Interplay between gain and loss in arrays of nonlinear plasmonic nanoparticles: toward parametric downconversion and amplification.

With the help of a theoretical model and finite-difference time-domain (FDTD) simulations based on the hydrodynamic-Maxwell model, we examine the effect of difference-frequency generation (DFG) in an array of L-shaped metal nanoparticles (MNPs) characterized by intrinsic plasmonic nonlinearity. The outcomes of the calculations reveal the spectral interplay between gain and loss in the vicinity of the fundamental frequency of the localized surface plasmon resonances. Subsequently, we identify different array thicknesses and pumping regimes facilitating parametric amplification and spontaneous parametric downconversion. Our results suggest that the parametric amplification regime becomes feasible on a scale of hundreds of nanometers and spontaneous parametric downconversion on the scale of tens of nanometers, opening up new exciting opportunities for developing building blocks of photonic metasurfaces.

Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets.

G1Δnab is a mutant human IgG1 constant region with a lower ability to interact with FcγR than the natural IgG constant regions. Radiolabelled RBCs and platelets sensitised with specific G1Δnab Abs were cleared more slowly from human circulation than IgG1-sensitised counterparts. However, non-destructive splenic retention of G1Δnab-coated RBCs required investigation and plasma radioactivities now suggest this also occurred for platelets sensitised with an IgG1/G1Δnab mixture. In vitro assays with human cells showed that G1Δnab-sensitised RBCs did not cause FcγRI-mediated monocyte activation, FcγRIIIa-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) or macrophage phagocytosis although they did adhere to macrophages. Thus, FcγRII was implicated in the adhesion despite the Δnab mutation reducing the already low-affinity binding to this receptor class. Additional contacts via P-selectin enhance the interaction of sensitised platelets with monocytes and this system provided evidence of FcγRII-dependent activation by G1Δnab. These results emphasise the physiological relevance of low-affinity interactions: It appears that FcγRII interactions of G1Δnab allowed splenic retention of G1Δnab-coated RBCs with inhibitory FcγRIIb binding preventing RBC destruction and that FcγRIIb engagement by G1Δnab on IgG1/G1Δnab-sensitised platelets overcame activation by IgG1. Considering therapeutic blocking Abs, G1Δnab offers lower FcγR binding and a greater bias towards inhibition than IgG2 and IgG4 constant regions.

Severity and interference of chronic pain in methadone-maintained outpatients.

OBJECTIVES: Patients with opioid use disorder maintained on methadone report more chronic pain than the general population. The current study characterized chronic pain in patients with opioid use disorder. DESIGN: A one-time self-report survey. SETTING: The Addiction Treatment Services methadone-maintenance clinic, located on the campus of Johns Hopkins Bayview Medical Center in Baltimore MD. SUBJECTS: A convenience sample of 227 methadone-maintained patients. METHODS: Participants completed a one-time self-report administration of the brief pain inventory (BPI) and a demographic survey; additional treatment variables were obtained directly from clinic records. RESULTS: Sixty percent of the sample endorsed chronic pain. Patients with pain were significantly older, had a higher mean methadone dose, and provided more benzodiazepine-positive urine samples. Pain was primarily located in the lower extremities (59%) and back (51%), and mean BPI severity and interference subscale scores were 5.7 and 5.4 out of 10, respectively. Logistic regressions indicated that age (P < 0.001) and methadone dose (P < 0.001) were significantly associated with having pain and that pain was a significant predictor of benzodiazepine use (P = 0.01). Only 13% (N = 18) of patients with pain were receiving pain management, and few were being treated with any nonopioid adjuvant analgesics. Yet patients who did receive treatment reported a mean 51% improvement in their pain, indicating they are not treatment refractory. CONCLUSIONS: Results suggest there is a large discrepancy in the percent of patients who may need treatment for pain and those receiving treatment for pain and that more efforts should be made to provide standard pain management techniques to patients with opioid use disorder to reduce their overall level of pain and potentially improve their overall treatment outcomes.

