The clinical view through the Archives: the clinical notes of 2009

The Clinical Notes published in 2009 serve as a resource to reflect on clinical aspects relevant to different clinical entities. Through this review an attempt is likewise made to bring the reader closer to the clinical reality of our environment.     

Halomethane-induced cytotoxicity and cell proliferation in human lung MRC-5 fibroblasts and NL20-TA epithelial cells

Halomethanes (HMs) can be formed during the chlorination process to obtain drinking water. In liver cells, HMs had been shown to be mutagenic and carcinogenic; however, their bioactivation by CYP 2E1 and GSTT1 is required. Although inhalation is the most common pathway of exposure, reports on the toxic effects induced by HMs in human lung are contradictory. The aim of this study was therefore to evaluate in vitro cytotoxicity and cell proliferation induced by CH(2)Cl(2), CHCl(3) and BrCHCl(2) in human lung NL20-TA epithelial cells and MRC-5 fibroblasts, and their relationship with CYP 2E1 and GSTT1 activity. High concentrations of these HMs induced cytotoxicity, particularly in cells treated with BrCHCl(2). Low concentrations of BrCHCl(2) stimulated hyperproliferation of fibroblasts, the most probable consequence of which is regenerative proliferation related to collagen induction. Fibroblasts exposed to BrCHCl(2) exhibited low levels of CYP 2E1 activity suggesting that released bromine is able to alter this activity by affecting the active site or auto regulating the activity itself. GSTT1 was up to ten times more active than CYP 2E1 in both cell lines, indicating that potential lung damage is due to formation of pro-carcinogens such as formaldehyde.     

Diphenyl diselenide ameliorates cognitive deficits induced by a model of menopause in rats

Ovarian hormone loss contributes to cognitive decline in postmenopausal women. Studies have demonstrated a positive role of the level of the element selenium in cognitive performance. The present study investigated the effects of the synthetic organoselenium compound diphenyl diselenide (PhSe)? on cognitive functions in ovariectomized rats. Ninety-day-old female Wistar rats were subjected to ovariectomy (OVX) or Sham operation. One week after surgery, rats were orally treated with (PhSe)? (5 mg/kg, per oral route) or vehicle once a day for 30 days. Next, the rats were evaluated in behavioral tests [Morris water maze (MWM) and open-field tests] and biochemical [cerebral acetylcholinesterase (AChE)] analyses were carried out. In MWM probe trial, (PhSe)? decreased the latency to reach the platform location and increased the number of crossings over the platform location, protecting against cognitive impairment induced by OVX. Furthermore, (PhSe)? prevented the stimulation of AChE activity caused by OVX. In conclusion, the present study showed a cognition-enhancing effect of (PhSe)? treatment for 30 days in ovariectomized rats in the MWM test, which could be related to its ability to prevent the stimulation of AChE activity caused by OVX in rats. These findings suggest that (PhSe)? might have a promising role in preventing the cognitive decline related to menopause.     

IMP dehydrogenase deficiency in Leishmania donovani causes a restrictive growth phenotype in promastigotes but is not essential for infection in mice

Leishmania cannot synthesize purines de novo and therefore must scavenge purines from its host for survival and growth. Biochemical and genomic analyses have indicated that Leishmania species express three potential routes for the synthesis of guanylate nucleotides: (1) a two-step pathway that converts IMP to GMP; (2) a three-step pathway that starts with the deamination of guanine to xanthine, followed by phosphoribosylation to XMP and then conversion to GMP; or (3) direct guanine phosphoribosylation by HGPRT. To determine the role of the first of these pathways to guanylate nucleotide synthesis, an L. donovani line deficient in IMP dehydrogenase (IMPDH), the first step in the IMP to GMP pathway, was constructed by targeted gene replacement. The Δimpdh lesion triggered a highly restrictive growth phenotype in promastigotes in culture but did not impact parasitemias in mice. The dispensability of IMPDH in vivo is the first definitive demonstration that intracellular L. donovani amastigotes have access to a sufficient pool of guanine, xanthine, or guanylate precursors from the host.     

The epigenetics of Alzheimer's disease--additional considerations

The critical commentaries following our review of the epigenetics of Alzheimer's disease (AD) amplify a number of key points with respect to the role of 1-carbon metabolism, the phenomenon of allele-specific methylation, the potentially critical explanatory link provided by epigenetic mechanisms for genome-wide association and large-scale gene expression array studies, and new therapeutic approaches afforded by epigenetic manipulation in Alzheimer's disease.     

Surgical approach of complicated diverticulitis with colovesical fistula: technical note in a particular condition

Background: Diverticular disease of the colon is common in the Western world. With the first episode of diverticulitis, most patients will benefit from medical therapy, but in 10% to 20% of cases some complications will develop, such as intra-abdominal abscesses, obstructions, fistulas. In these conditions it is important to define the most appropriate surgical approach. Discussion: The management of diverticular disease has been successful owing to the advances in diagnostic methods, intensive care and surgical experience, but there is debate about the best treatment for some conditions. Fistulas complicating diverticulitis are the result of a localized perforation into adjacent viscera. In particular, the connection between the colon and the urinary tract is a serious anatomical abnormality that must be urgently corrected before a serious urinary infection results. Indications, timing and surgical procedures are determined by the severity of the disease and the patient’s general condition. Summary: Diverticular disease can lead to many complications. One of the most difficult to correct is an internal fistula, such as a colo-vesical fistula. The correct approach in cases where the disorder is clinically suspected has always been controversial, and the guidelines for sigmoid diverticulitis have not established the most appropriate method for diagnosis and treatment. At present, the surgical strategy for these cases requires interruption of the fistula and resection to remove the inflamed colonic segment, with or without primary anastomosis, focusing attention on the construction of the anastomosis to well vascularized and anatomically healthy tissues. It is clear, therefore, that establishing guidelines is difficult, because many pathological situations may be related to diverticulitis, and so, as our experience shows, the surgical approach has to be tailored to the patient’s general and local condition.     

Aurora B kinase expression in laryngeal squamous cell carcinoma and its prognostic implications

García‐Fernández E, De Diego J I, Collantes‐Bellido E, Mendiola M, Prim M P, Pérez‐Fernández E, Miguel‐Martín M, Nistal M & Hardisson D
(2011) Histopathology 58 , 368–376
Aurora B kinase expression in laryngeal squamous cell carcinoma and its prognostic implications Aims: To investigate the clinical and prognostic significance of Aurora B in laryngeal squamous cell carcinomas (LSCC). Methods and results: Aurora B protein expression was analysed in 259 LSCC. The proliferation index (Ki67) and the expression of other cell cycle control proteins, such as Aurora A, survivin and p53 was also determined. Aurora B was highly expressed in 55.4% of LSCC. High Aurora B expression levels were correlated with tumour recurrence (P = 0.01), death from disease (P = 0.05) and decreased disease‐free survival (P = 0.013) and overall survival (P = 0.04). Survivin expression was neither associated with clinicopathological characteristics nor with survival. However, survivin expression in the nucleus paralleled Aurora B expression (P = 0.014). Aurora A expression was associated significantly with increased tumour grade (P = 0.008). Multivariate analysis indicated that Aurora B was an independent predictor for LSCC‐specific disease‐free survival [hazard ratio (HR), 2.10; 95% confidence interval (95% CI), 1.25–3.52 (P = 0.005)] and overall survival [HR, 1.91; 95% CI 1.01–3.34 (P = 0.023)]. Conclusions: Aurora B may be a novel prognostic biomarker for LSCC and a potential therapeutic target in this type of tumour.