Another question not yet addressed by controlled trials is how early should a recent-onset psychosis patient who does not respond to the antipsychotic drugs be switched to clozapine. On the one hand, if, as suggested, a longer duration of untreated psychosis has long-term detrimental effects37 and if most other antipsychotics are not effective in treatment-refractory Inhibitors,research,lifescience,medical psychosis,38 then the switch should occur as soon as it becomes apparent that the individual patient might not respond to the initial drug. Accumulating data indicate

that lack of response during the first 1 to 3 weeks of treatment is predictive of lack of response during the subsequent weeks.35,39,40 On the other hand, because of the rare and manageable, but potentially lethal, clozapine-induced agranulocytosis, most recentonset psychosis patients in daily clinical practice are treated with several antipsychotic drugs before they are switched to clozapine. Whether Inhibitors,research,lifescience,medical this clinical practice is also the optimal one remains to be seen. Inhibitors,research,lifescience,medical Selleck ZD1839 negative symptoms and cognitive deficits In contrast to the remission or at least marked amelioration of the psychotic symptoms, most patients show inadequate improvement in negative symptoms23,24,32,33 and cognitive deficits.41 Even when negative symptoms and

cognitive deficits are improved by antipsychotic drugs, the benefit is limited to a 0.2 to 0.3 effect size. This is not surprising considering the process of drug development in schizophrenia and the nature of negative symptoms and cognitive deficits. In the absence of a good conceptual model for Inhibitors,research,lifescience,medical schizophrenia, since the serendipitous observation that chlorpromazine ameliorates psychosis, all subsequent drugs have been screened in vitro and in animal models on the basis of their similarities to chlorpromazine or to other drugs already proven to ameliorate psychosis. To reach the market, drugs had only to prove that they ameliorate Inhibitors,research,lifescience,medical psychotic symptoms in clinical trials, and not negative symptoms or cognitive

deficits. Therefore, currently available agents have not been designed or selected to affect the two later manifestations of schizophrenia, negative symptoms and cognitive deficit. It also appears that the cognitive deficits and, possibly, negative symptoms are not only of recent onset, but are long-standing, core features of the schizophrenic disease6,10 and that cognitive impairment is inherited independently of psychosis.42 EPSs and therapeutic dose range In addition to the fact that antipsychotic drugs benefit some but not other aspects of psychosis, many recentonset psychosis patients show enhanced sensitivity to EPSs even at doses of antipsychotic that are within accepted therapeutic ranges.43 The enhanced sensitivity to antipsychotic-induced EPSs appears to be true for both typical44 and atypical drugs.

Conceptual preliminaries What reasons ground the philosophical doubts? Are they plausible? Three preliminary remarks need to be made before any serious discussion can start. Cobimetinib consciousness and mind One should not identify thinking about the nature of consciousness with thinking about the nature of the mind in general. Consciousness is

but one aspect of the mind, so the problem of consciousness is not identical to what is often called “the mind-body problem.” There are other philosophical Inhibitors,research,lifescience,medical problems regarding the mind. For instance, the problem of intentionality: How can it be that certain mental states (beliefs and desires, say) refer to entities or states of affairs that are external to themselves? Or the problem of rationality: How can it be that certain mental states are not merely causally Inhibitors,research,lifescience,medical related to other events, but can also be right or wrong, good or bad, reasonable or unreasonable? These and other issues regarding mental states need not involve consciousness; at least, it is not trivial to assume that

they do and would require argument. Inhibitors,research,lifescience,medical Meanings of “consciousness” The term “consciousness” has different meanings (as do its cognates in other languages—French conscience, German Bewusstsein, and so on). We speak of people Inhibitors,research,lifescience,medical being conscious when they are

generally aware or open to sensory stimulation, as opposed to being asleep, anesthetized, or in a coma. This basic consciousness is a precondition, but not identical to, phenomenal consciousness; the Inhibitors,research,lifescience,medical different feelings of pleasure and pain, or the sensations also of various kinds hinted at in du BoisReymond’s statement. The distinction is important. Flohr maintains that anesthesia studies may well point to a physical explanation of consciousness, and argues more specifically for the role of N-methyl-D-aspartate (NMDA) synaptic activity as a necessary and sufficient condition for the presence of consciousness.29,30 However, what explains our being aware at all need not be what explains specific qualitative features of consciousness. Among those who have produced alternative neuroscientific accounts of basic awareness, Crick and Koch31 have carefully avoided conflating it with phenomenal consciousness.

