanism by which this decrease in intraocular pressure occurs is not understood. [ABSTRACT FROM AUTHOR]

Objectives: Although cognitive behavioural therapy (CBT) is an empirically supported treatment for major depressive disorder (MDD), individual differences in the effectiveness of CBT have been observed. Preliminary evidence suggests that positive outcome expectancies for treatment predict better therapy outcomes (Constantino, Arnkoff, Glass, & Smith, 2011); however, researchers have not examined whether avoidance, an important predictor of depressive symptoms (Ottenbreit & Dobson, 2004), may play an important role in this association. In the present study, we examined whether the association between positive outcome expectancies and therapy outcome is associated with patients' levels of avoidance. Design: Data were collected as part of a prospective, longitudinal study. Methods: The sample consisted of 51 patients diagnosed with MDD who underwent CBT. Prior to treatment, clinicians rated patients on their levels of avoidance and positive outcome expectancies. A self-report rating of positive outcome expectancies was also obtained, and the Beck Depression Inventory (BDI-II; Beck, Steer, & Brown, 1996) was completed pre- and post-treatment. A hierarchical regression analysis was conducted to examine the association between positive outcome expectancies and avoidance for predicting changes in depressive symptoms after CBT. Results: For patients with lower levels of positive outcome expectancies, lower levels of avoidance predicted greater improvement after CBT and higher levels of avoidance predicted poorer treatment outcomes. Conclusions: These findings suggest that the impact that lower positive outcome expectancies have on therapy outcome can be attenuated if patients do not avoid dealing with emotionally difficult material in session. Practitioner Points The detrimental effects of lower positive outcome expectancies for therapy may be lessened in patients who do not demonstrate avoidance at the outset of therapy., Clinicians' early reinforcement of patient engagement in therapy may help patients increase their positive outcome expectancies for treatment., The importance of avoidance and lower positive outcome expectancies has only been examined in patients referred for cognitive behavioural therapy in a University Teaching Unit and the findings may not apply to other psychotherapies in other contexts., The interaction between avoidance and positive outcome expectancies has only been examined in patients with major depressive disorder and the findings may not extend to patients with other psychological disorders. [ABSTRACT FROM AUTHOR]

Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission. We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease. Binding selectively to the fast-skeletal-troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates. Notably, we show that sensitization of the fast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised. [ABSTRACT FROM AUTHOR]

To describe the development of context therapy, a new intervention approach designed for a randomized controlled trial. Therapists were trained to change task and environmental factors to achieve parent-identified functional goals for children with cerebral palsy. Therapists did not provide any remediation strategies to change the abilities of the child. Theoretical constructs were developed using dynamic systems theory and the principles of family-centered care. A primary therapist model was used. A three-step intervention strategy was developed. Therapists adhered to the treatment protocol. Parents participated in the development of both functional goals and intervention strategies. A therapy approach focusing on changing the task and the environment rather than children's impairments can be a viable treatment strategy and merits further investigation. The detailed description of the context therapy approach allows replication by both researchers and clinicians. Such intervention descriptions are an important methodological consideration in rehabilitation research. [ABSTRACT FROM AUTHOR]

Isoflavones are phytoestrogens that have pleiotropic effects in a wide variety of cancer cell lines. Many of these biological effects involve key components of signal transduction pathways within cancer cells, including prostate cancer cells. Epidemiological studies have raised the hypothesis that isoflavones may play an important role in the prevention and modulation of prostate cancer growth. Since randomized phase III trials of isoflavones in prostate cancer prevention are currently lacking, the best evidence for this concept is presently provided by case control studies. However, in vitro data are much more convincing in regard to the activity of a number of isoflavones, and have led to the development of genistein and phenoxodiol in the clinic as potential treatments for cancer. In addition, the potential activity of isoflavones in combination with cytotoxics or radiotherapy warrants further investigation. This review focuses on the clinical pharmacology of isoflavones and its relevance to their development for use in the prevention of prostate cancer, and it evaluates some of the conflicting data in the literature. [ABSTRACT FROM AUTHOR]

