No prior studies have shown that pre‐operative loco‐regional therapy for hepatocellular carcinoma (HCC) improves survival following orthotopic liver transplantation (OLT). We performed subgroup ...analyses according to pathologic HCC stage among 168 patients who underwent OLT to test the hypothesis that pre‐operative loco‐regional therapy confers a survival advantage in a subgroup at intermediate risk for HCC recurrence. Patients with pathologic T3 HCC meeting the proposed UCSF expanded criteria (single lesion not exceeding 6.5 cm or two to three lesions none > 4.5 cm with total tumor diameter within 8 cm) had a similar 5‐year recurrence‐free survival as patients with pathologic T2 HCC (88.5% vs. 93.8%; p = 0.56). In the subgroup with pathologic T2 or T3 HCC, the 5‐year recurrence‐free survival was 93.8% for the 85 patients who received pre‐operative loco‐regional therapy, versus 80.6% for the other 41 patients without treatment (p = 0.049). The treatment benefit, according to 5‐year recurrence‐free survival, appeared greater for pathologic T3 (85.9% vs. 51.4%; p = 0.05) than T2 HCC (96.4% versus 87.1%; p = 0.12). In conclusion, although the lack of a randomized controlled design precludes drawing firm conclusions, our results suggest that pre‐operative loco‐regional therapy may confer a survival benefit after OLT in the subgroup with pathologic T2 and T3 HCC.
Cirrhosis is frequently complicated by ascites that may become resistant to diuretic therapy. Transjugular intrahepatic portosystemic shunts (TIPS) represent a new treatment for this debilitating ...condition. The aim of this study was to ascertain the clinical efficacy of TIPS, as well as its impact on renal function and on hormonal parameters. Five inpatients with refractory ascites were studied prospectively before TIPS, and 3 and 14 days after TIPS. After TIPS, ascites completely resolved or was minimal in all patients. Diuretics were discontinued in three subjects and decreased by at least 50% in two. One patient developed liver failure after TIPS and required liver transplantation; the others remained stable after a mean follow‐up of 14 months. Mean urinary sodium excretion increased from 2.1 ± 0.6 mEq/24 hr before TIPS to 13.0 ± 4.3 mEq/24 hr 14 days after TIPS. Mean serum creatinine and glomerular filtration rate also tended to improve during the study period. With the exception of the patient who developed liver failure, plasma aldosterone concentration decreased from a mean of 126.0 ± 29.9 ng/dL to 22.8 ± 6.8 ng/dL (P = .04), and plasma renin activity decreased from a mean of 9.0 ± 3.0 μg/L/h to 0.9 ± 0.1 μg/L/h (P = .08). Additionally, 19 patients who underwent TIPS for refractory ascites outside of this protocol were followed prospectively for a mean of 282 days. Clinical improvement in ascites control was noted in 74%, and the mean dose of diuretics was decreased by more than 50%. Nonresponders more often had underlying renal disease. In conclusion, TIPS is an effective therapy for refractory ascites in most patients. TIPS improves renal function and in most patients reverses underlying hormonal derangements. TIPS may have an adverse effect on hepatic function, necessitating careful patient selection.
Cerebral edema and intracranial hypertension, commonly present in fulminant hepatic failure, may lead to brainstem herniation and limit the survival of comatose patients awaiting liver ...transplantation before a donor organ becomes available. Also, they are likely responsible for postoperative neurological morbidity and mortality. Although intracranial pressure monitoring has been proposed to aid clinical decision making in this setting, its use in the prevention of brainstem herniation preoperatively, in the selection of patients for liver transplantation who have the potential for neurological recovery and in the maintenance of cerebral perfusion during liver transplantation has not been examined in detail. To address these issues, we established a protocol for intracranial pressure monitoring in comatose patients with fulminant hepatic failure as part of their preoperative and intraoperative management. Twenty adults and three children underwent intracranial pressure monitoring. Ten patients required preoperative medical therapy with mannitol, barbiturates or both for a rise in intracranial pressure above 25 mm Hg. Four patients had a sustained lowering of intracranial pressure, three of whom survived hospitalization. Six patients had intracranial hypertension refractory to medical management, were removed from a waiting list for a donor organ and died with brainstem herniation. Of the remaining 17 patients, 3 died of other causes while awaiting a donor organ, 2 recovered spontaneously without neurological sequelae and 12 underwent liver transplantation. All but one patient undergoing liver transplantation had transient intraoperative intracranial hypertension develop, requiring medical treatment. The 12 patients who had transplants recovered neurologically and were discharged from the hospital.
