Climate adaptation for rural water and sanitation systems in the Solomon Islands: A community scale systems model for decision support.

Delivering water and sanitation services are challenging in data poor rural settings in developing countries. In this paper we develop a Bayesian Belief Network model that supports decision making to increase the availability of safe drinking water in five flood-prone rural communities in the Solomon Islands. We collected quantitative household survey data and qualitative cultural and environmental knowledge through community focus group discussions. We combined these data to develop our model, which simulates the state of eight water sources and ten sanitation types and how they are affected by season and extreme events. We identify how climate and current practices can threaten the availability of drinking water for remote communities. Modelling of climate and intervention scenarios indicate that water security could be best enhanced through increased rainwater harvesting (assuming proper installation and maintenance). These findings highlight how a systems model can identify links between and improve understanding of water and sanitation, community behaviour, and the impacts of extreme events. The resultant BBN provides a tool for decision support to enhance opportunities for climate resilient water and sanitation service provision.

Associations of osteoprotegerin with coronary artery calcification among women with systemic lupus erythematosus and healthy controls.

Objective We tested the hypothesis that higher circulating levels of osteoprotegerin (OPG) are related to higher levels of coronary artery calcification (CAC) among women with systemic lupus erythematosus (SLE) compared with healthy controls (HCs). Methods Among 611 women in two age- and race-matched SLE case-control studies, OPG was assayed in stored blood samples (HEARTS: plasma, n cases/controls = 122/124, and SOLVABLE: serum, n cases/controls = 185/180) and CAC was measured by electron beam computed tomography. Results In both studies, SLE patients had higher OPG and CAC levels than HCs. Higher OPG was associated with high CAC (>100 vs.100) among SLE, and with any CAC (>0 vs. 0) among HCs. Multivariable-adjusted OR (95% CI) for OPG tertile 3 vs. 1 was 3.58 (1.19, 10.76), p trend = 0.01 for SLE, and 2.28 (1.06, 4.89), p trend = 0.04 for HCs. Associations were attenuated when age-adjusted, but remained significant for HC women aged ≥ 40 and SLE women aged ≥ 50. ROC analyses identified 4.60 pmol/l as the optimal OPG cutpoint for predicting high CAC (>100) among SLE patients with sensitivity = 0.74 and specificity = 0.61, overall, but 0.92 and 0.52, respectively, for SLE patients aged ≥ 50. Conclusion Our cross-sectional results suggest that higher OPG levels are related to higher CAC levels among women with SLE vs. healthy controls.

Sanitation marketing: A systematic review and theoretical critique using the capability approach.

Sanitation is a human right that benefits health. As such, technical and behavioural interventions are widely implemented to increase the number of people using sanitation facilities. These include sanitation marketing interventions (SMIs), in which external support agencies (ESAs) use a hybrid of commercial and social marketing tools to increase supply of, and demand for, sanitation products and services. However, there is little critical discourse on SMIs, or independent rigorous analysis on whether they increase or reduce well-being. Most available information is from ESAs about their own SMI implementation. We systematically reviewed the grey and peer-reviewed literature on sanitation marketing, including qualitatively analysing and calculating descriptive statistics for the parameters measured, or intended to be measured, in publications reporting on 33 SMIs. Guided by the capability approach to development we identified that publications for most SMIs (n = 31, 94%) reported on commodities, whilst fewer reported on parameters related to impacts on well-being (i.e., functionings, n = 22, 67%, and capabilities, n = 20, 61%). When evaluating future SMIs, it may be useful to develop a list of contextualised well-being indicators for the particular SMI's location, taking into account local cultural norms, with this list ideally co-produced with local stakeholders. We identified two common practices in SMIs that can reduce well-being and widen well-being inequalities; namely, the promotion of conspicuous consumption and assaults on dignity, and we discuss the mechanisms by which such impacts occur. We recommend that ESAs understand sanitation marketing's potential to reduce well-being and design SMIs to minimize such detrimental impacts. Throughout the implementation phase ESAs should continuously monitor for well-being impacts and adapt practices to optimise well-being outcomes for all involved.

Antecedent anti-NMDA receptor encephalitis in two patients with multiple sclerosis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder characterised by psychiatric symptoms, movement disorder and seizures often evolving into a severe encephalopathy. An overlap has recently been recognised between anti-NMDAR encephalitis and inflammatory demyelinating disorders, particularly neuromyelitis optical spectrum disorder (NMOSD). In this case report, we describe two patients with an initial presentation consistent with anti-NMDAR encephalitis who have subsequently developed relapsing-remitting multiple sclerosis (MS) and discuss the literature pertaining to potential overlap between NMDAR encephalitis and inflammatory demyelinating disorders.

