Replacement risk of amalgam treatment modalities: 15-year results

OBJECTIVES: To develop a protocol capable of identifying deletions in mitochondrial DNA and use it to identify the breakpoints of a mtDNA deletion in a patient with chronic progressive external ophthalmoplegia (CPEO). DESIGN AND METHODS: Deletions in mtDNA were identified by a combination of long range PCR and Southern blotting. The precise breakpoints were determined by automated DNA sequencing. RESULTS: A series of DNA samples from patients with suspected mitochondrial disease was subjected to a protocol, which combines long range PCR and Southern blotting. We found a unique deletion in a patient with CPEO and we identified the precise location of this deletion through DNA sequencing. CONCLUSIONS: Long range PCR has the advantages of speed, minimal samples requirements, and sensitivity. Southern blotting is better able to evaluate heteroplasmy and detect duplications. We suggest a protocol that enables us to identify precisely the breakpoints in a unique mutation of mtDNA in a patient with CPEO.     

Diabetes associated with a novel 3264 mitochondrial tRNA(Leu)(UUR) mutation

OBJECTIVE: To present a novel mitochondrial DNA mutation in a diabetic family RESEARCH DESIGN AND METHODS: The proband was a 64-year-old man. In the family, diabetes was maternally inherited. He had diabetes, cerebellar ataxia, cervical lipoma, hearing loss, olfactory dysfunction, ophthalmoplegia, and facial nerve bilateral palsy. On examination, early insulin secretion was blunted, and the M value on glucose clamp test was low. In muscle, ragged red fibers were not found. T-to-C mutation at position 3264 was detected in the proband (0.5% mutant DNAs in leukocyte and 30% in muscle), but was not detected in 201 normal individuals. RESULTS: Heteroplasmy of mutation, maternal inheritance of diabetes, and symptoms related to mitochondrial dysfunction suggest the pathogenecity of this 3264 mutation. As for diabetes etiology, both impaired insulin secretion and decreased insulin sensitivity seem to be important. In phenotypic characteristics, the combination of cerebellar ataxia and lipoma is a symptom sometimes found in myoclonic epilepsy and ragged red fibers (MERRFs). Ophthamoplegia is a symptom of chronic progressive external ophthalmoplegia (CPEO). These suggest that our proband had phenotypic overlap with MERRF and CPEO. Conversely, facial nerve bilateral palsy is a rare finding. The pictures that focused on his cranial nerves were thus unique, suggesting the heterogeneity of mitochondrial DNA (mtDNA)-related diabetes. CONCLUSIONS: A novel 3264 mitochondrial DNA mutation in diabetes gives new insight to the etiology of mitochondrial diabetes. Its pathogenecity supports the belief that the tRNA(Leu)(UUR) gene is an etiological hot spot of mitochondrial diseases.     

LTP, NMDA, genes and learning

PURPOSE: To describe the results of strabismus surgery on three patients with chronic progressive external ophthalmoplegia, a group of rare disorders characterized by ptosis and slowly progressive ophthalmoparesis that has been shown to result from defects in mitochondrial DNA. METHODS: Strabismus surgery using the adjustable suture technique was performed in three patients with strabismus and chronic progressive external ophthalmoplegia confirmed by clinical, biochemical, histopathologic, and genetic criteria. All three patients had mitochondrial DNA deletions. Two patients were exotropic; one patient was esotropic. RESULTS: Rectus muscle recessions were initially unsuccessful in correcting strabismus in one patient, although a subsequent procedure employing rectus muscle resections was successful in alleviating a significant head turn and improved ocular alignment. In the two other patients, a single procedure consisting of rectus muscle recessions combined with large rectus muscle resections successfully achieved good postoperative alignment. The amount of surgery performed in these three patients exceeded that predicted in standard strabismus tables. CONCLUSIONS: The myopathic process that results in chronic progressive external ophthalmoplegia renders rectus muscle recessions less effective compared with resections for correcting the associated strabismus seen in these patients. Rectus muscle resections therefore should be an integral procedure in the surgical management of the strabismus associated with chronic progressive external ophthalmoplegia.     