The intestinal mucosa metabolizes fatty acids differently when presented to the lumenal or basolateral membrane. Expression of both liver and intestinal fatty acid binding proteins (L- and I-FABPs) ...uniquely in the enterocyte offers a possible explanation of this phenomenon. An organ explant system was used to analyze the relative binding of fatty acids to each protein. More fatty acid was bound to L-FABP than to I-FABPs (28% vs. 6% of cytosolic radioactivity), no matter on which side the fatty acid was added. However, a 2–3-fold increase in fatty acid binding to the intestinal paralog was noted after apical addition of palmitic or oleic acid in mucosa from chow fed rats. When oleic acid was added apically, a 1.4-fold increase in binding to I-FABP was observed in mucosa derived from chronically fat fed rats, consistent with the previously observed 50% increase in the content of that protein. Immunocytochemical localization of both FABPs in vivo demonstrated an apical cytoplasmic localization in the fasting state, and redistribution to the entire cytoplasm after fat feeding. These data are consistent with the hypothesis that I-FABP may contribute to the metabolic compartmentalization of apically presented fatty acids in the intestine.
Both the enzymes of peroxisomal fatty acid beta-oxidation and the liver fatty acid-binding protein (L-FABP) are induced in
the liver by peroxisome proliferators, such as clofibrate (CF), as well as ...high fat diets. One proposed mechanism for this
induction is that it represents an adaptive response to altered intracellular fatty acid fluxes, mediated by dicarboxylic
fatty acids formed via the cytochrome P-450IVA1 omega-oxidation pathway. The studies presented in this paper were designed
to investigate the role of the products of P-450IVA1 omega-oxidation in the regulation of peroxisomal beta-oxidation and L-FABP.
In primary hepatocyte cultures exposed to CF, the increase in P-450IVA1 activity preceded the induction of peroxisomal beta-oxidation
and L-FABP. The CF-mediated increases in peroxisomal beta-oxidation and L-FABP, but not P-450IVA1, could be significantly
inhibited pretranslationally by concurrent exposure of cultured hepatocytes to inactivators of cytochromes P-450, such as
1-aminobenzotriazole and 10-undecynoic acid. Hexadecanedioic acid, a 16-carbon dicarboxylic fatty acid, that is poorly metabolized
in hepatocytes, induced peroxisomal beta-oxidation and L-FABP, but not P-450IVA1, via a pretranslational mechanism that was
not inhibited by 1-aminobenzotriazole. Long-chain monocarboxylic acids were without such inducing effect. In further studies,
non-beta-oxidizable dicarboxylic acid analogs were found to display greater potency as inducers of peroxisomal beta-oxidation
when compared to hexadecanedioic acid. The inducing effects of the dicarboxylic acid analogs were also independent of the
P-450 omega-oxidation pathway. The results of these studies suggest that the regulation of peroxisomal beta-oxidation enzymes
and L-FABP is mediated, to a significant extent, by poorly metabolized long-chain dicarboxylic acids formed via the P-450IVA1
pathway.
The purpose of this work is to create and synthesize a new class of chemicals: 3-cyano-2-substituted pyridine compounds with expected multitarget inhibition of histone deacetylase (HDAC) and tubulin.
...The target compounds (
and
) were synthesized utilizing 6-(4-methoxyphenyl)-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-cyanopyridine, with various linkers and zinc-binding groups (ZBGs).
Most of the tested compounds showed promising growth inhibition, and hydroxamic acid-containing hybrids possessed higher HDAC inhibition than other ZBGs. Compound
possessed the highest potency; however, it showed the most tubulin polymerization inhibition. Docking studies displayed good binding into HDAC1 and six pockets and tubulin polymerization protein.
Compound
could be considered a good antitumor candidate to go further into
and clinical studies.
