The <Emphasis Type="Italic">Arg</Emphasis>194<Emphasis Type="Italic">Trp</Emphasis> polymorphism in DNA repair gene XRCC1 and the risk for sporadic late-onset Alzheimer's disease

Abstract Alzheimer's disease (AD) is defined pathologically by the presence of β-amyloid plaques, neurofibrillary tangles and extensive neuronal loss. Evidence indicates that increased DNA damage may contribute to neuronal loss in AD. Recently, it has been shown that in AD neurons have a reduced capacity for some types of DNA repair. Polymorphisms in DNA repair genes may be associated with differences in repair efficiency of DNA damage. Variants of several DNA repair genes, including the base excision repair gene XRCC1, have been described previously. We hypothesised that Arg194Trp polymorphism of XRCC1 gene may contribute to genetic susceptibility for AD. In order to test this hypothesis, we investigated Arg194Trp polymorphism at the XRCC1 gene in the DNA samples of 98 patients with AD and 95 healthy subjects. The frequency of the Trp allele was more pronounced among cases (11.2%) compared with controls (5.8%). On combining the homozygous and heterozygous variants of each codon, the variants seemed to be at twofold risk of AD, although the risk estimates were not statistically significant (OR=1.95, 95% CI 0.88–4.34, p=0.09). In addition, the 194Trp allele revealed a borderline significance (OR=2.05, 95% CI 0.96–4.37, p=0.056). According to our results, it may be speculated that the polymorphic variants of XRCC1 codon 194 have a role in the development of AD.     

Dydrogesterone-induced hepatitis and autoimmune hemolytic anemia.

Dydrogesterone, similar to women's natural progesterone, has been used in a wide range of gynecological conditions. Despite its widespread use, dydrogesterone-induced hepatotoxicity and dydrogesterone-induced hemolytic anemia have, to the best of our knowledge, never been reported previously. We describe a case of hepatitis and warm antibody hemolytic anemia due to dydrogesterone.     

The adverse effect of treatment prolongation in cervical cancer by high-dose-rate intracavitary brachytherapy.

BACKGROUND AND PURPOSE: The potential risk of prolongation of treatment time in cervical cancer has been reported for many low-dose rate (LDR) studies, with an estimated loss of local control ranging from 0.3 to 1.6% per day of treatment prolongation. Since the treatment schedule for fractionated high-dose rate intracavitary brachytherapy (HDRICB) is not directly comparable with that for low-dose rate studies, this report aims to evaluate the adverse effect of treatment prolongation specifically for cervical cancer treated with HDRICB. MATERIAL AND METHODS: From September 1992 to December 1997, 257 patients diagnosed with uterine cervical cancer (35 Ib, 26 IIa, 122 IIb, 10 IIIa, 57 IIIb, 7 IVa), who underwent external radiotherapy combined with between two and four courses of HDRICB and a minimum of 3 years of follow-up (median 57 months), were analyzed. Treatment consisted of irradiation of the whole pelvis with 44-45 Gy consisting of 22-25 fractions by 5 weeks, with the dose boosted to 54-58 Gy (with central shielding) for patients diagnosed as FIGO stage IIb-IVa bilateral parametrial disease. HDRICB was performed using an Ir-192 remote afterloading technique at 1-week intervals. The standard prescribed dose for each course of HDRICB was 7.2 Gy to point A for three insertions (before July 1995), or 6.0 Gy to point A for four insertions (after July 1995). Total prescribed point A doses (external beam radiotherapy+HDRICB) ranged from 58 to 71.6 Gy (median, 65.6 Gy) for stage IB-IIA, while analogous dosage for larger lesions (stage IIb-IVa) ranged from 59 to 75.6 Gy (median, 65.6 Gy). Kaplan-Meier and multivariate analyses were used to test the effect of treatment time on pelvic control rate (PCR) and cause-specific survival (CSS) at 5 years. RESULTS: Median treatment time was 63 days. For all stages of disease, the 5-year CSS and PCR were significantly different comparing treatment times of less than and greater than or equal to 63 days [83% and 65% (P=0.004], 93% and 83% (P=0.02), respectively]. These associations were also significant for stage Ib/IIa [97% and 79% (P=0.01), and 100% and 87% (P=0.02), respectively), but not for stage IIb [75% and 72% (P=0.79), and 93% and 87% (P=0.83), respectively] or stage III [66% and 49% (P=0.2), and 83% and 72% (P=0.21), respectively]. Multivariate analysis identified three prognostic factors for CSS, stage (P<0.001), tumor response to external RT (P=0.001), and overall treatment time (OTT; P=0.006). Prognostic factors for pelvic failure were stage (P<0.001), tumor response to external RT (P=0.001), and OTT (P=0.03). Prolongation of treatment time resulted in a daily decrease in pelvic control rate of 0.67% overall, and 0.43% for stage Ib-IIa, 0.57% for stage IIb, and 0.73% for stage III patients. CONCLUSION: Analysis of the data from the current study demonstrates that the adverse effect of treatment prolongation was observed later in the treatment course for the high-dose rate (HDR) series compared to the LDR analog, however, treatment-time prolongation still negatively influenced the cause-specific survival and pelvic control rate for both dosage groups.     

