Global colorectal cancer research, 2007-2021: Outputs and funding

The purpose of this study was to provide an evidence base for colorectal cancer research activity that might influence policy, mainly at the national level. Improvements in healthcare delivery have lengthened life expectancy, but within a situation of increased cancer incidence. The disease burden of CRC has risen significantly, particularly in Africa, Asia and Latin America. Research is key to its control and reduction, but few studies have delineated the volume and funding of global research on CRC. We identified research papers in the Web of Science (WoS) from 2007 to 2021, and determined the contributions of the leading countries, the research domains studied, and their sources of funding. We identified 62 716 papers, representing 5.7% of all cancer papers. This percentage was somewhat disproportionate to the disease burden (7.7% in 2015), especially in Eastern Europe. International collaboration increased over the time period in almost all countries except in China. Genetics, surgery and prognosis were the leading research domains. However, research on palliative care and quality-of-life in CRC was lacking. In Western Europe, the main funding source was the charity sector, particularly in the UK, but in most other countries government played the leading role, especially in China and the USA. There was little support from industry. Several Asian countries provided minimal contestable funding, which may have reduced the impact of their CRC research. Certain countries must perform more CRC research overall, especially in domains such as screening, palliative care and quality-of-life. The private-non-profit sector should be an alternative source of support.     

Responsiveness of the urban primary health care delivery system in Bangladesh: A comparative analysis

This study analyses the responsiveness of outpatient care to assess the quality of urban primary health care among all 5 types of health care providers in Bangladesh, namely, the Urban Primary Health Care Services Delivery Project, the NGO Health Services Delivery Project (NHSDP), NGOs, private hospitals, and the Ministry of Health and Family Welfare (MOHFW). Other than some public‐private comparisons, there is an absolute knowledge gap regarding responsiveness in urban health systems, particularly in the context of Bangladesh, and this gap motivates this study. The study used primary data collected from 810 randomly selected outpatients. The survey used a structured questionnaire on all 7 domains of responsiveness of outpatient care suggested by the World Health Organization. The estimated mean responsiveness score reveals that overall, approximately 33% of the patients rated the responsiveness of the system as poor. In reported responsiveness, the NHSDP was ranked at the top and the MOHFW at the bottom. The latter is quite expected. Overall, prompt attention and autonomy were the worst‐performing domains, and choice of provider, dignity, and clear communication were the better‐performing ones. The results suggest the need to improve the degree of responsiveness of all domains, especially those that are more concerned with access to health care, namely, prompt attention, dignity, clear communication, and confidentiality. The Ministry of Health and Family Welfare facilities should give additional consideration to promote prompt attention, autonomy, and quality of basic amenities. Private facilities should also provide additional stress on improving prompt attention and autonomy. The nontherapeutic quality of health care needs to be emphasized in the medical education system. Further research based on household surveys could be worthwhile to measure responsiveness more comprehensively.     

Genome-wide association scan for childhood caries implicates novel genes

Dental caries is the most common chronic disease in children and a major public health concern due to its increasing incidence, serious health and social co-morbidities, and socio-demographic disparities in disease burden. We performed the first genome-wide association scan for dental caries to identify associated genetic loci and nominate candidate genes affecting tooth decay in 1305 US children ages 3-12 yrs. Affection status was defined as 1 or more primary teeth with evidence of decay based on intra-oral examination. No associations met strict criteria for genome-wide significance (p < 10E-7); however, several loci (ACTN2, MTR, and EDARADD, MPPED2, and LPO) with plausible biological roles in dental caries exhibited suggestive evidence for association. Analyses stratified by home fluoride level yielded additional suggestive loci, including TFIP11 in the low-fluoride group, and EPHA7 and ZMPSTE24 in the sufficient-fluoride group. Suggestive loci were tested but not significantly replicated in an independent sample (N = 1695, ages 2-7 yrs) after adjustment for multiple comparisons. This study reinforces the complexity of dental caries, suggesting that numerous loci, mostly having small effects, are involved in cariogenesis. Verification/replication of suggestive loci may highlight biological mechanisms and/or pathways leading to a fuller understanding of the genetic risks for dental caries.     

