The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia.

Formation of the secondary palate is a complex step during craniofacial development. Disturbance of the events affecting palatogenesis results in a failure of the palate to close. As a consequence of deformity, an affected child will have problems with feeding, speech, hearing, dentition and psychological development. Cleft palate occurs frequently, affecting approximately 1 in 1,500 births; it is usually considered a sporadic occurrence resulting from an interaction between genetic and environmental factors. Although several susceptibility loci have been implicated, attempts to link genetic variation to functional effects have met with little success. Cleft palate with ankyloglossia (CPX; MIM 303400) is inherited as a semidominant X-linked disorder previously described in several large families of different ethnic origins and has been the subject of several studies that localized the causative gene to Xq21 (refs. 10-13). Here we show that CPX is caused by mutations in the gene encoding the recently described T-box transcription factor TBX22 (ref. 14). Members of the T-box gene family are known to play essential roles in early vertebrate development, especially in mesoderm specification. We demonstrate that TBX22 is a major gene determinant crucial to human palatogenesis. The spectrum of nonsense, splice-site, frameshift and missense mutations we have identified in this study indicates that the cleft phenotype results from a complete loss of TBX22 function.

Epidemiology of traumatic spinal cord injuries in Iceland from 1975 to 2009.

STUDY DESIGN: Retrospective population-based epidemiological study. OBJECTIVES: To assess the nationwide, population-based incidence, causes, age, gender, extent and prevalence of spinal cord injuries (SCIs) in Iceland from 1975 to 2009. SETTING: Landspitali University Hospital in Iceland, the single referral center for SCIs in Iceland. METHODS: A retrospective review of hospital records on all admissions due to SCIs. Analysis of incidence, causes, age, gender, extent of injury and prevalence. RESULTS: A total of 207 patients with traumatic spinal cord injury (TSCI) were admitted: males 72%, females 28%. The percentage of females with TSCI increased to 37% in 2000-2004. Mean age at injury was 38 years. Average incidence per million population per year was 30 in 1975-1979, 12.5 in 1995-1999 and 33.5 in 2005-2009. Thirty-day mortality was 6.3%. Causes of injury were road traffic accidents (RTA) in 42.5% of the cases; the majority did not use seatbelts. Falls amounted to 30.9%, with an increase of low falls among the elderly causing incomplete cervical lesions. Sport/leisure activities were the cause in 18.8%, of which 54% occurred after 2000. The main single cause of TSCI in sport/leisure were horse-riding accidents, followed by winter sport accidents, especially among women. Other causes constituted 7.7%. The injury was complete in 39%; cervical lesions were 57% and thoracic/lumbar lesions were 43%. In December 2009, the crude prevalence rate was 526 per million population. CONCLUSIONS: The findings showed a significant increase of TSCI in 2005-2009, especially in sport/leisure accidents and incomplete cervical lesions due to falls among elderly. Prevention strategies need to focus on these risk groups and on seatbelt use.

Reduction in mortality after epidural anaesthesia and analgesia in patients undergoing rectal but not colonic cancer surgery: a retrospective analysis of data from 655 patients in central Sweden.

BACKGROUND: There is some evidence that epidural analgesia (EDA) reduces tumour recurrence after breast and prostatic cancer surgery. We assessed whether EDA reduces long-term mortality after colorectal cancer surgery. METHODS: All patients having colorectal cancer surgery between January 2004 and January 2008 at Linköping and Örebro were included. Exclusion criteria were: emergency operations, laparoscopic-assisted colorectal resection, and stage 4 cancer. Statistical information was obtained from the Swedish National Register for Deaths. Patients were analysed in two groups: EDA group or patient-controlled analgesia (PCA group) as the primary method of analgesia. RESULTS: A total of 655 patients could be included. All-cause mortality for colorectal cancer (stages 1-3) was 22.7% (colon: 20%, rectal: 26%) after 1-5 yr of surgery. Multivariate regression analysis identified the following statistically significant factors for death after colon cancer (P<0.05): age (>72 yr) and cancer stage 3 (compared with stage 1). A similar model for rectal cancer found that age (>72 yr) and the use of PCA rather than EDA and cancer stages 2 and 3 (compared with stage 1) were associated with a higher risk for death. No significant risk of death was found for colon cancer when comparing EDA with PCA (P=0.23), but a significantly increased risk of death was seen after rectal cancer when PCA was used compared with EDA (P=0.049) [hazards ratio: 0.52 (0.27-1.00)]. CONCLUSIONS: We found a reduction in all-cause mortality after rectal but not colon cancer in patients having EDA compared with PCA technique.

Screen for CACNA1A and ATP1A2 mutations in sporadic hemiplegic migraine patients.

