Successful multimodality treatment of recalcitrant necrobiotic xanthogranuloma using electron beam radiation and intravenous immunoglobulin.

Necrobiotic xanthogranuloma (NXG) is a rare dermatosis with a poorly understood pathophysiology. Studies comparing treatments for such lesions are limited. We present the case of a patient with a 30-year history of NXG refractory to several individual therapeutic interventions [excision, intravenous immunoglobulin (IVIg), systemic chemotherapies and immunosuppressants, cryotherapy and laser therapy], who ultimately responded to a combination of treatment with electron beam radiation therapy (EBRT) in conjunction with IVIg. This combined treatment resulted in flattening of the NXG lesions and a reduction of symptomatic pruritus within the treatment zone. EBRT may represent a potent treatment for NXG, and formal trials evaluating its effectiveness may yield insights into the management of NXG.

Over expression of a cytochrome P450 (CYP6P9) in a major African malaria vector, Anopheles Funestus, resistant to pyrethroids.

Anopheles funestus Giles is one of the major African malaria vectors. It has previously been implicated in a major outbreak of malaria in KwaZulu/Natal, South Africa, during the period 1996 to 2000. The re-emergence of this vector was associated with monooxygenase-based resistance to pyrethroid insecticides. We have identified a gene from the monooxygenase CYP6 family, CYP6P9, which is over expressed in a pyrethroid resistant strain originating from Mozambique. Quantitative Real-Time PCR shows that this gene is highly over expressed in the egg and adult stages of the resistant strain relative to the susceptible strain but the larval stages showed almost no difference in expression between strains. This gene is genetically linked to a major locus associated with pyrethroid resistance in this A. funestus population.

Psychosis in Parkinson's disease.

Psychosis is common in Parkinson's disease (PD), particularly in its later stages. The symptoms range from comparatively minor illusions, vivid dreams, and occasional, non-disturbing visual hallucinations to frank psychosis. The pathogenesis of psychosis in PD is not fully known. Management of psychosis in PD requires a multidisciplinary approach. Some of the newer atypical antipsychotics are effective against psychosis with no significant worsening of PD. Psychosis in PD is associated with poor quality of life for patients and the carers.

Update on myasthenia gravis.

Myasthenia gravis is an autoimmune disorder caused by autoantibodies against the nicotinic acetylcholine receptor on the postsynaptic membrane at the neuromuscular junction and characterised by weakness and fatigability of the voluntary muscles. It has a bimodal peak of incidence with first peak in the third decade and the second peak in the sixth decade. It is probably underdiagnosed in the very old population. Our understanding of the pathogenesis, immunology, and molecular biology of myasthenia gravis has greatly improved in last three decades. It is almost always possible to establish the diagnosis of myasthenia gravis with the current tests. The modern treatment is highly successful and the mortality of treated myasthenia gravis is practically zero. However, there are still important gaps in our knowledge of the origin of myasthenia gravis, the factors that contribute to chronic disease, and the way to cure the disease. In this article the current knowledge of the various aspects of myasthenia gravis are outlined.

Long term motor complications of levodopa: clinical features, mechanisms, and management strategies.

Levodopa is the most effective symptomatic treatment of Parkinson's disease. However, after an initial period of dramatic benefit, several limitations become apparent including, "dopa resistant" motor symptoms (postural abnormalities, freezing episodes, speech impairment), "dopa resistant" non-motor signs (autonomic dysfunction, mood and cognitive impairment, etc), and/or drug related side effects (especially psychosis, motor fluctuations, and dyskinesias). Motor complications include fluctuations, dyskinesias, and dystonias. They can be very disabling and difficult to treat. Therefore, strategies should ideally be developed to prevent them. Though mechanisms underlying motor complications are only partially understood, recent work has revealed the importance of pulsatile stimulation of postsynaptic dopamine receptors and the disease severity. As a result of intermittent stimulation there occurs a cascade of changes in cell signalling leading to upregulation of the N-methyl-D-aspartate subtype of gamma-aminobutryric acid-ergic neurones. Modified preparations of levodopa (controlled release preparations, liquid levodopa), catecholamine-o-methyltransferase inhibitors, dopamine agonists, amantidine, and various neurosurgical approaches have been used in the prevention and/or treatment of motor complications. Current management of motor complications is less than satisfactory. With better understanding of the pathogenetic mechanisms, it is hoped that future therapeutic strategies will provide a safer and targeted treatment.

