Safety and Efficacy of Ureteroscopic Laser Lithotripsy in the Management of Ureteric Calculi in Pregnancy-Experience of a Tertiary Care Center.

Introduction: Ureteric colic in pregnancy is one of the common non-obstetric reasons for emergency department visits. Ureteric calculi present a significant threat to maternal and fetal health and definitive management often becomes necessary. Our aim is to assess the safety and efficacy of ureteroscopic laser lithotripsy in the management of ureteric stones in pregnancy. Material and methods: This is a prospective observational study of 3 years carried at a tertiary referral center. It includes all pregnant patients who underwent ureteroscopic laser lithotripsy for ureteric stones. Results: A total of 29 pregnant patients underwent ureteroscopic laser lithotripsy at our center in 3 years. The mean age of patients was 33.5 ± 6.2 years, and the mean gestation age at the time of ureteroscopy was 23.34 ± 5.9 weeks. The average stone size was 8.3 ± 3.6 mm and was predominantly found in upper ureter (62%). The mean operative time was 31 ± 8.9 min, and the average laser energy spent was 4.3 ± 1.1 kJ/case. There was no major Intraoperative complication, and the average hospital stay was 2.5 ± 1.5 days. Complete stone clearance was achieved in 93.1% of cases. Conclusion: Ureteroscopic laser lithotripsy is safe and effective treatment of ureteric stones in terms of obstetric outcome and stone clearance in pregnancy.

Photoinduced metal-free trifluoro/perfluoroalkylation of heteroarenes.

A practical and straightforward protocol to access trifluoromethylated/perfluoroalkylated heteroarenes via radical-type nucleophilic substitution rather than typical radical-type electrophilic substitution is described here. The substrate scope was observed to be broad and diverse-covering arenes, heteroarenes (containing N, O, S), bioactive cores, and allylic cores. Mechanistic studies confirmed a radical-mediated reaction pathway.

Biodiversity and Bioactive Potential of Actinomycetes from Unexplored High Altitude Regions of Kargil, India.

The effectiveness of currently available antimicrobials and anticancer medications is steadily declining due to the emergence of drug resistance. Since actinobacteria are important producers of bioactive substances, we have isolated them from the soil samples of exotic North-Western Himalayan terrains. Out of 128 isolates, 39 strains were prioritized based on their bioactive potential. The diversity analysis revealed higher abundance distribution of actinomycetes in the soil of an open field (68.7%), followed by the mountainside (34.9%), from which most of the bioactive strains were obtained. The extract of the strain S26-11 was found to be highly active against Gram-positive Staphylococcus aureus and Bacillus subtilis with a MIC of 0.5 µg/mL and 1 µg/mL respectively. A cytotoxicity assay (sulforhodamine B) was performed on a series of cancer cell lines (PC-3, MCF-7, A-549, and HCT-116). The extract of the strain S26-11 showed cytotoxic activity against all cancer cell lines with an IC50 of 2 µg/mL against PC-3, 1.9 µg/mL against MCF-7, 0.52 µg/mL against A-549, and 0.83 µg/mL against HCT-116. Moreover, the antioxidant activity was assessed using a DPPH-based assay and the results revealed that the S17-8 isolate showed the highest antioxidant activity with IC50 of 114.136 µg/mL. The Response Surface Methodology (RSM) had helped to optimize the physical parameters for scaling up of the bioactive strain S26-11. The unexplored soil niches of Kargil (UT, Ladakh), India, is rich in actinomycetes which are having potential bioactivities, would be worth to explore for the discovery of bioactive compounds. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01133-1.

Mini-PCNL - a boon for CKD patients with nephrolithiasis.

