XL184 nm

Although there is no direct proof, it is probable that the dilatation of the anterior horn of the lateral ventricle, one of the most robust findings in schizophrenia,13 has something to do with a volume PD184352 reduction of frontal white matter. Here again, it seems to be a case of hypotrophy as well as atrophy.“ Voxel-based morphometry has mainly highlighted the probability of a reduction in white matter in the subcortical frontal region and the corpus callosum. Abnormal microscopic organization

Inhibitors,research,lifescience,medical of white matter has been repeatedly described with diffusion tensor imaging (DTI), although multiple and not overlapping areas were concerned in the studies.15,16 Reduced myelinization has also been suggested due to signal reduction in magnetization transfer imaging.17 This is in accordance with phosphorous Inhibitors,research,lifescience,medical magnetic resonance spectroscopy showing an increased breakdown of phospholipids at the onset of the disorder (increased phosphodiesters in patients at the first episode)18,19

and a pervasive reduction in synthesis (reduction in phosphomonocster)20-22 in the prefrontal region. The latest evidence for white matter decrease comes from the observation of a reduction in oligodendrocyte gene expression.23-25 In brief, there is also substantial support for a Inhibitors,research,lifescience,medical reduction in long-range connectivity. Erroneous connections In about 30% of schizophrenic patients, persistent subplate neurons have been found.26,27 As their disappearance is important for the maturation of thalamocortical connections, Inhibitors,research,lifescience,medical some authors have raised the point that this might be an example of erroneous connections,

ie, persistent connection with subplate instead of layer 4 neurons. Pyramidal cell disarray in internal temporal cortices28 could also be accompanied by such abnormalities of connectivity. However, many of these results have been hard to replicate, and the false target Inhibitors,research,lifescience,medical hypothesis remains speculative, although interesting to look into. Both local and long-range reductions in anatomical connectivity, together with possible erroneous connections, have led several authors to rejuvenate the “sejunction hypothesis” under the updated appellation of disconnéetivity.27,29-33 A disorder of functional integration? The functional counterpart of heptaminol these anatomical disorders could be an abnormal coordination between neurons of the same (local) and/or distant (long-range) areas. Functional integration is thought to allow segregated neurons to interact as a global assembly. Such a process is supposed to allow information to be streamed and bound into the coherent whole that we experience as consciousness.34-36 It is viable to think that this could be the process which breaks down in schizophrenic patients.37,38 An initial way to assess integration is by functional connectivity, defined as the amount of dependency between pairs of regions.

Given the scope and magnitude of the impact of losing a loved one

Given the scope and magnitude of the impact of losing a loved one, it is notable that relatively few negative long-term consequences usually occur. Most people meet the coping demands, with the help of supportive companions, and find a pathway that leads to restoration of a potentially satisfying and meaningful life.2 However, an important minority, currently estimated at about 7% of bereaved people,3 does not cope effectively with bereavement. Instead, they become Inhibitors,research,lifescience,medical entangled in grief, caught up in a futile struggle of silent

protest, trying to avoid reminders, and being carried helplessly on endless waves of acutely painful emotion. These people are suffering from complicated grief (CG), a syndrome in which healing is impeded and acute grief is intense Inhibitors,research,lifescience,medical and prolonged. Clinicians need to recognize symptoms of CG and differentiate this condition from usual acute grief, as well as depression and anxiety disorders. It is useful to have a framework for conceptualizing CG in order to better accomplish the differential diagnosis and to recognize risk factors and understand principles used to treat CG. Keeping terminology straight Using the terms Inhibitors,research,lifescience,medical bereavement, grief, and mourning interchangeably is a problem. To do so is not wrong, but it is more useful to allow the terms to denote specific components of the

experience of loss. Therefore, in this paper, the term bereavement PF-04691502 research buy refers to the experience of Inhibitors,research,lifescience,medical having lost someone close. Grief is the psychobiological response to bereavement whose hallmark is a blend of yearning and sadness, along with thoughts, memories, and images of the deceased person. Insofar as we never stop feeling sad that loved ones are gone, or stop missing them, grief is permanent. However, the acute, all-consuming intensity usually moderates over Inhibitors,research,lifescience,medical time, as grief becomes deeper, less intrusive, and integrated into our lives. Mourning is the array of psychological processes that are set

in motion by bereavement in order to moderate and integrate grief by coming to terms with the loss and reorienting to a world without our loved one in it. Different kinds of bereavement Urease When we look, we can discern a general framework for grief, but its day-to-day manifestations are variable and wide-ranging, influenced by many factors. Important and among them is the relationship to the bereaved person and specific circumstances of the death. Several studies suggest that grief is most intense and difficult for people bereaved of a child or a life partner, and these are the people most likely to experience CG. In general, death of a child is the most difficult kind of loss, and bereaved family members are at elevated risk for depression and anxiety for close to a decade after the loss.4,5 In addition these parents are at risk for a range of physical illnesses.