Value of routine duodenal biopsy in diagnosing coeliac disease in patients with iron deficiency anaemia.

BACKGROUND: Iron deficiency anaemia (IDA) is a recognised feature of coeliac disease in adults and can be its only presentation. OBJECTIVE: To determine the yield of routine distal duodenal biopsies in diagnosing coeliac disease in adult and elderly patients with IDA whose endoscopy revealed no upper gastrointestinal cause of iron deficiency. STUDY DESIGN: Prospective study in a teaching hospital endoscopy unit. METHOD: Altogether 504 consecutive patients with IDA, aged 16-80 years, attending for endoscopy were included in this study. At least two distal duodenal biopsies were taken if endoscopy revealed no cause of iron deficiency. RESULT: In nine (1.8%) patients duodenal biopsies revealed typical histological features of coeliac disease. Of these, five patients were above 65 years old. CONCLUSION: In adult and elderly patients undergoing endoscopy for IDA, the endoscopist should take distal duodenal biopsies to exclude coeliac disease if no upper gastrointestinal cause of anaemia is found. Coeliac disease is not an uncommon cause of IDA in patients >65 years of age and a history of chronic diarrhoea increases diagnostic yield in this age group.

Acceptability of oesophagogastroduodenoscopy without intravenous sedation: patients' versus endoscopist's perception with special reference to older patients.

BACKGROUND: Unsedated oesophagogastroduodenoscopy (OGD) is considered by most endoscopists to be a quick, safe, and well tolerated procedure. Older patients are said to tolerate it better than younger patients. However, patients' perception of the discomfort for the unsedated OGD has not been well studied. OBJECTIVE: This study was undertaken to compare (1) patients' perception of discomfort with the endoscopist's perception of patients' discomfort for the unsedated OGD, (2) tolerability between older (> or =75 years) and younger (<75 years) patients. DESIGN AND SUBJECTS: A total of 130 consecutive patients attending a day case endoscopy unit were recruited for the study. The patients and endoscopist recorded their assessment using a visual analogue scale (VAS). The results were analysed using non-parametric tests. Thirty patients were excluded from the study based on exclusion criteria. Sixty three (57%) patients were aged > or =75 years and 37 (43%) were <75 years. RESULTS: A significant difference was noted between patients' perception of the discomfort and the endoscopist's assessment of the patient's discomfort as suggested by the overall higher VAS scores for patients (median 4.9, SD 2.6) than those of the endoscopist (median 2.2, SD 1.2), giving a significant difference in median VAS score of 3.4 (p<0.001). Older and younger patients had similar scores, with median (SD) VAS scores of 4.8 (2.5) for > or =75 years and 4.9 (2.8) for <75 years. The endoscopist's median scores for these two groups were 2.2 (1.2) and 2.1 (1.3), respectively. CONCLUSIONS: Patients' discomfort during OGD performed without sedation was greatly underestimated by the endoscopist. There was no significant difference in acceptability between old and the young patients.

Neuropsychiatric non-motor aspects of Parkinson's disease.

Parkinson's disease is often recognised as a motor disease characterised by rest tremor, rigidity, bradykinesia, and postural disturbances. However, there are several non-motor aspects of the disease that are of at least equal importance in the management of patients with Parkinson's disease. They include depression, cognitive impairment, anxiety, and psychosis among others. It is important to recognise them, as they are common and they contribute significantly to patients' morbidity, quality of life, and institutionalisation to long term care homes. In addition to the disease duration and severity, other factors including drugs may contribute to their occurrence. Pathogenesis of these aspects is not fully understood, though there has been a significant increase in the knowledge in recent years. Management of these aspects involves a multidisciplinary approach.

