Severe Histological Abnormalities Research Articles

Assessing Oral Acute Toxicity and Histopathological Effects of Strelitzia reginae Aiton Leaf Extracts in Zebrafish (Danio rerio Hamilton)

Strelitzia reginae, commonly known as the Bird of Paradise, is a decorative shrub endemic to southern Africa. This study marks the first comprehensive investigation into the safety of S. reginae leaf extract through oral acute toxicity assessments and histopathological examinations in Zebrafish (Danio rerio). The interest in this research arises from the historical use of S. reginae components by various indigenous South African societies to treat conditions like swollen glands and sexual problems. GC-MS analysis was used along with traditional methods to look at the phytochemical parts of S. reginae. The results showed the presence of several substances, such as eicosane, hexacosane, 1-octadecene, and neophytadiene. Notably, the analysis also identified certain chemicals with potential cytotoxic properties, such as octacosane and bis (2-ethylhexyl) phthalate. Drawing upon the biological similarities between Zebrafish and humans, who share a majority of their genes, this study represents the first attempt to evaluate the toxicity and histopathology of S. reginae using D. rerio as the test model, aligning with the OECD recommendations outlined in Article 203. The oral acute toxicity tests were done using ethanolic leaf powdered extracts of S. reginae. Higher concentrations (1200 mg/L) were toxic, but lower doses were less harmful to D. rerio. As observed in the histopathology examination, exposure to higher concentrations of S. reginae extract induced severe histological abnormalities in the Zebrafish's gills, liver, kidneys, intestines, and brain. This work contributes greatly to our understanding of S. reginae's safety profile and its potential therapeutic applications for enhancing well-being.

Biochemical and histopathological effects in muscular tissue of carp fish (Labeo rohita, Hamilton 1822) following exposure to untreated and treated sewage water.

Present work describes a laboratory study aiming at assessing the impact of sewage treatment plant (STP) effluents on fish health by means of biochemical and histopathological biomarkers in muscular tissue of fish. Labeo rohita (7.62 ±0.25 cm, 8.25±0.32 g) was exposed to sub-lethal concentrations of untreated (UT) and treated (T) sewage water obtained from STP, Ludhiana, India. Following the determination of the 96h lethal concentration (LC50), the fish were exposed to control (de-chlorinated tap water), treated sewage water, 1/10th of LC50 UT and 1/20th of LC50 UT sewage water. The experiment was conducted for the period of 60 days. Experimental results depicted significant reduction (p<0.05) in muscle-somatic index of 1/10th LC50 UT and 1/20th LC50 UT groups compared to control and treated groups. Fish toxicity induced by untreated sewage water was evident from the significant decrease (p<0.05) in the levels of proteins and significant increase (p<0.05) in content of total lipids in muscular tissue of exposed group fingerlings. Drastic changes in the fatty acids profile and severe histological abnormalities viz. shortening of muscle bundles, edema, hyper-vacuolization, elongation of muscle bundles, gap formation in myofibrils, degenerated myotomes, hemorrhage, inter-myofibrillar space, necrosis, were also recorded in muscular tissue of exposed fingerlings. The intensity of muscular damage in L.rohita was found to increase with increase in duration of exposure. Results demonstrated that untreated sewage water could potentially induce physiological stress and somatic cell toxicity in fish L.rohita. Genotoxicity studies on germ cells of L.rohita fingerlings are further suggested to examine the genotoxic potential of untreated sewage water at high concentrations; this is especially of interest given that many effluents are genotoxic to fish.

Histopathological changes in dilated ascending aorta associated with aortic valve cuspidity.