Since then, although molecular detection methods based on gene mutation determination have been carried out for several years, the clinical utility of the many molecular markers and their clinical applications remain limited for colorectal cancer patients. Therefore, there is real need for new molecular markers to improve tumour subclassification and prediction of clinical outcome. Inhibitors,research,lifescience,medical Microarray technology and gene expression profiling studies in colorectal cancer stimulated an interest in potential results that could be directly used in the routine clinical setting. Gene expression signatures

predictive of disease outcome and response to adjuvant therapy have been generated and are being evaluated in the clinical setting. Such molecular diagnostics and their promise of tailored therapy generated much excitement among researchers however they have yet to be fully incorporated into today’s standard of care as they are limited by difficulties in reproducibility, standardisation and lack proof of significance beyond traditional prognostic tools. One of the primary aims of this study was to characterise Inhibitors,research,lifescience,medical the Inhibitors,research,lifescience,medical expression profiles of candidate genes in colorectal tissue. Rigourous evaluation of appropriate genes with which to normalise real-time quantitative PCR data see more identified PPIA and B2M as the most

stably expressed genes in colorectal tissue samples. This enabled the development of a robust experimental approach which ensured that subsequent profiling of gene expression levels would be measured accurately and reproducibly in colorectal tissue. As a result, a comprehensive list of genes with highly differential

expression patterns was derived. CXCL12 and its receptors CXCR4 and CXCR7 The first candidates Inhibitors,research,lifescience,medical to be examined were the chemokine CXCL12 and its receptors CXCR4 Inhibitors,research,lifescience,medical and CXCR7, whose gene expression levels were, determined in 107 tumour and tumour associated normal colorectal tissues, the largest patient cohort reported to date. Significant down-regulation of CXCL12 in tumour compared to normal colorectal tissue was found, in contrast to CXCR4, which showed non-significant up-regulated expression levels in tumour tissues. The reduced expression of CXCL12 was noticed in both polyps and tumours. This could be explained by the role of CXCL12 in tumour immunology; however, it may highlight a possible tumour suppressor function of this gene. Investigation of the interaction between CXCL12, CXCR4 and CXCR7 not may provide some understanding of their functions and the role of each gene in regulating the expression of the others. Despite the reciprocal patterns of expression, strong positive correlation of CXCL12/CXCR4 and CXCL12/CXCR7 in both tumour and normal colorectal tissue was found. Moreover, CXCR4 and CXCR7 expression patterns correlated in the same manner. Saigusa et al. also reported significant positive correlation between expression levels of CXCL12 and CXCR4 in patients with rectal cancer who underwent preoperative CRT.

This discussion summarizes the relatively well-established scientific literature using cross-sectional, longitudinal, observational, and randomized controlled trials examining the effect of physical activity or cardiorespiratory fitness on regional gray matter volume. These studies have consistently

reported that higher fitness levels are associated with larger brain volumes, and that participation in only modest amounts of physical activity is sufficient for increasing gray matter volume in select brain regions. In addition, these results are in line with the animal literature and human cognitive literature described in preceding sections demonstrating the brain plasticity Inhibitors,research,lifescience,medical and specificity of the effects of greater amounts of physical activity. Volumetric data has proven useful in identifying how physical activity could alter the morphology of the adult brain. However, other neuroimaging methods including functional magnetic resonance imaging (fMRI) and resting state connectivity (rs) MRI approaches allow for an investigation of the Inhibitors,research,lifescience,medical effects of physical activity on brain network dynamics. In one of the earliest studies to examine this, Colcombe et al43 employed a task measuring selective attention and executive

control in a two-part Inhibitors,research,lifescience,medical experiment. In the first experiment, higher cardiorespiratory fitness levels were associated with better performance on the task and this was paralleled by increases in fMRI activity Inhibitors,research,lifescience,medical in the dorsolateral prefrontal and parietal

