Frontiers in nephrology: heterologous immunity, T cell cross-reactivity, and alloreactivity

Established memory T cell responses to a previously encountered pathogen can have a major impact on the course and outcome of a subsequent infection with an unrelated pathogen. This phenomenon, known as heterologous immunity, is dependent on the sequence of infections and can be either beneficial or detrimental to the host. Examples of heterologous immunity between unrelated viruses and alloantigens are mounting, and the role of cross-reactive T cells both in the pathogenesis of infections and in transplant rejection is now being explored. Memory T cells seem to be part of a continually evolving interactive network in which with each new infection, an alteration in the frequencies, distributions, and activities of memory cells is generated in response to previous infections and alloantigens.     

Reconstruction of iliac crest with rib to prevent donor site complications: A prospective study of 26 cases

Background:

The tricortical bone graft from the iliac crest are used to reconstruct the post corpectomy spinal defects. The donor iliac area defect is large and may give rise to pain at donor site, instability of pelvis, fracture of ilium, donor site muscle herniation or abdominal content herniation. Rib removed during thoracotomy was used by us to reconstruct the iliac crest defect.

Materials and Methods:

Twenty-six patients who underwent thoracotomy for dorsal spine corpectomy or curettage for various spinal pathologies from June 2002 to May 2004 were included in the study. After adequate decompression the spine was reconstructed by tricortical bone graft from iliac crest and reconstruction of the iliac crest was done with the rib removed for exposure during thoracotomy.

Results:

The mean follow up was 15 months. All patients had good graft incorporation which was evaluated on the basis of local tenderness and radiographs. One patient had graft displacement.

Conclusion:

The reconstruction of iliac crest by rib is a simple and effective procedure to prevent donor site complications.     

Synthesis and evaluation of 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridines as potassium-competitive acid blockers

7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines with excellent physicochemical and pharmacological properties were identified that represent interesting candidates for further development as potassium-competitive acid blockers (P-CABs). The title compounds were prepared following synthetic pathways that relied either on a Claisen rearrangement/cross-metathesis reaction or on the (asymmetric) reduction of prochiral ketones. The influence of the character of the substituents R3, R6, and Ar on the biological activity and the physicochemical properties of the target compounds was examined. In contrast to the parent system (R6 = H), compounds in which R6 represents a carboxamide residue generally show improved in vivo activity and favorable pKa/log D values. Whereas variation of R3 is useful to obtain target compounds with modified basicity and lipophilicity, strong inhibition of the H+/K+-ATPase and potent in vivo activity is observed for R3 = methyl only. Small modifications of the aryl group, e.g., replacement of hydrogen versus a fluoro atom or a methyl group, are allowed. The (9S)-enantiomers are responsible for the gastric acid secretion inhibiting action, whereas the (9R)-enantiomers are virtually inactive.     

Energy demands of walking in persons with postpoliomyelitis syndrome: relationship with muscle strength and reproducibility

OBJECTIVES: To describe the energy demands of walking in subjects with postpoliomyelitis syndrome (PPS) in comparison with the demands in healthy subjects, and to assess the reproducibility of walking energy measurements. DESIGN: Four repeated measurements with a 1-week interval between each measurement. SETTING: Outpatient clinic of a university hospital. PARTICIPANTS: Fourteen subjects with PPS and 14 age- and sex-matched healthy subjects. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Walking speed and energy cost of walking. The correlation parameter was lower-extremity muscle strength sum (MSS). The reproducibility parameters were standard error (SE) of measurement and smallest detectable difference (SDD). RESULTS: Walking speed in subjects with PPS (61.8 m/min) was significantly lower (-28%) and energy cost (4.8 J.kg(-1).m(-1)) was significantly higher (40%) than in healthy subjects. MSS correlated strongly with energy cost (r=-.84, P=.000), explaining 71% of the variance. The SE of measurement of energy cost measurements ranged between 1.7% and 3.4% for PPS subjects and between 1.2% and 2.4% for healthy subjects. The SDD ranged between 4.6% and 9.4% for PPS subjects and between 3.3% and 6.6% for healthy subjects, depending on the number of repeated measurements that were considered. CONCLUSIONS: Energy cost of walking in subjects with PPS is strongly related to the extent of muscle weakness in the lower extremities. Although variability was greater for PPS subjects than for healthy subjects, reproducibility of energy cost measurements was high. Therefore, metabolic assessment of energy cost of walking is a sensitive tool that can reveal clinically relevant changes even in the condition of a person with PPS.     

