SERUM NESFATIN-1 LEVEL IN HEALTHY SUBJECTS WITH WEIGHT-RELATED ABNORMALITIES AND NEWLY DIAGNOSED PATIENTS WITH TYPE 2 DIABETES MELLITUS; A CASE-CONTROL STUDY.

CONTEXT: Nesfatin-1 is a novel peptide with both central and peripheral anorexigenic regulatory properties. Besides its effects on food intake, few studies have suggested a possible role for this peptide in the pathogenesis of diabetes mellitus type 2. OBJECTIVE: To compare serum levels of nesfatin-1 between healthy, normal-weight persons and three groups including healthy underweight, healthy obese and diabetic subjects. DESIGN: Prospective, case-control study, performed between January 2015 and January 2016. SUBJECTS AND METHODS: Fasting levels in serum nesfatin-1 were measured in 30 healthy, normal-weight individuals (controls), 30 healthy underweight persons, 30 healthy obese persons, and 30 patients with newly diagnosed diabetes type 2 using standard enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: The mean serum nesfatin-1 level was significantly higher in controls (2.61 ng/mL) compared to that in obese (1.13 ng/mL) and diabetic (0.99 ng/mL) patients; and significantly lower than that in the underweight group (3.50 ng/mL). The obese and diabetic groups were comparable in this regard. No significant association was found between serum nesfatin-1 level and age, sex, or body mass index. CONCLUSIONS: Serum nesfatin-1 is possibly associated with weight-related abnormalities in otherwise healthy subjects and diabetes type 2. Obesity and diabetes type 2 may share a common pathologic point in this regard.

Retrograde amnesia after intravenous sedation and general anaesthesia in a dental hospital.

Midazolam, a benzodiazepine, is commonly used for intravenous sedation for dental procedures and, together with other benzodiazepines, can cause anterograde amnesia. Retrograde amnesia, however, is rare. It is defined as a loss of access to memory of events that occurred, or information that was learned, before the injury or event that caused the amnesia. We know of no reports of this occurring after the intravenous use of midazolam alone and few after general anaesthesia. We present two cases of retrograde amnesia: one after intravenous sedation and one after general anaesthesia.

A review of the indicator of sedation need (IOSN): what is it and how can it be improved?

The indicator of sedation need (IOSN) is a tool that has been devised to help with clinical decision-making, health needs assessment and commissioning purposes for the provision of sedation services. It can potentially increase access for patients to sedation when used as a screening tool, however, there are some shortcomings in the IOSN, such as the fact that it is not speciality specific, that can reduce its efficacy. As such, in its current form the IOSN may not be robust enough to be used as a sole commissioning tool and may in fact create barriers to patients that would benefit from sedation. By addressing these issues and understanding its limitations, the IOSN can be used more effectively for its intended purposes.

Prospective evaluation of two-stage hepatectomy combined with selective portal vein embolisation and systemic chemotherapy for patients with unresectable bilobar colorectal liver metastases.

BACKGROUND: Liver resection is contraindicated in patients with multiple bilobar colorectal liver metastases because of the small liver remnant. An alternative strategy which may be curative is a two-stage hepatectomy in which the cancer is resected from one lobe and regeneration allowed prior to contralateral lobe resection. OBJECTIVE: To assess the feasibility, risks, and outcomes in a prospectively applied strategy for two-stage hepatectomy. METHODS: Over a 6-year period, 14 of 280 patients undergoing liver resection for colorectal liver metastases (5%) were considered for two-stage hepatectomy. Surgery was combined with chemotherapy in all (n = 14) and portal vein embolisation (PVE) selectively (n = 5). Median follow-up was 43 months. RESULTS: Both stages were completed in 11 of 14 patients (78%). There were no deaths. Post-operative complication rates were 0% (1st hepatectomy) and 27% (2nd hepatectomy). The 5-year survival after the second hepatectomy was 50%. The mean disease-free survival was 25 +/- 7.5 months. CONCLUSION: Two-stage hepatectomy combined with systemic chemotherapy and PVE can produce long-term survival in patients with multiple bilobar colorectal liver metastases.

