Associations between a fetal imprinted gene allele score and late pregnancy maternal glucose concentrations.

AIM: We hypothesised that some of the genetic risk for gestational diabetes (GDM) is due to the fetal genome affecting maternal glucose concentrations. Previously, we found associations between fetal IGF2 gene variants and maternal glucose concentrations in late pregnancy. METHODS: In the present study, we tested associations between SNP alleles from 15 fetal imprinted genes and maternal glucose concentrations in late pregnancy in the Cambridge Baby Growth and Wellbeing cohorts (1160 DNA trios). RESULTS: Four fetal SNP alleles with the strongest univariate associations: paternally-transmitted IGF2 rs10770125 (P-value=2×10-4) and INS rs2585 (P-value=7×10-4), and maternally-transmitted KCNQ1(OT1) rs231841 (P-value=1×10-3) and KCNQ1(OT1) rs7929804 (P-value=4×10-3), were used to construct a composite fetal imprinted gene allele score which was associated with maternal glucose concentrations (P-value=4.3×10-6, n=981, r2=2.0%) and GDM prevalence (odds ratio per allele 1.44 (1.15, 1.80), P-value=1×10-3, n=89 cases and 899 controls). Meta-analysis of the associations including data from 1367 Hyperglycaemia and Adverse Pregnancy Outcome Study participants confirmed the paternally-transmitted fetal IGF2/INS SNP associations (rs10770125, P-value=3.2×10-8, rs2585, P-value=3.6×10-5) and the composite fetal imprinted gene allele score association (P-value=1.3×10-8), but not the maternally-transmitted fetal KCNQ1(OT1) associations (rs231841, P-value=0.4; rs7929804, P-value=0.2). CONCLUSION: This study suggests that polymorphic variation in fetal imprinted genes, particularly in the IGF2/INS region, contribute a small but significant part to the risk of raised late pregnancy maternal glucose concentrations.

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

The chromosome 3q25 locus associated with fetal adiposity is not associated with childhood adiposity.

Increased newborn adiposity is associated with later adverse metabolic outcomes. Previous genome-wide association studies (GWAS) demonstrated strong association of a locus on chromosome 3 (3q25.31) with newborn sum of skinfolds, a measure of overall adiposity. Whether this locus is associated with childhood adiposity is unknown. Genotype and sum of skinfolds data were available for 293 children at birth and age 2, and for 350 children at birth and age 6 from a European cohort (Belfast, UK) who participated in the Hyperglycemia and Adverse Pregnancy Outcome GWAS. We examined single nucleotide polymorphisms (SNPs) at the 3q25.31 locus associated with newborn adiposity. Linear regression analyses under an additive genetic model adjusting for maternal body mass index were performed. In both cohorts, a positive association was observed between all SNPs and sum of skinfolds at birth (P=2.3 × 10(-4), ß=0.026 and P=4.8 × 10(-4), ß=0.025). At the age of 2 years, a non-significant negative association was observed with sum of skinfolds (P=0.06; ß =-0.015). At the age of 6 years, there was no evidence of association (P=0.86; ß=0.002). The 3q25.31 locus strongly associated with newborn adiposity had no significant association with childhood adiposity suggesting that its impact may largely be limited to fetal fat accretion.

Maternal testosterone levels are associated with C-peptide levels in the Mexican American subset of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study cohort.

Altered sex hormone levels are thought to play an important role in adult-onset diseases including obesity, cardiovascular disease, and diabetes. They contribute to these complex diseases through changes in their availability, which is influenced, in part, by binding proteins. Insulin resistance, which is characteristic of these diseases, along with increased insulin secretion, is a physiologic change that occurs normally during pregnancy. To determine the relationship between insulin resistance and sex hormone levels, we examined the associations of sex hormone-binding globulin (SHBG) and testosterone with measures of glycemia and insulinemia in a healthy pregnant population. We measured fasting serum SHBG and testosterone levels in 215 Hispanic mothers of Mexican ancestry from the HAPO Study cohort and tested for associations between SHBG and testosterone levels and maternal plasma glucose and C-peptide. After adjusting for confounding variables, serum total testosterone (TT) was positively associated with fasting C-peptide (0.18 µg/l higher for TT higher by 1 SD, p=0.001) and 1-h C-peptide (0.79 µg/l higher for TT higher by 1 SD, p<0.001). Free testosterone (FT) was also positively associated with fasting C-peptide (0.19 µg/l higher for FT higher by 1 SD, p<0.001), and 1-h C-peptide (0.83 µg/l higher for FT higher by 1 SD, p<0.001). Although these findings are from a single cohort, this study provides evidence for an association between testosterone and C-peptide during pregnancy in a nondiabetic Hispanic obstetric population.