Replication-competent viruses are being tested as tumor therapy agents. The fundamental premise of this therapy is the selective infection of the tumor cell population with the amplification of the virus. Spread of the virus in the tumor ultimately should lead to eradication of the cancer. Tumor virotherapy is unlike any other form of cancer therapy as the outcome depends on the dynamics that emerge from the interaction between the virus and tumor cell populations both of which change in time. We explore these interactions using a model that captures the salient biological features of this system in combination with in vivo data. Our results show that various therapeutic outcomes are possible ranging from tumor eradication to oscillatory behavior. Data from in vivo studies support these conclusions and validate our modeling approach. Such realistic models can be used to understand experimental observations, explore alternative therapeutic scenarios and develop techniques to optimize therapy. [ABSTRACT FROM AUTHOR]

The article discusses the stay well approach and its role in determining the illness trajectory of bipolar disorder. The approach is based on the theoretical principles of the Ottawa Charter for health promotion the focus on wellness in patients and applicable in physical and psychiatric conditions. The expertise of both health-care professionals and people with bipolar disorder is tackled since both provide important insights into health research. It is said that the stay well approach is unique since it is associated with the biopsychosocial model incorporating physical, psychological, social, environmental, economic and cultural factors and combining them with the wellness model.

Background: Many patients with invasive urothelial cell cancer are poor candidates for cisplatin-based chemotherapy, and many are high risk for cystectomy. Southwest Oncology Group Trial 8733 was designed to address treatment for such patients.Methods: Eligible patients had primary or recurrent muscle-invasive disease with transitional cell or squamous cell histology, a performance status from 0 to 2, no extrapelvic disease, a life expectancy >3 months, and adequate hematologic function. The treating clinician assigned patients to operable or inoperable groups. All patients received 2 cycles of 5-fluorouracil (5-FU) at a dose of 1000 mg/m(2) per day x 4 starting concurrently with radiation at a dose of 200 centigrays per day x 10 each cycle. After 2 cycles, operable patients with positive biopsies underwent cystectomy, and patients with negative biopsies received a third cycle of chemoradiotherapy. Patients in the inoperable group received 3 cycles without interim biopsy.Results: Eighteen of 24 eligible patients in the operable group were evaluable for response. Five patients had a complete response (CR), 9 patients had stable disease, 1 patient had progressive disease, and 3 patients were not assessable. The median progression-free survival was 10 months (95% confidence interval [95% CI], 4-14 months), and the median overall survival was 18 months (95% CI, 7-28 months). In the inoperable group, 35 of 37 eligible patients were evaluable for response with 17 CRs (49%; 95% CI, 31%-66%). The median progression-free survival was 13 months (95% CI, 10-17 months), and the median overall survival was 20 months (95% CI, 11-53 months). There were no episodes of grade 4 toxicity.Conclusions: In the current study, the combination of 5-FU and radiation was found to be tolerated well by patients with numerous comorbidities who could not tolerate cisplatin-based therapy or cystectomy. [ABSTRACT FROM AUTHOR]

We retrospectively analysed the outcomes of children transplanted for high-risk neuroblastoma (NB) at a single institution predominantly transplanted with total body irradiation and chemotherapy. The aims of this study were to determine the prognostic impact of clinical and biological features and to document long-term health outcomes. Forty patients were transplanted with a single unpurged autograft. Fourteen patients died from disease progression and two from late complications of treatment. Twenty-three patients are alive at a median of 4.6 years from diagnosis. Kaplan–Meier estimates of overall survival at 2, 5 and 10 years are 76±7.0, 60.2±8.4 and 54.7±9.3% following transplant. Response to induction therapy was significantly associated with survival (P<0.01). Long-term complications included growth (100%) and pubertal failure (83%), hearing impairment (73%), orthopaedic complications (63%), renal impairment (47%) and thyroid abnormalities (36%). Intrinsic and acquired resistance to chemotherapy remains the major obstacle to improving outcomes in high-risk NB. Although patients with chemo-sensitive disease are less likely to experience a relapse, substantial therapy-related toxicities result in poor long-term health outcomes for survivors.Bone Marrow Transplantation (2007) 40, 741–746; doi:10.1038/sj.bmt.1705809; published online 27 August 2007 [ABSTRACT FROM AUTHOR]