Patients with a bicuspid aortic valve (BAV) often present with a dilated ascending aorta. However, the underlying pathogenesis for the observed changes in the aortic wall and the resulting aneurysmal dilation remains a subject of debate. This study aims to compare the histological abnormalities of the ascending aorta in BAV and tricuspid aortic valve (TAV) patients and their correlation with aortic diameter and patient age. A total of 376 patients from our institution's clinical database were included in the retrospective analysis. These patients underwent either elective surgery for ascending aorta dilation or emergency surgery for aortic dissection, either isolated or with a structurally diseased aortic valve. After excision, the ascending aorta samples were analysed by a pathologist. On histological examination, a higher degree of elastic fibre fragmentation and loss and mucoid extracellular matrix accumulation was present in the samples from TAV patients when compared with that from BAV patients (P < 0.001). However, correlation was poor for all variables when considering aortic diameter and histological abnormalities or age and histological abnormalities in both BAV and TAV patients. Our study demonstrates a greater incidence of severe histological abnormalities in TAV patients when compared with BAV patients.

Histopathologic and Radiologic Assessment of Unused Donor Lungs: When to Decline or Not?

Donor organ shortage, in combination with a 70% decline rate of offered donor lungs, results in significant wait list mortality and time with poor quality of life. Assessing donor lungs for transplant suitability is based on donors' history, gas exchange, chest X-ray, bronchoscopy, and in situ visual inspection; but donor lung acceptance remains subjective. We performed an in depth histopathologic and radiologic assessment of retrieved but unused donor lungs. We assessed 62 donor lungs not used for transplantation for various reasons between 2010 and 2019. These lungs were air-inflated, frozen, scanned with computed tomography, systematically sampled on 4 different locations, assessed macroscopically and microscopically by two experienced lung pathologists and by an experienced thoracic radiologist, all blinded for the reason of decline. Reasons for non-use are summarized in the figure. Thirty-nine (63%) lungs were not used for allograft-related reasons. In 13/39 (33%) lungs, the reason for decline could not be confirmed by histologic assessment (emboli, n=7; pneumonia, n=3; contusion, n=2; emphysema, n=1), in an additional 8/39 (21%) lungs, histologic abnormalities were only considered focal and mild (emphysema, n=5; pneumonia, n=3). In 16/39 (41%) lungs, radiology could not confirm the reason for decline. Twenty-three (37%) of 62 unused donor lungs were not transplanted due to extra pulmonary causes, of which 3 (13%) lungs displayed severe histologic abnormalities (pneumonia, n=2; emphysema, n=1), in addition to mild emphysema in 9 (39%) lungs and mild bronchopneumonia in 1 lung (4%). Radiology revealed ground-glass opacities in 8/23 (35%) and emphysema in 4/23 (17%) of these donor lungs. Histologic and radiologic assessment of unused donor lungs revealed substantial discrepancy with the clinical reason for decline. Prior chest CT imaging and frozen sections in selected cases might contribute to adequate donor assessment and augment current yield of donor lungs.

Qingyi decoction protects against myocardial injuries induced by severe acute pancreatitis

BACKGROUNDWe studied the protective effects of Qingyi decoction (QYD) (a Traditional Chinese Medicine) against severe acute pancreatitis (SAP)-induced myocardial infarction (MI).AIMTo study the function and mechanism of QYD in the treatment of myocardial injuries induced by SAP.METHODSUltrasonic cardiography, hematoxylin and eosin staining, immunohistochemistry, qRT-PCR, western blot, enzyme-linked immunosorbent assays, and apoptosis staining techniques were used to determine the effects of QYD following SAP-induced MI in Sprague-Dawley rats.RESULTSOur SAP model showed severe myocardial histological abnormalities and marked differences in the symptoms, mortality rate, and ultrasonic cardiography outputs among the different groups compared to the control. The expression of serum cytokines [interleukin (IL)-1ß, IL-6, IL-8, IL-12, amyloid β, and tumor necrosis factor-α] were significantly higher in the SAP versus QYD treated group (P < 0.05 for all). STIM1 and Orai1 expression in myocardial tissue extracts were significantly decreased post QYD gavage (P < 0.001). There was no significant histological difference between the 2-aminoethyl diphenylborinate inhibitor and QYD groups. The SAP group had a significantly higher apoptosis index score compared to the QYD group (P < 0.001).CONCLUSIONQYD conferred cardio-protection against SAP-induced MI by regulating myocardial-associated protein expression (STIM1 and Orai1).