Continuous human cell lines inducibly expressing hepatitis C virus structural and nonstructural proteins

Mutations and deletions in mitochondrial DNA (mtDNA) lead to a number of human diseases characterized by neuromuscular degeneration. Accumulation of truncated mtDNA molecules (delta-mtDNA) lacking a specific 4977-bp fragment, the common deletion, leads to three related mtDNA diseases: Pearson's syndrome; Kearns-Sayre syndrome; and chronic progressive external ophthalmoplegia (CPEO). In addition, the proportion of delta-mtDNA present increases with age in a range of tissues. Consequently, there is considerable interest in the effects of the accumulation of delta-mtDNA on cell function. The 4977-bp deletion affects genes encoding 7 polypeptide components of the mitochondrial respiratory chain, and 5 of the 22 tRNAs necessary for mitochondrial protein synthesis. To determine how the accumulation of delta-mtDNA affects oxidative phosphorylation we constructed a series of cybrids by fusing a human osteosarcoma cell line depleted of mtDNA (rho0) with enucleated skin fibroblasts from a CPEO patient. The ensuing cybrids contained 0-86% delta-mtDNA and all had volumes, protein contents, plasma-membrane potentials and mitochondrial contents similar to those of the parental cell line. The bioenergetic consequences of accumulating delta-mtDNA were assessed by measuring the mitochondrial membrane potential, rate of ATP synthesis and ATP/ADP ratio. In cybrids containing less than 50-55% delta-mtDNA, these bioenergetic functions were equivalent to those of cybrids with intact mtDNA. However, once the proportion of delta-mtDNA exceeded this threshold, the mitochondrial membrane potential, rate of ATP synthesis, and cellular ATP/ADP ratio decreased. These bioenergetic deficits will contribute to the cellular pathology associated with the accumulation of delta-mtDNA in the target tissues of patients with mtDNA diseases.     

High proportions of mtDNA duplications in patients with Kearns-Sayre syndrome occur in the heart

Kearns-Sayre syndrome (KSS) is a sporadic multisystem mitochondrial disorder characterized by progressive external ophthalmoplegia, pigmentary retinopathy, onset before age 20, and severe cardiac conduction defects that can lead to death. KSS patients harbor partial deletions of mitochondrial DNA (delta-mtDNA), sometimes associated with the corresponding mtDNA duplication (dup-mtDNA). As reports on the distribution of dup-mtDNAs among KSS tissues are scarce, we searched for the presence of dup-mtDNAs in different autopsy tissues of two such patients, one of whom carried the so-called "common deletion." Using a newly developed long polymerase chain reaction (PCR) protocol in conjunction with Southern blot analyses, we found dup-mtDNAs in most of the examined tissues from both patients. The proportion of dup-mtDNA in these tissues was much lower than the proportion of delta-mtDNA, with one notable exception: in both patients, we found an unusually high level of dup-mtDNA in the heart. These data suggest that dup-mtDNAs may be more stable in heart tissue of KSS patients than in other long-lived postmitotic tissues.     

Anti-GQ1b ganglioside antibody and ophthalmoplegia of undetermined cause

BACKGROUND/AIM: Serum antibody against ganglioside GQ1b is reported to be closely associated with immune mediated ophthalmoplegia in the Fisher and Guillain-Barré syndromes. Its presence against glycolipids, in particular ganglioside GQ1b, was investigated in patients with ophthalmoplegia of unknown origin. METHODS: 16 patients with ophthalmoplegia, the cause of which could not be confirmed from clinical findings or diagnostic testing, were tested. 34 patients who had ophthalmoplegia of definite cause, 16 healthy people, and 23 patients with typical Fisher syndrome served as the controls. The ELISA was used to check for serum antibodies against glycolipids in all study participants. RESULTS: Two of the 16 patients with ophthalmoplegia of unknown cause had serum IgG antibody against GQ1b but not against other glycolipids, and 22 of the 23 patients with typical Fisher syndrome had this antibody. No anti-GQ1b antibodies were found in the patients with ophthalmoplegia of definite cause or in the normal controls. CONCLUSION: A common underlying cause appears to bring about the pathogenesis of palsy in Fisher syndrome and in the ophthalmoplegia with positive anti-GQ1b IgG antibody, called atypical Fisher syndrome. This antibody may prove a useful clinical marker for differentiating Fisher syndrome, typical and atypical, in patients with ophthalmoplegia.     