Improving community health through marketing exchanges: A participatory action research study on water, sanitation, and hygiene in three Melanesian countries.

Diseases related to poor water, sanitation and hygiene (WaSH) are major causes of mortality and morbidity. While pursuing marketing approaches to WaSH to improve health outcomes is often narrowly associated with monetary exchange, marketing theory recognises four broad marketing exchange archetypes: market-based, non-market-based, command-based and culturally determined. This diversity reflects the need for parameters broader than monetary exchange when improving WaSH. This study applied a participatory action research process to investigate how impoverished communities in Melanesian urban and peri-urban informal settlements attempt to meet their WaSH needs through marketing exchange. Exchanges of all four archetypes were present, often in combination. Motivations for participating in the marketing exchanges were based on social relationships alongside WaSH needs, health aspirations and financial circumstances. By leveraging these motivations and pre-existing, self-determined marketing exchanges, WaSH practitioners may be able to foster WaSH marketing exchanges consistent with local context and capabilities, in turn improving community physical, mental and social health.

Genetic variation in SH3-domain GRB2-like (endophilin)-interacting protein 1 has a major impact on fat mass.

OBJECTIVE: The SH3-domain GRB2-like (endophilin)-interacting protein 1 (SGIP1) gene has been shown to be differentially expressed in the hypothalamus of lean versus obese Israeli sand rats (Psammomys obesus), and is suspected of having a role in regulating food intake. The purpose of this study was to assess the role of genetic variation in SGIP1 in human disease. SUBJECTS: We performed single-nucleotide polymorphism (SNP) genotyping in a large family pedigree cohort from the island of Mauritius. The Mauritius Family Study (MFS) consists of 400 individuals from 24 Indo-Mauritian families recruited from the genetically homogeneous population of Mauritius. We measured markers of the metabolic syndrome, including diabetes and obesity-related phenotypes such as fasting plasma glucose, waist:hip ratio, body mass index and fat mass. RESULTS: Statistical genetic analysis revealed associations between SGIP1 polymorphisms and fat mass (in kilograms) as measured by bioimpedance. SNP genotyping identified associations between several genetic variants and fat mass, with the strongest association for rs2146905 (P=4.7 × 10(-5)). A strong allelic effect was noted for several SNPs where fat mass was reduced by up to 9.4% for individuals homozygous for the minor allele. CONCLUSIONS: Our results show association between genetic variants in SGIP1 and fat mass. We provide evidence that variation in SGIP1 is a potentially important determinant of obesity-related traits in humans.

Prevalence and risk factors for latent tuberculosis infection among health care workers in Georgia.

BACKGROUND: Tuberculosis (TB) is a major public health problem in Georgia, but few TB infection control measures have been implemented in health care facilities. OBJECTIVE: To assess the prevalence and risk factors for latent TB infection (LTBI) among Georgian health care workers (HCWs) using two diagnostic tests, the tuberculin skin test (TST) and the QuantiFERON-TB Gold In Tube test (QFT-3G), an interferon-gamma release assay. METHODS: A cross-sectional study was conducted between June and August 2006 among HCWs at the Georgian National TB Program. RESULTS: Of 265 HCWs enrolled, 177 (67%) had a positive TST and 159 (60%) had a positive QFT-3G; 203 (77%) had a positive result for at least one of the tests and 50% tested positive for both tests. There was moderately good agreement between the tests (74%, kappa = 0.43, 95%CI 0.33-0.55). In multivariate analysis, employment for >5 years was associated with increased risk of a positive TST (OR 5.09, 95%CI 2.77-9.33) and QFT-3G (OR 2.26, 95%CI 1.27-4.01); age >30 years was associated with an increased risk of a positive QFT-3G (OR 2.91, 95%CI 1.32-6.43). DISCUSSION: A high prevalence of LTBI was found among Georgian HCWs and longer duration of employment was associated with increased risk. These data highlight the need for effective TB infection control measures and provide important baseline information as TB infection control measures are implemented.

An evaluation of computer-aided disproportionality analysis for post-marketing signal detection.

