Kidney Proximal Tubular Epithelial-Specific Overexpression of Netrin-1 Suppresses Inflammation and Albuminuria through Suppression of COX-2-Mediated PGE2 Production in Streptozotocin-Induced Diabetic Mice

Inflammation plays a key role in the development and progression of diabetic kidney disease; however, the role of the anti-inflammatory molecule netrin-1 in diabetic kidney disease is unknown. We examined the role of netrin-1 in diabetes-induced kidney inflammation and injury using tubule-specific netrin-1 transgenic mice. Diabetes was induced using streptozotocin in wild-type and netrin-1 transgenic animals. Kidney function, fibrosis, glucose excretion, albuminuria, and inflammation were evaluated. The mechanism of netrin-1-induced suppression of inflammation was studied in vitro using a proximal tubular epithelial cell line. Diabetes was associated with increased infiltration of neutrophils and macrophages, chemokine expression, and tubular epithelial cell apoptosis in kidney. These changes were minimal in kidney of netrin-1 transgenic mice. In addition, diabetes induced a large increase in the excretion of prostaglandin E2 (PGE2) in urine, which was suppressed in netrin-1 transgenic mice. Netrin-1-induced suppression of PGE2 production was mediated through suppression of NFκB-mediated cyclooxygenase-2 (COX-2) in renal tubular epithelial cells. Furthermore, netrin-1 also increased albumin uptake by proximal tubular epithelial cells through the PI3K and ERK pathways without increasing glucose uptake. These findings suggest that netrin-1 is a major regulator of inflammation and apoptosis in diabetic nephropathy and may be a useful therapeutic molecule for treating chronic kidney diseases such as diabetic nephropathy.Diabetic nephropathy is the largest single cause of end-stage renal failure worldwide.¹ Despite the available modern therapies of glycemic and blood pressure control for diabetes, many patients continue to experience progressive renal damage.^2,3 It is extremely important, therefore, to identify novel interventions for halting the progression of diabetic nephropathy. Diabetic nephropathy has traditionally been considered a nonimmune disease; however, an increased presence of glomerular and interstitial immune cell infiltrates and increased expression of inflammatory cytokines in diabetic kidney have been reported in both human biopsies and animal models.^4–7 Moreover, recent studies suggest that diabetic nephropathy is also a tubular disease, and that early changes in tubular epithelial cells may be a critical factor in development of progressive kidney diseases.^8–12 Inflammation from tubular epithelial cells can damage other areas of the kidney, including the vasculature and glomerular mesangial cells, via inflammatory mediators such as prostanoid metabolites, cytokines, and chemokines. These mediators will induce hyperfiltration, matrix expansion, apoptosis, and vasodilation, and further increase the production of their own and other mediators of cell injury. Suppression of local inflammation in the tubular epithelium may therefore provide a more effective prevention strategy against the development of diabetic nephropathy, compared with treatments such as glycemic and blood pressure control. Recent studies from our laboratory have shown that netrin-1 effectively suppresses inflammation in an acute model of kidney disease. However, the role of netrin-1 in chronic kidney diseases is unknown. Moreover, the mechanisms as to how netrin-1 suppresses inflammation are unknown.Netrin-1 is a laminin-related secreted molecule that has been identified as a neuronal guidance cue, directing neurons and their axons to targets during development of the nervous system. However, guidance is unlikely to be the only function of netrin-1, netrins are widely expressed outside the nervous system, including in vascular endothelial^13,14 and kidney tubular epithelial cells. Vascular endothelial cells form a critical barrier for leukocyte migration into organs by producing repellent factors to leukocytes, such as netrin-1. Down-regulation of netrin-1 during organ injury is reported to exacerbate inflammation.^13,14 We have reported that administration or overexpression of netrin-1 protects the kidney against ischemia-reperfusion injury.¹³ However, nothing was known about the involvement of netrin-1 in diabetic nephropathy, warranting further investigation. The purpose of the present study was to determine the effect of tubular-specific overexpression of netrin-1 on diabetes-induced inflammation and nephropathy in mice.     

