Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRN™) and wild-type mice

Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN?) mice exhibit normal hepatic and extrahepatic biotransformation enzyme activities when compared to wild-type (WT) mice, but express no functional hepatic cytochrome P450 activities. When incubated in vitro with [¹⁴C]-diclofenac, liver microsomes from WT mice exhibited extensive biotransformation to oxidative and glucuronide metabolites and covalent binding to proteins was also observed. In contrast, whereas glucuronide conjugates and a quinone-imine metabolite were formed when [¹⁴C]-diclofenac was incubated with HRN? mouse liver, only small quantities of P450-derived oxidative metabolites were produced in these samples and covalent binding to proteins was not observed. Livers from vehicle-treated HRN? mice exhibited enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration and necrosis and inflammatory cell infiltration, which were not present in livers from WT mice. Elevated liver-derived alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities were also observed in plasma from HRN? mice. When treated orally with diclofenac for 7 days, at 30 mg/kg/day, the severities of the abnormal liver histopathology and plasma liver enzyme findings in HRN? mice were reduced markedly. Oral diclofenac administration did not alter the liver histopathology or elevate plasma enzyme activities of WT mice. These findings indicate that HRN? mice are valuable for exploration of the role played by hepatic P450s in drug biotransformation, but poorly suited to investigations of drug-induced liver toxicity. Nevertheless, studies in HRN? mice could provide novel insights into the role played by inflammation in liver injury and may aid the evaluation of new strategies for its treatment.     

Spontaneous regression of extramedullary plasmacytoma--a case report

A case of extramedullary plasmacytoma in the soft tissues of the posterior chest wall of an 80-year old man is reported herein. Immunofluorescence study showed that the tumor cells produced IgG lambda. An M-component was also detected in the patient's serum by paper electrophoresis. Two months following the open biopsy done to establish diagnosis, the tumor underwent spontaneous regression and the M-component in the serum also disappeared. This is the first case report of spontaneous regression of an extramedullary plasmacytoma and the probable reasons for this spontaneous regression are discussed herein.     

Six novel heterozygous MLH1, MSH2, and MSH6 and one homozygous MLH1 germline mutations in hereditary nonpolyposis colorectal cancer

Most hereditary nonpolyposis colorectal cancer (HNPCC) cases are caused by germline mutations of mismatch repair (MMR) genes (i.e., MLH1, MSH2, or MSH6). Here we describe six novel mutations in patients referred for genetic assessment. All of these mutations lead to premature translation termination. Five single base pair deletions lead to frameshift (MLH1: g.38-39insCCCA, g.1971del.T; MSH2: g.163del.C, g.746del.A; MSH6: g.3320del.A) and one nonsense mutation in MSH2 g.1030C>T leads to a stop codon: p.Q344X. In one patient, the previously described MLH1 nonsense mutation g.806C>G was found in a homozygous state. In this patient, the familial histories of both the mother and father suggested HNPCC syndrome. This patient developed colon cancer at 22 years of age, suggesting a more aggressive phenotype. The results of our study provide further insight into the mutational spectrum of MMR genes in HNPCC families.     

The role of 5-hydroxytryptophan (5-HTP) in the regulation of the sleep/wake cycle in parachlorophenylalanine (p-CPA) pretreated rat: a multiple approach study

Summary In the rat, the insomnia which follows the administration of parachlorophenylalanine (p-CPA), a serotonin synthesis inhibitor, is transiently reversed either by intra-cisternal injection of L-5-HTP or by an associated injection of 5-HTP and an L-aromatic-aciddecarboxylase inhibitor (benserazide). Histochemical, immunohistochemical and chemical investigations showed that 5-HTP administration does not lead to a detectable increase in cerebral 5-HT. These findings suggest that the restoration of sleep after p-CPA treatment could be mediated by the central action of 5-HTP.     

Dietary docosahexaenoic acid-enriched phospholipids normalize urinary melatonin excretion in adult (n-3) polyunsaturated fatty acid-deficient rats.

Melatonin (MEL) plays an essential role in physiologic functions associated with darkness. We examined the effects of docosahexaenoic acid (DHA)-enriched phospholipids from pig brains (BPL) or hen eggs (EPL), as sources of DHA, on lipid FA composition of pineal membranes and daytime and nighttime concentrations of 6-sulfatoxymelatonin (aMT6) in adult male control and (n-3)-deficient rats fed BPL and EPL diets for 5 wk. In two experiments, at 3 wk of age, rats were divided into subgroups and fed semipurified diets containing either peanut oil [(n-3)-deficient group] or peanut plus rapeseed oil (control group) and two dietary formulas containing either 3.5 g/100 g diet of BPL (Experiment 1) or 5.0 g/100 g diet of EPL (Experiment 2). BPL and EPL diets provided approximately 200 mg of DHA/100 g diet. During the daytime, aMT6 concentrations were not significantly different among groups. Conversely, the (n-3)-deficient rats had significantly lower nighttime aMT6 concentrations than the control rats. BPL and EPL did not affect urinary nighttime aMT6 concentration in the control group, whereas (n-3)-deficient + BPL or EPL groups exhibited significantly higher nighttime aMT6 concentrations than the (n-3)-deficient group (76 and 110%, respectively). The level of DHA was significantly higher in the pineal glands of control rats than in (n-3)-deficient rats. In rats fed EPL and BPL, the level of DHA reached a plateau, between 10 and 11 mg/100 mg total fatty acids in control + BPL or EPL and (n-3)-deficient + BPL or EPL groups. These findings suggest that new DHA-enriched formulas may be used as an efficient alternative source of (n-3) polyunsaturated fatty acids to normalize MEL secretion.     

