壳聚糖防止输卵管阻塞介入再通术后的复发性黏连

目的评价壳聚糖(几丁糖)在输卵管介入再通术后防止复发性黏连的疗效。方法309例患者随机分为对照组206例和试验组103例。对照组在输卵管阻塞介入复通术中常规注射松解液(α-糜蛋白酶?地塞米松、灭滴灵?庆大霉素)做术后防止黏连。试验组在术中常规注射松解液的基础上联合应用医用几丁糖防止黏连,术后通水治疗。随访观察两组病例松解输卵管的通畅情况。结果试验组,经子宫输卵管碘水造影阻塞190条,缺如10条;介入复通188条,再通率为98.9%;术后随访3个月通水达到无阻力180条,再黏连率4.26%(8/188)。对照组输卵管造影确认堵塞390条,缺如22条,复通385条,复通率为98.7%,术后随访3个月,通水达到无阻力330条,再黏连率14.28%(55/385)。两组术后3个月再黏连率有差异(P<0.01)。结论输卵管介入再通术后应用几丁糖能有效降低输卵管术后复发性黏连。     

壳聚糖防止输卵管阻塞介入再通术后的复发性黏连

目的 评价壳聚糖(几丁糖)在输卵管介入再通术后防止复发性黏连的疗效.方法 309例患者随机分为对照组206例和试验组103例.对照组在输卵管阻塞介入复通术中常规注射松解液(α-糜蛋白酶、地塞米松、灭滴灵、庆大霉素)做术后防止黏连.试验组在术中常规注射松解液的基础上联合应用医用几丁糖防止黏连,术后通水治疗.随访观察两组病例松解输卵管的通畅情况.结果 试验组,经子宫输卵管碘水造影阻塞190条,缺如10条;介入复通188条,再通率为98.9%;术后随访3个月通水达到无阻力180条,再黏连率4.26%(8/188).对照组输卵管造影确认堵塞390条,缺如22条,复通385条,复通率为98.7%,术后随访3个月,通水达到无阻力330条,再黏连率14.28%(55/385).两组术后3个月再黏连率有差异(P＜0.01).结论 输卵管介入再通术后应用几丁糖能有效降低输卵管术后复发性黏连.     

Array based CGH and FISH fail to confirm duplication of 8p22-p23.1 in association with Kabuki syndrome

Background: Kabuki (Niikawa–Kuroki) syndrome comprises a characteristic facial appearance, cleft palate, congenital heart disease, and developmental delay. Various cytogenetically visible chromosomal rearrangements have been reported in single cases, but the molecular genetic basis of the condition has not been established. A recent report described a duplication of 8p22–p23.1 in 13/13 patients.

Objective: To determine the frequency of an 8p duplication in a cohort of patients with Kabuki syndrome.

Methods: An 8p duplication was sought using two independent methods—array based comparative genomic hybridisation (aCGH) and fluorescence in situ hybridisation (FISH)—in 15 patients with a definitive clinical diagnosis of Kabuki syndrome.

Results: No evidence for a duplication of 8p was obtained by FISH or aCGH in any of the 15 patients.

Conclusions: 8p22–p23.1 duplication may not be a common mechanism for Kabuki syndrome. Another genetic abnormality may be responsible for the aetiology in many patients.

     