Purpose: The prevalence of urinary stone disease in ESRD is 3.2%, leading to renal damage due to obstructive uropathy, infection, and frequent surgical intervention. PCNL, the gold standard for complex renal stone disease, has evolved with smaller access sheaths (14-20 F), improved optics, and fluoroscopic equipments. This study aims to assess the safety and feasibility of mini- PCNL in CKD patients with respect to postoperative outcome and its effect on stage of CKD. Patients and methods: This prospective study was conducted in the Department of Urology, Sher-I-Kashmir Institute of Medical Sciences, from January 2022 to October 2022. This study included adult patients with nephrolithiasis at CKD stage 3 or higher. The primary objective of this research was to assess the impact of mini-PCNL on renal function, specifically measuring changes in estimated glomerular filtration rate (eGFR) from baseline to a 6-month follow-up. The secondary objective was to evaluate the feasibility of mini-PCNL in CKD patients in terms of complications, stone clearance rate, and duration of hospital stay. Four variable Modification of Diet in Renal Diseases(MDRD) equation was used to calculate the estimated GFR(eGFR) of each patient and NKF/KDOQI classification system to classify the stage of CKD. Results: A total of 46 patients were included in the study. We found that for management of nephrolithiasis in CKD patients, mini-PCNL leads to significant improvement in eGFR at 6 months follow-up (mean difference = 14.25 ml/min/1.73 m2; p-value <0.01) with high stone-free rates (89.5%). The complication rates were comparable to standard PCNL. Conclusions: mini-PCNL is a bonanza for management of CKD patients with nephrolithiasis.

Correction to 1,2,3-Triazole Tethered Hybrid Capsaicinoids as Antiproliferative Agents Active against Lung Cancer Cells (A549).

[This corrects the article DOI: 10.1021/acsomega.2c03325.].

Efficacy and Rationale of Endoscopic Ultrasound-Guided Thrombin Injection in Visceral Artery Pseudoaneurysm Not Amenable to Angioembolization.

BACKGROUND: Pseudoaneurysm usually occurs after vascular injuries or erosions such as in trauma or inflammation like pancreatitis and is associated with high morbidity and mortality. AIM: The aim of study is to assess efficacy and safety of EUS-guided thrombin injection in pseudoaneurysm. MATERIALS AND METHODS: Prospective data collection was done at SMS Hospital, Jaipur, from January 2015 to March 2023. All patients with pseudoaneurysm were consecutively enrolled. RESULTS: Twenty patients (M/F, 18:2) with median age of 41 years (25-58 years), were studied. Underlying etiology of pseudoaneurysm was chronic pancreatitis in 75% of the patients, blunt trauma abdomen in 15% of the patients, recurrent acute pancreatitis in 5%, and idiopathic in 5% of the patients. At the time of admission, mean hemoglobin was 6.7 g/dL (3.4-8.2), with median blood transfusion requirement was 2 units (0-6 units). Hemoglobin values after 4-6 weeks showed a significant improvement ( t = 9.21, P < 0.05).Mean dose of human thrombin required for complete obliteration of pseudoaneurysm was 520 ± 188.6 IU per patient (300-800 IU). Amount of thrombin (IU) dose needed to achieve complete obliteration correlated well significantly with the dimension of pseudoaneurysm, P value less than 0.05 ( R = 0.80). Median follow-up duration in this study was 44 months (3-84 months), which was the longest follow-up period by far. CONCLUSIONS: Endoscopic ultrasound-guided thrombin injection in visceral artery pseudoaneurysm is a safe and effective alternative for patients not amenable for digital subtraction angiography-guided angioembolization.

Therapeutic Potential of HMF and Its Derivatives: a Computational Study.

Over the past century, chemicals and energy have increasingly been derived from non-renewable resources. The growing demand for essential chemicals and shrinking inventory make reliable, sustainable sources essential. Carbohydrates offer by far the greatest carbon supply. Furan compounds, a particular family of dehydration products, are believed to offer high chemical potential. Here, we analyze 5-HMF (5, hydroxymethylfurfural) and some of its derivatives in particular, a furan-type platform chemical. To analyze the therapeutic potential of HMF and its derivatives, this study utilized cutting-edge technologies such as computer-aided drug design, virtual screening, molecular docking, and molecular dynamic simulation. We conducted 189 docking simulations and examined some of the most promising dock poses using the molecular dynamic simulator. As for the receptors for our compounds, the leading candidates are human acetylcholinesterase, beta-lactamases, P. aeruginosa LasR, and S. aureus tyrosyl-tRNA synthetases. Out of all derivatives considered in this study, 2,5-furandicarboxylic acid (FCA) performed best.

Raloxifene, a SERM targets PD-L1: an in-silico study.

