Ocular Complications of Chloroquine Therapy

Ocular complications of long-term chloroquine therapy were observed in 18 of 45 patients so treated. This therapy was used in patients with rheumatoid arthritis, lupus erythematosus, sarcoidosis, discoid lupus and other chronic “collagen disease”. Thirteen patients had reversible corneal opacifications, and seven had irreversible retinal changes, with visual loss and visual field defects. Pathological evidence of chloroquine retinopathy was obtained in one patient. Physicians are therefore warned to use this drug only after careful consideration. If it is used, repeated ocular examinations should include assessment of visual acuity, visual fields on a tangent screen and fundus examination through a dilated pupil.     

Chloroquine retinopathy and secondary trauma

This report describes a patient who initially presented with established chloroquine retinopathy resulting in reduced distance visual acuity, color vision anomalies and maculopathy in each eye. Subsequent trauma to the left side of the head produced a further decline in vision, accompanied by iritis and macula edema. A differential diagnosis, classification and treatment plan for patients with chloroquine retinopathy is presented.     

Retinal blood flow in diabetic retinopathy.

OBJECTIVES--(a) To report on the basic parameters of retinal blood flow in a population of diabetic patients with and without retinopathy and non-diabetic controls; (b) to formulate a haemodynamic model for the pathogenesis of diabetic retinopathy from this and other studies. DESIGN--Laser-Doppler velocimetry and computerised image analysis to determine retinal blood flow in a large cross sectional study. SETTING--Diabetic retinopathy outpatient clinic. SUBJECTS--24 non-diabetic controls and 76 diabetic subjects were studied (63 patients with insulin dependent diabetes, 13 with non-insulin dependent diabetes). Of the diabetic subjects, 12 had no diabetic retinopathy, 27 had background retinopathy, 13 had pre-proliferative retinopathy, 12 had proliferative retinopathy, and 12 had had pan-retinal photocoagulation for proliferative retinopathy. MAIN OUTCOME MEASURES--Retinal blood flow (microliters/min) and conductance (rate of flow per unit of perfusion pressure). RESULTS--In comparison with non-diabetic controls (9.52 microliters/min) and diabetic patients with no diabetic retinopathy (9.12 microliters/min) retinal blood flow was significantly increased in all grades of untreated diabetic retinopathy (background 12.13 microliters/min, pre-proliferative 15.27 microliters/min, proliferative 13.88 microliters/min). There was a significant decrease in flow after pan-retinal photocoagulation in comparison with all the other groups studied (4.48 microliters/min). Conductance of the retinal circulation was higher in the untreated diabetic retinopathy groups. These results were independent of age, sex, type of diabetes, duration of diabetes, glycated haemoglobin concentration, blood glucose concentration, blood pressure, and intraocular pressure. CONCLUSIONS--Retinal blood flow is significantly increased in diabetic retinopathy in comparison with non-diabetic controls and diabetic subjects with no retinopathy. This has implications for controlling hypertension and hyperglycaemia as a strategy in reducing morbidity from diabetic retinopathy.     

Prevalence of retinopathy in a diabetic clinic.

In a prospective study lasting 14 months an attempt was made to measure the visual acuity and examine the fundi, after mydriasis, of all patients attending the diabetic clinic of a district general hospital. Of 704 patients, 160 (22.7%) had some evidence of retinopathy, and 52 (7.4%) of these were already attending an ophthalmologist. A further 18 (2.6%) were known to have retinopathy and were being followed up in the diabetic clinic. Ninety (12.8%) new patients with diabetic retinopathy were discovered. Most had minimal changes, but 30 (4.3%) were considered to have changes severe enough to be referred to an ophthalmologist. Twenty-two (2.1%) underwent, or were awaiting, photocoagulation, and half of these had had no visual symptoms when first seen. Although some of these patients were already being treated or observed for retinopathy, it is encouraging that relatively few new patients needing treatment for retinopathy were discovered. If retinopathy could be detected early enough physicians might be able to deal with it and so ease pressure on ophthalmological services.     

