The origins of a research community in the Majengo observational cohort study,Nairobi, Kenya

Background  

Since the 1980s the Majengo Observational Cohort Study (MOCS) has examined sexually transmitted infections, in particular HIV/AIDS, in a cohort of sex workers in Majengo, an impoverished urban village in Nairobi, Kenya. The MOCS investigators have faced criticism since the women have remained in the sex trade for the duration of their participation in the study, prompting concerns about exploitation. Yet despite these concerns, the cohort has survived for almost 30 years.     

Accelerated hypofractionated adjuvant whole breast radiation with simultaneous integrated boost using volumetric modulated arc therapy for early breast cancer: A phase I/II dosimetric and clinical feasibility study from a tertiary cancer care centre of India

Background

Hypofractionation has become standard of care after Breast Conserving Therapy (BCT) in many European and few others western countries. Though still debatable, tumor cavity boost is routinely practised in our centre. Hypofractionation is not yet the current standard of practice in Asian countries. Employing hypofractionation and simultaneous integrated boost to lumpectomy cavity with conformal technique is not the current practice in this region. Hence the study was performed to see whether accelerated hypofractionation and simultaneous boost can be combined using volumetric modulated arc therapy (VMAT) in treating early breast cancer (EBC) patients.

Delayed diagnosis of anorectal malformations: are current guidelines sufficient?

Aim: To determine the frequency and presenting features of infants with delayed diagnosis of anorectal malformations (ARM) referred to an Australian tertiary paediatric institution. Methods: Infants referred to our institution with a final diagnosis of ARM were retrospectively reviewed between 2001 and 2009. The first cohort consisted of patients that were referred between November 2001 and November 2006 with the diagnosis of an ARM that had been delayed for more than 48 h. The second cohort was those referred between December 2006 and May 2009 with whom the diagnosis of ARM had not been made within 24 h of birth. Results: Nineteen infants were referred with delayed diagnosis of an ARM over the 7.5 years of the study. Of 44 patients referred to our institution between December 2006 and May 2009, diagnosis of an ARM was delayed more than 24 h in 14 (32%). There was no difference in gender, birth weight, prematurity, type of malformation or presence of associated anomalies between those with timely and delayed diagnosis of their ARM. A significantly greater proportion of those with a delayed diagnosis presented with obstructive symptoms (86% vs. 27%, P < 0.001), including abdominal distension (57%) and delayed passage of meconium or stool (29%). Despite undergoing neonatal examination, the diagnosis of ARM was missed in 12 patients overall. Conclusion: Delayed diagnosis of an ARM appears to be common, occurring in approximately 32% of patients referred to our institution over the last 2.5 years. Current guidelines appear insufficient to ensure prompt diagnosis of ARM.     

The Nigerian national blindness and visual impairment survey: Rationale, objectives and detailed methodology

Background

Despite having the largest population in Africa, Nigeria has no accurate population based data to plan and evaluate eye care services. A national survey was undertaken to estimate the prevalence and determine the major causes of blindness and low vision. This paper presents the detailed methodology used during the survey.

Methods

A nationally representative sample of persons aged 40 years and above was selected. Children aged 10–15 years and individuals aged <10 or 16–39 years with visual impairment were also included if they lived in households with an eligible adult. All participants had their height, weight, and blood pressure measured followed by assessment of presenting visual acuity, refractokeratomery, A-scan ultrasonography, visual fields and best corrected visual acuity. Anterior and posterior segments of each eye were examined with a torch and direct ophthalmoscope. Participants with visual acuity of < = 6/12 in one or both eyes underwent detailed examination including applanation tonometry, dilated slit lamp biomicroscopy, lens grading and fundus photography. All those who had undergone cataract surgery were refracted and best corrected vision recorded. Causes of visual impairment by eye and for the individual were determined using a clinical algorithm recommended by the World Health Organization. In addition, 1 in 7 adults also underwent a complete work up as described for those with vision < = 6/12 for constructing a normative data base for Nigerians.

Discussion

The field work for the study was completed in 30 months over the period 2005–2007 and covered 305 clusters across the entire country. Concurrently persons 40+ years were examined to form a normative data base. Analysis of the data is currently underway.

Conclusion

The methodology used was robust and adequate to provide estimates on the prevalence and causes of blindness in Nigeria. The survey would also provide information on barriers to accessing services, quality of life of visually impaired individuals and also provide normative data for Nigerian eyes.     

Apoptosis and macrophage-mediated deletion of precursor B cells in the bone marrow of E mu-myc transgenic mice

Transgenic mice expressing the c-myc proto-oncogene under the control of the Ig heavy chain enhancer (E mu-myc) all eventually develop clonal pre-B- or B-cell tumors. The preneoplastic period is characterized by increased polyclonal proliferation of pro-B and pre-B cells in the bone marrow (BM) associated with a reduced number of B cells, suggesting a high degree of B-cell loss. To examine the mechanisms of this cell loss, we have identified B220+ B-lineage cells within the BM of pretumorous E mu-myc transgenic mice by in vivo radiolabeling and electron microscope radioautography. Large mitotic B220(+)-labeled cells form prominent clusters in the extravascular compartment of the BM. Some B220+ small lymphocytes, as well as large lymphoid cells, enter BM sinusoids. However, in addition, large numbers of B220+ cells exhibit nuclear chromatin condensation, fragmentation, and other morphologic features characteristic of apoptotic cell death. Propidium iodide staining and flow cytometry of BM cells from pretumorous E mu- myc transgenic mice, as well as agarose gel electrophoresis of DNA, confirm extensive apoptosis. Many B220+ apoptotic cells are closely associated with the extensive processes of prominent macrophages that contain numerous B220+ apoptotic bodies and complex lysosomal systems. These results suggest that the constitutive expression of c-myc oncogene in BM B-lineage cells, which increases the proliferation of precursor B cells, also leads to increased apoptotic cell death and rapid elimination by resident macrophages. Further mutations may be needed to block these protective mechanisms and permit surviving c-myc- dysregulated cells to leave the BM and to initiate tumorigenesis.     

Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C-->T, is present at an unexpectedly high frequency in the general population, as was the case for 625G-->A, together conferring susceptibility to ethylmalonic aciduria

We have shown previously that a variant allele of the short-chain acyl- CoA dehydrogenase ( SCAD ) gene, 625G-->A, is present in homozygous form in 7% of control individuals and in 60% of 135 patients with elevated urinary excretion of ethylmalonic acid (EMA). We have now characterized three disease-causing mutations (confirmed by lack of enzyme activity after expression in COS-7 cells) and a new susceptibility variant in the SCAD gene of two patients with SCAD deficiency, and investigated their frequency in patients with elevated EMA excretion. The first SCAD-deficient patient was a compound heterozygote for two mutations, 274G-->T and 529T-->C. These mutations were not present in 98 normal control alleles, but the 529T-->C mutation was found in one allele among 133 patients with elevated EMA excretion. The second patient carried a 1147C-->T mutation and the 625G- ->A polymorphism in one allele, and a single point mutation, 511C-->T, in the other. The 1147C-->T mutation was not present in 98 normal alleles, but was detected in three alleles of 133 patients with elevated EMA excretion, consistently as a 625A-1147T allele. On the other hand, the 511C-->T mutation was present in 13 of 130 and 15 of 67 625G alleles, respectively, of normal controls and patients with elevated EMA excretion, and was never associated with the 625A variant allele. This over-representation of the haplotype 511T-625G among the common 625G alleles in patients compared with controls was significant ( P < 0.02), suggesting that the allele 511T-625G-like 511C-625A- confers susceptibility to ethylmalonic aciduria. Expression of the variant R147W SCAD protein, encoded by the 511T-625G allele, in COS-7 cells showed 45% activity at 37 degrees C in comparison with the wild- type protein, comparable levels of activity at 26 degrees C, and 13% activity when incubated at 41 degrees C. This temperature profile is different from that observed for the variant G185S SCAD protein, encoded by the 511C-625A allele, where higher than normal activity was found at 26 and 37 degrees C, and 58% activity was present at 41 degrees C. These results corroborate the notion that the 511C-625A variant allele is one of the possible underlying causes of ethylmalonic aciduria, and suggest that the 511C-->T mutation represents a second susceptibility variation in the SCAD gene. We conclude that ethylmalonic aciduria, a commonly detected biochemical phenotype, is a complex multifactorial/polygenic condition where, in addition to the emerging role of SCAD susceptibility alleles, other genetic and environmental factors are involved.      

The spine: changes in T2 relaxation times from disuse

Magnetic resonance imaging of the spine was performed in six healthy male volunteers before and after 5 weeks of continuous bed rest. Imaging studies consisted of a single 1-cm sagittal section obtained with a spin-echo technique through the center of the spinal column. The T2s of the lumbar vertebral body and nucleus pulposus and the area of the latter were measured. In both vertebrae and disks, there was a significant decrease in T2 after bed rest. The nucleus pulposus also decreased in size with bed rest. The decrease in relaxation time of the lumbar vertebrae could be explained by the replacement of hematopoietic marrow by fatty marrow, a known consequence of paralytic immobilization. The decreases in size and T2 of the disks probably represent loss of water. The significance of these changes to the mechanical integrity of these structures after immobilization or space flight is not known but will depend in part on whether changes are progressive with increasing length of immobilization and on the rate and extent that they are reversed after reambulation. These results indicate that relaxation times can be altered by simple disuse, which often accompanies the underlying disease.     

Critical analysis of radiologist-patient interaction

A critical incident interview technique was used to identify features of radiologist-patient interactions considered effective and ineffective by patients. During structured interviews with 35 radiology patients and five patients' parents, three general categories of physician behavior were described: attention to patient comfort, explanation of procedure and results, and interpersonal sensitivity. The findings indicated that patients are sensitive to physicians' interpersonal styles and that they want physicians to explain procedures and results in an understandable manner and to monitor their well-being during procedures. The sample size of the study is small; thus further confirmation is needed. However, the implications for training residents and practicing radiologists in these behaviors are important in the current competitive medical milieu.     

Physiological characteristics of capacity constraints in working memory as revealed by functional MRI

A fundamental characteristic of working memory is that its capacity to handle information is limited. While there have been many brain mapping studies of working memory, the physiological basis of its capacity limitation has not been explained. We identified characteristics of working memory capacity using functional magnetic resonance imaging (fMRI) in healthy subjects. Working memory capacity was studied using a parametric 'n-back' working memory task involving increasing cognitive load and ultimately decreasing task performance. Loci within dorsolateral prefrontal cortex (DLPFC) evinced exclusively an 'inverted-U' shaped neurophysiological response from lowest to highest load, consistent with a capacity-constrained response. Regions outside of DLPFC, in contrast, were more heterogeneous in response and often showed early plateau or continuously increasing responses, which did not reflect capacity constraints. However, sporadic loci, including in the premotor cortex, thalamus and superior parietal lobule, also demonstrated putative capacity-constrained responses, perhaps arising as an upstream effect of DLPFC limitations or as part of a broader network-wide capacity limitation. These results demonstrate that regionally specific nodes within the working memory network are capacity-constrained in the physiological domain, providing a missing link in current explorations of the capacity characteristics of working memory.