Inherent Rhythms Research Articles

Chronotherapy for Cancer Treatment: A Review of Timing Strategies

Chronotherapy, the delivery of drugs in accordance with the body's circadian cycle, has become a promising strategy to increase the effectiveness and lower the toxicity of cancer treatment. Cell division, DNA repair, and metabolism are three physiological functions regulated by the circadian clock that are known to affect how well anti-cancer treatments work. This study reviews the present status of research on timing techniques in order to offer a thorough overview of chronotherapy in the treatment of cancer. The review starts off by going over the basic ideas of circadian rhythms and how they relate to cancer biology. The justification for adopting chronotherapy to improve treatment results is then discussed, including the possibility of increasing therapeutic efficacy while reducing side effects. A full analysis of preclinical research is then provided, emphasizing the influence of treatment scheduling on drug metabolism, host-tumor interactions, and tumor growth inhibition. The significance of taking circadian rhythms into account while developing cancer treatment plans is emphasized in this study. The complicated interactions between circadian biology, tumor dynamics, and treatment effects are highlighted, underscoring the need for more study. In the end, utilizing the power of chronotherapy has the potential to transform cancer treatment by customizing regimens based on each patient's inherent rhythms.

Hierarchical amplitude modulation structures and rhythm patterns: Comparing Western musical genres, song, and nature sounds to Babytalk.

Statistical learning of physical stimulus characteristics is important for the development of cognitive systems like language and music. Rhythm patterns are a core component of both systems, and rhythm is key to language acquisition by infants. Accordingly, the physical stimulus characteristics that yield speech rhythm in "Babytalk" may also describe the hierarchical rhythmic relationships that characterize human music and song. Computational modelling of the amplitude envelope of "Babytalk" (infant-directed speech, IDS) using a demodulation approach (Spectral-Amplitude Modulation Phase Hierarchy model, S-AMPH) can describe these characteristics. S-AMPH modelling of Babytalk has shown previously that bands of amplitude modulations (AMs) at different temporal rates and their phase relations help to create its structured inherent rhythms. Additionally, S-AMPH modelling of children's nursery rhymes shows that different rhythm patterns (trochaic, iambic, dactylic) depend on the phase relations between AM bands centred on ~2 Hz and ~5 Hz. The importance of these AM phase relations was confirmed via a second demodulation approach (PAD, Probabilistic Amplitude Demodulation). Here we apply both S-AMPH and PAD to demodulate the amplitude envelopes of Western musical genres and songs. Quasi-rhythmic and non-human sounds found in nature (birdsong, rain, wind) were utilized for control analyses. We expected that the physical stimulus characteristics in human music and song from an AM perspective would match those of IDS. Given prior speech-based analyses, we also expected that AM cycles derived from the modelling may identify musical units like crotchets, quavers and demi-quavers. Both models revealed an hierarchically-nested AM modulation structure for music and song, but not nature sounds. This AM modulation structure for music and song matched IDS. Both models also generated systematic AM cycles yielding musical units like crotchets and quavers. Both music and language are created by humans and shaped by culture. Acoustic rhythm in IDS and music appears to depend on many of the same physical characteristics, facilitating learning.

The valve movement response of three freshwater mussels Corbicula fluminea Müller 1774, Hyriopsis cumingii Lea 1852, and Anodonta woodiana Lea 1834 exposed to copper

Biological early warning system (BEWS) is an innovative system for real-time water quality monitoring based on different behavioral responses of aquatic organisms. Mussels easily meet the requirement for optimal organisms in BEWS. However, little emphasis has been placed on freshwater mussels. In this study, the Hall element sensor system has been used to investigate exposure–response relationships of valve movement in freshwater Corbicula fluminea, Hyriopsis cumingii, and Anodonta woodiana exposed to a copper (Cu2+) gradient of 0, 0.01, 0.1, 1, and 10 mg l−1. The measured behavioral parameters were compared to determine if a response could be elucidated, including the amplitude of valve opening (AVO) and frequency of valve adduction (FVA). The results suggest that the mean AVO was significantly decreased in C. fluminea exposed to 0.1 and 1 mg l−1, and decreased for H. cumingii and A. woodiana after exposure to 10 mg l−1. The mean FVA was significantly decreased in H. cumingii exposed to 1 and 10 mg l−1, while A. woodiana revealed lower frequencies only at 10 mg l−1. The three species showed inherent rhythms of valve movements and dose-dependent responses upon copper exposure, and H. cumingii showed the most obvious profile of a copper dose-valve movement response.

