Difficulties in the management of retinal capillary haemangiomas associated with von Hippel Lindau disease. / Dificultades en el manejo de los hemangiomas capilares retinianos asociados a enfermedad de von Hippel-Lindau.

CLINICAL CASE: A 29-year-old female with bilateral retinal capillary haemangiomas (RCH). A genetic analysis was carried out due to the suspicion of von Hippel-Lindau (VHL) disease, with negative results on 2occasions. There was progression of the RCH in the left eye, leading to a macular epiretinal membrane. The patient was treated with laser, intravitreal ranibizumab, and vitrectomy. Finally, a third genetic test detected a de novo mutation in the VHL gene, and led to the genetic diagnosis. DISCUSSION: VHL syndrome causes a complex ocular disease with a difficult diagnosis that requires early treatment of the RCH in order to modify its visual prognosis.

Risk of wound infection and safety profile of amoxicillin in healthy patients which required third molar surgery: a systematic review and meta-analysis.

The aim of this systematic review and meta-analysis was to assess the risk of surgical wound infection and the adverse effects of amoxicillin in healthy patients who required excision of third molars. We identified eligible reports from searches of PubMed, Medline®, the Cochrane Library, Imbiomed, LILACS, and Google Scholar. Studies that met our minimum requirements were evaluated using inclusion and exclusion criteria and the Oxford Quality Scale. Those with a score of 3 or more on this Scale were included and their data were extracted and analysed. For evaluation of the risk of infection the absolute risk reduction, number needed to treat, and 95% CI were calculated. For evaluation of the risk of an adverse effect the absolute risk increase, number needed to harm, and 95% CI were calculated using the Risk Reduction Calculator. Each meta-analysis was made with the help of the Mantel-Haenszel random effects model, and estimates of risk (OR) and 95% CI were calculated using the Review Manager 5.3, from the Cochrane Library. A significant risk was assumed when the lower limit of the 95% CI was greater than 1. Probabilities of less than 0.05 were accepted as significant. The results showed that there was no reduction in the risk of infection when amoxicillin was given before or after operation compared with an untreated group or placebo. In conclusion, this study suggests that amoxicillin given prophylactically or postoperatively does not reduce the risk of infection in healthy patients having their third molars extracted.

[Fungal keratitis caused by Colletotrichum spp. A presentation of case]. / Queratitis fúngica por Colletotrichum spp. A propósito de un caso.

CASE REPORT: A 23 years old male with an unremarkable past medical history suffered an injury with a branch of a lemon tree in the right eye two days prior to presentation. The slit-lamp examination showed a central corneal erosion with a white tree-shaped stromal infiltrate and Tyndall +/++ in anterior chamber. Cultivation of corneal scraping was positive for Colletotrichum spp. The patient responded favourably to topical amphotericin. DISCUSSION: Colletotrichum spp. is an uncommon cause of keratitis, usually secondary to corneal erosion caused by plant material and should be included in the differential diagnosis of fungal keratitis.

Bilateral Internuclear Ophthalmoplegia in a Patient with Devic's Neuromyelitis Optica.

An unusual presentation of Devic's neuromyelitis optica (NMO) disease associated with bilateral internuclear ophthalmoplegia (INO) is described. A 32-year-old pregnant patient was diagnosed with NMO. First symptoms were headache and sudden visual loss in her right eye (RE). Eighteen months ago, she reported other neurologic symptoms such as paresthesia. Based on her visual field, fundoscopy and Ishihara test, she was diagnosed with retrobulbar neuritis of the RE. After delivery, new neurologic symptoms resembling transverse myelitis appeared. She was treated with methylprednisolone and plasmapheresis, which improved her visual acuity; however, a sudden bilateral INO appeared, with adduction defect and nystagmus with abduction in both eyes. No improvement was obtained after treatment with azathioprine and rituximab. Paresis of the legs and the right arm persisted, but double vision and OIN gradually disappeared. At the end, the patient had a residual exophoria in the RE and nystagmus with abduction in the left eye. Prevalence of NMO is lower than one case per one million inhabitants, and it is not likely to affect the encephalic trunk; furthermore, bilateral INO in NMO is rare. Two major criteria and at least two of the three minor ones are required to confirm a NMO diagnosis, and our patient fulfilled these diagnosis criteria.

