Shockwave Therapy in the Management of Complex Regional Pain Syndrome in Medial Femoral Condyle of the Knee

The aim of this prospective study was to assess the efficacy of shockwave (SW) therapy in the management of complex regional pain syndrome (CRPS). In this study, 30 patients (pts) who were affected by CRPS of the medial femoral condyle and unresponsive to previous standard physiotherapeutic and pharmacological treatment underwent 3 SW sessions at 72-h intervals, each consisting of 4000 shocks emitted by a MiniLith SL1 Storz electromagnetic generator. An energy flux density (EFD) of 0.035 or 0.09 mJ/mm² was used, depending on how well the patient endured the pain during the treatment. Satisfactory results were observed in 76.7% of the cases (23 pts) at the 2-month follow-up (FU) visit, and in 80% (24 pts) at the 6-month FU visit. The therapeutic effects of SW were caused by decreasing pain. The significant improvements we obtained bear witness to the potential value of SW therapy in the management of CRPS. (E-mail: angelanotarnicola@yahoo.it)     

IAP inhibitors enhance co-stimulation to promote tumor immunity

The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell–dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.The inhibitor of apoptosis proteins (IAPs) were initially identified as caspase inhibitors capable of blocking both extrinsic and intrinsic apoptotic signals. Recent work has established diverse roles for the IAP family, in which they have been shown to regulate apoptosis through the modulation of NF-κB signaling downstream of several TNF family receptors and to play an essential role in the modulation of FAS-induced cell death (Hu et al., 2006; Leulier et al., 2006; Rigaud et al., 2006; Gaither et al., 2007; Lu et al., 2007; Petersen et al., 2007; Varfolomeev et al., 2007, 2008; Vince et al., 2007, 2008; Xu et al., 2007; Bertrand et al., 2008; Mahoney et al., 2008; Matsuzawa et al., 2008; Srinivasula and Ashwell, 2008; Wang et al., 2008; Csomos et al., 2009; Jost et al., 2009). All IAPs contain baculovirus inhibitory repeat domains that mediate protein binding, and several, including cellular IAP-1 (cIAP-1) and cIAP-2, X-linked IAP (XIAP), and melanoma-IAP/Livin, contain RING finger E3 ubiquitin ligase domains, which can cause autoubiquitination as a means of regulating apoptosis (Schile et al., 2008; Srinivasula and Ashwell, 2008). IAPs are regulated endogenously by second mitochondrial-derived activator of caspases (SMAC), which interacts with IAP baculovirus inhibitory repeat domains via a tetrapeptide motif. Several pharmacologic SMAC mimetics have been developed that induce tumor death through binding to the RING domain containing IAPs and leading to ubiquitin-mediated destruction (Gaither et al., 2007; Petersen et al., 2007; Varfolomeev et al., 2007; Vince et al., 2007; Wang et al., 2008). These pharmacologic SMAC mimetics act as broad antagonists of the RING domain containing IAPs and are actively being investigated as a potential novel class of cancer chemotherapeutics.In addition to roles in tumor biology, several studies suggest important functions for the IAPs in immunoregulation. XIAP-deficient humans develop X-linked lymphoproliferative disease and were initially reported to lack NKT cells, although the specificity of this finding has recently been challenged (Rigaud et al., 2006; Marsh et al., 2009). XIAP-deficient mice have difficulty controlling Listeria monocytogenes infections and are more susceptible to infection with MHV-68 (mouse herpes virus 68); however, the mechanism for this immunodeficiency is unknown and is not associated with decreased NKT cell function (Bauler et al., 2008; Rumble et al., 2009). cIAP-2 is involved in a recurrent translocation in mucosal-associated lymphoid tissue lymphoma and has been reported to function as an E3 ligase for BCL10 in lymphocytes, although the physiological importance of this activity is unknown (Hu et al., 2006). More recently, the cIAPs were shown to be critical for c-Jun N-terminal kinase activation downstream of CD40 and to negatively regulate alternative NF-κB activation by the BAFF (B cell activation factor of the TNF family) receptor (Matsuzawa et al., 2008; Vallabhapurapu et al., 2008; Zarnegar et al., 2008). These findings position the cIAPs as potentially key regulators of B cell homeostasis, although how the cIAPs regulate B cell–dependent immune responses has, at present, been incompletely explored. In addition to roles in adaptive immunity, the cIAPs and XIAP have been shown to be required for NOD-1 and -2 (nucleotide biding and oligomerization domain 1 and 2) signaling and downstream cytokine production after exposure to muramyl dipeptide (Bertrand et al., 2009; Krieg et al., 2009). Furthermore, cIAP-2–deficient mice show altered responses to lipopolysaccharide that may indicate a role for cIAP-2 in inflammatory cytokine-induced apoptosis in macrophages (Conte et al., 2006). Moreover, neuronal apoptosis inhibitor protein (NAIP), a member of both the NOD-like receptor and IAP families, is a component of the inflammasome and is required for control of Legionella pneumophila infections (Diez et al., 2003; Rigaud et al., 2006).Although evidence now links the IAP family to regulation of both tumor cell survival and immune function, the impact of IAP inhibitors on antitumor immune responses is unknown. In particular, the consequences of IAP antagonism in the key effector cells responsible for antitumor immunity such as CD4⁺ and CD8⁺ T cells, NKT cells, and NK cells has not been explored. Given the potential for IAP antagonists to simultaneously induce tumor cell death and modulate immunity, understanding how IAP antagonism might alter nascent antitumor responses and responses to other forms of tumor immunotherapy may have implications for the use of these agents to treat cancer.In this study, we examine the consequences of IAP antagonism on T cell function both in vitro and in the context of a tumor vaccine in vivo. Unexpectedly, we find that IAPs function as negative co-stimulators during T cell stimulation and that small molecule IAP antagonists can augment both human and mouse T cell responses to physiologically relevant stimuli, including tumor antigens, without producing responses in unstimulated cells.     

