Non-Hodgkin’s lymphoma, the fourth common worldwide malignancy in

Non-Hodgkin’s lymphoma, the fourth common worldwide malignancy in males with a frequency of 6.1%,24 is another cause. History Taking Taking a complete history of the patient is necessary to determine the etiology of LAP. Age, time of presentation, duration of symptoms, underlying diseases, and circumstances in which LAP was detected are of great value. Furthermore, a history of exposure to animals, ingestion of certain drugs and foods, risky behaviors, and history of recurrent infection and immunodeficiency can help the diagnosis. A history of environmental exposure to tobacco, alcohol, Inhibitors,research,lifescience,medical and ultraviolet radiation increases the suspicion of the metastatic carcinoma

of Inhibitors,research,lifescience,medical the internal organs, head, and neck as well as skin malignancies. Immune deficient patients, like those with AIDS, have wide differential causes of LAP and malignancies like Kaposi’s sarcoma; however, non-Hodgkin’s lymphoma should always be taken into consideration.16 A family history of malignant disorders may raise the Inhibitors,research,lifescience,medical physician’s suspicion to distinct etiologies of LAP such as breast carcinomas, melanoma, and dysplastic nevus syndrome.16 Also, if LAP lasts less than two weeks or over one

year without increasing in size, the probability of malignancy is quite low.16 Related Symptoms and Signs A recent upper respiratory infection can cause cervical LAP, which is usually self-limited. A triad of moderate to high fever, MK-2206 in vivo pharyngitis, and moderately tender lymph node with splenomegaly (>50%) characterizes classic infectious mononucleosis.25Cytomegalovirus, toxoplasmosis, HIV, and human herpes virus type 1 can cause mononucleosis-like syndrome.25The typical symptoms of Inhibitors,research,lifescience,medical toxoplasmosis are flu-like symptoms, with a single swollen cervical lymph node.14,16HIV in the acute phase presents with mononucleosis-like syndrome. Its presentation consists

of fever, fatigue, pharyngitis, rash, malaise, Inhibitors,research,lifescience,medical arthralgia, and LAP, which appear 2-6 weeks after exposure to the HIV virus.26,27 A recent travel to an endemic area or exposure to an infected patient with TB along with painless, MycoClean Mycoplasma Removal Kit gradually progressive, single or matted lymph nodes can suggest mycobacterium TB involvement.28The coexistence of LAP and symptoms like arthralgia, muscle weakness, unusual rash, and anemia may direct the diagnosis of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematous, and dermatomyositis.1,16 On the other hand, whenever dermatomyositis is diagnosed, the underlying malignancy should be ruled out. Significant fever, night sweats, and unexplained weight loss (more than 10% in less than 6 months) are the “B symptoms” of lymphoproliferative disorders, but they may also be seen in TB or collagen vascular diseases.29 Petechiae and purpura associated with LAP and splenomegaly may be detected in acute leukemias.

Reaction time The participants must respond to a yellow spot appe

Reaction time The participants must respond to a yellow spot appearing in the screen by moving the hand away from the press pad button. Reaction time is divided between a single point and a five-choice reaction time phase. Reaction time primarily measures processing speed. Outcome measures were reaction time (the speed with which the subject releases the press pad button in response to the onset of a ON-01910 molecular weight stimulus in either a single location or a five-choice location);

Inhibitors,research,lifescience,medical and movement time (the time taken to touch the stimulus after the press pad button has been released in trials in which stimuli appear in a single location or a five-choice location). A lower score is better for both tests. Outcome measures were also accuracy scores (the total number of trials in which the response is recorded as correct for assessment trials in which the stimuli appear Inhibitors,research,lifescience,medical in a single or a five-choice

location), with a higher score being better. Spatial working memory A number of colored boxes are shown on the touch screen. By touching the screen and using a process of elimination, the participant searches for Inhibitors,research,lifescience,medical blue ‘tokens’ in the boxes. Participants are instructed not to return to a box where a token has been found previously. The number of boxes is gradually increased to a maximum number of eight. Spatial working memory primarily measures working memory. Outcome measures were between errors (defined as times the subject revisits a box in which a token has previously been found); within errors (defined as the number of errors made within a search, that is, the number of times a subject revisits a box already found to be empty during the same search); strategy (counting the number of times Inhibitors,research,lifescience,medical the subject begins a new search with a different box for six- and eight-box problems only); mean time to first Inhibitors,research,lifescience,medical response (the mean time between the problem being presented to the subject and the subject first touching the screen to open a box); and

