Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection.

A prophylactic HIV vaccine would ideally induce protective immunity prior to sexual debut. Children develop broadly neutralizing antibody (bnAb) responses faster and at higher frequencies than adults, but little is known about the underlying mechanisms or the potential role of Fc-mediated effector functions in disease progression. We therefore performed systems immunology, with immunoglobulin profiling, on HIV-infected children with progressive and nonprogressive disease. Pediatric nonprogressors (PNPs) showed distinct immunoglobulin profiles with an increased ability to elicit potent Fc-mediated natural killer (NK)-cell effector functions. In contrast to previous reports in adults, both groups of children showed high levels of gp120-specific IgG Fc glycan sialylation compared to bulk IgG. Importantly, higher levels of Fc glycan sialylation were associated with increased bnAb breadth, providing the first evidence that Fc sialylation may drive affinity maturation of HIV-specific antibodies in children, a mechanism that could be exploited for vaccination strategies.IMPORTANCE To protect future generations against HIV, a vaccine will need to induce immunity by the time of sexual debut and hence requires immunization during childhood. Current strategies for a prophylactic HIV vaccine include the induction of a broadly neutralizing antibody response and the recruitment of potent effector functions of immune cells via the constant antibody Fc region. In this study, we show that nonprogressing HIV-infected children mounted antibody responses against HIV that were able to mediate potent Fc effector functions, which may contribute to the control of HIV replication. Children who had specific glycan structures on the Fc portion of antibodies against HIV were able to neutralize a broader range of HIV variants, providing evidence of a potential role of Fc glycovariation in the development of bnAbs against HIV. These findings complement our knowledge of the distinct immune landscape in early life that could be exploited in the development of vaccine strategies.

[Uveal Melanoma Cell Under Oxidative Stress - Influence of VEGF and VEGF-Inhibitors]. / Uveale Melanomzellen unter oxidativem Stress ­ Einfluss von VEGF und VEGF-Inhibitoren.

BACKGROUND: The role of oxidative stress in cancer is complex. While the pathological alterations induced by oxidative stress may be involved in the induction of tumours, in the late stages of tumour development, it can facilitate the loss of tumour cells and might even prevent metastasis. Tumour cells show metabolic alterations, often inducing an increased production of reactive oxygen species, which makes these cells particularly vulnerable to additional oxidative stress. This is an important mode of action in the use of many chemotherapeutics and in the application of ionizing radiation. Uveal melanoma is the most frequent primary tumour in the adult eye. For metastasis of this tumour, which affects about 50 % of the patients, no appropriate treatment is currently available. However, the primary tumour can efficiently be treated with ionizing radiation. A frequent side effect of this treatment is radiation retinopathy, which is treated with vascular endothelial growth factor (VEGF) antagonists. A therapy of the primary tumour with VEGF antagonists is under discussion. So far, little data is available on this subject, however, a paradoxical worsening of the situation has been found in a mouse model of uveal melanoma treated with bevacizumab. METHODS: We have investigated the effect of VEGF and of the VEGF-antagonist bevacizumab on the survival of five different melanoma cell lines under oxidative stress treatment with hydrogen peroxide. In addition, we investigated the expression of relevant proteins and the effect of bevacizumab on the proliferation of the cells as well as its effect on the angiogenic behaviour of endothelial cells, co-cultured with uveal melanoma cells. RESULTS: Our study showed that not only VEGF but also, paradoxically, the VEGF-antagonist bevacizumab is able to protect uveal melanoma cells from oxidative stress-induced cell death. Bevacizumab did not influence the proliferation of the cells and showed only limited effectiveness to reduce angiogenic structures. CONCLUSION: Considering that oxidative stress is the mode of action for ionizing radiation to induce cell death, a protective effect of bevacizumab on uveal melanoma cells against oxidative stress is worrisome and argues against the use of VEGF in uveal melanoma.

[YAG laser vitreolysis for treatment of symptomatic vitreous opacities]. / YAG-Laser-Vitreolyse zur Behandlung von störenden Glaskörpertrübungen.

YAG laser vitreolysis is an innovative procedure to treat symptomatic vitreous floaters. The treatment decision is based on taking a comprehensive patient history, thorough clinical examination, realistic expectations, and detailed patient information including risk of the procedure. Manifestation of vitreous opacities and possible subjective impairments are considerably variable. Dynamic changes over time are possible. Therefore, not all vitreous opacities are suitable for laser treatment. A classification according to histoanatomical origin can aid the treatment decision. In comparison to other ophthalmic YAG laser applications, YAG laser vitreolysis differs predominantly by its specific technical equipment requirements. In addition, treatment is more complex and time consuming, requires appropriate experience and knowledge of the surgeon, and should be carried out with utmost care and accuracy.

Unmet needs of high-risk mothers reduce success of antiretroviral treatment in HIV-infected infants.