Association of the KCNJ11 variant E23K with type 2 diabetes in Indo-Trinidadians.

OBJECTIVE: To examine the effect of genetic variation in KCNJ11 on the risk of Type 2 diabetes mellitus in Trinidadians. METHODS: The coding and bordering intron-exon regions of the KCNJ11 gene were sequenced in 168 diabetic and 61 non-diabetic subjects who historically were thought to be of South Asian Indian ancestry as well as 66 diabetic and 59 non-diabetic subjects of African ancestry. Allele and haplotype frequency differences were calculated between cases and controls and linkage equilibrium was assessed across the KCNJ11 region. RESULTS: We identified novel missense mutations in both subject groups including A94P and R369C in a diabetic Indo-Trinidadian subject, S113G in a non-diabetic Indo-Trinidadian subject, and S118L in a diabetic Afro-Trinidadian subject. It is unknown if these mutations are pathogenic as other family members were not available for study. Additionally, the common variant E23K was associated with Type 2 diabetes in the Indo-Trinidadian group (OR = 1.797 [1.148-2.814], p = 0.0098). CONCLUSIONS: Rare variants in KCNJ11 are segregating in the Indo- and Afro-Trinidadian populations and further studies are needed to determine their contribution, if any, to the overall prevalence of diabetes in these groups. Common variants such as E23K may increase the risk in the Indo-Trinidadian population.

The role of the polycystic ovary syndrome susceptibility locus D19S884 allele 8 in maternal glycemia and fetal size.

CONTEXT: The high incidence of insulin resistance, type 2 diabetes, and metabolic syndrome in Western societies and their impact on quality of life emphasize the importance of identifying underlying susceptibility loci for metabolic diseases. The polycystic ovary syndrome (PCOS) susceptibility locus D19S884 allele 8 (A8) is associated with measures of insulin resistance, beta-cell dysfunction, and other metabolic phenotypes in PCOS families. We now investigate the role of D19S884 A8 in pregnancy. OBJECTIVE: Using the multiethnic Hyperglycemia and Adverse Pregnancy Outcome cohort, we assessed the associations of D19S884 A8 with measures of maternal glycemia and fetal size. DESIGN: We tested for association of maternal D19S884 A8 with maternal outcomes (fasting, 1-h, and 2-h plasma glucose, and fasting and 1-h C-peptide from an oral glucose tolerance test) and fetal and maternal D19S884 A8 with fetal outcomes (birth weight, length, head circumference, sum of skin folds, fat mass, cord C-peptide, and 2-h neonatal plasma glucose). SUBJECTS: We analyzed 4424 Caucasian mothers and 3347 offspring of northern European ancestry, 1957 Thai mothers and 2089 offspring from Bangkok, 1208 Afro-Caribbean mothers and 1209 offspring from Barbados, and 774 Hispanic mothers and 762 offspring from Bellflower, California. RESULTS: After adjusting for confounding variables and multiple testing, neither maternal nor fetal D19S884 A8 showed significant evidence for association with any of the outcomes tested. CONCLUSIONS: The PCOS susceptibility locus, D19S884 A8, is not a major factor contributing to glycemia during pregnancy or fetal size in a general obstetric population.

Grade III acromioclavicular joint injury in Australian Rules Football.