Borderline personality disorder and chronic pain: a practical approach to evaluation and treatment.

Patients with chronic pain present a spectrum of complexity that can be overwhelming for the individual practitioner. These patients require thoughtful care and a comprehensive treatment plan. This complexity should be acknowledged, not avoided, and the patient should be engaged, not shunned. A practical approach will assist in developing expertise and proceeding empathically. The presence of a superimposed personality disorder significantly increases the difficulty of caring for these patients. Studies investigating the prevalence of borderline personality disorder in patients with chronic pain averaged 30 %, highlighting the importance of being able to effectively treat this patient population. Appropriate management of these patients should focus on a collaboration to practice productive behaviors despite intense emotional distress. Longitudinal research provides a foundation for an optimistic prognosis that can be enhanced with this rehabilitative approach.

Human IgG isotypes and activating Fcγ receptors in the interaction of Salmonella enterica serovar Typhimurium with phagocytic cells.

Several classes and multiple subclasses of immunoglobulins are produced towards protein and polysaccharide antigens in response to Salmonella infection and play a key role in protection against systemic disease. The targeting of Salmonella to Fc receptors (FcR) on phagocytes is a key step in the antibody-mediated antibacterial functions of host cells. We wished to compare the relative efficiency of different human IgG subclasses, which targeted the Salmonella enterica OmpA surface protein in modulating the interaction of bacteria with human phagocytes. To this end, we developed a novel system by tagging OmpA with a foreign CD52 mimotope (TSSPSAD) and opsonizing the bacteria with a panel of humanized CD52 antibodies that share the same antigen-binding V-region, but have constant regions of different subclasses. Our data revealed that opsonization with all the IgG subclasses increases Salmonella uptake by human phagocytes. IgG3 resulted in the highest level of bacterial uptake and the highest average bacterial load per infected cell, which was closely followed by IgG1, then IgG4 and lastly IgG2. Phagocytosis mediated by IgG1, IgG3 and IgG4 had a higher dependency on FcγRI than FcγRIIA, whereas IgG2-mediated phagocytosis required FcγRIIA more than FcγRI. The results show that IgG binding to OmpA increases the uptake of Salmonella by human phagocytic cells and that the efficiency of this process depends both on the subclass of the IgG and the type of FcR that is available for antibody binding.

From stigmatized neglect to active engagement.

Chronic pain and substance abuse are common problems. Each entity represents a significant and independent burden to the patients affected by them, the healthcare system caring for them, and society at large supporting them. If the two problems occur together, all of these burdens and their consequences are magnified. Traditional treatments fail a substantial percentage of even the most straightforward cases. Clearly, new approaches are required for the most complex of cases. Success is possible only if multiple disciplines provide integrated care that incorporates all of the principles of substance abuse and chronic pain rehabilitation treatment into one package. While experience provides the foundation for implementing these programs, research that documents the methods behind successful outcomes will be needed to sustain support for them.

A behaviorist perspective.

Chronic pain is a sensory experience that produces suffering and functional impairment and is the result of both sensory input as well as secondary adaptation of the nervous system. The sensitization of the nervous system to pain is influenced by physical activity (or inactivity) and medication exposure. Medication taking and physical activity are behaviors that are increased or decreased by positive and negative reinforcement. Patients often have comorbid psychiatric conditions at presentation, including addictions, mood disorders, personality vulnerabilities and life circumstances that amplify their disability and impede their recovery. Behavioral conditioning contributes to chronic pain disorders in the form of both classical (Pavlov) and operant (Skinner) conditioning that increases the experience of pain, the liability to ongoing injury, the central amplification of pain, the use of reinforcing medications such as opiates and benzodiazepines, and behaviors associated with disability. The term 'abnormal illness behavior' has been used to describe behaviors that are associated with illness but are not explained physiologically. Behavioral conditioning often amplifies these abnormal behaviors in patients with chronic pain. Addiction can also be seen as a behavior that is reinforced and conditioned. The same factors that amplify abnormal illness behaviors also increase the liability to addiction. Psychiatric comorbidities also complicate and amplify abnormal illness behaviors and addictive behaviors and further contribute to the disability of chronic pain patients. Model interventions that reinforce healthy behaviors and extinguish illness behaviors are effective in patients with addictions and chronic pain. Maladaptive behaviors including addictive behaviors can be used as targets for classical and operant conditioning techniques, and these techniques are demonstrably effective in patients with chronic pain and addictions.