Imagined Temporal Groupings Tune Oscillatory Neural Activity for Processing Rhythmic Sounds

Temporal patterns within complex sound signals, such as music, are not merely processed after they are heard. We also focus attention to upcoming points in time to aid perception, contingent upon regularities we perceive in the sounds’ inherent rhythms. Such organized predictions are endogenously maintained as meter — the patterning of sounds into hierarchical timing levels that manifest as strong and weak events. Models of neural oscillations provide potential means for how meter could arise in the brain, but little evidence of dynamic neural activity has been offered. To this end, we conducted a study instructing participants to imagine two-based or three-based metric patterns over identical, equally-spaced sounds while we recorded the electroencephalogram (EEG). In the three-based metric pattern, multivariate analysis of the EEG showed contrasting patterns of neural oscillations between strong and weak events in the delta (2–4 Hz) and alpha (9–14 Hz), frequency bands, while theta (4–9 Hz) and beta (16–24 Hz) bands contrasted two hierarchically weaker events. In two-based metric patterns, neural activity did not drastically differ between strong and weak events. We suggest the findings reflect patterns of neural activation and suppression responsible for shaping perception through time.

Lobar cerebral microbleeds associated with transient focal neurological symptoms followed by symptomatic intracerebral hemorrhage

Cerebral microbleeds (CMBs) are defined as all discrete round-shaped hypointense areas on T2*-weighted magnetic resonance images (MRIs) with a gradient-echo (GRE) sequence [11]. CMBs can be regarded as a marker of vessel wall disorders with a higher tendency for intracerebral hemorrhage (ICH) [11]. It has been suggested that microbleeds increase the risk of ICH following antithrombotic administration for acute ischemic stroke [9, 14], though this issue remains controversial. In addition, there have been few reports of symptomatic ICH that has occurred at the site of microbleeds in the literature [2, 13]. However, these lesions themselves have been considered asymptomatic. We present a case of CMBs presenting with transient neurologic symptoms that developed into subsequent ICH. A 65-year-old man with no previous neurological history visited our hospital because of incoherent speech and headache. He had a history of diabetes mellitus and chronic hepatitis B. He had been diagnosed with hepatocellular carcinoma prior to this presentation. Neurological examination revealed that he had language disturbances with jargon speech and abnormal comprehension. These symptoms fluctuated and persisted for about half an hour after symptom onset. The results of other physical examinations were normal. Electroencephalography showed that there were no epileptiform discharges or abnormal inherent rhythms. There were also no acute ischemic brain lesions or hemorrhages on initial brain MRI (Fig. 1a). GRE images showed multiple CMBs in the left temporo-parieto-occipital lobe relevant to language disturbance (Fig. 1b). However, there were no CMBs in the deep subcortical area and brainstem. There were no CMBs on previous GRE images obtained at a local clinic 1 month prior to this presentation as well (Supplemental Figure). While he had no symptoms at this time, he underwent brain MRI as part of a medical check-up. All laboratory tests, including coagulation profiles, were normal. He was tentatively diagnosed with (1) recurrent transient ischemic attacks and (2) mood disorder associated with medical condition. During admission, he was treated with antihypertensive agents and 100 mg of aspirin for prevention of secondary ischemic stroke. On the fourth day of admission, he suddenly developed global aphasia and right hemiparesis. Follow-up GRE images showed a large lobar hematoma with perilesional edema in the left temporo-parietal lobe where the CMBs were previously seen (Fig. 1c). Although he was referred to the Department of Neurosurgery for surgical management, he was discharged with a modified Rankin scale of 5. Our case illustrates that localized CMBs can be related to transient neurological symptoms and subsequent ICH. Although this is a single case that represents a causal relationship between CMBs and transient neurological symptoms, the association between CMBs and subsequent ICH could not be clarified, suggesting that transient Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6504-8) contains supplementary material, which is available to authorized users.