Histopathologic and radiologic assessment of nontransplanted donor lungs.

Donor organ shortage results in significant waiting list mortality. Donor lung assessment is currently based on donors' history, gas exchange, chest X-ray, bronchoscopy findings, and ultimately in situ inspection but remains subjective. We correlated histopathology and radiology in nontransplanted donor lungs with the clinical indications to decline the offered organ. Sixty-two donor lungs, not used for transplantation (2010-2019), were procured, air-inflated, frozen, scanned with computed tomography, systematically sampled, and histologically and radiologically assessed. Thirty-nine (63%) lungs were declined for allograft-related reasons. In 13/39 (33%) lungs, histology could not confirm the reason for decline, in an additional 8/39 (21%) lungs, histologic abnormalities were only considered mild. In 16/39 (41%) lungs, radiology could not confirm the reason for decline. Twenty-three (37%) donor lungs were not transplanted due to extrapulmonary causes, of which three (13%) lungs displayed severe histologic abnormalities (pneumonia, n=2; emphysema, n=1), in addition to mild emphysema in 9 (39%) lungs and minor bronchopneumonia in 1 (4%). Radiology revealed ground-glass opacities in 8/23 (35%) and emphysema in 4/23 (17%) lungs. Histopathologic and radiologic assessment of nontransplanted donor lungs revealed substantial discrepancy with the clinical reason for decline. Optimization of donor lung assessment is necessary to improve current organ acceptance rates.

Donepezil improves neuropathy through activation of AMPK signalling pathway in streptozotocin-induced diabetic mice

Diabetic neuropathy (DN) is a common complication of diabetes mellitus and is associated with structural changes in the nerves. However, the molecular basis for DN is poorly understood. Adenosine monophosphate activated protein kinase (AMPK) has been shown to regulate the activity of some kinases including protein kinase B (AKT), mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin complex 1 (mTORC1) that represent important signalling pathways modulating the function of peripheral nociceptive neuron. Donepezil can activate AMPK and exerts neuroprotective effects. In this study, streptozotocin (45 mg/kg for 5 Day, i.p.) was used to induce experimental DN. After confirmation of development of neuropathy, mice were randomly distributed into five groups: Group 1; negative control group received saline (0.9%NaCl), Group 2; diabetic mice received saline, Group (3–5); diabetic mice received daily donepezil (1, 2 or 4 mg/kg, p.o.) respectively for 20 days. Mice were then sacrificed under anesthesia then their sciatic nerve and spinal cord were dissected out and processed for biochemical and histopathological studies. Diabetic mice revealed severe histological abnormalities including degenerated neurons in the spinal cord and swollen myelin sheath with inflammatory edema observed in sciatic nerves. In addition, diabetic mice showed reduced expression of p-AMPK in sciatic nerves with consequent activation of AKT/MAPK/4EBP1. A significant upregulation of the N-Methyl-d-aspartate (NMDA) receptors in both cervical and lumbar regions of spinal cord of diabetic mice was also demonstrated. Donepezil, an AMPK activator, blocked the phosphorylation of AKT/MAPK/4EBP1, down regulate the expression of NMDA receptors and reversed hyperalgesia developed in diabetic mice. Therefore, Donepezil could be a potential pharmacological agent for management of DN.