Optimizing treatment with opioids and beyond.

Patients with both chronic pain and substance use disorders offer special challenges and opportunities. They represent a large number of patients with significant costs to themselves and society that translate into poor outcome. The challenges in defining addiction in patients with chronic pain, particularly in those treated with chronic opioid therapy, have distracted the healthcare community from designing effective treatment programs. Traditional treatment programs for chronic pain disorders or substance use disorders are incapable of addressing the issues of the patients' 'other' problem. Treatment devolves to prescribing opioid medications with the belief that both disorders will be treated at least in part, which is deemed better than receiving no treatment at all. Patients are actually concerned about the risks of this type of treatment, and even if it did offer significant benefits, physicians demonstrate a lack of knowledge and skill in administering opioids to these patients. The inadequate treatment of either chronic pain or addiction interferes with the treatment of the other condition and necessitates the design of new treatment paradigms. A new approach to patients with both chronic pain and addiction should start with an evaluation and formulation of these patients to determine the different domains that contribute to their disability (diseases, dimensions, behaviors, life stories). A comprehensive formulation provides the appropriate platform for the implementation of an integrated program of therapy for both conditions that can be intensified to provide more, rather than less, care for the patient that does not meet the goals of functional rehabilitation.

Psychiatric issues in chronic pain.

Chronic pain requires comprehensive care. While interdisciplinary approaches are recommended, the role of psychiatrists is often misunderstood. Psychiatrists should be involved with the care of patients with chronic pain as early as possible to maximize outcome. Psychiatrists offer an expertise that specifically addresses important deficiencies in the care of patients with chronic pain: 1) the lack of a detailed formulation, 2) the lumping of all psychopathology, and 3) the failure to effectively use psychopharmacologic treatments. This review provides a framework for formulating the diagnoses and treatments of patients with chronic pain.

PECAM-1 polymorphism affects monocyte adhesion to endothelial cells.

BACKGROUND: Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) plays an important role in leukocyte-endothelial cell adhesion and transmigration. Single nucleotide polymorphisms of PECAM-1 encoding amino acid substitutions at positions 98 leucine/valine (L/V), 536 serine/asparagine (S/N), and 643 arginine/glycine (R/G) occur in strong genetic linkage resulting in two common haplotypes (LSR and VNG). These PECAM-1 polymorphisms are associated with graft-versus-host disease after hematopoietic stem cell transplantation and with cardiovascular disease, but whether they influence PECAM-1 function is unknown. METHODS: We examined the effect of homozygous and heterozygous expression of the PECAM-1 LSR and VNG genotypes on the adhesive interactions of peripheral blood monocytes and activated endothelial cell monolayers under shear stress in a flow-based cell adhesion assay. RESULTS: There was no difference in monocyte adhesion between the two homozygous genotypes of PECAM-1 but when monocytes expressed both alleles in heterozygous form, firm adhesion of monocytes to endothelial cells was markedly increased. PECAM-1 polymorphism expressed in homozygous or heterozygous form by endothelial cells did not influence monocyte adhesion. CONCLUSIONS: This is, to our knowledge, the first demonstration that PECAM-1 genotype can alter the level of monocyte binding to endothelial cells and a demonstration that heterozygous expression of a polymorphic protein may lead to altered function.