Early increase of peripheral B cell levels in kidney transplant recipients with CMV infection or reactivation

BACKGROUND: Cytomegalovirus (CMV) infection or reactivation is a frequent complication of renal transplantation. Diagnosis of these conditions relies on the detection of circulating antigen, or of specific IgM and/or IgG, which develop over several weeks. Evocative clinical features may be detected earlier, but lack specificity. Rapid and early changes in the partition of lymphocyte subsets could be an additional indication of pending CMV infection. METHODS: A systematic follow-up of peripheral B lymphocytes identified immunophenotypically by the determination of surface immunoglobulins (sIg), performed in 97 kidney transplant recipients, allowed to identify transient increases apparently predictive of CMV primo-infection or reactivation over the next 3 months. To better define the nature of these B cells, an extended investigation was performed for 14 prospective patients. In addition to surface Ig, membrane CD19, HLA-DR, and CD80 expression were explored. The cytoplasmic presence of mu, kappa, and lambda chains was also examined. B cell function was investigated using the ELISPOT technique, which allows an enumeration of the populations of IgG, IgA, and IgM secreting B cells. RESULTS: Retrospective analysis of the clinical outcome of the cohort of 97 patients evidenced that early transient increases in B cell levels were significantly (P<0.0001) associated with CMV infection. The same trend was noted in the smaller series of patients who benefited from a more extensive investigation of B cells, 10 of whom presented clinical or biological signs of CMV infection. Mature B cells, expressing surface Ig, CD19, DR, and CD80 are those presenting transient increases. No significant variation of preB (cmu+/kappalambda-) or activated (spot-forming) cells was evidenced in these patients. CONCLUSION: Individual examination of each patient's immune reconstitution profile allows to detect transient peaks of mature B cell during the initial immunosuppressive therapy, that appear to be predictive of oncoming CMV infection or reactivation.     

Isolated hepatic tuberculosis: An uncommon presentation of a common culprit

Hepatic tuberculosis (HTB) is commonly encountered in patients with widespread miliary disease. Isolated affection of the liver is extremely rare. We present a case of a young woman who presented with a subacute afebrile hepatic failure. Investigations including a liver biopsy proved that the presentation was due to granulomatous hepatitis secondary to mycobacterial infection of the liver. It is important that tuberculosis (TB) be kept in mind especially in endemic areas even in atypical clinical scenarios by clinicians, radiologists, and pathologists. Use of anti-tuberculous drugs in such cases is usually successful and must be instituted early.     

Reversible electrophysiological abnormalities in hypokalemic paralysis: Case report of two cases

Compound muscle action potential (CMAP) amplitude declines during a paralytic attack in patients with hypokalemic periodic paralysis (HPP). However, serial motor nerve conduction studies in hypokalemic paralysis have not been commonly reported. We report two cases with hypokalemic paralysis, who had severely reduced CMAPs in all motor nerves at presentation during the episode of quadriparesis. However, the amplitude of CMAPs increased and reached normal levels, as the serum potassium concentration and motor power returned to normal state.     

Association between shape of the mandibular condylar head and the occurrence of unilateral condylar fracture – A retrospective computed tomographic study

This retrospective study aims to evaluate the correlation between the shape of the mandibular condylar head and the incidence of unilateral condylar fracture using computed tomography.Medical records of patients diagnosed with unilateral condylar fractures from the year 2012–2019 were reviewed. The shape of the condylar head on the non - fractured side was analysed using a Radiant Dicom Viewer. The analysis was done using both visual and analytical methods. In the analytical method, a horizontal line was drawn at the base of the curvature of the condylar head. The highest peak point of the head was marked, and a perpendicular line was drawn connecting the highest point to the horizontal line. The shape was categorized into four types as convex, flat, angled, and round based on these lines.201 CT scans were examined, of which 69 were excluded as they did not meet the inclusion criteria. The remaining 132 were included in our study. On examining the shape, flat-shaped condyle was seen in 57 scans (43.2%), followed by convex in 31 scans (23.4%), angled in 30 (22.7%) and round in 14 scans (10.6%). The relationship between the shape of the mandibular condylar head and the incidence of unilateral condylar fracture was analysed using a chi-square test, which showed high statistical significance (p value 0.0001). The flat-shaped condylar head was more prone to fracture, and the round-shaped condylar head was least prone to fracture.In conclusion, the shape of the mandibular condylar head had a statistically significant association with the incidence of unilateral condylar fracture. The assessment of the shape of the condylar head can be taken as a guide to suspect condylar fractures and other associated mandibular fractures.