brain regions. The second experiment was a randomized exercise intervention in which adults were assigned to either receive a structured exercise regimen for 6 months or to a stretching and toning control group for the same amount of time. The participants performed the same selective attention task as the participants in the first experiment. The results from the randomized trial were strikingly similar to the results from the crosssectional Inhibitors,research,lifescience,medical study. That is, after 6 months of the intervention, the exercise group showed increased activity in the dorsolateral prefrontal cortex and parietal cortex and decreased activity in areas that support conflict monitoring such as the anterior cingulate cortex. These results are important because they demonstrate that in addition to volumetric changes resulting from exercise there are also significant changes in task-evoked brain function. Hence, the brain processes Resminostat task demands more efficiently after only 6 months of exercise. Although there are only several published studies using fMRI paradigms, each of these studies has found increased fMRI activity in prefrontal regions including during a semantic memory task,44 the digit symbol substitution task,45 and the selleck chemicals Stroop task46 as a function of either higher cardiorespiratory fitness levels or greater physical activity levels.

However, at 16 hours p.i., a clear difference is observed in the accumulated doxorubicin tumor concentrations, confirming earlier findings that efficacy improves with CTT2-peptide-bound liposomal

delivery systems. The extended times of accumulation may be a consequence of the different liposomal formulations used. Doxorubicin concentrations, in the form of CTT2-SL-DSPE-PEG3400 liposomes, continued Inhibitors,research,lifescience,medical to rise at later time points, as against the notable decreases in tumor concentrations observed with the untargeted CTT2-Caelyx-like liposomes. Future kinetic studies should monitor time-varying changes in tumor doxorubicin concentrations (in the form of CTT2-peptide targeted liposomes) at delayed time intervals (i.e., >16hrs p.i.) in order to determine whether antitumor efficacy studies could benefit from employing a dosing regimen reflecting longer, sustained tumor concentrations. Figure 11 Serum doxorubicin levels. Concentration of doxorubicin in (a) serum and (b) OV-90 xenograft mice Inhibitors,research,lifescience,medical (n = 3) treated with CTT2-SL-DSPE-PEG3400. Data are represented as a mean ± SEM. 4. Conclusions

Gelatinases, as extracellular targets, offer a viable alternative Inhibitors,research,lifescience,medical for tumor targeting. In gelatinase-expressing tumors, such as OV-90, targeted liposomal constructs, 125I-CTT2-SL and doxorubicin-containing CTT2, were found to be promising nanotherapeutic delivery vehicles for achieving therapeutic efficacy. Table 1 summarizes the tumor uptakes of various targeted and nontargeted liposomal formulations. Differences in tumor uptake were observed range ovarian cancer models, with Inhibitors,research,lifescience,medical the largest uptake values (i.e., ~17% ID/g at 6hrs) achieved in OV-90 hindlimb xenografts using CTT2-peptide-bound liposomes (~500 peptides per liposome). Further, CTT2-bound micelles and liposomes, as well as the CTT2 peptide, Inhibitors,research,lifescience,medical demonstrated equivalent overall tumor uptake values, suggesting similar

bioactivity. However, to achieve controlled and sustained drug release, we chose a nanoformulation instead of a prodrug approach (i.e., drug-peptide coupling). Our findings show that the utilization of these targeted nanoformulations results in a more efficient method for delivering therapeutics Adenosine than passive (i.e., nontargeted) liposomal products (i.e., Caelyx). The development of CTT2-peptide-bound liposomes as a clinically promising targeting therapeutic that has the potential to improve drug delivery to human ovarian cancers will rest on the additional assessment of shelf and in vivo stability studies and formal toxicity testing. Table 1 Tumor uptake of various liposomal constructs. ​ Figure 3 Schematic illustration of CTT2-PEG-3400-DSPE TGF-beta assay liposome [22].
Live cells are protected from the surrounding environment by the cell membrane, which only allows compounds with a small molecular size to pass this barrier into the cell. Some drug molecules, on the other hand, are large hydrophilic molecules, and this creates major limitations for their penetration through the cell membrane.

