1M standard NaOH solution According to the volume of NaOH betwee

1M standard NaOH solution. According to the volume of NaOH between the second and third pH leap, the content of amino group was calculated from the formula Content  of  free  amino =(V3−V2)×CNaOH×240.07WSample, (1) where V2 and V3 are the volumes (mL) of standard NaOH solution used in the second and third pH leap, respectively, CNaOH is the concentration of

standard NaOH solution, WSample represents the weight (g) of the sample, and 240.07 is the average molecular weight of each saccharide unit in an OCM-CS molecule. Degree of Substitution. Degree of substitution (DS) is the number of carboxymethyl group that binds to the glucosamine (skeleton unit) in an OCM-CS molecule. The DS of OCM-CS was determined Inhibitors,research,lifescience,medical by dissolving OCM-CS (300mg) in 0.1M HCl (30mL) Inhibitors,research,lifescience,medical and titrating with 0.1M aqueous NaOH. The DS value was calculated as follows [17, 18]: DS=161A(MOCM-CS−58A),A=VNaOH·CNaOH, (2) where VNaOH and CNaOH were the volume and molarity of aqueous

NaOH, respectively, MOCM-CS was the mass of OCM-CS, and 161 and 58 are the molecular weights of the glucosamine and the carboxymethyl group, respectively. 2.2.3. Preparation of OCM-CS and CS NPs In the present study, OCM-CS and CS NPs were prepared Inhibitors,research,lifescience,medical by ionic gelation method which was induced by adding 1% w/v solutions of calcium chloride (CaCl2) and TPP, respectively [19, 20]. Briefly, OCM-CS (4mg/mL) was dissolved in distilled water whereas CS (4mg/mL) was dissolved in glacial acetic Inhibitors,research,lifescience,medical acid and pH of CS solution was adjusted to 5.5 with sodium acetate buffer pH 5.5. OCM-CS and CS NPs were formed spontaneously at room temperature when CaCl2 and TPP solutions were added to the aqueous solution of OCM-CS and CS under magnetic stirring, respectively. After complete addition of CaCl2 and

TPP, solutions were further Inhibitors,research,lifescience,medical stirred for 30min to ensure complete gelation of NPs. Different weight ratios (1:1 to 6:1) of OCM-CS:CaCl2 and CS:TPP were used in order to determine the weight ratio providing NPs with optimum nanosize particles. For the preparation of drug-loaded NPs, DRZ was added in the polymer solution. Different DRZ concentrations were used, 10%, 20%, 25%, 50%, and 75% (w/w) based on polymer weight, in order to study the effect of the DRZ loading on the particle size, PI, zeta potential, entrapment efficiency, and in vitro release profile. Every batch was prepared in triplicate and the results Dichloromethane dehalogenase represent the average value. The DRZ loaded NPs were centrifuged at 30,000rpm for 30min at 4°C using Optima Max XP ultracentrifuge (Beckman Coulter, USA), supernatant was discarded, and pellets were resuspended in distilled and lyophilized by adding mannitol as cryoprotectant. Particle Size PI and Zeta Potential of NPs. The particle size distribution, NPs was determined by dynamic light scattering (DLS) using a Malvern Zetasizer Nano ZS (Malvern Dinaciclib molecular weight Instruments Ltd., Worcestershire, UK) at 25°C. The NP dispersions were diluted in distilled and filtered water (Millex-HV Filter, 0.