10.1007/s11183-008-2001-4

Most plants are constructed from repeating modular units such as phytomers, merophytes, and cell packets. Even an organism as simple as the filamentous cyanobacterium Anabaena shows recurrent patterns of differentiated cellular structures, notably with respect to its heterocysts. These examples reflect the inherent rhythms established within developmental processes of living organisms. In the present article, attention is paid to repetitious production of idioblasts—isolated cells, or clusters of cells, with an identity different to that of neighbouring cells from which they are derived. In higher plant root tissues, idioblasts are contained within cell packets that grow up from mother cells during the course of a number of cycles of cell production. The heterocysts of Anabaena are also discussed; they, too, are a type of idioblast. The idioblasts of root tissues originate as small cells which result from unequal cell divisions. Such divisions are usually the final ones within a cell packet which has already undergone a number of division cycles and are characteristically located at one or both ends of a packet. The packet end walls are suggested to have a role in regulating division asymmetry. Idioblastic systems discussed are root cortical trichosclereids and diaphragm cells; in their earliest stage, the cells from which lateral root primordia arise are also considered as clusters of idioblasts because they, too, are the products of asymmetric divisions of pericyclic mother cells. The division patterns of all these idioblastic systems were modelled in a consistent way using L-systems, with the assumption that the age of a cell-packet end wall plays a special role in cell determination.

Periodically Discontinuous Induction of Bone Marrow Stem Cells toward Osteogenic Differentiation in Vitro

This paper reveals that a discontinuous in vitro induction, namely, the periodic presence and absence of foreign induction factors, might be, under a certain condition, more effective to stimulate stem cells' differentiation than a continuous induction. Bone marrow stem cells (BMSCs) derived from Sprague Dawley rats were employed to examine the effects of discontinuous additions of osteogenic supplements with a series of alternate frequency in contrast to those with continuous induction or no induction. The results demonstrated that a suitable discontinuous induction was more able to achieve osteogenesis than not only no induction but also the associated continuous induction. Additionally, the osteogenic supplements were confirmed to enhance cell differentiation but suppress cell proliferation. So, the combination of differentiation extent per cell and cell number accounts for the "unexpected" good osteogenic effect of the discontinuous induction. The induction effect was found to be dependent upon alternate frequency, and the optimum alternate period in our experimental systems was determined to be around 4 days. Since it is very common to change culture medium every 2-4 days, such a strategy of discontinuous induction does not bring any extra manual work but reduces the consumption of foreign induction factors and significantly enhances the global differentiation efficacy. Our work thus affords a convenient and practical approach to achieve differentiation of BMSCs, which might be useful for potential large-scale culture and differentiation of stem cells. Meanwhile, the existence of optimum frequency implies some unknown inherent rhythms of cell proliferation and differentiation.

Rhythmic plant morphogenesis: Recurrent patterns of idioblast cell production

Most plants are constructed from repeating modular units such as phytomers, merophytes, and cell packets. Even an organism as simple as the filamentous cyanobacterium Anabaena shows recurrent patterns of differentiated cellular structures, notably with respect to its heterocysts. These examples reflect the inherent rhythms established within developmental processes of living organisms. In the present article, attention is paid to repetitious production of idioblasts—isolated cells, or clusters of cells, with an identity different to that of neighbouring cells from which they are derived. In higher plant root tissues, idioblasts are contained within cell packets that grow up from mother cells during the course of a number of cycles of cell production. The heterocysts of Anabaena are also discussed; they, too, are a type of idioblast. The idioblasts of root tissues originate as small cells which result from unequal cell divisions. Such divisions are usually the final ones within a cell packet which has already undergone a number of division cycles and are characteristically located at one or both ends of a packet. The packet end walls are suggested to have a role in regulating division asymmetry. Idioblastic systems discussed are root cortical trichosclereids and diaphragm cells; in their earliest stage, the cells from which lateral root primordia arise are also considered as clusters of idioblasts because they, too, are the products of asymmetric divisions of pericyclic mother cells. The division patterns of all these idioblastic systems were modelled in a consistent way using L-systems, with the assumption that the age of a cell-packet end wall plays a special role in cell determination.

Blood pressure changes in acute haemorrhagic stroke

The relationship between hypertension and cerebrovascular disease is well established. As blood pressure is a dynamic and continually distributed variable, 24 h ambulatory blood pressure monitoring may be valuable as a risk stratifying tool in determining the "hypertensive load" as assessed by the presence of dipping or non-dipping status of an individual. Indeed, the association between reduced nocturnal blood pressure dipping and increased target organ damage is well established. Raised blood pressures are often seen in those presenting with strokes, although the precise mechanisms are uncertain. The relationship between intracerebral haemorrhage, which accounts for up to 15% of strokes in Caucasians, and blood pressure patterns is not well known. Understanding these inherent diurnal rhythms of blood pressure variation could help us unravel their significance and impact on cerebrovascular disease.

