Management of haemophilia in Greece

A short review is given on several aspects of the management of haemophilia in Greece. A total number of 429 patients with congenital haemorrhagic disorders has been registered. The incidence of F. VIII deficiency is 85.9% and that of F. IX 12.9%. Information concerning distribution throughout the country, age, social standard, financial position and education is given too. Haemophiliacs are systematically treated by Athens specialized Haemophilia Treatment Centres. The most widely therapeutic material still used, is fresh frozen plasma. Lyophilized cryoprecipitate and F. IX (prothrombincomplex) concentrate are also prepared but they are not for every day use. Imported concentrates are used only for very serious cases. Home therapy is attempted in limited scale and it is largely discussed. Consultation, out-patients treatment and hospitalization, if needed, are free of charge for haemophiliacs regardless of their financial position or their national insurance.     

Management of haemophilia in the developing world

We used a dynamic shoulder-testing apparatus and nine fresh-frozen, entire upper extremities from cadavera to evaluate the effects of varying degrees of capsulolabral injury on the kinematics of the glenohumeral joint during abduction in the scapular plane and external rotation. Joint kinematics were recorded with use of a six-degrees-of-freedom magnetic tracking device before and after the creation of each capsulolabral lesion in a progressive manner. Dislocation did not occur after simulation of a large Bankart lesion or even after sectioning of the anterior aspect of the joint capsule. However, division of the entire joint capsule (that is, both the anterior aspect and the posterior aspect) resulted in a significant increase (p < 0.05) in posterior translation during abduction in the scapular plane, and two of the nine shoulders dislocated posteriorly. External rotation of the abducted extremity produced no increase in anterior or posterior translation.     

Mutations in haemophilia A

In the present study DNA from 281 unrelated haemophilia A patients including 15 inhibitor patients has been analysed by Southern blotting technique. Using various restriction enzymes, cloned factor VIII cDNA probes and genomic fragments we have identified 14 mutations. Six of the mutations are novel partial factor VIII gene deletions. One deletion affects exon 1, two deletions concern exon 6, another deletion, of which breakpoints are sequenced, takes part of exon 16 and two deletions affect exon 26. Besides the deletions, eight point mutations have been found at the TaqI restriction sites of exons 18, 24 and 26. Five C-->T mutations resulted in nonsense mutations, one in exon 18, one in exon 26 and three in exon 24. Two G-->A mutations caused a missense mutation in exon 24 leading to an arginine/glutamine exchange. Although two patients showed this mutation, their clinical phenotypes were different, possibly due to an additional unidentified sequence polymorphism. A G-->T mutation in exon 26 substituted the arginine with leucine. All deletions and seven of the point mutations are associated with severe disease with a detectable inhibitor in the patient with the TaqI-point mutation in exon 18. One of the G-->A mutations is associated with mild haemophilia but the patient also has developed an inhibitor. Amongst these mutations the origin of the mutation could be determined in four kindred, one of which showed maternal mosaicism.     

Proprioceptive training in haemophilia

Joint and muscle injury associated with direct damage to the tissues and muscle atrophy may ensue following immobility. Rehabilitation of the injury is linked with the return to normal functional values such as range of motion, muscle strength, and muscle tone. It is, however, likely that subtle changes or differences still exist in the site of injury or haemarthrosis. In particular proprioception may be distorted due to the direct injury of sensory receptors and to feedback systems. The implications of such damage are important, where proprioception plays an important part in the control, timing and organisation of coordinated bodily actions.     

Progression of HIV in haemophilia

A series of permeability thresholds to Ca2+ metabolites and macromolecules, occurring at different times when cells are attacked by complement, has been established by imaging HeLa cells transiently expressing a recombinant cytosolic fusion protein of firefly luciferase and aequorin (luciferase-aequorin) to measure changes in ATP and cytosolic free Ca2+. Nuclear fluorescence of propidium was used as a measure of permeability to small molecules, and luciferase activity imaged to assess lysis. The rise in cytosolic free Ca2+ observed after C9 attack preceded by at least 60 s both the increase in propidium fluorescence, measured in single cells, and the decrease in ATP monitored by luciferase light emission. These effects were dependent on the concentration of C9. At concentrations of C9 up to 4 micrograms/ml no loss of luciferase-aequorin protein was detected at the end of the experiment. Thus the membrane integrity of the cells remained intact, even though the cells were permeable to propidium. These results confirmed our earlier observations that propidium permeability in cells attacked by complement was not a reliable measure of cell death. They also show that it is vital to take account of cellular heterogeneity if the mechanisms by which cells respond to membrane pore former attack are to be correctly interpreted.     

