Vitamin D3 and brain development

Evidence for the presence of the vitamin D receptor in brain implies this vitamin may have some function in this organ. This study investigates whether vitamin D-3 acts during brain development. We demonstrate that rats born to vitamin D-3-deficient mothers had profound alterations in the brain at birth. The cortex was longer but not wider, the lateral ventricles were enlarged, the cortex was proportionally thinner and there was more cell proliferation throughout the brain. There were reductions in brain content of nerve growth factor and glial cell line-derived neurotrophic factor and reduced expression of p75(NTR), the low-affinity neurotrophin receptor. Our findings would suggest that low maternal vitamin D3 has important ramifications for the developing brain. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.

A pathology of the animal spirits – the clinical neurology of Thomas Willis (1621–1675) Part II – Disorders of intrinsically abnormal animal spirits

Thomas Willis (1621-1675), author of the classical work Cerebri Anatome (1664), was arguably the father of the modern era of neurology. His clinical neurology, as described in his Pathologiae Cerebri (1667) and De Anima Brutorum (1672), was largely derived from personal observations and not from traditional authorities and was based around his concept of the animal spirits, a fictitious entity in many ways analogous to the present day idea of the nerve impulse. This concept allowed him to develop a pathology of the animal spirits which embraced the whole content of the clinical neurology and psychiatry of his times. The anatomical and physiological background to Willis' concepts of animal spirit dysfunction, and those disorders he regarded as due to disturbed function of intrinsically normal animal spirits, have been dealt with in the previous part of this paper. The disorders he attributed to intrinsically abnormal animal spirits, dealt with in this part of the paper, comprised two categories. In one, the animal spirits possessed explosive properties, whilst in the other the abnormalities were non-explosive in their nature. The former category included epilepsy, hysteria and hypochondriasis, whilst the latter included mainly disorders now considered psychiatric e.g. delirium, melancholy, madness and stupidity. Willis' ideas about the pathogenesis of nervous system disorder seem never to have been generally accepted, partly because they appeared at a time when others were increasingly calling into question the existence of the animal spirits. Nevertheless, Willis' attempt to record and interpret all nervous system disease on the basis of disorder of function of a single underlying mechanism represents a formidable synthetic intellectual endeavour on the part of a very busy physician. (C) 2002 Elsevier Science Ltd. All rights reserved.

Effects of pathophysiological concentrations of albumin on NHE3 activity and cell proliferation in primary cultures of human proximal tubule cells

The progression of renal disease correlates strongly with hypertension and the degree of proteinuria, suggesting a link between excessive Na+ reabsorption and exposure of the proximal tubule to protein. The present study investigated the effects of albumin on cell growth and Na+ uptake in primary cultures of human proximal tubule cells (PTC). Albumin (1.0 mg/ml) increased cell proliferation to 134.1 +/- 11.8% (P < 0.001) of control levels with no change in levels of apoptosis. Exposure to 0.1 and 1.0 mg/ml albumin increased total Na-22(+) uptake to 119.1 &PLUSMN; 6.3% (P = 0.005) and 115.6 &PLUSMN; 5.3% (P < 0.006) of control levels, respectively, because of an increase in Na+/H+ exchanger isoform 3 (NHE3) activity. This was associated with an increase in NHE3 mRNA to 161.1 +/- 15.1% (P < 0.005) of control levels in response to 0.1 mg/ml albumin. Using confocal microscopy with a novel antibody raised against the predicted extracellular NH2 terminus of human NHE3, we observed in nonpermeabilized cells that exposure of PTC to albumin (0.1 and 1.0 mg/ml) increased NHE3 at the cell surface to 115.4 &PLUSMN; 2.7% (P < 0.0005) and 122.4 +/- 3.7% (P < 0.0001) of control levels, respectively. This effect was paralleled by significant increases in NHE3 in the subplasmalemmal region as measured in permeabilized cells. These albumin-induced increases in expression and activity of NHE3 in PTC suggest a possible mechanism for Na+ retention in response to proteinuria.