[Imiquimod in treatment of palpebral mycosis fungoides]. / Imiquimod como tratamiento de la micosis fungoide palpebral.

CLINICAL CASE: Our patient was a 37-year-old male with palpebral mycosis fungoides, the most common T-cell cutaneous lymphoma. He had been treated previously with topical corticosteroids. We treated him with Imiquimod cream (5%) three times a week. DISCUSSION: A clinical improvement was obtained with this drug, so we believe immuno-modulating agents need to be considered in the treatment of palpebral mycosis fungoides, especially because of its capacity of being a reflection of leukaemia.

Imiquimod como tratamiento de la micosis fungoide palpebral / Imiquimod in treatment of palpebral mycosis fungoides

Caso clínico: Presentamos el caso de un varón de37 años de edad que presentaba una micosis fungoide,el más frecuente de los linfomas T cutáneos,con localización exclusivamente palpebral quehabía sido tratado previamente con corticoides tópicos.Se instauró un tratamiento con Imiquimod al5% en crema tres veces semanales.Discusión: Con el uso de este medicamento, seconsiguió una gran mejoría clínica del paciente, porlo que consideramos muy importante tener en cuentaeste inmunomodulador para el tratamiento deesta enfermedad, de importancia por su capacidadde leucemización

Clinical case: Our patient was a 37-year-old male with palpebral mycosis fungoides, the most common T-cell cutaneous lymphoma. He had been treated previously with topical corticosteroids. We treated him with Imiquimod cream (5%) three times a week. Discussion: A clinical improvement was obtained with this drug, so we believe immuno-modulating agents need to be considered in the treatment of palpebral mycosis fungoides, especially because of its capacity of being a reflection of leukaemia

Effect of treatment with the selective oestrogen receptor modulator LY117018-HCl on pituitary sensitivity to GnRH and subsequent ovulation.

The effects of LY117018-HCl (LY; a benzothiophene similar to raloxifene) were examined on various reproductive parameters in female rats. Four-day cyclic rats were treated (10:00 h on dioestrus) with LY (0.01, 0.1, 0.5, 1, 2, 4 or 16 mg kg(-1) p.o.) and assessed for ovulation at oestrus. LY inhibited ovulation at doses as low as 0.5 mg kg(-1), and ovulation did not occur at doses of 4 and 16 mg kg(-1). LY (16 mg kg(-1)) reduced wet uterine mass and LH concentrations at the time of the expected ovulatory surge. Ovulation induced by hCG in pentobarbital-treated rats was not altered by LY treatment, indicating normal ovarian sensitivity to gonadotrophins. LY, however, completely blocked the effects of oestradiol (under either negative or positive feedback modes) on LH secretion in ovariectomized rats. GnRH secretion into hypophyseal portal blood during pro-oestrus was not affected by treatment with LY, whereas the concentrations of serum LH remained reduced. Finally, treatment with LY markedly reduced pituitary sensitivity to GnRH during pro-oestrus, as it completely blocked GnRH-induced LH secretion. These results demonstrate that LY inhibits oestradiol action in the uterus and prevents ovulation in normal cyclic rats. LY-induced inhibition of ovulation is not caused by an alteration of the ovarian response to gonadotrophins or an impairment of GnRH secretion at the hypothalamus, but by a reduction in the sensitivity of gonadotrophs to the stimulatory effects of GnRH during pro-oestrus.

[Papilledema secondary to cerebral venous sinus thrombosis]. / Papiledema secundario a trombosis cerebral de los senos venosos.