Control of the synovium in haemophilia

The method of administration of alteplase has evolved since its introduction to clinical practice in the late 1980s. The initial dosage regimen of a graded administration of 100 mg was replaced by the front-loaded weight adjusted regimen, the efficacy of which was demonstrated in the GUSTO 1 trial. Double bolus administration was shown to achieve superior TIMI 3 patency of the infarct related artery in a small angiographic study, but the COBALT trial failed to show equivalence and indeed showed a slightly higher mortality and incidence of stroke, so cannot be recommended. Reteplase, a deletion mutant of alteplase, also showed superior efficacy in achieving coronary patency but no clinical superiority in outcomes in the 15,000 patient GUSTO 3 trial. The case of administration of reteplase, however, has some attraction as an alternative to alteplase. Trials of newer agents based on further modifications of alteplase are ongoing, but at present the front-loaded alteplase regimen remains the standard for clinical practice.     

Creutzfeldt-Jakob disease in Sweden

OBJECTIVES: To find and investigate, retrospectively, as many cases as possible of Creutzfeldt-Jakob disease (CJD) in Sweden dying during the period 1 January 1985 to 31 December 1996 and to detect any possible case(s) of new variant CJD. METHODS: The patients were found through computer search of all death certificates in Sweden on which CJD was mentioned, through information from the Swedish neuropathologists, and spontaneous reports from Swedish doctors and hospitals. Data concerning the patients were then collected from patients' case records and from brain histopathology reports. RESULTS: In total 72 cases of spongiform encephalopathy were confirmed as definite by neuropathology, one of them with Gerstmann-St?ussler-Scheinker disease. In 51 further cases there were no brain pathology data but the diagnosis "probable" (37 patients) or "possible" (14 patients) CJD according to WHO criteria could be made on clinical grounds. There was a variation in number of deaths/year, from a minimum of five (1985) to a maximum of 16 (1990). Sixty patients died during the period 1985-90 and 62 during 1991-6. The sex ratio was nearly 1:1. Calculated for a population of 8.6 million (mean of 12 years) in Sweden this gives 1.18/million/year. Age at the time of the presenting symptoms ranged from 34 to 84 years. Only one patient was under 40 at the onset of symptoms. He had a spongiform encephalopathy but prion protein staining was negative. The duration of symptoms that could be attributed to CJD was 6 months or less in 75 cases, 7-12 months in 16 cases, 1 to 2 years in 15 cases, and more than 2 years in 16 patients. By definition all patients were demented. Other more common symptoms and signs were aphasia, dysphasia, dysathria, ataxia, myoclonus, pareses of the extremities, rigidity or spasticity, different types of hyperkinesias, and other psychiatric symptoms (depression, anxiety, and aggressiveness). Less common symptoms were hallucinations (mainly visual), visual defects, sensory symptoms (paraesthesias, itching, or pain), apraxia of swallowing, and disorders of eye movements. CONCLUSIONS: The incidence, the symptomatology, the age distribution (age in years at onset and at death), and the duration of illness were similar to those of other countries except for the cases of new variant CJD in the United Kingdom. There is so far no indication of any cases of new variant CJD in Sweden.     

Bladder cancer in Sweden

The survival of patients with bladder cancer has not improved significantly during the past decades in spite of new diagnostic methods and treatment modalities. This observation underlines the need for improved routines to ensure earlier detection of the disease by patients and doctors and thereby start the treatment sooner. The common finding of treatment failures in patients who have shown no sign of local recurrence but have undergone radical cystectomy indicates that subclinical metastases are primarily responsible for the poor outcome in most cases. This indicates that, in addition to radical surgery, effective chemotherapy is needed to counteract the systemic spread of the disease.     