Knowledge about the research and ethics committee at Makerere University,Kampala

Background

All research involving human participants should be reviewed by a competent and independent institutional research and ethics committee. Research conducted at Makerere University College of Health Sciences should be subjected to a rigorous review process by the ethics committee in order to protect human participants'' interests, rights and welfare.

Objective

To evaluate researchers'' knowledge about the functions and ethical review process of the College of Health Sciences research and ethics committee.

Methods

A cross sectional study. 135 researchers consented to participate in the study, but 70 questionnaires were answered giving a 52% response.

Results

Age ranged between 30 to 61 years, majority of participants 30–39 years. Most of the respondents do agree that theREC functions include Protocol review 86%, protection of research participants 84.3%, and monitoring of ongoing research. During ethical review, the RECpays special attention to scientific design [79.7%] and ethical issues [75.3%], but less to the budget and literature review. More than 97% of the respondents believe that the REC is either average or very good, while 2.8% rank it below average.

Conclusion

Respondents knew the major functions of the committee including protection of the rights and welfare of research participants, protocol review and monitoring of on going research, and the elements of protocol review that are given more attention include ;scientific design and ethical issues. Overall performance of the REC was ranked as average by respondents. The committee should limit delays in approval and effectively handle all functions of the committee.     

HLA class I and II polymorphisms in Azores show different settlements in Oriental and Central islands

Human leucocyte antigen-A, -B, -Cw, -DRB1, -DQA1 and -DQB1 polymorphisms were examined in the Azorean population. The data were obtained at high-resolution level, using polymerase chain reaction (PCR) with sequence-specific primer, PCR-sequence-specific oligonucleotides and sequence-based typing. The most frequent allele in each locus was: A*0201 (24.5%), B*510101 (9.8%), Cw*0401 (14.8%), DRB1*070101 (18.3%), DQA1*0201 (17.4%) and DQB1*0301 (19.4%). The predominant extended haplotype was A*0202-B*1503-Cw*0202-DRB1*090102-DQA1*0303- DQB1*0202 (1.9%), which was found to be absent in the Portuguese mainland. The present study corroborates historical sources that say the Azores were populated not only by Portuguese but also by other Europeans, mostly Flemish people. Despite dendrogram analysis showing some remote Asian genetic affinities, the lack of specific alleles and haplotypes from those populations does not allow us to conclude for direct influence. Haplotype and allele frequencies in Azores show no homogeneous distribution between Oriental and Central islands of this archipelago. The Oriental islands harbour several haplotypes already found in mainland Portugal and identified as Mediterranean and European. The Central group of islands on the contrary clearly shows an influence of north Europeans (most probably derived from a well-documented Flemish settlement), with much less affinity to mainland Portugal.     

