D-Penicillamine administration and the incidence of retinopathy of prematurity.

OBJECTIVE: We compared the development of retinopathy of prematurity (ROP) among 49 preterm neonates:; 15 who were treated during the first 2 weeks of life with D-penicillamine and 34 who were not. METHODS: During a 15-month period beginning 1 March, 2005, 15 preterm neonates <1000 g birth weight or < or =29 weeks gestation enterally received a 14-day course of D-penicillamine, and 34 did not, in an open-label non-randomized trial. We compared the outcomes of developing 'ROP any stage' and 'ROP requiring surgery' in the recipients vs the non-recipients. Potential toxicities of the D-penicillamine were examined by comparing specific laboratory tests, growth velocities, transfusion requirements, discharge hemoglobin concentrations and supplemental O(2) at discharge. RESULTS: The 34 non-treated and the 15 D-penicillamine treated patients were of similar gestational age (26.5+/-1.8 vs 26.6+/-2.2 weeks, mean+/-s.d.) and birth weight (887+/-222 vs 849+/-187 g). Four of the 34 non-recipients died. Eighteen of the 30 survivors (60%) developed ROP and seven of the 30 (23%) had ROP surgery. One of the 15 D-penicillamine recipients died. Three of the 14 survivors (21%) developed ROP (P=0.01 vs non-recipients) and all three had ROP laser surgery. No increase in elevated creatinine, direct or indirect bilirubin, thrombocytopenia or neutropenia was apparent in those treated with D-penicillamine. The D-penicillamine recipients did not receive more transfusions and did not have lower hemoglobin concentrations at discharge. They did not have lower velocities of weight gain at 14, 28 and 56 days, and were not discharged on supplemental O(2) at a rate exceeding that of the non-recipients. CONCLUSIONS: In this non-randomized, single-centered comparison analysis, a 14-day course of D-penicillamine resulted in no apparent short-term toxicity. The treatment was associated with elimination of Stage I and Stage II ROP, decreasing the overall odds of developing ROP from 60 to 21%. However, this approach did not reduce the odds of ROP surgery. Perhaps higher doses of D-penicillamine or longer treatment periods or other prophylactic approaches will be required to reduce ROP surgery among the most immature neonates.

Current research priorities in chronic fatigue syndrome/myalgic encephalomyelitis: disease mechanisms, a diagnostic test and specific treatments.

Chronic fatigue syndrome (CFS) is an illness characterised by disabling fatigue of at least 6 months duration, which is accompanied by various rheumatological, infectious and neuropsychiatric symptoms. A collaborative study group has been formed to deal with the current areas for development in CFS research--namely, to develop an understanding of the molecular pathogenesis of CFS, to develop a diagnostic test and to develop specific and curative treatments. Various groups have studied the gene expression in peripheral blood of patients with CFS, and from those studies that have been confirmed using polymerase chain reaction (PCR), clearly, the most predominant functional theme is that of immunity and defence. However, we do not yet know the precise gene signature and metabolic pathways involved. Currently, this is being dealt with using a microarray representing 47,000 human genes and variants, massive parallel signature sequencing and real-time PCR. It will be important to ensure that once a gene signature has been identified, it is specific to CFS and does not occur in other diseases and infections. A diagnostic test is being developed using surface-enhanced, laser-desorption and ionisation-time-of-flight mass spectrometry based on a pilot study in which putative biomarkers were identified. Finally, clinical trials are being planned; novel treatments that we believe are important to trial in patients with CFS are interferon-beta and one of the anti-tumour necrosis factor-alpha drugs.

A placebo-controlled, double-blind, randomized controlled trial of a natural killer cell stimulant (BioBran MGN-3) in chronic fatigue syndrome.

BACKGROUND: Previous research has suggested that natural killer (NK) cell activity may be reduced in patients with chronic fatigue syndrome (CFS). AIM: To evaluate the effectiveness of a putative NK cell stimulant, BioBran MGN-3, in reducing fatigue in CFS patients. DESIGN: Randomized, double-blind, placebo-controlled trial. METHODS: We recruited 71 patients with CFS (according to the Centers for Disease Control 1994 criteria) attending an out-patient specialist CFS service. Participants were given oral BioBran MGN-3 for 8 weeks (2 g three times per day) or placebo equivalent. The primary outcome measure was the Chalder physical fatigue score. Self-reported fatigue measures, self-assessment of improvement, change in key symptoms, quality of life, anxiety and depression measures were also included. RESULTS: Data were complete in 64/71 patients. Both groups showed marked improvement over the study duration, but without significant differences. Mean improvement in the Chalder fatigue score (physical scale) was 0.3 (95%CI -2.6 to 3.2) lower in the BioBran group. DISCUSSION: The findings do not support a specific therapeutic effect for BioBran in CFS. The improvement showed by both groups over time highlights the importance of placebo controls when evaluating interventions in CFS.