The natural history of HIV disease in haemophilia

Fulminant hepatic failure is a serious complication of acetaminophen overdose. The cascade of complications starts with an alert patient that can quickly result in hepatic coma and even death. The nurse completes a poisoning history, provides an antidote, and assesses the extent of hepatic failure from an overdose. This article uses a case study to describe the problems and nursing care for the patient with hepatic failure from acetaminophen overdose. Advanced assessment skills by the critical care nurse enable prompt recognition of postoverdose complications for early intervention and treatment. Acute care nurse practitioners, utilizing the same techniques, can develop protocols for emergency or intensive care units where these patients may be admitted and subsequently cared for.     

The molecular basis of haemophilia B

PURPOSE OF THE STUDY: High tibial osteotomy (HTO) is a routine procedure for medial gonarthrosis. Mid-term results are known to be satisfactory, but they deteriorate with longer follow-up. The authors present a long term survival analysis of 109 out of 111 consecutive HTO with a minimal potential follow-up of ten years. MATERIAL AND METHODS: 111 patients were consecutively operated on for isolated primary varus gonarthrosis between 1977 and 1985: 57 men and 54 women, with a mean age of 53 years (range, 27 to 79 years). X-ray measurements were done on stance, hip-ankle view. Global axial deformation was defined as the angle between mechanical axes of femur and tibia. The respective part of congenital and degenerative tibial deformation was assessed according to Dejour. The angle between femoral and tibial bicondylar lines, representing lateral instability, was added to the tibial degenerative deformation to represent the total degenerative deformation. The goal of correction was a 3 to 7 degree mechanical valgus angulation. At the time of bone healing, 82 patients (74 per cent) had an optimal correction. Two patients were excluded from the follow-up study because of a severe complication (1 bacterial arthritis and 1 tibia non union) which could interfere with the long term result. The 109 remaining patients were followed for a minimal period of 1 year (mean: 8.4 years). GUEPAR pain grading and the occurrence of a revision were prospectively analyzed. 57 non reoperated patients could be re-examined at a mean maximal follow-up of 13.5 years (range, 10 to 18 years). Failure was defined as either the occurrence of a grade 2 or 3. GUEPAR pain during the whole follow-up, or a clinical or functional Knee Society score < 80 points at final follow-up, or revision. Failure and revision rates were calculated according to Kaplan and Meier. RESULTS: 11 patients were reoperated on before final examination (10 per cent): 2 medial unicondylar and 9 total knee prostheses. At final follow-up, the mean clinical and functional scores were respectively 87.0 points (range, 24 to 100 points) and 86.3 (range, 45 to 100 points). The cumulative failure rate was 33 per cent after 10 years and 54 per cent after 15 years; the respective revision rates were 9 per cent and 19 per cent. A pre-operative total degenerative deformation superior to 3 degrees led to a 3.5 fold increased failure rate (p < 0.000,1). A pre-operative medial joint space narrowing over the half of the normal, lateral one led to a 2.2 fold increased failure rate (p = 0.014). An optimal post-operative correction led to a 3.2 fold decreased failure rate (p = 0.000,1). For a given total degenerative deformation, patients with a congenital deformation superior to 5 degrees had a significant lower failure rate (p < 0.000,1). No factor significantly influenced the revision rate. DISCUSSION: Ideal patients for HTO, with an expected survival rate of 100 per cent after 13 years, have moderate degenerative changes and a congenital deformation superior to 5 degrees. Patients with advanced degenerative changes and no congenital deformation experienced a 35 per cent failure rate after 10 years. In this population, unicondylar replacement should be considered as a valuable alternative.     

The molecular basis of haemophilia A

1H-NMR spectroscopy was performed on a 6-month-old boy with pachygyria. A MRI study demonstrated an abnormally thick cortex localized in the right occipital lobe. 1H-NMR spectrums were collected from the lesion and the contralateral cortex that appeared normal on MRI. The N-acetylaspartate (NAA)/Cre (creatine) ratio was markedly lower in the abnormal cortex than in the contralateral cortex and the occipital cortex. NAA localizes to neurons, axons, dendrites and synaptic connections and increases with maturation of neurons. Its decrease is considered to represent the decrease in the number of these structures and/or disturbance of neuronal maturation. We conclude that NAA/Cre can be an important index that reflects the pathogenesis of pachygyria.     