Extending the capability paradigm to address the complexity of disability

Amartya Sen looks at people's well-being in terms of functioning and freedom, rather than in terms of the amount of goods or services consumed. The capability approach, developed by Sen, deals with what people are able to achieve by using these commodities. Concerning disability, he wrote: “We must take note that a disabled person may not be able to do the many things that an able-bodied individual can, with the same bundle of commodities” [Sen, A. K. (1985). Commodities and capabilities. Oxford: Oxford University Press [1999], p. 7]. The capability approach makes it possible to analyse the economic situation of people with disabilities in a different way. What becomes important is their functioning, i.e. what they are able to achieve within a given context. In fact, the capability set includes not only what a person is effectively able to achieve, but also the potential functionings that he/she can choose. This expresses the degree of freedom that a person with disability benefits from in a given environment. The challenge is therefore to reduce the constraints that the environment adds to a person's impairment in order to expand their capability set and to allow them to live a life which they value. This paper reviews the paradigms that address disability and the ways of assessing a person's capability set within this framework. Achieved functionings are easily measured through cross-sectional surveys, using counterfactual analysis to compare the situations of disabled and non-disabled people. This was done in 2005 in Afghanistan when a national disability survey was carried out on a random sample of households. Measuring detailed capabilities, especially their freedom dimension, is quite complex and requires identifying people's potential choices in an ever-changing environment. This implies a need to extend the philosophical framework and to adopt appropriate statistical methodologies.     

Genetic diversity of the Leptospiral immunoglobulin-like (Lig) genes in pathogenic Leptospira spp.

Recent serologic, immunoprotection, and pathogenesis studies identified the Lig proteins as key virulence determinants in interactions of leptospiral pathogens with the mammalian host. We examined the sequence variation and recombination patterns of ligA, ligB, and ligC among 10 pathogenic strains from five Leptospira species. All strains were found to have intact ligB genes and genetic drift accounting for most of the ligB genetic diversity observed. The ligA gene was found exclusively in L. interrogans and L. kirschneri strains, and was created from ligB by a two-step partial gene duplication process. The aminoterminal domain of LigB and the LigA paralog were essentially identical (98.5 ± 0.8% mean identity) in strains with both genes. Like ligB, ligC gene variation also followed phylogenetic patterns, suggesting an early gene duplication event. However, ligC is a pseudogene in several strains, suggesting that LigC is not essential for virulence. Two ligB genes and one ligC gene had mosaic compositions and evidence for recombination events between related Leptospira species was also found for some ligA genes. In conclusion, the results presented here indicate that Lig diversity has important ramifications for the selection of Lig polypeptides for use in diagnosis and as vaccine candidates. This sequence information will aid the identification of highly conserved regions within the Lig proteins and improve upon the performance characteristics of the Lig proteins in diagnostic assays and in subunit vaccine formulations with the potential to confer heterologous protection.     