Relationships Between Daily Acute Glucose Fluctuations and Cognitive Performance Among Aged Type 2 Diabetic Patients

OBJECTIVE

The mean amplitude of glycemic excursions (MAGE) is a significant determinant of overall metabolic control as well as increased risk for diabetes complications. Older individuals with type 2 diabetes are more likely to have moderate cognitive deficits and structural changes in brain tissue. Considering that poor metabolic control is considered a deranging factor for cognitive performance in diabetic patients, we evaluated whether the contributions of MAGE to cognitive status in older patients with type 2 diabetes were independent from the main markers of glycemic control, such as sustained chronic hyperglycemia (A1C), postprandial glycemia (PPG), and fasting plasma glucose (FPG).

RESEARCH DESIGN AND METHODS

In 121 older patients with type 2 diabetes, 48-h continuous subcutaneous glucose monitoring (CSGM) were assessed. MAGE and PPG were evaluated during CSGM. The relationship of MAGE to performance on cognitive tests was assessed, with adjustment for age, glycemic control markers, and other determinants of cognitive status. The cognitive tests were a composite score of executive and attention functioning and the Mini Mental Status Examination (MMSE).

RESULTS

MAGE was significantly correlated with MMSE (r = 0.83; P < 0.001) and with cognition composite score (r = 0.68; P < 0.001). Moreover, MAGE was associated with the MMSE (P < 0.001) and cognition composite score (P < 0.001) independently of age, sex, BMI, waist-to-hip (WHR) ratio, drug intake, physical activity, mean arterial blood pressure, FPG, PPG, and A1C.

