Leptin and the maintenance of elevated body weight.

Obesity represents the single most important risk factor for early disability and death in developed societies, and the incidence of obesity remains at staggering levels. CNS systems that modulate energy intake and expenditure in response to changes in body energy stores serve to maintain constant body adiposity; the adipocyte-derived hormone leptin and its receptor (LEPR) represent crucial regulators of these systems. As in the case of insulin resistance, a variety of mechanisms (including feedback inhibition, inflammation, gliosis and endoplasmic reticulum stress) have been proposed to interfere with leptin action and impede the systems that control body energy homeostasis to promote or maintain obesity, although the relative importance and contribution of each of these remain unclear. However, LEPR signalling may be increased (rather than impaired) in common obesity, suggesting that any obesity-associated defects in leptin action must result from lesions somewhere other than the initial LEPR signal. It is also possible that increased LEPR signalling could mediate some of the obesity-associated changes in hypothalamic function.

Large-Scale Variability of Inpatient Tacrolimus Therapeutic Drug Monitoring at an Academic Transplant Center: A Retrospective Study.

BACKGROUND: Inpatient tacrolimus therapeutic drug monitoring (TDM) lacks standardized guidelines. In this study, the authors analyzed variability in the preanalytical phase of the inpatient tacrolimus TDM process at their institution. METHODS: Patients receiving tacrolimus (twice-daily formulation) and tacrolimus laboratory analysis were included in the study. Times of tacrolimus administration and laboratory study collection were extracted, and time distribution plots for each step in the inpatient TDM process were generated. RESULTS: Trough levels were drawn appropriately in 25.9% of the cases. Timing between doses was consistent, with 91.9% of the following dose administrations occurring 12 ± 2 hours after the previous dose. Only 38.1% of the drug administrations occurred within 1 hour of laboratory study collection. Tacrolimus-related patient safety events were reported at a rate of 1.9 events per month while incorrect timing of TDM sample collection occurred approximately 200 times per month. Root cause analysis identified a TDM process marked by a lack of communication and coordination of drug administration and TDM sample collection. Extrapolating findings nationwide, we estimate $22 million in laboratory costs wasted annually. CONCLUSIONS: Based on this large single-center study, the authors concluded that the inpatient TDM process is prone to timing errors, thus is financially wasteful, and at its worst harmful to patients due to clinical decisions being made on the basis of unreliable data. Further work is needed on systems solutions to better align the laboratory study collection and drug administration processes.

Autoantibodies Against Bestrophin in Non-Paraneoplastic Acute Exudative Polymorphous Vitelliform Maculopathy.

Acute exudative polymorphous vitelliform maculopathy (AEPVM) has recently been identified as a paraneoplastic manifestation of various cancers. Yet, the first reported cases of AEPVM in the literature were reported in seemingly healthy individuals. It is not clear whether those individuals harbored unidentified mutations or occult cancers, or truly represented a separate subset of AEPVM. Here, we report two cases of mutation-negative, autoantibody-positive non-paraneoplastic AEPVM. We present multimodal ocular imaging to demonstrate the presentation of this subset of AEPVM. [Ophthalmic Surg Lasers Imaging Retina 2024;55:51-54.].

The Cost of Standard and Complex Pars Plana Vitrectomy for Retinal Detachment Repair Exceeds Its Reimbursement.

OBJECTIVE: To measure the total costs and reimbursements associated with standard and complex pars plana vitrectomy using time-driven activity-based costing (TDABC). DESIGN: Economic analysis at a single academic institution. SUBJECTS: Patients who underwent standard or complex pars plana vitrectomy (PPV; Current Procedural Terminology codes 67108 and 67113) at the University of Michigan in the calendar year 2021. METHODS: Process flow mapping for standard and complex PPVs was used to determine the operative components. The internal anesthesia record system was used to calculate time estimates, and financial calculations were constructed from published literature and internal sources. A TDABC analysis was used to determine the costs of standard and complex PPVs. Average reimbursement was based on Medicare rates. MAIN OUTCOME MEASURES: The primary outcomes were the total costs for standard and complex PPVs and the resulting net margin at current Medicare reimbursement levels. The secondary outcomes were the differential in surgical times, costs, and margin for standard and complex PPV. RESULTS: Over the 2021 calendar year, a total of 270 standard and 142 complex PPVs were included in the analysis. Complex PPVs were associated with significantly increased anesthesia time (52.28 minutes; P < 0.001), operating room time (51.28 minutes; P < 0.0001), surgery time (43.64 minutes; P < 0.0001), and postoperative time (25.95 minutes; P < 0.0001). The total day-of-surgery costs were $5154.59 and $7852.38 for standard and complex PPVs, respectively. Postoperative visits incurred an additional cost of $327.84 and $353.86 for standard and complex PPV, respectively. The institution-specific facility payments were $4505.50 and $4935.14 for standard and complex PPV, respectively. Standard PPV yielded a net negative margin of -$976.93, whereas complex PPV yielded a net negative margin of -$3271.10. CONCLUSIONS: This analysis demonstrated that Medicare reimbursement is inadequate in covering the costs of PPV for retinal detachment, with a particularly large negative margin for more complex cases. These findings demonstrate that additional steps may be necessary to mitigate adverse economic incentives so that patients continue to have timely access to care to achieve optimal visual outcomes after retinal detachment. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Iatrogenic Paracentral Visual Field Defect After Pars Plana Vitrectomy for Macula-On Retinal Detachment Repair.