New insights into the role of cytokines in asthma

Asthma is a triad of intermittent airway obstruction, bronchial smooth muscle cell hyperreactivity to bronchoconstrictors, and chronic bronchial inflammation. From an aetiological standpoint, asthma is a heterogenous disease, but often appears as a form of immediate hypersensitivity. Many patients with asthma have other manifestations of atopy, such as rhinitis or eczema. Even among non-atopic patients with asthma, the pathophysiology of airway constriction is similar, raising the hypothesis that alternative mechanisms of mast cell degranulation may underlie the disease. The primary inflammatory lesion of asthma consists of accumulation of CD4⁺ T helper type 2 (TH2) lymphocytes and eosinophils in the airway mucosa. TH2 cells orchestrate the asthmatic inflammation through the secretion of a series of cytokines, particularly interleukin 4 (IL-4), IL-13, IL-5, and IL-9. IL-4 is the major factor regulating IgE production by B cells, and is required for optimal TH2 differentiation. However, blocking IL-4 is not sufficient to inhibit the development of asthma in experimental models. In contrast, inhibition of IL-13, another TH2 cytokine whose signal transduction pathway overlaps with that of IL-4, completely blocks airway hyperreactivity in mouse asthma models. IL-5 is a key factor for eosinophilia and could therefore be responsible for some of the tissue damage seen in chronic asthma. IL-9 has pleiotropic activities on allergic mediators such as mast cells, eosinophils, B cells and epithelial cells, and might be a good target for therapeutic interventions. Finally, chemokines, which can be produced by many cell types from inflamed lungs, play a major role in recruiting the mediators of asthmatic inflammation. Genetic studies have demonstrated that multiple genes are involved in asthma. Several genome wide screens point to chromosome 5q31–33 as a major susceptibility locus for asthma and high IgE values. This region includes a cluster of cytokine genes, and genes encoding IL-3, IL-4, IL-5, IL-9, IL-13, granulocyte macrophage colony stimulating factor, and the ß chain of IL-12. Interestingly, for some of these cytokines, a linkage was also established between asthma and their receptor. Another susceptibility locus has been mapped on chromosome 12 in a region that contains other potential candidate cytokine genes, including the gene encoding interferon γ, the prototypical TH1 cytokine with inhibitory activities for TH2 lymphocytes. Taken together, both experimental and genetic studies point to TH2 cytokines, such as IL-4, IL-13, IL-5, and IL-9, as important targets for therapeutic applications in patients with asthma.

Key Words: asthma • cytokines • interleukins • treatment of asthma • interferon γ

     

Fallopian tube origin of supposed ovarian high-grade serous carcinomas

INTRODUCTION:

Serous carcinomas are the most frequent histologic type of ovarian and peritoneal cancers, and can also be detected in the endometrium and fallopian tubes. Serous carcinomas are usually high‐grade neoplasms when diagnosed, yet the identification of an associated precursor lesion remains challenging. Pathological examination of specimens obtained from prophylactic bilateral salpingo‐oophorectomies that were performed for patients harboring BRCA1/2 mutations suggests that high‐grade serous carcinomas may arise in the fallopian tubes rather than in the ovaries.

OBJECTIVE:

To investigate the presence and extent of fallopian tube involvement in cases of serous pelvic carcinomas.

METHODS:

Thirty‐four cases of serous pelvic carcinoma with clinical presentations suggesting an ovarian origin were analyzed retrospectively. Histologic samples of fallopian tube tissues were available for these cases and were analyzed. Probable primary site, type of tubal involvement, tissues involved in the neoplasia and vascular involvement were evaluated.

RESULTS:

Fallopian tube involvement was observed in 24/34 (70.6%) cases. In 4 (11.8%) of these cases, an intraepithelial neoplasia was present, and therefore these cases were hypothesized to be primary from fallopian tubes. For an additional 7/34 (20.6%) cases, a fallopian tube origin was considered a possible primary.

CONCLUSIONS:

Fallopian tubes can be the primary site for a subset of pelvic high‐grade serous carcinomas.     

Comparative genomic hybridisation using a proximal 17p BAC/PAC array detects rearrangements responsible for four genomic disorders

Background: Proximal chromosome 17p is a region rich in low copy repeats (LCRs) and prone to chromosomal rearrangements. Four genomic disorders map within the interval 17p11–p12: Charcot–Marie–Tooth disease type 1A, hereditary neuropathy with liability to pressure palsies, Smith–Magenis syndrome, and dup(17)(p11.2p11.2) syndrome. While 80–90% or more of the rearrangements resulting in each disorder are recurrent, several non-recurrent deletions or duplications of varying sizes within proximal 17p also have been characterised using fluorescence in situ hybridisation (FISH).

