Novel mutation in ATP13A2 widens the spectrum of Kufor-Rakeb syndrome (PARK9).

Kufor-Rakeb syndrome (KRS) is a rare autosomal recessive inherited juvenile parkinsonian syndrome caused by mutations in ATP13A2. We describe six patients from a consanguineous Greenlandic Inuit family, homozygous for a novel frame-shift mutation in exon 22 of ATP13A2 (c.2473C>AA, p.Leu825AsnfsX32). Disease onset varied from 10 to 29 years of age, the latest reported, and the clinical features were highly variable within a wide spectrum of an extrapyramidal-pyramidal syndrome with cognitive/psychiatric features. Ataxia was seen in two patients and axonal neuropathy in one, features not previously related to KRS. Dopamine transporter scans showed symmetrical, severely reduced uptake in striatum in two patients. Magnetic resonance imaging was without atrophy in one patient despite disease duration of 17 years, and cerebral and cerebellar atrophy was seen in another patient after 4 years of disease duration. The molecular pathogenic mechanisms of ATP13A2 mutations are discussed. The observation that the mutant transcript is not degraded by nonsense-mediated RNA decay and the fact that none of the eight heterozygous carriers from the family have KRS symptoms suggest that the mutant protein does not interfere and destroy the function of the wild-type ATP13A2 protein.

Derivatives of 2-methylenepropane-1,3-diol as new antagonists of platelet activating factor.

Two new achiral platelet activating factor (PAF) antagonists, N-[5-[[2-methylene-3- [[(octadecylamino)carbonyl]oxy]propoxy]carbonyl]pentyl]pyridinium bromide and 3-[6-[[2-methylene-3- [[(octadecylamino)carbonyl]oxy]propoxy]carbonyl]hexyl]thiazolium bromide were synthesized from 2-methylenepropane-1,3-diol. Platelet aggregation in platelet-rich plasma from rabbits, induced by racemic C16-PAF, was competitively antagonized by 9 or 10. At concentrations less than or equal to 10(-4) M, neither compound 9 nor compound 10 caused platelet aggregation, nor did they inhibit platelet aggregation induced by collagen or adenosine diphosphate. Bronchoconstriction in the guinea pig and hypotension in the rat, induced by racemic C16-PAF, were also effectively antagonized by 9 and 10. Both appear to be more potent as PAF antagonists than Takeda's CV-3988.

Dopaminergic supersensitivity: influence of dopamine agonists, cholinergics, anticholinergics, and drugs used for the treatment of tardive dyskinesia.

Single and repeated administration of neuroleptics induce supersensitivity to dopamine agonists like apomorphine and methylphenidate. The degree of this supersensitivity depends on the period of the preceding administration of the neuroleptic. In the development phase additional administration of apomorphine can reverse the hyperdopaminergic behaviour, whereas addition of cholinergic/anticholinergic treatment does not modify the enhanced receptor response. In the supersensitivity phase additional treatment with deanol does not modify the supersensitivity. Pheobarbital, diazepam, and muscimol increase and cis (Z)-flupenthixol decreases the supersensitivity. It is concluded that supersensitivity induced by neuroleptics is time-dependent and that it can be prevented by additional treatment with DA-agonists but not by cholinergic/anticholinergic treatment. In the supersensitivity phase, the syndrome is suppressed by dopamine antagonists but enhanced by GABA-agonists, benzodiazepine and phenobarbital.

On the supersensitivity of dopamine receptors, induced by neuroleptics.

