Acinetobacter baumannii has emerged as a highly troublesome pathogen for many institutions globally. As a consequence of its immense ability to acquire or upregulate antibiotic drug resistance determinants, it has justifiably been propelled to the forefront of scientific attention. Apart from its predilection for the seriously ill within intensive care units, A. baumannii has more recently caused a range of infectious syndromes in military personnel injured in the Iraq and Afghanistan conflicts. This review details the significant advances that have been made in our understanding of this remarkable organism over the last 10 years, including current taxonomy and species identification, issues with susceptibility testing, mechanisms of antibiotic resistance, global epidemiology, clinical impact of infection, host-pathogen interactions, and infection control and therapeutic considerations.

Acinetobacter baumannii: Emergence of a Successful Pathogen

The aim of the DEWS Definition and Classification Subcommittee was to provide a contemporary definition of dry eye disease, supported within a comprehensive classification framework. A new definition of dry eye was developed to reflect current understanding of the disease, and the committee recommended a three-part classification system. The first part is etiopathogenic and illustrates the multiple causes of dry eye. The second is mechanistic and shows how each cause of dry eye may act through a common pathway. It is stressed that any form of dry eye can interact with and exacerbate other forms of dry eye, as part of a vicious circle. Finally, a scheme is presented, based on the severity of the dry eye disease, which is expected to provide a rational basis for therapy. These guidelines are not intended to override the clinical assessment and judgment of an expert clinician in individual cases, but they should prove helpful in the conduct of clinical practice and research.

The definition and classification of dry eye disease: Report of the definition and classification subcommittee of the international Dry Eye WorkShop (2007)

Platelet-derived growth factor (PDGF) is a major mitogen for connective tissue cells and certain other cell types. It is a dimeric molecule consisting of disulfide-bonded, structurally similar A- and B-polypeptide chains, which combine to homo- and heterodimers. The PDGF isoforms exert their cellular effects by binding to and activating two structurally related protein tyrosine kinase receptors, denoted the alpha-receptor and the beta-receptor. Activation of PDGF receptors leads to stimulation of cell growth, but also to changes in cell shape and motility; PDGF induces reorganization of the actin filament system and stimulates chemotaxis, i.e., a directed cell movement toward a gradient of PDGF. In vivo, PDGF has important roles during the embryonic development as well as during wound healing. Moreover, overactivity of PDGF has been implicated in several pathological conditions. The sis oncogene of simian sarcoma virus (SSV) is related to the B-chain of PDGF, and SSV transformation involves autocrine stimulation by a PDGF-like molecule. Similarly, overproduction of PDGF may be involved in autocrine and paracrine growth stimulation of human tumors. Overactivity of PDGF has, in addition, been implicated in nonmalignant conditions characterized by an increased cell proliferation, such as atherosclerosis and fibrotic conditions. This review discusses structural and functional properties of PDGF and PDGF receptors, the mechanism whereby PDGF exerts its cellular effects, and the role of PDGF in normal and diseased tissues.

https://www.physiology.org/doi/pdf/10.1152/physrev.1999.79.4.1283

Mechanism of Action and In Vivo Role of Platelet-Derived Growth Factor

The subcommittee reviewed the prevalence, incidence, risk factors, natural history, morbidity and questionnaires reported in epidemiological studies of dry eye disease (DED). A meta-analysis of published prevalence data estimated the impact of age and sex. Global mapping of prevalence was undertaken. The prevalence of DED ranged from 5 to 50%. The prevalence of signs was higher and more variable than symptoms. There were limited prevalence studies in youth and in populations south of the equator. The meta-analysis confirmed that prevalence increases with age, however signs showed a greater increase per decade than symptoms. Women have a higher prevalence of DED than men, although differences become significant only with age. Risk factors were categorized as modifiable/non-modifiable, and as consistent, probable or inconclusive. Asian ethnicity was a mostly consistent risk factor. The economic burden and impact of DED on vision, quality of life, work productivity, psychological and physical impact of pain, are considerable, particularly costs due to reduced work productivity. Questionnaires used to evaluate DED vary in their utility. Future research should establish the prevalence of disease of varying severity, the incidence in different populations and potential risk factors such as youth and digital device usage. Geospatial mapping might elucidate the impact of climate, environment and socioeconomic factors. Given the limited study of the natural history of treated and untreated DED, this remains an important area for future research.