Involvement of PAF (Platelet-Activating Factor) in chloroquine-induced retinopathy]

Chloroquine retinopathy is a severe toxic retinal impairment which may result in loss of vision by alterations of the pigmentary epithelium and photoreceptors. Currently, there is no specific treatment for this retinopathy. In order to test the possible involvement of Platelet-Activating Factor (PAF) in chloroquine-induced retinopathy and the use of PAF antagonists for prevention of this condition, we have examined the effect of these substances on the electroretinogram (ERG) of isolated rat retina. When retinas from normal rats were perfused with chloroquine (10(-6) M), a marked and rapid decrease in ERG b-wave amplitude was observed. In contrast, chloroquine had no effect on the ERG of retina isolated from animals pretreated with the PAF antagonist, BN 50730 (30 mg/kg/day i.p., 5 days). The results obtained indicate that (i) chloroquine is a toxic drug for retinal function, (ii) PAF plays a key role in chloroquine retinopathy and (iii) PAF antagonists may constitute valuable agents for the treatment of this retinal impairment.     

Randomised controlled trial of vancomycin for pseudomembranous colitis and postoperative diarrhoea.

The efficacy of vancomycin in pseudomembranous colitis was assessed in a prospective randomised controlled trial. Forty-four patients with postoperative diarrhoea were allocated to five days'' treatment with either 125 mg vancomycin six-hourly or a placebo. Sixteen patients had high titres of the neutralised faecal toxin characteristic of pseudomembranous colitis; nine received vancomycin and seven placebo. At the end of treatment faecal toxins were present in one patient given vancomycin compared with five of the controls. Vancomycin caused the disappearance of Clostridum difficile from the stool in all except one patient, whereas toxicogenic strains of Cl difficile persisted in all but one of the controls. Histological evidence of psuedomembranous colitis had disappeared by the end of treatment in six out of seven patients given vancomycin compared with only one out of seven patients given vancomycin compared with only one out of five patients given placebo. In patients with faecal toxins bowel habit had returned to normal in seven of the vancomycin group compared with only one of the controls, but there was no significant difference in clinical response among patients without faecaal toxins. The results suggest that vancomycin eliminates toxin-producing Cl difficile from the colon and is associated with rapid clinical and histological improvement in patients with pseudomembranous colitis.     

Proliferative diabetic retinopathy: treatment with xenon-arc photocoagulation. Interim report of multicentre randomised controlled trial.

One hundred patients with symmetrical proliferative diabetic retinopathy had one eye randomly chosen for treatment with xenonarc photocoagulation while the other was left untreated as a control. Patients were subdivided into those with new vessels on both optic discs and those with only peripheral new vessels. In patients with new vessels on the optic discs the vision of the untreated eyes deteriorated more than that of the treated eyes and the difference in deterioration was significant after one, two, and three years. There was no such difference in patients who had only peripheral new vessels. Eighteen patients had become blind in one or both eyes by the last assessment, but only one patient became blind in the treated eye without concomitant blindness in the untreated eye. Thirteen were blind only in the untreated eye. Both photographic and ophthalmoscopic examinations showed that new vessels on the disc regressed more in the treated eyes than in the untreated ones. As some forms of diabetic retinopathy are now treatable, early diagnosis and evaluation is increasingly important.     

Ocular Manifestations of Hemoglobin S-C Disease

Three patients with hemoglobin S-C disease, all with ocular lesions, were studied and contrasted with four other patients who had predominantly either hemoglobin S or C but no ocular lesions. Attention is drawn to the diagnostic value of hemoglobin electrophoresis in such cases. With this technique a diagnosis of hemoglobin S-C disease was made in a patient previously thought to the “Eales'' disease”; one sister was found to have asymptomatic hemoglobin S-C disease and unsuspected early ocular lesions. The number of persons in Canada with hemoglobinopathies is increasing. Awareness of an association between abnormal hemoglobins and ocular disease may lead to the recognition of an unsuspected blood disorder or of an unsuspected retinopathy.     

