A Rapid and Satisfactory Outcome with Combined Immunosuppressive Therapy in Acquired Haemophilia A with Underlying Tuberculosis.

Acquired haemophilia A (AHA) is a rare disorder with an incidence of 1.5 cases per million per year in the United Kingdom. The incidence could be underestimated due to difficulty in diagnosis and also due to the fact that people with low titre inhibitor levels are asymptomatic. It is usually a disease affecting elderly but a disease peak in the younger population is known. The common underlying diseases are autoimmune disorders, malignancies, infections, and drugs. However, approximately 50% of the cases do not have a specific aetiology and about 10% will not have bleeding manifestations. Therefore, an isolated prolongation of APTT should be evaluated, especially prior to any haemostatic challenges. We report a case of a middle-aged man who presented with bleeding due to AHA associated with high inhibitory titres and active pulmonary tuberculosis. He was treated with both antituberculous and combined-aggressive immunosuppressive therapy which resulted in satisfactory disease remission.

Skeletal fluorosis in Vavuniya District: an observational study

Background: The WHO recommended safe upper limit for fluoride in drinking water is 1.5 mg/l. Groundwater sources in many parts of Sri Lanka often exceed this limit. The high fluoride content of groundwater and high environmental temperatures in Vavuniya District predispose to pre-skeletal fluorosis and skeletal fluorosis in adults. Objectives: To identify residents of Vavuniya District with clinical features of pre-skeletal and skeletal fluorosis; to describe their clinical, biochemical and radiographic features; to determine the fluoride content of blood and urine in individuals with established diagnoses, and of their drinking water. Methods: In 98 volunteers we detected 60 with clinical features of pre-skeletal and skeletal fluorosis. Clinical examination, biochemical and radiographic investigations were performed. Forty four with confounding factors were excluded. The balance 16 had radiographic investigation for fluoride bone disease, and assessment of clinical features for pre-skeletal fluorosis. The radiographic criteria of skeletal fluorosis were trabecular haziness, osteosclerosis, osteophytes, cortical thickening and ligamentous or muscle attachment ossification. All 16 had "spot" samples of 15 ml of venous blood taken for biochemical tests and fluoride estimation; and 30 ml of urine, and water from 16 dug wells for fluoride. Results: The 16 selected (11 males) had BMI between 20.6 and 31.9 kg/m2, and were between 22 and 84 years (x̅ = 59.9 + 20.4). They used water from domestic dug wells for drinking. All had adequate renal function. All serum and urine samples had raised fluoride levels way above the reference ranges for serum (0.02 ­ 0.18 mg/l) and urine (0.6 ­ 2.0 mg/l). The 16 water samples showed a mean fluoride content of 2.90 +0.93 mg/l. Interpretation: In a cohort of 60 individuals in Vavuniya with symptoms suggestive of skeletal fluoride toxicity, 6 had skeletal fluorosis, 10 had pre-skeletal fluorosis, and groundwater sources had fluoride levels much higher than WHO recommended upper limit for drinking water. Residents in Vavuniya are predisposed to pre-skeletal and skeletal fluorosis. All 16 had been misdiagnosed as various types of arthritis.

High prevalence of dental fluorosis among schoolchildren in three villages in Vavuniya District: an observational study

Background: Studies of groundwater sources in Sri Lanka show that in the entire Northern, North Central, Uva and Eastern Provinces, and also in a large area of the North Western Province, groundwater fluoride content is within the range 1.0 mg/l and 3.0 mg/l. The WHO recommended safe upper limit of fluoride for drinking water is 1.5 mg/l. Objective: Our objective was to determine the prevalence and degree of dental fluorosis in a cohort of schoolchildren in Sinnasippikulam in Vavuniya District, the fluoride content in their serum and urine, and fluoride levels in drinking water in dug wells of the area. Methods: Invitations in Tamil and Sinhala were sent to all households by courier. Demographic information and oral hygiene practices of 307 responsive children were recorded by interviewing children and their mothers. Detailed clinical examinations were performed according to WHO basic methods, with some modifications. Assessment of dental fluorosis in the children was done according to Dean's Index codes and criteria. Results: We found drinking water sources (dug wells) in Sinnasippikulam (n= 82) to have a high mean concentration of fluoride ( x̄ 1.58+ 0.69 mg/l). Of 307 children examined, 224 (72.9%) had clinical evidence of dental fluorosis of varying degrees of severity. The mean fluoride level in serum of schoolchildren was 0.198 mg/l (SD + 0.074; S.E.M. 0.013), and in their urine, 1.44 mg/l (SD + 0.59; SEM 0.11). Conclusions: Our results show that harmful levels of fluoride are extremely common in groundwater sources in the study area, and consequently, dental fluorosis is highly endemic (72.9%) among resident schoolchildren.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a patient from Sri Lanka.

We report the first patient from Sri Lanka (the third patient from the Indian subcontinent) with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The patient experienced a young onset familial stroke with an 856T>G missense mutation in exon 5 of the NOTCH3 gene resulting in a C260G mutation in the sixth epidermal growth factor-like repeat. We believe this is the first reported Sri Lankan patient. CADASIL is probably underdiagnosed in the region.

Plasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in a phase I trial.

DACA [N-[2-(dimethylamino)ethyl]acridine-4-carboxamide] is an acridine derivative with high activity against solid tumours in mice and a dual mode of cytotoxic action involving topoisomerases I and II. The plasma pharmacokinetics of DACA were studied in 28 patients with solid tumours in a phase I trial. A single dose was given every 3 weeks, being escalated from a starting dose of 18 mg/m2 (as the dihydrochloride trihydrate salt) to a maximal dose, limited by severe pain in the infusion arm, of 1000 mg/m2. Drug was given by constant intravenous infusion with a target delivery period of 3 h. Blood samples were taken from the contralateral arm before, during and for up to 72 h after the infusion. DACA was separated from plasma by solid-phase extraction and was analysed by reversed-phase high-performance liquid chromatography (C18 column) using fluorescence detection. A two-compartment pharmacokinetic model provided the best fit for the concentration-time profiles obtained for most patients showing clearance of 1.00+/-0.36 l h(-1) kg(-1), a volume of distribution of the central compartment of 0.72+/-0.55 l/kg, an initial half-life of 0.28+/-0.19 h and a terminal half-life of 2.04+/-0.94 h. All pharmacokinetic parameters were independent of dose, indicating first-order kinetics. As DACA binds strongly to alpha1-acid glycoprotein, plasma concentrations of this protein were determined and used to estimate free-drug fractions in plasma. Estimated values for the free fraction varied from 0.9% to 3.3% and were lower than those determined by equilibrium dialysis for mice and rats (15% and 16%, respectively). At the maximum tolerated dose (MTD) of 750 mg/m2, the area under the drug concentration-time curve (AUC) was 46.2+/-4.4 microM h, exceeding that obtained in mice treated at the MTD (23.4 microM h). On the other hand, the corresponding free-drug AUC was 0.92+/-0.03 microM h, much lower than the corresponding value (3.5 microM h) determined for mice. These results suggest that free-drug rather than total drug concentrations are more appropriate for interspecies dose comparisons when significant differences exist in the free plasma fraction.

A case of multifocal motor neuropathy.

We report here a patient with multifocal motor neuropathy (MMN). He had typical clinical features, and electrophysiological investigations confirmed the diagnosis. This is the first case of MMN to be documented in Sri Lanka.

Methadone: a potent inhibitor of rat liver aldehyde oxidase.

Several drugs with structural similarities to SKF-525A were tested for their ability to inhibit rat liver aldehyde oxidase using the experimental antitumour agent N-[(2'-dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601316; acridine carboxamide) as substrate. The antihistamine D-chlorpheniramine, and the antiarrhythmics disopyramide, procainamide and lignocaine were ineffective in inhibiting this reaction. The antihistamines diphenhydramine, pheniramine, doxylamine, orphenadrine, methapyrilene and pyrilamine, gave IC50 values of 100-500 microM. The narcotic analgesics D-propoxyphene and, in particular, methadone were potent inhibitors of acridine formation with IC50 values of 15.5 and 0.31 microM, respectively. Further analysis indicates mixed non-competitive type inhibition by methadone with inhibition constants (Kis and Kii, respectively) of 0.03 +/- 0.01 (SE) and 0.57 +/- 0.12 microM.

DNA-directed aniline mustards based on 9-aminoacridine: interaction with DNA.

A series of 4-substituted aniline mustards ArNH(CH2)nOpC6H4N(CH2CH2Cl)2, where Ar is an acridine and n varies from 2 to 5, interact with DNA. Scatchard analysis shows the compounds bind tightly, with a binding site size similar to that of 9-aminoacridine. The rate of hydrolysis of the mustards, measured by HPLC, is essentially constant across the series. With increasing length of the polymethylene linker, non-covalent binding becomes less strong, but the rate of DNA alkylation increases. Viscometric helix extension measurements and electrophoretic analyses using closed circular supercoiled DNA show that all the compounds are DNA intercalating ligands. Despite these similarities, the compounds are known to have quite different patterns of DNA alkylation, switching from guanine to adenine alkylation as the chain length is extended.

Non familial juvenile distal spinal muscular atrophy of upper extremity.

An uncommon variety of non familial, juvenile onset, spinal muscular atrophy with asymmetric distal upper extremity affection is described. One hundred and two patients with a one to 14 year follow up are analysed. Spinal muscular atrophies with a distal distribution are rare. However, in the past three decades, previously unrecognised varieties of neurogenic muscular atrophy have been described in Asia (Japan, India, Sri Lanka and Singapore) under a variety of names. These provide interesting data for discussion of Asian neurogenic muscular atrophies with distal affection, in the context of diseases of the motor neuron.

The treatment of Guillain-Barré syndrome by modified plasma exchange--a cost effective method for developing countries.

Six patients with the Guillain-Barré syndrome were treated by modified plasma exchange. Five of them showed a rapid improvement which was not consistent with the natural history of the disease. The improvement was assessed by monitoring vital capacity and muscle power, grading the ability to perform motor functions and by the duration of the hospital stay. The method of plasma exchange we used was simpler and cheaper than the conventional method. We recommend the use of our method, especially in developing countries with financial constraints and poor facilities.