However, neither of the educational level and patients’ age are

However, neither of the LY411575 manufacturer educational level and patients’ age are associated with the complaint of somatization. These results indicated that somatization as a complaint in the patients with major depressive disorder is independent from age and educational level. One explanation could be that somatization as a complaint in Iranian culture is commonly expressed in both higher and lower educated class. Conclusions Inhibitors,research,lifescience,medical This is a preliminary study to delineate the depressive symptoms

in Iranian population. The principal finding of this study is that somatic symptoms especially headache and pain in other areas of the body have a significant weight in the chief complaints of depressed patients. Therapists need to pay attention to the various ways of presentation of this disorder in different cultures in order to understand the symptoms of patients with depression. Hence, more extensive studies in other areas of the country are required to obtain a more reliable profile of depression Inhibitors,research,lifescience,medical symptoms in Iranian population. Conflict of interest: Inhibitors,research,lifescience,medical None declared
Hydatid disease is caused by Echinococcus granulosus and is endemic in many parts of the world, including Iran. This parasitic tapeworm can produce cysts in almost every organ of the body, with the liver and lung being the most frequently targeted organs. However, the cyst tends to appear

in different and sometimes unusual body sites in various geographical areas of the world. This review provides information on the reported cases of the unusual body sites of the hydatid cyst from Iran in the last 20 years. A literature search Inhibitors,research,lifescience,medical was performed through PubMed, Scopus, Google Scholar, IranMedex,

Society Information Display (SID), Magiran, and Irandoc using the keywords of “hydatid cyst and Iran” and “Echinococcus granulosus and Iran”, and 463 published cases of the hydatid cyst in unusual body sites from Iran were reviewed, evaluated, and discussed. The most common locations were the central nervous system (brain, spinal cord, and orbit), musculoskeletal system, heart, and kidney, Inhibitors,research,lifescience,medical while some less common locations were the spleen, pancreas, appendix, thyroid, salivary gland, adrenal gland, breast, and ovary. Key Words: Hydatid cyst, Location, Unusual, Iran Introduction The hydatid cyst is a zoonosis caused by adult or larval stages of tapeworms unless belonging to the genus Echinococcus granulosus.1 The tapeworm stage is harbored in the intestine of carnivores such as dogs, which constitute the definitive host,2 and the eggs are passed in the feces of the infected carnivores and ingested by herbivores such as sheep, which comprise the intermediate host. Humans are the incidental intermediate host. Larvae emerge from the eggs in the intestine; and after invasion to the blood vessels, they can migrate into almost every part of the body.

Environment-related factors External or environment-related facto

Environment-related factors External or environment-related factors included relationship with physician, stigma of disease, living situation and family support. Relationship with physician A prospective study [Linden et al. 2001] found that both nonadherent and adherent patients had a good relationship with their physicians. However, adherent patients trusted their physicians significantly more, and they expected that physicians would be helpful in treatment (p < 0.05). Another prospective study [Loffler et al. 2003] found that 41% of patients considered

a positive relationship with physicians and therapists to be important for medication Inhibitors,research,lifescience,medical adherence. Furthermore, a review [Velligan et al. 2009] reported that the ‘positive relationship with clinical staff’ was a significant predictor of good adherence. However, ‘difficulties in building a therapeutic alliance’ and ‘poor Inhibitors,research,lifescience,medical clinician–patient relationship’ were

among significant predictors of nonadherence. A cross-sectional study [Rettenbacher et al. 2004] assessed a link between the person who inquires (i.e. psychiatrist, relatives Inhibitors,research,lifescience,medical or others) about drug intake and adherence. Forty-one percent of adherent patients were asked about drug intake most frequently by their psychiatrist while none of the nonadherent patients reported this (p = 0.074). Among nonadherent patients, a higher proportion (60% versus 9% of adherent patients) stated that their relatives inquired most often about their drug intake. Other environmental factors A prospective study [Hudson et al. 2004] found that the most common barriers to patient adherence to medication were related to the stigma of taking medication and lack of support. Furthermore, a review [Velligan et al. 2009] reported that predictors of nonadherence included a disorganized Inhibitors,research,lifescience,medical or chaotic living situation, this website financial problems, housing problems and logistic problems, while predictors of good adherence included family and social support. Greater social activity was also found to be a predictor of good adherence (OR 1.26; p < 0.001) Inhibitors,research,lifescience,medical [Novick et al. 2010]. Physician perception