The cyto- and genotoxicity of organotin compounds is dependent on the cellular uptake capability.

Organotin compounds have been widely used as stabilizers and anti-fouling agents with the result that they are ubiquitously distributed in the environment. Organotins accumulate in the food chain and potential effects on human health are disquieting. It is not known as yet whether cell surface adsorption or accumulation within the cell, or indeed both is a prerequisite for the toxicity of organotin compounds. In this study, the alkylated tin derivatives monomethyltin trichloride (MMT), dimethyltin dichloride (DMT), trimethyltin chloride (TMT) and tetramethyltin (TetraMT) were investigated for cyto- and genotoxic effects in CHO-9 cells in relation to the cellular uptake. To identify genotoxic effects, induction of micronuclei (MN), chromosome aberrations (CA) and sister chromatid exchanges (SCE) were analyzed and the nuclear division index (NDI) was calculated. The cellular uptake was assessed using ICP-MS analysis. The toxicity of the tin compounds was also evaluated after forced uptake by electroporation. Our results show that uptake of the organotin compounds was generally low but dose-dependent. Only weak genotoxic effects were observed after exposure of cells to DMT and TMT. MMT and TetraMT were negative in the test systems. After forced uptake by electroporation MMT, DMT and TMT induced significant DNA damage at non-cytotoxic concentrations. The results presented here indicate a considerable toxicological potential of some organotin species but demonstrate clearly that the toxicity is modulated by the cellular uptake capability.

Trimethylantimony dichloride causes genotoxic effects in Chinese hamster ovary cells after forced uptake.

In our study, we demonstrate that trimethylantimony dichloride (TMSb) does not induce micronucleus (MN) formation, chromosome aberrations (CA) or sister chromatid exchanges (SCE) under normal conditions in Chinese hamster ovary (CHO-9) cells in vitro up to an applied concentration of 1 mM, nor is it significantly cytotoxic. TMSb is taken up by the cells in a dose-dependent manner, but the percentage uptake of incubation substrate is low (max 0.05%). Intracellular TMSb concentration is two-fold increased after electroporation and under these forced uptake conditions MN formation is also significantly elevated. These data indicate that resistance to TMSb in CHO-9 cells occurs at the uptake and not at the intracellular level.

Forced uptake of trivalent and pentavalent methylated and inorganic arsenic and its cyto-/genotoxicity in fibroblasts and hepatoma cells.

Mammals are able to convert inorganic arsenic to mono-, di-, and trimethylated metabolites. In previous studies we have shown that the trivalent organoarsenic compounds are more toxic than their inorganic counterparts and that the toxicity is associated with the cellular uptake of the arsenicals. In the present study, we investigated cyto-/genotoxic effects of the arsenic compounds arsenate [As(i)(V)], arsenite [As(i)(III)], monomethylarsonic acid [MMA(V)], monomethylarsonous acid [MMA(III)], dimethylarsinic acid [DMA(V)], dimethylarsinous acid [DMA(III)], and trimethylarsine oxide [TMAO(V)] after an extended exposure time (24 h) and compared the uptake capabilities of fibroblasts (CHO-9 cells: Chinese hamster ovary) used for genotoxicity studies, with those of hepatic cells (Hep G2: hepatoma cell-line). To find out whether the arsenic compounds are bound to membranes or if they are present in the cytosol, the amount of arsenic was measured in whole-cell extracts and in membrane-removed cell extracts by inductively coupled plasma-mass spectrometry (ICP-MS). In addition, we forced the cellular uptake of the arsenic compounds into CHO-9 cells by electroporation and measured the intracellular arsenic concentrations before and after this procedure. Our results show that organic and inorganic arsenicals are taken up to a higher degree by fibroblasts compared to hepatoma cells. The arsenic metabolite DMA(III) was the most membrane permeable species in both cell lines and induced strong genotoxic effects in CHO-9 cells after an exposure time of 24 h. The uptake of all other arsenic species was relatively low (<1% by Hep G2 and <4% by CHO cells), but was dose-dependent. Electroporation increased the intracellular arsenic levels as well as the number of induced MN in CHO-9 cells. With the exception of As(i)(III) and DMA(III) in CHO-9 cells, the tested arsenic compounds were not bound to cell membranes, but were present in the cytosol. This may indicate the existence of DMA(III)-specific exporter proteins as are known for As(i)(III). Our results indicate that the uptake capabilities of arsenic compounds are highly dependent upon the cell type. It may be hypothesized that the arsenic-induced genotoxic effects observed in fibroblasts are due to the high uptake of arsenicals into this cell type. This may explain the high susceptibility of skin fibroblasts to arsenic exposure.

