Connectomic Basis for Tremor Control in Stereotactic Radiosurgical Thalamotomy.

BACKGROUND AND PURPOSE: Given the increased use of stereotactic radiosurgical thalamotomy and other ablative therapies for tremor, new biomarkers are needed to improve outcomes. Using resting-state fMRI and MR tractography, we hypothesized that a "connectome fingerprint" can predict tremor outcomes and potentially serve as a targeting biomarker for stereotactic radiosurgical thalamotomy. MATERIALS AND METHODS: We evaluated 27 patients who underwent unilateral stereotactic radiosurgical thalamotomy for essential tremor or tremor-predominant Parkinson disease. Percentage postoperative improvement in the contralateral limb Fahn-Tolosa-Marin Clinical Tremor Rating Scale (TRS) was the primary end point. Connectome-style resting-state fMRI and MR tractography were performed before stereotactic radiosurgery. Using the final lesion volume as a seed, "connectivity fingerprints" representing ideal connectivity maps were generated as whole-brain R-maps using a voxelwise nonparametric Spearman correlation. A leave-one-out cross-validation was performed using the generated R-maps. RESULTS: The mean improvement in the contralateral tremor score was 55.1% (SD, 38.9%) at a mean follow-up of 10.0 (SD, 5.0) months. Structural connectivity correlated with contralateral TRS improvement (r = 0.52; P = .006) and explained 27.0% of the variance in outcome. Functional connectivity correlated with contralateral TRS improvement (r = 0.50; P = .008) and explained 25.0% of the variance in outcome. Nodes most correlated with tremor improvement corresponded to areas of known network dysfunction in tremor, including the cerebello-thalamo-cortical pathway and the primary and extrastriate visual cortices. CONCLUSIONS: Stereotactic radiosurgical targets with a distinct connectivity profile predict improvement in tremor after treatment. Such connectomic fingerprints show promise for developing patient-specific biomarkers to guide therapy with stereotactic radiosurgical thalamotomy.

Meat eating and nutritional quality of lambs sired by high and low muscle density rams.

Intramuscular fat (IMF) content affects eating and nutritional quality of lamb meat. Muscle density measured by computer tomography is an in vivo proxy measure of IMF content that affects eating and nutritional quality of lamb meat. Lambs sired by high muscle density (HMD) or low muscle density (LMD) rams, selected for slaughter on commercial criteria were measured for meat quality and nutritional traits. A restricted maximum likelihood model was used to compare lamb traits. Additionally, regression analysis of sire estimated breeding value (EBV) for muscle density was performed for each meat quality trait. Muscle density EBV had a negative regression with IMF content (P < 0.001). For each unit increase in muscle density EBV, there was a significant decrease in loin (-1.69 mg/100 g fresh weight) and topside IMF (-0.03 mg/100 g fresh weight). Muscle density EBV had a negative regression with grouped saturated and monounsaturated fatty acids concentration (and monounsaturated proportion P < 0.001). Muscle density EBV had a negative regression with loin sensory traits tenderness, juiciness and overall liking and many novel tenderness sensory traits measured (P < 0.05). Selecting for LMD EBV increased IMF content and favourable meat eating quality traits. In contrast, sire muscle density EBV had a positive regression with loin polyunsaturated:saturated fat ratio and grouped polyunsaturated proportion traits (including total polyunsaturated proportion, total omega-6 (n-6) and total omega-3 (n-3) fatty acids (P < 0.001). This is explained by the fact that as sire muscle density EBV increases, polyunsaturated fatty acid proportion increases and the proportion of saturated and monounsaturated fatty acid content decreases. Muscle density EBV had a positive regression with shear force and the novel toughness sensory traits (P < 0.05). Selection for HMD EBV's increased shear force and toughness traits, which is unfavourable for the consumer. Low muscle density sired meat had higher meat colour traits chroma/saturation (+0.64, SD 2.30, P = 0.012), redness (+0.52, SD 1.91, P = 0.012) and yellowness (+0.31, SD 1.49, P = 0.08) compared to HMD sired meat. Selection for LMD could be used within a breeding programme to increase IMF content and enhance both meat colour and improve eating quality parameters.

Association of Ethnicity With Multisystem Inflammatory Syndrome in Children Related to SARS-CoV-2 Infection: An International Case-Referent Study.