We have reviewed fourteen Australian Rules Football players who were seen consecutively by a single surgeon with grade III acromioclavicular joint injuries between January 1993-June 1997. After discussion at initial consultation eight players elected for non-operative management and six for operative management. Two players in the non-operative group subsequently underwent surgical reconstruction after failure of non-operative treatment. The mean return time to non-contact training was 2.4 weeks (range 1-4, S.D. 1.52) in the non-operative group and 6.3 weeks (range 3.5-10, S.D. 2.99) in the operative group. However return to sports specific training (contact training) was at a mean of 20.8 weeks (range 10-32. S.D. 8.56) in the non-operative group and 13.6 weeks (range 6-24. S.D. 7.06) in the operative group. Return to competitive football matches for the non-operative group was at a mean of 26.2 weeks (range 10-34,S.D. 8.84) and 18.8 weeks (9.5-28. S.D. 8.05) for those treated operatively. These results were not statistically significant. At final follow up the subjective scores for the current overall condition of the shoulder when compared to the uninjured side, were 72.5 (range 20-100, S:D.24.9) for the non operative group and 87.3 (range 75-100, S:D.10.61) for the operative group and this difference was also not statistically significant. Conclusions in this study are limited by small numbers and lack of statistically significant results. The results show a trend towards faster return to ARF and a more satisfactory outcome for patients undergoing surgery compared to their non operative cohorts.

Thermal inactivation kinetics of bovine cathepsin D.

Cathepsin D, the principal indigenous acid proteinase in bovine milk, is a lysosomal proteinase, which exists in milk in four forms, including the inactive zymogen procathepsin D. The thermal inactivation kinetics of bovine cathepsin D, isolated from spleen and milk, were studied under isothermal conditions, using a specific HPLC assay to determine residual activity. Inactivation of the blood enzyme preparation followed first order kinetics, with z-values in phosphate buffer (pH 6.7) and skimmed milk of 6.5 and 7.6 degrees C, respectively, the enzyme being far more stable in the latter environment. Inactivation kinetics of the enzyme purified from milk were more complex, and could be best approximated by a double exponential model. Again, stability was higher in milk than in buffer. The double exponential model may indicate differing heat stabilities of isoforms of the enzyme, or stabilization of the enzyme by some milk constituent. It is clear that the enzyme can survive, at least partially, processes such as heating at 55 degrees C for 30 min during manufacture of high-cook cheese varieties (45% survival), and HTST pasteurization (8% survival), and thus may contribute to proteolysis in a range of dairy products.

Novel, bedside, tissue factor-dependent clotting assay permits improved assessment of combination antithrombotic and antiplatelet therapy.

BACKGROUND: Because optimal use of combinations of antiplatelet and antithrombotic drugs requires improved methods for assessment of therapeutic efficacy, we developed an assay designed to increase sensitivity that is based on initiation of clotting by tissue factor in minimally altered whole blood. METHODS AND RESULTS: Blood samples were obtained from healthy subjects, and the contact pathway of coagulation was inhibited with corn trypsin inhibitor (a specific factor XIIa inhibitor without effect on other coagulation factors). Clotting was initiated with relipidated tissue factor and detected with a Hemochron ACT instrument. Results were reproducible with samples from 25 healthy volunteers (mean time to clot, 125+/-17 seconds). Blood was also exposed to pharmacological concentrations of antithrombotic and antiplatelet agents in vitro. Heparin (0.25 anti-IIa/Xa U/mL) prolonged the time to clot by 2.4-fold (172 seconds, P:<0.05); hirudin (1.0 anti-IIa U/mL), by 3-fold (250 seconds P:<0.05); and enoxaparin (0.6 anti-Xa U/mL), by 2 -fold (123 seconds, P:<0.05). Additive effects of antiplatelet agents were readily detectable with both heparin and hirudin. Thus, addition of 3 microg/mL abciximab to 1.0 anti-IIa/Xa U/mL heparin and to 1.0 anti-IIa U/mL hirudin further prolonged the times to clot by 140 and 67 seconds, respectively (P:<0.05 for each). Addition of abciximab to enoxaparin did not further prolong the time to clot (increment, 13 seconds; P:=NS). CONCLUSIONS: The assay developed should facilitate improved dose selection, titration, and monitoring of combination antithrombotic and antiplatelet treatment regimens.

Context of maternal lineages in the Greater Southwest.