Hyperhomocysteinaemia as a risk factor for deep-vein thrombosis.

OBJECTIVE: Several studies have shown a relation between hyperhomocysteinaemia and vascular disease. To assess the risk of deep-vein thrombosis (DVT) associated with hyperhomocysteinaemia, we studied plasma homocysteine levels in patients with deep-vein thrombosis and in normal control subjects. MATERIALS AND METHODS: We measured plasma homocysteine levels in 48 patients with deep-vein thrombosis and in 33 healthy controls matched to the patients according to age and sex. Plasma homocysteine levels were measured with high performance liquid chromatography and fluorescence detection. Hyperhomocysteinaemia was defined as a plasma homocysteine level about 15 micromol/L in both groups. The diagnosis of all patients with deep-vein thrombosis (n=48) was verified by Doppler ultrasonography. RESULTS: Plasma homocysteine levels were found to be increased in the deep-vein thrombosis group compared the control group (p<0.001, t-test). The mean plasma homocysteine level in the patients was 17.1 SD 5.13 micromol/L (range 6.4-31.3), and that in the controls was 9.0 SD 1.27 micromol/L (range 6.0-11.5). The association between elevated homocysteine levels and venous thrombosis was stronger among men than among women. CONCLUSIONS: The increased plasma homocysteine levels we have observed may have a causative role in the development of deep-vein thrombosis.     

Neglected rupture of the Achilles tendon treated with peroneus brevis transfer: A functional assessment of 5 cases

The purpose of this study was to review the clinical results of 5 patients who underwent repair of a chronic Achilles tendon rupture using a combination of peroneus brevis transfer and plantaris tendon augmentation. The technique belongs to the group of local tendon transfer procedures making use of the transferred peroneus brevis tendon as strengthening material together with the plantaris tendon as suturing material. There were 4 males and 1 female with an average age of 49.4 years and an average time to presentation postinjury of 19.8 weeks (range 5-40 wk). All patients underwent Cybex strength testing before and approximately 1 year after surgery. This testing demonstrated a postoperative improvement in peak plantarflexion torque (Newton-meters/body weight) in all cases. The peak torque of plantar flexion increased in all patients (range, 21%-410%). Four patients were found to have an increase of the dorsal flexors peak torque (range, 31%-290%), whereas one patient showed a decrease (-37%). No patient experienced wound closure complications, postoperative pain, or functional limitations. In spite the possibility of residual lateral ankle instability, we found this modification to be a valuable innovation that offers a very good functional result, low morbidity, technical advantages to the surgeon and, most important, a durable and satisfactory result for the patients.     

Comparison and validation of scoring systems in a cohort of patients treated for perforated peptic ulcer

Background and aims The aim of this study is to evaluate the predictive accuracy of different scoring systems on surgery for perforated peptic ulcer referred to an academic department of general surgery in a tertiary reference center. Patients and methods Seventy-five consecutive patients (Male/female ratio = 64:11; mean age, 44 years; range, 16–85) with perforated peptic ulcer disease were investigated. Disease severity scores and mortality predictions were calculated using the collected data during admission. Discrimination and calibration characteristics of each system, namely, the acute physiology and chronic health evaluation II and III, the simplified acute physiology score II, and the mortality probability models (MPM) II, were determined by using the area under receiver operating characteristics curve and the Hosmer–Lemeshow goodness-of-fit test, respectively. Results Among the 75 patients included, there were eight (10.6%) mortalities. All systems had a reliable power of discrimination and calibration. Among the systems tested, MPM II was the best performing as far as discrimination and calibration characteristics were considered. The parameters of MPM II system that were related to systemic perfusion of the patient were significantly positive in patients who died compared to those who survived. Conclusions MPM II that predicted mortality at admission is better than the other systems in predicting mortality. Results also indicate the importance of maintenance of systemic perfusion of the patient at the early phases of peptic ulcer perforation.