“de novo” trisomy 1q32→1qter and monosomy 3p25→3pter

Summary The syndrome of familial lymphedema (type Meige) with distichiasis was observed in father and son. The association with uvula bifida and submucous cleft of the palate is described for the first time.     

Uvular transposition: a new method of cleft palate repair

This prospective study was done to determine whether a new cleft palate repair utilizing uvular transposition improved speech outcome as measured objectively by a speech pathologist. In the uvular transposition procedure, the palate was lengthened with tissue from the uvula by a double-opposing Z-plasty; an intravelar veloplasty was performed, and two-thirds of the mass of the uvula was transposed to the nasal surface of the soft palate. This procedure facilitates velopharyngeal closure by significantly lengthening the palate, anatomically reconstructing the muscles of the palate, and decreasing the palatal excursion necessary to achieve closure. Sixty-two children with a cleft palate were treated with this procedure performed by the senior surgeon between the years of 1988 and 1995. These children were then enrolled in cleft lip and palate clinic at age 2 to 3 years and blindly evaluated yearly by a single speech pathologist who specialized in pediatric speech pathology. Postoperative clinical follow-up ranged from 36 to 112 months (mean, 56.8 months). Perceptual nasal emission was found to be normal in 59 of the 62 patients (95 percent). Nasometry was performed in all 62 of these patients, and the mean score was 15.7 percent, well within the accepted normal range of 25 or less at our institution. Only two of these children (3 percent) required a pharyngeal flap for velopharyngeal insufficiency. These findings suggest that the uvula transposition cleft palate repair may result in good normalization of speech with negligible rates of velopharyngeal insufficiency.     

Cytochrome P4502C9 (CYP2C9) allele frequencies in Canadian Native Indian and Inuit populations.

CYP2C9 is the major P450 2C enzyme in human liver and contributes to the metabolism of a number of clinically important substrate drugs. This polymorphically expressed enzyme has been studied in Caucasian, Asian, and to some extent in African American populations, but little is known about the genetic variation in Native American populations. We therefore determined the 2C9*2 (Arg144Cys) and 2C9*3 (Ile359Leu) allele frequencies in 153 Native Canadian Indian (CNI) and 151 Inuit subjects by PCR-RFLP techniques. We also present genotyping data for two reference populations, 325 Caucasian (white North American) and 102 Chinese subjects. Genotyping analysis did not reveal any 2C9*4 alleles in the CNI, Inuit, Caucasian, or Chinese individuals. The 2C9*2 allele appears to be absent in Chinese and Inuit populations, but was present in CNI and Caucasian subjects at frequencies of 0.03 and 0.08-0.15, respectively. The 2C9*3 allele was not detected in the Inuit group, but occured in the CNI group (f = 0.06) at a frequency comparable to that of other ethnic groups. This group of Inuit individuals are the first population in which no 2C9*2 or *3 alleles have been detected so far. Therefore, these alleles may be extremely rare or absent, and unless other novel polymorphisms exist in this Inuit group one would not anticipate any CYP2C9 poor metabolizer subjects among this population.     

Computational analysis of a flapping uvula on aerodynamics and pharyngeal wall collapsibility in sleep apnea

Studying the airflows and the resultant aerodynamic pressure/force in the pharyngeal airway is critical for understanding the pathophysiology of snoring and sleep apnea. In this work, an experiment-driven computational study was conducted to examine the aerodynamics in human pharyngeal airway. An anatomically accurate pharynx model associated with different uvula kinematics was reconstructed from human magnetic resonance image (MRI) and high-speed photography. An immersed-boundary-method (IBM)-based direct numerical simulation (DNS) flow solver was adopted to simulate the corresponding unsteady flows in all their complexity. Analyses were performed on vortex dynamics and pressure fluctuations in the pharyngeal airway and force oscillations on the pharyngeal wall under the influence of varying airway obstructions, uvula flapping mode, and uvula flapping frequencies. It was found the vortex formation, aerodynamic pressure, and pharyngeal wall force were significantly affected by the width of the pharyngeal airway. By contrast, the influences from the uvula flapping mode were insignificant when other parameters were similar. Fast Fourier transformation (FFT) and continuous wavelet transform (CWT) analysis of the pressure time history revealed the existence of higher order harmonics of base frequency with significant pressure amplitudes and energy intensities. It was also found the airway pressure and pharyngeal wall force oscillate more dramatically at higher uvula flapping frequencies, which tends to promote the collapse of pharyngeal wall and initiates sleep apnea.     