Recently, we developed a simple, three-parameter model that consi

Recently, we developed a simple, three-parameter model that considers reversible drug-carrier interaction and first-order release of lipophilic drugs from liposomes, leading to a closed-form analytical solution [20]. Here, the model is used to analyze drug release from a variety of nanocarriers, including liposomes and polymeric nanocapsules, NPs, fibers, and Inhibitors,research,lifescience,medical hollow fibers. The study is focused on analyzing the influences of carrier composition (i.e., molecular weight, copolymer composition, additives) and property (i.e., pore size,

hydrophobicity) and external stimuli (i.e., pH, temperature) on the release kinetics of drugs. Our goal is to reveal how carrier composition and property as well as external stimuli may modulate drug-carrier interaction

and diffusion-driven Inhibitors,research,lifescience,medical release. To achieve this goal, a systematic parameter study is pursued to illustrate how each model parameter influences release kinetics. The model is then fitted to more than 60 sets of release data obtained Inhibitors,research,lifescience,medical from various delivery systems. Last, statistical analysis using bootstrapping is pursued to validate the model in selected cases. 2. Theory 2.1. Diffusion-Driven Drug Release Many drug release systems can be represented by one of the configurations illustrated in Figure 1. In this study, we consider the encapsulated drug molecules in two states: (1) the drug has been molecularly Inhibitors,research,lifescience,medical dispersed in the system and (2) drug molecules form aggregates, crystals, complexes with excipient and/or are absorbed. The latter is collectively referred as an associated drug, while the former is referred as disassociated drug molecules ready for release. Considering the reversible association/disassociation Inhibitors,research,lifescience,medical and the nonconstant concentration of a disassociated drug, the diffusion process of the molecularly dispersed drug molecules in configurations (a) and (b) in Figure 1 follows the first-order

kinetics [18]: Figure 1 Schematics of drug release from various systems, including core-shell (a–c), porous (d), and monolithic systems (e). (a) A core functions as a drug reservoir while a shell found controls release rate. (b) A special core-shell system (e.g., hollow NPs, … dmdt=d(Vc)dt=−Ak1c or dcdt=−kSc, (1) where t is time, m and c are the drug amount and average drug concentration in a carrier, V and A are the volume and surface area of the carrier, and k1 is the rate constant. Here, k1 may be defined as k1 = DK/l, where D is the diffusion coefficient of the drug within the AT13387 cost rate-controlling shell, K is the partition coefficient of the drug between the shell and the core, and l is the thickness of the shell [18]. The parameter kS = Ak1/V in the rearranged form of (1) suggests that a high surface-to-volume ratio (A/V) of nanostructured carriers enhances drug release.

Five implants were kept at 4°C and five were kept at 37°C Every

Five implants were kept at 4°C and five were kept at 37°C. Every 7 days, the solution in each container was mixed to ensure homogeneity and 350μL was then removed and placed into a cryo-tube for analysis. Following sample removal, isotonic saline (350μL) was added to the container so the volume was kept consistent. Samples were collected for a total of 28 weeks and were kept in a −80°C freezer until analysis. Saline samples were analyzed using HPLC with ultraviolet absorption. The system consisted

of a 2695 separations module, a 2487 absorbance detector (Waters, Milford, MA, USA). Terbinafine was extracted from saline samples using a hexane extraction and was separated Inhibitors,research,lifescience,medical on a Symmetry Shield C18 (4.6 × 100mm, 5μm) column with a guard column. The mobile phase was a mixture of (A) 20mM phosphoric acid with 0.1% triethylamine adjusted to pH 3.0 and (B) acetonitrile (65:35). The flow rate was 1.1mL/min and the column temperature ambient. Absorbance was measured at 224nm. Standard curves for analysis were