Morphine versus mexiletine for treatment of postamputation pain: a randomized, placebo-controlled, crossover trial.

BACKGROUND: Stump and phantom pains are debilitating sequelae of amputations that are often resistant to treatment. The efficacy of pharmacologic therapies, including opioids and sodium channel blockers, for postamputation pain is uncertain. METHODS: The authors conducted a double-blind, randomized, placebo-controlled, crossover study in adult patients with postamputation pain of 6 months or longer and greater than 3 on a 0-10 numeric pain rating scale. Each of the three treatment periods (morphine, mexiletine, or placebo) included a 1-week drug-free interval followed by 4-week titration, 2-week maintenance, and 2-week drug-taper phases. The primary outcome measure was change in average pain intensity from the drug-free baseline to the last week of maintenance. RESULTS: Sixty amputees were enrolled; data were analyzed from 56 subjects for one drug period, 45 subjects for two drug periods, and 35 subjects who completed all three drug periods. The mean morphine and mexiletine dosages were 112 and 933 mg, respectively. Morphine treatment provided lower pain scores compared with placebo and mexiletine (P = 0.0003). The mean percent pain relief during treatment with placebo, mexiletine, and morphine was 19, 30, and 53%, respectively (P < 0.0001, morphine vs. placebo and mexiletine). The numbers needed to treat to obtain 50% and 33% decreases in pain intensity with morphine were 5.6 and 4.5, respectively. Treatment with morphine was associated with a higher rate of side effects. CONCLUSIONS: Therapy with morphine, but not mexiletine, resulted in a decrease in intensity of postamputation pain but was associated with a higher rate of side effects and no improvement in self-reported levels of overall functional activity and pain-related interference in daily activities.

Human IgG lacking effector functions demonstrate lower FcRn-binding and reduced transplacental transport.

We have previously generated human IgG1 antibodies that were engineered for reduced binding to the classical Fcγ receptors (FcγRI-III) and C1q, thereby eliminating their destructive effector functions (constant region G1Δnab). In their potential use as blocking agents, favorable binding to the neonatal Fc receptor (FcRn) is important to preserve the long half-life typical of IgG. An ability to cross the placenta, which is also mediated, at least in part, by FcRn is desirable in some indications, such as feto-maternal alloimmune disorders. Here, we show that G1Δnab mutants retain pH-dependent binding to human FcRn but that the amino acid alterations reduce the affinity of the IgG1:FcRn interaction by 2.0-fold and 1.6-fold for the two antibodies investigated. The transport of the modified G1Δnab mutants across monolayers of human cell lines expressing FcRn was approximately 75% of the wild-type, except that no difference was observed with human umbilical vein endothelial cells. G1Δnab mutation also reduced transport in an ex vivo placenta model. In conclusion, we demonstrate that, although the G1Δnab mutations are away from the FcRn-binding site, they have long-distance effects, modulating FcRn binding and transcellular transport. Our findings have implications for the design of therapeutic human IgG with tailored effector functions.

Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain.

Despite the number of patients affected by diabetic peripheral neuropathic pain (DPNP), little consensus exists about the pathophysiology, best diagnostic tools, and primary treatment choices. Theories about the causes of DPNP are inextricably linked with the causes of diabetic neuropathles, yet most patients with such neuropathies do not experience pain. The factors that differentiate patients with pain from those without remain unknown and are the subject of much research. When choosing treatment for patients with DPNP, physicians are confronted with a myriad of choices, none of which has been shown to be effective for all patients. This article reviews the evidence for these treatments and attempts to guide physicians in choosing those treatments based on evidence from well-designed clinical trials to support their use. Two agents, duloxetine and pregabalin, are formally approved by the Food and Drug Administration for the treatment of DPNP. In addition, several other agents, including the tricyclic class of antidepressants, have been effective in clinical trials. Ultimately, treatment choice must also Include consideration of adverse effects, individual patient factors such as comorbidities, and often cost.

