The Synergy between Palmitate and TNF-α for CCL2 Production Is Dependent on the TRIF/IRF3 Pathway: Implications for Metabolic Inflammation.

The chemokine CCL2 (also known as MCP-1) is a key regulator of monocyte infiltration into adipose tissue, which plays a central role in the pathophysiology of obesity-associated inflammation and insulin resistance. It remains unclear how CCL2 production is upregulated in obese humans and rodents. Because elevated levels of the free fatty acid (FFA) palmitate and TNF-α have been reported in obesity, we studied whether these agents interact to trigger CCL2 production. Our data show that treatment of THP-1 and primary human monocytic cells with palmitate and TNF-α led to a marked increase in CCL2 production compared with either treatment alone. Mechanistically, we found that cooperative production of CCL2 by palmitate and TNF-α did not require MyD88, but it was attenuated by blocking TLR4 or TRIF. IRF3-deficient cells did not show synergistic CCL2 production in response to palmitate/TNF-α. Moreover, IRF3 activation by polyinosinic-polycytidylic acid augmented TNF-α-induced CCL2 secretion. Interestingly, elevated NF-κB/AP-1 activity resulting from palmitate/TNF-α costimulation was attenuated by TRIF/IRF3 inhibition. Diet-induced C57BL/6 obese mice with high FFAs levels showed a strong correlation between TNF-α and CCL2 in plasma and adipose tissue and, as expected, also showed increased adipose tissue macrophage accumulation compared with lean mice. Similar results were observed in the adipose tissue samples from obese humans. Overall, our findings support a model in which elevated FFAs in obesity create a milieu for TNF-α to trigger CCL2 production via the TLR4/TRIF/IRF3 signaling cascade, representing a potential contribution of FFAs to metabolic inflammation.

Sero-prevalence of Nipah antibodies among close contacts of the index case during 2019 Ernakulam outbreak.

Introduction: Nipah virus (NiV) infection is a fatal emerging zoonotic disease. Infection with NiV has a wide range of clinical spectrum which can range from asymptomatic cases to acute respiratory distress syndrome (ARDS). The index case of NiV infection of 2019 outbreak in Ernakulam district was a 23-year-old male who presented with features of encephalitis. This study was undertaken to address the subclinical or asymptomatic NiV infection amongst the close contacts of this index case by using NiV-specific Immunoglobulin IgM and IgG antibodies. The index case was first treated in a primary care center. He survived the infection and was discharged after a period of 108 days from the tertiary care facility where he was treated eventually. Methods: Serum samples from 49 close contacts of the index case were collected and tested for anti-NiVIgM and anti-NiVIgG antibodies. The contacts included health care workers including those from the primary care facility, family members, and his friends. Results: Most common type of exposure included physical contact (59.2%), followed by exposure to body fluids (22.4%). Conclusion: None of the 49 contacts tested positive for anti-NiV human IgM and anti-NiVIgG antibodies. There were no subclinical cases amongst the close contacts of Nipah index case during the 2019 Kerala outbreak.

Mechanisms of photoreceptor death and survival in mammalian retina.

The mammalian retina, like the rest of the central nervous system, is highly stable and can maintain its structure and function for the full life of the individual, in humans for many decades. Photoreceptor dystrophies are instances of retinal instability. Many are precipitated by genetic mutations and scores of photoreceptor-lethal mutations have now been identified at the codon level. This review explores the factors which make the photoreceptor more vulnerable to small mutations of its proteins than any other cell of the body, and more vulnerable to environmental factors than any other retinal neurone. These factors include the highly specialised structure and function of the photoreceptors, their high appetite for energy, their self-protective mechanisms and the architecture of their energy supply from the choroidal circulation. Particularly important are the properties of the choroidal circulation, especially its fast flow of near-arterial blood and its inability to autoregulate. Mechanisms which make the retina stable and unstable are then reviewed in three different models of retinal degeneration, retinal detachment, photoreceptor dystrophy and light damage. A two stage model of the genesis of photoreceptor dystrophies is proposed, comprising an initial "depletion" stage caused by genetic or environmental insult and a second "late" stage during which oxygen toxicity damages and eventually destroys any photoreceptors which survive the initial depletion. It is a feature of the model that the second "late" stage of retinal dystrophies is driven by oxygen toxicity. The implications of these ideas for therapy of retinal dystrophies are discussed.

Vitreous fluorophotometry in patients with senile macular degeneration.

Twenty-two phakic eyes of 16 patients with varying stages of senile macular degeneration (SMD) underwent vitreous fluorophotometry. The upper tolerance limit of the penetration ratio in 17 eyes of 17 age-matched controls was 6.33 X 10(-6) min-1. Ten of the 22 eyes with SMD had values exceeding this, indicating abnormal blood-retinal barrier function. When the fluorescence recorded in the vitreous but not related to the local intravitreal dye was evaluated, it was greater in those eyes with more severe forms of the disease. All ten eyes with drusen alone and no SMD had normal fluorophotometry values. Vitreous fluorophotometry may be helpful in the diagnosis and classification of SMD.