Multiple myeloma is a systemic malignancy that remains incurable with current therapy. Myeloma is highly radiosensitive, and radiation-based therapies have the potential to provide significant clinical benefit. Effective deployment of radiotherapy as a systemic modality in myeloma depends on maximizing its therapeutic index by efficiently and accurately delivering the radiation to sites of myeloma cell growth and increasing the radiosensitivity of myeloma cells relative to normal tissues. In this review, we discuss various strategies that are currently under investigation to enhance clinical benefit of radiotherapy in multiple myeloma. [Copyright &y& Elsevier]

Because of their ability to replicate, the dose–response relationships of oncolytic viruses cannot easily be predicted. To better understand the pharmacokinetics of virotherapy in relation to viral dose and schedule, we administered MV-CEA intraperitoneally in an orthotopic mouse model of ovarian cancer. MV-CEA is an attenuated oncolytic measles virus engineered to express soluble human carcinoembryonic antigen (CEA), and the virus is currently undergoing phase I clinical testing in patients with ovarian cancer. Plasma CEA levels correlate with numbers of virus-infected tumor cells at a given time, and were used as a surrogate to monitor the profiles of viral gene expression over time. The antineoplastic activity of single- or multiple-dose MV-CEA was apparent over a wide range of virus doses (103–108 TCID50), with little reduction in observed antitumor efficacy, even at the lowest tested dose. However, analysis of CEA profiles of treated mice was highly informative, illustrating the variability in virus kinetics at different dose levels. The highest doses of virus were associated with higher initial levels of tumor cell killing, but the final outcome of MV-CEA therapy at all dose levels was a partial equilibrium between virus and tumor, resulting in significant slowing of tumor growth and enhanced survival of the mice.Cancer Gene Therapy (2006) 13, 732–738. doi:10.1038/sj.cgt.7700948; published online 10 March 2006 [ABSTRACT FROM AUTHOR]

The section of "Nonwoven Wound Dressings" focuses on wound healing. Wound dressings are used to clean, cover and protect wounds in order to promote healing, and nonwoven fabrics are increasingly significant din this area. Hydrogel dressings are said to have a calming effect on tissues and can significantly reduce the pain. They are able to give moisture to dehydrated tissue and absorb some moisture from an exuding wound. Hydrogels are available in two forms, sheet hydrogels and amorphous hydrogels.

Oncolytic viruses are promising cytoreductive agents for cancer treatment but extensive human testing will be required before they are made commercially available. Here, we investigated the oncolytic potential of two commercially available live attenuated vaccines, Moraten measles and Jeryl-Lynn mumps, in a murine model of intraperitoneal human ovarian cancer and compared their efficacies against a recombinant oncolytic measles virus (MV-CEA) that is being tested in a phase I clinical trial. The common feature of these viruses is that they express hemagglutinin and fusion therapeutic proteins that can induce extensive fusion of the infected cell with its neighbors, resulting in death of the cell monolayer. In vitro, the three viruses caused intercellular fusion in human ovarian cancer cells but with marked differences in fusion kinetics. MV-CEA was the fastest followed by Jeryl-Lynn mumps virus while Moraten measles virus was the slowest, although all viruses eventually caused comparable cell death 6 days postinfection. Tumor-bearing mice treated with 106 or 107 pfu (one thousand times the vaccine dose) of each of the three viruses responded favorably to therapy with significant prolongations in survival. All three viruses demonstrated equivalent antitumor potency. Commercially available Moraten measles and Jeryl-Lynn mumps vaccines warrant further investigation as potential anticancer agents.Cancer Gene Therapy (2005) 12, 593–599. doi:10.1038/sj.cgt.7700823 Published online 4 March 2005 [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibodies (MAbs) can target therapy to tumours while minimising normal tissue exposure. Efficacy of immunoconjugates containing peptide 101, designed around the first 22 amino acids of bee venom, melittin, to maintain the amphipathic helix, to enhance water solubility, and to increase hemolytic activity, was assessed in nude mice bearing subcutaneous human prostate cancer xenografts. Methods: Mouse MAbs, J591 and BLCA-38, which recognise human prostate cancer cells, were cross-linked to peptide 101 using SPDP. Tumour-bearing mice were used to compare biodistributions of radiolabeled immunoconjugates and MAb, or received multiple sequential injections of immunoconjugates. Therapeutic efficacy was assessed by delay in tumour growth and increased mouse survival. Results: Radiolabeled immunoconjugates and antibodies showed similar xenograft tropism. Systemic or intratumoural injection of immunoconjugates inhibited tumour growth in mice relative to carrier alone, unconjugated antibody and nonspecific antibody-peptide conjugates and improved survival for treated mice. Conclusions: Immunoconjugates deliver beneficial effects; further peptide modifications may increase cytotoxicity. [ABSTRACT FROM AUTHOR]