We present mitochondrial haplogroup characterizations of the prehistoric Anasazi of the United States (US) Southwest. These data are part of a long-term project to characterize ancient Great Basin and US Southwest samples for mitochondrial DNA (mtDNA) diversity. Three restriction site polymorphisms (RSPs) and one length polymorphism identify four common Native American matrilines (A, B, C, and D). The Anasazi (n = 27) are shown to have a moderate frequency of haplogroup A (22%), a high frequency of haplogroup B (56%), and a low frequency of C (15%). Haplogroup D has not yet been detected among the Anasazi. In comparison to modern Native American groups from the US Southwest, the Anasazi are shown to have a distribution of haplogroups similar to the frequency pattern exhibited by modern Pueblo groups. A principal component analysis also clusters the Anasazi with some modern (Pueblo) Southwestern populations, and away from other modern (Athapaskan speaking) Southwestern populations. The Anasazi are also shown to have a significantly different distribution of the four haplogroups as compared to the eastern Great Basin Great Salt Lake Fremont (n = 32), although both groups cluster together in a principal component analysis. The context of our data suggests substantial stability within the US Southwest, even in the face of the serious cultural and biological disruption caused by colonization of the region by European settlers. We conclude that although sample numbers are fairly low, ancient DNA (aDNA) data are useful for assessing long-term populational affinities and for discerning regional population structure.

Shoulder pathology associated with symptomatic acromioclavicular joint degeneration.

We report the incidence and nature of shoulder disease found in association with symptomatic degenerative change in the acromioclavicular joint in 218 shoulders. Coexisting pathologic conditions were present in 213 shoulders: rotator cuff degeneration in 176 shoulders (79 with complete thickness tears), labral tears in 72, glenohumeral degeneration in 31, and biceps tendon disease in 49. In 59 shoulders findings were unexpected. We looked specifically at 2 age groups: <50 years and > or =50 years. In the <50 years group labral tears were seen in 42% (30 of 71) and rotator cuff disease in 65% (46 of 71). Cuff tears tended to be incomplete. In the older age group only 14% (21 of 147) had an intact cuff, with 72 shoulders having a full-thickness tear. Labral tears were seen in 29% (42 of 147). We recommend that all patients undergo shoulder arthroscopy at the time of acromioclavicular surgery.

Spatial and temporal stability of mtDNA haplogroup frequencies in native North America.

Mitochondrial DNA lineage frequencies in prehistoric Aleut, eastern Utah Fremont, Southwestern Anasazi, Pyramid Lake, and Stillwater Marsh skeletal samples from northwest Nevada and the Oneota of western Illinois are compared with those in 41 contemporary aboriginal populations of North America. The ancient samples range in age from 300 years to over 6,000 years. The results indicate that the prehistoric inhabitants of North America exhibit the same level of mtDNA variability as contemporary populations of the continent. Variation in modern mtDNA haplogroup frequencies is highly geographically structured, and the prehistoric samples exhibit the same geographic pattern of variation. This indicates that differentiation of regional patterns of mtDNA lineage variation occurred early in North American prehistory (much more than 2,000 years B.P.), has remained relatively stable since its origin, and was little influenced by the disruptions hypothesized for other genetic systems as a result of population declines and relocations at contact.

Open and arthroscopic techniques for the treatment of traumatic anterior shoulder instability in Australian rules football players.

Australian Rules football (ARF) is a potentially violent, overhead, body-contact sport. We reviewed 56 shoulders in patients who sustained their initial traumatic anterior subluxation or dislocation during ARF and who underwent reconstructive surgery for traumatic anterior instability, whether by arthroscopic or by open techniques. Patients were followed up for a mean of 29.4 months after operation, and clinical evaluation was performed with the Rowe grading system. Three types of surgical procedures were performed: arthroscopic suture repair, arthroscopic Bankart repair with an absorbable polyglyconate tack, and open capsular shift with repair of the Bankart lesion. Shoulders treated with arthroscopic suture repair had a 70% rate of recurrent subluxation or dislocation on return to ARF Dislocations treated arthroscopically with the biodegradable tack had a 38% rate of recurrence of instability; three fourths of the recurrences were after minimal to moderate trauma. Shoulders treated with an open capsular shift and Bankart procedure had a 30% rate of recurrent instability, with half of the recurrences caused by violent trauma. In the open group there were no failures in patients who did not return to ARF. We suggest that arthroscopic repair in shoulders with anterior instability and recurrent dislocation does not adequately address the plastic deformation of the anterior capsule that may occur after repeated episodes of dislocation. We advocate open shoulder procedures in ARF athletes to address all areas of the capsulolabral pathologic condition and to provide the most secure repair possible with minimal chance of recurrence.