mean time to last response (the time between the problem being presented to the subject and the subject’s last screen touch to open a box to locate the final token for the problem). A lower score was better for all tests. Verbal recognition/recognition memory Participants are instructed to remember words, a total of 15, presented individually on the screen in front of them. PAK6 Participants are asked to recall as many of the presented words initially after the presentation. Twenty minutes after the initial recall phase, a second retrieval phase, a recognition test is conducted. Words are presented sequentially and participants are asked to press ‘yes’ or ‘no’, according to their recognition of the words as being presented previously or not. Verbal recognition/recognition memory primarily measures verbal learning and memory.

No major complication such as fetal distress or death was reporte

No major complication such as fetal distress or death was reported during the month among the participating women. Discussion The growing concern about the risks of

fasting during Ramadan in adults with medical problems, especially among diabetes patients, have prompted authorities all around the world, particularly in countries with Muslims majority, to update recommendations and guidelines on the management of diabetes during Ramadan.8,9 The revised recommendations are made to reduce possible complications especially with hypoglycemia during the fasting period as well as NVP-AUY922 mw uncontrolled hyperglycemia after Inhibitors,research,lifescience,medical the sunset meal.10,11 Ramadan-focused educations have resulted in minimizing the complications of hypoglycemia during

pregnancy by Inhibitors,research,lifescience,medical empowering pregnant patients to change their lifestyles.11,12 All the medical diabetes guidelines formulated so far,8,9,13 for Ramadan fasting prohibit pregnant diabetes from fasting during Ramadan, since it is categorized as a high risk pregnancy. Despite being exempted from Ramadan fasting by Islamic Inhibitors,research,lifescience,medical fiqh rulings, in reality many of pregnant women including those with diabetes during pregnancy insist on carrying out this religious duty as they perceive themselves to be healthy. As health providers, it is our obligation to ensure that the fasting is carried out without complications so as to ensure the safety of women with pregnant diabetes and their fetuses. Denying patients’ wishes to fast may complicate the matters since, such patients may ignore Inhibitors,research,lifescience,medical the medical advices and modify their own treatment, which can endanger their health and that of their fetuses. Consenting to their request, on the other hand, will ensure their compliance Inhibitors,research,lifescience,medical and reduce any untoward effect of their decision. Over the three years period in which the present study was performed, a

total of 37 pregnant diabetic women insisted on carrying out the Ramadan fasting despite medical advices. To ensure safety, they had to commit themselves to good glycemic controls after Rebamipide being told of possible untoward risks to themselves and their fetuses. Clinical features of these women did not reveal any statistical difference with majority (64.9%) of them being Type 2 diabetes. Many women in their second trimester fasted as they felt physically better as compared to their hyperemesis period, which had occurred in their first trimester. However, more patients did not fast in their third trimester, since this period is more physically demanding and the patients are more likely to feel tired. Although the mean ages (table 1) in the T2DM and GDM groups were about the same, majority of T2DM group who fasted were primigravidae and majority of patients in the GDM group were multiparae.

The current guidelines of the World Federation of Societies

The current guidelines of the World Federation of Societies

of Biological Psychiatry (WFSBP) for the pharmacological selleck products treatment of OCD24 grant the highest category of evidence (“A”, ie, full evidence from several RCTs) for the SSRIs escitalopram, fluvoxamine, fluoxetine, paroxetine, and sertraline, as well as for the TCA clomipramine, but not for any other drug. Because Inhibitors,research,lifescience,medical clomipramine is less well tolerated than the SSRIs, it was given a recommendation grade of 2 (moderate risk benefit ratio), while the SSRIs received the highest recommendation grade 1 (good risk:benefit ratio). As for citalopram, only one positive double-blind, placebo-controlled study was published, and only a recommendation grade Inhibitors,research,lifescience,medical of 3 (limited evidence from controlled studies) was given. This WFSBP guideline mentions that usually lower response rates are achieved in OCD in comparison with other anxiety disorders, and that sometimes only partial remission is achieved. As a rule, somewhat higher doses are used for these drugs in OCD than for other anxiety disorders, higher doses being associated with greater efficacy in some, but not all, evaluations. Inhibitors,research,lifescience,medical In several longterm and relapse-prevention studies, SRIs were shown to be superior