Short-term effect of chloroquine on the infectivity of Plasmodium chabaudi gametocytes.

The short-term enhancing effect of chloroquine on gametocyte infectivity was investigated with Plasmodium chabaudi chabaudi, a synchronous parasite which is highly sensitive to chloroquine. In comparison with control groups, oocyst numbers increased in mosquitoes fed on mice 12 hours after the injection of 5 mg/kg chloroquine (180% of controls) although it was not statistically significant. No effect was seen with 1 mg/kg chloroquine. The authors interpretation is that chloroquine impaired the schizogony, thus reducing also the release of toxic material of parasite origin which blocks gametocytes infectivity. Results of similar experiments with other rodent species of Plasmodium are compared and discussed in relation with the chronobiological characteristics of these parasites.     

Elevated plasma CD105 and vitreous VEGF levels in diabetic retinopathy

Diabetic retinopathy is the leading cause of blindness in the industrialized world. Hyperglycaemia induces retinal hypoxia that upregulates a range of vasoactive factors which may lead to macular oedema and/or angiogenesis and hence potentially sight threatening retinopathy. In this study, we have focused on the association of CD105 and vascular endothelial growth factor (VEGF) with the development and progression of diabetic retinopathy by means of quantifying their expression in the plasma and vitreous of diabetic patients. CD105 levels were quantified in the plasma of 38 type I diabetic patients at various stages of retinopathy and 15 non-diabetic controls. In an additional cohort of 11 patients with advanced proliferative retinopathy and 23 control subjects, CD105 and VEGF were measured in the vitreous. The values were expressed as median (range) and statistical analysis was carried out using the non-parametric Mann-Whitney U test. Plasma CD105 levels were significantly increased in diabetic patients [1.8 (1.1-2.4) ng/ml] compared with non-diabetic controls [0.7 (0.3-1.8) ng/ml] (p<0.01). Plasma CD105 levels were elevated in diabetic patients with all stages of retinopathy, the highest level was observed in background retinopathy [2.3 (2.1-2.5) ng/ml] followed by proliferative retinopathy [2.1 (0.9-2.8) ng/ml] and advanced proliferative retinopathy [1.4 (0.6-1.8) ng/ml]. Vitreous contents of CD105 did not differ between controls and patients with advanced proliferative retinopathy, but vitreous levels of VEGF were elevated by approximately 3-fold in patients with advanced proliferative retinopathy [7.2 (1.90-15.60) ng/ml] compared with the control subjects [1.80 (1.10-2.210)] (p<0.01). These observations indicate that plasma levels of CD105 and vitreous levels of VEGF are associated with diabetic retinopathy, suggesting that CD105 and the angiogenic factor VEGF may play a critical role in the development and progression of diabetic retinopathy. Further studies are required to determine whether circulating CD105 levels could serve as a surrogate marker for early stage retinopathy and for monitoring disease progression.     