Purpose: To determine patient radiation doses for interventional radiology and neuroradiology procedures, to identify procedures associated with higher radiation doses, and to determine the effects of various parameters on patient doses.Materials and Methods: A prospective observational study was performed at seven academic medical centers. Each site contributed demographic and radiation dose data for subjects undergoing specific procedures in fluoroscopic suites equipped with built-in cumulative dose (CD) and dose-area-product (DAP) measurement capability compliant with International Electrotechnical Commission standard 60601-2-43. The accuracy of the dosimetry was confirmed by comprehensive measurements and by frequent consistency checks performed over the course of the study.Results: Data were collected on 2,142 instances of interventional radiology procedures, 48 comprehensive physics evaluations, and 581 periodic consistency checks from the 12 fluoroscopic units in the study. There were wide variations in dose and statistically significant differences in fluoroscopy time, number of images, DAP, and CD for different instances of the same procedure, depending on the nature of the lesion, its anatomic location, and the complexity of the procedure. For the 2,142 instances, observed CD and DAP correlate well overall (r = 0.83, P <.000001), but correlation in individual instances is poor. The same is true for the correlation between fluoroscopy time and CD (r = 0.79, P <.000001). The correlation between fluoroscopy time and DAP (r = 0.60, P <.000001) is not as good. In 6% of instances (128 of 2,142), which were principally embolization procedures, transjugular intrahepatic portosystemic shunt (TIPS) procedures, and renal/visceral artery stent placements, CD was greater than 5 Gy.Conclusions: Most procedures studied can result in clinically significant radiation dose to the patient, even when performed by trained operators with use of dose-reducing technology and modern fluoroscopic equipment. Embolization procedures, TIPS creation, and renal/visceral artery stent placement are associated with a substantial likelihood of clinically significant patient dose. At minimum, patient dose data should be recorded in the medical record for these three types of procedures. These data should include indicators of the risk of deterministic effects as well as the risk of stochastic effects. [ABSTRACT FROM AUTHOR]

The Escherichia coli enzyme (purine nucleoside phosphorylase, PNP) gene is delivered directly into PC3 tumors by one injection of replication-deficient human type-5 adenovirus (Ad5). Expressed PNP converts the systemically administered prodrug, 6MPDR, to a toxic purine, 6MP, causing cell death. We sought to increase the specificity of recombinant Ad vectors by controlling PNP expression with the promoter region from the androgen-dependent, prostate-specific rat probasin (Pb) gene. To increase its activity, the promoter was combined with the SV40 enhancer (SVPb). Cell lines were transfected with plasmids containing both a reporter gene, under SVPb control, and a reference gene cassette to allow normalization of expression levels. Plasmids expressed ∼20-fold more reporter in prostate cancer than in other cells, but surprisingly, the SVPb element was both androgen-independent and retained substantial prostate specificity. Killing by Ad5-SVPb-PNP vector of cell lines cultured with 6MPDR for 6 days was 5- to 10-fold greater in prostate cancer than in liver or lung cells. In vivo, a single intratumoral injection of Ad5-SVPb-PNP (4×108 pfu), followed by 6MPDR administration twice daily for 6 days, significantly suppressed the growth of human prostate tumors in nude mice and increased their survival compared to control animals. Thus, the androgen-independent, prostate-targeting Ad5 vector reduces human prostate cancer growth significantly in vitro and in vivo. This first example of an androgen-independent vector points the way toward treatment of emerging androgen-independent prostate cancer in conjunction with hormone ablation therapy at a time when the tumor burden is low. Cancer Gene Therapy (2002) 9, 443–452 DOI: 10.1038/sj/cgt/7700451 [ABSTRACT FROM AUTHOR]

Survey of hospitals and clinics where atomic bomb survivors and their comparisons reported having received radiation therapy confirmed that 137 were so treated. The malignancies of five subjects were possibly related to their earlier radiation therapy rather than their atomic bomb radiation exposure, stressing the importance of recording all medical X-ray exposures as a potential variable in epidemiological studies of cancer etiology. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 52-year-old Hispanic woman who underwent Mohs micrographic surgery to treat a nonhealing erosion on her left nasal crease. The patient received mupirocin ointment and oral doxycycline, but the erosion did not improve after two weeks of antibiotic treatment. The clinical suspicion of pemphigus vulgaris (PV) was confirmed after direct immunofluorescence was performed.

