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Patterning of the neocortical projections from the raphe nuclei in perinatal rats: investigation of potential organizational mechanisms.

Serotoninergic (5-HT) fibers in the cerebral cortex of perinatal rats have a pattern that coincides with the boundaries of primary sensory areas and within the primary somatosensory cortex form the rattunculus. This patterned immunoreactivity (IR) appears about 60 hours after birth and disappears between postnatal days (P-) 12 and 15. Three experiments were carried out to evaluate mechanisms that might underlie the precise patterning of the 5-HT-IR. Retrograde labelling with fluorescent tracers in perinatal rats revealed only a coarse rostrocaudal topography in the raphe-cortical projection and the existence of raphe cells projecting to multiple cortical locations. Thus, a precise point-to-point, raphe-cortical projection does not underlie the patterned cortical 5-HT-IR. Ablation of the thalamus prior to the age at which patterned 5-HT-IR could be seen in the developing cortex caused a complete loss of patterned immunoreactivity. This suggests that 5-HT fibers may require the presence of thalamocortical axons to achieve the pattern observed in normal animals. Serotoninergic raphe neurons transplanted to the cortices of newborn rats exhibited extensive axonal outgrowth, but did not form a somatotopic pattern. This result also suggests that specific spatiotemporal interactions between growing 5-HT and thalamocortical axons may be necessary for the somatotopic patterning of the former fibers.

Aging↗

Prospective study of three major dietary patterns and risk of gastric cancer in Japan.

Dietary pattern analysis is an alternative and complementary approach to identify the relationship between diet and the risk of chronic disease. This study was aimed at investigating the associations between dietary patterns and the risk of gastric cancer in Japan. Using baseline data from a prospective study of 20,300 men and 21,812 women, we conducted factor analysis and identified 3 major dietary patterns, healthy, traditional and Western, and calculated the factor scores of each pattern for individuals. During 10 years of follow-up, 400 cases of gastric cancer were identified. We found an inverse association between the healthy pattern and gastric cancer risk in women [rate ratio for highest quartile (RR) = 0.56; 95% CI = 0.32-0.96; p for trend = 0.03], but not in men. In contrast, the traditional pattern was significantly associated with the increased risk of gastric cancer in both genders (for men, RR = 2.88, 95% CI = 1.76-4.72; for women, RR = 2.40, 95% CI = 1.32-4.35). The Western pattern was not associated with risk. These associations persisted in histologic subtypes. Our findings support the idea that the healthy pattern decreased the risk of gastric cancer among females, while the traditional pattern increased the risk in both genders.

Cohort Studies↗

Dietary patterns and the risk of postmenopausal breast cancer.

The association between individual foods and breast cancer has been inconsistent. Therefore, we examined the association between diet and risk of postmenopausal breast cancer by the alternative approach of dietary patterns. Dietary patterns were identified with factor analysis from food consumption data collected from a food frequency questionnaire in 1984. Relative risks were computed using proportional hazard models and adjusted for known risk factors for breast cancer. Between 1984 and 2000, we ascertained 3,026 incident cases of postmenopausal breast cancer. We identified 2 major dietary patterns. The prudent pattern is characterized by higher intake of fruits, vegetables, whole grains, low-fat dairy products, fish and poultry, while the Western pattern is characterized by higher intake of red and processed meats, refined grains, sweets and desserts and high-fat dairy products. Neither of the patterns was associated with overall risk of postmenopausal breast cancer. However, a positive association between the Western pattern score was observed among smokers at baseline (relative risk = 1.44, comparing top to bottom quintiles; 95% CI = 1.02-2.03; p for trend = 0.03). An inverse association was observed between the prudent pattern and estrogen receptor-negative cancer (relative risk = 0.62; 95% CI = 0.45-0.88; p for trend = 0.006). Among the major food groups, higher consumptions of fruits (relative risk for 1 serving/day increase = 0.88; 95% CI = 0.80-0.97; p = 0.009) and vegetables (relative risk = 0.94; 95% CI = 0.88-0.99; p = 0.03) were significantly associated with decreased risk for ER(-) breast cancer. In conclusion, we did not observe an overall association between the prudent or Western pattern and overall breast cancer risk. However, a Western-type diet may elevate risk of breast cancer among smokers, and a prudent diet may protect against estrogen receptive-negative tumors.