The aim of this study was to investigate the involvement of the CACNA1A and ATP1A2 gene in a population-based sample of sporadic hemiplegic migraine (SHM). Patients with SHM (n = 105) were identified in a nationwide search in the Danish population. We sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes in 100 patients with SHM to search for possible SHM mutations. Novel DNA variants were discovered in eight SHM patients, four in exons of the CACNA1A gene and four in exons of the ATP1A2 gene. Six of the variants were considered non-pathogenic. The causal role of the two remaining DNA variants is unknown until functional studies have been made or independent genetic evidence is discovered. Only very few DNA variants were identified in 100 SHM patients, and regardless of whether the identified variants are causal the CACNA1A and ATP1A2 genes are not major genes in SHM.

The genetic spectrum of a population-based sample of familial hemiplegic migraine.

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura and transient hemiplegia. FHM mutations are known in three genes, the CACNA1A (FHM1) gene, the ATP1A2 (FHM2) and the SCN1A (FHM3) gene and seem to have an autosomal-dominant mode of inheritance. The aim of this study was to search for FHM mutations in FHM families identified through a screen of the Danish population of 5.2 million people. FHM patients were diagnosed according to the International Classification of Headache Disorders and all FHM patients had a physical and neurological examination by a physician. A total of 147 FHM patients from 44 different families were identified; 43 FHM families participated in this study. Linkage analysis of these families shows clear linkage to the FHM locus (FHM1) on chromosome 19, supportive linkage to the FHM2 locus whereas no linkage was found to the FHM3 locus. Furthermore, we sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes and screened for the Q1489K mutation in the SCN1A gene. CACNA1A gene mutations were identified in three of the FHM families, two known FHM mutations, R583Q and T666M and one novel C1369Y mutation. Three FHM families were identified with novel mutations in the ATP1A2 gene; a family with a V138A mutation, a family with a R202Q mutation and a family with a R763C mutation. None of the Danish FHM families have the Q1489K mutation in the SCN1A gene. Our study shows that only 14% (6/42) of FHM families in the general Danish population have exonic FHM mutations in the CACNA1A or ATP1A2 gene. The families we identified with FHM mutations in the CACNA1A and ATP1A2 genes were extended, multiple affected families whereas the remaining FHM families were smaller. The existence of many small families in the Danish FHM cohort may reflect less bias in FHM family ascertainment and/or more locus heterogeneity than described previously.

Validation of the deCODE Migraine Questionnaire (DMQ3) for use in genetic studies.

We assessed the reliability of the diagnosis of migraine with aura (MA) and migraine without aura (MO) based on the third edition of the deCODE Migraine Questionnaire (DMQ3) using a physician-conducted interview as an empirical index of validity. Amongst Danish migraine families recruited from specialist practice we selected 200 cases diagnosed according to the International Classification of Headache Disorders 2nd Edition in a validated physician-conducted telephone interview: 50 patients with exclusively MA, 50 with both MA and MO, 50 with exclusively MO and 50 controls. A written copy of the DMQ3 was mailed to the participant. The DMQ3-based diagnosis was compared with the interview-based diagnosis. Overall, the DMQ3 diagnosed migraine (MA, MO or both) with a sensitivity of 99% (109/110), a specificity of 86% (32/37) and a kappa statistic of 0.89. The most reliable subtype of migraine was MA (with or without co-occurring attacks of MO) which was diagnosed with a sensitivity of 92% (71/77), a specificity of 93% (65/70) and a kappa statistic of 0.85. Exclusively MO was diagnosed with a sensitivity of 91% (30/33), a specificity of 93% (106/114) and a kappa statistic of 0.80. Weakest was the diagnosis of both MO and MA which was diagnosed with a sensitivity of 63% (24/38), a specificity of 92% (100/109) and a kappa statistic of 0.57. In conclusion, the DMQ3 is a valid tool for diagnosing patients with migraine for genetic studies.

UGA codon context which spans three codons. Reversal by ms2i6A37 in tRNA, mutation in rpsD(S4) or streptomycin.

Mutant UGA codon contexts which previously have been identified at different positions in the lacI part of a fused lacIlacZ gene were characterized with respect to translational readthrough in another genetic surrounding at a constant location. Although readthrough levels are systematically higher in this new location the "tight/leaky" characteristics of these codon contexts are essentially fully determined by the two codons flanking the nonsense codon itself. Analysis of some UGA hybrid contexts shows that the contribution to the codon context character by the codon either at the 5'-side (CCA or AGC) or at the 3'-side (NGU) is independent of the nature of the codon at the other side of UGA if this codon is decoded by trpT(Su9) suppressor tRNA. In a trpT(Su9), miaA double mutant strain, which lacks the ms2i6A37 modification in this tRNA, suppression is decreased at all UGA contexts investigated. However, in one case the contribution to the codon context character by the determinant flanking at one side is negatively affected by the nature of the codon at the other side of UGA. Thus, the character of a nonsense codon context in this case results from both flanking codons acting in a co-operative manner with the tRNA reading the middle UGA codon. This negative context effect is counteracted by a rpsD12 (ribosomal protein S4) mutation or by a sublethal concentration of streptomycin in the growth medium. It is suggested that the ms2i6A37 base in trpT(Su9) suppressor tRNA increases the efficiency of this tRNA by protecting it from ribosomal proofreading which is induced by codon context.