Different neuroleptics caused dopamine receptor blockade (antagonism against methylphenidate-induced compulsive gnawing) for varying lengths of time. When the receptor blockade had expired, supersensitivity to dopamine agonists (occurrence of apomorphine-induced compulsive gnawing and enhancement of methylphenidate-induced gnawing) developed and persisted for varying periods of time. The degree and duration of supersensitivity was related to the degree and duration of the preceding receptor blockade. Inhibition of catecholamine or 5-HT synthesis had no influence on development of supersensitivity. Stimulation with a dopamine agonist, apomorphine, during the period of the development of supersensitivity did not modify the enhanced receptor supersensitivity. A cholinergic-dopaminergic balance was shown to be involved in the manifestation of compulsive behavior during the supersensitivity phase. Tolerance to the dopamine antagonistic effect of a neuroleptic also developed after a single neuroleptic treatment, most likely due to increased sensitivity of the receptors for the dopamine agonist. It is concluded, that the dopamine receptor blockade induced by a single dose of a neuroleptic agent is a dynamic phenomenon which in the course of time is replaced by an increased sensitivity of the receptors to dopamine agonists. Noradrenergic or 5-HT neuron systems do not seem to be involved in the neuroleptic-induced supersensitivity, whereas a dopaminergic-cholinergic balance is operative in the supersensitivity situation.

Deprotonation and hydride shifts in nitrenium and iminium forms of aminoimidazole-azaarene mutagens.

The mutagenicity of many 2-aminoimidazole-azaarenes (AIA) is thought to be mediated by the nitrenium form of the exocyclic amine. This hypothesis is supported by the numerous correlations found between calculated and experimentally-measured chemical properties for the nitreniums and the mutagenic potencies of the nitreniums and their parent amines. One factor favoring high mutagenic potency is the presence of a methyl substituent in the 1- or 3-imidazole position. In this paper, we investigate both the deprotonation of the imidazole ring nitrogens in non-N-methylated AIA mutagens and the plausibility of a chemical pathway involving a 1-4 hydride shift to form an iminium ion, thereby stabilizing the cationic N-methyl substituted AIA mutagens. It has been widely noted that factors that stabilize the nitrenium moiety lead to significantly higher mutagenic potency; hence, the transformation of the nitrenium to a more stable species might be expected to increase the potency, provided that it does not eliminate the electrophilic reactivity of the compound. Using ab initio quantum chemistry and polarizable continuum solvation models, we find that the imidazole ring nitrogens of the nitrenium ions are extremely acidic. This suggests that upon formation of the exocyclic nitrenium these sites will deprotonate to form a neutral imine. We have also studied the 1-4 hydride shift from an imidazole ring methyl to the exocyclic nitrenium to form an iminium. We predict that for AIA mutagens with just two fused rings the resulting iminium species are more stable in the gas phase than the corresponding nitreniums. For mutagens with larger conjugated systems, the nitrenium is stabilized by resonance and is more stable than the corresponding iminium. In the aqueous phase, however, the iminium form is predicted to be more stable than the nitreniums for all polycyclic compounds studied. Although equilibrium calculations favor the iminium form, these have been experimentally shown to be short-lived and their actual concentration will depend on the complex kinetics of AIA mutagen metabolism. The quantum chemical results also show a strong correlation between the relative iminium-nitrenium energy difference and the charge on the exocyclic nitrogen.

Kielbone in new attachment attempts in Humans.

The purpose of this investigation was to evaluate, in humans, the use of Kielbone as a substitute for fresh autogenous bone in treating periodontal intrabony defects. A total of 92 intrabony defects were treated with a previously described new attachment procedure utilizing free mucosal grafts to cover the intrabony defects following bone grafting. Kielbone was placed in 46 of these defects, while the remaining 46 defects were treated with autogenous bone grafts. The results were evaluated after 6 months by periodontal probing and assessment of the bone level as seen on periodical, identical radiographs. No differences were observed between the amount of clinical gain of attachment obtained in defects treated with Kielbone and those treated with autogenous jaw bone. This indicates that in surgical procedures attempting to restore lost connective tissue attachment, Kielbone constitutes a suitable replacement for fresh autogenous bone. The results are discussed in th light of recent studies that challenge the beneficial effect of bone grafts in the treatment of intrabony defects.

Hemoglobinopathies in Danish families.