The entry of pegylated liposomes from blood vessels and their acc

The entry of pegylated liposomes from blood vessels and their accumulation in tumours have been tested in mice bearing C-26 colon carcinoma tumours and in transgenic mice with KS-like lesions. The pegylated liposomes also combine a low permeability lipid matrix with an internal aqueous buffer system that keeps doxorubicin hydrochloride encapsulated as long as liposomes remain in the blood stream. http://www.selleckchem.com/products/gdc-0068.html Myocet (liposome-encapsulated doxorubicin Inhibitors,research,lifescience,medical citrate) is another form of encapsulated doxorubicin hydrochloride consisting of a drug delivery system with a highly rigid bilayer [20]. Myocet (LD) also provides a more prolonged circulating time than conventional doxorubicin

and, in addition, liposome-encapsulation significantly modifies the biodistribution of doxorubicin, resulting in reduced toxicity. The clearance of LD was 5.1 ± 4.8L/h and steady-state volume of Inhibitors,research,lifescience,medical distribution (Vd) was 56.6 ± 61.5L whereas, after conventional doxorubicin elimination and (Vd) were 46.7 ± 9.6L/h and 1.451 ± 258L, respectively [21]. In animals (Table 1), liposome-encapsulated doxorubicin reduced the distribution to the heart

and the gastrointestinal mucosa compared to conventional doxorubicin, while antitumor efficacy was maintained. However, when compared with conventional doxorubicin, LD did not prove to be more active in Inhibitors,research,lifescience,medical doxorubicin-resistant cell lines. Table 1 Comparison of AUC and t1/2 in various tissues in dogs following the administration of TLC D-99 and conventional doxorubicin. Single dose 1.5mg/kg (30mg·m−2), IV [18]. Doxorubicin plasma pharmacokinetics in patients receiving LD showed a high degree of interpatient variability. Nonetheless, as a rule, total doxorubicin plasma levels were significantly higher with Inhibitors,research,lifescience,medical LD than with conventional doxorubicin, while free doxorubicin peak plasma levels were lower.

Similarly, the peak levels of the main circulating doxorubicin metabolite, doxorubicinol (synthesized Inhibitors,research,lifescience,medical via aldo-keto-reductase) appeared in plasma later with LD than with conventional doxorubicin. Available pharmacokinetic data preclude settling strong conclusions regarding the relationship between plasma levels of total/free doxorubicin and its influence on the efficacy/safety of LD. 3. Anthracycline Toxicity Anthracyclines have a well-known toxicity profile. Their more frequent side effects include myelosuppression, mucositis, alopecia, and emesis. Other isothipendyl less frequent although highly relevant side effects are cardiotoxicity and the occurrence of secondary leukemias. The emetogenic potential of anthracyclines is moderate even though it is potentiated by other agents when administered in combination. The lowest blood cell count (nadir) is reached between 10 and 14 days after administration. Doxorubicin is a potent vesicant agent and its extravasation may cause necrosis of the skin and soft tissue.

We showed no alteration in their melatonin secretion (plasma leve

We showed no alteration in their melatonin secretion (plasma level or circadian profiles) which strongly suggests that ELF-EMF do not have cumulative effects on melatonin secretion in humans, and thus clearly rebuts the melatonin hypothesis that

a decrease in blood melatonin concentration (or a disruption in its secretory pattern) explains the occurrence of clinical disorders or cancers possibly related to ELF-EMF.125 Table IIIa. Magnetic field reports on a melatonin secretion decrease Inhibitors,research,lifescience,medical in humans. Mel, melatonin; aMT6s, 6 sulfatoxymelatonin; M, male; F: female; MF, magnetic field; NG, not given Table IIIb. Magnetic field reports on the lack of effect on melatonin secretion in humans. Mel, melatonin; Pl, plasma; Ser, serum; Sal, saliva; aMT6s, 6 sulfatoxymelatonin; M, male; F, Inhibitors,research,lifescience,medical female; BMI, body mass index; MF, magnetic field; RF, radio frequency; NG, not … ELF-EMF effects on cortisol and corticosterone In contrast to the number of studies on the effects of ELF-EMF on melatonin secretion, few data are available in the literature on the pituitary adrenal axis. The hormones under

study (corticosterone for rats, cortisol for other mammals), exposure characteristics (short- and long-term), and timing and duration of exposure Inhibitors,research,lifescience,medical (1 to 6 months) in different animal species are detailed in Table IV. Table IV. Effects of EMF on cortisol or corticosterone secretion in different animal species. Pl, plasma; Se, serum; NG, not given While the majority of papers failed to find any effect,131-137 others have