In the era of effective prevention of mother-to-child transmission of HIV, the same psychosocioeconomic factors that predispose to mother-to-child transmission also substantially increase the likelihood of antiretroviral therapy failure in infected infants. For HIV-infected infants to benefit from early infant diagnosis and treatment initiation, into which much funding and effort is now invested, it is vital that these unmet needs of high-risk mothers are urgently attended to. From an ongoing study of early infant diagnosis and treatment following in utero transmission in KwaZulu-Natal, South Africa, we describe four cases to highlight these challenges facing transmitting mothers that contribute to treatment failure in their infants.

Long-term follow-up of lamellar macular holes and pseudoholes over at least 5 years.

PURPOSE: To assess morphological and functional changes of lamellar macular holes and pseudoholes with or without vitrectomy and membrane peeling with at least 5 years follow-up. METHODS: Retrospective study of 73 eyes with lamellar macular hole (LH, n = 28), macular pseudohole (PH, n = 31), and pseudohole with cleaved edges (cleavedPH, n = 14). Forty-six eyes were merely observed without vitreoretinal intervention (observation group), and 27 eyes underwent vitrectomy with membrane peeling (vitrectomy group). Outcome measures were best corrected visual acuity (BCVA) and morphological retinal parameters evaluated with optical coherence tomography (TD-OCT and SD-OCT). RESULTS: Mean follow-up was 8.3 years (5-12); mean age was 67 years (46-84). In the observation group, median BCVA (logMAR) at first exam was 0.2 (LH), 0.1 (PH), 0.2 (cleavedPH) and at last exam 0.3 (LH, p = 0.02), 0.2 (PH), 0.15 (cleavedPH). In the vitrectomy group, median BCVA at first exam was 0.4 (LH), 0.3 (PH), 0.25 (cleavedPH); before vitrectomy BCVA was 0.5 (LH), 0.35 (PH), 0.35 (cleavedPH); and at last exam BCVA increased to 0.3 (LH), 0.2 (PH, p < 0.05), 0.1 (cleavedPH, p < 0.05). At last exam, BCVA of LH was significantly worse compared to PH and cleavedPH. In the observation group, 6 of 29 eyes with PH or cleavedPH showed a spontaneous resolution of the epiretinal membrane with improvement of the foveal contour. Nine of 16 eyes with LH and 2/20 eyes with PH presented lamellar hole-associated epiretinal proliferation (LHEP) in SD-OCT. CONCLUSIONS: LH, PH, and cleavedPH are often stable over a very long time. LH tends to worse visual function compared to PH and cleavedPH. A spontaneous separation of epiretinal membranes in the long-term is not uncommon. Vitreoretinal intervention should be considered in cases with significant visual loss or functional and morphological progression.

[Orbital screwdriver injury in a toddler]. / Orbitale Schraubenzieherverletzung bei einem Kleinkind.

Presentation of a patient with an orbital intracranial penetrating screwdriver injury. The patient had been playing with the screwdriver at the time of the accident, he fell and the screwdriver penetrated his right orbit. Imaging revealed the position of the foreign body, which went from the medial orbital wall, extraconal and medial of the right internal carotid artery, through the sella turcica to the dorsum sellae. The patient had no intracranial hemorrhage. There was hardly any bleeding. The surgical removal of the screwdriver was carried out without complications.

[Vision Loss in Association with Silicone Oil]. / Die Visusminderung in Zusammenhang mit Silikonöltamponaden.

Silicone oil tamponades have been a key feature of vitreoretinal surgery for more than 40 years. The use of these durable vitreous substitutes has not only been limited to tractive retinal detachments, inflammatory chorioretinopathies or other complicated vitreoretinal diseases, but also to macular holes and rhegmatogenous retinal detachment. During the last 12 years, an increasing number of cases of vision loss during or after the removal of silicone oil have been reported in the literature. In up to one third of patients with uncomplicated macula-attached retinal detachment with good preoperative vision, continuing vision loss is seen. In most of these cases, thinning of the inner retinal layers can be found. The underlying pathological mechanism is unknown. A direct connection to silicone oil is likely, but has not been proven. However, the increasing number of reports raises evidence that silicone oil itself might be the reason for this phenomenon, which is not observed in gas tamponades. Vision loss during or after the removal of silicone oil is an underestimated problem. The safety and toxicity of silicone oil should be reexamined systematically. The search for novel vitreous replacements is indispensable. The use of silicone oil should be strictly evaluated and balanced against other possible tamponades in every individual case.

The role of pigment epithelial detachment in AMD with submacular hemorrhage treated with vitrectomy and subretinal co-application of rtPA and anti-VEGF.

