Dutch National Registry of GH Treatment in Adults: patient characteristics and diagnostic test procedures.

OBJECTIVE: The Dutch National Registry of GH Treatment in Adults was established in 1998 as an initiative of the Ministry of Health. The main goals were to gain more insight into long-term efficacy, safety, and costs of GH therapy (GHT) in adult GH-deficient (GHD) patients in The Netherlands. METHODS: Baseline patient characteristics and diagnostic test procedures were evaluated. RESULTS: Until January 2009 in roughly 10 years, 2891 patients (1475 men and 1416 women, mean age 43.5±16.5 years) were registered. GHD was of childhood-onset (CO) in over 20% of the patients and of isolated in 11%. The most common causes of GHD were pituitary tumors and/or their treatment, craniopharyngiomas, and idiopathic GHD. In 85% of the patients, a GH stimulation test was performed, in the majority an insulin tolerance test (ITT) (49%) or a combined GHRH-arginine test (25%). In 12% of the patients, IGF1 levels were ≤-2 s.d. combined with two or more additional pituitary hormone deficits, and in 2%, it concerned patients with CO-GHD continuing GHT in adulthood. Over the years, the test of first choice shifted from ITT toward GHRH-arginine test. CONCLUSION: Nearly, 2900 patients were included in the nationwide surveillance database of the Dutch National Registry of GH Treatment in Adults until January 2009. Baseline patient characteristics are comparable to that reported previously. In 85% of these patients, the diagnosis of GHD was established by provocative testing, particularly an ITT or a combined GHRH-arginine test, with an evident increase in the percentage of GHRH-arginine tests being performed in the last years.

Multiple sources of information for the hypothalamus.

The cross-talk between several parts of the gut and the brain involves the exchange of information that enables an individual to optimize metabolism and to adapt it to potentially huge variations in caloric intake during, e.g. fasting and eating. It also ensures that already parts of the gut downstream of the oropharynx are informed about what kind of food will arrive soon and what to do with it. These phenomena are largely mysteries to us, but some light is shed over these fields. This review will address some of the developments that illustrate how sophisticated these ancient mechanism of cross-talk are and what they could mean to us as highly developed 'modern' mammals.

IL-10 promotor haplotypes associated with susceptibility to and severity of bacterial corneal ulcers.

Interleukin-10 plays an important role in modulating inflammation and antimicrobial defences. In animal models for bacterial corneal ulcers, high IL-10 levels were associated with a better clinical outcome. We investigated whether IL-10 promotor haplotypes, known to determine IL-10 expression in vitro, are associated with susceptibility to and/or clinical outcome of bacterial corneal ulcers in patients. IL-10 promotor polymorphisms C-819T, G-1082A, A-2763C, and A-2849G for 83 patients with bacterial corneal ulcers and 115 healthy controls were determined by restriction fragment length PCR analysis. For 63 patients and all healthy controls the most frequently occurring IL-10 promotor haplotypes were inferred from these data using the program SNPHAP. A significant underrepresentation of the A-2849A genotype was observed in patients as compared to healthy controls. Both the -2763A allele and the IL-10.1 promotor haplotype were associated with a poor clinical outcome, whereas a favourable clinical outcome was seen in patients carrying the IL-10.2 promotor haplotype. Together, IL-10 promotor haplotypes associated with low IL-10 levels seem to protect against the onset of bacterial corneal ulcers. Once a corneal ulcer has developed, patients carrying IL-10 haplotypes associated with a high IL-10 expression may have a favourable outcome.

Herpetic encephalitis is a risk factor for acute retinal necrosis.