What''s in a name? The 22q11.2 deletion

PURPOSE: To document that lacunar, atrophic lesions of the retinal pigment epithelium, previously reported as a complication of treatment, can result from the natural course of retinopathy of prematurity. METHODS: We reviewed photographs of patients diagnosed with retinopathy of prematurity at the Casey Eye Institute between 1979 and 1996. Lacunar atrophic lesions of the retinal pigment epithelium were correlated with the clinical records of the affected patients. RESULT: Three untreated eyes of three patients with retinopathy of prematurity had lacunar atrophic lesions of the retinal pigment epithelium. CONCLUSIONS: The spectrum of findings associated with untreated retinopathy of prematurity includes lacunar, atrophic lesions of the retinal pigment epithelium. These lesions are distinct from scars secondary to treatment and are possibly linked to macular dragging and exudative or serous retinal detachment.     

A case of chronic progressive external ophthalmoplegia with severe scoliosis

The Authors reports a case of myopathy with severe scoliosis which can be classified within the context of chronic progressive external ophthalmoplegia (CPEO) and discusses the complex etiopathogenetic, histological and clinical aspects of this mitochondrial myopathy. In particular, they underlines the severity of the scoliosis and muscular, bone and respiratory symptoms in this case and the important role played by histological, histochemical and biochemical aspects in the diagnosis.     

Long-term results of the Angelchik prosthesis for gastro-oesophageal reflux

INTRODUCTION: Between 1982 and 1989, 46 patients had insertion of an Angelchik prosthesis for gastro-oesophageal reflux. Eleven patients (24 per cent) subsequently had the prosthesis removed, all but one for intractable dysphagia. METHODS: Thirty-six of the original patients were followed by questionnaire, and 32 of these had a barium marshmallow swallow investigation. RESULTS: A high proportion of patients (20 of 26) with a prosthesis in situ had symptoms of dysphagia. On objective evaluation by marshmallow swallow, the transit time was significantly slower than that of an age-matched control group (P < 0.01), but showed no significant deterioration with time compared with previous postinsertion studies. CONCLUSION: The Angelchik prosthesis causes long-term dysphagia in a high proportion of patients, severe enough in one-quarter to necessitate its removal. Its continued use cannot, therefore, be recommended.     

Percutaneous removal of a fractured and extruded telectronics accufix atrial retention wire: new approach preserving pacing function

We describe a two-generation family with combined clinical features of myoclonic epilepsy, progressive external ophthalmoplegia (PEO), proximal myopathy, pigmentary retinopathy, progressive deafness, basal ganglia calcification, and ragged-red fibers in a muscle biopsy specimen. One family member died unexpectedly at age 22 years. The molecular tests revealed an A-to-G transition at nucleotide position 3243 of the mitochondrial tRNA(Leu(UUR)) gene. No one in this family had stroke-like episodes. Although the propositus (a 28-year-old woman) had a significant number of white hairs, the percentage of mutant mtDNA in white-hair roots was not different from that in the colored-hair roots. Our findings suggest that the 3243 mutation can be associated with mixed clinical features of myoclonic epilepsy with ragged-red fibers (MERRF) and PEO and that a preferential increase in the levels of the mutant mtDNA is not related to graying of hair, and hence to the hypothesized production of premature aging of cells.     