reported either an increase in the hormonal concentrations138-144 or a decreased concentration.145 The results of these studies are thus Inhibitors,research,lifescience,medical inconsistent and contradictory. Comparison between studies revealed that the discrepancy in the results might be due in part to the difference in the animal species used (rabbit, ewe lambs, cows, rats, or mice), class of age, and duration and intensity of exposure. Another Inhibitors,research,lifescience,medical factor that should be taken into account is that glucorticoids (ie, cortisol or corticosterone) levels are sensitive to many stressors that might affect hormone levels. It is well known that handling or bleeding animals increase corticosterone, a stress marker, and it is thus important MycoClean Mycoplasma Removal Kit to ensure that any external confounding stressor has to be controlled. Overall, these data suggest that no consistent effects have been seen in the stress-related hormones of the pituitary-adrenal axis in a variety of mammalian species. Data on ELF-EMF effects on cortisol in click here humans are scarce. We have found 7 papers on the matter (Table V).109,124,146-149 All of these papers report only on short exposure of adult volunteers to ELF-EMF, and all failed to find any effect. Table V. Magnetic field reports on cortisol secretion in humans. Ser, serum; Pl, plasma; M, male; F, female; MF, magnetic field Conclusion We are all exposed to electric and magnetic fields of weak intensity.

The lesion was causing displacement of the bowel loops and abutti

The lesion was causing displacement of the bowel loops and abutting the anterior abdominal wall with well-maintained planes (Figure 1). The mesenteric vessels were posterior to the lesion. No calcification was evident. Small, rounded, non-enhancing lesions suggestive of simple cysts were seen in both kidneys. MRI showed a large lobulated mass lesion anterior to the left psoas, appearing hypointense on T1WI and heterogeneously hyperintense on T2WI.

Bowel loops were displaced anteriorly. Biochemistry panel was within Inhibitors,research,lifescience,medical normal limits. Figure 1 Heterogeneously enhancing lesion placed anterior to the mesenteric vessels. The patient was taken up for surgery after obtaining fitness for general anaesthesia. On laparotomy, a large, multilobulated tumour approximately 20 cm × 20 cm in size was seen arising from the mesentery of the jejunum. The overlying jejunal loop was densely adherent to the tumour. The tumour was not invading the superior mesenteric vessel or its main Inhibitors,research,lifescience,medical branches.

The rest of the small bowel loops were pushed to the right lower Carfilzomib in vitro quadrant and the pelvis. The small bowel along with the growth was eviscerated and the main feeding vessel was located. The superior mesenteric vessels were identified AT AN Inhibitors,research,lifescience,medical EARLY STAGE and 2 feet of the jejunum with its involved mesentery was resected just 10 cm distal to the duodenojejunal flexure. A hand-sewn single layer anastomosis was performed to restore bowel continuity. The rest of the visualized viscera and bowel were Inhibitors,research,lifescience,medical grossly normal. No lymphadenopathy was noted. The tumour weighed approximately 1.8 kilograms (Figure 2). The cut surface had a variegated appearance with yellow/tan areas and regions of necrosis. On histopathological examination the specimen showed features suggestive Inhibitors,research,lifescience,medical of pleomorphic sarcoma. The tumour showed

high mitotic activity, marked pleomorphism and intranuclear inclusions. A large number of giant cells were noted with a few showing multivacuolated cytoplasm with peripherally compressed nuclei. Tumour cells were positive for S-100 and negative for SMA/Desmin. Figure 2 Large multilobulated tumour arising from the jejunal mesentery. This patient developed an anastomotic leak on the 5th post-operative day as evidenced by bilious effluent in the intra-abdominal drain which was controlled by Megestrol Acetate conservative management. The patient was advised postoperative radiotherapy and chemotherapy but he refused any further treatment and left against medical advice. Discussion In comparison with the retroperitoneal liposarcoma, the primary mesenteric liposarcoma is extremely rare and is treated by aggressive surgical management i.e. wide excision with adequate margins (in the absence of distant metastases). Among the malignant mesenteric tumours, lymphoma is most common followed by leiomyosarcoma. Occurring usually in the 5th to 7th decades, the incidence has been seen to be slightly higher in males (15).