Based on cases referred for investigation, as well as a questionnaire sent to all medical and pediatric departments in Denmark, 48 cases of hemoglobinopathy in 15 families of Danish ancestry are reviewed. 18 Danes in six families have been identified as having beta-thalassemia, and remarkably one - a homozygote - has beta-thalassemia intermedia requiring treatment with iron-chelation therapy. A further 36 Danes in 9 families have a hemoglobin variant: five unstable hemoglobins (Volga, Niteroi, and three unidentified), one hereditary methemoglobinemia (M-Arhus), one polycythemia (Ty Gard) and 2 asymptomatic (Athens-Georgia and Hafnia). Although rare in Danish families, a hemoglobinopathy should be considered in families with an unexplained chronic hemolytic anemia, cyanosis or polycythemia.

Linkage of Cholestasis Familiaris Groenlandica/Byler-like disease to chromosome 18.

In East Greenland (Tasiilaq) a common recessive disease, Cholestasis Familiaris Groenlandica (CFG)/Byler-like disease, occurs in Eskimo children. Samples from 123 persons, from a large consanguineous pedigree in East Greenland including 7 affected and 3 small families from West Greenland with a total of 4 affected children, have been collected for linkage and homozygosity studies. An earlier hint of linkage to chromosome 18q (lod score of 1.5 to blood group JK) is now raised to a multipoint lod score of Z = 3.25 in the area of the DNA markers D18S851 and D18S858. Different haplotypes follow the disease gene among Inuits in West Greenland and a possibility of locus heterogeneity of CFG between East and West Greenland exist.

Cholestasis Familiaris Groenlandica: an epidemiological, clinical and genetic study.

OBJECTIVES: Accumulation of Cholestasis Familiaris Groenlandica (CFG) or progressive familial intrahepatic cholestasis type 1 (PFIC1) occurs in indigenous Inuit families in Greenland. It is an autosomal recessive inherited liver disease. From early childhood the children suffer from failure to thrive, jaundice, pruritus and enlarged liver. Affected persons generally die very young. STUDY DESIGN: Patients' information has been collected from the Greenlandic death register and hospital records. METHODS: Detailed genealogy including clinical description and examination if possible. Interviews of parents and relatives, linkage and DNA analysis of the probands and the closest relatives have been studied. RESULTS: 46 affected cases from a highly inbred population have been diagnosed since 1943. The disease is caused by a missense mutation in the FIC1 gene ATP8B1, chromosome 18q21. Six affected children are alive aged 1-21 years. Among the tested relatives 220 are heterozygote. One prenatal diagnosis has been performed. CONCLUSION: The mutation causing Cholestasis Familiaris Groenlandica is widespread in Greenland, but accumulation is seen in certain areas. The disease is burdensome for the child, the parents and the Greenlandic society. Genetic counselling and carrier screening are strongly recommended.

Cholestasis Familiaris Groenlandica/Byler-like disease in Greenland--a population study.

OBJECTIVES: Cholestasis Familiaris Groenlandica (CFG, or progressive familiar intrahepatic cholestasis type 1 (PFIC1)) is a very common lethal recessive inherited disease in Greenland. A missense mutation, 1660G>A (asp554asn) in the gene ATP8B1 causes the disease (Klomp et al. 2000). STUDY DESIGN: A family study examining medical files from the period 1951-2003 from East Greenland resulted in 46 cases of PFIC1 and more than 220 relatives showing carrier status. Further, random blood sample testing 953 anonymous persons from 11 major cities or districts all over Greenland have been analysed for carrier status of the mutation. METHODS: A sensitive PCR method is developed to distinguish between normal and mutant alleles for ATP8B1 in the Greenland population. RESULTS: The mutation 1660G>A is found in all areas of Greenland, and the frequency of the mutant allele vary all over the country. A shockingly high frequency for the mutant allele is found in East Greenland in Ittoqqortoormiit (0.16) and in Tasiilaq (0.077), whereas in Northwest Greenland lower frequencies are found in Uummannaq and Ilulissat (0.032), and Maniitsoq (0.005). CONCLUSIONS: The high frequency of the mutation in East and Northwest Greenland strongly indicates that routine screening of the population for carrier status should be done.

