The parabrachial to central amygdala pathway is critical to injury-induced pain sensitization in mice.

The spino-ponto-amygdaloid pathway is a major ascending circuit relaying nociceptive information from the spinal cord to the brain. Potentiation of excitatory synaptic transmission in the parabrachial nucleus (PBN) to central amygdala (CeA) pathway has been reported in rodent models of persistent pain. However, the functional significance of this pathway in the modulation of the somatosensory component of pain was recently challenged by studies showing that spinal nociceptive neurons do not target CeA-projecting PBN cells and that manipulations of this pathway have no effect on reflexive-defensive somatosensory responses to peripheral noxious stimulation. Here, we showed that activation of CeA-projecting PBN neurons is critical to increase both stimulus-evoked and spontaneous nociceptive responses following an injury in male and female mice. Using optogenetic-assisted circuit mapping, we confirmed a functional excitatory projection from PBN→CeA that is independent of the genetic or firing identity of CeA cells. We then showed that peripheral noxious stimulation increased the expression of the neuronal activity marker Fos in CeA-projecting PBN neurons and that chemogenetic inactivation of these cells decreased behavioral hypersensitivity in models of neuropathic and inflammatory pain without affecting baseline nociception. Lastly, we showed that chemogenetic activation of CeA-projecting PBN neurons is sufficient to induced bilateral hypersensitivity without injury. Together, our results indicate that the PBN→CeA pathway is a key modulator of pain-related behaviors that can increase reflexive-defensive and affective-motivational responses to somatosensory stimulation in injured states without affecting nociception under normal physiological conditions.

The parabrachial to central amygdala circuit is a key mediator of injury-induced pain sensitization.

The spino-ponto-amygdaloid pathway is a major ascending circuit relaying nociceptive information from the spinal cord to the brain. Potentiation of excitatory synaptic transmission in the parabrachial nucleus (PbN) to central amygdala (CeA) pathway has been reported in rodent models of persistent pain. At the behavioral level, the PbN→CeA pathway has been proposed to serve as a general alarm system to potential threats that modulates pain-related escape behaviors, threat memory, aversion, and affective-motivational (but not somatosensory) responses to painful stimuli. Increased sensitivity to previously innocuous somatosensory stimulation is a hallmark of chronic pain. Whether the PbN→CeA circuit contributes to heightened peripheral sensitivity following an injury, however, remains unknown. Here, we demonstrate that activation of CeA-projecting PbN neurons contributes to injury-induced behavioral hypersensitivity but not baseline nociception in male and female mice. Using optogenetic assisted circuit mapping, we confirmed a functional excitatory projection from PbN→CeA that is independent of the genetic or firing identity of CeA cells. We then showed that peripheral noxious stimulation increases the expression of the neuronal activity marker c-Fos in CeA-projecting PbN neurons and chemogenetic inactivation of these cells reduces behavioral hypersensitivity in models of neuropathic and inflammatory pain without affecting baseline nociception. Lastly, we show that chemogenetic activation of CeA-projecting PbN neurons is sufficient to induce bilateral hypersensitivity without injury. Together, our results demonstrate that the PbN→CeA pathway is a key modulator of pain-related behaviors that can amplify responses to somatosensory stimulation in pathological states without affecting nociception under normal physiological conditions. Significance Statement: Early studies identified the spino-ponto-amygdaloid pathway as a major ascending circuit conveying nociceptive inputs from the spinal cord to the brain. The functional significance of this circuit to injury-induced hypersensitivity, however, remains unknown. Here, we addressed this gap in knowledge using viral-mediated anatomical tracers, ex-vivo electrophysiology and chemogenetic intersectional approaches in rodent models of persistent pain. We found that activation of this pathway contributes to injury-induced hypersensitivity, directly demonstrating a critical function of the PbN→CeA circuit in pain modulation.

22q11 MICRODELETION (DIGEORGE) SYNDROME WITH MICROVASCULAR MACULOPATHY.

PURPOSE: To describe a novel retinal finding of 22q11 microdeletion syndrome. METHODS: Retrospective chart review of a single patient. RESULTS: A 32-year-old man with genetically confirmed 22q11.2 microdeletion syndrome was found to have bilateral tortuous retinal vessels and right microvascular microangiopathy with microaneurysms, hard exudate, and cystoid macular oedema. Other underlying causes for this including diabetic and hypertensive retinopathy were excluded. No treatment was required because he was asymptomatic, and the visual acuity remained 20/30 in that eye with over one year of follow-up. CONCLUSION: 22q11 microdeletion syndrome can be associated with microvascular microangiopathy.