Igg Subclasses Targeting the Flagella of Salmonella enterica Serovar Typhimurium Can Mediate Phagocytosis and Bacterial Killing.

Invasive non-typhoidal Salmonella are a common cause of invasive disease in immuno-compromised individuals and in children. Multi-drug resistance poses challenges to disease control, with a critical need for effective vaccines. Flagellin is an attractive vaccine candidate due to surface exposure and high epitope copy number, but its potential as a target for opsonophacytic antibodies is unclear. We examined the effect of targeting flagella with different classes of IgG on the interaction between Salmonella Typhimurium and a human phagocyte-like cell line, THP-1. We tagged the FliC flagellar protein with a foreign CD52 mimotope (TSSPSAD) and bacteria were opsonized with a panel of humanised CD52 antibodies with the same antigen-binding V-region, but different constant regions. We found that IgG binding to flagella increases bacterial phagocytosis and reduces viable intracellular bacterial numbers. Opsonisation with IgG3, followed by IgG1, IgG4, and IgG2, resulted in the highest level of bacterial uptake and in the highest reduction in the intracellular load of viable bacteria. Taken together, our data provide proof-of-principle evidence that targeting flagella with antibodies can increase the antibacterial function of host cells, with IgG3 being the most potent subclass. These data will assist the rational design of urgently needed, optimised vaccines against iNTS disease.

Human IgG1 antibodies suppress angiogenesis in a target-independent manner.

Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world's population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab's Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

The INNs and outs of antibody nonproprietary names.

An important step in drug development is the assignment of an International Nonproprietary Name (INN) by the World Health Organization (WHO) that provides healthcare professionals with a unique and universally available designated name to identify each pharmaceutical substance. Monoclonal antibody INNs comprise a -mab suffix preceded by a substem indicating the antibody type, e.g., chimeric (-xi-), humanized (-zu-), or human (-u-). The WHO publishes INN definitions that specify how new monoclonal antibody therapeutics are categorized and adapts the definitions to new technologies. However, rapid progress in antibody technologies has blurred the boundaries between existing antibody categories and created a burgeoning array of new antibody formats. Thus, revising the INN system for antibodies is akin to aiming for a rapidly moving target. The WHO recently revised INN definitions for antibodies now to be based on amino acid sequence identity. These new definitions, however, are critically flawed as they are ambiguous and go against decades of scientific literature. A key concern is the imposition of an arbitrary threshold for identity against human germline antibody variable region sequences. This leads to inconsistent classification of somatically mutated human antibodies, humanized antibodies as well as antibodies derived from semi-synthetic/synthetic libraries and transgenic animals. Such sequence-based classification implies clear functional distinction between categories (e.g., immunogenicity). However, there is no scientific evidence to support this. Dialog between the WHO INN Expert Group and key stakeholders is needed to develop a new INN system for antibodies and to avoid confusion and miscommunication between researchers and clinicians prescribing antibodies.

Pain coping strategies play a role in the persistence of pain in post-herpetic neuralgia.

Post-herpetic neuralgia (PHN) is a neuropathic pain state that is often difficult to treat. Although frequently discussed in the clinical literature, little is known about the impact of pain on daily function and the extent to which psychosocial factors, in particular pain coping strategies, influence adaptation to this chronic illness. In the context of a crossover pharmacological trial, 68 patients with PHN completed a battery of psychological measures during a first drug-free baseline period. Following discontinuation of approximately 8 weeks of treatment, 49 of these patients completed data collection during a second drug-free assessment prior to beginning a second drug phase. Twice-weekly telephone pain ratings were combined with questionnaire measures of perceived interference due to pain, overall activity level, depressive symptoms, and pain coping strategies. Cross-sectional hierarchical regression analyses indicated that catastrophizing correlated with depressive symptoms but not pain, and coping self-statements were correlated with higher levels of overall activity. Prospective hierarchical regression analyses indicated that catastrophizing at baseline predicted level of pain 8 weeks later, an effect that was independent of baseline pain and depressive symptoms. Patients who reported increasing their activity in response to pain also reported more perceived interference due to pain 8 weeks later. Higher levels of ignoring pain sensations at baseline were prospectively correlated with more depressive symptoms 8 weeks later. These findings support a role for the continued investigation of cognitive-behavioral factors affecting the adaptation of elderly individuals experiencing PHN.