A pilot trial testing the feasibility of administering D-penicillamine to extremely low birth weight neonates.

OBJECTIVE: We enterally administered a 14-day course of 3-mercapto-D-valine (D-penicillamine) to five extremely low birth weight (ELBW) neonates, as a step toward assessing this therapy as a means of reducing the incidence or severity of retinopathy of prematurity (ROP). METHODS: The study drug (100 mg/ml) was given by nasogastric tube at a dose of 100 mg/k every 8 h for three days, and then 50 mg/k once per day for 11 additional days. Logbooks were maintained by the bedside nurses to record signs of possible immediate intolerance. Laboratory tests assessed hepatic, renal, and hematologic toxicity. ROP was scored according to the ICROP guidelines. Comparisons were with a cohort of 139 consecutive recent neonates of the same birth weight and gestational age range. RESULTS: Five neonates were enrolled in the study, and all received the full course of study drug as planned. Signs of immediate intolerance of the study drug were not observed in any. The study patients did not have a higher incidence, than that of the cohort group, in creatinine elevation, thrombocytopenia, neutropenia, hyperbilirubinemia, or abnormal liver function test. Four of the five had no ROP and one developed transient stage 1, compared with a 54% occurrence of ROP in the cohort. CONCLUSIONS: It is feasible to enterally administer a 14-day course of 3-mercapto-D-valine to ELBW neonates and the suspension appears to be well tolerated. These results suggest that phase II safety and preliminary efficacy trials can be undertaken.

Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) is a multisystem disease, the pathogenesis of which remains undetermined. AIMS: To test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared with normal healthy persons. METHODS: To gain further insight into the pathogenesis of this disease, gene expression was analysed in peripheral blood mononuclear cells from 25 patients with CFS diagnosed according to the Centers for Disease Control criteria and 25 normal blood donors matched for age, sex, and geographical location, using a single colour microarray representing 9522 human genes. After normalisation, average difference values for each gene were compared between test and control groups using a cutoff fold difference of expression > or = 1.5 and a p value of 0.001. Genes showing differential expression were further analysed using Taqman real time polymerase chain reaction (PCR) in fresh samples. RESULTS: Analysis of microarray data revealed differential expression of 35 genes. Real time PCR confirmed differential expression in the same direction as array results for 16 of these genes, 15 of which were upregulated (ABCD4, PRKCL1, MRPL23, CD2BP2, GSN, NTE, POLR2G, PEX16, EIF2B4, EIF4G1, ANAPC11, PDCD2, KHSRP, BRMS1, and GABARAPL1) and one of which was downregulated (IL-10RA). This profile suggests T cell activation and perturbation of neuronal and mitochondrial function. Upregulation of neuropathy target esterase and eukaryotic translation initiation factor 4G1 may suggest links with organophosphate exposure and virus infection, respectively. CONCLUSION: These results suggest that patients with CFS have reproducible alterations in gene regulation.

Hydrogen peroxide as a protective agent during reperfusion. A study in the isolated perfused rabbit heart subjected to regional ischemia.