on important factors of nonadherence In the expert survey [Velligan et al. 2009] on potential contributors to adherence problems in schizophrenia, experts were asked to rate factors as very important, somewhat important and not important for medication adherence. The factors rated as very important included ‘poor insight into having an illness’ and ‘distress associated with persistent Carnitine palmitoyltransferase II side effects or fear of potential side effects’. The key factors out of 12 factors rated as somewhat important related to efficacy, beliefs about medication, substance abuse and social support. The survey revealed a wide range of factors that clinicians found to be the potential factors of nonadherence. Consequences of nonadherence Three main types of consequences of nonadherence included consequences to patients, society and healthcare systems.

52 Kidney volume was found to be proportional to

52 Kidney volume was found to be proportional to nephron number in this study. Mutations in other genes such as Imx-1, Eya-1, Six1, Sall1, and tcf2 also result in a reduced nephron number, small kidney size, and disorganized renal tissue, in addition to other extrarenal manifestations.53 OTHER CLINICAL CORRELATES OF NEPHRON NUMBER Except for rough estimates of the nephron number by renal MRI or kidney biopsy, an accurate count can only be done post mortem.15,43,54 In humans, thus far, LBW and prematurity are Inhibitors,research,lifescience,medical the strongest clinical correlates of low nephron number. In animals, however, low nephron

number has been reported in the absence of LBW, and, conversely, not all LBW animals have reduced nephron numbers; therefore birth weight alone may not be a universal surrogate marker for nephron number.55,56 Several additional clinical surrogates for Inhibitors,research,lifescience,medical nephron number have been examined (Figure 1), which, although not absolute, may also serve to increase awareness of the possibility of low nephron number, with the attendant risks for hypertension and renal disease, and may therefore impact

on optimization of other risk factors. Anthropomorphic Factors Females are estimated to have 12% fewer glomeruli than males.43,57,58 Increasing age is associated with a predicted Inhibitors,research,lifescience,medical reduction of 3,676 glomeruli per kidney per year after age 18.15,43 Adult height has been found to correlate positively with nephron number, with an estimated increase of 28,000 glomeruli per centimeter increase in height, and height was found to contribute to two-thirds of the variance in glomerular number.15,43,58 Birth weight Inhibitors,research,lifescience,medical tends to

be associated with subsequent height and therefore may be a confounder in this relationship, but adult height is much more readily available than birth weight in clinical practice and therefore useful.59 Glomerular Volume Although nephron number does not increase after birth, the kidney matches its filtration capacity to the body’s demands by increasing the glomerular size through hypertrophy.5,11,12,57,58 As such, mean glomerular volumes have consistently Inhibitors,research,lifescience,medical been found to correlate inversely with glomerular number and directly with current body size.43 Keller et al. reported a 133% BI-6727 higher mean glomerular volume and a 46.6% reduction in glomerular number in hypertensive subjects, compared to controls.6 Lower nephron below number, black race, hypertension, and body size all correlate with an increase in individual glomerular volume within a single kidney.14,17,43 Larger glomeruli therefore suggest a lower nephron number, although in African-Americans glomerular volume appears to be globally increased but still in inverse proportion to nephron number, suggesting additional factors contribute to glomerular size in this population.9 Kidney Mass Kidney weight can only be measured ex vivo, but from autopsy studies, nephron number correlates directly with kidney weight in adults and children.15,52 Zhang et al.

The maximum biomass of all cultures was approximately 10 g at 240

The maximum biomass of all cultures was approximately 10 g at 240 h. It is obvious that elicitation had no immediate inhibitory effects on the growth of treated grape cell cultures compared to that of the control samples. These results

suggest that in situations in which biomass is the goal of production, no treatment is needed. BIBF 1120 ic50 Nevertheless, treated grape cells were found to trigger many metabolic pathways for the synthesis of secondary metabolites of economic interest. There was a rapid Inhibitors,research,lifescience,medical accumulation of phenolic acids in the cultures treated with MCoA and IN reaching its maximal after 2 h and 48 h respectively. The highest concentration of phenolic acids after treatment with LG and IS was detected after 24 h. The highest phenolic acid content per cell unit was 3.5-fold (MCoA: 2 h); 1.6-fold (IN: 48 h) and 1.5-fold (IS: 24 h) at the distinct time where the highest concentration was detected, compared to the concentration at the same time of the corresponding control sample without elicitation. Estimates of phenolic acid concentration per cell Inhibitors,research,lifescience,medical unit