to placebo, pointing to the requirement of long-term treatment of OCD. According to a systematic review on all long-term, placebo-controlled trials with SSRIs in OCD,25 the likelihood of relapse during 24 to 52 weeks of treatment was significantly lower on an SSRI than with placebo. Inhibitors,research,lifescience,medical Thus, successful treatment with SSRIs should be maintained at the maximal effective dose for at least 12 months. An extensive display of the many acute Inhibitors,research,lifescience,medical treatment studies on SSRIs versus placebo, different doses of SSRIs, SSRIs versus other SSRIs, clomipramine versus placebo, SSRIs versus clomipramine, SSRIs versus placebo, or clomipramine for continuation

treatment and SSRIs vs placebo or clomipramine for relapse-prevention treatment can also be found in the guidelines on core interventions in the treatment Resveratrol of OCD of the National Institute for Health and Clinical Excellence (NICE) of the British Psychological Society and the Royal College of Psychiatrists.21 According to these guidelines, the initial pharmacological treatment in adults with OCD should be one of the following SSRIs: fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram. Of note, studies on the efficacy of escitalopram in OCD were published only later.26 A current Cochrane review of placebo-controlled SSRI trials in OCD, comprising 17 studies with 3097 participants, also showed efficacy for all SSRIs included (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline).27 The authors detected no statistical differences in short-term therapeutic action among the individual SSRIs.

52 Fmr1 knockout mice confirm the global upregulation of transcri

52 Fmr1 knockout mice confirm the global upregulation of transcripts. In FXS, synaptic transcript products upregulate through FMRP’s failure to recruit CYFIP1, a cytoplasmic FMRl-interacting protein that is also a eukaryotic

translation initiation factor 4E (eIF4E) binding protein. Interestingly, loss of FMRP in both mice and humans results in abnormal dendritic spine morphology, a Inhibitors,research,lifescience,medical characteristic of many intellectual disability-associated disorders. Case studies of nonsyndromic forms of autism have identified de novo variants in genes involved in translational control. Of note, eIF4E is downstream of several of these signaling pathways, and mutations directly in eIF4E have been discovered in three autistic individuals.53 This study found de novo

gene disruptions in 14 autism candidate genes and 13 CNVs that overlapped with FMRP target genes,30 which supports the notion that FXS-associated autistic phenotypes may result from disrupted expression levels of specific gene products. It is hypothesized that disrupted protein translation may lead to abnormal neuronal Inhibitors,research,lifescience,medical morphology and, hence, abnormal synaptogenesis. This faulty brain connectivity may be responsible for the global impairment in learning and memory associated with disorders of intellectual disability like FXS. However, comorbid autism in these disorders could reflect a disruption of the same developmental mechanism but perhaps of more specialized Inhibitors,research,lifescience,medical circuits or synapses responsible for social learning. Inhibitors,research,lifescience,medical Many candidate genes for ASD pathology map onto the endosomal pathway.54 A family of protein exchangers localized on endosomes have recently been studied in syndromic autism. Christiansen syndrome, which presents like Angelman syndrome, has been associated with the functional loss of the endosomal Na+/H+ exchanger NHE6 (also known as SLC9A6).55,56 Many cases of nonsyndromic autism have been linked to deficits in cellular trafficking of proteins57; an autistic individual with a chromosomal

inversion Inhibitors,research,lifescience,medical that disrupts receptor expression-enhancing protein 3 (REEP3), a putative regulator of vesicle trafficking between the ER and Golgi network58; two individuals with mutations in the small GTPase RAB39B and an individual with a haploinsufficiency of the small GTPase RAB39B59; Megestrol Acetate a translocation that disrupts the NEUROBEACHIN (NBEA) gene.58 This evidence suggests mostly GTPases and their regulators of the recycling endosomes at the presynapse are affecting the transport of specific cargo. A recent study reported that collapse of the recycling endosome results in a decrease in spine density in an activity-dependent manner.61 We can predict how mutations in genes involved in protein trafficking can directly affect neurite morphogenesis and synaptogenesis. Cellular trafficking of proteins is also indirectly critical for membrane dynamics underlying mechanisms of synaptic plasticity and neurotransmission.