2010) The underlying mechanisms for OL differentiation

a

2010). The underlying mechanisms for OL differentiation

are rather complex. Many cytokines, including members of IGF family, CNTF/LIF (leukemia inhibitory factor) family of cytokines, certain chemokines and neurotrophins, have been shown to enhance OL differentiation (Mayer et al. 1994; Heinrich et al. 1999; Hsieh et al. 2004; Xiao et al. 2009). Those extracellular ligands activate intracellular signaling pathways leading to transcriptional regulation of myelin proteins such as MBP, PLP, and CNPase (Wegner 2008; Emery 2010b). Although the current work did not explore much of the mechanisms underlying MCDM-enhanced OL differentiation, we speculate that IGF-1 may play such a role, as IGF-1 levels were more than sixfold higher in Inhibitors,research,lifescience,medical MCDM than in ACDM. Many studies have Inhibitors,research,lifescience,medical reported that Akt and Erk pathways are involved in OL differentiation (Pang et al. 2007; Guardiola-Diaz et al. 2012). However, in the current study neither pAkt nor pErk was detected in OLs upon MCDM exposure. Interestingly, CREB was weakly activated in OLs, suggesting a possible involvement of this signaling pathway in MCDM-enhanced OL differentiation. In Inhibitors,research,lifescience,medical fact, accumulating evidence suggests that CREB is a potential downstream pathway involved in OL differentiation (Paez et al. 2004; Shiga et al. 2005; Bhat et al. 2007). Whether activation of CREB pathway principally underlies MCDM-enhanced OL differentiation needs

to be addressed in future studies. Myelination is a relatively late developmental event of mammalian nervous system, which is fine turned by a comprehensive transcription network (Bradl and Lassmann 2010). Neuron-derived factors, including neurotrophins and Rapamycin manufacturer axonal surface molecules are known to play critical roles in initiating myelination (Xiao et al. 2009). As for glial cells, astrocytes have been Inhibitors,research,lifescience,medical implicated to affect myelination, presumably through secreted factors. However, most of the Inhibitors,research,lifescience,medical data regarding the role of astrocytes in myelination are observed from studies of multiple sclerosis, in which astrocytes

are often activated. Nevertheless, a few studies directly investigated the effect of astrocytes on myelination in cell cultures. For example, Ishibashi et al. (2006) reported that astrocytes could promote myelination in response to neuronal activity by releasing of LIF. Watkins et al. (2008) showed that the presence of astroctyes in myelinating cultures could increase the speed of myelin wrapping around axons, but was not Farnesyltransferase required for the initiation of myelination. The lack of myelin promoting effect of ACDM in the current study is not clear, but may be due to several factors. First, astrocytes were presented in the cocultures (Pang et al. 2012), and astrocyte-derived factors may contribute to the baseline level of myelination. Therefore, ACDM may no longer show additional effect. Second, the phenotypes of astrocytes seem to be important in determining whether astrocytes affect myelination positively or negatively (Nash et al.

To measure the entire volume, the exact borders of the studied r

To measure the entire volume, the exact borders of the studied region have to be establish ed,82,83 so that sampling is confined to the region within these borders. Unfortunately, in most studies of mood disorders in postmortem tissue, limited availability of the complete tissue region, as well as limitations in reliably distinguishing cytoarchitectonic borders of a studied region, have prevented the estimation of a total tissue volume and, consequently, total cell number. In one study where the total cell number was estimated in the subgenual cortex,

a loss of glial but not neuronal cells has been demonstrated in familial mood disorders.1 Glial reductions reported in this study may Inhibitors,research,lifescience,medical in fact reflect a true loss of glial cells since the neuroimaging studies in the same cortical region show a reduction in the volume of gray matter.84 There are unquestionable limitations to the use of postmortem brain tissue in studying the mood disorders.56 Some