In spite of extensive research during the last decade it has not been possible to prove that endogenously generated hydrogen peroxide or any reduced oxygen species reaches sufficient concentration during reperfusion after myocardial ischemia to contribute significantly to irreversible cell injury. In an attempt to further test this hypothesis we subjected isolated perfused rabbit hearts to 30 min regional ischemia followed by reperfusion and supplied hydrogen peroxide in low levels with or without catalase during the first 30 min of reperfusion and thereafter continued the reperfusion for a total of 120 min. Five different groups were studied: controls, and hearts supplied with 2 microM H2O2, 1 microM H2O2, 1 microM H2O2 + catalase (IU/l) or catalase alone in the initial part of the reperfusion. At the end of 120 min reperfusion, area at risk was measured with fluorescent particles and infarct zone size with tetrazolium staining. The results were: in the control group 32 +/- 5.0% of the risk zone infarcted, in the 2 microM H2O2 group 16.3 +/- 5.6% and in the 1 microM H2O2 group 6.9 +/- 0.8% (P < 0.05 compared to control). The reduction in infarct size was not present when catalase was added to the hydrogen peroxide-containing solution (26.4 +/- 4.5) or if catalase was present alone (22.9 +/- 1.8% infarction). In conclusion, hydrogen peroxide, 1 microM, protected the heart during reperfusion and reduced the amount of cell death after 120 min of reperfusion. The study demonstrated reduction or delay in infarction based only on treatment in the reperfusion period. The mechanism behind this protection remains to be determined.

Pattern dystrophy and retinitis pigmentosa caused by a peripherin/RDS mutation.

PURPOSE: To describe the clinical and molecular genetic findings in members of a family with features of autosomal dominant retinitis pigmentosa (RP) and pattern dystrophy. METHODS: Members of a four-generation family underwent ophthalmoscopic examination, electrophysiologic testing, and screening of blood samples for rhodopsin and peripherin/RDS mutations. RESULTS: Three members of the family had clinical evidence of both RP and pattern dystrophy, and another family member had symptoms suggestive of RP. In one case of pattern dystrophy, pigment deposition in an unusual ring-like configuration was seen. All affected family members were found to have a Pro216Ser mutation in the peripherin/RDS gene on chromosome 6p, a mutation not found in unrelated (normal) spouses or in a normal control population. CONCLUSION: In members of this family, both autosomal dominant RP and pattern dystrophy were associated with a Pro216Ser mutation in the peripherin/RDS gene.

Personal continuity and the care of patients with epilepsy in general practice.

BACKGROUND: So far no study has shown that patients with a chronic illness benefit from seeing the same doctor in general practice although many believe this to be so. AIM: Epilepsy was chosen as an example to test the hypothesis that if patients see the same doctor more often in general practice they are more likely to discuss personally important aspects of their illness. METHODS: In this cross-sectional survey 99 patients aged 15-84 years with active epilepsy were interviewed at home and then their records were reviewed. The patients came from four large Southampton group practices, one with a strict personal list system and three with combined lists. Outcome measures included reported discussion of feelings about stopping medication, stigma and concealment and the patient's relationship with practice doctors. Continuity was assessed from the records. RESULTS: Discussion of epilepsy was not significantly associated with continuity of doctor but was significantly associated with ease of talking to one or more doctors. CONCLUSION: Encouraging patients with epilepsy to see the same doctor may be less important than improving doctors' communication skills and paying specific attention to the psychosocial aspects of epilepsy as well as to seizure control. It is recommended that a simple checklist including these items is used when a patient's care is reviewed.

Evidence that the adenosine A3 receptor may mediate the protection afforded by preconditioning in the isolated rabbit heart.

OBJECTIVE: Agonists selective for the A1 adenosine receptor mimic the protective effect of ischaemic preconditioning against infarction in the rabbit heart. Unselective adenosine antagonists block this protection but, paradoxically, the A1 adenosine receptor selective antagonist 8-cyclopentyl- 1,3-dipropylxanthine (DPCPX) does not. The aim of this study was to test the hypothesis that the newly described A3 adenosine receptor, which has an agonist profile similar to the A1 receptor but is insensitive to DPCPX, might mediate preconditioning. METHODS: Isolated rabbit hearts perfused with Krebs buffer experienced 30 min of regional ischaemia followed by 120 min of reperfusion. Infarct size was measured by tetrazolium staining. RESULTS: In control hearts infarction was 32.2(SEM 1.5)% of the risk zone. Preconditioning by 5 min ischaemia and 10 min reperfusion reduced infarct size to 8.8(2.3)%. Replacing the regional ischaemia with 5 min perfusion with 10 microM adenosine or 65 nM N6-[2-(4-aminophenyl)ethyl]adenosine (APNEA), an adenosine A3 receptor agonist, was equally protective. The unselective antagonist 8-p-sulphophenyl theophylline at 100 microM abolished protection by preconditioning, adenosine, and APNEA, but 200 nM DPCPX did not block protection by any of the interventions. Likewise the potent but unselective A3 receptor antagonist 8-(4-carboxyethenylphenyl)-1,3-dipropylxanthine (BW A1433) completely blocked protection from ischaemic preconditioning. CONCLUSIONS: Because protection against infarction afforded by ischaemic preconditioning, adenosine, or the A3 receptor agonist APNEA could not be blocked by DPCPX and because the potent A3 receptor antagonist BW A1433 blocked protection from ischaemic preconditioning, these data indicate that the protection of preconditioning is not exclusively mediated by the adenosine A1 receptor in rabbit heart and could involve the A3 receptor.

