Inhibition of renin-angiotensin system in experimental acute pancreatitis in rats: A new therapeutic target?

ObjectivePancreatic renin-angiotensin system has been implied to play a role in the regulation of pancreatic functions and could be a new therapeutic target in acute pancreatitis. The aim of this study was to evaluate the therapeutic potential of angiotensin-converting-enzyme inhibition by captopril and angiotensin II type1 receptor inhibition by L-158809 and losartan experimentally in acute pancreatitis.DesignRats were randomly divided into 15 groups. Acute edematous pancreatitis was induced by injection of cerulein 20 μg/kg SC four times at hourly intervals. Severe necrotizing pancreatitis was induced by retrograde injection of 3% taurocholate into the biliary-pancreatic duct.InterventionsCaptopril, L-158809 and losartan were given intraperitoneally. Main outcome features: pancreatic pathology, pancreatic myeloperoxidase activity and serum amylase activity were assessed.ResultsCaptopril decreased serum amylase (10,809±1867 vs. 4085±1028 U/L, p<0.01), myeloperoxidase activity (3.5±0.5 vs. 1.5±0.1, p<0.05) and histopathological score (5.0±0.4 vs. 1.1±0.5, p<0.01) in acute edematous pancreatitis. In taurocholate induced severe necrotizing pancreatitis captopril ameliorated histopathological score (10.1±1.2 vs. 3.4±0.5, p<0.01), pancreatic parenchymal necrosis (4.5±0.6 vs. 0.0±0.0, p<0.001), fatty necrosis (2.8±0.9 vs. 0.1±0.1, p<0.01) and edema (2.1±0.3 vs. 1.4±0.3, p<0.05). However, L-158809 did not have similar beneficial effects on acute pancreatitis in rats while losartan decreased pancreatic parenchymal necrosis and neutrophil infiltration.ConclusionsThis study not only demonstrated the differential effects of captopril, losartan and L-158809 in acute pancreatitis but also showed that there is still much to investigate about pancreatic renin-angiotensin system. Inhibition of angiotensin-converting enzyme should be evaluated carefully as a potential new therapeutic target in acute pancreatitis.     

Does central nitric oxide chronically modulate the acute hypoxic ventilatory response in conscious rats?

Aim: Hypoxia initiates an increase in ventilation (V_E) through a cascade of events of which central nitric oxide (NO) has been implicated as an important neuromodulator. There have not been any reports describing the consequences of long‐term imbalances in the central NO pathways on the modulation of the acute hypoxic ventilatory response (HVR). Chronic hypoxia (CH) can potentially modify the HVR, and so we hypothesized that central NO may be involved. In this study we describe the long‐term role of central NO in the modulation of HVR before and after CH. Methods: Male Sprague–Dawley rats (BW c. 200–320 g; n = 21) were implanted with an osmotic pump for continuous intracerebroventricular administration of either artificial cerebrospinal fluid (control), N^ω‐nitro‐l ‐arginine methyl ester (l ‐NAME) (150 μg kg^?1 day^?1) or the NO‐donor, 3‐[4‐morpholinyl]‐sydnonimine‐hydrochloride (SIN‐1) (100 μg kg^?1 day^?1). The V_E response to acute poikilocapnic hypoxia (8% O₂ for 20 min) was measured by plethysmography seven days after surgery, in normoxia, and again after 14 days of exposure to CH (CH = 12% O₂). Results: The magnitude of the HVR (c. 230% increase in V_E) was unaltered by centrally infusing either l ‐NAME or SIN‐1 for 1 week. CH did not modify the HVR, although baseline V_E and HVR were shifted downward by l ‐NAME during CH – because of a reduction in the frequency component. Conclusions: These results suggest that long‐term alterations in central NO levels may not alter the HVR under moderate CH, presumably because of the onset/development of compensatory mechanisms. However, NO appears to be an important component of the HVR following CH.     

Does soluble triggering receptor expressed on myeloid cells‐1 play any role in the pathogenesis of septic shock?

In order to define the significance of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) upon progression from sepsis or severe sepsis to septic shock a prospective study was designed with 90 enrolled patients with septic syndrome due to ventilator-associated pneumonia. Blood was sampled on seven consecutive days upon initiation of symptoms and concentrations of tumour necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), IL-8 and sTREM-1 were estimated in serum by an enzymeimmunoassay. No differences in concentrations of TNFalpha, IL-6 and IL-8 were found between patients with sepsis, severe sepsis and septic shock on the first day of presentation of symptoms. Patients presenting with septic shock had concentrations of sTREM-1 significantly higher than both patients with sepsis and severe sepsis on the first day; no difference was found between patients with sepsis and severe sepsis. A positive correlation was detected between sTREM-1 and the white blood cell count. Serum levels of sTREM-1 were significantly lower in patients where VAP resolved compared to those where VAP did not resolve; similar findings were noted between patients who eventually survived and those who died. IL-6 followed the kinetics of sTREM-1 in correlation to patients's prognosis; levels of TNFalpha and IL-8 were unrelated to prognosis. It is concluded that sTREM-1 is particularly increased upon evolution from sepsis or severe sepsis to septic shock. Its sustained increase is an indication of poor outcome. The underlined pathophysiological role of sTREM-1 for the transition from sepsis or severe sepsis to septic shock might constitute a novel target for immunomodulatory therapy.     