Vaccines and therapeutics targeting viral surface glycoproteins are a major component of disease prevention for respiratory viral diseases. Over the years, vaccines have proven to be the most successful intervention for preventing disease. Technological advances in vaccine platforms that focus on viral surface glycoproteins have provided solutions for current and emerging pathogens like SARS-CoV-2, and our understanding of the structural basis for antibody neutralization is guiding the selection of other vaccine targets for respiratory viruses like RSV. This review discusses the role of viral surface glycoproteins in disease intervention approaches. [ABSTRACT FROM AUTHOR]

The emergence of SARS-CoV-2 and subsequent COVID-19 pandemic has resulted in a significant global public health burden, leading to an urgent need for effective therapeutic strategies. In this article, we review the role of SARS-CoV-2 neutralizing antibodies (nAbs) in the clinical management of COVID-19 and provide an overview of recent randomized controlled trial data evaluating nAbs in the ambulatory, hospitalized and prophylaxis settings. Two nAb cocktails (casirivimab/imdevimab and bamlanivimab/etesevimab) and one nAb monotherapy (bamlanivimab) have been granted Emergency Use Authorization by the US Food and Drug Administration for the treatment of ambulatory patients who have a high risk of progressing to severe disease, and the European Medicines Agency has similarly recommended both cocktails and bamlanivimab monotherapy for use in COVID-19 patients who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19. Efficacy of nAbs in hospitalized patients with COVID-19 has been varied, potentially highlighting the challenges of antiviral treatment in patients who have already progressed to severe disease. However, early data suggest a promising prophylactic role for nAbs in providing effective COVID-19 protection. We also review the risk of treatment-emergent antiviral resistant "escape" mutants and strategies to minimize their occurrence, discuss the susceptibility of newly emerging SARS-COV-2 variants to nAbs, as well as explore administration challenges and ways to improve patient access. [ABSTRACT FROM AUTHOR]

The section of "Nonwoven Wound Dressings " focuses on testing methods, standards and characterization for nonwoven wound dressings. In the British Standards, six methods have been established for wound dressings: moisture-vapour transmission rate, absorbency, conformability, waterproofness, odour control and bacterial barrier properties. Four more standards have been defined for nonwovens used in medical devices and wound-care materials: nonwoven fabrics used for manufacturing compresses, uncoated and adhesive-coated nonwoven medical-packaging materials and finished nonwoven compresses used in wound care.

The section of "Nonwoven Wound Dressings" focuses on wounds and its healing. Wound can be defined as an interruption of normal anatomic structure and function. In terms of clinical practice, wounds are basically divided into two types: chronic and acute. Wound healing is defined as a complex dynamic process which leads to the restoration of anatomic continuity and function and it usually includes an orderly sequence of biological events. Wound healing may be referred to as first or second intention.

As a child's primary caretaker, the parent plays a significant role in the management of paediatric pain. Is this what physicians want and allow? This paper analyses the results of a survey conducted among paediatricians. Three hundred and fourteen consultant paediatricians were sent questionnaires about their attitudes towards parental presence during medical procedures performed on children under local anaesthesia. Paediatricians were asked under what circumstances they allowed parents to remain, and what factors led to their exclusion. The response rate was high-60.8%. Though 98.5% of paediatricians were willing to let parents remain, 57.5% excluded some parents from certain procedures, particularly if parents were anxious and the procedure difficult or painful. Ninety-one per cent relied on verbal explanations alone to prepare parents prior to procedures. [ABSTRACT FROM AUTHOR]

This article discusses the use of annual vaccines and antiviral drugs to treat seasonal influenza. It assesses the effectiveness of the drugs against the effect of influenza strains on immune systems. It explores the discovery of an antibody against influenza. The use of protein engineering and adjuvants in the treatment of influenza is also noted.