Methods: A BAC/PAC array based comparative genomic hybridisation (array-CGH) method was tested for its ability to detect these genomic dosage differences and map breakpoints in 25 patients with recurrent and non-recurrent rearrangements.

Results: Array-CGH detected the dosage imbalances resulting from either deletion or duplication in all the samples examined. The array-CGH approach, in combination with a dependent statistical inference method, mapped 45/46 (97.8%) of the analysed breakpoints to within one overlapping BAC/PAC clone, compared with determinations done independently by FISH. Several clones within the array that contained large LCRs did not have an adverse effect on the interpretation of the array-CGH data.

Conclusions: Array-CGH is an accurate and sensitive method for detecting genomic dosage differences and identifying rearrangement breakpoints, even in LCR-rich regions of the genome.

     

The dispersion of indicator flowing through simplified models of the circulation and its relevance to velocity profile in blood vessels

1. The distribution of velocity (velocity profile) was studied in water flowing through simple models of the circulation. Dye was injected and the distribution of velocity was assessed from indicator concentration—time curves recorded with a photomultiplier.

2. Observations were made on straight and curved tubes and on a tube containing a short region with an elliptical cross-section. With steady flow, the rate was varied over the range 24-870 ml./min (Reynolds number 102-3690). Sinusoidal pulsations were imposed on the steady flow in some experiments.

3. Bends gave rise to large secondary flows. These caused mixing across the flow and a marked reduction in the variation of velocity over the cross-section of the tube. The effect of bends on velocity distribution was maximal at a Reynolds number of ca. 1000. Similar, but far smaller, effects were seen in a region with an elliptical cross-section and when the flow was made pulsatile. Secondary motion due to bends was capable of preventing a heavier-than-water indicator (sp.gr. 1·375) from settling out of the flow.

4. The experimental findings suggest that there may be secondary flows in vascular beds. Under certain conditions, these would prevent the establishment of Poiseuille type laminar flow. The possible physiological importance of the findings is discussed.

     

Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome

Background: A new syndrome has been recognised following thorough analysis of patients with a terminal submicroscopic subtelomeric deletion of chromosome 9q. These have in common severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, thickened lower lip, carp mouth with macroglossia, and conotruncal heart defects. The minimum critical region responsible for this 9q subtelomeric deletion syndrome (9q–) is approximately 1.2 Mb and encompasses at least 14 genes.

Objective: To characterise the breakpoints of a de novo balanced translocation t(X;9)(p11.23;q34.3) in a mentally retarded female patient with clinical features similar to the 9q– syndrome.

Results: Sequence analysis of the break points showed that the translocation was fully balanced and only one gene on chromosome 9 was disrupted—Euchromatin Histone Methyl Transferase1 (Eu-HMTase1)—encoding a histone H3 lysine 9 methyltransferase (H3-K9 HMTase). This indicates that haploinsufficiency of Eu-HMTase1 is responsible for the 9q submicroscopic subtelomeric deletion syndrome. This observation was further supported by the spatio-temporal expression of the gene. Using tissue in situ hybridisation studies in mouse embryos and adult brain, Eu-HMTase1 was shown to be expressed in the developing nervous system and in specific peripheral tissues. While expression is selectively downregulated in adult brain, substantial expression is retained in the olfactory bulb, anterior/ventral lateral ventricular wall, and hippocampus and weakly in the piriform cortex.

Conclusions: The expression pattern of this gene suggests a role in the CNS development and function, which is in line with the severe mental retardation and behaviour problems in patients who lack one copy of the gene.

