Additional investigations, such as a cranial magnetic resonance imaging (MRI) scan, 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET), cerebrospinal fluid (CSF) examination, and AD biomarkers (β-amyloid42 [Aβ42], total tau protein [t-tau], and tau phosphorylated at

position threonine 181 [p-tau]), may Inhibitors,research,lifescience,medical further help to establish the correct diagnosis. A typical clinical picture for AD consists of a slowly progressive memory loss and loss of other neuropsychological functions (eg, praxis, speech), absence of medical, neurological, or psychiatric condition that may explain the memory loss, brain imaging that is in line with AD, and biomarkers supporting the diagnosis Inhibitors,research,lifescience,medical of AD.5 Atypical symptoms such as early neurological symptoms, mood disorder, visual hallucinations, or an atypical sudden onset may hint at a diagnosis other than AD. Comprehensive information on the clinical diagnosis and management of the most important dementing diseases other than AD (eg, vascular cognitive impairment, frontotemporal dementia (FTD), Lewy body dementia (LBD), corticobasal syndrome, progressive supranuclear palsy, Parkinson’s disease-related dementia, Huntington’s disease, prion diseases, normal-pressure hydrocephalus, limbic Apoptosis inhibitor encephalitis and other toxic and metabolic disorders) is provided Inhibitors,research,lifescience,medical in the recent EFNS-ENS guidelines (European

Federation of Neurological societies-European Neurological Society).6 Inhibitors,research,lifescience,medical For the first time, the recently released revised diagnostic criteria for AD involve biomarkers to support the diagnosis of AD: (i) reduced

CSF Aβ42; (ii) raised CSF tau (t-tau and p-tau); (iii) positive PET amyloid imaging; (iv) typical patterns in 18F-FDG-PET; and Inhibitors,research,lifescience,medical (v) disproportionate atrophy involving medial, basal, and lateral temporal lobes and medial and lateral parietal cortices.5,7-9 If available, these biomarkers may be helpful in the distinction between AD and non-AD memory impairment. However, some alterations and biomarker constellations thought to be typical for AD may also be found in other neurodegenerative disorders, possibly hampering the discrimination between AD and non-AD etiology of memory impairment. For example, CSF Aβ42 values have been found to be decreased in AD as well as in LED patients,10 and CNS amyloid accumulation can be observed in patients Levetiracetam with AD and LED using amyloid imaging.11 Hippocampal atrophy, as seen in many AD patients, is also found in patients with frontotemporal dementia (FTD), possibly due to hippocampal sclerosis related to this disease.12 Neuropsychological testing During the diagnostic process for memory complaints, it is essential to objectively assess memory impairment, and the impact on activities of daily living, in order to discriminate between subjective memory impairment (SMI), mild cognitive impairment (MCI), and dementia (mild, moderate, or severe).

1993; Estrada and DeFelipe 1998; Attwell et al. 2010); (2) during an increase

in cortical activity callosal fibers, consistent with their origin from glutamatergic neurons (Barbaresi et al. 1987), release glutamate along their course (Kukley et al. 2007; Ziskin et al. 2007) possibly excitating NO-producing intracallosal neurons (Iadecola and Nedergaard 2007) through NMDA receptors (Garthwaite 1991, 2008); interaction of glutamate with NMDA receptors could therefore be necessary for BOLD responses in the cc as in other CNS regions, where application Inhibitors,research,lifescience,medical of NMDA receptor antagonists attenuates blood flow responses (Iadecola et al. 1996; Nielsen and Lauritzen 2001; Gsell et al. 2006; Hoffmeyer et al. 2007; Busija Inhibitors,research,lifescience,medical et al. 2007; Tiede et al. 2012).

