Whole-exome sequencing reveals genetic variants associated with chronic kidney disease characterized by tubulointerstitial damages in North Central Region,Sri Lanka

Objectives

The familial clustering observed in chronic kidney disease of uncertain etiology (CKDu) characterized by tubulointerstitial damages in the North Central Region of Sri Lanka strongly suggests the involvement of genetic factors in its pathogenesis. The objective of the present study is to use whole-exome sequencing to identify the genetic variants associated with CKDu.

Methods

Whole-exome sequencing of eight CKDu cases and eight controls was performed, followed by direct sequencing of candidate loci in 301 CKDu cases and 276 controls.

Results

Association study revealed rs34970857 (c.658G > A/p.V220M) located in the KCNA10 gene encoding a voltage-gated K channel as the most promising SNP with the highest odds ratio of 1.74. Four rare variants were identified in gene encoding Laminin beta2 (LAMB2) which is known to cause congenital nephrotic syndrome. Three out of four variants in LAMB2 were novel variants found exclusively in cases.

Conclusion

Genetic investigations provide strong evidence on the presence of genetic susceptibility for CKDu. Possibility of presence of several rare variants associated with CKDu in this population is also suggested.     

Exploring lignification in conifers by silencing hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyltransferase in Pinus radiata

The enzyme hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyltransferase (HCT) is involved in the production of methoxylated monolignols that are precursors to guaiacyl and syringyl lignin in angiosperm species. We identified and cloned a putative HCT gene from Pinus radiata, a coniferous gymnosperm that does not produce syringyl lignin. This gene was up-regulated during tracheary element (TE) formation in P. radiata cell cultures and showed 72.6% identity to the amino acid sequence of the Nicotiana tabacum HCT isolated earlier. RNAi-mediated silencing of the putative HCT gene had a strong impact on lignin content, monolignol composition, and interunit linkage distribution. AcBr assays revealed an up to 42% reduction in lignin content in TEs. Pyrolysis-GC/MS, thioacidolysis, and NMR detected substantial changes in lignin composition. Most notable was the rise of p-hydroxyphenyl units released by thioacidolysis, which increased from trace amounts in WT controls to up to 31% in transgenics. Two-dimensional 13C-1H correlative NMR confirmed the increase in p-hydroxyphenyl units in the transgenics and revealed structural differences, including an increase in resinols, a reduction in dibenzodioxocins, and the presence of glycerol end groups. The observed modifications in silenced transgenics validate the targeted gene as being associated with lignin biosynthesis in P. radiata and thus likely to encode HCT. This enzyme therefore represents the metabolic entry point leading to the biosynthesis of methoxylated phenylpropanoids in angiosperm species and coniferous gymnosperms such as P. radiata.     

Vascular type of Ehlers-Danlos syndrome in a patient with ruptured aneurysm of the splenic artery

A 39-year-old woman presented with a ruptured aneurysm of the splenic artery. The postoperative course was complicated by poor wound healing. This, in combination with a history of easy bruising and joint hypermobility, made us consider a connective tissue disease as underlying cause. The vascular type of Ehlers-Danlos syndrome was diagnosed by identifying collagen III deficiency and the corresponding gene mutation in cultured fibroblasts from a skin biopsy.     

Rectal tuberculosis: A rare cause of recurrent rectal suppuration

Tuberculosis affecting the rectum is a rare extra‐pulmonary form of the disease that needs recognition, because it requires specific treatment and avoids multiple, unwarranted surgical interventions. The following discussion is centred on a case of rectal tuberculosis, a disease that rarely affects the anorectal region. The condition was diagnosed on histology and was successfully treated medically with complete resolution.     

N-Methyl-4-hydroxy-2-pyridinone analogues from Fusarium oxysporum

Three new N-methyl-4-hydroxy-2-pyridinone analogues, 6-epi-oxysporidinone (3), the dimethyl ketal of oxysporidinone (4), and N-demethylsambutoxin (5), along with the known compounds (-)-oxysporidinone (1), (-)-sambutoxin (2), wortmannin (6), enniatin A (7), enniatin A1 (8), and enniatin B1 (9) were isolated from Fusarium oxysporum (N17B) by bioassay-guided fractionation. Compounds 1 and 3 showed selective fungistatic activity against Aspergillus fumigatus, and wortmannin had selective potent activity against Candida albicans. Moderate activity was observed with the enniatins 7-9 against C. albicans, Cryptococcus neoformans, and Mycobacterium intracellulare. Compounds 1-5 had no activity against the agriculturally important fungi Fusarium verticillioides (syn. F. moniliforme) and Aspergillus flavus.     

Observations on gastro-oesophageal reflux,central apnoea and heart rate in infants

Respiratory movements and heart rate were monitored continuously during the course of 2 h radionuclide studies to detect gastro-oesophageal reflux (GOR) in 22 infants following a milk feed. Twenty infants had GOR, to upper oesophageal/pharyngeal level in 19, and 17 had central apnoea between 3 and 15s. Prolonged central apnoea (greater than 20s) was not observed. Bradycardia, defined as a heart rate less than 80 beats/min for 10s or more, was observed in only 1 infant who did not have GOR. No correlation was found between the number or duration of reflux episodes and the frequency of respiratory pauses between 3 and 17s. When data from individual infants were examined a possible temporal relation between the occurrence of GOR and central apnoea was seen in only two infants; in each case, detailed examination suggested that apnoea was more closely associated with sleep than with GOR. Although the respiratory monitoring system did not include airflow sensors, the almost complete absence of bradycardia suggested that prolonged obstructive apnoeas did not occur. We conclude that any relation between GOR and central apnoeas less than 15 s is not of a direct cause/effect nature.     

Tracheomalacia-Lethal Factor in a 17-month-Old Child

A case is reported of a child who died at age 17 months after having repeated respiratory incidents, probably related to mild infections. After a fatal respiratory episode, tracheomalacia was detected at necropsy. No other abnormalities were found. This condition, unless suspected clinically, could easily be overlooked at necropsy.     

Safety considerations in laparoscopic surgery: A narrative review

Laparoscopic surgery has many advantages over open surgery. At the same time, it is not without its risks. In this review, we discuss steps that could enhance the safety of laparoscopic surgery. Some of the important safety considerations are ruling out pregnancy in women of the childbearing age group; advanced discussion with the patient regarding unexpected intraoperative situations, and ensuring appropriate equipment is available. Important perioperative safety considerations include thromboprophylaxis; antibiotic prophylaxis; patient allergies; proper positioning of the patient, stack, and monitor(s); patient appropriate pneumoperitoneum; ergonomic port placement; use of lowest possible intra-abdominal pressure; use of additional five-millimetre (mm) ports as needed; safe use of energy devices and laparoscopic staplers; low threshold for a second opinion; backing out if unsafe to proceed; avoiding hand-over in the middle of the procedure; ensuring all planned procedures have been performed; inclusion of laparoscopic retrieval bags and specimens in the operating count; avoiding 10-15 mm ports for placement of drains; appropriate port closures; and use of long-acting local anaesthetic agents for analgesia. Important postoperative considerations include adequate analgesia; early ambulation; careful attention to early warning scores; and appropriate discharge advice.