Background: It has been suggested that children and infants can develop multisystem inflammatory syndrome in children (MIS-C) in response to a SARS-CoV-2 infection and that Black children are overrepresented among cases. The aim of the current study was to quantify the association between Black, Asian, or other non-White genetic background and COVID-19-related MIS-C in children and infants. Methods: Eight different research groups contributed cases of MIS-C, potentially related to SARS-CoV-2 infection. Several sensitivity analyses were performed, including additional data available from the literature. Analyses were stratified by geographical region. Results: Seventy-three cases from nine distinct geographical regions were included in the primary analyses. In comparison to White children, the relative risk for developing MIS-C after SARS-CoV-2 infection was 15 [95% confidence interval (CI): 7.1 to 32] for Black children, 11 (CI: 2.2 to 57) for Asian, and 1.6 (CI: 0.58 to 4.2) for other ethnic background. Conclusion: Pediatricians should be aware of the fact that the risk of COVID-19-related MIS-C is severely increased in Black children.

Review: The Perioperative Use of Thromboelastography for Liver Transplant Patients.

Thromboelastography (TEG) is a viscoelastic test that allows rapid evaluation of clot formation and fibrinolysis from a sample of whole blood. TEG is increasingly utilized to guide blood product resuscitation in surgical patients and transfusions for liver transplant patients. Patients with severe liver failure have significant derangement of their clotting function due to impaired production of procoagulant and anticoagulant factors. Traditional coagulation studies are limited by the short time needed for the result and provide little information about the dynamics and strength of clot formation. In addition, traditional coagulation studies do not correlate well with bleeding episodes and may lead to over-transfusion of various blood products. Evidence is less robust regarding the use of TEG for transfusion management decisions in severe liver failure patients awaiting, undergoing, or immediately after liver transplant surgery. However, the available evidence suggests that systematic implementation of TEG rather than traditional coagulation studies results in the administration of fewer blood products without increased mortality or complications. The purpose of this study is to review the literature regarding the use of TEG in liver failure patients prior to liver transplant, intraoperatively, and postoperatively. Additional high-quality randomized controlled studies should be performed to evaluate the use of TEG to guide transfusion decisions, particularly in the postoperative period following liver transplantation.

The Mayak Worker Dosimetry System (MWDS 2013): Soluble Plutonium Retention in the Lungs of An Occupationally Exposed USTUR Case.

For the first time, plutonium retention in human upper airways was investigated based on the dosimetric structure of the human respiratory tract proposed by the International Commission on Radiological Protection (ICRP). This paper describes analytical work methodology, case selection criteria, and summarizes findings on soluble (ICRP 68 Type M material) plutonium distribution in the lungs of a former nuclear worker occupationally exposed to plutonium nitrate [239Pu(NO3)4]. Thirty-eight years post-intake, plutonium was found to be uniformly distributed between bronchial (BB), bronchiolar (bb) and alveolar-interstitial (AI) dosimetric compartments as well as between the left and right lungs. 239+240Pu and 238Pu total body activity was estimated to be 2333 ± 23 and 42.1 ± 0.7 Bq, respectively. The results of this work provide key information on the extent of plutonium binding in the upper airways of the human respiratory tract.

Photic entrainment of circannual rhythms in golden-mantled ground squirrels: role of the pineal gland.

Entrainment of circannual rhythms of body mass and reproduction was monitored for 3 years in female golden-mantled ground squirrels maintained in a simulated natural photoperiod. Both pinealectomized and pineal-intact squirrels generated circannual rhythms of body mass and estrus, but only the intact animals entrained these rhythms to a period of 365 days. In the second and third years after treatment, the period of the body mass rhythm was significantly shorter than 365 days for pinealectomized squirrels, and variance in tau among these animals was significantly greater than for intact squirrels. A similar pattern was evident in the rhythm of reproduction, which was phase-disrupted in pinealectomized squirrels but entrained in intacts. Seasonal changes in duration of nocturnal melatonin secretion by the pineal appear to be necessary to produce phase-delays required to entrain the circannual clock to a period of 12 months.

Hodgkin's disease: is there a price for successful treatment? A 25-year experience.