Epidemiology of Dupuytren's disease: clinical, serological, and social assessment. The Reykjavik Study.

Dupuytren's disease or palmar fibromatosis is a common disabling hand disorder, mainly confined to Caucasians of northwestern European origin. The prevalence of Dupuytren's disease and possible risk factors related to the disease were evaluated in a random sample of 1297 males and 868 females, aged 46 to 74 years. Blood samples were collected and biochemical parameters were evaluated. The possible relation between the disease and clinical, social, and biochemical parameters were estimated with age-adjusted univariate logistic regression analysis. Altogether 19.2% of the males and 4.4% of the female participants had clinical signs of Dupuytren's disease. The prevalence increased with age, from 7.2% among males in the age group 45-49 years up to 39.5% in those 70-74 years old. The more severe form of the disease, finger contractures, was found in 5.0% of the men and 1.4% had required operation, while this was rarely seen among women. In men elevated fasting blood glucose (P < 0.04), low body weight, and body mass index were significantly correlated with the presence of the disease (P < 0.001). Dupuytren's disease was common among heavy smokers (P = 0.02) and those having manual labor as occupation (P = 0.018). These results show that Dupuytren's disease is common in the Icelandic population and occupation and lifestyle seem to be related to the disease.

The penetration of metrizamide into the brain after routine lumbar myelography as shown by cerebral computed tomography and its effect on auditory brainstem transmission time.

Metrizamide is a widely used contrast medium with some well known adverse reactions. In a preliminary study, CT scans and brain stem evoked potentials (BAEP) were done before and 18 hours following lumbar myelography on 12 patients. A statistically significant prolongation of the BAEP was observed. Metrizamide therefore seems to be a potent substance in clinical use as indicated by its effect on BAEP. BAEP should not be done within the first few days after myelography with metrizamide.

Repair of the contracted eye socket using a flap from the upper eyelid.

Repair of the contracted eye socket with a flap from the upper eyelid is proposed. The availability of nearby tissue with good blood supply could make this a method of choice in many patients with this condition.

A psychosocial study of Icelandic individuals with cleft lip or cleft lip and palate.

Questionnaires were sent to 63 Icelandic individuals with cleft lip and cleft lip and palate who had undergone surgical repair of those defects. The questions focused on the following areas: social characteristics, clinical characteristics, attitudes toward consequences of clefts, and attitudes toward appearance and treatment. The CL and CLP groups were compared, as were females and males. A comparison group was used with respect to two social factors. The data indicated relatively good psychosocial adjustment. However, fewer individuals were married or living together in the cleft group than in the comparison group. The subjects did not perceive that cleft lip or palate had influenced their lives to a great extent, yet females seemed to be more self-conscious than males in respect to how others viewed their appearance. Overall, the subjects were satisfied with the treatment and the members of the treatment team. However, their expectations exceeded the actual outcome of surgery. Suggestions are offered for future research.

[Overview and follow up study of cleft patients.].

On the average 8.2 children with different types of facial clefts are born in Iceland every year, which means approximately 1.87 per 1000 births. Until just before the middle of this century most of those children were treated by general surgeons or not at all, and a few were sent abroad. Around 1950 an orthopedic surgeon with some training in plastic surgery joined the staff at Landspitalinn (University Hospital in Reykjavik). Soon practically all children with clefts were referred to him and as the only obstetrical and gynaecological and only pediatric unit in the country were stationed there, Landspitalinn became a center for cleft treatment and has remained so. The senior author (AB) took over the treatment of clefts between 1955 and 1960 and treated about 90% of the children until 1993. The aim of the paper is to give an overview over treatment of clefts in Iceland over this period. Landspitalinn was founded in 1930. All hospital records for patients with clefts were looked into, classified and devided into three groups after the ICD system. A simple record was made for each patient with general informations and special records for those born between 1955-1984, 312 in all, for special scrutiny. In those records all known informations are to be found; kinship, mothers use of drugs in pregnancy, operations, time of operations and surgeon's name were recorded. The operations were devided into main groups and sub groups, auxiliary treatment was recorded as were all complications and diseases related to the clefts. It was also recorded if the cleft was a part of a syndrome or associated with other major congenital deformities. The informations so gained will be a basis for further studies related to evaluation of the treatment and further genetic studies.