Breast Neoplasms↗

Patterning hydroxyapatite biocoating by electrophoretic deposition.

Patterned bioceramic coatings may find potential applications in orthopedic implants and biosensors. In this study, various hydroxyapatite (HA) patterns were created on silicon and titanium substrates. Electrophoretic deposition technique was used together with surface patterning of the cathode specimen. When gold/palladium patterns (hexagons, spherical dots, etc.) were created on the cathode surface, HA colloidal particles in ethanol would preferentially deposit on the gold-coated area and form patterns. When silicon, instead of gold, was evaporated onto a conducting cathode surface, HA mainly deposited on the exposed area of the substrate. Detailed mechanisms for forming HA patterns may involve local concentration of the electric field when a second metal is patterned on the cathode. The difference in electric field across the two metals on the cathode also enhances HA patterning through an electrohydrodynamic process. This study demonstrated the possibility and flexibility of electrophoretic deposition in patterning charged particles onto a substrate.

Chemistry, Physical↗

Native variant limb skeletal patterns in the red-backed salamander, Plethodon cinereus, are not regenerated.

Species of the salamander genus Plethodon have a characteristically uniform morphology. Morphological conservation at the level of interspecific comparisons, however, is not always reflected within species. Perhaps the most extreme example of intraspecific variation is the recent description of extensive variability in limb-skeletal patterning both within and between populations of the widespread species P. cinereus. We utilized limb regeneration following experimental amputation as a tool to examine whether naturally occurring variant skeletal patterns result from limb loss and regeneration in nature, and to assay the intrinsic (i.e., genetic) component of between-individual variation in mesopodial patterning. We observed the following. First, regenerate patterns are strikingly different from native patterns: interelement fusions in regenerates are typically between proximodistally adjacent cartilages, whereas interelement fusions in native variant limbs occur exclusively between laterally adjacent cartilages. Fusions also are over ten times more frequent in regenerates than in native limbs. Second, there is no strong correlation between native limb pattern (typical vs. variant) and the regenerate pattern. We conclude that variability in field-collected P. cinereus reflects extensive intrapopulation variation in limb-skeletal patterning during original limb development, rather than regeneration in nature, and that limb regeneration analysis provides no evidence of a strong genetic component to between-individual variation. Finally, unusual mesopodial patterns produced during limb regeneration may be related to the mechanical factors impinging on the regenerating limb in this terrestrial species.

Animals↗

Pattern analysis of electromyographic linear envelopes exhibited by subjects with uninjured and injured knees during free and fast speed walking.

We wished to determine whether anterior cruciate ligament (ACL) injury caused changes in patterns of activity of individual or groups of muscles that control the knee joint. The electromyographic (EMG) patterns of six muscles in 26 individuals with uninjured knees and 20 individuals with ruptured ACL were studied during free and fast speed walking. A previously developed clustering technique was used for analysis. This technique involves making the Fourier transform of the average linear envelope (LE) of each muscle for each subject and using the amplitude and phase angles of the lower frequency harmonics as features to describe a pattern. These features are then grouped to subdivide the population of EMG patterns into different types. The results of analyses on single muscles showed that there exists a typical or "normal" pattern for each muscle which most uninjured and some injured subjects exhibit as well as several atypical patterns which mostly injured subjects exhibit, and that the atypical patterns are much more evident at fast walking speed. The characteristics of atypical patterns with respect to normal include time shifts in the peak of major phases of activity, the absence of a second phase of activity, and the existence of additional phases of activity. Synergy analysis showed that if one muscle has an atypical pattern, then several do; i.e., ACL injury induces major changes in the control strategy of the knee. The implications are that for rehabilitation programs one must focus on the training and strengthening of more than one muscle, and that for reconstructive procedures the changes in mechanics of the joint can possibly induce a significant change in its control strategy.

Adolescent↗

Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia.