BACKGROUND: Acute retinal necrosis (ARN) has been observed in several cases after herpetic encephalitis (HE). ARN is a devastating ocular disease with a very disappointing visual outcome. Therefore, early recognition and diagnosis are crucial. OBJECTIVE: To study the association between ARN and preceding neurologic illness, especially the co-occurrence of HE in patients with ARN; to compare the causal agent in ARN and HE; and to determine the visual outcome of ARN with HE vs ARN without HE. METHODS: A retrospective study including ophthalmologic and neurologic follow-up together with virologic data of patients with ARN. PARTICIPANTS: Seven patients with ARN diagnosed with a history of HE (13.5%) out of a source population of 52 patients with ARN admitted to a major academic ophthalmologic referral center between 1983 and 2008. RESULTS: In five out of seven patients unilateral ARN occurred after HE under immunocompetent conditions, and both ARN and HE were caused by the herpes simplex virus (HSV), whereas the other two patients were immunocompromised, had bilateral ARN, and both ARN and HE were caused by the varicella zoster virus (VZV). The latency period between the HE and the ARN was shorter when VZV was involved than with HSV (5 weeks vs 20.6 months). The visual outcome in patients with ARN with HE, as defined by legally blind eyes after a follow-up of 1 year, did not differ significantly from patients with ARN without HE. CONCLUSION: Herpetic encephalitis seems to be a risk factor for acute retinal necrosis syndrome. Since treatment may improve the outcome at least for the second eye, it is relevant for clinicians to be aware of this association.

[Ghrelin, an important hormone produced by the stomach]. / Ghreline, een belangrijk hormoon geproduceerd door de maag.

Ghrelin is a hormone produced by endocrine cells in the stomach. Ghrelin stimulates the secretion of growth hormone by the anterior pituitary. This effect is mediated by hypothalamic growth-hormone secretagogue receptors. Binding to these receptors not only stimulates growth hormone secretion, but also has vascular effects (positive inotropic effects), modifies (decreases) insulin sensitivity, affects glucose metabolism (hyperglycaemia) and stimulates gastric-acid production. Antiproliferative effects of ghrelin have been described on experimental tumour models. Ghrelin seems to play a role in stimulating the appetite as well as promoting a more effective storage of food components. Whether or not ghrelin could play any role in the induction of weight gain has yet to be established. This is also true for the role of potential ghrelin antagonists in the induction of weight loss in case of obesity.

Influence of HLA-A, HLA-B, and HLA-DR matching on rejection of random corneal grafts using corneal tissue for retrospective DNA HLA typing.

AIM: To establish if coincidental HLA-A, HLA-B, and HLA-DR tissue matching is associated with a reduced likelihood of corneal graft rejection. METHODS: Organ culture preserved random donor corneas were used for penetrating keratoplasty (PKP). Corneal tissue from all graft recipients and donors or blood samples from recipients after repeated transplantation were obtained in order to perform retrospective molecular HLA typing. A group of 21 recipients with a rejection episode (cases) after corneal transplantation was compared with a control group of non-rejectors (n = 43). 31 graft recipients were considered as high risk patients. The influence of HLA-A, HLA-B, and HLA-DR matching on rejection free graft survival time was analysed with Kaplan-Meyer statistics and Cox regression. RESULTS: A prolonged rejection free survival time was observed in graft recipients with one or two HLA-A matches (log rank test, p = 0.034). This effect was also observed in high risk graft recipients with one or two HLA-DR matches (log rank test, p = 0.030). CONCLUSIONS: Coincidental HLA-A and HLA-DR matches were observed and associated with a prolonged rejection free survival time in the total group and in the high risk group, respectively. These results support the beneficial effect of prospective HLA-A and HLA-DR typing upon corneal graft survival.

Herpes simplex virus type 1 (HSV-1)--induced retinitis following herpes simplex encephalitis: indications for brain-to-eye transmission of HSV-1.

Herpes simplex encephalitis is a severe neurological disease with high mortality and morbidity rates. Reactivated herpes simplex virus type 1 (HSV-1) can cause relapses and might even spread to the retina, where it can induce a potentially blinding eye disease, known as acute retinal necrosis. In the present study, the HSV-1 strains in the brain and eye of 2 patients with acute retinal necrosis following an episode of herpes simplex encephalitis were genotyped. The HSV-1 strains in both the brain and eye were identical in each patient, but they differed interindividually. The data suggest brain-to-eye transmission of HSV-1 in these patients.

Uveitis masquerade syndromes.

