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BACKGROUND Treatment options for severe ocular von Hippel-Lindau (VHL) disease are limited. This trial evaluated preliminary safety and potential efficacy of combination intravitreous injection with ranibizumab, a vascular endothelial growth factor (VEGF) inhibitor, and E10030, a PDGF inhibitor, for eyes with VHL disease-associated retinal hemangioblastoma (RH) not amenable or responsive to thermal laser photocoagulation. METHODS This was a prospective, single-arm, open-label phase 1/2 study, comprised of three adults with VHL-associated RH and vision loss. Intravitreous injections of ranibizumab (0.5 mg) and E10030 (1.5 mg) were given unilaterally every 4 weeks in the study eye through 16 weeks, then every 8 weeks through 48 weeks. Supplementary standard care therapies were allowed without restriction after 40 weeks. The primary outcome was the ocular and systemic adverse effect profile at 52 weeks. Secondary outcomes included changes in best-corrected visual acuity (BCVA), RH size, exudation, epiretinal proliferation and retinal traction, and need for ablative treatment of RH or ocular surgery at week 52. RESULTS Three participants each received nine injections prior to week 52 and were followed for 104 weeks. One participant manifested mild episodic ocular hypertension in the study eye. Change in BCVA in the study eye at week 52 for the three participants was -5, -12 and +2 letters. No reduction in RH size was measured at 52 weeks. Variable mild improvements in exudation in two participants at week 16 were not sustained through week 52. CONCLUSIONS Combination intravitreous injection with ranibizumab and E10030 demonstrated a reasonable preliminary safety profile, but limited treatment effect.

Retinitis pigmentosa (RP), a disease characterized by the progressive degeneration of mutation-bearing photoreceptors, is a significant cause of incurable blindness in the young worldwide. Recent studies have found that activated retinal microglia contribute to photoreceptor demise via phagocytosis and proinflammatory factor production, however mechanisms regulating these contributions are not well-defined. In this study, we investigate the role of CX3CR1, a microglia-specific receptor, in regulating microglia-mediated degeneration using the well-established rd10 mouse model of RP. We found that in CX3CR1-deficient (CX3CR1(GFP/GFP) ) rd10 mice microglial infiltration into the photoreceptor layer was significantly augmented and associated with accelerated photoreceptor apoptosis and atrophy compared with CX3CR1-sufficient (CX3CR1(GFP/+) ) rd10 littermates. CX3CR1-deficient microglia demonstrated increased phagocytosis as evidenced by (1) having increased numbers of phagosomes in vivo, (2) an increased rate of phagocytosis of fluorescent beads and photoreceptor cellular debris in vitro, and (3) increased photoreceptor phagocytosis dynamics on live cell imaging in retinal explants, indicating that CX3CR1 signaling in microglia regulates the phagocytic clearance of at-risk photoreceptors. We also found that CX3CR1 deficiency in retinal microglia was associated with increased expression of inflammatory cytokines and microglial activation markers. Significantly, increasing CX3CL1-CX3CR1 signaling in the rd10 retina via exogenous intravitreal delivery of recombinant CX3CL1 was effective in (1) decreasing microglial infiltration, phagocytosis and activation, and (2) improving structural and functional features of photoreceptor degeneration. These results indicate that CX3CL1-CX3CR1 signaling is a molecular mechanism capable of modulating microglial-mediated degeneration and represents a potential molecular target in therapeutic approaches to RP. GLIA 2016;64:1479-1491.