A Parabrachial-to-Amygdala Circuit That Determines Hemispheric Lateralization of Somatosensory Processing.

BACKGROUND: The central amygdala (CeA) is a bilateral hub of pain and emotional processing with well-established functional lateralization. We reported that optogenetic manipulation of neural activity in the left and right CeA has opposing effects on bladder pain. METHODS: To determine the influence of calcitonin gene-related peptide (CGRP) signaling from the parabrachial nucleus on this diametrically opposed lateralization, we administered CGRP and evaluated the activity of CeA neurons in acute brain slices as well as the behavioral signs of bladder pain in the mouse. RESULTS: We found that CGRP increased firing in both the right and left CeA neurons. Furthermore, we found that CGRP administration in the right CeA increased behavioral signs of bladder pain and decreased bladder pain-like behavior when administered in the left CeA. CONCLUSIONS: These studies reveal a parabrachial-to-amygdala circuit driven by opposing actions of CGRP that determines hemispheric lateralization of visceral pain.

An inhibitory circuit from central amygdala to zona incerta drives pain-related behaviors in mice.

Central amygdala neurons expressing protein kinase C-delta (CeA-PKCδ) are sensitized following nerve injury and promote pain-related responses in mice. The neural circuits underlying modulation of pain-related behaviors by CeA-PKCδ neurons, however, remain unknown. In this study, we identified a neural circuit that originates in CeA-PKCδ neurons and terminates in the ventral region of the zona incerta (ZI), a subthalamic structure previously linked to pain processing. Behavioral experiments show that chemogenetic inhibition of GABAergic ZI neurons induced bilateral hypersensitivity in uninjured mice and contralateral hypersensitivity after nerve injury. In contrast, chemogenetic activation of GABAergic ZI neurons reversed nerve injury-induced hypersensitivity. Optogenetic manipulations of CeA-PKCδ axonal terminals in the ZI further showed that inhibition of this pathway reduces nerve injury-induced hypersensitivity whereas activation of the pathway produces hypersensitivity in the uninjured paws. Altogether, our results identify a novel nociceptive inhibitory efferent pathway from CeA-PKCδ neurons to the ZI that bidirectionally modulates pain-related behaviors in mice.

Nutritional supplementation in the prevention and treatment of glaucoma.

Glaucoma is a chronic optic neuropathy that creates a significant burden on public health. Oxidative stress is hypothesized to play a role to glaucoma progression, and its reduction is being analyzed as a therapeutic target. Dietary antioxidants play a crucial role in helping provide insight into this hypothesis. We reviewed 71 trials, interventional, in-vivo and Iin vitro, including 11 randomized controlled trials, to determine if adjunctive nutritional supplementation could lead to a reduction in oxidative stress and prevent glaucomatous progression. Many laboratory findings show that vitamins and natural compounds contain an abundance of intrinsic antioxidative, neuroprotective and vasoprotective properties that show promise in the treatment and prevention of glaucoma. Although there is encouraging early evidence, most clinical findings are inconclusive. The group of B vitamins appear to have the greatest amount of evidence. Other compounds such as flavonoids, carotenoids, curcumin, saffron, CoQ10, gingko biloba, and resveratrol however warrant further investigation in glaucoma patients. Studies of these antioxidants and other nutrients could create adjunctive or alternative preventative and treatment modalities for glaucoma to those currently available.

Missing Internal Limiting Membrane during Macular Hole Repair in Alport Syndrome.

The aim of this manuscript is to describe a novel retinal finding of Alport syndrome during surgical management of an associated macular hole. A retrospective chart review of a 65-year-old man with a diagnosis of Alport syndrome confirmed by renal biopsy was found to have an associated full-thickness macular hole. Pars-plana vitrectomy surgery with internal limiting membrane (ILM) peeling was attempted, but intraoperatively the ILM was found to be absent at the macula. Alport syndrome may be associated with the absence of the ILM. This can complicate attempts at macular hole repair.

Cytomegalovirus retinitis following dexamethasone intravitreal implant.

PURPOSE: To describe a case of Cytomegalovirus (CMV) Retinitis in an immunocompetent patient following Dexamethasone Intravitreal Implant (DII). OBSERVATIONS: Retrospective chart review of a single patient. An 80-year-old immunocompetent male presented with floaters in his left eye 10 weeks after his DII. He was noted to have a visual acuity of 20/1200 in his left eye and a panuveitis with CMV retinitis. The patient underwent a vitreous biopsy and given immediate intravitreal foscarnet and an ongoing management regimen of oral valganciclovir for two months. His vision improved to 20/200 and his CMV retinitis resolved. CONCLUSION AND IMPORTANCE: DII can trigger CMV retinitis in immunocompetent patients.