TFOS DEWS II Epidemiology Report.

Infection with human immunodeficiency virus type 1 (HIV-1) is frequently complicated in its late stages by the AIDS dementia complex, a neurological syndrome characterized by abnormalities in cognition, motor performance, and behavior. This dementia is due partially or wholly to a direct effect of the virus on the brain rather than to opportunistic infection, but its pathogenesis is not well understood. Productive HIV-1 brain infection is detected only in a subset of patients and is confined largely or exclusively to macrophages, microglia, and derivative multinucleated cells that are formed by virus-induced cell fusion. Absence of cytolytic infection of neurons, oligodentrocytes, and astrocytes has focused attention on the possible role of indirect mechanisms of brain dysfunction related to either virus or cell-coded toxins. Delayed development of the AIDS dementia complex, despite both early exposure of the nervous system to HIV-1 and chronic leptomeningeal infection, indicates that although this virus is "neurotropic," it is relatively nonpathogenic for the brain in the absence of immunosuppression. Within the context of the permissive effect of immunosuppression, genetic changes in HIV-1 may underlie the neuropathological heterogeneity of the AIDS dementia complex and its relatively independent course in relation to the systemic manifestations of AIDS noted in some patients.

https://science.sciencemag.org/content/sci/239/4840/586.full.pdf

The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex

Corneal nerves: structure, contents and function.

PURPOSE. Corneal wound healing is impaired in diabetic cornea. The purpose of this study was to examine patients with type 1 diabetes mellitus for changes in corneal morphology and to correlate corneal sensitivity, subbasal nerve morphology, and degree of polyneuropathy with each other. METHODS. Forty-four eyes of 23 patients with diabetes and nine control eyes were included. Corneal sensitivity was tested with a Cochet‐Bonnet esthesiometer (Luneau, Paris, France), and corneal morphology and epithelial and corneal thickness were determined by in vivo confocal microscopy. The density of subbasal nerves was evaluated by calculating the number of long subbasal nerve fiber bundles per confocal microscopic field. The degree of polyneuropathy was evaluated using the clinical part of the Michigan Neuropathy Screening Instrument (MNSI) classification, and retinopathy was evaluated using fundus photographs. RESULTS. A reduction of long nerve fiber bundles per image was noted to have occurred already in patients with mild to moderate neuropathy, but corneal mechanical sensitivity was reduced only in patients with severe neuropathy. Compared with control subjects the corneal thickness was increased in patients with diabetes without neuropathy. The epithelium of patients with diabetes with severe neuropathy was significantly thinner than that of patients with diabetes without neuropathy. CONCLUSIONS. Confocal microscopy appears to allow early detection of beginning neuropathy, because decreases in nerve fiber bundle counts precede impairment of corneal sensitivity. Apparently, the cornea becomes thicker in a relatively early stage of diabetes but does not further change with the degree of neuropathy. A reduction in neurotrophic stimuli in severe neuropathy may induce a thin epithelium that may lead to recurrent erosions. (Invest Ophthalmol Vis Sci. 2000;41: 2915‐2921)

Corneal structure and sensitivity in type 1 diabetes mellitus.

PURPOSE. Despite the rapidly growing popularity of laser in situ keratomileusis (LASIK) in correction of myopia, the tissue responses have not been thoroughly investigated. The aim was to characterize morphologic changes induced by myopic LASIK in human corneal stroma. METHODS. Sixty-two myopic eyes were examined once at 3 days to 2 years after LASIK using in vivo confocal microscopy for measurement of flap thickness, keratocyte response zones, and objective grading of haze. RESULTS. Confocal microscopy revealed corneal flap interface particles in 100% of eyes and microfolds at the Bowman’s layer in 96.8%. The flaps were thinner (112 6 25 mm) than intended (160 mm). The keratocyte activation in the stromal bed was greatest on the third postoperative day. Patients with increased interface reflectivity due to abnormal extracellular matrix or activated keratocytes at $1 month (n 5 9) had significantly thinner flaps than patients with normal interface reflectivity (n 5 18; 114 6 12 versus 132 6 22 mm, P 5 0.027). After 6 months the mean density of the most anterior layer of flap keratocytes was decreased. CONCLUSIONS. Keratocyte activation induced by LASIK was of short duration compared with that reported after photorefractive keratectomy. The flaps were thinner than expected, and microfolds and interface particles were common complications. The new findings such as increased interface reflectivity associated with thin flaps and the apparent loss of keratocytes in the most anterior flap 6 months to 2 years after surgery may have important clinical relevance. (Invest Ophthalmol Vis Sci. 2000;41:369 ‐376)