mtDNA variation in Inuit populations of Greenland and Canada: migration history and population structure

We examined 395 mtDNA control-region sequences from Greenlandic Inuit and Canadian Kitikmeot Inuit with the aim of shedding light on the migration history that underlies the present geographic patterns of genetic variation at this locus in the Arctic. In line with previous studies, we found that Inuit populations carry only sequences belonging to haplotype clusters A2 and D3. However, a comparison of Arctic populations from Siberia, Canada, and Greenland revealed considerable differences in the frequencies of these haplotypes. Moreover, large sample sizes and regional information about birthplaces of maternal grandmothers permitted the detection of notable differences in the distribution of haplotypes among subpopulations within Greenland. Our results cast doubt on the prevailing hypothesis that contemporary Inuit trace their all of their ancestry to so-called Thule groups that expanded from Alaska about 800-1,000 years ago. In particular, discrepancies in mutational divergence between the Inuit populations and their putative source mtDNA pool in Siberia/Alaska for the two predominant haplotype clusters, A2a and A2b, are more consistent with the possibility that expanding Thule groups encountered and interbred with existing Dorset populations in Canada and Greenland.     

The many faces of aggressive aortic pathology: Loeys-Dietz syndrome

Background: Loeys-Dietz syndrome (LDS) is a newly recognised disorder of connective tissue which shares overlapping features with Marfan syndrome (MFS) and the vascular type of Ehlers- Danlos syndrome, including aortic root dilatation and skin abnormalities. It is clinically classified into types 1 and 2. LDS type 1 can be recognised by craniofacial characteristics, e.g. hypertelorism, bifid uvula or cleft palate, whereas these are absent in LDS type 2. It is important to recognise LDS because its vascular pathology is aggressive. We describe nine LDS patients from four families, relate their features to published cases, and discuss important aspects of the diagnosis and management of LDS in order to make clinicians aware of this new syndrome. Results: Characteristics found in the majority of these LDS patients were aortic root dilatation, cleft palate and/or a bifid/abnormal uvula. Conclusion: Because aortic dissection and rupture in LDS tend to occur at a young age or at aortic root diameters not considered at risk in MFS, and because the vascular pathology can be seen throughout the entire arterial tree, patients should be carefully followed up and aggressive surgical treatment is mandatory. Clinicians must therefore be aware of LDS as a cause of aggressive aortic pathology and that its distinguishing features can sometimes be easily recognised. (Neth Heart J 2008;16:299-304.)     

Assessment of frequency-dependent alterations in the level of extracellular Ca2+ in the synaptic cleft.

The synaptic cleft may be represented as a very thin disk of extracellular fluid. It is possible that at high stimulation frequencies the interval between pulses would be insufficient for diffusion of Ca2+ from the periphery of the cleft to replace extracellular Ca2+ depleted at the center of the cleft as a result of activation of postsynaptic, Ca2(+)-permeable channels. Computer modeling was employed to assess the impact of activation of glutamate receptor channels (GRCs) in the postsynaptic membrane on the level of extracellular Ca2+ within the synaptic cleft. The model includes calcium influx from the synaptic cleft into the postsynaptic compartment through GRC and calcium efflux through calcium pumps and Na/Ca exchangers. Concentrations of extracellular Ca2+ inside the cleft are estimated by using a compartmental model incorporating flux across the postsynaptic membrane and radial diffusion from the edges of the cleft. The simulations suggest that substantial extracellular Ca2+ depletion can occur in the clefts during activation of GRCs, particularly at high stimulation frequencies used to induce long-term potentiation (LTP). Only minimal transitory changes in extracellular Ca2+ are observed at low frequencies. These frequency-dependent alterations in extracellular Ca2+ dynamics are a direct reflection of the activity of GRCs and could be involved in the modulation of presynaptic function via a retrograde messenger mechanism, if there are extracellular Ca2+ sensors on the presynaptic membranes. The recently cloned extracellular Ca2(+)-sensing receptors that are known to be present in nerve terminals in hippocampus and other areas of the brain could potentially play such a role.     