of the critical issues to be considered when interpreting Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical the studies of postmortem brain tissue include the psychiatric status of the subject at the time of death and the underlying psychiatric disorder, whether “control” click here subjects were psychiatrically normal, the cause of death of the subjects (suicide or by other means), evolving criteria used to establish psychiatric diagnoses, the possible Inhibitors,research,lifescience,medical inclusion of subjects with concurrent psychoactive substance use disorders, the regional and hemispheric localization of the brain regions being studied, and the presence and duration of treatment with a psychotropic medication. Other frequent drawbacks to studies of postmortem brain tissue include low numbers of subjects per cohort, or inadequate expertise in cytoarchitectonic delineation of individual brain regions. Ideally, longitudinal clinical studies on wellcharacterized patients should be linked to subsequent postmortem

studies Inhibitors,research,lifescience,medical of the same subjects. It is important to seek to control for the potential effects of suicide on postmortem biological observations in depression. In two of our studies,5,36 enough depressed nonsuicide subjects were available to tentatively determine that the main findings of these studies appear to persist regardless of whether the depressed subjects died by suicide or natural causes. While suicide makes many tissues available for most postmortem studies of depression, the results obtained with this cohort must be cautiously interpreted since the majority of living individuals with depression do not attempt or commit suicide. In the mood disorders, the alterations in cell density and size are likely to be related to the disorder itself and not to the age of subjects at the time of death, postmortem delay, or the time of fixation of the tissue.

52,53 In Parkinson’s disease, “frontal” functions are doubly jeop

52,53 In Parkinson’s disease, “frontal” functions are doubly jeopardized by the combination of caudate nuclear Adriamycin dopamine deficiency, which creates a partial “disconnection syndrome” of subcortical origin,54-56 and the lesser reduction of dopamine in the dorsolateral prefrontal cortex.57,58 In this disorder, specific cognitive deficits involving working memory, cognitive sequencing, and attention shifting may respond, at least partially, to dopaminergic therapies.59,60 This is explainable by the fact that dopamine modulation in the basal ganglia locks the gate to working

memory.61 However, incomplete Inhibitors,research,lifescience,medical reversal of cognitive deficits with dopamine agonists is typically noted in Parkinson’s disease,59 reflecting the likely role of dysfunction of nondopaminergic neuronal systems in Parkinson’s disease dementia.62 Psychiatric syndromes including schizophrenia, depression, and obsessivecompulsive disorder manifest executive dysfunction. The presence of executive abnormalities is these disorders imply that frontalsubcortical Inhibitors,research,lifescience,medical circuit function is compromised. Cognitive enhancement in these disorders will focus on facilitating frontalsubcortical function. In attentiondeficit/hyperactivity Inhibitors,research,lifescience,medical disorder andTourette’s

syndrome, various agents having important effects on the noradrenergic system, the dopaminergic system, or both may ameliorate at least some features of executive dysfunction.63,64 Such drugs include deprenyl, stimulant medications, Inhibitors,research,lifescience,medical low-dose tricyclic antidepressants, and the oc2adr énergie agonists clonidine and guanfacine.65,66 Both clonidine and guanfacine

have been shown to enhance working memory performance in aged monkeys,67,68 and cognitive tasks mediated by prefrontal cortex, such as Trails B, word fluency tasks, and the Stroop task, are improved by clonidine in patients with schizophrenia and Korsakoff’s syndrome.69,70 In patients with dementia of the frontal Inhibitors,research,lifescience,medical lobe type, executive function may be selectively enhanced by the α2-adrenergic antagonist idazoxan.71 These observations are consistent with psychopharmacological and anatomical studies implicating the noradrenergic and dopaminergic systems as important modulators of frontal lobe Dichloromethane dehalogenase function.72 The anterior cingulate circuit Neurons of the anterior cingulate serve as the origin of the anterior cingulate-subcortical circuit. From Brodmann’s area 24, they provide input to the ventral striatum35 which includes the ventromedial caudate, ventral putamen, nucleus accumbens, and olfactory tubercle. This area is termed the limbic striatum.73 Projections from the ventral striatum innervate the rostromedial GPi and ventral pallidum (the region of the GP inferior to the anterior commissure), as well as the rostrodorsal SN.74 There may also be a less well-defined indirect loop projecting from the ventral striatum to the rostral pole of the GPe.