BACKGROUND: Incorrect diagnosis of the uveitic masquerade syndromes (UMS) may have severe consequences. In this study, the frequency, clinical manifestations, and informative diagnostic tests for UMS are described. DESIGN: Retrospective observational case series. PARTICIPANTS: Forty patients with UMS were identified in a cohort of 828 consecutive patients with uveitis. The mean follow-up was 4.5 years. METHODS: A review of clinical, laboratory, photographic, and angiographic records was performed. MAIN OUTCOME MEASURES: Clinical features, associated systemic diseases, diagnostic procedures and their role in the diagnostic process, and systemic and visual outcomes. RESULTS: Nineteen patients had intraocular malignancy (48% of all with UMS; 2.3% of all with uveitis), mainly intraocular lymphoma (n = 13) and leukemia (n = 3). The ophthalmologist was the first to recognize malignant disease in 11 of 19 patients (58%). Of 21 patients with nonmalignant UMS, 10 had an ocular vascular disease and 5 a hereditary ocular disorder. The patients with malignant UMS were older than those with nonmalignant UMS (average age, 50 vs 44 years, P: < 0.05). During follow-up, 9 of 19 patients with malignant UMS died. The most informative diagnostic procedure for malignant UMS was intraocular fluid analysis; for nonmalignant UMS, fluorescein angiography. The cytologic analysis of intraocular fluids yielded the best results for diagnosing intraocular malignancies (7 of 11 patients, 64%); the association of negative cytologic results with the recent administration of systemic corticosteroids was noted. Immunophenotyping of the aqueous confirmed the diagnosis of hematologic malignancy for 3 of 5 patients examined. Panuveitis was the most frequent manifestation of malignant UMS. Intraocular lymphomas presented with isolated vitreitis (n = 6), chorioretinal lesions (n = 5) and iris infiltration (n = 2). Clinical presentation of nonmalignant UMS was diverse but consisted mainly of abnormalities of the retinal vasculature. CONCLUSIONS: UMS was diagnosed in 5% of the patients with uveitis at a tertiary center. Despite the variety of underlying disorders and different clinical presentations, a high frequency of malignant and vascular diseases was found. Awareness of the clinical manifestations of UMS and application of the correct diagnostic procedures should promote timely diagnosis and treatment, which are essential not only for visual acuity but also for the life of the patient.

Herpes simplex virus type 1 (HSV-1)--induced retinitis following herpes simplex encephalitis: indications for brain-to-eye transmission of HSV-1.

Herpes simplex encephalitis is a severe neurological disease with high mortality and morbidity rates. Reactivated herpes simplex virus type 1 (HSV-1) can cause relapses and might even spread to the retina, where it can induce a potentially blinding eye disease, known as acute retinal necrosis. In the present study, the HSV-1 strains in the brain and eye of 2 patients with acute retinal necrosis following an episode of herpes simplex encephalitis were genotyped. The HSV-1 strains in both the brain and eye were identical in each patient, but they differed interindividually. The data suggest brain-to-eye transmission of HSV-1 in these patients.

Detection of herpes simplex virus type 1, 2 and varicella zoster virus DNA in recipient corneal buttons.

AIM: To study the value of polymerase chain reaction (PCR) analysis, to detect viral DNA in recipient corneal buttons taken at the time of penetrating keratoplasty (PKP) in patients with an initial diagnosis of herpetic stromal keratitis (HSK). Since HSK has a tendency to recur, an accurate diagnosis of previous HSK could be the reason to start antiviral treatment immediately, thereby possibly decreasing the number of graft failures due to recurrent herpetic keratitis. METHODS: Recipient corneal buttons and aqueous humour (AH) samples were obtained at the time of PKP from HSK patients (n=31) and from other patients (n=78). Eye bank corneas were also used (n=23). Herpes simplex virus type 1 (HSV-1), type 2 (HSV-2), and varicella zoster virus (VZV) infection were assessed by PCR and antibody detection. RESULTS: The clinical diagnosis HSK could be confirmed by PCR for HSV-1 in 10/31 (32%). In these corneal buttons HSV-2 DNA was detected in 1/31 (3%) and VZV DNA in 6/31 (19%). Intraocular anti-HSV antibody production was detected in 9/28 AH samples tested (32%). In the other patient derived corneas HSV-1 DNA was detected in 13/78 (17%), including eight failed corneal grafts without clinically obvious herpetic keratitis in the medical history. In clear eye bank corneas HSV-1 was detected in 1/23 (4%). CONCLUSIONS: PCR of HSV-1 on corneal buttons can be a useful diagnostic tool in addition to detection of intraocular anti-HSV antibody production. Furthermore, the results were suggestive for the involvement of corneal HSV infection during allograft failure of corneas without previous clinical characteristic signs of herpetic keratitis.