CASE REPORT: A 14 year old patient showing bilateral frontal headache during the previous four months was studied. Ophtalmoscopic examination revealed presence of bilateral papilledema. Magnetic resonance angiography showed presence of thrombosis in upper sagital and transverse sinuses. Patient was treated with oral acetazolamide (500 mg a day), one month later, headhache had disappeared and papilledema decreased. DISCUSSION: Aseptic cerebral venus thrombosis is an infrecuent condition that often is cause of neurologic complications that may become severe. Treatment should aim at decreasing intracranial pressure in order to avoid optic nerve atrophy and visual loss.

Papiledema secundario a trombosis cerebral de los senos venosos / Papilledema associated to cerebral venous sinus thrombosis

Caso clínico: Presentamos el caso de un varón de 14 años con cefalea frontal bilateral de 4 meses de evolución, siendo diagnosticado de papiledema bilateral. La angiorresonancia magnética reveló la existencia de una trombosis de los senos sagital superior y transversos. El paciente fue tratado con 500 mg/día de acetazolamida por vía oral. Un mes después de iniciar el tratamiento, la cefalea había desaparecido y el papiledema había disminuido de tamaño. Discusión: La trombosis venosa cerebral aséptica es un proceso infrecuente, que suele causar complicaciones neurológicas que pueden ser muy graves. El objetivo del tratamiento es disminuir la hipertensión intracraneal (HIC) causada por el proceso (AU)

Otx genes are required for tissue specification in the developing eye.

Patterning of the vertebrate eye appears to be controlled by the mutual regulation and the progressive restriction of the expression domains of a number of genes initially co-expressed within the eye anlage. Previous data suggest that both Otx1 and Otx2 might contribute to the establishment of the different eye territories. Here, we have analysed the ocular phenotype of mice carrying different functional copies of Otx1 and Otx2 and we show that these genes are required in a dose-dependent manner for the normal development of the eye. Thus, all Otx1(-/-); Otx2(+/-) and 30% of Otx1(+/-); Otx2(+/-) genotypes presented consistent and profound ocular malformation, including lens, pigment epithelium, neural retina and optic stalk defects. During embryonic development, optic vesicle infolding was severely altered and the expression of pigment epithelium-specific genes, such as Mitf or tyrosinase, was lost. Lack of pigment epithelium specification was associated with an expansion of the prospective neural retina and optic stalk territories, as determined by the expression of Pax6, Six3 and Pax2. Later in development the presumptive pigment epithelium region acquired features of mature neural retina, including the generation of Islet1-positive neurones. Furthermore, in Otx1(-/-); Otx2(+/-) mice neural retina cell proliferation, cell differentiation and apoptotic cell death were also severely affected. Based on these findings we propose a model in which Otx gene products are required for the determination and differentiation of the pigment epithelium, co-operating with other eye patterning genes in the determination of the specialised tissues that will constitute the mature vertebrate eye.

Sex steroids modulate luteinizing hormone-releasing hormone secretion in a cholinergic cell line from the basal forebrain.

The function of a particular neuronal population is in part determined by its neurotransmitter phenotype. We have found that a neuronal-derived septal cell line (SN56), known for its cholinergic properties, also synthesizes and releases luteinizing hormone-releasing hormone. In addition, these cells express the messenger RNAs encoding estrogen and progesterone receptors. The activation of these receptors by their respective ligands cooperatively modulates the depolarization-induced release of luteinizing hormone-releasing hormone in these cells. We have also found that a number of septal neurons in postnatal (1-week-old) mice are immunoreactive to both choline acetyltransferase and luteinizing hormone-releasing hormone. These results indicate that both neurotransmitters, acetylcholine and luteinizing hormone-releasing hormone, may co-exist in septal neurons of the CNS and that they could be modulated by gonadal hormones, and suggest that luteinizing hormone-releasing hormone could be involved in some of the actions of sex steroids on cholinergic neurotransmission.

Vitronectin regulates Sonic hedgehog activity during cerebellum development through CREB phosphorylation.