Thus, fiber tractography together with functional neuroimaging is

Thus, fiber tractography together with functional neuroimaging is an ideal combination to explore the role of regional cortico-limbic-striatal connectivity in emotion and cognition and their dysregulation in alcoholism. Acknowledgments This work was supported by NIAAA grants AA0 180 2 2, AA010723, AA017168, and AA012388. We thank Margaret Rosenbloom, MA, and

Fiona Baker, PhD, for selleck products comments on this manuscript.
Patients Inhibitors,research,lifescience,medical with schizophrenia manifest a wide range of symptoms, including delusions, hallucinations, and impairments in communication, as well as motor, volitional, and emotional disorders. Through careful and comprehensive research it has become increasingly apparent that, in addition to the diverse symptoms that form the clinical definition of the illness, the disorder is, to a variable

Inhibitors,research,lifescience,medical degree, accompanied by a cognitive impairment.1,2 Various observations (for review see ref 2) have led to the hypothesis that compromised cognitive functioning is a core feature of schizophrenia and not an artifact Inhibitors,research,lifescience,medical of other symptoms, treatment for the illness, or aspects of the course of the illness.3,4 It has further been proposed that the well-known diversity of schizophrenia in terms of functional outcome and recovery from the illness is best characterized by cognitive deficits, not by the classical symptoms.5 DSM-5, acknowledging the importance of cognition in schizophrenia, is likely to recommend obtaining a formal neuropsychological assessment in individuals with psychosis.6 This paper will provide an overview of findings from studies of cognitive functioning in schizophrenia. It will highlight cognitive Inhibitors,research,lifescience,medical functions which are severely impaired, as well as functions that are relatively

spared; compare cognitive functioning across psychotic disorders; discuss the classification of cognitive impairment at the individual level, and present common cognitive assessment Inhibitors,research,lifescience,medical batteries. Cognitive impairment in schizophrenia Most neuropsychological assessment batteries used in schizophrenia studies have been adapted from clinical neuropsychology, which assesses the profile of neuropsychological strengths and weaknesses of an individual.7 In the first section of this paper we will review the study of cognitive functioning in schizophrenia. 3-mercaptopyruvate sulfurtransferase We will define the main cognitive ability areas, and describe the degree of impairment in each ability area as found in studies of schizophrenia patients. For descriptive purposes we have adopted the convention proposed by Cohen,8 and applied in meta-analytic studies that cognitive functioning is within normal limits if performance scores are within one fifth of a standard deviation of the normative standards, is mildly impaired if scores fall between 0.2 and 0.5 SDs below the normative standards, is moderately impaired between 0.5 and 0.

2 Further confusing

matters, depression is a heterogeneou

2 Further confusing

matters, depression is a heterogeneous syndrome, making it difficult to identify the underlying pathophysiology, and thereby complicating the diagnosis and treatment of depression and related mood disorders. Despite these problems, significant progress is being made in identifying the brain regions and circuits that control emotion, mood, and anxiety, and the neurochemical and cellular alterations underlying depression and stress-related disorders. Emerging from these Inhibitors,research,lifescience,medical basic research and clinical studies is evidence that stress and depression cause neuronal atrophy and loss in brain regions that control mood and emotion, resulting in disconnection Inhibitors,research,lifescience,medical and loss of function.3-5 This includes a reduction in the number of spine synapses, the key points of connection between neurons. There is also evidence of hypertrophy and increased function of other brain regions that could contribute to dysregulation of mood and anxiety. Progress has also been made in characterizing the pathophysiological processes that contribute to the structural alterations in the brain and to depressive behaviors. In addition to the well-established role of elevated hypothalamic-pituitary-adrenal