OBJECTIVES: Immunotherapeutic interventions in cancer have been considerably successful and widely accepted for cancer treatment, but are costly and cannot be afforded by all patients. Because of the high cost, the pharmaceutical research groups across the world are sufficiently motivated to discover or design small molecule inhibitors to treat cancer through inhibition of the immune checkpoint proteins previously targeted with monoclonal antibodies. The presented study was designed with an aim to establish raloxifene, a selective estrogen receptor modulator (SERM) as a potential ligand of the immune checkpoint protein Programmed death ligand-1 (PD-L1). METHODS: In the presented study, the in-silico approach was used for identifying a lead molecule against PD-L1. The hits were screened using the similarity-search method, and drug-likeliness analysis, and the leads were identified through ligand-docking using Autodock. In-vitro cytotoxicity analysis was carried out using the standard sulphorhodamine B (SRB) assay and the wound healing analysis to show the inhibition of cellular migration was performed using the standard scratch assay. RESULTS: The in-silico study revealed that raloxifene showed a high drug likelihood and higher binding affinity with PD-L1 as compared to the positive control (BMS-1166; BMS is Bristol Myers Squibb). The binding of raloxifene was shown to occur in the same region as the FDA-approved monoclonal antibodies atezolizumab and durvalumab, indicating the potential of raloxifene for PD1/PD-L1 blockade. In the in-vitro studies, raloxifene showed a time-dependent reduction in IC50 values for the cell line HCT116 (colon cancer). The scratch assay also revealed that raloxifene significantly reduced the migratory potential of HCT-116 cells in-vitro. CONCLUSIONS: PD-L1 is a potential target of the SERM raloxifene in-silico. Overall, this study is one step further towards immune checkpoint blockade using small-molecule inhibitors.

Improving Surgical Safety in Living Donor Renal Transplantation With Antiseptic Skin Preparation, Bladder Irrigation, Corner-Saving Vascular Anastomosis, DJ Stenting, and Extravesical Ureteroneocystostomy Modifications: A Comprehensive Approach.

Introduction The antiseptic skin preparation, bladder irrigation, corner-saving vascular anastomosis, DJ stenting, and extravesical ureteroneocystostomy (ABCDE) approach encompasses a range of modifications applied during different stages of the surgical procedure in renal transplantation. These modifications include the following: A, antiseptic skin preparation sequentially with cetrimide 3.35%, chlorhexidine scrub 4%, spirit, and povidone-iodine 10%; B, bladder irrigation with amikacin and betadine solution; C, corner-saving end-to-side vascular anastomosis; D, DJ stenting with early postoperative removal within three weeks; and E, extravesical ureteroneocystostomy using our institute's modified Lich-Gregoir technique. Methods This prospective observational study was conducted at our institution between March 2021 and May 2023. Data were collected from the patients' medical records and analyzed using Statistical Package for the Social Sciences (SPSS) (IBM SPSS Statistics, Armonk, NY, USA). Statistical tests, including t-test, Mann-Whitney test, chi-square test, and Fisher's exact test, were used for analysis. The study assessed various recipient, donor, intraoperative, and post-transplant factors, as well as surgical complications and stent-related factors. Results Out of 72 renal transplantations, 12 (16.6%) had the following surgical complications: urinary (n = 4; 5.5%), wound-related (n = 3; 4.1%), and lymphocele (n = 5; 6.9%). The most common complications were lymphocele (n = 5; 6.9%) and urinary leak (n = 4; 5.5%). Surgical complications were more common in male recipients (91.6% versus 8.3%), as well as in recipients with longer dialysis duration (24 ± 17 versus 11.0 ± 7 months) and had extended hospitalization time (16.4 ± 8.6 versus 8.0 ± 2.9 days) (p < 0.05). Wound infection correlated with longer surgeries (>300 minutes) and other complications. Lymphocele patients had higher drain output (>500 mL) on day 1 and longer hospital stays (>15 days). Urinary tract infections (UTIs) were linked to dialysis duration (>24 months), diabetes, and longer indwelling times of DJ stents and urinary catheters. Early DJ stent removal (<3 weeks) reduced UTI incidence and symptoms (p < 0.05). All complications were categorized as minor (3a or less), according to the Clavien-Dindo classification. Conclusion The modified ABCDE surgical approach in renal transplantation decreased the complications, showing favorable outcomes compared to those in the literature.

Prevelance of Hearing Loss and Factors Association in Chronic Kidney Disease Patients.