Cytokines in aqueous humour and serum before and after corneal transplantation and during rejection.

Cytokine profiles in aqueous humour were studied in relation to corneal disease and subsequent corneal graft survival or rejection. Cytokine levels in samples obtained from eyes with clear grafts (n = 59) were all within the normal range. At the time of penetrating keratoplasty (n = 146), intraocular levels of IL-6 were increased in 38% (50/131), most markedly in eyes with previous allograft failure or herpetic stromal keratitis. The level of IL-10 was increased in 1 eye (n = 144) and of IL-4 and IFN-gamma in none. During rejection (n = 10), the levels of IL-6 in aqueous humour were increased in 75% (3/4), of IL-10 in 50% (3/6), of IL-4 in none (0/4) and of IFN-gamma in 40% (2/5). In conclusion, the levels of total protein and IL-6 were increased prior to penetrating keratoplasty in eyes with previous inflammation. These results could however not predict the final outcome of the graft. Increased intraocular levels of IL-6, IL-10 and IFN-gamma were observed during rejection.

Anterior uveitis with sectoral iris atrophy in the absence of keratitis: a distinct clinical entity among herpetic eye diseases.

OBJECTIVE: To determine the cause and describe the clinical features of unilateral anterior uveitis with sectoral atrophy of the iris in the absence of associated keratitis. DESIGN: Retrospective, observational case series. PARTICIPANTS: Thirty-one patients with unilateral anterior uveitis with sectoral iris atrophy and without (previous) keratitis. METHODS: The patients were selected from our database of 592 patients with anterior uveitis. MAIN OUTCOME MEASURES: We reviewed the clinical data on the 31 patients and the results of diagnostic anterior chamber fluid analysis for 24 of the 31 patients. Specifically, production of local antibodies against herpes simplex virus (HSV) and varicella zoster virus (VZV) was determined and the polymerase chain reaction was performed to demonstrate the DNA of HSV, VZV, and cytomegalovirus (CMV) in the aqueous samples. RESULTS: Main clinical characteristics of anterior uveitis with iris atrophy included unilateral involvement with a prolonged course and recurrent exacerbations in all cases. Elevated intraocular pressure during intraocular inflammation occurred in 90% of patients (28 of 31). Visual outcome was favorable because 29 of 31 patients (94%) retained a visual acuity of 20/32 or more. The causal agent was identified as HSV in 83% (20 of 24) and VZV in 13% (3 of 24) and was inconclusive in one case. The patients with HSV uveitis were younger than those with VZV uveitis (mean age at onset 34 and 65 years, respectively; P = 0.0056). CONCLUSIONS: Unilateral anterior uveitis with sectoral atrophy of the iris without associated (previous) keratitis is a distinct entity among herpetic eye diseases. Recurrent unilateral anterior uveitis with iris atrophy and/or elevated intraocular pressure has most likely been caused by HSV.

Amplification of reiterated sequences of herpes simplex virus type 1 (HSV-1) genome to discriminate between clinical HSV-1 isolates.

Herpes simplex virus type 1 (HSV-1)-related disease ranges from a localized, self-limiting illness to fatal disease in immunocompromised individuals. The corneal disease herpetic keratitis may develop after reactivation of a latent virus or reinfection with an exogenous herpesvirus. Molecular analysis of the virus involved may allow distinction between these two options. The HSV-1 genome contains several hypervariable regions that vary in numbers of reiterating regions (reiterations I to VIII [ReI to ReVIII]) between individual strains. Twenty-four HSV-1 clones, derived by subcloning of HSV-1 (strain F) twice in limiting dilutions, were tested in a PCR-based assay to analyze the stabilities of ReI, ReIII, ReIV, and ReVII. ReI and ReIII proved to vary in size upon subcloning, whereas ReIV and ReVII were stable. Subsequently, 37 unrelated isolates and 10 sequential isolates from five patients, all with HSV-1-induced keratitis, were genotyped for ReIV and ReVII. Of the 37 unrelated samples, 34 (92%) could be discriminated, while the genotypes of the viruses in sequential samples were identical for each individual. Conclusively, the data show that the approach presented allows the rapid and accurate discrimination of HSV-1 strains in studies that address the transmission and pathogenesis of HSV-1 infections.