     

Leukemia inhibitory factor (LIF) is immunohistochemically localized in tubal ectopic pregnancy

Leukemia inhibitory factor (LIF) is essential for implantation of the embryo in the endometrium. It is not clear whether the blastocyst requires expression of LIF for implantation into tissues other than endometrium. Immunohistochemical localization of LIF was performed in the fallopian tube of 20 women with ectopic pregnancies, 7 women with normal pregnancies and 20 healthy non-pregnant women. Fallopian tubes were evaluated from specimens taken during tubal ligation in normal pregnancies and non-pregnant fertile women or at operation for tubal surgery in ectopic pregnancies. Biopsies were assayed by immunohistochemistry. Semi-quantitative immunohistochemical reaction scores (IRS) were used for immunohistochemical analyses. Immunolabeling of LIF was detected in the surface epithelium and stroma of fallopian tubes in all subjects. IRS score in the epithelium and stroma of non-pregnant women and women with intrauterine pregnancy were similar (p>0.05). However, women with ectopic pregnancy had significantly increased labeling of LIF compared to others (p<0.05). Immunohistochemical labeling of LIF in the fallopian tube was found to be increased in ectopic pregnancies compared to non-pregnant and healthy pregnant controls. This may indicate a role of LIF in the ectopic implantation of embryos.     

Mucosal carcinoma of the fallopian tube coexists with ovarian cancer of serous subtype only: a study of Japanese cases

Previous studies in Western countries have revealed that mucosal carcinoma of the fallopian tube frequently coexists with pelvic (ovarian, tubal, and peritoneal) serous carcinomas, and early tubal carcinoma is now regarded as a possible origin of these tumors. However, the relationship between early tubal carcinoma and non-serous ovarian cancer, such as clear cell adenocarcinoma, has not been studied in detail. In this study, we sought to examine the coexistence of mucosal carcinoma of the fallopian tube in Japanese ovarian cancer cases. We submitted the fallopian tubes in toto for histological examination in 52 ovarian carcinoma cases and three peritoneal serous carcinoma cases. The ovarian tumors included 12 serous adenocarcinomas, 23 clear cell adenocarcinomas, nine endometrioid adenocarcinomas, three mucinous adenocarcinomas, and four mixed epithelial carcinomas. Mucosal carcinoma of the fallopian tube did not coexist with non-serous adenocarcinoma (n = 40). In contrast, mucosal carcinoma of the fallopian tube was observed in six cases of ovarian serous adenocarcinoma and one case of peritoneal serous adenocarcinoma. In these cases, the p53 immunophenotypes were similar in tubal lesions and invasive ovarian or peritoneal carcinomas. Tumors were negative for p53 in four of seven cases, and one of the p53-negative serous adenocarcinomas showed low-grade morphology. We believe that some ovarian and peritoneal serous adenocarcinomas develop from early tubal carcinomas. However, it should be noted that early tubal carcinomas are not always p53-positive immunohistochemically. Finally, it is unlikely that early tubal lesions are involved in the carcinogenesis of clear cell adenocarcinoma and other non-serous adenocarcinomas.     

Apolipoprotein E4 is only a weak predictor of dementia and cognitive decline in the general population

Background: Apolipoprotein E (APOE) polymorphisms are unequivocally associated with risk for Alzheimer's disease (AD). It is crucial to understand how this genetic factor affects dementia risk in the general population, as well as in narrowly diagnosed, selected, patient groups.

Methods: We assessed the cross sectional association between APOE genotype and dementia status in a community based sample, the MRC Cognitive Function and Ageing Study (MRC CFAS). In addition, we tested the effects of APOE genotypes on the differences in MMSE scores between the first and third assessment waves (about six years apart), an index of cognitive decline.

Results: The APOE ε4 allele conferred increased risk for dementia (OR=1.5, 95% CI=1.1 to 2.2) compared to ε3 in the MRC CFAS sample. Compared with APOE ε3/ε3 subjects, those with the ε3/ε4 genotypes were not at significantly higher risk for dementia (OR=1.1, 95% CI=0.6 to 1.9), although ε4/ε4 subjects were (OR= 3.8, 95% CI=1.0 to 14.0). Risk estimates were not different between men and women. Notably, our risk estimates for dementia were significantly lower than those reported for a diagnosis of Alzheimer's disease. MMSE scores at wave 3 and the difference in MMSE between baseline and at the third assessment wave were not different across APOE genotypes.