Prevalence and the duration of linear enamel hypoplasia: a comparative study of Neandertals and Inuit foragers

As a dental indicator of generalized physiological stress, enamel hypoplasia has been the subject of several Neandertal studies. While previous studies generally have found high frequencies of enamel hypoplasia in Neandertals, the significance of this finding varies with frequencies of enamel hypoplasia in comparative samples. The present investigation was undertaken to ascertain if the enamel hypoplasia evidence in Neandertals suggests a high level of physiological stress relative to a modern human foraging group, represented here by an archaeological sample of Inuit from Point Hope, Alaska. Unlike previous studies, this study focused specifically on linear enamel hypoplasia (LEH), emphasizing systemic over localized causes of this defect by considering LEH to be present in an individual only if LEH defects occur on two anterior teeth with overlapping crown formation periods. Moreover, this study is the first to evaluate the average growth disruption duration represented by these defects in Neandertals and a comparative foraging group. In the prevalence analysis, 7/18 Neandertal individuals (from Krapina and southern France) and 21/56 Neandertal anterior teeth were affected by LEH, or 38.9% and 37.5% respectively. These values do not differ significantly from those of the Inuit sample in which 8/21, or 38.1% of individuals, and 32/111, or 28.8% of anterior teeth were affected. For the growth disruption duration analysis, 22 defects representing separate episodes of growth disruption in Neandertals were compared with 22 defects in the Inuit group using three indicators of duration: the number of perikymata (growth increments) in the occlusal walls of LEH defects, the total number of perikymata within them, and defect width. Only one indicator, the total number of perikymata within defects, differed significantly between the Inuit and Neandertal groups (an average of 13.4 vs. 7.3 perikymata), suggesting that if there is any difference between them, the Inuit defects may actually represent longer growth disruptions than the Neandertal defects. Thus, while stress indicators other than linear enamel hypoplasia may eventually show that Neandertal populations were more stressed than those of modern foragers, the evidence from linear enamel hypoplasia does not lend support to this idea.     

A prospective evaluation of the prevalence of submucous cleft palate in patients with isolated cleft lip versus controls.

Although there is an established relationship between cleft lip and overt cleft palate, the relationship between isolated cleft lip and submucous cleft palate has not been investigated. To test the hypothesis that patients with isolated cleft lip have a greater association with submucous cleft palate, a double-armed prospective trial was designed. A study group of 25 consecutive children presenting with an isolated cleft lip, with or without extension through the alveolus but not involving the secondary palate, was compared with a control group of 25 children with no known facial clefts. Eligible patients were examined for the presence of physical criteria associated with classic submucous cleft palate, namely, (1) bifid uvula, (2) absence of the posterior nasal spine, and (3) zona pellucida. Nasoendoscopy was subsequently performed just after induction of general anesthesia, and the findings were correlated with digital palpation of the palatal muscles. Patients who did not satisfy all three physical criteria and in whom nasoendoscopy was distinctly abnormal relative to the control group were classified as having occult submucous cleft palate. Classic submucous cleft palate was found in three study group patients (12 percent), all of whom had flattening or a midline depression of the posterior palate and musculus uvulae on nasoendoscopy and palpable diastasis of the palatal muscles under general anesthesia. An additional six study group patients (24 percent) had similar nasoendoscopic criteria and palpable diastasis of the palatal muscles; they were classified as having occult submucous cleft palate. No submucous cleft palate was identified in the control group. Seventeen patients in the study group had an alveolar cleft with a 53 percent (9 of 17) prevalence of submucous cleft palate. In the present study, classic submucous cleft palate in association with isolated cleft lip was 150 to 600 times the reported prevalence in the general population. All children with an isolated cleft lip should undergo peroral examination and speech/resonance assessment no later than the age of 3 years. Any child with an isolated cleft lip with velopharyngeal inadequacy or before an adenoidectomy should be assessed by flexible nasal endoscopy to avoid missing an occult submucous cleft palate.     