Aetiological study of the presumed ocular histoplasmosis syndrome in the Netherlands.

AIM: To investigate whether presumed ocular histoplasmosis syndrome in the Netherlands is caused by Histoplasma capsulatum and whether other risk factors might play a role in the pathogenesis of this syndrome. METHODS: 23 patients were clinically diagnosed as having presumed ocular histoplasmosis syndrome based on the following criteria: peripapillary atrophy, punched out lesions, a macular disciform lesion or scar in one eye without vitritis. As controls, 66 sex and age matched healthy volunteers were used. Serum samples from both patients and controls were tested for the presence of antibodies against H capsulatum, Toxoplasma gondii, Toxocara canis et cati, Ascaris sp, and for the presence of antigens of Cryptococcus neoformans. Serum samples were also tested for the presence of autoantibodies against retinal or choroidal proteins. To investigate other risk factors, patients and controls were asked to fill in a health and travel related questionnaire. Ten patients with ocular toxoplasmosis were used as a disease control group. RESULTS: None of the patients with presumed ocular histoplasmosis syndrome or controls had circulating antibodies directed against H capsulatum. No risk factors could be identified and no indications for autoimmunity and no evidence for the role of the other infectious agents could be demonstrated. CONCLUSIONS: In a Dutch group of patients fulfilling the criteria of a disease currently named presumed ocular histoplasmosis syndrome, no risk factors or relation with the fungus H capsulatum could be detected.

Are cytokine patterns in aqueous humour useful in distinguishing corneal graft rejection from opacification due to herpetic stromal keratitis?

PURPOSE: Intra-ocular cytokine profiles were determined to study the immunological mechanisms of corneal graft opacification due to rejection and/or herpetic stromal keratitis (HSK). METHODS: Sera and aqueous humour (AH) were sampled shortly after the onset of corneal graft opacification, group I (n=18). In eyes with clear grafts, samples were taken 5 months after transplantation, group II (n=59). Samples of non-inflamed eyes, prior to cataract surgery, were used to determine baseline cytokine levels, group III (n=49). Total protein (TP) levels were measured with Bradford reagent and interleukin (IL)-6, IL-10, IL-4 and interferon (IFN)-gamma with ELISAs. RESULTS: All patients who's corneal grafts showed clinical evidence of graft opacification due to rejection and/or HSK were sampled. In the AH-samples of group I, increased levels of TP were found in 60% (9/15), IL-6 in 79% (11/14), IL-10 in 39% (7/18) and IL-4 in none (0/12). IFN-gamma was detected in 19% (3/16), in the case of HSK only. In contrast, samples obtained from patients with clear grafts in group II showed increased levels of TP in 36% (20/55), IL-6 in 14% (8/57) and IL-10, IL-4 or IFN-gamma in none (n=58). CONCLUSIONS: During corneal graft rejection and/or HSV-infection, increased levels of TP and IL-6 in AH confirmed anterior chamber inflammation with breakdown of the blood-aqueous barrier. Based on the data presented, cytokine patterns in the AH do not appear to distinguish corneal opacification due to graft rejection from that due to herpes keratitis.

Analysis of immunoregulatory cytokines in ocular fluid samples from patients with uveitis.