Three hundred-twenty patients with Hodgkin's disease (HD) were studied retrospectively to assess the impact of treatment on survival and the development of second malignant neoplasms (SMN). All stages of HD were considered. Treatment groups included XRT only, XRT + multiagent chemotherapy (MAC), XRT + single agent chemotherapy (SAC), and chemotherapy only (Chemo). MAC was subdivided into MOPP and non-MOPP regimens. Twenty-one patients developed 23 SMN, only two of which were acute leukemias. Survival was greatest for XRT only because of a large proportion of early stage HD in this group. SMN were seen in all treatment groups except Chemo only. The XRT + MAC group had a significantly elevated observed-to-expected ratio for SMN, but it was difficult to attribute this to either MOPP or non-MOPP due to very small numbers of patients. The actuarial risk of SMN for both MOPP and non-MOPP rises dramatically between 10 and 15 years, however, extrapolation cannot be done, again because of very small numbers. We conclude that there is an increased risk of SMN in patients treated aggressively for HD, but that the exact cause of SMN is difficult to determine.

Design and synthesis of 4H-3,1-benzoxazin-4-ones as potent alternate substrate inhibitors of human leukocyte elastase.

4H-3,1-Benzoxazin-4-ones are alternate substrate inhibitors of the serine proteinase human leukocyte elastase (HL elastase) and form acyl enzyme intermediates during enzyme catalysis. We have synthesized a large variety of benzoxazinones using specific methods that have been adapted to achieve the pattern of ring substitution dictated by theoretical considerations. The results of the inhibition of HL elastase by 175 benzoxazinones are reported herein with reference to hydrophobicity constants D, alkaline hydrolysis rates kOH-, inhibition constants Ki, and their component acylation and deacylation rate constants, kon and koff, respectively. The ranges for the compounds are considerable; alkaline hydrolysis rates and kon span 6, koff covers 5, and ki spans 8 orders of magnitude. Multiple regression on this large data set has been used to isolate the contributions of electronic and steric effects, as well as other factors specific to compound stability and elastase inhibition. Essentially, a simple electronic parameter is sufficient to account for almost all the variance in the alkaline hydrolysis data, indicating that electronic factors are the major determinants of this type of benzoxazinone reactivity. Factors that significantly enhance the potency of benzoxazinones I are R5 alkyl groups and electron withdrawal by R2. Bulk in R7 and R8 and compound hydrophobicity are not significant, but substitution in R6 is highly unfavorable as are substituents linked via carbon to C2. The physiochemical factors that underlie these trends in Ki are further analyzed in terms of equations that describe kon and koff. A conclusion that emerges is that chemically stable, potent benzoxazinone inhibitors of HL elastase with inhibition constants in the nanomolar range can be designed with (1) R5 alkyl groups to inhibit enzyme-catalyzed deacylation, (2) small alkyl substituents linked via heteroatoms to C2 to enhance acylation and limit deacylation rates, and (3) strongly electron-donating groups at C7 to stabilize the oxazinone ring to nucleophilic attack. Thus, 2-(isopropylamino)-5-n-propyl-7-(dimethylamino)benzoxazinone 95 has kOH = 0.01 M-1 s-1, which extrapolates to a half-life at pH 7.4 of over 8.5 years, and 2-ethoxy-5-ethylbenzoxazinone 38 has Ki = 42 pM.

A dose ranging study to evaluate dermatan sulphate in preventing deep vein thrombosis following total hip arthroplasty.

Dermatan sulphate catalyses thrombin inhibition by heparin cofactor II; it has a lower haemorrhagic to antithrombotic ratio than that of heparin in animal models. Consecutive patients aged forty years or more, electively undergoing total hip replacement under general anaesthesia, were randomly allocated to one of three dosage regimens of dermatan sulphate (MF701, Mediolanum Farmaceutici) given intramuscularly. These were 200 mg once daily (n = 50), 200 mg twice daily (n = 52) and 300 mg twice daily (n = 51), administered from twenty-four hours pre-operatively until the tenth postoperative day. The overall incidence of DVT assessed by bilateral venography was 53%, 51% and 34% respectively (Chi-square test for trend p = 0.06). The incidence of major proximal DVT was 10.6%, 8.5% and 2.1% respectively. Pulmonary embolism (PE) and bleeding were assessed in all 153 patients. There was one case of PE in each dose group. The incidence of bleeding episodes, volume of blood lost and blood transfusion requirements were low and showed no increase with increasing dose. The patients were followed up 4-8 weeks after discharge. We conclude that the two lower doses were subtherapeutic in this population, however dermatan sulphate given 300 mg twice daily, proved to be efficacious with an incidence of proximal major DVT of 2.1% and a low incidence of bleeding complications. A trial of dermatan sulphate 300 mg twice daily compared to standard prophylactic agents is needed.