Phenotypic Differences Between Natural and Selected Populations of Picea Abies. II. Apical Mitotic Activity and Growth Related Parameters

Apical mitotic index (MI) and growth of non-juvenile Norway spruce [Picea abies (L.) Karst.] populations growing in northern Sweden (63°54' N) were monitored in 1996. Annual leader shoot lengths and shoot growth components for the period 1990-1997 were measured in 1997. In 1997 populations transferred more than approximately 3° in latitude were found to be shorter than local populations. MI levels were initially high in all populations in mid-April. In spring, populations originating north of 63°30' N showed higher MI levels, and started shoot growth earlier, than populations originating further south. In autumn, MI levels were higher in populations originating south of 63°30' N than in populations originating further north and higher in seed orchard populations than in natural populations of similar latitudinal origin. The number of stem-units (NSU) was correlated with tree height and leader shoot length. NSU and elongation of stem-units appeared to be primarily influenced by summer temperature. Prolonged MI activity in autumn did not result in high NSU but appeared to be associated with a higher risk of frost damage to buds. The results are discussed in relation to climatic factors, seed transfer, selection and inherent growth rhythms.

Phenotypic Differences Between Natural and Selected Populations of Picea Abies. I. Frost Hardiness

The frost hardiness of non-juvenile Norway spruce [Picea abies (L.) Karst.] populations growing in northern Sweden (63°54' N) was monitored during 1996-1997. The investigated progenies originated from 12 natural populations and six seed orchards located between 58° N and 68° N in Sweden. Frost hardiness of needles was assessed by measuring chlorophyll fluorescence and electrolyte leakage after freezing. The loss of frost hardiness in 1-yr-old needles during spring occurred slightly earlier in populations originating north of 63°30' N than in those originating further south. Dehardening was slightly delayed in selected populations compared with natural populations of similar origin. The level of frost hardiness during autumn was higher in populations originating north of 63°30' N than in those originating south of this latitude, but there were no clear differences in frost hardiness between selected and natural populations of similar origin. The results are discussed in relation to climatic factors and inherent growth rhythms.

Circadian rhythms have no effect on cycling performance.

The aim of this research was to determine if circadian rhythms have an effect on time trial cycling performance of 15 min duration. Seven males (Mean+/-SD): age, 22.3+/-4.9 yr; height 179.0+/-7.9 cm, body mass 74.5+/-15.5 kg; VO2max 68.0+/-5.7 ml x kg(-1) x min(-1) who were all competitive cyclists or triathletes with previous experience in laboratory testing procedures volunteered to participate in this study. Each of the seven subjects underwent a series of four tests; one VO2 max test, and three 15 min maximal performance tests, at varying times during a 24 hr period. Testing times were at 08.00-10.00; 14.00-16.00 and 20.00-22.00 hours. Heart rate was recorded during the last 10-15 seconds of each minute and blood lactate levels were taken at 5 and 10 min during exercise and again immediately post-exercise. O2 consumption was measured continuously using open circuit spirometry. RPE was measured using the Borg scale at 5 and 10 min during, and again immediately following the completion of testing. Resting oral temperature was the only variable to show a significant time of day effect (p<0.05). Oral temperature during the afternoon was higher than both morning and evening results by 0.76 degrees C and 0.09 degrees C respectively. Total work (kJ) and average power output (W) were recorded at their highest during the morning session and reached a trough during the afternoon session, but these differences were not significant (p = 0.9997 and 0.9972 respectively). The results obtained in this study indicate that while certain biological rhythms are present, they appear to have no effect on this type of cycling performance. Although athletic performance may be enhanced by training programs that are compatible with an individuals body clock, the ability to perform and train at various times has an adaptive response which appears to over-ride these naturally inherent rhythms.

Seasonal variation in proliferative response and subpopulations of lymphocytes from mice housed in a constant environment.

A seasonal variation in the proliferative response to mitogens and in the proportion of splenic lymphocyte subpopulations was found in mice housed in a constant environment. The lymphoproliferative responses to T-cell and B-cell mitogens reached maximum values in autumn and summer. Identification of lymphocyte subpopulations by flow cytometry demonstrated that the proportion of T cytotoxic-suppressor (Tcs) lymphocytes was significantly higher in autumn and summer than in spring and winter. However, the proportion of B lymphocytes was significantly lower in spring than in the other three seasons, whereas the proportions of T and T helper (Th) cells did not show any seasonal variation. On the other hand, we observed a significant correlation between the level of mitogenic responsiveness and the proportion of Tcs cells, but not between the former and the proportions of B, T or Th cells. These data suggest that the seasonal variation in murine lymphoproliferative responses may depend on the cyclic changes in the proportion of Tcs lymphocytes; these changes, in turn, may be predetermined by the inherent internal biological rhythms of the animal.