Comparative Histology of Aortic Dilatation Associated With Bileaflet Versus Trileaflet Aortic Valves

A more aggressive posture toward resection of the dilated aorta has been advocated when associated with bicuspid aortic valve (BAV), based on the notion that aortic material properties are weaker in this setting despite scant data to support or refute this position. The hypothesis that histologic abnormality reflects aortic wall strength was tested by comparing aortas from patients with BAV and trileaflet aortic valve. Resected aortas associated with BAV (n = 60) and trileaflet aortic valve (n = 24) were compared with normal diameter aortas from patients undergoing cardiac transplantation (n = 16) by five histologic criteria: elastic fiber loss (graded 0-4), smooth muscle cell loss (graded 0-4), medial proteoglycan accumulation (graded 0-3), medial fibrosis (graded 0-3), and atherosclerosis (graded 0-3). Patients with known connective tissue disorders, systemic inflammatory conditions, dissection, or prior heart surgery were excluded. Patients with BAV were a decade younger and more often had functional stenosis. The extent of elastic fiber loss, smooth muscle cell loss, medial fibrosis, and atherosclerosis was more severe in trileaflet aortic valve than BAV when considered across all diameters and when stratified to those between 4 and 5 cm. More severe histologic abnormalities associated with trileaflet aortic valve compared with BAV, especially when stratified by diameter, do not support a more aggressive approach to surgical intervention for dilatation associated with BAV. Indeed, if based on histologic diagnosis alone, our findings are suggestive that the converse might be true. Additionally, the lack of correlation between aortic diameter and histologic abnormality in the setting of BAV highlights the inadequacy of diameter alone as a criterion for aortic resection.

Effect of invariant natural killer T cells with IL-5 and activated IL-6 receptor in ventilator-associated lung injury in mice

ABSTRACTMechanical ventilation (MV) is well known to potentially cause ventilator-associated lung injury (VALI). It has also been reported recently that activation of invariant natural killer T (iNKT) cells is involved in the onset/progression of airway inflammation. We analyzed the roles of inflammatory cells, including iNKT cells, and cytokines/chemokines in a mouse model of VALI. C57BL/6 and Vα14+NKT cell-deficient (Jα18KO) female mice were subjected to MV for 5 hours. The MV induced lung injury in the mice, with severe histological abnormalities, elevation in the percentages of neutrophils in the bronchoalveolar lavage fluid (BALF), and increase in the number of iNKT cells in the lung. Jα18KO mice subjected to MV for 5 hours also showed lung injury, with decrease of the PaO2/FiO2 ratio (P/F ratio) and elevation of the levels of total protein, IL-5, IL-6, IL-12p40, and keratinocyte-derived cytokine (KC) in the BALF. Intranasal administration of anti-IL-5 monoclonal antibody (mAb) or anti-IL-6 receptor (IL-6R) mAb into the Jα18KO mice prior to the start of MV resulted in significant improvement in the blood oxygenation. In addition, the anti-IL-5 mAb administration was associated with a decrease in the levels of IL-5, IL-9, and IL-6R in the BALF, and anti-IL-6R mAb administration suppressed the mRNA expressions of IL-5, IL-6, IL-6R, and KC. These results suggest that iNKT cells may play a role in attenuating the inflammatory caused by ventilation through IL-5 and IL-6R.

The elusive link between aortic wall histology and echocardiographic anatomy in bicuspid aortic valve: implications for prophylactic surgery

Prediction of aortic dissection or rupture is extremely difficult in patients with bicuspid aortic valve. We aimed to identify clinical and echocardiography predictors of histological abnormalities of the aortic wall in patients with bicuspid aortic valve undergoing aortic surgery. We assessed the histology of the aortic wall and clinical and echocardiography variables in a cohort of patients with bicuspid aortic valve (n = 127) and a wide spectrum of valvar disease who underwent replacement of the ascending aorta (with or without aortic valve surgery). Histology was classified using a 5-grade system developed by Larson and Edward. Histological alterations of the aortic wall were absent/mild (grade 0-1) in 77 patients (61%) and moderate/severe (grade 2-3) in 50 (39%). Patients with moderate/severe histological alterations were younger (47 ± 17 vs 53 ± 16; p = 0.042). Eighteen patients out of 48 (38%) with an ascending aorta diameter ≤ 4.5 cm had grade 2-3 aortic wall disease as did 8 out of 18 (44%) with a diameter ≤ 4 cm. Nineteen out of 46 (41%) patients with a maximal ascending aortic area/height ratio < 10 cm(2) m(-1) had moderate/severe histological alterations. Multivariate logistic regression analysis showed that the indexed diameter of the aortic annulus was significantly associated with grade 2-3 aortic wall disease (odds ratio (OR): 12.22, 95% confidence interval (CI): 1.65-90.38, p = 0.014). A high proportion of patients with bicuspid aortic valve and mild to moderate aortic dilatation have severe histological abnormalities of the aortic wall that are not predictable by clinical and echocardiographic findings. These observations suggest that risk stratification for aortic dissection or rupture in patients with bicuspid aortic valve is so far quite suboptimal and future investigations are warranted.

Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of Tuberous Sclerosis Complex

Tuberous Sclerosis Complex (TSC) is an autosomal dominant, multi-system disorder, typically involving severe neurological symptoms, such as epilepsy, cognitive deficits and autism. Two genes, TSC1 and TSC2, encoding the proteins hamartin and tuberin, respectively, have been identified as causing TSC. Although there is a substantial overlap in the clinical phenotype produced by TSC1 and TSC2 mutations, accumulating evidence indicates that TSC2 mutations cause more severe neurological manifestations than TSC1 mutations. In this study, the neurological phenotype of a novel mouse model involving conditional inactivation of the Tsc2 gene in glial-fibrillary acidic protein (GFAP)-positive cells (Tsc2(GFAP1)CKO mice) was characterized and compared with previously generated Tsc1(GFAP1)CKO mice. Similar to Tsc1(GFAP1)CKO mice, Tsc2(GFAP1)CKO mice exhibited epilepsy, premature death, progressive megencephaly, diffuse glial proliferation, dispersion of hippocampal pyramidal cells and decreased astrocyte glutamate transporter expression. However, Tsc2(GFAP1)CKO mice had an earlier onset and higher frequency of seizures, as well as significantly more severe histological abnormalities, compared with Tsc1(GFAP1)CKO mice. The differences between Tsc1(GFAP1)CKO and Tsc2(GFAP1)CKO mice were correlated with higher levels of mammalian target of rapamycin (mTOR) activation in Tsc2(GFAP1)CKO mice and were reversed by the mTOR inhibitor, rapamycin. These findings provide novel evidence in mouse models that Tsc2 mutations intrinsically cause a more severe neurological phenotype than Tsc1 mutations and suggest that the difference in phenotype may be related to the degree to which Tsc1 and Tsc2 inactivation causes abnormal mTOR activation.

In Vivo Effects of Single Intra-Articular Injection of 0.5% Bupivacaine on Articular Cartilage

Single intra-articular injections of local anesthetics are commonly used clinically. Recent in vitro studies have demonstrated chondrotoxic effects of local anesthetics, with the greatest emphasis on bupivacaine toxicity. This in vivo study was conducted to determine whether a single intra-articular injection of 0.5% bupivacaine results in chondrocyte morbidity and rapid chondrolysis. Forty-eight Sprague-Dawley rats received a 100-microL injection of sterile 0.9% saline solution (negative control) into one stifle joint and 100 microL of either preservative-free 0.5% bupivacaine (experimental group) or 0.6 mg/mL monoiodoacetate (positive control) into the contralateral joint. The rats were killed at one week, four weeks, twelve weeks, or six months. Live and dead cells were quantified with use of three-dimensional confocal reconstructions of fluorescent-stained tissues at standardized locations on the distal part of the femur. Histological findings were graded with use of a modified Mankin score, and cell density was quantified with use of custom image-analysis software. In the specimens injected with bupivacaine, the chondral surfaces remained intact as seen with gross and histological examination. No differences in superficial chondrocyte viability or modified Mankin scores were observed between the saline-solution and bupivacaine groups at any location or time point (p > 0.05). Quantitative histological analysis of the bupivacaine-treated knees at six months revealed an up to 50% reduction in chondrocyte density compared with that of the saline-solution-treated knees (p < or = 0.01). Monoiodoacetate injection resulted in death of up to 87% of the superficial chondrocyte cells at one week and chondrolysis at six months. Despite severe histological abnormalities by four weeks after monoiodoacetate injection, cartilage injury was not evident on gross inspection until six months. This in vivo study showing reduced chondrocyte density without cartilage tissue loss six months after a single intra-articular injection of 0.5% bupivacaine suggests bupivacaine toxicity. The effects of bupivacaine were milder than those of an injection of 0.6% monoiodoacetate, which resulted in chondrolysis over the same time period.