Reduction in Ophthalmic Presentations to Australian Emergency Departments During the COVID-19 Period: Are We Seeing the Full Picture?

PURPOSE: To examine changing patterns of ophthalmic presentations to emergency departments (EDs) during the lockdowns associated with the first wave of the COVID-19 pandemic in Australia and the two months immediately following lockdown relaxation. PATIENTS AND METHODS: This was a retrospective audit of triage coding and ICD-10-AM coding for all patient presentations to four Australian EDs from March 29 to May 31 in 2019 and 2020 (the COVID-19 lockdown period and the corresponding period in 2019), and from June 1 to July 31 in 2019 and 2020 (the post-lockdown period and the corresponding period in 2019). Number of ophthalmic presentations triaged per day and number of seven common and/or time-sensitive, vision threatening ophthalmic diagnoses were examined. Differences in mean daily presentation numbers were assessed with non-paired Student's t-test with Bonferroni correction. RESULTS: Total ophthalmic presentations per day during COVID-19 lockdowns fell by 16% compared to the corresponding period in 2019 (13.0 ± 4.0 in 2019 vs 10.8 ± 3.3 in 2020, mean ± standard deviation; p=0.01). There was also a significant decrease in presentations of atraumatic retinal detachment, conjunctivitis, and eye pain. In the two months following easing of lockdown restrictions, total ophthalmic presentations per day returned to the same level as that of the corresponding period in 2019 (12.2 ± 4.3 in 2019 vs 12.3 ± 4.1 in 2020, p=0.97). CONCLUSION: Total ophthalmic presentations and presentations of atraumatic retinal detachment, conjunctivitis and, eye pain to EDs fell during the lockdowns associated with the first wave of COVID-19 in Australia. These may represent delays in patients seeking appropriate medical attention and may have implications on patient morbidity long after the COVID-19 pandemic.

Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis.

Antibodies against neuronal receptors and synaptic proteins are associated with a group of ill-defined central nervous system (CNS) autoimmune diseases termed autoimmune encephalitides (AE), which are characterized by abrupt onset of seizures and/or movement and psychiatric symptoms. Basal ganglia encephalitis (BGE), representing a subset of AE syndromes, is triggered in children by repeated group A Streptococcus (GAS) infections that lead to neuropsychiatric symptoms. We have previously shown that multiple GAS infections of mice induce migration of Th17 lymphocytes from the nose into the brain, causing blood-brain barrier (BBB) breakdown, extravasation of autoantibodies into the CNS, and loss of excitatory synapses within the olfactory bulb (OB). Whether these pathologies induce functional olfactory deficits, and the mechanistic role of Th17 lymphocytes, is unknown. Here, we demonstrate that, whereas loss of excitatory synapses in the OB is transient after multiple GAS infections, functional deficits in odor processing persist. Moreover, mice lacking Th17 lymphocytes have reduced BBB leakage, microglial activation, and antibody infiltration into the CNS, and have their olfactory function partially restored. Th17 lymphocytes are therefore critical for selective CNS entry of autoantibodies, microglial activation, and neural circuit impairment during postinfectious BGE.

Bilateral acute anterior uveitis: a rare ocular side effect of erlotinib.

Erlotinib used in the treatment of advanced non-small cell lung cancer (NSCLC) is a first-generation small-molecule tyrosine kinase inhibitor which reversibly inhibits the kinase domain of epithelial growth factor receptor (EGFR). The incidence of ocular toxicities as adverse effects (AE) of erlotinib is relatively common. However, post-marketing, acute anterior uveitis (AAU) has been reported in a small number of cases as a putative AE resulting from erlotinib therapy. We present a case of a 67-year-old, Caucasian woman, lifelong non-smoker with stage IV NSCLC who presents with decreased visual acuity and 'floaters' 6 weeks after commencing erlotinib. She was later diagnosed with erlotinib-associated bilateral AAU. This is the fifth documented case of erlotinib-associated bilateral AAU since 2010, highlighting the rarity of this AE. Thus, the possibility of AAU should always be considered in patients on EGFR-blocking therapies as significant ocular damage can occur if ophthalmic complaints are not triaged and assessed quickly.

Evaluation of a cystic fibrosis transition program from pediatric to adult care.