A Reply to Ulrich Wegner

lrich Wegner's experiments in cognitive ethnomusicology with Baganda musicians (1993:201-42) proved fascinating reading for one who has for years interested himself in the Kiganda musical repertory and that of their neighbours in southern Uganda. But I was a little disconcerted to find my own views as expressed in an early article (Cooke 1970) misquoted. Ulrich wrote as follows: Peter Cooke, about inherent patterns in amadinda music ... indicated that-if they exist at all-they are than 'incidental to the main object which is to present known songs effectively' (1993:225). The omission of the word no before the more leads the reader to suppose that I was contradicting myself in the same sentence. Wegner has since told me that during the processing of the article the word no had been accidentally deleted. A first reading of his paper though was enough to send me scurrying to obtain my old contribution so as to verify what I actually did write. was: If it is accepted that xylophone repertoire is based on the attempt to outline songs then... an answer should be given to the question: does concern for inherent rhythms affect the content of xylophone parts? My view is that they are to a large extent a coincidental feature of the [compositional] process (1970:77). On the following page I added It is also possible that some inherent rhythms only vaguely suggest words to performers who then make minor modifications (ebisoko) of either part to make the pattern prominent and better fitting to the suggested text. In both cases, however, they are incidental to the main object, which is to present known texts effectively. I was puzzled also to read that I was skeptical about inherent patterns: this may have arisen from misunderstandings in his reading of the same early article and perhaps also of friendly and useful correspondence we have had with each other since then. could well be that I was insufficiently forthcoming about the importance of inherent patterns as far as the Baganda

A Zimbabwean mbira: a Tradition in African Music and its Potential for Music Education

This article aims to encourage the provision of the Zimbabwean mbira dzavadzimu in schools as a means of experiencing a novel musical system. It provides an outline of the mbira's cultural context within an oral tradition. The basic structure of the mbira pattern is abstracted and represented by four types of notation which makes the music accessible to a range of people. However, the characteristic ‘inherent rhythms’ that emerge kaleidoscopically from patterns and variations throughout performance give the music an elusive quality, the dimensions of which cannot be captured in staff notation. The simplicity of the separate components of a composition can be individually explored on a variety of instruments, while the resultant combination of its interlocking melodic lines is one of complexity and ever-shifting musical images. The mbira introduces a new aesthetic into the classroom and is ideal for both solo and ensemble playing.

FACTORS CONTROLLING EMERGENCE OF PINK SHRIMP (PENAEUS DUORARUM) FROM THE SUBSTRATE

1. A close relationship exists between the day-night cycle and the times of activity of pink shrimp. The shrimp bury beneath the substrate during the day but emerge at the time of sunset and are active at night.2. Emergence from the substrate is markedly synchronized in all members of the population. This study elucidates the mechanisms whereby this synchrony is maintained.3. The persistence of the pattern of nocturnal activity for several days under conditions of constant low light intensity confirmed that emergence and subsequent activity were under rhythmic control.4. Resynchronization of the phase of the rhythm controlling emergence to a shift in the light-dark cycle indicated that the light-dark cycle itself, or some component of it, is responsible for maintaining the relationship between emergence and the day-night regime.5. The close association between emergence and the time of light-dark transition indicated the possibility that the latter was the important component of the Zeitgeber responsible for the control of the time of emergence. This was supported by experiments in which a changing responsiveness was shown to light-dark transitions imposed at various times during the light period. Maximum response (in terms of the rate and degree of emergence from the substrate) occurred when a light-dark transition was imposed at a time (18:00) to which the shrimp had previously been entrained to receive the onset of the dark period.6. Experiments in which shrimp, which had been fed 24 hours previously, emerged from the substrate and carried out food-searching movements, in the absence of food and despite high intensity illumination, which would normally suppress emergence, indicated the presence of a feeding rhythm with an approximate 24-hour periodicity.7. The feeding rhythm probably accounts for the fact that the phase of the rhythm of emergence was resynchronized to a shifted light-dark cycle in three days among shrimp fed immediately following the light-dark transition of the shifted cycle, as opposed to six days in those deprived of food during this time of entrainment. The phases of the two rhythms, being almost identical, probably supplement each other.8. Shrimp smaller than 4 cm. (total length) emerged significantly earlier than larger individuals. This possibly reflects the lesser dependence of the early juveniles on inherent rhythms and consequently their greater receptivity to exogenous stimuli.9. The most obvious advantage of the circadian rhythm controlling emergence and subsequent activity is to confine the times of activity of shrimp to the hours of darkness when predation by fish is minimal. The proximity of the phase of the 24-hour feeding rhythm to the circadian rhythm of emergence and activity probably serves to strengthen the entrainment properties of the latter such that the time of emergence is further synchronized between all members of the population. The synchrony of the time of emergence is probably important for the maintenance of cohesion between aggregations of shrimp.