Interpretation: The APOE ε4 allele is a weaker predictor for dementia in the general population than for AD. This may be because dementia can be caused by non-AD pathological processes and because most prevalent dementia occurs at an age when the APOE ε4 effect on AD risk (and therefore dementia) has started to decline.

     

Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome)

Background: EEM syndrome is the rare association of ectodermal dysplasia, ectrodactyly, and macular dystrophy (OMIM 225280).

Methods: We here demonstrate through molecular analysis that EEM is caused by distinct homozygous CDH3 mutations in two previously published families.

Results: In family 1, a missense mutation (c.965A→T) causes a change of amino acid 322 from asparagine to isoleucine; this amino acid is located in a highly conserved motif likely to affect Ca²⁺ binding affecting specificity of the cell-cell binding function. In family 2, a homozygous frameshift deletion (c.829delG) introduces a truncated fusion protein with a premature stop codon at amino acid residue 295, expected to cause a non-functional protein lacking both its intracellular and membrane spanning domains and its extracellular cadherin repeats 3–5. Our mouse in situ expression data demonstrate that Cdh3 is expressed in the apical ectodermal ridge from E10.5 to E12.5, and later in the interdigital mesenchyme, a pattern compatible with the EEM phenotype. Furthermore, we discuss possible explanations for the phenotypic differences between EEM and congenital hypotrichosis with juvenile macular dystrophy (HJMD), which is also caused by CDH3 mutations.

Conclusions: In summary, we have ascertained a third gene associated with ectrodactyly and have demonstrated a hitherto unrecognised role of CDH3 in shaping the human hand.

     

Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans

Background: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on κ-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant µ-opioid receptor.

Objective: To characterise sensitivity to pain and µ-opioid analgesia in mice and humans with non-functional melanocortin-1 receptors.

Methods: Comparisons of spontaneous mutant C57BL/6-Mc1r^e/e mice to C57BL/6 wildtype mice, followed by a gene dosage study of pain and morphine-6-glucuronide (M6G) analgesia in humans with MC1R variants.

Results: C57BL/6-Mc1r^e/e mutant mice and human redheads—both with non-functional MC1Rs—display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to the µ-opioid selective morphine metabolite, M6G. In both species the differential analgesia is likely due to pharmacodynamic factors, as plasma levels of M6G are similar across genotype.

Conclusions: Genotype at MC1R similarly affects pain sensitivity and M6G analgesia in mice and humans. These findings confirm the utility of cross species translational strategies in pharmacogenetics.

     

TLR4 and TNF-alpha polymorphisms are associated with an increased risk for severe sepsis following burn injury

Context: Sepsis, organ failure, and shock remain common among patients with moderate to severe burn injuries. The inability of clinical factors to identify at-risk patients suggests that genetic variation may influence the risk for serious infection and the outcome from severe injury.

Objective: Resolution of genetic variants associated with severe sepsis following burn injury.

Patients: A total of 159 patients with burns 20% of their total body surface area or any smoke inhalation injury without significant non-burn related trauma (injury severity score (ISS)16), traumatic or anoxic brain injury, or spinal cord injury and who survived more than 48 h post-admission.

Methods: Candidate single nucleotide polymorphisms (SNPs) within bacterial recognition (TLR4 +896, CD14 –159) and inflammatory response (TNF-α –308, IL-1ß –31, IL-6 –174) loci were evaluated for association with increased risk for severe sepsis (sepsis plus organ dysfunction or septic shock) and mortality.