To understand the value of computer-aided disproportionality analysis (DA) in relation to current pharmacovigilance signal detection methods, four products were retrospectively evaluated by applying an empirical Bayes method to Merck's post-marketing safety database. Findings were compared with the prior detection of labeled post-marketing adverse events. Disproportionality ratios (empirical Bayes geometric mean lower 95% bounds for the posterior distribution (EBGM05)) were generated for product-event pairs. Overall (1993-2004 data, EBGM05> or =2, individual terms) results of signal detection using DA compared to standard methods were sensitivity, 31.1%; specificity, 95.3%; and positive predictive value, 19.9%. Using groupings of synonymous labeled terms, sensitivity improved (40.9%). More of the adverse events detected by both methods were detected earlier using DA and grouped (versus individual) terms. With 1939-2004 data, diagnostic properties were similar to those from 1993 to 2004. DA methods using Merck's safety database demonstrate sufficient sensitivity and specificity to be considered for use as an adjunct to conventional signal detection methods.

Greater occipital nerve injection in primary headache syndromes--prolonged effects from a single injection.

Most patients with primary headache syndromes who have frequent attacks of pain have tenderness in the sub-occipital region. Injection of the greater occipital nerve (GON) with local anesthetic and corticosteroids has been widely used in clinical practice for many years, yet there is no clear understanding of its mechanisms of action. Moreover, there is no current gold-standard of practice regarding GON injections in the management of headache. We audited of our practice to generate hypotheses about the range of primary headaches that might benefit, to determine response rates to power future studies, and to assess whether we should continue to do this procedure. Twenty-six of fifty-seven injections in 54 migraineurs yielded a complete or partial response that lasted for the partial response a median of 30 days. For cluster headache 13 of 22 injections yielded a complete or partial response lasting for a median of 21 days for the partial response. Tenderness over the GON was strongly predictive of outcome, although local anesthesia after the injection was not. The presence or absence of medication overuse did not predict outcome. Apart from two patients with a small patch of alopecia the injection was well tolerated. GON injection is a useful tool in some patients that provides interim relief while other approaches are explored. It is remarkable that in all conditions in which an effect is observed the response time so much exceeds the local anesthetic effect that the mechanism of action may well be through changes in brain nociceptive pathways.

Assessment of effects in mink caused by consumption of carp collected from the Saginaw River, Michigan, USA.

Polychlorinated hydrocarbons, including polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs), are ubiquitous environmental contaminants that bioconcentrate in the food chain. Numerous studies have demonstrated mink (Mustela vison) to be one of the most sensitive species to this group of compounds. In recent studies, a lesion characterized by osteoinvasion of epithelial cells into the mandible and maxilla of young mink fed diets containing 3,3',4,4',5-pentachlorobiphenyl (PCB 126) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was observed. The objective of the present study was to determine if proliferation of maxillary and mandibular squamous epithelia could be induced in ranch mink exposed to environmentally-derived polychlorinated hydrocarbons (PCBs, PCDDs, and PCDFs) in utero, during lactation, and throughout the growth period. Adult female mink were fed diets containing 0, 10, 20, or 30% carp (Cyprinus carpio) collected from the Saginaw River, Bay City, Michigan, USA, that provided 0.03, 0.83, 1.1, and 1.7 mg total PCBs (tPCBs)/kg feed and 2.5, 28, 47, and 73 ng TCDD toxic equivalents (TEQs)/kg feed, respectively, three weeks prior to breeding through weaning of the resulting offspring. Mink kits were maintained on their respective diets for up to 27 weeks of age. At 6 and 27 weeks of age, six to eight mink in each treatment group were necropsied and their jaws examined for evidence of maxillary and mandibular squamous epithelial proliferation. Results indicated that inclusion of up to 30% carp in the diet (1.7 mg tPCBs/kg feed, 73 ng TEQs/kg feed) had no effect on mink reproduction and kit survivability. However, maxillary and mandibular squamous epithelial proliferation was evident in four of the seven 27-week-old juveniles in the 20% carp group (1.1 mg tPCBs/kg feed, 47 ng TEQs/kg feed) and six of the eight juveniles in the 30% carp group (1.7 mg tPCBs/kg feed group, 73 ng TEQs/kg feed). Hepatic concentrations of tPCBs and TEQs increased in both the 6-week-old kits and the 27-week-old juveniles as the percentage of dietary carp increased. The livers of 6-week-old kits were also assessed for the presence of polybrominated diphenyl ethers, which increased as the percentage of Saginaw River carp in the diet increased.