Uptake of inorganic and organic derivatives of arsenic associated with induced cytotoxic and genotoxic effects in Chinese hamster ovary (CHO) cells.

Humans are exposed to arsenic and their organic derivatives, which are widely distributed in the environment, via food, water, and to a lesser extent, via air. Following uptake, inorganic arsenic undergoes biotransformation to mono- and dimethylated metabolites. Recent findings suggest that the methylation reactions represent a toxification rather than a detoxification pathway. In the present study, the genotoxic effects and the cellular uptake of inorganic arsenic [arsenate, As(i)(V); arsenite, As(i)(III)] and the methylated arsenic species monomethylarsonic acid [MMA(V)], monomethylarsonous acid [MMA(III)], dimethylarsinic acid [DMA(V)], dimethylarsinous acid [DMA(III)], trimethylarsenic oxide [TMAO(V)] were investigated in Chinese hamster ovary (CHO-9) cells. The chemicals were applied at different concentrations (0.1 microM to 10 mM) for 30 min and 1 h, respectively. Cytotoxic effects were investigated by the trypan blue extrusion test and genotoxic effects by the assessment of micronucleus (MN) induction, chromosome aberrations (CA), and sister chromatid exchanges (SCE). Intracellular arsenic concentrations were determined by ICP-MS techniques. Our results show that MMA(III) and DMA(III) induce cytotoxic and genotoxic effects to a greater extent than MMA(V) or DMA(V). Viability was significantly decreased after incubation (1 h) of the cells with > or = 1 microM As(i)(III), > or = 1 microM As(i)(V), > or = 500 microM MMA(III), > or = 100 microM MMA(V), and 500 microM DMA(V) and > or = 0.1 microM DMA(III). TMAO(V) was not cytotoxic at concentrations up to 10 mM. A significant increase of the number of MN, CA and SCE was found for DMA(III) and MMA(III). As(i)(III + V) induced CA and SCE but no MN. TMAO(V), MMA(V) and DMA(V) were not genotoxic in the concentration range tested (up to 5 mM). The nuclear division index (NDI) was not affected by any of the tested arsenic compounds after a recovery period of 14 to 35 h. When the uptake of the chemicals was measured by ICP-MS analysis, it was found that only 0.03% MMA(V) and DMA(V), and 2% MMA(III), As(i)(III) and (V) were taken up by the cells. In comparison, 10% of the DMA(III) dose was taken up. The total intracellular concentration of all arsenic compounds increased with increasing arsenic concentrations in the culture medium. Taken together, these data demonstrate that arsenic compounds in the trivalent oxidation state exhibit the strongest genotoxic effects. Trivalent organoarsenic compounds are more membrane permeable than the pentavalent species. The potency of the DNA damage decreases in the order DMA(III) > MMA(III) > As(i)(III and V) > MMA(V) > DMA(V) > TMAO(V). We postulate that the induction of genotoxic effects caused by the methylated arsenic species is primarily dependent upon their ability to penetrate cell membranes.