were as follows; Inhibitors,research,lifescience,medical grape cells treated with MCoA was about 1,000 µmol after 2 h compared to control with about 300 µmol. Interestingly, the concentration of phenolic acids after 2 days after IN treatment per cell unit was 1,250 µmol whereas the amount in untreated cells was about 1,020 µmol. This is similar to the suspension cells treated with LG (24 h). In addition, in this case, their phenolic acid content was only slightly higher than that of the control. Based

on multiple comparison tests, there were strong statistically significant differences between the treated grape cells treated with MCoA, (LG and IS) and IN after 2, 24 and 48 h and their corresponding control counterparts (p < 0.0001). The effect Inhibitors,research,lifescience,medical of the biological elicitors to enhance the synthesis of phenolic acid within the first 48 h was MCoA > IN > IS > LG. MCoA showed the fastest response. However, this strong enhancement in phenolic acid content by the different biological stimulants (MCoA, IN, IS and LG) is gradually lost over time because of homeostatic balance within the cells. These results Inhibitors,research,lifescience,medical suggest that although all treatments did enhance phenolic acid many synthesis; for a rapid harvest of high yield phenolic acid, it will be better to treat grape cells with malonyl coenzyme A. 2.2. Chemical Analysis of in Vitro Grape Cells with HPLC Figure 2 is an HPLC chromatogram from extracts of suspension cell cultures (V. vinifera) of untreated samples. Two major phenolic compounds; 3-O-glucosyl-resveratrol and 4-(3,5-dihydroxyphenyl)-phenol (compound 5 and 6) as well as the internal standard p- coumaric acid were identified. The HPLC chromatogram shows the identified phenolic compounds at their respective retention time (min). The reproducibility of phenolic compounds was very efficient with high correlation coefficients (R2 = 0.9998) for the different linear equations.

Information from some 6 to 8 months’ maintenance therapy trials h

Information from some 6 to 8 months’ maintenance therapy trials have found continued efficacy over time,14-17 but since GAD is often a long-term and unremitting disorder,18 it needs to be stated that pharmacotherapy, whether with BZs or other drugs, may need to continue for many

years in a significant, number of patients. Results generally show that approximately 70% of patients will respond to adequate BZ treatment (up to 40 mg/day of diazepam or equivalent for at least 3-4 weeks), but less than two thirds will achieve remission of symptoms. In long-term use, tolerance to side effects does occur, but tolerance to the anxiolytic effect of the BZs does not appear.19 Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical With regard to dependence

and withdrawal, compounds with a slower onset, of action, for example, oxazepam, have little reinforcing potential, while those with a long half -life, for example, diazepam and chlordiazepoxide, have a lower propensity to produce withdrawal symptoms, even if stopped abruptly. Inhibitors,research,lifescience,medical Anyway, discontinuation of acute treatment should be slow because of the potential for rebound anxiety and/or clinical relapse, and an adequate pretreatment assessment should be an important step to evaluate whether a subject would be suitable for BZ therapy, including previous history of withdrawal, liability of abuse, or likelihood of poor compliance. For this reason, and because of the high prevalence of comorbid depression, attention has focused also on different medications and antidepressants as potential treatment for GAD (Table Inhibitors,research,lifescience,medical II). Table II. Generalized anxiety disorder (GAD): therapeutic

strategies. BZ, benzodiazepine; SSRI, selective serotonin reuptake inhibitor; TCA, tricylic anti-depressant. Azapirones Ilic first pharmacological treatment for GAD beyond BZs was the azapirone buspirone, a partial 5-hydroxytryptamine (serotonin, 5-HT)-lA (5-HT1A) agonist, which decreases the function of postsynaptic 5-HT2 receptors. It has been demonstrated Inhibitors,research,lifescience,medical to show efficacy in GAD10,20-22 and has been ERK inhibitor concentration associated with maintenance of efficacy over a period of several months.15,16 Buspirone is given in two or three divided doses up to 60 mg/day, and its effect is usually not apparent until 2 to 3 weeks into treatment, in contrast to the almost immediate effects first of BZs. It is not sedating like the BZs; it is not associated with psychomotor impairment, tolerance, dependence, or withdrawal; and it docs not interact with alcohol. The drug works well when there are conspicuous symptoms of worry, apprehensive tension, and irritability,10 and where depressive symptoms are intermixed with anxiety,23 while it is less effective than BZs on somatic and autonomically driven symptoms.