Using the APLS formula, 45.6% of children were within 10% of actual measured weights, whereas 42.3% of children were within 10% of actual weights using the Luscombe and Owens formula. Using the derived formula, 47.5% of children would have had estimated weights within 10% of their actual weights. After Chi squared testing, these differences were not found to be statistically significant. Inhibitors,research,lifescience,medical Discussion The APLS formula to calculate weight in children is a commonly used method, especially for critically ill children in whom it is impractical or unsafe to acquire weight on a scale. During resuscitation of children, weight is used to

guide drug dosages, intravenous Inhibitors,research,lifescience,medical (IV) fluid boluses, equipment size, defibrillation and cardioversion dosages. As described

in the introduction, there are a number of methods used to estimate weight in children [3-9]. However, At the Eric Williams Medical selleck chemicals Sciences Complex, the most commonly used method is the APLS formula. It has been shown by several studies that the original APLS Inhibitors,research,lifescience,medical formula underestimates weight, however all of these studies have been performed on non-Caribbean populations [3-7]. In 2007, Luscombe and Owens examined data from over 17000 children and found that the APLS formula was found to have underestimated weight by a mean of 18.8% [3]. Several subsequent studies in Australia and the United Kingdom also demonstrated the tendency for the APLS formula to underestimate weight in children in developed countries [4-6,9]. Inhibitors,research,lifescience,medical This included a review of 93827 children over a 5year period from 2003 to 2008 by Luscombe et al. [10]. In light of this, the most Inhibitors,research,lifescience,medical recent edition of the APLS manual recommends the use of the Luscombe and Owens formula in children aged 6 – 12years old, with retention of the original

APLS formula for those aged 1 – 5years. In India, however, Varghese et al. examined 500 outpatient children and found the APLS formula to overestimate weight in their population by a mean of 2–3kg [7]. In addition, a 2010 study click here of the accuracy of various weight estimation methods in South African children concluded that the APLS formula and Broselow tape were more accurate than the Luscombe and Owens formula over all age groups in this population [11]. The Broselow tape was designed for use in children from 45cm to 145cm in length [5]. Although it has been validated in several studies as a reliable tool for estimating weight [5,7,11-13], it is not commonly used in Trinidad. One of the largest studies of the Broselow tape was performed by Lubitz et al. in the United States of America [1]; out of 937 patients it was found that 79% of patients had estimated weights using the Broselow tape which were within 15% of their actual weights. Krieser et al.

Microinjection of bicuculline into the RVLM of the OVX and OVX+E rats led to a significant increase on the MAP with no significant effect on HR compared with their pre-injection value (OVX: ΔMAP: 30.4±5.2 mmHg and ΔHR: 12.2.0±8.3 bpm; OVX+E: ΔMAP: 35.95±4.4 mmHg and ΔHR: 9.2±6.11 bpm, P<0.01). Similar to pervious experiments, 10 minutes later, glutamate was injected into the BST of the OVX and OVX+E rats. The depressor Inhibitors,research,lifescience,medical and bradycardic responses caused by stimulation of the BST were similar to those of the pervious experiments

(OVX: ΔMAP: -22.5±2.68 mmHg and ΔHR: -12.2±2.1 bpm; OVX+E: ΔMAP: -28.1±3.7 mmHg and ΔHR: -14.2±3.5 bpm, P<0.01, t test). The magnitude of depressor response during stimulation of the BST 10 minutes after bicuculline microinjection Inhibitors,research,lifescience,medical into the RVLM were reduced to almost 50% of their control value (OVX: ΔMAP: -11.9±3.3 mmHg and ΔHR: -10.0±2.5 bpm; OVX+E: ΔMAP: -16.3±2.4 mmHg and ΔHR: -7.5±1.7 bpm, P<0.01). 60 min after the microinjection of bicuculline into the RVLM, the magnitude of depressor and bradycardic responses by re-stimulation of the BST approximately returned to their control value (OVX: ΔMAP: -15.8±3.7 mmHg and ΔHR: -9.0±4.5 bpm; OVX+E: ΔMAP: -23.0±3.6 mmHg and ΔHR: -12.5±2.5 bpm, figures 6