Well differentiated cerebellar tissue within a mature cystic teratoma

OBJECTIVE: Oesophageal self-expanding metal endoprostheses (SEMS, or stents) are recognized as a safe means of palliating dysphagia caused by malignancy. Stent designs that have covered or uncovered walls are now available. The purpose of this study was to compare the outcome of use of these two designs. DESIGN: Thirty consecutive cases were reviewed. All the patients had been referred over a period of 25 months for palliation of dysphagia caused by malignant obstruction. Either a covered or an uncovered stent was placed in each patient. Palliation of dysphagia, 30 day mortality, mean survival time, and the number of endoscopic re-interventions required, were assessed. RESULTS: Uncovered Ultraflex stents were used in 14 patients, and Schneider Wallstents were used in 16 patients. Dysphagia improved by one grade or more in 69% of patients. The 30 day mortality was 27%, with an overall mean survival time of 99 days. There was no significant difference between the two groups for these three parameters. Ten patients needed a total of 28 repeat endoscopic procedures to maintain stent patency, with overall rates for each group of 1.64 procedures per patient, for uncovered stents, compared with 0.31 for covered stents (significant at the P < 0.05 level). The number of repeat procedures increased with survival time. CONCLUSION: The use of covered self-expanding metal oesophageal endoprostheses is associated with a significant reduction in the need for endoscopic reintervention after stent placement.     

Endoscopic treatment of Zenker's diverticulum using CO2 laser. 17 cases

OBJECTIVES: Various treatment regimens have been used for the management of Zenker's diverticulum. These include surgery (transcervical diverticulectomy, myotomy) and endoscopic treatment with rigid instruments or flexible endoscope. The aim of this study is to report the results of the treatment of Zenker's diverticulum with rigid endoscope applied CO2 laser and to compare them with other types of treatment. PATIENTS AND METHODS: Between May 1991 and November 1996, 17 patients (8 males, 9 females) with symptomatic Zenker's diverticulum underwent endoscopic treatment under short general anesthesia applied CO2 laser. The mean age of the patients was 73.2 years (range: 54 to 97 yrs). All patients had significant symptoms such as dysphagia (15 patients out of 17). All patients were clinically evaluated after the procedure. RESULTS: The endoscopic incision was performed in one session per patient. Symptoms and dysphagia disappeared in all patients except one (dysphagia). Two complications (one cervical emphysema, one fistula) were managed clinically. Mortality was 0%. Mean follow-up was 17 months. There was no recurrence of dysphagia, all patients remained asymptomatic. CONCLUSIONS: Rigid endoscopic treatment of symptomatic Zenker's diverticulum applied with laser CO2 is an efficient and safe method. It should be considered as an alternative therapy for Zenker's diverticulum, especially for patients at a high surgical risk.     

Miller-Fisher syndrome: electrophysiological serial study of five patients

OBJECTIVE: The object of the present study is to show the spectrum of neurophysiological findings during clinical course of Miller Fisher syndrome (MFS), avoiding the controversy over a combined central and peripheral pathology. PATIENTS AND METHODS: We report five patients with a syndrome of ophthalmoplegia, ataxia and areflexia. A similar episode had been suffered previously by 2 of these patients, 14 and 13 years before. In one of them the second episode evolved to a typical Guillain-Barré syndrome (GBS). Motor and sensory conduction velocity of upper and lower limbs, F waves, blink-reflex and somatosensory evoked potentials were recorded in all cases. Needle electromyography in four and brainstem evoked potentials in three of them and the jaw-reflex in another one. RESULTS: In all patients there was a markedly reduced amplitude of the distal sensory evoked response, and no signs of denervation in the EMG. The other results were variable both interindividually and intraindividually. The severity of abnormalities was also different between different patients. The clinical recovery was always accompanied by a improvement of neurophysiological parameters. CONCLUSIONS: The electrophysiological findings in MFS can be variable but they appear always related with the clinical symptomatology. We report for the first time a case in whom the jaw-reflex was abnormal whereas the blink-reflex was normal.     

Swallowing changes in cerebrovascular accidents: incidence, natural history, and repercussions on the nutritional status, morbidity, and mortality