X-linked cleft palate and ankyloglossia in an Icelandic family.

Information was available on 293 family members and spouses of seven generations in an Icelandic family with high frequency of cleft of secondary palate and ankyloglossia. The authors have personally investigated 182 individuals in generations IV-VII and have drawn blood from over 100 members for genetic marker studies. The senior author, Dr. Björnsson, has operated on two-thirds of the affected individuals. Twenty-six family members had cleft palate (CP) and, of these, 19 (17 male and two females) had ankyloglossia as well (CP + A). Twenty females and one male had only ankyloglossia (A). All mothers in one of two branches of the family who had sons with CP + A had ankyloglossia themselves. This was not the case in the other branch, in which the mothers of affected sons were themselves unaffected. Fathers affected with CP, CP + A, or high vaulted palate (HVP) never had affected sons. As reported earlier, the condition has been mapped to the q13-q21 region of the X chromosome using restriction fragment length polymorphism (RFLP) techniques (Moore et al, 1987). Our conclusion is that this midline defect is X-linked but varies in the severity of expression.

Occipital nerve release in patients with whiplash trauma and occipital neuralgia.

The results of 18 greater occipital nerve release operations in 13 patients were analyzed. All patients had deep aching pain in the occipital area due to a whiplash trauma, and in all cases the pain was relieved temporarily by local anesthesia of the occipital nerve. The time from accident to operation was 6 to 96 months. The results of 13 (72.2%) operations were reported as good or excellent, although complete pain relief was not attained in any patient. It is concluded that neurolysis of the greater occipital nerve after whiplash injury can give meaningful pain relief in selected patients.

[Mortality from burns in Iceland 1971-1992.].

A retrospective study was made on mortality due to burn injuries in Iceland 1971-1992. Data was obtained from the Bureau of Statistics, the Icelandic University Hospital and Department of Forensic Medicine. Analyzed were etiology, sex and age distribution, associated risk factors and mortality rate. In addition there were analyzed wound size and depth, complications and cause of death for patients admitted to the Burn Unit at the University Hospital. Mortality Model was used to calculate probability of death. Following burn injury 46 died, the overall mortality rate was 0.9/100,000 persons per year, the mortality rate had decreased and was 0.5/ 100,000 persons during 1983-92. Admitted to the University Hospital were 27. The cause of death was due to complications of the burn injury, except in two cases where death was due to preexisting disease and they had the lowest probability of death. Probability of death over 0.45 had 80 percent and 60 percent over 0.8. Only one patient died the last 10 years with probability of death lower than 0.8. Mortality due to burns has decreased over the last decade and later causes of death have proportionally increased. Calculated probability of death was very high and it is therefore assumed that the result of treatment was acceptable.

Accumulation of a mRNA decay intermediate by ribosomal pausing at a stop codon.

A RNA fragment which is protected from degradation by ribosome pausing at a stop codon has been identified in growing Escherichia coli. The fragment is 261 nt long and corresponds to the 3'-end of the mRNA expressed from a semi-synthetic model gene. The 5'-end of the RNA fragment, denoted rpRNA (ribosomal pause RNA), is located 13 bases upstream of the stop codon. In vivo decay of the complete mRNA and accumulation of rpRNA are dependent on the nature of the stop codon and its codon context. The data indicate that the rpRNA fragment arises from interrupted decay of the S3A'mRNA in the 5'-->m3'direction, in connection with a ribosomal pause at the stop codon. RF-2 decoding of UGA is less efficient than RF-1 decoding of UAG in identical codon contexts, as judged from rpRNA steady-state levels. The half-life of UGA-containing rpRNAs is at least 5 min, indicating that ribosomal pausing can be a major factor in stabilising downstream regions of messenger RNAs.

The second to last amino acid in the nascent peptide as a codon context determinant.

Forty-two different sense codons, coding for all 20 amino acids, were placed at the ribosomal E site location, two codons upstream of a UGA or UAG codon. The influence of these variable codons on readthrough of the stop codons was measured in Escherichia coli. A 30-fold difference in readthrough of the UGA codon was observed. Readthrough is not related to any property of the upstream codon, its cognate tRNA or the nature of its codon-anticodon interaction. Instead, it is the amino acid corresponding to the second upstream codon, in particular the acidic/basic property of this amino acid, which seems to be a major determinant. This amino acid effect is influenced by the identity of the A site stop codon and the efficiency of its decoding tRNA, which suggests a correlation with ribosomal pausing. The magnitude of the amino acid effect is in some cases different when UGA is decoded by a wildtype form of tRNA(Trp) as compared with a suppressor form of the same tRNA. This indicates that the structure of the A site decoding tRNA is also a determinant for the amino acid effect.