Body Weight Control by a High-Carbohydrate/Low-Fat Diet Slows the Progression of Diabetic Kidney Damage in an Obese, Hypertensive, Type 2 Diabetic Rat Model

Obesity is one of several factors implicated in the genesis of diabetic nephropathy (DN). Obese, hypertensive, type 2 diabetic rats SHR/NDmcr-cp were given, for 12 weeks, either a normal, middle-carbohydrate/middle-fat diet (MC/MF group) or a high-carbohydrate/low-fat diet (HC/LF group). Daily caloric intake was the same in both groups. Nevertheless, the HC/LF group gained less weight. Despite equivalent degrees of hypertension, hyperglycemia, hyperlipidemia, hyperinsulinemia, and even a poorer glycemic control, the HC/LF group had less severe renal histological abnormalities and a reduced intrarenal advanced glycation and oxidative stress. Mediators of the renoprotection, specifically linked to obesity and body weight control, include a reduced renal inflammation and TGF-beta expression, together with an enhanced level of adiponectin. Altogether, these data identify a specific role of body weight control by a high-carbohydrate/low-fat diet in the progression of DN. Body weight control thus impacts on local intrarenal advanced glycation and oxidative stress through inflammation and adiponectin levels.

The effect of restraint stress on experimental colitis is IFN-γ independent

Stress, a protective reaction to external threats, may be deleterious if linked to an inflammatory stimulus. Stress may influence intestinal immunity, thereby contributing to the development of colitis. Less severe histological abnormalities and clinical scores were detected in dextran sulphate sodium (DSS)-induced colitis in IFN-γ −/−, compared to Wt, mice. Disease severity was increased by restraint stress in DSS-treated IFN-γ −/− and Wt mice, accompanied by suppressed colonic pro and anti inflammatory cytokine responses. Our data suggest that IFN-γ is important in the development of acute colitis. Stress increases the severity of colitis, but is independent of the IFN-γ pathway.

Furazolidone, tetracycline and omeprazole: a low-cost alternative for &amp;lt;i&amp;gt;Helicobacter pylori&amp;lt;/i&amp;gt; eradication in children

To evaluate furazolidone, tetracycline and omeprazole as first line therapy for Helicobacter pylori in children with digestive symptoms. Prospective and consecutive open trial. The study included patients older than 8 years old with functional dyspepsia, functional abdominal pain, severe histological abnormalities (intestinal metaplasia, gastric atrophy or mucosa-associated lymphoid tissue lymphoma) or peptic ulcer. H. pylori status was defined based both upon histology and rapid urease test. Drug regimen was a 7-day course of omeprazol, tetracycline (or doxycycline) and furazolidone twice daily. Eradication was assessed by upper endoscopy 2 months after treatment (histology and rapid urease test). Further clinical evaluation was done 7 days and 2 months after treatment. Thirty-six patients (21 female/15 male) were included. Age ranged from 8 to 19 years (mean 12.94+/-2.89 years). On intention-to-treat analysis (n = 36), eradication rate was 83.3% (95%CI 77.1-89.5) whereas in per-protocol analysis (n = 29), it was 89.7% (95%CI 84.6-94.7). Compliance was better when doxycycline was used, but the success rates were similar for the two tetracyclines. There was no variable associated with treatment failure. Side effects were reported in 17 patients (47.2%), mainly abdominal pain (11/30.5%), nausea (seven/19.4%) and vomiting (five/13.9%). Triple therapy with furazolidone and tetracycline is a low-cost alternative regimen to treat H. pylori infection.