During development of the cerebellum, Sonic hedgehog (SHH) is expressed in migrating and settled Purkinje neurons and is directly responsible for proliferation of granule cell precursors in the external germinal layer. We have previously demonstrated that SHH interacts with vitronectin in the differentiation of spinal motor neurons. Here, we analysed whether similar interactions between SHH and extracellular matrix glycoproteins regulate subsequent steps of granule cell development. Laminins and their integrin receptor subunit alpha6 accumulate in the outer most external germinal layer where proliferation of granule cell precursors is maximal. Consistent with this expression pattern, laminin significantly increases SHH-induced proliferation in primary cultures of cerebellar granule cells. Vitronectin and its integrin receptor subunits alpha(v) are expressed in the inner part of the external germinal layer where granule cell precursors exit the cell cycle and commence differentiation. In cultures, vitronectin is able to overcome SHH-induced proliferation, thus allowing granule cell differentiation. Our studies indicate that the pathway in granule cell precursors responsible for the conversion of a proliferative SHH-mediated response to a differentiation signal depends on CREB. Vitronectin stimulates phosphorylation of cyclic-AMP responsive element-binding protein (CREB), and over-expression of CREB is sufficient to induce granule cell differentiation in the presence of SHH. Taken together, these data suggest that granule neuron differentiation is regulated by the vitronectin-induced phosphorylation of CREB, a critical event that terminates SHH-mediated proliferation and permits the differentiation program to proceed in these cells.

Estrogen modulates norepinephrine-induced accumulation of adenosine cyclic monophosphate in a subpopulation of immortalized luteinizing hormone-releasing hormone secreting neurons from the mouse hypothalamus.

A subpopulation of luteinizing hormone-releasing hormone (LHRH)-producing cells that express the intermediate filament protein vimentin and the neuronal marker neurofilament 145, but not neurofilament 200 nor glial fibrillary acidic protein, has been isolated from GT1-7 cultures. These cells express the mRNA encoding estrogen receptor alpha (ERalpha) and respond to physiological concentrations of 17beta-estradiol (E2) by reducing the accumulation of cyclic adenosine monophosphate induced by norepinephrine, but not that induced by direct activation of adenylate cyclase. These results indicate that the activity of LHRH-producing neurons may be directly modulated by estrogen. In addition, they are suggestive of an estrogen-dependent desensitization of the beta-adrenoceptor in these cells.

Vitronectin is expressed in the ventral region of the neural tube and promotes the differentiation of motor neurons.

The extracellular matrix protein vitronectin and its mRNA are present in the embryonic chick notochord, floor plate and in the ventral neural tube at the time position of motor neuron generation. When added to cultures of neural tube explants of developmental stage 9, vitronectin promotes the generation of motor neurons in the absence of either notochord or exogenously added Sonic hedgehog. Conversely, the neutralisation of endogenous vitronectin with antibodies inhibits over 90% motor neuron differentiation in co-cultured neural tube/notochord explants, neural tube explants cultured in the presence of Sonic hedgehog, and in committed (stage 13) neural tube explants. Furthermore, treatment of embryos with anti-vitronectin antibodies results in a substantial and specific reduction in the number of motor neurons generated in vivo. These results demonstrate that vitronectin stimulates the differentiation of motor neurons in vitro and in vivo. Since the treatment of stage 9 neural tube explants with Sonic hedgehog resulted in induction of vitronectin mRNA expression before the expression of floor plate markers, we conclude that vitronectin may act either as a downstream effector in the signalling cascade induced by Sonic hedgehog, or as a synergistic factor that increases Shh-induced motor neuron differentiation.

Control of early cell death by BDNF in the chick retina.