Outcome of orthotopic liver transplantation in patients with haemophilia

As part of environmental toxicology, it is important to assess both the carcinogenic potential of xenobiotics and their mode of action on target cells. Since dysregulation of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, is considered as an early and essential component in the process of multistage carcinogenesis, we have studied the mode of ODC induction in Syrian-hamster-embryo(SHE) cells stage-exposed to carcinogens and to non-carcinogens. One-stage (5 hr) treatment of SHE cells with 50 microM clofibrate (CLF), a non-genotoxic carcinogen, or with 0.4 microM benzo(a)pyrene (BaP), a genotoxic carcinogen, slightly decreased basal ODC activity. Using the 2-stage exposure, 1 hr to carcinogen, then replacement by TPA for 5 hr, the ODC activity was higher than that obtained with TPA alone. This ODC superinduction was not observed when SHE cells were similarly pre-treated with non-carcinogenic compounds. Several environmental chemicals, pesticides, solvents, oxidizers and drugs were investigated with this SHE cell model. With one-stage exposure, some xenobiotics decreased basal ODC activity, while for others ODC changes were not noticeable. With 2-stage exposure (chemical followed by TPA), all carcinogens amplified the TPA-inducing effect, resulting in ODC superinduction. Comparative studies of the action of carcinogens and of non-carcinogens, using 2-stage exposure protocols, clearly show a close relationship between ODC induction rate and morphological transformation frequency.     

Factor concentrates for haemophilia in the developing world

A total of 191 patients were evaluated at our department for azoospermia, and 11 were found to have azoospermia due to ejaculatory duct obstruction as proved by normal serum hormones, normal testicular biopsy, low ejaculate volume and absence of fructose in semen. Also transrectal ultrasound was performed, revealing distended seminal vesicles and dilated ejaculatory ducts. All these criteria together suggested ejaculatory duct obstruction as a cause of azoospermia. All patients underwent endoscopic management for treatment of their ejaculatory duct obstruction in the form of resection and/or incision of the ejaculatory duct ostium inside the urethra and patency was checked intraoperatively by injection of sterile methylene blue in the vas and visualizing the efflux of the blue dye endoscopically. Intraoperative patency was documented in 10 patients and postoperative patency by follow-up semen analysis in 7 patients (70% patency rate) of which 2 (20% pregnancy rate) were able to conceive within 2 years of endoscopic treatment. Postoperative complications included acute urinary retention in 1 patient, haematuria in 5 and recurrent epididymitis in 2 patients.     

Cost of management of patients with haemophilia

The cost of managing 114 adult haemophiliacs in the west of Scotland was assessed for the period 1 March 1971 to 28 February 1974. Altogether 23 of them (20%) accounted for 80% of the resources used. The cost of hospital treatment of these patients during the period was compared with the predicted cost of home treatment, given the availability of freeze-dried factor VIII concentrate in sufficient amounts. We calculate that adequate on-demand home treatment would cost only 16% more than the present treatment, which is substantially less efficient.     

Assessment and treatment of liver disease in Japanese haemophilia patients

OBJECTIVES: To examine the efficacy of various parameters obtained by transrectal ultrasonography (TRUS) as predictors of the onset of acute urinary retention in patients with benign prostatic hyperplasia (BPH). METHODS: From April 1993 to March 1997, 331 men aged 51 to 84 years with symptoms of BPH were enrolled in this study. Among them, 64 patients presented to our clinic because of acute urinary retention. TRUS was used to calculate the transition zone (TZ) volume, the transition zone index (TZ index = TZ volume/total prostate volume), the total prostate volume, and presumed circle area ratio (PCAR). To compare the usefulness of the various indices, the area under the receiver-operator characteristic (ROC) curve was calculated for each index. RESULTS: There were significant differences in the American Urological Association (AUA) symptom score, total prostate volume, TZ volume, TZ index, and PCAR between patients with and without acute urinary retention, but no significant differences in age and quality of life score. In patients with acute urinary retention, the area under the ROC curve was 0.924 for the TZ index, 0.834 for the TZ volume, 0.753 for the PCAR, 0.684 for the total prostate volume, and 0.628 for the AUA symptom score. CONCLUSIONS: The TZ index is an accurate predictor of acute urinary retention in patients with BPH and may be a useful method for deciding between surgical intervention and antiandrogen treatment.