Does antiepileptogenesis affects sleep in genetic epileptic rats?

Recently it was established that early long lasting treatment with the anti-absence drug ethosuximide (ETX) delays the occurrence of absences and reduces depressive-like symptoms in a genetic model for absence epilepsy, rats of the WAG/Rij strain. Here it is investigated whether anti-epileptogenesis (chronic treatments with ETX for 2 and 4 months) affects REM sleep in this model. Four groups of weaned male WAG/Rij rats were treated with ETX for 4 months, two groups for 2 months (at 2-3 and 4-5 months of age), the fourth group was untreated. Next, the rats were recorded 6 days after the last day of the treatment for 22.5 h. Non-REM sleep and REM sleep parameters and delta power were analyzed in four characteristic and representative hours of the recoding period. Four months treatment with ETX reduced the amount of REM sleep and REM sleep as percentage of total sleep time. Other sleep parameters were not affected by the treatment. Clear differences between the various hours of the light-dark phase in amounts of non-REM and REM sleep and delta power were found, in line with commonly reported circadian sleep patterns. It can be concluded that the reduction of REM sleep is unique for the early and long lasting chronic treatment. The outcomes may explain our earlier finding that a reduction of REM sleep might alleviate depressive like symptoms.     

Does polyomavirus infection interfere with bladder cancer fluorescence in situ hybridization?

Urine cytology is a proven and widely used screening tool for the detection of urothelial carcinoma. However, morphologic features of polyomavirus infected cells, characterized by nuclear inclusions (decoy cells) are a known source of diagnostic confusion with malignancy. Fluorescence in situ hybridization (FISH) is now routinely used to support the cytological diagnosis of urothelial carcinoma and monitor for recurrence. We sought to determine whether polyomavirus infection could result in positive FISH results (aneuploidy). This study deals with retrospective study of 100 polyomavirus‐infected urine samples from patients with no history of urothelial carcinoma or organ transplantation. All cases were stained with Papanicolaou and acid hematoxylin stain. One slide from each sample was de‐stained and FISH was performed using chromosome enumeration probes 3, 7, 17, and locus‐specific probe 9p21. Adequate cells for FISH analysis (25 cells) were present in 81 cases; 19 cases were insufficient due to loss of cells during de‐staining and FISH preparation process. All polyomavirus‐infected cells (decoy cells) exhibited a normal chromosome pattern. Four cases were FISH positive, but there were no positive decoy cells. Decoy cells did not exhibit aneuploidy by FISH. The presence of decoy cells does not exclude the possibility of concurrent urothelial carcinoma. Acid hematoxylin stain appeared to supplement the Papanicolou stain in identifying and confirming the presence of polyomavirus infection. Diagn. Cytopathol. 2014;42:225–229. © 2013 Wiley Periodicals, Inc.     

Does pretraining spare the spatial deficit associated with anterior thalamic damage in rats?

Rats that had been pretrained on 2 tests of allocentric memory (water maze and T maze) received bilateral cytotoxic lesions in the anterior thalamic nuclei (ATN) or transection of the fimbria-fornix (FF). After surgery, both groups of rats were impaired on both tasks, although the preoperative training resulted in a rapid initial reacquisition of the water maze task. Those rats with lesions largely restricted to the ATN were impaired at a level comparable to that produced by FF lesions. This finding is consistent with a close functional relationship between the hippocampus and the ATN, necessary for the acquisition and on-line processing of allocentric spatial information but not for the maintenance/retrieval of procedural information. The rats with more extensive thalamic lesions were more impaired in both tasks and did show a loss of procedural information.     

Is macrophage migration inhibitory factor (MIF) the “control point” of vascular hypo-responsiveness in septic shock?

Macrophage migration inhibitory factor (MIF), a member of the cytokine family, is beginning to be recognized as a pleiotropic proinflammatory molecule. MIF exerts function via antagonistic regulation of glucocorticoids, inhibition to apoptosis-mediated p53, influence on vasodilator gas NO and inducible nitric oxide synthase (iNOS), feedback counter-regulation of complement C5a controlling MIF release, and interaction with major cations as well. Interestingly, aforementioned glucocorticoids, apoptosis, NO, iNOS, C5a, Ca2+, Mg2+, Na+, K+, and H+ that are greatly associated with vascular tone or vasomotion. Nevertheless, the elevated serum and cytosolic concentrations of MIF exactly affect all above facets in septic shock models and patients, during which vasodilation of the peripheral resistance vessels occurs, and accompanied with decreased responsiveness to vascular pressors. Thus MIF may bring into play as one of point-controlling proteins in the onset of sustained vascular hypo-reactivity during the process of septic shock.     