However, a concomitant role of astrocytes in neurovascular coupling (Attwell et al. 2010) in the cc cannot be ruled out. As the present findings indicate that glial cells lack NO-producing enzymes, glutamate released from callosal axons could induce release of vasoactive Inhibitors,research,lifescience,medical agents other than NO from astrocyte end feet, like for example, cyclo-oxygenase (COX) products, whose inhibition significantly reduces vasodilation (Zonta et al. 2003; Takano et al. 2006). Paclitaxel Conclusion In summary, we demonstrated that the adult rat cc contains a sizeable population of NADPH-d+/nNOSIP Inhibitors,research,lifescience,medical neurons amounting to over 2000 intracallosal cells. Their distribution shows a lateromedial gradient, a greater number of neurons being found in the lateral stereotaxic planes than in the more medial ones. NADPH-d+/nNOS+ intracallosal cells present a considerable Inhibitors,research,lifescience,medical morphological heterogeneity. In addition, their location in the ependymal regions of the cc and their association with intracallosal blood vessels suggests an active role for them in regulating both CSF composition and intracallosal blood vessels. Acknowledgments

We are grateful to Silvia Modena for the language review. This paper is dedicated to the memory of Tullio Manzoni (1937–2011) who devoted his life to studying the corpus callosum. Conflict of Interest None declared.
Depression is a complex disorder adversely affecting millions of individuals, with enormous Histamine H2 receptor social and economic costs (WHO 2001). The World Health Organization has predicted depression will be the second leading cause of disability worldwide by 2020 (Murray and Lopez 1996). Despite its public health importance, the biological mechanisms underlying the depression etiology remain uncertain. Studies suggest that genetic factors play an important role in depression (Duffy et al.

g. bleeding, obstruction, perforation) or cases where the

hepatic metastases may be rendered resectable. In the latter two groups, the following treatment strategies have been employed: (I) resection of the primary followed by systemic chemotherapy followed by liver resection ± additional systemic chemotherapy (Staged approach), (II) systemic chemotherapy followed by simultaneous resection of the primary and hepatic metastases (Synchronous approach) and (III) systemic chemotherapy followed by resection of hepatic metastases followed by resection of the primary (so-called “Reverse Strategy”) Inhibitors,research,lifescience,medical (5). The potential risks and benefits of synchronous compared to staged resections are summarized in Table 1. Advocates of a staged approach endorse this strategy due to concerns about increased morbidity and mortality associated with simultaneous resection of the colorectal primary and hepatic metastases. Concerns about the potential safety and technical feasibility of rectal

resections and major hepatic resections have been raised as concerns Inhibitors,research,lifescience,medical regarding simultaneous resections (6). In addition, some surgeons and oncologists have pointed to complications associated Inhibitors,research,lifescience,medical with the unresected primary tumor as another reason for not adopting synchronous resections (7,8). In contrast, proponents of synchronous resections point to the morbidity associated with multiple procedures as a major advantage of a simultaneous resection approach. From an oncologic standpoint, synchronous resection following neoadjuvant chemotherapy provides insight into the GDC-0449 cost patient’s tumor biology and prevents a delay in administering systemic therapy which may occur due to complications

following resection of Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical the colorectal primary. Table 1 Potential risks and benefits of synchronous versus staged resection. The current discussion will review the existing literature on staged versus synchronous resection of colorectal cancer and isolated hepatic metastases. Two key issues will be considered: the safety of each resection strategy and oncologic outcomes followed a synchronous versus staged resection. Lastly, we will examine the emerging data available regarding a minimally invasive approach to synchronous colorectal disease with hepatic metastases. Safety of simultaneous versus staged resections The first question to be addressed when considering Mephenoxalone a synchronous versus staged resection for colorectal tumors with hepatic metastases is the safety of each approach. A study by Vogt et al. was among the first to examine the safety of synchronous resection for colorectal cancer (9). The authors compared operative mortality between 19 patients who underwent a synchronous resection to 17 patients who had a staged resection (median 2 months between resections). There were no perioperative deaths in either group.

A feasible strategy of limiting glutamate release could be the use of ligands for metabotropic receptors, that could be safer than compounds directly affecting the machinery of release. AMPAkines, drugs potentiating the function of AMPA EGFR inhibitor receptors have also been in development for some time. Tianeptine, an antidepressant, that has been for some years in the market, has shown unique properties in the regulation of neuroplasticity, and this effect, seems

to be Inhibitors,research,lifescience,medical mediated by its modulation of the glutamatergic system.116-119 A novel approach to depression, regulation of circadian rhythms, has been the basis for the development, of an antidepressant, with an entirely new mechanism of action. Changes in the sleep-wake cycle and in the periodicity of circadian rhythm profoundly influence the state of mood. Sleep disturbances and depression/mood disorders are interlinked.120 Among the typical and recurring features of depressed individuals is insomnia Inhibitors,research,lifescience,medical with early-morning awakenings; indeed, disturbed sleep is one of the diagnostic criteria in Inhibitors,research,lifescience,medical DSM-IV. likewise, it has been shown that manipulations of circadian rhythms, such as total or REM sleep deprivation or phase