PURPOSE: To assess the incidence of pigment epithelial detachment (PED) in age-related macular degeneration (AMD) with submacular hemorrhage (SMH) and its response to treatment with pars plana vitrectomy (ppV), subretinal co-application of recombinant tissue plasminogen activator (rtPA) and anti-VEGF, and an intravitreal gas tamponade. METHODS: Consecutive interventional case series of 132 eyes of 129 patients with neovascular AMD with SMH. All eyes underwent ppV with subretinal co-application of rtPA and bevacizumab followed by a gas tamponade. Postoperatively, two additional intravitreal anti-VEGF injections were applied monthly, followed by intravitreal anti-VEGF injections applied PRN thereafter. PEDs and SMHs were evaluated with SD-OCT pre- and postoperatively. RESULTS: Preoperatively, 88 of 132 (67%) eyes were examined by OCT, and in 81 of these eyes the RPE could be visualised. A PED was found in 74 (91%) eyes, and no PED was found in five (6%) eyes. Median height of preoperative PED was 503 µm (range 150-1242, n = 65) and reduced to 344 (n = 62) and 306 µm (n = 27) after 3 and 12 months respectively. Two eyes showed a pre-existing rip of the RPE. Postoperatively, a rip was documented in 12 of 128 (9%) eyes. Median height of SMH was 762 µm (range 217-1840), median diameter was 4.3 (1.5-15) disc diameter. A complete displacement of the SMH from the fovea was achieved in 112 of 129 (87%) eyes. Overall, median best-corrected logMAR visual acuity (BCVA) improved significantly from preoperative 1.6 (0.5-2.0, n = 132) to 1.0 (0.2-2.0) 3 (n = 132) and 12 months (n = 74) postoperatively. Excluding eyes with pre-existing macular scars (n = 22), BCVA 3 months postoperatively was 0.8. Height of PED or SMH did not correlate with postoperatively BCVA, while size of SMH showed a mild correlation (rho = 0.25, p = 0.005). CONCLUSION: PpV with subretinal co-application of rtPA and bevacizumab and an intravitreal gas tamponade effectively displaces SMH and improves BCVA. Preoperatively, PED is found in the majority of eyes. Height of PED or SMH did not correlate with postoperatively BCVA. Tears of the RPE occur as frequently as in exudative AMD without SMH.

[Extensive yellowish fundus changes in a 6-year-old child]. / Großflächige gelbliche Fundusveränderungen bei 6­jährigem Kind.

We describe a 6-year-old, symptom-free girl presenting with a best corrected visual acuity of 0.6 on both eyes. Clinically we found yellowish subretinal lesions in the macula and around the vessel arcade without signs of vasculitis or abnormal vessels in the angiography. Fundus autofluorescence was marked and SD-OCT showed subretinal hyperreflective masses. With the help of molecular genetics we could make the diagnosis of an autosomal recessive bestrophinopathy (ARB). The natural history over 22 months revealed a slight recovery of the visual acuity as well as a slight reduction of the subretinal deposits.

Paediatric non-progression following grandmother-to-child HIV transmission.

BACKGROUND: In contrast to adult HIV infection, where slow disease progression is strongly linked to immune control of HIV mediated by protective HLA class I molecules such as HLA-B*81:01, the mechanisms by which a minority of HIV-infected children maintain normal-for-age CD4 counts and remain clinically healthy appear to be HLA class I-independent and are largely unknown. To better understand these mechanisms, we here studied a HIV-infected South African female, who remained a non-progressor throughout childhood. RESULTS: Phylogenetic analysis of viral sequences in the HIV-infected family members, together with the history of grand-maternal breast-feeding, indicated that, unusually, the non-progressor child had been infected via grandmother-to-child transmission. Although HLA-B*81:01 was expressed by both grandmother and grand-daughter, autologous virus in each subject encoded an escape mutation L188F within the immunodominant HLA-B*81:01-restricted Gag-specific epitope TL9 (TPQDLNTML, Gag 180-188). Since the transmitted virus can influence paediatric and adult HIV disease progression, we investigated the impact of the L188F mutant on replicative capacity. When this variant was introduced into three distinct HIV clones in vitro, viral replicative capacity was abrogated altogether. However, a virus constructed using the gag sequence of the non-progressor child replicated as efficiently as wildtype virus. CONCLUSION: These findings suggest alternative sequences of events: the transmission of the uncompensated low fitness L188F to both children, potentially contributing to slow progression in both, consistent with previous studies indicating that disease progression in children can be influenced by the replicative capacity of the transmitted virus; or the transmission of fully compensated virus, and slow progression here principally the result of HLA-independent host-specific factors, yet to be defined.

[Ligneous conjunctivitis]. / Conjunctivitis lignosa.

CASE REPORT: We report the case of a 3-year-old female patient with therapy refractive recurrent conjunctivitis and membrane formation of the upper eyelid. After surgical removal the histological examination showed an image compatible with ligneous conjunctivitis. A manifest serum plasminogen deficiency (22 %) supported the diagnosis. TREATMENT: The treatment with corticosteroids, heparin-containing and fresh frozen plasma (FFP) eye drops, renewed surgical ablation with perioperative intravenous FFP administration and local cyclosporine A eye drops achieved a stable condition with low disease activity. CONCLUSION: The combination of these therapy approaches has been performed here for the first time and has not been described in the literature so far.