The liver is a highly vascularized organ which frequently hosts metastases in patients with colorectal adenocarcinomas. The hypothesis of this study is that the hypoxic drive of angiogenesis might be minimal or absent in those growing liver metastases which are capable of preserving the stromal structure, including the numerous sinusoidal blood vessels. Representative paraffin sections of liver metastases from 26 patients with colorectal adenocarcinoma were investigated. Three different growth patterns were found. In the desmoplastic and in the pushing growth patterns (42% and 46% of all metastases, respectively), the architecture of the liver parenchyma was not preserved. In the replacement growth pattern (12% of all cases), the reticulin pattern of the liver parenchyma was conserved within the metastases at the tumour-liver parenchyma interface. The endothelial cells of the blood vessels near the interface in the metastases of the replacement type did not express CD34, nor were they surrounded by alpha-smooth muscle actin-positive mural cells. In the desmoplastic and in the pushing growth patterns, 23% and 52% of all blood vessels in this area were covered by pericytes. The fraction of proliferating endothelial cells was low in the metastases with a desmoplastic or a replacement growth pattern (about 3%), compared with metastases with a pushing growth pattern (11%). Tumour cell apoptosis was highest in the pushing-type metastases and was inversely correlated with microvessel density in liver metastases. The ratio of the proliferating tumour cell fraction and the proliferating endothelial cell fraction, roughly representing the degree of angiogenesis-dependent growth, was three- to four-fold higher in the replacement-type metastases compared with the other metastases. In summary, the present study has demonstrated that liver metastases are a heterogeneous group, with different growth patterns which predict the fraction of immature blood vessels, the fraction of proliferating endothelial cells, and the fraction of apoptotic tumour cells. The replacement growth pattern expands with minimal angiogenesis by co-opting the stroma with the sinusoidal blood vessels of the liver.

Actins↗

Molecular printboards on silicon oxide: lithographic patterning of cyclodextrin monolayers with multivalent, fluorescent guest molecules.

Three compounds bearing multiple adamantyl guest moieties and a fluorescent dye have been synthesized for the supramolecular patterning of beta-cyclodextrin (CD) host monolayers on silicon oxide using microcontact printing and dip-pen nanolithography. Patterns created on monolayers on glass were viewed by laser scanning confocal microscopy. Semi-quantitative analysis of the patterns showed that with microcontact printing approximately a single monolayer of guest molecules is transferred. Exposure to different rinsing procedures showed the stability of the patterns to be governed by specific supramolecular multivalent interactions. Patterns of the guest molecules created at CD monolayers were stable towards thorough rinsing with water, whereas similar patterns created on poly(ethylene glycol) (PEG) reference monolayers were instantly removed. The patterns on CD monolayers displayed long-term stability when stored under N(2), whereas patterns at PEG monolayers faded within a few weeks due to the diffusion of fluorescent molecules across the surface. Assemblies at CD monolayers could be mostly removed by rinsing with a concentrated CD solution, demonstrating the reversibility of the methodology. Patterns consisting of different guest molecules were produced by microcontact printing of one guest molecule and specific adsorption of a second guest molecule from solution to non-contacted areas, giving well-defined alternating assemblies. Fluorescent features of sub-micrometer dimensions were written using supramolecular dip-pen nanolithography.

Acrylonitrile↗

Patterns of inheritance of colonic polyps.

While the inheritance pattern of familial polyposis coli is established as an autosomal dominant pattern, the expression of the various extracolonic manifestations associated with the neoplastic polyposis is less well understood. The discrete polyp cancer syndrome may not be recognized unless both polyps and colon cancer are considered in the inheritance pattern. The hamartomatous polyps follow a Mendelian-dominant inheritance pattern for the Peutz-Jeghers syndrome, while the inheritance pattern for the juvenile polyposis syndromes is less clear. Cowden's disease appears in a Mendelian dominant pattern, but the occurrence of colonic polyps is less well documented. The ganglioneuromas follow a mendelian dominant inheritance pattern, while the relationship and occurrence of colonic polyps in association with Torre's syndrome is uncertain. The Mendelian dominant inheritance pattern for the cancer family syndrome is documented; the role of colon polyps in this syndrome is less well understood. A further understanding of the inheritance patterns of these various colon polyps will lead to more understanding of the basic disease and help in prevention and early detection for treatment and cure.

Adenomatous Polyposis Coli↗

Effect of prenatal exposure to anticonvulsant drugs on dermal ridge patterns of fingers.