Is personal continuity of care compatible with free choice of doctor? Patients' views on seeing the same doctor.

While much has been written about the benefits of personal continuity of care there has been little research about the views of patients. In this cross sectional study 111 patients from three group practices (one of which ran a personal list system) were interviewed at home within a week of consulting a general practitioner. Patients were selected randomly from a systematic series of consulting sessions and a semi-structured interview was administered. Patients receiving more personal continuity of care were likely to be older, to have booked their most recent appointment further in advance, to desire personal continuity of care, to have an external health locus of control and to have a lower extroversion score. In the practice with a personal list, patients had a high level of continuity of care, were satisfied and showed little interest in having a choice of doctor. In the combined list practices patients valued their choice of doctor but often could not exercise it enough and they were more critical. They made more suggestions for change than those in the practice with a personal list system, mostly about receptionists and appointments. It is concluded that most patients like to see the same doctor, but they may not be willing to wait two days for this if there is a quicker option. It may be difficult to deliver both personal continuity of care and choice in group practice.

Complications of retinotomies for subretinal fluid drainage.

We reviewed 287 cases of pars plana vitrectomy performed between January 1985 and June 1990 in which retinotomies were created for drainage of subretinal fluid or blood. We found subretinal neovascularization associated with the retinotomy site in two cases (1%) and focal proliferative vitreoretinopathy associated with the retinotomy site in seven cases (2%). These complications were more likely to occur with retinotomies made within the superior macular region (p = 0.002).

Pars plana vitrectomy for macular degenerative disorders.

We describe nine patients (10 eyes) treated with pars plana vitrectomy for vitreous hemorrhage secondary to disciform macular degeneration. Nine of the eyes showed improved acuity at about 3 months and at the last follow-up visit (6 to 30 months). Two of the patients had ambulatory acuity (counting fingers or better) before surgery, compared with all the patients at the last follow-up visit. Vitrectomy may be beneficial in this subgroup of patients with macular degeneration.

How much personal care in four group practices?

OBJECTIVE: To establish the degree of continuity of care in general practice. DESIGN: Retrospective study of the records of all eligible patients attending the surgery at randomly selected sessions. SETTING: Four large group practices in the Southampton Health District, one of which operated a strict system of personal lists. PATIENTS: 776 Patients who had been registered for at least two years and had consulted at least 12 times over six years or less. MAIN OUTCOME MEASURES: Continuity score for each patient calculated from the number of consultations (out of the past 12) with his or her usual doctor. Number of the times the patients had consulted the doctor with whom they were registered. RESULTS: In the practice with personal lists a mean of 10 of the 12 consultations had been with the same doctor (83% of consultations), but in the three practices with combined lists the means were 5.9 (49%), 6.2 (52%), and 6.9 (58%). Continuity was associated with increased age and with the recording of a major problem. In the practices with combined lists 63 of 72 children consulted at least five different doctors. Only 140 of 489 patients currently in the practice who were identified as being registered with a doctor had most usually consulted that doctor in the practices with combined lists. CONCLUSIONS: Personal continuity of care may be fairly low in group practice, especially for younger and healthier patients registered at practices with combined lists. These findings support the Department of Health's recent decision to make "target payments" (for cervical smears and childhood immunisations) to groups rather than to individual principals but pose a question for the future of individual clinical responsibility.

Clinical evaluation of the Holladay and SRK II formulas.

We compared the accuracy of the Holladay and SRK II intraocular lens power calculation formulas with that of two commonly used formulas, the Binkhorst and SRK. We found no significant difference between the accuracy of the four formulas in cases of posterior chamber lens implantation. For anterior chamber lenses, the SRK II formula was significantly less accurate than the other three formulas in eyes with long axial length.

Evaluation of the biocompatibility and fixation of a new silicone intraocular lens in the feline model.