Pain coping strategies predict perceived control over pain.

Perceptions of control over pain and specific pain coping strategies are associated with a number of positive outcomes in patients with chronic pain conditions. Transactional models of stress have emphasized coping as a process that is both determined by, and influences appraisals of control. While perceptions of control and coping efforts are associated with better adjustment, little is known about the specific coping strategies that contribute to perceptions that pain is controllable. One hundred and ninety-five (65% female) individuals with chronic pain conditions admitted to an inpatient unit completed the Multidimensional Pain Inventory, the Survey of Pain Attitudes and the Coping Strategies Questionnaire. Stepwise multiple regression analyses were used to predict perceived pain control from measures of pain severity and coping. After controlling for pain severity and education, coping self-statements and reinterpreting pain sensations predicted greater perceptions of control over pain, whereas ignoring pain sensations predicted lower perceptions of control over pain. The coping strategies did not interact with pain severity in predicting perceptions of control. Coping flexibility, or the number of pain coping strategies reported at a high frequency, also predicted perceptions of control over pain and did not interact with pain severity. The present findings suggest that, regardless of pain severity, the use of specific cognitive pain coping strategies may increase perceptions of control over pain. Since the existing coping literature largely identifies maladaptive pain coping strategies, it is especially critical to establish which pain coping strategies are adaptive. Specific cognitive strategies, particularly coping self statements, are important components for cognitive-behavioral interventions for chronic pain management. Future research will need to determine whether other adaptive cognitive strategies such as reinterpreting pain sensations can be increased with cognitive interventions, since this strategy is infrequently used.

The effect of recombinant IgG antibodies against the leucine-33 form of the platelet beta3 integrin (HPA-1a) on platelet function.

Recombinant HPA-1a antibodies with Fc, mutated to remove destructive effector functions, have been developed as a potential therapy for fetomaternal alloimmune thrombocytopenia (FMAIT), via blockade of binding of human HPA-1a polyclonal antibodies to fetal HPA-1a1b platelets. We have assessed the effect of the IgG1 HPA-1a antibody B2G1 and two mutated derivatives in various functional assays in resting and agonist-stimulated platelets of the three HPA-1 genotypes. With HPA-1a1b platelets (fetal genotype), the antibodies did not activate signalling or CD62P expression in resting platelets, did not change in vitro bleeding time (IVBT), and did not inhibit platelet adhesion to collagen in flowing blood. Adhesion of HPA-1a1b platelets to fibrinogen was reduced by 20%, and aggregation induced by ADP by 50%, but collagen-related peptide (CRP-XL)-induced aggregation was normal. With HPA-1a1a platelets, aggregation to both ADP and CRP-XL was inhibited, with total blockade of adhesion to fibrinogen and of IVBT responses. Interestingly, a monovalent antibody fragment with identical specificity had no inhibitory effect on aggregation. In static adhesion assays using human alphaIIbbeta3 or alphaVbeta3 transfectants of HPA-1a (Leu(33)) phenotype, attachment to fibrinogen of the latter but not of the former was completely blocked by the HPA-1a antibodies. These observations are best explained by antibody-mediated blockade of the RGD binding site on beta3 by a mechanism of steric hindrance. As the effect on platelet function is modest with HPA-1a1b (fetal type) platelets, the mutated HPA-1a antibodies described here could be developed further for FMAIT therapy.