Results: After adjustment for age, full-thickness burn size, ethnicity, and gender, carriage of the TLR4 +896 G-allele imparted at least a 1.8-fold increased risk of developing severe sepsis following a burn injury, relative to AA homozygotes (adjusted odds ratio (aOR) 6.4; 95% confidence interval (CI) 1.8 to 23.2). Carriage of the TNF-α –308 A-allele imparted a similarly increased risk, relative to GG homozygotes (aOR = 4.5; 95% CI 1.7 to 12.0). None of the SNPs examined were significantly associated with mortality.

Conclusions: The TLR4 +896 and TNF-α –308 polymorphisms were significantly associated with an increased risk for severe sepsis following burn trauma.

     

Organization of the fibrous connective tissue of the fallopian tubes in fertile and climacteric periods: a scanning electron microscopic and stereologic study

The extracellular matrix (ECM) of the fallopian tubes is subject to several changes due to hormonal influences and aging. However, there is a lack of studies regarding its arrangement in older women. We aimed to analyze the organization of ECMcomponents, including collagen and elastic fibers, in the fallopian tube’s ampulla from young and old women by means of scanning electron microscopical and stereological methods. Twenty-one samples were analyzed: 12 from female cadavers in a fertile age (G1) and 9 from the climacteric period (G2). Masson’s trichrome stain was used to observe collagen and smooth muscle, while Weigert’s Fuchsin-Resorcin was employed to observe elastic fibers. Statistical analysis was performed by the Wilcoxon-Mann-Whitney test with the aid ofthe R^© software. The tissue was also fixed for scanning electron microscopic analysis in a modified Karnovsky solution and the three-dimensional organization of fibrous connective tissue was observed and compared. Statistically significant differences (P < 0.01) were found in all stereologic comparisons of the extracellular matrix between the groups, which revealed a higher volumetric density of the fibrous tissue in the climacteric group. Scanning electron microscopy showed degenerative alterations of extracellular matrix. According to our results, aging caused significant changes to the elements of the extracellular matrix and the smooth muscle of the fallopian tubes.     

Enterobius vermicularis infection of the fallopian tube in an infertile female

Enterobius vermicularis (EV) is the most common nematode to infect humans. It inhabits the intestinal lumen, but rare, ectopic infections have been documented. The female genital tract is the most common ectopic site. We present a unique case of an EV infection of the fallopian tube resulting in inflammation, tubal obstruction, and infertility. A 30-year-old woman presented with infertility. Investigations included a laparoscopy with hydrotubation using methylene blue dye. This showed a left fallopian tube obstruction and extensive pelvic adhesions. A left salpingectomy was performed. Microscopic examination of the fallopian tube revealed numerous calcified and non-calcified ova associated with granulomatous reaction. The microscopic features were compatible with EV infection. Ectopic EV infections of the female genital tract result when the gravid female worm migrates from the perianal area to the vagina and ascends through the uterus and fallopian tubes to the peritoneal cavity. Microscopic examination of these ectopic sites can reveal adult worms or ova with granulomata formation, eosinophilic infiltrate, chronic inflammatory reaction, and fibrosis. The ova have a characteristic asymmetric oval configuration with flattening on one side. We postulate that our patient’s salpingitis due to EV with accompanying fibrosis is a cause of her infertility.     

Zur atypischen Hyperplasie des Tubenepithels beim Endometrium-Carcinom

Zusammenfassung Bei 50 Carcinomen des Endometrium fanden sich im ampullären Abschnitt beider Tuben regelmäßig atypische Proliferationen des Schleimhautepithels, die denen des carcinomatösen Endometriumepithels weitgehend glichen. Das Tubenepithel gleichaltriger Patientinnen ohne Endometriumcarcinom war demgegenüber altersatrophisch. Diese Befunde lassen sich zwanglos nur über die Annahme einer gleichzeitigen Beeinflussung der Targetorgane durch Oestrogen erklären und erscheinen im Hinblick auf die Genese des Endometriumcarcinoms von besonderem Interesse.