Elderly persons tend to go to bed earlier, and the duration of th

Elderly persons tend to go to bed earlier, and the duration of their sleep is often decreased. This has been interpreted as secondary to a lesser secretion of melatonin, as found in many studies,53 or to the fact that cell death in the SCN leads the remaining neurons to generate a shorter endogenous circadian rhythm with age. Indeed, experiments with partial destruction of the SCN in laboratory rodents have shown that the circadian

period becomes shorter under these conditions, but there are also negative findings. In elderly persons, the secretion of melatonin is decreased, Inhibitors,research,lifescience,medical and this decrease could in part be due to the lack of exposure to daytime light, since a trial in a small population of subjects indicated that exposure to light could increase the nocturnal secretion of melatonin with a concomitant improvement Inhibitors,research,lifescience,medical in sleep.54 There are, however, studies reporting no changes in melatonin with age in humans.55 The neurodegeneration of the nucleus selleck chemical basalis of Meynert, a major Inhibitors,research,lifescience,medical source of cholinergic innervation, might explain sleep alteration in dementia,

since this group of cells is involved in rest/activity and is among the structures that send efferent messages to the SCN.56 Measurements in human chronobiology Chronobiological protocols can be cumbersome for two reasons. First, because of the necessity to study several biological cycles. Indeed, one cannot conclude that a change occurred in the frequency of any phenomenon when the study duration is too short for repetitions of the phenomenon to have occurred. This is a challenging issue for

psychiatry, where many disorders show recurrent decompensations. An observation Inhibitors,research,lifescience,medical lasting 1 to 2 times the theoretical duration of a cycle is necessary to infer that one has indeed identified a periodic change and to measure the Inhibitors,research,lifescience,medical duration of that cyclic change. A clinical observation of a patient during a time equivalent to 3 to 4 times the theoretical duration of a cycle is necessary to conclude that a treatment has influenced the course of a recurrent disorder. When the manifestation recur Sodium butyrate in shorter cycles, such as with 48-h rapid cycling bipolar disorder, or with the premenstrual syndromes, the duration of studies becomes a lesser constraint. The second reason for which chronobiological protocols are complex is the nature of the measured phenomena. Indeed, biological rhythms are found in brain waves, in hormone concentration in blood, and in cognitive abilities. Measuring these phenomena can be difficult and necessitate more or less invasive methods, while less invasive techniques only allow long-term studies. Among these, the simplest one remains the repeated use of questionnaires to evaluate subjective biological functions such as mood, energy, or pain.

Whilst CNS disorders are currently largely diagnosed based on the

Whilst CNS disorders are currently largely diagnosed based on their clinical presentation, they show heterogeneous clinical courses and response to the treatment. Here molecular imaging has begun to provide evidence of different molecular pathologies within

the same syndrome, potentially explaining some of the heterogeneity in CNS disorders. Inhibitors,research,lifescience,medical This has clear translational potential in schizophrenia where the finding that there are “dopaminergic” and “nondopaminergic” subtypes suggests the latter group could be identified for emerging alternatives to the dopamine blocking drugs that are currently available. The use of DaTscan for differentiation of parkinsonian syndromes has already made it to the clinic. Furthermore, as shown in schizophrenia and dementia, molecular imaging is beginning to be applied to identify high-risk groups prior to the onset of the frank disorder. There is thus the potential to intervene early, before disability has progressed, to prevent the onset of disorder. How molecular imaging can be applied for the development Inhibitors,research,lifescience,medical of new Icotinib ic50 treatments Molecular imaging has the potential to inform drug discovery in a number of ways. Firstly, it enables Inhibitors,research,lifescience,medical specific drug targets to be identified during the development and progression of a disorder. In schizophrenia, for example, molecular imaging has determined that current drug treatments act downstream of the major dopaminergic

abnormality, and has identified the presynaptic regulation of dopaminergic function as a key new target for drugs, whilst in AD the identification of neuroinflammation early in the disease has contributed to the development of anti-inflammatory Inhibitors,research,lifescience,medical treatments for the disease. Secondly, Inhibitors,research,lifescience,medical molecular imaging provides biomarkers to monitor treatments and provide pathophysiologically relevant end points to evaluate new therapies, as illustrated by the use of [18F]DOPA to monitor stem cell transplants in PD and [11C]PIB

to assess the efficacy of antiplaque agents in AD. Thirdly, it identifies endophenotypes to stratify patients Thalidomide with a given disorder on the basis of their underlying neurobiology. Such neurobiologcally defined endophenotypes will trigger significant paradigm shifts in new drug development for CNS disorders, from the past empirical approach based on trying treatments in heterogenous patient samples to targeting treatments to patients with a homogenous pathophysiology. Finally, the identification of molecular imaging biomarkers in a number of CNS disorders means it is possible to predict the efficacy of new treatments in animal models by measuring biomarkers, and to design clinical trials in an efficient way by subject stratification based on the endophenotypes. Acknowledgments Dr Kim thanks Sang Bin Hong for her kind assistance. Dr Kapur was supported by the NIHR BRC to SLaM NHS Trust.