Perfluorocarbon liquid (PFCL) is an important adjunct in pars plana vitrectomy (PPV) for complex retinal detachment (RD). Complete removal of PFCL is critical to prevent retinal inflammation and cellular toxicity, but removal is not risk-free. We report a case of a new postoperative onset paracentral visual field defect after PPV with PFCL use for treatment of a macula-on RD. We present pre- and postoperative imaging that suggests a likely perioperative iatrogenic cause. [Ophthalmic Surg Lasers Imaging Retina 2022;53:644-646.].

Synergistic activation of NF-{kappa}B by bacterial chemoattractant and TNF{alpha} is mediated by p38 MAPK-dependent RelA acetylation.

In the host immune system, leukocytes are often exposed to multiple inflammation inducers. NF-κB is of considerable importance in leukocyte function because of its ability to activate the transcription of many proinflammatory immediate-early genes. Tremendous efforts have been made toward understanding how NF-κB is activated by various inducers. However, most research on NF-κB regulation has been focused on understanding how NF-κB is activated by a single inducer. This is unlike the situation in the human immune system where multiple inflammation inducers, including both exogenous and endogenous mediators, are present concurrently. We now present evidence that the formylated peptide f-Met-Leu-Phe (fMLP), a bacterial chemoattractant, synergizes with TNFα to induce NF-κB activation and the resultant inflammatory response in vitro and in vivo. The mechanism of synergistic activation of NF-κB by bacterial fMLP and TNFα may be involved in the induction of RelA acetylation, which is regulated by p38 MAPK. Thus, this study provides direct evidence for the synergistic induction of NF-κB-dependent inflammatory responses by both exogenous and endogenous inducers. The ability of fMLP to synergize with TNFα and activate NF-κB represents a novel and potentially important mechanism through which bacterial fMLP not only attracts leukocytes but also directly contributes to inflammation by synergizing with the endogenous mediator TNFα.

An atypical protein kinase C (PKC zeta) plays a critical role in lipopolysaccharide-activated NF-kappa B in human peripheral blood monocytes and macrophages.

We have reported that the bacterial LPS induces the activation of NF-kappaB and inflammatory cytokine gene expression and that this requires the activity of small GTPase, RhoA. In this study, we show that an atypical protein kinase C isozyme, PKCzeta, associates functionally with RhoA and that PKCzeta acts as a signaling component downstream of RhoA. Stimulation of monocytes and macrophages with LPS resulted in PKCzeta activation and that inhibition of PKCzeta activity blocks both LPS-stimulated activation of NF-kappaB and IL-1beta gene expression. Our results also indicate that transforming growth factor beta-activated kinase 1 acts as a signaling component downstream of PKCzeta in cytokine gene transcription stimulated by LPS in human peripheral blood monocytes and macrophages. The specificity of this response suggests an important role for the Rho GTPase/PKCzeta/transforming growth factor beta-activated kinase 1/NF-kappaB pathway in host defense and in proinflammatory cytokine synthesis induced by bacterial LPS.

Synergistic induction of inflammation by bacterial products lipopolysaccharide and fMLP: an important microbial pathogenic mechanism.