Disaccharidase Activity in Infants and Comparison Based on Symptoms and Histological Changes

There is uncertainty regarding disaccharidase activity (DA) in infants. In this study, values for DA in infants were established and compared with symptoms and intestinal mucosal histological appearance. Disaccharidase activity and histological appearance of endoscopically obtained intestinal mucosal biopsy specimens from 131 infants (75 males; mean age 180 days; range 20-364 days) obtained during an 8-year period were reviewed. Patients were divided into 2 groups on the basis of absence (group 1; n = 56) or presence (group 2; n = 75) of failure to thrive (FTT) and/or diarrhea. These groups were subdivided into 3 subgroups on the basis of histological findings: normal histological appearance (A), mild histological abnormalities (B), and moderate to severe histological abnormalities (C). The DA from patients in group 1A represent values in infants who were free of diarrhea/FTT and who had normal intestinal mucosal histological appearance. The geometric means (95% CI) in units of DA were as follows: lactase 33.7 (normal range 29.0-39.1), sucrase 48.9 (normal range 44.2-54.1), maltase 160.5 (normal range 144.4-178.3), and palatinase 11.2 (normal range 9.7-12.9). Differences in DA were not related to symptoms, in the absence of histological abnormalities (1A vs 2A), but rather on the presence of histological abnormalities even in the absence of symptoms (1A vs 1B). Differences were also found when patients with FTT and/or diarrhea with abnormal histological appearance (2B and 2C) were compared with patients with no FTT and/or diarrhea with a normal brush border (1A). We outline DA values in a large cohort of infants. DA in infants, as in children, relates to intestinal mucosal histological appearance rather than to symptoms.

Renal haemodynamics and function in weanling rats treated with enalapril from birth

1. Inhibition of the renin-angiotensin system (RAS) during kidney development produces chronic alterations in renal morphology and function that have been characterized in detail in adult animals. The aim of the present study was to determine the consequences of neonatal angiotensin-converting enzyme (ACE) inhibition on renal haemodynamics and function in rats at a much earlier age, namely 3-4 weeks. 2. Male Wistar pups received daily intraperitoneal injections of enalapril (10 mg/kg) or isotonic saline from birth until 24-28 days of age, when renal haemodynamics and function were assessed using clearance techniques under pentobarbital anaesthesia. 3. Enalapril-treated rats showed significant reductions in glomerular filtration rate (GFR; -44 +/- 6%; P < 0.05), effective renal plasma flow (ERPF; -33 +/- 6%; P < 0.05) and filtration fraction (-16 +/- 3%; P < 0.05) compared with saline-treated controls. Although mean arterial pressure tended to be lower in enalapril-treated rats, this group demonstrated a significant increase in renal vascular resistance compared with control rats (RVR; 46 +/- 6 vs 32 +/- 3 mmHg/mL per.min per g.kidney weight, respectively; P < 0.05). In enalapril-treated rats, urine osmolality was reduced (-59 +/- 5%; P < 0.05) and urine flow rate and fractional urinary excretion rates of sodium and potassium were markedly elevated compared with controls (P < 0.05). Enalapril-treated rats showed severe renal histological abnormalities, including wall thickening of cortical arterioles, papillary atrophy and tubulointerstitial alterations, mimicking those described previously in similarly treated rats examined in adulthood. 4. In conclusion, neonatal ACE inhibition in rats induces pronounced alterations in renal haemodynamics and function, characterized by reductions in ERPF and GFR, increased RVR and impaired tubular sodium and water reabsorption, which are evident at weaning.

Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain

Questions have been raised about the potential neurotoxicity of the neuraxial use of ketamine although ketamine and its active enantiomer S(+)-ketamine have been used intrathecally and epidurally (caudally) for the management of perioperative pain and in a variety of chronic pain syndromes. Clinical experience following neuraxial administration of S(+)-ketamine has been documented without reference to local central nervous system toxicity following this approach. In addition, there are no preclinical safety data regarding stability, compatibility, and neurotoxicity on intrathecal use of single S(+)-ketamine or combinations of S(+)-ketamine, morphine, bupivacaine, and clonidine. In the present case, the continuous intrathecal administration of S(+)-ketamine, in combination with morphine, bupivacaine, and clonidine resulted in adequate pain relief in a patient suffering from intractable neuropathic cancer pain. However, postmortem observation of the spinal cord and nerve roots revealed severe histological abnormalities including central chromatolysis, nerve cell shrinkage, neuronophagia, microglial upregulation, and gliosis. Based on our results, neuraxial administration of S (+)-ketamine cannot be recommended for clinical practise before a systematic study of toxicology of neuraxial S(+)-ketamine in animals or humans has been performed.

Ionic current abnormalities associated with prolonged action potentials in cardiomyocytes from diseased human right ventricles

This study was designed to determine whether ionic currents in right ventricular myocytes from explanted human transplant recipient hearts are related to right ventricular histopathology and function. Cardiac action potential duration (APD) is prolonged in ventricular tissues/cells from patients with heart failure, but the ionic mechanisms are not well documented. Membrane currents and transmembrane action potentials in myocytes from right ventricular epicardium of explanted human hearts were recorded using whole-cell patch clamp technique. Data from cells from right ventricles with severe histologic and functional abnormalities (abnormal histology group [AH]) and from right ventricles with preserved histology and function (relatively normal histology group [RNH]) were compared. We found that APD at 50% (APD(50)) and 90% repolarization (APD(90)) were significantly longer in AH cells than in RNH cells. Early afterdepolarizations (EADs) were observed in 20% of AH cells and none of the RNH cells. Inwardly rectifying K(+) current (I(K1)) was decreased (both inward and outward components). Both transient outward K(+) current (I(to1)) and slowly delayed rectifier K(+) current (I(Ks)) were down-regulated in AH cells. L-type Ca(2+) (I(Ca.L)) was not altered in AH cells. I(K1), I(to1), and I(Ks) are down-regulated in AH cells of human heart failure. This down-regulation contributes to APD prolongation that favors the occurrence of arrhythmogenic EADs and suggests a link between human cardiac histopathologic/functional abnormalities and arrhythmogenic ionic remodeling.

Glucoamylase Activity in Infants and Children: Normal Values and Relationship to Symptoms and Histological Findings

ABSTRACTBackground:Starch digestion is dependent on a combination of pancreatic and salivary amylase and the intestinal brush border enzymes glucoamylase and sucrase‐isomaltase. Glucoamylase splits successive glucose molecules from the nonreducing end of starch molecules and is particularly important in infants who are relatively deficient in pancreatic amylase.Methods:The authors measured glucoamylase activity in endoscopic mucosal biopsies submitted for measurement of disaccharidase activity from 214 patients aged 1 month to 20 years. Glucoamylase activity was measured using glucose polymers (polycose) as the substrate. The authors also related enzyme activity to histologic appearance and clinical indication for endoscopy.Results:The most common reasons for biopsy were abdominal pain, gastroesophageal reflux, and vomiting. Disaccharidase activity by age was similar to previous reports. Glucoamylase activity did not differ with age, but was 2 to 3 times the activity reported previously. Glucoamylase activity was significantly depressed in children with the most severe histologic abnormalities. Normal glucoamylase activity (±2 SD) was 80.6 ± 54.8 μmoles of glucose produced per minute per gram of protein.Conclusions:Glucoamylase activity is 2 to 3 times higher when glucose polymers are used as substrate than when glycogen is used. Severe mucosal disease is associated with reduced glucoamylase activity. Quantitation of glucoamylase activity with glucose polymers is more appropriate in evaluating children since these polymers are commonly used as carbohydrate source in the diet.