PURPOSE: To investigate the T-helper cell cytokine profiles in two well-defined clinical uveitis entities caused by an infectious mechanism. METHODS: Cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, and interferon [IFN]-gamma) were measured in ocular fluid samples obtained from patients with herpes simplex- or varicella-zoster virus-induced acute retinal necrosis (ARN; n = 17) and toxoplasma chorioretinitis (n = 27) using enzyme-linked immunosorbent assay techniques. The data were compared with data for 51 control samples taken during cataract surgery (n = 10), vitrectomy in diabetic retinopathy (n = 10), eye bank eyes (n = 10) and with samples from patients with "autoimmune" uveitis (n = 21). RESULTS: Interleukin-6 was detected in 44 of 51 control samples and 43 of 44 eyes of patients with uveitis. The highest levels in the control samples were detected in 9 of 10 vitreous samples from patients with diabetic retinopathy (mean, 648 pg/ml). In 8 of 10 samples taken from patients during cataract surgery and in 7 of 10 eye bank eyes the amount of IL-6 was significantly lower (mean, 10 pg/ml and 136 pg/ml, respectively). Interleukin-6 levels in patients with ARN (mean, 1436 pg/ml) were significantly higher than in those with toxoplasma chorioretinitis (mean, 272 pg/ml). Interleukin-2 was detected in one of the samples from patients with toxoplasma chorioretinitis (1105 pg/ml) and in three samples from the control subjects suffering from Fuchs' heterochromic anterior uveitis (mean, 752 pg/ml). No IL-4 (<2 pg/ml) was detected either in patient or control samples. Interferon-gamma could be detected in 7 of 17 ARN patients (range, 277-3483 pg/ml), in 13 of 27 samples from patients with toxoplasma chorioretinitis (range, 12-250 pg/ml), and in 1 of 21 of the samples from control subjects with uveitis (31 pg/ml) but was absent in nonuveitic control samples. Interleukin-10 was detected in 10 of 17 ARN patients (range, 29-3927 pg/ml), in 13 of 27 samples from patients with toxoplasma chorioretinitis (range, 4-67 pg/ml), and in only 3 of 51 control samples (6 pg/ml, 16 pg/ml, and 20 pg/ml). CONCLUSIONS: Various immunoregulatory cytokines (IL-6, IL-10, and IFN-gamma) were detected in ocular fluid samples from patients with uveitis. A separate role for either a T-helper type 1 or T-helper type 2 response in the pathogenesis of clinical uveitis could not be proven.

T cells specific for the triggering virus infiltrate the eye in patients with herpes simplex virus-mediated acute retinal necrosis.

Acute retinal necrosis (ARN) is a rare, potentially blinding retinal disease resulting from ocular infections with herpes simplex virus (HSV) or varicella-zoster virus (VZV). To determine the antigen specificity and functional characteristics of ocular infiltrating T cells in ARN, T cells were isolated and expanded nonspecifically from intraocular fluid (IOF) samples from 2 patients with HSV-1- and 3 with VZV-mediated ARN. HSV-specific T cell reactivity could be detected only in the IOF-derived T cell lines (TCLs) of the 2 patients with HSV-mediated ARN. These TCLs consisted of both HSV type-common and type-specific CD4+ and CD8+ T cell clones (TCCs) with differential T cell receptor usage. Irrespective of their phenotype, the TCCs were cytolytic and secreted interferon-gamma, tumor necrosis factor-alpha, interleukin-4, and interleukin-5. In both patients, the antigen specificity of a substantial number of HSV-1-specific TCCs could be mapped to approximately 0.67-0.73 HSV-1 map units. The data presented suggest the contribution of T cells, specific for the triggering virus, to the pathogenesis of ARN.

Cytomegalovirus (CMV) strain differences between the eye and blood in AIDS patients with CMV retinitis.

OBJECTIVE: To investigate possible differences in cytomegalovirus (CMV) strain distribution between the eye and blood in AIDS patients with CMV retinitis. METHODS: CMV DNA sequences from aqueous humour and peripheral blood leukocytes (PBL), obtained from 13 AIDS patients with CMV retinitis, were compared. DNA was isolated and the CMV IE-1 sequence (part of the immediate early-1 gene) and the a-sequence (located in the a-region) were amplified by polymerase chain reaction (PCR). The PCR products of the a-sequence were analysed by Southern blotting for amplified fragment-length polymorphisms. The level of divergence between the a-sequences of aqueous humour- and PBL-derived CMV was studied in two patients by cloning these sequences followed by sequence analysis. RESULTS: CMV DNA could be detected in all aqueous humour samples and in 10 out of 13 paired blood samples. In the 10 patients, with CMV DNA detectable in both aqueous humour and PBL, seven cases showed differences between the amplified products of both compartments. Sequence analysis in two patients revealed that the aqueous humour and PBL of the same patient can harbour both identical, similar and highly divergent CMV a-sequences. CONCLUSION: These results indicate that despite the haematogenous spread of CMV, the eye, being a relatively shielded organ, may contain CMV strains different from those found in the blood.