Calcium channels modulate nociceptive transmission in the trigeminal nucleus of the cat.

Clinical observations and genetic studies have suggested a role for high-threshold voltage-dependent calcium channels (VDCCs) in the pathogenesis of migraine. This study investigated the role of P/Q-, L- and N-type VDCCs in post-synaptic action potential generation in trigeminovascular nociceptive afferents in the trigeminocervical complex (TCC) of the cat in vivo. Trigeminovascular nociceptive afferents were identified in the TCC by electrical stimulation of the superior sagittal sinus. Forty-six cell bodies were identified by their response to microiontophoresis of l-glutamate and their bipolar action potential shape. Blockade of VDCCs was accomplished by microiontophoresis of omega-agatoxin IVa/TK (P/Q-), omega-conotoxin GVIa (N-) and calciseptine (L-type). Non-selective antagonism was studied using cadmium ions. Non-selective blockade of high threshold VDCC with cadmium resulted in a reduction in l-glutamate-evoked neuronal activity (P=0.01). Blockade of P/Q: TK- (P<0.001), IVA- (P=0.007), L- (P<0.001) and N-type (P<0.001) VDCCs resulted in significant reductions in post-synaptic action potential generation in response to l-glutamate. High threshold VDCCs, including P/Q-, L- and N-type VDCCs, can therefore modulate nociceptive transmission in the trigeminocervical complex in vivo. We discuss the evidence to suggest a role for VDCCs in the pathophysiology of primary headache disorders, and how abnormalities of function may contribute to their pathogenesis.

Exposure to rizatriptan during pregnancy: post-marketing experience up to 30 June 2004.

Merck & Co., Inc. evaluates outcomes of the use of rizatriptan during pregnancy through a Pregnancy Registry in the United States (US) and spontaneous reports for pregnancies reported from sources outside the US. Review of the outcomes of 25 prospective pregnancy reports in the Pregnancy Registry and reports from other sources does not suggest that treatment with rizatriptan predisposes patients to spontaneous abortions or congenital anomalies. However, the number of reports is small. Healthcare providers in the United States are encouraged to report any prenatal exposure to rizatriptan by calling the Pregnancy Registry at +1 (800) 986 8999 or visiting the Registry's website at http://www.merckpregnancyregistries.com.

Genotype-phenotype correlation in a family with Arg135Leu rhodopsin retinitis pigmentosa.

AIM: To describe the clinical characteristics and disease course of a large family with retinitis pigmentosa (RP) from an Arg135Leu change in rhodopsin. METHODS: 29 patients in this family were evaluated. Goldmann visual fields were performed on 14 affected individuals, Ganzfeld electroretinography (ERG) on eight individuals (11-56 years), and blood samples collected on 10 individuals (11-58 years). Patient visual field data were compared with previously reported patients with different rhodopsin mutations using linear regression. RESULTS: An Arg135Leu mutation was identified in rhodopsin. Distinct stages of clinical evolution were identified for this family ranging from normal, white dots, classic bone spicules and, finally, ending with extensive retinal pigment epithelium (RPE) atrophy. 9/16 patients over the age of 20 years also demonstrated marked macular atrophy. All patients who underwent full field ERG testing demonstrated non-recordable ERGs. The overall regression model comparing solid angles of visual fields from patients with rhodopsin mutations (Pro23His, Pro347Ala, Arg135Leu) shows significant effects for age (p = 0.0005), mutation (p = 0.0014), and interaction between age and mutation (p = 0.018) with an R(2) of 0.407. CONCLUSIONS: An Arg135Leu change in rhodopsin results in a severe form of RP that evolves through various fundus appearances that include white dots early in life and classic appearing RP later. This transmembrane change in rhodopsin proves to be more severe than in a family with an intradiscal change and a family with a cytoplasmic change.

Neutron tomography developments and applications.

