Glycogen storage disease type Ia: Four novel mutations (175delGG,R170X,G266V and V338F) identified

Deficient activity of glucose‐6‐phosphatase (G6Pase) causes glycogen storage disease type Ia (GSD Ia). We analysed the G6Pase gene of 16 GSD Ia patients using single strand conformation polymorphism (SSCP) analysis prior to automated sequencing of exon(s) revealing an aberrant SSCP pattern. In all GSD Ia patients we were able to identify mutations on both alleles of the G6Pase gene, indicating that this method is a reliable procedure to identify mutations. Four novel mutations (175delGG, R170X, G266V and V338F) were identified. © 1998 Wiley‐Liss, Inc.     

Serological responses of patients with ectopic pregnancy to epitopes of the Chlamydia trachomatis 60 kDa heat shock protein

Clinical and histopathological correlations of immunoreactivity to Chlamydia trachomatis and to epitopes of the C. trachomatis 60 kDa heat shock protein (hsp60) among women with ectopic pregnancy were evaluated in a case-control study. Serological responses to 13 synthetic peptides corresponding to major epitopes of the chlamydial hsp60 were determined in 67 women treated for ectopic pregnancy and 45 women with uncomplicated pregnancy in utero. Plasma cell salpingitis was detected in 29 (43.3%) of the ectopic patients. Its presence correlated with antibodies to two hsp60 epitopes, encompassing amino acids 260-271 and 411-422 (P = 0.02). Antibodies to these two epitopes, along with five other epitopes, also correlated with peritubal adhesion formation in ectopic pregnant patients (P < 0.01). Antibodies to epitopes 260-271 and 188-199 also correlated with a history of pelvic inflammatory disease (PID; P = 0.05). Patients with ectopic pregnancy were also more likely than their intrauterine pregnant controls to have present anti- chlamydial immunoglobulin G (P < 0.005). Women positive for both C. trachomatis and hsp60 epitope antibodies had an increased prevalence over controls of salpingitis, pelvic adhesions or history of PID (P < 0.05). In contrast, patients who were positive for only C. trachomatis antibodies or only hsp60 epitope antibodies did not differ from antibody-negative patients in each of these categories.      

Circulating antibodies to a conserved epitope of the Chlamydia trachomatis 60 kDa heat shock protein (hsp60) in infertile couples and its relationship to antibodies to C.trachomatis surface antigens and the Escherichia coli and human HSP60

To evaluate the relationship between immunity to specific regions of the Chlamydia trachomatis 60 kDa heat shock protein (hsp60), autoimmunity to human HSP60 and infertility, sera from 50 women and 45 men seen for an infertility evaluation were tested. Humoral immunity to human HSP60 was detected in 18% of women and 8.9% of men while antibodies to the Escherichia coli hsp60 were detected in 12% of women and 4.4% of men. These differences were not statistically significant. In contrast, antibodies to a synthetic peptide epitope of the chlamydial hsp60, encompassing amino acids 260-271 (chsp 260-271), were present in sera from 16 (32%) of the women but in only six (13.3%) of the men (P=0.03). Antibodies to chsp 260-271 were present in 11 out of 17 (64.7%) individuals with high titre (>1:160) immunoglobulin (Ig)G antibody to C.trachomatis surface antigens as opposed to only two out of 15 (13.3%) with low titre antibody and two out of of 17 (11.8%) with undetectable chlamydial antibody (P < 0.004). Antibodies to chsp 260- 271 were also associated with humoral immunity to human HSP60. 50% of sera with, as opposed to only 18.6% of sera without, anti-human HSP60 IgG were positive for antibodies to chsp 260-271 (P=0.03). In contrast, there was no relationship found between immunity to the E.coli hsp60 and antibodies to human HSP60. Antibodies to chsp 260-271 were more prevalent in women with at least two spontaneous abortions (eight out of 13, 61.5%) than in women with other infertility diagnoses (six out of 35, 17.1%) (P=0.004). Thus, immunity to chsp 260-271 is more prevalent in women than in men, associated with autoimmunity to human HSP60 and may be an immunological marker for spontaneous abortion.      