Autosomal recessive colobomatous microphthalmia.

Colobomatous microphthalmia was studied in multiple relatives of 5 families. In these families, the disorder was an autosomal recessive trait as opposed to the usual autosomal dominant form of the disorder. A relatively high incidence of this recessive allele is found in the Iranian Jewish community.

Variability of Stickler syndrome.

Stickler syndrome is a dominantly inherited disorder characterized by ocular and nonocular manifestations. The phenotype of the affected patients is known to be variable. Our study of 3 families and a review of the literature show that the variability is mostly interfamilial while in each family less variability is present. In one family all the patients had high myopia and most developed a retinal detachment at a young age. In the second family the major symptoms were cleft palate and characteristic facial changes in presence of mild ocular changes. In the third family, all patients had a marfanoid habitus, high myopia, and mental retardation. Interfamilial variability coupled with intrafamilial similarities in clinical manifestation may indicate that the so-called Stickler syndrome represents in fact a phenotype and not a single genetic entity.

Mucolipidosis type IV: a mild form with late onset.

A 16-year-old girl is presented with mild clinical manifestations and late onset of mucolipidosis type IV (MLIV). The patient, an Ashkenazi Jew, has had minor motor difficulties and mild psychological disturbances since early childhood. Her vision began deteriorating at 12 years of age, due to bilateral corneal opacities and retinal degeneration. At present she attends a regular high school, although she is slow and scholastic achievements are lower than average. Electron microscopic examination and biochemical studies were typical for MLIV, namely, abnormal ganglioside retention and typical pattern of phospholipids accumulation. This very mild presentation of MLIV suggests a broader spectrum of heterogeneity of this disorder and raises the possibility that MLIV, at least among Ashkenazi Jews, might be more frequent than estimated hitherto, due to undiagnosed mild patients.

Neurofibromatosis type I (NFI) in Israeli families: linkage analysis as a diagnostic tool.

Linkage analysis of 18 neurofibromatosis type I (NFI) families was performed using intragenic and flanking polymorphic markers. The aims of the analysis were prenatal diagnosis of at-risk fetuses, and of asymptomatic individuals who were relatives of NFI patients. Prenatal diagnosis was performed in 9 pregnancies of 7 families; 5 fetuses were diagnosed as affected. In 6 families with an affected spouse, the request was to identify informative polymorphisms to be used in future pregnancies. Presymptomatic diagnosis was performed in 4 families. One individual, a brother of an NFI patient, was found to have Lisch nodules as the only NFI symptom. Linkage analysis indicated that if this person is a carrier of the NFI gene, he must be a product of intragenic crossover. In 2 individuals with a new NFI mutation, the origin of the NFI-bearing chromosomes was paternal. The same observation was noted by others. A summary of published cases shows that some 90% of the NFI-bearing chromosomes of patients with new mutations were of paternal origin. We therefore suggest that for the purpose of prenatal diagnosis in carriers of NFI new (and unidentified) mutations, the paternal chromosome will be considered as the NFI-bearing chromosome.

Retinitis pigmentosa associated with Fuchs' heterochromic uveitis.

OBJECTIVE: To investigate whether the combination of Fuchs' heterochromic uveitis (FHU) and retinitis pigmentosa (RP) in the same patient is coincidental or represents a true association. METHODS: We have examined the frequency of FHU in 338 patients with RP and in 1984 patients who were seen in our primary care ophthalmic clinic because of reasons other than RP. RESULTS: Of 338 patients with RP, 4 (1.2%) had the typical findings of FHU. Three of them had Usher syndrome type II, and 1 had RP simplex. By contrast, only 1 patient in the control group had FHU (5%), and the difference in the frequency of FHU between the 2 groups was significant (P=.002, Fisher exact test). CONCLUSIONS: Fuchs' heterochromic uveitis is associated with RP. Since autoimmune phenomena have been previously described in patients with RP, it is conceivable that RP predisposes to the development of FHU. Arch Ophthalmol. 2000;118:800-802

Retinitis pigmentosa.

The authors review the symptomatic and genetic aspects of the various entities of isolated retinitis pigmentosa (R.P), both in its typical form and in the forms associated with the affection of other ocular tissues. Syndromes in which R. P. is associated with the affection of other organs and systemic disorders are also cconsidered. Origin, diagnosis and the course of the disease are discussed with regard to electrophysiology, histopathology, fluorescein angiography and biochemistry. Animal research has provided new realizations about the ultrastructure and physiological mechanisms of retinal photoreceptors, and better understanding of abnormal changes. The possible pathogenesis of the human disease, based on research findings, is onsidered. Although R.P. is generally thought to be to be an "untreatable" disease, therapy may be effective in several pathological entities. Methods and results of therapy with vitamins, light deprivation and vision aids are discussed.

Uniocular congenital blindness as a complication of midtrimester amniocentesis.