Inhibitors,research,lifescience,medical and ​and7).7). Figure 6 This figure shows tracings of blood pressure and heart rate responses elicited by microinjection of glutamate into the BST before (control) and after injection of bicuculline Inhibitors,research,lifescience,medical (1 mM/50 nl) into the RVLM and re-stimulation of BST at 10 and 60 minutes after … Figure 7 This figure shows the cardiovascular effect of glutamate (0.25 M/20 nl) injection into the BST before (control) and 10, 20, 40, and 60 min after injection of bicuculline into the RVLM in OVX and OVX+E rats. *Significant difference with pre-injection Doxorubicin values … Cardiovascular Response Elicited by Glutamate Injected into the BST after the Injection

of Phaclophen in the RVLM To find the possible effects of GABAB receptors of the RVLM on the cardiovascular responses of the BST, phaclophen, a GABAB antagonist, Inhibitors,research,lifescience,medical was microinjected into the RVLM of the OVX and OVX+E Chlormezanone rats. No significant difference was found in both MAP and HR compared with their pre-injection values (OVX: ΔMAP: 4.3±1.1 mmHg and ΔHR: 3.3±2.1 bpm; OVX+E: ΔMAP: 6.9±1.4 mmHg and ΔHR: 8.7±3.2 bpm). Similar to pervious experiments, microinjection of glutamate into the BST elicited bradycardic and depressor responses (OVX: ΔMAP: -26.1±3.0 mmHg and ΔHR: -16.9±3.1 bpm; OVX+E: ΔMAP: -26.8±2.62 mmHg and ΔHR: -13.6±5 bpm, P<0.01, t test). Unlike the effect of bicuculline, microinjection of phaclophen did not alter the magnitude of depressor and bradycardic responses by re-stimulation of the BST, 10, 20, 40, and 60 minutes after microinjection of phaclophen into the cardiovascular site of RVLM (figures 8 and ​and99).

The loss of regional interneuronal homeostasis must not necessarily affect huge brain areas; it might be only limited to certain small and circumscripted regions in the brain. As a consequence, clinicians should be able to choose the pharmacologically appropriate medication for the affected brain region.71 Concluding remarks Stem-cell maintenance and generation take place in a distinct microenvironment where appropriate external signals can best exert their regulatory function

Inhibitors,research,lifescience,medical on these cells. Signals provided by neural growth factors are responsible for neural stem-cell growth. Since components of regular stem-cell maintenance like BDNF are also implicated in mechanistic models characteristic of mood disorders, they thus offer new targets for pharmacologic intervention in neuropsychiatrie disease. More thorough knowledge about this complex connection mayhelp us render antidepressant treatment more efficient and reduce the check details undesirable side effects that impair patient compliance. Inhibitors,research,lifescience,medical So far there is no stem-cell-based approach really on the horizon for treating depression or any other psychosis. Selected abbreviations and acronyms 5-HT serotonin BDNF brain-derived neurotrophic factor CREB cAMP response element binding protein ES cells embryonic stem cells SCBI stem cell-based interventions
Pharmacological developments in the 20th

century have produced a wide range of drugs that have greatly improved the treatment of many Inhibitors,research,lifescience,medical serious diseases. In psychopharmacology, the discoveries of antipsychotic, Inhibitors,research,lifescience,medical tranquillizing, or antidepressant agents, such as selective serotonin reuptake inhibitors (SSRIs), were milestones in the treatment of mental illness. However, compared with the general pharmacological progress, the psychopharmacological development, whilst noteworthy, has been somewhat less spectacular. Despite

heavy investments Inhibitors,research,lifescience,medical in mental health-related research,1 there have been few important discoveries since the 1950s, when a number of psychopharmacological agents were discovered that are still in use. For example, clozapine was synthesized over 50 years ago but continues to be described as the “most effective antipsychotic drug” for the treatment of schizophrenia,2 and is recommended in the UK National Institute of Health and Clinical Excellence (NICE) 2009 update to its schizophrenia guidance.3 Traditionally, Tolmetin the drugs developed have been “one size fits all,” ie, standardized drugs targeting symptoms or syndromes that can be shared by various diseases, rather than being disease-specific, let alone patient-specific. Even though health care is by definition personalized in the sense that the patient’s needs broadly determine the nature of recommended treatment, eg, type and dosage of medication, traditional medication leaves little room for individual variations in responses to treatment, notably through the randomized double -blind procedure used in clinical trials that is incompatible with individualized assessment.