Pharmacokinetics and effects on the renin-angiotensin system of ramipril in elderly patients.

Converting enzyme inhibitors are likely to be prescribed with increasing frequency in elderly patients. The pharmacokinetics of ramipril, a new potent long-acting non-sulphydryl converting enzyme inhibitor, and its effects on blood pressure, plasma renin activity and angiotensin II concentrations were studied in a group of 8 elderly volunteers (mean age 77, range 61 to 84). Circulating concentrations of the active diacid formed from its parent drug were consistently higher in this group despite apparently normal renal function, assessed by serum creatinine and urea concentrations, compared with younger volunteers (age range 21 to 30). The initial dose of ramipril should be lower in older subjects. The study emphasizes the importance of careful extrapolation of data obtained from young volunteers to older subjects.

Influence of organic acid excretion on cuticle pH and drug absorption by Haemonchus contortus.

To determine if a cuticle microenvironment pH is maintained by adult Haemonchus contortus, organic acid excretion kinetics and absorption kinetics of selected model weak acids and a weak base were measured in incubation media that varied in buffer capacity (0.25-20 mM HEPES or 5 mM glycine) and initial pH (7.5 or 3.5). To evaluate the importance of the cuticle as a pathway for organic acid excretion and drug absorption the pharynx was paralyzed with 1 nM ivermectin. H. contortus changed the media pH from initial values of 7.5 or 3.25 to an asymptotic value of approximately 5.6. The rate of pH change depended on the buffer capacity, but was not affected by chemical ligation with ivermectin. The intrinsic rate of excretion of organic acids (0.045 +/- 0.016 micromol/cm2 x h) was constant during the first 8-12 h of incubation and was independent of initial pH, buffer capacity or ivermectin ligation. The rates of absorption of the model weak acids, benzoic acid and p-nitrophenol, and the model weak base, aniline, were not affected by initial pH, buffer capacity or ivermectin ligation. These results suggest that H. contortus excretes organic acid endproducts of carbohydrate metabolism across its cuticle, and that these acids maintain a microenvironment pH within the water-filled pores of the cuticle that controls the rate of adsorption of weakly acidic or basic drugs.

Melatonin binding sites in sciurid and hystricomorph rodents: studies on ground squirrels and guinea pigs.

Little is known about the distribution of binding sites for the pineal hormone melatonin in non-myomorph rodents. We used 2-[125I]iodomelatonin (IMEL) to analyze the distribution, affinity, and specificity of binding sites in the golden-mantled ground squirrel, a sciurid rodent that reportedly lacks IMEL binding sites in the brain. Specific binding was found not only in the pars tuberalis, but also in several telencephalic and diencephalic areas including the hypothalamic suprachiasmatic region. The affinity and specificity of IMEL binding are comparable to those reported in other rodents. IMEL binding studies in a hystricomorph rodent, the guinea pig, revealed high concentrations of receptor in the nucleus accumbens and dorsolateral thalamus. Central melatonin binding sites have now been demonstrated in species of all three rodent families. The heterogeneous distribution of melatonin receptors appears similar in the species studied, and no evidence is found to link IMEL binding sites at any particular locus to photoperiodic, circannual, or non-seasonal breeding patterns.

Striatal glutamatergic function: modifications following specific lesions.

The effects of specific lesions of the striatum: (a) hemidecortication; (b) striatal injection of (+/-) ibotenate; and (c) 6-hydroxydopamine injections into the substantia nigra, were investigated on specific [3H]glutamate binding to striatal membranes. One month after decortication, there was a substantial reduction of calcium-dependent, stimulated glutamate release from striatal slices, indicating effective loss of glutamatergic fibres. Striatal glutamate binding increased by approximately 30% and this supersensitivity could be attributed solely to an increased receptor density. Ibotenate lesions which destroy target neurones for the glutamatergic fibres (sparing terminals), reduced glutamate binding in the striatum, as did nigral 6-OHDA lesions which delete striatal dopaminergic terminals. This finding supports the concept of there being glutamate receptors on pre-synaptic dopamine terminals in the striatum, involved in regulation of dopamine release. 6-OHDA lesions also result in a supersensitivity of the dopamine receptors localized on the cortico-striatal afferent terminals, as evidenced by the enhanced ability of dopamine to inhibit the K+-evoked, calcium-dependent release of endogenous striatal glutamate.