However, the long-term efficacy of this agent still needs to be e

However, the long-term efficacy of this agent still needs to be evaluated. Neuroendocrine impairment Impairment, in the hypothalamic-pituitary-adrenal (HPA) axis activity is another physiological mechanism proposed to underlie the development of AD.103-106 Hypercortisolemia and

reduced negative feedback inhibition of Cortisol secretion are noted concomitants of AD.107-110 However, investigations of the relationship between dementia severity and Cortisol Inhibitors,research,lifescience,medical levels have yielded mixed findings. While some investigations observe a relationship between dementia severity and/or progression,111-115 others do not observe this relationship between HPA MLN8237 dysfunction and either severity or disease progression in AD.116-118 However, variations in age of onset and stage of illness may impact the relationship between hypercortisolemia and disease progression. Moreover, the nature of the relationship between Cortisol and cognitive decline in AD may be more difficult to assess Inhibitors,research,lifescience,medical as the disease progresses. As many suggest, the degenerative process of hippocampa! damage in AD patients may, with time, reduce the responsivity of this area to elevations in glucocorticoids. Thus, many investigators argue that impairments in neuro-endocrine function observed in AD reflect, rather than cause the neuronal degeneration in this

illness. However, the observations Inhibitors,research,lifescience,medical of a negative impact of elevated Cortisol levels on cognition in normal aging have led others to consider therapeutic approaches to AD based upon this pathophysiological mechanism. Currently, a clinical trial of AD patients, utilizing the glucocorticoid antagonist, mifepristone, is Inhibitors,research,lifescience,medical in progress. Cerebrovascular and cardiovascular impairments While cerebrovascular deficiencies arc typically associated with vascular dementia, an increasing body of evidence suggests that vascular factors may also contribute to the development, of AD.119 Many recent studies have found Inhibitors,research,lifescience,medical arterial hypertension to be associated with cognitive impairment120-123 and increased risk of AD has also

been observed in individuals with higher systolic-diastolic blood pressure values.124 Hofman et al125 observed patients with AD to be affected by more pronounced arteriosclerotic carotid lesions, and atrial fibrillation was found to be more strongly associated with AD (with cerebrovascular disease) than with vascular dementia. Some investigators have argued that vascular almost factors such as arterial hypertension may have a direct role in the pathogenesis of AD by increasing the production of β-amyloid. Animal studies have found ischemia to result in increased β-amyloid production in the hippocampus.126 Moreover, the observation of increased concentrations of senile plaques in the brains of hypertensive, nondemented patients further implicates the role of ischemia.127 Investigators have started to consider the use of antihypertensive agents as a potential.

The same concept can be transferred to adult patients with ADHD a

The same concept can be transferred to adult patients with ADHD and/or BD to examine whether treatment-emergent bipolarity (mania in particular) in ADHD patients may also produce higher diagnostic rates of BD. A comparison of such longitudinal results on adults with data obtained from children and adolescents could also help to determine whether a specific group of children and adolescents with PBD and ADHD

symptoms may be at a specific risk of developing bipolar symptoms in adolescence Inhibitors,research,lifescience,medical and later adulthood, and whether this risk could be related to early exposure to stimulants and/or antidepressants. Such research could contribute to developing concepts on how to identify those children and juveniles at risk, and to develop strategies for prevention and treatment. Clinical aspects In considering potential explanations for the co-occurrence Inhibitors,research,lifescience,medical of PBD with ADHD, it was proposed that the presence of PBD symptoms could lead to an artificial increase in diagnostic rates for PBD in