Re-irradiation for prophylaxis of heterotopic ossification after hip surgery.

Heterotopic ossification (HO) may occur after total hip arthroplasty, but fortunately most patients are asymptomatic. Rick factors for HO include previous HO, hypertrophic osteoarthritis, diffuse idiopathic skeletal hyperostosis, ankylosing spondylitis, Paget's disease and post-traumatic arthritis. Both pre-operative and post-operative radiotherapy are effective in the prevention of HO in 85-95% of high-risk patients treated. In the few patients who needed re-operation for a variety of reasons, we found that re-irradiation is possible and safe. These case reports present our experience with single dose re-irradiation of the hip in an attempt to prevent post-operative HO.

A single point mutation in the V3 region affects protein kinase Calpha targeting and accumulation at cell-cell contacts.

Given the importance of intercellular adhesion for many regulatory processes, we have investigated the control of protein kinase Calpha (PKCalpha) targeting to the cell-cell contacts. We have previously shown that, upon treatment of the pituitary cell line GH3B6 with thyrotropin-releasing hormone (TRH) or phorbol 12-myristate 13-acetate (PMA), human PKCalpha (hPKCalpha) is selectively targeted to the cell-cell contacts (42). Here we show that the D294G mutation of hPKCalpha, previously identified in a subpopulation of human tumors, induces the loss of this selective targeting. The D294G mutant is instead targeted to the entire plasma membrane, including the cell-cell contacts, and the duration of the first rapid and transient translocation induced by TRH (42) is longer than that of the wild-type enzyme (93.3 versus 22.5 s), coinciding with the duration of the [Ca(2+)](i) increase. We found that in the presence or absence of PMA, RACK1 is never localized at the cell-cell contacts nor was it coimmunoprecipitated with hPKCalpha wild type or the D294G mutant. In contrast, PMA treatment or long-term TRH stimulation resulted in the presence of F-actin and beta-catenin at the cell-cell contacts and their exclusion from the rest of the plasma membrane. Upon disruption of the F-actin network with phalloidin or cytochalasin D, wild-type hPKCalpha translocates but did not accumulate at the plasma membrane and beta-catenin did not accumulate at the cell-cell contacts. In contrast, the disruption of the F-actin network affected neither translocation nor accumulation of the D294G mutant. These results show that the presence of PKCalpha at the cell-cell contacts is a regulated process which depends upon the integrity of both PKCalpha and the actin microfilament network.

Outcome of renal replacement therapy in the very elderly.

BACKGROUND: In a retrospective case-note and computer database analysis we assessed the outcome of very elderly patients (> or = 75 years old) with end-stage renal disease (ESRD) on renal replacement therapy (RRT). METHODS: Fifty-eight individuals aged 75 or over (group 1) commenced RRT between 1 January 1991 and 31 December 1995. Comparisons were made with other patients commencing RRT who were divided into two groups: group 2 (201 individuals 65-74 years old) and group 3 (379 patients <65 years old). All subjects were followed up until the point of assessment (30 June 1998), the time of death, or withdrawal from dialysis. Survival rates in the three groups were compared using Kaplan-Meier method. The number of hospital admissions, length of in-patient stay, and complications rate on RRT were assessed for group 1. RESULTS: One-year survival rates in groups 1, 2 and 3 were 53.5, 72.6, and 90.6% respectively and the 5-year survival rates were 2.4, 18.8, and 61.4% respectively. The very elderly spent 20% of their time in hospital, 46% had two co-morbid factors at the outset, and 26% developed multiple complications while on RRT. Withdrawal from dialysis remained the most common cause of death in this group of individuals (38%), followed by cardiovascular causes (24%) and infections (22%). CONCLUSION: Very elderly ESRD patients on RRT have a very poor outcome and, since they are the largest growing group of RRT patients, this has important implications for future health policies.

Intraluminal brachytherapy for malignant endobronchial tumors: an update on low-dose rate versus high-dose rate radiation therapy.