C-terminal region of activation-induced cytidine deaminase (AID) is required for efficient class switch recombination and gene conversion

Activation-induced cytidine deaminase (AID) introduces single-strand breaks (SSBs) to initiate class switch recombination (CSR), gene conversion (GC), and somatic hypermutation (SHM). CSR is mediated by double-strand breaks (DSBs) at donor and acceptor switch (S) regions, followed by pairing of DSB ends in two S regions and their joining. Because AID mutations at its C-terminal region drastically impair CSR but retain its DNA cleavage and SHM activity, the C-terminal region of AID likely is required for the recombination step after the DNA cleavage. To test this hypothesis, we analyzed the recombination junctions generated by AID C-terminal mutants and found that 0- to 3-bp microhomology junctions are relatively less abundant, possibly reflecting the defects of the classical nonhomologous end joining (C-NHEJ). Consistently, the accumulation of C-NHEJ factors such as Ku80 and XRCC4 was decreased at the cleaved S region. In contrast, an SSB-binding protein, poly (ADP)-ribose polymerase1, was recruited more abundantly, suggesting a defect in conversion from SSB to DSB. In addition, recruitment of critical DNA synapse factors such as 53BP1, DNA PKcs, and UNG at the S region was reduced during CSR. Furthermore, the chromosome conformation capture assay revealed that DNA synapse formation is impaired drastically in the AID C-terminal mutants. Interestingly, these mutants showed relative reduction in GC compared with SHM in chicken DT40 cells. Collectively, our data indicate that the C-terminal region of AID is required for efficient generation of DSB in CSR and GC and thus for the subsequent pairing of cleaved DNA ends during recombination in CSR.Activation-induced cytidine deaminase (AID) is essential for three different genetic events: class switch recombination (CSR), gene conversion (GC), and somatic hypermutation (SHM), which contribute to Ig gene diversification (1–5). Although AID generates single-strand breaks (SSBs) in the Ig genes, subsequent repair steps for CSR and GC are similar to each other but are distinct from SHM in their mechanistic properties, i.e, in (i) generation of the double-strand breaks (DSBs), (ii) recombination, and (iii) the requirement for uracil-DNA-glycosylase (UNG) for the pairing of the DSB ends (6–10). Despite the similarities between GC and CSR, their repair mechanisms have distinct features: CSR recombination requires nonhomologous end joining (NHEJ), and GC depends on homologous recombination (HR). During CSR, DSB ends normally are joined by classical NHEJ (C-NHEJ), which requires specific repair proteins such as Ku80, XRCC4, or DNA ligase IV (11, 12). In the absence of C-NHEJ, a back-up end-joining pathway called “alternative end joining” (A-EJ), which is reported to be slower and also more error prone than C-NHEJ, joins the broken DSBs ends (13). On the other hand, HR, the most common form of homology-directed repair, requires long sequence homology between donor and acceptor DNA to complete the recombination step by recruiting a distinct set of repair proteins such as RAD54, RAD52, and RAD51 to the break sites (14, 15).Various studies on AID mutations in the N-terminal or C-terminal regions (4, 8, 9, 16–19) have shown that N-terminal AID mutants are compromised for CSR and are defective in SHM, indicating that the N-terminal region of AID is required for DNA cleavage (9, 16, 19). On the other hand, the C-terminal region of AID, which contains a nuclear-export signal and is responsible for AID’s shuttling activity between the nucleus and cytoplasm, is required for CSR-specific activity but not for DNA cleavage activity and SHM (8, 16). Among the series of AID C-terminal mutants examined, two mutants show characteristic features: P20, which has an insertion of 34 amino acids at residue 182 and normal nuclear-cytoplasmic shuttling activity, and JP8Bdel, which has a 16-amino acid truncation at residue 183, accumulates in the nucleus, and shows higher DNA break activity at the donor switch (S) region (16, 17). Although several reports suggest that the C-terminal region of AID is involved in protein stability (20, 21), C-terminal mutants of AID stabilized by fusing the hormone-binding domain of estrogen receptor (ER) also show similar CSR-defective phenotypes (8). Taken together, these data suggest that the DNA cleavage activity and CSR-specific activity depend on different regions of AID (8, 19). In addition, the C-terminal region of AID is essential for the interaction of AID with poly (A)⁺ RNA via a specific cofactor (22). Because CSR requires de novo protein synthesis, we proposed that after DNA cleavage the C-terminal region of AID may be involved in the regulation of the recombination step through generation of a new protein (8, 16, 22).DSBs induced by AID during CSR ultimately are joined by the efficient DNA repair pathway that requires C-NHEJ factors such as Ku70/80 (12, 23). However, in the absence of C-NHEJ, the A-EJ pathway that relies on microhomology can join the broken DNA ends, although this pathway is associated with chromosomal translocations (11, 24). Previously, we reported that JP8Bdel enhances aberrant c-myc/IgH translocations and that it fails to carry out the efficient recombination between donor and acceptor S regions in the IgH locus (8). Therefore, it is important to examine whether the AID C-terminal mutants affect the S–S joining in CSR.In the current work we examined whether the C-terminal region of AID is involved in DNA synapse formation and recombination during CSR in CH12F3-2 and spleen B cells. We also examined the effect of AID C-terminal mutations on GC in chicken DT40 cells, which depends on HR between pseudo V genes and the downstream IgVλ region. Using these CSR- and GC-monitoring systems, we demonstrate that efficient CSR and GC require the C-terminal region of AID for the formation of DSB from SSB and subsequent end synapse. Considering these findings together, we conclude that, in addition to DNA cleavage, AID has a unique function in the generation of DSBs, which is required for S–S synapse formation and joining in CSR and recombination in GC.     

