In vitro potency of 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione against drug-resistant and non-replicating persisters of Mycobacterium tuberculosis

ABSTRACT: Objectives: New antituberculosis agents active against drug-resistant and non-replicating tubercle bacilli are required. We evaluated a previously identified hit, 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (PAMCHD), against several clinical Mycobacterium tuberculosis isolates, including multidrug-resistant (MDR) strains and non-replicating drug-tolerant persisters of M. tuberculosis H37Rv. Methods: PAMCHD's potential against drug-resistant M. tuberculosis was investigated by broth microdilution. CFU enumeration was performed to determine PAMCHD's activity against five types of dormant bacilli. Results: No significant differences in MICs of PAMCHD were observed against M. tuberculosis H37Rv (2.5–5 µg/mL) and eight drug-susceptible strains (1.25–5 µg/mL) as well as drug-resistant strains including six isoniazid (INH)-resistant (2.5–10 µg/mL), one INH + ethambutol (EMB)-resistant (5 µg/mL), one rifampicin (RIF) + EMB-resistant (5 µg/mL) and three MDR (2.5–10 µg/mL) strains. Thus, PAMCHD maintains activity against all kinds of clinical strains, especially MDR. Regarding drug-tolerant persisters, INH and RIF killed, respectively, 0.5 and 5.0 log10 CFU of non-replicating persisters developed by hypoxia and 1.5 and 2.5 log10 CFU developed by nutrient starvation at 64 × of their respective MIC against actively dividing cultures. In contrast, PAMCHD sterilised persister cultures developed by hypoxia (killed 6.5 log10 CFU) or starvation (killed 7.5 log10 CFU). PAMCHD sterilised RIF-tolerant (tolerance level up to 100 µg/mL of RIF) 100-day-old static persisters at 64 × MIC, while moxifloxacin killed only 1.0 log10 CFU of these persisters at 64 × MIC. Conclusion: PAMCHD offers significant potential against MDR-TB and exhibits notable potency against non-replicating drug-tolerant M. tuberculosis persisters. These findings warrant further studies of PAMCHD for further anti-TB drug development

Primary hyperoxaluria: a case series

Abstract Background Primary hyperoxaluria (PH) is a rare genetic disorder characterized by the excessive production and accumulation of oxalate. We present five cases of PH, each exhibiting varying manifestations of the disorder including a case presenting as postpartum kidney failure. Notably, three of these cases involve a previously unreported mutation. Case presentations We evaluated five Indian patients who presented with varying manifestations of PH. The first case, a 30 year old woman, presented as post-partum kidney failure and was found to be having oxalate nephropathy precipitated by dietary oxalate overload in the setting of previously undiagnosed PH. Genetic analysis revealed a previously unreported mutation in the alanine-glyoxylate aminotransferase gene. The patient underwent simultaneous kidney liver transplant. The second and third cases, 26 and 28 year old women respectively, were asymptomatic siblings of the first patient, who were diagnosed through screening. The fourth case is a 12 year boy with PH type 1 presenting as nephrolithiasis and rapidly worsening kidney function requiring combined kidney liver kidney transplant. Case 5 is a 6 year old male child with type 2 PH presenting with nephrolithiasis, nephrocalcinosis and normal kidney function. All the patients were born to consanguineous parents. Conclusions Due to limited clinical suspicion and inadequate diagnostic resources in certain countries with limited resources, it is possible for PH to go undiagnosed. The manifestations of the disease can range from no noticeable symptoms to severe disease. Interestingly, in some individuals with primary hyperoxaluria, the disease may not exhibit any symptoms until it is triggered by a high intake of dietary oxalate

Unusual Cause of Hemobilia

Hemobilia is one of the rare causes of upper gastrointestinal (GI) bleeding. Causes of hemobilia vary from benign lesions, malignant tumors, to vascular causes. Rupture of a hepatic artery aneurysm into common bile duct is rarely encountered in clinical practice, and sometimes can be very tricky to diagnose if the clinician is not aware of this cause of GI bleeding. We diagnosed a young female who has had a recent gallbladder surgery and presented with a massive upper GI bleeding. She was managed with coil embolization of the right hepatic artery

Ambulatory Blood Pressure Monitoring versus Office Blood Pressure Monitoring to Identify the True Hypertension Status of Living Kidney Donors

Ambulatory blood pressure monitoring (ABPM) is a reliable modality and is preferred over office blood pressure monitoring (OBPM) for detecting hypertension. However, despite its advantages, the utilization of 24-h ABPM in evaluating living kidney donors has not been universally adopted by transplant centers, partly because of the lack of data about the utility of ABPM. This study aimed to identify patients with masked and white-coat hypertension, thereby ensuring appropriate identification of their true hypertension status and assessments of the risk to donors. This study included 73 potential living kidney donors. BP was measured in the office using a standardized protocol as well as by ABPM. Detailed clinical and biochemical parameters were assessed. Target organ damage was assessed in all the donors by assessing proteinuria, hypertensive retinopathy, and echocardiography. Out of the 73 donors, 64.4% were females and 35.6% were males. The average age of individuals in our donor population was 42.0 ± 11.28 years. In total, 31.5% were detected to be hypertensive by OBPM. With ABPM, only 21.9% of donors were hypertensive. The overall prevalence of white-coat hypertension was 30.4%; that of masked hypertension was 6.0%. In donors diagnosed as hypertensive by OBPM, three individuals were identified as having target organ damage. However, two additional donors who were initially missed as hypertensive using OBPM had target organ damage. OBPM overestimated the prevalence of hypertension compared with ABPM. ABPM is the better modality in terms of diagnosing white coats and masked hypertension. ABPM also more reliably correlates with target organ damage than OBPM