Factors and outcomes associated with the induction of labour in Latin America

Objective  To describe the prevalence of labour induction, together with its risk factors and outcomes in Latin America.
Design  Analysis of the 2005 WHO global survey database.
Setting  Eight selected Latin American countries.
Population  All women who gave birth during the study period in 120 participating institutions.
Methods  Bivariate and multivariate analyses.
Main outcome measures  Indications for labour induction per country, success rate per method, risk factors for induction, and maternal and perinatal outcomes.
Results  Of the 97 095 deliveries included in the survey, 11 077 (11.4%) were induced, with 74.2% occurring in public institutions, 20.9% in social security hospitals and 4.9% in private institutions. Induction rates ranged from 5.1% in Peru to 20.1% in Cuba. The main indications were premature rupture of membranes (25.3%) and elective induction (28.9%). The success rate of vaginal delivery was very similar for oxytocin (69.9%) and misoprostol (74.8%), with an overall success rate of 70.4%. Induced labour was more common in women over 35 years of age. Maternal complications included higher rates of perineal laceration, need for uterotonic agents, hysterectomy, ICU admission, hospital stay >7 days and increased need for anaesthetic/analgesic procedures. Some adverse perinatal outcomes were also higher: low 5-minute Apgar score, very low birthweight, admission to neonatal ICU and delayed initiation of breastfeeding.
Conclusions  In Latin America, labour was induced in slightly more than 10% of deliveries; success rates were high irrespective of the method used. Induced labour is, however, associated with poorer maternal and perinatal outcomes than spontaneous labour.     

Effects of high-dose methotrexate on rat alveolar and inflammatory macrophage populations

Methotrexate (MTX) is used clinically in high doses to treat a variety of neoplastic diseases. Although it has been recognized that such aggressive chemotherapy can result in suppression of cellular host defense mechanisms, phagocytic cell function during MTX therapy remains poorly understood. The present study was designed to examine the effects of a single high dose of MTX on alveolar and inflammatory peritoneal cell populations in the rat. Male Sprague-Dawley rats were treated with a single intraperitoneal injection of MTX (25 or 50 mg/kg) and subsequent alterations in the composition of peripheral blood white cells (WBC), a peritoneal inflammatory exudate, and the resident alveolar macrophage (AM) were measured 1–4 days after MTX treatment. A severe depression in the polymorphonuclear leukocyte (PMNL) and monocyte populations in the peripheral blood was observed 72 and 96 h after either dose of MTX. Similarly, the total number of peritoneal exudate cells, collected 72 h after a casemate inflammatory stimulus, was reduced by 50% after MTX treatment. When the cellular composition of the peritoneal exudate was examined, it was observed that macrophage and lymphocyte numbers were selectively depressed. In addition, the number of AM obtained by lung lavage was significantly reduced 72 and 96 h after MTX injection. Although both peritoneal and alveolar macrophage numbers were diminished, in vitro phagocytic activity was not impaired 72 h after MTX injection. These studies demonstrate that a single, clinically relevant dose of MTX, in addition to depressing PMNL and monocyte levels in the peripheral blood, can also impair the accumulation of macrophages at a site of tissue injury and the influx of macrophages into lung alveoli. These findings suggest that the capacity of the mononuclear phagocyte system to respond to an infectious or tumor cell challenge may be severely compromised during MTX treatment.     

PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus–Merzbacher disease in a girl

Fonseca ACS, Bonaldi A, Costa SS, Freitas MR, Kok F, Vianna‐Morgante AM. PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus–Merzbacher disease in a girl. PLP1 (proteolipid protein1 gene) mutations cause Pelizaeus–Merzbacher disease (PMD), characterized by hypomyelination of the central nervous system, and affecting almost exclusively males. We report on a girl with classical PMD who carries an apparently balanced translocation t(X;22)(q22;q13). By applying array‐based comparative genomic hybridization (a‐CGH), we detected duplications at 22q13 and Xq22, encompassing 487–546 kb and 543–611 kb, respectively. The additional copies were mapped by fluorescent in situ hybridization to the breakpoint regions, on the derivative X chromosome (22q13 duplicated segment) and on the derivative 22 chromosome (Xq22 duplicated segment). One of the 14 duplicated X‐chromosome genes was PLP1.The normal X chromosome was the inactive one in the majority of peripheral blood leukocytes, a pattern of inactivation that makes cells functionally balanced for the translocated segments. However, a copy of the PLP1 gene on the derivative chromosome 22, in addition to those on the X and der(X) chromosomes, resulted in two active copies of the gene, irrespective of the X‐inactivation pattern, thus causing PMD. This t(X;22) is the first constitutional human apparently balanced translocation with duplications from both involved chromosomes detected at the breakpoint regions.     

RFP2, c13ORF1, and FAM10A4 are the most likely tumor suppressor gene candidates for B-cell chronic lymphocytic leukemia

Occurrence of 13q14 deletions between D13S273 and D13S25 in B-cell chronic lymphocytic leukemia (B-CLL) suggests that the region contains a tumor suppressor gene. We constructed a PAC/cosmid contig largely corresponding to a 380-kb 13q14 YAC insert that we found deleted in a high proportion of B-CLL patients. We found seven genes by exon trapping, cDNA screening and analysis/cDNA extension of known expressed sequence tags. One appeared to originate from another region of 13q. Recent publications have focused on two of the genes that most likely do not have a tumor suppressor role. This study evaluates the remaining four genes in the region by mutation scanning and theoretical analysis of putative encoded products. No mutations suggestive of a pathogenic effect were found. The 13q14 deletions may be a consequence of an inherent instability of the region, an idea supported by our finding of a considerable proportion of AluY repeats. Deletion of putative enhancer sequences and/or genes in the region may result in an inactivation of tumor suppression by a haploinsufficiency mechanism. We conclude that RFP2, c13ORF1, and a chromosome 13-specific ST13-like gene, FAM10A4, are the most likely candidates for such a type of B-CLL TSG.     

Pathologic findings following false-positive screening tests for ovarian cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial

Objective

In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), ovarian cancer screening with transvaginal ultrasound (TVU) and CA-125 produced a large number of false-positive tests. We examined relationships between histopathologic diagnoses, false-positive test group, and participant and screening test characteristics.

Methods

The PLCO ovarian cancer screening arm included 39,105 women aged 55-74 years assigned to annual CA-125 and TVU. Histopathologic diagnoses from women with false-positive tests and subsequent surgery were reviewed in this analysis: all CA125+ (n = 121); all CA125+/TVU+ (n = 46); and a random sample of TVU+ (n = 373). Demographic and ovarian cancer risk factor data were self-reported. Pathologic diagnoses were abstracted from surgical pathology reports. We compared participant characteristics and pathologic diagnoses by category of false-positive using Pearson χ², Fisher's exact, or Wilcoxon-Mann-Whitney tests.

Results

Women with a false-positive TVU were younger (P < 0.001), heavier (P < 0.001), and reported a higher frequency of prior hysterectomy (P < 0.001). Serous cystadenoma, the most common benign ovarian diagnosis, was more frequent among women with TVU+ compared to CA-125+ and CA-125+/TVU+ (P < 0.001). Benign non-ovarian findings were commonly associated with all false-positives, although more frequently with CA-125+ than TVU+ or CA-125+/TVU+ groups (P = 0.019). Non-ovarian cancers were diagnosed most frequently among CA-125+ (P < 0.001).

Conclusions

False-positive ovarian cancer screening tests were associated with a range of histopathologic diagnoses, some of which may be related to patient and screening test characteristics. Further research into the predictors of false-positive ovarian cancer screening tests may aid efforts to reduce false-positive results.