Summary Microglia, the primary resident immune cells of the central nervous system (CNS), exhibit dynamic behavior involving rapid process motility and cellular migration that is thought to underlie key functions of immune surveillance and tissue repair. Although age-related changes in microglial activation have been implicated in the pathogenesis of neurodegenerative diseases of aging, how dynamic behavior in microglia is influenced by aging is not fully understood. In this study, we employed live imaging of retinal microglia in situ to compare microglial morphology and behavioral dynamics in young and aged animals. We found that aged microglia in the resting state have significantly smaller and less branched dendritic arbors, and also slower process motilities, which probably compromise their ability to survey and interact with their environment continuously. We also found that dynamic microglial responses to injury were age-dependent. While young microglia responded to extracellular ATP, an injury-associated signal, by increasing their motility and becoming more ramified, aged microglia exhibited a contrary response, becoming less dynamic and ramified. In response to laser-induced focal tissue injury, aged microglia demonstrated slower acute responses with lower rates of process motility and cellular migration compared with young microglia. Interestingly, the longer term response of disaggregation from the injury site was retarded in aged microglia, indicating that senescent microglial responses, while slower to initiate, are more sustained. Together, these altered features of microglial behavior at rest and following injury reveal an age-dependent dysregulation of immune response in the CNS that may illuminate microglial contributions to age-related neuroinflammatory degeneration.

Melatonin inhibited the proliferation of hormone-independent LNCaP prostate cancer cells partly via MT1 receptor activation both in vitro and in nude mice xenograft model. In this study, the melatonin receptor expression in the prostate cancer tissue of a patient with bone metastases and the effect of melatonin on the biochemical progression of hormone-refractory prostate tumor which later developed in the same patient were reported. Saturation and competition 2-[125I]iodomelatonin binding assays were conducted on prostate tumor tissue obtained by transurethral resection of the prostate from the index patient. The receptor subtype identity of melatonin receptor expressed in the cancer tissue was determined by comparison of the rank order of inhibition constants (Ki) of various melatonergic ligands and the affinity of 4-phenyl-2-propionamidotetraline relative to melatonin in inhibiting 2-[125I]iodomelatonin binding to the tumor sample and to human cell lines stably transfected with MT1 or MT2 melatonin receptor subtype. MT1 receptor expression in the cancer tissue was also examined by immunohistochemistry. The surgically castrated patient later developed biochemical relapse of his disease. His serum total prostate-specific antigen (PSA) level was monitored before and during treatment with 5 mg/day oral melatonin at 20:00 hr. High-affinity (Kd = 103.7 pm) MT1 melatonin receptor subtype was expressed by the patient's prostate cancer. As indicated by his PSA levels, melatonin induced stabilization of his hormone-refractory disease for 6 wk. This report validates melatonin's oncostatic action on prostate cancer and the potential involvement of MT1 receptor subtype in the attendant antiproliferative signal transduction as suggested by recent preclinical laboratory findings in a human.

OBJECTIVES: To compare tuberculosis (TB) in older and younger patients. DESIGN: A retrospective and comparative observational study. SETTING: Four chest clinics and two chest hospitals in Hong Kong. PARTICIPANTS: All notifications from the participating hospitals and clinics in 1996 were extracted from the TB notification registry. The characteristics of patients aged 65 and older were compared with a one-in-three random sampling of those aged 16 to 64. MEASUREMENTS: Demographic, clinical, radiological, and laboratory data of the two groups were compared alongside treatment and outcomes. RESULTS: Older people with TB were more likely to be male, to smoke, to have had TB previously, to have coexisting medical diseases, to be socioeconomically disadvantaged, and to weigh less than younger people with TB. Dyspnea, weight loss, and malaise were more common, whereas extrathoracic lymph node enlargement was less common. Chest radiograph showed more extensive disease and lower zone involvement. Positive tuberculin test was present in only 61.9%. Sputum bacteriology was more likely to be positive. There was a longer delay in presentation and commencement of treatment, and 77.2% required at least one admission. Adverse effects of treatment, notably hepatic dysfunction, occurred more commonly. Fluoroquinolones appeared well tolerated. Only 72.5% of the older people were cured or completed their treatment. Mortality was 16%. Age of 65 and older, comorbidity, socioeconomic disadvantage, moderate-extensive disease, positive sputum smear, and poor adherence were factors independently associated with unfavorable outcomes (P < .001 to P = .01; odds ratios = 1.61–27.02). CONCLUSION: Substantial differences were found between older and younger TB patients. Many of these were associated with unfavorable outcome. Increased awareness in disease recognition and better medical and social support are therefore needed in addressing the growing problem of TB in older people.