A contest is currently underway between synthetic nonviral vectors and recombinant viral vectors to determine supremacy in gene therapy applications. Viruses have a considerable advantage, with a head start of several hundred thousand years in perfecting the art of gene delivery. Humans are very fast learners, however, and the gap between viral and nonviral vectors. Researchers used a yeast expression system to generate hollow lipid nanoparticles displaying the hepatitis B virus (HBV)attachment protein, and filled them with plasmid DNA (or protein) by electroporation. The resulting DNA-loaded vector particles are able to mediate efficient targeted gene delivery to cultured human hepatocytes The target-specific nature of tPA-coupled erythrocytes has significant potential advantages over undirected agents, such as intravenous anticoagulants (e.g., unfractionated and to human hepatoma cells both in vitro and in vivo. Moreover, the target cell specificity of the vectors can be redirected by engineering a cell-targeting domain into the nanoparticle coat.

Background: The term 'difficult' is pervasively used in relation to medically unexplained symptoms (MUS) and patients with MUS. This article scrutinises the use of the term by analysing interview data from a study of secondary care specialists' experiences with and attitudes towards patients suffering from MUS.Design: Qualitative design employing semi-structured open-ended interviews systematically analysed in three stages: first, data were analysed according to the principles of content analysis. The analysis subsequently focused on the use of the term 'difficult'. Iterations of the term were extracted by summative analysis and thematic coding revealed its different meanings. Finally, alternative expressions were explored.Setting: Three NHS trust secondary care hospitals in North-East England.Participants: 17 senior clinicians from seven medical and two surgical specialities.Results: Unsolicited use of the term 'difficult' was common. 'Difficult' was rarely used as a patient characteristic or to describe the therapeutic relationship. Participants used 'difficult' to describe their experience of diagnosing, explaining, communicating and managing these conditions and their own emotional reactions. Health care system deficits and the conceptual basis for MUS were other facets of 'difficult'. Participants also reported experiences that were rewarding and positive.Conclusions: This study shows that blanket statements such as 'difficult patients' mask the complexity of doctors' experiences in the context of MUS. Our nuanced analysis of the use of 'difficult' challenges preconceived attitudes. This can help counter the unreflexive perpetuation of negative evaluations that stigmatize patients with MUS, encourage greater acknowledgement of doctors' emotions, and lead to more appropriate conceptualizations and management of MUS. [ABSTRACT FROM AUTHOR]

Purpose: To administer recombinant erythropoietin to patients with rheumatoid arthritis who had significant anemia, while monitoring hematologic and rheumatologic clinical responses as well as potential toxicity.Patients and Methods: Seventeen patients with rheumatoid arthritis from five rheumatology care settings were studied. The patients had initial hematocrits of 34% or less and stable clinical status, and were not being treated with second-line drugs or corticosteroids. An 8-week randomized double-blind study involving various dosages of recombinant erythropoietin, as well as placebo, was followed by a 24-week open-label study in which dosage could be titrated to achieve a normal hematocrit.Results: In the 8-week randomized study, four of 13 patients who received injections of recombinant erythropoietin showed a hematologic response, arbitrarily defined as at least a 6-unit increase in hematocrit. None of four placebo-treated patients showed a meaningful hematologic response. All 11 patients who completed the subsequent 24-week open-label study reached a normal hematocrit level at some time during the study, and 10 of 11 showed an increase of hematocrit 6 units or greater. At least one adjustment, i.e., an increase, decrease, or omission of the erythropoietin dosage, was required in all patients to maintain the hematocrit at a target range of 35% for women or 40% for men. Meaningful changes were not seen in patients' capacity to perform activities of daily living or pain levels during either the 8-week randomized study or the 24-week open-label study. No adverse effects were associated with recombinant erythropoietin therapy.Conclusion: Patients with rheumatoid arthritis showed excellent hematologic responses to recombinant erythropoietin, without toxicity, during careful monitoring for appropriate dosage adjustment, although a meaningful change in rheumatologic clinical status was not seen. [ABSTRACT FROM AUTHOR]