Keeping with the beat: movement trajectories contribute to movement timing

Previous studies of paced repetitive movements with respect to an external beat have either emphasised (a) the form of movement trajectories or (b) timing errors made with respect to the external beat. The question of what kinds of movement trajectories assist timing accuracy has not previously been addressed. In an experiment involving synchronisation or syncopation with an external auditory metronome we show that the nervous system produces trajectories that are asymmetric with respect to time and velocity in the out and return phases of the repeating movement cycle. This asymmetry is task specific and is independent of motor implementation details (finger flexion vs. extension). Additionally, we found that timed trajectories are less smooth (higher mean squared jerk) than unpaced ones. The degree of asymmetry in the flexion and extension movement times is positively correlated with timing accuracy. Negative correlations were observed between synchronisation timing error and the movement time of the ensuing return phase, suggesting that late arrival of the finger is compensated by a shorter return phase and conversely for early arrival. We suggest that movement asymmetry in repetitive timing tasks helps satisfy requirements of precision and accuracy relative to a target event.     

The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms

The recently isolated gene for neuroflbromatosls type 2 (NF2)encodes a 595 amlno acid protein, named merlin, which Is relatedto the cytoskeleton-assoclated proteins moesln, ezrin and radlxin.To Identify evolutionarily conserved regions and to providesequence Information necessary for the establishment of a mousemodel for NF2, we have determined the cDNA sequence of the mouseNF2 tumor suppressor gene, and mapped It In the mouse genome.Mouse merlin is a 596 amino acid protein, 98% identical to humanmerlin, but one amlno acid longer due to the Insertion of aproline residue near the C-terminus. Of the nine amlno aciddifferences between mouse and humans, seven occur in the C-termlnal20% of the protein, far from the protein 4. 1 domain that definesthis family. Two of the NF2 cDNA clones reveal evidence of alternativesplicing events that alter the predicted merlin product, oneremoving a 45 amlno acid segment from the middle section ofthe protein and the other changing the C-terminus. The existenceof several different forms of merlin potentially with differentprimary roles will complicate the Identification of the precisefunction that must be disrupted to cause the NF2-assoclatedtumors. The mouse NF2 homologue maps to Chr 11, in a regionhomologous to human Chr 22, but devoid of any mouse mutationswhich could be models of the human disorder.     

Delayed presentation of intraperitoneal bladder rupture following domestic violence in pregnancy

Trauma during pregnancy can present a unique challenge because of care for the mother and the fetus. About 6-7% of all pregnant patients are exposed to some sort of trauma, especially during the third trimester, with 0.3-0.4% requiring hospitalization. Although mostly accidental, injuries are sometimes caused by intentional violence. There is no published report on bladder rupture following trauma in pregnancy. We report a case of bladder injury following abdominal trauma in a pregnant woman.     

Emerging trends of Nipah virus: A review

Since emergence of the Nipah virus (NiV) in 1998 from Malaysia, the NiV virus has reappeared on different occasions causing severe infections in human population associated with high rate of mortality. NiV has been placed along with Hendra virus in genus Henipavirus of family Paramyxoviridae. Fruit bats (Genus Pteropus) are known to be natural host and reservoir of NiV. During the outbreaks from Malaysia and Singapore, the roles of pigs as intermediate host were confirmed. The infection transmitted from bats to pigs and subsequently from pigs to humans. Severe encephalitis was reported in NiV infection often associated with neurological disorders. First NiV outbreak in India occurred in Siliguri district of West Bengal in 2001, where direct transmission of the NiV virus from bats‐to‐human and human‐to‐human was reported in contrast to the role of pigs in the Malaysian NiV outbreak. Regular NiV outbreaks have been reported from Bangladesh since 2001 to 2015. The latest outbreak of NiV has been recorded in May, 2018 from Kerala, India which resulted in the death of 17 individuals. Due to lack of vaccines and effective antivirals, Nipah encephalitis poses a great threat to public health. Routine surveillance studies in the infected areas can be useful in detecting early signs of infection and help in containment of these outbreaks.     

Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.      