Editor, Retinal inflammatory vasculopathy can be a sight-threatening manifestation of systemic inflammatory disease. Despite extensive investigation, the etiology of inflammatory retinal vasculopathy in many cases remains elusive. In the absence of a medical history suggestive of systemic disease, the utility of systemic evaluation can have a low diagnostic yield.(George et al., 1996). The use of whole-body gallium-67 scintigraphy, however, may shed light on the etiology of inflammatory retinal vasculopathy in such cases. We report the findings of four consecutive patients who presented over a two year period with retinal inflammatory vasculopathy without any signs or symptoms of systemic disease. Three patients were African-American and one was Caucasian, with an age range of 42–59 years. All patients exhibited inflammatory changes of the retina including periphlebitis, peripheral nonperfusion, aneurysmal changes, macular edema, and neovascularization. Anterior uveitis was absent in all cases, but unilateral mild vitritis associated with papillitis was seen in one patient. Serum angiotensin converting enzyme (ACE) levels were normal in all patients. Radiological examinations to detect pulmonary disease including chest x-ray, high-resolution chest CT, and whole-body gallium-67 scanning were negative. All patients tested negative for anti-Ro and anti-La antibodies, which excluded the diagnosis of Sjogren syndrome. Syphilis testing (FTA-ABS) was also negative. Three patients had negative reaction to purified protein derivative (PPD) skin testing, while one patient had a remote history of a positive PPD test that had been treated with isoniazid (INH). Investigations for hypercoagulability, sickle cell disease, and connective tissue disease were negative. Gallium-67 scintigraphy, however, showed in all 4 cases characteristic bilateral increased uptake in the lacrimal glands that in 2 out of 4 cases was associated with concurrent parotid gland involvement. The retinal vascular findings in our series of patients have been previously described in patients with sarcoidosis,(Rothova and Lardenoye, 1998; Steahly, 1988; Verougstraete et al., 2001) and are considered suggestive of ocular sarcoidosis. However, the patients in our series did not have elevated ACE levels or pulmonary involvement on chest imaging typically associated with systemic sarcoidosis. They did, however, have extrapulmonary gallium-67 uptake in the lacrimal glands with additional involvement of the parotid glands in 2 cases. The lacrimal glands are the most common extrapulmonary site of gallium-67 uptake, and the most characteristic pattern of extrapulmonary gallium uptake is the “panda sign” (bilateral lacrimal and parotid gland uptake).(Sulavik et al., 1990). Increased gallium-67 uptake in the lacrimal and parotid glands is not specific for sarcoidosis but can also be seen in tuberculosis, lymphoma, and Sjogren syndrome. The bilateral involvement, African-American predominance, negative serological testing, and negative PPD skin testing or prior treatment for tuberculosis in our series made these alternate diagnoses unlikely The patients in our series were presumed to have an isolated ocular form of sarcoidosis without any systemic involvement. Three patients with periphlebitis and macular edema were treated with a periocular injection of triamcinolone, while one patient with peripheral neovascularization was treated with scatter laser photocoagulation and mycophenolate mofetil. All patients had complete resolution of their disease, supporting an inflammatory etiology for their clinical findings. The utility of gallium-67 scintigraphy in the routine investigation of sarcoidosis has not been established. However, gallium-67 scintigraphy may be useful in a select group of patients with retinal vasculopathy suggestive of sarcoidosis with a normal systemic work-up including serum ACE and chest imaging. The finding of lacrimal gland involvement with or without salivary gland involvement may suggest the diagnosis of an isolated ocular form of sarcoidosis in these cases. Diagnosis of sarcoidosis ultimately requires histological confirmation. Biopsy of the lacrimal and/or salivary glands, guided by the results of gallium-67 scintigraphy, may be warranted in cases like those presented in this report.