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Summary The fallopian tubes of fifty post-menopausal patients with endometrial carcinoma showed excessive epithelial proliferation in the ampullary portion. The type of proliferation varied from patient to patient but always resembled the type of differentiation exhibited by the carcinoma of that patient. The fallopian tubes of patients of equivalent ages but without carcinoma disclosed, as expected, an atrophic epithelium. Since both the endometrial and the tubular epithelium are target cells for estrogen, the hyperplastic changes are most likely related to the same hormonal stimulus. The estrogen theory of endometrial carcinoma receives further support from these observations.

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Mit Unterstützung der Deutschen Forschungsgemeinschaft.     

Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population

Objective: To investigate the contribution of polymorphic variation in genes involved in the folate-dependent homocysteine pathway in the aetiology of neural tube defects (NTD).

Design: Case-control association study.

Subjects: A total of 530 individuals from families affected by NTD, 645 maternal controls, and 602 healthy newborn controls from the northern UK.

Main outcome measures: Seven polymorphisms in six genes coding for proteins in the folate-dependent homocysteine pathway (MTHFR 677C→T, MTHFR 1298A→C, MTRR 66A→G, SHMT 1420C→T, CßS 844ins68, GCPII 1561C→T, RFC-1 80G→A). The impact of each polymorphism and the effect of gene–gene interactions (epistasis) upon risk of NTD were assessed using logistic regression analysis.

Results: The MTHFR 677C→T polymorphism was shown to represent a risk factor in NTD cases (CC v CT+TT odds ratio (OR) 2.03 [95% confidence interval (CI) 1.09, 3.79] p = 0.025) and the MTRR 66A→G polymorphism was shown to exert a protective effect in NTD cases (AA v AG+GG OR 0.31 [95% CI 0.10, 0.94] p = 0.04). When statistical tests for interaction were conducted, three genotype combinations in cases (MTRR/GCPII; MTHFR 677/CßS; MTHFR 677/MTRR) and one combination in case mothers (CßS/RFC-1) were shown to elevate NTD risk. Maternal–fetal interaction was also detected when offspring carried the MTHFR 677C→T variant and mothers carried the MTRR 66A→G variant, resulting in a significantly elevated risk of NTD.

Conclusion: Both independent genetic effects and gene–gene interaction were observed in relation to NTD risk. Multi-locus rather than single locus analysis might be preferable to gain an accurate assessment of genetic susceptibility to NTD.

     

Effects of enzyme replacement therapy on pain and health related quality of life in patients with Fabry disease: data from FOS (Fabry Outcome Survey)

Background: Fabry disease is an X linked lysosomal storage disease caused by deficiency of the lysosomal enzyme α-galactosidase A. This leads to accumulation of globotriaosylceramide in nearly all tissues, including the blood vessels, kidney, myocardium, and nervous system. Symptoms often begin in childhood and include acroparaesthesia, with burning or tingling pain that spreads from the extremities to more proximal sites.

Aims: This study set out to evaluate pain and its influence on quality of life in patients with Fabry disease receiving enzyme replacement therapy (ERT) with agalsidase alfa.

Methods: Data were obtained from the Fabry Outcome Survey. Pain was measured using the Brief Pain Inventory (BPI), and health-related quality of life (HRQoL) was documented with the European Quality of Life Questionnaire (EQ-5D).

Results: The mean (SD) score for "pain at its worst" on the BPI prior to ERT was 5.1 (2.7). One year after commencement of ERT, this had improved by 0.5, and improved by a further 0.6 after 2 years (p<0.05). Similar statistically significant improvements were seen for "pain on average" and "pain now" after 2 years of ERT. The mean HRQoL utility score prior to ERT was 0.66 (0.32). After 12 months of treatment with agalsidase alfa, this had improved to 0.74 (0.26; p<0.05); this improvement was maintained after 2 years.

Conclusions: ERT with agalsidase alfa significantly reduces pain and improves quality of life in patients with Fabry disease.