Cofilin interacts with ClC-5 and regulates albumin uptake in proximal tubule cell lines

Receptor-mediated endocytosis is a constitutive high capacity pathway for the reabsorption of proteins from the glomerular filtrate by the renal proximal tubule. ClC-5 is a voltage-gated chloride channel found in the proximal tubule where it has been shown to be essential for protein uptake, based on evidence from patients with Dent's disease and studies in ClC-5 knockout mice. To further delineate the role of ClC-5 in albumin uptake, we performed a yeast two-hybrid screen with the C-terminal tail of ClC-5 to identify any interactions of the channel with proteins involved in endocytosis. We found that the C-terminal tail of ClC-5 bound the actin depolymerizing protein, cofilin, a result that was confirmed by GST-fusion pulldown assays. In cultured proximal tubule cells, cofilin was distributed in nuclear, cytoplasmic, and microsomal fractions and co-localized with ClC-5. Phosphorylation of cofilin by overexpressing LIM kinase 1 resulted in a stabilization of the actin cytoskeleton. Phosphorylation of cofilin in two proximal tubule cell models (porcine renal proximal tubule and opossum kidney) was also accompanied by a pronounced inhibition of albumin uptake. This study identifies a novel interaction between the C-terminal tail of ClC-5 and cofilin, an actin-associated protein that is crucial in the regulation of albumin uptake by the proximal tubule.

Homocysteine and cardiovascular disease in renal disease

Elevated homocysteine (hyperhomocysteinaemia) in renal patients is a major concern for physicians. Although cause and effect between homocysteine and cardiovascular disease (CVD) has not been established in either the general population or renal patients, there is much evidence that this relationship does exist. Purported mechanisms that may explain this effect include increases in endothelial injury, smooth muscle cell proliferation, low-density lipoprotein oxidation and changes in haemostatic balance. Renal patients have a much greater incidence of hyperhomocysteinaemia and this may be explained by decreases in either the renal or extrarenal metabolism of the compound. We conclude that data from long-term placebo-controlled trials are urgently required to determine whether hyperhomocysteinaemia in renal patients is a cause of CVD events and requires therapeutic targeting.

Floral structure, breeding system and fruit-set in the threatened sub-shrub Tetratheca juncea Smith (Tremandraceae)

Tetratheca juncea Smith (Tremandraceae) has undergone a range contraction of approx. 50 km in the last 100 years and is now listed as a vulnerable sub-shrub restricted to the central and north coast regions of New South Wales, Australia. There are approx. 250 populations in a 110 km north-south distribution and populations are usually small with fewer than 50 plants/clumps. The reproductive ecology of the species was studied to determine why seed-set is reportedly rare. Flowers are bisexual, odourless and nectarless. Flowers are presented dependentally and there are eight stamens recurved around the pistil. Anthers are poricidal, contain viable pollen and basally contain a deep-red tapetal fluid that is slightly oily. Thus flowers are presented for buzz pollinators, although none were observed at flowers during our study. The species was found to be facultatively xenogamous with only one in 50 glasshouse flowers setting seed autogamously, i.e. without pollinator assistance. Field studies revealed fertile fruit in 24 populations but production varied significantly across sites from exceedingly low (0.6 fruits per plant clump) to low (17 fruits per plant clump). Fruit-set ranged from 0 to 65%, suggesting that pollen vectors exist or that autogamy levels in the field are variable and higher than glasshouse results. Fruit production did not vary with population size, although in three of the five populations in the south-west region more than twice as much fruit was produced as in populations elsewhere. A moderately strong relationship between foliage volume and fruit : flower ratios suggests that bigger plants may be more attractive than smaller plants to pollinators. A review of Tetratheca pollination ecology revealed that several species are poorly fecund and pollinators are rare. The habitat requirements for Tetratheca, a genus of many rare and threatened species, is discussed. (C) 2003 Annals of Botany Company.