Immunocompromised patients are highly susceptible to influenza virus infections. Although neuraminidase inhibitor (NAI) therapy has proved effective in these patients, the treatment regimens require optimization, which can be partly addressed via animal models. Here, we describe a pharmacologically immunosuppressed mouse model for studying the pathogenesis of influenza B viruses and evaluating the efficacy of antiviral treatment. We modeled clinical regimens for dexamethasone and cyclophosphamide to immunosuppress BALB/c mice that were then inoculated with B/Phuket/3073/2013 (Yamagata lineage) or B/Brisbane/60/2008 (BR/08, Victoria lineage) virus. Although both viruses caused morbidity and mortality in immunosuppressed mice, BR/08 was more virulent, consistently inducing greater morbidity and 100% lethality in mice inoculated with at least 10 3 TCID 50 /mouse. The replication of both viruses was prolonged in the lungs of immunosuppressed mice, but the extent of pulmonary inflammation in these mice was markedly less than that in immunocompetent animals. Most of the examined cytokines, including IFN-γ, IL-1β, and RANTES, were significantly decreased in the lungs of immunosuppressed mice, as compared to immunocompetent animals, until at least 10 days post-infection. Treatment with the NAI oseltamivir for 8 or 16 days increased the mean survival time and reduced virus spread in the lungs of immunosuppressed mice challenged with a lethal dose of BR/08 but did not completely provide protection or decrease the virus titers. Our data suggests that the synergy of the viral load and aberrant immune responses is a key contributor to the severity of infection, as well as the limited efficacy of oseltamivir, which in immunosuppressed mice curtails virus release without clearing infected cells. [ABSTRACT FROM AUTHOR]

[Display omitted] A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials. Although interim data showed target engagement and functional improvements, ezutromid ultimately failed to meet its clinical endpoints. We recently described the identification of a new class of hydrazide utrophin modulators which has a different mechanism of action to ezutromid. In this study we report our early optimisation studies on this hydrazide series. The new analogues had significantly improved potency in cell-based assays, increased sp3 character and reduced lipophilicity, which also improved their physicochemical properties. A representative new analogue combining these attributes increased utrophin protein in dystrophic mouse cells showing it can be used as a chemical tool to reveal new insights regarding utrophin upregulation as a strategy for DMD therapeutic intervention. [ABSTRACT FROM AUTHOR]

Site specific targeting remains elusive for gene and stem cell therapies in the cardiovascular field. One promising option involves use of devices that deliver larger and more sustained cell/gene payloads to specific disease sites using the versatility of percutaneous vascular access technology. Smooth muscle cells (SMCs) engineered to deliver high local concentrations of an angiogenic molecule (VEGF) were placed in an intravascular cell delivery device (ICDD) in a porcine model of chronic total occlusion (CTO) involving ameroid placement on the proximal left circumflex (LCx) artery. Implanted SMC were retained within the ICDD and were competent for VEGF production in vitro and in vivo. Following implantation, micro-CT analyses revealed that ICDD-VEGF significantly enhanced vasa vasora microvessel density with a concomitant increase in tissue VEGF protein levels and formation of endothelial cell colonies suggesting increased angiogenic potential. ICDD-VEGF markedly enhanced regional blood flow determined by microsphere and contrast CT analysis translating to a functional improvement in regional wall motion and global left ventricular (LV) systolic and diastolic function. Our data indicate robust, clinically relevant angiogenesis can be achieved in a human scale porcine chronic vascular occlusion model following ICDD-VEGF-based delivery of angiogenic cells. This may have implications for percutaneous delivery of numerous therapeutic factors promoting creation of microvascular bypass networks in chronic vaso-occlusive diseases. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a malignant plasma cell neoplasm that affects more than 20,000 people each year and is the second most common hematologic malignancy, It is part of a spectrum of monoclonal plasma cell disorders, many of which do not require active therapy. During the past decade, considerable progress has been made in our understanding of the disease process and factors that influence outcome, along with development of new drugs that are highly effective in controlling the disease and prolonging survival without compromising quality of life. Identification of well-defined and reproducible prognostic factors and Introduction of new therapies with unique modes of action and impact on disease outcome have for the first time opened up the opportunity to develop risk-adapted strategies for managing this disease. Although these risk-adapted strategies have not been prospectively validated, enough evidence can be gathered from existing randomized trials, subgroup analyses, and retrospective studies to develop a working framework. This set of recommendations represents such an effort--the development of a set of consensus guidelines by a group of experts to manage patients with newly diagnosed disease based on an interpretation of the best available evidence. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a neoplastic plasma cell dyscrasia that on a yearly basis affects nearly 17,000 individuals and kills more than 11,000. Although no cure exists, many effective treatments are available that prolong survival and improve the quality of life of patients with this disease. The purpose of this consensus is to offer a simplified, evidence-based algorithm of decision making for patients with newly diagnosed myeloma. In cases in which evidence is lacking, our team of 18 Mayo Clinic myeloma experts reached a consensus on what therapy could generally be recommended. The focal point of our strategy revolves around risk stratification. Although a multitude of risk factors have been identified throughout the years, including age, tumor burden, renal function, lactate dehydrogenase, β2-microglobulin, and serum albumin, our group has now recognized and endorsed a genetic stratification and patient functional status for treatment. [ABSTRACT FROM AUTHOR]