OBJECTIVE: To determine the frequency of dysphagia in CVA, its natural history and value as a risk factor of respiratory infection, malnutrition and death. PATIENTS AND METHODS: A prospective study was made of 187 consecutive patients with cerebrovascular accidents (CVA). A standardized test for dysphagia was done during the first two days of the illness and repeated three days a week. The levels of urea, total proteins and albumin were determined on admission and on discharge. The patients were questioned by phone after 6 months. RESULTS: There was dysphagia of liquids in 36.4% of the patients. The incidence of dysphagia for semisolids was of the same frequency but more severe. Coma was the cause of inability to swallow in 25.7% of the patients. During their stay in hospital one third of the patients with dysphagia died, one third became normal and one third still had dysphagia when they were discharged. After one week, one, three and six months respectively, the cure rate for dysphagia was 29.4%, 4.1%, 55.9% and 55.9%, and survival 83.8%, 67.6%, 61.8% and 60.3%. Thus after 6 months only 3 patients (4.4%) were alive and dysphagic. Half of the 'cures' occurred in the first week, and none occurred after more than 77 days. As compared to the non-dysphagic patients, the dysphagic patients had 10 times more risk of respiratory infection, 18 times higher risk of death, greater loss of albumin and less loss of urea. CONCLUSIONS: There is a high prevalence of dysphagia in CVA and although functional prognosis is not unfavorable, respiratory infections, malnutrition and death are frequent.     

Cost-effective screening for diabetic retinopathy using a nonmydriatic retinal camera in a prepaid health-care setting

OBJECTIVE: To assess the efficacy of using a nonmydriatic Polaroid retinal camera as a method for screening diabetic patients for treatable diabetic retinopathy. RESEARCH DESIGN AND METHODS: All 522 diabetic patients followed in a health maintenance organization-affiliated diabetes program had retinal photos taken. Compliance with the routine referral to one of two retinal specialists (the examiners) was 74%. The results from the examiners were compared with the results of the reader of the retinal photos. RESULTS: Sensitivity was 100% and specificity was 82% for the diagnosis of serious diabetic retinopathy (preproliferative or proliferative retinopathy or macular edema) by the examiners compared with the diagnosis of any diabetic retinopathy by the reader. No patient had serious diabetic retinopathy inside or outside the photographic field that was missed because all patients with serious diabetic retinopathy showed some diabetic retinopathy within the photographic field. The reader tended to underrate the severity of the diabetic retinopathy, but when the reader diagnosed serious diabetic retinopathy, it was always present on exam. CONCLUSIONS: The nonmydriatic retinal camera is easy to use, inexpensive, and can be used as part of a general diabetes exam, independent of a physician, in patients who should, but may not, be referred to an ophthalmologist. Any patient with abnormal findings on photos should be referred to an ophthalmologist, and any patient with findings of serious diabetic retinopathy on the photos should be referred immediately for possible laser therapy.     

Chronic progressive external ophthalmoplegia

Two cases of chronic progressive external ophthalmoplegia were described. Both of them presented with progressive bilateral ptosis and gradual impairment of ocular mobility. One of the patients had abnormal cerebrospinal fluid protein level. Another patient had muscle biopsy which was compatible with mitochondrial myopathy. Other possible causes of chronic progressive external ophthalmoplegia had been excluded by appropriate investigations. Chronic progressive external ophthalmoplegia is now considered as one type of mitochondrial diseases. Missed diagnosis of this syndrome is common in clinical practice.     

Binding of squalene, lanosterol, desmosterol, and cholesterol to proteins in brain and liver 105,000 g supernatant fractions: evidence for specific binding sites

Peak angular saccadic velocities were measured during 30 degrees saccades in 18 patients with internuclear ophthalmoplegia who had full or nearly full adduction range, and 25 normal subjects. The following observations were made: 1. In the normal group adduction velocities were significantly faster than abduction velocities and centring movements were faster than decentring movements. 2. In patients with internuclear ophthalmoplegia adduction movements were significantly slower than in normal subjects and were significantly slower than abduction velocities. 3. Abduction velocities in patients with internuclear ophthalmoplegia were significantly slower than abduction velocities in normal subjects. It was concluded that measurements of peak angular velocities during saccades may be useful in detecting internuclear ophthalmoplegia or confirming the presence of suspected internuclear ophthalmoplegia. Slow abduction suggests that many patients with internuclear ophthalmoplegia (60 per cent in this series) have lesions affecting the supranuclear pathways subserving horizontal conjugate gaze.     