Compensatory responses of CO2 exchange and biomass allocation and their effects on the relative growth rate of ponderosa pine in different CO2 and temperature regimes.

Increases in the concentration of atmospheric carbon dioxide may have a fertilizing effect on plant growth by increasing photosynthetic rates and therefore may offset potential growth decreases caused by the stress associated with higher temperatures and lower precipitation. However, plant growth is determined both by rates of net photosynthesis and by proportional allocation of fixed carbon to autotrophic tissue and heterotrophic tissue. Although CO2 fertilization may enhance growth by increasing leaf-level assimilation rates, reallocation of biomass from leaves to stems and roots in response to higher concentrations of CO2 and higher temperatures may reduce whole-plant assimilation and offset photosynthetic gains. We measured growth parameters, photosynthesis, respiration, and biomass allocation of Pinus ponderosa seedlings grown for 2 months in 2×2 factorial treatments of 350 or 650µ bar CO2 and 10/25° C or 15/30° C night/day temperatures. After 1 month in treatment conditions, total seedling biomass was higher in elevated CO2, and temperature significantly enhanced the positive CO2 effect. However, after 2 months the effect of CO2 on total biomass decreased and relative growth rates did not differ among CO2 and temperature treatments over the 2-month growth period even though photosynthetic rates increased ≈7% in high CO2 treatments and decreased ≈10% in high temperature treatments. Additionally, CO2 enhancement decreased root respiration and high temperatures increased shoot respiration. Based on CO2 exchange rates, CO2 fertilization should have increased relative growth rates (RGR) and high temperatures should have decreased RGR. Higher photosynthetic rates caused by CO2 fertilization appear to have been mitigated during the second month of exposure to treatment conditions by a ≈3% decrease in allocation of biomass to leaves and a ≈9% increase in root:shoot ratio. It was not clear why diminished photosynthetic rates and increased respiration rates at high temperatures did not result in lower RGR. Significant diametrical and potentially compensatory responses of CO2 exchange and biomass allocation and the lack of differences in RGR of ponderosa pine after 2 months of exposure of high CO2 indicate that the effects of CO2 fertilization and temperature on whole-plant growth are determined by complex shifts in biomass allocation and gas exchange that may, for some species, maintain constant growth rates as climate and atmospheric CO2 concentrations change. These complex responses must be considered together to predict plant growth reactions to global atmospheric change, and the potential of forest ecosystems to sequester larger amounts of carbon in the future.

Theoretical perspectives on anthelmintic drug discovery: interplay of transport kinetics, physicochemical properties, and in vitro activity of anthelmintic drugs.

This multidisciplinary study demonstrates the utility of the biophysical model approach to assess biological activity of anthelmintics in light of drug-delivery principles. The relationships between drug absorption and efficacy for a set of structurally disparate anthelmintics were determined in cultures of Haemonchus contortus, a nematode that parasitizes the ruminant gastrointestinal tract. Uptake, parameterized by the permeability coefficient, Pe, was shown to occur by absorption across the cuticle. Rates of drug appearance in nematode carcasses paralleled rates of drug disappearance from the medium, and absorption reached an apparent equilibrium within a few hours. The parasite/medium partition coefficient, K, was derived from the ratio of drug concentration in the parasite vs the medium at equilibrium. Pe and K values for each anthelmintic were correlated with lipophilicity (as measured by the partition coefficient (PC) in n-octanol/water) and both parameters plateaued at log PC approximately 2.5, with maximum Pe approximately 8 x 10(-4) cm/min and log K < or = 2.0. Absorption kinetics were related to in vitro potency by monitoring motility of H. contortus. The time required to reduce motility by 50% (t* 50) and Pe were used to calculate Cn*, the drug concentration in the parasite at t* 50, as an indicator of intrinsic potency. The quantitative interplay of apparent biological activity expressed as t* 50, dose, and intrinsic potency highlights the important contribution of drug-uptake kinetics.

Anthelmintic profile of the cyclodepsipeptide PF1022A in in vitro and in vivo models.

