Adrenocortical suppression increases the risk of relapse in nephrotic syndrome

Objective

Children with nephrotic syndrome (NS) are usually treated with long‐term low dose alternate day prednisolone with or without glucocorticoid sparing therapy, such as levamisole or ciclosporin, to maintain remission. The degree of hypothalamic‐pituitary‐adrenal axis (HPA) suppression with such therapeutic strategies has not been studied systematically. HPA suppression could cause a relapse or adrenal crisis.

Study design

To study the risks of HPA suppression, a modified low dose synacthen test (0.5 μg) was administered to 32 patients (22 male,10 female) with a mean age of 9.7 years (range 3.8–17.6 years) with NS receiving long‐term alternate day prednisolone for over 12 months. Twelve patients received alternate day prednisolone, 11 alternate prednisolone+levamisole and nine alternate prednisolone+ciclosporin. All patients were followed up for 3 years and the relapse rate noted.

Results

20/32 (62.5%) patients had a peak serum cortisol concentration of <500 nmol/l, which suggested suboptimal cortisol secretion and possible HPA suppression. 10/12 children in the prednisolone group and 8/11 in the levamisole group had a suboptimal cortisol response compared with 2/9 in the ciclosporin group. During follow‐up, the 20 children who had a suboptimal cortisol response had significantly more relapses (95 relapses) compared to the 12 children with a normal cortisol response who had 24 relapses (p = 0.01).

Conclusions

Children with NS receiving long‐term alternate day prednisolone therapy are at risk of developing HPA suppression and should be evaluated using the modified synacthen test. Children with evidence of HPA suppression are at a greater risk of relapse.     

Small junction,big problems: Neuromuscular junction pathology in mouse models of amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with an extremely heterogeneous clinical and genetic phenotype. In our efforts to find therapies for ALS, the scientific community has developed a plethora of mouse models, each with their own benefits and drawbacks. The peripheral nervous system, specifically the neuromuscular junction (NMJ), is known to be affected in ALS patients and shows marked dysfunction across mouse models. Evidence of pathology at the NMJ includes denervated NMJs, changes in endplate size and loss of terminal Schwann cells. This review compares the temporal disease progression with severity of disease at the NMJ in mouse models with the most commonly mutated genes in ALS patients (SOD1, C9ORF72, TARDBP and FUS). Despite variability, early NMJ dysfunction seems to be a common factor in models with SOD1, TARDBP and FUS mutations, while C9ORF72 models do not appear to follow the same pattern of pathology. Further work into determining the timing of NMJ pathology, particularly in newer ALS mouse models, will confirm its pivotal role in ALS pathogenesis and therefore highlight the NMJ as a potential therapeutic target.     

Novel thiazole derivatives incorporating phenyl sulphonyl moiety as potent BRAFV600E kinase inhibitors targeting melanoma

Novel thiazole derivatives possessing phenyl sulfonyl moiety were designed and synthesized as B-RAFV600E kinase inhibitors based on the clinically-approved anticancer drug, dabrafenib. All target compounds showed significant inhibition of B-RAFV600E kinase enzyme at nanomolar levels. Compounds 7b and 13a revealed excellent B-RAFV600E inhibitory activity, superior to that of dabrafenib with IC₅₀ values of 36.3 ± 1.9, 23.1 ± 1.2, and 47.2 ± 2.5 nM, respectively. Moreover, the title compounds were much more selective toward B-RAFV600E kinase than B-RAF wild type. In addition, the most potent compounds were further evaluated for their anticancer activity against B-RAFV600E-mutated and wild type melanoma cells. A positive correlation between the cytotoxic activity and selectivity for B-RAF V600E over B-RAF wild type was clearly observed for compounds 7b, 11c, 13a, and 17. All the screened compounds potently inhibited the growth of WM266.4 melanoma cells with IC₅₀ values in the range from 1.24 to 17.1 μM relative to dabrafenib (IC₅₀ = 16.5 ± 0.91 μM). Compounds 7b, 11a and 11c, 13a, and 17 were much more potent than dabrafenib against B-RAFV600E-mutated WM266.4 melanoma cells. Furthermore, compound 7b suppressed the phosphorylation of downstream ERK1/2 from WM266.4 cells. Also, the docking study revealed the proper orientation and well-fitting of the title compounds into the ATP binding site of B-RAFV600E kinase.

Thiazole derivatives 7b and 13a were superior to dabrafenib against B-RAFV600E kinase and potently inhibited the growth of WM266.4 melanoma cells. Compound 7b suppressed the phosphorylation of downstream ERK1/2 from WM266.4 cells.     

Genotypic distribution of human papillomavirus and phylogenetic analysis of E6 and E7 gene of HR-HPV variants isolated from Pakistani population

High-risk-human papillomavirus (HR-HPV)-induced cervical cancer is the second most common cause of death among females worldwide. HPV16 is the most prevalent HR-HPV infection worldwide. This study found the genotypic distribution of HR-HPV in the local population and investigated the sequence variations among the E6 and E7 oncogenes of the local HPV16 genotype to the E6 and E7 oncogenes of the foreign HPV16 genotypes and constructed a phylogenetic relationship based on nucleotide sequence comparison among the variants identified in our study along with previously reported isolates that were obtained from different regions of the world. The samples were collected from patients with cervical cancer. Genomic DNA was extracted, and HR-HPV genotypes were determined using real-time PCR. The HPV16 E6 and E7 genes were amplified and sequenced. A HPV16 phylogenetic tree was constructed using the maximum likelihood method with MEGA 7. HPV16 was the most prevalent human papillomavirus (HPV) type identified in the present study. HPV16 isolates belonged to the A1 sublineage of the European branch. Twenty-one nucleotide sequences were included in this analysis. The first, second, and third codon positions are also included. The final dataset included 776 positions.     

A -mode ultrasonography in maxillary sinusitis

Fifty cases of either sex (30 males and 20 females) of chronic hypertrophic maxillary sinusitis were studied during a period of eight months in E.N.T. Out-patients clinic of J. N. Medical College, Aligarh Muslim University, Aligarh. The cases were analysed on the basis of subjective symptoms, objective signs transillumination test. Ultrasonography conventional X-ray of maxillary antrum, routine haematological and urine examination. Diagnostic antrum puncture was invariably done in all the cases subjected to ultrasonographic evaluation. The results of ultrasonography, conventional X-ray (Occipitomental view), and proof puncture were analysed. It has been found that ultrasonography plays an important role in therapeutic decision without performing the diagnostic puncture.     

Esophageal foreign bodies

In a review of 40 children with esophageal foreign bodies, between 1983 and 1986, 25(62.5%) were males and 15(37.5%) females, of them 34 (85%) were below five years of age. Inorganic material was the causative agent in 39(97.5%). Coins being the commonest present in 34 (85%) patients. A history of foreign body ingestion was obtained in all the patients. Radioopaque foreign bodies were seen in 39 (97.5%). All patients had their foreign body removed 38(95%) endoscopically and 2(5%) by esophagotomy. There was no mortality in this study.