Neuromuscular synapses mediate motor axon branching and motoneuron survival during the embryonic period of programmed cell death

The embryonic period of motoneuron programmed cell death (PCD) is marked by transient motor axon branching, but the role of neuromuscular synapses in regulating motoneuron number and axonal branching is not known. Here, we test whether neuromuscular synapses are required for the quantitative association between reduced skeletal muscle contraction, increased motor neurite branching, and increased motoneuron survival. We achieved this by comparing agrin and rapsyn mutant mice that lack acetylcholine receptor (AChR) clusters. There were significant reductions in nerve-evoked skeletal muscle contraction, increases in intramuscular axonal branching, and increases in spinal motoneuron survival in agrin and rapsyn mutant mice compared with their wild-type littermates at embryonic day 18.5 (E18.5). The maximum nerve-evoked skeletal muscle contraction was reduced a further 17% in agrin mutants than in rapsyn mutants. This correlated to an increase in motor axon branch extension and number that was 38% more in agrin mutants than in rapsyn mutants. This suggests that specializations of the neuromuscular synapse that ensure efficient synaptic transmission and muscle contraction are also vital mediators of motor axon branching. However, these increases in motor axon branching did not correlate with increases in motoneuron survival when comparing agrin and rapsyn mutants. Thus, agrin-induced synaptic specializations are required for skeletal muscle to effectively control motoneuron numbers during embryonic development. (C) 2003 Elsevier Science (USA). All rights reserved.

Fetal endoscopic telesurgery using an Internet protocol connection: clinical and technical challenges

Until recently, fetoscopic laser surgery to seal the placental anastomoses that cause severe twin-to-twin transfusion syndrome has been available in only a few centres worldwide. The technique typically takes a long time to learn. We have used a dedicated Internet Protocol (IP) connection for tele-education to assist the introduction of fetoscopic laser surgery to Australia. During the implementation of the international telemedicine link, there were multiple clinical and technical problems, which were eventually overcome. The quality of images and of video-sequences was comparable to that supported by an ISDN connection. Pictures of live surgery performed by an expert in Florida, USA, were transmitted and viewed by a novice team in Brisbane, Australia. The Australian team has performed 19 fetoscopic laser operations to date. Preliminary results are comparable to those from centres that have performed over 100 procedures.

The renin-angiotensin system and male reproduction: new functions for old hormones

The blood-borne renin-angiotensin system (RAS) is known best for its role in the maintenance of blood pressure and electrolyte and fluid homeostasis. However, numerous tissues show intrinsic angiotensin-generating systems that cater for specific local needs through actions that add to, or differ from, the circulating RAS. The male reproductive system has several sites of intrinsic RAS activity. Recent focus on the epididymis, by our laboratories and by others, has contributed important details about the local RAS in this tissue. The RAS components have been localized morphologically and topographically; they have been shown to be responsive to androgens and to hypoxia; and angiotensin has been shown to influence tubular, and consequently, fluid secretion. Components of the RAS have also been found in the testis, vas deferens, prostate and semen. Angiotensin II receptors, type 1 and, to a lesser extent, type 2 are widespread, and angiotensin IV receptors have been localized in the prostate. The roles of the RAS in local processes at these sites are still uncertain and have yet to be fully elucidated, although there is evidence for involvement in tubular contractility, spermatogenesis, sperm maturation, capacitation, acrosomal exocytosis and fertilization. Notwithstanding this evidence for the involvement of the RAS in various important aspects of male reproduction, there has so far been a lack of clinical evidence, demonstrable by changes in fertility, for a crucial role of the RAS in male reproduction. However, it is clear that there are several potential targets for manipulating the activity of the male reproductive system by interfering with the locally generated angiotensin systems.