The biocompatibility and fixation of a new silicone intraocular lens was evaluated in the cat eye. Following extracapsular lens extraction, 14 cats were implanted with a silicone lens (SLM 2/UV type) with polypropylene modified J loops in one eye and a poly(methyl methacrylate) (PMMA) lens (Perspex CQ) of a similar design in the fellow eye. Half the lenses were placed in the ciliary sulcus and half in the capsular bag. The eyes were evaluated for up to one year. Neither lens material showed any signs of toxicity clinically or histopathologically. Both lenses achieved stable fixation in the capsular bag; however, some inflammatory reaction and lens dislocation were noted with sulcus placement of both lens types. The amount of proteinaceous and cellular debris on the explanted silicone lenses was significantly less than that on the PMMA lenses as assessed with methylene blue staining. All retrieved lenses were optically clear and no significant change in the lens surface morphology, clarity and/or optical properties was observed.

Long-term course of surgically induced astigmatism.

We performed an analysis of surgically induced astigmatism in 229 cases of extracapsular cataract extraction and posterior chamber lens implantation. The average length of follow-up for patients in this study was 34.4 months (2.87 years). We found that surgically induced astigmatism continued to change for at least three years after surgery. The preoperative astigmatism was found to have only minimal effect on the postoperative astigmatism if the corneal curvature was controlled with keratometry at the time of surgery. The optimal amount of with-the-rule astigmatism at three to five weeks postoperatively was found to be 0.75 diopter to 1.25 diopters for one surgeon and surgical technique.

Transcorneal extrusion of anterior chamber intraocular lenses. A report of three cases.

We examined three cases of transcorneal extrusion of anterior chamber intraocular lenses. In each case a preexisting condition (rheumatoid arthritis, glaucoma, and herpes zoster ophthalmicus, respectively) contributed to corneal necrosis and subsequent extrusion of the pseudophakos. The clinicopathologic correlations of this condition are discussed, as well as some causes of corneal decompensation associated with anterior chamber lenses. We emphasize the need for careful evaluation of patients who have preexisting disease before intraocular lens implantation.

Anterior chamber lenses. Part I: Complications and pathology and a review of designs.

Clinicopathologic data to assist ophthalmologists in choosing a safe and efficacious anterior chamber intraocular lens (IOL) are rapidly becoming available. Two important factors that have led to an increased success rate with some anterior chamber IOL styles are (1) attention to lens design and (2) attention to modern manufacturing and lens finishing techniques. We now know much more about how to achieve appropriate lens flexibility, which decreases the need for perfect sizing. Increased attention has been given to the anterior-posterior vaulting characteristics of IOLs. This has reduced the incidence of various complications such as the intermittent touch syndrome and the uveal chafing syndrome. We recognize several design flaws in some lens styles. For example, there is now a considerable decrease in the number of small-diameter, round-looped anterior chamber IOLs being implanted, particularly those with a closed-loop configuration. Several problems have been and continue to be caused by some poorly manufactured anterior chamber lenses with sharp optic and haptic edges. Technology to assure smooth lens finishing and polishing is available and readily accessible to all manufacturers. Defective lenses should soon be a thing of the past.

Anterior chamber lenses. Part II: A laboratory study.

An analysis of 606 surgically removed anterior chamber intraocular lens (IOL) specimens revealed that 351 or 58% of these were small-diameter, round loop, closed-loop styles. Because of the extremely high percentage of IOLs with this design received in our laboratory and the correlation of clinical histories with our histopathologic findings, we have concluded that such IOLs do not provide the safety and efficacy achieved by other anterior chamber lens designs. The finely polished, one-piece, all-PMMA styles fared well in our study. Although these one-piece styles comprise well over 50% of the American market share of anterior chamber IOLs, they comprise only 14% of all anterior chamber IOLs accessioned in our laboratory, compared to 58% for closed-loop designs. We believe that implantation of anterior chamber lenses with small-diameter, round, closed loops is no longer warranted. Patients in whom these IOLs have already been implanted should be carefully followed. It is our opinion that the FDA should recall or closely monitor all IOLs of this design and that implantation of closed-loop lenses should be discontinued in the United States. Furthermore, we believe that an IOL deemed to be not medically sound or worthy of implantation in the United States should not be marketed or donated outside of this country.