Tumor vascularity predicts recurrence in differentiated thyroid carcinoma

Insulin treatment is reportedly associated with the transient progression of retinopathy, possibly with the development of macular oedema in middle-aged Type 2 diabetic patients. The purpose of this study was to investigate the effect of insulin treatment on eye-grounds in elderly (> 65-year-old) Type 2 diabetic patients with secondary failure of oral antidiabetic-drug therapy. Eye examinations were performed in 37 patients randomized to insulin (n = 19) or sulphonylurea (n = 16) treatment and re-investigated after one year. Insulin treatment reduced HbA1c from 9.3% to 7.3% (p < 0.001) after one year. In the sulphonylurea-treated group, HbA1c did not change (9.1 vs. 9.3%). At the start, 65% of the patients had retinopathy, and after one year progression was noted in 7/35 patients (20%; 5 insulin- and 2 sulphonylurea-treated). In the insulin-treated group, the 5 patients with progression had higher initial fasting blood-glucose levels than other patients in the group (15.8 vs 13.1 mmol/L, p < 0.05). Initial HbA1c levels did not differ between the groups (9.8 vs. 9.1%, n.s.), nor the reduction of HbA1c levels during treatment (2.2 vs. 1.3% n.s.). Thus, diabetic retinopathy in this study was common among elderly Type 2 diabetic patients. The progression of retinopathy may in fact be associated with insulin treatment or improvement of metabolic control.     

Longer-term visual outcome of eyes with retinopathy of prematurity treated with cryotherapy or diode laser

AIMS: Visual outcome of 66 eyes in 37 patients who had undergone treatment with either cryotherapy or diode laser for threshold retinopathy of prematurity was assessed. METHODS: 17 patients, representing 30 eyes treated with cryotherapy, were examined at between 56 and 98 months corrected age (median 68 months). 20 patients representing 36 eyes treated with diode laser, were examined at between 30 and 66 months corrected age (median 51 months). Structural outcome was categorised as: optimal--flat posterior pole; suboptimal--macular ectopia, optic nerve hypoplasia, retinal fold involving the macula, and retinal detachment involving the macula. RESULTS: Optimal structural outcome was, in the absence of amblyopia, associated with optimal visual acuity (of 6/12 or better) in all cases, with most eyes achieving a visual acuity of 6/9 or 6/6. Suboptimal structural outcome was invariably associated with suboptimal visual acuity. Amblyopia was present in eight out of 20 cryotherapy treated eyes and in five out of 26 laser treated eyes with an optimal structural outcome. Refractive errors were significantly less in laser treated eyes as was the incidence of anisometropic amblyopia. CONCLUSION: Eyes treated with either cryotherapy or diode laser for threshold retinopathy of prematurity with optimal structural outcome are associated with development of optimal visual acuity--that is, 6/12 or better. Treatment with either cryotherapy or laser does not in itself reduce the visual potential of these eyes.     

Endoscopic treatment of malignant dysphagia

Palliative endoscopic treatment of dysphagia in patients with inoperable oesophageal cancer includes: dilation, Nd:YAG laser photocoagulation and intubation, used alone or in combination. Such procedures are usually performed on an outpatient basis and are associated with a low rate of morbidity and mortality. From 1978 to 1988, 476 patients (401 males, 75 females) were treated at the Endoscopy division of the National Cancer Institute of Milan for inoperable primary or recurrent malignancies of the oesophagus or cardia or for extra-oesophageal neoplasms causing dysphagia. Dilation was used in 172 cases, Nd:YAG laser photocoagulation in 90, prosthesis insertion in 72, dilation and laser in 97, and prosthesis and laser in 45. Functional improvement was reported in 75% of patients after dilation, in 89% after laser treatment, in 80% after intubation, in 80% after dilation and photocoagulation, and in 89% after laser and intubation. The median duration of dysphagia-free interval was 4 weeks in dilated patients, 6-8 weeks in photocoagulated patients and 20 weeks intubate patients. Overall median survival was 6.2 months. The complication rate was: 1.4% in dilation treatment, 1.4% in laser photocoagulation, and 8.8% in prosthesis intubation. Mortality related to endoscopic treatment was 2.1% (10/476 patients). Relief of dysphagia is one of the most important goals of palliative treatment in patients with inoperable oesophageal neoplasms. Moreover, endoscopic palliation improves the quality of life in the patients, with a low complication rate.