Aim: Chronic kidney disease (CKD) is becoming a great concern, especially in developing countries and SNHL among patients with CKD is considerably higher than general population. So, current study aims evaluation and assessment of degree of hearing loss in chronic kidney disease patients using pure tone audiogram and correlation of hearing loss with its contributing factors. Materials and methods:70 patients with CKD were included in this prospective observational cross sectional study performed in tertiary care hospital. A detailed history; general physical, otological examination, blood investigation was done.CKD staging was done using KDIGO guidelines and hearing assessment using pure tone audiometry. Hearing loss association with CKD and contributing factors were studied. Result: Out of 70 participants, SNHL was seen in twenty one participants. Hearing loss was present in 3 out of 22 participants of CKD-3; 6 out of 12 participants of CKD-4 and 12 out of 15 participants of stage CKD-5. A statistically significant association of hearing loss was found with CKD stage, albuminuria, hemodialysis, hypertension and other factors. Discussion: Since hearing impairment may well have a negative impact on the social function of an affected individual, the use of pure tone audiogram to monitor CKD patients should be considered as a routine procedure. Patients with CKD would benefit from early detection of hearing loss which will allow for early rehabilitative measures to be taken.

A novel carissic acid from fruits of Carissa carandas induced apoptotic cell death in A-549 cells following the activation of caspases.

This study was designed to identify cytotoxic compounds from Carissa carandas extract. The cytotoxic activity of extract and fractions were assessed against eight cancer cell lines. The chloroform fraction obtained from methanolic extract exhibited significant activity against MCF-7, HT-29, A-549 with IC50 values of 3.98 µg/mL (MCF-7), 1.28µg/mL (HT-29) and 1.48 µg/mL (A-549) respectively. Further investigation led to the isolation of novel compound carissic acid (CA), which was confirmed by detailed spectroscopy studies. CA exhibited notable activity with IC50 values of 3.47 µM for A-549, 2.65 µM for HT-29 and 13.58 ± 0.59 µM for MCF-7 cells. CAcaused chromatin condensation with decrease of mitochondrial membrane potential and also confirmed cell death via Reactive Oxygen Species (ROS) generation and significantly decreased the colony formation in dose-dependent manner. The overall findings suggested that CA demonstrates cytotoxic effect by inhibiting cell proliferation and promoting apoptosis in lung (A-549) carcinoma cell line.

Staying and Returning dynamics of young children's attention.

In this paper, we decompose selective sustained attending behavior into components of continuous attention maintenance and attentional transitions and study how each of these components develops in young children. Our results in two experiments suggest that changes in children's ability to return attention to a target locus after distraction ("Returning") play a crucial role in the development of selective sustained attention between the ages of 3.5-6 years, perhaps to a greater extent than changes in the ability to continuously maintain attention on the target ("Staying"). We further distinguish Returning from the behavior of transitioning attention away from task (i.e., becoming distracted) and investigate the relative contributions of bottom-up and top-down factors on these different types of attentional transitions. Overall, these results (a) suggest the importance of understanding the cognitive process of transitioning attention for understanding selective sustained attention and its development, (b) provide an empirical paradigm within which to study this process, and (c) begin to characterize basic features of this process, namely its development and its relative dependence on top-down and bottom-up influences on attention. RESEARCH HIGHLIGHTS: Young children exhibited an endogenously ability, Returning, to preferentially transition attention to task-relevant information over task-irrelevant information. Selective sustained attention and its development were decomposed into Returning and Staying, or task-selective attention maintenance, using novel eye-tracking-based measures. Returning improved between the ages of 3.5-6 years, to a greater extent than Staying. Improvements in Returning supported improvements in selective sustained attention between these ages.

Site-Selective Synthesis of C-17 Ester Derivatives of Natural Andrographolide for Evaluation as a Potential Anticancer Agent.

A library of 57 compounds of natural andrographolide was designed, synthesized, and screened for in vitro studies against four human cancer cell lines: A594, PC-3, MCF-7, and HCT-116. Most of the synthesized compounds displayed better cytotoxic profile against all tested cells compared to the parent andrographolide (1). The tested semisynthetic derivatives of andrographolide were found to be more sensitive toward lung carcinoma (A594) and prostate carcinoma (PC-3) cell lines. Among the synthesized compounds, the C-17 p-methoxy phenyl ester analog 8s inhibited cell proliferation effectively in A549 (IC50: 6.6 µM) and PC-3 (IC50: 5.9 µM) cell variants, and compound 9s exhibited the most potent activity against the A594 cell line, with an IC50 value of 3.5 µM. Further anticancer mechanistic investigation demonstrated that compound 9s displayed nuclear morphological changes and increased reactive oxygen species (ROS) with disturbed mitochondrial membrane potential (MMP) that can lead to apoptosis. To know the exact structure confirmation of intermediate compounds 4 and 5, single X-ray crystallography was performed, which supported the complete reaction design of this work.