BACKGROUND: An altered frequency of specific dermal ridge patterns on fingertips, such as an increased number of arches, has been observed in children exposed in utero to anticonvulsants and other teratogens. Asymmetry of the distribution of dermal ridge patterns has been attributed to environmental exposures and genetic factors. METHODS: We evaluated all of the dermal ridge patterns of 66 children who had been exposed to either the anticonvulsant phenytoin alone or phenytoin and phenobarbital. We determined the frequency of each pattern, concordance between the fingers on the left and right hands, sex differences and total ridge counts in the drug-exposed children and compared them to the findings in 716 unexposed comparison children. The frequency of each pattern was established in comparison to the most common type of pattern (ulnar loop), which showed that there were alterations in the frequency of arches, radial loops and whorls on specific fingers. RESULTS: Eight (12.1%) of 66 children had three or more arch patterns, with all but one having been exposed to phenytoin and phenobarbital. Only one of these eight children was considered by the masked examiner to have fingernail hypoplasia. There was no evidence of asymmetry in the anticonvulsant-exposed children. There were minor differences in the distribution of total ridge count. CONCLUSIONS: Subtle differences in several dermal ridge patterns, not just arch patterns, were present in anticonvulsant-exposed children, primarily in those exposed to polytherapy: phenytoin and phenobarbital.

Abnormalities, Drug-Induced↗

Pattern learning by honeybees: conditioning procedure and recognition strategy.

In recognizing a pattern, honeybees Apis mellifera, may focus either on its ventral frontal part, or on the whole frontal image. We asked whether the conditioning procedure used to train the bees to a pattern determines the recognition strategy employed. Bees were trained with the same patterns presented vertically on the back walls of a Y maze. Conditioning was either absolute, that is, bees should learn to choose a rewarded pattern when there is no alternative, or differential, that is, bees should learn to choose a rewarded pattern that is paired with a different, nonrewarded one. Bees used different pattern recognition strategies depending on the conditioning procedure: absolute conditioning restricted recognition to the lower half whilst differential conditioning extended it to the whole pattern. Bees trained with absolute conditioning saw and learned the features of the upper part of the trained patterns, but assigned more weight to the lower part. Bees trained with differential conditioning learned not only the features of the reinforced stimulus in an excitatory way, but also those of the nonreinforced one in an inhibitory way. Thus, conditioning tasks that involve not only excitatory acquisition of the conditioned stimulus per se, but also discrimination of nonreinforced stimuli, result in an increase in the visual field assigned to the recognition task. Conditioning tasks that involve only excitatory acquisition of the rewarded stimulus result in a higher weighting of the lower pattern half and thus in a more reduced field assigned to the recognition task. This difference may reflect that existing between a conditioned and an incidental behavioural modification. Copyright 1999 The Association for the Study of Animal Behaviour.

Journal Article↗

Meal pattern and nutrient intake among adult Finns.

The purpose of this study was to investigate the relationship between meal pattern and diet. Nutrient contents of meals, snacks and other eating occasions were compared and differences in dietary intake analysed between respondents following a conventional meal pattern and others. A random sample of 1861 adults aged 25-64 from four regions of Finland completed a mailed questionnaire and 3-day food record in the spring of 1992. A conventional meal pattern was defined on the basis of national dietary guidelines as including breakfast, warm lunch and warm dinner, and subjects were identified with the help of the questionnaire. Meals and snacks were defined according to the respondents subjective criteria. Forty-four percent of all respondents followed the conventional meal pattern. Meal pattern has no effect on nutrient intake in men and small effects in women. Women following the conventional meal pattern had higher energy and cholesterol intake and lower alcohol and vitamin C intake than other women. Meals contributed to energy, protein and fat intake, and snacks to sugar and alcohol. Meal pattern had only a small effect on diet and conventional meal pattern cannot be considered healthier than other meal patterns.

Adolescent↗

Effect of respiratory pattern on ozone injury to the airways of isolated rat lungs.