advance in the sleepwake cycle, may have therapeutic action in the treatment of depression.121 It is not clear whether sleep disturbances are part, of the clinical picture of depression or represent a causative factor; some studies have shown that changes in sleep architecture persist into the remission phase, while improvement in clinical state is frequently preceded by sleep changes.120,121 The first (and so far only) antidepressant in this class is agomelatine, an agonist, of MT1/MT2 melatonergic receptors

Inhibitors,research,lifescience,medical and antagonist of serotonin 5-HT2C receptor. Agomelatine was shown to induce synchronization of circadian rhythms and to be efficient in preclinical studies with different animal models of depression. ‘ITtic antidepressant efficacy of the drug in humans was positively tested in several Inhibitors,research,lifescience,medical clinical trials,122 and its regulation of the sleep-wake cycle has been proven.123,124 A recent study of long-term (10 months) treatment showed efficacy of agomelatine against placebo, while the percentage of patients mafosfamide reporting adverse effects was similar in the two groups.125 Furthermore, it presents clinical benefits such as respect of sexual function, absence of discontinuation symptoms, and no effect, on body weight.126,127 Agomelatine could be the first, antidepressant, with a really new mechanism of action to hit the market which will also achieve a better quality of remission by directly acting on the residual symptoms. Finally, among the novel compounds in development there are also a few monoamine-based putative antidepressants, namely agonists or antagonists of the most. ) recently characterized subtypes of serotonin receptors, 5-HT4, 5-HT6, and 5-HT7 (Table II) .

Validation of these data in future cohorts of patients will need to be conducted. Conclusion AG,

ACAG, and BD failed to detect the presence of clinically significant hyperlactatemia. The PP2 assessment of AG in critically ill patients is highly limited given the prevalence of hypoalbuminemia. If an assessment of the AG is needed, it should be done in concert with serum albumin and serum lactate measurements (ACAG and ALCAG). We believe that serum lactate levels should be routinely obtained in all patients admitted to the ICU in whom the possibility of shock/hypoperfusion Inhibitors,research,lifescience,medical is being considered. Unmeasured anions exclusive of serum lactate and serum albumin are frequently present in significant quantities in patients who are critically ill. Competing

interests The authors declare that they have no competing interests. Authors’ contributions Inhibitors,research,lifescience,medical SS participated in the conduct, design, and data acquisition of the study. DD conducted the surveys, and helped draft the manuscript. CJ participated in its design and coordination of the study. MS participated in the design of the study and helped to draft the manuscript. LC conceived of the study, participated in its design and coordination, performed the statistical analysis, and helped to draft the manuscript. All authors read and approved Inhibitors,research,lifescience,medical the final manuscript. About the authors LC is a nephrologist and intensivist. SS is a general surgeon. DD is an intensivist. CJ is an anesthesiologist and an intensivist. MS is the Director of the ICU at George Washington University Hospital. Pre-publication history The pre-publication history Inhibitors,research,lifescience,medical for this paper can be accessed here: http://www.biomedcentral.com/1471-227X/8/18/prepub Acknowledgements This paper was supported by Satellite Research: Norman S. Inhibitors,research,lifescience,medical Coplon Extramural Research Grant.
For some time, health services research has focused on the issue of frequent use of the ED. This growing literature finds that smaller subgroups of patients with repeat visits use disproportionate

amounts of services. [1-4] From both clinical and policy perspectives, few would argue that frequent use of the ED is an optimal next treatment approach. It is incumbent upon the field to identify the health and social issues driving frequent use of the ED and to identify suitable interventions to improve care and reduce the strain on scarce ED resources. Research on frequent users of the ED find that they have fewer resourcesand higher rates of mortality and morbidity than non-frequent users. [5,6] Psychiatric and substance use problems are commonly found to be contributing factors to frequent ED use. [3,7-14] Little research, however, has focused on the association between substance use and psychiatric comorbidity and the frequency of ED use. A group of studies has found that comorbid substance use disorders were associated with increased ED use among persons with schizophrenia.