Correction to "LC-PDA-MS/MS-Based Dereplication Guided Isolation of a New Optical Isomer of 19,20-Epoxycytochalasin-N and Its Cytotoxic Activity".

[This corrects the article DOI: 10.1021/acsomega.2c03037.].

Comparison of positional artifacts in myocardial perfusion imaging in supine and semi-reclining position using dedicated D-SPECT cardiac camera: validation using CT based attenuation correction.

BACKGROUND: Soft-tissue attenuation remains a major limitation of SPECT-MPI which interferes with the diagnosis of CAD. The current study aims to evaluate the pattern of attenuation artifacts in supine and semi-reclining positions on CZT cardiac camera and their interaction with gender, BMI and stress protocols. METHODS: We prospectively analysed 150 patients acquired in supine and semi-reclining positions on CZT camera. The images were evaluated for severity and extent of defect using 17-segment model. An additional CT scan was acquired to generate AC image in the first 50 patients studied to assist investigator learning for comparison of artifact vs true defects in the two SPECT systems. The defects present in one position or showing change in severity within two positions were considered as positional artifacts and further validated using CTAC supine image. RESULTS: In overall analysis, higher extent and severity of positional artifacts were observed more in semi-reclining position affecting the apex, apico-inferior, inferolateral and inferoseptal segments. Females showed more positional artifacts than males with inferior wall attenuation in the semireclining position and anterior wall attenuation in the supine position. A positive correlation of the extent and severity of positional artifacts was noted with an increasing BMI. In patients with BMI > 30, mid inferior and inferolateral segments were most affected followed by anterior wall segments. Highest correction of artifactual perfusion defects by CTAC was noted in inferior wall followed by inferolateral segments. CONCLUSION: The incidence of positional artifacts was greater in semi-reclining position in females, higher BMI groups and adenosine stress subsets. Knowledge of the pattern of positional artifacts appears to be a reliable alternative of CTAC for correct interpretation of myocardial perfusion images.

A synbiotic combination of Bifidobacterium longum Bif10 and Bifidobacterium breve Bif11, isomaltooligosaccharides and finger millet arabinoxylan prevents dextran sodium sulphate induced ulcerative colitis in mice.

Decreased bifidobacterial abundance, disrupted gut barrier function, dysregulated immune response and ulceration have been reported in the gut microbiota of IBD patients. Non-digestible carbohydrates with bifidogenic effect enrich the gut microbiota with Bifidobacterium spp. and could help in overcoming inflammatory gut conditions. In this study, the protective effect of Bifidobacterium longum Bif10 and Bifidobacterium breve Bif11; isomaltooligosaccharides (IMOS); Finger millet arabinoxylan (FM-AX) and their Synbiotic mix were evaluated against dextran sodium sulphate (DSS) induced UC in male Balb/c mice for 25 days. All the interventions ameliorated symptoms of colitis such as disease activity index (DAI), histological damage to the colon, gut-bacterial dysbiosis and inflammation. However, the synbiotic mix was more potent in amelioration of some of the parameters such as decreased TNF-α and lipocalin levels; increased anti-inflammatory markers (IL-10 and IL-22), and improved short chain fatty acids (SCFAs) levels in the cecum content. Furthermore, mouse colitis histological scoring (MCHI) also suggested the preventive role of synbiotic mix. All the dietary interventions aid in improving the DAI and immune parameters; restoration or regeneration of the altered selected gut bacteria, enhances the SCFA production, strengthens gut barrier, prevents gut inflammation and decreases the colonic MCHI score in DSS fed mice.

Post Covid-19 Sinonasal Candidiasis: A Crisis Within the Pandemic.