We did not preclude about the exact determination of the different phases but rather a global trend of variations

in DTI parameters reflecting physiological changes relative to WM maturation. Although the harmlessness of MR examination on fetuses during gestation has been well documented, only the clinical use of fetal MRI is ethically justifiable in humans. Reasons to perform fetal MRI are related to a pathological risk for the fetus. Nevertheless, for these Inhibitors,research,lifescience,medical fetuses, conventional MRI was totally normal according to neuropediatric radiology expert (NG). Finally, a last limitation is relative to the cross-sectional design of the study that does not provide the maturation processes at the Selleckchem Everolimus individual level. However, from an ethical point of view, it appears impossible to obtain longitudinal data from the same normal fetuses during gestation. Conclusion The present study demonstrates the feasibility of in utero DTI tractography to evidence different phases of WM maturation Inhibitors,research,lifescience,medical and different time courses in the myelination maturation processes occurring during gestation in human large WM bundles. DTI appears as a promising tool to investigate noninvasively

brain maturation of human fetuses. Nevertheless, Inhibitors,research,lifescience,medical significant improvements in sequence design and postprocessing are required to allow a real clinical transfer of this powerful technique to characterize in utero developmental maturation and brain disorders. Inhibitors,research,lifescience,medical Acknowledgments This work is supported by the CNRS.
Handedness is an important aspect of human psychology, however, its origins, neurobiological substrates, and function are not well understood.

Apart from obvious functional differences, subtle cognitive and behavioral differences have been demonstrated in relation to various handedness measures (Cherbuin and Brinkman 2006; Leask and Crow 2006; Siengthai et al. 2008) but their ecological Inhibitors,research,lifescience,medical significance is uncertain. In this paper, we will review the available evidence investigating a link between handedness and short- and long-term biological and cognitive vulnerabilities, and we will test such an association in a large sample using a longitudinal design less open to bias than cross-sectional investigations. A number of competing theories have been developed to account for handedness differences in humans. A main genetic origin of handedness is widely Casein kinase 1 accepted and Annett’s and McManus’ theories of a single gene, two-allele determinant of handedness have accumulated substantial supporting evidence. Annett (1998) proposed that a gene responsible for handedness phenotype could present either with a dominant allele for handedness direction (RS+), which shifts handedness to the right or a neutral allele (RS−), which leaves direction of handedness to chance.

Caveats to this approach, and

for the initial combined resection-ablation strategy, are that for conventional thermal tumor ablation, lesions should be less than 4 cm. If bilobar disease is present, then ablation should not compromise inflow or outflow tracts as a consequence of hepatic swelling, as this may compromise future liver resection. Utilization of intra-operative ultrasound is employed both for targeting TTA, avoiding treatment failure, and protecting vital intrahepatic structures. Use of ablation for management of synchronous CRHM during primary tumor resection may limit the morbidity when compared to simultaneous colorectal and liver resections, selleck chemical Although both can be performed Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical safely in selected patients (46). It is worth noting that in the setting of CRHM, the need for resection of the primary tumor in the absence of over bleeding or obstruction may not be necessary and could delay more pressing issues including the management of CRHM or extrahepatic disease (47,48). Bilobar CRHM with the ability to render an appropriate volume of liver free

of disease, upon which the future hepatic remnant can be based This is perhaps the most common clinical scenario in which ablation complements resection. Any staged treatment plan Inhibitors,research,lifescience,medical will ultimately require that after planned interventions, a portion of liver remains with uncompromised inflow and outflow, ideally completely clear of disease. Although not the focus of this review, portal vein embolization (PVE) has enabled the hepatic surgeon to offer staged approaches to a greater number of CRHM patients through the optimization of Inhibitors,research,lifescience,medical future liver remnant volume (49,50). Consider the patient with right hepatic lobe dominant disease and an isolated CRHM in segment III. The authors would advocate Inhibitors,research,lifescience,medical that this patient should proceed to undergo a partial left hepatic lobectomy (laparoscopic approach preferred) and thermal tumor ablation

of any lesion at risk of crossing the main portal scissurae as defined by the middle hepatic vein. Subsequently, the right portal vein is embolized to induce left liver hypertrophy in anticipation of a right formal hepatectomy. In a patient with more extensive, bilobar CRHM in segments II/III, IV, VIII (dome), and VI lesion, several approaches are why possible. The optimal strategy would be based on the relationship of the tumors to major vascular and biliary structures, in addition to optimizing liver remnant volume. One approach would be to perform a formal left hemi-hepatectomy (clearing II/III and IV-A) and non-anatomic resections of the segment VIII and segment VI lesions. Another approach, again depending on proximity to vital intrahepatic structures, would be to use thermal ablation for the segment VIII lesion and resect the others as previously proposed.