Corneal Stromal Changes Induced by Myopic LASIK

Purpose To review the pathophysiology of LASIK-associated dry eye conditions and provide insights into prophylaxis to decrease the incidence of dry eye after LASIK and to treat the condition when it occurs. Methods A review of the literature was performed on LASIK-associated dry eye and the experience of the authors was summarized. Results LASIK has a neurotrophic effect on the cornea, along with other changes in corneal shape, that affect tear dynamics causing ocular surface desiccation. Dry eye is one of the most common complications of LASIK surgery. Symptoms of dryness may occur in more than 50% of patients, with other complications such as fluctuating vision, decreased best spectacle-corrected visiual acuity, and severe discomfort occurring in approximately 10% of patients. Preoperative dry eye condition is a major risk factor for more severe dry eye after surgery and should be identified prior to surgery. Optimization with artificial tears, nutrition supplementation, punctal occlusion, and topical cyclosporine A in patients with symptoms or signs of dry eye prior to LASIK decreases the incidence of more bothersome symptoms following surgery. Patients with LASIK-induced neurotrophic epitheliopathy often respond to topical cyclosporine A treatment, which treats the underlying inflammation and may benefit nerve regeneration. Conclusions LASIK-induced dry eye and neurotrophic epitheliopathy are common complications of LASIK surgery. Optimization of the ocular surface prior to surgery decreases the incidence and severity of postoperative symptoms of the condition.

LASIK-associated Dry Eye and Neurotrophic Epitheliopathy: Pathophysiology and Strategies for Prevention and Treatment

Purpose To analyze the in vivo morphology of the different corneal sublayers and corneal nerves in primary Sjogren's syndrome (SS). Methods Ten eyes of 10 patients with primary SS and 10 eyes of 10 sex- and age-matched control subjects were investigated. Diagnosis was based on American-European consensus criteria. In vivo confocal microscopy with through-focusing was used to investigate corneal morphology and to measure corneal sublayer thickness. Results Epithelial punctate staining with fluorescein was observed in 6 of 10 SS and none of 10 control corneas. In addition, Schirmer I test results were significantly lower in SS. Epithelial thickness did not differ between the SS and control groups. Confocal microscopy revealed patchy alterations or irregularities in surface epithelial cells in 6 of 10 SS corneas, whereas the basal epithelium appeared normal in all corneas. Average corneal thickness was lower in the SS group (515.9 +/- 22.0 micro m) than in the control (547.4 +/- 42.0 micro m; P = 0.050, t-test). Accordingly, the mean intraocular pressure was lower in the SS group (13.9 +/- 2.1 mm Hg) than in the control (16.7 +/- 2.9 mm Hg; P = 0.022). The subbasal nerve plexus and stromal nerve fiber bundles were present in all corneas. No difference was noted in nerve density. However, in 4 of 10 SS eyes, the subbasal nerve plexus showed structures resembling nerve sprouting, suggesting ongoing active neural growth. None of the control corneas exhibited such features. Signs of anterior keratocyte activation were observed in 5 of 10 SS corneas. Conclusions In SS, the corneal surface epithelium was irregular and patchy. Anterior keratocytes frequently showed morphologic features of activation. The subbasal nerve fiber bundles revealed abnormal morphology, and the central corneal thickness was reduced by stromal thinning. The findings confirm epithelial, stromal, and neural abnormalities in the corneas of patients with SS.

Timo Tervo

Papers

Corneal nerves: structure, contents and function.

Corneal structure and sensitivity in type 1 diabetes mellitus.

Corneal Stromal Changes Induced by Myopic LASIK

LASIK-associated Dry Eye and Neurotrophic Epitheliopathy: Pathophysiology and Strategies for Prevention and Treatment

Corneal innervation and morphology in primary Sjögren's syndrome.