HLA genes in Portugal inferred from sequence-based typing: in the crossroad between Europe and Africa

The human leukocyte antigen-A (HLA-A), -B and -DRB1 polymorphism was examined in the Portuguese population, discriminating between North, Centre and South inhabitants. All data were obtained at high-resolution level, using sequence-based typing. The most frequent allele at each locus was A* 020101 (26%), B* 440301 and B* 510101 (12% each) and DRB1* 070101 (15%). The predominant three-locus haplotype was A*020101-B*440301-DRB1*070101 (3.1%), highly frequent in North Portugal (5.4%), lower in Centre (2%) and absent in the South. The present study demonstrates that the Portuguese population has been genetically influenced by Europeans and North Africans, via several historic immigrations. North Portugal seems to concentrate, probably due to the pressure of Arab expansion, an ancient genetic pool originated from several North Africans and Europeans, influences throughout millenniums. South Portugal shows a North African genetic influence, probably of recent origin by means of Berbers accompanying Arab expansion. We found that Centre Portugal is the distribution limit of some alleles and haplotypes that characterize the North or the South of the country. Despite North, Centre and South Portugal not being significantly different in allele frequencies, this study shows that HLA allele and haplotype frequencies are not homogeneous in the country. North and South Portugal show more similarity to North Africans in opposition to Centre which appears closer to Europeans.     

Methylenetetrahydrofolate reductase gene, homocysteine and coronary artery disease: the A1298C polymorphism does matter. Inferences from a case study (Madeira, Portugal)

Elevated levels of plasma homocysteine, an independent risk factor and a strong predictor of mortality in patients with coronary artery disease (CAD), can result from nutritional deficiencies or genetic errors, including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms. The contribution of these polymorphisms in the development of CAD remains controversial. We analysed the impact of MTHFR C677T and A1298C on fasting homocysteine and CAD in 298 CAD patients proved by angiography and 510 control subjects from the Island of Madeira (Portugal). After adjustment for other risk factors, plasma homocysteine remained independently correlated with CAD. Serum homocysteine was significantly higher in individuals with 677TT and 1298AA genotypes. There was no difference in the distribution of MTHFR677 genotypes between cases and controls but a significant increase in 1298AA prevalence was found in CAD patients. In spite of the clear effect of C677T mutation on elevated homocysteine levels we only found an association between 1298AA genotype and CAD in this population. The simultaneous presence of 677CT and 1298AA genotypes provides a significant risk of developing the disease, while the 1298AC genotype, combined with 677CC, shows a significant trend towards a decrease in CAD occurrence. The data shows an independent association between elevated levels of homocysteine and CAD. Both MTHFR polymorphisms are associated with increased fasting homocysteine (677TT and 1298AA genotypes), but only the 1298AA variant shows an increased prevalence in CAD group. Odds ratio seem to indicate that individuals with the MTHFR 1298AA genotype and the 677CT/1298AA compound genotype had a 1.6-fold increased risk for developing CAD suggesting a possible association of MTHFR polymorphisms with the risk of CAD in Madeira population.     

Relationship between neuromuscular body functions and upper extremity activity in children with cerebral palsy

Aim Our aim was to investigate the relationship between the dimensions of neuromuscular body function and elbow, forearm, and hand activity in the upper extremities in children/adolescents with spastic cerebral palsy (CP), within the framework of the World Health Organization International Classification of Functioning, Disability and Health. Method Twenty‐three participants (10 males, 13 females, mean age 13y, SD 3y, range 8–18y) with spastic CP (21 with hemiplegia, two with diplegia) at Manual Ability Classification System levels I to III participated in the study. Neuromuscular body function measures were (1) muscle strength in the elbow, forearm, and grip, (2) muscle tone in elbow flexors and forearm supinators, (3) active supination range and elbow extension range, and (4) force control at submaximal level in elbow flexion. Activity measures were actual use of the affected hand in bimanual activities (Assisting Hand Assessment) and instructed use of the affected hand (Melbourne Assessment of Unilateral Upper Limb Function). Results Nearly all the neuromuscular body function variables were significantly correlated with activity. The combination of active supination range and strength explained 74% of the variance in actual use, and the combination of active supination range and force control explained 74% of the variance in instructed use. Interpretation In high‐functioning children and adolescents with CP, limited active supination range and difficulties in generating and modulating force are strongly related to limitations in hand activity. Further studies are needed to establish cause and effect in this relationship.