III型神经中丝蛋白基因与中国高度近视人群相关性的研究

为了检测peripherin基因（PRPH）的突变与高度近视的病因有无相关关系,采用PCR-SSCP检测180例中国人高度近视先证者及60例正常人中PRPH基因所有外显子有无突变;对有突变的外显子区域进行克隆测序。结果表明,分析180例高度近视先证者PRPH基因编码区9个外显子及其邻近内含子,分别发现有下列核苷酸改变：密码子21TTC→TTT(Phe21Phe、4/180),nt2138C→G（IVS3、1/180）,密码子277GCC→ACC（Ala277Thr、8/180）,密码子237CCA→TCA（Arg237stop、1/180）,密码子292GCG→GCA(Ala292Ala,1/180),密码子361CUG→CUC（Leu361Leu,12/180）,密码子369AAA→AAG（Lys369Lys,12/180）,nt3331G→C（IVS7、3/180）,其中GCC277ACC为错义突变（Ala277Thr）;CCA237TCA为无义突变（Arg237stop）;密码子361CUG→CUC,密码子369AAA→AAG属于同义突变并且相连锁。Ala277Thr突变尚存在于正常人群中（1/60）,亦存在于患者正常亲属中;Arg237stop仅见于一个常染色体隐性遗传家系的患者中,为杂合性突变。分析180例高度近视先证者PRPH基因,未发现致病突变,可排除PRPH基因与高度近视病因的相关性。在中国人群中PRPH基因有多种变异。 Variation of the Peripherin Gene in Chinese with or Without High Myopia LI Jiang1,ZHANG Qing-jiong1,FU Rong2,XIAO Xue-shan1,LI Jia-zhang3,ZHANG Feng-sheng4, LI Shi-qiang1,LI Wei5,LI Tuo3,JIA Xiao-yun1,GUO Li1,GUO Xiang-ming 1.Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangzhou 510060,China; 2.Shenzhen Municipal People's Hospital,Shenzhen 518000,China; 3.Department of Opthalmolgy,The people's Hospital of Enshi Autonomous Prefecture,Enshi 445000,Hubei,China; 4.Chaoju Eye Hospital,Baotou,Inner Mongolia 014000,China; 5.Shenzhen 2nd People's Hopital,Shenzhen 518000,China Abstract:To analyze the relationship of the peripherin gene(PRPH,OMIM17071) mutations with high myopia,genomic DNA was collected from 180 probands with high myopia (≤-6.0 dipoters) and 60 unrelated persons without high myopia.The coding sequences of PRPH gene in 240 subjects were analyzed using exon-by-exon PCR-heteroduplex-SSCP analysis and sequencing.Variations at codon21TTC→TTT(Phe21Phe、4/180),nt2138C→G（IVS3、1/180）,codon277 GCC→ACC（Ala277Thr、8/180）,codon237 CCA→TCA （Arg237stop、1/180）,codon292CCG→CCA (Ala292Ala,1/180),codon361CUG→CUC（Leu361Leu,12/180）,codon369 AAA→AAG（Lys369Lys,12/180）,nt3331G→C（IVS7、3/180）were detected in a number of probands as indicated in the blanket.Of the 8 variations one( codon 277,G→A,Ala277Thr) is a missense mutation identified in 8 of the 180patients and one of 60 controls;The mutation of codon361 and codon 369were synonymous one and linkage each other;Another one(codon237,CCA→TCA,Arg237stop) is a heterozygous nonsense mutation identified in one patient with autosomal recessive inheritance mode population but not in the 60 normal controls.The others were synonymous mutations.Eight nucleotide variations were found in the PRPH gene.We found no evidence that mutations in the PRPH gene are responsible for the high myopia in Chinese. Key words：high myopia; peripherin gene; PCR-SSCP     

Mechanisms of retinal damage in chloroquine retinopathy

The paper presents the results of comparative electron microscopic, electrophysiological and biochemical studies of chloroquine effect on lipid peroxidation (LPO) both in vitro and in vivo (rabbits and rats). It has been shown that the progress of chloroquine retinopathy was not accompanied by the increment of the initial LPO level, and the use of ionol antioxidant did not protect the retina from the adverse effect of chloroquine. Besides, chloroquine was shown to suppress LPO in vitro. The results obtained substantiate the idea that LPO is not the primary mechanism in chloroquine retinopathy.     

Referral patterns to an ophthalmic outpatient clinic by general practitioners and ophthalmic opticians and the role of these professionals in screening for ocular disease.