Although the evolution from low-dose rate (LDR) to high-dose rate (HDR) brachytherapy for malignant endobronchial tumors was presumably based on economy, patient convenience, and radiation protection, our experience with both modalities permits assessment of the pros and cons of each technique. In November 1991, our HDR remote afterloading brachytherapy unit became operational. By that time, we had treated 110 patients (group 1) with malignant endobronchial obstruction with LDR brachytherapy. Since then, all patients have been treated with HDR brachytherapy. The outcome of our first 110 patients (group 2) treated with HDR brachytherapy is presented in this communication, using group 1 as the historic control group. In group 1, patients were treated with 1 or 2 sessions of 30-60 Gy, each calculated at a 1-cm radius. In group 2, patients received 3 or 4 weekly treatments of 7 Gy, each calculated at a 1-cm radius. The majority of patients in each group had previously received a full course of external beam irradiation, and a history of laser bronchoscopy was also similar for the 2 groups. Differences in bronchoscopic response rate (82% vs. 96%, respectively) and complications (3.6% vs. 2.7%, respectively) were statistically insignificant between the LDR group and the HDR group. We believe HDR brachytherapy is the state-of-the-art modality in intraluminal therapy for endobronchial malignancies.

A case of isolated ACTH deficiency presenting with hypercalcaemia.

A 76-year-old man presented with a subacute history of weight loss, malaise and anorexia. Laboratory investigations revealed serially increasing hypercalcaemia, correlating with deterioration in his clinical status. He was subsequently shown to have hypocortisolaemia, which improved with the administration of intravenous steroids. Subsequent biochemical testing revealed the endocrinological defect to be one of isolated ACTH deficiency, which, unlike Addison's disease, does not classically include hypercalcaemia in its presentation.

Radiation therapy for heterotopic ossification.

Heterotopic ossification is a common complication after bone and joint surgery. If the disease progresses, it may cause pain and disability, eventually defeating the purpose of surgery in the first place. Today, prophylactic treatment is indicated after surgery. Both nonsteroidal antiinflammatory drugs and radiation therapy are effective. Radiation therapy is associated with fewer side effects and is preferred. Single-dose postoperative irradiation has been found to be as effective as fractionated radiation therapy.

Characterization of insertions of IS476 and two newly identified insertion sequences, IS1478 and IS1479, in Xanthomonas campestris pv. campestris.

Thirty-two plasmid insertion mutants were independently isolated from two strains of Xanthomonas campestris pv. campestris in Taiwan. Of the 32 mutants, 14 (44%), 8 (25%), and 4 (12%) mutants resulted from separate insertions of an IS3 family member, IS476, and two new insertion sequences (IS), IS1478 and IS1479. While IS1478 does not have significant sequence homology with any IS elements in the EMBL/GenBank/DDBJ database, IS1479 demonstrated 73% sequence homology with IS1051 in X. campestris pv. dieffenbachiae, 62% homology with IS52 in Pseudomonas syringae pv. glycinea, and 60% homology with IS5 in Escherichia coli. Based on the predicted transposase sequences as well as the terminal nucleotide sequences, IS1478 by itself constitutes a new subfamily of the widespread IS5 family, whereas IS1479, along with IS1051, IS52, and IS5, belongs to the IS5 subfamily of the IS5 family. All but one of the IS476 insertions had duplications of 4 bp at the target sites without sequence preference and were randomly distributed. An IS476 insertion carried a duplication of 952 bp at the target site. A model for generating these long direct repeats is proposed. Insertions of IS1478 and IS1479, on the other hand, were not random, and IS1478 and IS1479 each showed conservation of PyPuNTTA and PyTAPu sequences (Py is a pyrimidine, Pu is a purine, and N is any nucleotide) for duplications at the target sites. The results of Southern blot hybridization analysis indicated that multiple copies of IS476, IS1478, and IS1479 are present in the genomes of all seven X. campestris pv. campestris strains tested and several X. campestris pathovars.

Alteration of myogenic regulatory components in a rat myoblast GLUT 3(-) mutant.