Neutron radiography has been in use as a nondestructive testing technique for the past 50 years. The neutrons' unique ability to image certain elements and isotopes that are either completely undetectable or poorly detected by other NDI methods makes neutron radiography an important tool for the NDI community. Neutron radiography like other imaging techniques takes a number of different forms (i.e., film, radioscopic, transfer methods, tomography, etc.) This paper will describe the neutron tomography system developed at the University of California, Davis McClellan Nuclear Radiation Center (UC Davis/MNRC), and the applications for both research and commercial uses. The neutron radiography system at the UC Davis/MNRC has been under development for 4 years. The initial system was developed to find very low concentrations of hydrogen (i.e., <200 ppm). In order to achieve these low detection levels, it was necessary to perform both pre- and post-processing of the tomographs. The pre-processing steps include corrections for spatial resolution and random noise effects. Images are corrected for systematic noise errors and beam hardening. From these data the attenuation coefficient is calculated. The post-processing steps include alignment of the collected images, determining the center of mass, and, finally, using the filtered back-projection routine from the Donner Algorithms Library to obtain the final images. Since its initial development, the tomography system has been used very successfully to find low levels of hydrogen in a metal matrix. Further uses of the system have been to verify the exact placement, in three dimensions, of "O-rings" in large metal valve bodies, and to map the location and extent of veins in porous and high-density rocks of various different kinds. These examples show that neutron tomography is becoming a needed inspection technique for the 21st century.

Neutron radiography inspection of investment castings.

Investment casting, also known as the lost wax process, is a manufacturing method employed to produce near net shape metal articles. Traditionally, investment casting has been used to produce structural titanium castings for aero-engine applications with wall thickness less than 1 in (2.54 cm). Recently, airframe manufacturers have been exploring the use of titanium investment casting to replace components traditionally produced from forgings. Use of titanium investment castings for these applications reduces weight, cost, lead time, and part count. Recently, the investment casting process has been selected to produce fracture critical structural titanium airframe components. These airframe components have pushed the traditional inspection techniques to their physical limits due to cross sections on the order of 3 in (7.6 cm). To overcome these inspection limitations, a process incorporating neutron radiography (n-ray) has been developed. In this process, the facecoat of the investment casting mold material contains a cocalcined mixture of yttrium oxide and gadolinium oxide. The presence of the gadolinium oxide, allows for neutron radiographic imaging (and eventual removal and repair) of mold facecoat inclusions that remain within these thick cross sectional castings. Probability of detection (POD) studies have shown a 3 x improvement of detecting a 0.050 x 0.007 in2 (1.270 x 0.178 mm2) inclusion of this cocalcined material using n-ray techniques when compared to the POD using traditional X-ray techniques. Further, it has been shown that this n-ray compatible mold facecoat material produces titanium castings of equal metallurgical quality when compared to the traditional materials. Since investment castings can be very large and heavy, the neutron radiography facilities at the University of California, Davis McClellan Nuclear Radiation Center (UCD/MNRC) were used to develop the inspection techniques. The UCD/MNRC has very unique facilities that can handle large parts up to 39 ft (12 m) in length and 13 ft (4 m) high weighing up to 5000 lbs (2300 kg). These handling systems are robotically driven. The neutron radiographic system consists of a highly thermalized neutron beam. The neutron beam has an intensity of 5.6 x 10(6) n/cm2 s, with a L/D = 200 at a power of 2 MW. A divergent beam collimator is used which provides a beam of approximately 22 in (56 cm) in diameter at the film plane. A vacuum cassette with a gadolinium vapor deposited screen is used to collect the image. Exposure times can be as short as 3 min, or up to 30 min.

Varicella vaccine exposure during pregnancy: data from the first 5 years of the pregnancy registry.

OBJECTIVE: To assess the risks of congenital varicella syndrome and other birth defects in offspring of women who inadvertently received varicella vaccine during pregnancy or within 3 months of conception. METHODS: Pregnant women inadvertently exposed to varicella vaccine, reported voluntarily, were enrolled in the Pregnancy Registry for VARIVAX (Merck & Co., Inc., West Point, PA). The pregnancies were monitored and the outcomes ascertained from questionnaires completed voluntarily by the health care providers. The rates of congenital varicella syndrome and congenital anomalies were calculated for seronegative women prospectively reported to the registry. RESULTS: From March 17, 1995 through March 16, 2000, 362 pregnancy outcomes were identified from prospective reports. Ninety-two women were known to be seronegative to varicella, of whom 58 received their first dose of vaccine during the first or second trimester. No cases of congenital varicella syndrome were identified among 56 live births (rate 0%, 95% confidence interval [CI] 0, 15.6). Among all the prospective reports of live births, five congenital anomalies were reported. No specific pattern was identified in either the susceptible cohort or the sample population as a whole. CONCLUSION: No abnormal features have been reported that suggested the occurrence of congenital varicella syndrome or other birth defects related to vaccine exposure during pregnancy. Because of the small numbers, this study has limited precision, so continued surveillance is warranted. However, these results should provide some assurance to health care providers and women with inadvertent exposure before or during pregnancy.