The early results of the Brunelli procedure for trapeziometacarpal instability.

We report the results of Brunelli's abductor pollicis longus transfer for symptomatic instability of the trapeziometacarpal joint in 15 hands (14 patients) at a mean follow-up of 21 months. Patients were assessed subjectively, and objectively by an independent observer. All but one of the patients were very satisfied with the result of the operation, including the six patients who had significant degeneration of the carpometacarpal joint surface preoperatively. Four patients said they had no pain and the mean pain score overall on a visual analogue scale was 1.2 (out of a maximum of 10). Overall the outcome was rated good or excellent in 11 of the 15 thumbs.

Arthroscopic repair of glenolabral injuries with an absorbable fixation device.

In view of potential problems with metallic implants around the shoulder a bioabsorbable tact has been used in arthroscopic repair of labral lesions in the shoulder joint. We report on a consecutive series of 70 patients (71 shoulders) who had arthroscopic stabilization of Bankart lesions, SLAP lesions, and other labral detachments with the Suretac device. Minimum follow-up time was 12 months (range 12 to 27 months). Clinical outcome was assessed with the Constant score. The recurrence of dislocation or subluxation in the 42 unstable shoulders was 12% (5 of 42), and in 78% (33 of 42) the Constant score was rated good or excellent. The recurrence of dislocation in true anteroinferior dislocators was 3.2% (1 of 31). A total of 82.3% (14 of 17) of patients with SLAP repairs were rated good or excellent, and 53% (9 of 17) returned to their preinjury level of sporting activities. Eight (67%) of 12 patients with labral detachments other than Bankart and SLAP lesions were rated good or excellent, and 64% (7 of 11) returned fully to sports.

Richard Lane: a tireless fighter for treatment of drug addiction.

After a long and courageous battle with cancer, Richard Lane died in 1994. He had been a long-term heroin addict and spent 12 years in prisons. After commencing treatment with methadone, he began to work with other addicts and helped to start Man Alive, the first methadone program in Baltimore. He later became Executive Director of Man Alive and a national leader in the effort to improve and expand methadone maintenance treatment. Among the innovations he promoted within the methadone program were on-site alcoholism treatment, protocols for poly-drug abuse, services for patients with acquired immune deficiency syndrome, improved pain management for methadone patients, and fewer restrictions for socially rehabilitated patients on methadone. He fought tirelessly for acceptance of methadone maintenance treatment by those in medicine, law enforcement, and politics. His accomplishments can inspire all in the addiction field to continue their efforts to improve the care of the addict.

Arthroscopic treatment of adhesive capsulitis.

Although conservative management with or without manipulation performed with the patient under anesthesia is the generally accepted treatment strategy for adhesive capsulitis, considerable interest is being shown in arthroscopic surgical procedures for this disorder. This study reviews the outcome of patients who underwent an arthroscopic release of the inferior capsule, reproducing in a controlled fashion the traumatic disruption of the inferior capsule commonly caused by manipulation with the patient under anesthesia. The outcome of 24 patients (26 shoulders) was assessed with an average follow-up of 13.5 months. A total of 88% of patients were very satisfied with the procedure, and no operative complications occurred. A return to normal or near normal shoulder function in 76% or more of the study group for forward flexion, abduction, and external rotation was demonstrated. A total of 50% of patients still had some restriction in internal rotation. The Constant Scoring system, also used to assess clinical shoulder function, revealed 87% of patients had achieved an excellent or good result when compared with the contralateral normal shoulder score. Our results suggest that arthroscopic capsular release is a safe and effective treatment for adhesive capsulitis, with patterns of recovery that compare favorably to other treatment modalities.