Myogenesis is a complex process characterized by both biochemical and morphological differentiation. Recent transfection studies suggested a close relationship between the GLUT 3 transporter and the myogenic ability of rat skeletal L6 myoblast. In this study, the myogenic properties of GLUT 3- mutants were examined. Studies using three different GLUT 3- mutants (D2, D9 and D23) revealed that these mutants were defective not only in the GLUT 3 transporter, but also in the expression of myogenesis-associated genes. The properties of mutant D23 were further characterized. Overexpression of an exogenous functional GLUT 3 transporter was unable to restore the myogenic defects of this mutant. This mutant was subsequently found to be altered in components acting on at least two different sites of the L6 myogenic pathway. Transfection studies revealed that mutant D23 was deficient in component(s) essential for the myogenin promoter activity. The second component was required for the transcription of muscle-specific protein genes, as overexpression of myogenin was unable to rescue the inability of this mutant to express muscle-specific genes and to form myotubes. Mutant D23 was therefore thought to be deficient in a regulatory component which controlled the expression of GLUT 3, myogenin and muscle-specific genes.

The role of the GLUT 4 transporter in regulating rat myoblast glucose transport processes.

Previous studies revealed an inverse relationship between GLUT 1 and GLUT 4 expression in rat myoblasts [L. Xia, Z. Lu, T.C.Y. Lo, J. Biol. Chem., 268 (1993) 23258-23266]. It was not clear whether these were coincidental or causal occurrences. To examine the regulatory roles of the GLUT 4 isoform, rat L6 myoblasts were transfected with full length GLUT 4 cDNAs (2.5 kb) in the sense or antisense orientation. L6 myoblasts transfected with the GLUT 4 sense cDNA (L6/G4S transfectants) possessed much elevated levels of both endogenous GLUT 4 transcripts (1.4 kb and 2.8 kb). Transport and immunofluorescence studies showed that this GLUT 4 sense cDNA was responsible for a functional GLUT 4 transporter. L6 cells transfected with the GLUT 4 antisense cDNA (L6/G4A transfectants) possessed only 6% of the L6 level in day 6 cultures. These antisense transfectants were essentially devoid of any functional GLUT 4 transporter. The activation of transcription of the endogenous GLUT 4 gene in L6/G4S myoblasts suggested auto-regulation of GLUT 4 expression. GLUT 3 expression and activity were not altered in both sense and antisense GLUT 4 transfectants. More interestingly, GLUT 1 expression was reduced in L6/G4S myoblasts, whereas it was elevated in L6/G4A myoblasts. This was the first direct evidence indicating GLUT 4 might play an important role in suppressing GLUT 1 expression.

The effect of the nasopharyngeal air cavity on x-ray interface doses.

We investigated the impact of air cavities in head and neck cancer patients treated by photon beams based on clinical set-ups. The phantom for investigation was constructed with a cubic air cavity of 4 x 4 x 4 cm3 located at the centre of a 30 x 30 x 16 cm3 solid water slab. The cavity cube was used to resemble an extreme case for the nasal cavity. Apart from measuring the dose profiles and central axis percentage depth dose distribution, the dose values in 0.25 x 0.25 x 0.25 cm3 voxels at regions around the air cavity were obtained by Monte Carlo simulations. A mean dose value was taken over the voxels of interest at each depth for evaluation. Single-field results were added to study parallel opposed field effects. For 10 x 10 cm2 parallel opposed fields at 4, 6 and 8 MV, the mean dose at regions near the lateral interfaces of the cavity cube were decreased by 1 to 2% due to the lack of lateral scatter, while the mean dose near the proximal and distal interfaces was increased by 2 to 4% due to the greater transmission through air. Secondary build-up effects at points immediately beyond the air cavity cube are negligible using field sizes greater than 4 x 4 cm2. For most head and neck treatment, the field sizes are usually 6 x 6 cm2 or greater, and most cavity volumes are smaller than our chosen dimensions. Therefore, the influence of closed air cavities on photon interface doses is not significant in clinical treatment set-ups.