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Circadian rhythms of physiology, behavior, and metabolism have an endogenous 24 h period that synchronizes with environmental cycles of light/dark and food availability. Alterations in light cycles are stressful and disrupt such diurnal oscillations. Recently, we witnessed a sudden rise in studies describing the mechanisms behind the interaction between the key characteristics of mitochondrial functions, peripheral clocks, and stress responses. To our knowledge, there is no study in the suprachiasmatic nuclei (SCN) describing the dysregulated mitochondrial bioenergetics under abnormal lighting conditions, which is common in today’s modern world. Thus, we aimed to investigate the existence of daily changes in mitochondrial bioenergetics (respiratory control rate, RCR), mitochondrial abundance (mtDNA/nDNA), plasma corticosterone, and to test whether disturbances in the lighting conditions might influence such rhythms. To confirm this, mice were sacrificed, mitochondria were isolated from the suprachiasmatic nuclei in the brain and blood was collected, every 3 h at various time points zeitgeber time/circadian time, (0, 3, 6, 9, 12, 15, 18, 21, and 24 h) under 12:12 h light-dark (LD, 150 lux L: 0 lux D) cycle and chronic artificial dim lighting (LL, 5 lux: 5lux) conditions, of a 24 h period, respectively. Our results demonstrate the existence of robust daily rhythmicity in RCR, mtDNA/nDNA and plasma CORT under a normal LD cycle. However, these rhythms were significantly disrupted and clock genes expressions were dysregulated under chronic dim LL. Furthermore, mitochondrial abundance was significantly reduced during LL compared to their numbers under LD cycle. Our data demonstrate that the circadian clock regulates mitochondrial functions (RCR, number), essential for accomplishing daily energy demands and supply by the SCN neurons. Abnormal light exposure dysregulates mitochondrial functions in the SCN and may alter metabolism, resulting in obesity, diabetes, and other metabolic disorders. Therefore, properly designing lighting conditions in workplaces is essential to mitigate the adverse consequences of light on humans.

Medical expulsive therapy (MET) in ureteric stones has 2 goals: 1) accelerate stone passage and therefore avoid surgery and 2) reduce analgesic requirement. In this setting, a RCT [1] done prior to the publication of the SUSPEND trial [2] is published in this issue of the CEJU, comparing the efficacy of tadalafil against tamsulosin in MET. It is regrettable that a placebo arm was not included in this trial. Nevertheless, even if one were to presume that tamsulosin is only as good as placebo, a robust case is made for the superiority of tadalafil – the mean stone size in this trial is 7 mm; all the stones were in the distal ureter; stone passage was confirmed with CT scan; the tadalafil group had a 84% passage rate compared to 68% in the tamsulosin group; mean analgesic requirement and time to stone expulsion were significantly reduced in the tadalafil group. Tamsulosin and nifedipine are supposed to be beneficial in MET, but high-quality RCTs in this area were lacking [3, 4]. PDE-5 inhibitors have been investigated as alternative agents in MET [5]. The SUSPEND trial concluded that there is no benefit to using tamsulosin or nifedipine in MET, compared to placebo. However, the conclusions were not supported by its methodology. Trials are scientifically rigorous pursuits; if diluted with ‘real-world’ or ‘pragmatic’ labels, they defeat the objective. The primary outcome to look into the effectiveness of MET is spontaneous passage of stone – confirmed, ideally, with CT scan or the patient submitting a stone that was passed per urethrem. Any other outcome measure is unlikely to yield the same result. The SUSPEND trial used lack of surgical intervention as a proxy for its primary outcome, citing radiation safety and costs for not using CT scans. The trial also suffers from other anomalies: ∼75% of the stones in each arm of the trial was ≤5 mm; only ∼65% of the stones were in the lower ureter; using maximal stone dimension rather than ureteral cross sectional dimension (attribution bias). The study from Bengaluru gives hope to patients and clinicians alike through the possibility of using agents other than tamsulosin and nifedipine in MET. Higher quality trials are required to establish the role of specific agents in MET, tailored to size and location of stones. In the absence of RCTs that are rigorous in their methodology, urologists are likely to continue prescribing agents for MET. One cannot help but be reminded of Yogi Berra's malapropism here: “You've got to be very careful if you don't know where you are going, because you might not get there”.