Contributor Information Hidenobu Suzuki, Department of Psychiatry

Contributor Information Hidenobu Suzuki, Department of Psychiatry, Tanzawa Hospital, 557 Horiyamashita, Hadano, Kanagawa, 259-1304, Japan. Yuichi Inoue, Shakomae Kokorono Clinic [Y.I.], Tokyo, Japan. Akiyoshi Nishiyama, Department of Psychiatry, Tokai University Hachioji Hospital [A.N.], Tokyo, Japan. Katsunaka Mikami, Department of Psychiatry, Course of Specialized Clinical Science, Tokai University School of Medicine Inhibitors,research,lifescience,medical [K.M.], Kanagawa, Japan. Keishi Gen, Department of Psychiatry, Seimo Hospital [K.G.], Gunma, Japan.
Sleep disturbances constitute a core symptom of bipolar disorder (BD). Up to 90% of individuals

experiencing a major depressive episode (MDE) complain of sleep disturbance, typically sleep-onset insomnia, click here frequent nocturnal arousals, and early morning Inhibitors,research,lifescience,medical awakenings [Tsuno et al. 2005]. Insomnia is a risk factor for the development of MDEs and may precede the onset of depression in those with recurrent illness [Breslau et al. 1996; Ford and Cooper-Patrick, 2001]. Sleep disturbance is also a risk factor for suicide [Liu and Buysse, 2005]. Hence, patient care and treatment should include an assessment focusing on sleep function, as well as appropriate measures to improve and optimize sleep architecture. Normal sleep Inhibitors,research,lifescience,medical architecture can be separated into rapid eye movement (REM) and non-REM (NREM) sleep, which

alternate in a cyclic fashion. The first hours of sleep include a high percentage of time spent in the Inhibitors,research,lifescience,medical four stages of NREM sleep. Stages 1 and 2 are described as a transition from drowsiness to light sleep, whereas stages 3 and 4 are collectively known as slow wave sleep (SWS). As sleep progresses, more time is spent in the REM stage. This normal sleep architecture is altered in BD. Sleep of patients with bipolar depression Inhibitors,research,lifescience,medical is fragmented by REM disinhibition, reduced SWS duration, and impaired sleep continuity [Kupfer, 1995]. REM disinhibition features shortened latency to REM sleep and prolonged total REM duration [Kupfer, 1995]. Impairments in sleep continuity include prolonged sleep

latency, and increased number of intermittent arousals and early morning awakenings [Argyropoulos and Wilson, 2005]. The reciprocal interaction model assumes that Adenosine sleep disturbance in depression is due to dysfunction of the central neurotransmitter systems: acetylcholine (Ach), norepinephrine (NE) and serotonin (5-HT), all of which modulate mood and sleep wakefulness [Hobson et al. 1975]. Ach stimulates REM sleep, whereas NE and 5-HT inhibit it. Depression is strongly associated with an overactive cholinergic system and deficient monoaminergic transmission. This imbalance has been held responsible for disinhibiting REM sleep and may also promote increased wakefulness resulting in reduced sleep continuity and efficiency [Sharpley et al. 2005].

McClure et al75 found that sad, happy, and fearful peer facial ex

McClure et al75 found that sad, happy, and fearful peer facial expressions were misinterpreted more often by children with bipolar disorder in comparison with children with anxiety disorders or subjects with no psychiatric diagnosis. In addition, when viewing neutral faces, youth with bipolar disorder perceived more hostility and experienced more anxiety in comparison with youth without a psychiatric disorder.76 In another study, children and adolescents with Inhibitors,research,lifescience,medical bipolar disorder were more likely

to mistakenly characterize facial emotions than youths without a psychiatric disorder.77 Moreover, the pediatric patients with bipolar disorder were less likely to choose appropriate responses when presented with interpersonal situation vignettes when compared with a healthy control group.77 These emotional and social interpretation deficits may Inhibitors,research,lifescience,medical be due to neural circuitry differences. For example, Rich et al78 found that youths with bipolar disorder have less functional connectivity in areas that may be involved in processing facial expressions and emotional stimuli. These areas include