The aim of this study was to find out the association of sinonasal candidiasis and Covid-19 infection. A prospective observational study was conducted at a tertiary care centre from April to September 2021, involving all patients with invasive candidiasis of the paranasal sinuses having a history of Covid-19 infection. A total of 18 patients of covid associated sinonasal candidiasis among the 475 cases of fungal rhinosinusitis were studied. All patients had involvement of nose and sinuses and 2 patients had orbital involvement with no loss of vision, while 3 had intracranial extensions and 1 had pulmonary involvement. Mandible was involved in 1 patient alone, while the maxilla and palate were involved in 5 patients. 15 patients were hypertensive, 12 diabetics and 1 had aplastic anaemia. Cultures showed that 8 patients had C. parapsilosis, 5 had C. albicans, 3 had C. tropicalis and 2 had mixed fungal infections. All patients underwent surgical debridement and antifungal administration. They were followed up for a minimum of 3 months. There was only one mortality (with aplastic anaemia), rest 17 were disease free at the time of writing this article. This is perhaps the first case series of post covid sinonasal candidiasis in the world. Invasive sinonasal candidiasis is a newer sequela of COVID-19 infection. Uncontrolled diabetes and over-zealous use of steroids at the time of Covid-19 are few of the known risk factors. Early surgical intervention and anti-fungal treatment should be sought for management.

In vitro characterization of lactic acid bacterial strains isolated from fermented foods with anti-inflammatory and dipeptidyl peptidase-IV inhibition potential.

Probiotics are known to stimulate, modulate, and regulate host immune response by regulating specific sets of genes and improve glucose homeostasis through regulating dipeptidyl peptidase (DPP-IV) activity, but the mechanism behind their protective role is not clearly understood. Therefore, the present study was designed to isolate indigenous lactic acid bacterial (LAB) strains from different fermented food samples, vegetables, and human infant feces exhibiting anti-inflammatory, antioxidant, and DPP-IV inhibitory activity. A total of thirty-six Gram-positive, catalase-negative, and rod-shaped bacteria were isolated and screened for their anti-inflammatory activity using lipopolysaccharide (LPS)-induced inflammation on the murine (RAW264.7) macrophages. Among all, sixteen strains exhibited more than 90% reduction in nitric oxide (NO) production by the LPS-treated RAW264.7 cells. Prioritized strains were characterized for their probiotic attributes as per the DBT-ICMR guidelines and showed desirable probiotic attributes in a species and strain-dependent manner. Accordingly, Lacticaseibacillus rhamnosus LAB3, Levilactobacillus brevis LAB20, Lactiplantibacillus plantarum LAB31, Pediococcus acidilactici LAB8, and Lactiplantibacillus plantarum LAB39 were prioritized. Furthermore, these strains when co-supplemented with LPS and treated on RAW264.7 cells inhibited the mitogen-activated protein kinases (MAPKs), i.e., p38 MAPK, ERK1/2, and SAPK/JNK, cyclooxygenase-2 (COX-2), relative to the LPS-alone-treated macrophages. LAB31 and LAB39 also showed 64 and 95% of DPP-IV inhibitory activity relative to the Lacticaseibacillus rhamnosus GG ATCC 53103, which was used as a reference strain in all the studies. Five prioritized strains ameliorated the LPS-induced inflammation by downregulating the JNK/MAPK pathway and could be employed as an alternative bio-therapeutic strategy in mitigating gut-associated inflammatory conditions. The potential mechanism of action of prioritized LAB strains in preventing the LPS-induced inflammation in RAW 264.7 macrophage cells.

COVID Associated Invasive Aspergillosis.

To study the possible association between invasive fungal sinusitis (aspergillosis) and coronavirus disease. An observational study was conducted at a tertiary care centre over 6 months, involving all patients with aspergillosis of the paranasal sinuses suffering from or having a history of COVID-19 infection. 92 patients presented with aspergillosis, all had an association with COVID-19 disease. Maxillary sinus (100%) was the most common sinus affected. Intraorbital extension was seen in 34 cases, while intracranial extension was seen in 5 cases. Diabetes mellitus was present in 75 of 92 cases. All had a history of steroid use during their coronavirus treatment. New manifestations of COVID-19 are appearing over time. The association between coronavirus and aspergillosis of the paranasal sinuses must be given serious consideration. Uncontrolled diabetes and overzealous use of steroids are two main factors aggravating the illness, and both of these must be properly checked.