Potentilla mooniana Wight. (Rosaceae) is a plant found in the Himalayan region where the root is traditionally used to treat stomach problems including gastric-ulcer.To scientifically validate the gastro-protective effect and derive the possible mechanistic activity of the ethanol root extract from P. mooniana (EPM).The gastroprotective effect of EPM (100-400 mg/kg, p.o.) was evaluated on both the physical (Pyloric ligation, PL; Cold restrain stress, CRS) and chemical (absolute ethanol, EtOH; aspirin, ASP) ulcerogens induced ulceration in rats. The mechanistic activity of EPM was tested on various gastric-ulcer parameters, namely gastric pH, volume, acid-pepsin output, DNA content, histamine level, H(+)K(+)-ATPase activity, mucus content, microvascular permeability, antioxidant markers, and gastric-histopathological study.EPM significantly reduces the ulcer score against all the four tested gastric-ulcer models. In the PL model, EPM showed significant reduction (p 0.05) in acid-pepsin output and cell shedding; however, no significant effect was observed on gastric volume, cell proliferation, stomach glandular weight, and histamine levels. EPM (400 mg/kg, p.o.) when compared with ulcer control showed significant increase in gastric pH by 41.6% and decrease in H(+)K(+)-ATPase activity by 47.73%. In addition, EPM showed significant increase in mucus content by 58.60% and a decrease in the microvascular permeability of Evans Blue by 85.00%, justifying its protective effects. Furthermore, EPM also showed significant antioxidant activity and histopathologically possessed excellent cytoprotective effect.The gastro-protective effect of EPM is attributed mainly to the defensive mechanism owing to the presence of a good quantity of polyphenolic components.

Psychological stress is considered as one of the limiting factors in the management of type-2 diabetes mellitus (T2DM). Therefore, the basic objective of the present study was to evaluate the antidiabetic effect of metformin, diazepam, and their combination in cooccurring T2DM and stress condition (DMS). T2DM was induced in the male rats by administering streptozotocin (45 mg/kg,i.p.) and nicotinamide (110 mg/kg,i.p.) with time lag of 15 min. Rats were subjected to two sessions of cold restraint stress paradigm for one hour on the sixth and seventh day after streptozotocin injection. Administration of metformin (25 mg/kg,p.o.) and diazepam (1 mg/kg,p.o.) in combination from the seventh to thirteenth day after streptozotocin injection showed better improvement in glucose tolerance and insulin sensitivity compared to monotherapy of either drug. In addition, the combination significantly attenuated DMS-induced hyperglycemia, hypertriglyceridaemia, hypercorticosteronemia, anxiety-like behavior, and insulin resistance through modulating insulin signaling pathway in the liver compared to monotherapy. Further, improvement of mitochondrial function, integrity, and oxidative stress in hippocampus, hypothalamus, prefrontal cortex, striatum, amygdala, and nucleus accumbens was observed with the combination. Therefore, metformin in combination with diazepam may be a better therapeutic option in the management of T2DM with cooccurring stress condition.

Introduction Sildenafil (Viagra®) is one of the drugs used in the first line therapy of male erectile dysfunction (MED). We have recorded outcomes, adverse events and acceptability of Sildenafil (Viagra) therapy in an unselected group of men presenting with ED to a British district general hospital. Methods In this prospective observational study, 147 men with ED were seen since Oct 1999. Study patients were reviewed at 4, 12 and 52 weeks. All the patients filled the International Index of Erectile Function (IIEF) questionnaire and were asked about their willingness to pay (WTP) for treatment. Results All suitable men accepted Viagra as first line therapy. 91% of our patients found sildenafil treatment successful. 80% of these patients were willing to continue with sildenafil therapy. Side effect profile of sildenafil was different in this study with much higher incidence of headache, dyspepsia, flushing and abnormal vision. 92% of men with ED expect to be treated by the NHS. Of those men eligible for treatment in the NHS, 30% qualify under the clinical categories and 18% under the 'distress' category. Only 55% of those with cardiovascular risk factors qualify for NHS treatment. Conclusions Sildenafil is widely accepted as first line therapy among British men with ED and has a success rate of 91%. Nearly half of men with ED qualify for NHS treatment. Nearly half of those with vascular risk factors do not qualify for NHS treatment. Most men with ED could possibly be managed in primary care.