Non traumatic coma

Objective: To study the etiology and clinical profile of non-traumatic coma in children and to determine the clinical signs predictive of outcome.Methods: 100 consecutive cases of nontraumatic coma between 2 months to 12 years. Clinical signs studied were temperature, pulse, heart rate, blood pressure, coma severity by Glasgow coma scale (GCS), respiratory pattern, pupillary and corneal reflex, extra ocular movements, motor patterns, seizure types and fundus picture. These were recoded at admission and after 48 hours of hospital stay. Etiology of coma was determined on basis of clinical history, examination and relevant laboratory investigations by the treating physician. The outcome was recorded as survived or died, and among those who survived as normal, mild, moderate, or severe disability. Chi-square test and logistic regression analysis were done to determine predictors of outcome.Results: Etiology of coma in 60% cases was CNS infection (tubercular meningitis19, encephalitis18, bacterial meningitis16, others7); other causes were toxic-metabolic conditions (19%), status epilepticus (10%), intracranial bleed (7%), and miscellaneous (4%). 65 children survived, 11 were normal, 14 had mild disability, 21 had moderate disability and 14 were severely disabled and dependent. Survival was significantly better in patients with CNS infection (63%) as compared to those with toxic-metabolic causes (27%) and intracranial bleed (43%, P < 0.05). On bivariate analysis age <-3 years, poor pulse volume, abnormal respiratory pattern and apnoea, abnormal pupillary size and reaction, abnormal extra ocular movements, absent corneal reflex, abnormal motor muscle tone at admission or 48 hours correlated significantly with mortality. Survival was better with increasing GCS (Spearman rho =. 32, P < 0.001). On logistic regression age < 3 years, poor pulse volume, absent extraocular movements and papilloedema at admission and 48 hours after admission were independent significant predictors of death.Conclusion: CNS infections were the most common cause of non-traumatic coma in childhood. Simple clinical signs were good predictors of outcome     

Predictive value of electroencephalography and computed tomography in childhood non-traumatic coma

Objectives: To study value of electroencephalogram (EEG) and computed tomography (CT Scan) in predicting outcome of non-traumatic coma in children.Methods: 100 consecutive children, between 2 months to 12 years, with nontraumatic coma, (Glasgow Coma Scale score <-8). Demographic and clinical data was recorded at admission. EEG and CT scan were done within 24 hours of admission. Etiologic diagnosis was assigned on basis of clinical data and relevant laboratory investigations. The outcome was recorded as survived and died. Among survivors it was graded as no disability, or mild, moderate, or severe disability. Odds ratio and/or relative risk (RR) with 95% confidence interval (CI) were calculated.Results: EEG could be done in 60 patients (43 survived; 7 were normal, 8 had mild, 17 moderate and 11 severe disability) CT scan in 93 patients (60 survived; 11 were normal, 14 had mild, 21 moderate and 14 severe disability). A normal/borderline EEG was associated with good outcome (P = 0.001); 11 of 12 survived and of survivors 55% had no or mild disability. Electrocerebral silence on EEG was a predictor of death (OR = 44; 95% CI -1.5-7372; P =0.01). An abnormal EEG was associated with significant increase in risk of disability among survivors (RR=2.6, 95% CI= 1.2–5.4, P=0.03). Among CT abnormalities intracranial bleed suggested increased risk of death (RR = 2.1; 95% CI-0.8-5.3; P = 0.058), while, hydrocephalus was associated with better survival (RR = 0.7; 95% CI-0.5 to 0.96; P = 0.029). However, hydrocephalus when compared with other abnormal CT scan findings, was associated with higher risk of moderate and severe disability among survivors (P= 0.046)Conclusion: A normal CT scan and EEG, and some of the specific findings could be helpful in predicting outcome in children with non-traumatic coma. EEG and CT scan should be done at admission in all patients with non-traumatic coma if feasible     

Laser Treatment of a Tracheal Inflammatory Myofibroblastic Tumor

Background

Inflammatory myofibroblastic tumors of the trachea are rare childhood quasi-neoplastic lesions.

Case characteristics

7-year-old boy with recurrent episodes of cough, breathing difficulty and wheeze, initially treated as asthma.

Intervention

CT chest and flexible bronchoscopy revealed a mass lesion of the trachea, which was excised by diode laser through the ventilating bronchoscope. Histopathology confirmed it as the inflammatory myofibroblastic tumor.

Message

Use of laser ensured complete endotracheal excision of the tumor.