Effects of hormone replacement therapy on clinical fractures and height loss: The Heart and Estrogen/Progestin Replacement Study (HERS).

PURPOSE: To determine if estrogen plus progestin reduces the incidence of fractures or height loss in postmenopausal women with coronary disease. SUBJECTS AND METHODS: We enrolled 2,763 postmenopausal women with coronary disease and with an intact uterus into the Heart Estrogen/progestin Replacement Study, a randomized double-blind, placebo-controlled secondary prevention trial of cardiovascular disease. Radiographically documented clinical fractures were a prespecified secondary endpoint. Height loss was used as a surrogate for vertebral fractures. The average age of the women was 66.7 +/- 6.7 years, and fewer than 15% of the women had osteoporosis based on their bone density. Women were randomly assigned to either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1,380) or placebo (n = 1,383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 64% at the end of the study. RESULTS: During 10,554 person years of follow-up, 286 women experienced a fracture: 138 in the treatment group (26.3 per 1,000 person years) and 148 in the placebo group (28.0 per 1,000 person years); relative hazard, 0.94; 95% confidence interval 0.8 to 1.2, P = 0.61). These included 58 wrist fractures (1.01; 0.6 to 1.7); 27 hip fractures (1.09; 0.5 to 2.3); 32 spine fractures (0.69; 0.3 to 1.4), and 192 other fractures (0.91; 0.7 to 1.2). There was no difference in average height loss between the treatment and placebo groups or in the percent of women who lost more than 2 cm in height: 10.6% in the treatment group and 12.1% in the placebo group. CONCLUSIONS: There was no evidence of a reduction in the incidence of fractures or rate of height loss in older women not selected for osteoporosis. Randomized studies are needed to clarify the effect of hormone replacement therapy on fracture risk among women with and without osteoporosis.

Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.

Mutations in the genes that code for collagen VI subunits, COL6A1, COL6A2, and COL6A3, are the cause of the autosomal dominant disorder, Bethlem myopathy. Although three different collagen VI structural mutations have previously been reported, the effect of these mutations on collagen VI assembly, structure, and function is currently unknown. We have characterized a new Bethlem myopathy mutation that results in skipping of COL6A1 exon 14 during pre-mRNA splicing and the deletion of 18 amino acids from the triple helical domain of the alpha1(VI) chain. Sequencing of genomic DNA identified a G to A transition in the +1 position of the splice donor site of intron 14 in one allele. The mutant alpha1(VI) chains associated intracellularly with alpha2(VI) and alpha3(VI) to form disulfide-bonded monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the mutant chain were not secreted. This triple helical deletion thus resulted in production of half the normal amount of collagen VI. To further explore the biosynthetic consequences of collagen VI triple helical deletions, an alpha3(VI) cDNA expression construct containing a 202-amino acid deletion within the triple helix was produced and stably expressed in SaOS-2 cells. The transfected mutant alpha3(VI) chains associated with endogenous alpha1(VI) and alpha2(VI) to form collagen VI monomers, but dimers and tetramers did not form and the mutant-containing molecules were not secreted. Thus, deletions within the triple helical region of both the alpha1(VI) and alpha3(VI) chains can prevent intracellular dimer and tetramer assembly and secretion. These results provide the first evidence of the biosynthetic consequences of structural collagen VI mutations and suggest that functional protein haploinsufficiency may be a common pathogenic mechanism in Bethlem myopathy.

Large kindred with Ehlers-Danlos syndrome type IV due to a point mutation (G571S) in the COL3A1 gene of type III procollagen: low risk of pregnancy complications and unexpected longevity in some affected relatives.

Ehlers-Danlos syndrome (EDS) type IV is an autosomal dominant connective tissue disorder. Early morbidity and mortality results from rupture of vessels and internal organs. A large kindred with EDS type IV was studied clinically, and the biochemical defects and underlying mutation in the COL3A1 gene that encodes the chains of type III procollagen were identified. A G-->A transition results in a single amino acid substitution, G571S, in the triple helical domain of the products of one COL3A1 allele. Although the clinical findings seen on examination are characteristic of EDS type IV, longevity is longer than that seen in many families and there is less pregnancy-associated morbidity or mortality than in some families. This suggests that some clinical aspects of EDS type IV may be related to the nature of the mutation and its effect on the behavior of the protein.