Ozone stimulates the "defensive" C-fibers in the lungs, changing breathing pattern to rapid and shallow. We hypothesized that when ozone is administered to the isolated lung with a rapid shallow breathing pattern rather than a slow deep pattern, relatively less airway epithelial damage would occur. Four groups of isolated buffer perfused rat lungs were exposed to ozone (1 ppm) or to filtered air for 90 min with either a slow deep (SDB, tidal volume 2.4 ml, frequency 40 breaths/min) or a rapid shallow breathing pattern (RSB, tidal volume 1.2 ml, frequency 80 breaths/min), resulting in an equivalent inspired dose. The absorbed dose of ozone did not differ between the exposed groups. Ethidium homodimer-1 was then instilled into the trachea to identify injured airway epithelial cells. The lungs were fixed, the airways were microdissected, and the airway epithelial cells were counterstained with YPRO-1 prior to evaluation with confocal microscopy. Ozone-induced airway epithelial cell injury occurred to a lesser overall degree when lungs were exposed by the RSB pattern (p = 0.003). The relative reduction in injury was greater (p < 0.05) in the proximal axial airway than in its adjacent airway branch and terminal bronchioles. Ozone induced an increase in pulmonary resistance with the SDB pattern but not with the RSB pattern. Thus, at an equivalent dose of inspired ozone, a RSB pattern resulted in less total damage than a SDB pattern and the distribution of protection was heterogeneous with proximal axial airways displaying the greatest relative reductions in epithelial damage.

Animals↗

A two dimensional field theory for motion computation. First order approximation; translatory motion of rigid patterns.

The local extraction of motion information from brightness patterns by individual movement detectors of the correlation-type is considered in the first part of the paper. A two-dimensional field theory of movement detection is developed by treating the distance between two adjacent photoreceptors as a differential. In the first approximation of the theory we only consider linear terms of the time interval between the reception of a contrast element and its delayed representation by the detector and linear terms of the spatial distances between adjacent photoreceptors. As a result we may neglect terms of higher order than quadratic in a Taylor series development of the brightness pattern. The responses of pairs of individual movement detectors are combined to a local response vector. In the first approximation of the detector field theory the response vector is proportional to the instantaneous pattern velocity vector and linearly dependent on local properties of the moving pattern. The linear dependence on pattern properties is represented by a two by two tensor consisting of elements which are nonlinear, local functionals of the moving pattern. Some of the properties of the tensor elements are treated in detail. So, for instance, it is shown that the off-diagonal elements of the tensor disappear when the moving pattern consists of x- and y-dependent separable components. In the second part of the paper the tensor relation leading to the output of a movement detector pair is spatially integrated. The result of the integration is an approximation to a summation of the outputs of an array of detector pairs. The spatially integrated detector tensor relates the translatory motion vector to the resultant output vector. It is shown that the angle between the motion vector and the resultant output vector is always smaller than +/- 90 degrees whereas the angle between the motion vector and local response vectors, elicited by detector pairs, may cover the entire angular range. In the discussion of the paper the limits of the field theory for motion computation as well as its higher approximations are pointed out in some detail. In a special chapter the dependence of the detector response on the pattern properties is treated and in another chapter questions connected with the so called aperture problem are discussed. Furthermore, properties for compensation of the pattern dependent deviation angle by spatial physiological integration are mentioned in the discussion.

Animals↗

Order parameters for the neural organization of single, multijoint limb movement patterns.

Subjects performed two patterns of coordination between the elbow and wrist joints of the right arm: 1) wrist flexion synchronized with elbow flexion and wrist extension with elbow extension (homologous muscle groups); and 2) wrist extension synchronized with elbow flexion and wrist flexion with elbow extension (nonhomologous muscle groups). As a parameter, cycling frequency, was increased, an abrupt switch in the phase relation between the elbow and wrist joints occurred. Similar effects were observed in underlying neuromuscular (EMG) timing patterns. Observed transitions depended on whether the forearm was prone or supine, not simply on the muscle pairing across the joints. With the forearm supine, transitions were from pattern (2) to pattern (1) above, and with the forearm prone the transitions were from pattern (1) to pattern (2). When subjects were initially prepared in pattern (1) with the forearm supine or in pattern (2) with the forearm prone, switching did not occur. En route to transitions, enhanced fluctuations in the phase relation occurred, indicating that loss of stability is at the origin of pattern change. Accompanying such changes in coordination were characteristic effects on end effector trajectories and velocity profiles. Possible neurophysiological mechanisms for context dependence in multijoint coordination are discussed.

Adult↗

Diverse patterns of performance in copying and severity of unilateral spatial neglect.