A wide variety of stimuli have been shown to induce inflammation, but bacteria products/components are considered the major inducers during bacterial infections. We previously demonstrated that bacterial products/components such as LPS, a glycolipid component of the bacterial outer membrane, and formylated peptides (fMLP), a bacterial-derived peptide, induced proinflammatory cytokine gene expression in human peripheral blood monocytes. We now present evidence that mixtures of bacterial products/components LPS and fMLP behave synergistically in the induction of inflammation in vitro and in vivo. Furthermore, our results indicate that the TLR4 and the IKKbeta-IkappaBalpha signaling pathways are involved in the synergistic induction of inflammatory cytokines. The mechanism of synergistic activation of NF-kappaB is depended on nuclear translocation of p65 and phosphorylation of p65 at both Ser536 and Ser276 sites. These results demonstrate an important role for bacterial products/components from lysed bacteria in the pathogenesis of infectious diseases. We believe that this synergistic induction of inflammation by bacterial products LPS and fMLP represents an important pathogenic mechanism during bacterial infection, which may suggest novel therapeutic strategies or targets to minimize host injury following bacterial infection.

The innate immune system in diabetic retinopathy.

The prevalence of diabetes has been rising steadily in the past half-century, along with the burden of its associated complications, including diabetic retinopathy (DR). DR is currently the most common cause of vision loss in working-age adults in the United States. Historically, DR has been diagnosed and classified clinically based on what is visible by fundoscopy; that is vasculature alterations. However, recent technological advances have confirmed pathology of the neuroretina prior to any detectable vascular changes. These, coupled with molecular studies, and the positive impact of anti-inflammatory therapeutics in DR patients have highlighted the central involvement of the innate immune system. Reminiscent of the systemic impact of diabetes, immune dysregulation has become increasingly identified as a key element of the pathophysiology of DR by interfering with normal homeostatic systems. This review uses the growing body of literature across various model systems to demonstrate the clear involvement of all three pillars of the immune system: immune-competent cells, mediators, and the complement system. It also demonstrates how the relative contribution of each of these requires more extensive analysis, including in human tissues over the continuum of disease progression. Finally, although this review demonstrates how the complex interactions of the immune system pose many more questions than answers, the intimately connected nature of the three pillars of the immune system may also point to possible new targets to reverse or even halt reverse retinopathy.

Integrative Biology of Diabetic Retinal Disease: Lessons from Diabetic Kidney Disease.

Diabetic retinal disease (DRD) remains the most common cause of vision loss in adults of working age. Progress on the development of new therapies for DRD has been limited by the complexity of the human eye, which constrains the utility of traditional research techniques, including animal and tissue culture models-a problem shared by those in the field of kidney disease research. By contrast, significant progress in the study of diabetic kidney disease (DKD) has resulted from the successful employment of systems biology approaches. Systems biology is widely used to comprehensively understand complex human diseases through the unbiased integration of genetic, environmental, and phenotypic aspects of the disease with the functional and structural manifestations of the disease. The application of a systems biology approach to DRD may help to clarify the molecular basis of the disease and its progression. Acquiring this type of information might enable the development of personalized treatment approaches, with the goal of discovering new therapies targeted to an individual's specific DRD pathophysiology and phenotype. Furthermore, recent efforts have revealed shared and distinct pathways and molecular targets of DRD and DKD, highlighting the complex pathophysiology of these diseases and raising the possibility of therapeutics beneficial to both organs. The objective of this review is to survey the current understanding of DRD pathophysiology and to demonstrate the investigative approaches currently applied to DKD that could promote a more thorough understanding of the structure, function, and progression of DRD.

Photoreceptor metabolic reprogramming: current understanding and therapeutic implications.

Acquired and inherited retinal disorders are responsible for vision loss in an increasing proportion of individuals worldwide. Photoreceptor (PR) death is central to the vision loss individuals experience in these various retinal diseases. Unfortunately, there is a lack of treatment options to prevent PR loss, so an urgent unmet need exists for therapies that improve PR survival and ultimately, vision. The retina is one of the most energy demanding tissues in the body, and this is driven in large part by the metabolic needs of PRs. Recent studies suggest that disruption of nutrient availability and regulation of cell metabolism may be a unifying mechanism in PR death. Understanding retinal cell metabolism and how it is altered in disease has been identified as a priority area of research. The focus of this review is on the recent advances in the understanding of PR metabolism and how it is critical to reduction-oxidation (redox) balance, the outer retinal metabolic ecosystem, and retinal disease. The importance of these metabolic processes is just beginning to be realized and unraveling the metabolic and redox pathways integral to PR health may identify novel targets for neuroprotective strategies that prevent blindness in the heterogenous group of retinal disorders.

Hemorrhagic Occlusive Retinal Vasculitis Associated With Triamcinolone-Moxifloxacin Use During Uncomplicated Cataract Surgery.

This case series describes the outcomes of cataract extraction with intraocular lens placement in 2 patients.