the neural circuitry between the left amygdala and areas bordering the right posterior cingulate/precuncus and the right fusiform gyrus/parahippocampal gyrus. Other studies have found that youths with bipolar disorder Inhibitors,research,lifescience,medical exhibit less cognitive flexibility in adapting Inhibitors,research,lifescience,medical to changing contingencies in cognitive testing.77,79 Pavuluri et al80 found evidence to suggest that activation patterns in brain regions are different in pediatric bipolar patients in comparison with healthy controls when subjects observed angry and happy faces. These Inhibitors,research,lifescience,medical activation differences implicate a disturbance in affect neurocircuitry which may contribute to emotional dysregulation

and social cognitive deficits in youths with bipolar disorder.80 An understanding of these emotional and cognitive processing findings may have clinical relevance, as they might allow clinicians to direct a portion of their psychotherapy to address Resminostat interpersonal skills and allow educators to modify lesson plans in order to accommodate the possible cognitive deficits. Neurochemical differences Similarly to serotonergic dysfunction observed in depressive conditions, using positron emission tomography (PET), a lower serotonin transporter binding potential (proportional to serotonin transporter number) was found in adults with bipolar disorder in comparison with adults with no psychiatric conditions.81 In addition, using magnetic resonance spectroscopy (MRS), elevated gray matter lactate and y-aminobutyric acid levels have been found in adults with bipolar disorder in comparison with adults without a psychiatric diagnosis.

Allen et al (59) reported on pump complications in 544 patients

Allen et al. (59) reported on pump complications in 544 patients treated at MSKCC between 1986 and 2001. The overall pump complication rate was 22%. These complications consisted of arterial thrombosis (6%), extrahepatic perfusion (3%), incomplete hepatic perfusion (2%), and hemorrhage (2%). However, the complications during the earlier half of the study period (1986-1993) were significantly

higher (25%) than the later half of the study time (1994-2001, 18%, P=0.05). The majority of complications were also salvaged, with 80% of pumps functioning for a minimum Inhibitors,research,lifescience,medical of 2 years. Overall pump failure rates were 9% at 1 year and 16% at two years. Hepatobiliary toxicity is the most serious and dose-limiting complication of HAI. It occurs at a higher incidence with FUDR (60). Elevation of serum transaminase Inhibitors,research,lifescience,medical levels is often the first sign of hepatotoxicity. Increases in alkaline phosphatase and Vemurafenib manufacturer bilirubin are more serious and show evidence of more significant hepatic

damage. Therefore, changes in liver functions should be monitored Inhibitors,research,lifescience,medical regularly during treatment with HAI FUDR. A dose-adjusting algorithm has been devised based on changes in liver function tests (61). Addition of dexamethasone to HAI of FUDR may reduce incidence of bilirubin elevation and also increase the rate of treatment response as demonstrated by Kemeny et al. (6,7). In the adjuvant pump studies at MSKCC, more than twofold increase in alkaline phosphatase levels was observed in 14% to 43% of patients. Total bilirubin elevation > 3.0 mg/dL was seen in 0 to 19%, and biliary stents were placed in 0 to 8%. A higher incidence of biliary toxicity was seen in Inhibitors,research,lifescience,medical the study where FUDR dose was 0.14 (as compared to 0.12 in the newer studies). In a new study that was recently published in JCO, patients

Inhibitors,research,lifescience,medical were randomized to receive Bev versus no Bev in addition to HAI + FOLFOX or FOLFIRI. In the group that received Bev, bilirubin ≥3 mg/dL was seen in 5 of 35 versus zero of 38 patients (P=0.02) and biliary stents were placed in four versus zero patients (P=0.05). This study was terminated early due to biliary toxicity. Biliary sclerosis is not observed with HAI of 5-FU (58) which tends to associate more with increased risk of myelosupression (58). Therefore, one logical approach to reduce biliary toxicity is to alternate between HAI FUDR and HAI 5-FU. Davidson et al. (62) used HAI FUDR at a dose of below 0.1 mg/kg/day for seven days followed by HAI boluses of 5-FU 15 mg/kg on days 14, 21, and 28. With this schedule, 12 (21%) patients had temporary liver enzyme elevations and only 2 patients (3.5%) developed biliary sclerosis. In another study, HAI FUDR was administered for seven days, and HAI 5-FU bolus was given on days 15, 22 and 29, with the cycle repeated every 35 days. None of the patients in this study had treatment terminated because of hepatobiliary toxicity (63).