Diazepam-induced cleft palate in the mouse and lack of correlation with the H-2 locus

Cleft palate frequencies were studied in AJ and SW mice following either 1- or 2-day dosing schedules with the anxiolytic drug diazepam (DAZ). In all cases, mice were food and water deprived for 24 and 48 hours in the 1- and 2-day dosing schedules, respectively. High cleft palate frequencies in control mice of both strains resulting from 48-hour food and water deprivation (on days 13.5 and 14.5 of gestation) were reduced in mice deprived for 24 hours, indicating a stress related effect. Two-day dosing with DAZ (400 mg/kg) produced a net increase in cleft palate frequency in SW (33%) and AJ (18%) mice. Mice treated only on day 13.5 had reduced control and DAZ cleft palate frequencies, neither of which were significant. Clefting was significant but reduced following 1-day dosing on day 13/20 of gestation (13 days 20 hours) in SW mice (18%), whereas no clefting was seen in the AJ strain. This strain difference was shown not to be related to differences in developmental timing. Production of cleft palate seen in AJ mice after 2 days of dosing may be indicative of an interaction of DAZ with the stresses resulting from food and water deprivation. Genes of the major histocompatibility locus, H-2, have been shown to regulate cleft palate formation following glucocorticoid and phenytoin administration to mice. Despite pharmacological similarities between DAZ and phenytoin, comparison of cleft palate frequencies following administration of DAZ to various strains of mice of different H-2 haplotypes indicated that genes associated with the H-2 locus do not regulate DAZ-induced cleft palate in these strains.     

The apolipoprotein E polymorphism in Greenland Inuit in its global perspective

Apolipoprotein E (apoE) genotypes were determined in Inuit population samples from Nuuk on the south-west coast of Greenland (n = 100) and from the Ammassalik region on the south-east coast (n = 78). The ɛ2 allele was absent in the latter sample, and the ɛ4 allele frequency was relatively high, about 23%. As in most other populations, mean plasma lipoprotein-related variables, except high-density lipoprotein (HDL) cholesterol, were higher in both Inuit men and women with ɛ4 than in ɛ3ɛ3 genotypes (P < 0.05 for triglycerides in men, and for non-HDL cholesterol and apolipoprotein B in women). The estimated apoE allele frequencies were combined with data from other studies of aboriginal peoples to outline a world map of apoE allele frequencies. A recent study of non-human primates suggests that ɛ4, and not ɛ3, is the ancestral allele in humans and we have used the map to generate additional hypotheses regarding the history of the apoE polymorphism in humans. Received: 30 November 1995 / Revised: 15 June 1996     

Caribou (<Emphasis Type="Italic">Rangifer tarandus</Emphasis>) and Inuit Nutrition Security in Canada

Caribou (Rangifer tarandus) has been fundamental to the diet and culture of Arctic Indigenous Peoples for thousands of years. Although caribou populations observe natural cycles of abundance and scarcity, several caribou herds across the Circumpolar North have experienced dramatic declines in recent decades due to a range of interrelated factors. Broadly, the objectives of this study are to examine food and nutrition security in relation to wildlife population and management status across Inuit Nunangat (the Inuit homeland, consisting of four regions across the Canadian Arctic). Specifically, we: (1) characterize the contribution of caribou to Inuit nutrition across northern Canada and (2) evaluate the population and management status of caribou herds/populations harvested by Inuit. Dietary data were derived from the 2007–2008 Inuit Health Survey, which included dietary information for Inuit adults (n?=?2097) residing in thirty-six communities, spanning three regions (the Inuvialuit Settlement Region, Nunavut, and Nunatsiavut) of the Canadian North. Published information regarding the range, abundance, status, and management status of caribou herds/populations was collected through document analysis and was validated through consultation with northern wildlife experts (territorial governments, co-management, and/or Inuit organizations). While caribou contributed modestly to total diet energy (3–11% of intake) across the regions, it was the primary source of iron (14–37%), zinc (18–41%), copper (12–39%), riboflavin (15–39%), and vitamin B12 (27–52%), as well as a top source of protein (13–35%). Restrictions on Inuit subsistence harvest (harvest quotas or bans) are currently enacted on at least six northern caribou herds/populations with potential consequences for country food access for over twenty-five Inuit communities across Canada. A holistic multi-sectorial approach is needed to ensure the sustainability of wildlife populations, while supporting Inuit food and nutrition security in the interim.     