GAP between knowledge and skills for the implementation of the ACCM/PALS septic shock guidelines in India: Is the bridge too far?

Objective:

To determine whether physicians were aware of and had the skills to implement the American College of Critical Care Medicine/Pediatric Advanced Life Support Course septic shock protocol.

Design:

A cross-sectional questionnaire survey.

Setting:

Four academic institutions in Chennai, Manipal, Mangalore, and Trivandrum - cities representing the three southern states of Tamil Nadu, Karnataka, and Kerala, respectively, between February and April 2006.

Interventions:

Pre and post lecture questions. They were evaluated using 11 questions testing knowledge and 10 questions testing their comfort level in performing interventions related to the initial resuscitation in septic shock.

Measurement and Main Result:

The ACCM/PALS sepsis guidelines were taught during the PALS course conducted in the four academic institutions. A total of 118 delegates participated, of whom 114 (97%) were pediatricians and four (3%) were anaesthetists. The overall mean number of correct responses for the 11 questions testing knowledge before and after the lecture was 2.1 and 4.07, respectively P=0.001(paired t test). Although, 42% of the respondents (n=50) were aware of the ACCM guidelines, 88% (n=104) did not adhere to it in their practice. A total of 86% (n=101) and 66% (n=78) did not feel comfortable titrating inotropes or intubating in the ED; 78% (n=92) and 67% (n=78), respectively felt that central venous access (CVA) and arterial pressure (AP) monitoring were unimportant in the management of fluid refractory shock. Of the physicians, 20% (n=24) had never intubated a patient, 78% (n=92) had not introduced a central venous catheter, and 76% (n=90) had never introduced an intra-arterial catheter.

Conclusions:

In view of the lack of skills and suboptimal knowledge, the ACCM/PALS sepsis guidelines may be inappropriate in its current format in the Indian setting. More emphasis needs to be placed on educating community pediatricians with a simpler clinical protocol, which has the potential to save many more children.     

Does central nitric oxide elicit pulmonary hypertension in conscious rats?

The mechanisms involved in the pathogenesis of pulmonary arterial hypertension (PAH) remain unclear. Nitric oxide (NO) centrally attenuates sympathetic outflow and, therefore, may chronically modulate pulmonary arterial pressure (PAP), especially during the development of chronic hypoxia-induced PAH. To test this hypothesis, 20 male Sprague-Dawley rats (B.W. approximately 200-320 g) were chronically implanted with a telemetric transmitter for the continuous measurement of PAP, and an osmotic pump for intracerebroventricular (i.c.v.) administration of either aCSF (control), L-NAME (150 microg/kg/day) or the NO-donor, SIN-1 (100 microg/kg/day). Rats spent 7 days in normoxia, and then 14 days in hypoxia (CH=12% O2). In normoxia, exogenous NO elevated PAP by approximately 64%, although this increase in PAP could be prevented by isoproterenol (200 mug/kg). PAH occurred in all rats following 14 days of hypoxia. L-NAME did not alter baseline MPAP or the physiological responses to hypoxia. Our results suggest that central NO increases MPAP, although the mechanisms involved remain to be fully elucidated.     

Does the meniscus exist in the elbow joint in children?

The authors report a case of meniscus at the elbow joint in a 15-month-old infant causing a limitation of elbow extension. Histological examination demonstrated that this tissue was not a synovial fold or a chondroid metaplasia of the synovial fold. As a meniscus does not appear at any stage of the embryological evolution of the elbow joint, it has been concluded that the presence of the meniscus can be considered as an abnormal condition.     

Does the mendosal suture exist in the adult?

There is a paucity of information in the literature regarding the mendosal suture. Furthermore, reports of the closure of this presumed suture of childhood are variable. This study seeks to establish the presence or absence of this structure in the adult. Fifty adult skulls were evaluated for the presence or absence of the mendosal suture. Sixteen percent of specimens were found to have a mendosal suture. Six specimens were found to have these sutures bilaterally, and two had sutures on the right side only. Most sutures were linear in nature. The mendosal suture approximated the superior nuchal line in all specimens and more or less traveled medial and perpendicular to the lambdoidal suture. The length of these sutures ranged from 0.8 to 1.4 cm (1.1 cm). Our hopes are that these data will prove useful to both the anatomist and clinicians, so that, when present, misinterpretation of the mendosal suture will be avoided.