PURPOSE: As the cystic fibrosis (CF) patient population median survival increase, the need for transitioning their care to adult care centers increase as well. We have a structured transition program since the early 1980s. The purpose of this study is to evaluate the experiences and opinions of patients in our adult CF center who went through a formal transition versus those who did not, in an attempt to evaluate the overall process and to identify means for improvement. METHODS: A questionnaire was given to adult CF patients at the University of Michigan during a clinic visit or inpatient hospitalization, after consent was obtained. Inclusion criteria included diagnosis of CF in childhood, previous care in a pediatric center, and current participation in our adult CF clinic. RESULTS: A total of 91 patients completed the questionnaire. 44 went through our structured transition program. On average, patients who participated in a formal transition process had higher satisfaction with both CF programs, perceived health status, and independence but no differences in their level of anxiety about transferring to the adult program. Patient opinions regarding when to transfer care were considered more often in patients who participated in a transition program (88% vs. 62% and P = 0.02). CONCLUSION: Although structured transitions programs do not appear to decrease patient anxiety during this stressful period, it does appear to improve patient satisfaction, perceived health status, and independence. These findings suggest that establishing a transition program could be important in optimizing patient health, continuity of care and improving adherence.

Role of immunoflourescence in the diagnosis of glomerulonephritis.

OBJECTIVE: To correlate the findings of immunoflorescence (IF) with morphology in renal biopsies of patients with glomerulonephritis (GN) of both primary and secondary nature. METHODS: The cross-sectional analytical study was conducted at the Shifa International Hospital's Department of Pathology form March 2007 to August 2008, during which a total of 207 renal biopsies were done. Of them, the study included 92 cases which were diagnosed as primary or secondary glomerulonephritis under light microscope. Those cases were selected in which both light microscopy (LM) and immunoflorescence were done. RESULTS: Of the 92 patients, 79 (85.8%) were adults (> or = 19 years) and 13 (14%) were children (< 19 years). The mean age of adults was 36.44 +/- 11.55 (range 19-69 years) and that of the children was 10.54 +/- 3.85 years (range 4-18 years). immunoflorescence changed the morphologic diagnosis in 20 (21.73%) cases. The pattern of disease was: membranous glomerulonephritis in 24%, focal segmental glomerulosclerosis (FSGS) in 18.4%, mesangiocapillary glomerulonephritis in 2%, and minimal change disease (MCD) in 16% of the cases. CONCLUSION: Light microscopy alone can misdiagnose renal disease. This is especially important in cases of early stage membranous, IgA nephropathy (IgAN), Lupus nephritis and IgM nephropathy (IgMN), as these entities can only be diagnosed by correlating the microscopic, immunoflorescence findings and clinical details.

Identifying barriers to treatment adherence and related attitudinal patterns in adolescents with cystic fibrosis.

INTRODUCTION: The treatment of cystic fibrosis (CF) is directed toward correction of organ dysfunction and relief of symptoms resulting from the disease. Lack of adherence to daily treatment regimens may have substantial short-term and long-term effects on patients with CF. In this study, we attempted to identify barriers to treatment adherence which could be predicted by objective measures and explore ways to improve adherence in adolescents with CF. METHODS: A questionnaire was given to patients 12.0-20.9 years of age, designed with focus on specific barriers to adhering to treatment plan and related attitudinal patterns. Observational and analytical results were collected. RESULTS: We obtained questionnaires and objective health data for 60 respondents. The most commonly identified barriers to adherence were forgetting or losing medications (32/60) and being too busy (23/60). Attitudinal patterns that played a significant role for nonadherence included unintentional forgetting (40/60), feeling that following CF treatments resulted in less freedom in their lives (30/60), and believing it is acceptable to miss a treatment every few days (18/60) or to miss treatments when busy (18/60). DISCUSSION: There were a few statistically significant differences of adherence patterns between demographic subgroups in our study. Males were more likely to agree that it is acceptable to miss doses if they are made up with extra doses later (24% vs. 3%, P = 0.04). Patients who perceived themselves to be less healthy agreed more to statements of limited freedom, nonsympathetic medical providers, and difficulty adhering during times of decreased symptoms. This highlights an unexpected risk: as CF progresses and patients perceive themselves to be less healthy, they may become less likely to be adherent during the periods they are feeling the best, while at the same time becoming less likely to perceive empathy from their physicians. CONCLUSIONS: Survey results describe a variety of beliefs and attitudinal patterns which contribute to nonadherence in CF treatment, especially relating to time management. While patients largely understood the importance of treatments to their health, predictors of risky behaviors could lead to targeted interventions by CF centers to address these challenges and improve adherence.