6 times more likely to have suicidal thoughts, 2.9 times more likely to have a plan for suicide, and 3.7 times more likely to have made a suicide attempt themselves. The pain of dealing with the loss of a loved one by suicide coupled with shame, rejection, anger, perceived responsibility, and other risk factors, can be too much to bear, and to some, suicide seems like the only way to end the pain.

Inhibitors,research,lifescience,medical Some may feel closer to their loved one by taking their life in the same way. Indeed, a survivor told us of how her mother’s death by suicide was so difficult to bear for her sister who, like her father, also struggled with bipolar disorder, that her sister completed suicide in the exact same way the following year, on the same date, Inhibitors,research,lifescience,medical at the same time. Finally, as with other types of losses, yearning for a loved one can be so intense, that the desire to join the loved one in death can be overwhelming. Complicated grief in survivors of suicide While research results are mixed regarding whether grief differs by mode of death,43 data suggest that the incidence of CG is Inhibitors,research,lifescience,medical high among survivors of suicide, as survivors of suicide loss are at higher risk of developing CG.11,19 Specifically, Mitchell and colleagues57 selleck chemicals reported that the rate of CG was 43% among their pilot study population

of 60 Caucasian, Christian, employed, mostly female suicide bereaved participants grieving a total of 16 deaths collectively. This is at least double the rates of up to 10% to 20% of CG reported in the Inhibitors,research,lifescience,medical general population.17,18 Further, Mitchell and colleagues report that suicide survivors closely related to the deceased experience rates of complicated grief at twice the level as friends, coworkers, and relatives (57% to 80% vs 14% to 28%). Individuals from that same sample who developed CG were almost 10 times more likely to have reported suicidal ideation 1 month after the death of their loved ones, controlling for depression.30 In another sample of participants with Inhibitors,research,lifescience,medical CG, suicide bereaved participants reported twice the rate of recurrent and current depression compared with other bereaved individuals, reported higher rates of

suicidal ideation before the death, and were at least as likely to report suicidal ideation since the death as other bereaved participants not suffering from complicated grief.58 Finally, Latham and Prigerson found that CG is associated with higher levels of suicidal ideation independent of PTSD and depression.29 One study49 suggests that 3 to 5 years is the time point at which grief after a suicide loss begins to integrate, raising the question of how the time frame used in discussions of normal and integrated grief applies to grief after suicide, and therefore what is the “normal” timeline for grief after suicide. That said, in at least one sample studied,59 symptoms of traumatic grief 6 months after a peer suicide predicted the onset of depression or PTSD at subsequent timepoin Is.

Ward and Weisz41,42

demonstrated that male offspring of a rat dam stressed during gestation were demasculinized, with lower testosterone levels (on critical gestational days) and deficient adult male mating behavior.43 Moore et al44 observed that the size of the sexually dimorphic spinal nucleus of the bulbocavernosus as well as adult male mating selleck kinase inhibitor behavior were in part determined by maternal licking of the anogenital region of the pup, which in turn appeared to be elicited by androgens in the rat pup urine. Finally, reproductive hormones interact with environmental factors during development to determine the adult behavioral repertoire. Adult aggressive behavior in Inhibitors,research,lifescience,medical mice can Inhibitors,research,lifescience,medical be attenuated by prepubertal castration; the attenuation, however, is blunted to the extent to which the mouse has already been exposed to aggressive encounters.45 ‘ITticse examples demonstrate that current

and past environments and experience can create a context in which the same hormonal or environmental stimulus may elicit any of a range of behavioral responses. Gender context Early hypotheses that the brain displays sex-related differences in structure and function were confirmed by the demonstrations by Pfaff46 of sexual dimorphisms in rat brain morphology and by Raisman and Field47 of sexrelated Inhibitors,research,lifescience,medical differences in the synaptic density of the preoptic area in the rat. There is now an impressive literature detailing sexual dimorphisms at all levels of the neuroaxis, Inhibitors,research,lifescience,medical including differences in the following: nuclear volume; neuron number, size, density, morphology, and gene expression; signal transduction; neuronal neuritic branching patterns;