Essential fatty acid status of neonates born to Inuit mothers: comparison with Caucasian neonates and effect of diet.

Fatty acid compositions were determined of phospholipids isolated from venous cord plasma and from the walls of umbilical arteries and veins, collected from healthy, a terme, Inuit and Caucasian (Dutch) neonates. The Inuit fatty acid profiles were characterized by a lower essential fatty acid (EFA) status, with higher levels of monounsaturated fatty acids, of Mead acid [20:3(n-9)] and its direct elongation product, and with lower amounts of the longer chain (greater than or equal to 20 carbon atoms), highly unsaturated (greater than or equal to 4 double bonds) fatty acids of both the (n-3) and (n-6) families. Levels of linoleic- and dihomo-gamma-linolenic acids were higher in Inuit as compared to Caucasian neonates, which suggests a low activity of the delta-5-desaturase in the Inuit. Within the Inuit group, a higher intake of marine food was associated with a better neonatal (n-3) status. Although the differences between Inuit and Caucasian neonates may be of genetic rather than of dietary origin, the results imply that dietary long-chain (n-3) or (n-6) fatty acids may be particularly important during pregnancy in Inuit mothers. Further studies are indicated with respect to the EFA content of the habitual Inuit diet and levels of delta-5-desaturase activity in the Inuit.     

Elements in autopsy liver tissue samples from Greenlandic Inuit and Danes. III. zinc measured by X-ray fluorescence spectrometry

The aim of the study was to measure the content of zinc (Zn) in liver tissue samples from Greenlandic Inuit using X-ray fluorescence spectrometry, and compare the results with those obtained in liver samples from Danes. Normal liver tissue samples was obtained at autopsy from 50 Greenlandic Inuit (27 men) with a median age of 61 years (range 23–83) and from 74 Danes (44 men) with a median age of 60 years (range 15–87). In the entire series, liver zinc content in Inuit was not significantly different compared with Danes. There was no significant gender difference in liver zinc content either in Inuit or in Danes. The content of zinc given as median (5–95 percentile) was in Inuit 3.809 mmol/kg dry liver (2.355–7.406), and in Danes 3.992 mmol/kg dry liver (2.499–8.645). There was a significant, positive correlation between liver zinc content and age in Danish women (r_s = 0.43, p = 0.02), which could not be demonstrated in Danish men or in Inuit. Median hepatic zinc index (zinc content in mmol/kg dry weight divided by age in years) in Inuit was 0.073, and in Danes 0.080 (p = 0.3) without any significant difference between the two genders. In Inuit and Danes there was an inverse correlation between hepatic zinc index and age both in the two genders and in the entire series: Inuit: r_s = −0.62, p < 0.0001; Danes: r_s = −0.70, p < 0.0001. The results indicate that Inuit have liver zinc levels, which are similar to those found in Danes.     

Northern obstetrics: a 5-year review of delivery among Inuit women.

There are over 18,000 Inuit in the Northwest Territories. As a group they have the highest birth rate, the lowest cesarean section rate and one of the highest perinatal death rates in Canada. We reviewed the obstetric experience of 512 Inuit women who either gave birth at Stanton Yellowknife Hospital or were referred from Yellowknife and gave birth at a southern facility between January 1981 and December 1985. Our experience is consistent with that documented in earlier reviews, which concluded that Inuit women tend to have efficient uterine action, to endure labour well and to rarely have dystocia. During the periods covered by these reviews delivery was frequently in the settlements; now hospital delivery is the norm. Substantial improvements in perinatal outcome are evident, but there remains a considerable gap between the northern and southern experience. Those attempting further progress must recognize that the need for obstetric care away from the home community is not fully appreciated by Inuit women, their families or their communities.     