The developing chick retina undergoes at least two discrete periods of programmed cell death. The earlier period coincides with the main onset of neuron birth and migration (embryonic day 5-7), whereas the latter one corresponds to the well-documented process of retinal ganglion cell death following tectal innervation (embryonic day 10-14; Rager, G. H. (1980) Adv. Anat. Embryol. Cell Biol. 63, 1-92). In the early period, apoptosis is induced by nerve growth factor (NGF) acting via its p75 receptor (Frade, J. M., Rodríguez-Tébar, A. and Barde, Y.-A. (1996) Nature 383, 166-168). Here, we show that the application of brain-derived neurotrophic factor (BDNF) to chick embryos in ovo prevented retinal cell death in the early period, whereas exogenously applied NGF and neurotrophin-3 had no such effect. The addition of BDNF to embryos resulted in about 70% increase in the number of retinal ganglion cells in both E6 and E9 retinas relative to controls. BDNF is first expressed in both the pigment epithelium and neural retina of embryonic day 4 embryos, and at the same stage of development, its TrkB receptor is expressed in the neural retina. Our data indicate that early cell death is an important process in the neurogenesis of retinal ganglion cells and is regulated by locally produced BDNF.

Laminin-1 selectively stimulates neuron generation from cultured retinal neuroepithelial cells.

Signals derived from the extracellular matrix (ECM) largely influence neuron differentiation and development. However, the action of specific ECM components in these processes is poorly understood. This had led us to investigate the role of different laminins in the survival, proliferation, and neuron differentiation of cultured neuroepithelial cells from the developing chicken retina. Dissociated retinal neuroepithelial cells from 5-day-old chicken embryos, cultured on laminin-1, survived, proliferated, and differentiated into neurons, as assessed by both [3H]-thymidine uptake and acquisition of neuronal markers. Nevertheless, these effects took place only in the presence of cell-cell contact. In contrast, RN22 Schwannoma-derived laminin (devoid of alpha 1 chain) and merosin (bearing an alpha 2 chain), which also promoted proliferation when cell-cell contact occurred, led to reduced cell survival and failed to foster neuron differentiation. Furthermore, the laminin-1 P1 fragment (containing the rod-like portions of the short arms of the molecule) also failed to support neuron generation. In contrast, the laminin-1 E8 fragment (containing the long arm of the molecule) supported such a process to the same extent as the whole laminin-1 molecule, although a similar activity cannot be ruled out in other globular domains of the short arms. However, these results stress the importance of the carboxy-terminal part of alpha 1 chain in neuronal development. A cDNA fragment of a chicken alpha 1 chain was cloned and semiquantitative PCR amplification revealed that its mRNA is expressed in retinal neuroepithelial cells at the time of neuron differentiation. Our data strongly suggest that an alpha 1-like chain-containing laminin is needed for differentiation of neuron precursor cells.

Developmentally regulated vitronectin influences cell differentiation, neuron survival and process outgrowth in the developing chicken retina.

Vitronectin is a multifunctional protein involved in the regulation of the immune system and blood coagulation. Here we report that the expression of vitronectin is developmentally regulated in the embryonic retina of the chicken. Vitronectin immunoreactivity was detected in chicken retinas from embryonic day 5, encompassing the cell bodies of most neuroepithelial cells. At this developmental stage, alpha v integrin subunit expression was distributed across the retina, suggesting a ligand/receptor interaction. Expression of both vitronectin and alpha v increased during development and reached a maximum at embryonic day 9, a time when most differentiated neurons grow processes and initiate synapse formation. At this age, vitronectin immunoreactivity appeared to be located predominantly in the fiber and inner plexiform layers of the differentiated stratified retina. alpha v immunoreactivity and mRNA expression was seen associated with all layers formed by differentiated neurons, being most abundant in the ganglion cell and inner nuclear layers. Later in development, levels of vitronectin decreased and immunoreactivity appeared exclusively associated with the fiber layer. In accordance with this pattern of expression, vitronectin as a substrate sustained both proliferation and differentiation of cultured neuroepithelial cells from embryonic day 5 retinas. At later stages, vitronectin supported survival and neurite outgrowth of most differentiated neurons. Our data suggest that vitronectin is a ubiquitous component of the retinal extracellular matrix, serving as a substrate for developmental processes such as proliferation, differentiation of neuron progenitors, cell survival, and axonal and dendritic growth of differentiated neurons.