prepared Inhibitors,research,lifescience,medical by fortifying saline with terbinafine to produce a linear concentration range of 5–1500ng/mL. Average recovery for terbinafine was 95% while intra- and interassay variability were less than 10%. The lower limit Inhibitors,research,lifescience,medical of quantification was 5ng/mL. Following HPLC analysis, the amount of terbinafine released by each implant during each interval was calculated. The mean release of terbinafine with standard deviations was PARP inhibitor calculated for the different temperatures at each time point. Data was tested for normalcy with a Bartlett’s test for inequality of variances. If the values were normally distributed, a t-test was performed to determine if a significant difference in amount of terbinafine released was present at the Inhibitors,research,lifescience,medical two temperatures. If the data was not normally

distributed, a Mann-Whitney/Wilcoxon Inhibitors,research,lifescience,medical two-sample test was used to determine if differences existed. Significance was set at P < 0.05 and analysis was performed with EpiInfo (CDC, Atlanta, GA, USA). 3. Results Samples were collected and analyzed with HPLC for a total of 28 weeks after initial placement into isotonic saline. A sample was not collected during week 23. The mean amount released from the implants at the two different temperatures during the 28 weeks is shown in Table 1/Figure 2. The amount released from the Sodium butyrate implants at 37°C was significantly greater than 4°C at the 1 (P < 0.01), 17 (P < 0.01), 26 (P = 0.03), and 28 (P = 0.04) week time points; the amount released from implants at 4°C was greater than 37°C at the 2 (P = 0.04) and 3 (P = 0.02) week time points. The mean amount of terbinafine released weekly across the 28 weeks was approximately 1.7μg at 4°C and 4.3μg at 37°C. Figure 2 Terbinafine impregnated implants were placed into isotonic saline at 4°C (n = 5) and 37°C (n = 5). Samples were collected every 7 days and terbinafine concentrations were determined with HPLC.

102 The role of these drugs in the prevention

and treatme

102 The role of these drugs in the prevention

and treatment of vascular depression can be examined in patients with ischemic events participating in acute intervention and secondary prevention trials. Treatment of vascular depression Psychotropic drugs used in depressed elderly patients may influence recovery from ischemic lesions. Animal studies suggest that the dopamine receptor blocker haloperidol, the α1-adrenergic receptor antagonists trazodone and amitriptyline, Inhibitors,research,lifescience,medical the ;2-adrenergic receptor clonidine, and GABA agonists such as diazepam and phenytoin interfere with motor recovery after ischemic lesions.102-104 In contrast, amphetamine, desipramine, the dopamine agonist bromocriptine, and the ;2-adrenergic receptor antagonists yohimbine and idazoxan may be beneficial to recovery from ischemic injury.102-104 A clinical study has observed that fluoxetine may facilitate and maprotiline may hinder recovery in poststroke hémiplégie patients undergoing rehabilitation.105

Inhibitors,research,lifescience,medical Studies may examine which psychotropic agents influence the incidence of poststroke depression or alter the course of vascular depression, and identify antidepressants suitable for prophylaxis of vascular Inhibitors,research,lifescience,medical depression. The presence of subcortical abnormalities and their adverse impact on the treatment response and the longterm outcome of vascular depression provide the rationale for studies of agents that influence the neurotransmitter systems of frontostriatal circuitry. Further Inhibitors,research,lifescience,medical research may determine the efficacy of drugs acting on the dopamine, acetylcholine, and opiate systems of prefrontal pathways in patients with vascular depression. We have observed a relationship between disability and abnormal scores of initiation/perseveration and psychomotor retardation,10 abnormalities that frequently occur in vascular depression. Disability is also associated with anxiety Inhibitors,research,lifescience,medical and depressive ideation in depressed

elderly patients.10 Cognitive behavioral therapy combined with rehabilitation approaches have been found to reduce depression and improve quality of life.106 Such interventions may be useful in disabled patients with vascular depression provided that they are individualized and address the cognitive deficits of these patients. Conclusion Clinical and neuroimaging Carnitine palmitoyltransferase II studies suggest that cerebrovascular disease may predispose, initiate, or perpetuate late -life depression, perhaps by compromising the integrity or regulation of CSPTC systems. The heuristic value of the vascular depression hypothesis is that it provides the background for studies of mechanisms of depression. Lesions at specific locations may promote, have no Enzalutamide in vitro effect, or even protect patients from depression. The lesion burden concept may be relevant to some cases of vascular depression.