Strength indices of the proximal femur and shaft in prepubertal female gymnasts

Introduction/Purpose: The role of impact loading activity on bone mass is well established; however, there are little data on the effects of exercise on bone geometry and indices of bone strength. The primary purpose of this study was to compare indices of bone strength at the proximal femur (PF) between elite premenarcheal gymnasts (N = 30) and age-matched controls (N = 30). Methods: Structural properties of the proximal femur were derived from the hip analyses program and included measurement of subperiosteal width, endosteal diameter, cross-sectional area, bone mineral density, cross-section moment of inertia (CSMI), and section modulus (Z). These parameters were measured for two regions of the PF: the narrow neck (NN), and the shaft (S). In addition, a strength index (S-SI) was calculated at the shaft by dividing the Z at the shaft by the femur length. A secondary purpose was to compare bone mineral content (BMC) values at the total body, lumbar spine, and three sites at the PF (neck, trochanter, and total) between the groups. All dependent values were compared adjusting for height and weight using an ANCOVA procedure and for relative lean body mass post hoc. Results: The gymnasts had significantly greater size-adjusted strength indices (CSMI, Z, and SI) at the NN and S. Gymnasts also had significantly greater size-adjusted BMC at all sites investigated. However, these differences disappeared when adjusted for relative lean body mass. Conclusion: When adjusted for body size, gymnasts had significantly greater indices of both axial strength and bending strength at the NN region of the PF and S, as well as a greater bone SI at the femoral shaft. These differences may be related to greater relative lean body mass attained in gymnastics training.

Human brain regions required for the dividing and switching of attention between two features of a single object

This combined PET and ERP study was designed to identify the brain regions activated in switching and divided attention between different features of a single object using matched sensory stimuli and motor response. The ERP data have previously been reported in this journal [64]. We now present the corresponding PET data. We identified partially overlapping neural networks with paradigms requiring the switching or dividing of attention between the elements of complex visual stimuli. Regions of activation were found in the prefrontal and temporal cortices and cerebellum. Each task resulted in different prefrontal cortical regions of activation lending support to the functional subspecialisation of the prefrontal and temporal cortices being based on the cognitive operations required rather than the stimuli themselves. (C) 2003 Elsevier Science B.V. All rights reserved.

Characterization of acute whiplash-associated disorders

Study Design. An experimental study of motor and sensory function and psychological distress in subjects with acute whiplash injury. Objectives. To characterize acute whiplash injury in terms of motor and sensory systems dysfunction and psychological distress and to compare subjects with higher and lesser levels of pain and disability. Summary of Background Data. Motor system dysfunction, sensory hypersensitivity, and psychological distress are present in chronic whiplash associated disorders ( WAD), but little is known of such factors in the acute stage of injury. As higher levels of pain and disability in acute WAD are accepted as signs of poor outcome, further characterization of this group from those with lesser symptoms is important. Materials and Methods. Motor function ( cervical range of movement [ ROM], joint position error [JPE]; activity of the superficial neck flexors [EMG] during a test of craniocervical flexion), quantitative sensory testing ( pressure, thermal pain thresholds, and responses to the brachial plexus provocation test), and psychological distress (GHQ-28, TAMPA, IES) were measured in 80 whiplash subjects ( WAD II or III) within 1 month of injury, as were 20 control subjects. Results. Three subgroups were identified in the cohort using cluster analysis based on the Neck Disability Index: those with mild, moderate, or severe pain and disability. All whiplash groups demonstrated decreased ROM and increased EMG compared with the controls ( all P < 0.01). Only the moderate and severe groups demonstrated greater JPE and generalized hypersensitivity to all sensory tests ( all P < 0.01). The three whiplash subgroups demonstrated evidence of psychological distress, although this was greater in the moderate and severe groups. Measures of psychological distress did not impact on between group differences in motor or sensory tests. Conclusions. Acute whiplash subjects with higher levels of pain and disability were distinguished by sensory hypersensitivity to a variety of stimuli, suggestive of central nervous system sensitization occurring soon after injury. These responses occurred independently of psychological distress. These findings may be important for the differential diagnosis of acute whiplash injury and could be one reason why those with higher initial pain and disability demonstrate a poorer outcome.