Bisphosphonates are effective in the prevention and treatment of bone disease in multiple myeloma (MM). Osteonecrosis of the jaw is increasingly recognized as a serious complication of long-term bisphosphonate therapy. issues such as the choice of bisphosphonate and duration of therapy have become the subject of intense debate given patient safety concerns. We reviewed available data concerning the use of bisphosphonates in MM. Guidelines for the use of bisphosphonates in MM were developed by a multidisciplinary panel consisting of hematologists, dental specialists, and nurses specializing in the treatment of MM. We conclude that intravenous pamidronate and intravenous zoledronic acid are equally effective and superior to placebo in reducing skeletal complications. Pamidronate is favored over zoledronic acid until more data are available on the risk of complications (osteonecrosis of the Jaw). We recommend discontinuing bisphosphonates after 2 years of therapy for patients who achieve complete response and/or plateau phase. For patients whose disease is active, who have not achieved a response, or who have threatening bone disease beyond 2 years, therapy can be decreased to every 3 months. These guidelines were developed in the interest of patient safety and will be reexamined as new data emerge regarding risks and benefits. [ABSTRACT FROM AUTHOR]

Objective: Multiple myeloma (MM) is an incurable B cell malignancy and novel therapeutics are urgently needed. Live attenuated measles virus (MV) has potent oncolytic activity against MM tumor xenografts. The virus is tumor selective and preferentially targets cells that express high levels of CD46 receptors. However, CD46 levels on MM have not previously been evaluated. In this study, we investigated the potential of CD46 as a target for MM therapy and correlated surface levels of CD46 on MM cells with their susceptibility to MV-induced cytopathic effects. Materials and Methods: CD46 expression on neoplastic plasma cells (PCs) and nonplasma cells (NPCs) from 38 MM patients was analyzed by flow cytometry and receptor numbers were quantitated using BD QuantiBRITE PE beads. Results: Results showed that malignant PCs expressed significantly higher levels of CD46 receptors compared to NPCs (p < 0.0001). The mean CD46 receptor numbers on PCs and NPCs were 49,130/cell and 7340/cell, respectively. Potent cytopathic effects of extensive intercellular fusion were observed in measles-infected PCs but not in NPCs. The extent of MV-induced cytopathic effects of cell fusion correlated with CD46 expression levels on the MM cells. Normal plasma cells do not overexpress CD46 and colony-forming assays demonstrated that MV was not cytotoxic to normal bone marrow progenitor cells. Conclusion: The present study establishes CD46 as a surface antigen that is expressed more abundantly on primary MM cells compared to normal hematopoietic cells of various lineages in the bone marrow, making CD46 a promising surface marker for targeted cytoreductive therapy of MM. [Copyright &y& Elsevier]

The POEMS syndrome is associated with elevated vascular endothelial growth factor (VEGF) levels. Several studies have compared serum VEGF levels between POEMS patients and other disease entities showing higher serum VEGF in POEMS syndrome; however, it is unknown whether serum levels are reliable and reproducible given variable platelet release of VEGF. We therefore compared plasma levels of VEGF in 29 patients with POEMS syndrome with those of other disorders (n = 76). We demonstrated that plasma VEGF levels are useful in differentiating POEMS from other plasma cell dyscrasias, neuropathic processes, and multisystem illnesses. Plasma VEGF is also useful in monitoring disease activity after treatment and correlates with clinical improvements better than hematologic response. [ABSTRACT FROM AUTHOR]