However, the right-to-left shunt through

this persistent

However, the right-to-left shunt through

this persistent vein is usually not sufficient enough to provoke clinically significant systemic desaturation. Therefore, if clinically suspected, a complete evaluation for this anomaly should also be considered. There are many devices used to occlude vessels, the Amplatzer® vascular device is easily conformable and has a wide range of sizes.9) After device closure, the patient was followed-up regularly thereafter and she is free from additional neurologic GSK1363089 nmr attacks, and on follow-up TTE, no residual Inhibitors,research,lifescience,medical shunting through both device was detected. In conclusion, we report a successful simultaneous closure of PFO using the Amplatzer® PFO occluder (St. Jude Inhibitors,research,lifescience,medical Medical, St. Paul, MN, USA) and persistent LSVC connection to LSPV using the Amplatzer® Vascular Plug II (St. Jude Medical, St. Paul, MN, USA). In routine work-up performed on TIA or stroke patients, in order to increase the chance of diagnosing additional right-to-left shunting other than PFO, the authors suggest performing contrast echocardiography through the left arm peripheral IV line, or on both arm if the patients consent to it.10)
Fabry disease (FD) is an X-linked lysosomal storage disorder

caused by α-galactosidase A (α-Gal A) deficiency. Because the disease Inhibitors,research,lifescience,medical is X-linked, males are predominantly Inhibitors,research,lifescience,medical affected. This enzyme deficiency leads to widespread deposition of neutral glycosphingolipids (mainly globotriaosylceramide and, to a lesser extent, galabiosylceramide) on blood vessel walls throughout the body, resulting in a multiple-system disorder with a wide spectrum of physical signs and symptoms that predominantly affect the central and peripheral nervous systems, skin, heart,

kidneys, and eyes.1) In the heart, glycosphingolipids deposition causes progressive left ventricular hypertrophy (LVH) that mimics the morphological and clinical characteristics of Inhibitors,research,lifescience,medical hypertrophic cardiomyopathy (HCM).2),3) Enzyme replacement therapy is effective in reversing the microvascular changes in FD by catabolizing the lipid deposits and improving cardiac function in patients with cardiac the involvement.4),5) We report a case of FD with end-stage renal disease (ESRD) which was suspected based upon two-dimensional transthoracic echocardiographic finding. Case A 44-year-old man was admitted to evaluation of aggravated exertional dyspnea with orthopnea for two weeks in 2010. He had been diagnosed with ESRD of unknown etiology at age 41 followed by renal transplantation in 2007. He had been admitted for azotemia three times after renal transplantation. Percutaneous biopsy of the transplanted kidney was performed three times in 2008, 2009, 2010.

Results Clinical diagnosis To provide a comparison for the accura

Results Clinical diagnosis To provide a comparison for the accuracy of imaging data, and evaluate its cost-benefit characteristics, we first provide information on the accuracy of clinical diagnosis against postmortem neuropathology. Simple screening measures, such as the Mini-Mental

State Examination (MMSE), often provide good diagnostic accuracy. For example, Muller et al and Wahlund et al reported reasonable sensitivity and specificity values for the MMSE alone and in combination with a verbal recall test.12,13 More informative results were obtained with standardized clinical measures when validated against neuropathological diagnosis. In Inhibitors,research,lifescience,medical Jobst et al, 200 affected cases were compared with normal controls by standardized clinical measures, and then validated with histopathologic diagnosis.14 Using NINCDS Inhibitors,research,lifescience,medical possible or probable AD criteria, Jobst et al reported a maximum sensitivity of 96%, with associated specificity of 61 %. In the same study, the use of DSM-III-R criteria applied to

the same study groups resulted in a sensitivity of 51%, and specificity of 97%. Other authors, Inhibitors,research,lifescience,medical noted in Table I, obtained similar results.15-21 Overall, the range of sensitivity of clinical diagnosis was 39% to 98%, and the range of specificity was 33% to 100%. There was a significant negative correlation (r = -0.79, P=0.01) between sensitivity and specificity, Inhibitors,research,lifescience,medical as expected, reflecting the necessary tradeoff. Thus, for instance, to achieve