ADHD samples, and that ADHD could be an early and prodromal manifestation of PBD. This proposition was then linked with the findings on treatment-emergent mania – mania triggered by pharmacological treatment Inhibitors,research,lifescience,medical with stimulants and/or antidepressants.16 Following this, it was proposed that ADHD and its associated factors, such as treatment with stimulants, may induce PBD symptoms, and that PBD and ADHD could have

an underlying common etiology Inhibitors,research,lifescience,medical as regards genetic and neurobiological risk factors.15 In a recent review analysis, Singh et al have provided evidence that individuals at risk of developing ADHD symptoms may represent early prodromal states of PBD, and that PBD with comorbid ADHD may constitute a particular phenotype of early-onset disturbed mood and impaired affective regulation referred to as early PBD.16 However, these findings are Inhibitors,research,lifescience,medical far from definite, and the extent of comorbidity and the severity of symptom overlap between ADHD and PBD is not yet clear. Moreover, there Resveratrol are also nonoverlapping symptoms, as depicted in (Figure 3). Figure 3. DSM-IV symptoms of attention deficit-hyperactivity disorder and bipolar mania not showing an overlap. Adapted from ref 23: Wingo AP, Ghaemi SN. A systematic review of rates in diagnostic validity of comorbid adult attention-deficit/hyperactivity disorder … Clarification on these issues is handicapped by the lack of longitudinal data on developmental processes in juvenile PB D, which can in part be put down to problems of feasibility in investigations, one of which constitutes patient recruitment for Adriamycin price follow-up measures. In research, the Child Behavior Checklist (CBCL) has frequently been implemented as a tool for the diagnosis of PBD.

Thus, the 5-HTTLPR polymorphism affects not only central 5-HT fun

Thus, the 5-HTTLPR polymorphism affects not only central 5-HT function, but also seems to be involved in the regulation of biobehavioral characteristics.57 The G-protein-β3 subunit (Gβ3) gene Neurotransmitter molecules do not cross the postsynaptic membranes, but induce a cascade of reactions via their initial binding to surface receptors within the postsynaptic membrane, which are often coupled to guanine-nucleotide-binding proteins (G proteins). These G proteins represent initial regulatory components in transmembrane signaling

and are thus key elements in signal transduction, MDV3100 regulating many biological responses.58 In one subunit of these Inhibitors,research,lifescience,medical G proteins, the Gβ3 subunit, a polymorphism was identified (a C to T exchange at position 825 in exon 10), which leads to the occurrence of a splice variant (Gβ3-s) with deletion of 41 amino acids. It is now fairly well established that the T allele of this polymorphism, which results in increased ion flux across the membrane and increased signal Inhibitors,research,lifescience,medical transduction, is associated with hypertension and obesity.59,60 However, this genetic variant is not just important for somatic disorders, because we also found an increased frequency of the T allele in patients with affective psychosis.61 In an extended sample, using the DNA of

201 patients with Inhibitors,research,lifescience,medical major depression without increased proportions of hypertensives, Inhibitors,research,lifescience,medical we were able to replicate our previous results of increased frequency of allele T and increase in TT homozygotes (χ2=14.8; df=2; P=0.0006). Thus, our results are consistent with the hypothesis that disturbances in the signal transduction cascade on the level of G proteins are involved as contributing factor in the pathophysiology

of major depression, despite its importance in essential hypertension.62 The ACE gene Angiotensin-converting enzyme (ACE) Inhibitors,research,lifescience,medical is a zinc metallopeptidase involved in blood pressure regulation via the angiotensin-renin cascade, generating angiotensin II (ATII) from angiotensin I, and via degradation of the powerful vasodilator bradykinin. However, the effects of this enzyme are not restricted to the vasculature, as several PD184352 (CI-1040) studies have demonstrated that ACE might also be involved in HPA axis regulation and catecholamine production via the generation of ATII63 and is thus required for sympathoadrenal activation during stress. Further evidence suggests an involvement of the brain renin-angiotensin system in regulation of mood, because of the colocalization of angiotensin with dopamine-synthesizing neurons,64 the fact that ACE is involved in the metabolism of the neuropeptide substance P, which, in turn, is supposed to play a role in depression,65 and the clinical observation that the application of ACE inhibitors in hypertensives can induce euphoric or depressive states.