We analysed the performances of 69 patients with left unilateral spatial neglect in copying a multi-object figure, as well as their performance of the line cancellation and line bisection tests. Three patterns of copying were mainly observed. The first pattern was almost satisfactory performance in copying the central figure with occasional omission of the elements located more laterally to the left. The second pattern was omission of the left half of the whole figure, which was the pattern expected of patients with typical left unilateral spatial neglect. The third pattern was left unilateral spatial neglect when copying the central figure, with favourable copying of left lateral objects; this may be regarded as "object-centered" neglect. Performance of the line cancellation test, which requires exploratory ability, was significantly better for the patients with the third pattern than for those with the second pattern. A significant difference was also observed between the two groups of patients in performance of the line bisection test, in which exploratory ability plays a more minor role. No significant difference was found in performance of the line cancellation and line bisection tests between the patients with the third and first patterns, in spite of remarkable differences in their copying performances. No distinctive characteristics were found for any group of patients as regards lesion, age, duration after onset, education, and WAIS scores. Therefore we concluded that in most of our patients with neglect, these diverse patterns of copying deficits resulted from different levels of neglect severity but not from different types of unilateral spatial neglect.

Adult↗

Microstamp patterns of biomolecules for high-resolution neuronal networks.

A microstamping technique has been developed for high-resolution patterning of proteins on glass substrates for the localisation of neurons and their axons and dendrites. The patterning process uses a microfabricated polydimethylsiloxane stamp with micrometer length features to transfer multiple types of biomolecules to silane-derivatised substrates, using glutaraldehyde as a homobifunctional linker. To test the efficacy of the procedure, substrates are compared in which poly-d-lysine (PDL) was physisorbed and patterned by photoresist with those stamped with PDL. Fluorescein isothiocyanate labelled poly-l-lysine was used to verify the presence and uniformity of the patterns on the glass substrates. As a biological assay, B104 neuroblastoma cells were plated on stamped and physisorbed glass coverslips. Pattern compliance was determined as the percentage of cells on the pattern 8 h after plating. Results indicate that the stamping and photoresist patterning procedure are equivalent. Substrates stamped with PDL had an average pattern compliance of 52.6 +/- 4.4%, compared to 54.6 +/- 8.1% for physisorbed substrates. Measures of background avoidance were also equivalent. As the procedure permits successive stamping of multiple proteins, each with its own micropattern, it should be very useful for defining complex substrates to assist in cell patterning and other cell guidance studies.

Cell Biology↗

Hierarchical control of different elbow-wrist coordination patterns.

The present paper focused on the role of mechanical factors arising from the multijoint structure of the musculoskeletal system and their use in the control of different patterns of cyclical elbow-wrist movements. Across five levels of cycling frequency (from 0.45 Hz up to 3.05 Hz), three movement patterns were analyzed: (1) unidirectional, including rotations at the elbow and wrist in the same direction; (2) bidirectional, with rotation at the joints in opposite directions, and (3) free-wrist pattern, which is characterized by alternating flexions and extensions at the elbow with the wrist relaxed. Angular position of both joints and electromyographic activity of biceps, triceps, the wrist flexor, and the wrist extensor were recorded. It was demonstrated that control at the elbow was principally different from control at the wrist. Elbow control in all three patterns was similar to that typically observed during single-joint movements: elbow accelerations-decelerations resulted from alternating activity of the elbow flexor and extensor and were largely independent of wrist motion at all frequency plateaus. The elbow muscles were responsible not only for the elbow movement, but also for the generation of interactive torques that played an important role in wrist control. There were two types of interactive torques exerted at the wrist: inertial torque arising from elbow motion and restraining torque arising from physical limits imposed on wrist rotation. These interactive torques were the primary source of wrist motion, whereas the main function of wrist-muscle activity was to intervene with the interactive effects and to adjust the wrist movement to comply with the required coordination pattern. The unidirectional pattern was more in agreement with interactive effects than the bidirectional pattern, thus causing their differential difficulty at moderate cycle frequencies. When cycling frequency was further increased, both the unidirectional and bidirectional movements lost their individual features and acquired features of the free-wrist pattern. The deterioration of the controlled patterns at high cycling frequencies suggests a crucial role for proprioceptive information in wrist control. These results are supportive of a hierarchical organization of control with respect to elbow-wrist coordination, during which the functions of control at the elbow and wrist are principally different: the elbow muscles generate movement of the whole linkage and the wrist muscles produce corrections of the movement necessary to fulfill the task.

Elbow Joint↗