Case notes of 1113 consecutive new patients referred to a consultant ophthalmologist at a district general hospital were reviewed to determine the source and efficacy of referrals and the current screening practices of general practitioners and ophthalmic opticians. General practitioners initiated referral in 546 cases (49%) and ophthalmic opticians referral in 439 (39%). Visual loss or visual disturbance was the most important single reason for referral (345 cases; 31%), followed by suspected glaucoma (145 cases; 13%), abnormalities of binocular vision (140; 12.5%), disorders of eyelids or ocular adnexa (127; 11%), and red eye (86; 8%). General practitioners referred many more patients with disorders of the eyelids and adnexa and ophthalmic opticians many more patients with suspected glaucoma. Ophthalmic opticians were far more likely than general practitioners to refer patients with suspected glaucoma correctly. A total of 180 patients (16%) were referred from ocular screening, in 149 cases by ophthalmic opticians and in 10 by general practitioners. Seventy patients had glaucoma or incomplete features of glaucoma, all of them referred by ophthalmic opticians. Of eight diabetic patients referred by ophthalmic opticians, three had asymptomatic disease and in two diabetes was diagnosed as a result of ocular screening. No patient was referred for asymptomatic diabetic retinopathy from screening by general practitioners. Ophthalmic opticians were more likely than general practitioners to diagnose retinopathy requiring photocoagulation. Use of a community based service to screen for glaucoma could save unnecessary consultant outpatient appointments. A similar service could facilitate detection of diabetic retinopathy at a stage when treatment is most effective.     

Association between retinal neuronal degeneration and visual function impairment in type 2 diabetic patients without diabetic retinopathy

The changes in retinal thickness and visual function in type 2 diabetic patients without clinical evidence of diabetic retinopathy were evaluated. A total of 141 diabetic subjects without retinopathy and 158 healthy subjects were enrolled in this study. Superior macular ganglion cell complex thicknesses were significantly decreased in diabetic cases, and no significant peripapillary retinal nerve fiber layer thickness changes were observed. The contrast sensitivities at all space frequencies were significantly different between diabetic patients and controls. The mean P50 amplitude from pattern electroretinogram results was reduced significantly in the diabetic group. In the diabetic group, average superior ganglion cell complex thicknesses positively correlated with both contrast sensitivities at high spatial frequencies and P50 amplitudes. The results indicated that ganglion cell complex thickness and visual function changes could be observed in diabetic subjects before the onset of any significant diabetic retinopathy. Macular ganglion cell complex reduction occurred much earlier than peripapillary retinal nerve fiber layer thinning in diabetic patients without retinopathy.     

Decrease in circulating DNA, IL-10 and BAFF levels in newly-diagnosed SLE patients after corticosteroid and chloroquine treatment

Arsenal of pattern-recognition receptors alongside antibody production machinery make B cells vulnerable to autoimmune response if an autoantigen elicits both pathways in a self-sustained fashion. Systemic lupus erythematosus is an autoimmune disease characterized by autoantibodies to DNA, RNA and related structures. Murine studies demonstrated autoreactive B cell activation upon TLR9 stimulation with DNA-containing immune complexes. This activation could be abolished with chloroquine, a drug used in SLE treatment that also blocks TLR9 signaling. We investigated whether chloroquine modulates TLR9 expression, circulating DNA levels and B cell-related cytokines in newly discovered, untreated SLE patients. TLR9 was measured in peripheral blood B cells by flow cytometry, serum DNA by real-time PCR, and IL-10 and BAFF by ELISA before treatment, after 3weeks on corticosteroids, and 3months after introduction of chloroquine. We found that circulating DNA is higher in SLE patients than in controls in every time-point and decreases significantly after chloroquine treatment. Untreated patients had higher serum IL-10 than controls or patients on corticosteroids. Also, corticosteroids decreased and chloroquine completely abolished CpG-mediated CD86 upregulation on B cells and IL-10 secretion in PBMC culture. Providing the TLR9 pathway activation demonstrates its importance in pathogenesis of human SLE, this data supports continuation of chloroquine in SLE treatment protocol. In addition, observed modulation of cytokine and DNA levels after immunomodulatory treatment prompts for inclusion of untreated patients in studies of human immune disorders.     