CONCLUSIONS

MAGE during a daily period was associated with an impairment of cognitive functioning independent of A1C, FPG, and PPG. The present data suggest that interventional trials in older patients with type 2 diabetes should target not only A1C, PPG, and FPG but also daily acute glucose swings.It is widely known that older individuals with type 2 diabetes are more likely to experience cognitive decline than those without type 2 diabetes (1). The underlying mechanisms, however, are still unclear, but emerging evidence suggests that a relationship between measures of glucose control and cognitive function exists (2). For instance, a cross-sectional analysis in 378 high-functioning individuals with diabetes showed that higher A1C but not fasting plasma glucose (FPG) levels were consistently associated with lower scores on two cognitive tests (3). Further evidence comes from studies using other indexes of dysglycemia, such as postprandial glycemia (PPG) and acute hyperglycemia (4,5). Therefore, despite the fact that several studies have investigated and compared the roles of the different glycemic indexes participating in diabetic cognitive disorders, an accurate assessment of their respective contributions is still difficult. Considering that the brain is dependent on an appropriate supply of glucose as its principal energy source, one cannot rule out the possibility that plasma glucose instability over 24 h may affect cognitive functioning. From a more practical point of view, exposure to glycemic disorders can be described as a function of two components: 1) the duration and magnitude of chronic sustained hyperglycemia and 2) the acute fluctuations of glucose over a daily period (6,7). The first component was integrated by A1C, which depends on both interprandial and postprandial hyperglycemia, the percentage of each contributor being modulated by the degree of diabetic control (8). The acute fluctuations of glucose around a mean value is more difficult to assess, but the recent development of devices that allow continuous glucose monitoring on an ambulatory basis certainly represents a new approach for studying the influence of acute blood glucose fluctuations in real life (9). By applying this technology, we have attempted to gain further insight into the respective role of both sustained chronic hyperglycemia and acute glucose fluctuations over a daily period on global cognitive functioning as well as executive and attention functioning neuropsychological tests.     

Anaerobic environment of the intestine primes pathogenic Shigella for infection

Marteyn et al. have investigated the role of oxygen and the regulator FNR in infection by the intracellular enteric pathogen Shigella flexneri. FNR is active under anaerobic conditions like those present in the lumen of the distal intestine. FNR causes elongation of a secretion apparatus required for bacterial entry into cells and represses secretion of proteins that trigger entry. Higher oxygen levels present at the intestinal cell surface are sufficient to inactivate FNR, thereby derepressing secretion. Thus, bacteria are 'primed' in the anaerobic environment of the lumen, and entry is triggered by the aerobic conditions at the intestinal cell surface. FNR is conserved among many enteric pathogens, suggesting that regulation of virulence in response to oxygen may be widely conserved.     

Mismatched human leukocyte antigen alleles protect against heterosexual HIV transmission.

Genetic variation at the human leukocyte antigen (HLA) loci has been shown to be an important risk factor for progression to HIV disease, but its significance in infection is less well understood. We have investigated its role in HIV transmission in a cohort of individuals at risk for heterosexual infection. Analysis of over 80 individuals revealed that that the degree of concordance at HLA A, B, and DR loci differs significantly between transmitting and nontransmitting couples at risk for heterosexual HIV transmission (p <.02), suggesting that allogeneic immune responses may confer a degree of protection against HIV infection. Analysis of the frequencies of specific alleles at the A, B, and DR loci revealed a significantly higher frequency of HLA DR5 among exposed uninfected individuals, relative to population controls.     

Effect of a self-etch primer/adhesive on the shear bond strength of orthodontic brackets

Conventional adhesive systems use 3 different agents (an enamel conditioner, a primer solution, and an adhesive resin) during the bonding of orthodontic brackets to enamel. A unique characteristic of some new bonding systems in operative dentistry is that they combine the conditioning and priming agents into a single product. Combining conditioning and priming saves time and should be more cost-effective to the clinician and, indirectly, to the patient. The purpose of this study was to determine the effects of the use of a self-etch primer on the shear bond strength of orthodontic brackets and on the bracket/adhesive failure mode. Brackets were bonded to extracted human teeth according to 1 of 2 protocols. In the control group, teeth were etched with 37% phosphoric acid. After the sealant was applied, the brackets were bonded with Transbond XT (3M Unitek, Monrovia, Calif) and light cured for 20 seconds. In the experimental group, a self-etch acidic primer (ESPE Dental AG, Seefeld, Germany) was placed on the enamel for 15 seconds and gently evaporated with air, as suggested by the manufacturer. The brackets were then bonded with Transbond XT as in the first group. The present in vitro findings indicate that the use of a self-etch primer to bond orthodontic brackets to the enamel surface resulted in a significantly (P = .004) lower, but clinically acceptable, shear bond force (mean, 7.1 +/- 4.4 MPa) as compared with the control group (mean, 10.4 +/- 2.8 MPa). The comparison of the adhesive remnant index scores indicated that there was significantly (P = .006) more residual adhesive remaining on the teeth that were treated with the new self-etch primer than on those teeth that were bonded with the use of the conventional adhesive system.     

Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma.

Radiation dosimetry studies were performed in patients with non-Hodgkin's lymphoma (NHL) treated with 90Y Zevalin (90yttrium ibritumomab tiuxetan, IDEC-Y2B8) on a Phase III open-label prospectively randomized multicenter trial. The trial was designed to evaluate the efficacy and safety of 90Y Zevalin radioimmunotherapy compared to rituximab (Rituxan, MabThera) immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed NHL. An important secondary objective was to determine if radiation dosimetry prior to 90Y Zevalin administration is required for safe treatment in this patient population. METHODS: Patients randomized into the Zevalin arm were given a tracer dose of 5 mCi (185 MBq) (111)In Zevalin (111indium ibritumomab tiuxetan) on Day 0, evaluated with dosimetry, and then administered a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90Y Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve Zevalin biodistribution. Following administration of (111)In Zevalin, serial anterior and posterior whole-body scans were acquired and blood samples were obtained. Residence times for 90Y were estimated for major organs, and the MIRDOSE3 computer software program was used to calculate organ-specific and total body radiation absorbed dose. Patients randomized into the rituximab arm received a standard course of rituximab immunotherapy (375 mg/m(2) weekly x 4). RESULTS: In a prospectively defined 90 patient interim analysis, the overall response rate was 80% for Zevalin vs. 44% for rituximab. For all patients with Zevalin dosimetry data (N=72), radiation absorbed doses were estimated to be below the protocol-defined upper limits of 300 cGy to red marrow and 2000 cGy to normal organs. The median estimated radiation absorbed doses were 71 cGy to red marrow (range: 18-221 cGy), 216 cGy to lungs (94-457 cGy), 532 cGy to liver (range: 234-1856 cGy), 848 cGy to spleen (range: 76-1902 cGy), 15 cGy to kidneys (0.27-76 cGy) and 1484 cGy to tumor (range: 61-24274 cGy). Toxicity was primarily hematologic, transient, and reversible. The severity of hematologic nadir did not correlate with estimates of effective half-life (half-life) or residence time of 90Y in blood, or radiation absorbed dose to the red marrow or total body. CONCLUSION: 90Y Zevalin administered to NHL patients at non-myeloablative maximum tolerated doses delivers acceptable radiation absorbed doses to uninvolved organs. Lack of correlation between dosimetric or pharmacokinetic parameters and the severity of hematologic nadir suggest that hematologic toxicity is more dependent on bone marrow reserve in this heavily pre-treated population. Based on these findings, it is safe to administer 90Y Zevalin in this defined patient population without pre-treatment (111)In-based radiation dosimetry.     

Assimilative Integration: Short-term Dynamic Psychotherapy for Treating Affect Phobias

An integrative model of short-term dynamic psychotherapy (STDP) is presented that assimilates interventions from a variety of therapy orientations to accelerate patient improvement. Affect phobia therapy (APT) is a name given to McCullough's STDP to highlight the main treatment focus and to guide therapists to the most efficient and effective interventions. This treatment model is based on the hypothesis that conflicts about feelings, or "affect phobias," are the fundamental issues underlying many Axis I and Axis II disorders. Systematic desensitization, or stepwise exposure to feelings and defense response prevention, is hypothesized to be the fundamental agent of therapeutic change. APT focuses primarily on the resolution of affective conflicts in a psychodynamic framework, but videotape review and process studies of this STDP model have discovered that interventions from cognitive, behavior, Cestalt, and experiential therapy, as well as self-psychology, have been instrumental in patient change. Therapy is made briefer by clarifying treatment objectives, simplifying the selection criteria, and using principles of systematic desensitization for the resolution of affect phobias.