synapse formation; and physiological and behavioral response.48,49 Given the ability of reproductive steroids to regulate virtually all stages of brain development from neurogenesis to neural migration, differentiation, synaptogenesis, survival, and death,49 the wide range of brain dimorphisms is not surprising. Nonetheless, the source and significance Inhibitors,research,lifescience,medical of many of the dimorphisms are far from clear. For example, while exposure to reproductive steroids is believed to organize (perinatally) or activate (adulthood) most dimorphisms, Reiscrt and Pilgrim50 showed that dimorphisms in the course of development of embryonic mesencephalic and diencephalic neurons appear under genetic control (ie, they are determined well before the appearance Phosphatidylinositol diacylglycerol-lyase of any differences in reproductive steroid levels). Similarly, both the morphologic (eg, neuritic extension) and functional (eg, signal transduction) responses of cultured neurons and glia to reproductive steroids have been shown to display dramatic sexual dimorphisms despite exposure to identical levels of steroid,17,51,52 ie, the dimorphic response cannot be attributed to differences in the steroid milieu of males and females.

In such a scenario, cytokine-driven sickness behavior can account for much of the observed psych opathology and subjective misery95,96 and will often offer a RAD001 purchase better explanation than will medication-induced depression. In addition, in a withdrawn patient, a hypoactive delirium secondary to an infection might be mistaken for “depression.”97 Antibiotic medications Most antibiotics used to treat

infections are well tolerated and are unlikely to cause MDD. Nonetheless, isolated case reports (eg, “fluoroquinolone -induced depression”) describe the development of depressive symptoms.98 Inhibitors,research,lifescience,medical Interestingly, some antibiotics have even played a role in the development of effective, modern antidepressants (eg, isoniazid),99 and some antibiotics (including the ß-lactam, ceftriaxone) are currently being investigated as antidepressants due to their effect on glutamate transmission.100 Numerous case reports link anti-infective Inhibitors,research,lifescience,medical agents to depression (including antituberculous agents [eg, cycloserine, ethionamide], metronidazole, or quinolones).101 Antituberculosis

agents (eg, isoniazid, cycloserine, and fluoroquinolones) have been associated (rarely) with seizures and psychosis; these manifestations, if left unrecognized, could be mistaken for depression.102 Antiretroviral medications Effective treatment for Human Immunodeficiency Virus (HIV) infection/ Inhibitors,research,lifescience,medical Acquired Immunodeficiency Syndrome (AIDS) involves the use of combination antiretroviral therapies

(cART). One commonly used first-line cART regimen Inhibitors,research,lifescience,medical includes the non-nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz. Among the antiretroviral agents, efavirenz has been frequently associated with neuropsychiatric side effects (eg, vivid dreams, anxiety, depressive Inhibitors,research,lifescience,medical symptoms).103 Such side effects seem to be transient in most patients104 and dose-related.105 Moreover, a polymorphism in the CYP2D6 gene has been associated with efavirenz plasma concentrations.106 While genotype-based dose reduction was reported as a successful strategy in reducing efavirenz-associated CNS symptoms,107 the role of pharmacogenetics and therapeutic drug monitoring (TDM) for optimal efavirenz dosing needs further refinement. Some medications used in the treatment of HIV-infection/AIDS might mimic depression. all The first antiretroviral agent to treat HIV infection, zidovudine (AZT), for example, causes fatigue associated with significant anemia.108 AZT has also been linked with a variety of CNS effects (including insomnia, restlessness, and irritability) that can be mistaken for manifestations of agitated depression, if the reasonably well established AZTinduced mania is missed.109 Interferon-α IFN-α, in combination with ribavirin, is an effective treatment for chronic hepatitis C virus (HCV) infection.

These proteases cleave APP within the extracellular domain, probably in the endosomal-lysosomal pathway following reinternalization of extracellular membrane-bound APP that escapes α-secretase cleavage.26 Action of the putative protease γ-secretase at a second site

releases free Aβ of between 40 and 42 amino acids, depending on the exact site of cleavage. The γ-secretase site is unusual Inhibitors,research,lifescience,medical in that it is buried within the lipid bilayer. Mutations in APP and the formation of Aβ Activity of all three secretases can be found in normal brain. Aβ and APPs can be detected from normal cells, and, in humans, Aβ is detectable by enzyme-linked immunosorbent assay (ELISA) in cerebrospinal fluid (CSF) as well as in Inhibitors,research,lifescience,medical serum. These, then, are not pathological processes per se, but rather they suggest that disease results from a tendency towards the amyloidogenic combination of secretases resulting, over a lifetime, in increased Aβ formation and increased plaque formation. What then are the known influences on these, essentially normal, processes? The first