Evaluation of Vertical Bone Gain Following Alveolar Distraction Osteogenesis in the Anterior Edentulous Mandible: A Clinical Study

Aim and Objectives

To calculate the gain in bony height and volume of the distracted upper segment using an extraosseous unidirectional device to improve the retention of the future prosthesis.

Materials and Methods

Ten cases with completely or partially edentulous but severely or considerably resorbed anterior mandibles were managed by vertical alveolar distraction osteogenesis. All the patients were evaluated preoperatively, intraoperatively and post-operatively for various parameters clinically and radiographically i.e. on OPG, lateral cephalogram and on CT scan, at different time intervals. In all cases there was increase in vertical bone height.

Results

The study showed mean vertical bone gain (VBG) on OPG as 8.2 mm. The mean VBG on lateral cephalogram was 8.1 mm. The mean VBG on CT scan at right canine was 8.35 mm, at left canine was 8.2 mm and at midline was 8.27 mm.

Conclusion

Alveolar distraction osteogenesis is a predictable method for restoring alveolar ridges prior to implant placement or prosthesis. Distraction osteogenesis is ideally suited for recreating missing tissue in the anterior esthetic zone by increasing vertical bone height as well as good width and soft tissue growth.     

Physicochemical aspects of inorganic nanoparticles stabilized in N-vinyl caprolactam based microgels for various applications

The vinyl caprolactam (VCL) based microgel system has become the center of great attention due to its versatile properties. Copolymerization of VCL with an ionic monomer imparts pH responsive properties into the microgel system in addition to thermo-sensitivity. Stimuli responsive behavior of VCL-based microgels makes them prospective and appealing candidates for practical applications covering the fields of drug delivery, catalysis and optical devices. In the last few years, VCL-based microgels have been used as microreactors and stabilizers for the synthesis and stabilization of inorganic nanoparticles to obtain hybrid microgels. The present review article provides a summary of the present-day progress of fabrication, stabilization, categorization and analysis of VCL-based microgels and their hybrids with different morphologies. The stimuli responsive properties and applications of VCL-based hybrid microgels have been reviewed critically. The remaining problems which need to be addressed have been pointed out for further advancement in this field.

The present review provides recent research progress of fabrication, stabilization, characterization and applications of N-vinyl caprolactam based microgels loaded with inorganic nanoparticles.     

Corneal confocal microscopy for the diagnosis of diabetic autonomic neuropathy

Introduction: A case series of acute intermittent porphyria (AIP) is described that focuses on the clinical course of the disease with regard to neurological manifestations of the peripheral nervous system. Methods: Eight patients were diagnosed with AIP on the basis of characteristic clinical findings, erythrocyte porphobilinogendeaminase activity, neuropathic patterns, serial changes in nerve conduction studies (NCS), and temporal relationship of central nervous system involvement. Results: Six patients diagnosed with AIP <2 months after symptom onset had neuropathy that was predominantly upper extremity, motor, and proximal. NCS recovery rates were slower in the lower than the upper limbs. Two patients diagnosed >2 months after symptom onset had distal sensorimotor polyneuropathy. Conclusions: The findings from this case series suggest that the peripheral nerves may be differentially and selectively involved in different diagnostic stages of porphyric neuropathy. Muscle Nerve 51 : 363–369, 2015