Chloroquine alters the processing of secretin in isolated rat pancreatic acinar cells

In this study we considered the effect of chloroquine on the processing and intracellular distribution of internalized secretin radioligand in acinar cells. Chloroquine (100 microM) had no effect on the total amount of 125I-secretin bound but had marked effects on the processing of this radioligand in acinar cells. After an initial 60 min of radioligand binding in the presence and absence of chloroquine, cells were washed free of unbound radioligand, resuspended and then processed for different times at 37 degrees C. During 60, 120 and 180 min of processing, the amount of internalized radioligand in the presence of 100 microM chloroquine was increased by 116, 194 and 273%, respectively, compared to untreated control samples. Chloroquine also increased the amount of intact 125I-secretin radioligand within the cell as measured by rebinding to pancreatic plasma membranes. After 120 and 180 min of processing, intact peptide within the acinar cell was 25 and 66% greater in the presence of this agent than in control samples (P less than or equal to 0.01). To determine if chloroquine affected intracellular localization of the secretin radioligand, we measured the amount of radioactivity in soluble and particulate fractions of cell homogenates. Chloroquine decreased radioactivity entering particulate fractions of the cell by greater than 35% after 120 and 180 min of processing (P less than or equal to 0.01). This study demonstrates that (1) chloroquine inhibits the intracellular degradation of secretin in acinar cells and (2) chloroquine alters intracellular localization of this peptide during processing.     

Stage-related decrease in natural killer cell activity in untreated patients with mycosis fungoides

Summary Natural killer activity of peripheral blood mononuclear cells against the human cell line K 562 was evaluated in 11 patients with mycosis fungoides and simultaneously in 10 age-and sex-matched controls. In the patient group, nine had no previous treatment and in two topical therapy had been discontinued more than 3 months before. None had any associated disease or concurrent therapy that could interfere with the immune system. Patients with early disease showed a mean specific lysis and a range of individual data similar to the controls whereas patients with advanced disease had a significant defect of natural killer activity at effector: target ratios of 100:1, 50:1, and 25:1, as shown by the Mann-Whitney test. Preincubation of effector cells with -interferon for 1 h in a single patient with low natural killing capacity led to a clear increase of the specific lysis, suggesting reduced functional activity rather than depletion of effector cells.     

Treatment of renal failure from diabetic nephropathy with cadaveric homograft

We report two patients with terminal renal failure secondary to diabetic nephropathy treated with cadaveric kidney transplantation. Neither of these patients had peripheral vascular disease or peripheral neuropathy. There was a proliferative diabetic retinopathy with hemorrhages and exudates in one patient and only background diabetic changes in the ocular fundi of the other; there have been no significant changes in visual acuity or retinopathy in either patient following the transplantation. Both have good kidney function after 8 and 15 months and are completely rehabilitated.The requirement for insulin decreased in both patients during the period of renal insufficiency and increased following transplantation; this seemed to be related to the large dose of steroids given because now that a maintenance level of steroids has been established, both patients require the same dosage of insulin as they did before the onset of renal insufficiency.     

红参粉末治疗糖尿病视网膜病变的临床观察

目的：观察红参粉末治疗糖尿病视网膜病变的临床效果。方法：随机选取2012年1月至2012年12月在我院接受治疗的2型糖尿病合并糖尿病视网膜病变（Diabetic Retinopathy,DR）患者103例。其中30例（57眼）仅采用常规方法治疗,即对照组;其余73例（125眼）在常规治疗的基础上加用红参粉末,即观察组。治疗180天后,观察并比较两组患者的视力、眼底镜、荧光血管造影等检查结果的变化情况。结果：在观察组中,患者经红参粉末治疗后的视力与治疗前相比有所提高,差异具有统计学意义（P〈0．05）;而对照组中,患者治疗前后的视力变化无统计学意义（P〉0．05）;观察组治疗有效率为76．7％,而对照组治疗有效率为46．7％,差异有显著意义（P〈0．05）。观察组中,男性DR患者治疗有效率为68．8％、女性为92．0％;早期DR治疗有效率为85．4％、晚期为65．1％;糖尿病病程不超过10年的DR患者治疗有效率为88．9％、超过10年的为64．9％,差异均具有统计学意义（P〈0．05）。结论：尽早的发现和及时的治疗可减少糖尿病患者视网膜病变的发生率,从而避免因视网膜病变而引起的严重的视力下降,甚至失明。红参粉末治疗糖尿病视网膜病变有显著的临床效果,特别是对早期糖尿病视网膜病变的疗效更佳,值得临床推广。