In Europe, the benefits of neoadjuvant radiation therapy (both sh

In Europe, the benefits of neoadjuvant radiation therapy (both short-course and a protracted course) have been shown in randomized phase III trials, but the role of PKA inhibitor concurrent chemotherapy remains a question of debate. The importance pre-therapy staging is stressed as sequencing of therapy appears to significantly impact outcome. In addition, close follow-up in the post-treatment setting Inhibitors,research,lifescience,medical appears of great importance both in terms of managing treatment-related side-effects and for early recurrence detection.
In this issue of the Journal of Gastrointestinal

Oncology, Katkoori et al report on the impact of the pro-apoptotic protein Bax and its ratio

to the anti-apoptotic portein Bcl2 (Bax/Bcl2) by immunohistochemistry grading on the outcome of patients Inhibitors,research,lifescience,medical with colorectal cancer treated with curative intent surgery or curative intent surgery followed by 5-FU-based chemotherapy (1). The chemotherapy group was selected from a patient population treated with curative intent surgery followed by at least 3 months of infusional 5-FU based chemotherapy or 6 months of bolus 5-FU-based chemotherapy between the years 1987-1993. The surgical control group was matched to the chemotherapy group by age, sex, stage, ethnicity, differentiation, and tumor location. The investigators Inhibitors,research,lifescience,medical demonstrate a better survival outcome Inhibitors,research,lifescience,medical in patients with increased Bax expression vs low Bax expression in the absence of chemotherapy (surgery only). A trend towards a worsened survival outcome is noted in patients with increased Bax expression vs low Bax expression in the presence of chemotherapy. Furthermore, a low Bax/Bcl2 ratio was associated with a better survival outcome in comparison to high Bax/Bcl2 ratio in the presence of 5-FU based chemotherapy. The authors conclude that patients with higher Bax expression may not benefit from adjuvant chemotherapy. One

has to recognize that Inhibitors,research,lifescience,medical there are several limitations to the Katkoori study. First, the study suffers from a small and heterogeneous population. Twenty-five percent also of patients investigated in this study had stage IV disease. Therefore, data extrapolation from this heterogeneous population to adjuvant treatment in stage II-III disease cannot be applied. If the intent of the study is to investigate the impact of Bax on the effectiveness of adjuvant chemotherapy, it would have been advisable to limit the study population to stages II-III disease. Second, it is impossible from the current study design to conduct a meaningful evaluation of the impact of Bax or Bax/Bcl2 or p53 on OS within the surgical and chemotherapy groups.

Indeed, Claude Bernard makes a distinction between the

Indeed, Claude Bernard makes a distinction between the essence of life and the mechanisms acting in life.26 In my opinion this distinction is valid today, as it was 145 years ago. Generally speaking, what used to be called science

until modern times did not differentiate between the mechanisms CI-1033 price functioning in the world and the essence of the world itself. Nature was understood as expressing a purpose, meaning, or value embodied in the phenomena. The conception of nature and the world in terms of meaning dictated the way people looked on natural Inhibitors,research,lifescience,medical data. For example, the Aristotelian-Ptolemaic conception of the celestial bodies revolving with uniform velocities in circular orbits was not derived from observation. In fact, observations suggested Inhibitors,research,lifescience,medical all these movements to be neither circular nor uniform, but because circular and uniform movement was deemed as the perfect movement, and nature was supposed to express this meaning, an astronomy was devised in order to comply with the paramount notion of a perfect and meaningful universe. This is the background for the long-standing confrontation between “religion” and “science”. If the content and conclusions about natural phenomena bear specific meanings and are expressions of these values, then matters of science are on the same plane as matters of faith, namely both enterprises Inhibitors,research,lifescience,medical deal

with questions of meaning. If this view is accepted, then religion and science may be intertwined, mutually antagonistic, or supplementary as the case may be. However, today we have no “science”

in the sense of the Middle Ages, in which religion and science meet. Modern science and the Torah are entirely alien to each other. Since natural sciences have gradually and progressively Inhibitors,research,lifescience,medical liberated themselves from the task of discovering the meaning of reality and become exclusively interested in functional relationships, they Inhibitors,research,lifescience,medical have become indifferent to any and all issues of meaning, purpose, or value (an important qualification: the practice of medicine is a problematic discipline in relation to other sciences, in that its practice has major moral and value consequences and therefore should not be considered in the present discussion). This is the only context in which natural science is objective; it is uniform and common to all who understand it and is independent of the varying outlooks and values of those involved in scientific Tryptophan synthase discourse. While the scientific discourse should be (by definition) understandable to anybody who acquires the knowledge of its language, the religious discourse, the language of the Torah is infinitely “incomprehensible” and needs constant interpretation. “The Torah speaks in the language of man” – we should always recognize that we are talking only in metaphors (This expression frequently arises in the Talmud as representing Rabbi Ishmael’s approach.