a specificity greater than 80%, four out. of five studies had to settle for sensitivity lower than 70%. This correlation is depicted in Figure 1 Figure 1. Sensitivity and specificity of clinical diagnosis against neuropathological diagnosis. Table I. Sensitivity and specificity of clinical measurements. AD, Alzheimer’s disease; CERAD, CERAD (Consortium to Establish a Registry for Alzheimer Disease) probable or definite AD (neuropathology); Other, other neuropathological review; DSM-III-R, Inhibitors,research,lifescience,medical Diagnostic … A number of studies used the criteria “NINCDS possible or probable AD” or other nonstandard clinical measures (data not shown). 14-18,20,22-27 While clinical diagnosis is often those used to validate imaging findings, and neuro-pathological diagnosis is the overall “gold standard,” and despite the existence of Selleckchem CP868596 modern standardized criteria, the application of these standards should not be considered free of ambiguity. A good example is provided by Hoffman et al.15 The clinical NINCDS criteria allow the definition of probable or possible AD, reflecting different, degrees of confidence. The Consortium to Establish a Registry for Alzheimer Disease (CERAD) pathological criteria allow the finding of “pure” AD or AD in addition to other pathology.

T gondii has also been linked to behavioral effects in nontarget

T. gondii has also been linked to behavioral effects in nontarget hosts, including humans, where gender-specific effects on personality traits including self-control,

warmth, and novelty seeking (eg, tendency towards highrisk activities) have been observed.11-13 Many www.selleckchem.com/products/ZSTK474.html viruses affect behavior; for example, bornavirus (has been related to mania and schizoaffective disorders14-16); human immunodeficiency virus (linked to cognitive impairment, affective disorders, and psychosis17-19), rabies (a zoonotic infection caused by an enveloped single-stranded RNA virus that in its fulminant form is associated with hydrophobia20). The same is true of bacteria; cognitive Inhibitors,research,lifescience,medical and emotional disturbances have been associated with Brucella suis infection21; manic and psychotic symptoms resistant to antipsychotics but treatable with antibiotics during infection with Leptospira 22; baseline depression and anxiety caused by Mycobacterium tuberculosis 23; and obsessive-compulsive disorder (OCD) and pediatric autoimmune neuropsychiatric disorders associated with Inhibitors,research,lifescience,medical streptococcal Inhibitors,research,lifescience,medical infections (PANDAS).24,25 Poorly understood from a mechanistic perspective,

but perhaps more intriguing, are cases where an entire microbial community impacts host behavior. These effects have been noted when comparing the phenotypes of mice reared from birth and from generation to generation under sterile conditions in specialized gnotobiotic isolators that prevent any exposure to environmental microbes (“germ-free” animals) with mice that have been reared in Inhibitors,research,lifescience,medical the presence of microbes but under specified pathogen-free conditions (“conventionally raised” animals), or mice that were reared germ-free and then colonized at a given point in postnatal or adult life with a microbiota transplanted from a conventionally raised donor (so called “conventionalized” animals). For example, germ-free mice exhibit basal behaviors in the elevated plus maze (EPM) that are indicative of reduced anxiety levels.26 Using an implantable detector of locomotion for quantitative phenotyping, Backhed et al27 Inhibitors,research,lifescience,medical found that germ-free wild-type

(C57Bl/6J) mice have significantly increased movement compared with Endonuclease their microbe-laden counterparts, whether on a standard plant polysaccharide-rich, low-fat chow diet or a diet high in simple sugars and fat (Western diet). Conventionallyraised genetically engineered mice lacking Toll-like Receptor 5 (TLR5), a component of the innate immune system that recognizes bacterial flagellin, have an altered gut microbiota, eat substantially more than their conventionally-raised wild-type counterparts, and become obese. The same phenotype can be transmitted to germfree wild-type mice by transplanting a gut microbiota from a conventionally-raised TLR5 knockout donor,28 suggesting that it is the induced change in the microbiota that is changing the eating behavior.