influence on APP metabolism to be discovered was the mutations in APP. Autosomal dominant AD in a few rare families results from mutations that cluster adjacent to the regions of α-, β-, or γ-secretase cleavage. The first set of mutations to be discovered were those clustering at, or adjacent to, the γ-secretase Inhibitors,research,lifescience,medical cleavage Inhibitors,research,lifescience,medical site (APP717). Expression of these mutated APP cDNAs in cells confirmed that the mutation does indeed alter APP metabolism, as relatively more of the longer forms of Aβ were generated in mutation-carrying cells.27,28 Mutations at the c-terminal end of the Aβ sequence within APP also alter APP metabolism, presumably by

interfering with BACE. These mutations, the double Swedish mutation (APP670/671), also alter APP metabolism in cultured cells, and the amount of Aβ Inhibitors,research,lifescience,medical in serum or CSF of patients carrying either the mutations near the γ- or the β-secretase site is increased.29,30 Two very interesting mutations occur within the Aβ region close to the α-secretasc site. One, at APP693, is associated with a rare disorder, hereditary cerebral Carnitine dehydrogenase hemorrhage with amyloidosis, Dutch type, and the other, at APP692, with presenile dementia and cerebral hemorrhage due to cerebral amyloid angiopathy – a clearly related, but, not identical, disorder. In the APP692 disorder, but not in APP693 disease, there was not only angiopathy but, large plaques and neurofibrillary tangles.31 In cells, the effect of the APP692 mutation is to increase both Aβ40 and Aβ42 secretion, whereas APP693 does not. Thus there is, in the APP mutations, convincing evidence in favor of the amyloid ABT-378 cascade hypothesis – mutations associated with AD increase either all Aβ or the longer and more fibrillogenic forms of Aβ, whereas mutations associated withother disease do not.

While drugs are effective in treating psychiatric disorders, some patients have no or only a partial response to treatment. This affects not only the patient, but also the family and the professionals caring for that patient. The lack of response should be considered as a multifaceted problem, involving variables inherent to the illness itself, as well as those relating to the patient and psychosocial factors. Although Inhibitors,research,lifescience,medical it may seem very basic, one of the main factors to be considered when evaluating a patient responding poorly to treatment is the way in which the treatment is being carried out. There are two concepts related to the way in which treatment is carried out: compliance and adherence.

Compliance includes many Inhibitors,research,lifescience,medical variables, but refers mainly to the degree to which patients follow physicians’ instructions (primarily the number of pills taken daily according to the schedule prescribed). For many authors, compliance is a passive behavior on the part of the patient. In contrast, FHPI purchase adherence implies active behavior in which a patient’s beliefs with respect to mental illness and drugs are key to the decision of whether to cooperate voluntarily with the treatment regimen.1,2 In most psychiatric cases, patients with the freedom to do so choose professionals who have the same ideas as Inhibitors,research,lifescience,medical themselves, which should increase likelihood

of adhering to the prescriptions. However, Inhibitors,research,lifescience,medical in a group of patients in primary health care, suffering from dysthymia and mild depression, it was found that their beliefs did not predict a greater adherence to treatment, and even that the individuals who did not consider depression to be a biological illness responded best to antidepressants.3 Noncompliance in self-administered treatment is frequent, especially in long-term therapy,

when compliance can be as low as 50%. In cases of antibiotic treatment for acute infections, compliance is 75% at the beginning of treatment, but drops to 25% at the end of the regimen.4 In addition, compliance and adherence are frequently overestimated Inhibitors,research,lifescience,medical and, consequently, when a patient responds poorly to treatment, these variables are rarely considered responsible for the result.1 Overdosage, underdosage, or taking medication at erratic intervals can bring on adverse effects and make treatment ineffective. Noncompliance is associated with poor clinical evolution. The ideal combination is compliance and successful treatment; this situation Thalidomide should bring about a “virtuous circle” to help maintain long-term treatment. However, there are times when a patient has a high level of compliance, but treatment is only partially successful, in which case the diagnosis and/or treatment must be reevaluated. An issue worthy of further research is the compliance threshold necessary for obtaining an acceptable response to therapy. Compliance depends on numerous factors.