The tomato leafminer, Tuta absoluta, now a major pest of tomato crops worldwide, is primarily controlled using chemical insecticides. Recently, high levels of resistance to the insecticide spinosad ...have been described in T. absoluta populations in Brazil. Selection of a resistant field-collected strain led to very high levels of resistance to spinosad and cross-resistance to spinetoram, but not to other insecticides that target the nicotinic acetylcholine receptor (nAChR). In this study the mechanisms underlying resistance to spinosad were investigated using toxicological, biochemical and molecular approaches. Inhibition of metabolic enzymes using synergists and biochemical assessment of detoxification enzyme activity provided little evidence of metabolic resistance in the selected strain. Cloning and sequencing of the nAChR α6 subunit from T. absoluta, the spinosad target-site, from susceptible and spinosad-resistant strains were done to investigate the role of a target-site mechanism in resistance. A single nucleotide change was identified in exon 9 of the α6 subunit of the resistant strain, resulting in the replacement of the glycine (G) residue at position 275 observed in susceptible T. absoluta strains with a glutamic acid (E). A high-throughput DNA-based diagnostic assay was developed and used to assess the prevalence of the G275E mutation in 17 field populations collected from different geographical regions of Brazil. The resistant allele was found at low frequency, and in the heterozygous form, in seven of these populations but at much higher frequency and in the homozygous form in a population collected in the Iraquara municipality. The frequency of the mutation was significantly correlated with the mortality of these populations in discriminating dose bioassays. In summary our results provide evidence that the G275E mutation is an important mechanism of resistance to spinosyns in T. absoluta, and may be used as a marker for resistance monitoring in field populations.
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•Selection in laboratory of field T. absoluta population led to very high resistance to spinosad.•Metabolism plays a minor role in resistance of T. absoluta to spinosad.•The G275E mutation in the Taα6 confers high level of resistance to spinosad in T. absoluta.•The target-site alteration in Taα6 highly correlated with the susceptibility of field T. absoluta populations.
Since our interim report of the intention-to-treat outcome of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC), we have performed a follow-up analysis of an expanded cohort ...of 70 patients to further assess whether the observed pattern and predictors of dropout are consistent with the rationale behind current HCC-adjusted Model for End Stage Liver Disease (MELD) organ allocation scheme. All except one patient had pretransplantation staging meeting our proposed expanded criteria—a single lesion ≤6.5 cm, or three or fewer lesions none >4.5 cm and total tumor diameter ≤8 cm. Thirty-eight patients received OLT. The cumulative probabilities of dropout at 6, 12, and 18 months were 7.2%, 37.8%, and 55.1%, respectively. The respective dropout probabilities would have been 11.0%, 57.4%, and 68.7% if the United Network for Organ Sharing (UNOS) criteria for exclusion (single lesion ≤5 cm or three or fewer lesions none >3 cm) were applied. Predictors of dropout with either criteria included three tumor nodules and a single lesion >3 cm at initial presentation, whereas preoperative chemoembolization or ablation therapies were associated with a lower risk for dropout only when applying the UNOS criteria for patient exclusion. In the subgroup with two or three lesions or a solitary tumor >3 cm, the cumulative probabilities of dropout were nine-fold higher than those with a single lesion ≤3cm (
P = .004). In conclusion, the low dropout rate in the first 6 months and the differing dropout risks based on tumor characteristics support further refinements in the HCC-adjusted MELD organ allocation scheme. (
Liver Transpl 2003;9:684-692.)
Cephalometric measurement of the face in terms of aesthetics
can be difficult and misleading due to the variability of the
intra-cranial reference lines. Extra-cranial references are
more accurate, ...but can be time-consuming to apply. The Aesthetic
Horizontal is an intuitive datum line related to the photographic
position of the head, which is expedient in use and clinically
relevant. A new and straightforward technique is presented for
transferring the Aesthetic Horizontal directly from the patient
to any recent radiograph, which can then be used as the reference
line for an aesthetic analysis of the facial profile. The instrument
used for measuring the profile angle and the transfer is readily
constructed from a protractor and small weight. The technique
can also be used to transfer any other orientation (e.g. Natural
Head Position or Natural Head Posture) from the patient to a
recent radiograph.
The prevalence of patent foramen ovale in patients presenting with non-haemorrhagic stroke or transient ischaemic attacks under the age of 40 years was determined by contrast echocardiography. ...Studies were performed at rest and with a Valsalva manoeuvre in 40 stroke patients and in an age and sex matched control group. Right-to-left shunting was found in 20 (50%) of the stroke patients and 6 (15%) of the controls (p less than 0.001). Paradoxical embolism through a patent foramen ovale may be an under-recognised cause of stroke in young adults.
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