A novel cyclodepsipeptide of fungal origin, PF1022A, recently was reported to have anthelmintic activity. To supplement published reports and determine potential utility of PF1022A as a ruminant anthelmintic, the compound was examined in in vitro and in vivo models. Assays used measured motility of Haemonchus contortus (intrinsic drug potency), ATP levels (parasite death), and activity against H. contortus, Ostertagia ostertagi, and Trichostrongylus colubriformis in the jird (spectrum, potency, and efficacy by various routes). The potency of PF1022A in reducing motility is greater than commercial anthelmintics. Examination of ATP levels in PF1022A-paralyzed H. contortus indicates that worms are not killed, suggesting the compound acts as a neurotoxin in nematodes. In the jird, PF1022A has activity orally against each of the parasites studied and at doses comparable to all commercial anthelmintics, except the macrocyclic lactones which are more potent. Unfortunately, for some nematode species, parenteral delivery is ineffective at realistic doses.

Thrombo-embolic prophylaxis in total knee replacement. Evaluation of the A-V Impulse System.

We performed a prospective randomised controlled trial of a new mechanical method of prophylaxis for venous thrombo-embolism in 60 patients undergoing knee replacement surgery. The method uses the A-V Impulse System to produce cyclical compression of the venous reservoir of the foot. The overall incidence of deep-vein thrombosis was 68.7% in patients receiving no prophylaxis and 50% in those using the device. The difference was not significant. There was, however, a reduction of the extent of thrombosis in the treated group. There were 13 major calf-vein thrombi and six proximal-vein thrombi in the control group compared with only five major calf-vein thrombi in the treated group. This difference was significant (p = 0.014). No patient developed clinical features of a pulmonary embolism.

Deep vein thrombosis after elective knee surgery. An incidence study in 312 patients.

The incidence of venous thromboembolism after elective knee surgery has previously been studied almost exclusively in patients receiving total knee replacements, in whom the risk of a deep vein thrombosis is approximately 60%. We report the results of ipsilateral ascending venography in 312 patients undergoing a wide variety of elective knee operations under tourniquet ischaemia, none of whom received any specific prophylaxis against thromboembolism. Total knee replacement was confirmed to carry a high risk with ipsilateral deep vein thrombosis in 56.4% and symptomatic pulmonary embolism in 1.9%. By contrast, arthroscopy was associated with a low incidence of venous thrombosis (4.2%). Meniscectomy, arthrotomy, patellectomy, synovectomy and arthrodesis were all high-risk procedures, particularly in patients over 40 years of age, and were associated with deep vein thrombosis rates of 25% to 67%. On the basis of these findings, we advise prophylaxis against venous thromboembolism in all patients over 40 years of age undergoing elective knee surgery other than arthroscopy.

Heparin and dihydroergotamine prophylaxis against thrombo-embolism after hip arthroplasty.

A prospective study involving 500 consecutive patients undergoing hip replacement was performed to find out whether a combination of heparin and dihydroergotamine was effective in preventing postoperative fatal and non-fatal emboli. Deep-vein thrombosis was demonstrated in 131 cases (26.2%), in 99 of whom thrombi were confined to the ipsilateral (operated) limb and in 13 to the contralateral limb; 19 patients developed bilateral thrombi. Nine patients (1.8%) died during the first four weeks after operation, before they were discharged from hospital; in one, major emboli were demonstrated in the right pulmonary artery. Three of the 500 patients developed non-fatal pulmonary emboli. Excessive bleeding occurred in 21 (4.2%) and in 19 of these prophylaxis was discontinued. Wound haematomas developed in 25 patients (5.0%); only six required evacuation but in none of these six did deep infection occur while in hospital; in three patients, however, the wound haematoma prolonged the stay in hospital. Thus the combination of heparin and dihydroergotamine proved an effective prophylaxis against pulmonary embolism in patients undergoing total hip replacement. The risk of bleeding complications is wholly acceptable when balanced against the advantages of the therapy.

Sympathetic innervation of the jejunal villus.

Using fluorescent histochemical methods it has been shown that the noradrenergic nerves in the jejunal villus are associated with the capillaries underlying the basolateral membrane of the epithelium. Noradrenergic fibres were also seen to lie between the epithelial basolateral membrane and the capillaries but were never observed close to the epithelium unless accompanied by an underlying capillary. The distribution of noradrenergic fibres suggests that it is unlikely that noradrenaline diffuses directly from the varicosity to the epithelial basolateral membrane. Noradrenaline may, therefore, act on the capillary itself and in some way affect fluid absorption. However, noradrenaline released adjacent to a capillary might diffuse into the capillary to be distributed at another site along its course.