The phenomenon of inherent rhythms in East and Central African instrumental music

African composers take advantage in a marvellous way of a psycho-acoustic fact. The human ear - like the eyes - does not perceive isolated particles but always a gestalt. In a sequence of notes with large intervals the ear is inclined to pick out those of approximately the same level of pitch, and group them together separately. If this sequence of notes is, moreover, rhythmically regular, perception in different conflicting gestalten is enormously stimulated. This gestalt-psychological element plays a great part in listening to and composing some kinds of African instrumental music.

RESPONSE OF THE MALE REPRODUCTIVE SYSTEM OF LIZARDS (ANOLIS CAROLINENSIS) TO UNNATURAL DAY-LENGTHS IN DIFFERENT SEASONS

1. The reproductive system of adult male anoles was stimulated by artificially lengthened days at all seasons of the year. At least a few males were brought into full breeding condition in experiments initiated from November through August. Sperm were produced at all seasons. 2. A refractory period, such as occurs in passerine birds, did not appear to be present in Anolis. 3. A previous exposure to short days was not essential for obtaining a response to a long photoperiod. 4. Both the testes and accessory sex organs exhibited progressively greater responses in successive experiments through the fall, winter, and spring. 5. The seasonal gradient of response which produced increasingly larger testes could be accounted for by the increasingly larger number of spermatogonia at the beginning of each experiment. The gradient in response of the accessory sex organs was dependent on the normal cyclic fluctuations of their histology and the abundance of hypertrophied interstitial cells. 6. The inherent rhythms of both the gonad and accessory sex organs were not disturbed by 60 days' exposure to 9- or 6-hour photoperiods during the fall and winter. However, such exposures near or after the peak of spermatogenesis resulted in premature atrophy of all reproductive organs. 7. Comparison of the effects of 14-, 16-, and 18-hour day-lengths suggested that the longer the day-length the more rapid the response. Extremely long days, however, appeared to have detrimental effects upon some individuals. 8. Most immature lizards of less than 55 mm. snout-vent length responded poorly to the experimental conditions. All that responded well were growing rapidly. Those that grew to 60 mm. or more had reproductive organs as large or larger than older adults. 9. Captive lizards exposed to natural day-length for 60 days at any time between February and July tended to have larger testes than wild lizards sacrificed on the same date.

The production of atrioventricular rhythm in man after the administration of atropin. (Preliminary Communication.)

During the past year two patients with cardiac complaints were given repeated injections of 1 mg. atropin sulphate and on each occasion atrioventricular rhythm was observed. This usually appeared in from eight to ten minutes after the drug was given, it persisted for only a few minutes, and disappeared before the maximum effect of the drug was reached. In order to determine whether this tendency to A-V rhythm was peculiar to these patients or whether it exists normally, a series of experiments on normal individuals was carried out. Eighteen subjects, all under twenty-eight years of age and all with apparently normal hearts, were given hypodermic injections of 1 mg. of atropin. The effect of deep breathing and of ocular pressure upon the cardiac mechanism was studied both before and during the atropin action. Before the injection, A-V rhythm was not produced in any of the subjects tested. Between eight and fifteen minutes after the injection, however, A-V rhythm could be produced by ocular pressure or deep respiration in the majority of the subjects. After the atropin effect had reached its height A-V rhythm could no longer be produced. Three types of A-V rhythm were observed. In the first, which occurred most frequently, the P-R interval was reduced and P was inverted; in the second, the P-R interval was zero; while in the third there was an R-P interval. The last was observed in only two subjects. These differences evidently depended upon the level of the pacemaker in the junctional tissues. These observations may be explained on the assumption that atropin releases the A-V tissues from vagus control somewhat before it releases the sinus node. At this time stimulation of the vagus slows the sinus rhythm without a correspondingly great effect upon the inherent rhythms of the lower centers.