5hr interval Again, it is hypothesized that with such a short in

5hr interval. Again, it is hypothesized that with such a short interval, drug “overlapped”

from dose to dose which caused the nonabsorbable portion to increase thereby reducing the exposure (similar to a s.i.d. dose). Better efficiency was achieved when the dose buy AG-1478 interval increased to 2.5hrs. Better drug delivery efficiency was achieved when the dose interval increased to 1.5 and 2.5hrs. This is not surprising, since for a low solubility drug, the nonabsorbable portion increases when the dose Inhibitors,research,lifescience,medical increases due to solubility limited absorption. It is also understood that the dose interval should be Tmax (from single dose) dependent. The overlap from the shorter dosing interval becomes more significant and the nonabsorbable portion increases as dose increases; thus, the dosing interval and the dose are interdependent, and both must be considered Inhibitors,research,lifescience,medical in order to minimize the “drug overlap” in the GI track. The Cmax and AUC (Tables ​(Tables44 and ​and5)5) obtained from

the 1.5hrs dosing scheme are comparable to the values obtained from the s.i.d. dose (Table 2. 1000mg/kg). Cmax and AUC from the 2.5hrs dosing scheme well exceed the values obtained from the s.i.d. dose of 1000mg/kg. The obtained Cmax of 200mg/kg tandem dose (with 2.5hr interval) was 26.3 ± 4.0μM, and AUC/Dose Inhibitors,research,lifescience,medical (for 2.5hr interval) was calculated to be 0.87 ± 0.08μM*hr/mg/kg.This suggests that for this dose (100mg/Kg X3) 1.5hrs may be sufficient to separate two doses; however, Inhibitors,research,lifescience,medical the 2.5hr interval delivers the best results. Similarly, the data obtained from the 1.5hr interval exhibits higher variability when compared to the 2.5hr interval. This again suggests that 1.5hrs may not be the ideal

interval for higher doses as the risk of drug overlap in the GI is higher and may contribute to higher variability in exposures. The variability could also be subject dependent. The simulated exposure (2.5hrs interval) versus obtained exposure for 200mg/kg X3 tandem dose Inhibitors,research,lifescience,medical is presented in Figure 8. A Wagner-Nelson plot (see Section 2) was used to calculate drug absorbed and to assess the absorption as a function of time for the 200mg/kg X3 dose is presented why as Figure 9. Similarly, a noticeable increase in beta phase half-life was observed for the tandem doses versus the predicted curve using our linear PK model. It is possible that via accumulation drug exposure has reached the nonlinear range (saturated the CL), and therefore a linear PK model underpredicts the beta phase half-life. It is also possible that this phenomena was due to the larger amount of drug dosed which altered some physiological factor (i.e., transit time) in the animal or saturated the absorption. Thus, the parameters generated by simple PK studies at a lower dose may not be sufficient to predict every aspect of a higher dose study. However, since both AUC and Cmax were actually well within our target, we believed this model work well.

It has long been recognized that the incidence of disease In huma

It has long been recognized that the incidence of disease In humans can show annual fluctuation. Meteorological conditions favor the spread of many infections during either the cold or hot or damp months. Centuries ago In France, the lack of vitamins in food during winter was a cause of visual Impairment

during early spring, described in Inhibitors,research,lifescience,medical poor people such as the French peasants. More recently, clinical and epidemiological studies have shown that given syndromes or disorders tend to occur more frequently at given astronomical times, for example myocardial Infarction during the very early hours of the morning.3 Although the role of astronomical Inhibitors,research,lifescience,medical time In the occurrence and the incidence of various disorders was recognized centuries ago, basic and medical research on biological clocks Is only recent. In the 18th century, the French

scientist Jean-Jacques Dortous de Malran (1678-1771) described a circadian rhythm In plant leaf movements that was independent of the Inhibitors,research,lifescience,medical lighting schedule. Then, In the early 20th century, studies on the capacity of the hon-eybee to remember the time of day when a given food was available led to the Idea of a memory of time. Inhibitors,research,lifescience,medical Whether this was more than a mere memory, and whether It reflected an endogenous production of time was then evaluated, leading to the discovery of biological clocks, a concept very different from that of memory of time. Biological clocks are defined by the fact that they Inhibitors,research,lifescience,medical generate a rhythm with Selleck SB202190 cycles that exist Independently of any exogenous

cycles, such as the Influence from astronomical time (also named clock time or external light/dark cycle). Circadian rhythms (circa means around or approximately unless and dies means day) occur In activityrest cycles as well as In body temperature and In the secretion of many hormones, even when a subject lives without any external clues about time. This was clearly demonstrated by the French researcher Michel Slffre, who lived in an underground cave during 1962 and then In 1972. At the end of the first experiment, he believed that 43 days had passed rather than 60, and at the end of the second experiment, he believed that only 175 days had passed Instead of 205. He had had a few rest-activity cycles that extended up to 50 hours, of which he had remained unaware.