A 6-month-old baby girl with congenital unilateral blindness had an eyelid coloboma and clear evidence of an old vascularized corneal perforation, indicating that the cause of the blindness was an ocular trauma sustained during a midtrimester amniocentesis.

Schirmer test and break-up time of tear film in normal subjects.

We examined the precorneal film, the Schirmer test No. 1, and the break-up time tests in 440 healthy young students. There were no statistically significant differences (1) between men and women from the same origin who were brought up in the same environment, (2) between students from different ethnic origins who were brought up in the same environment, and (3) between students of the same origin who were brought up in different environments. Gradual seasonal changes in climatic factors, such as temperature, humidity, visibility, and barometric pressure, seem to have no appreciable effect on the Schirmer test No. 1 or break-up time test.

Conjunctival ultrastructure in Niemann-Pick disease type C.

A 5-year-old girl with Niemann-Pick disease type C had normal eyes but the conjunctival ultrastructure was abnormal. Lamellar cytoplasmic bodies, characteristic of Niemann-Pick disease, were found in epithelial cells, stromal fibroblasts, endothelial cells, and pericytes of the stromal capillaries. The basement membrane of the capillaries was multilayered. The Golgi apparatus was unusually well developed. The combination of ocular findings and conjunctival ultrastructure may be helpful in the differential diagnosis of Niemann-Pick disease and its subtypes.

Refractive power of premature children at infancy and early childhood.

We evaluated the refraction of 198 children born prematurely with birth-weights of 2,000 g or less, without any ocular disease. Between the ages of 6 months to 3 1/2 years these children had a mild hypermetropia. The refractive error did not change between the ages of 6 months and 3 1/2 years. The refraction of the prematurely born children was similar to that found in children born at full term.

Delayed-onset chloroquine retinopathy.

Delayed-onset chloroquine retinopathy was diagnosed in a patient seven years after cessation of treatment by a total dose of 730 g of chloroquine for rheumatoid arthritis. Visual functions continued to deteriorate after the diagnosis. Periodic examinations by ophthalmoscopy and by functional tests such as EOG and visual fields should be continued in patients at risk of delayed-onset chloroquine retinopathy after discontinuance of the drug.

Brittle cornea, blue sclera, and red hair syndrome (the brittle cornea syndrome).

A syndrome of red hair, blue sclera, and brittle cornea with recurrent spontaneous perforations is presented in 2 siblings of a Tunisian Jewish family. The genetic transmission of this disorder is autosomal recessive. This is the second description of this syndrome, which should be called the 'brittle cornea syndrome'. This syndrome has so far been reported only in Tunisian Jewish families.

Intraocular pressure in retinal vein occlusion.

The intraocular pressure of 59 patients with retinal vein occlusion was studied. Central retinal vein occlusion (CVO) was diagnosed in 24 patients and branch retinal vein occlusion (BVO) was diagnosed in the rest. The intraocular pressure of a sex and age matched group of controls was also studied for comparison. The intraocular pressure in the CVO group were significantly different from those of the matched controls (p less than 0.001). A statistically significant difference of a lesser degree (p less than 0.05) was also found in a comparison of the intraocular pressures of the BVO group with those of their sex and age matched group of controls. These findings may indicate the possible role of increased intraocular pressure in the pathogenesis of CVO and BVO.

Ocular side effects of disopyramide.

A patient who suffered from severe decrease of accommodation and pupillary dilatation following the systemic use of disopyramide is described. The ocular side effects when this drug is used in large doses result from its anticholinergic action.

Corneal subepithelial monoclonal kappa IgG deposits in essential cryoglobulinaemia.

A 60-year-old man suffering from photophobia and visual disturbances was found to have bilateral superficial corneal grey-white gelatinous deposits. An abnormal cold-precipitable serum component was found and characterised as homogeneous IgG-kappa immunoglobulin. Corneal immunohistochemical examination revealed subepithelial IgG-kappa deposits, focally replacing Bowman's layer. The patient underwent superficial keratectomy in both eyes with satisfactory visual results.

Cone and rod dysfunction in the NARP syndrome.

AIMS: Description of the ophthalmic manifestations of the NARP (neuropathy, ataxia, retinitis pigmentosa) syndrome that is associated with a point mutation in position 8993 of the mitochondrial DNA (mtDNA). METHODS: A mother and her two children, all carrying the 8993 mtDNA mutation, were examined. Two had manifestations of the NARP syndrome. A complete ocular and systemic examination was performed on all three patients. RESULTS: The clinical examination, electroretinogram, and visual fields revealed a typical cone-rod dystrophy in the son, and a typical cone dystrophy in the daughter. The mother had no ocular manifestations of the disease. CONCLUSIONS: NARP is a recently described, maternally inherited mitochondrial syndrome in which a retinal dystrophy, among other abnormalities, is related to a mutation of the mtDNA at nucleotide 8993. This study demonstrates the great variability of the ocular manifestations in the NARP syndrome. It also indicates that the retinal dystrophy in at least some NARP patients affects primarily the cones.