Epilepsy among children in Greenland.

INTRODUCTION: Epilepsy has been considered to be more frequent in Greenland than in Denmark, where the prevalence among children is 0.40%. STUDY DESIGN: Evaluation of the prevalence, diagnosis and treatment of epilepsy among children in Greenland aged 0-15 years. METHODS: During autumn 2000, 13 out of 18 hospitals in Greenland were visited. The population of children in the areas visited was 11,965 of a total of 15,226 in Greenland. All children with the diagnosis of epilepsy were referred for evaluation and the diagnosis was confirmed. When possible, informed consent was obtained to collect data from medical records. RESULTS: 43 children (18 boys) had the diagnosis of epilepsy. For 38 (15 boys) further data were obtained. Mean age was 8.5 years (3-14) for boys and 7.9 years (2-14) for girls. The age at diagnosis was 4.9 years (1-11) for boys and 4.2 years (0-10) for girls. The prevalence of epilepsy was 0.34%. In 31 cases an electroencephalograph (EEG) recording was done, comprising sleep recordings in 26 cases. Medication was according to recommendations in Denmark. CONCLUSION: The prevalence of epilepsy in children and the medical treatment of epilepsy among children in Greenland is the same as in Denmark.

Microvascular free flaps in the treatment of defects of the lower legs.

Thirty-four microvascular free flaps were used to treat defects in the lower extremities after injuries. Twenty patients (74%) had severe open fractures (Gustilo type III B & C). Latissimus dorsi (n = 16) and iliac osteocutaneous (n = 7) flaps were most commonly used for coverage, and the overall failure rate was 9% (3/34). At follow up 29 of the patients (94%) had a reduced range of movement of the ankle, nine (29%) had some swelling and oedema, and 13 (42%) had occasional pain in the leg. Sixteen (52%) of the patients were limping, but 26 (84%) could walk one kilometre or more with no problems. No legs were amputated. The unemployment rate increased from 1/34 (3%) to 6/31 (19%) at follow up. Twenty-seven (87%) of our patients were satisfied with the results, despite the considerable and persistent limitation of function, and the increase in the unemployment rate.

Measurements of tissue oxygen tension in vascularised jejunal autografts in pigs.

Tissue oxygen measurements were evaluated as a monitor of the jejunal flap in seven female landrace pigs. A small polarographic sensor (diameter 0.55 mm) was used in which interstitial tissue oxygen tension was measured continuously in a jejunal flap and a muscle flap (rectus abdominis) during arterial and venous occlusion. Mean (SEM) tissue oxygen tension in the two types of flap were 44(9) mmHg (jejunal flap) and 47(8) mmHg (rectus flap). After arterial occlusion for 30 minutes the values dropped to 17(4) mmHg for the jejunal flap and 12(2) mmHg for the muscle flap. The decline became significant after five minutes. During venous occlusion (30 minutes) the values fell to 20(4) mmHg and 14(1) mmHg. The arterial occlusion was undetectable by the naked eye, but the enteric tissue after venous occlusion became severely congested and blue-black in colour. The condition returned to normal after release of the clamp. We conclude that direct measurement of tissue oxygen tension in a jejunal flap is a reliable method of detecting impaired perfusion. This method may in the future be used to monitor vascularised jejunal autografts.

[Free jejunal autograft for reconstruction of the pharynx and cervical esophagus]. / Frit jejunum-autotransplantat ved rekonstruktion af pharynx/cervikale esophagus.

Reconstruction of the pharynx and cervical oesophagus by transplantation and revascularisation of a free jejunal graft is reported in a 47-year old male with cancer of the pharynx. The time interval from operation to oral intake was 12 days.