Left cleft lip predominance and genetic similarities of L line and CL/Fr strain mice

Newborn litters of the L line and CL/Fr and A/JFr strains were examined, and sex, frequency and type of cleft lip (left, right or bilateral) were recorded. Embryos and fetuses from crosses between these strains and line were collected on days 13 to 16 of gestation, and frequency and type of cleft lip recorded. Overall cleft frequencies in L X CL/Fr, CL/Fr X L, and CL/Fr X A/JFr crosses (female stated first) were similar, while in A/JFr X L (10.3%) they were significantly lower than in L X A/JFr (23.3%). The data suggested that the same maternal effect genes were present in CL/Fr and the related L line and absent from A/JFr. In the L, CL/Fr, and A/JFr newborns, there was a tendency for males to have higher frequencies of cleft lip and bilateral cleft lip and the latter was significant for L. Left cleft lip frequency was significantly higher than right for L and CL/Fr newborns and in embryos of the CL/Fr X L and L X CL/Fr cross. No significant differences in laterality were found in the A/JFr strain, A/JFr X L, L X A/JFr, and CL/Fr X A/JFr crosses. It was concluded that (1) the embryonic and maternal effect genes for cleft lip are similar or identical in CL/Fr and L; and (2) using data from the literature, there are additional genetic factor(s) increasing left cleft lip occurrence acting in the embryo, which are present in CL/Fr, L, A/HeJ, A/He, and A/St and absent from A/JKt, A/J, A/JFr, and A/WySn.     

Ethnic differences in the expression of Epstein-Barr virus latent membrane protein-1 mutations in nasopharyngeal carcinoma

The latent membrane protein-1 (LMP1) of Epstein-Barr virus (EBV) is a viral oncoprotein implicated in several EBV-associated pathologies. Many studies have characterized carboxy-terminal mutations within LMP1, errors in this area are critical since this portion contains sequences responsible for LMP1 targeting, half-life and association with host cell proteins. Although, data suggests that mutations in this area extend LMP1 half-life and increase its oncogenesis, some studies have not shown this to be true for all EBV-associated tumors. In order to evaluate 3'-end LMP1-DNA mutations in three different ethnic populations with nasopharyngeal carcinoma (NPC), we examined EBV-DNA in 34 patients of various origins (Caucasian, Chinese and Inuit). While 68% of the total group expressed EBV-antigens, only 56% of Caucasians but 86% of Inuit expressed this viral protein. Over 67% of Inuit NPC tissue contained the characteristic 30 bp deletion that was observed in only 20% of Caucasians and 33% of Chinese samples. DNA sequencing revealed that the Inuit population showed the most frequent DNA mutations and corresponding amino acid alterations in LMP1. Our results suggest that EBV-associated NPC-DNA mutations in LMP1 do not occur at equal rates in different racial groups and are more common at distinct sites in NPC tissue from Chinese and Inuit sources.     

Linkage analysis in a large Brazilian family with van der Woude syndrome suggests the existence of a susceptibility locus for cleft palate at 17p11.2-11.1.

van der Woude syndrome (VWS), which has been mapped to 1q32-41, is characterized by pits and/or sinuses of the lower lip, cleft lip/palate (CL/P), cleft palate (CP), bifid uvula, and hypodontia (H). The expression of VWS, which has incomplete penetrance, is highly variable. Both the occurrence of CL/P and CP within the same genealogy and a recurrence risk <40% for CP among descendants with VWS have suggested that the development of clefts in this syndrome is influenced by modifying genes at other loci. To test this hypothesis, we have conducted linkage analysis in a large Brazilian kindred with VWS, considering as affected the individuals with CP, regardless of whether it is associated with other clinical signs of VWS. Our results suggest that a gene at 17p11.2-11.1, together with the VWS gene at 1p32-41, enhances the probability of CP in an individual carrying the two at-risk genes. If this hypothesis is confirmed in other VWS pedigrees, it will represent one of the first examples of a gene, mapped through linkage analysis, which modifies the expression of a major gene. It will also have important implications for genetic counseling, particularly for more accurately predicting recurrence risks of clefts among the offspring of patients with VWS.