(HPA) axis activity, a hallmark of stress responses, disruptions of Inhibitors,research,lifescience,medical neurotrophic/growth factors have been the focus of work in recent years and could be involved in the atrophy and loss of neurons in response to stress and depression. Although the development of novel therapeutic agents has proven extremely difficult, recent studies have found that previously Inhibitors,research,lifescience,medical known psychotropic drugs are capable of producing startling antidepressant responses. Most notably, N-methyl-D-aspartate (NMDA) receptor

Inhibitors,research,lifescience,medical antagonists (eg, ketamine) produce rapid and long-lasting antidepressant actions in treatment-resistant patients.6,7 Similarly, only the muscarinic receptor antagonist scopolamine also produces rapid antidepressant actions.8,9 These rapid effects, by mechanisms completely different from typical monoamine reuptake inhibitors, represent the most significant SB939 price findings in the field of depression in over 60 years. Moreover, we have found that the actions of ketamine and scopolamine are dependent on the induction of new spine synapses, which rapidly reverse the synaptic atrophy caused by stress and depression, resulting in reconnection of critical cortical-limbic circuits. These findings represent a fundamental shift in our understanding of the mechanisms underlying the rapid actions of NMDA and muscarinic receptor blockade, and identify novel targets for the treatment of depression.

Fourth, it is equally clear that reproductive steroids do not, by

Fourth, it is equally clear that Vorinostat order reproductive steroids do not, by themselves, cause reproductive endocrine-related mood disorders; ie, women with these disorders are differentially sensitive to levels or changes in reproductive steroids that are without

effect on mood in women lacking these disorders. This differential sensitivity, the fact that people respond differently to the same reproductive endocrine stimulus, is important for three reasons. First, the failure to consider this phenomenon has been the keystone of the argument Inhibitors,research,lifescience,medical that reproductive endocrine-related mood disorders do not exist. The syllogism is as follows: The effects of reproductive hormones should be similar across individuals; not all individuals have the same behavioral concomitants Inhibitors,research,lifescience,medical of changes in reproductive endocrine function; therefore, reproductive hormones have nothing to do with behavior. In other words, if changes in

reproductive steroids do not precipitate mood disorders in everyone, they must do so in no one. As will be shown below, this argument Inhibitors,research,lifescience,medical is fallacious and serves to obscure rather than clarify. Second, the principle that the response to a biologic stimulus depends upon the context in which the stimulus is administered is gcneralizablc and underlies much of our physiology. Third, by understanding the means by which reproductive steroids can Inhibitors,research,lifescience,medical trigger affective change in some but not other women, we will be in a far more powerful position to understand the substrate underlying

susceptibility to affective disorder in general, which is better conceptualized as a differential response to a stimulus rather than as a “deficiency” state. The remainder of this paper, then, will address the central question in reproductive psychiatry/neuroscience: how is it that reproductive steroids can trigger a depression, and why does this occur only in some individuals? Reproductive steroids: modulators of brain Inhibitors,research,lifescience,medical function The observed links between reproductive function and behavior date back at least several millennia to Aristotle, who noted that castration of immature male birds prevented the development of characteristic male singing and sexual behavior.1 By the end of the 19th century, Brown-Séquard and other “organotherapists” to claimed that the administration of ground-up extracts from animal gonads could successfully treat a variety of human mood disorders, including depression and the anergy of senescence:2-5 In the 1920s and 1930s, the potential mediators of these effects – the steroid hormones estradiol, progesterone, and testosterone (and not sperm, as Brown-Séquard believed) – were isolated and characterized. Forty years later, Jensen and Jacobsen” demonstrated that the actions of estradiol occurred through its binding to an intracellular protein, the estrogen receptor (HR), which was isolated and identified 4 years later.